4-hydroxyfuran-2-ones, cyclooctyl or benzopyran-2-ones, 4 - hydroxy-2h-piran-2-ones and 4-hydroxy-cyclooctadiene-2-ones

 

(57) Abstract:

4-Hydroxyfuran-2-ones of the formula I, where R1-N; R2- C3-5-alkyl, phenyl- (CH2)2that gets-SO2NH- (CH2)2cyclopropyl- (CH2)2forfinal-(CH2)2that gets-SO2NH-phenyl, trifluoromethyl-(CH2)2or R1and R2together form a double bond; R3- fragmentarily(A),R4,-phenyl,het,cyclopropyl,bromine,azido,gets-SO2NH-(values other radicals cm in paragraph (1 formulas, and their derivatives are useful for the inhibition of retrovirus in human cells infected with the indicated retrovirus.

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4 C. and 35 C.p. f-crystals, 119 schemes. 3 table.

The invention relates to compounds useful for the inhibition of retrovirus in human cells infected with the indicated retrovirus. In the present invention, in particular, claimed Piran-2-ones, 5,6-dihydropyran-2-ones, 4 - hydroxybenzophenone-2-ones, 4-hydroxycyclohexyl[b] Piran-2-ones and their derivatives as inhibitors of HIV protease.

Background of the invention

In the last decade, acquired immunodeficiency syndrome (AIDS) of medical curiosities, which struck only a small number ibitors", DN&P 5(3), April 1992, pages 153-169. Figures cited by the world health organization suggests that worldwide registered 360,000 cases of AIDS, including over 175,000 cases in the United States. Of those, about 100,000 cases (50,000 in the U.S.) registered in the last 12 months. Assume that in the USA the number of people with positive serological reaction is approximately two million people and the number of people with positive serological reaction around the world is approximately 5-10 million people. Saunders and Storer, page 153.

Co first description of the disease ten years ago, acquired immunodeficiency syndrome (AIDS) and its devastating consequences are subject to constant and careful lighting in non-special, and the scientific literature. The whole issue of "Sientific American" was dedicated to AIDS (Sientific American, (1988), 289, N 4), and the number of messages about the disease and the virus already is that they are almost impossible to detail quote.

March 20, 1987 the Federal act on medicines approved the use of compounds of eiduladha (AZT) for the treatment of AIDS patients with primary attacks plasmocytomas pneumonia, patients SP absolute CD4 cell counts less than 200 per ml of blood peripheral blood system. AZT is a known inhibitor of the reverse transcriptase of the virus, an enzyme required for replication of human immunodeficiency virus. In U.S. Patent 4724232 claimed method of treatment of humans suffering from AIDS, using 3'-azido-3'-deoxythymidine (azidothymidine, AZT).

After the discovery of anti-HIV activity of AZT efforts of many researchers in search of funds, with the best action, were sent to various analogs of dideoxynucleosides. In the case of series 2'.3'-dideoxy, connection ddC and ddI showed potential activity against HIV in vitro and have been subjected to clinical trials. Saunders and Storer, page 160. Connection ddC currently produced by the company Hoffman-La Roche Co." as potential drugs against AIDS. Toxicity limits their use in the treatment of the people, manifested in peripheral neuropathy, which is reversible at low doses. Raymond R. Schinazi, Jan R. Mead and Paul M. Feorino, "Insights Into HIV Chemotherapy", AIDS Research and Human Retroviruses, Vol. 8, Number 6, 1992, pages 963-990. It is approved by the Federal act on drugs for AIDS therapy in combination with AZT. Connection ddI was also subjected to clinical trials. The toxicity of this drug, restricting its use p the t hepatic glycolysis, which leads to irreversible liver damage. Schinazi, Mead and Feorino, page 966. This compound recently approved by the Federal act on medicinal products for the treatment of HIV-1 infections in adults and children who cannot tolerate AZT or whose health has deteriorated significantly during treatment with AZT. Schinazi, Mead and Feorino, page 966.

Among these approved drugs AZT currently remains the only medicine that has been shown to reduce mortality and the incidence of infections of conditionally pathogenic microorganisms due to AIDS. Schinazi, Mead and Feorino, page 963.

The human immunodeficiency virus (HIV) in a long time was considered to be the agent causing AIDS, although there have been several opposing views (in particular, P. Duesberg, Proc. Natl. Acad. Sci., USA., (1989), 86: 755-764). Analysis of primary structure of genomes isolated from infectious and non-infectious HIV isolates, helped largely to shed light on the structure of the virus and the types of molecules that are important for replication and maturation into infectious species. HIV-protease responsible for the processing of polypeptides gag and gag-pol virus in Mature proteins of the virion. L. Ratner et al., Nature, 313: 277-284 (1985); L. H. Pearl and W. R. Taylor, Nature, 329: anee; S. Wain-Hobson et al. Cell 40: 9-17 (1985); R. Sanches-Pescador et al. Science 227: 484-492 (1985); and M. A. Muesing e-t al. Nature, 313: 450-458 (1985).

Reverse transcriptase is an enzyme unique to retroviruses, which catalyzes the conversion of viral RNA into double-stranded DNA. Lock at any stage of the transcription process, under the action of AZT or other abberant of deoxynucleosides not capable of extension, should lead to dramatic consequences for virus replication. A large number of works devoted to the reverse transcriptase, which are largely based on the fact that the nukes, like AZT, easily delivered into cells. However, the inefficiency of the stages of phosphorylation to the triphosphate, the lack of specificity and, consequently, the toxicity are the main disadvantages of the use of AZT and other nucleoside blocked or missing 3'-hydroxyl group.

The HIV receptor cells T4, the so-called CD4 molecule, is also the target of intervention in the treatment of AIDS. R. A. Fisher et al. Nature, 331: 76-78 (1988); R. E. Hussey et al., Nature, 331: 78-81 (1988); and K. S. Deen et al. Nature, 331: 82-84 (1988). The outer part of this transmembrane protein, a molecule containing a 371 amino acid residue (sCD4), einchecken tests of the obtained product from the autumn of 1987. It has been shown that CD4 has a narrow spectrum of activity against wild-type virus and is not yet able to control HIV infection in humans. Schinazi, Mead and Feorino, page 963. The idea of therapy based on CD4, is that molecules can neutralize HIV, preventing adherence of the virus to T4 and other cells that Express CD4 on their surface. A variation on this theme is the attachment of cellular toxins to CD4, with the purpose of specific binding and delivery in infected cells, which reproduce on their surface glycoprotein gp-120. M. A. Till et al. Science, 242: 1166-1168 (1988); and V. Director K. et al. Nature, 335: 369-372 (1988).

Another target in the treatment of AIDS is the inhibition of the viral protease (or proteinase), which is important for processing of precursor polypeptides of the fusion of HIV. For the human immunodeficiency viruses and other retroviruses, it was found that the proteolytic maturation of the polypeptides of the fusion of gag and gag/pol (a process necessary for the generation of infectious virus particles) is initiated by a proteinase, which, in turn, is encoded po1 region of the viral genome. Y. Yoshinaka et al., Proc. Natl. Acad. Sci., USA, 82: 1618-1622 (1985); Y. Yoshinaka et al., J. Virol., 55: 870-873 (1985); Y. Yoshinaka et al., J. Virol., 57: 826-832 (1986); K. von der the x mammals and HIV replication in T-lymphocytes. T. J. McQuade et al. Science, 247: 454 (1990).

Protease (or proteinase), containing a total of 99 amino acid residues, is one of the smallest of the known enzymes, as demonstrated by gomologichnosti aspartates, such as pepsin and renin (L. H. Pearl and W. R. lor. Nature (1987) 329: 351-354; and I. Katoh et al. Nature (1987) 329: 654-656) forces us to come to conclusions about the three-dimensional structure and mechanism of action of the enzyme (L. H. Pearl and W. R. Taylor, see earlier), which was later confirmed experimentally. Active HIV protease is expressed in bacteria (see, in particular, P. L. Darke et. al., J. Biol. Chem., (1989) 264: 2307-2312) and can be synthesized by chemical methods (J. Schneider and S. B. Kent, Cell (1988) 54: 363-368, and R. F. Nutt et al., Proc. Natl. Acad. Sci., USA (1988) 85: 7129-7133). Site - directed mutagenesis (P. L. Darke et al., see earlier and N. E. Kohl et al., Proc. Natl. Acad. Sci., USA (1988) 85: 4686-4690) and inhibition of pepstatin (P. L. Darke et al., J. Biol. Chem. , (1989) 264: 2307-2312; S. Seelmeier et al., Proc. Natl. Acad. Sci. USA (1988) 85: 6612-6616; C.-Z. Giam and I. Borsos, J. Diol. Chem., (1988) 263: 14617-14720; and J. Hansen et al., EMBO J. (1988) 7: 1785-1791) confirm the mechanistic function of HIV protease as aspartates. Studies have shown that protease performs the splitting of the expected places in peptides modeled from areas that really split under the action of the enzyme in productory analysis of HIV protease (M. A. Navia et al., Nature (1989) 337: 615-620) and related enzyme retrovirus from sarcoma virus Rus (M. Miller et al. Nature (1989) 337: 576-579) allows to detect the active site of the protease dimer, which is identical to the active site in other aspartates, and forces us to assume (L. H. Pearl and W. R. Taylor, see earlier) that the HIV enzyme active in the form of a dimer. Cm. also Joseph A. Martin, "Recent Advances in the Design of HIV Proteinase Inhitors", Antiviral Research, 17 (1992) 265-278.

Currently, the scientific search for the most effective and safe methods of inhibiting a retrovirus in humans infected with the indicated virus, and thus, effective treatment of diseases caused by this virus, such as acquired immunodeficiency syndrome (AIDS).

Published information

In JO 3227-9 23-(Sawai Seiyaku KK") describes the use of 4-hydroxycoumarins as therapeutic agents for HIV-infected patients; however, only the unsubstituted 4-hydroxycoumarin is the only connection that is specially used for the specified purpose.

In the International application WO 91/04663 (University of California in Oakland) are 6-amino-1,2-benzopyrone, which are useful for the treatment of viral for what is the use of N-phenyl-N-methyl-1,2 - dihydro-4-hydroxy-1-methyl-2-oxazinone-3-carboxamide, also known Linomidefor the treatment of retroviral infections.

In International publication WO 89/07939, published September 8, 1989, claimed specific coumarins, which are reverse transcriptase inhibitors.

In U.S. Patent numbers 3489774 and 3493586 claimed derivative 3-[beta-aryl-beta-(arieti)(or Arellano)] propionyl derivatives or Piron, useful as parasiticides.

In Biochemical and Biophysical Research Communications, Vol. 188, No. 2, 1992, pages 631-637 describes chromone containing hydroxyl substituents and phenolic groups in the 2-position (flavones), which has activity against HIV-1 proteinase.

In Antimicrobial Patent Fast-Alert, Week Ending 4 September 1992, are gamma dowels, gamma pyridone and gamma tiospirone as anti-virus tools.

In International publications WO 92/04326, 92/04327 and 92/04328, published March 19, 1992, describes antivirus heterocyclic derivatives, such as chinoline and benzopyrene, as replication inhibitors for the treatment of herpes simplex 1 and 2, cytomegaly virus and Epstein-Barr.

In C. A. Selects: Antitumor Agents, Issue 19, 1992, page 25, N 117: 90147g (international application WO 92/06687) describes how to obtain 5-iodine-5-amino-1,2-benzopyrone is described and you are not offered the use of 4-hydroxy-alpha-dowels as HIV protease inhibitors or substances possessing antiviral activity.

In Phytochemistry, 31(3): 953-956 (1992) are such compounds as methyl ester of 4-hydroxy-alpha-(4-methoxy-phenyl)-6-[2-(4-methoxyphenyl)ethynyl]-2-oxo- (E)-(-)-2H-Piran-3-carboxylic acid.

In Tetrahedron, 48(9): 1695-1706 (1992) (see also Tetrahedron Lett., (1989) 30(23): 3109-12) describes compounds such as 3-[1-(4-chlorophenyl)-3-(4-nitrophenyl)-2-propenyl] -4-hydroxy-6-methyl-2H-Piran-2-he; 3-[3-(4-chlorophenyl)-1-(4-nitrophenyl)-2 - propenyl]-4-hydroxy-6-methyl-2H-Piran-2-he; 4-hydroxy-3-[3-(4-methoxyphenyl)-1-(4-nitrophenyl)-2-propenyl]-6-methyl-2H - Piran-2-he; and 4-hydroxy-3-[1-(4-methoxyphenyl)-3-(4-nitrophenyl) -2-propenyl]-6-methyl-2H-Piran-2-it.

In Tenneh Yuki Kagobutsu Toronkai Koen Yoshishu, 30: 17-24 (1988) describes such compounds as methyl ester of 4-hydroxy-beta-(4-methoxyphenyl)-6-[2-(4-methoxyphenyl)ethynyl] -2-oxo-(E)- (-)-2H-Piran-3-propanoic acid.

In Chem. Abstr. 53: 15072f describes compounds such as Delta-lactone, alpha-1,3-dihydroxy-2-butenolide-beta-ethyl-hydroxycortisol acid.

In Chem. Abstr. 53: s describes compounds such as Delta-lactone, alpha-1,3-dihydroxy-2-butenolide-beta-isopropyl - hydroxycortisol acid.

In Arch. Pharm. (Weinheim, Ger. ), 316(12): 988-94 (1983) describes compounds such as 3-[1-(4-chlorophenyl)-3-oxaeg. , 110(3): 1047-57 (1977) are compounds such as 6-(3,4-acid)-3-[2-(3,4-acid)-1- (4-methoxy-2-oxo-2H-Piran-6-yl)ethyl] -4-hydroxy-2H-Piran-2-it 3-[2-(3,4-acid)-1-(4-methoxy-2-oxo-2H-Piran-6-yl) ethyl] -4-hydroxy-6-[2-(4-methoxyphenyl)-ethyl]-2H-Piran-2-it.

In Heterocycl. Chem., 23(2): 413-16 (1986) are such compounds as 3-[(4-chlorophenyl)-1-piperidinylmethyl]-4-hydroxy-6-methyl-2H-Piran-2-it.

In the following applications published under the patent cooperation Treaty, provides peptides which are useful as protease inhibitors of retrovirus: international publication WO 91/06561 (published may 16, 1991) and international publication WO 92/17490 (published 15 October 1992).

The following publications describe the pyrone derivatives, which are known from the technical field connections:

In EP-443449 (in German) are 3-hexyl-5,6-dihydro-6-pentyl-2H-Piran - 2-he and 3-ethyl-6-hexadecyl-5,6-dihydro-4-hydroxy-2H-Piran-2-it. In Pestic. Sci. , 27(1): 45-63 (1989) are 5,6-dihydro-4 - hydroxy-6-methyl-6-(1-methyl-1-propenyl)-3-(1-oxobutyl)-2H-Piran - 2-he and 6-cyclopropyl-5,6-dihydro-4-hydroxy-6-methyl-3- (1-oxobutyl)-2H-Piran-2-it. In Acta. Chem. Scand., 43(2): 193-95 (1989) is 4-(atomic charges)-5,6-dihydro-3,6-dimethyl-2H-Piran - 2-it. In J. Org(2): 277-80 (1993) provides a (6R)-3-hexylthio-6-undecyl-2H-Piran-2,4 (3H)-dione. In J. Chem. Soc. Perkin Trans. , 1(6): 1157-9 (1985) provides dihydro-3-methyl-6-nonyl-6-[[(tetrahydro-2H-Piran-2-yl) oxy]-methyl]-2H-Piran-2,4-(3H)-dione. In J. Chem. Ecol. , 9(6): 703-14 (1983) is 5,6-dihydro-4-hydroxy-3,6-dimethyl-2H - Piran-2-it. In J. Org. Chem., 48 (7): 1123-5 (1983) given (Z)(+-)-6-(2-chloro-1-methylethenyl-5,6-dihydro-4-hydroxy-3-methyl-2H - Piran-2-it. In Acta Chem. Scand., 43(2): 193-95 (1989) and Tetrahedron Lett., 21 (6): 551-4 (1980) is 5,6-dihydro-4-hydroxy-3,6-dimethyl-2H-Piran-2-it. In Helv. Chem. Acta, 59(7): 2393-2401 (1976) is 4-[(3,6-dihydro-4-hydroxy-5-methyl-6-oxo-2H-Piran-2-yl)methyl]-2,6-piperidinedione. In Acta Chem. Scand. , 30 (7): 613-18 (1976) and Tetrahedron Lett; 22: 1903-4 (1976) provides 5,6-dihydro-4-hydroxy-3-methyl-6-(1-methyl-1-propenyl)-2H-Piran-2-(E) - 3,3'-[(4-nitrophenyl)methylene]bis[5,6-dihydro-4-hydroxy-6-methyl]-2H-Piran-2-he and 3,3'-(phenylmethylene)bis-[5,6-dihydro-4-hydroxy-6-methyl]-2H-Piran-2-it is described in Synth. Commun,. 20 (18): 2827-2836 (1990).

In the International application WO 93/07868, published April 29, 1993, provides new derivatives of nitrobenzophenone, nitrobenzamide and nitrosothiols as inhibitors testosteroneboosters for the treatment of viral infections and cancer.

International application WO 93/07128, published April 15, 1993, relates to substituted cyclic CARBONYLS and their derivatives, useful as a * tested for anti-cancer and anti-AIDS activity and proved to be inactive.

In the Journal of Antibiotics, 46 (7) : 1126 (July 1993) reported that germicides, which is 6-(2-butyl)-3-ethyl-4-hydroxy-2-pyrone, is autoregulatory inhibitor development Streptomyces viridochromogenes NRRL B-1551.

In Derwent Abstracts, 93-168920/21 European patent application 543201 describes the use of coumarin derivatives such as 1-(N-morpholin)-6-(4-hydroxybenzoic acid ethyl ester) hexane for the treatment of viral infections such as influenza or acute rhinitis.

In J. Org. Chem. , 48(22): 3945-7 (1983) Chem. Pharm. Bull., 29(10): 2762-8 (1981) are such compounds as 4-hydroxy-6-(3-pyridinyl) -2H-Piran-2-it. In J. Labelled Compd. Radiopharm., 28(10): 1143-8 (1990) describes compounds such as 4-hydroxy-6-methyl-2H-Piran-2 - it.

In J. Am. Chem. Soc., 113(25): 9585-95 (1991) are such compounds as 3-(3-phenyl-2-propen-1-yl)-6-methyl-4-hydroxy-2H - Piran-2-it.

In CA 54:14239d and 53: s are such compounds as Delta-lactone, alpha-(alpha, gamma dihydroxycinnamate) hydracarina acid.

In CA 53:15072f describes compounds such as Delta-lactone, alpha-1,3-dihydroxy-2-butenolide-beta-ethyl-hydroxycortisol acid.

In Synth. Commun., 20(18):2827-36 (1990) are compounds such as 3,3'-[(4-nitrophenyl)methylene] bis[5,6-dihydro-4-hydroxy): 3383-9 (1989) provides such compounds, as 5,6-dihydro-4-hydroxy-3,6,6-trimethyl-2H-Piran-2-it.

In Derwent Abstracts, 92-166863/20 European patent application 553248 describes the use of new derivatives of 5-iodine-6-amino-1,2-benzopyrone, which are inhibitors of diphosphoribose, for the treatment and prevention of viral infections and tumors caused by AIDS.

In the Synthesis of Heterocycles. XV. 4-Hydroxy-2 - pyronocyclenes. E. Ziegler, H. Junek and E. Nolken, Monatsh., 89: 678-82 (1958) (CA 53: 12283-4) are the following compounds: 4 - hydroxy-3-benzyl-5,6-octamethylene-2-pyrone; 4-hydroxy-3-benzyl - 5,6-pentamethylene-2-pyrone; 4-hydroxy-3-benzyl-5,6-heptamethyl-2 - pyrone; 4-hydroxy-3-benzyl-5,6-hexamethylen-2-pyrone; and 4-hydroxy-3-benzyl-5,6-tridecapeptide-2-pyrone.

In R. Effenberger, T. Ziegler, K.-H. Schonwalder, T. Kesmarszky, C. Bauer, Chem. Ber. , 119: 3394-3404 (1986) describes pyrone derivatives, such as indicated by formula J-1 (where n is 4; see below in Scheme J).

In Monatsh. Chem., 119(6-7): 727-37 (1988) (CA 110(13): 114430k) are such compounds as 10-hydroxy-9-(phenylmethyl)-8H-azento[1,2-b] Piran-8-he and 1-hydroxy-2-(phenylmethyl)indeno[2,1-b]Piran-3(5H)-he.

In CA 54: 14239b describes the connection of 3-benzyl-4-hydroxy-2-oxoindole-[1,2-b]Piran.

In Monatsh. Chem., 113(4): 475-84 (1982) are such compounds as 6,7-dihydro-4-hydroxy-6-(3-were)-7-phenyl-3-(Fe is SS="ptx2">

In Monatsh. Chem. , 90: 594-9 (1959) (CA 54:14238g,h) are such compounds as Delta-lactone, alpha-benzyl-6,7-dihydro-beta-9-dihydroxy - 5H-benzocycloheptene-8 acrylic acid and 3-benzyl-5,6,7,8-tetrahydro-4-hydroxy-8-isopropyl-5-methylcoumarin.

In Bull. Soc. Chim. Fr. 5: 1719-23 (1969) (CA 71(21): 101655p) describes the connection of 3-benzyl-5,6,7,8-tetrahydro-4-hydroxycoumarin.

In WO 8804652 (similar to AU 8810440 (jap.)) describes 3-(4-chloro-2-nitrobenzoyl)-5,6,7,8-tetrahydro-4-hydroxy-2H-1-benzopyran-2-it.

In Monatsh. Chem. , 92:246-53 (1961) Gr (CA 55:27296d) are compounds such as 3-(3,5-dimethylstyryl)-5,6,7,8-tetrahydro-4-hydroxycoumarin.

In CA 94(9):65472 describes 5,6,7,8,9,10-hexahydro-3 - phenyl-2H-cycloocta[b] Piran-2-he and 6,7,8,9-tetrahydro-4-hydroxy - 3-phenyl-2H-cyclohepta[b] Piran-2(5H)-he.

In J. Org. Chem., 28(11):3112-14 (1963) (SA 59: 15185e) provides a connection Delta-lactone 2-[hydroxy(2-hydroxy-1-cyclopenten-1-yl) methylene] hexadienoic acid.

In Antimicrobial Patent Fast-Alert, Week Ending 30 April 1993, are cyclic urea and the like, which are useful as protease inhibitors of retroviruses.

There are a large number of compounds of the type 4-hydroxycoumarin. For example, in the following publications - CA 54: 577e, g, h (1960); U.S. Patent 2872457 (CA 53: e (1959)); CA 51: 14826f, h (1957); the displayed following compounds: 4-hydroxy-3-(1-phenylbutyl)coumarin; 4-hydroxy-3- (1-fenilpentil)coumarin; 3-(cyclohexylmethyl)-4-hydroxycoumarin; 4-hydroxy-3-(2-methyl-1-phenylpropyl) coumarin; 4-hydroxy-3-(2-phenylpropyl) -coumarin; 4-hydroxy-3-(1,3-diphenylpropyl)coumarin; 4-hydroxy-3- (1-(4-were)butyl)coumarin; 4-hydroxy-3-(1-(1-naphthyl)-propyl) coumarin; 4-hydroxy-7-methyl-3-(1-phenylpropyl)coumarin; 7-chloro-4-hydroxy-3-(1-phenylpropyl)coumarin; 4-hydroxy-3-[1-(4-methoxyphenyl)propyl]coumarin; 3-(alpha - ethyl-p-fluoro-benzyl)-4-hydroxycoumarin; 3-(alpha-ethyl-p - methoxybenzyl)-4-hydroxycoumarin and 3-(1-phenylpropyl)-4 - hydroxycoumarin.

As far as we know (see our review), in the above publications are not informed about the use of these compounds as inhibitors of HIV protease. Reported use of these compounds as rodenticides for reducing the amount of prothrombin in the blood, as anticoagulants blood and pesticides.

The following publications provide additional derivatives of 4-hydroxycoumarin:

In Indian. J. Chem., Sect. In, 25V: 1167-70 (1986) (CA 107(17): 154201f) and CA 93(23): 220546-f describes 4-hydroxy-3- (1-phenyl-2-propenyl)coumarin.

In CA 96(19): h; CA 90(1): 1707f; CA 84(9) 55338f; CA 79(13): 74969a and CA 71(15): 69677j is the compound 4-hydroxy-3-[1-(1,2,3,4-tetrahedra 4-hydroxy-3-(1-naphthylmethyl)coumarin; in CA 63: s provides connection 3-(1'-(2-methoxy-3-methyl-5-chlorophenyl)propyl)-4 - hydroxycoumarin; SA 64: 12969b provides connection 3- -acetonyl - acetylphenyl)-4-hydroxycoumarin. In CA 79(13): 74969a; Chim. Ther. 7(4): 300-6 (1972) (FR.) (CA 78(7): 38016h); CA 52: 5399b; CA 54: 5699e; CA 54: e and SA 72(15): 78882v describes derivatives of 4-hydroxycoumarin, substituted in the 6 - or 7-position, for example, METI scrap, methoxy group or a chlorine atom.

In J. M. Mulder, U.S. Patent 3835161 (published 10 sentara 1974) claimed connection 3-[1-[4-(2-bromacil)phenyl] -ethyl]-4-hydroxy-2H-1-benzopyran-2-it.

Merck Index, Eleventh Edition, (1989), Entry 9950 describes warfarin (its chemical name is 3-alpha-phenyl-beta-acetylethyl-4 - hydroxycoumarin) and its use as a rodenticide and an anticoagulant. In J. Med. Chem. , 1978, Vol. 21, N 2: 231-234 reported antivitamin K activity warfarina and discussed anticoagulant activity of several 3-substituted 4-hydroxycoumarins, such as 4-hydroxy-3-(1-phenylbutyl) coumarin and 4-hydroxy-3-(alpha-methylbenzyl)coumarin. In J. Am. Chem. Soc. 83: 2676-9 (1961) (CA 55: e (1961) discussed the method of splitting and absolute configuration of warfarina and describes how to obtain such compounds as 4-hydroxy-3-(1-phenylbutyl) coumarin.

in Journal of Labelled Compounds and Radiopharmaceuticals Vol. XXIII, No. 2 the holding tag deuterium analogue connections 4-hydroxy-7-methoxy-3-(1-phenylpropyl)coumarin.

In J48023942 are such compounds as 4-hydroxy-3-(alpha-methylbenzyl)coumarin; 4-hydroxy-3-(3-methyl - 1-phenylbutyl)coumarin; and 2H-1-benzopyran-2-it, 4-hydroxy-7-methoxy-3-(1-phenylpropyl)coumarin (already described earlier) and their use as rodenticides.

In proceedings of the Voronezh Institute of technology, 19(2): 27-30 (1971), Abstract N 1 zh 274 describes the connection 4-hydroxy-3-phenethyl-coumarin. In this publication, and in Helv. Chim. Acta, 74 (7): 1451-8(1991) is 4-hydroxy-3-(3-phenylpropyl)coumarin.

In J. Org. Chem., 33(1): 437-8 (1968) and Eur. J. Med. Chem.-Chim. Ther., 12(2): 125-30 (1977) are such compounds as 4-hydroxy-3-diphenylethylamine.

In U.S. Patent 3764693 describes the connection 4-hydroxy-3-(3-hydroxy-1 - phenylbutyl) coumarin and its anticoagulant and rodent activity.

In J. Med. Chem., 18(5): 513-19 (1975) (CA 83(5): 37913q); J. Chromatorg. , 338(2): 325-34 (1985); J. Chromatorg., 562(1-2): 31-8 (1991); J. Lebelled Compds. Radiophar. , 23(2): 137-48 (1986) (see earlier); and J. Chromatorg., 529(2): 479-85 (1990) are such compounds as 4-hydroxy-3-[1-[3- (phenylmethoxy)phenyl]propyl]-2H-1-benzopyran-2-he; 4-hydroxy-8-(phenylmethoxy)-3-(1-phenylpropyl)-2H-1-benzopyran-2-he; 4-hydroxy-3-[1-(4-hydroxyphenyl)propyl]coumarin; 4-hydroxy-6-methoxy-3-(1-phenylpropyl)coumarin; 4,7-dihydroxy-3-(1-phenylpropyl)-coumarin; 4,6-digit/P> AIDS 1993, Vol. 7, No. 1, pages 129-130 discusses the effect of warfarina on the replication and spread of HIV-1.

CA Selects: AIDS & Related Immunodeficiences, Issue 24, 1993, Abstract 119: 195147j describes the inhibitory effect of a single dose of coumarin derivatives, warfarina, 4-hydroxycoumarin, umbelliferon on the replication of HIV-1 and the spread of the virus in the cells and in the extracellular environment.

At the First conference on human retroviruses and related infections, 12-16 December 1993, Washington, D.C., reported that the coumarins, such as warfarin, and the dowels, such as 3-(thiophenyl)-6-phenyl-4-hydroxypyrene, are in the process of testing the inhibitory activity against HIV protease.

In Biochemical and Biophysical Research Communications, Vol. 201, No. 1, pages 290-294 (30 May 1994) reported that warfarin and structurally related analogues derivatives are inhibitors of HIV protease.

In J. Med. Chem., 37: 2664-2677 (1994) reported that 4-hydroxy-3-(3-phenoxypropan)-2H-1-benzopyran-2-it and its structural analogues, in particular, 4,7-dihydroxy-3-[4-(2-methoxyphenyl)butyl] -2H-1-benzopyran-2-ones, are inhibitors of HIV protease.

In Biochemical and Biophysical Research Communications, Vol. 200, No. 3, pages 1658-1664 (16 May 1994) indicated that 4-hydroxy-3-(3-phenoxypropan)-1-benzopyran-2-he is AMI HIV protease.

In J. Am. Chem. Soc., 116: 6989-6990 (1994) reported that 4-hydroxy-6-phenyl-3-(phenylthio)Piran-2-it and its structural analogues are inhibitors of HIV-1 protease.

Acta, Virol., 37: 241-250 (1993) describes anti-HIV activity of coumarin derivatives, warfarina, 4-hydroxycoumarin and umbelliferon.

In Antiviral Research, 24: 275-288 (1994) describes bicyclic imidazolidone (imidazothiazole and imidazopyridine), which inhibit HIV-1 by interaction with reverse transcriptase.

In U.S. Patent 3325515 (J. Schmitt et al.) indicated that coumarin derivatives, such as methyl ether 3-(4-hydroxy-3-coumarinyl)-3-phenyl-1-propionic acid, exhibit anticoagulant activity.

In U.S. Patent 2723277 (A. Grussner et al.) come derivatives melonova acids such as 3-[1'-p-chlorophenyl)- propyl]-4-hydroxycoumarin as anticoagulants.

In French Patent 1276654 claimed 4-hydroxycoumarin, such as (2'-hydroxy)-3-benzyl-4-hydroxycoumarin that have anticoagulant, antibacterial or antifungal properties.

In Belgium Patent A674997 claimed derivatives of 4-hydroxycoumarin, such as 3-(5-methoxyacetyl-(1))-4 - hydroxycoumarin, as a means of combating grow, such as 3-(1-phenyl-2-acetyl)-ethyl-4 - hydroxycoumarin and 3-(1-furan-2-acetyl)-ethyl-4-hydroxycoumarin that effective as anticoagulants and rodenticides.

In The Application of Computer-Assisted Drug Design in the Discovery of Nonpeptide HIV-1 Protease Inhibitors", Parke-Davis Pharm. Res. , Keystone Symposia, 5-11 March 1994, Santa Fe, NM is 4 - hydroxy-3-(3-phenoxypropan)-1-benzopyran-2-inhibitor of HIV protease.

In Structurial Biology, 1(1): 199-200 (April 1994) indicated that rat poison of warfarin useful to search for inhibitors of HIV. In SA 85: 78002b (1976) indicates that derivatives of 3-(2,4,6-trihydroxyphenyl)-4-hydroxy-2H-Piran-2 - it possess antibacterial activity.

In French Patent A1092278 (Hoffman) (1955) claimed method of receiving coumarin derivatives such as 3-[1'-phenylpropan-(1')-yl)-4-hydroxycoumarin.

In International publication WO 94/11361 dated may 26, 1994 are Piran-2-ones and 5,6-dihydroxyfuran-2-ones as inhibitors of proteases retrovirus.

In International publication WO 94/18188 on August 18, 1994 are 4-hydroxybenzophenone-2 - ones and 4-hydroxycyclohexyl[b]Piran-2-ones as inhibitors of proteases retrovirus.

The following links are provided as analogues of the present invention and characterize the current l.); U.S. patent 5294724 (Jendralla et al.); Patent application Australia 219371 (Enders et al.); Patent Canada 1171424 (Willard et al.); Patent application UK 836740 (Bayer); European patent application 0024348 (Willard et al.); European patent application 0588137 (Fischer et al. ); French patent 1276654 (Molho) (see earlier) and international publication WO 94/1136 (Thaisrivongs et al.) (see earlier).

In "Collaborative Structure-Based Design of Small Organic Molecules as Inhibitors of HIV Protease", Keystone Symposia, Santa Fe, NM (5-11 March 1994) provides crystallographic complexes of HIV-1 and HIV-2 protease with such compounds as 3-(alpha-active compounds)-6-(alpha-ethylphenyl)-4-hydroxy-2H-Piran-2-it.

In "Descovery and Properties of Small Organic Molecules of Inhibiting HIV-I Protease", Keystone Symposia, Santa Fe, NM (5-11 March 1994) provides an analytical method for the detection of inhibitory activity of compounds such as 3-(alpha - active compounds)-6-(alpha-ethylphenyl)-4-hydroxy-2H - Piran-2-it.

In "Structure-based Design of Non-peptide HIV Protease Inhibitors", 35th Annual Buffalo Medical Chemistry Symposium, Buffalo, NY (22-25 May 1994) are such compounds as 3- (alpha-active compounds)-6-(alpha-ethylphenyl)-4-hydroxy-2H-Piran-2 - he as a potential therapeutic anti-HIV funds.

Hruby et al. (J. Org. Chem., (1993) 58(26): 7567) describe catalyzed by copper connection aryl Grignard reagent to unsaturated chiral and the house and 2-methoxy-2-methyl-1,3 - dioxolane. Description of the method of obtaining 2-methoxy-2-methyl-1,3 - dioxolane can be found at Santry et al. (J. Am. Chem. Soc., (1988) 110(9): 2910). About the reaction between the enol ether and ketone watch Dongala et al. Tetrahedron Letters, 4983 (1973) and Mitsui et al. Tetrahedron, 23: 4271 (1967). About the reaction between amidon of enol and ketone see Viteva et al. Tetrahedron, 50: 7193 (1994); Oare et al., J. Org. Chem., 55: 132 (1990); Hullot et al., Can. J. Chem., 55: 266 (1977); Woodbury et al., J. Org. Chem. , 42: 1688 (1977); Stefanovsky et al. Tetrahedron, 42: 5355 (1986); and Mathew et al. U.S. patent 5284975.

G. Garganico, P. Cozzi, G. Orsini, J. Med. Chem., 26: 1767-1769 (1983) lead synthetic compounds containing the methyl and hydroxyl groups at the 4 - position dihydropyrazolo rings and do not contain substituents in 3-position. Compounds of the present invention contain a ketone group in the 4-position (which may be in the enol form) and have the substituent in 3-position.

D. T. Wtiak et al., J. Med. Chem., 31: 1437-1445 (1988) provide benzopyran-2-ones with a hydroxyl group at the 3-position. Compounds of the present invention contain in this position of the alkyl substituent.

C. Tait, Winter Conference on Bioorganic Medicinal Chemistry, 29 Jan. -2 Feb. 1995, Steamboat Springs, Colorado reports dihydropyrano containing a phenyl group and pentelow group in 6-position, and-S-CH2-CH2is a phenyl group at the 3-position in the field of HIV protetyka (+)-3-[cyclopentyl(cyclopentyl)methyl] -4-hydroxy-6-phenyl-2H - Piran-2-inhibitor of HIV-1 protease.

Brief description of the invention

In the present invention stated:

The compound of Formula I,

where R1denotes a hydrogen atom;

R2means (a) (C3-C5)alkyl, (b) the group phenyl-(CH2)2(c) group, a heterocycle-SO2NH-(CH2)2-, (d) group cyclopropyl-(CH2)2-, (e) group forfinal-(CH2)2-, (f) group, a heterocycle-SO2NH-phenyl, or (g) a trifluoromethyl group-(CH2)2-,

or R1and R2together form a double bond;

R3represents a fragment of formula X;

R4represents (a) phenyl, (b) a heterocycle; (c) cyclopropyl, (d) the group H3C-[O(CH2)2]2-, (e) group, a heterocycle-SO2NH-, (f) a bromine atom, (g) azido-group, or (h) a group of HO3S(CH2)2-N(CH3)-C(O)-(CH2)6- C(O)-NH;

R5denotes a hydrogen atom;

R6means (a) the group of R4-(CH2)n-CH(R8)-, (b) the group H3C-[O(CH2)2]2CH2(C) - (C3-C5)alkyl, (d) the group phenyl-(CH2)2-, (e) group, a heterocycle-SO2NH-(CH2)2-, (f) group (HOCH2)3C-NH-C(O)-NH-(CH2)3(g) group (HO2C)(H2N)CH-(CH2)2-C(O)-NH-(CH2)-(CH2)6- C(O)-NH-(CH2)3(j) group cyclopropyl-(CH2)2-, (k) the group forfinal-(CH2)2-, (l) group, a heterocycle-SO2NH-phenyl, or (m) group F3C-(CH2)2-;

n represents zero (0), one (1) or two (2);

R7means (a) cyclopropyl, (b) ethyl or (c) tert-butyl;

R8means (a) ethyl or (b) the group-CH2-cyclopropyl;

R9means (a) the group-NR12SO2-heterocycle, (b) the group-NR12SO2is phenyl, unsubstituted or substituted with one R11(c) the group-CH2-SO2is phenyl, unsubstituted or substituted with one R11or (d) the group-CH2-SO2-heterocycle;

where the heterocycle denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group comprising nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocycles condensed with a benzene ring or another heterocycle; unsubstituted or substituted with one R10;

where R10means (a) methyl, (b) cyano group, (c) hydroxyl group, (d) ethoxycarbonyl group, (e) triptorelin group, (f) amino group, or (9) amide GU;

where R12represents (a) hydrogen atom or (b) methyl; or its pharmaceutically acceptable salt.

In the present invention, in particular, stated:

The compound of Formula 1,

where R1denotes a hydrogen atom;

R2means (a) (C3-C5)alkyl, (b) the group phenyl-(CH2)2or (C) a group of the heterocycle-SO2NH-(CH2)2-;

or R1and R2together form a double bond;

R3represents a fragment of formula X;

R4represents (a) phenyl, (b) heterocycle, (c) cyclopropyl, (d) the group H3C-[O(CH2)2] 2-, (e) group, a heterocycle-SO4NH-, (f) a bromine atom, (g) azido-group, or (h) a group of HO3S(CH2)2-N(CH3)-C(O)-(CH2)6- C(O)-NH-;

R5denotes a hydrogen atom;

R6means (a) the group of R4-(CH2)n-CH(R8)-, (b) the group H3C-[O(CH2)2]2CH2, (C) (C3-C5)alkyl, (d) the group phenyl-(CH2)2(e) group, a heterocycle-SO2NH-(CH2)2-, (f) group (HOCH2)3C-NH-C(O)-NH-(CH2)3-, (g) group (HO2C)(H2N)CH-(CH2)2-C(O)-NH-(CH2)3-, (h) group piperazine-1-yl-C(O)-NH-(CH2)3or (i) groupsize (1) or two (2);

R7means (a) cyclopropyl, (b) ethyl or (C) tert-butyl;

R8means (a) ethyl or (b) the group-CH2-cyclopropyl;

R9means (a) the group-NR12SO2-heterocycle, (b) the group-NR12SO2is phenyl, unsubstituted or substituted with one R11, (C) the group-CH2-SO2is phenyl, unsubstituted or substituted with one R11or (d) the group-CH2-SO2-heterocycle;

where the heterocycle denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group comprising nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocycles condensed with a benzene ring or another heterocycle; unsubstituted or substituted with one R10;

where R10means (a) methyl, (b) cyano group, (C) hydroxyl group, or (d) ethoxycarbonyl group;

where R11means (a) cyano group, (b) a fluorine atom, (C) hydroxyl group, or (d) a nitro group;

where R12represents (a) hydrogen atom or (b) methyl;

or its pharmaceutically acceptable salt.

In the present invention claimed such compounds, in which the heterocycle inil, (b) imidazol-2-yl, (C) imidazol-4-yl, (d) benzimidazole-2-yl, (e) quinoline-8-yl, (f) quinoline-2-yl, (g) pyrimidine-2-yl, (h) chincholi-2-yl, (i) purine-6-yl, (j) thiazol-2-yl, (k) thiazol-4-yl, (l) 2-pyrazolyl, (m) 2-pyrazinyl, (n) tetrahydropyran-4-yl, or (o) tetrahydropyran-3-yl.

In the present invention, in particular, stated:

The compound of Formula I,

where R1denotes a hydrogen atom;

R2means (a) propyl, (b) the group phenyl-(CH2)2-, (C) ISO-butyl or (d) of pentyl;

or R1and R2together form a double bond;

R3represents a fragment of formula X;

R4represents (a) phenyl), (b) heterocycle, (C) cyclopropyl, (d) the group H3C-[O(CH2)2]2-, (e) group, a heterocycle-SO2NH, (f) a bromine atom, (g) azido-group, or (h) a group of HO3S(CH2)2-N(CH3)-C(O)-(CH2)6-C (O)-NH;

R5denotes a hydrogen atom;

R6means (a) the group of R4-(CH2)n-CH(R8)-, (b) the group H3C-[O(CH2)2]2CH2-, (s) propyl, (d) the group phenyl-(CH3)2-, (e), ISO-butyl, or (f) of pentyl;

n represents zero (0), one (1) or two (2);

R7means (a) cyclopropyl or (b) ethyl;

R8means (a) ATG-NHSO2is phenyl, unsubstituted or substituted with one R11; where heterocycle refers to the following group, unsubstituted or substituted with one R10(a) 2-pyridinyl, (b) imidazol-2-yl, (C) imidazol-4-yl, (d) quinoline-8-yl, (e) tetrahydropyran-4-yl, (f) tetrahydropyran-3-yl, or (g) benzimidazole-2-yl;

where R10means (a) methyl;

where R11means (a) cyano group, (b) a fluorine atom, or (C) a nitro group;

or its pharmaceutically acceptable salt.

In particular, the present invention applying the compound of formula VI,

where R2means (a) propyl, (b) the group phenyl-(CH2)2-, (C) ISO-butyl or (d) of pentyl;

R3represents a fragment of formula X;

R6means (a) propyl, (b) the group phenyl-(CH2)2-, (C) ISO-butyl, or (d) of pentyl;

R7means (a) ethyl or (b) cyclopropyl;

R9means (a) group-NHSO22is phenyl, substituted with one R11or (b) the group-NHSO2-heterocycle;

where heterocycle refers to the following group, unsubstituted or substituted with one R10(a) imidazol-4-yl or (b) quinoline-8-yl;

where R10denotes methyl;

where R11means (a) a cyano group, or (b) a fluorine atom.

In addition t the ly X;

R4represents (a) phenyl, (b) heterocycle, (C) cyclopropyl, (d) the group H3C-[O(CH2)2] 2-, (e) group, a heterocycle-SO2NH, (f) a bromine atom, (g) azido-group, or (h) a group of HO3S(CH2)2-N(CH3)-C(O)- (CH2)6-C(O)-NH;

R6means (a) the group of R4-(CH2)n-CH(R8) or (b) the group H3C-[O(CH2)2]2CH2-;

R7denotes cyclopropyl;

R8means (a) ethyl or (b) the group-CH2-cyclopropyl;

R9means (a) group-NHSO2-heterocycle, or (b) the group NHSO2is phenyl, unsubstituted or substituted with one R11;

where n denotes the zero (0), one (1) or two (2);

where heterocycle refers to the following group, unsubstituted or substituted with one R10(a) imidazol-4-yl, (b) imidazol-2-yl, (s) quinoline-8-yl, (d) tetrahydropyran-3-yl, (e) tetrahydropyran-4-yl, (f) 2-pyridinyl, or (g) benzimidazole-2-yl;

where R10denotes methyl;

where R11means (a) a nitro group; (b) a fluorine atom; or (C) a cyano group; or its pharmaceutically acceptable salt.

In the present claimed invention is also the compound of formula II, where

R10and R20together form:

a) f is odorata;

R2represents (a) hydrogen atom, (b) methoxy group, or (C) the group CH3O-[(CH2)2O]3-;

R3represents a fragment of formula V;

R4means (a) cyclopropyl or (b) ISO-butyl;

R5means (a) the group-NR9SO2is phenyl, unsubstituted or substituted with one R6(b) the group-NR9SO2-heterocycle, (C) the group-CH2-SO2is phenyl, unsubstituted or substituted with one R6or (d) the group-CH2- SO2-heterocycle;

where R6means (a) cyano group, (b) a fluorine atom, (C) methyl, (a) a carboxyl group, or (e) a hydroxyl group;

where the heterocycle denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group comprising nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocycles condensed with a benzene ring or another heterocycle; unsubstituted, substituted with one or two R7;

where R7means (a) methyl, (b) cyano group, (C) ethoxycarbonyl group, or (d) a hydroxyl group;

R8represents (a) hydrogen atom, (b) propyl, (C) the group-CH2-cyclopropyl, or (d) acceptable salt.

In the present invention claimed such compounds, in which the heterocycle denotes the following groups, which do not contain substituents or with one substituent R7(a) 2-pyridinyl, (b) imidazol-2-yl, (C) imidazol - 4-yl, (d) benzimidazole-2-yl, (e) quinoline-8-yl, (f) quinoline-2-yl, (g) pyrimidine-2-yl, (h) hinzelin-2-yl, (i) purine-6-yl, (j) thiazol-2-yl, (k) thiazol-4-yl, (l) 2-pyrazolyl, (m) 2-pyrazinyl, (n) tetrahydropyran-4-yl, or (o) tetrahydropyran-3-yl.

In the present invention, in particular, there is a compound of formula II, where

R10and R20together form:

a) a fragment of the formula III or

b) a fragment of formula IV;

where p is equal to four (4);

R1denotes a hydrogen atom;

R2denotes a methoxy group or (b) the group CH3O-[(CH2)2O]3-;

R3represents a fragment of formula V;

R4means (a) cyclopropyl or (b) ISO-butyl;

R5means (a) the group-NR9SO2is phenyl, unsubstituted or substituted with one R6(b) the group-NR9SO2-heterocycle, (C)

the group-CH2-SO2is phenyl, unsubstituted or substituted with one R6or (d) the group-CH2-SO2-heterocycle;

where R6means (a) cyano-gr is replaced or substituted with one R7:

(a) imidazol-4-yl, (b) quinoline-8-yl, (C) 2-pyridinyl, or (d) 4-pyridinyl;

where R7denotes methyl;

R8represents (a) hydrogen atom or (b) propyl;

R9represents (a) hydrogen atom or (b) methyl; or its pharmaceutically acceptable salt.

In particular, the present invention applying the compound of formula VIII, where

R3represents a fragment of formula V;

R4means (a) cyclopropyl or (b) ISO-butyl;

R5means (a) the group-NR9SO2is phenyl, unsubstituted or substituted with one R6(b) the group-NR9SO2-heterocycle, or (C) the group-CH2-SO2is phenyl;

where R6means (a) a cyano group, or (b) a fluorine atom;

where heterocycle refers to the following group, unsubstituted or substituted with one R7:

(a) 2-pyridinyl, (b) 4-pyridinyl, or (C) imidazol-4-yl;

where R7denotes methyl;

R8represents (a) hydrogen atom or (b) propyl;

R9represents (a) hydrogen atom or (b) methyl;

or its pharmaceutically acceptable salt.

In particular, the present claimed invention is also the compound of formula IX, where

R1denotes a hydrogen atom;

R2opment formula V;

R4denotes cyclopropyl;

R5refers to a group-NHSO2-heterocycle;

where heterocycle refers to the following group, unsubstituted or substituted with one R7(a) imidazol-4-yl, (b) 2-pyridinyl, or (C) quinoline-8-yl;

where R7denotes methyl.

In the present invention claimed compound of formula VI, where

R2means (a) ethyl; (b) cut; (C) the group cyclopropyl-(CH2)2-; (d) the group forfinal-(CH2)2-; (e) group, a heterocycle-SO2NH-phenyl-; (f) ISO-butyl; (g) the group phenyl-(CH2)2or (h) trifluoromethyl-(CH2)2-;

R3represents a fragment of formula X;

R6means (a) ethyl; (b) cut; (C) the group cyclopropyl-(CH2)2-; (d) the group forfinal-(CH2)2-; (e) group, a heterocycle-SO2NH-phenyl-; (f) ISO-butyl; (g) the group phenyl-(CH2)2-; or (h) trifluoromethyl-(CH2)2-;

R7means (a) ethyl; (b) tert-butyl or (c) cyclopropyl;

R9means (a) group-NHSO2-heterocycle, or (b) the group-NHSO2is phenyl, substituted with one R11;

where heterocycle refers to the following group, unsubstituted or substituted with one R10:

(a) imidazol-4-yl, (b) 2-pyridylamino group or (f) an amide group;

where R11denotes a cyano group.

In the present claimed invention is also the compound of formula XI,

where R1refers to a group -(CH2)p-CH(R2)-(CH2)o-Ar1;

where R2means (a) (C1-C5)alkyl or (b) a group -(CH2)q- cycloalkyl;

where Ar1represents (a) phenyl, unsubstituted or substituted with one R3or (b) phenyl substituted by a group of m-NHSO2Ar2;

where Ar2represents (a) phenyl, unsubstituted or substituted with one R3; or (b) a heterocycle,

where the heterocycle denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group comprising nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heteroatoms condensed with a benzene ring or another heterocycle; unsubstituted, substituted with one R4;

where R3means (a) cyano group, (b) a fluorine atom, (C) hydroxyl group, or (d) a nitro group;

where R4means (a) methyl, (b) cyano group, (C) hydroxyl group, (J) ethoxycarbonyl group, (e) triptorelin group, or (f) amino group;

n p is (3), inclusive,

q is zero (0) to three (3) inclusive;

or its pharmaceutically acceptable salt.

In particular, the present invention is claimed connection,

where R1refers to a group-CH(R2)-Ar1;

where R2means (a) ethyl or (b) tert-butyl;

where Ar1denotes phenyl, substituted by a group of m-NHSO2Ar2;

where Ar2represents 2-pyridinyl substituted with one R4;

where R4means (a) a cyano group, or (b) triptorelin group;

where n denotes a number from two (2) to four (4) inclusive.

In the present claimed invention is also a method of obtaining the compounds of formula W-10,

where R1means (a) n-propyl or (b) phenethyl; which involves the following stages:

a) treatment of compounds of formula W-9, where the value of XAearlier, chloride titanium (IV);

b) treatment of the product obtained in stage a), aminoven base and

(C) interaction of the product obtained in stage b), with 4-heptanone or Propylenediamine with the formation of the compounds of formula W-10.

The method further includes the steps:

d) processing the compounds of formula W -10 hydride or sodium tert-piperonyl potassium, forming Safarali W-11 with the formation of the compounds of formula W-12, where a value of R1stated previously;

f) processing the compounds of formula W-12 chloride sulfonium formula D-7 wherein R4denotes 5-trifluoromethyl-2-pyridinyl, in an organic solvent in the presence of an organic base, you get a compound of the formula W-13, where a value of R1stated previously.

In the present claimed invention is also a method of obtaining the compounds of formula X-10, where

R1means (a) n-propyl or (b) phenethyl; which involves the following stages:

a) treatment of compounds of formula X-9, where the value of XAearlier, chloride titanium (IV);

b) treatment of the product obtained in stage a), aminoven base and

(C) the interaction of the product obtained at stage b), with 4-heptanone or Propylenediamine with the formation of the compounds of formula X-10.

The method further includes the steps:

(d) processing the compounds of formula X-10 hydride or sodium tert-piperonyl potassium, forming a compound of the formula X-11,

where R1means (a) n-propyl or (b) phenethyl;

e) hydrogenation of the compounds of formula X-11 with the formation of the compounds of formula X-12, where a value of R1stated previously;

f) processing the compounds of formula X-12 chloride sulfanilamides Foundation, you get a connection formula X-13, where a value of R1stated previously.

In the present claimed invention is also a method of obtaining the compounds of formula GGG-10, where

R1means (a) n-propyl or (b) phenethyl, which involves the following stages:

a) treatment of compounds of formula GGG-9, where the value of XAearlier, chloride titanium (IV);

b) treating the product obtained in stage a), aminoven base and

(C) interaction of the product obtained in stage b), with 4-heptanone or 1-phenyl-3-hexanone with the formation of the compounds of formula GGG-10.

The method further includes the steps:

d) processing the compounds of formula GGG-10 hydride or sodium tert-piperonyl potassium, thereby forming the compound of formula GGG-11

R1means (a) n-propyl or (b) phenethyl;

e) hydrogenation of the compounds of formula GGG-11 with the formation of the compounds of formula GGG-12, where a value of R1stated previously;

f) processing the compounds of formula GGG-12 chloride sulfonium formula D-7 wherein R4denotes 5-trifluoromethyl-2-pyridinyl, in an organic solvent in the presence of an organic base, you get a compound of the formula CGG-13A, where a value of R1stated previously.

Spoish stage:

a) treatment of compounds of formula HHH-9, where the value of XAearlier, chloride titanium (IV);

b) treatment of the product obtained in stage a), aminoven base and

(C) interaction of the product obtained in stage b), with 4-heptanone or 1-phenyl-3-hexanone with the formation of the compounds of formula HHH-10.

The method further includes the steps: (d) treatment of compounds of formula HHH-10 hydride or sodium tert-piperonyl potassium, forming a compound of formula HHH-11

R1means (a) n-propyl or (b) phenethyl;

e) hydrogenation of the compounds of formula HHH-11 with the formation of the compounds of formula HHH-12, where the values of R1stated previously;

f) processing the compounds of formula HHH-12 chloride sulfonium formula D-7 wherein R4means (a) 5-trifluoromethyl-2-pyridinyl or (b) 5-cyano-2 - pyridinyl, in an organic solvent in the presence of an organic base, you get a compound of formula HHH-13A, where a value of R1stated previously.

The method of obtaining the compounds of formula LLL-10, where

R1means (a) n-propyl or (b) phenethyl; which involves the following stages:

a) treatment of compounds of formula LLL-9, where the value of XAearlier, chloride titanium (IV);

b) obrabotkami b), 4-heptanone or 1-phenyl-3-hexanone with the formation of the compounds of formula LLL-10.

The method further includes the steps:

d) processing the compounds of formula LLL-10 hydride or sodium tert-piperonyl potassium, thereby forming the compound of formula LLL-11

R1means (a) n-propyl or (b) phenethyl;

e) hydrogenation of the compounds of formula LLL-11 with the formation of the compounds of formula LLL-12, where a value of R1stated previously;

f) processing the compounds of formula LLL-12 chloride sulfonium formula D-7 wherein R4means (a) 5-trifluoromethyl-2-pyridinyl or (b) 5-cyano-2-pyridinyl, in an organic solvent in the presence of an organic base, you get a compound of formula LLL-13A, where a value of R1stated previously.

The method of obtaining the compounds of formula JJJ-10,

where R1means (a) n-propyl or (b) phenethyl; which involves the following stages:

a) treatment of compounds of formula JJJ-9, where the value of XAearlier, chloride titanium (IV);

b) treatment of the product obtained in stage a), aminoven base and

(C) interaction of the product obtained in stage b), with 4-heptanone or 1-phenyl-3-hexanone with the formation of the compounds of formula JJJ-10.

The method further vkluchaetsia compound of formula JJJ-11,

where R1means (a) n-propyl or (b) phenethyl;

e) hydrogenation of the compounds of formula JJJ-11 with the formation of the compounds of formula JJJ-12, where a value of R1stated previously;

f) processing the compounds of formula JJJ-12 chloride sulfonium formula D-7 wherein R4means (a) 5-trifluoromethyl-2-pyridinyl or (b) 5-cyano-2-pyridinyl, in an organic solvent in the presence of an organic base, you get a compound of the formula JJJ-13A, where a value of R1stated previously.

It is most preferable in the present invention applying the compound of formula VI, where

R2means (a) drunk or (b) the group phenyl-(CH2)2-;

R3represents a fragment of formula X;

R6means (a) drunk or (b) the group phenyl-(CH2)2-;

R7means (a) ethyl or (b) tert-butyl;

R9means (a) group-NHSO2-heterocycle;

where heterocycle refers to the following group, substituted with one R10:

(a) imidazol-4-yl or (b) 2-pyridinyl;

where R10means (a) methyl, (b) cyano group, or (C) triptorelin group.

Compounds of the present invention is designated in accordance with the nomenclature systems IUPAC or CAS. the CI, specifying a minimum or maximum number of carbon atoms in the fragment, in particular, the prefix Ci-Cjdenotes the fragment in which the number of carbon atoms is from "i" to "j" inclusive. So, for example, (C1-C3)alkyl means alkyl containing from one to three carbon atoms, inclusive, or methyl, ethyl, propyl and ISO-propyl, its shape with straight and branched chain.

In addition, the content of carbon atoms in various hydrocarbon fragments according to the present invention is indicated as a subscript integer indicator, which indicates the number of carbon atoms and hydrogen atoms in this fragment, in particular, "CnH2n" refers to a fragment, which contains "n" carbon atoms, inclusive, and "2n" of hydrogen atoms inclusive. For example, "CnH2n" where n is equal to three, represents from one to three carbon atoms inclusive and from two to six hydrogen atoms inclusive, or methyl, ethyl, propyl and ISO-propyl and all its isomeric forms with straight and branched chain.

Examples of Akilov containing from one to nine carbon atoms, are methyl, ethyl, propyl, b Examples of alkenyl, containing two to five carbon atoms, inclusive, are ethynyl, propenyl, butenyl, pentenyl and all their isomeric forms with straight and branched chain.

By "halogen" is understood conventional halogen atoms such as fluorine, chlorine, bromine or iodine.

The compounds of formula I and II according to the present invention inhibit proteases retroviruses and, thus, inhibit viral replication. They are useful for the treatment of patients infected with human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) and related diseases.

In particular, the compounds of the present invention are useful as new inhibitors of retroviral protease person. The compounds inhibit protease retroviruses and, thus, inhibit viral replication. They are useful for treating patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or virus leukemia T-cells (HTLV-1 or HTLV-2), which causes acquired immunodeficiency syndrome (AIDS) and/or related diseases.

The capsid and replicative enzymes (in particular, protease, reverse transcriptase, integrase) retrobeat in the Mature protein; they can be found in the capsid and necessary to carry out the functions of virus replication. If reverse transcriptase is missing or not functioning, the virus cannot replicate. It was found that the reverse transcriptase of retrovirus, such as the reverse transcriptase of HIV-1, is aspartates, the characteristics of the active site which are similar to the characteristics of a more complex aspartates - renin.

The term retrovirus person includes the human immunodeficiency virus type I, human immunodeficiency virus type II their strains and the virus leukemia T-cells (HTLV-1 or HTLV-2) or strains, obvious to a person skilled in the art that refer to the same or related families, and which have the same physiological effect on humans, and human retroviruses.

Patients who undergo treatment are the following individuals: 1) patients infected by one or more strains of human retrovirus that is determined by the presence of detectable quantities of either antibodies of the virus or antigen in the serum, and 2) in the case of HIV, individuals who have symptoms Venially or pulmonary candidiasis, including pneumocystitis pneumonia, iv) lymphoma other than Hodgkin's lymphoma, or v) sarcoma Kaposi, and the patient's age does not exceed sixty years; or individuals who have an absolute value of the number of CD4+ lymphocytes in the peripheral blood blood system is less than 500 / ml. Treatment consists of keeping the patient inhibitory concentration of the compounds used in accordance with the present invention, up until the appearance of the following symptoms of infection caused by AIDS, will not show the need to change therapy.

In particular, an example of one such human retrovirus is the human immunodeficiency virus (HIV insuasty as well as HTLV-III or LAV), which was identified as the agent that causes human acquired immunodeficiency syndrome (AIDS). P. Duesberg, Proc. Natl. Acad. Sci. USA, 86: 755 (1989). HIV contains encoded by the retrovirus protease, HIV-1 protease, which cleaves polypeptides merge into functional proteins of Mature virus particles, E. P. Lillehoj et al., J. Virology, 62: 3053 (1988); C. Debuck et al., Proc. Natl. Acad. Sci. USA, 84: 8903 (1987). The specified enzyme HIV-1 protease classified as aspartates and was shown his gomologichnosti other isartorplatz HIV and thus, it is useful in the treatment of AIDS in humans, E. D. Clerq, J. Med. Chem., 29: 1561 (1986). Inhibitors of HIV-1 protease useful in the treatment of HIV-infected patients without symptoms or with symptoms of AIDS.

Pepstatin A General inhibitor of aspartates, described as an inhibitor of HIV-1 protease, S. Seelmeier et al., Proc. Natl. Acad. Sci. USA, 85: 6612 (1986). Provides other obtained from the culture medium inhibitors containing reduced isostere or statin at the split part, M. L. Moore et al., Biochem. Biophys. Res. Commun., 159: 420 (1989); S. Billich et al., J. Biol. Chem., 263: 17905 (1988); Sandoz, D. E. 3812-576.

Thus, the compounds of the present invention are useful for treating diseases caused by retroviruses, such as acquired immunodeficiency syndrome (AIDS).

Compounds useful for the treatment of animals other than human, infected with a retrovirus, such as cats infected with feline leukemia virus. Other viruses that infect cats, include, for example, feline infectious virus letonica, mosaic virus, rabbit virus, feline immunodeficiency virus, feline parvovirus (virus parlakimidi) and feline chlamydia. Specific doses, forms and methods of appointment of the compounds of the present invention the R.

The compounds of formula I and II according to the present invention receives, as described in the Schemes, Preparations and Examples below, or obtained using methods similar to those shown, which are well known and readily available to specialists in the field of organic chemistry.

SCHEME A

The nitration of cyclopropylacetylene formula A-1, which is commercially available, with "Smoking" nitric acid at a temperature of minus 40oC get the mixture of isomers in a ratio of about 2:1. Target m-nitro-derivatives of the formula A-2 is easily separated from the crude mixture by recrystallization from methanol. Catalytic hydrogenation of cyclopropyl-(3-nitrophenyl) methanone formula A-2 using 10% platinum on coal in methanol receive aniline of formula A-3. Aniline then condense with benzosulphochloride in the presence of pyridine in methylene chloride and receive derived sulfonamida formula A-4. Reaction of the ketone with sodium borohydride in tetrahydrofuran and ethanol carbinol of the formula A-5.

Dianion of cyclooctatetraene formula A-6, obtained as described in Scheme B, generate using di-ISO-propylamide lithium in tetrahydrofuran at a temperature of 0oC, and then alkylate is ormula A-5 condensed, using p-toluensulfonate in methylene chloride, and get derived sulfonamida formula A-8.

SCHEME IN

Commercially available amine of formula B-1 protects using benzylchloride and sodium bicarbonate in a mixture of tetrahydrofuran/water and get the connection formula b-2. The aldehyde of formula b-2 is then introduced into the reaction with the Grignard reagent and receive a secondary alcohol of formula b-3, where, in particular, R1denotes ISO-butyl. Known cyclooctadiene formula B-4 is produced by acylation trimethylsilyl enol ether of cyclooctanone using malonaldehyde, as described in R. Effenberger, T. Ziegler, K.-H. Schonwalder, So Kesmar-szky, C. Bauer, Chem. Ber., 119: 3394-3404 (1986). The alcohol of formula b-3 is then used for the alkylation of cyclooctatetraene formula B-4 in boiling toluene in the presence of p-toluenesulfonic acid and obtain the connection formula-5, where, in particular, R1denotes ISO-butyl. At this stage, the enantiomers of formula-5 share on chiral column liquid chromatography high resolution. Protective benzyloxy group is removed using 10% palladium on coal in hexane, and get an amine of formula B-6, where, in particular, R1denotes ISO-butyl, which is then injected into the interaction of 2
denotes 1-Mei.

DIAGRAM

3-Bromobenzylamine alcohol of formula C-1, which is produced industrially, in tetrahydrofuran, at a temperature of minus 78oC sequentially processed by methyllithium, n-butyllithium and cyclopropanecarboxaldehyde. The resulting solution was allowed to warm to room temperature and then refluxed, getting the alcohol of formula C-2. The resulting alcohol was dissolved in dichloromethane and treated with molecular sieves 4-hydroxy-5,6,7,8,9,10-hexahydrocyclooct[b]Piran-2-one of formula-8, obtained as described in Scheme B, and p-toluensulfonate. The solution is refluxed and get the alcohol of formula C-3. Benzyl alcohol is treated cetarehhloristam carbon and triphenylphosphine in dichloromethane at a temperature of 0oC and after treatment with an aqueous solution of salt and allocation of product is obtained the compounds of formula C-4 and C-5 in the form not amenable to separation of the mixture. The mixture is then treated with any thiol (in particular, thiophenols) and organic base and refluxed getting the sulfides of the formula C-6. After finishing compounds of formula C-6 axonom in a mixture of tetrahydrofuran, methanol and water is twinneh 5,6-dihydropyrones catalyzed by aluminum chloride condensation of 3-nitrobenzaldehyde. So, catalyzed by aluminum chloride reaction of compounds of formula D-1, obtained as described below in the Preparations (in particular, where R1denotes phenethyl or propyl; R2denotes phenethyl or propyl) 3-nitrobenzaldehyde (formula D-2), manufactured, leads to compounds of formula D-3 (where, in particular, R1denotes phenethyl or propyl; R2denotes phenethyl or propyl). Subsequent reaction with trialkylaluminium or Grignard reagents in the presence of complex copper bromide (1) dimethyl sulfide (CuBr-Me2S) leads to compounds of formula D-4 (where, in particular, R1denotes phenethyl or propyl; R2denotes phenethyl or propyl, R3denotes ethyl or cyclopropyl). Exchange hydrogenation using palladium on coal and ammonium formate obtain the compounds of formula D-5 (where, in particular, R1denotes phenethyl or propyl; R2denotes phenethyl or propyl, R3denotes ethyl or cyclopropyl). Treatment of compounds of formula D-5 chloride sulfonium formula D-7, where the values of R4stated previously, and pyridine in methylene chloride obtain the compounds of formula D-6 (where, in particular, R1denotes phenethyl or propyl; R2putting the l, 1-Mei-4-yl, quinoline-8-yl, 2-pyridyl, 4-cyano-2-pyridyl, quinoline-2-yl, 2-hydroxyphenyl, 2 pirimidil, 2-hinzelin, 7H-purine-6-yl, 1H-imidazol-2-yl, 1H-benzimidazole-2-yl or thiazol-2-yl).

SCHEME E

Processing of industrially produced 4-hydroxy-6-methyl-2-pyrone of formula E-1 three equivalents of di-ISO-propylamide lithium in tetrahydrofuran and hexamethylphosphoramide with subsequent processing bromelicola get compound of formula E-2. The interaction of the compounds of formula E-2 and compound F-5, obtained as described in Scheme F, in benzene in the presence of molecular sieves and p-toluenesulfonic acid as catalyst to obtain the compound of formula E-3. The hydrogenolysis of the compound of formula E-3 in methanol with hydrogen over palladium on coal receive a free amine of formula E-4. By treating compound E-4 with two equivalents of pyridine in dichloromethane followed by treatment with one equivalent of 4-forbindelsesfaneblad get compound of formula E-5 (where, in particular, R represents 4-forfinal), which is the compound N-(3-{cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl) -4-forbindelsesfaneblad.

In a similar situation get soeiety pyridine to form compounds of formula E-5, where R denotes an alkyl, aryl or heteroaryl. In addition, for example, the enantiomers of the compounds of formula E-9 share chromatographic method chiral liquid chromatography high resolution and obtain the compounds of formula E-10 and E-11. Similar conditions obtain final compounds of the present invention of the formula E-6, E-7, E-8, E-12, E - 16.

SCHEME F

Nitration of industrially produced cyclopropylacetylene formula F-1 "fuming" nitric acid to obtain the compound of formula F-2. The restoration of the compounds of formula F-2 hydrogen in methanol in the presence of platinum on coal receive amine of formula F-3. The compound of formula F-3 is treated with benzylchloride and di-ISO-propylamino in dichloromethane and get the connection formula F-4. The restoration of the compounds of formula F-4 with sodium borohydride in tetrahydrofuran and ethanol compound of formula F-5.

SCHEME G

Dianion of industrially produced 4-hydroxy-6-methyl-2-pyrone of the formula G-0 generated by deprotonation using two equivalents of di-ISO-propylamide lithium in tetrahydrofuran and hexamethylphosphoramide. The alkylation of 2-(2-methoxy-ethoxy)ethyliodide, which is derived from industrially produced alcohol is melamineformaldehyde, the compounds of formula F-5, obtained as described in Scheme F, in dichloromethane with p-toluensulfonate as a catalyst in the presence of molecular sieves get compound of formula G-2. The hydrogenolysis of compounds of formula G-2 in ethanol hydrogen and pallidum coal receive free amino of the formula G--3. Treatment of the free amine of formula G-3 with two equivalents of pyridine in dichloromethane followed by treatment with one equivalent of 1 - Mei-4-sulfochloride leads to the compound of formula G-4, which is the compound N-(3-{cyclopropyl-[4 - hydroxy-6-(3-{2-methoxy-ethoxy} -propyl)-2-OK-with-2H-Piran-3 - yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide.

