Pornomovie compounds and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new Paramonova compounds useful for the inhibition of retrovirus in human cells infected with the indicated retroviruses. Describes pornomovie compounds of General formula (I), where the values of R1-R3, R10and R11specified in paragraph 1 of the formula. Also described pharmaceutical composition on the basis of the above compounds with the specified purpose. 2 C. and 23 C.p. f-crystals, 4 tab., 60 Il.

The invention relates to compounds useful for the inhibition of retrovirus in human cells infected with the indicated retroviruses. More specifically, the present invention provides Piran-2-ones and 5,6-dihydropyran-2-ones as inhibitors of HIV protease.

In the past decade, acquired immunodeficiency syndrome (AIDS) has progressed from the stage, having the status of a medical curiosity, causing anxiety or suffering only a small number of individuals, to problems of great importance both medically and economically. Authors John Saunders and Richard Storer [John Saunders and Richard Storer, "New Developments in RT Inhibitors". SN&P 5(3), April 1992, pages 153-169] Apache in the United States. Of these, roughly about 100,000 in the world (5000 in the US) was reported for the preceding period of 12 months. In the USA the number of seropositive individuals is considered to be approximately two million, and, according to the assessment, I believe that the world can be 5-10 million people. Data Saunders and Storer, page 153.

Since the first description of this disease in the beginning of this decade, acquired immunodeficiency syndrome (AIDS) and its devastating sequences were subject to continuous and intensive coverage, both Amateurs and scientific press. In fact, one of the editions of Scientific American was entirely devoted to AIDS (Scientific American 289, No. 4 (1988)), and the literature on this disease and this virus is so vast that it defies careful citation.

20 March 1987, the FDA approved the use of compounds of zidovudine (AZT) for the treatment of AIDS patients with fresh initial attacks pneumocystosis pneumonia (pneumocystis carinii pneumonia), AIDS patients with conditions other than pneumocystosis pneumonia or patients infected with the virus, with the absolute number of CD4 lymphocytes is less than 200/cubic mm in the peripheral blood. AZT is a well-known the man. In U.S. patent 4724232 the claimed method of treatment of persons with acquired immunodeficiency syndrome, using 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).

After the discovery of anti-HIV activity of azidothymidine huge efforts have been aimed at a wide variety of other dideoxynucleoside analogues in finding more superior agents. In the case of 2',3'-dideoxy number of ddC and ddI showed strong activity against HIV in vivo, and have been evaluated in clinical trials. Saunders, Storer, page 160. Connection ddC is currently the subject of a development company Hoffman La Roche Co. as potential drugs against AIDS. Its limiting from the standpoint of toxicity for people factor is 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, No. 6, 1992, page 963-990. It was approved by the FDA for the treatment of AIDS in combination with AZT. Connection ddI also been evaluated in clinical trials. Its limiting factors of toxicity is peripheral neuropathy and pancreatitis. It was also shown that it stimulates glycolysis in the liver, leading to irreversible liver damage. Schinazi, Mead and Feorin who who cannot tolerate treatment, or whose health has deteriorated significantly after treatment with AZT. Schinazi, Mead and Feorino, p. 966.

Among these approved drugs AZT is currently the only drug that has been shown to reduce mortality and the frequency of infections caused by opportunistic pathogens associated with AIDS. Schinazi, Mead and Feorino, p. 963.

The human immunodeficiency virus (HIV) has been long considered to be the cause of AIDS, although in the minority, it has been argued that the opposite (for example, P. Duesberg, Proc, Natl, Acad, Sci, USA, 86: 755-764 (1989)). Analysis of the sequences of complete genomes from several infectious and non-infectious HIV isolates has shed considerable light on the structure of the virus and the types of molecules that are essential for its replication and maturation to infectious species. HIV protease is essential for the processing of viral gag and gag-pol polypeptide in proteins of the Mature virion. L. Ratner and others, Nature, 313: 277-284 (1985); L. H. Pearl and W. R. Taylor, Nature, 329:351 (1987). HIV finds the same organization gag/pol/env prominent in other retroviruses. L. Ratner and others, Nature, 313:277-284 (1985); S. Wain-Hobson, and other Cell. 40:9-17 (1985); R. Sanchez-Pescador, etc., Science, 227: 484-492 (1985) and M. A. Muesing, and others, Nature, 313: 450-458 (1985).