SCHEME H

By the reaction of industrially produced 4-hydroxy-6-methyl-2-pyrone of the formula H-0 and meta-benzyloxycarbonylglycine, the target compounds of formula F-5, obtained as described in Scheme F, in dichloromethane with p-toluensulfonate as a catalyst in the presence of molecular sieves get compound of formula H-1. Alkylation triunion the compounds of formula H-1, obtained using three equivalents of di-ISO-Propylamine lithium in tetrahydrofuran, methyl-ethyl receive the compound of formula H-2. Processing connection the General formula H-3. The hydrogenolysis of compounds of formula H-3 in ethanol with hydrogen and palladium on coal receive a free amine of formula H-4. Treatment of the free amine of formula H-4 with two equivalents of pyridine in dichloromethane followed by treatment with one equivalent of 1-Mei-4-sulfochloride leads to the compound of formula H-5, which is the compound N-(3-{cyclopropyl-[6-(1-ethyl-3-{ 2 - methoxy-ethoxy}propyl)-4-hydroxy-2-oxo-2H-Piran-3 - yl]methyl}phenyl)-1-methyl-1H-imidazole-4-sulfonamide. Similar conditions obtain compounds of the present invention by the reaction of an amine of formula H-1 alkyl-, aryl - and heteroarylboronic in the presence of pyridine to form additional compounds of formula H-5.

SCHEME I

Treatment of compounds of formula H-2, obtained as described in Scheme H, three equivalents of di-ISO-propylamide lithium in tetrahydrofuran and ethylene oxide receive the compound of the formula I-1. The reaction of compounds of formula I-1 with triphenylphosphine and tetrabromide carbon in tetrahydrofuran get compound of formula I-2. Treatment of compounds of formula I-2 sodium azide in aqueous solution of ethanol, the compound of formula I-3. The reaction of compounds of formula I-3 with hydrogen and palladium on coal in atenololbuy processing 1-Mei-4-sulfochloride get compound of formula I-5. The interaction of the compounds of formula I-5 with a solution of ammonia in methanol to obtain compound of formula I-6, which is the compound N-(3-{ cyclopropyl-[6-(1-ethyl-3-{1-methyl-1H - imidazol-4-sulfonamide} propyl)-4-hydroxy-2-oxo-2H-Piran - 3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide.

SCHEME J

By hydrogenolysis in ethanol compounds of the formula I-1, obtained as shown in scheme I with hydrogen and palladium on coal produce the compound of formula J-1. Treatment of compounds of formula J-1 triphenylphosphine and cetarehhloristam carbon in tetrahydrofuran get compound of formula J-2. The reaction of the compound of formula J-2 with pyridine in dichloromethane, followed by interaction with 1-Mei-4-sulfochloride get compound of formula J-3, which is a combination of N-(3-{[6-(3-bromo-1 - ethylpropyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] cyclopropylmethyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide. Treatment of compounds of formula J-3 sodium azide in aqueous ethanol, the compound of formula J-4, which is a combination of N-(3-{ [6- (3-azido-1-ethylpropyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] - cyclopropylmethyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide. The interaction of the compounds of formula J-4 with hydrogen, Pallady mirovoi salt Suleymanova acid (B. D. Anderson, R. A. Conradi, K. E. Knuth, J. Pharm. Sci., (1985) 74: 365) and 1,3-di-ISO-propyl-carbonyldiimidazole get compound of formula J-6, which is a sodium salt of N-(3-{ cyclopropyl-[6-(1-ethyl-3-{ N-[8-(methyl-{ 2-sulfoethyl} amino)-1,8-dioxaoctyl]aminopropyl})-4-hydroxy-2-oxo-2H-Piran-3-yl]-methyl - phenyl)-1-methyl-1H-imidazol-4-sulfonamida.

SCHEME K

Obtaining the compounds of formula K-8, which is the compound N-(3-{ cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl) -4-hydroxy-2-oxo-2H-Piran-3-yl] -methyl} -phenyl)-1-methyl-1H-imidazole-4-sulfonamide, shown in Scheme K. Recovery of industrially produced tetrahydropyran-4-carboxylic acid of the formula K-1 borane in tetrahydrofuran get a connection K-2. The compound of formula K-2 is treated with p-toluenesulfonyl chloride, receive appropriate tauziat formula K-3, which is converted into iodide of the formula K-4 by treatment with potassium iodide in boiling acetone. Alkylation dianion of industrially produced 4-hydroxy-6-methyl-2-pyrone of formula K-10 methyl-ethyl in tetrahydrofuran and hexamethylphosphorotriamide get through derivative of formula K-9. The compound of formula K-4 is used for the alkylation of compounds of formula K-9 6-alpha-position and receive the connection is described in Scheme F, and produce the compound of formula K-6. Remove benzyloxycarbonyl protective group is carried out using the method of exchange hydrogenation, and receive amine of formula K-7. Processing amine of formula K-7 1-Mei-4-sulfochloride in the presence of pyridine get compound of formula-8.

SCHEME L

As shown in figure L, dianion manufactured 4-hydroxy-6-methyl-2-pyrone of the formula L-1 generated by deprotonation of two equivalents of di-ISO-propylamide lithium in tetrahydrofuran and hexamethylphosphoramide. Alkylation of methyl-benzyl get the compound of formula L-2, which is then treated with two equivalents of di-ISO-propylamide lithium in tetrahydrofuran and hexamethylphosphoramide followed by treatment of ethyl iodide and get the connection formula L-3. The interaction of the compounds of formula L-2 and the compounds of formula F-5, obtained as described in Scheme F, in benzene, using p-toluensulfonate as a catalyst, in the presence of molecular sieves get compound of formula L-4, which is 3-[(3-benzyloxycarbonylamino) cyclopropyl-methyl] -6-(1-ethylphenyl)-4-hydroxy-2H-Piran-2-it. The hydrogenolysis of compounds of formula L-4 in methanol using palladium is s L-5, which is 3-[(3-AMINOPHENYL) cyclopropyl-methyl] -6-(1-ethylphenyl)-4-hydroxy-2H-Piran-2-it. The interaction of the compounds of formula L-5 and the corresponding sulfochloride obtain the target compound of the present invention.

SCHEME M

As shown in Scheme M, manufactured onomatology ether of triethylene glycol is treated with p-toluenesulfonyl chloride and pyridine and get toilet formula M-2, which is then used for the alkylation of industrial 2,4-dihydroxyacetophenone and get the connection formula M-3. Condensation using diethylmalonate synthesize the compound of the formula M-4. The closing of the cycle of compounds of formula M-4 with the formation of compounds of formula M-5 is carried out in boiling acetic acid. The compound of formula M-5 alkylate in the 3-position using the carbinol of formula F-5, synthesized as described in Scheme F, and a catalytic amount of p-toluenesulfonic acid and obtain the connection formula M-6. Remove benzyloxycarbonyl protective group is carried out by the method of exchange hydrogenation and receive amine of formula M-7. Processing amine 1-Mei-4-sulfochloride in the presence of pyridine obtain the target compound of the formula M-8, which PR is Il-1H-imidazole-4 - sulfonamide.

SCHEME N

The nitration of cyclopropylacetylene formula N-1, which is produced industrially using "fuming" nitric acid at a temperature of minus 40oC get the mixture of isomers in a ratio of about 2:1. Target m-nitro-derivatives of the formula N-2 is easily separated from the crude mixture by recrystallization from methanol. Catalytic hydrogenation of cyclopropyl-(3-nitrophenyl)methanone formula N-2 with 10% platinum on coal in methanol at 0oC get the aniline of the formula N-3. The product distinguish by filtration and evaporation. Amino group, then protect by using benzylchloride and di-ISO-propylacetamide in methylene chloride and receive a ketone of the formula N-4. The ketone may be restored with sodium borohydride in a mixture of 5:1 tetrahydrofuran and ethanol and receive an alcohol of the formula N-5.

The compound of the formula N-5 then used for alkylation of 4-hydroxy-5,6,7,8,9,10-hexahydrocyclooct[b]Piran-2-it, obtained as described in R. Effenberger, T. Ziegler, K.-H. Schonwalder, So Kesmarsky, C. Bauer, Chem. Ber. , 119: 3394-3404 (1986) and get a connection formula N-6. Preferred conditions for the reaction of alkylation include boiling under reflux with p-toluensulfonate in methylene chloride in a Soxhlet extraction apparatus with metodom exchange hydrogenation. Best results when carrying out this reaction are obtained by using 10% palladium on coal in pure cyclohexane.

SCHEME ON

Processing amine of the formula O-1, obtained as described in Scheme N, sulfochlorides and a base such as pyridine in dichloromethane, get sulfonamides of the formula O-2, where R60for example, denotes 4-nitrophenyl. These sulfonamides then modify as described in the literature procedures that are obvious to a person skilled in the art, and get a sulfonamide of formula-3, where R61for example, denotes 4-nitrophenyl and other functional groups that cannot easily be obtained from the available sulfochlorides. For example, the nitro-group in the N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo - 2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-4-nitrobenzenesulfonamide restore catalytic hydrogenation in ethyl acetate palladium on coal and receive amine 4-amino-N-[3-[cyclopropyl-(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]benzosulfimide. In addition carboxyl group at the 3-[[[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)-methyl]phenyl]amino] sulfonyl] benzoic acid etherification meta, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] amino] sulfonyl] benzoic acid. The sulfonamide of the formula O-3 is also obtained from compounds of the formula O-2 further functionalization of reactive functional groups. For example, the amino group in 3-amino-N-[3-[cyclopropyl- (5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] benzosulfimide enter into interaction with benzoyl chloride and a base such as pyridine, and get benzamide 3-[[[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl]-amino]sulfonyl]benzamide. Using the available sulfochloride receive additional compounds of the present invention of formula II, where R10and R20represent a fragment of formula IV.

Sulfochloride which are used for the synthesis of compounds of the present invention, can easily be obtained by specialists in the art according to the methods described in the literature, as the following examples show. Reaction of the appropriate thiol with biperiden potassium in a mixture of water/methanol and gaseous chlorine receive sulfited (D. J. Brown, J. A. Hoskins, Aust. J. Chem., (1972) 25: 2641), which is then converted into the required sulfochloride (T. Norris, J. indicate the target sulfochloride (G. Pala, Ed. Sci., (1958) 13: 461; W. J. Close, J. Am. Chem. Soc., (1960) 82: 1132). The reaction of heteroaromatic compounds with "fuming" sulfuric acid get heteroaromatic acid, and subsequent treatment with phosphorus oxychloride and chloride of phosphorus (V) receive target sulfochloride (V. Gergian, R. J. Harrison, L. L. Skaletzky, J. Org. Chem., (1962) 27: 4571. The reaction of heteroaromatic compounds with manganese dioxide and sodium sulfite in water get a target acid, and subsequent treatment with phosphorus oxychloride and chloride of phosphorus (V) receive target sulfochloride (N. A. Androva, Izvest., 455 (1972); J. O. Morley, J. Chem. Commun., (1976) 88). Processing of the corresponding heteroaromatic chloride sodium sulfate and an aqueous solution of hydrochloric acid to obtain the desired acid and subsequent treatment with phosphorus oxychloride and chloride of phosphorus (V) receive target sulfochloride (T. R. Norton, J. Amer. Chem. Soc., (1946) 68: 1330). Processing of the corresponding hydroxyl derivative of N, N-dimethylthiocarbamate (M. S. Newman, F. W. Hetzel, Org. Synth. Coll. Vol. IV: 824 (1988); M. S. Newman, H. A. Karnes, J. Org. Chem., (1966) 31: 3980) with further processing, as indicated above, get the target sulfochloride. The interaction of the corresponding thio-heteroaromatic compounds containing a protective group, with chlorine in acetic is using the technique, get heteroaromatic sulfochloride of the present invention.

SCHEME P

The preferred method of obtaining heteroaryl sulfonamides of formula P-2 is shown in figure R. Sulfonation amine of formula R-1, obtained as shown in Scheme N using different heteroarylboronic formula R-3, where R, in particular, represents 2-pyridyl, 4-pyridyl, 5-cyano-2-yl, 2-pyrazinyl, 2-pyrimidinyl, 4,6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, get sulfonamides of formula P-2, where R denotes the appropriate Deputy.

SCHEME q

Dianion of industrially produced methyl ester of acetoacetic acid, which generate successive deprotonation with sodium hydride and n-butyllithium in tetrahydrofuran at a temperature of 0oC, enter into interaction with the ketone of formula Q-1, obtained as described in Scheme S (equation S-4). The obtained intermediate hydroxyether cyclist dilute aqueous hydroxide solution, and then treated with a solution of hydrochloric acid and obtain the connection formula Q-2. The compound of formula Q-2 condense manufactured with 3-nitrobenzaldehyde in tetrahydrofuran, using as catalyst team in the presence of complex broil copper (1) - dimethyl sulphide, receiving compound of the formula Q-3. Method exchange catalytic hydrogenation using ammonium formate over palladium on coal in methanol receive the compound of formula Q-4. The compound of formula Q-4 are processed with the proper sulfochloride and pyridine in dichloromethane and get the target compound of the formula Q-5 (where, for example, R1denotes 5-cyano-2-pyridyl or 1-Mei-4-yl).

SCHEME R

Catalytic hydrogenation of industrially produced 3-nitropropiophenone formula R-1 receive amine of the formula R-2. Amine of the formula R-2 is treated with di-ISO-propylamino and methyl-benzyl, receiving compound of formula R-3. Dianion of industrially produced methyl ester of acetoacetic acid, generated by treatment with sodium hydride and n-butyllithium in tetrahydrofuran at a temperature of 0oC, enter into interaction with the ketone of formula R-3. The obtained intermediate hydroxyether cyclist dilute aqueous hydroxide solution, and then treated with a solution of hydrochloric acid and obtain the connection formula R-4. The compound of the formula R-4 condensed with 3-nitrobenzaldehyde in tetrahydrofuran, using as catalyst trichloride aluminum, and intermediate the d copper (1) - dimethyl sulphide, receiving compound of the formula R-5. Catalytic hydrogenation over palladium on coal receive a diamine of the formula R-6. The compound of the formula R-6 are processed with the proper sulfochloride and pyridine in dichloromethane and get the target compound of the formula R-7 (where, for example, R1denotes 5-cyano-2-pyridyl or 1-Mei-4-yl).

SCHEME S

Industrial output 4-pontenova acid of the formula S-1 condensed with N,O-dimethylhydroxylamine in the presence of bis-(2-oxo-3-oxazolidinyl)fatfingered and get amide of the formula S-2. Amide of the formula S-2 is injected into the interaction with 3-butenyl-minibrains and tetrahydrofuran and receive a ketone of the formula S-3. The ketone of formula S-3 is treated with metallic zinc, copper chloride and diiodomethane and receive a ketone of the formula S-4 (see also above formulas Q-1 on the Diagram Q).

T

The compound of formula T-2 (see also formula (D-1) (obtain separately is shown in figure D and 17 of Drug manufactured methyl ester of acetoacetic acid and 1-phenyl-3-hexanone (formula T-1)) condense with 3-nitrobenzaldehyde in tetrahydrofuran, using as catalyst trichloride aluminum, with subsequent reaction of the intermediate obtained benzine, 2-iodine-2-methylpropane, copper cyanide and lithium chloride) and produce the compound of formula T-3. (Preparation of the ORGANOMETALLIC reagent is described in the product J). Catalytic exchange hydrogenation with ammonium formate and palladium on coal in methanol receive the compound of formula T-4. The compound of formula T-4 are processed with the proper sulfochloride and pyridine in dichloromethane and get the target compound of formula T-5 (where, for example, R1denotes 5-cyano-2-pyridyl or 1-Mei-4-yl).

SCHEME U

Industrial output 4-forgetomori.com acid of the formula U-1 condensed with N,O-dimethylhydroxylamine in the presence of diethyl ether cyanophosphonate acid and get amide of formula U-2. Amide is treated with n-propylaniline and receive ketone U-3. Ketone condensate with gianina methyl ester of acetoacetic acid and subsequent hydrolysis of the intermediate ester and cyclization and release dihydropyran formula U-4. Dihydropyran enter into interaction with the aldehyde of formula b-2, obtained as indicated in the Diagram, in the presence of trichloride aluminum and receive benzimidazole derivative of the formula U-5; subsequent interaction with Grignard reagents or trialkylamine is, R1denotes ethyl, tert-butyl or cyclopropyl). Remove menthoxycarbonyl (CBZ) protective group is carried out using ammonium formate and palladium on coal and receive amines of formula U-7 (where, in particular, R1denotes ethyl, tert-butyl or cyclopropyl). Amines treated with sulfochloride and pyridine in dichloromethane and get sulfonamides of formula U-8 (where, in particular, R1denotes ethyl, tert-butyl or cyclopropyl, and R2denotes alkyl, aryl or heteroaryl).

SCHEME V

Manufactured 4-forbindelse formula V-1 condensed with acetone in the presence of a base and obtain 1,5-bis-(4-forfinal)-Penta-1,4-Dien-3-one formula V-2. Dienen restore magnesium in methanol and receive a ketone of formula V-3. The ketone of formula V-3 is transformed into derivatives dihydropyrone formula V-8, using a sequence of reactions similar to those shown in Scheme U, for the synthesis of compounds U-8 connection U-3.

SCHEME W

Manufactured TRANS-2-pontenova acid of the formula W-1 is transformed into the corresponding acid chloride with chloride of oxalyl in methylene chloride and receive the product of the formula W-2. Amide lithium of the formula W-3, which is easily obtained by processing Promyshlennaya the acid chloride of the formula W-2 and receive unsaturated amide of formula W-4. Amide of formula W-4 are added to a solution of tetrahydrofuran containing industrially produced complex bromide copper (1) - dimethyl sulfide and 3-[bis(trimethylsilyl)amino] phenylmagnesium at a temperature of minus 20oC, and after the usual acid get compound of formula W-5 (Hruby et al. , J. Org. Chem. , (1993) 58(26): 7567). Aniline of the formula W-5 is injected into the interaction boiling with methyl-benzyl and sodium carbonate in a mixture of water/methylene chloride, or potassium carbonate in boiling acetonitrile and get the connection formula W-6. Amide of formula W-6 is treated with titanium chloride (IV) with subsequent processing aminoven base in a solvent such as methylene chloride, and at temperatures below minus 20oC, preferably at a temperature of minus 78oC, type 2-methoxy-2-methyl-1,3-dioxolan formula W-7 (produced as described Santry et al., J. Am. Chem. Soc., (1988) 110(9): 2910) and produce the compound of formula W-8. After a short treatment of compounds of formula W-8 protovol acid get beta ketone formula W-9. Further processing of the compounds of formula W-9 chloride titanium (IV) and subsequent processing aminoven base, and then 4-heptanone or propylresorcinol leads to the compound of formula W-10, where R1represents n-propyl and what xicom potassium in the ether solvent and produce pyrone of the formula W-11. The hydrogenation of the compounds of formula W-11 using, in particular, palladium on coal as a catalyst to get the connection formula W-12. Finally, the compound of formula W-12 is administered in cooperation with sulfochloride formula D-7 wherein R4denotes 5-trifluoromethyl-2-pyridinyl, in an organic solvent such as methylene chloride, in the presence of organic bases such as pyridine, and obtain the target compound of the formula W-13, where R1denotes n-propyl or phenethyl (if R1denotes phenetyl, the compound exists as a pair of diastereomers).

SCHEME X

End (R)-enantiomer of formula X-13, where R1denotes n-propyl or phenethyl receive in accordance with the procedure shown in Scheme W.

SCHEME Y

To acetyl chloride of the formula Y-1 add lithium amide of formula Y-2 or H-3), which is easily obtained by treatment of industrially produced (R)-(-)-4-phenyl-2-oxazolidone n-butyllithium in tetrahydrofuran at a temperature of minus 78oC, and get the product of formula Y-3. The compound of formula Y-3 initially treated with titanium chloride (IV) in methylene chloride at a temperature lower than room, and then add the tertiary amine base followed is aminobenzaldehyde with methyl-benzyl and potassium carbonate or sodium carbonate or acetonitrile, or in a mixture of water/methylene chloride) and get a connection formula Y-5. Add amide of the formula Y-5 to a solution of industrially produced complex bromide copper (1) - dimethyl sulfide and ethylaniline in tetrahydrofuran at a temperature of minus 20oC and obtain the connection formula Y-6. Or the manufactured compound of the formula Y-7 treated with chloride accelerom and get the connection formula Y-8. The compound of the formula Y-8 then added to a solution of the compounds of formula Y-2 or H-3), which is easily obtained by treatment of industrially produced (R)-(-)-4-phenyl-2-oxazolidone n-butyllithium in tetrahydrofuran at a temperature of minus 78oC, and obtain the connection formula Y-9. The compound of the formula Y-9 restore the metallic iron in water-ethanol solution and obtain the connection formula Y-10. The compound of the formula Y-10 handle bromide with benzyl and potassium carbonate or sodium carbonate or acetonitrile or in a mixture of water/methylene chloride) and get a connection formula Y-5, which, as indicated previously, is converted into a compound of the formula Y-6. The compound of the formula Y-6 is transformed into the final product, as described for the conversion of compounds of formula W-6 in the compound of formula W-13 (where R1denotes the PCC is ANO in the Diagram above Y, except, that is used as a compound of the formula Z-2 or W-3). The compound of the formula Z-6 is transformed into the final product, as shown in the Diagram Z, according to methodology described for the conversion of compounds of formula X-6 in the compound of the formula X-13 (where R1denotes propyl or phenethyl).

DIAGRAM AA

Getting 3(S), 6(S) diastereomers AA-12 and AA-14: add the unsaturated amide of formula AA-1 (or Y-5) in a solution of industrially produced complex bromide copper (1) - dimethyl sulfide and ethylaniline in tetrahydrofuran at a temperature of minus 20oC and obtain the connection formula AA-2 (or Y-6). The restoration of the compounds of formula AA-2 metal hydride (sodium borohydride, lithium aluminum hydride) get the connection formula AA-3. The compound of formula AA-3 oxidize (method Swarna) and obtain the aldehyde of formula AA-4, which is treated with trimethylsilylcyanation and produce cyanohydrin formula AA-5, with trimethylsilyloxy protection. Alternatively the compound of formula AA-2 is treated with trimethylaluminum and then N-methyl-O-methylhydroxylamine and get amide of formula AA-6, which is treated with lithium aluminum hydride and produce the aldehyde of formula AA-4. Trimethylsilylcyanation formula AA-5 is injected into the interaction with a strong base Scheme BB) and get a connection formula AA-8. The compound of formula AA-8 dissolved in methylene chloride and cooled to minus 78oC add chloride titanium (IV) and the tertiary amine. To the resulting solution add triethylorthoformate and an additional amount of titanium chloride (IV) and get a connection formula AA-9. The compound of formula AA-9 is treated with a base, and then trimethylsilylpropyne, oxidizing agent (ozone), tetrabutylammonium and or tert-piperonyl potassium, or sodium hydride in a simple broadcast and receive the compound of formula AA-10. The compound of formula AA-10 hydronaut and get the connection formula AA-11. Finally, the compound of formula AA-11 treated with sulfochloride formula D-7, obtained as shown in Scheme D, where R4means, in particular, 5-trifluoromethyl-2-pyridinyl, in an organic solvent such as methylene chloride, in the presence of organic bases such as pyridine, and obtain the connection formula AA-12.

Moreover, the addition of the compounds of formula AA-1 to the solution of industrially produced complex bromide copper (1) - dimethyl sulfide and ethylaniline in tetrahydrofuran at a temperature of minus 20oC get the compound of formula AA-13. Compound AA-13 turn in the final product compounds of formula describes asymmetric synthesis of epoxides of formula BB-7 and BB-12. The alkylation of 2-methyl-2-propen-1-ol (BB-1) industrial output methyl-benzyl get allyl alcohol of formula BB-2 (see C. H. Lipshutz et al., Synthesys 1992, 191). Catalytic epoxydecane method of Sharpless using commercially available (+)-diethyl-L-tartrate get epoxied formula BB-8 (see (a) A. Pfenniger 1986, 89; (b) R. A. Johnson, K. B. Sharpless, In: "Catalytic Asymmetric Synthesis, I. Ojima, Ed; VCH: New York, 1993, Chapter 4.1, 103). Alkylation of compounds of formula BB-8 benzylbromide (see C. H. Lipshutz et al., Synthesis 1992, 191) get the connection formula BB-9. The reaction of the compound of formula BB-9 industrial manufactured by ethylmagnesium receive tertiary alcohol of formula BB-10 (see R. M. Hanson, Chem. Rev., 1991, 91, 437). Catalytic hydrogenolysis of compounds of formula BB-10 get diol of formula BB-11. The compound of formula BB-11 turn in chiral epoxide of formula BB-12 by a standard method (about obtaining epoxides of vicinal diols, see O. Mitsunobu, In: "Comprehensive Organic Synthesis, B. M. Trost, Ed., Pergamon Press: Oxford; Vol. 6, Chapter 1.1, 1; 1991).

Similarly, the epoxide of formula BB-7 receive at the end of apocopate formula BB-3, which, in turn, is produced by oxidation of allyl alcohol BB-2 by the method of Sharpless, manufactured using industrial (-)-diethyltartrate-D.

Another way is x get toilet formula BB-13. The interaction of compounds CC-13 with ethylmagnesium in conditions similar to those described for nucleophilic opening of a cycle arenesulfonates derived ephedrinemore alcohol (see J. M. Klunder, So Onami, K. C. Sharpless, J. Org. Chem., 1989, 54: 1295) receive a mixture of the target epoxide of formula BB-12 and hydroxyethylated formula BB-14. Hydroxyethyl formula BB-14 is easily converted into epoxide BB-12 by the action of potassium carbonate in methanol.

SCHEME SS

Getting 3(S), 6(R) diastereomers SS-12 and SS-14: these diastereomers receive as described in Scheme AA, except that use of the epoxide of formula SS-7 (or BB-7).

DIAGRAM DD

Getting 3(R), 6(S) diastereomers DD-12 DD-14: these diastereomers receive as described in Scheme AA, except that the use of amide of formula DD-1 (or Z-5).

THE SCHEME OF ITS

Getting 3(R), 6(R) diastereomers HER 12 and 14: these diastereomers get as indicated on the DD Scheme, except that the use of the epoxide of Formula-7 (or BB-7).

DIAGRAM FF

Amide lithium formula FF-2, which is easily receive processing of industrially produced (S)-(+)-4-phenyl-2 - oxazolidinone, n-butyllithium in tetrahydrofuran at a temperature of minus 78oC BB the FF-3 chloride titanium (IV) with subsequent treatment with trialkylamines and manufactured by trimethylacetaldehyde get compound of formula FF-4. Amide of formula FF-4 are added to a solution of industrially produced complex bromide copper (1) - dimethyl sulfide and 3-[bis(trimethylsilyl)amino]phenyl-minikleid in tetrahydrofuran at a temperature of minus 20oC and get after acid treatment of the compound of formula FF-5. Aniline of formula FF-5 is treated with methyl-benzyl and sodium carbonate in a mixture of water/methylene chloride by boiling or potassium carbonate in boiling acetonitrile and get the connection formula FF-6.

Amide lithium formula FF-7, which is easily receive processing of industrially produced (S)-(-)-4-benzyl-2-oxazolidinone, n-butyllithium in tetrahydrofuran at a temperature of minus 78oC, enter into interaction with acetylchloride formula FF-1 and get amide of formula FF-8. Treatment of compounds of formula FF-8 chloride titanium (IV) with subsequent treatment with trialkylamines and manufactured by trimethylacetaldehyde get compound of formula FF-9. Amide of formula FF-9 are added to a solution of industrially produced complex bromide copper (1) - dimethyl sulfide and 3-[bis(trimethylsilyl)amino]phenyl-minikleid in tetrahydrofuran at a temperature of minus 20oC and get a mixture of compounds of formula FF-10a and FF-10b. Aniline of formula FF-10 handle broom acetonitrile and get the connection formula FF-11. Treatment of compounds of formula FF-11 chloride titanium (IV) in methylene chloride followed by treatment of the tertiary amine and 2-methyl-2-methoxy-1,3-dioxolane receive intermediate dioxolane (see W-8 on the Diagram W), which is treated with mild acid and get the connection formula FF-12. Treatment of compounds of formula FF-12 chloride titanium (IV) in methylene chloride followed by the addition of either 4-heptanone, or 1-phenyl-3-hexanone get derived aldol formula FF-13. The compound of formula FF-13 treated with either sodium hydride or tert-piperonyl potassium in a simple broadcast and receive the compound of formula FF-14. The compound of formula FF-14 next hydronaut in hydrogen atmosphere in the presence of palladium on coal as a catalyst and obtain the connection formula FF-15. Finally, the compound of formula FF-15 treated with sulfochloride formula D-7, is shown in Scheme D, where R4in particular, denotes a 5-vermeil-2-pyridyl, in an organic solvent such as methylene chloride, in the presence of organic bases such as pyridine, and obtain the target compound of formula FF-16, where, in particular, R1denotes propyl or phenethyl.

SCHEME G

The intermediate compound of formula GG-6, and the final product Faure is inane (R)-(-)-4-phenyl-2-oxazolidinone and (R)-(+)-4-benzyl-2-oxazolidinone.

THE SCHEME HH

The compound of formula HH-1 (W-6), obtained as described in Scheme W is converted into an ester of formula HH-2, where R is tert-butyl, adding tert-butoxide potassium to a solution of the compounds of formula HH-1 in tetrahydrofuran at a temperature of 0oC. the Compound of formula HH-2, where R is tert-butyl, can also be obtained from HH-1 in two stages. First, oxazolidinone group otscheplaut by treating compound of formula HH-1 lithium hydroxide and hydrogen peroxide at 0oC in a mixture of tetrahydrofuran and water. Then the intermediate acid is treated with tert-butylacetate N,N-dimethylformamide in boiling benzene and receive an ester of formula HH-2 (R represents tert-butyl). An ester of formula HH-2, where R denotes methyl, obtained by heating a mixture of titanium chloride (IV) and compounds of formula HH-1 in methanol. The compound of formula HH-3 is produced by treatment of ester of formula HH-2 di-ISO-propylamide lithium or hexamethyldisilazide sodium with the formation of enolate, which then bind with ethyl formate and get the connection formula HH-3. Thus obtained intermediate compound is treated with mozillateam in 1,2-dimethoxyethane and get the connection formula HH-4, which then become Obedinenie formula HH-5 then deprotonated using tert-utility in tetrahydrofuran at low temperature. Add epoxide of formula HH-6 (BB-7) obtained as shown in Scheme BB, and one equivalent of epirate boron TRIFLUORIDE and get the connection formula HH-7. The obtained intermediate compound in situ cyclist in the compound of formula HH-8 or isolated and treated with sodium hydride in tetrahydrofuran, receiving a cyclic compound of formula HH-8. Sulfur-containing group then hydrolyzing with either sodium hydroxide in acetonitrile or aqueous solution of copper chloride and receive the derived dihydropyrone formula HH-9. Benzyl protective group is then removed by catalytic hydrogenation over 10% palladium on coal in ethyl acetate. The obtained amine of formula HH-10 turn in the target derived sulfonamida formula HH-11 processing 5-cyanopyridine-2-sulfochloride synthesized according to methodology described in Scheme O and pyridine in dichloromethane.

SCHEME II-00

The diastereoisomer of formula II-7 receive in accordance with Scheme II by methods similar to the above to obtain the diastereomeric products by the Scheme HH. Similarly, stereometry formula JJ-11, CC-7, LL-11, MM-7, NN-11 and OO-7 receive in accordance with Schemes JJ, KK, LL, MM, NN and OO, respectively, by methods similar to those described for Scheme HH.

the Ute processing tert-butyl ester of formula PP-1 (HH-5), obtained, as shown in the Diagram HH, aqueous acid solution. The compound of formula PP-2 and then treated with tert-butyllithium in tetrahydrofuran at low temperature and receive intermediate dianion, which is treated with epoxide of the formula RR-3 (BB-7) obtained as shown in Scheme BB, and one equivalent of epirate boron TRIFLUORIDE and produce the compound of formula PP-4 (HH-8).

SCHEMA QQ-WW

The diastereoisomer of formula QQ-3 (ll-4) receive, in accordance with the Scheme QQ techniques, similar to the following to obtain the diastereomeric products by the Scheme PP. Similarly, stereometry formula RR-4 (JJ-8), SS-3 (ACS-4), TT-4 (LL-8), UU-3 (MM-4), VV-4 (NN-8) and WW-3 (OO-4) receive, in accordance with Schemes RR, SS, TT, UU, VV and WW, respectively, by methods similar to those described for Scheme PP.

SCHEME XX

The compound of formula XX-6 (HH-9) are obtained as described in Scheme XX. The compound of formula XX-1 (HH-2) obtained in accordance with the Scheme HH, heated without solvent commercially available Tris(dimethylamino) methane, bis-(dimethylamino) -methoxymethane or tert-butoxy-bis(dimethylamino)-methane and receive the intermediate compound of formula XX-2. To a solution of ester obtained in tetrahydrofuran added at low temperature the oxide of formula XX-3 (BB-7), obtained as described in Scheme BB, and one equivalent of epirate boron TRIFLUORIDE and produce the compound of formula XX-4. The intermediate compound of formula XX-4 cyclist ih in situ derived dihydropyrone XX-5 or XX-4 is isolated and cyclist processing tert-piperonyl potassium or sodium hydride in tetrahydrofuran. Similarly, the intermediate compound of formula XX-5 hydrolyzing in situ with the formation of compounds of formula XX-6 (HH-9) or isolated and transformed into dihydropyran formula XX-6 (HH-9) by treatment with an aqueous solution of acid or aqueous solution of the base.

SCHEMA YY-EEE

The diastereoisomer of formula YY-5 (II-5) are obtained in accordance with the Scheme YY according to the methods similar to the above to obtain diastereomeric product Scheme XX. Similarly, stereometry formula ZZ-6 (JJ-9), AAA-5 (CC-5), BBB-6 (LL-9), MOP-5 (MM-5), DDD-6 (NN-9) and EEE-5 (OO-5) receive, in accordance with Schemes ZZ, AAA, BBB, CCC, DDD, EEE, respectively, by methods similar to those described for Scheme XX.

SCHEME FFF

The diastereomers of the formula FFF-5 and FFF-7 is also obtained by the division diastereomeric intermediate compounds. The mixture of diastereomers of the formula FFF-1 (W-11) obtained in accordance with the Scheme W is separated into the individual diastereomers of the formula FFF-2 (less Poligrafia high resolution. Benzyl protective groups in compounds FFF-2 and FFF-3 then removed by catalytic hydrogenation using 10% palladium on coal in ethyl acetate, and get amines of the formula FFF-4 and FFF-6, respectively. Intermediate amines obtained is then converted into the target sulfonamides of formula FFF-5 (HH-11) and FFF-7 (II-7), respectively, by treatment with 5-cyanopyridine-2-sulfochloride, which are synthesized by the methods shown in Scheme O and pyridine in dichloromethane.

SCHEME GGG

The acid chloride m-nitrocatechol acid (obtained by treatment of industrially produced acid chloride accelerom) formula GGG-1 are added to a solution of dithiooxamide formula GGG-2 (easily synthesized from commercially available (R)-(+)-4-benzyl-2-oxazolidinone the action of n-utility) in the air and get the compound of formula GGG-3. The compound of formula GGG-3 process or a solution of SnCl22H2About in ethanol or iron powder in a mixture of ethanol/water containing ammonium chloride, and carry out the restoration of the nitro-group, receiving the corresponding amino group in the compound of formula GGG-4. The compound of formula GGG-4 is treated with excess benzyl bromide in the presence of potassium carbonate or sodium in an organic solvent (also add the mixture is Anya added to a mixture of tetrahydrofuran/dimethyl sulphide, containing cuprate reagent, prepared from ethylacetamide and complex bromide copper (1) - dimethyl sulphide, and obtain the connection formula GGG-6. The compound of formula GGG-6 is treated with chloride of titanium (IV), and then tertiary amine and 2-methyl-2-methoxy-1,3-dioxolane of formula GGG-7 and get the compound of formula GGG-8. Treatment of compounds of formula GGG-8 perchloro acid to obtain the compound of formula GGG-9. Otherwise, the compound of formula GGG-6 is treated with a strong base, such as di-ISO-propylamide lithium in ether solvent at a temperature below room temperature and add a solution of acetyl chloride in ether solution, cooled to a temperature below room temperature) and get a connection formula GGG-9. The compound of formula GGG-9 is treated with titanium chloride (IV) in methylene chloride followed by the addition of tertiary amine and either 4-heptanone, or 1-phenyl-3-hexanone and produce the compound of formula GGG-10. The compound of formula GGG-10 then treated with either sodium hydride or tert-piperonyl potassium in the ether solvent and obtain the connection formula GGG-11. The compound of formula GGG-11 next hydronaut, receiving the compound of formula GGG-12. Then the compound of formula GGG-12 turn in the final target compound by treatment solarmeter-2-pyridinyl, in an organic solvent such as methylene chloride, in the presence of organic bases such as pyridine, highlighting the target compound of formula CGG-13, where R1in particular, denotes n-propyl or phenethyl.

Otherwise the addition of the compounds of formula GGG-5 to a solution of dimethyl sulfide in tetrahydrofuran containing a mixture of tert-butylacrylamide and complex bromide copper (1) - dimethyl sulfide at a temperature below 0oC, get a mixture of compounds of formula GGG-14a and GGG-14b. Both the compounds of formula GGG-14a and GGG-14b make the final connection GGG-19 GGG-20 by the method outlined in Scheme GGG for the synthesis of C-3 ethyl derivative of formula GGG-13.

SCHEME HHH

The final compounds of formula IUU-13, IUU-19 and IUU-20 get similar methodology described in Scheme GGG, to obtain the final compounds.

SCHEME III

Manufactured acid of the formula III-1 is converted into a compound of formula III-2 by treating the chloride accelerom. The acid chloride of the formula III-3 then condense with sociooccupational formula III-3 (easily obtained by treatment of industrially produced (S)-(-)-4-benzyl-2-oxazolidinone n-butyllithium in the ether solvent) and get a connection formula III-4. Amide of formula III-4 D. is)amine]formanilide in tetrahydrofuran at a temperature of minus 20oC and get after acid treatment of the corresponding compounds of formula III-5a and III-5b. These compounds separated by chromatography on silica gel. The compound of formula III-5a treated with methyl-benzyl or acetonitrile or in a mixture of methylene chloride/water in the presence of either potassium carbonate or sodium carbonate and receive compound of formula III-6. The compound of formula III-6 is treated with titanium chloride (IV) in methylene chloride, and then the tertiary amine and 2-methyl-2-methoxy-1,3-dioxolane of the formula III-7 and get the compound of formula III-8. Treatment of compounds of formula III-8 perchloro acid to obtain the compound of formula III-9. The compound of formula III-9 treated with titanium chloride (IV) in methylene chloride followed by the addition of tertiary amine and either 4-heptanone, or 1-phenyl-3-hexene - on and produce the compound of formula III-10. The compound of formula III-10 then treated with either sodium hydride or tert-piperonyl potassium in the ether solvent and obtain the connection formula III-11. The compound of formula III-11 next hydronaut, receiving the compound of formula III-12. Finally, the compound of formula III-12 turn in the final target compound by treatment with sulfochloride formula D-7, which is produced in accordance with the CX is methylene chloride, in the presence of organic bases such as pyridine, highlighting the target compound of formula III-13, where R1in particular, denotes n-propyl or phenethyl.

Similarly, starting with the compounds of formula III-5, are also the target compound of formula III-14.

SCHEME JJJ

The final compounds of formula JJJ-13 and JJJ-14 receive the methodology described in Scheme III.

SCHEME KKK

The compound of formula KKK-1 (the same thing that JJJ-9) is treated with titanium chloride (IV) in methylene chloride, and then add the tertiary amine. To the resulting solution was added industrial output hydroxycotinine aldehyde and get the connection formula KKK-2. The compound of formula KKK-2 oxidizes (in particular, with the help of Me2SOSO3/pyridine) and get a connection formula KKK-3. The compound of formula KKK-3 is treated with propyleneglycol (where R1in particular, denotes phenyl) and obtain the compounds of formula KKK-4a and KKK-4b. Depending on the specific reaction conditions, the ratio of the KKK-4a/KKK-4b changing. Otherwise adding allylcarbamate or allylsilanes in the presence of titanium chloride (IV) or n-Bu4NF (see Taniguchi et al. Chemistry Letters 2135, 1992) to the compound of formula KKK-3 with subsequent hydrogenation get TSA. Connection KKK-4a treated with either sodium hydride or tert-piperonyl potassium and receive compound of formula KKK-5. After processing KKK-3 allylcarbamate, allylsilanes or propyleneglycol intermediate alkoxide of metal (where the metal is magnesium, zinc and titanium) can undergo spontaneous cyclization with formation of an intermediate unsaturated compounds, which after hydrogenation leads directly to the compound of formula KKK-5 without releasing KKK-4a. The compound of formula KKK-5 hydronaut and get the connection formula KKK-6. Finally, treatment of compounds of formula KKK-6 sulfochloride formula D-7, which is obtained in accordance with Scheme D, where R4in particular, denotes 5-trifluoromethyl-2-pyridinyl, in an organic solvent such as methylene chloride, in the presence of organic bases such as pyridine, and produce the target compound of formula KKK-7a, where R1and R2in particular, represent phenyl or propyl, respectively. Similarly to the stages described for the conversion of compounds of formula KKK-4a in the compound of formula KKK-7a, the compound of formula KKK-4b is converted into a compound of formula KKK-7b.

Similar to the methods described for the conversion of compounds R2correspondingly represent methyl or phenethyl, taking as a starting compound of formula KKK-8 (or III-6).

Similar to the methods described for the conversion of compounds of formula KKK-1 and the compounds of formula KKK-8 (each of which contains an auxiliary 4 - benzyl-2-oxazolidinone) in the final products of formula KKK-7a and KKK-7b and final products of formula KKK-14a and KKK-14b, respectively, the compounds of formula KKK-15 and the compound of formula KKK-19 (each of which contains an auxiliary 4-benzyl-2-oxazolidinone) turn in final products of formula KKK-7a and KKK-7b and final products of formula KKK-14a and KKK-14b, respectively, where, in particular, R1and R2correspondingly represent methyl or phenethyl.

SCHEME LLL

The compound of formula LLL-1 (analogues: AA-1, where R denotes phenyl; GGG-5, where R denotes benzyl) are added to a solution of tetrahydrofuran containing a mixture of industrial tert-butylacrylamide and complex bromide copper (1) - dimethyl sulfide at a temperature below 0oC and obtain the connection formula LLL-2 as the primary diastereomeric product. The compound of formula LLL-2, where R is a benzyl, chloride is treated with titanium (IV) in methylene chloride at a temperature below 0oC the latter is of formula LLL-3 handle protovol acid and obtain the connection formula LLL-4. The compound of formula LLL-4 is treated with titanium chloride (IV) in methylene chloride at a temperature below 0oC and then aminoven base and then 4-heptanone or 1-phenyl-3-hexanone and get the connection formula LLL-5, where R1in particular, denotes n-propyl or phenethyl respectively. The compound of formula LLL-5 is treated with a hydride or sodium tert-piperonyl potassium in the ether solvent and produce the pyrone of formula LLL-6. The hydrogenation of the compound of formula LLL-6 using, in particular, palladium on coal as a catalyst to get the connection formula LLL-7. Finally, the compound of formula LLL-7 enter into interaction with sulfochloride formula D-7, the receipt of which is shown in the Diagram D, where R4in particular, denotes 5-trifluoromethyl-2-pyridinyl, in an organic solvent such as methylene chloride, in the presence of organic bases such as pyridine, and obtain the target compound of formula LLL-8, where R1in particular, denotes propyl or phenethyl.

The compound of formula LLL-2, where R denotes phenyl, chloride is treated with titanium (IV) in methanol and receive compound of formula LLL-9. The compound of formula LLL-9 is treated with a base, stimulating the hydrolysis, and get a connection uly LLL-11. The ketone of formula LLL-11 treated with titanium chloride (IV) in methylene chloride at a temperature below 0oC and then aminoven base and then 4-heptanone or 1-phenyl-3-hexanone and get the connection formula LLL-12, where R1in particular, denotes n-propyl or phenethyl, respectively. The compound of formula LLL-12 is treated with a titanium chloride (IV) in methylene chloride at a temperature below 0oC and then aminoven base and then triethylorthoformate and get the connection formula LLL-13. The compound of formula LLL-13 in an organic solvent, such as tetrahydrofuran or methylene chloride is treated with a base followed by the addition of tributyltinchloride. The solvent is distilled off and the resulting tertiary alcohol containing a protective group, oxidizing (e.g., using ruthenium as a catalyst in tert-butyl alcohol: see Murahashi et al. Chemistry Letters 2237, 1992; trailerforum in methylene chloride: see Mukaiyama et al. , Chemistry Letters 1255, 1985; ozone/methylene chloride: see Can. J. Chem. 29, 2465, 1971) and get the lactone LLL-6 in one stage or in two stages, where the intermediate ester is converted into a lactone with sodium hydride, tert-butoxide potassium or H-Bu4NF in the ether solvent. The transformation of compounds of formula LLL-6 in the final is ormula LLL-23, where R1denotes propyl or phenethyl.

SCHEME MMM

The diastereomers of the formula MMM-5 and MMM-7 also get split diastereomeric mixture of these two compounds. Otherwise diastereomers mix formula MMM-1 (X-11, where R1in particular, denotes phenetyl), obtained as shown in Scheme X is separated into the individual diastereomers of the formula MMM-2 and MMM-3 chiral column method of preparative chromatography high resolution. Benzyl protective group connection MMM-2 (less polar diastereoisomer) and connection MMM-3 (more polar diastereoisomer) then removed by catalytic hydrogenation using 10% palladium on coal in ethyl acetate, and get amines of the formula MMM-4 and MMM-6, respectively. Intermediate amines are then transformed into the target sulfonamidnuyu derivatives MMM-5 and MMM-7, respectively, by treatment of 5-vermeil-2-pyridinesulfonamide, the synthesis of which is shown in the Diagram O and pyridine in methylene chloride.

SCHEME NNN

Manufactured (1R,2S)-(-)-ephedrine formula NNN-2 is treated with triethylamine and the acid chloride of the acid of formula NNN-1 (W-2), whose synthesis is shown in Scheme W, and get amide of formula NNN-3. The solution of this amide in tert-butyl methyl ether at 0oC posledovatelno.spasibo, stirred for three hours at a temperature of 0oC, washed with a solution of ammonium chloride and evaporated in vacuum, obtaining the compound of formula NNN-4. Otherwise, the above reaction mixture may be washed not with a solution of ammonium chloride, a 1N solution of hydrochloric acid to obtain the compound of formula NNN-4. Amin turned into a derivative of formula NNN-5 by heating a mixture of the compounds of formula NNN-4, 2.2 equivalent of benzyl bromide and 2.2 equivalents of potassium carbonate in acetonitrile. The intermediate compound of formula NNN-5 then treated with 2 equivalents of di-ISO-propylamide lithium in tetrahydrofuran to form enolate lithium, which is associated acetylchloride and get beta ketone formula NNN-6. The solution of this amide in methylene chloride at low temperature can be treated with one equivalent of titanium tetrachloride and one equivalent of di-ISO-propylacetamide, and then 4-heptanone and to obtain the compound of formula NNN-7. The transformation of the amide of formula NNN-7 dihydropyran formula NNN-8 can either be achieved by using sodium hydride in tetrahydrofuran or aqueous acid solution. Protective benzyl group can be removed by catalytic hydrogenation using 10% palladium on coal in ethyl acetate. Received am what oredom, the synthesis of which is shown in the Diagram O and pyridine in dichloromethane.

SCHEME OOO

The compound of formula OOO-7 (NNN-8) can also be obtained, as shown in the Diagram OOO. Amide of formula OOO-1 (NNN-5) treated with an aqueous acid solution and obtain the connection formula OOO-2. Methyl ether of the formula OOO-3 are obtained from the compounds of formula OOO-2 from methanol by acid catalysis. Methyl ether of the formula OOO-3 is treated with di-ISO-propylamide lithium and then trimethylsilylpropyne and get the connection formula OOO-4. This intermediate compound is treated with either 2-methoxy-2-methyl-1,3-dioxolane with subsequent hydrolysis or acetylchloride and get beta ketoester formula OOO-5. Specified beta ketoester converted into the compound of the formula OOO-6 processing or enolate titanium (generate by using one equivalent of titanium tetrachloride and one equivalent of di-ISO-Propylamine in methylene chloride at low temperature), or lithium dianion (generate by using two equivalents of di-ISO-propylamide lithium in tetrahydrofuran at low temperature) 4-heptanone. Dihydropyridin formula OOO-7 (NNN-8) is obtained by treatment of compounds of formula OOO-6 or sodium hydride, or an aqueous solution of the base.

SCHEME PPP

Vosstanie subsequent in situ alkylation with 2-phenethylamine or 2-phenetylamine get the alcohol of formula PPP-2. Oxidation of the alcohol in Turn receive a ketone of formula PPP-3. The ketone is converted into dihydropyran formula RRR-4 alkylation by gianina methyl ester of acetoacetic acid, followed by saponification to the acid and receiving the lactone under the action of base.

SCHEME QQQ

On-catalyzed trichloride aluminum reaction dihydropyrone formula QQQ-1 (PPP-4), the receipt of which is shown in the Diagram PPP, using CBZ-protected 3-aminobenzaldehyde (synthesized by the interaction of benzylchloride with industrially produced 3-aminobenzaldehyde) formula QQQ-2 and subsequent interaction with trialkylaluminium or Grignard reagent in the presence of bromide complex of copper (1) - dimethyl sulfide obtain the compounds of formula QQQ-3. Individual stereoisomers are separated by liquid chromatography high resolution using chiral column with a stationary phase and there are four possible isomers of formula QQQ-4, QQQ-5, QQQ-6 and QQQ-7. Exchange hydrogenation of each stereoisomer over palladium on coal in the presence of ammonium formate get amines of the formula QQQ-8, QQQ-9, QQQ-10 and QQQ-11. Treatment of amines with sulfochloride General formula QQQ-12 and pyridine in methylene chloride obtain compounds of General formula QQQ-13, QQQ-14, QQQ-15="ptx2">

THE SCHEME OF RRR

The method of obtaining compounds with RRR-11 RRR-15 shows the Scheme of RRR. Piron RRR-A condensate containing Cbz protective group benzaldehyde RRR-B in tetrahydrofuran in the presence of trichloride aluminum with subsequent treatment of the obtained intermediate product with R1MgX, where X = Br or Cl, in tetrahydrofuran in the presence of complex CuBrMe2S and get RRR-1. Remove protection from the resulting intermediate compound is carried out in methanol using 10% palladium on coal in the presence of ammonium formate and allocate RRR-2. Racemic compound RRR-1 split on its four enantiomer and get connection with RRR-3 RRR-6. Remove protection from the received intermediate compounds is carried out in methanol using 10% palladium on coal in the presence of ammonium formate and get a free amines with RRR-7 RRR-10. Treatment of amines with RRR-7 RRR-10 and RRR-2 corresponding sulfochlorides allows you to get sulfonamides with RRR-11 RRR-14 and RRR-15, respectively.

THE SSS

The method of obtaining compounds of formula SSS-7 SSS-9 is shown in Scheme SSS. Piron SSS-A condensate containing Cbz protective group benzaldehyde SSS-B in tetrahydrofuran in the presence of trichloride aluminum with a pic is not in the presence of complex CuBrMe2S and get SSS-1. Remove protection from the resulting intermediate compound is carried out in methanol using 10% palladium on coal in the presence of ammonium formate and allocate SSS-2. Racemic compound SSS-1 split on two enantiomers and receive connections SSS-3 and SSS-4. Remove protection from the received intermediate compounds is carried out in methanol using 10% palladium on coal in the presence of ammonium formate and get a free amines SSS-5 and SSS-6. Processing amines corresponding sulfochlorides allows you to get sulfonamides with SSS-7 SSS-9.

THE TTT DIAGRAM

The method of obtaining compounds of formula TTT-6 and TTT-7 shows the TTT Diagram. Piron TTT And condense with containing Cbz protective group benzaldehyde TTT-In in tetrahydrofuran in the presence of trichloride aluminum with subsequent treatment of the obtained intermediate product with R1MgX, where X = Br or Cl, in tetrahydrofuran in the presence of complex CuBrMe2S and get TTT-1. Racemic compound TTT-1 split on two enantiomers and receive connections TTT-2 and TTT-3. Remove protection from the received intermediate compounds is carried out in methanol using 10% palladium on coal in the presence of formate enamide with TTT-6 TTT-7.

SCHEME UUU

The interaction of industrially produced thiourea in hot ethanol industrially produced 2-chloro-5-nitropyridine formula UUU-1 are derived estimacion formula UUU-2. Treatment of compounds of formula UUU-2 aqueous solution of sodium carbonate and sodium hydroxide receive a derivative of the thiol of formula UUU-3. The compound of formula UUU-3 oxidizes gaseous chlorine, get derived sulfochloride formula UUU-4. Treatment of compounds of formula D-5 (in particular, the compounds of formula T-4, where R1denotes 2-phenethyl, R2denotes propyl, R3denotes a tert-butyl) in dichloromethane two equivalents of pyridine followed by treatment with one equivalent of a compound of formula UUU-4 gain derived sulfonamida formula UUU-5 (where R1denotes 2-phenethyl, R2denotes propyl, R3denotes a tert-butyl). The restoration of the compounds of formula UUU-5 palladium on coal in the presence of ammonium formate get compound of formula UUU-6, which is the compound 5-amino-N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl - 2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide (formula UUU-6: R1denotes 2-phenethyl, R2denotes propyl, R3Ob-carbamoylation, get described in the literature method (J. Chem. Soc. 1948, 1939-1945). Treatment of a suspension of this compound in dilute hydrochloric acid with gaseous chlorine at a temperature of 0oC get sulfochloride formula VVV-2.

SCHEME WWW

Amines of General formula WWW-1 is introduced into the reaction bisikletforum and receive contains a protective group CBZ derivative WWW-2. Individual stereometry formula WWW-2 usually share method chiral liquid chromatography high resolution, and then again turn into the free amines WWW-3 by hydrolysis. Sulfonation of amines is conducted in the usual way known to specialists in this field of technology, and get the final products of formula WWW-4 in stereochemical pure form.

SCHEME XXX

Dihydropyran XXX-1, which is obtained by the method similar to that shown in Preparations 17 and 84, condense with mechanicalbiological in the presence of trichloride aluminum and receive intermediate benzylidene derivative of formula XXX-2. The method of mounting the recovery of double bonds using cyanoborohydride sodium and subsequent reduction of the nitro group by catalytic hydrogenation receive amine of formula XXX-4, which pre is>SCHEMA YYY

Dihydropyrone formula YYY-1, where R1and R2denote propyl or phenethyl, which are synthesized by the method described in Preparation 84, condense with the aldehyde of formula b-2 in the presence of trichloride aluminum and receive intermediate benzylidene derivative of formula YYY-2. Paired accession tert-butylacrylamide in the presence of bromide complex of copper (1) - dimethyl sulfide receive compound of formula YYY-3. Removing the protection is carried out by hydrogenolysis and get amines of formula YYY-4, which in turn sulfonamides YYY-5 processing corresponding sulfochloride in dichloromethane in the presence of pyridine. This procedure is similar to that shown in Scheme D.

SCHEME ZZZ

Polymer m-aminobenzaldehyde protect using benzylbromide and potassium carbonate in acetonitrile boiling and receive compound of formula ZZZ-2. The vinyl anion generated from 2-bromonitromethane formula ZZZ-3 processing tert-butyllithium in the temperature range from minus 78oC to minus 20oC. Obtained by way of the vinyl anion is cooled to minus 78oC and add contains two protective group m-aminobenzaldehyde formula ZZZ-2, receiving targeted of al is haunted reagents (in particular, chloride, acetyl, pyridine, methylene chloride, 0oC). These compounds participate in catalyzed by palladium allylic substitutions, which are given in the Diagrams AAAA SSSS (C. G. Frost, J. Howarth, J. M. J. Williams, Tetrahedron: Asymmetry (1992) 3: 1089-1122).

SCHEME AAAA

Sodium salt of methyl ester of acetoacetic acid of formula AAAA-1, which is generated by processing at 0oC methyl ester of acetoacetic acid, sodium hydride, or in dimethylformamide or tetrahydrofuran, plays the role of the nucleophile in catalyzed by palladium allylic substitution. If the above reaction is carried out using as the source of palladium dimer of allylchloride palladium formula AAAA-3 and chiral phosphine ligand (P. von Matt, A. Pfaltz, Angew. Chem. Int. Ed. Engl. (1993) 32: 566-568), kinetic decomposition of the original ZIOC scientists or carbonate leads to the production of optically enriched product containing allyl group, of formula AAAA-4. If the reaction with the nucleophile proceeds slowly, the acetate, which is generated from the intermediate generated PI-allylpalladium, sometimes in two possible diastereoisomeric PI-allyl complex, so that it may be carried out stereoselective synthesis products containing allyl group (B. M. Trost, R. E. Strege, the ri boiling receive not containing silyl group of the olefin of formula AAAA-5. Derived dihydropyrone formula AAAA-7 receive, generating dianion beta keeeper under standard conditions (J. R. Peterson, T. J. Winger, S. P. Miller, Syn. Commun. (1988) 18(9): 949-963) (sodium hydride, n-utility, tetrahydrofuran) and associating it with a suitable symmetric ketone of formula AAAA-6 (such as 4-heptanone). Hydrolysis of ester (a 1.0 N solution of sodium hydroxide/tetrahydrofuran) and acid treatment of the reaction mixture gives the derived dihydropyrone formula AAAA-7. In standard conditions the hydrogenation restore olefin and delete a group, which protects the amino group. Subsequent processing of amino appropriate sulfochloride formula AAAA-8 (pyridine, methylene chloride) leads to the target sulfonamidnuyu the protease inhibitor of formula AAAA-9.

SCHEME BBBB

Alternatively, catalyzed by palladium allylic substitution can be carried out with the sodium anion of the desired dihydropyrone (J. P. Peterson, T. J. Winger, S. P. Miller, Syn. Commun. (1988) 18(9): 949-963) formula www-1 (dihydropyran, sodium hydride, tetrahydrofuran or dimethylformamide, 0oC) as the nucleophilic partner. In this case, if the catalyst is used dimer of allylchloride palladium formula BBBB-3 and chiral phosphine ligand (P. P. von wodnego, containing the allyl group of the formula www-4; and stereoselective synthesis product containing allyl group, occurs if the reaction with the nucleophile proceeds slowly compared to the isomerization of the two possible diastereomeric PI-allyl complexes under the action of acetate, regenerierung formed from the intermediate PI-allylpalladium. Further, the removal of the silyl group (t-toluensulfonate, acetonitrile), the recovery of olefin, delete a group protecting the amino group with hydrogen on palladium on coal) and sulfonylurea amine (arylsulfonate, pyridine, methylene chloride) of the formula www-5 leads to the target dihydropyrano the protease inhibitor of formula www-6.

SCHEME CCCC

The processing of m-bis(benzyl)aminobenzoic acid of the formula SSSS-1 chloride accelerom education chloranhydride acid and interaction with bis (trimethylsilyl) acetylene and aluminum chloride in methylene chloride receive propargilovyh ketone of formula SSSS-2. Asymmetric recovery ketone chiral borane (N. With.Brown, Beeraraghavan Ramachandram,P. ACE. Chem. Res. (1992) 25: 16-24), such as DIP chloride [(+)- or (-)-beta-chlorodiisopinocampheylborane] and recovery of acetone using a PEDAL receive allowhardterminate, pyridine, methylene chloride 0oC) and catalyzed by palladium reaction of allylic substitution using the required dihydropyrone formula SSSS-5 as Neulevel results mainly one enantiomer dihydropyrone containing the allyl group of the formula SSSS-6 (save configuration) (T. Hayashi, T. Hagihara, M. Konishi, M. J. Kumada, J. Am. Chem. Soc., (1983) 105: 7768-7770). The resulting product is converted into the target protease inhibitor of formula CCCC-7, as previously described for Scheme BBBB.

SCHEME DDDD

Known Cyclopentanone formula DDDD -1 is obtained by acylation of the ester of trimethylsilanol corresponding cycloalkylation using malonaldehyde, as described in R. Effenberger, T. Ziegler, C.-N. Schonwalder, So Kesmarszky, B. Bauer, Chem. Ber., 119: 3394-3404 (1986). Catalytic hydrogenation of cycloalkylation formula DDDD-1 platinum oxide in acetic acid get cycloalkylation formula DDDD-2. The condensation of the compounds of formula DDDD-2 manufactured 3-nitrobenzaldehyde catalyzed by trichloride aluminum, receive intermediate connection DDDD-3. Subsequent reaction of the intermediate DDDD-3 trialkylaluminium in the presence of bromide complex of copper (1) -dimethyl sulfide or zinc reagent generi the s DDDD-4, which contains C - 3 branched Deputy. Catalytic hydrogenation of compounds of formula DDDD-4 over palladium on coal in the ethanol amine derivative of formula DDDD-5. Treatment of compounds of formula DDDD-5 sulfochloride formula DDDD-6 and pyridine in methylene chloride obtain the compounds of formula DDDD-7 (in particular, n is 1, 2 or 3; R1ethyl or tert-butyl; R2denotes 4-cyanophenyl or 5-cyano-2-pyridyl).

The techniques used to obtain the compounds of the present invention, are described in International application PCT/US93/10645, filed November 9, 1993 (WO 94/11361, published may 26, 1994), and International application PCT/US94/ 00938, filed February 3, 1994 (WO 94/181888, published on August 18, 1994), which are given here for reference.

To a person skilled in the art it is obvious that the compounds of the present invention can exist in several diastereoisomeric forms depending on the configuration around the asymmetric carbon atom. All these diastereomeric forms are included in the scope of claims of the present invention.

In addition, dihydropyrone of the present invention can be separated into individual stereoisomers or received in the form of individua C-6 is a mixture. All of these enantiomeric and diastereomeric forms are included in the scope of claims of the present invention.

Compounds of the present invention of formula I can exist in multiple tautomeric forms, including, in particular, enol forms, indicated by formulas I and IA, and ketone form of the formula IB. (For formulas I, IA and IB dotted line indicates that a double bond may be present or absent). All of these tautomeric forms are included in the scope of claims of the present invention. For compounds of the present invention, which are 4-hydroxyfuran-2-ones of formula VII, enol form is predominant. For compounds of the present invention, which represents a 5,6-dihydro-4-hydroxyfuran-2-ones of the formula VI, you can usually expect a mixture of enol and ketone forms.

Compounds of the present invention of the formula II can also exist in several tautomeric forms 4-hydroxypyrazolo rings, including, in particular, enol forms, depicted by formulas II and IIA, and, in particular, ketonic forms represented by formula IIB, and mixtures thereof. All of these tautomeric forms are included in the scope of claims of the present invention.

Deadinside (previously not protected) amino groups, hydroxyl groups or other reactive groups are protected. As the protective groups can be used any known from the engineering group. Examples of protective groups for the nitrogen atom or the oxygen atom are given in the monographs T. W. Green, "Protective Groups in Organic Synthesis", Wiley, New York (1981); J. F. W. McOmie, ed. "Protective Groups in Organic Chemistry", Plenum Press (1973); J. Fuhrhop and G. Benzlin, "Organic Synthesis", Verlag Chemie (1983). Among the protective groups for the nitrogen atom can be called tert-butoxycarbonyl (BOC), benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl etc.

In the present invention are claimed compounds of formula I and II or their pharmacologically acceptable salts and/or hydrates. Pharmacologically acceptable salts of such salts are well known to experts in the field of pharmaceutical chemistry, which is equivalent to the compounds from which they are derived, their properties, such as structure, stability, patient tolerability and bioavailability. Examples of compounds of formula I are acidic salts such as salts with sodium, potassium, lysine, arginine or calcium, and basic salts such as hydrochloride, in which the substituent R in the formula I contains a fragment of the base. Examples of salts of compounds of formula II vkluchau. In addition, as salts of the compounds of formula I and II according to the present invention include bis-salts such as bis-arginine, bis-lysine, bis-chloride, bis-potassium and bis-calcium salt, provided that the compound contains, for example, group-NHSO2-, -SO3H, -CONH, -OH or-COOH. Most preferred are bis-sodium salt.

Compounds of the present invention are useful for the treatment of patients infected with human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) and related diseases. With this purpose, these compounds can be administered orally, through the nose, through the skin, subcutaneous and parenteral (including intramuscular and intravenous) doses from 0.1 mg to 100 mg per kilogram of body weight per day.

Specialists in the art will know how to prepare the compositions of the compounds of the present invention in the form of appropriate pharmaceutical dosage forms. Examples of dosage forms include oral compositions such as tablets or capsules, or such parenteral compositions, as sterile solutions.

If the compounds of the present invention is prescribed orally, the effective number of the note can be prepared in the form of a solid, and in the form of liquid dosage forms. Solid compositions, such as compressed tablets, get, mixing compounds of the present invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminosilicate, calcium sulfate, starch, lactose, gum, methylcellulose or functionally similar pharmaceutical diluents or carriers. Capsules get by mixing the compounds of the present invention with an inert pharmaceutical diluent and placing the mixture in a solid capsule of appropriate size of the gelatin. Soft capsules made of gelatin receive by placing a suspension or solution of the compound of the present invention in an acceptable inert oil, such as vegetable oil or light liquid petrolatum, in the capsule using a special machine.

Pharmaceutically acceptable compositions of Dimitrievich salts of the compounds of the present invention include: soft elastic capsules containing a suspension of a salt; tablets; balls of sugar-coated salt solution spraying; or matrix intersolubility and enterosalivary polymers containing dried salt solution, which is applied by sputtering technique.

The comp is in the form of the free acid form, preferably contain free acid in a noncrystalline form. Examples of such compositions include: soft elastic capsules containing a solution of the free acid; noncrystalline matrix intersolubility and enterosalivary polymers containing dried salt solution, which is applied by a spray method; or a solid non-crystalline matrix of free acid in polyethylene glycol or Gelucire 44/14 ("Gattefosse", Saint-priest, France).

Syrups are prepared by dissolving the compounds of the present invention in an aqueous medium and adding sugar, aromatic flavoring and preservatives. Elixirs are prepared through aqueous-alcoholic medium, such as ethanol, suitable podslushivala, such as sugar or saccharin, and aromatic fragrances. Suspension is prepared using a water carrier and a suspending means, such as gum, tragant or methylcellulose.

If the compounds of the present invention prescribe parenteral, they can be administered as an injection or intravenous infusion. The effective amount is from about 0.1 mg to 100 mg per kilogram of body weight. Parenteral solutions are prepared by dissolving the compounds of the present invention Jew in the s. Parenteral suspensions are prepared almost the same way, except that they use sterile media for suspension and connection of the present invention are sterilized before suspendirovanie in the media with ethylene oxide or other suitable gas.

Specific destination path, the dose or frequency assignment can easily be determined by a specialist in the art and depend on the age, weight, General physical condition, and other clinical symptoms, specific to the patient, the treatment is carried out.

Patients who undergo treatment are the following individuals: 1) patients infected by one or more strains of human retrovirus that is determined by the presence of detectable quantities of either antibodies of the virus or antigen in the serum, and 2) in the case of HIV, individuals who have symptoms of HIV infection or the symptoms of the infection caused by AIDS, such as (i) disseminated histoplasmosis, ii) isoprenes, iii) bronchial or pulmonary candidiasis, including pneumocystitis pneumonia, iv) lymphoma other than Hodgkin's lymphoma, or v) sarcoma Kaposi, in this age of the patient not more than sixty years; the subject is less than 500 / ml. Treatment consists of keeping the patient inhibitory concentration of the compounds used in accordance with the present invention, up until the appearance of the following symptoms of infection caused by AIDS, will not show the need to change therapy.

The usefulness of representatives of the compounds according to the present invention was demonstrated when carrying out biological tests, which are given next.

Method of screening HIV-protease based on the use of containing fluorescent labeled substrate, which may be separated from not containing the label of the product decomposition with the help of special balls, coated with streptavidin. The substrate biotinylated N-terminal arginine and put fluorescent label using fluoresceinisothiocyanate C-terminal lysine. This analysis is used to detect new ones inhibitors of HIV-1 protease. The substrate (20 μl 0.2 μm solution), sample (10 ál of the desired concentration) and the enzyme (10 μl of 0.1 ám solution) is placed in the tablet of the 96 wells. The analysis carried out in 0.1 M buffer sodium acetate at pH 5.5 with 1.0 M solution of sodium chloride and 0.05% NP-40 and incubated at room temperature in the dark. D is mostate at room temperature for another hour. Cleavage products containing the label is separated from unreacted substrate by filtration and read by the reader of the firm "Idexx". Data is analyzed using an appropriate computer algorithm and determine the percentage of inhibition.

To determine the values of Kjuse the same materials and equipment, and to determine the percentage of inhibition. Conduct a series of serial twofold dilutions of the inhibitor, since concentrations of 2, 3 or 4, and receive a total of 24, 36 and 48 individual concentrations of the inhibitor. These dilution is carried out with the use of robotic systems company "Biomek". The analysis includes 10 μl of 40 nm solution of HIV-1 protease, 10 μl of various concentrations of inhibitor and 20 µl of 200 µm of substrate solution (40 μl). Give reaction to develop at room temperature for 90 minutes, interrupt it by adding 40 μl of beads with Avidya and processed (see earlier). Inhibitor with a known value of Kianalyze in parallel, in order to confirm the validity of the analysis. The data is analyzed by a computer program using a non-linear analysis of least-squares and get the values of KiOia, studied by the method of screening of HIV protease below in Table 1.

When performing the above analysis on the inhibition of enzyme sensitivity of detection values of Kipartially limited by the ability to study at low concentrations of the enzyme for compounds with a high affinity binding. To prevent de-dimerization at low concentrations, get tandemly linked enzymes, in which the two monomers are covalently bound through elongated amino acid residues. Using these enzymes, the assay sensitivity by inhibition improves, because they can be used to significantly lower concentrations of the enzyme, compared with the conditions which are used for the wild-type enzymes.

The method of determining the values of Kjusing tandem HIV protease: Due to the greater stability (de-dimerization missing) single-chain linked (tandem) enzyme HIV protease, in which the two Monomeric units are produced using genetic engineering and associated polypeptide processes, the method of determining the values of Kifor inhibitor use very low concentrations of enzyme (0.2 nm) and Uwe is lnasty measurement values of Kifor very strong inhibitors. The initial concentration of inhibitors is determined on the basis of the preliminary screening results inhibition of the enzyme, which allow to assess the potential ability of the inhibitor. Then prepare the concentration of inhibitor devices Biomek 1000 (firm "Beckman") and Quadry 96 (firm Tomtec"). The substrate (biotinylating N-terminal arginine and fluorescent label fluorescein C-terminal lysine), the inhibitor and the tandem enzyme is allowed to react in solution with pH 5.5 (buffer solution similar to that used with native dimeric enzyme) in the dark for 96 hours. To terminate the reaction, add beads made of polystyrene, coated with streptavidin. Products raceplane containing the label is separated from unreacted substrate by filtration. The residual fluorescence assessed quantitatively using reader Idexx SM 2000 ("Idexx") and the data analyzed using the program NLLSF.

The percentage of inhibition and/or values of Kifor certain compounds of the present invention, studied by the method of screening of HIV protease and/or method of analysis of tandem HIV protease below in Table II.

Several joint is ylpropyl) phenyl] -1-methyl-1H-imidazole-4-sulfonamide, were tested in known human cell lines, such as line of T-cells, in particular, MT4 and H9, which infect with HIV-1SWand some of these compounds further experience in managernew cells of the peripheral blood system, infected with HIV-1 (isolate obtained in a clinical setting). It was found that the compounds inhibit the replication of the retrovirus.

Preferred are the following compounds of the present invention:

5-cyano-N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6-phenethyl-6-propyl-2H - Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide;

N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H - Piran-3-yl]-2,2-dimethylpropyl)phenyl]-methyl-1H-imidazole-4 - sulfonamide;

N-[3-(1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl) propyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl) -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-5-cyanopyridine-2 - sulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl)-6 - propyl-2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-is} phenyl] -1-methyl-1H-imidazole-4 - sulfonamide;

N- [3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran - 3-yl)-2,2-dimethylpropyl}phenyl]-5-cyanopyridine-2-sulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran - 3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide;-

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl - 2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-1-methyl-1H-imidazole-4-sulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2 - oxo-6,6-bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-5-cyanopyridine-2-sulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-forfinal)ethyl)- 2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-forfinal) ethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-methyl-1H - imidazole-4-sulfonamide;

N-[3-(1-[6,6-bis-(2-cyclopropylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl]-2,2 - dimethylpropyl)phenyl]-5-cyano-2-pyridinesulfonamide;

N-[3-(1-[6,6-bis-(2-cyclopropylethyl)-5,6-dihydro-4-hydroxy-2-oxo - 2H-Piran-3-yl]propyl)phenyl]-5-cyano-2-pyridine-sulfonamide;

N-[3-(1-[6,6-bis-(2-cyclopropylethyl)-5,6-dihydro-4 - hydroxy-2-oxo-2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-1-methyl - 1H-imidazole-4-sulfonamide;

5-cyano-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl) -6(R or S)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl)-2H-Piran-3-yl] -2,2 - dimethylpropyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide;

5-amino-N-(R or S)-[1-[-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6- (R or S)-(3,3,3-cryptochromes)-2H-Piran-3-yl[-2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide;

N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo - 6-(2-phenethyl)-[6(R or S)-propyl]-2H-Piran-3-yl]-2,2 - dimethyl-propyl]phenyl]-2-pyridinesulfonamide;

5-trifluoromethyl-N-[3-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl - 5,6-dihydro-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide;

5-trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl]phenyl]-2-pyridine-sulfonamide or (3R or S)-N-[3-[1- (5,6-dihydro-4-hydroxy-2-oxo-6,6-di-propyl-2H-Piran-3-yl)propyl]-phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide;

5-trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-Piran-3 - yl]propyl]phenyl]-2-pyridine-sulfonamide;

5-trifluoromethyl-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6- (2-phenethyl)-6-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]-phenyl]-2 - pyridinesulfonamide;

5-trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6 (R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] -2 - pyridinesulfonamide;

5-trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6 (R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl] propyl]phenyl]-2-pyridinesulfonamide or (3R or S, 6R, S)-N-[3-1-(5,6-dihydro-4-hydroxy-2-the Idro-4-hydroxy-2-oxo-6-(2-phenylethyl) -6-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide;

5-cyano-N-[3(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl] -2-pyridinesulfonamide;

5-cyano-N-[3-(1-[5,6-dihydro-6,6-Diisobutyl-4-hydroxy-2-oxo-2H-Piran-3 - yl]-2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide;

N-[3 (R or S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethyl-propyl]phenyl]-1-methyl - 1H-imidazole-4-sulfonamide; 6-cyano-N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo - 6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]cyclopropylmethyl)phenyl]-2 - pyridinesulfonamide;

5-amino-N-[3(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6 (R or S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl) phenyl]-2-pyridinesulfonamide;

5-amino-N-[3(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6- (R or S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]propyl)-phenyl-2 - pyridinesulfonamide;

5-amino-N-[3(R or S)-(1-[6(R or S)-(2-[4-florfenicol] -5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl) phenyl]-2-pyridinesulfonamide;

N-[3(R or S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H - Piran-3-yl]-2,2-dimethylpropyl)phenyl]-1-methyl-1H-imidazole-4-sulfonamide;

5-amino-N-[3(R or S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo - 2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide;

5-cyano-N-[3(R or S)-(1-[5,6-dihydro-6,6-dypatil)-5,6-dihydro-4-hydroxy-2-oxo - 2H-Piran-3-yl]propyl)phenyl]-1-methyl-1H-imidazole-4-sulfonamide;

N-[3(R or S)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo - 2H-Piran-3-yl]-propyl)phenyl]-5-cyano-2-pyridinesulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(1-phenylethyl)-2H-Piran-3-yl)-propyl}phenyl]-5-cyanopyridine-2-sulfonamide;

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S) -phenethyl-6-propyl-2H-Piran-3-yl)-propyl}phenyl]-5-cyanopyridine-2-sulfonamide;

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S or R) -phenethyl-6-propyl-2H-Piran-3-yl)-propyl}phenyl]-1-methyl-1H-imidazole-4 - sulfonamide;

N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis (2-phenylethyl)-2H-Piran-3-yl)-2, 2-dimethylpropyl}phenyl]-1 - methyl-1H-imidazole-4-sulfonamide;

N-[3-{ 1 (R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide;

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethyl-propyl}phenyl]-1 - methyl-1H-imidazole-4-sulfonamide;

N-[3-{ 1(S or R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl) -2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-5-aminopyridine-2-sulfonamide;

N-[3-{ 1(S or R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis (2-phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-1-methyl-1H-imidazole-4-sulfonamide;

N-[3-{1(S or R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6--5,6-dihydro-2-oxo-6,6-dipropyl)-2H - Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide.

More preferred are the following compounds of the present invention:

5-cyano-N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl) -6-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide;

5-cyano-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6- (2-phenethyl)-6(R or S)-(3,3,3-cryptochromes)-2H-Piran-3-yl]- 2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide;

5-trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2-oxo - 6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl] -2 - pyridinesulfonamide or (3R or S)-N-[3-[1-(5,6-dihydro-4 - hydroxy-2-oxo-6,6-di-propyl-2H-Piran-3-yl)-propyl]phenyl]-5- (trifluoromethyl)-2-pyridinesulfonamide;

5-trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H - Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide or (3R or S, 6R, S)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo - 6-propyl-6-phenethyl-2H-Piran-3-yl)propyl] phenyl]-5-(trifluoromethyl)-2 - pyridinesulfonamide;

5-cyano-N-[3(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2 - pyridinesulfonamide;

N-[3(R or S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6(R or S) -[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide;

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo - 6(S or R)-Veneto-6(R or S)- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide;

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-1-methyl-1H-imidazole-4-sulfonamide; and

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl) -2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide.

Most preferred are the following compounds of the present invention (see Scheme EEE):

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S or R) -phenethyl-6-propyl-2H - Piran-3-yl)-propyl} phenyl] -5-cyanopyridine-2-sulfonamide of formula EEE-1;

N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-di-propyl-2H-Piran-3-yl) -propyl}phenyl]-5-cyanopyridine-2-sulfonamide of formula EEE-2;

N-[3(R or S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6(R or S) -[2-phenylethyl]-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl]-phenyl]-1-methyl-1H - imidazole-4-sulfonamide of formula EEE-3;

5-trifluoromethyl-N-[3 (R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6 (R or S)-n-propyl-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide formula EEE-4 or (3R or S, 6R, S)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-Piran-3-yl] propyl] phenyl] -5-(trifluoromethyl) -2-persulfonic;

5-trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6 - dihydro-2H-Piran-3-yl] propyl] phenyl]-2-pyridinesulfonamide formula EEE-5 or (3R ID.

Most preferred are the following compounds of the present invention, which can be easily obtained by using the above-described synthetic methods:

(3R)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6,6-di-propyl-2H-Piran-3 - yl)propyl]phenyl]-5-(tryptophanyl)-2-sulfonamide;

(3R)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H - Piran-3-yl)propyl]phenyl]-5-(tryptophanyl)-2-sulfonamide.

Description of the preferred ways of carrying out the invention

In the Preparations and Examples below use the following abbreviations:

1H-NMR indicates the range of proton magnetic resonance (PMR);

13C-NMR indicates a range of magnetic resonance in carbon nuclei;

denotes the chemical shift (in ppm, memorial plaques) in relation to the TMC;

CBZ refers to benzyloxycarbonyl;

DMSO refers to dimethylsulfoxide;

EI MS refers to mass spectrometry with excitation by electron impact;

FAB MS refers to mass spectrometry with excitation by fast atom bombardment;

HOBT refers to the hydrate of 1-hydroxybenzotriazole;

M denotes the molar concentration;

mm RT. the article refers to millimeters of mercury;

N stated the chromatogram relative to the solvent front;

TPA means triperoxonane acid;

TMS refers to tetramethylsilane was;

TLC means thin layer chromatography.

The following Preparations and Examples illustrate the present invention.

Preparation 1. Cyclopropyl-(3-nitrophenyl)methanon (formula A-2). Cm. Scheme A.

In a round-bottom three-neck flask with a capacity of 500 ml, equipped with a tube for the gas outlet and addition funnel with a capacity of 250 ml with tap to equalize the pressure, put cyclopropylamine formula A-1 (30 ml) and cooled to a temperature of minus 40oC. the addition funnel is placed nitric acid (180 ml) and add it dropwise to the reaction mixture for two hours. The reaction mixture is stirred at a temperature of minus 40oC for 3.5 hours, and then interrupt the reaction, pouring the mixture onto ice (500 ml). The mixture is extracted with three portions of 150 ml of ethyl acetate. The organic extracts are combined, washed with two portions of 250 ml of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated, getting 41,117 g of yellow substance in orange oil. Recrystallized from 65 ml of methanol and receive 20,664 g of the desired product as crystals, light yellow, ,43, 8,33, 7,70, 2,72, 1,36-1,31, 1,20-1,14 M. D.

The drug 2. Cyclopropyl-(3-AMINOPHENYL)methanon (formula A-3). Cm. Scheme A.

In a Parr apparatus with a capacity of 500 ml was placed 2.1 g of 10% platinum on coal and the target solution of the product of Preparation 1 (20.6 g) in 250 ml of methanol. The reaction mixture was shaken for 50 minutes under a hydrogen pressure of 44 pounds-force/square inch (303,4 kPa), and then filtered twice through celite. The resulting solution of light green evaporated and get 15,744 g of the desired product in the form of oil is green in color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,42, 7,30-7,23, 6,88, 3,83, 2,63, 1,24-1,19, 1,05-0,99 M. D.

Preparation 3. N-[Cyclopropylmethanol]benzosulfimide (formula A-4). Cm. Scheme A.

In a round-bottom three-neck flask with a capacity of 500 ml, equipped with a tube for supplying nitrogen, placed the target product of Preparation 2 (15.7 g) and 200 ml of methylene chloride. Add benzosulphochloride (12 ml) and pyridine (7.8 ml) and the reaction mixture was stirred at room temperature for 45 minutes. To terminate the reaction, add 10% acetic acid (200 ml). The organic layer is separated, dried over magnesium sulfate, filtered and evaporated, come get the target product (22,264 g) in a solid pink color with so pl. 98-101oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,81-7,73, 7,62, 7,55-7,35, 2,60, 1,30- 1,25, 1,10-1,03 M. D.

Range13C-NMR (deuterochloroform): 200,4, 138,8, 137,2, 133,0, 129,5, 129,0, 127,0, 125,1, 124,7, 120,5. 17,3, 12.1 M. D.

IR spectrum (mineral oil): 3239, 3222, 1653, 1449, 1339, 1259, 1176, 1165, 1093, 939, 687 cm-1.

Elemental analysis, found: C, 63,70; H, free 5.01; N, 4,78.

Mass spectrum (E1): m/e 301, 260, 160, 141, 77.

The mass spectrum of high resolution, found: 301,0772.

Preparation 4. N-[3-Cyclopropylmethanol]benzosulfimide (formula A-5). Cm. Scheme A.

In a round-bottom three-neck flask with a capacity of 500 ml, equipped with a tube for supplying nitrogen, placed the target product of Preparation 3 (21,133 g), 200 ml of tetrahydrofuran and 100 ml of ethanol. The flask was cooled to 0oC in a bath of ice and small portions over 20 minutes, add sodium borohydride (10.6 g). The reaction mixture was stirred at room temperature for about 18 hours and again cooled to a temperature of 0oC. are added dropwise 10% hydrochloric acid (100 ml) for 45 min and stirred the mixture at a temperature of 0oEven within one hour. The reaction mixture was then extracted with three on the live and evaporated, getting 25,015 g oil pale yellow color. After column chromatography using 150 g of silica gel (elute 50-65% solution of ether in hexane, and then 2-5% solution of methanol in methylene chloride), get 18,692 g of the target product in a solid white color with so pl. 112-114oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,69, 7.42, 7,32, 7,25, 7,12, 7,05-6,96, 3,82, 3,19, 1,03-0,94 M. D.

Range13C-NMR (deuterochloroform): 147,0, 139,7, 137,4, 132,9, 129,3, 128,6, 126,8, 121,8, 118,5, 117,8, 75,0, 19,2 3,1, 2,3 M. D.

IR spectrum (in mineral oil): 3523, 3249, 1449, 732 cm-1.

Elemental analysis, found: C, 63,41, H, 5,79; N, 4,86.

Mass spectrum (E1): m/e 303, 275, 262, 77.

The mass spectrum of high resolution, found: 303,0935.

The drug 5. 4-Hydroxy-10-propyl-2H-cycloocta[b] Piran-2 - he (formula A-7). Cm. Scheme A.

In a round-bottom three-neck flask with a capacity of 250 ml, equipped with a tube for supplying nitrogen and addition funnel with a capacity of 125 ml with tap to equalize the pressure placed di-ISO-Propylamine (3.6 ml) and 15 ml of tetrahydrofuran. In an addition funnel was placed 4 - hydroxy-2H-cycloocta[b]Piran-2-it formula A-6 (2,292 g) and 35 ml of tetrahydrofuran. The flask was cooled to 0ooC for 15 minutes. Within 15 minutes added dropwise a solution of 4-hydroxy-2H-cycloocta[b] Piran-2-it is in tetrahydrofuran and the mixture is stirred at a temperature of 0oC for 35 minutes. In one type of hexamethylphosphoramide (4 ml) and added dropwise over 2 minutes add propyl iodide (1.3 ml). Allow the reaction mixture to warm to room temperature and stirred for approximately 18 hours. Add 30 ml of 10% hydrochloric acid and the aqueous layer was separated. the pH of the aqueous layer decreased from 10 to 2 with concentrated hydrochloric acid and the aqueous layer was extracted with two portions of 50 ml of methylene chloride. The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated, getting an orange oil, which was poured into a mixture of 100 ml of 1N sodium hydroxide solution and 50 ml of ether. the pH of the aqueous layer reduces from 14 to 1 using concentrated hydrochloric acid and extracted with two portions of 50 ml of methylene chloride. The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated, getting an orange oil, which was diluted with 100 ml ether and washed with three portions of 25 ml of 10% hydrochloric acid solution. The organic phase is dried nanoclay chromatography using 100 g of silica gel (elute 0-10% solution of methanol in methylene chloride) get 1,358 g solid light orange color. After repeated column chromatography using 150 g of silica gel (elute 10% solution of ether and 1% solution of acetic acid in methylene chloride), get 0,705 g of the target product in a solid yellow color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 11,38, 5,68, 3,02-2,93, 2,20, 1,98-1,82, 1,73-1,58, 1,46-1,25, 1,24- 1,08, 0,89 M. D.

Range 13C-NMR (deuterochloroform): 172,3, 168,3, 165,3, 114,8, 89,7, 38,6, 36,0, 33,3, 30,1, 27,2, 25,5, 22,9, 21,0, 13,9 M. D.

IR spectrum (in mineral oil): 1679, 1641, 1617, 1492 cm-1.

Elemental analysis, found: C, 70,90; H, at 8.36.

Mass spectrum (E1): m/e 236, 208, 166.

The mass spectrum of high resolution, found: 236,1414.

Example 1. N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-10-propyl-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] benzosulfimide (formula A-8). Cm. Scheme A.

In a round-bottom three humps flask with a capacity of 100 ml equipped with a dropping funnel with a capacity of 35 ml with tap to equalize the pressure, which fill with 3 A molecular sieves, reverse x is g) and 30 ml of methylene chloride. Add target product of Preparation 4 (0,252 g) and the reaction mixture is refluxed for two hours, and then stirred at room temperature for another hour. The reaction mixture was then diluted with 20 ml of methylene chloride and washed with 60 ml of a mixture of 1:1 saturated sodium bicarbonate solution and saturated aqueous salt solution, 30 ml of water and 30 ml of saturated salt solution. The aqueous layers are combined and extracted with 30 ml of methylene chloride. The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated, getting 0,576 g crude product. After column chromatography using 35 g of silica gel (elute 20-80% solution of ether in hexane), get 0,096 g of target compound in a solid white color with so pl. 87-90oC (decomposition).

Mass spectrum (E1): m/e 521, 493, 380, 275, 262, 249, 144, 77.

The mass spectrum of high resolution, found: 521,2236.

Examples 2-7

According to the methods similar to the above, also get the following compounds of the present invention:

2) 4-Cyano-N-[3(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-(R or S)-10 - propyl-2H-cycloocta [b]Piran-3-yl)methyl]phenyl] benzosulfimide

3) 4-Tzia the phenyl]benzosulfimide

4) 4-Cyano-N-[3(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-(R or S)-10-benzyl-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl) methyl]phenyl]benzosulfimide

5) N-[3(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro - 4-hydroxy-2-oxo-(R or S)-10-propyl-2H-cycloocta[b]-Piran-3-yl) methyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide

6) N-[3(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-(R or S)-10-cyclopropylmethyl-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl) methyl]phenyl] -1-methyl-1H-imidazole-4-sulfonamide

7) N-[3(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-(R or S)-10-benzyl-4-hydroxy-2-oxo-2H-cycloocta[b] -Piran-3-yl)methyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide

Preparation 6. Fenilmetilovy ether (3-benzaldehyde)carbamino acid (formula B-2). Cm. Scheme B.

Into a flask equipped with a tube for supplying nitrogen, placed sodium bicarbonate (10.4 g) in 200 ml of tetrahydrofuran and 200 ml of water, and then add m-aminobenzaldehyde formula B-1 (10.0 g) and benzyl ether of Harborview acid (13,6 ml). The mixture is stirred at room temperature for 40 minutes. Add ether, the organic layer is separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated, obtaining a brown oil. After column obrazec for analysis is recrystallized from a mixture of ethyl acetate: hexane.

The substance has the following physical characteristics:

Melting point 100-104oC.

Range PMR (deuterochloroform): 9,98, 7,91, 7,69, 7,59, 7,43-7,35, 6,83, 5,23 M. D.

Range13C-NMR (deuterochloroform): 191,8, 153,0, 138,6, 137,1, 135,6, 129,7, 128,6, 128,4, 128,3, 124,6, 124,2, 119,1, 67,2 M. D.

IR spectrum (mineral oil): 3269, 2954, 2925, 2868, 2855, 1729, 1682, 1597, 1560, 1465, 1455, 1326, 1294, 1237, 1229, 1170, 1155, 1048, 695 cm-1.

Elemental analysis, found: C, 70,74; H, 5,14; N, 5,33.

Mass spectrum (E1) m/e 255, 211, 91.

The mass spectrum of high resolution, found: 255,0900.

Preparation 7. Fenilmetilovy ester [3-(1-hydroxy-3-methylbutyl)phenyl]carbamino acid (formula B-3, where R1denotes ISO-butyl). Cm. Scheme B.

Into a flask equipped with a tube for supplying nitrogen, placed the target compound of Preparation 6 (4.0 g) and 60 ml of dry tetrahydrofuran. The mixture is cooled to 0oC and add ISO-butylmagnesium (17,2 ml). Allow the reaction mixture to warm to

room temperature and stirred for 2 hours. To terminate the reaction, add a saturated solution of ammonium chloride and poured into a mixture of ether and water. The organic layer was separated, washed with water and evaporated, getting 5,78 g butter W is in the form of white crystals with so pl. 73-77oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,41-7,33, 7,25, 7,05, 6,74, 5,19, 4,73- 4,65, 1,91, 1,73-1,65, 1,47, 0,93 M. D.

IR spectrum (liquid paraffin): 3400, 3249, 3085, 2953, 2925, 2869, 2855, 1697, 1615, 1602, 1563, 1450, 1283, 1245, 1177, 1067, 1017, 798, 773, 740, 696 cm-1.

Elemental analysis, found: 72,58; H 7,25; N 4,55.

Mass spectrum (E1): m/e 313, 257, 213, 91.

Preparation 8. Fenilmetilovy ether [3-[1-(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran - 3-yl)-3-methylbutyl] phenyl] carbamino acid (formula B-5, where R1denotes ISO-butyl). Cm. Scheme B.

In a three-neck flask with a capacity of 200 ml, provided with a nozzle Dean-stark and a tube for supplying nitrogen, was placed a solution of p-toluenesulfonic acid (0.66 g) in toluene (100 ml) and boiled for collecting trapped in a Dean-stark 20 ml of fluid. The reaction mixture is cooled to room temperature and the trap is released. To the reaction mixture is added 4-hydroxy-2H-cycloocta[b] Piran-2-it formula B-4 (2,48 g) and the product of Preparation 7 (4.0 g) and refluxed for 6.5 hours. The reaction mixture is stored overnight at room temperature and poured into 350 ml of ethyl acetate, washed with two portions of 25 ml water, 25 ml of a saturated E. column chromatography, using 150 g of silica gel (elute 10-50% solution of ethyl acetate in hexane), get 0,217 g of the target product as a foamy substance whitish with so pl. 73-78oC (decomposition).

Range PMR (deuterochloroform): 7,38-7,25, 7,13, 6,72, 6,01, 5,19, 4,48, 2,58, 2,41, 1,93, 1,74, 1,62-1,33, 0,96 M. D.

Preparation 9. Fenilmetilovy ether (R or S)-[3-[1-(5,6,7,8,9,10- hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)-3-methylbutyl]phenyl] carbamino acid (formula B-5,where R1denotes ISO-butyl). Cm. Scheme B.

The original solution of the target product of Preparation 8 (32 mg/ml) in 30% ISO-propyl alcohol and 0.1% acetic acid in hexane chromatographic in column (2.0 x 25 cm (R,R) Whelk-0,1, using automated chromatographic system and 2 ml per injection. Aliremove a controlled substance at the wavelength of 310 nm at a feed rate of the solution 10 ml/min and the appropriate fractions after repeated injection combined and evaporated in a vacuum, getting snegouborochnie substance of white color.

The substance has the following physical characteristics:

Retention time for the target connection is 18.8 minutes.

The drug 10. Fenilmetilovy ether (R or S)- [3-[1-(5,6,7,8,9,10-hexahydro-4-the guy who gets ISO-butyl). Cm. Scheme B.

The target product of Preparation 8 share in accordance with the methodology described above for the Preparation of 9.

The substance has the following physical characteristics:

Retention time for the target compound is 22.1 minutes.

The drug 11. (R or S)-3-[1-(3-AMINOPHENYL)-3-methylbutyl]- 5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] peranan (formula B-6, where R1denotes ISO-butyl). Cm. Scheme B.

Into a flask equipped with a tube for supplying nitrogen, was placed a solution of the target compound of Preparation 9 (0,637 g) in 6 ml of ethanol. Add cyclohexene (6 ml) and 10% palladium on coal (0.16 g) and the reaction mixture is refluxed for two hours. The mixture was then filtered through celite and evaporated, getting 0,205 g of target compound in the form of a foamy substance whitish with so pl. 158-162oC.

Mass spectrum (E1): m/e 355, 312, 299, 161, 106.

The mass spectrum of high resolution, found: 355,2144.

Example 8. (R or S)-N-[3-1-(5,6,7,8,9,10-Hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)-3 - methylbutyl]phenyl]-1-methyl-2H-imidazole-4-sulfonamide (formula B-7, where R1denotes ISO-butyl, a R2denotes 1-Mei). Cm. Scheme B.

-4-sulphonylchloride (0,048 g) and 5 ml of methyl chloride. Add pyridine (0,53 ml) and the reaction mixture was stirred at room temperature for approximately 18 hours. A precipitate, which is filtered off and get 0,097 g solid white. Recrystallized from methanol - chloroform and get 0,065 g of target compound in the form of a white powder with so pl. 207-210oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 10,4, 10,0, 7,70, 7,11, 7,05, 6,92, 4,21, 3,64, 2,54, 2,16, 1,62, 1,53, 1,43, 1,34, 0,85 M. D.

Mass spectrum (E1): m/e 499, 456, 443, 306, 251, 160, 145.

The mass spectrum of high resolution, found: 499,2151.

Preparation 12. (R or S)-3-[1-(3-AMINOPHENYL)-3-methylbutyl]- 5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] peranan (formula B-6, where R1denotes ISO-butyl). Cm. Scheme B.

In accordance with the General method described for Preparation 11, and after minor changes, replacing, however, the target product of Preparation 9 to the target product of Preparation 10, get 0,189 g of target compound in the form of a solid gray color.

The substance has the following physical characteristics:

Mass spectrum (E1): m/e 355, 312, 299, 161.

The mass spectrum of high resolution, on butyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula B-7, where R1denotes ISO-butyl, a R2denotes 1-Mei). Cm. Scheme B.

In accordance with the General method described for Example 8, and after minor changes, but replacing the target product of Preparation 11 to the target product of Preparation 12, get 0,047 g of target compound in a solid white color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 10,45, 10,06, 7,70, 7,11, 7,05, 6,94, 4,21, 3,64, 2,55, 2,16, 1,62, 1,53, 1,42, 1,35, 0,86 M. D.

Mass spectrum (E1): m/e 499, 456, 443,354,306,160, 145.

The mass spectrum of high resolution, found: 499,2146.

Preparation 13. [3-Cyclopropyl-hydroxymethyl)phenyl]-methanol (formula C-2). Cm. Scheme C.

To a solution of 6.5 ml of 3-bromobenzylamine alcohol of formula C-1 in 900 ml of tetrahydrofuran in a nitrogen atmosphere at a temperature of minus 78oC add 46 ml of 1.4 M solution metallice in diethyl ether. The solution is stirred for 25 minutes and add 6 ml of cyclopropanecarboxaldehyde. The solution is stirred for one and a half hours, warmed to 0oC and stirred for 40 minutes. Then allow the solution to warm to room temperature and stirred for 30 minutes. Finally, the solution is boiled with the opposite hill hydrochloric acid and bring the pH to approximately the value 6. The layers separated, the aqueous phase is extracted with two portions of ethyl acetate. The organic extracts are combined, dried (over sodium sulfate), filtered and evaporated, receiving a yellow oil, which chromatographic using 900 g of silica gel 230-400 mesh mesh (elute with a mixture of 2:1 ethyl acetate : hexane), get of 6.61 g (68%) of the desired product as yellow oil.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,41-7,26, 4,67, 3,99-3,96, 2,18, 1,28-1,14, 0,68 M. D.

Preparation 14. [3-Cyclopropyl-[3-[hydroxymethyl]phenyl]methyl]- 5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he (formula C-3). Cm. Scheme C.

To a solution of 501 mg of the target product of Preparation 13 in 50 ml of dichloromethane in the presence of molecular sieves 3A in nitrogen atmosphere add 492 mg of 4-hydroxy-5,6,7,8,9,10-hexahydro-cycloocta[b]Piran-2-it, and then 49 mg of the monohydrate of p-toluenesulfonic acid. The solution is refluxed for two hours, add additional 105 mg of the monohydrate of p-toluenesulfonic acid and heated for another hour. The solution is evaporated in vacuum and get a white foamy substance that is treated with water and 1N solution of sodium hydroxide and extracted once with ethyl acetate. About the thief hydrochloric acid and extracted with three portions of ethyl acetate. The organic extracts are combined, dried (over sodium sulfate) and evaporated in vacuum, obtaining a yellow oil, which chromatographic using 180 g of silica gel 230-400 mesh mesh (elute with a mixture of 2:1 ethyl acetate : hexane), and receive 436 mg target benzyl alcohol in the form of a foamy substance white with so pl. 65-70oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,25-7,03, 4,36, 3,70-3,67, 2,41-2,37, 2,24- 2,23, 1,53-1,50, 1,35-1,05, 0,54-0,43, 0,42-0,21, 0,07-0,02 M. D.

Preparation 15. 3-[Cyclopropyl-[3-[methyl bromide]phenyl]methyl]- 5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; and 3-[cyclopropyl-[3-[chloromethyl] phenyl]methyl]-5,6,7,8,9,10-hexahydro - 4-hydroxy-2H-cycloocta[b] Piran-2-he (formula p-4, 5). Cm. Scheme C.

To a solution of 1.01 g of the target product of Preparation 14 in 70 ml of dichloromethane in a nitrogen atmosphere at a temperature of 0oC successively added to 2.00 g of triphenylphosphine and 2.58 g chetyrehpostovye carbon. The resulting solution is stirred for one hour and poured into a saturated solution of salt. The layers are separated and the aqueous phase is shaken out three times with ethyl acetate. The organic extracts are combined, dried (over sodium sulfate) and evaporated, receiving a yellow oil, which was triturated with er the g of silica gel 230-400 mesh mesh (elute with a mixture of 1:1 ethyl acetate : hexane), and get 374 mg of the desired product as a mixture of bromo - and chlorinated. The solids obtained after filtration, chromatographic as indicated previously and additionally receive 699 mg of the desired product as a mixture of bromo - and chlorinated.

The substance has the following physical characteristics:

Mass spectrum: m/e 418, 416 (M+ B), 388, 374, 372, (M+ C1), 337, 246, 233, 220, 207, 195, 179, 153, 143, 129.

Preparation 16. 3-[Cyclopropyl[3-[(phenylthio)methyl]phenyl] methyl]-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he (formula C-6). Cm. Scheme C.

To a solution of 138 mg of the target product of Preparation 15 in 5 ml of dichloromethane successively added 0.04 ml of thiophenol and 0.17 ml of di-ISO-propylacetamide. The solution is refluxed for one hour and left overnight at room temperature. The solution was poured in a saturated salt solution and add 5% solution of hydrochloric acid. The layers are separated and the aqueous phase is shaken out three times with ethyl acetate. The organic extracts are combined, dried (over sodium sulfate) and evaporated, receiving a yellow oil, which chromatographic using 80 g of silica gel 230-400 mesh mesh (elute with a mixture of 2:1, hexane : ethyl acetate), and obtain 111 mg of the target sulfide in the form of a foamy ACC-spectrum: m/e 446 (M+), 418, 337, 295, 233, 220, 207, 185, 145, 128, 109, 91, 79, 55, 40.

Example 10. 3-[Cyclopropyl[3-[(phenylsulfonyl)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he (formula C-7). Cm. Scheme C.

To a solution of 119 mg of the target product of Preparation 16 in 5 ml of tetrahydrofuran and 5 ml of methanol at a temperature of 0oC add a solution of 279 mg oxone in 5 ml of water. The solution is stirred for 2.5 hours, warmed to room temperature and stirred for 2 hours. The solution is filtered, the solids washed with chloroform. The filtrate is diluted with water and the layers separated. The aqueous phase is shaken out three times with ethyl acetate. The organic extracts are combined, dried (over sodium sulfate) and evaporated, getting a clear oil, which chromatographic using 80 g of silica gel 230-400 mesh mesh (elute with a mixture of 1: 1 hexane : ethyl acetate), and obtain 78 mg of the target product as a foamy substance so pl. 80-85oC.

The substance has the following physical characteristics:

Mass spectrum: m/e 479 (M+1), 463, 450, 391, 337, 309, 207, 161, 149, 127, 115, 71, 57, 41.

The mass spectrum of high resolution, found: 479,1885.

Examples 11-39

According to the methods similar to the above, obtain the following connection nassi-2H - cycloocta[b]Piran-2-he

The original 4-cyanobenzoyl obtained from 4-cyanobenzaldehyde in accordance with the General methodology described in the literature: A. W. Wagner, Ber. Deutsch. Chem. Ges., 99: 375 (1966).

The substance has the following physical characteristics:

The melting temperature of 100-105oC.

Mass spectrum: m/e 504 (M+1), 337, 247, 207, 143.

The mass spectrum of high resolution, found: 504,1843.

12) 3-[Cyclopropyl[3-[(4-perpenicular)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he

The substance has the following physical characteristics:

The melting temperature of 95-100oC.

Range PMR (deuterochloroform): 7,61-7,57, 7,40-7,37, 7,27-7,20, 7,13-7,07, 7,02-6,99, 6,42, 4,30, 3,88-3,85, 2,64-2,61, 2,51-2,47, 1,83-1,40, 1,40-1,27, 0,69-0,58, 0,48-0,43, 0,19-0,14.

13) 3-[Cyclopropyl[3-[(4-methylphenylsulfonyl) methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he

The substance has the following physical characteristics:

The melting temperature of 100-105oC.

Range PMR (deuterochloroform): 7,37-7,34, 7,25-7,22, 7,17-7,05, 6,86- 6,84, 4,15, 3,60-3,58, 2,52-2,42, 2,42-2,30, 2,28, 1,70-1,14, 0,57-0,32, 0,32-0,20, 0,06-(-)0,16.

14) 3-[Cyclopropyl[3-[(4-carboxypenicillins)methyl] phenyl] methyl] - 5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]C.

Mass spectrum: m/e 523 (M+1), 337, 247, 207, 143.

The mass spectrum of high resolution, found: 523,1785.

15) 3-[Cyclopropyl[3-[(2-(1-methylimidazol)sulfonyl)methyl]phenyl]methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H - cycloocta[b]Piran-2-he

The substance has the following physical characteristics:

Melting point 95-103oC.

Range PMR (deuterochloroform): 7,36-7,34, 7,29-7,27, 7,14, 7,06-7,03, 6,98 (singlet, 1H), 6,86, 4,30, 3,73-3,70, 3,20, 2,67-2,54, 1,90-1,36, 0,71-0,50, 0,46-0,33, 0,18-0,03.

16) 3-[Cyclopropyl[3-[(2-pyrimidinemethanol)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H - cycloocta[b]Piran-he

17) 3-[Cyclopropyl[3-[(2-pyridylsulfonyl)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he

18) 3-[Cyclopropyl[3-[(1-methyl-4-imidazolidinyl)methyl]phenyl]methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H - cycloocta[b]Piran-2-he

19) 3-[Cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl) methyl]phenyl]methyl] -5,6,6,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he

20) 3-[Cyclopropyl[3-[(2-benzimidazolylthio)methyl] phenyl]methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he

21) 3-[Cyclopropyl[3-[(2-hyalinization)methyl] phenyl] methyl] - 5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he

22) 3-[Cyclopropyl[3-phenyl]methyl] -4-hydroxycoumarin

24) 3-[Cyclopropyl[3-[(1-methyl-4-imidazolidinyl)methyl]phenyl]methyl] -4-hydroxycoumarin

25) 3-[Cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl)methyl] phenyl]methyl] -4-hydroxycoumarin

26) 3-[Cyclopropyl[3-[(2-benzimidazolylthio)methyl] phenyl]methyl] -4-hydroxycoumarin

27) 3-[Cyclopropyl[3-[(2-hyalinization)methyl] phenyl]methyl]-4-hydroxycoumarin

28) 3-[Cyclopropyl[3-[(4-cyanophenylacetic)methyl]phenyl]methyl] -4-hydroxy-6-[1-(phenylmethyl)propyl]-2H-Piran-2-he

29) 3-[Cyclopropyl[3-[(2-pyridylsulfonyl)methyl] phenyl] methyl]-4-hydroxy-6-[1-(phenylmethyl)propyl]-2H-Piran-2-he

30) 3-[Cyclopropyl[3-[(1-methyl-4-imidazolidinyl)methyl]phenyl]methyl] -4-hydroxy-6-[1-(phenylmethyl)propyl]- 2H-Piran-2-he

31) 3-[Cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl)methyl] phenyl]methyl] -4-hydroxy-6-[1-(phenylmethyl)propyl]-2H-Piran-2-he

32) 3-[Cyclopropyl[3-[(2-benzimidazolylthio) methyl]phenyl]methyl]-4-hydroxy-6-[1-(phenylmethyl)propyl]-2H - Piran-2-he

33) 3-[Cyclopropyl[3-[(2-hyalinization)methyl] phenyl]methyl] -4-hydroxy-6-[1-(phenylmethyl)propyl]-2H-Piran-2-he

34) 3-[Cyclopropyl[3-[(4-cyanophenylacetic)methyl]phenyl]methyl] -4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-Piran-2-he

35) 3-[Cyclopropyl[3-[(2-pyridylsulfonyl)methyl] phenyl]methyl]-4-hydranal]methyl] -4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H - Piran-2-he

37) 3-[Cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl)methyl] phenyl]methyl] -4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro - 2H-Piran-2-he

38) 3-[Cyclopropyl[3-[(2-benzimidazolylthio)methyl] phenyl]methyl]-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H - Piran-2-he

39) 3-[Cyclopropyl[3-[(2-hyalinization)methyl] phenyl]methyl]-4-hydroxy-6-(2-phenylethyl)-6 (1-propyl)-5,6 - dihydro-2H-Piran-2-he

The drug is 17. 5,6-Dihydro-4-hydroxy-6-phenethyl-6-propyl-2H - Piran-2-he (formula D-1: R1denotes phenethyl, R2denotes propyl). Cm. Scheme D.

Methyl ester of acetoacetic acid (1,47 ml) are added to a suspension of sodium hydride (567 mg, 60% dispersion in mineral oil) in tetrahydrofuran (30 ml) at a temperature of 0oC. After 15 minutes, added dropwise n-utility (8.5 ml, 1.6 M solution in hexane) and the resulting mixture is stirred for 15 minutes. Then use the syringe to quickly add 1-phenyl-3-hexanone (2.0 g). The reaction mixture is stirred for another hour and then poured into a saturated solution of ammonium chloride. Extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated in vacuum. The resulting substance was dissolved in tetrahydrofuran (25 ml) and add 0.1 N sodium hydroxide solution. Stirred talati and the reaction mixture is extracted with methylene chloride (3 x 25 ml), dried over anhydrous magnesium sulfate and evaporated, obtaining the target product in a solid white color.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuterochloroform): 0,96, 1,21, 1,48, 1,72, 1,98, 2,73, 3,43, 7,15-7,32 M. D.

Elemental analysis, found: 73,77; H of 7.96.

Preparation 18. 4-Hydroxy-3[1-(3-nitrophenyl)propyl]-5,6 - dihydro-6-phenethyl-6-propyl-2H-Piran-2-he (formula D-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl). Cm. Scheme D.

To a solution of the target product of Preparation 17 (formula D-1: R1denotes phenethyl, R2denotes propyl) (1 g) and 3-nitrobenzaldehyde (formula D-2) (581 mg) in dry tetrahydrofuran at 0oC in one type of solid trichloride aluminum (1.0 g). The cooling bath is removed, give the yellow solution to warm to room temperature and stirred at room temperature for two hours. The reaction is interrupted by adding solid uranyl potassium carbonate (2.2 g) and vigorously stirred for 5 minutes. The mixture after dilution with ether, filtered through celite and the filtrate evaporated in vacuum to dryness. Intermediate benzylidene formula D-3 and complex bromide IU is mperature add a solution of triethylaluminum (to 4.23 ml, 1 M in hexane). Upon completion of the reaction, which is detected by thin layer chromatography, the process is stopped by adding water, and the reaction mixture was transferred into a separating funnel with ether. The aqueous layer was separated, extracted with ether (3 x 15 ml), the organic extracts are combined, washed with saturated salt solution, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining oil. Evaporative chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (3:1) obtain 1.1 g of the desired product in the form of a foamy substance light yellow color.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range PMR (300 MHz, deuteroacetone): 0,93, 1,37, 1,74, 1,82-2,14, 2,29, 2,52-2,71, 4,19, 6,98-7,24, 7,44, 7,72, 8,02, 8,28 M. D.

Preparation 19. 3-[Cyclopropyl-(3-nitrophenyl)methyl] -4 - hydroxy-5,6-dihydro-6-phenethyl-6-propyl-2H-Piran-2-he (formula D-4: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl). Cm. Scheme D.

To a solution of the target product of Preparation 17 (formula D-1: R1denotes phenethyl, R2denotes propyl) (1 g) and 3-nitro-benzaldehyde (formula D-2) (581 mg) in dry tetrahydrofuran is the resultant yellow solution to warm to room temperature and stirred at room temperature for two hours. The reaction is interrupted by adding solid uranyl potassium carbonate (2.2 g) and vigorously stirred for 5 minutes. The mixture after dilution with ether, filtered through celite and the filtrate evaporated in vacuum to dryness. Intermediate benzylidene formula D-3 and complex bromide copper (I) - dimethyl sulfide (237 mg) was dissolved in dry tetrahydrofuran and cooled to minus 78oC. is added dropwise within 10 minutes, add a solution of cyclopropylmagnesium (15.6 ml; 0.25 M in tetrahydrofuran) and the reaction mixture is stirred for 30 minutes. The reaction is stopped by adding water, and neutralized by adding 1N hydrochloric acid. The reaction mixture was transferred into a separating funnel with ether. The aqueous layer was separated and extracted with ether (3 x 15 ml). The organic extracts are combined, washed with saturated salt solution, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining oil. Evaporative chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (3: 1) obtain 0.9 g of the desired product in the form of a foamy substance light yellow color.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range AMINOPHENYL)propyl]-4-hydroxy-5,6 - dihydro-6-phenethyl-6-propyl-2H-Piran-2-he (formula D-5: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl). Cm. Scheme D.

To a solution of the target product of Preparation 18 (formula D-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl) (350 mg) in methanol at room temperature and add 10% palladium on coal (35 mg) and ammonium formate (521 mg). The resulting mixture is stirred for two hours and filtered through celite using methylene chloride. The filtrate is evaporated in vacuo and the residue three times triturated with methylene chloride (3 x 10 ml). The organic solutions are combined and evaporated in a vacuum, receiving 325 mg of target compound in the form of a foamy substance yellow.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range PMR (300 MHz, deuterochloroform): 0,89, 1,40, 1,64-2,07, 2,20, 2,62, 3,94, 6,54, 6,72-7,25 M. D.

Similarly receive the compounds of formula D-5, where R1denotes propyl, R2denotes a propyl, a R3denotes ethyl or tert-butyl.

The compounds of formula D-5, where R1denotes propyl, R2denotes a propyl, a R3denotes ethyl or tert-butyl possess SUB>f= 0,32 (10% solution of ethyl acetate in dichloromethane).

Example 40. 4-Cyano-N-[3-[1-(4-hydroxy-2-oxo-6 - phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]benzosulfimide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 4-cyanophenyl). Cm. Scheme D.

To a solution of the target product of Preparation 20 (formula D-5: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl) (30 mg) and 4-cyanobenzenesulfonyl formula D-7 wherein R4denotes cyanophenyl (16.1 mg) in methylene chloride (1 ml) at room temperature, added with a syringe pyridine (13 μl). The resulting solution was stirred for three hours, during which the starting amine is completely reacts. Evaporative chromatography on silica gel, elwira 5% solution of ethyl acetate in methylene chloride, to obtain 21 mg of the desired product in the form of a foamy substance of white color.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range PMR (300 MHz, deuterochloroform): 0,6-1,1, 1,2-2,2, 2,4-2,7, 3,86-4,01, 6,89-7,45, 7,66-7,92 M. D.

The mass spectrum of high resolution found: dasol-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol in ethyl acetate, isolated amorphous solid off-white color.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers and tautomerism.

Range PMR (300 MHz, deuterochloroform): 0,75-0,96, 1,17-1,43, 1,45-2,11, 2,43-2,68, 3,24, 3,64, 3,94, 6,72-7,51 M. D.

The mass spectrum of high resolution, found: 538,2383.

Example 42. N-[3-[2-(4-Hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -6 - chinaincorporated (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4means quinoline-8-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula formula D-7, where R4means quinoline-8-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers and tautomerism.

Range PMR (300 MHz, deuterochloroform): 0,66, 0,90, 1,17-1,44, 1,58-2,03, 2,38-2,64, 3,77, 6,68-7,27, 7,35-7,69, 8,02, 8,26, 9,14 M. D.

The mass spectrum of high resolution, found: 585,2402.

Example 43. N-[3-[1-(4-Hydroxy-2-oxo-6,6-dipropyl-5,6 - dihydro-2H-Piran-3-yl)propyl] phenyl] -8 - chinaincorporated (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denotes inolin-8-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes ethyl) and 8-chinaincorporated formula D-7 wherein R4means quinoline-8-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, allocate AMI:

Range of PMR is complicated by the presence of diastereomers and tautomerism.

Range PMR (300 MHz, deuteroacetone): 0,67, 0,85, 1,27, 1,54, 2,01, 3,73, 6,78, 6,90, 7,04, 7,57, 8,12, 8,29, 8,38, 9,13 M. D.

The mass spectrum of high resolution, found: 523,2276.

Elemental analysis, found: 66,09; H 6,60; N 5,13.

Example 44. N-[3-[1-(4-Hydroxy-2-oxo-6,6-dipropyl-5,6 - dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4 - sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes ethyl) and 1-Mei-4-sulfochloride formula D-7 wherein R1denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol in ethyl acetate, isolated amorphous solid off-white color.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,88, 1,32, 1,64, 1,93, 2,16, 2,56, 3,68, 3,91, 6,87, 7,03, 7,14, 7,53, 7,64 M. D.

The mass spectrum of high resolution shall solarpanel (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denotes 4-forfinal). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes ethyl and 4-forbindelsesteknologi formula D-7 wherein R4denotes 4-forfinal, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers and tautomerism.

Range PMR (300 MHz, deuterochloroform): 0,51-1,03, 1,15-1,73, 1,81-2,48, 2,73, 3,91, 6,69, 6,88, 7,09, 7,78 M. D.

The mass spectrum of high resolution, found: 490,2085.

Example 46. 4-Cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6 - dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl]phenyl] benzosulfimide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denotes 4-cyanophenyl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1the convoy is de R4denotes 4-cyanophenyl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers and tautomerism.

Range PMR (300 MHz, deuterochloroform): 0,68- 0,96, 1,15-1,42, 1,44-1,76, 1,83-2,12, 3,18, 3,88, 6,69-7,18, 7,71, 7,85 M. D.

The mass spectrum of high resolution, found: 497,2126.

Example 47. N-[3-[1-(4-Hydroxy-6,6-di-ISO-butyl-2 - oxo-5,6-dihydro-2H-Piran-3-yl)propyl]phenyl]-1-methyl-1H - imidazole-4-sulfonamide (formula D-6: R1denotes ISO-butyl, R2denotes ISO-butyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes ISO-butyl, R2denotes ISO-butyl, R3denotes ethyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol and physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,82-0,94, 1,52-1,83, 1,86-2,03, 2,06-2,22, 2,60, 3,68, 3,92, 6,87, 7,03, 7,16, 7,56, 7,65.

The mass spectrum of high resolution, found: 504, 2531.

Elemental analysis, found: 62,03; H 7,43; N 8,20.

Example 48. N-[3-[1-(4-Hydroxy-2-oxo-6,6-dipropyl - 5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -1-methyl-1H - imidazolecarboxamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol in ethyl acetate, isolated amorphous solid off-white color.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,12, 0,43, 0,68, 0,90-0,97, 1,36, 1,71, 2,60, 3,12, 3,67, 6,88, 7,06, 7,24, 7,51, 7,65 M. D.

The mass spectrum of high resolution, found: 488,2225.

Elemental analysis, Naidenov] -8-chinaincorporated (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl, R4means quinoline-8-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl) and 8-chinaincorporated formula D-7 wherein R4means quinoline-8-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): -0,14, 0,01, 0,35, 0,89, 1,35, 1,63, 2,52, 2,94, 6,79, 6,94, 7,09,7,64, 8,12, 8,28, 8,41, 9,13 M. D.

The mass spectrum of high resolution found: 535,2256.

Elemental analysis, found: 67,58; H 6,53; N 5,11.

Example 50. 4-Cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6 - dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]benzosulfimide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 4-cyanophenyl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-is fklorida formula D-7, where R4denotes 4-cyanophenyl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,13, 0,44, 0,62, 0,91, 1,19, 1,67, 2,57, 3,14, 6,80, 7,12, 7,25, 7,83 M. D.

The mass spectrum of high resolution, found: 509,2096.

Elemental analysis, found: 65,86; H to 6.39; N 5,48.

Example 51. 4-Fluoro-N-[3-[1-(4-hydroxy-2-oxo-6,6 - dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]benzosulfimide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 4-forfinal). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl) and 4-forbindelsesteknologi formula D-7 wherein R4denotes 4-forfinal, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, isolated amorphous Citect PMR (300 MHz, deuteroacetone): 0,11, 0,43, 0,62, 0,92, 1,34, 1,65, 2,57, 3,13, 6,79, 7,03-7,24, 7,75 M. D.

The mass spectrum of high resolution, found: 502,2063.

Elemental analysis, found: 63,96; H 6,29; N 2,71.

Preparation 21. Cleavage of 4-hydroxy-3-[1-(3-nitrophenyl)propyl] -5,6-dihydro-6,6-dipropyl-2H-Piran-2-she (formula D-4: R1denotes propyl, R2denotes propyl, R3denotes ethyl). Cm. Scheme D.

The target solution of the product of Preparation 18 (formula D-4: R1denotes propyl, R2denotes propyl, R3denotes ethyl) (30 mg/ml) in a 15% solution of ISO-propyl alcohol in hexane chromatographic in column (2.0 x 25 cm (R,R) Whelk-O 1 (from Regis Technologies, Inc.", Morton Grove, IL 60053), injective 1 ml using automated chromatographic system. Aliremove a controlled substance at the wavelength of 270 nm and the corresponding fractions after repeated injection combined and evaporated in vacuum, obtaining oil copper brown color. Faction after numerous injection to analyze column and 0.46 x 25 cm (S,S) Whelk-O 1, using the same solvent with a feed rate of 1.0 ml/min the First peak from the column 1.0 cm is > 99% EE (Rtmeasured in minutes), and the last peak has a 92% EE (Rtmeasured in minutes). Before long elwira a mixture of hexane/ethyl acetate (3:1). Subjected to the splitting of a substance is transformed into amines of the formula D-5 in accordance with the methods provided for the Preparation of 20.

Substances have the following physical characteristics:

It was found that the PMR spectra and TLC-parameters subjected to the decomposition of substances identical to the corresponding spectra and the parameters of racemic substances.

Example 52. (R or S)-N-[3-[1-(4-Hydroxy-2-oxo-6,6-dipropyl - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -8-chinaincorporated (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4means quinoline-8-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 21 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes ethyl) and 8-chinaincorporated formula D-7 wherein R4means quinoline-8-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

PMR-spectrum and behavior when conducting thin-layer chromatography identification is,67, 0,85, 1,27, 1,54, 2,01, 3,73, 6,78, 6,90, 7,04, 7,57, 8,12, 8,29, 8,38, 9,13 M. D.

Mass spectrum: m/e (Rel. %) 523 (100), 524 (34), 129 (11), 525 (11), 522 (10), 130 (7), 139 (5), 134 (4).

Example 53. (R or S)-N-[3-[1-(4-Hydroxy-2-oxo-6,6 - dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl - 1H-imidazole-4-sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 21 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes ethyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol in ethyl acetate, isolated amorphous solid off-white color.

The substance has the following physical characteristics:

PMR-spectrum and behavior when conducting thin-layer chromatography identical to the corresponding spectrum and the parameters of the racemic mixture.

Range PMR (300 MHz, deuteroacetone): 0,88, 1,32, 1,64, 1,93, 2,16, 2,56, 3,68, 3,91, 6,87, 7,03, 7,14, 7,53, 7,64 M. D.

Mass spectrum: m/e (Rel. %) 476 (100), 477 (28), 139 (14), 492 (yl)propyl]phenyl]-8-chinaincorporated (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4means quinoline-8-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 21 (formula D-5: R1denotes propyl, R2denotes propyl, R3< / BR>
denotes ethyl) and 8-chinaincorporated formula D-7 wherein R4means quinoline-8-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

PMR-spectrum and behavior when conducting thin-layer chromatography identical to the corresponding spectrum and the parameters of the racemic mixture.

Range PMR (300 MHz, deuteroacetone): 0,67, 0,85, 1,27, 1,54, 2,01, 3,73, 6,78, 6,90, 7,04, 7,57, 8,12, 8,29, 8,38, 9,13 M. D.

Mass spectrum: m/e (Rel. %) 523 (100), 524 (34), 522 (24), 539 (13), 525 (10), 129 (10), 130 (5), 134 (5), 128 (4), 540 (5).

Example 55. (S or R)-N-[3-[1-(4-Hydroxy-2-oxo-6,6 - dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl - 1H-imidazole-4-sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denoted by R1denotes propyl, R2denotes propyl, R3denotes ethyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol in ethyl acetate, isolated amorphous solid off-white color.

The substance has the following physical characteristics:

PMR-spectrum and behavior when conducting thin-layer chromatography identical to the corresponding spectrum and the parameters of the racemic mixture.

Range PMR (300 MHz, deuteroacetone): 0,88, 1,32, 1,64, 1,93, 2,16, 2,56, 3,68, 3,91, 6,87, 7,03, 7,14, 7,53, 7,64 M. D.

Mass spectrum: m/e (Rel. %) 476 (100), 477 (28), 139 (19), 490 (15), 498 (14), 83 (12), 478 (9), 55 (9), 145 (9), 134 (7).

Example 56. (R or S)-N-[3-[1-(4-Hydroxy-2-oxo-6,6 - dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 21 (formula D-5: R1denotes propyl, R2denotes propyl, R3oboznachaetsya with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol in ethyl acetate, isolated amorphous solid off-white color.

The substance has the following physical characteristics:

PMR-spectrum and behavior when conducting thin-layer chromatography identical to the corresponding spectrum and the parameters of the racemic mixture.

Range PMR (300 MHz, deuteroacetone): 0,12, 0,43, 0,68, 0,90-0,97, 1,36, 1,71, 2,60, 3,12, 3,67, 6,88, 7,06, 7,24, 7,51, 7,65.

Mass spectrum: m/e (Rel. %) 488 (100), 489 (30), 139 (18), 145 (14), 490 (10), 55 (10), 83 (9), 564 (7), 146 (7), 510 (7).

Example 57. (S or R)-N-[3-[1-(4-Hydroxy-2-oxo-6,6 - dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 21 (formula D-5: R1denotes propyl, R2denotes propyl, R3denotes cyclopropyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 4% solution of methanol in ethyl acetate, allocate amore:

PMR-spectrum and behavior when conducting thin-layer chromatography identical to the corresponding spectrum and the parameters of the racemic mixture.

Range PMR (300 MHz, deuteroacetone): 0,12, 0,43, 0,68, 0,90-0,97, 1,36, 1,71, 2,60, 3,12, 3,67, 6,88, 7,06, 7,24, 7,51, 7,65.

Mass spectrum: m/e (Rel. %) 488 (100), 489 (29), 139 (18), 145 (16), 83 (10), 55 (10), 490 (10), 510 (8), 146 (8), 144 (7).

Example 58. 4-Cyano-N-[3-[1-(4-hydroxy-2-oxo-6 - phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] benzosulfimide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 4-cyanophenyl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl) and 4-forbindelsesteknologi formula D-7 wherein R4denotes 4-cyanophenyl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,11, 0,42, 0,61, 0,95, 1,24, 1,74-2,00, 2,61-2,73, 3,30, 6,83-7,23, 7,71-7,86- phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)cyclopropyl-methyl] phenyl] benzosulfimide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 4-forfinal). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl) and 4-forbindelsesteknologi formula D-7 wherein R4denotes 4-forfinal, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range PMR (300 MHz, deuteroacetone): 0,11, 0,43, 0,67, 0,96, 1,41, 1,67-2,13, 2,62, 3,16, 6,84, 7,02-7,31, 7,72 M. D.

The mass spectrum of high resolution, found: 564,2211.

Example 60. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6 - dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]-8-chinaincorporated (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl, R4means quinoline-8-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formulaand formula D-7, where R1means quinoline-8-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid white.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range PMR (300 MHz, deuteroacetone): -0, 13, 0,01, 0,35, 0,93, 1,46, 1,54, 1,58-2,06, 2,56, 2,96, 6,81-7,23, 7,50-7,68, 8,08, 8,24, 8,37, 9,12 M. D.

The mass spectrum of high resolution, found: 597,2398.

Example 61. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] - 1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes phenethyl, R2denotes propyl, R3denotes cyclopropyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5%-the">

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range PMR (300 MHz, deuteroacetone): 0,13, 0,42, 0,67, 0,95, 1,44, 1,68-2,13, 2,56, 3,17, 6,91, 7,01-7,33, 7,52, 7,63 M. D.

The mass spectrum of high resolution, found: 550,2370.

Example 62. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -1-methyl-1H - imidazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes cyclopropyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes phenethyl, R2denotes phenethyl, R3denotes cyclopropyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid off-white color.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,13, 0,42, 0,68, 1,73, 1,88-2,17, 2,68, 3,19, 3,64, 6,93, 7,02-7,31, 7,52, 7,64 M. D.

ro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1means of pentyl, R2means of pentyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1means of pentyl, R2means of pentyl, R3denotes ethyl) and 1-Mei-4-sulfochloride formula D-7 wherein R4denotes 1-Mei-4-yl, in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid off-white color.

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,87, 1,25, 1,55-1,68, 1,92, 2,13, 2,57, 3,66, 3,93, 6,86, 7,03, 7,16, 7,55, 7,63 M. D.

Example 64. 4-Cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6 - dipentyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]benzosulfimide (formula D-6: R1means of pentyl, R2means of pentyl, R3denotes ethyl, R4denotes 4-cyanophenyl). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1means of pentyl, R2means of pentyl, R3denotes ethyl and 4-cyanobenzaldehyde formula D-7 wherein R4

The substance has the following physical characteristics:

Range PMR (300 MHz, deuteroacetone): 0,86, 1,23, 1,52-1,67, 1,93, 2,14, 2,56, 3,93, 6,80, 7,05, 7,18, 7,80, 7,86 M. D.

Examples 65-93

Using the General methodology described in Example 40, choose the appropriate source connection, you receive the following compounds of the present invention.

Example 65. N-[3-[1(R or S)-(6(R or S)-4-Hydroxy-2 - oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] - 1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

Example 66. N-[3-[1(R or S)-(6(S or R)-4-Hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

Example 67. N-[3-[1(S or R)-(6(R or S)-4-Hydroxy-2 - oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1obozna. Scheme D.

Example 68. N-[3-[1-(S or R)-(6(S or R)-4-Hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

Example 69. N-[3-[tert-Butyl(4-hydroxy-2-oxo-6 - phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl) methyl] phenyl]-1 - methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3represents tert-butyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

Example 70. 4-Cyano-N-[3-[tert-butyl(4-hydroxy-2-oxo-6 - phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)methyl]phenyl]benzosulfimide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3represents tert-butyl, R4denotes 4-cyanophenyl). Cm. Scheme D.

Example 71. 4-Fluoro-N-[3-[tert-butyl(4-hydroxy-2-oxo - 6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)methyl] phenyl] benzosulfimide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3represents tert-butyl, R4denotes 4-forfinal). Cm. Scheme D.

Example 72. N-[3-[tert-Butyl(4-hydroxy-2-oxo-6-phenethyl - 6-propyl-5,6-dig propyl, R3represents tert-butyl, R4denotes an 8-chinoline). Cm. Scheme D.

Example 73. N-[3-[1-(6-(2-(1-Methyl-1H-imidazol-4 - sulphonamido)ethyl)-4-hydroxy-2-oxo-6-propyl-5,6-dihydro-2H - Piran-3-yl)propyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes 2-(1-Mei-4-sulphonamido) ethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl). Cm. Scheme D.

Example 74. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-pyridine-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4represents 2-pyridyl). Cm. Scheme D.

Example 75. 4-Cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl]phenyl]-2-pyridinesulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4denotes 4-cyano-2-pyridyl). Cm. Scheme D.

Example 76. N-[3-[1-(4-Hydroxy-2-oxo-6,6 - definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-chinaincorporated (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4means quinoline-2-yl). Cm. Scheme D.

Example 77. 2-Hydroxy-N-[3-[1-(4-the guy who has phenethyl, R2denotes phenethyl, R3denotes ethyl, R4denotes 2-hydroxyphenyl). Cm. Scheme D.

Example 78. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-2-pyrimidinamine (formula D-6: R1denotes phenyl, R2denotes phenethyl, R3denotes ethyl, R4denotes 2-pyrimidinyl). Cm. Scheme D.

Example 79. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-2-ChineseSimplified (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4denotes hinosan-2-yl). Cm. Scheme D.

Example 80. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-7H-purine-6-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4means 7H-purine-6-yl). Cm. Scheme D.

Example 81. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl]phenyl]-1H-imidazole-2 - sulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4denotes 1 imidazo-2-yl). Cm. Scheme D.

Example 82. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] oznachaet ethyl, R4indicates 1H-benzimidazole-2 - yl). Cm. Scheme D.

Example 83. N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]thiazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4means thiazol-2-yl). Cm. Scheme D.

Example 84. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2 - pyridinesulfonamide (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4represents 2-pyridyl). Cm. Scheme D.

Example 85. 4-Cyano-N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl - 6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-pyridinesulfonamide (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4denotes 4-cyano-2-pyridyl). Cm. Scheme D.

Example 86. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl - 6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2 - chinaincorporated (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4means quinoline-2-yl). Cm. Scheme D.

Example 87. 2-Hydroxy-N-[3-[1-(4-hydroxy-2-oxo-6 - phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] benzosulfimide (formula D). Cm. Scheme D.

Example 88. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6 - propyl - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2 - pyrimidinamine (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4denotes 2 pirimidil). Cm. Scheme D.

Example 89. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2 - ChineseSimplified (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4denotes hinzelin-2-yl). Cm. Scheme D.

Example 90. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6-propyl - 5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-7H-purine-6-sulfonamide (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4means 7H-purine-6-yl). Cm. Scheme D.

Example 91. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl - 6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl]phenyl]-1H-imidazole - 2-sulfonamide (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4denotes a 1H-imidazol-2-yl). Cm. Scheme D.

Example 92. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-1H - benzimidazole-2-sulfonamide (formula D-6: R1denotes propyl, R2 Example 93. N-[3-[1-(4-Hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)propyl]phenyl]thiazole-4 - sulfonamide (formula D-6: R1denotes propyl, R2denotes phenethyl, R3denotes ethyl, R4means thiazol-2-yl). Cm. Scheme D.

Example 93A. 4-Fluoro-N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6 - propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] benzosulfimide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 4-forfinal). Cm. Scheme D.

The target compound is obtained from the amine of Preparation 20 (formula D-5: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl and 4-forbindelsesteknologi in accordance with the General method of sulfonylurea for Example 40 and after evaporation chromatography elwira 5% solution of ethyl acetate in methylene chloride, to produce an amorphous solid off-white color.

The substance has the following physical characteristics:

Range of PMR is complicated by the presence of diastereomers.

Range PMR (300 MHz, deuteroacetone): 0,75-0,96, 1,31- 1,48, 1,57-2,01, 2,09-2,22, 2,48-2,71, 3,92, 3,94, 6,86-7,24, 7,72 M. D.

Preparation 22. 6-(2-Cyclopropyl-1-cyclopropylmethyl)-4 - hydroxy-2H-Piran-is Propylamine in 9 ml of dry tetrahydrofuran in an argon atmosphere add to 6.2 ml of a 1.6 M solution of n-utility in hexane. The solution is heated to 0oC and add a solution of 378 mg of industrially produced 4-hydroxy-6-methyl-2-pyrone of formula E-1 in 8 ml hexamethylphosphoramide. Stirred for 30 minutes at a temperature of 0oC and add 0,32 ml bromelicola; after another ten minutes, add another one exactly the same portion. The reaction mixture was stirred, left overnight to warm to room temperature and poured into a mixture of ethyl acetate and an excess of dilute hydrochloric acid. The organic phase is washed with saturated salt solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by the method of evaporative chromatography using silica gel 60 (230-400 mesh mesh) (elute 25% solution of ethyl acetate in dichloromethane containing 1% acetic acid), and receive 371 mg of the target product and 206 mg monoalkylamines derived.

The substance has the following physical characteristics:

Range PMR: 0,0, 0,4, 0,6, 1,5, 1,6, 2,2, 5,6, 6,1, 7,2-7,3, 11,5.

Mass spectrum (E1): m/z = 234.

TLC: Rf0,29 (25% solution of ethyl acetate in dichloromethane containing 1% acetic acid).

Preparation 23. 3-(alpha-Cyclopropyl-meta (benzyloxycarbonyl-amino)benzyl-6-(2-new product of Preparation 22, 470 mg of the target product of the Drug F-5, 60 mg of the monohydrate of p-toluenesulfonic acid and 1 g of molecular sieves 3 in 5 ml of benzene is heated overnight in an argon atmosphere. The mixture is diluted with dichloromethane and ether and filtered through a layer of sodium sulfate. The solvent is distilled off under reduced pressure and the residue purified by the method of evaporative chromatography using silica gel 60 (230-400 mesh mesh) (elute 5-20% solution of ethyl acetate in dichloromethane), and get 399 mg of the target product.

The substance has the following physical characteristics:

Range PMR: -0,06, 0,3, 0,5, 1,4, 1,5, 2,5, 3,5, 5,1, 7,2-7,4 M. D.

The mass spectrum of high resolution, found: 513,2513.

TLC: Rf0,28 (5% solution of ethyl acetate in dichloromethane).

Preparation 24. 3-(alpha-Cyclopropyl-metakinesis)-6- (2-cyclopropyl-1-cyclopropylmethyl)-4-hydroxy-2H-Piran-2-he (formula E-4). Cm. Diagram E.

A mixture of 391 mg of the target product of Preparation 23 and 100 mg of 5% palladium on coal and 10 ml of ethanol is shaken overnight under a pressure of 40 pounds-force/square inch (275,8 kPa) of hydrogen. The mixture is filtered through celite and the filtrate evaporated in vacuum under reduced pressure, getting 280 mg of the target product.

Range PMR: 0,0, 0,2-N-(3-[Cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl] phenyl)-4-forbindelsesfaneblad (formula E-6). Cm. Diagram E.

To a mixture of 57 mg of the target product of Preparation 24 and 24 μl of pyridine in 0.5 ml of dichloromethane added 29 mg of 4-forbindelsesteknologi. Leave the mix overnight, the solution was diluted with ethyl acetate and washed with diluted hydrochloric acid, saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by the method of evaporative chromatography using silica gel 60 (230-400 mesh mesh) (elute 10% solution of ethyl acetate in dichloromethane), and obtain 56 mg of the target product.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): -0,07, 0,13, 0,33, 0,54, 1,39, 1,51, 1,72, 2,55, 3,39, 6,12, 6,87, 7,00, 7,08, 7,19, 7,27, 7,72, 9,72 M. D.

Mass spectrum (E1):[M+] = 537,1977.

Examples 95-97

In accordance with the above methods, using original materials and reagents that are available for professionals in the field of organic synthesis, additionally, you receive the following connections:

Example 95. 4-Cyano-N-(3-{cyclopropyl-[6-(2 - cyclopropyl-1-cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)benzosulfimide (formula E-7). Cm. Diagram E.

The substance has the following physical characteristics:

Spec (E1): [M+] = 544,2035.

Example 96. N-(3-{ Cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-8-chinaincorporated (formula E-8). Cm. Diagram E.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): -0,07, 0,18, 0,37, 0,54, 1,37, 1,51, 2,53, 3,31, 5,96, 6,87, 7,00, 7,13, 7,48, 7,54, 7,92, 8,23, 9,07 M. D.

Mass spectrum (E1): [M+] = 570,2188.

Example 97. N-(3-{ Cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3 - yl] methyl}phenyl)-1-methyl-1H-imidazole-4-sulfonamide (formula E-9). Cm. Diagram E.

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): -0,08, 0,13, 0,33, 0,56, 1,37, 1,51, 1,73, 2,54, 3,21, 3,60, 5,95, 6,82, 7,0, 7,19, 7,37, 7,5 M. D.

Mass spectrum (E1): [M+] = 523,2142.

Example 98. The separation method of chiral liquid chromatography high-resolution N-(3-{cyclopropyl-[6- (2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran - 3-yl] methyl}phenyl]-1-methyl-1H-imidazol-4-sulfonamida (formula E-9) to obtain (R or S)-N-(3-{cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl} phenyl] -1-methyl-1H-imidazol-4-sulfonamida (formula E-10 and E-11) Cm. Diagram E.