Reverse transcriptase (RT) is an enzyme which any point during the transcription process using AZT or any other aberrant (unusual deoxynucleoside-triphosphate, incapable of elongation should have dramatic consequences for viral replication. A large number of works on RT targets that are in the process of development, based in large measure on the fact that the nukes, like AZT, easily delivered into cells. However, the inefficiency of the stage of phosphorylation to the triphosphate, lack specificity and resulting toxicity are the main obstacles to the use of AZT and other nucleoside with blocked or missing 3 gidroksilnuyu group.

T4 cell receptor for HIV, the so-called CD4 molecule, was also in the spotlight as a point of intervention in the treatment of AIDS. R. A. Fisher and others, Nature, 331: 76-78 (1988); R. E. Hussey and others, Nature, 331-78-81 (1988); and K. C. Deen and others, Nature, 331: 82-84 (1988). The outer part of this transmembrane protein, a molecule of 371 amino acids (CD4) was expressed in Chinese hamster ovary (CHO), and the firm Genentech (D. H. Smith and others, Science, 238: 1704-1707 (1987)) since the autumn of 1987, is the product during clinical trials. It has been shown that CD4 has a narrow spectrum of activity against viruses of wild-type, and while it fails to deal with HIV infection in humans. Schinasi, Mead and Feorino, p. 963. The idea underlying the treatment with ispolzovaniem, which Express CD4 on their surface. A variation of this approach is the accession of cellular toxins to CD4 for specific binding and delivery to the infected cells that produce the glycoprotein gp 120 on its surface. M. A. Till and others, Science, 242: 1166-1168 (1988); and V. K. Director and others, Nature, 335: 369-372 (1988).

Another goal in the case of AIDS is the inhibition of the viral protease (or proteinase), which is essential for processing of polypeptide precursors of HIV-merge. It has been shown that HIV and other retroviruses proteolytic maturation of the polypeptides of the gag and gag/pol fusion (the process necessary to generate infectious viral particles), mediasuite protease, which in itself is encoded pol region of the viral genome. Y. Yoshinaka and others, Proc. Natl. Acad. Sci. USA, 82: 1618-1622 (1985); Y. Yoshinaka, etc., I. Virol, 55: 870-873 (1985); Y. Yoshinaka, etc. , J. Virol., 57: 826-832 (1986); and K. Von der Helm, Proc. Natl, Acad. Sci. USA, 74: 911-915 (1977). It was shown that inhibition of protease inhibits the processing of HIV p55 in mammalian cells and HIV replication in T-lymphocytes. T. J. McQuade and others, Science, 247:454 (1990).

Protease (or proteinase), consisting of only 99 amino acids, is among the smallest known enzymes, the 351-354 (1987); and L. Katoh and others, Nature, 329: 654-656 (1987)), has led to conclusions concerning the three-dimensional structure and mechanism of the enzyme (L. H. Pearl and W. R. Taylor, Nature, 329: 351-354 (1987)), which have since been exposed experimentally. Active HIV protease was expressed in bacteria (see, for example, P. L. Darke and others J. Biol. Chem., 264: 2307-2312 (1989)) and chemically synthesized (J. Schneider and S. B. Kent, Cell, 54:363-368 (1988); and R. F. Nutt and others, Proc.Natl.Acad.Sci., USA, 85:7129-7133 (1988)). Site directed mutagenesis (P. L. Darke, etc., J. Biol. Chem., 264:2307-2312 (1989); and N. E. Kohl and others, Proc. Natl. Acad. Sci., USA, 85:4686-4690 (1988)) and inhibition of pepstatin (P. L. Darke, etc., J. Biol. Chem., 264:2307-2312 (1989); S. Seelmeier and others, Proc. Natl. Acad. Sci., USA, 85-6612-6616 (1988); C.-Z. Giam and I. Borsos, J. Biol. Chem., 263:14617-14720 (1988); and J. Hansen and others, EMBO J., 7:1785-1791 (1988)) gave testimony mechanical function of HIV protease as aspirinplease. The study demonstrated that the protease is cleaved at sites expected in the simulated peptides, after the data area is actually split by the enzyme proteins gag and pol precursor during maturation of the virus. P. L. Darke and others, Biochem. Biophys. Res. Communs., 156:297-303 (1988). X-ray crystallographic analysis of HIV protease (M. A. Navia, and others, Nature, 337: 615-620 (1989)) and related retroviral enzymes from Rous sarcoma virus (M. Miller and others, Natere, 337:576-579 (1989)) found asset is I thus assumption (L. H. Pearl and W. R. Taylor, Nature, 329:351-354 (1987)) that the HIV enzyme is active in the form of a dimer. Cm. also Joseph A. Martin, "Recent Advances in the Design of HIV Proteinase Inhibitors", Antiviral Reseaech, 17 (1992), 265-278.