Prepare the source process,2% water in hexane) in ISO-propanol. The original solution is filtered with a syringe through a filter with a pore size of 0.45 micron and washed with ethanol, receiving of 14.0 ml of clear filtrate. The obtained filtrate chromatographic in column (2.0 x 2.5 cm (R,R) Whelk-O 1 ("Regis Technologies, Inc.", Morton Grove, I1 60053), using automated chromatographic system and a 3.50 ml per injection. Aliremove substance control and the corresponding functions after repeated injection unite, evaporated in vacuum and subjected to the azeotropic distillation with toluene. The residue is dissolved in methanol, filtered with a syringe and the filtrate evaporated under reduced pressure, obtaining the target compound (> 95% purity).

(R or S)-N-(3-{ Cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole - 4-sulfonamide (formula E-10).

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): -0,07, 0,14, 0,34, 0,57, 1,32, 1,55, 1,75, 2,51, 3,24, 3,60, 5,87, 6,85, 7,03, 7,15, 7,27, 7,37 M. D.

Mass spectrum (E1): [M+] = 523,2149.

(R or S)-N-(3-{ Cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)- 1-methyl-1H-imidazole-4-sulfonamide (formula E-11).

Wishesto, 0,33, 0,55, 1,33, 1,56, 1,75, 2,51, 3,23, 3,60, 5,88, 6,86, 7,03, 7,14, 7,27, 7,38 M. D.

Mass spectrum (E1): [M+]= 523,2137.

Examples 99-103

In accordance with the above methods, using original materials and reagents that are available for professionals in the field of organic synthesis, additionally, you receive the following connections:

Example 99. N-(3-{ Cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)- 2-pyridinesulfonamide (formula E-12).

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): -0,05, 0,07, 0,17, 0,34, 0,55, 1,35, 1,55, 1,7, 2,5, 3,24, 5,86, 6,90, 7,03, 7,15, 7,39, 7,78, 8,60 M. D.

Mass spectrum (E1): [M+] = 520

TCX: Rf0,35 (25% solution of ethyl acetate in dichloromethane).

Example 100. N-(3-[Cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-2-sulfonamide (formula E-13).

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): -0,05, 0,15, 0,35, 0,56, 1,35, 1,55, 1,75, 2,53, 3,23, 3,39, 5,89, 6,81, 6,90, 6,97, 7,09, 7,25 M. D.

Mass spectrum (E1): [M+] = 523

TLC: Rf0,31 (5% solution of methanol in dichloromethane).

Example Casal-2-sulfonamide (formula E-14).

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): -0,07, 0,1, 0,15, 0,35, 0,56, 1,38, 1,58, 1,65, 2,55, 3,28, 5,95, 6,73, 6,96, 7,10, 7,28, 7,58 M. D.

Mass spectrum (FAB): [M+H] = 560,2220.

Example 102. N-(3-{cyclopropyl-[6-(2-Cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3 - yl]methyl}phenyl)-1H-imidazole-2-sulfonamide (formula E-15).

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 0,0, 0,25, 0,4, 0,6, 1,4, 1,6, 1,65, 2,6, 3,35, 6,0, 6,8, 7,0, 7,2, 7,4 M. D.

Mass spectrum (E1): [M+] = 509

TCX: Rf0,25 (5% solution of methanol in dichloromethane).

Example 103. N-(3-[Cyclopropyl-[6-(2-cyclopropyl-1 - cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3 - yl] methyl} phenyl)-2-chinaincorporated (formula E-16).

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 0,0, 0,2, 0,4, 0,6, 1,4, 1,6, 1,7, 2,6, 3,3, 6,0, 7,0-7,2, 7,3, 7,7, 7,8-8,0, 8,2, 8,3 M. D.

Mass spectrum (E1): [M+] = 570

TCX: Rfof 0.53 (5% solution of methanol in dichloromethane).

Preparation 25. Cyclopropyl-meta-nitrophenolate (formula F-2). Cm. Diagram F.

In a three-neck flask with a capacity of 250 ml, equipped with a thermometer and kapelln who have dropwise 21 ml of industrially produced cyclopropylacetylene formula F-1. The addition of the reagent is carried out with such speed that the temperature of the reaction mixture was maintained at minus 10oC. after adding the obtained transparent yellow solution is stirred at a temperature of minus 10oC for 10 minutes and then poured onto 1 l of crushed ice. The precipitation was washed with 700 ml of toluene, the extract is washed twice with 5% sodium hydroxide solution, once with saturated salt solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is recrystallized from methanol at a temperature of minus 25oC and obtain 14.6 g of target compound in the form of prisms of pale yellow color. The mother liquor contains substantial amounts of ortho-isomer.

The substance has the following physical characteristics:

Range PMR: 1,2, 1,3, 2,7, 7,70, 8,3, 8,4, 8,85 M. D.

IR-spectrum: 1664, 1529, 1352, 1225, 1082, 1017, 852, 689 cm-1.

Elemental analysis, found: 62,89; H to 4.73; N 7,32.

Mass spectrum (E1): m/z 191

TLC: Rf0,32 (25% solution of ethyl acetate in hexane).

Preparation 26. meta Aminophenylacetate (formula F-3). Cm. Diagram F.

The solution 5,76 g of the target product of Preparation 25 obtained by heating the kind of one atmosphere. After 5 hours the mixture is filtered through celite and the filtrate evaporated under reduced pressure and get 4,89 g of target compound in the form of oil greenish color.

The substance has the following physical characteristics:

Range PMR: 1,0, 1,2, 2,6, 3,9, 6,8, 7,2, 7,4 M. D.

TCX: Rf0,50 (80% solution of ethyl acetate in hexane).

Preparation 27. meta Benzyloxycarbonylglycine (formula F-4). Cm. Diagram F.

To a cooled (0oC) stir the solution 4,89 g of the target product of Preparation 26 and 6.3 ml of di-ISO-Propylamine in 90 ml of dichloromethane is added dropwise to 4.7 ml of benzyl ether of Harborview acid. The resulting solution was allowed to warm to room temperature, stirred for four hours, washed with diluted hydrochloric acid and the aqueous portion extracted with two portions of dichloromethane. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a solid yellow color. It is ground with two portions of 30 ml of hexane, decanted, the remaining solid is dried in vacuum and get a total of 8.74 g of target compound.

The substance has the following physical characterizationelectrochemically (formula F-5). Cm. Diagram F.

To the cooled mixed solution, a total of 8.74 g of compound F-4 of 27 Drug in 100 ml of tetrahydrofuran and 100 ml of ethanol are added in several portions of 4.5 g of sodium borohydride. Stirred at room temperature for three hours and before adding 100 ml of 1N hydrochloric acid cooled mixture in the bath with ice. The layers are separated and the aqueous phase is shaken out three times with dichloromethane. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure; the residue chromatographic on silica gel 60 (230-400 mesh mesh) (elute 40% solution of ethyl acetate in hexane), and get 8,48 g of the desired product in the form of a solid crystalline substance of white color. It can be precrystallization from a mixture of ethyl acetate - hexane.

The substance has the following physical characteristics:

Range PMR: 0,3-0,6, 1,1, 2,35, 3,92, 5,17, 7,1, 7,2-7,4 M. D.

IR-spectrum: 1693, 1599, 1559, 1449, 1235, 1954, 697 cm-1.

Elemental analysis, found: 72,57; H 6,51; N br4.61.

Preparation 29. 4-Hydroxy-6-[3-(2-methoxy-ethoxy)propyl] Piran-2-he (formula G-1). Cm. Diagram G.

The flask was dried with a naked flame in a current of argon put 2,80 ml of di-ISO-Propylamine and 20.0 ml of dry tetrahydrofuran. The floor is 30 minutes heated to a temperature of 0oC and add 5.0 ml of dry hexamethylphosphoramide. To the obtained solution of di-ISO-propylamide lithium type of industrially produced 4-hydroxy-6-methyl-2-pyrone of the formula G-0 in the form of a solution in 16 ml of dry tetrahydrofuran and 14 ml of dry hexamethylphosphoramide. Stirred for 30 minutes and added 2.30 g of 2-(2-methoxy-ethoxy)ethyliodide in the form of a solution in 12 ml of dry tetrahydrofuran. The resulting mixture is stirred for one hour at a temperature of 0oC and allow it to warm to room temperature. Stirred for another hour and terminate the reaction by adding an excess of 1N hydrochloric acid. The mixture is evaporated under reduced pressure and poured into a mixture of dichloromethane and water. The aqueous layer was extracted with a sufficient number of dichloromethane, to completely isolate the target product. The organic extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The remainder chromatographic on silica gel 60 (230-400 mesh mesh) (elute starting a 30% solution of ethyl acetate in dichloromethane containing 3% acetic acid, and 80% solution of ethyl acetate in dichloromethane containing 5% acetic acid) and gain of 1.34 g of the target compound.

<, ,55, 5,55, 5,90 M. D.

TCX: Rf0,26 (50% solution of ethyl acetate in dichloromethane containing 5% acetic acid).

The drug 30. 3-(alpha-Cyclopropyl-meta(benzyloxycarbonyl - amino)benzyl)-4-hydroxy-6-[3-(2-methoxy-ethoxy)propyl] Piran-2-he (formula G-2). Cm. Diagram G.

A mixture of 146 mg of the target product of Preparation 29, 340 mg of the target product of Preparation 28 obtained as shown in Scheme F, 25 mg of the monohydrate of p-toluenesulfonic acid and 0.5 g of molecular sieve 3 in 5 ml of dichloromethane leave when heated at night. Cool the mixture and the solvent is removed under reduced pressure. The residue is purified by a method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 5-10% solution of methanol in ethyl acetate) and obtain 129 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,25, 0,45, 0,67, 1,77, 2,39, 3,38, 3,51, 5,13, 5,84, 7,17, 7,32, 7,42 M. D.

Mass spectrum (E1): [M+] = 507,2257

TLC: Rf0,28 (50% solution of ethyl acetate in dichloromethane).

Preparation 31. 3-(alpha-Cyclopropyl-meta-aminobenzyl)-4 - hydroxy-6-[3-(2-methoxy-ethoxy)propyl]Piran-2-he (formula G-3). Cm. Diagram G.

A mixture of 124 mg of the target product of Preparation 30 and 35 mg of 5%kPa) of hydrogen. The mixture is filtered through celite, washing the filter with ethanol. The combine filtrate, the solvent is distilled off under reduced pressure and obtain 92 mg of the target product.

The substance has the following physical characteristics:

TLC: Rf0,12 (ethyl acetate).

Example 104. N-(3-{Cyclopropyl-[4-hydroxy-6-(3-{2-methoxy-ethoxy}propyl)-2-oxo-2H - Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide (formula G-4). Cm. Diagram G.

To a mixture of 37 mg of the target product of Preparation 31 and 18 μl of pyridine in 0.5 ml of dichloromethane are added 20 mg of 1-methyl-imidazol-4-sulfochloride. Leave the mix overnight, the solvent is removed under reduced pressure. The residue is subjected to azeotropic distillation with toluene and then purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 2-8% solution of methanol in dichloromethane) and obtain 32 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,1, 0,24, 0,45, 0,65, 1,75, 1,85, 2,46, 3,30, 3,34, 3,50, 5,98, 6,98, 7,08, 7,19, 7,29, 7,42 M. D.

Mass spectrum (E1): [M+] = 517,1874

TCX: Rf0,22 (5% solution of methanol in dichloromethane).

Preparation 32. 3-(alpha-Cyclopropyl-meta(Ben is produced by 4-hydroxy-6-methyl-2-pyrone of the formula H-0, 592 mg of the target product of Preparation 28 obtained as shown in Scheme F, and 56 mg of the monohydrate of p-toluenesulfonic acid in 20 ml of dichloromethane is boiled for 6 hours under reflux via an addition funnel filled with 3 a molecular sieves. Cool the mixture and

the solvent is removed under reduced pressure. The residue is purified by a method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 60-100% solution of ethyl acetate in dichloromethane) and obtain 470 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,23, 0,43, 0,66, 1,78, 3,41, 5,09, 5,89, 7,00, 7,14, 7,29, 7,37, 10,1 M. D.

Mass spectrum (E1): [M+] = 405

TCX: Rfof 0.52 (ethyl acetate).

Preparation 33. 3-(alpha-Cyclopropyl-meta(benzyloxycarbonylamino)benzyl)-4-hydroxy-6-propelers-2-he (formula H-2). Cm. Diagram H.

The flask was dried with a naked flame in a current of argon put to 0.45 ml of di-ISO-Propylamine and 3.0 ml of dry tetrahydrofuran. The resulting solution is cooled to minus 78oC and add 2.0 ml (1.6 M solution in hexane) n-utillity. The solution for 15 minutes, heated to a temperature of 0oC, and then re-cooled to minus 78oC. To the floor of dry tetrahydrofuran. Is stirred for one hour and add 85 ál of bromide of ethyl. The resulting mixture is stirred for three hours at a temperature of minus 78oC and terminate the reaction by adding an excess of 1N hydrochloric acid. The mixture is heated and poured into a mixture of ethyl acetate and phosphate buffer solution. The aqueous layer was extracted twice with ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The remainder chromatographic on silica gel 60 (230-400 mesh mesh) (elute 10-20% solution of ethyl acetate in dichloromethane) and obtain 277 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,24, 0,45, 0,65, 0,88, 1,55, 1,79, 2,28, 3,42, 5,10, 5,95, 6,89, 7,15, 7,3, 10,0 M. D.

Mass spectrum (E1): [M+] = 433

TCX: Rf0,33 (10% solution of ethyl acetate in dichloromethane).

Preparation 34. 3-(alpha-Cyclopropyl-meta(benzyloxycarbonylamino)benzyl)-6-[1-ethyl-3-(2-methoxy-ethoxy)propyl] -4-hydroxyfuran-2-he (formula H-C). Cm. Diagram H.

The flask was dried with a naked flame in a current of argon put 0.3 ml of di-ISO-Propylamine and 2.0 ml of dry tetrahydrofuran. The resulting solution is cooled to minus 78oC and add 1.3 ml (1,b is cooled to minus 78oC. To the resulting solution of di-ISO-propylamide lithium type 277 mg of the target product of Preparation 33 in the form of a solution in 3 ml of dry tetrahydrofuran. Stirred at the same temperature for one hour and added 180 mg of 2-(2-methoxy-ethoxy)ethyliodide in 3 ml of tetrahydrofuran. The resulting mixture is stirred for three hours at a temperature of minus 78oC and terminate the reaction by adding an excess of 1N hydrochloric acid. The mixture is heated and poured into a mixture of ethyl acetate and phosphate buffer solution. The aqueous layer was extracted three times with ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The remainder chromatographic on silica gel 60 (230-400 mesh mesh) (elute 25-40% solution of ethyl acetate in dichloromethane) and obtain 198 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,25, 0,46, 0,66, 0,75, 1,5, 1,76, 2,36, 3,4, 5,15, 5,96, 7,2, 7,3, 7,42, 10,0 M. D.

Mass spectrum (E1): [M+] = 535

TCX: Rf0,29 (25% solution of ethyl acetate in dichloromethane).

Preparation 35. 3-(alpha-Cyclopropyl-meta-aminobenzyl)-6- [1-ethyl-3-(2-methoxy-ethoxy)propyl]-4-hydroxy-Piran-2-he (formula H-4). Cm. Diagram H.

Sm during the night under a pressure of 50 pounds-force/square inch (344,7 kPa) of hydrogen. The mixture is filtered through celite, washing the filter with ethanol. The combine filtrate, the solvent is distilled off under reduced pressure and obtain 127 mg of the target product.

The substance has the following physical characteristics:

TCX: Rfto 0.19 (ethyl acetate).

Example 105. N-(3-{Cyclopropyl-[6-(1-ethyl-3-{2-methoxy - ethoxy}propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide (formula H-5). Cm. Diagram H.

To a mixture of 32 mg of the target product of Preparation 35 and 13 μl of pyridine in 0.8 ml dichloromethane type of 14.5 mg of 1-methyl-imidazol-4-sulfochloride. Leave the mix overnight, the solvent is removed under reduced pressure. The residue is subjected to azeotropic distillation with toluene and then purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 1-4% solution of methanol in dichloromethane) and obtain 38 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,05, 0,25, 0,45, 0,65, 0,83, 1,5-2,0, 2,45, 3,3-3,5, 3,62, 6,00, 6,99, 7,1-7,3, 7,48 M. D.

Mass spectrum (E1): [M+] = 545,2186

TCX: Rf0,24 (5% solution of methanol in dichloromethane).

Example 106. 4-Cyano-N-{3-[cyclopropyl-[6-(1-etenia receive the previously described methodology, using starting materials and reagents that are available for professionals in the field of organic synthesis.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,15, 0,25, 0,45, 0,65, 0,78, 1,2-1,8, 2,4, 3,3-3,6, 3,54, 5,89, 6,95, 7,1-7,3, 7,6-7,9 M. D.

Mass spectrum (E1): [M+1] = 567,2176

TCX: Rf0,40 (50% solution of ethyl acetate in dichloromethane)

Preparation 36. 3-(alpha-Cyclopropyl-meta(benzyloxycarbonylamino)benzyl)-6-(1-ethyl-3-hydroxypropyl)-4-hydroxyfuran-2-he (formula I-1). Cm. Scheme I.

The flask was dried with a naked flame in a current of argon is placed in it and 0.46 ml of di-ISO-Propylamine and 3.5 ml of dry tetrahydrofuran. The resulting solution is cooled to minus 78oC and add 2.0 ml (1.6 M solution in hexane) n-utillity. The solution for 20 minutes, heated to a temperature of 0oC, and then re-cooled to minus 78oC. To the resulting solution of di-ISO-propylamide lithium type 433 mg of the target product of Preparation 33 in the form of a solution in 4 ml dry tetrahydrofuran. Stirred at the same temperature for one hour and within 5 minutes pass current of ethylene oxide. The mixture is stirred for 15 minutes at a temperature of minus 78oC and terminate the reaction by adding Izbira. The aqueous layer was extracted twice with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The remainder chromatographic on silica gel 60 (230-400 mesh mesh) (elute 2-8% solution of methanol in dichloromethane) and obtain 144 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,22, 0,45, 0,65, 0,7, 1,3-1,7, 1,8, 2,25, 3,4, 5,1, 5,91, 7,1-7,4 M. D.

Mass spectrum (FAB): [M+1] = 478

TCX: Rf0,29 (5% solution of methanol in dichloromethane).

Preparation 37. 6-(3-Bromo-1-ethylpropyl)-3-(alpha-cyclopropyl - meta(benzyloxycarbonylamino)benzyl)-4-hydroxy-Piran-2-he (formula I-2). Cm. Scheme I.

To a stirred solution of 114 mg of the target product of Preparation 36 in 3 ml of tetrahydrofuran added 160 mg of triphenylphosphine and 200 mg chetyrehpostovye carbon. After 2 hours the solvent is distilled off under reduced pressure and the residue purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 70-100% solution of diethyl ether in hexane) and obtain 113 mg of the target compound.

The substance has the following physical characteristics:
TCX: Rf0,29 (75% solution of diethyl ether in hexane).

Preparation 38. 6-(3-Azido-1-ethylpropyl)-3-(alpha-cyclopropyl - meta(benzyloxycarbonylamino)benzyl)-4-hydroxyfuran-2-he (formula I-3). Cm. Scheme I.

To a stirred solution of 113 mg of the target product of Preparation 37 in 2.0 ml of ethanol is added 55 mg of sodium azide and 0.5 ml of water. The reaction mixture is left under heating overnight, cooled, the solvent is distilled off under reduced pressure. The residue is purified by a method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh), elwira diethyl ether, and obtain 89 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,23, 0,33, 0,51, 0,68, 0,82, 1,4-2,0, 2,33, 3,1-3,3, 3,5, 5,15, 5,94, 6,84, 7,1-7,4 M. D.

Mass spectrum (E1): [M+] = 502

TCX: Rf0,52 (10% solution of ethyl acetate in dichloromethane).

Preparation 39. 6-(3-Amino-1-ethylpropyl)-3-(alpha-cyclopropyl - meta-aminobenzyl)-4-hydroxyfuran-2-he (formula I-4). Cm. Scheme I.

A mixture of 87 mg of the target product of Preparation 38 and 35 mg of 5% palladium on charcoal in 4 ml of ethanol is shaken for 4 hours under a pressure of 40 pounds-force/square inch (275,8 kPa) of hydrogen. The mixture ottom pressure and receive 70 mg of the desired product in the form of a mixture of 6-(3-amino-1-ethylpropyl)-3- (alpha-cyclopropyl-meta(benzyloxycarbonylamino)benzyl)-4 - hydroxyfuran-2-one.

The substance has the following physical characteristics:

TCX: Rfof 0.05 (5% methanol in dichloromethane).

The product 40. 3-(Cyclopropyl-{ 3-[1-methyl-1H-imidazol-4 - sulfonamide] phenyl}methyl)-6-(1-ethyl-3-[1-methyl-1H-imidazol-4 - sulfonamide]propyl)-2-oxo-2H-Piran-4-yl-1-methyl-1H - imidazol-4-sulfonate (formula I-5). Cm. Scheme I.

To 70 mg of a mixture of 6-(3-amino-1-ethylpropyl)-3-(alpha - cyclopropyl-meta-aminobenzyl)-4-hydroxyfuran-2-it 6-(Z-amino-1-ethylpropyl)-3-(alpha-cyclopropyl-meta (benzyloxycarbonylamino)benzyl)-4-hydroxy-Piran-2-she also obtained in Preparation 39, 1.5 ml of dichloromethane add 120 ál of di-ISO-propylacetamide and 92 mg of 1-methyl-imidazol-4-sulfochloride. Leave the mix overnight, the solvent is removed under reduced pressure. The residue is subjected to azeotropic distillation with toluene and then purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 2-6% solution of methanol in dichloromethane) and obtain 49 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,2-0,5, 0,75, 0,90, 1,4-2,0, 2,55, 3,0-3,4, 3,6-3,7, 6,63, 7,0-7,7 M. D.

Mass spectrum (FAB): [M+H] = 775

TCX: Rf0,14 (5% solution of meta is hydroxy-2-oxo-2H-Piran - 3-yl]methyl}phenyl-1-methyl-1H-imidazole-4-sulfonamide (formula I-6). Cm. Scheme I.

A solution of 49 mg of the target product of Preparation 40 in 40 ml of methanol containing ammonia, cooled to 0oC and treated with gaseous ammonia. After 5 minutes, the supply of ammonia ceased, the flask was carefully closed and heated to room temperature. Left overnight, the solvent is distilled off under reduced pressure and the residue purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 3-9% solution of methanol in dichloromethane) and obtain 32 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,2-0,5, 0,75, 0,90, 1,4-2,0, 2,55, 3,0-3,4, 3,6-3,7, 6,63, 7,0-7,7 M. D.

Mass spectrum (El): [M+H] = 523

TCX: Rf0,33 (5% solution of methanol in dichloromethane).

Preparation 41. 3-(alpha-Cyclopropyl-meta-aminobenzyl)-6- (1-ethyl-3-hydroxypropyl)-4-hydroxyfuran-2-he (formula J-1). Cm. Scheme j

The mixture 477 mg of the target product of Preparation 36 and 150 mg of 5% palladium on charcoal in 10 ml of ethanol is shaken for 4 hours under a pressure of 45 pounds-force/square inch (310,3 kPa) of hydrogen. The mixture is filtered through celite, washing the filter with ethanol. The combine filtrate, the solvent is distilled off, Prime characteristics:

TCX: Rf0,10 (5% methanol in dichloromethane).

Preparation 42. 6-(3-Bromo-1-ethylpropyl)-3-(alpha-cyclopropyl - meta-aminobenzyl)-4-hydroxyfuran-2-he (formula J-2). Cm. Scheme j

To a stirred solution of 340 mg of the target product of Preparation 41 in 7 ml of tetrahydrofuran, add 525 mg of triphenylphosphine and 663 mg chetyrehpostovye carbon. After 30 minutes the solvent is distilled off under reduced pressure and the residue purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh) (elute 30-50% solution of ethyl acetate in dichloromethane) and obtain 228 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 0,19, 0,42, 0,58, 0,75, 1,4-2,4, 3,14, 3,3, 5,26, 6,15, 6,47, 6,91, 7,00 M. D.

TCX: Rfto 0.45 (5% solution of methanol in dichloromethane).

Example 108. N-(3-{ [6-(3-Bromo-1-ethylpropyl)-4-hydroxy-2 - oxo-2H-Piran-3-yl]cyclopropylmethyl}phenyl)-1-methyl-1H - imidazole-4-sulfonamide (formula J-3). Cm. Scheme j

To a mixture of 102 mg of the target product of Preparation 42 and 40 μl of pyridine in 1.0 ml dichloromethane added 45 mg of 1-methyl-1H - imidazol-4-sulfochloride. Leave the mix overnight, the solvent is removed under reduced pressure. The remainder podvergautsya 60 (230-400 mesh mesh) (elute 2-5% solution of methanol in dichloromethane) and obtain 86 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 0,2, 0,44 0,60, 0,82, 1,4-2,2, 2,5, 3,1-3,4, 3,62, 5,93, 6,92, 7,07, 7,19, 7,30, 7,40 M. D.

Mass spectrum (FAB): [M+H] = 550,1037

TCX: Rf0,36 (5% solution of methanol in dichloromethane).

Example 109. N-(3-{ [6-(3-Azido-1-ethylpropyl)-4-hydroxy-2 - oxo-2H-Piran-3-yl]cyclopropylmethyl}phenyl)-1-methyl-1H - imidazole-4-sulfonamide (formula J-4). Cm. Scheme j

To a stirred solution of 113 mg of target compound of Example 108 in 1.2 ml of ethanol is added 50 mg of sodium azide and 0.4 ml of water. The reaction mixture is left under heating overnight, cooled, the solvent is distilled off under reduced pressure. The residue is purified by a method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh), elwira 3-6% solution of methanol in dichloromethane, and obtain 57 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 0,25, 0,48, 0,66, 0,90, 1,3-1,8, 2,42, 2,9-3,2, 3,68, 5,94, 6,93, 7,12, 7,19, 7,23, 7,35, 7,46 M. D.

Mass spectrum (FAB): [M+H] = 550,1037

TCX: Rf0,36 (5% solution of methanol in dichloromethane).

Preparation 43. N-(3-{[6-(3-Amino-1-ethylpropyl)-4-hydroxy-2 - oxo-2H-Piran-3-yl]Cyclops is inane of Example 109 and 30 mg of 5% palladium on charcoal in 22 ml of ethanol is shaken overnight under a pressure of 45 pounds-force/square inch (310,3 kPa) of hydrogen. The mixture is filtered through celite, washing the filter with methanol. The combine filtrate, the solvent is distilled off under reduced pressure and obtain 69 mg of the target compound.

The substance has the following physical characteristics:

TCX: Rfof 0.05 (5% methanol in dichloromethane).

Example 110. Monosodium salt 2-[[8-[[3-[3-[cyclopropyl [3-[[(1-methyl-1H-imidazol-4-yl)sulfonyl] amino] phenyl]methyl]-4-hydroxy-2-oxo-2H-Piran-6-yl] pentyl] amino] -1,8-dioxaoctyl] methylamino] econsultancy (formula J-6). Cm. Scheme j

To a suspension of 69 mg of the target product of Preparation 43 in 1.0 ml dichloromethane added to 0.22 ml (0.5 M solution in acetonitrile) salt Suleymanova acid with triethylamine and 25 μl of di-ISO-propylbromide. Is stirred for one hour and add 0.5 ml of dimethylformamide. Leave the mix overnight, the solvent evaporated under reduced pressure and the residue purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh), elwira 10-30% solution of methanol in dichloromethane. The crude product is dissolved in a saturated solution of n-butanol in water and add saturated aqueous solution of sodium sulfate. The organic layer is separated, the aqueous phase is advanced twice extra sodium and evaporated under reduced pressure, getting 94 mg of the target compound.

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 0,5-0,6, 0,83, 1,1-2,5, 2,9-3,7, 3,68, 5,84, 6,8-7,6 M. D.

Mass spectrum (FAB): [M+H] = 786,2838

TCX: Rf0,21 (20% solution of methanol in dichloromethane).

Examples 111-134.

In accordance with the above methods, using original materials and reagents that are available for professionals in the field of organic synthesis, additionally, you receive the following connections:

111) N-(3-{ Cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis {hydroxymethyl} ethyl)amino] carbonyl} aminopropyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)benzosulfimide

112) N-(3-{ Cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis {hydroxymethyl} ethyl)amino] carbonyl} aminopropyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-pyridinesulfonamide

113) N-(3-{ Cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis {hydroxymethyl} ethyl)amino] carbonyl} aminopropyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-imidazole-2-sulfonamide

114) N-(3-{ Cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis {hydroxymethyl} ethyl)amino] carbonyl} aminopropyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-benzimidazole-2-sulfonamide

115) N-(3-{ Cyclopropyl-[4-hydrox what-1H-imidazole-4-sulfonamide

116) N-(3-{ Cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis {hydroxymethyl} ethyl)amino] carbonyl} aminopropyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1-imidazol-sulfonamide

117) N-(3-{ Cyclopropyl-[4-hydroxy-6-(3-{ gamma-L - glutamyl}amino-propyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl) benzosulfimide

118) N-(3-{Cyclopropyl-[4-hydroxy-6-(3-{gamma-L-glutamyl}amino-propyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-pyridine-sulfonamide

119) N-(3-{ Cyclopropyl-[4-hydroxy-6-(3-{ gamma-L-glutamyl} amino-propyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-imidazolylidene

120) N-(3-{Cyclopropyl-[4-hydroxy-6-(3-{gamma-L-glutamyl}amino-propyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-benzenedisulfonamide

121) N-(3-{Cyclopropyl-[4-hydroxy-6-(3-{gamma-L-glutamyl}amino-propyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole-4-sulfonamide

122) N-(3-{Cyclopropyl-[4-hydroxy-6-(3-{gamma-L-glutamyl}amino-propyl) -2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole-2-sulfonamide

123) N-(3-{Cyclopropyl-[4-hydroxy-6-(3-{[piperazine-1-yl]carbonyl} amino-propyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)benzosulfimide

124) N-(3-{Cyclopropyl-[4-hydroxy-6-(3-{[piperazine-1-yl]carbonyl} amino-propyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-pyridinesulfonamide

125) N-(3-{Cyclopropyl-[4-hydro-{ Cyclopropyl-[4-hydroxy-(6-{[piperazine-1-yl]carbonyl}amino - propyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H - benzimidazole-2-sulfonamide

127) N-(3-{Cyclopropyl-[4-hydroxy-(6-(3-{[piperazine - 1-yl]carbonyl}amino-propyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide

128) N-(3-{ Cyclopropyl-[4-hydroxy-5-(3-{ [piperazine-1 - yl] carbonyl} amino-propyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)- 1-methyl-1H-imidazole-2-sulfonamide

129) Monosodium salt 2-[[8-[[3-[3-[cyclopropyl]3- [[phenylsulfonyl] amino] phenyl] methyl] -4-hydroxy-2-oxo-2H-Piran-6 - yl]propyl]amino]-1,8-dioxaoctyl/methylamine/econsultancy

130) Monosodium salt 2-[[8-[[3-[3-[cyclopropyl]3-[[(2-pyridyl)sulfonyl] amino] phenyl] methyl]-4 - hydroxy-2-oxo-2H-Piran-6-yl]propyl] amino]-1,8-dioxaoctyl[methylamino] econsultancy

131) Monosodium salt 2-[[8-[[3-[3-[cyclopropyl] 3-[[(1H-benzimidazole-2-yl) sulfonyl] amino] phenyl] methyl]-4-hydroxy-2-oxo-2H-Piran-6 - yl] propyl]amino]-1,8-dioxaoctyl[methylamino]econsultancy

132) Monosodium salt 2-[[8-[[3-[3-[cyclopropyl]3-[[(1H-imidazol-2-yl)sulfonyl] amino] phenyl] methyl] -4-hydroxy-2-oxo-2H-Piran-6-yl]propyl] amino]-1,8-dioxaoctyl[methylamino] econsultancy

133) Monosodium salt 2-[[8-[[3-[3-[cyclopropyl]3-[[(1-methyl-1H-imidazol-4-yl)sulfonyl] amino] phenyl]methyl]-4-hydroxy-2-oxo-2H-Piran-6-yl] propyl]amino]-1,8-dioxaoctyl[methylamino]econsultancy

134) Mon the RAS-6-yl] propyl]amino]-1,8-dioxaoctyl[ methylamino]econsultancy.

Preparation 44. (Tetrahydropyran-4-yl)methanol (formula K-2). Cm. Scheme K

To a cooled (0oC) a solution of 651 mg tetrahydropyran-4 - carboxylic acid in 2.5 ml of dry tetrahydrofuran in an argon atmosphere is added dropwise 10 ml of a 1.0 M solution of borane in tetrahydrofuran. Stirred for 18 hours at room temperature, again cooled the solution to 0oC and decompose the reaction mixture by adding 1 ml of 1 M solution of sodium hydroxide. Acidified with a mixture of 1 M hydrochloric acid and extracted four times with dichloromethane. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure, getting to 0.72 g of the target alcohol as a colorless liquid.

The substance has the following physical characteristics:

Range PMR: 1,2-1,4, 1,6, 1,8, 3,3-3,4, 3,6, 4,0 M. D.

Preparation 45. (Tetrahydropyran-4-yl) methyl ester of p-toluene-sulfonic acids (formula K-3). Cm. Scheme K

To a cooled (0oC) solution of 5 mmol of the target product of Preparation 44 and 0.81 ml of pyridine in 5 ml of dichloromethane added to 1.05 g of n-toluensulfonate and allow the solution to warm to room temperature. Stirred for 18 hours, poured into dilute hydrochloric acid and extracted with EA, filtered off. The solvent is evaporated under reduced pressure and the residue chromatographic on silica gel, elwira 50% solution of ethyl acetate in hexane, and gain of 1.23 g of the target compound as a colorless liquid.

The substance has the following physical characteristics:

Range PMR: 1,2-1,4, 1,6, 1,9-2,0, 2,46, 3,34, 3,85, 3,95, 7,3, 7,8 M. D.

Mass spectrum: 270

Preparation 46. (Tetrahydropyran-4-yl)methyliodide (formula K-4). Cm. Scheme K

A solution of 800 mg of tosylate obtained in Preparation 45, and 887 mg of sodium iodide in 6 ml of acetone is refluxed in nitrogen atmosphere for six hours, then poured into a solution of sodium thiosulfate and extracted with ether. The organic extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and carefully evaporated under reduced pressure, getting 648 mg of iodide in the form of a colourless liquid.

The substance has the following physical characteristics:

Range PMR: 1,2-1,4, 1,6-1,9, 3,1, 3,37, 3,97 M. D.

Preparation 47. 6-(1-(Tetrahydropyran-4-isomethyl)propyl)-4 - hydroxyfuran-2-he (formula K-5). Cm. Scheme K

To a cooled (-78oC) a solution of 0.90 ml of di-ISO-Propylamine in 5 ml of tetrahydrofuran in an atmosphere amerivault for 10 minutes and using a cannula add a solution of 431 mg of the target product of Preparation 50 in 3 ml hexamethylphosphoramide. After 20 minutes the resulting solution is dark red is cooled to minus 50oC and through the cannula add 605 mg of iodide Preparation 46 in 1 ml of tetrahydrofuran. Give the reaction mixture is slowly heated to a temperature of 0oC and decompose it by adding a phosphate buffer with a pH of 7. The tetrahydrofuran is distilled off under reduced pressure, and the residue is then acidified with diluted hydrochloric acid, the precipitated precipitate is extracted with two portions of ethyl acetate. The organic solution was washed with diluted hydrochloric acid and saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by the method of evaporative column chromatography on silica gel, elwira solution containing 5% acetic acid and 30-40% ethyl acetate in dichloromethane, and receive 553 mg of the target compound as a viscous yellow resin.

The substance has the following physical characteristics:

TCX: Rfof 0.21 (5% acetic acid and 65% ethyl acetate in dichloromethane).

Range PMR: 0,85, 1,2-1,8, 2,45, 3,34, 3,9, 5,56, 5,94 M. D.

Mass spectrum: 252

Preparation 48. 3-[(3-Benzyloxycarbonylamino)cyclopropylmethyl]-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-Piran-2-he (formula K-6). Cloprostenol and 60 mg of the monohydrate of p-toluenesulfonic acid in 5 ml of dichloromethane is refluxed in 10 ml of molecular sieves 3 for 18 hours. The solvent is distilled off under reduced pressure, the residue is purified by the method of evaporative column chromatography on silica gel (elute, starting with 25-100% solution of ethyl acetate in dichloromethane and ending with a 5% solution of methanol in ethyl acetate) and receive a 511 mg of the target compound in the form of resin dark brown color.

The substance has the following physical characteristics:

TCX: Rf0,32 (30% ethyl acetate in dichloromethane).

Range PMR: 0,2, 0,5, 0,7, 0,8, 1,3-1,7, 3,27, 3,42, 3,86, 5,13, 5,96, 7,1-7,4 M. D.

Mass spectrum: 531

Preparation 49. 3-[(3-AMINOPHENYL)cyclopropylmethyl]-6- (1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxyfuran-2-he (formula K-7). Cm. Scheme K

A mixture of 510 mg of the target product of Preparation 48, 605 mg of ammonium formate and 100 mg of 5% palladium on coal in 8 ml of methanol is stirred in an argon atmosphere for three hours, filtered through diatomaceous earth, the filtrate is evaporated under reduced pressure and the residue purified by the method of evaporative column chromatography on silica gel (elute 2-4% solution of methanol in dichloromethane) and obtain 280 mg of the target amine in the form of a solid white color.

The substance has the following physical characteristics is 6,5, 6,83, 6,9, 7,11 M. D.

Example 135. N-(3-{Cyclopropyl-[6-(1-tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl) - 1-methyl-1H-imidazole-4-sulfonamide (formula K-8). Cm. Scheme K

To a stirred solution of 60 mg of the amine of Preparation 49 and 24 μl of pyridine in dichloromethane added 27 mg of 1-methyl-1H-imidazol-4 - sulfochloride. After 18 hours the product was then purified by the method of evaporative column chromatography on silica gel (elute 3-6% solution of methanol in dichloromethane) and receive 70 mg of the target compound in a solid white color.

The substance has the following physical characteristics:

TCX: Rf0,24 (5% methanol in dichloromethane).

Range PMR: 0,12, 0,26, 0,45, 0,60, 0,82, 1,1-1,9, 2,3, 3,3, 3,58, 3,9, 6,00, 6,9-7,5 M. D.

The mass spectrum of the high-resolution: 541,2238.

The drug is 50. 4-Hydroxy-6-propelers-2-he (formula K-9). Cm. Scheme K

To a cooled (minus 78oC) a solution of 6.3 ml of di-ISO-Propylamine in 40 ml of dry tetrahydrofuran in an argon atmosphere with stirring using a cannula added 27.5 ml of 1.6 M solution of utility in hexane. The solution is heated to 0oC and through the cannula add a solution 2,52 g of 4-hydroxy-6-methylpyran formula K-10 in 20 ml hexameters 1.5 ml of methyl ethyl. Give the reaction mixture is slowly heated to a temperature of 0oC and decompose it by adding 60 ml of 1N hydrochloric acid. The tetrahydrofuran is distilled off under reduced pressure, and the residue is extracted five times with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by the method of evaporative column chromatography on silica gel, elwira solution containing 4% acetic acid and 16% ethyl acetate in dichloromethane, and gain of 2.34 g of target compound in the form of a waxy solid yellow color.

The substance has the following physical characteristics:

TCX: Rf0,29 (5% acetic acid and 15% ethyl acetate in dichloromethane).

Range PMR: 0,98, 1,6, 2,4, 5,63, 6,05 M. D.

Preparation 51. 4-Hydroxy-6-phenethyl-2H-Piran-2-he (formula L-2) Cm. Scheme L.

The flask was dried with a naked flame in a current of argon place in it of 0.90 ml of di-ISO-Propylamine and 6 ml of dry tetrahydrofuran. The resulting solution is cooled to minus 78oC and added to 4.0 ml of a 1.6 M solution of n-utility in hexane. The solution for 20 minutes, heated to a temperature of 0oC and through the cannula add a solution of p is pensii red slowly added to 6.0 ml distilled hexamethylphosphoramide and stirred for 30 minutes. To the resulting opaque solution red type of 0.36 ml of benzyl bromide. The reaction mixture quickly becomes dark orange color and it is stirred at a temperature of 0oC for 60 minutes. The mixture is decomposed by adding an excess of 1N hydrochloric acid, and the resulting two-phase mixture of yellow evaporated, remove the tetrahydrofuran. The residue is poured into water and extracted with dichloromethane. The organic extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is diluted with a large amount of diethyl ether and washed with diluted hydrochloric acid, once with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The remainder chromatographic on silica gel 60 (230-400 mesh mesh) (elute solution containing 1% acetic acid, and 20-40% ethyl acetate in dichloromethane) and obtain 440 mg of the target compound in a solid dark brown color with so pl. 137-138oC.

The substance has the following physical characteristics:

Range PMR: 2,7, 3,0, 5,46, 5,84, 7,1-7,3 M. D.

TCX: Rf0,38 (1% acetic acid and 25% ethyl acetate in dichloromethane).

PoC) the solution in a stream of argon to 0.29 ml of di-ISO-Propylamine in 4 ml of dry tetrahydrofuran with stirring, add 1.2 ml of a 1.6 M solution of n-utility in hexane. The solution is heated to a temperature of 0oC, stirred for 10 minutes, then cooled to a temperature of minus 30oC and through the cannula add a solution of the target product of Preparation 51 in 4 ml of tetrahydrofuran. The obtained heterogeneous mixture is heated to 0oC and add a sufficient quantity hexamethylphosphoramide (approximately 1 ml) to the mixture became almost homogeneous. Stirred for 30 minutes at a temperature of 0oC, and then added dropwise 77 μl of ethyliodide. After another 90 minutes, the reaction is decomposed by adding an excess of 1N hydrochloric acid and the tetrahydrofuran is distilled off under reduced pressure. The residue is extracted with three portions of ethyl acetate. The organic extracts are combined, washed with diluted hydrochloric acid, dried over magnesium sulfate and evaporated under reduced pressure. The remainder chromatographic on silica gel 60 (230-400 mesh mesh) (elute solution containing 1% acetic acid and 25% ethyl acetate in dichloromethane) and obtain 182 mg of the target compound.

The substance has a follow
TCX: Rf0,33 (1% acetic acid and 25% ethyl acetate in dichloromethane).

Preparation 53. 3-(alpha-Cyclopropyl-meta(benzyloxycarbonylamino)benzyl) -6-(alpha-ethyl-phenethyl)-4-hydroxy-2H-Piran-2-he (formula L-4). Cm. Scheme L.

A mixture of 181 mg of the target product of Preparation 52, 220 mg of the compounds of formula F-5, 28 mg of the monohydrate of p-toluenesulfonic acid and 600 mg of molecular sieves 3 in 2 ml of benzene is refluxed for 21 hours. Cooled, filtered through celite, the filtrate evaporated under reduced pressure, the residue is purified by the method of evaporative column chromatography on silica gel (elute 50-100% solution of ethyl acetate in dichloromethane) and receive 250 mg of a mixture of products. Again chromatographic on silica gel, elwira 5-20% solution of ethyl acetate in dichloromethane, getting 154 mg (40%) of target compound.

The substance has the following physical characteristics:

Range PMR: 0,26, 0,48, 0,67, 0,81, 1,6, 1,8, 2,5, 2,7, 2,9, 3,48, 5,14, 5,86, 6,81, 7,0-7,5, 9,46 M. D.

The mass spectrum of high resolution (E1): m/z = 523,2350

TCX: Rfa 0.27 (5% ethyl acetate in dichloromethane).

Preparation 54. 3-(alpha-Cyclopropyl-meta(aminobenzyl)-6- (alpha-ethyl-phenethyl)-4-hydroxy-2H-Piran-2-he (formula L-5). Cm. Scheme L.

Smev under pressure of 40 pounds-force/square inch (275,8 kPa) hydrogen, and then filtered through celite. The filtrate is evaporated under reduced pressure and obtain 105 mg (96%) of the target product.

The substance has the following physical characteristics:

Range PMR: 0,25, 0,5, 0,65, 0,81, 1,6, 2,5, 2,7, 2,9, 3,4, 5,79, 6,5, 6,8-7,3 M. D.

TCX: Rf0,38 (30% ethyl acetate in dichloromethane).

Examples 136-150.

Using the above techniques, is injected into the interaction of the compounds of formula L-5 with the corresponding sulfochloride and additionally obtain the following compounds. Individual stereoisomers allocate method chiral liquid chromatography high resolution of intermediates such as compounds of formula L-3, L-4, L-5 and L-6. (See Scheme L).

136) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy - 2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole-4 - sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,29 (5% methanol in dichloromethane).

Range PMR: 0,2, 0,5, 0,65, 0,86, 1,63, 1,80, 2,51, 2,8, 3,3, 3,62, 5,7, 6,8-7,4 M. D.

The mass spectrum of the high-resolution: 533,1998

137) N-(3-(R or S)-{Cyclopropyl-[6-(1-(R)-ethylphenyl) -4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H - imidazole-4-sulfonamide

The substance has with the Mr: 0,18, 0,43, 0,63, 0,83, 1,6, 1,75, 2,5, 2,7-2,9, 3,3, 3,55, 5,76, 6,9-7,4 M. D.

The mass spectrum of the high-resolution: 533,1983

138) N-(3-(R or S)-{Cyclopropyl-[6-(1-(R)-ethylphenyl) - 4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H - imidazole-4-sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,30 (5% methanol in dichloromethane).

Range PMR: 0,2, 0,5, 0,65, 0,86, 1,63, 1,80, 2,51, 2,8, 3,3, 3,62, 5,7, 6,8-7,4 M. D.

The mass spectrum of the high-resolution: 533,1993

139) N-(3-(R or S)-{Cyclopropyl-[6-(1-(S)-ethylphenyl) -4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)methyl-1H - imidazole-4-sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,30 (5% methanol in dichloromethane).

Range PMR: 0,2, 0,5, 0,65, 0,86, 1,63, 1,80, 2,51, 2,8, 3,3, 3,62, 5,7, 6,8-7,4 M. D.

The mass spectrum of the high-resolution: 533,1993

140) N-(3-(R or S)-{Cyclopropyl-[6-(1-(S)-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole-4-sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,30 (5% methanol in dichloromethane).

Range PMR: 0,17, 0,44, 0,62, 0,83, 1,6, 1,75, 2,50, 2,7-3,0, 3,3, 3,53, 5,80, 6,9-7,4 M. D.

The mass spectrum of the high-resolution: 533,1990

141) N-(3-(R or S)-{Cyclopropyl-[6-(1-(R)-ethylphenidate characteristics:

TCX: Rf0,34 (30% ethyl acetate in dichloromethane).

Range PMR: 0,2, 0,45, 0,6, 0,86, 1,5-1,9, 2,5, 2,8-3,0, 3,2, 5,7, 6,9-7,4, 7,8, 8,6 M. D.

Mass spectrum: 530

142) N-(3-(R or S)-{Cyclopropyl-[6-(1-(R)-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-pyridinesulfonamide

The substance has the following physical characteristics:

TCX: Rf0,35 (30% ethyl acetate in dichloromethane).

Range PMR: 0,11, 0,20, 0,43, 0,58, 0,85, 1,5-1,8, 2,5, 2,7-3,0, 3,3, 5,69, 6,9-7,4, 7,8, 8,6 M. D.

Mass spectrum: 530

143) N-(3-(R or S)-{Cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl} phenyl)-1-methyl-1H-imidazole-2-sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,34 (5% methanol in dichloromethane).

Range PMR: 0,19, 0,5, 0,65, 0,89, 1,6-1,9, 2,5, 2,8-3,0, 3,3, 3,40, 5,70, 6,8-7,4 M. D.

Mass spectrum: 533

144) N-(3-(R or S)-{Cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy-2 - oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole-2-sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,34 (5% methanol in dichloromethane).

Range PMR: 0,20, 0,44, 0,65, 0,88, 1,6-1,8, 2,5, 2,8-3,0, 3,3, 3,42, 5,73, 6,8-7,4 M. D.

Mass spectrum: 533

145) N-(3-{Cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4 - guide the definition characteristics:

TCX: Rf0,22 (5% methanol in dichloromethane).

Range PMR: 0,16, 0,24, 0,47, 0,64, 0,86, 1,2-1,9, 3,2-3,4, 3,47, 3,7-4,0, 5,89, 6,9-7,4 M. D.

Mass spectrum: 541

145A) N-(3-[Cyclopropyl[4-hydroxy-2-oxo-6-[1-[(tetrahydro-2H-Piran-3-yl) methyl]propyl]-2H-Piran-3-yl]methyl]phenyl)-8-chinaincorporated

The substance has the following physical characteristics:

Molecular mass found: m/z 588.

145B) N-(3-[Cyclopropyl[4-hydroxy-2-oxo-6-[1-[(tetrahydro-2H-Piran-3-yl) methyl] propyl] -2H-Piran-3-yl]methyl]phenyl)-1-methyl-1H-imidazolylidene

The substance has the following physical characteristics:

Molecular mass found: m/z 541.

146) N-(3-{ Cyclopropyl-[6-(1-(R)-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)benzimidazole-2 - sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,40 (50% ethyl acetate in dichloromethane).

Range PMR: 0,1-0,6, 0,85, 1,5-1,7, 2,5, 2,7-3,0, 3,3, 5,74, 6,7-7,3, 7,5-7,7 M. D.

The mass spectrum of the high-resolution: 570,2054

147) N-(3-{Cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy

-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-imidazole-2 - sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,31 (5% methanol in dichloromethane).


The substance has the following physical characteristics:

TCX: Rfto 0.47 (20% ethyl acetate in dichloromethane).

Range PMR: 0,1, 0,2, 0,4, 0,6, 0,84, 1,5-1,8, 2,5, 2,7-3,0, 3,3, 5,70, 6,9, 7,0-7,3, 7,6, 7,8 M. D.

The mass spectrum of the high-resolution: 554,1886

149) N-(3-(R or S)-{Cyclopropyl-[6-(1-(R)-ethylphenyl) -4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-4-cyano - benzosulfimide

The substance has the following physical characteristics:

TCX: Rf0,35 (15% ethyl acetate in dichloromethane).

Range PMR: 0,1, 0,2, 0,4, 0,6, 0,85, 1,5-1,9, 2,5, 2,7-3,0, 3,3, 5,7, 6,9-7,3, 7,6, 7,8 M. D.

The mass spectrum of the high-resolution: 554,1876

150) N-(3-{Cyclopropyl-[6-(1-ethylphenyl) -4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-4-nitrobenzenesulfonamide

The substance has the following physical characteristics:

TCX: Rf0,28 (10% ethyl acetate in dichloromethane).

Range PMR: 0,1, 0,2, 0,4, 0,6, 0,83, 1,5- 1,9, 2,5, 2,7-3,0, 3,3, 5,70, 6,9-7,3, 7,9, 8,2 M. D.

The mass spectrum of the high-resolution: 574,1773

Drug 55. (2-(2-(2-Methoxy-ethoxy)ethoxy)ethoxy)-p - toluensulfonate (formula M-2). Cm. Scheme m

To a stirred suspension of 19.1 g of n-toluensulfonate in 100 ml of dichloromethane added a mixture of 16 ml nanometrology ether of triethylene glycol and 10 ml of pyridine,the residue is poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic extracts are combined, washed with saturated sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by the method of evaporative chromatography on silica gel, elwira 25% solution of ethyl acetate in dichloromethane, and get 18,25 g of target compound in the form of a colourless liquid.

The substance has the following physical characteristics:

TCX: Rfa 0.27 (20% ethyl acetate in dichloromethane).

Range PMR: 2,45, 3,38, 3,5-3,8, 4,15, 7,35, 7,8 M. D.

IR-spectrum: 2879, 1357, 1190, 1177, 1108, 1099, 924, 665 cm-1.

Mass spectrum: 318

Preparation 56. 2-Hydroxy-4-(2-(2-(2-methoxy-ethoxy) ethoxy)ethoxy)acetophenone (formula M-3). Cm. Scheme m

A mixture of 1.52 g of 2,4-dihydroxyacetophenone, 3,82 g tosilata of the Drug 55, 3,26 g of cesium carbonate and 0.2 g of potassium iodide in 20 ml of dioxane is heated overnight to a temperature of 100oC, cooled, poured into dilute hydrochloric acid and twice extracted with dichloromethane. The organic extracts are combined washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by the method of evaporative chromatography on silica gel, elwira 85-100% solution of ethyl has the following physical characteristics:

TCX: Rf0,35 (80% ethyl acetate in hexane).

Range PMR: 2,56, 3,38, 3,5-3,9, 4,2, 6,4-6,5, 7,6 M. D.

IR-spectrum: 1635, 1372, 1257, 1133 cm-1.

Mass spectrum: 298

Preparation 57. Ethyl ester of 3-(2-hydroxy-4-(2-(2-(2- methoxy-ethoxy)ethoxy)ethoxy)phenyl)-3-oxo-propionic acid (formula M-4). Cm. Scheme m

To stir the solution for 1.49 g of the target product of Preparation 56 in 20 ml of diethylmalonate add portions 600 mg 60% dispersion of sodium hydride in mineral oil. The resulting mixture is heated to a temperature of 80oC for two hours, cooled, poured into dilute hydrochloric acid and extracted with dichloromethane. The organic extract is dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by the method of evaporative chromatography on silica gel, elwira 20-30% solution of ethyl acetate in dichloromethane, and gain of 0.91 g of target compound in the form of a yellow oil.

The substance has the following physical characteristics:

TCX: Rf0,44 (3% acetic acid and 30% ethyl acetate in dichloromethane).

Range PMR: 1,3, 3,38, 3,5-4,0, 4,2, 6,4-6,5, 7,6 M. D.

Mass spectrum: 370

Preparation 58. 4-Hydroxy-4-(2-(2-(2-methoxy-ethoxy) ethoxy)ethoxy)coumarin (F. the reflux for two hours and evaporated under reduced pressure. The residue is purified by the method of evaporative chromatography on silica gel, elwira 5-10% solution of acetic acid in ethyl acetate, and receive 634 mg of the target compound in a solid dark yellow color.

The substance has the following physical characteristics:

TCX: Rf0,31 (10% acetic acid in ethyl acetate).

Range PMR: 3,37, 3,5-3,9, 4,1, 5,67, 6,6, 6,7, 7,6 M. D.

Mass spectrum: 324

Preparation 59. 3-[(3-Benzyloxycarbonylamino)cyclopropylmethyl]-4-hydroxy-7-{ 2-[2- (2-methoxy-ethoxy)ethoxy] ethoxy}coumarin (formula M-6). Cm. Scheme M

A mixture of 704 mg of the target product of Preparation 58, 75 mg meta-benzyloxycarbonylglycine formula F-5 and 62 mg of the monohydrate of p-toluenesulfonic acid in 8 ml of dichloromethane is refluxed for 18 hours through a layer approximately 10 ml of molecular sieve 3 . The solution is evaporated under reduced pressure and the residue purified by the method of evaporative chromatography on silica gel, elwira 10-20% of the mixture (10% acetic acid in ethyl acetate) in dichloromethane, and obtain 760 mg of the target compound.

The substance has the following physical characteristics:

TCX: Rf0,33 (2% acetic acid and 20% ethyl acetate in dienyl)cyclopropylmethyl] -4 - hydroxy-7-{2-[2-(2-methoxy-ethoxy)ethoxy]ethoxy}coumarin (formula M-7). Cm. Scheme M

A mixture of 760 mg of the target product of Preparation 59, 800 mg of ammonium formate and 200 mg of 5% palladium on charcoal in 8 ml of methanol is stirred in an argon atmosphere for one hour and filtered through diatomaceous earth. The filtrate is evaporated under reduced pressure and the residue triturated with dichloromethane. The solvent is removed under reduced pressure and receive 591 mg of the target amine.

The substance has the following physical characteristics:

TCX: Rf0,29 (5% methanol in dichloromethane).

Example 151. N-(3-{Cyclopropyl-[7-(2-(2-(2-methoxy-ethoxy)ethoxy)ethoxy) -4-hydroxycoumarin-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide (formula M-8). Cm. Scheme M

To a mixed solution of 70 mg of the target product of Preparation 60 and 24 μl of pyridine in 0.5 ml of dichloromethane added 27 mg of 1-methyl-1H-imidazol-4-sulfochloride. After 18 hours the product was then purified using the evaporative chromatography on silica gel (elute 5-15% solution of methanol in dichloromethane) and obtain 76 mg of the target sulfonamida in the form of an amorphous foam substances pink.

The substance has the following physical characteristics:

TCX: Rfof 0.21 (5% methanol in dichloromethane).

Examples 152-154. Using the above technique, additionally, you receive the following connections.

152) N-(3-{ Cyclopropyl-[7-methoxy-4-hydroxycoumarin-3 - yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide

The substance has the following physical characteristics:

TCX: Rf0,29 (5% methanol in dichloromethane).

Range PMR: 0,18, 0,35, 0,50, 0,63, 1,61, 3,51, 3,7, 3,84, 6,7-6,8, 7,1-7,4, 7,7 M. D.

The mass spectrum of the high-resolution: 481,1301.

153) N-(3-{ Cyclopropyl-[7-(2-(2-(2-methoxy-ethoxy) ethoxy)ethoxy)-4-hydroxycoumarin-3-yl]methyl}phenyl)-8 - chinaincorporated

The substance has the following physical characteristics:

TCX: Rf0,41 (5% methanol in dichloromethane).

Range PMR: -0,03, 0,31, 0,47, 1,30, 3,36, 3,5-3,8, 3,9, 4,2, 6,6-7,6, 7,8, 8,0, 8,2 M. D.

The mass spectrum of the high-resolution: 661,2219.

154) N-(3-{ Cyclopropyl-[7-(2-(2-(2-methoxy-ethoxy) ethoxy)ethoxy)-4-hydroxycoumarin-3-yl]methyl}phenyl)-2 - pyridinesulfonamide

The substance has the following physical characteristics:

TCX: Rf0,31 (5% methanol in dichloromethane).

Range PMR: 0,13, 0,34, 0,49, 0,63, 1,6, 3,36, 3,5-3,9, 4,1, 6,68, 6,8, 7,1-7,4, 7,6-7,8, 8,5 M. D.

The mass spectrum of the high-resolution: 611,2051.

Examples 155-190

On the N-(3-{Cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl) -4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2 - pyridinesulfonamide

156) N-(3-{Cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)- 4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-4 - cyano-2-pyridinesulfonamide

157) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2 - chinaincorporated

158) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl) -2-hydroxybenzenesulfonate

159) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2 - pyrazolylborate

160) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)- 2-ChineseSimplified

161) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl) -7H-purine-6-sulfonamide

162) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)- 1H-imidazole-2-sulfonamide

163) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl) -benzimidazole-2-sulfonamide

164) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)- thiazole-4-sulfonamide

165) N-(3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - the 3-{ Cyclopropyl-[6-(1-(tetrahydropyran-4 - ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-3 - hydroxy-2-pyridinesulfonamide

167) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-pyridinesulfonamide

168) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2 - oxo-2H-Piran-3-yl]methyl}phenyl)-4-cyano-2-pyridinesulfonamide

169) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-chinaincorporated

170) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2 - hydroxybenzenesulfonate

171) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy - 2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-pyrazolylborate

172) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-ChineseSimplified

173) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-7H-purine-6-sulfonamide

174) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-imidazole-2 - sulfonamide

175) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy - 2-oxo-2H-Piran-3-yl]methyl}phenyl)benzimidazole-2-sulfonamide

176) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)thiazol-2-sulfonamide

177) N-(3-{Cyclopropyl-[6-(1-ethylphenyl)-4 - hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-4-etoxycarbonyl - 1H-imidazole-2-sulfonamide

178) N-(3-{Cyclopropyl ropyl-[4-hydroxycoumarin-3-yl] methyl} phenyl)-2-pyridinesulfonamide

180) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl] methyl}phenyl)-4-cyano-2-pyridinesulfonamide

181) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl] methyl} phenyl)-2-chinaincorporated

182) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl]methyl} phenyl)-2-hydroxybenzenesulfonate

183) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl] methyl}phenyl)-2-pyrazolylborate

184) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl] methyl}phenyl)-2-ChineseSimplified

185) N-(3-{Cyclopropyl-[4-hydroxycoumarin-3-yl] methyl}phenyl)-7H-purine-6-sulfonamide

186) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl]methyl}phenyl) -1H-imidazole-2-sulfonamide

187) N-(3-{Cyclopropyl-[4-hydroxycoumarin-3-yl]methyl} phenyl)benzimidazole-2-sulfonamide

188) N-(3-{Cyclopropyl-[4-hydroxycoumarin-3-yl] methyl}phenyl)thiazolecarboxamide

189) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl]methyl} phenyl)-4-etoxycarbonyl-1H-imidazole-2-sulfonamide

190) N-(3-{ Cyclopropyl-[4-hydroxycoumarin-3-yl]methyl} phenyl)-3-hydroxy-2-pyridinesulfonamide

Preparation 61. Cyclopropyl-(3-nitrophenyl)methanon (formula N-2). Cm. Scheme n

In a round bottom flask with a capacity of 1 l, equipped with a jacket, stirrer and dropping funnel, is placed in a nitrogen atmosphere 580 ml "fuming" nitric acid and cooled to minus 40oiNOS 35oC. Stirred for 3 hours, monitoring the progress of reaction by thin layer chromatography. The reaction mixture is poured into 3 kg of a mixture of ice with ice. Extracted with ethyl acetate (3 x 500 ml). The organic extracts are combined twice washed with 1.5 liters of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated, getting 138 g of the product. It is dissolved in 270 ml of methanol, cooled to minus 20oC for 18 hours, filtered, washed on the filter with cold methanol. The product is dried under reduced pressure for 72 hours, highlighting 63,86, Analysis by gas chromatography (column length of 15 m DB-1, T0= 100oC, 10oC/min, retention time - 6,0 min) shows that the purity of the product is > 98%.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 8,86, 8,43, 8,34, 7,70, 2,72, 1,33, 1,17 M. D.

IR spectrum (liquid paraffin): 2954, 2925, 1664, 1614, 1529, 1442, 1386, 1352, 1225, 1082, 1047, 852, 720, 689 cm-1.

Elemental analysis, found: C, 62,89; H, to 4.73; N, 7,32.

Mass spectrum (E1): m/z 191, 150, 104, 69.

Preparation 62. Cyclopropyl-(3-AMINOPHENYL)methanon (formula N-3). Cm. Scheme n

In the apparatus Parra zag is l) and heated in order to accelerate the dissolution, and then cooled to 9oC in the bath with ice. Hydronaut for 50 minutes, keeping the temperature below 35oC; the reaction course is monitored by means of thin layer chromatography. The reaction mixture is filtered and evaporated under reduced pressure, obtaining 70 g of the product.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,99, 7,47-7,19, 6,84, 3,84, 2,60, 1,23-1,15, 1,03-0,96 M. D.

Range13C-NMR (deuterochloroform): 200,9, 146,8, 139,1, 129,4, 119,3, 118,4, 113,9, 17,2, 11,6 M. D.

Preparation 63. Cyclopropyl-(3-iminocarbonothioyl)methanon (formula N-4). Cm. Scheme n

In a round bottom flask with a capacity of 3 l equipped with a mechanical stirrer and addition funnel, argon atmosphere will prevent cyclopropyl-(3-AMINOPHENYL)methanon Preparation 62 (70,0), di-ISO-propylethylene (90,2 ml) and methylene chloride (1.3 l). The reaction mixture was cooled to 0oC. Dilute benzylchloride (67,5 ml) methylene chloride (186 ml) and within an hour, add to the mixture in the flask, maintaining the temperature at 0-5oC. is Formed abundant precipitate. Give the mixture heated with stirring while controlling the course of the reaction using thin layer chromatography. Syliva. The phases are separated, the organic layer is dried over magnesium sulfate, filtered and evaporated to dryness. Suspended solids in the ratio of 3 ml/g in hexane, filtered and dried in vacuum, obtaining 125 g of product.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 8,01, 7,76-7,69, 7,43-7,33, 7,18, 5,21, 2,64, 1,25-1,20, 1,03-0,97 M. D.

Range13C-NMR (deuterochloroform): 200,6, 153,4, 138,7, 138,5, 135,9, 129,3, 128,6, 128,4, 123,1, 122,8, 118,1, 67,2, 17,3, 12,0 M. D.

Preparation 64. Cyclopropyl-(3-iminocarbonothioyl) methanol (formula N-5). Cm. Scheme n

In a round bottom flask with a capacity of 2 l, equipped with a top with a mechanical stirrer, under nitrogen atmosphere was placed cyclopropyl-(3-iminocarbonothioyl)methanon Preparation 63 (25 g) in tetrahydrofuran (450 ml) and ethanol (90 ml). The reaction mixture is cooled to 0-5oC for 30 minutes added in three equal portions granulated sodium borohydride (12.4 g). Allow the mixture to warm up to the temperature of the 23oC and stirred for 20 hours while monitoring the reaction by thin layer chromatography. Again cool the mixture to 0-5oC and slowly decompose, adding 90 ml of 1N hydrochloric acid solution and supporting those who ml). The phases are separated and the organic phase is washed with a saturated aqueous solution of sodium chloride (1 l). Dried over magnesium sulfate, filtered and evaporated, getting 23,7,

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,41-7,35, 7,33, 7,17 7,10, 5,17, 3,93, 2,36, 1,16-1,12, 0,60-0,32 M. D.

Range13C-NMR (deuterochloroform): 153,5, 145,0, 137,9, 136,1, 129,0, 128,6, 128,3, 121,2, 117,9, 116,5, 67,9, 67,0, 19,1, 3,6, 2,8 M. D.

Preparation 65. Fenilmetilovy ether [3-[cyclopropyl (5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]carbamino acid (formula N-6). Cm. Scheme n

In a three-neck round bottom flask with a capacity of 12 liters, equipped with a Soxhlet extraction apparatus, filled with 3 a molecular sieves (180 g), and a tube for supplying nitrogen, placed beta-2-hydroxy-lactone, cyclooctene-1-acrylic acid (to 59.6 g), p-toluensulfonate (14.9 g) and methylene chloride (7.2 l). Put the target product of Preparation 64 (90.0 g) and the reaction mixture is refluxed for one hour. The reaction mixture cooled down to 20oC and washed with a mixture of 1:1 saturated solutions of sodium chloride and sodium bicarbonate (3 l), water (3 l), a solution of sodium chloride (3 l). The washing water is additionally extra and evaporated to a volume of about 1.5 l The reaction mixture is cooled to minus 20oC for 72 hours, filtered and dried under reduced pressure, getting to 103.5 g of the product. The crude product is suspended in the ratio of 12.5 ml/g in hexane, filtered and dried, obtaining 102,4 g of target compound. The additional amount of target compound (10,9 g) are obtained by concentrating the mother liquor from recrystallization and precrystallization the residue from ethyl acetate.

The substance has the following physical characteristics:

Melting point 113-115oC (decomposition).

Range PMR (deuterochloroform): 7,48, 7,38-7,26, 7,17, 6,70, 6,29, 5,20, 3,95, 2,64-2,60, 2,37-2,43, 1,76-1,72, 1,61-1,42, 0,88, 0,73-0,72, 0,63-0,55, 0,29-0,26 M. D.

Range13C-NMR (deuterochloroform): 165,6, 164,0, 161,3, 142,2, 138,5, 129,9, 128,5, 128,3, 128,2, 122,9, 118,0, 117,9, 117,6, 110,7, 106,0, 67,0, 43,7, 30,7, 29,1, 28,8, 26,2, 25,8, 22,1, 13,0, 4,9, 3,8 M. D.

IR spectrum (liquid paraffin): 3304, 2995, 2953, 2923, 2855, 1734, 1698, 1665, 1666, 1633, 1610, 1595, 1553, 1491, 1463, 1455, 1445, 1406, 1377, 1313, 1222, 1175, 1085, 1068, 740, 696 cm-1.

Mass spectrum (E1):m/z 473, 445, 382, 338, 91.

The mass spectrum of high resolution, found: 473,2202

Preparation 66. 3-[(3-AMINOPHENYL)cyclopropylmethyl] -5,6,7,8,9, 10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he (formula N-7). Cm. Scheme n

In Proc. of escaut 10% palladium on coal (1.0 g) and the mixture of the desired product of the formula N-6, obtained in Preparation 65 (1,95 g) in cyclohexane (50 ml) and the mixture refluxed for 4 hours. The mixture was then filtered over celite, washed with methylene chloride and evaporated, receiving 1,25 g of target compound in a solid white color with so pl. 75-79oC.

The substance has the following physical characteristics:

IR spectrum (liquid paraffin): 2995, 2951, 2921, 2868, 1660, 1619, 1605, 1590, 1551, 1491, 1460, 1447, 1428, 1404, 1247, 1226, 1202, 1191, 1172, 1126 cm-1.

Mass spectrum (E1): m/z 339, 310, 213, 187, 159.

Range PMR (deuterochloroform): 7,16, 6,96, 6,84, 6,63, 5,67, 3,87, 2,61, 2,48-2,37, 1,98, 1,75, 1,63-1,26, 0,74-0,65, 0,61-0,53, 0,28-0,22 M. D.

Range13C-NMR (deuterochloroform): 164,2, 161,1, 142,8, 130,2, 117,7, 117,6, 114,7, 114,6, 114,5, 110,9, 106,2, 43,5, 30,6, 29,1, 28,8, 26,2, 25,8, 22,0, 12,8, 4,7, 3,7 M. D.

The mass spectrum of high resolution, found: 339,1845.

Preparation 67. 4-Cyano-N-[3-[cyclopropyl(5,6,7,8,9,10 - hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl) methyl] phenyl] benzosulfimide (formula O-3, where R61denotes 4-cyanophenyl) Cm. Scheme O.

The target solution of the product of Preparation 66 (660 mg), pyridine (320 μl) and 4-cyanobenzaldehyde (440 mg) in dichloromethane (40 ml) was stirred at room temperature for 18 hours. Cospolich target compound (641 mg) as amorphous solid white. This amorphous substance, in turn, is recrystallized from a mixture of acetone/hexane and receive 499 mg of the product so pl. 183-183,5oC.

The substance has the following physical characteristics:

Elemental analysis, found: C, 66,76; H, of 5.68; N, 5,38; S, 6,30;

Mass spectrum (E1): m/z 504, 463, 338, 309, 233, 220, 207, 195, 186, 153, 144, 130, 117, 102

The mass spectrum of the high-resolution: 504,1710

TCX (silica gel GF): Rf0,4 (50% ethyl acetate in hexane).

Example 191. Disodium-4-cyano-N-[3-[cyclopropyl (5,6,7,8,9,10 - hexahydro-4-hydroxy-2-oxo-2H - cycloocta[b] Piran-3-yl)methyl] phenyl]benzosulfimide

To of 12.6 g of the target product of Preparation 67 add 500 ml of methanol and, with vigorous stirring, 50 ml of 1N aqueous sodium hydroxide solution. Stirred the reaction mixture at room temperature for one hour and the resulting yellow solution evaporated to dryness at a temperature of 35oC, and the resulting amorphous residue is dissolved in absolute ethanol and again evaporated to dryness. The yellow residue is dried in high vacuum at room temperature for 18 hours and get 14 g of amorphous solid yellow color.

The substance has the following physical characteristics:

TCX (silica gel GF): Rfthe Nola

Loss of water at room temperature: 4,99%

The solid residue found: 7,83% calculated: 7,50% (adjusted 6,16% of water and 4.2% ethanol).

Preparation 68. N-Methyl-3-[(3-AMINOPHENYL)cyclopropylmethyl]- 5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he

To 678 mg of the target product of Preparation 66 add 100 ml of absolute ethanol and 330 mg of 10% palladium on coal. Add 183 μl of a 35% aqueous solution of formaldehyde in water and shake the mixture in a Parr apparatus under a pressure of 50 pounds-force/square inch (344,7 kPa) of hydrogen for two hours at room temperature. The reaction mixture is filtered through celite and washed on the filter with ethanol. The resulting solution was dark yellow evaporated to dryness. The obtained residue chromatographic, elwira 10% solution of ethyl acetate in methylene chloride and obtain 110 mg of the target product. It is used without further purification in the synthesis of the following sulfonamides.

The substance has the following physical characteristics:

TCX (silica gel GF): Rf0,5 (10% ethyl acetate in methylene chloride).

Range PMR (deuterochloroform): 7,19, 6,90, 6,71, 6,54-6,52, 3,90, 2,80, 2,63-2,59, 2,43-2,39, 1,75-1,26, 0,70-0,53, 0,28-0,22 M. D.

Example 192. 4-Cyano-N-methyl-N-[3-[colloege product of Preparation 68 (35 mg), pyridine (16 μl) and 4-cyanobenzaldehyde (20,1 mg) in dichloromethane (2 ml) was stirred at room temperature for 18 hours. The mixture chromatographic on silica gel, elwira 10% solution of ethyl acetate in methylene chloride, and obtain 27 mg of the target compound as an amorphous solid white.

The substance has the following physical characteristics:

Mass spectrum (E1): 518, 490, 352, 233, 207, 172, 158, 143, 129, 115, 102, 81, 54, 43

TCX (silica gel GF): Rf0,7 (10% ethyl acetate in methylene chloride).

Range PMR (deuterochloroform): 7,75-7,72, 7,63-7,60, 7,38-7,19, 6,97-6,94, 6,62, 3,86, 3,19, 2,66-2,62, 2,54-2,50, 1,76-1,20, 0,70-0,59, 0,47-0,42, 0,24-0,19 M. D.

Example 193. 4-Fluoro-N-methyl-N-[3-[cyclopropyl (5,6,7,8,9, 10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl) methyl] phenyl]benzosulfimide

The target solution of the product of Preparation 68 (20 mg), pyridine (11 μl) and 4-forbindelsesteknologi (10,7 mg) in dichloromethane (2 ml) was stirred at room temperature for 18 hours. The mixture chromatographic on silica gel, elwira 10% solution of ethyl acetate in methylene chloride, and obtain 19 mg of the target compound as an amorphous solid white.

The substance has the following physical characteri

TCX (silica gel GF): Rf0,7 (10% ethyl acetate in methylene chloride).

Range PMR (deuterochloroform): 7,53-7,48, 7,33-7,23, 7,13-7,07, 6,99-6,97, 6,38, 3,93, 3,16, 2,63-2,61, 2,49-2,46, 1,76-1,25, 0,78-0,61, 0,51-0,45, 0,30-0,17 M. D.

Example 194. N-Methyl-N-[3-[cyclopropyl(5,6,7,8,9,10 - hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl) methyl]phenyl]benzosulfimide

The target solution of the product of Preparation 68 (range 33.4 mg), pyridine (16 μl) and benzosulfimide (16.6 mg) in dichloromethane (2 ml) was stirred at room temperature for 18 hours. The mixture chromatographic on silica gel, elwira 10% solution of ethyl acetate in methylene chloride, and receive 20 mg of target compound in the form of an amorphous solid white.

The substance has the following physical characteristics:

TCX (silica gel GF): Rf0,7 (10% ethyl acetate in methylene chloride).

Range PMR (deuterochloroform): 7,59-7,41, 7,33-7,23, 6,98-6,96, 6,44, 3,90, 3,16, 2,64-2,60, 2,50-2,48, 1,75- 1,20, 0,67-0,40, 0,23-0,20 M. D.

Example 195. N-Methyl-N-[3-[cyclopropyl (5,6,7,8,9,10 - hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl) methyl] phenyl]-1H-imidazol-1-methylsulfonate

The target solution of the product of Preparation 68 (range 33.4 mg), pyridine (16 μl) and N-Mei-3-sulfochloride (16 mg) in dichloromethane (2 ml) the solution of ethyl acetate in methylene chloride, and obtain 28 mg of the target compound as an amorphous solid white.

The substance has the following physical characteristics:

TCX (silica gel GF): Rfof 0.5 (50% ethyl acetate in methylene chloride).

Range PMR (deuterochloroform): 7,43, 7,33, 7,27-7,15, 3,84-3,81, 3,69, 3,35, 2,63-2,59, 2,50-2,46, 1,75-1,26, 0,68, 0,55, 0,47-0,42, 0,24-0,20 M. D.

Using methods similar to the above, receive the following compounds of the present invention:

196) 5-Cyano-N-[3-[cyclopropyl (5,6,7,8,9,10-hexahydro - 4-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]- 2-pyridinesulfonamide

197) N-[3-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-2 - chinaincorporated

198) N-[3-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-2 - imidazolylidene

199) N- [3-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-2 - pyrimidinamine

200) N-[3-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-2 - benzimidazolecarbamic

201) N-[3-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl] phenyl]-2-ChineseSimplified

202) N-[3-[Cyclopropyl is[3-[cyclopropyl (5,6,7,8,9,10 - hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl]methyl]phenyl] -N-methyl-2-pyridinesulfonamide

204) N-[3-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl]methyl]phenyl]-N-methyl - 2-chinaincorporated

205) N-[3-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-N-methyl-2-imidazolylidene

206) N-[3-[Cyclopropyl(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-N-methyl - 2-pyrimidinamine

207) N-[3-[Cyclopropyl(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-N-methyl-2-benzimidazolecarbamic

208) N-[3-[Cyclopropyl(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-N - methyl-2-ChineseSimplified

209) N-[3-[Cyclopropyl(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-N - methyl-6-peninsulaand

210) N-[3-[Cyclopropyl(5,6,7,8,9,10-hexahydro - 4-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-N - methyl-4-thiazolecarboxamide

211) N-[3-[Cyclopropyl(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl] phenyl]-N-methyl-2-pyridinesulfonamide

212) 5-Cyano-N-[6-(1'-benzylparaben)-4-hydroxy-3- (1'-cyclopropylmethyl)-2-pyrone]-N-methyl-2-pyridinesulfonamide

213) N-[6-(1'-Benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl) -2-pyrone]-N-methyl-2-chinaincorporated

214) N-[6-(1 is propyl)-4-hydroxy-3-(1'-cyclopropylmethyl) -2-pyrone]-N-methyl-2-pyrimidinamine

216) N-[6-(1'-Benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl) -2-pyrone]-N-methyl-2-benzimidazolecarbamic

217) N-[6-(1'-Benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl) -2-pyrone]-N-methyl-2-ChineseSimplified

218) N-[6-(1'-Benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl) -2-pyrone]-N-methyl-6-peninsulaand

219) N-[6-(1'-Benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl) -2-pyrone]-N-methyl-4-thiazolecarboxamide

220) N-[6-(1'-Benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl) -2-pyrone]-N-methyl-2-pyridinesulfonamide

221) 5-Cyano-N-[3-(1'-cyclopropylmethyl)-4 - hydroxycoumarin]-N-methyl-2-pyridinesulfonamide

222) N-[3-(1'-Cyclopropylmethyl)-4-hydroxycoumarin] -N-methyl-2-chinaincorporated

223) N-[3-(1'-Cyclopropylmethyl)-4-hydroxycoumarin]-N-methyl-2-imidazolylidene

224) N-[3-(1'-Cyclopropylmethyl)-4 - hydroxycoumarin]-N-methyl-2-pyrimidinamine

225) N-[3-(1'-Cyclopropylmethyl)-4-hydroxycoumarin]-N-methyl - 2-benzimidazolecarbamic

226) N-[3-(1'-Cyclopropylmethyl)-4-hydroxycoumarin] -N-methyl-2 - ChineseSimplified

227) N-[3-(1'-Cyclopropylmethyl)-4-hydroxycoumarin]- N-methyl-6-peninsulaand

228) N-[3-(1'-Cyclopropylmethyl)-4-hydroxycoumarin]-N-methyl-4 - N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel - 5,6-dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-2 - pyridinesulfonamide

231) N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-2 - chinaincorporated

232) N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-2 - imidazolylidene

233) N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-2-pyrimidinamine

234) N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-2-benzimidazolecarbamic

235) N-[3-[1-[4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-2-ChineseSimplified

236) N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-6-peninsulaand

237) N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6-dihydro - 2H-Piran-3-yl)propyl]phenyl]-N-methyl-4-thiazolecarboxamide

238) N-[3-[1-(4-Hydroxy-2-oxo-6,6-definatel-5,6 - dihydro-2H-Piran-3-yl)propyl]phenyl]-N-methyl-2-pyridinesulfonamide

Example 239. N-[4-[Cyclopropyl(5,6,7,8,9,10 - hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl]-2-pyridinesulfonamide (formula P-2, R represents 2-pyridyl). Cm. The schema of R.

3-[(3-AMINOPHENYL)cyclopropylmethyl] -5,6,7,8,9,10 - hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he of Preparation 66 (100 mg) is dissolved in methylene chloride (3 ml) and add pyridine (70 μl). two hours. Add chloroform (25 ml), washed with 1N (20 ml) solution of hydrochloric acid and dried over magnesium sulfate. The solvent is distilled, collecting the resin pink color, which is cleaned by the method of evaporating column chromatography on silica gel, elwira 60% solution of ethyl acetate in hexane, and obtain the target compound in the form of solid white (80 mg).

The substance has the following physical characteristics:

Mass spectrum: m/z 480, 339, 338, 186, 145, 144, 132, 130, 78, 55

Example 240. N-[4-[Cyclopropyl (5,6,7,8,9,10 - hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl) methyl]phenyl]-4-pyridinesulfonamide (formula P-2, R represents 4-pyridyl). Cm. The schema of R.

The target connection receive according to the method described in Example 239, in the form of a solid white color.

The substance has the following physical characteristics:

Mass spectrum: m/z 480, 338, 207, 186, 145, 144, 117, 79, 78, 55.

Example 241. N-[4-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl]-5 - cyanopyridine-2-yl-sulfonamide (formula R-2: R is 5-cyanopyridine-2-yl). Cm. The schema of R.

The target connection receive according to the method described in Example 239.

Example 242. N-[4-[Cyclopropyl(5,6, which means 2-pyrazinyl) Cm. The schema of R.

The target connection receive according to the method described in Example 239.

Example 243. N-[4-[Cyclopropyl(5, 6,7,8,9,10-hexahydro-

4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] -2 - pyrimidinecarboxylic (formula R-2: R denotes a 2-pyrimidinyl). Cm. The schema of R.

The target connection receive according to the method described in Example 239.

Example 244. N-[4-[Cyclopropyl (5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] - -4,6-dimethylpyrimidin-2-yl-sulfonamide (formula R-2: R denotes 4,6-dimethylpyrimidin-2-yl) Cm. The schema of R.

The target connection receive according to the method described in Example 239.

Example 245. N-[4-[Cyclopropyl(5,6,7,8,9,10-hexahydro-4 - hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-4 - methylpyrimidin-3-yl-sulfonamide (formula R-2: R denotes 4-methylpyrimidin-2-yl) Cm. The schema of R.

The target connection receive according to the method described in Example 239.

Preparation 69. 6,6-Bis-(2-cyclopropylethyl)lepidopteran-2,4 - dione (formula Q-2) Cm. Scheme q

To a suspension of 150 mg of sodium hydride (60% dispersion in mineral oil) in 4 ml dry tetrahydrofuran in an argon atmosphere at a temperature of 0oC added dropwise to 0.38 ml metrov the minutes add a solution of 0.48 g of compound of formula Q-1 (produced as described in Preparation 79 (formula S-4, see Diagram S) in 3 ml of tetrahydrofuran. The reaction mixture is stirred for one hour and poured into a mixture of ethyl acetate and diluted hydrochloric acid. The organic layer is separated, the aqueous phase is additionally extracted twice with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is diluted with 5 ml of methanol and the resulting solution was added 12 ml of water, and then 3.0 ml of 1 M aqueous sodium hydroxide solution. Intensively stirred for two hours and the methanol is distilled off under reduced pressure. The aqueous phase is washed once with diethyl ether and the ether layer decanted. The aqueous phase is cooled to 0oC and acidified with diluted hydrochloric acid. The precipitate is extracted with four portions of dichloromethane. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in a mixture of diethyl ether - hexane and the solution is cooled, receiving at 0.42 g of the desired product in the form of a solid yellow color.

The substance has the following physical characteristics:

Range PMR: 0,0, 0,4, 0,6, 1,2, 1,7, 2,6, 3,4 M. D.

Preparation 70. 6,6-Bis-(2-zemachinima solution of 0.41 g of the target product of Preparation 69 (formula Q-2) and 0.25 g of 3-nitrobenzaldehyde in 5 ml of dry tetrahydrofuran, add a solution of 0.44 g of trichloride aluminum 4.5 ml of tetrahydrofuran. After two hours the reaction mixture is added 1.0 g of decahydrate sodium carbonate, stirred for 10 minutes, diluted with diethyl ether and finally, add magnesium sulfate. The resulting mixture is filtered through celite and washed three times in diethyl ether filtrate. The filtrate are combined and evaporated under reduced pressure. To the obtained residue, add 103 mg of the bromide complex of copper (1) - dimethyl sulphide and 5 ml dry tetrahydrofuran in an argon atmosphere. To the reaction mixture dropwise over 1.5 hours, add 2.5 ml of triethylaluminum (1.0 M solution in hexane). To the reaction mixture carefully add ice and poured into a mixture of diethyl ether and dilute hydrochloric acid. The organic layer is separated, the aqueous phase is additionally three times extragere diethyl ether. The organic extracts are combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by a method of evaporating column chromatography (elute with a mixture containing 20-40% ethyl acetate in hexane), and gain of 0.44 g of the target product as a foamy substance is dark brown.

The substance has the following physical characteristics:

To a solution of 0.44 g of the target product of Preparation 70 (formula Q-3) in 6 ml of methanol is added 0.65 g of ammonium formate and 50 mg of 10% palladium on coal. The resulting suspension black is stirred in an argon atmosphere for three hours and filtered through celite, washing on the filter with methanol. The filtrates are combined and the solvent evaporated under reduced pressure. The residue is triturated with four portions of dichloromethane. The obtained dichloromethane extracts are combined evaporated under reduced pressure and gain of 0.37 g of target compound in the form of a foamy substance of white color.

The substance has the following physical characteristics:

TCX: Rf0,08 (50% diethyl ether in hexane).

Example 246. N-[3-[1-[6,6-Bis-(2-cyclopropylethyl)-5,6 - dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] propyl]phenyl]-1 - methyl-1H-imidazole-4-sulfonamide (formula Q-5, R1denotes 1-Mei-4-yl). Cm. Scheme q

Into the flask containing 57 mg of the target product of Preparation 71 (formula Q-4) and 24 μl of pyridine in 1.0 ml dichloromethane added 27 mg of 1-methyl-1H-imidazol-4-sulfochloride. After 6 hours the reaction mixture is evaporated under reduced pressure. The pyridine is removed doctorno azeotrope of perigee from 2% to 6% methanol in dichloromethane), and obtain 51 mg of the desired product in the form of a foamy substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,0, 0,4, 0,6, 0,9, 1,1-1,4, 1,7-2,2, 2,5, 3,7, 3,95, 6,9, 7,1, 7,4, 7,5 M. D.

The mass spectrum of high resolution (FAB): 528,2537

Example 247. N-[3-(1-[6,6-Bis-(2-cyclopropylethyl)-5,6 - dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl]propyl)phenyl]-5 - cyano-2-pyridinesulfonamide (formula Q-5, R1denotes 5-cyano-2-pyridyl). Cm. Scheme q

In accordance with the General method of sulfonylurea described in Example 246, enter into interaction 57 mg of the amine of Preparation 71 (formula Q-4) with 30 mg of 5-cyano-2-pyridin-2-sulfochloride. Purify using the evaporative column chromatography on silica gel (elute with a mixture containing from 1 to 3% methanol in dichloromethane) and obtain 62 mg of the desired product in the form of a foamy substance is dark brown.

The substance has the following physical characteristics:

Range PMR: 0,0, 0,4, 0,6, 0,9, 1,1-1,4, 1,6-2,2, 2,5, 3,95, 6,9-7,2, 8,0, 8,2, 9,0 M. D.

The mass spectrum of high resolution (FAB): 550,2370

Preparation 72. 3-Aminopropiophenone (formula R-2). Cm. The schema of R.

To a solution of 3-nitropropiophenone (formula R-1) (1,79 g) in diethyl ether is added in to eshivot within 6 hours. The reaction mixture is filtered through celite and washed on the filter with additional diethyl ether. The filtrates are combined and evaporated under reduced pressure, getting 1,49 g of the desired product in the form of a fusible substance pale yellow color.

The substance has the following physical characteristics:

Range PMR: 1,2, 3,0, 6,9, 7,2-7,4 M. D.

TCX: Rf0,45 (33% ethyl acetate in hexane).

Preparation 73. 1-[3-(Dibenzylamino)phenyl] propane-1-he (formula R-3). Cm. The schema of R.

To a solution of the target product of Preparation 72 of the formula R-2 (1.5 g) in dichloromethane (50 ml) is added di-ISO-propylethylene (6,0 ml), and then benzyl bromide (3.6 ml). Stirred for 6 hours and the reaction mixture is left to boil for the night. Cooled to room temperature, diluted with diethyl ether (50 ml) and successively washed with diluted aqueous solution of potassium bisulfate, water, saturated aqueous sodium bicarbonate and saturated salt solution. The organic layer is dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by a method of evaporating column chromatography on silica gel (elute with a mixture containing from 5% to 20% ethyl acetate in hexane) is t the following physical characteristics:

Range PMR: 1,1, 2,9, 4,7, 6,9, 7,2-7,4 M. D.

Elemental analysis, found: C, 83,88; H, 7.03 is; N, 4,20.

Mass spectrum (El): 329

Preparation 74. 6-[3-(Dibenzylamino)phenyl]dihydropyran-2,4-he (formula R-4). Cm. The schema of R.

In accordance with the General method of forming dihydropyrrolo rings described in Preparation 69, enter into interaction 1,96 g of compound of formula R-3 Preparation 73 with gianina methyl ester of acetoacetic acid and cyclist education 0,76 g of target compound.

The substance has the following physical characteristics:

Range PMR: 0,8, 1,9, 2,6-2,9, 3,1-3,2, 4,7, 6,5-6,7, 7,1-7,4 M. D.

Mass spectrum (E1): 413

Drug 75. 6-[3-(Dibenzylamino)phenyl] -5,6-dihydro-6 - ethyl-4-hydroxy-3-[1-(3-nitrophenyl)propyl]Piran-2-he (formula R-5). Cm. The schema of R.

In accordance with the General method described for Preparation 70, conduct catalyzed trichloride aluminum condensation of 3-nitrobenzaldehyde with the compound of the formula R-4 Preparation 74 (727 mg), followed catalyzed stranded paired connection of triethylaluminum and receive 800 mg of target compound.

The substance has the following physical characteristics:

Range PMR: 0,6, 1,6-2,1, 2,8, 3,4, 3,8, 4,4, 6,4-6,6, 6,8-7,4, 7,7-8,0 M. D.

In accordance with the General method described for the Preparation 71, carry out the catalytic hydrogenation of the compounds of formula R-5 Drug 75 (114 mg) using ammonium formate and palladium on coal and obtain 61 mg of the target compound. Alternatively, the compound of the formula R-5 Drug 75 (114 mg) restore with hydrogen in the presence of palladium on coal and obtain 72 mg of the target compound.

The substance has the following physical characteristics:

Range PMR: 0,6-0,9, 1,8-2,1, 3,0, 3,8, 6,4-6,6, 6,95, 7,1 M. D.

TCX: Rfof 0.40 (10% methanol in dichloromethane).

Example 248. N-(3-[1-[6-Ethyl-5,6-dihydro-4-hydroxy-6- [3([(1-methyl-1H-imidazol-4-yl)sulfonyl] amino)phenyl] -2 - 2H-Piran-3-yl]propyl]phenyl)-1-methyl-1H-imidazole-4-sulfonamide (formula R-7: R1denotes 1-Mei-4-sulfonyl). Cm. The schema of R.

In accordance with the General method of sulfonylurea described in Example 246, is injected into the interaction of the compound of the formula R-6 of Preparation 76 (61 mg) with 1-methyl-1H-imidazol-4 - sulfochloride and obtain 59 mg of the target compound.

The substance has the following physical characteristics:

Range PMR: 0,3-0,7, 1,6 -2,0, 3,0, 3,4-3,7, 6,7-7,5 M. D.

The mass spectrum of high resolution the DRO-4-hydroxy-2-oxo-2H-Piran-3-yl) propyl] phenyl)-2-pyridinesulfonamide (formula R-7: R is 5-cyano-2-pyridyl). Cm. The schema of R.

In accordance with the General method of sulfonylurea described in Example 246, is injected into the interaction of the compound of the formula R-6 of Preparation 76 (66 mg) with 5-cyano-2-pyridinesulfonamide and receive 40 mg of target compound.

The substance has the following physical characteristics:

Range PMR: 0,3-0,9, 1,3, 1,6-2,0, 3,0, 3,7, 6,6-7,2, 7,9-8,2, 8,8-9,0 M. D.

The mass spectrum of high resolution (FAB): 699,1679.

Preparation 77. Amide N-methoxy-N-methyl-4-pentenol acid (formula S-2). Cm. The schema S.

To a suspension of 4-pentenol acid (formula S-1) (2.00 g) and hydrochloride of N, O-dimethylhydroxylamine (2.15 g) in dichloromethane (50 ml) at a temperature of 0oC add di-ISO-propyl-ethylamine (11.5 ml), and then bis(2-oxo-3-oxazolidinyl)phosphorochloridite (the ceiling of 5.60 g). Leave the mix overnight and then the reaction mixture is evaporated under reduced pressure. The residue is poured into a mixture of dilute solution of potassium bisulfate and diethyl ether. The organic layer is separated and the aqueous phase is additionally extracted twice with diethyl ether. The organic extracts are combined, washed with saturated salt solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by a method espiritana) and obtain 2.58 g of the desired product in the form of oil is dark brown.

The substance has the following physical characteristics:

Range PMR: 2,3-2,6, 3,20, 3,70, 4,9-5,1, 5,75-5,95 M. D.

TCX: Rf0,17 (25% diethyl ether in hexane).

Preparation 78. Nona-1,8-Dien-5-he (formula S-3). Cm. The schema S.

In drained an open flame flask containing a solution of the target product of Preparation 77 (formula S-2) (1.45 g) in dry tetrahydrofuran (10 ml) in an argon atmosphere at 0oC put 3-butenyl-1-minibrain (20 ml, 1 M solution in tetrahydrofuran; the receipt of this Grignard reagent of metal magnesium and 4-bromo-1-butene is described in J. Org. Chem., (1978) 43: 4247). Is stirred for one hour at a temperature of 0oC and allow the reaction mixture to warm to room temperature. The reaction mixture was poured into a mixture of dilute solution of potassium bisulfate and diethyl ether. The organic layer is separated and the aqueous phase is additionally extracted three times with diethyl ether. The organic extracts are combined, washed with saturated salt solution, dried over sodium sulfate and carefully evaporated under reduced pressure. The liquid residue is purified by distillation and get to 1.32 g of target compound in the form of oil is dark brown.

The substance has sleduyushiye in hexane).

Preparation 79. 1,5-Dicyclopropyl-3-one (formula S-4). Cm. The schema S.

In drained an open flame flask, equipped with reflux condenser containing metallic zinc (8.0 g) and chloride metal (1) (1.25 g) in an argon atmosphere add a solution of the target product of Preparation 78 (formula S-3) (1,32 g) in dry diethyl ether (10 ml). In the resulting suspension is injected diiodomethane (5.0 ml), the reaction flask is placed in an ultrasonic bath (Branson 2200) with a temperature of 40oC and exposed to ultrasound. After two hours heating stop and leave under ultrasound at night. The reaction mixture was diluted with diethyl ether (50 ml), cooled to 0oC and add an excess of an aqueous solution of ammonium chloride. Vigorously stirred for 0.25 hour, the mixture is filtered and the layers separated. The aqueous phase is additionally extracted twice with diethyl ether. The organic extracts are combined and sequentially washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and saturated salt solution, dried over magnesium sulfate and carefully evaporated under reduced pressure. The resulting residue is purified by a method of evaporating column chromatography on silicide oil.

The substance has the following physical characteristics:

Range PMR: 0,0, 0,4, 0,65, 1,45, 2,50 M. D.

TCX: Rfof 0.44 (10% diethyl ether in hexane).

Preparation 80. 3-[2,2-Dimethyl-1-(3-nitrophenyl)propyl] - 5,6-dihydro-4-hydroxy-6-phenethyl-6-propelers-2-he (formula T-3). Cm. Scheme T.

In drained an open flame flask containing the suspension 977 mg of activated zinc metal in 1.0 ml of dry tetrahydrofuran in an argon atmosphere to add 40 μl of 1,2-dibromethane. The reaction mixture is placed in an ultrasonic bath (Branson 2200) with a temperature of 45oC and under stirring exposed to ultrasound. After 10 minutes, add 0.25 ml of chlorotrimethylsilane (1.0 M solution in tetrahydrofuran). After 10 minutes the mixture is diluted with 4 ml of tetrahydrofuran and added dropwise 1,50 ml of 2-iodine-2-methylpropane. The mixture is stirred when exposed to ultrasound at a temperature of 45oC for three hours and cooled to room temperature without stirring. In a separate flask on an oil bath temperature of 110oC is heated in a vacuum 954 mg of anhydrous lithium chloride. Flask with lithium chloride, cooled to room temperature, rinsed with argon and placed 1.01 g of copper cyanide (1), and then 10 ml of t is 0oC and through the cannula add to strangenesses mixture obtained as described previously, in the first flask. The reaction mixture is heated with minus 30oC and 0oC, stirred for 10 minutes and then cooled to a temperature of minus 78oC. Receipt of this ORGANOMETALLIC reagent is carried out in accordance with methods (Org. Syn., (1991) 70: 195-203), described for the synthesis of related compounds.

In a separate flask to mix the solution of 1.56 g of 6-phenethyl-6-propertyhelper-2,4-dione of the formula T-2 (obtained from the compounds of formula T-1 as described above for the Preparation 17) and 915 mg of 3-nitrobenzaldehyde in 22 ml of dry tetrahydrofuran, add a solution of 1.60 g of trichloride aluminum in 14 ml of tetrahydrofuran. Stirred for two hours and added 3.6 g of decahydrate sodium carbonate, stirred for 5 minutes, diluted with diethyl ether and finally, add magnesium sulfate. The resulting mixture is filtered through celite, washing on the filter with diethyl ether. The filtrates are combined and evaporated under reduced pressure. The resulting residue is dissolved in a stream of argon in 9 ml of dry tetrahydrofuran and using the cannula is added to a chilled (minus 78oC) the solution of ORGANOMETALLIC reagent, recip is authorized temperature for 0.5 hour, poured into cold dilute solution of ammonium chloride and the aqueous phase is acidified with diluted hydrochloric acid. To the mixture is poured in ethyl acetate and filtered through celite, washing on the filter with ethyl acetate. The layers are separated and the aqueous phase is additionally extracted three times with ethyl acetate. The organic extracts are combined and washed with saturated aqueous sodium thiosulfate and saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue is purified by a method of evaporating column chromatography on silica gel (elute with a mixture containing from 30 to 50% ethyl acetate in hexane) and obtain 1.73 g of the desired product in the form of a foamy substance is dark brown.

The substance has the following physical characteristics:

Range PMR: 0,9, 1,1, 1,3, 1,6-2,0, 2,5-2,8, 4,3, 6,9-7,3, 7,8, 8,0, 8,5 M. D.

The mass spectrum of high resolution (FAB): 452,2449.

Drug 81. 3-[1-(3-AMINOPHENYL)-2,2-dimethylpropyl] -5,6 - dihydro-4-hydroxy-6-phenethyl-6-propelers-2-he (formula T-4). Cm. Scheme T.

To a solution 1,72 g of the target product of Preparation 80 (formula T-3) in 25 ml of methanol is added 3.0 g of ammonium formate and 400 mg of 10% palladium on coal. The resulting suspension cher is litre methanol. The filtrates are combined and the solvent evaporated under reduced pressure. The residue successively triturated with several portions of dichloromethane. The obtained dichloromethane extracts are combined evaporated under reduced pressure and the residue purified by the method of evaporating column chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane, and obtain 1.48 g of target compound in the form of a foamy substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,7-0,9, 1,1, 1,3-2,6, 4,2, 6,55, 6,9-7,3 M. D.

The mass spectrum of high resolution (FAB): 422,2686.

Example 250. N-[3-(1-[5,6-Dihydro-4-hydroxy-2 - oxo-6-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula T-5: R denotes 1-Mei-4-yl). Cm. Scheme T.

To a solution of 1.48 g of the target product of Preparation 81 (formula T-4) in 25 ml dichloromethane at a temperature of 0oC type of 0.57 ml of pyridine, and then 632 mg of 1-methyl-1H-imidazol-4-sulfochloride. After 3 hours the reaction mixture is heated to room temperature and evaporated under reduced pressure. The pyridine is removed double azeotropic distillation with toluene. The residue is purified by a method isparitelnogo product in a solid white color.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 0,97, 1,35-2,0, 1,6-2,0, 2,5-2,7, 3,6, 4,1, 6,9-7,5 M. D.

The mass spectrum of the high-resolution: 566,2684.

The following compounds are individual stereoisomers of this compound:

N-[3-(1(S)-[5,6-Dihydro-4-hydroxy-2-oxo-6(R)- (2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula KK-8, where R4refers to 1-methyl-1H-imidazol-4-yl). Cm. The diagram KK.

N-[3-(1(R)-[5,6-Dihydro-4-hydroxy-2-oxo-6(R)- (2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula LL-8, where R4refers to 1-methyl-1H-imidazol-4-yl). Cm. Circuit LL.

N-[3-(1(S)-[5,6-Dihydro-4-hydroxy-2-oxo-6(S)- (2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula MM-8, where R4refers to 1-methyl-1H-imidazol-4-yl). Cm. The MM scheme.

N-[3-(1(R)-[5,6-Dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6-propyl - 2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula NN-8, where R4refers to 1-methyl-1H-imidazol-4-yl). Cm. Scheme NN.

Example 251. 5-Cyano-N-[3-(1-[5,6-dihydro-4-hydroxy-2 - oxo-6-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] the General method of sulfonylamine, described in Example 250, enter into interaction 42 mg of the amine of Preparation 81 (formula T-4) with 20 mg of 5-cyano-2-pyridinesulfonamide and after cleaning using the evaporative column chromatography on silica gel (elute with a mixture containing from 1 to 3% methanol in dichloromethane) to obtain 56 mg of the desired product in the form of a foamy substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 0,92, 1,35, 1,6-2,0, 2,5-2,7, 4,0, 6,9-7,4, 8,0, 8,9 M. D.

The mass spectrum of the high-resolution: 588,2532.

Preparation 82. N-Methoxy, N-methyl-3-(4-forfinal)propionamide (formula U-2). Cm. Scheme U.

To a cooled (0oC) stirred solution of 5.0 g of 3-(4-forfinal)propionic acid of the formula U-1, 3.2 g of the hydrochloride of N,O-dimethylhydroxylamine and 11.4 ml of di-ISO-propylacetamide in 40 ml of dichloromethane is added slowly a solution of 5.0 ml of diethyl ether cyanophosphonate acid in 10 ml of dichloromethane. Stirred for 18 hours and evaporated the solution under reduced pressure. The residue is dissolved in ethyl acetate, washed with diluted hydrochloric acid, water, sodium bicarbonate solution, saturated salt solution and dried over magnesium sulfate. The solvent is distilled under reduced pressure:

Range PMR: 2,7, 2,9, 3,17, 3,61, 7,0, 7,2 M. D.

IR-spectrum: 1665, 1511, 1222, 1033, 990 cm-1.

TCX: Rf0,34 (5% ethyl acetate in dichloromethane).

Preparation 83. 1-(4-Forfinal)-3-hexane (formula U-3). Cm. Scheme U.

To a stirred solution of 4.68 g of the target product of Preparation 82 (formula U-2) in 25 ml dry tetrahydrofuran in a stream of argon, cooled to minus 15oC add 17 ml of 1 M solution of propylaniline in the air. The obtained solid mass is then warmed to 0oC, kept at this temperature for 90 minutes and poured into a mixture of ether and dilute hydrochloric acid. The aqueous phase is additionally extracted with ether, the organic extracts are combined, washed with saturated salt solution and dried over magnesium sulfate. The solvent is distilled at atmospheric pressure and the residue purified by distillation (temperature about 160oC, the residual pressure of 13 mm RT.CT.) and receive 3.51 g of the target compound as a colorless liquid.

The substance has the following physical characteristics:

Range PMR: 0,89, 1,6, 2,36, 2,7, 2,9, 6,9, 7,1 M. D.

IR-spectrum: 2965, 1714, 1511, 1222 cm-1.

Preparation 84. 5,6-Dihydro-4-hydroxy-6-(2-(4-forfinal) ethyl)-6-propyl-2H-Piran-2-he (formula U-4). Sale) in 30 ml dry tetrahydrofuran in an atmosphere of argon is added dropwise to 2.3 ml of methyl ester of acetoacetic acid. After 5 minutes add 13,5 ml utility (1.6 M solution in hexane). After another 5 minutes, add a solution of 3.51 g of the target product of Preparation 83 (formula U-3) in 4 ml of tetrahydrofuran. The reaction mixture is stirred for one hour and poured into a mixture of ethyl acetate and cold solution of dilute hydrochloric acid. The organic layer is separated, the aqueous phase is additionally extracted twice with ethyl acetate. The organic extracts are combined, washed with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and obtain the intermediate ester having the following physical characteristics:

TCX Rfto 0.45 (50% ethyl acetate in hexane).

Ester is stirred for 90 minutes in 20 ml of 1 M sodium hydroxide solution, 80 ml of water and 40 ml of methanol and then the methanol is distilled off under reduced pressure. The aqueous phase is washed once with diethyl ether and the ether layer is decanted and the aqueous phase is acidified with diluted hydrochloric acid. The precipitate is extracted with four portions of dichloromethane. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in a mixture of 1:1 diethyl ether - hexane and re, getting 3,24 g of target compound with so pl. 113-114,5oC.

The substance has the following physical characteristics:

Range PMR: 0,96, 1,4, 1,8, 2,0, 2,5, 2,7, 7,0, 7,1 M. D.

IR-spectrum: 2962, 1655, 1604, 1510, 1221 cm-1.

Elemental analysis, found: C, 68,85; H, 6,99.

Mass spectrum: M+ 278

TCX: Rfof 0.44 (5% methanol in dichloromethane).

Drug 85. 3-(1-(3-Benzyloxycarbonylamino)-2,2 - dimethylpropyl)-5,6-dihydro-4-hydroxy-6-(2-(4-forfinal) ethyl)-6-propyl-2H-Piran-2-he (formula U-6: R6denotes a tert-butyl). Cm. Scheme U).

To a stirred solution of 3.06 g of the target product of Preparation 84 (formula U-4) and of 2.81 g of the target product of Preparation 6 (formula B-2) in 30 ml dry tetrahydrofuran type of 2.93 g of trichloride aluminum in 20 ml of tetrahydrofuran. Stirred for two hours, add 6.4g of decahydrate sodium carbonate, stirred for five minutes and the mixture is filtered through celite, washing on the filter with ether. The solvent is distilled off under reduced pressure and get intermediate benzylidene derivative of the formula U-5.

To the obtained substance added 1.13 g of the bromide complex of copper (1) - dimethyl sulfide and 30 ml of tetrahydrofuran, the mixture is cooled to 0of for 10 minutes and poured into a mixture of diethyl ether and dilute hydrochloric acid. The organic layer is separated, washed with saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by a method of evaporating column chromatography (elute with a mixture containing 30-35% ethyl acetate in hexane) and receive 1.83 g of the target product as a foamy substance.

The substance has the following physical characteristics:

Range PMR: 0,87, 1,1, 1,3, 1,6-2,2, 2,5, 5,12, 6,8-7,6 M. D.

The mass spectrum of the high-resolution: 574,2955

TCX: Rf0,29 (35% ethyl acetate in hexane).

Drug 86. 3-(1-(3-AMINOPHENYL)-2,2-dimethylpropyl)-5,6 - dihydro-4-hydroxy-6-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran - 2-he (formula U-7: R1denotes a tert-butyl). Cm. Scheme U.

A mixture of 1.83 g of the target product of Preparation 85 (formula U-6), 2.0 g of ammonium formate and 400 mg of 10% palladium on coal in 25 ml of methanol is stirred in a stream of argon for 90 minutes and then filtered through celite. The solvent is evaporated under reduced pressure and the residue purified by the method of evaporating column chromatography, elwira 10% solution of ethyl acetate in dichloromethane, and obtain 1.24 g of the target product as a foamy substance of white color.

The substance possesses the following is a group of formula U-7, where R1denotes ethyl, obtained from the compounds of formula U-4 by the method similar to that of obtaining the compounds of formula U-7, where R1denotes tert-butyl (Drugs 85 and 86).

Example 252. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H - imidazole-4-sulfonamide (formula U-8: R1represents tert-butyl, R2denotes 1-Mei-4-yl). Cm. Scheme U.

To a cooled (0oC) a solution of 88 mg of the target product of Preparation 86 (formula U-7) and 32 μl of pyridine in 0.5 ml of dichloromethane added 36 mg of 1-methyl-1H-imidazol-4-sulfochloride. After 90 minutes the reaction mixture is purified by the method of evaporating column chromatography (elute with a mixture containing from 3-4% methanol in dichloromethane), and obtain 112 mg of the desired product in the form of a foamy substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 0,96, 1,3, 1,7, 2,35, 2,5, 3,6, 3,7, 6,8-7,5 M. D.

The mass spectrum of the high-resolution: 583,2525.

TCX: Rf0,31 (5% methanol in dichloromethane).

Example 253. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2 - dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfone is In accordance with the General method of sulfonylamine, described in Example 252, enter into interaction 88 mg of the amine of Preparation 86 (formula U-7, R1denotes a tert-butyl) 5-cyano-pyridine-2-sulfochloride and after cleaning using the evaporative column chromatography on silica gel (elute with a mixture containing 10-15% ethyl acetate in dichloromethane) to obtain 107 mg of the desired product as an amorphous solid white.

The substance has the following physical characteristics:

Range PMR: 0,92, 1,3, 1,7, 2,5, 6,8-7,5, 8,0, 8,9 M. D.

The mass spectrum of the high-resolution: 606,2423.

Example 254. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula U-8: R1denotes ethyl, R2denotes 1-Mei-4-yl). Cm. Scheme U.

In accordance with the General method of sulfonylurea described in Example 252, enter into interaction 82 mg of the amine of formula U-7, where R1denotes ethyl, 1-methyl-1H-imidazol - 4-sulfochloride and after cleaning using the evaporative column chromatography on silica gel (elute with a mixture containing 3% methanol in dichloromethane) to obtain 101 mg of the desired product as an amorphous solid white.

Substances

The mass spectrum of the high-resolution: 555,2192.

TCX: Rf0,29 (5% methanol in dichloromethane).

Example 255. N-[3(-1-(4-Hydroxy-5,6-dihydro-2-oxo-6- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl)phenyl]-5 - cyanopyridine-2-sulfonamide (formula U-8: R1denotes ethyl, R2denotes 5-cyanopyridine-2-yl). Cm. Scheme U.

In accordance with the General method of sulfonylurea described in Example 252, enter into interaction 82 mg of the amine of formula U-7, where R1denotes ethyl, 5-cyanopyridine-2-sulfochloride and after cleaning using the evaporative column chromatography on silica gel (elute with a mixture containing 10-15% ethyl acetate in dichloromethane) to obtain 101 mg of the desired product as an amorphous solid white.

The substance has the following physical characteristics:

Range PMR: 0,9, 1,3, 1,6-2,2, 2,5, 3,9, 6,9-7,3, 8,0, 8,1, 8,9 M. D.

The mass spectrum of the high-resolution: 557,2059.

TCX: Rfof 0.44 (20% ethyl acetate in dichloromethane).

Preparation 87. 1,5-Bis-(4-forfinal) Penta-1,4-Dien-3-one (formula V-2). Cm. Scheme V.

To stir vigorously at room temperature a solution of 10 g of sodium hydroxide in 100 ml of water and 80 ml of ethanol is added a mixture of 12.4 g of 4-feywet with water and dried in vacuum. Recrystallized from a mixture of ethyl acetate/hexane and obtain 10.7 g of target compound in the form of plates pale yellow with so pl. 152-154oC.

The substance has the following physical characteristics:

Range PMR: the 6.9 and 7.3, about 7.6 to 7.7 M. D.

IR-spectrum: 1653, 1587, 1508, 984, 835 cm-1.

Mass spectrum: M+ 270

Elemental analysis, found: C, 75,40; H, to 4.41.

TCX: Rf0,35 (dichloromethane).

Preparation 88. 1,5-Bis-(4-forfinal)pentane-3-one (formula V-3). Cm. Scheme V.

To a solution of 5,41 g dienone of Preparation 87 (formula V-2) in 10 ml of tetrahydrofuran and 50 ml of methanol, add 2.0 g of magnesium shavings. To maintain the temperature of about room use a water bath. After all the magnesium will react, pour the reaction mixture into dilute hydrochloric acid and twice extracted with dichloromethane. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by a method of evaporating column chromatography, elwira 50% solution of dichloromethane in hexane, and get 3,66 g of the desired product as yellow oil.

The substance has the following physical characteristics:

Range of PM is Rf0,28 (50% dichloromethane in hexane).

Preparation 89. 4-Hydroxy-5,6-dihydro-6,6-bis(2- (4-forfinal)ethyl)-2H-Piran-2-he (formula V-4). Cm. Scheme V.

In accordance with the General method of condensation of acetoacetic ester and cyclization provided for the Preparation 84 (formula V-4), of 3.9 g of the ketone of Preparation 88 (formula V-3) is transformed into 2.86 g of the target compound, which can be recrystallized from a mixture of dichloromethane/hexane.

The substance has the following physical characteristics:

Range PMR: 2,1, 2,57, 2,7, 7,0, 7,1 M. D.

IR-spectrum: 2924, 1659, 1578, 1508, 1241, 1216 cm-1.

Mass spectrum: M+ 358

Elemental analysis, found: C, 70,17; H, 5,50.

Melting point 140-141oC.

Drug 90. 3-[1-(3-Benzyloxycarbonylamino)-2,2 - dimethylpropyl] -6,6-bis[2-(4-forfinal)ethyl]-4-hydroxy-5,6 - dihydro-2H-Piran-2-he (formula V-6: R1denotes a tert-butyl). Cm. Scheme V.

In accordance with the General method benzylidene condensation and attach cuprate provided for the Preparation 85 (formula U-6), 1,075 g dihydropyrone Preparation 89 (formula V-4) in turn 707 mg of target compound (via the intermediate compound of formula V-5), which purify evaporative chromatography n the ski features:

Range PMR: 1,07, 2,0, 2,6, 3,9, 5,16, 6,8-7,5 M. D.

The mass spectrum of the high-resolution: 654,3023

TCX: Rf0,25 (40% ethyl acetate in hexane).

Drug 91. 3-[1-(3-AMINOPHENYL)-2,2-dimethylpropyl] - 6,6-bis[2-(4-forfinal)ethyl]-4-hydroxy-5,6-dihydro-2H - Piran-2-he (formula V-7: R1denotes a tert-butyl). Cm. Scheme V.

In accordance with the General method of exchange hydrogenation described for the Preparation 86 (formula V-7), 684 mg of the carbamate Preparation 90 (formula V-6, where R1denotes a tert-butyl) turn 497 mg of the target compound that cleans evaporative chromatography on silica gel, elwira 5-10% solution of ethyl acetate in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 1,09, 2,0, 2,6, 6,8-7,1 M. D.

TCX: Rf0,34 (10% ethyl acetate in dichloromethane).

The compound of formula V-7, where R1denotes ethyl, obtained from the compounds of formula V-4 by the method similar to that of obtaining the compounds of formula V-7, where R1denotes tert-butyl (Drugs 90 and 91).

Example 256. N-[3-{1-(4-Hydroxy-5,6-dihydro-2-oxo - 6,6-bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1 - methyl-1H-imidazole-4-sulfonamide (formula V-8: R1denotes tert-buthionine, described in Example 252, enter into interaction 78 mg of the amine of Preparation 91 (formula V-7, R1denotes a tert-butyl) 1-methyl-1H-imidazol-4-sulfochloride and after cleaning using the evaporative chromatography on silica gel (elute with a mixture containing 3-4% methanol in dichloromethane) to obtain 92 mg of the desired product as an amorphous solid white.

The substance has the following physical characteristics:

Range PMR: 0,94, 1,7-2,1, 2,5, 3,50, 6,8-7,4 M. D.

The mass spectrum of the high-resolution: 664,2647.

TCX: Rf0,34 (5% methanol in dichloromethane).

Example 257. N-[3-{1-(4-Hydroxy-5,6-dihydro-2-oxo - 6,6-bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide (formula V-8: R1represents tert-butyl, R2denotes 5-cyanopyridine-2-yl). Cm. Scheme V.

In accordance with the General method of sulfonylurea described in Example 252, enter into interaction 78 mg of the amine of Preparation 91 (formula V-7, R1denotes a tert-butyl) 5-cyanopyridine-2-sulfochloride and after cleaning using the evaporative chromatography on silica gel (elute with a mixture containing 10-15% ethyl acetate in dichloromethane) get of 91.5 mg of the desired product in the form of amorphous>/BR>Range PMR: 0,92, 1,9, 2,6, 3,2, 6,8-7,5, 8,0, 8,9 M. D.

The mass spectrum of the high-resolution: 686,2488.

TCX: Rf0,28 (10% ethyl acetate in dichloromethane).

Example 258. N-[3-{1-(4-Hydroxy-5,6-dihydro-2-oxo - 6,6-bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)propyl} phenyl] - 1-methyl-1H-imidazole-4-sulfonamide (formula V-8: R1denotes ethyl, R2denotes 1-Mei-4-yl). Cm. Scheme V.

In accordance with the General method of sulfonylurea described in Example 252, enter into interaction 74 mg amine

formula V-7, where R1denotes ethyl, 1-methyl-1H-imidazol-4-sulfochloride and after cleaning using the evaporative chromatography on silica gel (elute with a mixture containing 3-4% methanol in dichloromethane) to obtain 77 mg of the desired product as an amorphous solid white.

The substance has the following physical characteristics:

Range PMR: 0,87, 2,0, 2,6, 3,62, 4,0, 4,05, 6,8-7,5 M. D.

The mass spectrum of the high-resolution: 636,2350.

TCX: Rf0,31 (5%methanol in dichloromethane).

Example 259. N-[3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6 - bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)propyl} phenyl] -5 - cyanopyridine-2-sulfonamide (formula V-8: R1denotes ethyl, R2denotes 5-Are 252, enter into interaction 74 mg of the amine of formula V-7, where R1denotes ethyl, 5-cyanopyridine-2 - sulfochloride and after cleaning using the evaporative chromatography on silica gel (elute with a mixture containing 10% ethyl acetate in dichloromethane) to obtain 83 mg of the desired product as an amorphous solid white.

The substance has the following physical characteristics:

Range PMR: 0,83, 2,0, 2,6, 3,96, 6,8-7,2, 8,0, 8,8 M. D.

The mass spectrum of the high-resolution: 658,2200.

TCX: Rf0,49 (10% ethyl acetate in dichloromethane).

Example 260. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo - 6,6-dipropyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5 - cyanopyridine-2-sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3represents tert-butyl, R4denotes 5-cyanopyridine-2-yl) Cm. Scheme D.

In accordance with the General method of sulfonylurea described in Example 252, condense 54 mg of the amine of formula D-5 (where R1and R2denote propyl, R3denotes a tert-butyl), obtained similarly to the method of synthesis of compounds of formula D-5 (where R1-phenethyl, R2-propyl, R3denotes ethyl) Drug 20, with 5-cyanopyridine-2-sulfochloride formula is e (elute the mixture, containing 10-15% ethyl acetate in dichloromethane) to obtain 62 mg of the desired product as an amorphous solid white.

The substance has the following physical characteristics:

Range PMR: 0,90, 1,2-1,8, 2,5, 7,0-7,4, 8,1, 8,2, 8,9 M. D.

The mass spectrum of the high-resolution: 525,2305.

TCX: Rfof 0.44 (20% ethyl acetate in dichloromethane).

Example 261. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo - 6,6-dipropyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1 - methyl-1H-imidazole-4-sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3represents tert-butyl, R4denotes 1-Mei-4-yl) Cm. Scheme D.

In accordance with the General method of sulfonylurea described in Example 252, condense 54 mg of the amine of formula D-5 (where R1and R2denote propyl, R3denotes a tert-butyl) 1-methyl-1H-imidazol-4-sulfochloride formula D-7 (R4denotes 1-Mei-4-yl), and after purification by the method of evaporative chromatography on silica gel (elute with a mixture containing 3-5% methanol in dichloromethane) to obtain 53 mg of the desired product as an amorphous solid.

The substance has the following physical characteristics:

Range PMR: 0, who La in dichloromethane).

Example 262. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6 - dipropyl-2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2 - sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyano-pyridine-2-yl) Cm. Scheme D).

In accordance with the General method of sulfonylurea described in Example 252, condense 67 mg of the amine of formula D-5 (where R1and R2denote propyl, R3denotes ethyl) Drug 20, with 5-cyanopyridine-2-sulfochloride formula D-7 (R4denotes 5-cyanopyridine-2-yl), and after purification by the method of evaporative chromatography on silica gel (elute with a mixture containing 10% ethyl acetate in dichloromethane) to obtain 78 mg of the desired product as an amorphous solid.

The substance has the following physical characteristics:

Range PMR: 0,6-1,0, 1,2-1,8, 3,4, 3,5, 6,9-7,4, 8,0-8,2, 8,9 M. D.

The mass spectrum of the high-resolution: 498,2072.

TCX: Rf0,38 (15% ethyl acetate in dichloromethane).

Example 263. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6 - phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5 - cyanopyridine-2-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4about the Noah in Example 252, condense 79 mg of the amine of formula D-5 (where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl) Drug 20, with 5-cyanopyridine-2-sulfochloride formula D-7 (R4denotes 5-cyanopyridine-2-yl), and after purification by the method of evaporative chromatography on silica gel (elute with a mixture containing 10% ethyl acetate in dichloromethane) to obtain 102 mg of the desired product as an amorphous solid.

The substance has the following physical characteristics:

Range PMR: 0,7-1,0, 1,2-2,6, 3,4, 3,5, 6,9-7,3, 7,9-8,2, 8,9 M. D.

The mass spectrum of the high-resolution: 560,2231

TCX: Rf0,37 (15% ethyl acetate in dichloromethane).

Examples 264-265. The following connections receive in accordance with the General method of sulfonylurea shown in Example 246. Necessary amines receive the same techniques described for Preparations 80 and 81, of the compounds of formula Q-1 (Preparation 69).

264) N-[3-(1-[6,6-Bis-(2-cyclopropyl ethyl)-5,6 - dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl] -1-methyl-1H-imidazole-4-sulfonamide

The substance has the following physical characteristics:

Range PMR: 0,0, 0,4, 0,6, 1,0, 1,2, 1,7, 2,5, 3,7, 4,1, 6,9-7,6 M. D.

The mass spectrum of high resolution (FAB): 556,283 the pyridine-2-sulfonamide

The substance has the following physical characteristics:

Range PMR: 0,0, 0,4, 0,6, 1,0, 1,2, 1,7, 2,5, 4,1, 7,0-7,5, 8,0, 8,1, 9,0 M. D.

The mass spectrum of high resolution (FAB): 578,1689

The product 92. (3(2E),4S)-3-(2-Pentenyl)-4-phenyl-2 - oxazolidinone (formula W-4) Cm. The schema W.

In a round bottom flask with a capacity of 1 l, equipped with a tube for supplying nitrogen and addition funnel, is placed 6,92 g (S)-(+)-4-phenyl-2-oxazolidinone and 250 ml of tetrahydrofuran and then cooled to minus 78oC. To the resulting solution was added to 25.6 ml of n-utility of the reaction mixture falls solid W-3 white. To the resulting suspension add 4,88 g of TRANS-2-pentanolide formula W-2 (produced by processing of industrially produced TRANS-2-pentenol acid of the formula W-1 chloride accelerom) in a small volume of tetrahydrofuran. The obtained homogeneous solution was pale yellow allowed to warm to room temperature and stirred for another 20 minutes. The reaction mixture is decomposed by adding a saturated solution of ammonium chloride, and extracted with ethyl acetate. The organic layer is separated, washed with saturated salt solution, dried over magnesium sulfate, filtered and evaporated, getting solid white

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,42-7,23, 7,18-7,09, 5,49, 4,70, 4,28, 2,28, 1,08 M. D.

[]D(chloroform) = +109oC

Elemental analysis, found: 68,59: H 6,25; N 5,70

Preparation 93. (3(R),4S)-3-[3-(3-AMINOPHENYL)-1 - oxobutyl]-4-phenyl-2-oxazolidinone (formula W-5) Cm. The schema W.

In a round bottom flask with a capacity of 1 l, equipped with a tube for supplying nitrogen and addition funnel, is placed 8.90 g of the bromide complex of copper (1) - dimethyl sulfide and 125 ml of tetrahydrofuran and then cooled to a temperature of minus 40oC. To the resulting suspension is added dropwise within 15 minutes add 43 ml of 1 M solution of 3-[bis(trimethylsilyl)amino]formanilide in tetrahydrofuran. Within 30 minutes the resulting mixture is heated to 0oC and add 25 ml of tetrahydrofuran containing cent to 8.85 g (3(2E),4S)-3-(2-pentenyl)-4-phenyl-2-oxazolidinone of Preparation 92 (formula W-4). The reaction mixture is stirred for 30 minutes at a temperature of 0oC, decompose the reaction mixture by adding 1N hydrochloric acid, and then bring the pH of the mixture to a value of 8 with 1N solution of sodium hydroxide. The reaction mixture is washed with water, saturated salt solution and the organic layer is dried (over sulfate(elute with a mixture of ethyl acetate/hexane), and get to $ 7.91 g of the target product with so pl. 94-95oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,28-7,25, 7,07-6,99, 6,60-6,51, 5,38, 4,63, 4,16, 3,52-3,44, 3,10-2,92, 1,65-1,53, 0,76 M. D.

IR spectrum (mineral oil): 3437, 3335, 1773, 1696, 1605, 1337, 1322, 1299, 1263, 1212, 1096, 1070, 791, 762, 704 cm-1.

Elemental analysis, found: 71,00; H 6,67; N 8,17.

Mass spectrum (E1): /M+/ = 338

[]D(19,87 mg/2 ml chloroform) = +60oC

Drug 94. 3-[3-(3-[Bis(phenylmethyl)amino]phenyl)-1 - oxobutyl]-4-phenyl-2-oxazolidinone, (3R) (4S) (formula W-6) Cm. The schema W.

To a mixture of 25 ml of a solution of sodium carbonate and 80 ml of methylene chloride add of 7.90 g (3(R), 4S)-3-[3-(3-AMINOPHENYL)-1 - oxobutyl]-4-phenyl-2-oxazolidinone Preparation 93 (formula W-5), and then 15,94 g of benzyl bromide. The mixture is heated to 65oC for 18 hours, the layer of methylene chloride was separated, dried (over sodium sulfate) and the solvent evaporated, to give crude product as a dark viscous oil. This oil chromatographic, using 700 g of silica gel (elute 25% solution of ethyl acetate in hexane), and get 8,55 g of target compound with so pl. 92-93oC.

The substance has the following physical characteristics:

WHAT: OF 78.47; H OF 6.68; N 5,26.

[]D(19,602 mg/2 ml chloroform) = +32o< / BR>
The drug is 95. (3R)(4S)-3-[3-(3-[Bis(phenylmethyl)amino] phenyl) -2-(2-methyl-1,3-dioxolane-2-yl)-1-oxobutyl] -4-phenyl-2-oxazolidinone (formula W-8) Cm. The schema W.

To 25 ml of methylene chloride added 2.1 g of amide of formula W-6 Drug 94 and the resulting solution in a stream of nitrogen is cooled to minus 78oC. To this solution add 872 ml of pure titanium tetrachloride, and then add 732 μl of di-ISO-propylacetamide. The resulting mixture is heated within 30 minutes to a temperature of 0oC, and then re-cooled to minus 78oC, add 1.3 g of 2-methoxy-2-methyl-1,3-dioxolane of the formula W-7, the resulting reaction mixture is heated to 0oC and stirred for one hour and then decomposed with a saturated solution of ammonium chloride. Extracted with methylene chloride, the organic extracts dried (over sodium sulfate) and the solvent evaporated in vacuum to give crude product. It chromatographic using 100 g of the carrier (elute 10% hexane solution in methylene chloride), and gain of 1.76 g of the target product.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,36, 7,08, 5,99, 5,42, 4,80, 4,68 4,60, 4,25, 3,68, 3,57, 3,48, 3,07, 2,90,�a) = +25o< / BR>
Preparation 96. (3R)(4S)-3-[2-Acetyl-3-[3-(bis(phenylmethyl)amino)phenyl] -1-oxobutyl]-4-phenyl-2-oxazolidinone (formula W-9) Cm. The schema W.

To 25 ml of tetrahydrofuran and 10 ml of 30% aqueous solution of chloric acid is added 5.0 g of the target product of Preparation 95 (formula W-8) and the resulting solution was stirred for 3 hours at a temperature of 40oC. the Reaction mixture was neutralized with saturated sodium bicarbonate solution to achieve pH 8 and extracted with 400 ml of ether. The ether layer is separated, washed with water, saturated salt solution and dried (over sodium sulfate) and the solvent evaporated in vacuum, obtaining oil. It chromatographic using 300 g of silica gel (elute with a 15% solution of acetone in hexane), and obtain 4.12 g of the target product.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,31, 7,08, 6,59, 6,55, 5,42, 4,67, 4,61, 4,22, 3,09, 1,63, 1,56, 0,61 M. D.

Elemental analysis, found: 77,11; H 6,76; N 4,98.

[]D(20,172 mg/2 ml chloroform) = -10oC

Preparation 97. (3R)(4S)-3-[2-[1-(3-[Bis(phenylmethyl)amino]phenyl) propyl]-5-hydroxy-1,3-dioxo-5-prophilactic] -4-phenyl-2-oxazolidinone (formula W-10) Cm. The schema W.

To 25 ml of methylene chloride add to 1.32 g of compound Peut 279 μl of pure titanium tetrachloride and 450 ál of di-ISO-propylacetamide and stirred for one hour. To the resulting solution was added 689 μl of heptanone and the resulting reaction mixture for 1.5 hours, warmed to 0oC. Decomposing the reaction mixture with a saturated solution of ammonium chloride, extracted with methylene chloride, the organic extracts washed with saturated sodium bicarbonate solution, dried (over sodium sulfate) and the solvent evaporated in vacuum to give crude product. It chromatographic using 100 g of silica gel (elute with 5% hexane solution in methylene chloride), and gain of 1.16 g of the target product.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,36, 7,07, 6,58, 6,54, 5,44, 5,24, 4,69, 4,61, 4,27, 3,21, 3,01, 2,48, 1,90, 1,54, 1,15, 0,81, 0,76, 0,58 M. D.

Elemental analysis, found: 76,62; H 7,63; N 417.

[]D(15,380 mg/2 ml chloroform) = +16o< / BR>
Preparation 98. (3R)-3-[1-(3-[Bis(phenylmethyl)-amino)phenyl) propyl]-6,6-dipropyl-5,6-dihydro-4-hydroxy-2H-Piran-2-he (formula W-11) Cm. The schema W.

To 10 ml of dry tetrahydrofuran added 770 mg of the target product of Preparation 97 (formula W-10) and the resulting solution was cooled to 0oC in a stream of nitrogen. To the resulting solution was added 150 mg of sodium hydride as a 60% dispersion in oil, the reaction mixture is heated ammonium, and extracted with ethyl acetate. The extract is dried and evaporated in vacuum to give crude product. It chromatographic on 100 g of silica gel, elwira 15% solution of ethyl acetate in hexane, and obtain 560 mg of the target product.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,34, 6,69, 5,87, 4,69 4,60, 4,09, 2,28, 2,17, 1,89, 1,73, 1,55, 1,32, 0,88 M. D.

Elemental analysis, found: 79,71; H 8,07; N, 2,61.

[]D(15,998 mg/2 ml chloroform) = -56o< / BR>
The drug is 99. (3S)-3-[1-(3-AMINOPHENYL)propyl] -6,6 - dipropyl-5,6-dihydro-4-hydroxy-2H-Piran-2-he (formula W-12) Cm. The schema W.

The target compound of Preparation 98 (formula W-11) ((3S)-3-[1-(3-bisbenzylisoquinoline)propyl] -6,6-bis-propyl-5,6 - dihydro-4-hydroxy-Piran-2-one) in the amount of 110 mg was dissolved in 20 ml of ethyl acetate. To the resulting solution was added 50 mg of 10% palladium on coal and the resulting mixture hydronaut under pressure of 50 pound-force/square inch (344,7 kPa) of hydrogen for 6 hours. The reaction mixture is filtered through celite and obtain 83 mg of the target compound.

The substance has the following physical characteristics:

The IR spectrum of the: 2957, 2922, 2855, 2871, 2854, 1378, 1605, 1459, 1617, 1262, 1319, 1251, 1282, 1107 cm-1.

[]D(6,526 mg/2 S="ptx2">

In a three-neck round bottom flask with a capacity of 2 l, equipped with a tube for supplying nitrogen and addition funnel, was placed (R)-(-)-4-phenyl-2-oxazolidinone (31,2 g) and tetrahydrofuran (1.2 l) and cooled to minus 78oC. an addition funnel was placed n-utility (1.6 M solution in hexane, 117 ml), dropwise over 20 minutes added to the reaction mixture. A white precipitate is formed compound X-3. The reaction mixture is optionally stirred at a temperature of minus 78oC for 30 minutes. Into the addition funnel is placed TRANS-2-pentenoate formula X-2, derived from the acid of formula X-1 (24.4 g), and tetrahydrofuran (50 ml) and the resulting solution is added dropwise within 10 minutes to the reaction mixture. The obtained homogeneous solution was pale yellow allowed to warm to room temperature and stirred for another 30 minutes. Decompose the reaction mixture was added a saturated solution of ammonium chloride and extracted with ethyl acetate (2500 ml). The organic layer is separated, washed with saturated salt solution, dried over magnesium sulfate, filtered and evaporated, receiving 48 g of solid white. The obtained solid is recrystallized from ethyl acetate (100 ml) and hexane (200 ml) and VideoGet the following physical characteristics:

Range PMR (deuterochloroform): 7,42-7,23, 7,18-7,09, 5,49, 4,70, 4,28, 2,28, 1,08 M. D.

IR spectrum (mineral oil): 1785, 1764, 1686, 1638, 1349, 1336, 1329, 1257, 1234, 1214, 1087, 1076, 756, 716, 699 cm-1.

Mass spectrum (E1): /M+/ = 245

The product 101. (3(3S),4R)-3-[3-(3-AMINOPHENYL)-1-oxobutyl]-4 - phenyl-2-oxazolidinone (formula X-5) Cm. Scheme X.

In a round bottom flask with a capacity of 2 l, equipped with a tube for supplying nitrogen and addition funnel, place of 25.1 g of the bromide complex of copper (1) - dimethyl sulfide and 250 ml of tetrahydrofuran and then cooled to a temperature of minus 40oC. the addition funnel is placed 122 ml of 1 M solution of 3-[bis(trimethylsilyl)amino] formanilide in tetrahydrofuran, is added dropwise within 20 minutes added to the reaction mixture, allow the reaction mixture for 20 minutes to heat up from minus 40oC to minus 20oC. an addition funnel was placed 25 g of the target product of Preparation 100 (formula X-4) and tetrahydrofuran (100 ml) and the resulting solution was added dropwise within 30 minutes at a temperature of 0oC to the reaction mixture and stirred for 15 minutes at a temperature of 0oC, and then decompose the mixture, adding a saturated solution of ammonium chloride (pH adjusted mixture to a value of 8 with ammonium hydroxide solution). the battle color. The organic layer is separated, washed with water and dried over magnesium sulfate, filtered and evaporated, receiving 58 g of yellow oil. The crude product is stirred for one hour at room temperature with a suspension of silica gel (75 g) and methylene chloride (100 ml). The mixture is filtered, washed with methanol and evaporated, receiving 49 g of oil. After chromatography using 300 g of silica gel (elute with 10%-75% solution of ethyl acetate in hexane and 100% ethyl acetate) get 30,9 g butter yellow color. The oil is recrystallized from ethyl acetate (75 ml) and hexane (150 ml) and receive 21,4 g of target compound in a solid white color with so pl. 94-97oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,28-7,25, 7,07-6,99, 6,60-6,51, 5,38, 4,63, 4,16, 3,52-3,44, 3,10-2,92, 1,65-1,53, 0,76 M. D.

IR spectrum (mineral oil): 3437, 3355, 1773, 1696, 1605, 1337, 1322, 1299, 1263, 1212, 1096, 1070, 791, 762, 704 cm-1.

Mass spectrum (E1): /M+/ = 338

The product 102. (3(3S),4R)-3-[3-(3-bis-benzylaminopurine) pentanoyl]-4-phenyl-2-oxazolidinone (formula X-6) Cm. Scheme X.

To a mixture of 80 ml of sodium carbonate solution and 280 ml of methylene chloride add 21,0 g (3(3S),4R)-3-[3-(3-AMINOPHENYL)-1-oxobutyl]-4-phenyl-2-ox o'clock, the layer of methylene chloride was separated, dried (over sodium sulfate) and the solvent evaporated, to give crude product as a dark viscous oil. This oil chromatographic, using 700 g of silica gel (elute 25% solution of ethyl acetate in hexane), and get 31,42 g of target compound with so pl. 91,8-93,5oC. the Substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,32, 7,08, 6,60, 5,34, 4,67, 4,15, 3,43, 3,02, 2,91, 1,56, 0,65 M. D.

Preparation 103. (3S)(4S)-3-[3-(Bis(phenylmethyl)amino]phenyl]-2- (2-methyl-1,3-dioxolane-2-yl)-1-oxobutyl] -4-phenyl-2-oxazolidinone (formula X-8) Cm. Scheme X.

To 12 ml of methylene chloride added 1.55 g (3(3S),4R)- 3-[3-(3-bisbenzylisoquinoline)pentanoyl] -4-phenyl-2 - oxazolidinone (formula X-6) Drug 102 and the resulting solution in a stream of nitrogen is cooled to minus 78oC. To this solution was added 646 ml of pure titanium tetrachloride, and then add 525 μl of di-ISO-propylacetamide. The resulting mixture is heated within 30 minutes to a temperature of 0oC, and then re-cooled to minus 78oC add 886 μl of 2-methoxy-2-methyl-1,3-dioxolane (formula X-7) (also W-7) and the resulting reaction mixture is stirred for one hour and then decomposed with a saturated solution of chloride Ammonii evaporated and receive a viscous oil, which chromatographic using 150 g of silica gel (elute 7% hexane solution in methylene chloride), and get to 1.14 g of the target product.

The substance has the following physical characteristics:

IR spectrum (liquid paraffin): 2920, 2954, 2854, 2870, 1776, 1376, 1453, 1196, 699 cm-1.

Elemental analysis, found: 75,27; H of 6.68; N 4,55.

The product 104. (3S)(4R)-3-[2-Acetyl-3-[3-(bis(phenylmethyl)amino]phenyl] -1-oxobutyl]-4-phenyl-2-oxazolidinone (formula X-9) Cm. Scheme X.