To date ongoing scientific research is completely safe and effective means of inhibiting retroviruses in humans infected with this virus, and effective treatment with diseases caused by such viruses, such as acquired immunodeficiency syndrome (AIDS).

In engineering it is well known that certain undesirable physiological manifestations, such as ordinary coal, seborrhea, hirsutism, or excessive hair growth in women, male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation or excessive accumulation of testosterone or similar active hormones in target tissues. U.S. patent N 4377584, column 1, lines 18-24. In addition, it was shown that reduced levels of androgen exerts a therapeutic effect on prostate cancer. See, for example, U.S. patent 5017568, column 2, lines 4-6.

In the art it is also known that the main mediator or a mediator of androgenic act, is that it is formed locally in the target organ by the action of steroid-5-reductase. So it has been the position and demonstrated that inhibitors of steroid-5 - reductase will serve to prevent or reduce symptoms of hyperandrogenic stimulation. See, for example, U.S. patent 4377584, column 1, lines 38-45.

Examples of compounds that are anti-androgens because of their ability to inhibit testosterone-5 - reductase, disclosed in U.S. patent 4377584, 4760071 and 5017568.

Description information about the known prior art.

JO 3227-923-A (Sawai Seiyaku KK) discloses the use of 4-hydroxy-coumarins as therapeutic agents for patients infected with HIV.

WO 91/04663 (University of California in Oakland) discloses 6-amino-1,2-benzopyrone, which are useful for the treatment of viral diseases.

WO 91/12804 (CABI pharmaceutical) discloses the use of Linomide (p) for the treatment of retroviral infections.

International publication N WO 89/07939, published September 8, 1989, discloses specific coumarin compounds, which are inhibitors of the reverse transcriptase.

U.S. patents NN 3489774 and 3493586 describe 3-(beta-arivaca)-(epublication Biochemical and Biophysical Research Communications, volume 188, No. 2, 1992, pages 631-637 reveals chromone bearing hydroxyl substituents and phenolic group in 2-position (flavones), as having anti-HIV-1 proteinase activity.

In Antimicrobial Patent Fast-Alert, Week Ending September 4, 1992, disclosed gamma dowels, gamma pyridone and gamma-thio-dowels as antivirusnuyu agents.

International publication NN WO 92/04326, 92/04327 and 92/04328, all published March 19, 1992, discloses anti-virus heterocyclic derivatives, such as chinoline and benzopyrene, as inhibitors of replication for the treatment of herpes simples 1 and 2, cytomegalovirus virus and Epstein-Barr.

In C. A. Selects: Antitumor Agents, issue 19, 1992, page 25, No. 177: 90147q (international PCT application WO 92/06687) disclosed receipt of 5-iodine-5-amino-1,2-benzopyrones and analogues as cytotoxic and antiviral agents.

None of such links does not say and does not assume the use of 4-hydroxy-dowels as inhibitors of HIV protease, or as having antiviral activity.