To 15 ml of tetrahydrofuran added 960 mg (3(3S),4R)-3- [2-(2-methyl-1,3-dioxane-2-yl)-3-(3-bisbenzylisoquinoline) pentanoyl] -4-phenyl-2-oxazolidinone (formula X-8) Drug 103. To the resulting solution was added 4 ml of a 30% aqueous solution of chloric acid and the resulting solution was stirred for 2 hours at a temperature of 40oC. the Reaction mixture is cooled to room temperature and decompose the excess of saturated sodium bicarbonate solution. Extracted with 200 ml ether, the ether layer is separated, dried (over sodium sulfate) and the solvent evaporated in vacuum, getting 981 mg of crude product. It chromatographic using 100 g of silica gel (elute 10% pentane solution in methylene chloride), and receive 854 mg of target compound. Substances which, ,66, 4,61, 4,21, 3,09, 1,63, 1,65, 0,61 M. D.

IR spectrum (mineral oil): 1778, 1718, 1600, 1695, 1452, 1335, 1385, 1200 cm-1.

Mass spectrum (E1): /M+/ = 560

Elemental analysis, found: 76,81; H 6,59; N 4,84.

Preparation 105. (3S)(4R)-3-[2-[1-[3-[Bis(phenylmethyl)amino] phenyl]propyl] -5-hydroxy-1,3-dioxo-5-prophilactic]-4-phenyl-2-oxazolidinone (formula X-10) Cm. Scheme X.

To 8 ml of methylene chloride in a stream of nitrogen added 440 mg (3-(3S)(4R)-3-[2-(acetyl)-3-(3-bisbenzylisoquinoline)pentanoyl] -4 - phenyl-2-oxazolidinone (formula X-9) Drug 104 and the resulting solution is cooled to minus 78oC. To this solution was added 90 ml of pure titanium tetrachloride, and then 143 μl of di-ISO-propylacetamide. The solution for 40 minutes, heated to 0oC, and then re-cooled to minus 78oC add 126 ml of heptanone and the resulting reaction mixture for 1.5 hours, warmed to 0oC. Decomposing the reaction mixture with a saturated solution of ammonium chloride, extracted with methylene chloride (3 x 60 ml), the organic extracts are combined, dried over sodium sulfate and the solvent evaporated in vacuum to give crude product as oil. It chromatographic using 100 g of silica gel (elute 10% pentane solution in methylene chloride), and procspec PMR (deuterochloroform): 7,28, 7,07, 6,56, 6,56, 5,44, 5,24, 4,68, 4,61, 4,26, 3,21, 3,10, 2,48, 1,90, 1,55, 1,21, 0,81, 0,74, 0,58 M. D.

IR spectrum (mineral oil): 2929, 2931, 1779, 1720, 1690, 1600, 1494, 1452, 1385, 1359, 1334, 1238, 698 cm-1.

The product 106. (3R)-3-[1-[3-[Bis(phenylmethyl)amino] phenyl] propyl]-5,6-dihydro-4-hydroxy-6,6-dipropyl-2H-Piran-2-he (formula X-11) Cm. Scheme X.

To 3 ml of tetrahydrofuran is added in a stream of nitrogen 28 mg of sodium hydride. To the resulting suspension added 418 mg of (3(3S),4R)-3-[2-((3-hydroxy-3-propyl)hexanoyl) -3-(3-bisbenzylisoquinoline)pentanoyl]-4-phenyl-2-oxazolidinone (formula X-10) Drug 105 in 3 ml of tetrahydrofuran at a temperature of 20oC. the resulting solution was stirred for 16 hours, cooled to 0oC and the reaction is interrupted by adding 1N hydrochloric acid. Alkalinized by adding saturated sodium bicarbonate solution, and extracted several times with ethyl acetate. The extracts are dried (over sodium sulfate) and evaporated in vacuo, getting 518 mg of crude product. It chromatographic on silica gel, elwira 15% solution of ethyl acetate in hexane, and obtain 128 mg of the target compound.

The substance has the following physical characteristics:

IR spectrum (mineral oil): 2929, 2931, 2873, 1636, 1599, 1451, 1465, 1386, 1363, 1328, 1249, 1260, 696 cm-1.

Piran-2-he (formula X-12) Cm. Scheme X.

Dihydropyran formula X-11 ((3R)-3-[1-(3-bisbenzylisoquinoline)propyl]-6,6-dipropyl-5,6-dihydro-4 - hydroxyfuran-2-he) Drug 106 in the amount of 110 mg was dissolved in 20 ml of ethyl acetate. To the resulting solution was added 50 mg of 10% palladium on coal and the resulting mixture hydronaut under pressure of 50 pound-force/square inch (344,7 kPa) of hydrogen for 6 hours. The reaction mixture is filtered through celite and obtain 83 mg of the target compound.

The substance has the following physical characteristics:

IR spectrum (mineral oil): 2961, 2932, 2873, 1682, 1623, 1604, 1458, 1384, 1369, 1319, 1282, 1259, 1150, 1108 cm-1.

Mass spectrum (E1): [M+] = 331.

The product 108. 2-Phenethyl-2-propen-1-ol (formula BB-2) Cm. Scheme BB.

To a cooled (-10oC) solution of N,N,N,N-tetramethyl-1,2 - Ethylenediamine (24,1 ml) in hexane is added slowly utility (100 ml, 1.6 M solution in hexane). Stirred for 45 minutes at a temperature of minus 10oC, the mixture is cooled to minus 78oC and added dropwise 2-methyl-2 - propen-1-ol (BB-1, 6,41 ml). Allow the reaction mixture to warm to room temperature and stirred for 72 hours. Cool the mixture to minus 78oC and slowly add a solution of methyl benzene and then slowly warmed to room temperature. Stirred for two hours and the reaction mixture is decomposed by adding a saturated aqueous solution of ammonium chloride. The organic layer is separated, diluted with diethyl ether and washed with saturated salt solution, dried over magnesium sulfate, filtered and evaporated in vacuum. Clean evaporative chromatography, elwira a mixture of methylene chloride/ethyl acetate/hexane (1:1:6), and obtain the target compound (3.5 g) as oil.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,31-7,16, 5,07, 4,93, 4,09, 2,82-2,76, 2,41-2,36 M. D.

Range 13C-NMR (deuterochloroform): 148,30, 141,69, 128,24, 125,80, 109,76, 65,90, 34,52, 34,16 M. D.

Preparation 109. (2S)-2-Penetrationlatina (formula BB-8) Cm. Scheme BB.

To a cooled (-20oC) suspension of molecular sieves (4 , crushed and sizeaction, 150 mg) in methylene chloride (1.5 ml) is added diethyl ether L-tartaric acid (22 mg) and isopropoxide titanium (IV) (25 mg). The mixture is stirred for 30 minutes at a temperature of minus 20oC and add tert-butyl hydroperoxide (0,84 ml 5-6 M solution in nonane). Stirred for another 25 minutes at a temperature of minus 20oC and slowly add a solution of allyl alcohol of formula BB-2 (300 m night and heated to minus 10oC. Stirred for further 4 hours and the reaction mixture is heated to 0-5oC and the reaction is interrupted, adding water (1 ml). Warmed to room temperature, stirred for another hour and tartratami hydrolyzing by adding 30% aqueous sodium hydroxide solution, saturated sodium chloride (0.1 ml). After 30 minutes the mixture is filtered through celite and the aqueous phase is repeatedly extracted with methylene chloride. The combined organic phases, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining the remnant that purify evaporative chromatography, using as eluent hexane and the gradient of ethyl acetate (10-20%) and obtain the target compound of formula BB-3 (223 mg) as oil. The enantiomeric excess of the reaction, determined by analysis using the PMR spectroscopy (laterobasal) ester Moser obtained by the reaction of B-3 (S)-(+)-alpha-methoxy-alpha- (trifluoromethyl)phenylacetylcarbinol (J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem., (1969) 34: 2543), is 86%.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,34-7,16, 3,83-3,61, 2,89-2,87, 2,72-2,64, 2,17-2,04, 1,89-1,79 M. D.

Range 13C-NMR (deuterochloroform): 141, 17, 137,58, 128,49, 128,21, 126,11, 63,00, 59,57, 49,92, 33,58, 30,82 M. D.

< oC) suspension of sodium hydride (124 mg, 60% suspension in mineral oil) in tetrahydrofuran (10 ml) add the alcohol of formula BB-3 (460 mg) Drug 109. The mixture is stirred at the same temperature for five minutes, allow it to warm to room temperature and stirred for another 30 minutes. Add benzyl bromide (441 mg) and leave the mixture was mixed overnight. Terminate the reaction by adding a saturated solution of salt (10 ml) and diluted with ethyl ether. The organic layer is separated, washed with saturated salt solution, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining the remnant that purify evaporative chromatography, using as eluent hexane and the gradient of ethyl acetate (2-5%), and obtain the target compound (510 mg) as oil. The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,34-7,13, 4,59-4,49, 3,64-3,45, 2,75-2,59, 2,19-2,09, 1,94-1,84 M. D.

Range13C-NMR (deuterochloroform): 141,42, 137,93, 128,58, 128,38, 127,88, 125,94, 73,23, 71,98, 58,21, 50,37, 33,65, 30,83 M. D.

The drug 110a. (3S)-1-Phenyl-3-(phenylmethoxy)hexane-3-ol (formula BB-10) Cm. Scheme BB.

To a cooled (-45oC) a solution of Li2CuCl4(and 0.28 ml of 0.1 M solution in tetrahydrofuran is R brown was stirred at a temperature of minus 45oC for 45 minutes and added dropwise within about 10 minutes add the epoxide of formula BB-4 (150 mg) Drug 110. After an hour decompose the reaction mixture with a saturated solution of ammonium chloride and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining the remnant that purify evaporative chromatography, using as eluent 5% solution of ethyl acetate in hexane, and obtain the target compound (150 mg) in the form of butter.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,38-7,14, 4,54, 3,37, 2,66-2,58, 2,20, 1,88-1,76, 1,58-1,52, 1,39-1,25, 0,92 M. D.

Range13C-NMR (deuterochloroform): 142,61, 138,10, 128,41, 128,33, 127,71, 127,63, 125,68, 75,45, 73,79, 73,44, 38,95, 38,52, 29,86, 16,79, 14,37 M. D.

Preparation 110 b. (2R)-1-Phenylethyl-2-(p-toluensulfonyl)oxiran (formula BB-13) Cm. Scheme BB.

To a cooled (approximately minus 10oC) a solution of the compounds of formula BB-8 (245 mg) Drug 109 in methylene chloride (4 ml) is added 4-toluenesulfonyl chloride (302 mg), triethylamine (160 mg) and 4-dimethylaminopyridine (8 mg). The mixture is left to mix at a temperature in the Yong; washed with saturated aqueous sodium bicarbonate and saturated salt solution, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining the remnant that purify evaporative chromatography, using as eluent 5% solution of ethyl acetate in hexane, and obtain the target compound (448 mg).

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,79, 7,33, 7,28-7,08, 4,13-3,98, 2,64-2,58, 2,44, 2,11-2,00, 1,92-1,82 M. D.

Range13C-NMR (deuterochloroform): 145,17, 140,67, 132,53, 129,96, 128,48, 128,19, 127,95, 126,15, 71,98, 56,49, 50,63, 32,89, 30,37, 21,64 M. D.

The drug 110c. (2S)-1-Phenylethyl-2-prophylaxie (formula BB-12) Cm. Scheme BB.

To a cooled (-45oC) a solution of Li2CuCl4(0.3 ml of 0.1 M solution in tetrahydrofuran) in tetrahydrofuran (2 ml) add ethylmagnesium (0,22 ml of 3 M solution in ethyl ether). The resulting brown solution is stirred at a temperature of minus 45oC for 45 minutes, cooled to minus 65oC and added dropwise within about 10 minutes add toilet formula BB-13 (200 mg) Drug 110b. Stirred for 2.5 hours and within two hours the reaction mixture is heated to minus 50oC and different is serious unite, washed with saturated salt solution, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining the remnant that purify evaporative chromatography, using as eluent 5% solution of ethyl acetate in hexane, and obtain the target compound (60 mg) and gidrotsele formula BB-14 (47 mg).

Gidrotsele formula BB-14 converted into epoxide of formula BB-12 in the following manner. To a cooled (0-5oC) a solution of the compounds of formula BB-14 (43 mg) in methanol (2 ml) is added anhydrous potassium carbonate (20 mg). Stirred for 1 hour at a temperature of 0-5oC and the mixture is heated to room temperature, stirred for further 90 minutes and terminate the reaction by adding a saturated solution of ammonium chloride, and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried (over magnesium sulfate), filtered and evaporated in vacuum, obtaining the remnant that purify evaporative chromatography, using as eluent 5% solution of ethyl acetate in hexane, and get epoxide of formula BB-12 (20 mg).

Physical characteristics of BB-12:

Range PMR (deuterochloroform) 7,31-7,16, 2,68, 2,59, 1,98-1,82, 1,73-1,37, 0,94 M. D.

Range13C-NMR (damarohori PMR (deuterochloroform): 7,79, 7,34, 7,29-7,11, 3,90, 2,58-2,53, 2,44, 1,87, 1,77-1,72, 1,54-1,48, 1,31-1,21, 0,89 M. D.

Range 13C-NMR (deuterochloroform): 145,10, 141,66, 132,50, 129,97, 128,45, 128,25, 127,97, 125,96, 74,33, 73,07, 38,37, 37,87, 29,37, 21,66, 16,47, 14,48 M. D.

The drug 111. (4S)-3-Acetyl-4-phenyl-2-oxazolidinone (formula FF-3) Cm. Diagram FF.

To a solution of (S)-(+)-4-phenyl-2-oxazolidinone formula FF-2 (20 g) in anhydrous tetrahydrofuran (600 ml), cooled to minus 78oC add 1.6 M solution of n-utility in hexane (77,8 ml) and the resulting suspension is stirred at the same temperature for 30 minutes. Add acetyl chloride of formula FF-1 (10,23 ml) and allow the mixture to gradually warm to room temperature. Decompose the mixture, adding 1 l of a saturated solution of ammonium chloride, and then pour in a mixture of water and ethyl acetate. The organic layer is separated and the aqueous phase is additionally extracted twice with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated in vacuum, obtaining a solid residue which is recrystallized from a mixture of ethyl acetate/hexane and get 21,27 g of target compound in a solid white color with so pl. 86-87oC.

The substance has the following physical characteristic is P (deuterochloroform): 169,50, 153,71, 138,81, 128,97, 128,53, 125,73, 69,73, 57,20, 23,59 M. D.

The drug 112. (3(2E),4S)-3-[4,4-Dimethyl-(2-pentanoyl]-4 - phenyl-2-oxazolidinone (formula FF-4) Cm. Diagram FF.

To the compound of formula FF-3 of preparation 111 (21,27 g) in anhydrous methylene chloride (500 ml), cooled to minus 78oC dropwise added titanium tetrachloride (12.0 ml). To the suspension is added di-ISO-propylethylene (19.9 ml) and stirred under these conditions for 30 minutes. Then added to the suspension trimethylacetaldehyde (11,4 ml) and di-ISO-propylethylene (19.9 ml) and allow the mixture to gradually warm to room temperature. After one hour the reaction is interrupted, adding water (200 ml), and vigorously stirred for 15 minutes. The organic layer is separated and the aqueous phase is advanced twice extracted with methylene chloride. The organic extracts are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated in vacuum, obtaining a solid residue which is recrystallized from a mixture of ethyl acetate/hexane and get to 21.6 g of target compound in the form of a solid whitish with so pl. 148-149oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,42-7,05, 5,51-5,46, 4,69, 4,30-4,25, D.

Preparation 113. (3(3S),4R)-3-[3-(3-AMINOPHENYL)-4,4 - dimethylpentyl]-4-phenyl-2-oxazolidinone (formula FF-5) Cm. Diagram FF.

To a suspension of the bromide complex of copper (1) - dimethyl sulfide (18,76 g) in anhydrous tetrahydrofuran (60 ml), cooled to minus 78oC, add 1.0 M solution of 3-[bis(trimethylsilyl)- amino]formanilide in tetrahydrofuran (of 182.2 ml) and the resulting suspension is stirred at minus 78oWith in five minutes. Give the suspension for 15 minutes to warm up to a temperature of minus 15oC, and then cooled to a temperature of minus 78oC. using a funnel for solids add the compound of formula FF-4 of Preparation 112 (16.6 g) and stirred at minus 78oC for 3 hours. Pour the reaction mixture into saturated aqueous solution of ammonium chloride (200 ml) and extracted with ethyl acetate. The organic layer is separated, the aqueous phase (pH = 8) is alkalinized to pH = 9.5 with concentrated ammonium hydroxide solution. The aqueous layer was extracted three more times with ethyl acetate, the organic extracts are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated in vacuum. The crude residue is suspended with chloroform (400 ml) and 200 g specification of time chloroform, and then with methanol. The filtrate is evaporated in vacuo and the residue purified by the method of evaporative chromatography elwira a mixture of hexane/ethyl acetate (15-40%), and receive 17,52 g of target compound in the form of a solid pale yellow color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,26-7,12, 7,01, 6,74-6,70, 6,61-6,50, 5,32-5,28, 4,56, 4,11-3,95, 3,48, 2,97-2,91, 0,91 M. D.

Range 13C-NMR (deuterochloroform): 172,34, 153,51, 145,37, 142,24, 138,12, 128,67, 128,23, 127,68, 124,71, 119,80, 116,49, 113,02, 69,39, 57,39, 52,30, 34,75, 33,49, 27,83 M. D.

The product 114. (3(3S),4S)-3-[3-(3-Bisbenzylisoquinoline)- 4,4-dimethylpentyl]-4-phenyl-2-oxazolidinone (formula FF-6) Cm. Diagram FF.

To a solution of the compounds of formula FF-5 Preparation 113 (15.0 g) in methylene chloride (190 ml) at room temperature add a saturated solution of sodium carbonate (48.7 per ml), and then benzyl bromide (14,3 ml) and boil the mixture under reflux for 24 hours. Cooled to room temperature and poured into a mixture of water (300 ml) and methylene chloride. The organic layer was separated, washed with a saturated solution

salt, dried over anhydrous sodium sulfate and evaporated in vacuum. Purify using the evaporative chromatography elwira mixture Huck the society has the following physical characteristics:

Range PMR (deuterochloroform): 7,29-6,99, 6,69-6,49, 5,32-5,26, 4,71-4,50, 4,06-3,94, 2,90-2,81, 0,73 M. D.

Range13C-NMR (deuterochloroform): 172,79, 153,78, 148,32, 142,08, 139,04, 138,48, 129,07, 128,59, 128,37, 127,89, 126,83, 124,92, 118,44, 114,64, 110,87, 69,70, 57,68, 54,77, 52,97, 34,84, 33,79, 27,97 M. D.

Preparation 115. [S*,[R*S*(E)]]-N-(2-Hydroxy-1 - methyl-2-phenylethyl)methyl-N-pentanone (formula NNN-3) Cm. Scheme NNN.

In a three-neck round bottom flask with a capacity of 250 ml, equipped with a tube for supplying nitrogen and addition funnel, was placed a compound of formula NNN-1 (6.6 g) (produced by interaction of industrially produced TRANS-2-pentenol acid chloride accelerom) and tetrahydrofuran (80 ml). In an addition funnel will prevent a solution of (1R,2S)-ephedrine formula NNN-2 (7.2 g) and triethylamine (6.0 ml) in tetrahydrofuran (15 ml) and added dropwise to the reaction mixture. Stirred for hours, pour the reaction mixture into 200 ml of ethyl acetate, washed with three portions of 25 ml of water and evaporated in a vacuum, getting 13.5 g of oil. After column chromatography using 100 g of silica gel (elute 10-100% mixture of ethyl acetate/hexane), get of 10.75 g of the target compound as a colourless oil.

The substance has the following physical characteristics:

The mass spectrum of vitrocsa-1-methyl-2-phenylethyl) -N-methylbenzophenone (formula NNN-4) Cm. Scheme NNN.

In a three-neck round bottom flask with a capacity of 50 ml, equipped with a tube for supplying nitrogen, placed the target product of Preparation 115 (0,247 g) and 5 ml of tert-butyl methyl ether and cooled to 0oC. added dropwise propylaniline (0,55 ml of 2.0 M solution in ether) and the reaction mixture is stirred for 15 more minutes. Added dropwise 3-[bis(trimethylsilyl)-amino] formanilide (2.0 ml, 1.0 M solution in tetrahydrofuran, 2.0 mmol) and the resulting mixture is stirred at a temperature of 0oC for two hours. Terminate the reaction by adding a solution of ammonium chloride (pH adjusted to a value of 8 with ammonium hydroxide) and poured into a mixture of 100 ml of ether and 5 ml of water. The organic layer is separated, further washed with a solution of ammonium chloride and water and evaporated in a vacuum, getting to 0.72 g of yellow oil. Crude oil is dissolved in chloroform and added dropwise to the resulting solution silica gel. The resulting mixture was stirred at room temperature for 1.5 hours, filtered through celite, washing the filter with methanol and evaporated in vacuum, obtaining of 0.38 g of yellow oil. After column chromatography using 50 g of silica gel (elute 20-100% mixture of ethyl acetate/hexane), and poluchili:

The mass spectrum of the high-resolution: 340,2162.

Preparation 117. [1R*-[1R*(R*)2S*]]-3 - bis(phenylmethyl)amino]-beta-ethyl-N-(2-hydroxy-1-methyl-2 - phenylethyl)-N-methylbenzophenone (formula NNN-5) Cm. Scheme NNN.

In a three-neck round bottom flask with a capacity of 50 ml, equipped with a reflux condenser with a tube for supplying nitrogen, placed the target product of Preparation 116 (0,548 g) in 8 ml of acetonitrile. Add sodium carbonate (0.375 g) and benzyl bromide (0,42 ml) and the reaction mixture is refluxed for 4 hours. The reaction mixture was evaporated in vacuum and poured into 100 ml ethyl acetate and 10 ml of water. The organic layer is separated, further washed with 10 ml of water and evaporated in vacuum, obtaining 1.0 g of yellow oil. After column chromatography using 65 g of silica gel (elute compounds of 20-100% ethyl acetate/hexane and 5% methanol/methylene chloride), get 0,447 g of target compound in the form of oil is pale yellow in color.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 520,3102.

Preparation 118. 1-Phenyl-6,6,6-Cryptor-3-hexanol (formula RRR-2) Cm. The PPP scheme.

To a stirred solution of 4.0 g of 4,4,4-tripcomputer formula the Le) and the resulting solution was stirred for 90 minutes. In a separate flask, containing 680 mg of magnesium shavings and 5 ml of tetrahydrofuran, was added 1-phenyl-2-bromatan in 20 ml of tetrahydrofuran so that the mixture is evenly boiling. Refluxed for another hour, cooled to room temperature and using a cannula added to the previously obtained reaction mixture containing DiBAL-H. the resulting white suspension is stirred for 30 minutes at a temperature of minus 70oC and allow it to warm to room temperature. Decompose the reaction mixture was added a saturated solution of ammonium chloride, diluted with 1N hydrochloric acid to dissolve the precipitated salts, and extracted with ethyl acetate. The organic extracts are combined, washed with water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuum. The crude product was then purified using the evaporative chromatography on silica gel (elute compounds 20% solution of ethyl acetate in hexane) and obtain 2.0 g of the target compound as a colourless oil.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 232,1088.

IR spectrum (pure liquid): 3385, 2950, 1455, 1255, 1140, 700 cm-1.

Prepl in 10 ml of dichloromethane at a temperature of minus 60oC added dropwise 0,81 ml of dimethylsulfoxide. The resulting solution was stirred for 5 minutes and add 860 mg of 1-phenyl-6,6,6-Cryptor-3-hexanol (formula RRR-2) Preparation 118 in 5 ml dichloromethane and stirred for 15 minutes. Add triethylamine (1.5 ml), allow the mixture to warm to room temperature, diluted with water and the layers separated. The aqueous layer was extracted with dichloromethane, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting oil purified by the method of evaporative chromatography on silica gel and receive 600 mg of target compound in the form of butter.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,2-7,3, 2,9,2,7, 2,4 M. D.

Range13C-NMR (deuterochloroform): 206, 140, 129, 128, 126, 125, 44, 35, 30, 28.

The product 120. 5,6-Dihydro-4-hydroxy-phenethyl-6-(3', 3',3'- cryptochromes)-2H-Piran-2-he (formula PPP-4) Cm. The PPP scheme.

To a suspension of 350 mg of 50% sodium hydride in 10 ml of tetrahydrofuran at a temperature of 0oC added dropwise to 0.78 ml of methyl ester of acetoacetic acid. Stirred for 30 minutes, add 4.5 ml of 1.6 M solution of n-utility in hexane and stirred for 15 more minutes. Add the 0oC for 15 minutes, allow the mixture to warm to room temperature and stirred for another hour. Decomposing the reaction mixture with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic extracts are combined, washed with water and saturated salt solution, evaporated in vacuum and dissolved in 20 ml of tetrahydrofuran. The solution was diluted with 60 ml of water and treated with 20 ml of 1N sodium hydroxide solution, stirred for 3 hours at room temperature and acidified with concentrated hydrochloric acid. The mixture is extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated in vacuum. The crude product was then purified using the evaporative chromatography on silica gel (elute 30% solution of ethyl acetate in hexane) and obtain 870 mg of the target compound.

The substance has the following physical characteristics:

Elemental analysis, found: C, 61,14; H, the 5.45.

Preparation 121. Fenilmetilovy ether [3-[1-[5,6-Dihydro - 4-hydroxy-2-oxo-6-(2-phenethyl)-6-(3,3,3-cryptochromes)- 2H-Piran-3-yl]-2,2-dimethylpropyl] phenylcarbinol acid (formula QQQ-3, where R1denotes a tert-butyl) Cm. Scheme QQQ.

The target compound of Preparation 120 (850 mg) in 25 ml tetrat 700 mg of 3-benzyloxybenzaldehyde. The mixture is stirred at room temperature for 2 hours, and then add 2 g of the monohydrate of sodium carbonate and 0.1 ml of water, stirred for 30 minutes and filtered through celite, washing the filter with tetrahydrofuran. The filtrate is evaporated and the residue is dissolved in 25 ml of tetrahydrofuran, add 285 mg of the bromide complex of copper (1) - dimethyl sulfide and the mixture is stirred for 15 minutes and then for 15 to 20 minutes added dropwise 11 ml of 1 M solution of tert-butylacrylamide in tetrahydrofuran. The resulting mixture is brown stirred for further 15 minutes, cooled to 0oC and decompose, adding 50 ml of water. The layers are separated and the aqueous layer was acidified with hydrochloric acid to dissolve the inorganic salts, and then extracted with ethyl acetate. The organic extracts are combined, washed with water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and evaporated. Purify using the evaporative chromatography on silica gel, elwira solution of ethyl acetate in hexane, and obtain 1.19 g of target compound in the form of a foamy substance dark yellow color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,1-7,7, 6,7, 6,�Alenia phenylmethylene ether [3-[1-[5,6-Dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H-Piran-3-yl]-2,2 - dimethylpropyl]phenylcarbinol acid (formula QQQ-3, where R1denotes a tert-butyl) 4 isomer 3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R or S)-(2 - phenethyl)-6-(R or S)-(3,3,3-cryptochromes)-2H-Piran-3-yl] - 2,2-dimethylpropyl]phenylcarbinol acid (formula QQQ-4-7, where R1denotes a tert-butyl) Cm. Scheme QQQ.

The first phase splitting is performed on the column 5.1 x 25 cm (R,R)Whelk-O 1, elwira 15% (V/V) solution of ISO-propanol in hexane with a feed rate of 99 ml/min ((R,R)Whelk-O 1 is a trademark of "Regis Technologies, Inc. ", Morton Grove, IL 60053). Peaks that suiryudan over time, approximately 54 and 87 minutes, are, according to the analyses using the following System A pure isomer 3 and isomer 2, respectively. A mixture of undigested isomer 1 and isomer 4 eluted with time approximately 64 minutes and subjected to further processing as described below.

When carrying out the second phase of the cleavage mixture, which eluted over time, approximately 64 minutes, Inuktitut in column 2.1 x 25 cm Chiralcel OD (from Chiral Technologies, Inc.) and elute 35% (V/V) solution of ISO-propanol in hexane with a feed rate of 8 ml/min Peaks that suiryudan with approximately 8.7 times and 23.9 minutes represent isomer 1 and isomer 4, respectively.

oC.

Four components of the enantiomer in the order of output from A System is designated as Peak 1 , Peak 2 , Peak 3 and Peak 4. System A is a column and 0.46 x 25 cm Chiralcel OD-H, which elute 20% (V/V) solution of ISO-propanol in hexane with a feed rate of 1.0 ml/min (Chiralcel OD-H is a trademark of "Chiral Technologies, Inc.", Exton, PA 19341).

Preparation 123. 3(R or S)-[1-(3-AMINOPHENYL)-2,2 - dimethylpropyl]-4-hydroxy-5,6-dihydro-6(R or S)-phenethyl-6- (3,3,3-cryptochromes)-2H-Piran-2-he (formula QQQ-8, where R1denotes a tert-butyl) Cm. Scheme QQQ.

To a solution of 210 mg of the compound identified as peak 1 of 122 Drug in 10 ml of methanol, add 400 mg of ammonium formate and 40 mg of 10% palladium on charcoal, stirred for 2 hours, filtered through celite, washing on the filter with methanol. The filtrate is diluted with ethyl acetate and washed with water and saturated salt solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuum, receiving 160 mg of target compound in the form of a foamy substance of white color.

The substance has the following physically is): Rf0,24 (40% ethyl acetate in hexane).

Example 266. 5-Cyano-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3 - cryptochromes)-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2 - pyridinesulfonamide (formula QQQ-13: R1represents tert-butyl, R2denotes 5-cyano-2-pyridinyl) Cm. Scheme QQQ.

The target solution of the product of Preparation 123 (50 mg), pyridine (30 ml) and 5-cyanopyridine-2-sulfochloride (30 mg) in dichloromethane is stirred at a temperature of 0oC for two hours. The crude reaction mixture chromatographic on silica gel and get the target compound in the form of an amorphous solid white.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 642,2267.

Example 267. N-[3(R or S)-[1-[5,6-Dihydro-4-hydroxy - 2-oxo-6-(R or S)-(2-phenethyl)-6-(3,3,3-cryptochromes) -2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide (formula QQQ-13: R1represents tert-butyl, R2refers to 1-methyl-4-imidazolyl) Cm. Scheme QQQ.

The target connection receive according to the method described in Example 266, substituting 5-cyano-2-sulfochloride 1-Mei-4-sulfochloride.

The substance has the following physical the hydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3 - cryptochromes)-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2 - pyridinesulfonamide (formula QQQ-13: R1represents tert-butyl, R2denotes 5-amino-2-pyridinyl) Cm. Scheme QQQ.

The target solution of the product of Preparation 123 (50 mg), pyridine (30 ml) and 5-cyanopyridine-2-sulfochloride (30 mg) in dichloromethane is stirred at a temperature of 0oC for two hours. The crude reaction mixture chromatographic on silica gel and get the sulfonamide as an amorphous solid white. It is dissolved in 4 ml of methanol, add 25 mg of ammonium formate and 5 mg of 10% palladium on charcoal, stirred for 1 hour at room temperature, diluted with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated in vacuum, obtaining the target compound in the form of a solid amorphous material whitish color.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 632,2393.

The product 124. 3(R or S)-[1-(3-AMINOPHENYL)-2,2 - dimethylpropyl]-4-hydroxy-5,6-dihydro-6(R or S)-phenethyl-6- (3',3',3'-cryptochromes)-2H-Piran-2-he (formula QQQ-9, where R1denotes a tert-butyl) Cm. Scheme QQQ.

The target connection receive in accordance with the methodology described in Preparation 123, taking as starting compound, selected in the organic synthesis.

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 6,9-7,3, 6,6, 4,1, 2,6-2,7, 1,9-2,4, 1,0 M. D.

TLC (silica gel GF): Rf0,24 (40% ethyl acetate in hexane).

Example 269. 5-Cyano-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3-cryptochromes) -2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide (formula QQQ-13: R1represents tert-butyl, R2denotes 5-cyano-2-pyridinyl) Cm. Scheme QQQ

The target solution of the product of Preparation 124 (50 mg), pyridine (30 ml) and 5-cyanopyridine-2-sulfochloride (30 mg) in dichloromethane is stirred at a temperature of 0oC for two hours. The crude reaction mixture chromatographic on silica gel and get the target compound in the form of an amorphous solid white.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 642,2260.

Example 270. N-[3(R or S)-[1-[5,6-Dihydro-4-hydroxy - 2-oxo-6-(R or S)-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H - Piran-3-yl] -2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4 - sulfonamide (formula QQQ-14: R1represents tert-butyl, R2refers to 1-methyl-4-imidazolyl) Cm. Scheme QQQ.

The target connection receive according to the method,the Substance has the following physical characteristics:

The mass spectrum of the high-resolution: 619,2362.

Example 271. 5-Amino-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3 - cryptochromes)-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide (formula QQQ-14: R1represents tert-butyl, R2denotes 5-amino-2-pyridinyl) Cm. Scheme QQQ.

The target connection receive similarly to the method shown in Example 268.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 632,2387.

Preparation 125. 3(S or R)-[1-(3-AMINOPHENYL)-2,2 - dimethylpropyl]-4-hydroxy-5,6-dihydro-6-(R or S)-phenethyl-6-(R or S) -(3',3',3'-cryptochromes)-2H-Piran-2-he (formula QQQ-10, where R is a tert-butyl) Cm. Scheme QQQ.

The target connection receive in accordance with the methodology described in Preparation 123, taking as initial compound isolated in the form of peak 3 in Preparation 122, and using materials and reagents known or available to specialists in the field of organic synthesis.

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 6,9-7,3, 6,6, 4,1, 2,6-2,7, 1,9-2,4, 1,0 M. D.

TLC (silica gel GF): Rf0,24 (40% ethyl acetate in hexane).

Example propyl] phenyl[-2-pyridinesulfonamide (formula QQQ-15: R1represents tert-butyl, R2denotes 5-cyano-2-pyridinyl) Cm. Scheme QQQ.

The target solution of the product of Preparation 125 (50 mg), pyridine (30 ml) and 5-cyanopyridine-2-sulfochloride (30 mg) in dichloromethane is stirred at a temperature of 0oC for two hours. The crude reaction mixture chromatographic on silica gel and get the target compound in the form of an amorphous solid white.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 642,2254.

Example 273. N-[3(R or S)-[1-[5,6-Dihydro-4 - hydroxy-2-oxo-6-(R or S)-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H - Piran-3-yl] -2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula QQQ-15: R1represents tert-butyl, R2refers to 1-methyl-4-imidazolyl) Cm. Scheme QQQ.

The target connection receive according to the method described in Example 266, substituting 5-cyano-2-sulfochloride 1-Mei-4-sulfochloride.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 642,2397.

Example 274. 5-Amino-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3-cryptochromes)-2H - Piran-3-yl]-2,2-dimethylpropyl] phenyl]-2-feast of the QQQ.

The target connection receive similarly to the method shown in Example 268.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 632,2393.

The product 126. 3(S or R)-[1-(3-AMINOPHENYL)-2,2 - dimethylpropyl]-4-hydroxy-5,6-dihydro-6-(S or R)-phenethyl-6- (3',3',3'-cryptochromes)-2H-Piran-2-he (formula QQQ-11, where R1denotes a tert-butyl) Cm. Scheme QQQ.

The target connection receive in accordance with the methodology described in Preparation 123, taking as starting compound, isolated in the form of peak 4 in Preparation 122, and using materials and reagents known or available to specialists in the field of organic synthesis.

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 6,9-7,3, 6,6, 4,1, 2,6-2,7, 1,9-2,4, 1,0 M. D.

TLC (silica gel GF): Rf0,24 (40% ethyl acetate in hexane).

Example 275. 5-Cyano-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3 - cryptochromes)-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2 - pyridinesulfonamide (formula QQQ-16: R1represents tert-butyl, R2denotes 5-cyano-2-pyridinyl) Cm. Scheme QQQ.

The target solution of the product of Preparation 126 (50 mg), pyridine (30 masow. The crude reaction mixture chromatographic on silica gel and get the target compound in the form of an amorphous solid white.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 642,2248.

Example 276. N-[3(R or S)-[1-[5,6-Dihydro-4-hydroxy-2-oxo-6- (R or S)-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula QQQ-16: R1represents tert-butyl, R2refers to 1-methyl-4-imidazole) Cm. Scheme QQQ.

The target connection receive according to the method described in Example 266, substituting 5-cyano-2-sulfochloride 1-Mei-4-sulfochloride.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 620,2403.

Example 277. 5-Amino-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3 - cryptochromes)-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2 - pyridinesulfonamide (formula QQQ-16: R1represents tert-butyl, R2denotes 5-amino-2-pyridinyl) Cm. Scheme QQQ.

The target connection receive similarly to the method shown in Example 268.

The substance has the following physical characteristics- (2-phenethyl)-[6-(R or S)-propyl]-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide

The target connection get similar to previously described techniques, using isomer 2 of Preparation 143.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 562,2527.

Example 279. N-[3(R or S)-[1-[5,6-Dihydro-4-hydroxy-2-oxo-6- (2-phenethyl)-6-(R or S)-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide

The target connection get similar to previously described techniques, using isomer 1 of Preparation 143.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 562,2528.

Preparation 127. 2-Mercapto-4-triptorelin

To 1.0 g of 2-chloro-4-triptoreline (from Lancaster Chemical Co. ") add 10 ml of absolute ethanol and 417 g of thiourea. The reaction mixture is refluxed for 4 hours, and then add 1.25 ml of a solution 7,44 g of potassium hydroxide in 20 ml of water. Boil the mixture under reflux for one hour, cooled and poured into 100 ml of 1.0 N sodium hydroxide solution. The resulting solution is shaken out three times 100 ml of methylene chloride, and the aqueous phase is acidified to pH 4 using glacial acetic acid and three times extracted with 100 ml chloride is try to dryness, getting 501 mg of the crystalline substance is yellow.

The substance has the following physical characteristics:

Elemental analysis, found: 40,22; H 2,33; N 8,07; S 17,59.

The mass spectrum of the high-resolution: 179,0019.

Preparation 128. 2-Chlorosulfonyl-4-triptorelin

To 425 mg of 2-mercapto-4-triptoreline Drug 127 add 10 ml of 1N aqueous solution of hydrochloric acid. The reaction mixture cooled down to 0oC and chilled through the mixture for 15 minutes pass chlorine gas. The reaction mixture is filtered and the obtained solid is washed thoroughly with water. The obtained solid white is dissolved in methylene chloride and washed twice with saturated aqueous sodium bicarbonate solution and again with water. Dry the organic solution over sodium sulfate (anhydrous), filtered and evaporated to dryness, receiving 300 mg of 2-chlorosulfonyl-4-triptoreline, which is used without further purification and stored until use at a temperature of minus 78oC.

Preparation 129. 2-Chlorosulfonyl-5-triptorelin

Replacing if the reaction described earlier in the Drug 128, 2-mercapto-4-triptorelin 2 IU is passed slowly crystallizes. The resulting material is used without further purification and stored until use at a temperature of minus 78oC.

Drug 130. 3-[1-[5,6-Dihydro-4-hydroxy-2-oxo-6,6 - di-n-propyl-2H-Piran-3-yl] propyl] phenylcarbamoyl acid (formula SSS-1: R1denotes ethyl) Cm. The SSS.

To 7.2 g of trichloride aluminum at a temperature of minus 70oC in a stream of nitrogen add 180 ml of tetrahydrofuran. Mixture allowed to warm to a temperature of 0oC and stirred for 15 minutes and then add 5,38 g of compound of formula SSS-A. (See. The SSS), obtained by the method similar to that shown for the Drug 17. The reaction mixture is stirred for 15 minutes and add to 6.88 g of 3-Cbz-benzaldehyde (formula SSS-B, see Scheme SSS). The reaction mixture is stirred for 15 minutes at a temperature of 0oC, and then 3 hours at room temperature. The reaction mixture cooled down to 0oC with vigorous stirring, add 35 g of the monohydrate of sodium carbonate, and then 1.6 ml of water. Stirred at a temperature of 0oC for 15 minutes, add 120 ml of tetrahydrofuran and the mixture is filtered through celite. Celite is washed thoroughly with tetrahydrofuran and the resulting solution in tetrahydrofuran evaporated who give to minus 5oC and add 3.2 g of the bromide complex of copper (1) - dimethyl sulfide. The mixture is stirred for 15 minutes and added dropwise so that the temperature did not rise above 0oC add 65 ml of 2 M solution of etimani-chloride in tetrahydrofuran. Stir the mixture for 15 minutes, carefully add 9 ml of water, and then 45 ml of 1N hydrochloric acid. All operations is carried out at a temperature of 0oC. the resulting mixture was poured into 2 l of ethyl ether and add 200 ml of water. The aqueous layer was separated and the organic phase is advanced thrice washed with 10% aqueous solution of ammonium carbonate, and then once with water. The organic extract is dried over sodium sulfate, filtered and evaporated to dryness, obtaining 10.2 g of crude product as a foamy substance. The resulting substance chromatographic on silica gel, elwira 2% ethyl acetate in methylene chloride, and get 4,74 g of 3-[1-[5,6 - dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-Piran-3 - yl]propyl]phenyl-carbamino acid.

The drug 130A. 3-[1-[5,6-Dihydro-4-hydroxy-2-oxo-6 - phenethyl-6-propyl-2H-Piran-3-yl]propyl]phenyl-karamanova acid (formula RRR-1: R1denotes ethyl) Cm. The scheme of RRR.

The target connection receive according to the method described for Preparation 130, the perform:

Range PMR (deuteroacetone): 6,9-7,5, 5,1, 4,0, 1,4-2,7, 0,9 M. D.

TLC (silica gel GF: Rf0,28 (30% ethyl acetate in hexane).

Preparation 131

Preparative chiral splitting of 3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-Piran-3 - yl] propyl] phenyl-carbamino acid (formula SSS-1: R1represents ethyl; see chart SSS) receive two isomer 3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H-Piran-3 - yl] propyl] phenyl-carbamino acid (formula SSS-3 and SSS-4: R1represents ethyl; see chart SSS).

Samples of target compound of Preparation 130 Inuktitut in column 2.1 x 25 cm Chiracel OD and elute 20% solution (V/V) ISO-propanol in hexane with a feed rate of 10 ml/min. Substance eluted with time approximately of 19.1 minutes, is a 3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H - Piran-3-yl] propyl]phenyl-carbamino acid. []2D5= +26o(methanol) (formula SSS-3; see chart SSS) (peak 1) and the substance eluted with time approximately 37,7 minutes is a 3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6,6-di-n-propyl-2H - Piran-3-yl]propyl]phenyl-carbamino acid, []2D5= -27o(methanol) (formula SSS-4, see Diagram SSS) (p is ur bath is not more than 50oC) and get a solid white color.

Preparation 132. 3(R or S)-[1-(3-AMINOPHENYL)propyl]-4 - hydroxy-5,6-dihydro-6,6-dipropyl-2H-Piran-2-he (formula SSS-5: R1denotes ethyl) Cm. The SSS.

To 1.04 g of 3(R or S)-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6,6-di-n-propyl-2H-Piran-3-yl]propyl]phenyl-carbamino acid (formula SSS-3 see chart SSS) Drug 131, a connection that is identified as peak 1 after chiral cleavage product of Preparation 131, add 20 ml of methanol and 1.29 g of ammonium formate. When all substances will dissolve, add 275 mg of 10% palladium on coal and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture is filtered through celite and the methanol solution is evaporated to dryness. The crude product is poured into a mixture of methylene chloride and water. The organic layer is separated, washed twice with water and dried over sodium sulfate. Solution in methylene chloride is filtered off and evaporated to dryness, obtaining 625 mg of 3(R or S)-[1-(3-AMINOPHENYL)propyl]-4-hydroxy-5,6-dihydro-6,6 - dipropyl-2H-Piran-2-it is in the form of amorphous foamy substance.

The substance has the following physical characteristics:

Mass spectrum (E1): 131

[]2D5+38o1
denotes ethyl) Cm. The SSS.

To 825 mg of 3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo - 6,6-di-n-propyl-2H-Piran-3-yl] propyl] phenyl] -carbamino acid (formula SSS-4; see chart SSS) Drug 131, a connection that is identified as a peak after 2 chiral cleavage product of Preparation 131, add 20 ml of methanol and of 1.02 g of ammonium formate. When all substances will dissolve, add 210 mg of 10% palladium on coal and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture is filtered through celite and the methanol solution is evaporated to dryness. The crude product is poured into a mixture of methylene chloride and water. The organic layer is separated, washed twice with water and dried over sodium sulfate. Solution in methylene chloride is filtered off and evaporated to dryness, getting 483 mg of the target compound in the form of amorphous foamy substance.

The substance has the following physical characteristics:

Mass spectrum (E1): 331

[]2D5-39o(C = 0,2680, methanol).

Example 280. 5-Trifluoromethyl-N-[3-[1-[4-hydroxy-2-oxo - 6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl]- 2-pyridinesulfonamide (formula SSS-9: R1denotes ethyl, R2means oommittee with methods provided for the Preparation 132, and obtain the connection formula SSS-2. To 132 mg of the compounds of formula SSS-2 add 15 ml of methylene chloride and 66 μl of pyridine. The reaction mixture is cooled to minus 5oC and added 98 mg of 2-chlorosulfonyl-5-triptoreline (the product of Preparation 129). Stirred at a temperature of 0oC for 60 minutes and the solution is placed in a column with silica gel, elute 10% solution of ethyl acetate in methylene chloride and collect fractions with 5-trifluoromethyl-N-[3-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl - 5,6-dihydro-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide. Rfor = 0.6 (10% ethyl acetate in methylene chloride). The organic solvent is evaporated to dryness and obtain 177 mg of 5-trifluoromethyl-N-[3-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H - Piran-3-yl] propyl] phenyl] -2-pyridinesulfonamide.

The substance has the following physical characteristics:

Mass spectrum (E1): 540, 497, 411, 401, 383, 342, 331, 197, 174, 146, 133.

The mass spectrum of the high-resolution: 540,1938.

TCX: Rf0,6 (10% ethyl acetate in methylene chloride).

Range PMR (deuteroacetone): 8,91, 8,21-8,19, 7,12, 6,98-6,96, 6,86-6,83, 3,85-3,79, 2,46, 2,10-1,98, 1,84-1,75, 1,58-1,47, 1,27-1,15, 0,82-0,72 M. D.

Example 281. 5-Trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-shall reformational) Cm. The SSS.

66 mg of the target product of Preparation 132 (formula SSS-5, SSS) add 8 ml of methylene chloride and 33 μl of pyridine. The reaction mixture is cooled to minus 5oC and added 49 mg of 2-chlorosulfonyl-5-triptoreline (the product of Preparation 129). Stirred at a temperature of 0oC for 60 minutes and the solution is placed in a column with silica gel and elute 10% solution of ethyl acetate in methylene chloride and collect fractions with 5-trifluoromethyl-N-3(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-n - propyl-5,6-dihydro-2H-Piran-3-yl] propyl]phenyl]-2-pyridinesulfonamide. Rfor = 0.6 (10% ethyl acetate in methylene chloride). The organic solvent is evaporated to dryness and obtain 69 mg of the target compound.

The substance has the following physical characteristics:

Mass spectrum (E1): 540, 497, 411, 401, 383, 342, 331, 197, 174, 146, 133.

TCX: Rf0,6 (10 ethyl acetate in methylene chloride).

Range PMR (deuteroacetone): 8,91, 8,21-8,19, 7,12, 6,98-6,96, 6,86-6,83, 3,85-3,79, 2,46, 2,10-1,98, 1,84-1,75, 1,58-1,47, 1,27-1,15, 0,82-0,72 M. D.

Example 282. 5-Trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy - 2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl] -2 - pyridinesulfonamide (formula SSS-8: R1denotes ethyl, R2denotes 5-triptorelin) Cm. Neal] - 2-pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 281, taking as the initial product of Preparation 133 (formula SSS-6).

The substance has the following physical characteristics:

Mass spectrum (E1): 540, 497, 411, 401, 383, 342, 331, 197, 174, 146, 133.

TCX: Rf0,6 (10% ethyl acetate in methylene chloride).

Range PMR (deuteroacetone): 8,91, 8,21-8,19, 7,12, 6,98-6,96, 6,86-6,83, 3,85-3,79,2,46, 2,10-1,98, 1,84-1,75, 1,58-1,47, 1,27-1,15, 0,82-0,72 M. D.

Example 283. 4-Trifluoromethyl-N-[3(R or S)-[1-[4 - hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] - propyl]phenyl]-2-pyridinesulfonamide (formula SSS-7: R1denotes ethyl, R2denotes 4-triptorelin) Cm. The SSS.

4-Trifluoromethyl-N-3(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-n - propyl-5,6-dihydro-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 281, replacing pyridinesulfonamide the product of Preparation 128.

The substance has the following physical characteristics:

Mass spectrum (E1): 146, 145, 139, 133, 71, 57, 55, 43, 41

The mass spectrum of the high-resolution: 540,1902.

Example 284. 4-Trifluoromethyl-N-[3(R or S)-[1-[4 - hydroxy-2-oxo-6,6-di-n-propyl-5,6-d is AET 4-triptorelin) Cm. The SSS.

4-Trifluoromethyl-N-3(R or S)-[1-[4-hydroxy-2-oxo-6,6 - di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -propyl] phenyl] -2-pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 282, replacing pyridinesulfonamide the product of Preparation 128.

The substance has the following physical characteristics:

Mass spectrum (E1): 146, 145, 139, 133, 71, 57, 55, 43, 41.

The mass spectrum of the high-resolution: 540,1896.

Example 285. 5-Trifluoromethyl-N-[3(R or S)-[1-[4 - hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] - 2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide (formula TTT-6: R1represents tert-butyl, R2denotes propyl, R3denotes 5-trifluoromethyl-2-pyridinyl). Cm. The TTT diagram.

5-Trifluoromethyl-N-3(R or S)-[1-[4-hydroxy-2-oxo-6,6 - di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide obtained as an amorphous solid by the procedure described in Example 281 using isomer 1 of Preparation 144 (formula TTT-4; Scheme TTT; R1represents tert-butyl, R2denotes n-propyl).

The substance has the following physical characteristics:

Mass spectrum (E1): 163, 147, 146,69, 57, 56, 43, 41.

The mass spectrum of high RES-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide (formula TTT-7: R1represents tert-butyl, R2denotes n-propyl, R3denotes 5-triptorelin) Cm. The TTT diagram.

5-Trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2-oxo - 6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2 - pyridinesulfonamide obtained as an amorphous solid by the procedure described in Example 281 using isomer 2 of Preparation 144 (formula TTT-5; Scheme TTT; R1represents tert-butyl, R2denotes n-propyl).

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 568,2237.

Example 287. 5-Trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2 - oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl] -2 - pyridinesulfonamide (formula TTT-6: R1denotes ethyl, R2denotes phenyl, R3denotes 5-triptorelin) Cm. The TTT diagram.

The target product is obtained in the form of an amorphous solid by the procedure described in Example 281 using isomer 1 of Preparation 145 (formula TTT-4; Scheme TTT; R1denotes ethyl, R2denotes phenyl).

The substance has the following physical characteristics:

Mass spectrum (E1): 665, 647, 456, 455, 333, 134, 117, 105, 91.

Example 288. 5-Trifluoromethyl-N-[3(R or S)-[1-[oznachaet ethyl, R2denotes phenyl, R3denotes 5-triptorelin) Cm. The TTT diagram.

The target product is obtained in the form of an amorphous solid by the procedure described in Example 281 using isomer 2 of Preparation 145 (formula TTT-5; Scheme TTT; R1denotes ethyl, R2denotes phenyl).

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 665,2300.

Mass spectrum (E1): 665, 647, 456, 455, 333, 134, 133, 117, 105, 91.

Example 289. 4-Trifluoromethyl-N-[3(R or S) - [1-[4-hydroxy-2 - oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl] - propyl] phenyl] -2-pyridinesulfonamide (formula TTT-6: R1denotes ethyl, R2denotes phenyl, R3denotes 4-triptorelin) Cm. The TTT diagram.

The target product is obtained in the form of an amorphous solid by the procedure described in Example 281 using isomer 1 of Preparation 145 (formula TTT-4; Scheme TTT; R1denotes ethyl, R2denotes phenyl).

The substance has the following physical characteristics:

Mass spectrum (E1): 665, 665, 647, 134, 133, 117, 105, 91.

The mass spectrum of the high-resolution: 665,2306.

Example 290. 4-Trifluoromethyl-N-[3(R or S)-[1-[4 - hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3
denotes 4-triptorelin) Cm. The TTT diagram.

The target product is obtained in the form of an amorphous solid by the procedure described in Example 281 using isomer 2 of Preparation 145 (formula TTT-5; Scheme TTT; R1denotes ethyl, R2denotes phenyl).

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 665,2306.

Mass spectrum (E1): 665, 665, 647, 134, 133, 117, 105, 91.

Example 291. 4-Trifluoromethyl-N-[3-(R or S)-[1-[4 - hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] - 2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide (formula TTT-6: R1represents tert-butyl, R2denotes methyl, R3denotes 4-triptorelin) Cm. The TTT diagram.

4-Trifluoromethyl-N-3(R or S)-[1-[4-hydroxy-2-oxo - 6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2 - dimethylpropyl] phenyl]-2-pyridinesulfonamide receive in the form of amorphous solids by the method described in Example 283, by using isomer 1 of Preparation 144 (formula TTT-4; Scheme TTT; R1represents tert-butyl, R2denotes methyl).

The substance has the following physical characteristics:

Mass spectrum (E1): 525, 512, 428, 411, 302, 284, 258, 146, 57.

The mass spectrum of the high-resolution: 568,2209.

1represents tert-butyl, R2denotes methyl, R3denotes 4 - triptorelin) Cm. The TTT diagram.

4-Trifluoromethyl-N-[3(R or S)-[1-[4-hydroxy-2-oxo-6,6 - di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide receive in the form of amorphous solids by the method described in Example 283, by using isomer 2 of Preparation 144 (formula TTT-5; Scheme TTT; R1represents tert-butyl, R2denotes methyl).

The substance has the following physical characteristics:

Mass spectrum (E1): 569, 551, 511, 493, 439, 371, 360, 303, 284, 161, 139.

The mass spectrum of the high-resolution: 569,2297 (M1+H+)

Preparation 134. Fenilmetilovy ether N-[3-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(1-phenethyl)-6-n-propyl-2H-Piran-3-yl] - 2,2-dimethylpropyl]phenyl]carbamino acid (formula RRR-1: R1denotes a tert-butyl) Cm. The RR scheme.

To 4.8 g of trichloride aluminum in a stream of nitrogen at a temperature of minus 70oC add 120 ml of tetrahydrofuran. Mixture allowed to warm to a temperature of 0oC and stirred for 15 minutes and then add 4.68 g of the compounds of formula RRR-A Drug 17. The reaction mixture is stirred for 15 minutes and add 4,69 g 3-Cbz-benzaldehyde (formula RRR-B). The reaction is give the reaction mixture to 0oC with vigorous stirring, 26 g of the monohydrate of sodium carbonate (0.21 M) then 1,08 ml of water. Stirred at a temperature of 0oC for 15 minutes, add 120 ml of tetrahydrofuran and the mixture is filtered through celite. Celite is washed thoroughly with tetrahydrofuran, the resulting solution in tetrahydrofuran evaporated to dryness in a vacuum and get the amber resin. The residue is again dissolved in 120 ml of tetrahydrofuran, the solution is cooled to minus 5oC and add 2.1 g of the bromide complex of copper (1) - dimethyl sulfide. The mixture is stirred for 15 minutes and added dropwise so that the temperature did not rise above 0oC add 65 ml of 1 M solution of tert-butylacrylamide in tetrahydrofuran. Stirred the mixture at a temperature of 0oC for 15 minutes, carefully add 6 ml of water and then 30 ml of 1N hydrochloric acid. The resulting mixture was poured into 1.3 l of ethyl ether. The aqueous layer was separated and the organic phase is advanced thrice washed with 10% aqueous solution of ammonium carbonate, and then once with water. The organic solution is dried over sodium sulfate, filtered and evaporated to dryness, to give crude product as a foamy substance. The obtained substance of chromatography the A.

Preparation 135. Preparative cleavage phenylmethylene ether N-3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n - propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] carbamino acid (formula RRR-1: R1denotes a tert-butyl) 4 isomer phenylmethylene ether 3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6- (R or S)-(2-phenethyl)-6-(R or S)-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] carbamino acid (formula RRR-3-6, where R1denotes a tert-butyl) Cm. The scheme of RRR.

Four inserts the enantiomers are (in order of elution from the system (A) isomer 1 (formula RRR-4; see chart RRR), isomer 2 (formula RRR-3; see chart RRR), isomer 3 (formula RRR-5; see chart RRR) and isomer 4 (formula RRR-6; see chart RRR). The system includes A column and 0.46 x 25 cm Chiralcel OD-H, which elute with a mixture containing 20% ISO-propanol and 0.1% triperoxonane acid in hexane, with a feed rate of 0.5 ml/min (Chiralcel OD-H is a trademark of "Chiral Technologies, Inc, Exton, PA 19341). The first phase splitting is performed on the column 2.1 x 25 cm (R,R)Whelk-O 1, elwira 20% (V/V) solution of ISO-propanol in hexane with a feed rate of 12 ml/min ((R,R)Whelk-0 1 is a trademark of "Regis Technologies, Inc. ", Morton Grove, IL 60053). Peaks that suiryudan with time approximately 35 and 41 minutes, represent the baie mixture is subjected to further processing, as indicated below. When carrying out the second phase of the cleavage mixture, which eluted over time, approximately 41 minutes, Inuktitut in column 2.1 x 25 cm Chiralcel OD (from Chiral Technologies, Inc. ") and elute with a mixture containing 15% (V/V) ISO-propanol and 0.05% triperoxonane acid in hexane, with a feed rate of 9 ml/min Peaks that suiryudan times with approximately 11.0 and 22.0 minutes, are, in accordance with the system A, peaks 1 and 2, respectively.

During the final phase of the cleavage mixture, which eluted from the column Whelk-O time of approximately 35 minutes, Inuktitut column of 2.2 x 25 cm Chiralcel OD and elute with a mixture containing 35% (V/V) ISO-propanol and 0.1% triperoxonane acid in hexane, with a feed rate of 9 ml/min Isomer, which eluted with a retention time of approximately 9.7 minutes, is designated as peak 3, and the isomer, which eluted with a retention time of approximately 16.6 minutes, is designated as peak 4.

Drug 136. 3-[1-(3-AMINOPHENYL)-2,2-dimethylpropyl] -5,6 - dihydro-4-hydroxy-6-phenethyl-6-n-propelers-2-he (formula RRR-2) Cm. The scheme of RRR.

To 590 mg 3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2 - phenethyl)-6-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl - carbamino acid Drug is pushing coal and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture is filtered through celite), washed thoroughly with the filter with methanol and the methanol solution is evaporated in vacuum to give crude product as a solid. He is placed in a mixture of methylene chloride and water, the organic layer is separated, washed twice with water and dried over sodium sulfate and evaporated to dryness, getting 372 mg of 3-[1-(3-amino-phenyl)-2,2-dimethylpropyl]-5,6-dihydro-4 - hydroxy-6-phenethyl - 6-n-propyl-2H-Piran-2-it. The resulting substance is identical to the previously described (formula T-4: see figure T).

Preparation 137. 3(R or S)-[1-(3-AMINOPHENYL)-2,2 - dimethylpropyl]-5,6-dihydro-4-hydroxy-6(R or S)-phenethyl-6 (R or S)-propelers-2-he (formula RRR-7: R1denotes a tert-butyl) Cm. The RR scheme.

3(R or S)-[1-(3-AMINOPHENYL)-2, 2-dimethylpropyl]-5,6 - dihydro-4-hydroxy-6(R or S)-phenethyl-6(R or S)-propelers - 2-he receives in the form of amorphous foamy substance according to the method described for Preparation 136, substituting the compound of Preparation 134 for connection of Preparation 135, designated as peak 2.

The substance has the following physical characteristics:

Mass spectrum (E1): 421, 365, 164, 163, 147, 146, 118, 107, 91, 57.

The mass spectrum of the high-resolution: 421,2617.

Preparation 138. 3(R or S)-[1-(3-AMINOPHENYL)-2,2 - dimethylpropyl the m The scheme of RRR.

3(R or S)-[1-(3-AMINOPHENYL)-2,2-dimethylpropyl]-5,6 - dihydro-4-hydroxy-6(R or S)-phenethyl-6(R or S)-propelers-2 - he receives in the form of amorphous foamy substance according to the method described for Preparation 136, substituting the compound of Preparation 134 for connection of Preparation 135, designated as peak 1.

The substance has the following physical characteristics:

Mass spectrum (E1): 421, 365, 164, 163, 147, 146, 118, 107, 91, 57.

Example 293. 5-Trifluoromethyl-N-[3-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-Piran-3-yl] -2,2 - dimethylpropyl]phenyl]-2-pyridinesulfonamide (formula RRR-15: R1represents tert-butyl, R2denotes 5-trifluoromethyl) Cm. The scheme of RRR.

5-Trifluoromethyl-N-[3-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6-(2-phenethyl)-6-n-propyl-2H-Piran-3-yl]-2,2 - dimethylpropyl]phenyl]-2-pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 281, replacing the product of Preparation 132 of the product of Preparation 136.

The substance has the following physical characteristics:

Mass spectrum (E1): 497, 411, 401, 383, 343, 331, 197,174, 146, 133.

The mass spectrum of the high-resolution: 540,1938.

Example 294. 5-Trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6(R or S)-(2-phenethyl) -6(R or S)-n, 2denotes 5-trifluoromethyl) Cm. The scheme of RRR.

5-Trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4 - hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6 (R or S)-n-propyl - 2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] -2-pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 281, replacing the product of Preparation 132 of the product of Preparation 137.

The substance has the following physical characteristics:

Mass spectrum (E1): 373, 355, 201, 146, 145, 118, 117, 91, 57.

The mass spectrum of the high-resolution: 630,2394.

Example 295. 5-Trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]-2, 2-dimethylpropyl] phenyl] -2-pyridinesulfonamide (formula RRR-12: R1represents tert-butyl, R2denotes 5-trifluoromethyl) Cm. The scheme of RRR.

5-Trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] -2 - pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 281, replacing the product of Preparation 132 of the product of Preparation 138.

The substance has the following physical characteristics:

Mass spectrum (E1): 373, 355, 201, 146, 145, 118, 117, 91, 57.

oxo-6(R or S)-(2-phenethyl)-6(R or S) -n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl]-2 - pyridinesulfonamide (formula RRR-11: R1represents tert-butyl, R2denotes 4-trifluoromethyl) Cm. The scheme of RRR.

4-Trifluoromethyl-N-[3-(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6 (R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] -2-pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 294, replacing the product of Preparation 129 product of Preparation 128.

The substance has the following physical characteristics:

Mass spectrum (E1): 633, 632, 631, 614, 613, 346, 201, 146, 91, 57.

The mass spectrum of the high-resolution: 631,2444.

Example 297. 4-Trifluoromethyl-N-[3-(R or S)-[1-[5,6-dihydro - 4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2 - pyridinesulfonamide (formula RRR-12: R1represents tert-butyl, R2denotes 5-trifluoromethyl) Cm. The scheme of RRR.

4-Trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6 (R or S)-n-propyl - 2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] -2-pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 295, substituting the product of Preparation 129 product of Preparation 128.

The substance has the following physical characteristics:

Mass spectrum (E1): 633, 632, 631, Li S)-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]propyl]phenyl] -2-pyridinesulfonamide (formula RRR-11: R1denotes ethyl, R2denotes 5-trifluoromethyl) Cm. The scheme of RRR.

5-Trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]propyl]phenyl]-2 - pyridinesulfonamide receive in the form of amorphous foamy substance according to the method described in Example 294, taking as the initial product of the Drug 147A.

The substance has the following physical characteristics:

Mass spectrum (E1): 605, 604, 603, 602, 586, 585, 393, 201, 133, 91.

The mass spectrum of the high-resolution: 630,2153.

Example 298A. 5-Trifluoromethyl-N-[3(R or S)-[1-[5,6 - dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S) -n-propyl-2H-Piran-3-yl]propyl]phenyl] -2 - pyridinesulfonamide (formula RRR-12: R1denotes ethyl, R2denotes 5-trifluoromethyl) Cm. The scheme of RRR.

The target compound obtained as an amorphous foam substance according to the method described in Example 294, taking as the starting amine derived from isomer 1 of Preparation 147 (produced by the method described for Preparation 147A).

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 8,9, 8,2, 8,0, 7,0-7,3 3,9, 2,4-2,7, 1,2-2,2, 0,8-1,0 M. D.

TLC (silica gel GF): RF0,19 (40% utilize the UU.

To a solution 3,81 g of thiourea in 75 ml of hot absolute ethanol added to 7.61 g of 2-chloro-5-nitropyridine (formula UUU-1) and refluxed for 6 hours. Cool the mixture to 0oC and the precipitation is separated. The obtained solid is washed subsequently with cold absolute alcohol and chloroform, dried under vacuum and get 6,91 g of the desired product in the form of a solid light brown color with so pl. 175oC (decomposition).

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 7,9, 8,6, 9,4 M. D.

Preparation 140. 5-Nitro-2-dipyridine (formula UUU-3) Cm. Scheme UUU.

To a solution of 1.65 g of sodium carbonate in 50 ml water is added 2.35 g of the target product Preparation 139. Add to the mixture a solution of 2.75 g of sodium hydroxide in 50 ml of water and warmed to room temperature. Stirred under these conditions for one hour, then an hour heated mixture to a temperature of 95oC and cooled down to room temperature. The aqueous phase is extracted with two portions of diethyl ether and carefully acidified with 6N hydrochloric acid. Loose orange precipitate was separated and sequentially washed with cold razbavlen the substances orange with so pl. 167-170oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 7,4, 7,9, 8,5 M. D.

Preparation 141. 5-Nitro-2-pyridinesulfonamide (formula UUU-4) Cm. Scheme UUU.

Through a suspension of 1.27 g of the target product of Preparation 140 in 25 ml of 1N hydrochloric acid and 5 ml of glacial acetic acid at a temperature of 0oC vigorously bubbled chlorine gas. After 15 minutes, the flow of chlorine is stopped and the mixture is blown with nitrogen. The obtained solid substance was separated and sequentially washed with cold diluted hydrochloric acid and water. The solid is dried in vacuum and get to 1.60 g of the desired product in the form of a solid dark brown color with so pl. 77-80oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 8,3, 8,8, 9,6 M. D.

Preparation 142. N-[3-(1-[5,6-Dihydro-4-hydroxy-2-oxo - 6-(2-phenethyl)-6-propyl-2H-Piran-3-yl]-2,2 - dimethylpropyl)phenyl]-5-nitro-2-pyridinesulfonamide (formula UUU-5: R1denotes 2-phenethyl, R2denotes propyl, R3denotes a tert-butyl) Cm. Scheme UUU.

To a solution of 210 mg of the target product of Preparation 81 (formula T-4) in 2 ml of dihl is. the tute for the night to warm to room temperature and the reaction mixture was subjected to purification by the method of evaporating column chromatography on silica gel, elwira mixture containing from 3% to 9% ethyl acetate in dichloromethane, and get 303 mg of target compound in the form of a foamy substance yellow.

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 0,8-1,0, 1,2-1,4, 1,6-1,9, 2,4-2,7, 4,0, 6,9- 7,4, 8,0, 8,5, 9,4 M. D.

The mass spectrum of high resolution (E1): 608,2412.

Example 299. 5-Amino-N-[3-(1-[5,6-Dihydro-4-hydroxy - 2-oxo-6-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2 - dimethylpropyl)phenyl]-2-pyridinesulfonamide (formula UUU-6: R1denotes 2-phenethyl, R2denotes propyl, R3denotes a tert-butyl) Cm. Scheme UUU.

To a solution of 300 mg of the target product of Preparation 142 (formula UUU-5) in 5 ml of methanol in a stream of argon is added 500 mg of ammonium formate and 100 mg of 10% palladium on charcoal, stirred 1 hour, filtered through celite, washing on the filter with methanol. The filtrate are combined and evaporated under reduced pressure and the residue triturated with several portions of dichloromethane. The dichloromethane extracts are combined and evaporated under reduced pressure what tworoom 50% ethyl acetate in dichloromethane, and obtain 245 mg of the target compound in a solid white color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform-deuteroacetone): 0,8-1,0, 1,2-1,4, 1,5-2,0, 2,4-2,6, 4,0, 6,7, 6,8-7,3, 7,4, 7,9 M. D.

The mass spectrum of high resolution (E1): 577,2617.

Examples 300-327

In accordance with the above methods, using original materials and reagents known and available to experts in the field of organic synthesis of compounds separated from the following syntheses, receive additional compounds of the present invention, are shown in Table 3.

Preparation 143. Preparative separation of phenylmethanol ether N-3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n - propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenylcarbinol acid 4-isomer.

The target compound of Preparation 134 is divided into four components stereoisomer, which are (in order of elution from the system A) 4 isomers: isomer 1, isomer 2 isomer 3 isomer 4 with average retention times, components of, respectively, 10,5, 14,9, 21,4, and 65.2 minutes. The system includes A column and 0.46 x 25 cm Chiralcel OD-H, which elute with a mixture containing 20% ISO-propanol and 0.1% trifter the gies, Inc., Exton, PA 19341).

The first phase splitting is performed on the column 2.1 x 25 cm (R,R)Whelk-O 1, elwira 20% (V/V) solution of ISO-propanol in hexane with a feed rate of 12 ml/min ((R,R)Whelk-O 1 is a trademark of "Regis Technologies, Inc., Morton Grove, IL 60053). Peaks that suiryudan with time approximately 35 and 41 minutes, represent, respectively, the mixture of isomers 3 and 4 and the mixture of isomers 1 and 2, in accordance with the specified system A. Both the mixture is subjected to further processing as described below.

When carrying out the second phase of the cleavage mixture, which eluted over time, approximately 41 minutes, Inuktitut in column 2.1 x 25 cm Chiralcel OD(from Chiral Technologies, Inc.) and elute with a mixture containing 15% (V/V) ISO-propanol and 0.05% triperoxonane acid in hexane, with a feed rate of 9 ml/min Peaks that suiryudan with retention times of approximately 11.0 and 22.0 minutes, are, in accordance with the system And, isomer 1 and isomer 2, respectively.

During the final phase of the cleavage mixture, which eluted from the column Whelk-O time of approximately 35 minutes, Inuktitut column of 2.2 x 25 cm Chiralcel OD and elute with a mixture containing 35% (V/V) ISO-propanol and 0.1% triperoxonane acid is minutes, designated as isomer 3 and isomer, which eluted with a retention time of approximately 16.6 minutes, is designated as isomer 4. In the implementation of both stages of separation of the isomers, the corresponding fractions after analysis in A combined and evaporated to dryness on a rotary evaporator.

Preparation 144. Splitting phenylmethylene ether N-[3- (1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] - 2,2-dimethylpropyl)phenyl] carbamino acid on the 2-isomer.

Samples of the starting compound (1.0 g each load) is placed in column 5.1 x 25 cm Chiralcel OD (from Chiral Technologies, Inc."). Enantiomers suiryudan with a retention time of approximately 23 minutes (this corresponds containing protective benzyloxycarbonyloxy group analogue amine (isomer 1) (mass spectrum high resolution (E1): 359 /M+/; PMR spectrum (deuterochloroform-deuteroacetone): 7,1-6,9, 6,5, 4,2, 2,6-2,3, 1,8-1,2, 1,1, 0,9; TCX: Rf= 0,42 (10% ethyl acetate in dichloromethane) and approximately 33 minutes (this corresponds containing protective benzyloxycarbonyloxy group analogue amine (isomer 2) (mass spectrum high resolution (E1): 359 [M+] ; PMR spectrum (deuterochloroform-deuteroacetone): 7,1-6,9, 6,5, 4,2, 2,6-2,3, 1,8-1,2, 1,1, 0,9; TCX: Rf= 0,42 (10% ethyl acetate in dihormati is b), served with a speed of 60 ml/min Purity assessed on the column and 0.46 x 25 cm Chiralcel OD-H (from Chiral Technologies, Inc."). Mobile phases are 20% solution of ISO-propanol in hexane (V/V) and 0.1 % solution triperoxonane acid with a feed rate of 0.5 ml/min, the Observed retention time for isomer 1 and isomer 2 are 8,9 and 16.7 min, respectively (control at a wavelength of 238 nm).

Preparation 145. Splitting phenylmethylene ether N-[3-(1- [6,6-bis (2-phenethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran - 3-yl]propyl)phenyl]carbamino acid 2 isomer

Samples of the starting compound (1.3 g each load) is placed in column 5.1 x 25 cm Chiralcel OD (from Chiral Technologies, Inc."). Enantiomers elute with a mixture containing 20% ISO-propyl alcohol and 0.025% acetic acid in hexane (V/V) with a feed rate of 60 ml/min until then, until you start buyouts the first of isomers. After that (approximately 120 minutes) the feed rate is increased to 90 ml/min, to speed up the elution of the second enantiomer. Enantiomers suiryudan with a retention time of approximately 91,2 minutes (this corresponds containing protective benzyloxycarbonyloxy group analogue amine (isomer 1) and approximately 132 minutes (utaut on the column and 0.46 x 25 cm Chiralcel OD-H. The mobile phase is a 30% solution of ISO-propanol in hexane (V/V), feed rate is 0.5 ml/min

Example 146. 5-Carbamoylation-2-sulfochloride (formula VVV-2) Cm. Scheme VVV.

Through a cooled (0oC) a suspension of 400 mg of 2-mercapto 5-carbamoylation formula VVV-1 in 7.5 ml of 1N hydrochloric acid solution let a strong stream of gaseous chlorine. After 10 minutes, the flow of chlorine is stopped and the suspension is filtered and the obtained solid is washed with water and dried in vacuum. Receive 517 mg of the desired product in the form of an almost white solid.

Example 328. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2 - dimethylpropyl} phenyl]-4-cyanobenzenesulfonyl (formula U-8: R1represents tert-butyl, R2denotes 4-cyanophenyl) Cm. Scheme U.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 88 mg of the amine of Preparation 86 (formula U-7, R1denotes a tert-butyl) 4-cyanobenzaldehyde. After purification using the evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane, to obtain 117 mg of target compound in the form of an amorphous substance blog, ,6, 6,8-7,4, 7,6, 7,8 M. D.

The mass spectrum of the high-resolution: 605,2478.

TCX: Rf0,36 (10% ethyl acetate in dichloromethane).

Example 329. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2 - dimethylpropyl} phenyl]-8-chinaincorporated (formula U-8: R1represents tert-butyl, R2denotes an 8-chinolin). Cm. Scheme U.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 88 mg of the amine of Preparation 86 (formula U-7, R1denotes a tert-butyl) - 8-chinaincorporated. After purification using the evaporative chromatography on silica gel, elwira 5-10% solution of ethyl acetate in dichloromethane, to obtain 101 mg of the target compound in the form of an amorphous substance of white color.

The substance has the following physical characteristics:

Range PMR: 6,3, 0,9, 1,1, 1,3, 1,6-1,9, 2,4-2,6, 6,7-7,6, 8,0, 8,2, 9,1 M. D.

The mass spectrum of the high-resolution: 631,2638.

TCX: Rf0,30 (5% ethyl acetate in dichloromethane).

Example 330. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo - 6,6-bis(2-phenethyl)-2H-Piran-3-yl)propyl}phenyl]-1-methyl-1H - imidazole-4-sulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3obezglavlivanii, Example 252, enter into interaction 77 mg of the amine of formula D-5, where R1and R2denote phenethyl, a R3denotes ethyl 1-Mei-4-sulfochloride. After purification using the evaporative chromatography on silica gel elute 3% solution of methanol in dichloromethane, get 97,0 mg of target compound in the form of a crystalline substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,88, 1,9-2,2, 2,6, 3,6-3,8, 3,97, 6,9-7,5 M. D.

The mass spectrum of the high-resolution: 600,2521.

TLC: Rf0,31 (5% methanol in dichloromethane).

Example 331. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6 - bis(2-phenethyl)-2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2 - sulfonamide (formula D-6: R1denotes phenethyl, R2denotes phenethyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2 - yl) Cm. Scheme D.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 77 mg of the amine of formula D-5, where R1and R2denote phenethyl, and R3denotes ethyl 5-cyano-2-sulfochloride. After purification using the evaporative chromatography on silica gel, elwira 10% concrete is the same.

The substance has the following physical characteristics:

Range PMR: 0,85, 1,8-2,2, 2,5-2,7, 3,97, 6,9-7,4, 7,9, 8,8 M. D.

The mass spectrum of the high-resolution: 622,2355.

TCX: Rf0,28 (10% ethyl acetate in dichloromethane).

Example 332. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-carbamoylation-2-sulfonamide (formula U-8: R1denotes ethyl, R2denotes 5-carbamoylation-2-yl) Cm. Scheme U.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 82 mg of the amine of formula U-7, R1denotes ethyl 5-carbamoylation-2 - sulfochloride Drug 146. After purification using the evaporative chromatography on silica gel, elwira 3-6% solution of methanol in dichloromethane, get a 55.4 mg of target compound as an amorphous substance.

The substance has the following physical characteristics:

Range PMR: 0,7-0,9, 1,3, 1,6-2,1, 2,5, 3,9, 6,8-7,3, 7,8, 8,2 M. D.

The mass spectrum of the high-resolution: 596,2216.

TLC: Rf0,16 (5% methanol in dichloromethane).

Example 333. N-[3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6 - bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)propyl} phenyl] - 5-carbamoylation-2-Sul is P> In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 98 mg of the amine of formula V-7, R1denotes ethyl, 5-carbamoylation-2 - sulfochloride Drug 146. After purification using the evaporative chromatography on silica gel, elwira 3-6% solution of methanol in dichloromethane, get 58,3 mg of target compound as an amorphous substance.

The substance has the following physical characteristics:

Range PMR: 0,83, 1,8-2,2, 2,5-2,6, 6,8-7,2, 7,8, 8,1, 9,0 M. D.

The mass spectrum of the high-resolution: 676,2297.

TLC: Rf0,17 (5%methanol in dichloromethane).

Example 334. N-[3-{1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6 - dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-carbamoylation-2 - sulfonamide (formula D-6: R1denotes propyl, R2denotes propyl, R3denotes ethyl, R4denotes 5-carbamoylation-2-yl) Cm. Scheme D.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 66 mg of the amine of formula D-5 (R1and R2denote propyl, R3denotes ethyl) - 5-carbamoylation-2-sulfochloride Drug 146. After purification using the evaporative chromatography on silica gel, e white.

The substance has the following physical characteristics:

Range PMR: 0,7-0,9, 1,2-2,1, 3,87, 7,0-7,3, 7,8, 8,2 M. D.

The mass spectrum of the high-resolution: 516,2156.

TLC: Rf0,22 (5% methanol in dichloromethane).

Preparation 147. Splitting feedmyinbox ether N-[3-[1-(4-hydroxy-5,6-dihydro-2-oxo-6-phenethyl-6-propyl-2H - Piran-3-yl)propyl] phenyl]carbamino acid 4 isomers (formula WWW-2: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl) Cm. Schemes WWW and RRR.

Four isomers of the product of Preparation 130A (formula RRR-1; R1denotes ethyl) are (in order of increasing retention time in the System (B): (approximately 16.9 minutes) (isomer 1), (approximately 28,0 minutes) (isomer 2), (approximately 38,2 minutes) (isomer 3), (approximately 49.8 minutes) (isomer 4). System B includes a column and 0.46 x 25 cm Chiralcel OD-H (from Chiral Technologies, Inc."), which elute 25% solution of ISO-propanol in hexane (V/V) with a feed rate of 0.5 ml/min

When implementing the first phase of the full splitting Inuktitut samples 55 mg of the target product of the Drug 130A in column 2.1 x 25 cm (R,R)Whelk-01 (from Regis Technologies, Inc."). Isomers elute with a mixture containing 25% ISO-propanol and 0.5% acetic kisiwani approximately 12 minutes is a mixture of isomers 1 (formula RRR-4 in the Diagram RRR) and 2 (formula RRR-3 RRR), which is shown by injectionem aliquot of the System B. the Splitting of the mixture is conducted at the next stage, as described below.

The second phase splitting is performed on the column 2.1 x 25 cm Chiralcel OD, the temperature of which is supported on the 30oC. Inuktitut portion 60 mg, obtained after the first stage of cleavage, and enantiomers elute with a mixture containing 25% (V/V) ISO-propanol and 0.05% triperoxonane acid in hexane, with a feed rate of 9 ml/min Separately collect and concentrate the fractions that suiryudan with retention times of approximately 14.5 and 23.9 minutes, and get isomers 1 (formula RRR-4, where R1denotes ethyl Scheme RRR) and 2 (formula RRR-3, where R1denotes ethyl Scheme RRR), respectively.

The drug 147A. 3(R or S)-[1-(3-AMINOPHENYL)propyl]- 4-hydroxy-5,6-dihydro-6(R or S)-phenethyl-(R or S)- propelers-2-he (formula RRR-7: R1denotes ethyl) Cm. The scheme of RRR.

The target connection receive in accordance with the methods provided for the Preparation 132 using the connection identified as peak 2 (formula RRR-3; R1denotes ethyl Scheme RRR) in the product hiral the PMR Spectrum: 6,5-7,3, 3,9-4,0, 2,5-2,7, 1,2-2,3, 0,8-1,0 M. D.

TLC (silica gel GF): Rf0,31 (40% ethyl acetate in hexane)

Example 335. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(R or S)-phenethyl-6-propyl-2H-Piran-3-yl)- propyl} phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 1/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl). Amin receive from the first stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution 147 Drug. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-1,0, 1,2-2,6, 3,3-3,6, 6,9-7,3, 7,7-8,2, 8,8-9,0 M. D.

The mass spectrum of the high-resolution: 560,2210.

TLC: Rf0,41 (15% ethyl acetate in dichloromethane).

1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 2/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine, which is a product of the Drug 147A (formula WWW-3, where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl). Amin receive from the second stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD at Providence chiral liquid chromatography high resolution Drug 147A. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,6-2,6, 3,3-3,6, 6,9-7,3, 7,7-8,2, 8,8-9,0 M. D.

The mass spectrum of the high-resolution: 560,2215.

TLC: Rf0,41 (15% ethyl acetate in dichloromethane).

Example 337. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(R or S)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] - 5-cyanopyridine-2-sulfonamide (formula WWW-4: R1denotes phenethyl, R2the seat is spruce connection receive in accordance with the General method of sulfonylamine, Example 252, using the amine of formula WWW-3, where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl). Amin receive from the third stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution 147 Drug. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,6-2,6, 3,3-3,6, 6,9-7,3, 7,7-8,2, 8,8-9,0 M. D.

The mass spectrum of the high-resolution: 560,2210.

TLC: Rf0,41 (15% ethyl acetate in dichloromethane).

Example 338. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(S or R)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -5 - cyanopyridine-2-sulfonamide (formula WWW-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 4/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes phenethyl, R2

The substance has the following physical characteristics:

Range PMR: 0,7-1,0, 1,2-2,6, 3,3-3,6, 6,9-7,3, 7,7-8,2, 8,8-9,0 M. D.

The mass spectrum of the high-resolution: 560,2210.

TLC: Rf0,41 (15% ethyl acetate in dichloromethane).

Example 339. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(R or S)-phenethyl-6-propyl-2H-Piran-3-yl)- propyl} phenyl]- 1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl) /Isomer 1/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl). Amin receive from the first stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution 147 Drug. The target compound is isolated in the form of amorphous material after cleaning method isparameter the following physical characteristics:

Range PMR: 0,7-2,8, 3,2-3,7, 3,9, 7,0-7,6 M. D.

The mass spectrum of the high-resolution: 537,2317.

TLC: Rf0,36 (5% methanol in dichloromethane).

Example 340. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro - 2-oxo-6(R or S)-phenethyl-6-propyl-2H-Piran-3-yl)- propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl) /Isomer 2/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl. Amin receive from the second stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral zhidkostnoi chromatography high resolution 147 Drug. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 3-4% solution of methanol in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-2,7, 3,3-3,7, 4,0, 7,0-7,5 M. D.

The mass spectrum of the high-resolution: 537,2275.

TC is)-phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl) /Isomer 3/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl. Amin receive from the third stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution 147 Drug. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-2,7, 3,3-3,7, 4,0, 7,0-7,5 M. D.

The mass spectrum of the high-resolution: 537,2329.

TLC: Rf0,36 (5% methanol in dichloromethane).

Example 342. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(S or R)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -1 - methyl-2H-imidazole-4-sulfonamide (formula WWW-4: R1denotes phenethyl, R2denotes propyl, R3denotes ethyl, R4denotes 1-IU the second sulfonylamine, Example 252, using the amine of formula WWW-3, where R1denotes phenethyl, R2denotes propyl, R3denotes ethyl. Amin is obtained from the fourth stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution 147 Drug. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-2,8, 3,2-3,7, 3,9, 7,0-7,6 M. D.

The mass spectrum of the high-resolution: 537,2312.

TLC: Rf0,36 (5% methanol in dichloromethane).

Preparation 148. 3-[(3-Nitrophenyl)methyl] -6,6-definatel-4 - hydroxy-5,6-dihydro-2H-Piran-2-he (formula XXX-3) Cm. Scheme XXX.

To a solution of 172 mg of 6,6-definatel-4-hydroxy-5,6-dihydro-2H - Piran-2-it formula XXX-1 and 81 mg meta-nitrobenzaldehyde in 2 ml dry tetrahydrofuran in a stream of argon add a solution of 142 mg trichloride aluminum in 1 ml of tetrahydrofuran. The resulting solution was stirred at room temperature for two hours and decompose the mixture, adding 310 mg decahydrate sodium carbonate, razbavlenii and obtain 246 mg of crude benzylidene formula XXX-2. It is dissolved in 5 ml of methanol, cooled to 0oC and added 44 mg cyanoborohydride sodium. Stirred for 30 minutes and add 20 mg of cyanoborohydride sodium. After 30 minutes the mixture was acidified with diluted hydrochloric acid to pH = 1 and extracted with three portions of dichloromethane. The extract is dried (over magnesium sulfate) and evaporated under reduced pressure. Target connection number 211 mg emit in the form of amorphous material after purification of the residue by the method of evaporative chromatography on silica gel, elwira 5-20% solution of ethyl acetate in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 2,0, 2,7, 3,8, 7,0-7,4, 7,6, 8,0, 8,2 M. D.

Mass spectrum: M+ 457

TLC: Rf0,25 (5% ethyl acetate in dichloromethane).

Preparation 149. 3-[(3-AMINOPHENYL)methyl] -6,6-definatel-4 - hydroxy-5,6-dihydro-2H-Piran-2-he (formula XXX-4) Cm. Scheme XXX.

A mixture of 211 mg of the product of Preparation 148 (formula XXX-3) and 50 mg of 10% palladium on coal in 5 ml of methanol was stirred at room temperature under hydrogen pressure of 1 atmosphere. After two hours the mixture is filtered through celite and evaporated under reduced pressure. Target connection number 133,6 mg emit after cleaning ASS="ptx2">

The substance has the following physical characteristics:

Range PMR: 2,0, 2,6, 3,6, 4,1, 6,5, 6,6, 6,7, 6,9-7,3 M. D.

Mass spectrum: M+ 427

TLC: Rf0,33 (5% ethyl acetate in dichloromethane).

Example 343. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo - 6,6-bis(2-phenethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] - 1-methyl-1H-imidazole-4-sulfonamide (formula YYY-5) R1and R2denote phenethyl, R3denotes 1-Mei-4-yl) Cm. The schema YYY.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 77 mg of the amine of formula YYY-4 (R1and R2denote phenethyl) with 1-methyl-imidazol-4-sulfochloride. After purification using the evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane, get 90,7 mg of target compound in the form of an amorphous substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,96, 1,0, 1,6-2,7, 3,45, 6,8-7,5 M. D.

The mass spectrum of the high-resolution: 628,2832.

TLC: Rf0,38 (3% methanol in dichloromethane).

Example 344. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6 - bis(2-phenethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5 - cyanopyridine-2-sulfonamide (formula accordance with the General method of sulfonylamine, Example 252, enter into interaction 77 mg of the amine of formula YYY-4 (R1and R2denote phenethyl) with 5-cyanopyridine-2 - sulfochloride. After purification using the evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane, get 86,1 mg of target compound in the form of an amorphous substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,96, 1,8-2,2, 2,5-2,8, 4,1, 4,3, 6,9-7,4, 7,9-8,0, 8,9 M. D.

The mass spectrum of the high-resolution: 650,2681.

TCX: Rfa 0.27 (10% ethyl acetate in dichloromethane).

The product 150. Splitting phenylmethylene ether N-[3-[1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-forfinal)ethyl-6-propyl - 2H-Piran-3-yl)-2,2-dimethylpropyl]phenyl]carbamino acid 4 isomers (formula WWW-2: R1denotes 4-florfenicol, R2denotes propyl, R3denotes a tert-butyl) Cm. Scheme WWW.

For elution of the enantiomers and control preparative columns use the System S. the System includes a column and 0.46 x 25 cm Chiralcel OD-H (from Chiral Technologies, Inc."), which elute 15% solution of ISO-propanol in hexane (V/V) with a feed rate of 0.5 ml/min Peaks that suiryudan with the times, derivan 4. Isomers 3 and 4 are separated from the mixture by column 2.1 x 25 cm (R, R)Whelk - 01 (from Regis Technologies, Inc."). These two isomers suiryudan with retention times of approximately of 23.9 26.8 minutes when using a 20% aqueous solution of ISO-propanol in hexogene (V/V) with a feed rate of 10 ml/min at a temperature of 30oC. Target isomers suiryudan in the form of nerazdelennaya mixture with a retention time of 28.9 minutes and divide them into the second stage of cleavage. In the second phase splitting unrequited mixture is placed in column 2.1 x 25 cm Chiralcel OD (from Chiral Technologies, Inc. "), the temperature of which is supported on the 30oC and elute 12% solution of ISO-propanol in hexane (V/V) with a feed rate of 12 ml/min retention Time for isomer 1 is 14.5 minutes, and for isomer 2 - 20.8 minutes.

Example 345. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H - Piran-3-yl)-2,2-dimethylpropyl}phenyl]- 5-cyanopyridine-2 - sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3represents tert-butyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 1/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, and the em ethyl. Amin receive from the first stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution Drug 150. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-2,7, 3,2, 3,5, 3,6, 3,7, 4,1, 6,8-7,4, 7,5, 7,8-8,2, 8,8 M. D.

The mass spectrum of the high-resolution: 606,2429.

TCX: Rf0,40 (15% ethyl acetate in dichloromethane).

Example 346. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(S or R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3 - yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3represents tert-butyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 2/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl. Amin receive from the second stereoisomer of formula possible Drug 150. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,6, 0,7-2,6, 3,4, 3,5, 3,7, 4,2, 6,8-7,3, 7,5, 7,8-8,2, 8,8-9,0 M. D.

The mass spectrum of the high-resolution: 606,2434.

TLC: Rf0,40 (15% ethylacetate in dichloromethane).

Example 348. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro - 2-oxo-6(S or R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran - 3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2 - sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3represents tert-butyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 4/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl). Amin receive from the first stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution Drug 150. The target compound is isolated in the form of avrprog the Tata in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-2,7, 3,2, 3,5, 3,6,3,7, 4,1, 6,8-7,4, 7,5, 7,8-8,2, 8,8 M. D.

The mass spectrum of the high-resolution:606,2429.

TLC: Rf0,40 (15% ethyl acetate in dichloromethane).

Example 349. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3 - yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4 - sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3represents tert-butyl, R4denotes 1-Mei-4-yl) /Isomer 1/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl. Amin receive from the first stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution Drug 150. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane.

The substance has the following physical the Oia: 584,2585.

TLC: Rf0,34 (5% methanol in dichloromethane).

Example 350. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(S or R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran - 3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4 - sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3represents tert-butyl, R4denotes 1-Mei-4-yl) /Isomer 2/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl. Amin receive from the second stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution Drug 150. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-1,1, 1,3, 1,7, 2,3-2,7, 3,6, 3,9, 4,1, 6,8-7,5 M. D.

The mass spectrum of the high-resolution: 584,2585.

TCX: Rf0,34 (5% methanol in dichloromethane).

1denotes 4-florfenicol, R2denotes propyl, R3represents tert-butyl, R4denotes 1-Mei-4-yl) /Isomer 3/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl. Amin receive from the second stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution Drug 150. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,7-1,1, 1,3, 1,7, 2,3-2,7, 3,6, 3,9, 4,1, 6,8-7,5 M. D.

The mass spectrum of the high-resolution: 584,2591.

TLC: Rf0,34 (5% methanol in dichloromethane).

Example 352. N-[3-{ 1(S or R)-)4-Hydroxy-5,6-dihydro-2 - oxo-6(S or R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3 - yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2means are impregnated left connection receive in accordance with the General method of sulfonylamine, Example 252, using the amine of formula WWW-3, where R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl. Amin receive from the second stereoisomer of formula WWW-2, which eluted from the column Chiralcel OD when conducting chiral liquid chromatography high resolution Drug 150. The target compound is isolated in the form of amorphous material after treatment by the method of evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,4, 1,7, 2,3-2,7, 3,6, 3,9, 4,1, 6,8-7,5 M. D.

The mass spectrum of the high-resolution: 584,2580.

TCX: Rf0,34 (5% methanol in dichloromethane).

Example 353. N-[3-{ 1(4-Hydroxy-5,6-Ligero-2-oxo-6,6 - bis(2-phenylethyl)-2H-Piran-3-yl)methyl} phenyl] -5 - cyanopyridine-2-sulfonamide (formula XXX-5: R1denotes 5-cyanopyridine-2-yl) Cm. Scheme XXX.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 64 mg of the amine of formula XXX-4 with 5-cyanopyridine-2-sulfochloride. After purification using the evaporative chromatography on silica gel, elwira 2-3% solution of ethyl acetate in dichloromethane, poluda physical characteristics:

Range PMR: 1,8-2,1, 2,6, 6,9-7,3, 7,9, 8,8 M. D.

The mass spectrum of the high-resolution: 594,2068.

TCX: Rf0,40 (3% methanol in dichloromethane).

Example 354. N-[3-{ 1-(4-Hydroxy-5,6-dihydro-2-oxo-6,6 - bis(2-phenylethyl)-2H-Piran-3-yl)methyl} phenyl] -5 - aminopyridine-2-sulfonamide (formula UUU R1and R2denote phenethyl, R3denotes a hydrogen atom). Cm. Scheme UUU.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 69 mg of the amine of formula XXX-4 with 5-nitropyridine-2-sulfochloride. After purification using the evaporative chromatography on silica gel, elwira 2-3% solution of methanol in dichloromethane, to obtain 107 mg of the intermediate nitro-derivatives of formula UUU-5 (where R1and R2osoznaut phenethyl, and R3denotes a hydrogen atom). Recovery in Amin carried out with gaseous hydrogen over palladium on coal as a catalyst. Evaporative chromatography on silica gel, elwira 4-6% solution of methanol in dichloromethane, get 65,0 mg of target compound in the form of an amorphous substance of white color.

The substance has the following physical characteristics:

Range PMR: 1,9-2,1, 2,6, 3,5-4,0, 6,7, 6,9-7,3, 7,5, 7,9 M. D.

Inuktitut 40 mg initial substance in column 2,125 cm (R,R)Whelk-O 1 (from Regis Technologies, Inc."), the temperature of which is supported on the 30oC. 2 enantiomer suiryudan with retention times of approximately 37 minutes (enantiomer 1) and 43 minutes (enantiomer 2) when using 25% aqueous ISO-propanol and 0.05% acetic acid with a feed rate of 12 ml/min Corresponding fractions combine the results of the analysis in column 0,4625 cm (R,R)Whelk-0 1 if the elution of 30% ISO-propanol and 0.1% acetic acid (V/V) with a feed rate of 1.0 ml/min Isomers suiryudan with retention times of 19.1 minutes (isomer 1) and 23.0 minutes (isomer 2), respectively.

Example 355. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6,6-bis(2-phenethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-aminopyridine-2-sulfonamide (formula WWW-4: R1and R2denote phenethyl, R3represents tert-butyl, R4denotes 5-aminopyridine-2-yl) /Enantiomer 1/ Cm. Scheme WWW.

In the formula WWW-3 (R1and R2denote phenethyl, R3denotes a tert-butyl) 5-nitropyridine-2-sulfochloride. Used amine is obtained from the first enantiomer of formula WWW-2, which eluted from the column (R,R)Whelk-0 when conducting chiral liquid chromatography high resolution of Preparation 151. After purification using the evaporative chromatography on silica gel, elwira 5-10% solution of ethyl acetate in dichloromethane, get 94,0 mg of the intermediate nitro-derivatives of formula UUU-5 (R1and R2denote phenethyl, R3denotes a tert-butyl). Restore to Amin carried out with gaseous hydrogen in the presence of palladium on coal as a catalyst. After purification using the evaporative chromatography on silica gel, elwira 4% solution of methanol in dichloromethane, get 74,8 mg of target compound in the form of an amorphous substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,95, 2,0, 2,6, 6,8, 6,9-7,4, 7,5, 7,9 M. D.

The mass spectrum of the high-resolution: 640,2828.

TLC: Rfa 0.27 (5% methanol in dichloromethane).

Example 356. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6,6-bis(2-phenethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5 - aminopyridine-2-Suchet 5-aminopyridine-2-yl) /Enantiomer 2/ Cm. Scheme WWW.

In accordance with the General method of sulfonylurea shown in Example 252, enter into interaction 73 mg of the amine of formula WWW-3 (R1and R2denote phenethyl, R3denotes a tert-butyl) 5-nitropyridine-2-sulfochloride. Used amine is obtained from the second enantiomer of formula WWW-2, which eluted from the column (R,R)Whelk-0 when conducting chiral liquid chromatography high resolution of Preparation 151. After purification using the evaporative chromatography on silica gel, elwira 5-10% solution of ethyl acetate in dichloromethane, get of 91.3 mg of the intermediate nitro-derivatives of formula UUU-5 (R1and R2denote phenethyl, R3denotes a tert-butyl). Restore to Amin carried out with gaseous hydrogen in the presence of palladium on coal as a catalyst. After purification using the evaporative chromatography on silica gel, elwira 4% solution of methanol in dichloromethane, get to 54.3 mg of target compound in the form of an amorphous substance of white color.

The substance has the following physical characteristics:

Range PMR: 0,95, 2,0, 2,6, 6,8, 6,9-7,4, 7,5, 7,9 M. D.

The mass spectrum of the high-resolution: 640,2828.

TLC: Rfa 0.27 (5% methane is-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R1and R2denotes phenethyl, R3represents tert-butyl, R4refers to 1-methyl-1H-imidazol-4-yl) /Enantiomer 1/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1and R2denote phenethyl, R3represents tert-butyl. Used amine is obtained from the first enantiomer of formula WWW-2, which eluted from the column (R, R)Whelk-O when conducting chiral liquid chromatography high resolution of Preparation 151. After purification using the evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane, to obtain the target compound in the form of an amorphous substance.

The substance has the following physical characteristics:

Range PMR: 0,98, 2,0, 2,6, 3,6, 3,8, 6,9-7,5 M. D.

The mass spectrum of the high-resolution: 628,2832.

TLC: Rf0,38 (5% methanol in dichloromethane).

Example 358. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6,6-bis(2-phenethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1 - methyl-1H-imidazole-4-sulfonamide (formula WWW-4: R1and R2denote phenethyl, R3represents tert-butyl, R4refers to 1-methyl-1H-imidazopyridine, Example 252, using the amine of formula WWW-3, where R1and R2denote phenethyl, R3represents tert-butyl. Used amine is obtained from the second enantiomer of formula WWW-2, which eluted from the column (R,R) Whelk-0 when conducting chiral liquid chromatography high resolution of Preparation 151. After purification using the evaporative chromatography on silica gel, elwira 3% solution of methanol in dichloromethane, to obtain the target compound in the form of an amorphous substance.

The substance has the following physical characteristics:

Range PMR: 0,98, 2,0, 2,6, 3,6, 3,8, 6,9-7,5 M. D.

The mass spectrum of the high-resolution: 628,2838.

TLC: Rf0,38 (5% methanol in dichloromethane).

Example 359. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro - 2-oxo-6,6-bis(2-phenethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5 - cyanopyridine-2-sulfonamide (formula WWW-4: R1and R2denote phenethyl, R3represents tert-butyl, R4denotes 5-cyanopyridine-2-yl) /Enantiomer 1/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1and R2denote phenethyl, R3hereafter and of (R, R)Whelk-0 when conducting chiral liquid chromatography high resolution of Preparation 151. After purification using the evaporative chromatography on silica gel, elwira 10% solution of ethyl acetate in dichloromethane, to obtain the target compound in the form of an amorphous substance.

The substance has the following physical characteristics:

Range PMR: 0,87, 1,9, 2,6, 6,8-7,4, 7,9, 8,8 M. D.

The mass spectrum of the high-resolution: 650,2681.

TLC: Rf0,46 (15% ethyl acetate in dichloromethane).

Example 360. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6,6-bis(2-phenethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-cyanopyridine-2-sulfonamide (formula WWW-4: R1and R2denote phenethyl, R3represents tert-butyl, R4denotes 5-cyanopyridine-2-yl) /Enantiomer 2/ Cm. Scheme WWW.

The target connection receive in accordance with the General method of sulfonylurea shown in Example 252, using the amine of formula WWW-3, where R1and R2denote phenethyl, R3represents tert-butyl. Used amine is obtained from the second enantiomer of formula WWW-2, which eluted from the column (R, R)Whelk-0 when conducting chiral liquid chromatography high resolution of Preparation 151. After ochistka the target compound in the form of an amorphous substance.

The substance has the following physical characteristics:

Range PMR: 0,87, 1,9, 2,6, 6,8-7,4, 7,9, 8,8 M. D.

The mass spectrum of the high-resolution: 650,2681.

TLC: Rf0,46 (15% ethyl acetate in dichloromethane).

Preparation 152. Splitting phenylmethylene ether N-[3-[1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl) propyl] phenyl] carbamino acid 2 isomers (formula WWW-2: R1and R2denotes propyl, R3denotes ethyl) Cm. Scheme WWW.

The sample source connection Inuktitut in column 2.1 x 25 cm Chiralcel OD and elute 20% solution of ISO-propanol in hexane (V/V) with a feed rate of 10 ml/min. Substance eluted with retention times of approximately 19.1 per minute, is a single isomer (enantiomer 1) and the material that eluted with a retention time of approximately 37.7 minutes is another isomer (enantiomer 2). The appropriate fractions are combined and separately evaporated on a rotary evaporator (for about 30 minutes at a temperature in the bath is not more than 50oC) and get a solid white color.

Example 361. N-[3-{1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine is no 5-cyanopyridine-2-yl) /Enantiomer 1/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods using enantiomer 1 of the Drug 152.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,2-2,2, 3,90, 6,9-7,2, 8,0, 8,15, 8,9 M. D.

The mass spectrum of the high-resolution: 497,1984.

TLC: Rf0,38 (15% ethyl acetate in dichloromethane).

Example 362. N-[3-{1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2 - sulfonamide (formula WWW-4: R1and R2denote propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Enantiomer 2/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods using enantiomer 2 of the Drug 152.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,2-2,2, 3,90, 6,9-7,2, 8,0, 8,15, 8,9 M. D.

The mass spectrum of the high-resolution: 497,1980.

TLC: Rf0,38 (15% ethyl acetate in dichloromethane).

Example 363. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro - 2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5 - aminopyridine-2-sulfonamide (formula WWW-4: R1and R2denote propyl, R3denotes ethyl, R4hereafter the e above methods, using enantiomer 1 of the Drug 152.

The substance has the following physical characteristics:

Range PMR: 0,7-0,9, 1,2-2,2, 3,8, 6,8-7,2, 7,5, 7,9 M. D.

The mass spectrum of the high-resolution: 487,2122.

TCX: Rf0,28 (5% methanol in dichloromethane).

Example 364. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5 - aminopyridine-2-sulfonamide (formula WWW-4: R1and R2denote propyl, R3denotes ethyl, R4denotes 5-aminopyridine-2-yl) /Enantiomer 2/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods using enantiomer 2 of the Drug 152.

The substance has the following physical characteristics:

Range PMR: 0,7-0,9, 1,2-2,2, 3,8, 6,8-7,2, 7,5, 7,9 M. D.

The mass spectrum of the high-resolution: 487,2140.

TLC: Rf0,28 (5% methanol in dichloromethane).

Preparation 153. Splitting phenylmethylene ether N-[3-[1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl) -6-propyl-2H-Piran-3-yl)propyl} phenyl] carbamino acid 4 isomers (formula WWW-2: R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl) Cm. Scheme WWW.

Enantiomers determine the 0,56 x 25 cm Chiralcel OD-H (from Chiral Technologies, Inc."), which elute with a mixture containing 20% ISO-propanol and 0.05% triperoxonane acid in hexane (V/V), pumped at a rate of 0.5 ml/min the retention Time in this system are (isomer 1) 21.6 minutes (isomer 2) 34.5 minutes (isomer 3) 55.2 minutes (isomer 4) 66.6 minutes.

The enantiomers separated on a column (2.1 x 25 cm Chiralcel OD (from Chiral Technologies, Inc. "), which elute with a mixture containing 17.5% of ISO-propanol in hexane (V/V) delivered at a rate of 10 ml/min Corresponding fractions with retention times of approximately 24,6, 42,9, 66,3 and 77.4 minutes unite after analysis of the System D. In accordance with the order of elution, four isomers indicate, respectively, as the isomers 1-4.

In all cases, when performed removal of the solvent from the combined fractions, use the following methodology. The solvent is removed from the combined fractions on a rotary evaporator under a residual pressure of approximately 30 mm RT. Art. and the temperature in the bath 455oC. If the mixture is acetic acid, then add toluene in the amount of about 10 ml/l and evaporated to dryness. The final removal of solvent weighing is carried out at room temperature for 2-24 hours under on the Nile)ethyl)-6-propyl-2H-Piran-3 - yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 1/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods using isomer 1 of Preparation 153.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,3, 1,6-2,2, 2,5, 3,9, 6.8-7,3, 7,9-8,1, 8,9 M. D.

The mass spectrum of the high-resolution: 578,2120.

TLC: Rf0,35 (15% ethyl acetate in dichloromethane).

Example 366. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(S or R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl) propyl} phenyl] -5-cyanopyridine-2-sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 2/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods using isomer 2 of Preparation 153.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,3, 1,6-2,2, 2,5, 3,9, 6,8-7,3, 7,9-8,1, 8,9 M. D.

The mass spectrum of the high-resolution: 578,2120.

TLC: Rf0,35 (15% ethyl acetate in dichloromethane).

Example 367. N-[3-{ 1(S or R)-(4-Guide the MFA (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 3/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods, using the isomer 3 153 Drug.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,3, 1,6-2,2, 2,5, 3,9, 6,8-7,3, 7,9-8,1, 8,9 M. D.

The mass spectrum of the high-resolution: 578,2126.

TLC: Rf0,35 (15% ethyl acetate in dichloromethane).

Example 367A. N-[3-{ 1(S or R)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(S or R)-(2-(4-forfinal)ethyl)-6-propyl-2H - Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl, R4denotes 5-cyanopyridine-2-yl) /Isomer 4/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods, using the isomer 4 Preparation 153.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,3, 1,6-2,2, 2,5, 3,9, 6,8-7,3, 7,9-8,1, 8,9 M. D.

The mass spectrum of the high-resolution: 578,2126.

TLC: Rf0,35 (15% ethyl acetate in dichloromethane).

Example 368. N-[3-{ 1{ R or S)-(4-Gonemad (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl, R4denotes 1-Mei-4-yl) /Isomer 1/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods using isomer 1 of Preparation 153.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,3, 1,6-2,2, 2,6, 3,63, 4,0, 6,9-7,5 M. D.

The mass spectrum of the high-resolution: 556,2265.

TLC: Rf0,29 (5% methanol in dichloromethane).

Example 369. N-[3-{ 1(R or S)-(4-Hydroxy-5,6-dihydro-2 - oxo-6(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3 - yl)propyl} phenyl] -5-aminopyridine-2-sulfonamide (formula WWW-4: R1denotes 4-florfenicol, R2denotes propyl, R3denotes ethyl, R4denotes 5-aminopyridine-2-yl) /Isomer 1/ Cm. Scheme WWW.

The target connection receive by analogy with the previously described methods using isomer 1 of Preparation 153.

The substance has the following physical characteristics:

Range PMR: 0,8-1,0, 1,3, 1,6-2,2, 2,5, 3,9, 6,8-7,2, 7,5, 7,9 M. D.

The mass spectrum of the high-resolution: 568,2271.

TCX: Rfa 0.27 (5% methanol in dichloromethane).

Preparation 154. Hexahydro-2H-benzopyran-2,4(3H)-is D-1, where n is 1, in 100 ml of acetic acid are placed for 1.5 hours in a Parr apparatus for hydrogenation with an initial hydrogen pressure of 60 pounds-force per square inch (344,7 kPa). Then the reaction mixture was filtered through celite and evaporated in vacuum, obtaining a solid beige color. The crude product is purified by a method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh), elwira 0-5% solution of methanol in chloroform, and get to 0.94 g of target compound in a solid white color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 4,84-4,80, 3,54, 3,40, 2,60-2,53, 2,98-2,02, 1,79-1,65, 1,62-1,54, 1,44-1,40 M. D.

Range13C-NMR (deuterochloroform): 203,0, 167,4, 74,3, 47,7, 45,6, 29,1, 23,5, 23,2, 19,7 M. D.

IR-spectrum (mineral oil): 3092, 2768, 2714, 2695, 2662, 1657, 1614, 1577, 1444, 1352, 1345, 1340, 1323, 1308, 1295, 1287, 1260, 1244, 1211, 1188, 1057, 1004, 938, 909, 890, 843, 832, 600 cm-1.

Mass spectrum (E1): /M+/ = 168.

Elemental analysis, found: C, 64,16; H, 7,16.

Preparation 155. 4a, 5,6,7,8,8 and Hexahydro-4-hydroxy-3-[1- (3-nitrophenyl)propyl] -2H-1-benzopyran-2-he (formula DDDD-4, where N is 1, and R1denotes ethyl) Cm. Scheme DDDD.

A solution of 3,17 g trichloride aluminum in 30 ml of tetrahydrofuran are added to a solution 2 is eshivot at room temperature for 2.5 hours and add 7,28 g decahydrate sodium carbonate, then the reaction mixture is stirred for another 20 minutes. The mixture is dried over magnesium sulfate, filtered through celite and evaporated in vacuum, obtaining 6,05 g of a yellow resin. The crude product was immediately dissolved in 50 ml of tetrahydrofuran containing 0.73 g of the bromide complex of copper (1) - dimethyl sulphide, and the reaction mixture was added 13.1 ml of a 1.0 M solution of triethylaluminum in hexane. Stirred at room temperature for one hour and is decomposed by adding water. The resulting mixture was poured into a mixture of ether and water. The organic layer is separated, washed with saturated salt solution and evaporated in vacuum, obtaining 4.0 g of a yellow oil. The crude product is purified evaporative column chromatography, elwira 10-50% solution of ethyl acetate in hexane, and get to 0.63 g of target compound in the form of a foamy substance yellow.

The substance has the following physical characteristics:

Melting point 86-91oC.

IR-spectrum (mineral oil): 3085, 1635, 1569, 1528, 1448, 1394, 1365, 1349, 1325, 1307, 1288, 1270, 1251, 1244 cm-1.

Example 370. 5-Cyano-N-[3-1-(4a,5,6,7,8,8 a-hexahydro-4 - hydroxy-2-oxo-2H-1-benzopyran-3-yl)propyl]phenyl]-2 - pyridinesulfonamide (formula DDDD-7, where n is 1, R1oboznachaet 155 in 50 ml of ethanol and 0.3 g of 10% palladium on coal is placed for 3 hours in a Parr apparatus for hydrogenation with an initial hydrogen pressure of 50 lbs/sq. inch (344,7 kPa). Then the reaction mixture was filtered through celite and evaporated in vacuum, obtaining 0,519 g of intermediate compounds. 0.25 g of the specified intermediate connection immediately dissolved in 5 ml of methylene chloride and the resulting solution was added has 0.168 g of 5-cyano-2-pyridinesulfonamide and 0,134 ml of pyridine. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture is then purified by the method of evaporating column chromatography on silica gel 60 (230-400 mesh mesh), elwira 0-2,5% solution of methanol in chloroform, and get 0,164 g of target compound in the form of a foamy substance white with so pl. 122-125oC.

The substance has the following physical characteristics:

The mass spectrum of the high-resolution: 468,1611.

Example 371. 4-Cyano-N-[3-1-(4a,5,6,7,8,8 and hexahydro-4 - hydroxy-2-oxo-2H-1-benzopyran-3-yl)propyl]phenyl] benzosulfimide (formula DDDD-7, where n is 1, R1denotes ethyl, and R2denotes 4-cyanophenyl) Cm. Scheme DDDD.

In accordance with the General procedure described in Example 370, and conduct minor changes, get, substituting 5-cyano-2-pyridinesulfonamide 4-cyanobenzenesulfonyl, 0,236 g of target compound in the form of penoobrazovatelej:

The mass spectrum of the high-resolution: 466,1583.

Preparation 156. 4-Hexahydrophthalate[b]Piran-2,4(3H,4aH)- dione (formula DDDD-2, where n is equal to 2) Cm. Scheme DDDD.

In accordance with the General procedure described for the Preparation 154, and conduct minor changes, get, replacing cyclohexylphenol formula DDDD-1, where n is 1, cycloheptylamine formula DDDD-1, where n is equal to 2, of 0.337 g of target compound in a solid white color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 4,97-4,91, 3,52, 3,42, 2,64-2,58, 2,22-2,11, 2,01-1,72, 1,59-1,36 M. D.

Range13C-NMR (deuterochloroform): 203,0, 167,2, 78,0, 52,1, 46,5, 32,1, 28,6, 27,1, 25,7,21,3.

IR-spectrum (mineral oil): 3074, 2791, 2755, 2736, 2687, 2637, 2608, 2585, 1655, 1625, 1586, 1500, 1480, 1443, 1333, 1324, 1293 (singlet), 1265, 1254, 1240, 1222, 1196, 1173, 1082, 1053, 1016, 909, 889, 832, 611 cm-1.

Mass spectrum (E1): [M+] = 182.

Elemental analysis, found: C, 66,16; H, of 7.90.

Preparation 157. 5,6,7,8,9,9-Hexahydro-4-hydroxy-3-[1- (3-nitrophenyl)propyl] -cyclohepta[b] Piran-2(4aH)-he (formula DDDD-4, where n is 2, a R1denotes ethyl) Cm. Scheme DDDD.

In accordance with the General procedure described for the preparation 155, and making minor changes, get, replace the substances yellow with so pl. 75-78oC.

The substance has the following physical characteristics:

IR-spectrum (mineral oil): 3071, 2667, 1638, 1528, 1395, 1350, 1305, 1276, 1250, 1143, 1130, 1120, 1100, 1066, 782, 764, 741, 697, 685 cm-1.

The mass spectrum of high resolution, found: 345,1590.

Elemental analysis, found: C, 58,74; H, 5,63; N,3,48.

Example 372. 5-Cyano-N-[3-[1-(2,4 and,5,6,7,8,9,9 a-octahydro - 4-hydroxy-2-oxocyclopent[b] Piran-3-yl)propyl] phenyl]-2 - pyridinesulfonamide (formula DDDD-7, where n is 2, R1denotes ethyl, and R2denotes 5-cyano-2-pyridyl) Cm. Scheme DDDD.

In accordance with the General procedure described in Example 370, and conduct minor changes, get, replacing the target product of Preparation 155 to the target product of Preparation 157, 0,206 g of target compound in the form of a foamy substance white with so pl. 163-166oC.

The substance has the following physical characteristics:

IR-spectrum (mineral oil): 3352, 3128, 3100, 3073, 3029, 1760, 1726, 1641, 1608, 1593, 1584, 1411, 1397, 1355, 1295, 1282, 1242, 1207, 1173, 1125, 1106, 1086, 1074, 1028, 974, 967, 721, 701, 645, 638 cm-1.

The mass spectrum of high resolution, found: 481,1693.

Preparation 158. Octahydro-2H-cycloocta[b] Piran-2,4(3H)-dione (formula DDDD-2, where n is equal to 3). Cm. Scheme DDDD.

In soo cycloheptylamine formula DDDD-1, where n is equal to 2, cyclooctadiene formula DDDD-1, where n is 3, 1,72 g of target compound in a solid white color.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 4,84-4,78, 3,61, 3,40, 2,75-2,70, 2,14-1,97, 1,90-1,72, 1,68-1,44 M. D.

Range13C-NMR (deuterochloroform): 204,2, 167,2, 78,2, 49,5, 46,1, 28,5, 27,3, 26,2, 24,7, 23,9, 22,1 M. D.

IR-spectrum (mineral oil): 2659, 2617, 1650, 1612, 1579, 1444, 1356, 1332, 1307, 1287, 1265, 1244, 1227, 1209, 1041, 1035, 1003, 962, 946, 860, 832, 824 cm-1.

The mass spectrum of high resolution, found: 196,1100.

Elemental analysis, found: C, 67,06; H, 8,23.

Preparation 159. 3-[2,2-Dimethyl-1-(3-nitrophenyl)propyl]- 4a, 5,6,7,8,9,10,10 and octahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he (formula DDDD-4, where n is 3, a R1denotes a tert-butyl) Cm. Scheme DDDD.

A solution of 1.36 g of trichloride aluminum in 30 ml of tetrahydrofuran are added to a solution of 1.0 g of the target product of Preparation 158 and 0.77 g of 3-nitrobenzaldehyde in 20 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 2.3 hours and add a 3.06 g decahydrate sodium carbonate, after which the reaction mixture is stirred for 15 more minutes. The mixture is dried over magnesium sulfate, filtered of caricatura for use in the next stage.

In a dry flask of 0.82 g of activated zinc, 3 ml of tetrahydrofuran, a 0.035 ml dibromethane and 0.21 ml of 1 M solution of trimethylsilylacetamide in tetrahydrofuran. After addition of all reagents, the mixture is subjected in the course of 15 minutes, the effect of ultrasound at a temperature of 45oC. the Mixture is then diluted by adding 2 ml of tetrahydrofuran, and added dropwise to 1.32 ml iodide, tert-butyl. The resulting mixture was subjected to 3 hours of the exposure to ultrasound at a temperature of 45oC. Separately stirred mixture of 0.85 g of copper cyanide (1) and 0.80 g of lithium chloride in 4 ml of tetrahydrofuran at room temperature for 1 hour, until the mixture becomes almost homogeneous and cooled to a temperature of minus 30oC. the Solution tsinkorganicheskih derived then added via a cannula to a solution of copper cyanide, allow the mixture to warm to 0oC and stirred for 15 minutes. The reaction mixture is then cooled to minus 78oC and add the above solution of intermediate compounds. Stirred for 20 minutes at a temperature of minus 78oC and 30 minutes at a temperature of 0oC and then the reaction mixture is decomposed with a saturated aqueous solution of ammonium chloride and diluted with additionally EXT is toorange substances orange. The crude product is purified by a method of evaporating column chromatography, elwira 10-30% solution of ethyl acetate in hexane followed by recrystallization from a mixture of methylene chloride/hexane, and get to 0.60 g of target compound in a solid yellow color with so pl. 158-161oC.

The substance has the following physical characteristics:

IR-spectrum (mineral oil): 3077, 2646, 1632, 1599, 1529, 1477, 1450, 1396, 1357, 1349, 1334, 1317, 1283, 1273, 1252, 1232, 1217, 1205, 1181 cm-1.

Example 373. 5-Cyano-N-[3-[2,2-dimethyl-1-(4a, 5,6,7,8,9,10,10 a-octahydro-4 - hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)propyl] phenyl] -2-pyridinesulfonamide (formula DDDD-7, where n is 2, R1denotes ethyl, and R2denotes 5-cyano-2-pyridyl) Cm. Scheme DDDD.

In accordance with the General procedure described in Example 370, and making minor changes, get, replacing the target product of Preparation 157 to the target product Preparation 159, 0,034 g of target compound in the form of a crystalline substance of white color with so pl. 182-185oC.

The substance has the following physical characteristics:

IR-spectrum (mineral little): 3246, 3121, 3098, 2615, 1655, 1633, 1607, 1585, 1575, 1491, 1411, 1395, 1354, 1335, 1322, 1311, 1298, 1281, 1275, 1262, 1255, 1233, 1206, 1178, 1121, 1109, 1028, 977, 702, 657, 646, 635, 605 �: With, 63,86; H, 6,41; N, OF 7.82.

Preparation 160. (3(3R),4S)-3-[2-[1-[3-[bis(phenylmethyl) amino]phenyl]propyl] -5-hydroxy-1,3-dioxo-5-(2-phenylethyl) octyl] -4-phenyl-2-oxazolidinone (formula W-10, where R1denotes 2-phenylethyl) Cm. The schema W.

To 100 ml of methylene chloride add 5.0 g of target compound of Preparation 95 (formula W-8) and the resulting solution in a stream of nitrogen is cooled to minus 78oC. To this solution add 1.0 ml of pure titanium tetrachloride and 1.63 ml of di-ISO-propylacetamide and stirred for one hour. To the resulting solution was added 3,30 g of 1-phenyl-3-hexanone and the resulting reaction mixture for 2.5 hours, allowed to warm to a temperature of 0oC. Decomposing the reaction mixture with a saturated solution of ammonium chloride, extracted with methylene chloride, the organic extracts washed with saturated sodium bicarbonate solution and evaporated in a vacuum, getting 9.7 g of yellow oil. It chromatographic using 900 g of silica gel (elute 10% hexane solution in methylene chloride and 100% methylene chloride), and get 3,30 g of the target product as a foamy substance yellow with so pl. 121-126oC.

The substance has the following physical characteristics:

Range PMR (deutero the ptx2">

Range13C-NMR (deuterochloroform): 167,2, 167,1, 153,7, 142,6, 141,0, 138,2, 138,1, 129,6, 129,5, 129,2, 128,9, 128,8, 128,6, 128,4, 128,3, 127,0, 125,8, 125,6, 73,1, 70,0, 69,9, 63,9, 57,9, 54,8, 54,7, 51,5, 51,4, 48,3, 41,3, 41,0, 40,8, 40,5, 29,8, 29,6, 27,1, 26,9, 16,8, 16,6, 14,6, 11,7, 11,6 M. D.

IR-spectrum (mineral oil): 3525, 3061, 3026, 1777, 1720, 1690, 1601, 1495, 1361, 1335, 1238, 1199, 1104, 735, 698 cm-1.

Mass spectrum (E1): [M+] = 736.

Elemental analysis, found: C, 78,03; H, 7,11; N, 3,79.

The drug 161. (3S)-3-[1-[3-Bis(phenylmethyl)amino]phenyl] propyl]-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propelers-2-he (formula W-11, where R1denotes 2-phenylethyl) Cm. The schema W.

To 5 ml of dry tetrahydrofuran added 2.7 g of the target product of Preparation 160 and the resulting solution in a stream of nitrogen cooled to 0oC. To the resulting solution was added to 0.45 ml of 1 M solution of tert-butoxide potassium in tetrahydrofuran. Allow the reaction mixture to warm to 20oC and stirred for 2 hours. Decomposing the reaction mixture with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated in a vacuum, getting 0.28 g of yellow oil. It chromatographic using 80 g of silica gel (elute with 10%-30% solution of acetone in hexane), and gain of € 0.195 g foamy arises with so pl. 128-131oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,35-7,12, 6,73-6,64, 5,84, 4,73-4,57, 4,12, 2,69-2,61, 2,38-2,20, 1,95-1,65, 1,41- 1,32, 0,98-0,87 M. D.

Range 13C-NMR (deuterochloroform): 204,1, 204,0, 171,7, 171,4, 169,6, 140,9, 140,8, 140,6, 140,5, 140,4, 139,9, 139,8, 138,3, 129,7, 129,6, 129,5, 128,9, 128,6, 128,5, 128,4, 128,2, 128,1, 127,1, 126,9, 126,8, 126,7, 126,5, 126,4, 126,3, 126,2, 126,0, 125,9, 116,8, 112,6, 112,5, 112,4, 112,3, 112,2, 112,1, 112,0, 82,0, 81,9, 81,8, 80,4, 80,3, 58,6, 58,5, 54,5, 51,4, 50,4, 50,1, 49,9, 47,8, 47,4, 47,0, 46,6, 43,0, 42,9, 42,2, 41,9, 40,2, 40,1, 40,0, 39,2, 29,8, 29,7, 29,6, 29,1, 29,0, 26,8, 26,7, 24,7, 24,6, 24,3, 16,9, 16,5, 14,0, 12,3 M. D.

IR-spectrum (mineral oil): 3023, 1637, 1599, 1584, 1575, 1494, 1347, 1300, 1257, 1243, 1234, 920, 731, 704, 695 cm-1.

Mass spectrum (E1): [M+] = 573.

Elemental analysis, found: C, 81,53; H, of 7.82; N, 2,34.

[]D(chloroform) = -83o< / BR>
The product 162. (3S)-3-[1-(3-AMINOPHENYL)propyl]-5,6 - dihydro-4-hydroxy-6-(2-phenylethyl)-6-propelers-2-he (formula W-12, where R1denotes 2-phenylethyl) Cm. The schema W.

0,63 g of the target product of Preparation 161 dissolved in 45 ml of ethyl acetate and 15 ml of methanol. To the resulting solution was added to 0.47 g of 10% palladium on coal and the resulting mixture hydronaut for 2.5 hours under hydrogen pressure of 50 pounds-force per square inch (344,7 kPa). Then the reaction mixture was filtered through zaochnoi chromatography, using 80 g of silica gel (elute 20-50% solution of ethyl acetate in hexane), and get 0,389 g of target compound in the form of a solid whitish with so pl. 155-159oC.

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,26-7,20, 7,15-7,04, 6,95, 6,81, 6,74, 6,54-6,51, 3,98-3,91, 2,68-2,54, 2,25-2,17, 2,02-1,67, 1,43-1,28, 0,99-0,87 M. D.

Range13C-NMR (deuterochloroform): 171,2, 171,0, 148,5, 148,2, 143,9, 130,4, 130,2, 127,8, 120,8, 117,8, 115,3, 107,4, 82,7, 44,6, 44,4, 41,8, 41,7, 41,5, 38,4, 31,8, 26,8, 26,7, 18,8, 15,6, 14,3 M. D.

IR-spectrum (mineral oil): 3085, 3061, 3026, 1617, 1605, 1495, 1314, 1258, 1168, 1119, 1065, 1030, 923, 776, 699 cm-1.

Mass spectrum (E1): [M+] = 393.

Elemental analysis, found: C, 76,13; H, 8,16; N, 3,37.

[]D(methanol) = -41o< / BR>
Example 374. N-[3-[1-(S)-[5,6-Dihydro-4-hydroxy-2 - oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]propyl]phenyl]-5-(trifluoromethyl) -2-pyridinesulfonamide (formula W-13, where R1denotes 2-phenylethyl) Cm. The schema W.

To a solution 0,200 g of the target product of Preparation 162 in 5 ml of methylene chloride add to 0.12 ml of pyridine. The resulting mixture was cooled to 0oC and add 0,132 g 5-triptorelin-2 - sulfochloride. The reaction mixture was stirred at room temperature for 1.5 hours is the cosmology vacuum and obtain 0.39 g of oil rose color. Its clear column chromatography using 50 g of silica gel (elute 20-50% solution of ethyl acetate in hexane), and get 0,252 g of target compound in the form of a foamy substance white with so pl. 170-173oC.

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 8,95-8,92, 8,23-8,16, 8,04-8,00, 7,25-6,90, 4,86, 3,98-3,90, 3,31, 3,30, 2,69-2,46, 2,18-2,09, 1,96-1,65, 1,41-1,28, 0,99-0,81 M. D.

Range13C-NMR (deuterochloroform): 167,3, 147,7, 147,5, 142,9, 142,8, 137,7, 137,0, 129,5, 129,2, 126,9, 126,2, 126,1, 124,1, 122,6, 122,5, 120,3, 120,2, 81,8, 81,7, 43,6, 43,2, 40,9, 40,5, 37,5, 30,9, 25,8, 25,6, 17,9, 14,7, 13,3, 13,2 M. D.

IR-spectrum (mineral oil): 3087, 3027, 1642, 1606, 1595, 1327, 1260, 1173, 1142, 1110, 1074, 1016, 720, 700, 613 cm-1.

Mass spectrum (FAB): [M+H] = 603.

Elemental analysis, found: C, 61,79; H, 5,86; N, 4,48; S, 5,16.

[]D(methanol) = -31o< / BR>
Preparation 163. (3S, 6R)-3-[1-[3-Bis(phenylmethyl) amino]phenyl]-propyl]-5,6-dihydro-4-hydroxy-6-(2-phenylethyl) - 6-propelers-2-he (formula FFF-2) Cm. Scheme FFF.

The target compound of Preparation 161 chromatographic on a column of 5.1 x 30 cm Cyclobond I 2000, cooled in a bath of ice, injective 90 mg with automated chromatographic system; as the mobile phase using acetonitrile, containing, Corot supply of reagents is 45 ml/min Corresponding fraction after the second injection are combined and evaporated in a vacuum, getting 0,300 g of a dark oil. It is poured into a mixture of ethyl ether and a saturated aqueous solution of sodium bicarbonate. The organic layer is separated and evaporated in vacuum. The residue is purified column chromatography using 50 g of silica gel (elute 10-20% solution of acetone in hexane), and get 0,22 g of target compound as a colourless oil.

The substance has the following physical characteristics:

The retention time of the target compounds is 57 minutes.

Preparation 164. (3S,6S)-3-[1-[3-Bis(phenylmethyl)amino] phenyl]propyl]-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6 - propelers-2-he (formula FFF-3) Cm. Scheme FFF.

The target compound of Preparation 161 share as described above for the Preparation 163. After further purification as described for the Preparation 163, get 0,117 g of target compound as a colourless oil.

The substance has the following physical characteristics:

The retention time of the target compounds is 66 minutes.

Preparation 165. (3S, 6R)-3-[1-(3-(AMINOPHENYL)propyl]-5,6 - dihydro-4-hydroxy-6-(2-phenylethyl)-6-propeler the leading minor changes receive, replacing the target product of Preparation 161 to the target Product of Preparation 163, of 0.022 g of the target compound.

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 7,25-7,18, 7,15-7,12, 7,07-7,05, 6,97, 6,82, 6,76-6,71, 6,53, 4,00-3,92, 2,67- 2,54, 2,29-2,15, 2,06-1,92, 1,90-1,62, 1,46-1,28, 0,97-0,88 M. D.

Example 375. (3S,6R)-N-[3-[1-[5,6-Dihydro-4-hydroxy-2 - oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] propyl] phenyl] - 5-(trifluoromethyl)-2-pyridinesulfonamide (formula FFF-5) Cm. Scheme FFF.

In accordance with the General procedure described in Example 374, and making minor changes, get, replacing the targeted product 162 Drug to the target product of Preparation 165, 0,024 g of target compound in the form of a foamy substance white with so pl. 156-159oC.

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 8,90, 8,20-8,17, 8,02-7,99, 7,28-6,88, 4,00-3,90, 2,71-2,46, 2,20-2,10, 1,98-1,67, 1,41-1,28, 0,98-0,81 M. D.

Example 376. (S)-N-[3-[1-(5,6-Dihydro-4-hydroxy-2 - oxo-6,6-dipropyl-2H-Piran-3-yl)propyl] phenyl]-5-(trifluoromethyl) -2-pyridinesulfonamide (formula W-13) Cm. The schema W.

To a solution of 182 mg of the target product of Preparation 99 (formula W-12) in 5 ml of methylene chloride add 133 l of pyridine. The resulting mixture is cooling the e 30 minutes and the methylene chloride evaporated under vacuum. The residue is diluted with ethyl acetate, washed with water, saturated salt solution and dried over sodium sulfate. The solvent is evaporated and obtain 580 mg of crude product. Its clear column chromatography using 50 g of silica gel (elute 50% solution of ethyl acetate in hexane), and obtain 211 mg of the target compound in the form of a foamy substance of white color.

The substance has the following physical characteristics:

Elemental analysis, found: C, 57,80; H, 5,95; N, Of 5.05; S 5,64.

[]D(18,094 mg/2 ml chloroform) = -30o< / BR>
Example 377. (3R)-N-[3-[1-(5,6-Dihydro-4-hydroxy-2 - oxo-6,6-dipropyl-2H-Piran-3-yl)propyl] phenyl]-5- (trifluoromethyl)-2-pyridinesulfonamide (formula X-13) Cm. Scheme X.

To a solution of 170 mg of the target product of Preparation 107 (formula X-12) in 5 ml of methylene chloride add 136 μl of pyridine. The resulting mixture was cooled to 0oC and added 132 g of 5-triptorelin-2-sulfochloride. The reaction mixture is stirred for 30 minutes and the methylene chloride evaporated under vacuum. The residue is diluted with ethyl acetate, washed with water, saturated salt solution and dried over sodium sulfate. The solvent is evaporated and get the crude product. Its clear column chromatography, use the foamy substance of white color.

The substance has the following physical characteristics:

[]D(mg/2 ml chloroform) = +29o.

Preparation 166. (3S,4R)-3-[2-[1-[3-[bis(phenylmethyl) amino]phenyl]propyl]-5-hydroxy-1,3-dioxo-5-penetratin] -4-phenyl-2 - oxazolidinone (formula X-10, where R1denotes phenethyl) Cm. Scheme X.

To 1.12 g of target compound of Preparation 104 add 20 ml of methylene chloride and the resulting solution is cooled to minus 78oC and stirred for one hour. To this solution add 237 μl of titanium tetrachloride, and then 400 μl of di-ISO-propylacetamide and the resulting solution is stirred at minus 78oC for one hour. To the resulting solution was added 776 μl of 1-phenyl-3-hexanone and stirring at a temperature of minus 40oC continue for another 40 minutes, and then give the resulting reaction mixture for 1.5 hours, heated to a temperature of minus 10oC. Decomposing the reaction mixture with a saturated solution of ammonium chloride, extracted with methylene chloride and the organic extracts evaporated under vacuum. The crude product chromatographic using 200 g of silica gel (elute 10% hexane solution in methylene chloride), and obtain 870 mg of the target product.

Substance region is cm-1.

[]D(16,578 mg in chloroform) = +4o< / BR>
Mass spectrum: molecular ion 736.

Elemental analysis, found: C, 78,00; H, 7,14; N 3,61.

Preparation 167. (3R)-3-[1-[3-[Bis(phenylmethyl)amino] phenyl]propyl]- 5,6-dihydro-4-hydroxy-6-phenethyl-6-propelers-2-he (formula X-11, where R1denotes phenethyl) Cm. Scheme X.

The target compound of Preparation 166 (750 mg) add 5 ml of dry tetrahydrofuran, tert-piperonyl potassium (1.0 M solution in tetrahydrofuran). The reaction mixture is stirred at a temperature of 20oC for 30 minutes and decompose, adding a saturated solution of ammonium chloride. Extracted with ethyl acetate, the organic extracts are combined, washed with water and saturated salt solution and, finally, evaporated, give crude product. It chromatographic using 100 g of silica gel (elute with a 15% solution of ethyl acetate in hexane), and receive a 511 mg of the target compound.

The substance has the following physical characteristics:

IR-spectrum (mineral oil): 2956, 2855, 1628, 1599, 1577, 1494, 1385, 1364, 697 cm-1.

Elemental analysis, found: C, 81,30; H, to 7.68; N, 2,30.

Mass spectrum: molecular ion 573.

[]D(18,116 mg/2 ml methanol) = +38o< / BR>
Will prepoznacete phenethyl) Cm. Scheme X.

The target product of Preparation 167 (370 mg) is dissolved in 35 ml of ethyl acetate and 6 ml of methanol. To the resulting solution was added 200 mg of 10% palladium on coal as a catalyst and the resulting mixture hydronaut for 2 hours under hydrogen pressure of 50 pounds-force per square inch (344,7 kPa). Then the reaction mixture is evaporated and purified column chromatography using 60 g of silica gel, and get 244 mg of the target compound.

The substance has the following physical characteristics:

IR-spectrum (mineral oil): 3025, 2954, 2871, 2854, 1635, 1619, 1604, 1494, 1456, 1383, 1378, 1256 cm-1.

[]D(16,764 mg/2 ml methanol) = +39o< / BR>
Mass spectrum: molecular ion 393.

Elemental analysis, found: C, 75,79; H, with 8.05; N, 3.27 to.

Example 378. (3R)-N-[3-[1-(5,6-Dihydro-4-hydroxy-2-oxo - 6-propyl-6-phenethyl-2H-Piran-3-yl)propyl] phenyl] -5-(trifluoromethyl)-2 - pyridinesulfonamide (formula X-13, where R1denotes phenethyl) Cm. Scheme X.

To the product of Preparation 168 (156 mg) add 5 ml of methylene chloride. To the resulting solution was added to 96 μl of pyridine and cooled to 0oC. Then added 102 mg of 5-triptorelin-2 - sulfochloride. The reaction mixture is stirred for one hour, and then pour in this is the Aquum and the rest chromatographic, using 100 g of silica gel (elute 50% solution of ethyl acetate in hexane), and receive 200 mg of the target compound.

The substance has the following physical characteristics:

Mass spectrum: molecular ion 602.

IR-spectrum (mineral oil): 2953, 2922, 2870, 2853, 1642, 1605, 1459, 1457, 1326, 1259, 1180, 1171, 1141 cm-1.

UV spectrum (ethanol)max() 216 (22300), 264 shoulder(10700), 270 (11500), 279 (12100)

Elemental analysis, found: C, 57,53; H, 5,98; N, 4,84.

Example 379. (3R,6S)-N-[3-[1-(5,6-Dihydro-4-hydroxy-2 - oxo-6-propyl-6-phenethyl-2H-Piran-3-yl-propyl]phenyl]-5- (trifluoromethyl)-2-pyridinesulfonamide (formula X-13, where R1denotes phenethyl) Cm. Scheme X.

The target compound of Example 378 dissolved in ISO-propanol and Inuktitut in column 0,46 x 25 cm Cyclobond I 2000 (by "Advanced Separations Technologies, Inc. ", Whippany, new Jersey), cooled in a bath of ice. The sample elute with acetonitrile containing 0.1% diethylamine and 0.6% glacial acetic acid (V/V), at a speed of 1.0 ml/min Aliremove a controlled substance at the wavelength of 250 nm. The first of eluruumiks diastereomers identical to the compound of Example 298. The second of eluruumiks diastereomers purified column chromatography using 60 g of silica gel (elute 40% revizijskim characteristics:

The stereochemical configuration at C-6 of the opposite stereochemical configuration of the compound from Example 298.

Range PMR (deuteroacetone): 8,91, 8,19, 8,16, 8,02, 7,99, 7,25, 7,18, 7,15, 7,13, 7,11, 7,04, 6,97, 6,89, 6,75, 3,95, 2,69, 2,64, 2,53, 2,48, 2,13, 1,91, 1,71, 1,68, 1,37, 1,19, 1,17, 1,14, 0,94, 0,92, 0,89, 0,85, 0,83, 0,80, 0,93 M. D.

Preparation 169. Methyl ester of (3S)-3-[(3-bis(phenylmethyl)amino)phenyl]-4,4-dimethylpentane acid (formula LLL-9) Cm. Scheme III.