Phytochemistry, 31(3): 953-956 (1992) discloses such compounds as 4-hydroxy -- (4-methoxyphenyl)-6-[2-(4- methoxyphenyl)ethynyl]-2-oxo-, methyl ester, /E/-/-/-2H-Piran - 3-Oksana acid.

Tetrahedron, 48/9/:1695-1706 (1 is l)-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.

Tennen Yuki Kagobutsu Toronkai Keen Yoshishu 30:17-24 (1988) discloses compounds such as 4-hydroxy -- (4-methoxyphenyl)- 6-[2-(4-methoxyphenyl)ethynyl]-2-oxo-, methyl ester, (E)-(-)-2H - Piran-3-propanoic acid.

In Chem. Absts, 53: 15072 f disclosed compounds such as alpha-1,3-dihydroxy-2-butenolide-beta-ethyl - lactone, hydroxyurea acid.

In Chem. Absts. 53:15072 c disclosed compounds such as 1,3-dihydroxy-2-butenolide -- isopropyl-, - lactone, hydracarina acid.

Arch. Pharm. (Weinheim, Ger.), 316 (12):988-994 (1983) discloses such compounds as 3-[1-(4-chlorophenyl)-3-oxobutyl]- 4-hydroxy-6-methyl-2H-Piran-2-it, and 3-[1-(4-chlorophenyl)propyl]- 4-hydroxy-6-methyl-2H-Piran-2-it.

Chem. Ber. , 110(3): 1047-1057 (1977) discloses 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, and 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.

J. Heterocycl. Chem., 23(2): 413-416 (1986) reveals such oblikovanje PCT applications disclose peptides, useful as inhibitors of retroviral proteases: international publication N WO 91/06561, published may 16, 1991, and international publication N WO 92/17490, published October 15, 1992

The following references disclose pernovae compounds that are deemed to be representative compounds known in the art:

EP-443449. lang. ) discloses 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) describes 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-6-methyl-3- (1-oxobutyl)-2H-Piran-2-it. In Acta Chem. Scand., 43(2): 193-195 (1989) describes 4-(atomic charges)-5,6-dihydro-3,6-dimethyl-2H - Piran-2-it. In J.Org. Chem., 54(14): 3383-3389 (1989) describes 5,6-dihydro-4-hydroxy-3,6,6-trimethyl-2H-Piran-2-it. In J. Org. Chem. , 53(6):1218-1221 (1988) and Tetrahedron Lett., 34(2): 277-280 (1993) describes 3-hexylthio-6-undecyl-2H-Piran-2,4(3H)-dione, (6R)-. J. Chem. Soc. Perkins Trans., 1(6): 1157-1159 (1985) describes dihydro-3-methyl-6-nonyl-6-[[(tetrahydro-2H-Piran-yl)oxy] methyl] - 2H-Piran-2,4(3H)-dione. In J. Chem. Ecol. , 9(6): 703-714 (1983) disclosed 5,6-dihydro-4-hydroxy-3,6-dimethyl-2H-Piran-2-it. In J. Org. Chem., 48(7):1123-1125 (1983) describes 6-(2-chloro-1 - methylethenyl-5,6-dihydro-4-hydroxy-3-methyl-2H-Piran-2-it. (Z)-(. +-. )-. Acta Che59(7):2393-2401 (1976) describes 4-[(3,6-dihydro-4 - hydroxy-5-methyl-6-oxo-2H-Piran-2-yl)-methyl] -2,6-piperidine. In Acta Chem. Scand. , 30/7/: 613-618 (1976) and Tetrahedron Lett., 22:1903-1904 (1976) describes 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.

WO 93/07868, published April 29, 1993, describes new derivatives of nitroso-benzopyrone, - benzamide and athinaikon as inhibitors of adenosine di-phospho:abstracters for the treatment of viral infections and cancer.

WO 93/07128, published April 15, 1993, relates to substituted cyclic CARBONYLS and their derivatives, useful as inhibitors of retroviral protease.

In J. Indian Chem. Soc., 69:397-398 (July 1992) revealed that the coumarin-4-acetic acid were subjected to screening for their anti-cancer and anti-AIDS activity, and found that they are inactive.