To anhydrous ethanol (2 ml) at room temperature add the titanium tetrachloride (0,07 ml). The resulting solution light green color is stirred for 2 hours and add the compound of formula LLL-2, where R1denotes phenyl (100 mg) obtained in the same way as shown in the Diagram FF, and refluxed for 18 hours. The reaction mixture is cooled, poured into 1N hydrochloric acid and extracted with ether. The organic extract was washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated in vacuum. Clean evaporative chromatography, elwira a mixture of hexane/ethyl acetate (95:5), and obtain the target compound (58 mg) in the form of oil of amber.

The substance has the following physical characteristics: 7,32-7,20, 7,04, 6,61-6,48, 4,61, 3,48, 2,85-2,80,,54, 52,24, 51,40, 35,56, 33,65, 27,87 M. D.

Mass spectrum (E1): m/z 415.

Preparation 170. (3S)-3-[(3-Bis(phenylmethyl)amino)phenyl] - 4,4-dimethylpentane acid (formula LLL-10) Cm. Scheme III.

The compound of formula LLL-9 (406 mg) Drug 169 stirred in a mixture of glacial acetic acid (2.6 ml) and 6 N sulfuric acid. The reaction mixture is refluxed for five hours, cooled and poured into a mixture of water and diethyl ether. The aqueous layer was separated and extracted twice more with diethyl ether. The organic extracts are combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated in vacuum. The remainder light brown dissolved in diethyl ether and at a temperature of 0oC add dicyclohexylamine (0.16 ml). The formed solid substance was separated, washed with diethyl ether and dried in vacuum. The obtained solid light brown color suspended in diethyl ether and washed with 0.25 N hydrochloric acid. The organic layer was washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated in vacuum, obtaining the target product (54 mg) as an amorphous substance of light brown color.

Substance -2,56, 0,74 M. D.

Range13C-NMR (deuterochloroform): 179,15, 148,56, 142,28, 138,83, 128,55, 128,23, 126,76, 117,90, 114,49, 110,98, 54,51, 51,83, 35,45, 33,67, 27,84 M. D.

Mass spectrum (E1):m/z 401.

The drug is 171. Amide N-[(3S)-4-benzyl-2-oxazolidinone]-3 - aminoborane acid (formula HHH-4) Cm. Scheme HHH.

In one litre round bottom flask, equipped with a tube for supplying nitrogen and addition funnel, is placed 10,02 g of industrially produced (S)-4-benzyl-2-oxazolidinone and 260 ml of tetrahydrofuran and cooled to a temperature of minus 78oC. To the resulting solution was added 37 ml of a solution of n-utility from the reaction mixture of saliva. To the resulting suspension add 11,46 g of acid chloride of TRANS-3-nitrocatechol acid (produced by interaction of industrially produced 3-nitrocatechol acid and chloride of oxalyl) in a small volume of tetrahydrofuran. The obtained homogeneous solution was allowed to warm to room temperature, decompose, adding a saturated solution of ammonium chloride, and extracted with ethyl acetate. The organic layer is separated, washed with saturated salt solution and water, dried over magnesium sulfate, filtered and evaporated, receiving syrup red-brown color (formula HHH-3 HHH), which>
2H2O, and the resulting mixture is refluxed for 20 minutes. Cooled to room temperature and poured on ice. Bring the pH to a value of 9-10 saturated aqueous sodium carbonate, filtered and thoroughly washed on the filter with ethyl acetate. The filtrate is washed with saturated salt solution, the organic phase is dried (over sodium sulfate), filtered and evaporated in vacuum, obtaining a solid yellow color. It is recrystallized from ethanol and allocate to 11.56 g of the target product.

The substance has the following physical characteristics:

IR-spectrum (mineral oil): 3450, 3369, 2924, 1771, 1678, 1620, 1462, 1392, 1357, 1347, 1214 cm-1.

[]D(14,418 mg/ml chloroform) = +51o< / BR>
The drug is 172. Amide-N-[(3S)-4-benzyl-2-oxazolidinone]-3-(bis (phenylmethyl)aminacrine acid (formula HHH-5) Cm. Scheme HHH.

Amide of formula HHH-4 Preparation 172 (10,13 g), 10,48 g of potassium carbonate, and 8.3 ml of benzyl bromide and 100 ml of acetonitrile is refluxed for 3 hours. The reaction mixture cooled down to room temperature, poured into water and extracted with ethyl acetate. The organic extracts are combined, dried (over sodium sulfate), filtered and evaporated ucaut 8,87 g of target compound.

The substance has the following physical characteristics:

Range13C-NMR (deuterochloroform): 165, 153, 149, 147, 138, 135, 129,6, 129,3, 128,8, 128,6, 127, 126,9, 126,5, 116,54, 116,50, 114, 113, 65, 55, 54, 37 M. D.

IR-spectrum (mineral oil): 2954, 2870, 2854, 1776, 1677, 1616, 1595, 1493, 1454, 1353, 1209, 988 cm-1.

The drug is 173. (3S)(4S)-3-[3-(bis(phenylmethyl)AMINOPHENYL)pentanoyl]-4-phenyl-2-oxazolidinone (formula HHH-6) Cm. Scheme HHH.

In a three-neck flask with a capacity of 100 ál, equipped with stirrer, addition funnel with a tube to equalize the pressure capacity of 25 ml and a tube for supplying nitrogen, was placed a complex bromide copper (1) - dimethyl sulfide (1,69 g), 20 ml of tetrahydrofuran and 10 ml of dimethyl sulfide. Into the addition funnel is placed a target product Preparation 172 (2,747 g) and 10 ml of tetrahydrofuran. The reaction mixture cooled down to minus 40oC and added dropwise within 5 minutes, add a solution of ethylmagnesium (5.5 ml, 3.0 M solution in ether). The mixture of black color is stirred at a temperature of minus 40oC for 10 minutes and allow it to warm up to minus 10oC. for 17 minutes added dropwise to the reaction mixture of the target product Preparation 172 in tetrahydrofuran. Addition funnel rinse fresh portion 3 ml of tetrahydrofuran and reags 60oC. the Process stop, pouring 50 ml of saturated solution of ammonium chloride, the organic layer is separated and evaporated in vacuum. The residue is poured into a mixture of 75 ml of ethyl acetate and 50 ml of water and filtered through glass wool. The organic layer is separated, washed with two portions of 100 ml of 10% ammonium hydroxide solution and 50 ml of saturated salt solution, dried over magnesium sulfate, filtered and evaporated in vacuum, obtaining 3,59 g butter yellow color. Column chromatography using 150 g of silica gel (elute 5-15% solution of ethyl acetate in hexane), get two diastereomeric product. Target product (less polar diastereoisomer) was isolated in the form of oil is pale-yellow in the amount 1,602,

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,32-7,17, 7,06, 6,60, 6,55, 4,63, 4,43-4,37, 4,00, 3,85, 3,37, 3,20, 3,08, 3,02-2,92, 2,62, 1,71-1,48, 0,73 M. D.

From the column in the form of oil pale yellow also highlights the more polar diastereoisomer in the number 0,310,

The substance has the following physical characteristics:

Range PMR (deuterochloroform): 7,32-7,18, 7,12, 7,05, 6,64-6,56, 4,63, 4,60-4,52, 4,08-4,04, 3,48-3,38, 3,07-2,96, 2,48, 1,69-1,48, 0,73 M. D.

Advanced colon is diastereomers.

The product 174. (3S, 6S)-3-[1-(3-AMINOPHENYL)propyl] -5,6 - dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-2H-Piran-2-he (formula FFF-6) Cm. Scheme FFF.

In accordance with the General procedure described for the Preparation 162, and conduct minor changes, get, replacing the target product of Preparation 161 to the target product of Drug /U-141164/, 0,040 g of target compound. It immediately used without purification in the next stage.

Example 380. (3S,6S)-N-[3-[1-[5,6-Dihydro-4-hydroxy-2-oxo-6- (2-phenylethyl)-6-propyl-2H-Piran-3-yl] propyl] phenyl] -5-(trifluoromethyl) -2-pyridinesulfonamide (formula FFF-7) Cm. Scheme FFF.

In accordance with the General procedure described in Example 374, and making minor changes, get, replacing the targeted product 162 Drug to the target product of the Drug 174, 0.015 g of target compound in the form of a foamy substance of white color.

The substance has the following physical characteristics:

Range PMR (deuteroacetone): 8,95, 8,25-8,21, 8,07-8,02, 7,25-6,93, 3,94- 3,88, 2,70-2,51, 2,20-2,18, 1,97-1,66, 1,40-1,30, 0,92-0,81 M. D.

Compounds of the present invention include, for example, the following individual stereoisomers:

5-cyano-N-[3-(R)-[1-[5, -dihydro-4-hydroxy-2-oxo - 6-(2-phenethyl)-6-(R)-(3,3,3-cryptochromes)-2H-Piran-3-yl]- 2,2-diepenbroek)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2 - pyridinesulfonamide,

5-cyano-N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl) -6-(S)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2 - pyridinesulfonamide,

5-cyano-N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6- (2-phenethyl)-6-(R)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl[-2-pyridinesulfonamide,

N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenethyl)-6- (3,3,3-cryptochromes)-2H-Piran-3-yl]-2,2-dimethyl-

propyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

N-[3-(S) -[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenethyl)-6-(3,3, 3-cryptochromes)-2H-Piran-3-yl] -2, 2-dimethyl-propyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

N-[3-(R) -[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenethyl)-6-(3,3, 3-cryptochromes)-2H-Piran-3-yl] -2, 2-dimethylpropyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

N-[3-(S)-[1-[5, 6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenethyl)-6-(3,3, 3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethyl - propyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

5-amino-N-3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R) -(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2 - dimethylpropyl]phenyl]-2-pyridinesulfonamide,

5-amino-N-[3-(R)- [1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)- (3,3,3-cryptochromes)-2H-Piran-3-yl]-2,2 - dimethylpropyl]phenyl]-2-pyridinesulfonamide,

5-amino-N-[3-(S) -[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3, hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,3-cryptochromes)- 2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide,

N-[3-(R)-[1-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6- (R)-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide,

N-[3-(R)-[1-[5,6-dihydro-4-hydroxy - 2-oxo-6-(2-phenethyl)-6-(S)-propyl-2H-Piran-3-yl]-2,2 - dimethylpropyl]phenyl]-2-pyridinesulfonamide,

N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6-(2-phenethyl)-6-(R)-propyl-2H-Piran-3-yl]-2,2 - dimethylpropyl]phenyl]-2-pyridinesulfonamide,

N-[3-(S)-[1- [5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)- propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide,

5-trifluoromethyl-N-[3-(R)-[1-[4 - hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl-N-[3- (S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H - Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide,

4-trifluoromethyl-N -[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6 - dihydro-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide,

4-trifluoromethyl-N-[3-(S)-[1-[4-hydroxy-2-oxo-6,6-di-n - propyl-5,6-dihydro-2H-Piran-3-yl]propyl]phenyl]-2 - pyridinesulfonamide,

5-trifluoromethyl-N-[3-(R)-[1-[4 - hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl]-2, 2-dimethylpropyl]phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl-N- [3-(S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6 - dihydro-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide,

5-trifluoromethyl-N-[3-(R)-[1-[4 - [4-hydroxy-2-oxo-6,6 - di-phenethyl-5,6-dihydro-2H-Piran-3-yl]propyl]phenyl]- 2-pyridinesulfonamide,

4-trifluoromethyl-N-[3-(R)-[1-[4 - hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-Piran-3 - yl]propyl]phenyl]-2-pyridinesulfonamide,

4-trifluoromethyl-N-[3- (S)-[1-[4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H - Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide,

4-trifluoromethyl - N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6 - dihydro-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide,

4-trifluoromethyl-N-[3-(S)-[1-[4 - hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl]-2, 2-dimethylpropyl]phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl - N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2 - phenethyl)-6(R)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide,

5-trifluoromethyl-N-[3-(R)- [1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)- n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2 - pyridinesulfonamide,

5-trifluoromethyl-N-[3-(S)-[1-[5,6 - dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl - 2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl-N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo - 6(S)-(2-phenethyl)-6(S)-n-propyl-2H-Piran-3-yl]-2,2 - dimethyl-propyl]phenyl]-2-pyridinesulfonamide,

4-trifluoromethyl-N- [3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2 - phenethyl)-6(R)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide,

4-trifluoromethyl - N-[3-(R)-[1-[5,6-dihydro-4-vermeil-N-[3-(S) -[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R) -n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide,

4-trifluoromethyl-N-[3-(S)-[1-[5,6 - dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl - 2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl-N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-Piran-3-yl]propyl] phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl-N-[3-(R)-[1- [5, 6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)- n-propyl-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl-N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2 - oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-Piran-3 - yl]propyl]phenyl]-2-pyridinesulfonamide,

5-trifluoromethyl-N-[3- (S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6 (S)-n-propyl-2H-Piran-3-yl]propyl]phenyl]-2 - pyridinesulfonamide,

5-cyano-N-[3-(R)-(1-[5,6-dihydro-4 - hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]-2, 2-dimethylpropyl)phenyl]-2-pyridinesulfonamide,

5-cyano-N-[3- (R)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6 - propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide,

5-cyano-N-[3-(S)-(1-[5,6-dihydro-4-hydroxy-2 - oxo-6(R)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]-2,2 - dimethylpropyl)phenyl]-2-pyridinesulfonamide,

5-cyano-N-[3-(S) -(1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6 - propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2 - pyridinesulfonamide,

N-[3(R)-[1-(5,6-dihydro-4-hydroxy-2 - ox-dihydro-4-hydroxy-2-oxo-6(S)-[2-phenylethyl]- 6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl] -1-methyl - 1H-imidazole-4-sulfonamide,

N-[3(S)-[1-(5,6-dihydro-4 - hydroxy-2-oxo-6(R)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2, 2-dimethylpropyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

N-[3(S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6(S)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl]phenyl]-2-methyl - 1H-imidazole-4-sulfonamide,

5-amino-N-[3-(R)-(1-[5,6 - dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H - Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide,

5-amino-N-[3-(S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-(6R)-(2 - phenylethyl)-6-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2 - pyridinesulfonamide,

5-amino-N-[3-(S)-(1-[5,6-dihydro-4 - hydroxy-2-oxo-6(S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]- 2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide,

5-amino-N-[3- (R)-(1-[5,6-dihydro-4-hydroxy-2-oxo - 6(R)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]-2,2 - dimethylpropyl)phenyl]-2-pyridinesulfonamide,

5-amino-N-[3-(R) -(1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6 - propyl-2H-Piran-3-yl]propyl)phenyl]-2-pyridinesulfonamide,

5-amino - N-[3-(R)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2 - phenylethyl)-6-propyl-2H-Piran-3-yl]propyl]phenyl]-2 - pyridinesulfonamide,

5-amino-N-[3-(S)-(1-[5,6-dihydro-4 - hydroxy-2-oxo-6(R)-(2-phenylethyl)-6-propyl-2H-Piran-3 - yl]propyl)phenyl]-2-pyridinesulfonamide,

5-amino-N-[3-(S)- (1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6 - Pro is hydroxy-2-oxo-6-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl) phenyl]-2-pyridinesulfonamide,

5-amino-N-[3(R)-(1-[6 (S)-(2-[4-forfinal] ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6 - propyl-2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2 - pyridinesulfonamide,

5-amino-N-[3(S)-(1-[6(R)-(2- [4-forfinal] ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H - Piran-3-yl] -2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide,

5-amino-N-[3(S)-(1-[6(S)-(2-[4-forfinal] ethyl)-5,6 - dihydro-4-hydroxy-2-oxo-6-propyl-2H-Piran-3-yl]-2,2 - dimethylpropyl)phenyl]-2-pyridinesulfonamide,

N-[3 (R)-(1-[5, 6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2 - dimethylpropyl)phenyl]-1-methyl-1H-imidazole - 4-sulfonamide,

N-[3(S)-(1-[5,6-dihydro-6, 6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2 - dimethylpropyl)phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

5-amino - N-[3(R)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo - 2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2-pyridine-sulfonamide,

5-amino-N-[3(S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy - 2-oxo-2H-Piran-3-yl]-2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide,

5-cyano-N-[3(R)-(1-[5,6-dihydro-6,6 - dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl]-2,2-dimethylpropyl) phenyl]-2-pyridinesulfonamide,

5-cyano-N-[3(S)-(1-[5,6 - dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl]-2,2 - dimethylpropyl)phenyl]-2-pyridine-sulfonamide,

N-[3(R)-(1-[6, 6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl]propyl)phenyl]-1-methyl-1H-imil-1H-imidazole-4 - sulfonamide,

N-[3(R)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro - 4-hydroxy-2-oxo-2H-Piran-3-yl]propyl)phenyl]-5-cyano-2 - pyridinesulfonamide,

N-[3(S)-(1-[6,6-bis(2-phenylethyl)-5, 6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl]propyl)phenyl]-5 - cyano-2-pyridinesulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6 (R)-phenethyl-6-propyl-2H-Piran-3-yl)propyl}phenyl]-5-cyano-2 - pyridinesulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2 - oxo-6(S)-phenethyl-6-propyl-2H-Piran-3-yl)propyl}phenyl]-5 - cyano-2-pyridine-sulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6 - dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-cyano-2-pyridine-sulfonamide,

N-[3-{ 1(S)-(4 - hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-Piran-3 - yl)propyl}phenyl]-5-cyano-2-pyridinesulfonamide,

N-[3-{ 1(R) -(4-hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H - Piran-3-yl)propyl}phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6 - propyl-2H-Piran-3-yl)propyl}phenyl]-1-methyl-1H-imidazole-4 - sulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R) -phenethyl-6-propyl-2H-Piran-3-yl)propyl}phenyl]-1-methyl-1H - imidazole-4-sulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6 - dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl]-1-methyl-1H-imidazole-4-sulfonamide,

N-[3-{1(R)- (4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-ftoh - dihydro-2-oxo-6(S)-(2- (4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2 - dimethylpropyl} phenyl] -5-cyano-2-pyridinesulfonamide,

N-[3-{ 1 (S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal) ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5 - cyano-2-pyridinesulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6 - dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran - 3-yl)-2,2-dimethylpropyl} phenyl]-5-cyano-2-pyridinesulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4 - forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide,

N-[3-{1(R)- (4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6 - propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-1-methyl-1H - imidazole-4-sulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6 - dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran - 3-yl)-2,2-dimethylpropyl}phenyl]-1-methyl-1H-imidazole-4 - sulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6 (S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2 - dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2 - phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-5-amino - 2-pyridinesulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro - 2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2 - dimethylpropyl}phenyl]-5-amino-2-pyridinesulfonamide,

N-[3-{ 1 (R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H - Piran-3-yl)-2,2-dimethylpropyl}phenyl]-1-methyl - 1H-imidazole-4-sulfonamide is evil-4-sulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2 - phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-5-cyano-2 - pyridinesulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2 - oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2 - dimethylpropyl}phenyl]-5-cyano-2-pyridinesulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran - 3-yl)propyl}phenyl]-5-cyano-2-pyridinesulfonamide,

N-[3-{ 1(S)-(4 - hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl]-5-cyano-2-pyridinesulfonamide,

N-[3-{ 1(R)-(4 - hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl]-5-amino-2-pyridinesulfonamide,

N-[3-{ 1(S)-(4 - hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl]-5-amino-2-pyridinesulfonamide,

N-3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl) -6-propyl-2H-Piran-3-yl)propyl}phenyl]-5-cyano-2 - pyridinesulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2 - oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl) propyl}phenyl]-5-cyano-2-pyridinesulfonamide,

N-[3-{1(R)- (4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6 - propyl-2H-Piran-3-yl)propyl}phenyl]-5-cyano-2 - pyridinesulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl]phenyl]- 5-cyano-2-pyridinesulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihyd the(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4 - forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl]phenyl]-1 - methyl-1H-imidazole-4-sulfonamide,

N-[3-{1(R)-(4-hydroxy - 5,6-dihydro-2-oxo-6(S)- (2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4 - forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl}phenyl]-1-methyl - 1H-imidazole-4-sulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R) -(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-amino-2-pyridinesulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2- (4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-amino-2-pyridinesulfonamide,

N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2- (4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-amino-2-pyridinesulfonamide,

N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6 - propyl-2H-Piran-3-yl)propyl}phenyl]-5-amino-2-pyridinesulfonamide. 1. 4-Hydroxyfuran-2-ones of the formula I

< / BR>
where R1denotes a hydrogen atom;

R2means (a) (C3-C5)alkyl; (b) phenyl-(CH2)2-; (C) het-SO2NH-(CH2)2-; (d) cyclopropyl-(CH2)2-; (e) forfinal-(CH2)2-; (f) het-SO2NH-phenyl-; or (g) trifluoromethyl-(CH2)2-; or R1and R2together form a double bond;

R3represents a fragment of formula X

< / BR>2S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-;

R5denotes a hydrogen atom;

R6means (a) R4-(CH2)n-CH(R8)-; (b) H3C-[O(CH2)2]2-CH2-; (c) (C3-C5) alkyl; (d) phenyl-(CH2)2-; (e) het-SO2NH-(CH2)2-; (f) (HOCH2)3C-NH-C(O)-NH-(CH2)3-; (g) (HO2C)(H2N)CH-(CH2)2-C(O)-NH-(CH2)3-; (h) piperazine-1-yl-C(O)-NH-(CH2)3-; (i) HO3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-(CH2)3-;

(j) cyclopropyl-(CH2)2-; (j) forfinal-(CH2)2-; (l) het-SO2NH-phenyl or (m) F3C-(CH2)2-; n represents zero (0), one (1) or two (2); R7means (a) cyclopropyl; (b) ethyl or (C) tert-butyl; R8means (a) ethyl or (b) -CH2-cyclopropyl; R9means (a) -NR12SO2-gets; (b) -NR12SO2is phenyl, unsubstituted or substituted with one R11; (C) -CH2-SO2is phenyl, unsubstituted or substituted with one R11or (d) -CH2-SO2-het, where het represents a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) GE, is any of the above heterocyclic rings condensed with a benzene ring or another heterocycle, unsubstituted or substituted with one R10; where R10means (a) methyl; (b) cyano; (C) hydroxy; (d) etoxycarbonyl; (e) trifluoromethyl; (f) amino; or (g) -C(O)-NH2; R11means (a) cyano; (b) a fluorine atom; (C) hydroxy, or (d) nitro; R12represents (a) hydrogen atom or (b) methyl;

or its pharmaceutically acceptable salt.

2. Connection on p. 1 of the formula I

< / BR>
where R1denotes a hydrogen atom;

R2means (a) (C3-C5)alkyl; (b) phenyl-(CH2)2or (C) het-SO2NH-(CH2)2-, or R1and R2together form a double bond;

R3represents a fragment of formula X

< / BR>
R4represents (a) phenyl; (b) het; (C) cyclopropyl; (d) H3C-[O(CH2)2]2-; (e) het-SO2NH-; (f) a bromine atom; (g) azido; or (h) HO3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-;

R5denotes a hydrogen atom; R6means (a) R4-(CH2)n-CH(R8)-; (b) H3C-[O(CH2)2]2-CH2-; (c) (C3-C5) alkyl; (d) phenyl-(CH2)2-; (e) het-SO< )2-C(O)-NH-(CH2)3-; (h) piperazine-1-yl-C(O)-NH-(CH2)3-; or (i) HO3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-(CH2)3-; n represents zero (0), one (1) or two (2); R7means (a) cyclopropyl; (b) ethyl or (C) tert-butyl; R8means (a) ethyl or (b) -CH2-cyclopropyl; R9means (a) -NR12SO2-gets; (b) -NR12SO2is phenyl, unsubstituted or substituted with one R11; (C) -CH2-SO2is phenyl, unsubstituted or substituted with one R11or (d) -CH2-SO2-het, where het denotes a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and including any bicyclic group in which any of the above heterocyclic rings condensed with a benzene ring or another heterocycle; unsubstituted or substituted with one R10; where R10means (a) methyl; (b) cyano; (C) hydroxy, or (d) etoxycarbonyl; R11means (a) cyano; (b) a fluorine atom; (C) hydroxy, or (d) nitro; R12represents (a) hydrogen atom or (b) methyl;

or its pharmaceutically acceptable salt.

3. Connection on p. 2, in which idazole-2-yl; (C) imidazol-4-yl; (d)benzimidazole-2-yl; (e) quinoline-8-yl; (f) quinoline-2-yl; (q) pyrimidine-2-yl; (h) hinzelin-2-yl; (i) purine-6-yl; (j) thiazol-2-yl; (k) thiazol-4-yl; (l) 2-pyrazolyl; (m) 2-pyrazinyl; (n) tetrahydropyran-4-yl or (o) tetrahydropyran-3-yl.

4. Connection on p. 3 of the formula I

< / BR>
where R1denotes a hydrogen atom;

R2means (a) propyl; (b) phenyl-(CH2)2-; (C) (CH3)2CH-CH2or (d) of pentyl; or R1and R2together form a double bond;

R3represents a fragment of formula X

< / BR>
R4represents (a) phenyl; (b) het; (C) cyclopropyl; (d) H3C-[O(CH2)2]2-; (e) het-SO2NH-; (f) a bromine atom; (q) azido or (h) HO3S(CH2)2-N(CH3)-C(O)-(CH2)6-C(O)-NH-; R5denotes a hydrogen atom; R6means (a) R4-(CH2)n-CH(R8)-; (b) H3C-[O(CH2)2]2CH2-; (C) propyl; (d) phenyl-(CH2)2-; (e) (CH3)2CH-CH2or (f) of pentyl; n represents zero (0), one (1) or two (2); R7means (a) cyclopropyl or (C) ethyl; R8means (a) ethyl or (b) -CH2-cyclopropyl; R9means (a) NSO2-gets or (b) -NS2is phenyl, unsubstituted or substituted ognl; (b) imidazol-2-yl; (C) imidazol-4-yl; (d) quinoline-8-yl; (e) tetrahydropyran-4-yl; (f) tetrahydropyran-3-yl or (g) benzimidazole-2-yl; R10means (a) methyl; R11means (a) cyano; (b) a fluorine atom or (C) nitro;

or its pharmaceutically acceptable salt.

5. Connection under item 4 of the formula I

< / BR>
where R2means (a) propyl; (b) phenyl-(CH2)2-; (C) (CH3)2CH-CH2or (d) of pentyl;

R3represents a fragment of formula X

< / BR>
R6means (a) propyl; (b) phenyl-(CH2)2-; (C) (CH3)2CH-CH3or (d) of pentyl;

R7means (a) ethyl or (b) cyclopropyl;

R9means (a) NS2is phenyl, substituted with one R11; or (b) -NS2-het, where het is the following group, unsubstituted or substituted with one R10(a) imidazol-4-yl or (b) quinoline-8-yl; R10denotes methyl; R11means (a) cyano, or (b) a fluorine atom.

6. Connection on p. 4 formula VII

< / BR>
where R3represents a fragment of formula X

< / BR>
R4represents (a) phenyl; (b) het; (C) cyclopropyl; (d) H3C-[O(CH2)2]2-; (e) het-SO2NH-; (f) a bromine atom; (g) azido or (h) HO3S(CH2)2-N(CHC-[O(CH2)2]2-CH2-;

R7denotes cyclopropyl;

R8means (a) ethyl or (b) -CH2-cyclopropyl;

R9means (a) NS2-gets or (b) -NS2is phenyl, substituted with one R11; n represents zero (0), one (1) or two (2); het denotes the following groups, unsubstituted or substituted with one R10; (a) imidazol-4-yl; (b) imidazol-2-yl; (C) quinoline-8-yl; (d) tetrahydropyran-3-yl; (e) tetrahydropyran-4-yl; (f) 2-pyridinyl or (g) benzimidazole-2-yl; R10denotes methyl; where R11means (a) nitro; (b) a fluorine atom or (C) cyano;

or its pharmaceutically acceptable salt.

7. Connection on p. 2, selected from the group comprising: 3-[cyclopropyl[3-[(4-cyanophenylacetic)methyl] phenyl] methyl]-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-Piran-2-he; 3-[cyclopropyl[3-[(2-pyridylsulfonyl)methyl] phenyl] methyl] -4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-Piran-2-he; 3-[cyclopropyl[3-[(1-methyl-4-imidazolidinyl)methyl] phenyl]methyl]-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-Piran-2-he; 3-[cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl)methyl] phenyl] methyl] -4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-Piran-2-he; 3-[cyclopropyl[3-[(2-benzimidazolylthio)METI is)methyl]phenyl] methyl]-4-hydroxy-6-(2-phenylethyl)-6-(1-propyl)-5,6-dihydro-2H-Piran-2-he; 4-cyano-N - [[3[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] benzosulfimide; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -8-chinaincorporated; N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -8-chinaincorporated; N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; 4-fluoro-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] benzosulfimide; 4-cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] benzosulfimide; N-[3-[1-(4-hydroxy-6,6-di-ISO-butyl-2-oxo-5,6-dihydro-2H-Piran-3-yl)propyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl]phenyl] -8-chinaincorporated; 4-cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]-benzosulfimide; 4-fluoro-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -benzo is ID; (R or S)-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; (S or R)-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -8-chinaincorporated; (S or R)-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; (R or S)-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6 - dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; (S or R)-N-[3-[1-(4-hydroxy-2-oxo-6,6-dipropyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; 4-cyano-N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -benzosulfimide; 4-fluoro-N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -benzosulfimide; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl]-8-chinaincorporated; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)cyclopropylmethyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-dipentyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-ifname; N-[3-[1(R or S)-(6(R or S)- 4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl) propyl]phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-3-[1(R or S)-(6(S or R)-4-hydroxy-2-oxo-6 - phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1(S or R)-(6(R or S)-4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1(S or R)-(6(S or R)-4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-[tert-butyl(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)methyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; 4-cyano-N-[3-[tert-butyl(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)methyl] phenyl] benzosulfimide; 4-fluoro-N-[3-[tert-butyl(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)methyl] phenyl] benzosulfimide; N-[3-[tert-butyl(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)methyl] phenyl] -8-chinaincorporated; N-[3-[1-(6-(2-(1-methyl-1H-imidazol-4-sulfonylamino)ethyl)-4-hydroxy-2-oxo-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-pyridinesulfonamide; 4-cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6-what DRO-2H-Piran-3-yl)propyl] phenyl] -2-chinaincorporated; 2-hydroxy-N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]benzosulfimide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-2-pyrimidinamine; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-ChineseSimplified; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -7H-purine-6-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1H-imidazole-2-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1H-benzimidazole-2-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -thiazole-4-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-pyridinesulfonamide; 4-cyano-N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-2-pyridinesulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-chinaincorporated; 2-hydroxy-N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5, 6-dihydro-2H-Piran-3-yl)propyl]phenyl]benzosulfimide; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -2-pyrimidinamine; N-[3-[1-(4-hydroxy-2-oxo-6-peopel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -7H-purine-6-sulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1H-imidazole-2-sulfonamide; N- [3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -1H-benzimidazole-2-sulfonamide; N-[3-[l-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -thiazole-4-sulfonamide; 4-fluoro-N-[3-[1-(4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] benzosulfimide; 5-cyano-N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-N-methyl-2-pyridinesulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -N-methyl-2-quinoline-sulfonamide; N- [3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -N-methyl-2-imidazolidinone; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -N-methyl-2-pyrimidinamine; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-N-methyl-2-benzenedisulfonamide; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -N-methyl-2-ChineseSimplified; N-[3-[1-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl] -N-methyl-6-peninsulaand; N-[3-[l-(4-hydroxy-2-oxo-6,6-definatel-5,6-dihydro-2H-Piran-3-yl)propyl] phenyl]-N-methyl-4-ti is honami, N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(1(S)-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(1(R)-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3(1(S)-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(1(R)-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide; 5-cyano-N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6-phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide and N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide.

8. Connection on p. 2, verapramil] -2H-Piran-2-he; 3-[cyclopropyl[3-[(2-pyridylsulfonyl)methyl] phenyl] methyl] -4-hydroxy-6-[1(phenylmethyl)propyl] -2H-Piran-2-he; 3-[cyclopropyl[3-[(1-methyl-4-imidazolidinyl)methyl] phenyl]methyl]-4-hydroxy-6-[1-(phenylmethyl)propyl] -2H-Piran-2-he; 3-[cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl)methyl] phenyl]methyl]-4-hydroxy-6-[1-(phenylmethyl)propyl] -2H-Piran-2-he; 3-[cyclopropyl[3-[(2-benzimidazolylthio)methyl] phenyl] methyl-4-hydroxy-6-[1-(phenylmethyl)propyl] -2H-Piran-2-he; 3-[cyclopropyl[3-[(2-hyalinization)methyl]phenyl]methyl]-4-hydroxy-6-[1-(phenylmethyl)propyl] -2H-Piran-2-he; N-(3-{cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-4-fluoro-benzosulfimide; 4-cyano-N-(3-{cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)benzosulfimide; N-(3-{ cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-8-chinaincorporated; N-(3-{ cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; (R or S)-N-(3-{cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{ cyclopropyl-[6-(2-cyclopropyl-1-sapropel-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazol-2-sulfonamide; N-(3-{cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1H-benzimidazole-2-sulfonamide; N-(3-{cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1H-imidazole-2-sulfonamide; N-3-{ cyclopropyl-[6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-chinaincorporated; N-(3-{cyclopropyl-[4-hydroxy-6-(3-[2-methoxy-ethoxy} propyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{ cyclopropyl-[6-(1-ethyl-3-{ 2-methoxy-ethoxy}propyl) -4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; 4-cyano-N-(3-{ cyclopropyl-[6-(1-ethyl-3-{ 2-methoxy-ethoxy} propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-benzosulfimide; N-(3-{cyclopropyl-[6-(1-ethyl-3-{ 1-methyl-1H-imidazol-4-sulfonylamino}propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3{[6-(3-bromo-1-ethylpropyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] -cyclopropylmethyl}phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{[6-(3-azido-1-ethylpropyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] -cyclopropylmethyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; monosodium salt 2-[[8-[[3-[3-[cyclopropyl[3-[[(1-methyl-1H-imidazol-4-yl)sulfonyl] amino]phenyl]methyl]-4-g is hydroxy-6-(3-{ [(2-hydroxy-1,1-bis {hydroxymethyl}ethyl)amino]carbonyl} aminopropyl)-2-oxo-2H-Piran-3-yl] methyl}phenyl)benzosulfimide; N-(3-{ cyclopropyl-[4-hydroxy-6-(3-{ [(2-hydroxy-1,1-bis { hydroxymethyl} ethyl)amino]carbonyl}aminopropyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-2-pyridinesulfonamide; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis {hydroxymethyl} ethyl)amino]carbonyl}aminopropyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-imidazole-2-sulfonamide; N-(3-{ cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis { hydroxymethyl} ethyl)amino]carbonyl}aminopropyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1H-benzoimidazol-2-sulfonamide; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{[(2-hydroxy-1,1-bis {hydroxymethyl}ethyl)amino]carbonyl} aminopropyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{ cyclopropyl-[4-hydroxy-6-(3-{ [(2-hydroxy-1,1-bis (hydroxymethyl} ethyl)amino]carbonyl}aminopropyl)-2-oxo-2H-Piran-3-yl]methyl} phenyl)-1-methyl-1H-imidazol-2-sulfonamide; N-3-{cyclopropyl-[4-hydroxy-6-(3-{gamma-L-glutamyl}aminopropyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)benzosulfimide; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{gamma-L-glutamyl} aminopropyl)-2-oxo-2H-Piran-3-yl] methyl}phenyl)-2-pyridinesulfonamide; N-(3-{ cyclopropyl-[4-hydroxy-6-(3-{ gamma-L-glutamyl} aminopropyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1H-imidazolylidene; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{ gamma-L-glutamyl} aminopropyl)-2-oxo-2H-Piran-3-yl]N-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{gamma-L-glutamyl} aminopropyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazol-2-sulfonamide; N-(3-{ cyclopropyl-[4-hydroxy-6-(3-{ [piperazine-1-yl] carbonyl}aminopropyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)benzosulfimide; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{ [piperazine-1-yl] carbonyl} aminopropyl)-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-pyridinesulfonamide; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{[piperazine-1-yl]carbonyl} aminopropyl)-2-oxo-2H-Piran-3-yl]methyl} phenyl)-1H-imidazole-2-sulfonamide; N-(3-{cyclopropyl-[4-hydroxy-6-(3-{ [piperazine-1-yl] carbonyl} aminopropyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-benzoimidazol-2-sulfonamide; N-(3-{ cyclopropyl-[4-hydroxy-6-(3-{ [piperazine-1-yl] carbonyl} aminopropyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{ cyclopropyl-[4-hydroxy-6-(3-{ [piperazine-1-yl] carbonyl}aminopropyl)-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1-methyl-1H-imidazol-2-sulfonamide; monosodium salt 2-[[8-[[3-[3-[cyclopropyl[3-[[phenyl-sulfonyl] amino] phenyl]methyl]-4-hydroxy-2-oxo-2H-Piran-6-yl]propyl]amino]-1,8-dioxaoctyl]methylamino]econsultation; monosodium salt 2-[[8-[[3-[3-[cyclopropyl[3-[[(2-pyridyl) sulfonyl]amino]phenyl] methyl] -4-hydroxy-2-oxo-2H-Piran-6-yl] propyl]amino]-1,8-dioxaoctyl] metelli the Teal]-4-hydroxy-2-oxo-2H-Piran-6-yl] propyl]amino]-1,8-dioxaoctyl]methylamino]econsultation; monosodium salt 2-[[8-[[3-[3-[cyclopropyl[3-[[(1H-imidazol-2-yl)sulfonyl] amino] phenyl]methyl]-4-hydroxy-2-oxo-2H-Piran-6-yl]propyl] amino]-1,8-dioxaoctyl]methylamino]econsultation; monosodium salt 2-[[8-[[3-[3-[cyclopropyl[3-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]phenyl]methyl]-4-hydroxy-2-oxo-2H-Piran-6-yl]propyl]amino]-1,8-dioxaoctyl]methylamino] econsultation; monosodium salt 2-[[8-[[3-[3-[cyclopropyl[3-[[(1-methyl-1H-imidazol-2-yl)sulfonyl] amino] phenyl] methyl]-4-hydroxy-2-oxo-2H-Piran-6-yl]propyl]amino]-1,8-dioxaoctyl]methylamino]econsultation; N-(3-{ cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{ cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-(R or S)-{cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-(R or S)-{cyclopropyl-[6-(1-(S)-ethylphenyl) -4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} -phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-(R or S)-{cyclopropyl[6-(1-(R)-ethylphenyl) -4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-pyridinesulfonamide; N-(3-(R or S)-{cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1-m is methyl} phenyl)-1-methyl-1H-imidazol-2-sulfonamide; N-(3-[cyclopropyl[4-hydroxy-2-oxo-6-[1-[(tetrahydro-2H-Piran-3-yl)methyl] propyl] -2H-Piran-3-yl]methyl]phenyl] -8-chinaincorporated; N-(3-[cyclopropyl[4-hydroxy-2-oxo-6-[1-[(tetrahydro-2H-Piran-3-yl)methyl] propyl] -2H-Piran-3-yl] methyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)benzimidazole-2-sulfonamide; N-(3-{ cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-1H-imidazole-2-sulfonamide; N-(3-(R or S)-{cyclopropyl-[6-(1-(R)-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-4-cyanobenzenesulfonyl; N-(3-{ cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} -phenyl)-4-nitrobenzenesulfonamide; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-pyridinesulfonamide; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-4-cyano-2-pyridinesulfonamide; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-chinaincorporated; N-(3-{ cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl}phenyl)-2-hydroxybenzenesulfonate; N-(3-{ cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)Protel)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-ChineseSimplified; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-7H-purine-6-sulfonamide; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-1H-imidazole-2-sulfonamide; N-(3-{ cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)benzimidazole-2-sulfonamide; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl} phenyl)thiazole-4-sulfonamide; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl}phenyl)-4-etoxycarbonyl-1H-imidazole-2-sulfonamide; N-(3-{cyclopropyl-[6-(1-(tetrahydropyran-4-ylmethyl)propyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-3-hydroxy-2-pyridinesulfonamide; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-pyridinesulfonamide; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-4-cyano-2-pyridinesulfonamide; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-chinaincorporated; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-2-hydroxybenzenesulfonate; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-and ChineseSimplified; N-(3-{ cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-7H-purine-6-sulfonamide; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl}phenyl)-1H-imidazole-2-sulfonamide; N-(3-{ cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)benzimidazole-2-sulfonamide; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl}phenyl)-thiazole-4-sulfonamide; N-(3-{cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-4-etoxycarbonyl-1H-imidazole-2-sulfonamide; N-(3-{ cyclopropyl-[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl} phenyl)-3-hydroxy-2-pyridinesulfonamide; 5-cyano-N-[6-(1'-benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl)-2-pyrone] -N-methyl-2-pyridinesulfonamide; N-[6-(1'-benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl)-2-pyrone] -N-methyl-2-chinaincorporated; N-[6-(1'-benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl)-2-pyrone] -N-methyl-2-imidazolidinone; N-[6-(1'-benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl)-2-pyrone] -N-methyl-2-pyrimidinamine; N-[6-(1'-benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl)-2-pyrone] -N-methyl-2-benzenedisulfonamide; N-[6-(1'-benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl)-2-pyrone] -N-methyl-2-ChineseSimplified; N-[6-(1'-Ben is si-3-(1'-cyclopropylmethyl)-2-pyrone] -N-methyl-4-thiazolecarboxamide and N-[6-(1'-benzylparaben)-4-hydroxy-3-(1'-cyclopropylmethyl)-2-pyrone]-N-methyl-2-pyridinesulfonamide.

9. Cyclooctylamino-2-ones or benzopyran-2-ones of formula II

< / BR>
where R10and R20together form: a) a fragment of the formula III

< / BR>
or b) a fragment of the formula IV

< / BR>
where p = 4;

R1denotes a hydrogen atom;

R2represents (a) hydrogen atom; (b) methoxy; or (C) CH3-O-[(CH2)2O]3-;

R3represents a fragment of formula V

< / BR>
R4means (a) cyclopropyl or-CH2-CH(CH2)2;

R5means (a) -NR9SO2is phenyl, unsubstituted or substituted with one R6; (b) -NP9SO2-gets; (C) -CH2-SO2is phenyl, unsubstituted or substituted with one R6or (d) -CH2-SO2-het; where R6means (a) cyano; (b) a fluorine atom; (C) methyl; (d) carboxy, or (e) hydroxy; where het represents a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and including any bicyclic group in which any of the above heterocyclic rings condensed with a benzene ring or another heterocycle; unsubstituted or substituted by one or two R7where R7means (a) IU the B>-cyclopropyl or (d) -CH2is phenyl;

R9represents (a) hydrogen atom or (b) methyl;

or its pharmaceutically acceptable salt.

10. Connection on p. 9, in which het represents the following groups, which do not contain substituents or substituted with one R7(a) 2-pyridinyl; (b) 4-pyridinyl; and (C) imidazol-2-yl; (d) imidazol-4-yl; (C) benzimidazole-2-yl; (f) quinoline-8-yl; (g) quinoline-2-yl; (h) pyrimidine-2-yl; (i) hinzelin-2-yl; (j) purine-6-yl; (k) thiazol-2-yl; (l) the thiazol-4-yl; (m) 2-pyrazolyl; (n) 2-pyrazinyl; (o) tetrahydropyran-4-yl or (b) tetrahydropyran-3-yl.

11. Connection on p. 10 formula II

< / BR>
where R10and R20together form: a) a fragment of the formula III

< / BR>
or b) a fragment of the formula IV

< / BR>
where p is equal to four (4);

R1denotes a hydrogen atom;

R2means (a) methoxy, or (b) CH3O-[(CH2)2O]3-;

R3represents a fragment of formula V

< / BR>
R4means (a) cyclopropyl or (b) -CH2-CH(CH3)2;

R5means (a) -NR9SO2is phenyl, unsubstituted or substituted with one R6; (b) -NR9SO2-gets; (C) -CH2-SO2is phenyl, unsubstituted or substituted with one R6; or (d) -CH2-SO27(a) imidazol-4-yl; (b) quinoline-8-yl; (C) 2-pyridinyl, or (d) 4-pyridinyl; R7denotes methyl; R8represents (a) hydrogen atom or (b) propyl; R9represents (a) hydrogen atom or (b) methyl;

or its pharmaceutically acceptable salt.

12. Connection on p. 11 formula VIII

< / BR>
where R3represents a fragment of formula V

< / BR>
R4means (a) cyclopropyl or (b) -CH2-CH(CH3)2;

R5means (a) -NR9SO2is phenyl, unsubstituted or substituted with one R6; (b) -NR9SO2-gets or (s) -CH2-SO2is phenyl; R6means (a) cyano, or (b) a fluorine atom; het denotes the following groups, unsubstituted or substituted with one R7(a) 2-pyridinyl; (b) 4-pyridinyl or (C) imidazol-4-yl; R7denotes methyl; R8represents (a) hydrogen atom or (b) propyl; R9represents (a) hydrogen atom or (b) methyl;

or its pharmaceutically acceptable salt.

13. Connection on p. 11 formula IX

< / BR>
where R1denotes a hydrogen atom;

R2means (a) methoxy, or (b) CH3O-[(CH2)2O]3-;

R3represents a fragment of formula V

< / BR>the following groups, unsubstituted or zameshannye one R7(a) imidazol-4-yl; (b) 2-pyridinyl, or (C) quinoline-8-yl; R7denotes methyl.

14. Connection on p. 9, selected from the group comprising: N-[3-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-10-propyl-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]benzosulfimide; 4-cyano-N-[3-(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-(R or S)-10-propyl-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] benzosulfimide; 4-cyano-N-[3-(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-(R or S)-10-cyclopropylmethyl-4-hydroxy-2-oxo-2H-cycloocta [b] Piran-3-yl)methyl]phenyl] benzosulfimide; 4-cyano-N-[3-(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-(R or S)-10-benzyl-4-hydroxy-2-oxo-2H-cycloocta [b]Piran-3-yl)methyl]phenyl] benzosulfimide; N-[3-(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-(R or S)-10-propyl-2H-cycloocta[b]Piran-3-yl)methyl]phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro-(R or S)-10-cyclopropylmethyl-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R or S)-[cyclopropyl(5,6,7,8,9,10-hexahydro(R or S)-10-benzyl-4-hydroxy-2-oxo-2H-cycloocta[b] PYRAN-yl)methyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; (R or S)-N-[3-1-(5,6,7,8,9,10-hexahydro-4-hydroxy-2-about who yl)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta [b] Piran-2-he; 3-[cyclopropyl[3-[(4-cyanophenylacetic)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; 3-[cyclopropyl[3-[(4-perpenicular)methyl] phenyl] methyl]-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; 3-[cyclopropyl[3-[(4-methylphenylsulfonyl)methyl] phenyl] methyl]-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta [b]Piran-2-he; 3-[cyclopropyl[3-[(4-carboxypenicillins)methyl]phenyl]methyl]-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b]Piran-2-he; 3-[cyclopropyl[3-[(2-(1-methylimidazol)sulfonyl)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta)[b]Piran-2-he; 3-[cyclopropyl[3-[(2-pyrimidinemethanol)methyl] phenyl] methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; 3-[cyclopropyl[3-[(2-pyridylsulfonyl)methyl] phenyl]methyl]-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; 3-[cyclopropyl[3-[(1-methyl-4-imidazolidinyl)methyl] phenyl] methyl]-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; 3-[cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl)methyl]phenyl]methyl] -5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; 3-[cyclopropyl[3-[(2-benzimidazolylthio)methyl]phenyl]methyl]-5,6,7,8,9,10-hexahydro-4-hydroxy-2H-cycloocta[b] Piran-2-he; 3-[cyclopropyl[3-[(2-hyalinization)methyl] phenyl] methyl]-5,6,7,8-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]benzosulfimide; 4-cyano-N-methyl-N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]benzosulfimide; 4-fluoro-N-methyl-N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]benzosulfimide; N-methyl-N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]benzosulfimide; N-methyl-N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-1H-imidazol-1-methylsulfonate; 5-cyano-N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl] phenyl] -2-pyridinesulfonamide; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] -2-chinaincorporated; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] -2-imidazolidinone; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-2-pyrimidinamine; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-2-benzenedisulfonamide; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-2-ChineseSimplified; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-XI-2-oxo-2H-cycloocta[b]Piran-3-yl)methyl]phenyl]-N-methyl-2-pyridinesulfonamide; N-[3-[cyclopropyl(5,6,7,7,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-N-methyl-2-chinaincorporated; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-N-methyl-2-imidazolidinone; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-N-methyl-2-pyrimidinamine; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-2-benzenedisulfonamide; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-2-ChineseSimplified; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-N-methyl-6-peninsulaand; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-N-methyl-4-thiazolecarboxamide; N-[3-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-N-methyl-2-pyridinesulfonamide; N-[4-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-2-pyridinesulfonamide; N-[4-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-4-pyridinesulfonamide; N-[4-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-ciclo-2H-cycloocta[b] Piran-3-yl)methyl]phenyl]-2-pyrazinecarboxamide; N-4-cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] -2-pyrimidinecarboxylic; N-[4-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl] -4,6-dimethylpyrimidin-2-ylsulphonyl and N-[4-[cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)methyl] phenyl]-4-methylpyrimidin-2-ylsulphonyl.

15. Connection on p. 9, selected from the group comprising: 3-[cyclopropyl[3-[(4-cyanophenylacetic)methyl] phenyl] -methyl]-4-hydroxycoumarin; 3-[cyclopropyl[3-[(2-pyridylsulfonyl)methyl]phenyl]methyl]-4-hydroxycoumarin; 3-[cyclopropyl[3-[(1-methyl-4-imidazolidinyl)methyl]phenyl]methyl] -4-hydroxycoumarin; 3-[cyclopropyl[3-[(5-cyano-2-pyridylsulfonyl)methyl] phenyl] methyl] -4-hydroxycoumarin; 3-[cyclopropyl[3-[(2-benzimidazolylthio)methyl] phenyl] methyl] -4-hydroxycoumarin; 3-[cyclopropyl[3-[(2-hyalinization)methyl] phenyl]methyl]-4-hydroxycoumarin; N-(3-{cyclopropyl[7-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-hydroxycoumarin-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{cyclopropyl[7-methoxy-4-hydroxycoumarin-3-yl] methyl} phenyl)-1-methyl-1H-imidazole-4-sulfonamide; N-(3-{cyclopropyl[7-(2-(2-(2-methoxyethoxy) ethoxy)ethoxy)-4-hydroxycoumarin-3-yl] methyl} phenyl)-8-x is reincorporated; N-(3-{ cyclopropyl[4-hydroxycoumarin-3-yl]methyl}phenyl)-2-pyridinesulfonamide; N-(3-{ cyclopropyl[4-hydroxycoumarin-3-yl] methyl} phenyl)-4-cyano-2-pyridinesulfonamide; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl]methyl}phenyl)-2-chinaincorporated; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl)methyl}phenyl)-2-hydroxybenzenesulfonate; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl]methyl}phenyl)-2-pyrazolylborate; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl]methyl} phenyl)-2-ChineseSimplified; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl]methyl}phenyl)-7H-purine-6-sulfonamide; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl] methyl} phenyl)-1H-imidazole-2-sulfonamide; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl] methyl} phenyl)benzimidazole-2-sulfonamide; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl] methyl} phenyl) thiazole-4-sulfonamide; N-(3-{cyclopropyl[4-hydroxycoumarin-3-yl] methyl} phenyl)-4-etoxycarbonyl-1H-imidazole-2-sulfonamide; N-(3-{ cyclopropyl[4-hydroxycoumarin-3-yl] methyl}phenyl)-3-hydroxy-2-pyridinesulfonamide; 5-cyano-N-[3-(1'-cyclopropylmethyl)-4-hydroxycoumarin] -N-methyl-2-pyridinesulfonamide; N-[3-(1'-cyclopropylmethyl)-4-hydroxycoumarin] -N-methyl-2-chinaincorporated; N-[3-(1'-cyclopropylmethyl)-4-hydroxycoumarin] -N-methyl-2-imidazolidinone; N-[3-(1'-cyclopropylmethyl)-4-HYDR shall atlanpole; N-[3-(1'-cyclopropylmethyl)-4-hydroxycoumarin]-N-methyl-2-ChineseSimplified; -[3-(1'-cyclopropylmethyl)-4-hydroxycoumarin] -N-methyl-6-peninsulaand; -3-(1'-cyclopropylmethyl)-4-hydroxycoumarin]-N-methyl-4-thiazolecarboxamide; and -[3-(1'-cyclopropylmethyl)-4-hydroxycoumarin]-N-methyl-2-pyridinesulfonamide.

16. Connection on p. 1, in which the salt is a bis-arginine, bis-chloride, bis-or potassium bis-calcium salt, provided that the compound contains the group-NHSO2-, -SO3H-, -CONH, -HE or-COOH.

17. Connection on p. 16, in which the salt is a bis-sodium salt.

18. Connection on p. 9, in which the salt is a bis-arginine, bis-chloride, bis-or potassium bis-calcium salt, provided that the compound contains the group-NHSO2- HE or-COOH.

19. Connection on p. 18, in which the salt is a bis-sodium salt.

20. Connection on p. 1 of formula VI

< / BR>
where R2means (a) ethyl; (b) cut; (C) cyclopropyl-(CH2)2-; (d) forfinal-(CH2)2-; (e) het-SO2NH-phenyl-; (H3C)2HC-CH2; (g) phenyl-(CH2)2or (h) trifluoromethyl-(CH2)2-;

R32-; (d) forfinal-(CH2)2-; (e) het-SO2NH-phenyl-; (H3C)2HC-CH2; (g) phenyl-(CH2)2or (h) trifluoromethyl-(CH2)2-;

R7means (a) ethyl; (b) tert-butyl or (C) cyclopropyl;

R9means (a) NS2-gets or (b) -NS2is phenyl, substituted with one R11; het represents the following groups, unsubstituted or substituted with one R10(a) imidazol-4-yl; (b) 2-pyridinyl, or (C) quinoline-8-yl; R10means (a) methyl; (b) cyano; (C) trifluoromethyl; (d) amino or (e) -C(O)-NH2; R11denotes cyano.

21. Connection on p. 20, selected from the group comprising: N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis (2-(4-forfinal)ethyl)-2H-Piran-3-yl)propyl}phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,b-bis (2-(4-forfinal) ethyl)-2H-Piran-3-yl)-2.2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis (2-(4-forfinal)ethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-(1-[6,6-bis(2-cyclopropylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] propyl) phenyl]-1-methyl-1H-imidazolidinedione; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2, 2-dimethylpropyl}-phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-(3-[1-(6-ethyl-5,6-dihydro-4-hydroxy-6-[3-([(1-methyl-1H-imidazol-4-yl)sulfonyl] amino) phenyl]-2-2H-Piran-3-yl)propyl] phenyl)-1-methyl-1H-imidazole-4-sulfonamide; 5-cyano-N-(3-[1-(6-[3-([(5-cyano-2-pyridinyl)sulfonyl] amino)phenyl] -6-ethyl-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl)propyl] phenyl)-2-pyridinesulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2, 2-dimethylpropyl}phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-(1-[6,6-bis(2-cyclopropylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl)-2,2-dimethyl-propyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-(1-[6,6-bis(2-cyclopropylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl)-2,2-dimethylpropyl)phenyl] -5-cyano-2-pyridinesulfonamide; 5-cyano-N-[3-(R or S) - [1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2.2-dimethylpropyl] phenyl]-2-pyridinesulfonamide; 5-cyano-N-[3-(R)-[1-[5, 6-dihydro-4-hydroxy-2-oxo-6-(2 the hydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide; 5-cyano-N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,3-cryptochromes)-2H-Piran-3-yl]-2,2-dimethyl]propyl] phenyl] -2-pyridinesulfonamide; 5-cyano-N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; N-[3-(R or S)-[1-[5, 6-dihydro-4-hydroxy-2-oxo-6-(R or S)-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenethyl)-6-(3, 3,3-cryptochromes)-2H-Piran-3-yl]-2,2-dimethylpropyl]phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenethyl)-6-(3,3,3-cryptochromes)-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; 5-amino-N-[3-(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2 ropyl)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide; 5-amino-N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-(3,3,3-cryptochromes)-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; N-[3-(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R or S)-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide; N-[3-(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide; N-[3-(S')-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(R)-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide; N-[3-(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-(S)-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl]phenyl-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl]propyl]phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(S)-[1-[4-guide is 1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl] -2-pyridinesulfonamide; 4-trifluoromethyl-N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl]-2-pyridinesulfonamide; 4-trifluoromethyl-N-[3-(S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(R or S)-[1-[4-hydroxy-2-oxo - 6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-Piran-3-yl] -propyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-Piran-3-yl] -propyl]phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(S)-[1-[4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-Piran-3-yl] -propyl]phenyl]-2-pyridinesulfonamide; 4-trifluoromethyl-N-[3-(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-Piran-3-yl] -propyl] phenyl] -2-pyridinesulfonamide; 4-trifluoromethyl-N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-phenethyl-5,6-dihydro-2H-Piran-3-yl] - propyl]phenyl]-2-pyridinesulfonamide; 4-trifluoromethyl-N-[3-(S)-[1-[4-hydroxy-2-oxo-6,6-defenee-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2-dimethylpropyl] - phenyl-2-pyridinesulfonamide; 4-trifluoromethyl-N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 4-trifluoromethyl-N-[3-(S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl) -6(R)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(3)-(2-phenethyl)-6(S)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide; 4-trifluoromethyl-N-[3(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S)-N-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2-Pierre] phenyl] -2-pyridinesulfonamide; 4-trifluoromethyl-N-[3(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl]-2-pyridinesulfonamide; 4-trifluoromethyl-N-[3(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl] -2-pyridinesulfonamide; 4-trifluoromethyl-N-[3(S)-[1-5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl]phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenethyl)-6(R or S)-n-propyl-2H-Piran-3-yl]-2,2-dimethylpropyl] phenyl] -2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenethyl)-6(R)-n-propyl-2H-Piran-3-yl] -propyl] phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-Piran-3-yl] -propyl] phenyl-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(S)-[1-5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6(R)-n-propyl-2H-Piran-3-yl] -propyl]phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6(S)-n-propyl-2H-Piran-3-yl]-propyl]phenyl]-2-pyridinesulfonamide; 5-amino-N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2.2-dimethylpropyl] phenyl]-2-pyridinesulfonamide; 5-cyano-N-[3(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-fine the o-6(R)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide; 5-cyano-N-[3(R)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-cyano-N-[3(S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-cyano-N-[3(S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-cyano-N-[3-(1-[5,6-dihydro-6,6-Diisobutyl-4-hydroxy-2-oxo-2H-Piran-3-yl] propyl)phenyl] -2-pyridinesulfonamide; N-[3-(1-[5,6-dihydro-6,6-di-ISO-butyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl]-1-methyl-1H-imidazole-4-sulfonamide; 5-cyano-N-[3-(1-[5,6-dihydro-6,6-di-ISO-butyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; N-[3-(R or S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(R or S)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(R)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(S)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-(S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(R)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl) -2,2-dimethylpropyl] phenyl] -1-methyl-1H-imidazol-4-methyl-1H-imidazole-4-sulfonamide; 5-cyano-N-[3-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -cyclopropylmethyl)phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R or S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide; 5-amino-N-[3-(R)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl]-2-pyridinesulfonamide; 5-amino-N-[3-(S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(R)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl) phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(R or S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R or S)-(2-phenylethyl) -6-propyl-2H-Piran-3-yl] propyl)phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(R)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenylethyl)-6-propyl-2H-Piran-3-or propyl)phenyl]-2-pyridinesulfonamide; 5-amino-N-[3-(R)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(S)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] propyl)phenyl] -2-pyridinesulfonamide; 5-amino-N-[3-(S)-(1-[5,6-dihydro-4-hydroxy-2-oxo-6-(R)-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] propyl)phenyl]-2-pyridinecarboxamide; 5-amino-N-[3(R or S)-(1-[6(R or S)-(2-[4-forfinal] ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-amino-N-[3(R)-(1-[6(R)-(2-[4-forfinal] ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-amino-N-[3(R)-(1-[6(S)-(2-(4-forfinal] ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide; 5-amino-N-[3(S)-(1-[6(R)-(2-[4-forfinal] ethyl)-5,6-dihydro-4-hydroxy-2-oxo-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide; 5-amino-N-[3(S)-(1-[6(S)-(2-[4-forfinal] ethyl)-5,6-dihydro - 4-hydroxy-2-oxo-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide; N-[3(R or S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3(R)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3(S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; 5-amino-N-[3(R or S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-amino-N-[3(R)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimetyl ropyl)phenyl] -2-pyridinesulfonamide; 5-cyano-N-[3(R or S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-cyano-N-[3(R)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl] -2-pyridinesulfonamide; 5-cyano-N-[3(S)-(1-[5,6-dihydro-6,6-dipropyl-4-hydroxy-2-oxo-2H-Piran-3-yl] -2,2-dimethylpropyl)phenyl]-2-pyridinesulfonamide; N-[3(R or S)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] -propyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3(R)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] -propyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3(S)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] -propyl)phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3(R or S)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] -propyl)phenyl] -5-cyano-2-pyridinesulfonamide; N-[3(R)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] -propyl)phenyl] -5-cyano-2-pyridinesulfonamide; N-[3(S)-(1-[6,6-bis(2-phenylethyl)-5,6-dihydro-4-hydroxy-2-oxo-2H-Piran-3-yl] -propyl)phenyl]-5-cyano-2-pyridinesulfonamide; N-[3{ 1-[4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl] -2,2-dimethylpropyl}phenyl]-4-cyanobenzenesulfonyl; N-[3-{ 1-[4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-florfenicol)-6-propyl-2H-Piran-3-yl] -2,2 who drank} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-carbamoylation-2-sulfonamide; N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-(4-forfinal)ethyl)-2H-Piran-3-yl)-propyl} phenyl] -5-carbamoylation-2-sulfonamide; N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)-propyl} phenyl] -5-carbamoylation-2-sulfonamide; N-[3-{1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl}phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -1-methyl - 1H-imidazole-4-sulfonamide; N-[3-{1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} feilner] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-Piran-3-yl)-propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl) -2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl) -2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6-(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-is)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1()-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-aminopyridine-2-sulfonamide; N-[3-{1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl]-5-aminopyridine-2-sulfonamide; N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)- 2H-Piran-3-yl)-2,2-dimethylpropyl}phenyl]-5-aminopyridine-2-sulfonamide; N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ (R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2-Gimel)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)-2,2-dimethylpropyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl - 2H-Piran-3-yl)propyl}phenyl]-5-aminopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-aminopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl]-5-aminopyridine-2-sulfonamide; N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-cyanopyridine-2-with whom iridin-2-sulfonamide; N-[3-{1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl}phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4 - forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -1-methyl-1H-imidazole-4-sulfonamide; N-[3-{ 1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl}phenyl]-5-aminopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl)-5-aminopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -5-aminopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-(2-(4-forfinal)ethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-aminopyridine-2-sulfonamide; N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-(2-(4-forfinal)ethyl)-6-propyl-2H-Piran-3-yl)propyl} phenyl] -5] -5-(trifluoromethyl)-2-pyridinesulfonamide; (3S, 6R)-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] propyl] phenyl] -5 - trifluoromethyl)- 2-pyridinesulfonamide; (3S)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl] phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide; (3R)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl] phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide; (3R)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-Piran-3-yl)propyl] phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide; (3R, 6S)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-propyl-6-phenethyl-2H-Piran-3-yl)propyl] phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide; (3S, 6S)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl)propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide.

22. 4-Hydroxy-2H-Piran-2-ones selected from the group consisting of: N-[3-{ 1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)methyl} phenyl] -5-cyanopyridine-2-sulfonamida and N-[3-{1-(4-hydroxy-5,6-dihydro-2-oxo-6,6-bis(2-phenylethyl)-2H-Piran-3-yl)methyl} phenyl] -5-aminopyridine-2-sulfonamida.

23. 4-Hydroxy-cyclooctadiene-2-ones of the formula XI

< / BR>
where R1represents -(CH2)R-CH(R2)-(CH2)o-AG1where R2means (a) (C1-C5)alkyl or (b) -(CH2)q2AG2; Ar2represents (a) phenyl, unsubstituted or substituted with one R3or (b) het, het represents a 5-, 6 - or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and including any bicyclic group in which any of the above heterocyclic rings condensed with a benzene ring or another heterocycle; unsubstituted or substituted with one R4; R3means (a) cyano; (b) a fluorine atom; and (C) hydroxyl, or (d) nitro; R4means (a) methyl; (b) cyano; (C) hydroxyl; (d) etoxycarbonyl; (e) trifluoromethyl, or (f) amino; n is equal to the number from zero (0) to eight (8) inclusive; o is equal to the number from zero (0) to three (3) inclusive; p is from zero (0) to three (3) inclusive; q is equal to the number from zero (0) to three (3) inclusive,

or its pharmaceutically acceptable salt.

24. Connection on p. 23, in which R1denotes-CH(R2)-AG1; R2means (a) ethyl or (b) tert-butyl; AG1denotes phenyl, substituted by a group of meta-NHSO2Ar2; Ar2represents 2-pyridinyl substituted with one R4; R4means (a) cyano, or (b) trifluoromethyl; where n about causa: 5-cyano-N-[3-(1-(4A, 5,6,7,8,8 and hexahydro-4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)propyl] phenyl] -2-pyridinesulfonamide; 4-cyano-N-[3-[1-(4A, 5,6,7,8,6 and hexahydro-4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)propyl] phenyl] -benzosulfimide; 5-cyano-N-[3-[1-(2,4 a, 5,6,7,8,9,9-octahydro-4-hydroxy-2-oxo-cyclohepta[b] Piran-3-yl)propyl] phenyl]-2-pyridinesulfonamide and 5-cyano-N-[3-[2,2-dimethyl-1-(4A, 5,6,7,8,9,10,10 and octahydro-4-hydroxy-2-oxo-2H-cycloocta[b] Piran-3-yl)propyl]phenyl]-2-pyridinesulfonamide.

26. Connection on p. 20, in which R2means (a) drunk or (b) phenyl -(CH2)2-; R3represents a fragment of formula X; R6means (a) drunk or (b) phenyl-(CH2)2-; R7means (a) ethyl or (b) tert-butyl; R9means (a) NSO2-het, where het is the following group, substituted with one R10(a) imidazol-4-yl, or (b) 2-pyridinyl; R10means (a) methyl; (b) cyano; or (C) trifluoromethyl.

27. Connection on p. 26 selected from the group including: 5-trifluoromethyl-N-[3-(R or S)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl]phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3-(R)-[1-[4-hydroxy-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl] -2-pyridinesulfonamide; or (3R)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-OK the STI-2-oxo-6,6-di-n-propyl-5,6-dihydro-2H-Piran-3-yl] propyl] phenyl] -2-pyridinesulfonamide; or (3S)-N-[3-[1-(5,6-dihydro-4-hydroxy-2-oxo-6,6-di-propyl-2H-Piran-3-yl] propyl] phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R or S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R or S)-(2-phenylethyl)-6(R or S)-n-propyl-2H-Piran-3-yl] propyl] phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6(R)-n-propyl-2H-Piran-3-yl] propyl]phenyl]-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(R)-[1-[5,6-dihydro-4-hydroxy-2-oxo - 6(S)-(2-phenylethyl)-6(S)-n-propyl-2H-Piran-3-yl] propyl] phenyl] -2-pyridinesulfonamide; or (3R, 6S)-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-propyl-phenethyl-2H-Piran-3-yl)propyl] phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(R)-(2-phenylethyl)-6(R)-n-propyl-2H-Piran-3-yl] propyl] phenyl] -2-pyridinesulfonamide; or (3S, 6R)-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl] propyl] phenyl] -3-(trifluoromethyl)-2-pyridinesulfonamide; 5-trifluoromethyl-N-[3(S)-[1-[5,6-dihydro-4-hydroxy-2-oxo-6(S)-(2-phenylethyl)-6(S)-n-propyl-2H-Piran-3-yl] propyl] phenyl] -2-pyridinesulfonamide; or (3S, 6S)-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide; N-[3-[1-(S)-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-Piran-3-yl]propyl]phenyl] phenyl] -5-(trifluoromethyl)-2-pyridinesulfonamide; N-[3-(R or S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(R or S)-[2-phenylethyl]-6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(R)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-(R)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(S)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl] phenyl] -1 - methyl - 1H-imidazole-4-sulfonamide; N-[3-(S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(R)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-(S)-[1-(5,6-dihydro-4-hydroxy-2-oxo-6-(S)-[2-phenylethyl] -6-propyl-2H-Piran-3-yl)-2,2-dimethylpropyl]phenyl]-1-methyl-1H-imidazole-4-sulfonamide; N-[3-{1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl] phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6,6-dipropyl-2H-Piran-3-yl)propyl} phenyl] -5-cyanopyridine-2-sulfonamide; N-[3-{1(R or S)-(4-hydroxy-5,6-dihydro-2-oxo-6(R or S)-phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{ 1(R)-(4-hydroxy-5,6-dihydro-2-oxo-6(R)-phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-cyanopyridine-2-sulfonamide; N-[3-{1(R)-(4-hydroxy-5,6-di the DRO-2-oxo-6(R)-phenethyl-6-propyl-2H-Piran-3-yl)propyl} phenyl]-5-cyanopyridine-2-sulfonamide and N-[3-{ 1(S)-(4-hydroxy-5,6-dihydro-2-oxo-6(S)-phenethyl-6-propyl-2H-Piran-3-yl)propyl}phenyl]-5-cyanopyridine-2-sulfonamide.

Priority signs:

06.05.94 - values of the radicals R1, R2(a,b,c), R3, R4, R5, R6(a,b,c,d,e, f,g,h,i), R7, R8, R9, R10(a,b,c,d), R11, R12;

02.12.94 - values of the radicals R2(d,e,f), R6(j,k,l);

04.05.94 - values of the radicals R2(g), R6(m), R10(e,f,g).

 

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The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, possibly substituted C1-C8-alkyl; R3- peloid in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt
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