In The Journal of Antibiotics, 46/7/: 1126 (July 1993) revealed germicides, which is 6-(2-butyl)-3-butyl)-3-ethyl-4-hydroxy-2-pyrone, and says that he is an inhibitor autoregulatory germination Streptomyces viridochromogenes NRRL B-1551.

Derwent Abstracts, 93-168920/211 EP 543201 describes the use about the red infections, such as influenza or acute rhinitis.

B J. Org. Chem., 48/22/:3945-3947 (1983) Chem. Pharm. Bull., 29/10/: 2762-2768 (1981) describes such compounds as 4-hyroxy-6-(3-pyridinyl)-2H-Piran-2-it.

In J. Labelled Compd. Radiopharm., 28/10: 1143-1148 (1990) also describes compounds as 4-hydroxy-6-methyl-2H-Piran-2-it.

In J. Am. Chem. Soc., 113/25/:9585-9595 (1991) discloses compounds such as 3-(3-phenyl-2-propen-1-yl)-6-methyl-4-hydroxy-2H-Piran-2-it.

CA 54:14239d and CA 53:4272c disclose compounds such as (- dihydroxycinnamate)-, - lactone hydracarina acid.

In CA 53:15072f disclosed compounds such as 1,3-dihydro-2-butenolide -- ethyl - lactone hydracarina acid.

In Synth. Commun., 20(18):2827-2836 (1990) describes compounds such as 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.

In J. Chem Orh., 54(4): 3383-3389 (1989) disclosed compounds such as 5,6-dihydro-4-hydroxy-3,6,6-trimethyl-2H-Piran-2-it.

Derwent Abstracts, 92-166863/20 EP 553248 describes the new optionally substituted 5-iodine-6-amino-1,2-benzopyrone derivatives, which are inhibitors CI:phospho-ribose, for the treatment and prevention of viruses and cancers associated with AIDS.In U.S. patent 5017568 disclosed acrylate analogues of steroidal synthetic compounds having the activity of an inhibitor of 5 - reductase and therefore useful in the treatment of diseases such as common acne, seborrhea, excessive ovolosenie women, prostate disease such as benign prostatic hypertrophy and adenocarcinoma prostate, and male baldness.

Selective non-steroidal inhibitor of human steroid 5 - reductase type I avservice.exe the invention, in particular, it provides:

The compound of the formula I

< / BR>
in which R1is:

(a) -(CH2)n-CH(R5)-(CH2)m-R4;

b) -CH(aryl)-CH[C(O)-O-C1-C6-alkyl]2;

c) -C(C3-C5cycloalkyl)-(CH2)n-R4;

d) -C(aryl)=CH-aryl or

(e) -CH(R5)-S(CH2)m-R4;

R2is

a) hydrogen,

b) halogen,

c) C1-C6-alkyl-[O-(CH2)2]q- CH2)n- or

d) C1-C6-alkyl;

R3is:

a) C2-C10-alkyl, optionally substituted by halogen, in number from zero (0) to five (5).

b) C2-C10alkenyl,

c) R4-(CH2)m-CH(R6)-(CH2)n-,

d) R4-(CH2)p-,

e) R4-CH=CH-,

f) CH2=CH-(CH2)p-,

g) R4(CH2)mX1C(O)(CH2)n-,

h) R4(CH2)mC(O)X1(CH2n-,

i) aryl,

j) gets

k) C3-C7-cycloalkyl,

l) C1-C6-alkyl-O-C(O)-(CH2)n-,

m) C1-C6-alkyl-[O-(CH2)2]q- (CH2)n-,

n) R4-CH(R6-(CH2)m-X2-(CH2)n- (R7)HC-,

R4is:

a) aryl,

b) gets

c) C3-C7-cycloalkyl,

d) C2-C10alkenyl,

e) C1-C6-alkyl-[O-(CH2)2]q- CH2)n-,

f) halogen,

g) het-O-,

h) het-C(O)-,

i) aryl-(CH2)n-O-C(O)-, or

(j) trifluoromethyl:

R5is:

a) C1-C10-alkyl,

b) (2-10)C-alkenyl,

c) (3-7)C-cycloalkyl,

d) -(CH2)n-aryl,

(e) -(CH2)p-gets or

f) -(CH2)n-CH=CH-aryl:

R6is:

a) (1-10)C-alkyl,

b) R4-(1-5)C-alkyl,

(C) -(CH2)n-(3-7)C-cycloalkyl,

d) -(CH2)p-CH=CH2,

(e) -(CH2)p-aryl,

f) -(CH2)p-gets or

g) hydroxy:

X1is a group-NR7-;

R7is

a) hydrogen or

b) (1-5)C-alkyl:

aryl is:

a) phenyl substituted by zero (0) to three (3) R8,

(b) naphthyl, substituted by zero (0) to three (3) R8,

c) biphenyl, substituted with zero to three R8or

d) pageloader: where het represents a 5 - or 6-membered saturated or narasiman the abuser any bicyclic group, in which any of the above heterocyclic rings condensed with a benzene ring, (3-8)C cycloalkyl or another heterocycle and, if chemically possible, the nitrogen atoms and sulfur may be in the oxidized forms; and substituted by zero to three R9:

R8and R9are independently:

a) (1-8)C-alkyl, substituted 0-3 Halogens,

b) (2-8)C-alkenyl,

c) hydroxy,

(d) hydroxy-(1-5)C-alkyl,

(e) -(CH2)n-O-(1-5)C-alkyl, substituted by 0-3 groups hydroxy,

f) -(CH2)n-O-(2-7)C-alkenyl, substituted 0-3 hydroxy,

(g) halogen,

h) amino,

i) amino-(1-5)C-alkyl,

(j) a mono - or di-(1-5)C-alkylamino,

k) -C(O)-(1-5)C-alkyl,

l) -CHO,

m) -COOH,

n) -COO(1-5)C-alkyl,

o) -CON(R7)2,

p) (3-7)C cycloalkyl,

q) nitro,

r) -CN,

s) -SO3H,

t) -SO2NH2,

u) -O[(CH2)2-O]q-CH3,

v)- (CH2-O]q-(1-3)C-alkyl,

w) -(CH2)n-NHC(O)-O-(CH2p-R12,

x) -(CH2)n-NHC(O)-O-)CH2)p-R15,

y) -(CH2)n-R12,

z) -SO2-R12,

a1) -(CH2)n-X2-(CH2)n-R12,

b1) -(CH2)n-X2-(CH2),

e1) -(CH2)n-X2-(1-10)C-alkyl, substituted 0-3 Halogens,

f1) -(CH2)n-X2(2-5)C-alkenyl,

g1) -X2-(CH2)p-CH(NH2)(COOH),

h1) -NHCONH-SO2-R12,

i1) -X2-(CH2)p-NH-C(O)-O-(1-6)C-alkyl,

j1) -X2-CH(X3)-NH-C(O)-O-(1-6)C-alkyl,

k1) - X2-(CH2)p-CH[NH-C(O)-O-(CH2)p- R12]-C(O)-O-(CH2)p-R12.

l1) -(CH2)n-X4-N(C1-C3-alkyl)2,

m1) -(CH2)n-X4-OTHER12,

n1) -NH-AA-P1,

o1) -(CH2)p-N3,

p1) -(CH2)p-R12,

q1) -(CH2)p-R15,

r1) -(CH2)n-NHC(SCH3)=CHNO2,

s1) -(CH2)n-NHC(OTHER7)=CHNO2,

t1) -(CH2)n-NHC(SCH3-NCN, or

u1) -(CH2)n-NHC(OTHER7)=NCN;

where X2represents a

a) -NH-C(O)-,

b) -NH-SO2-,

c) -NH-C(O)-NH-, or

d) -SO2-NH-;

X3is

a) (1-6)C-alkyl, or

b) -(CH2)p-R15:

X4is

a) NH-C(O)-, or

b) -NH-SO2-;

R10hydrogen;

R11is

a) hydrogen,

b) (1-6C)-alkyl,

(C) -(CHSUB>10
and R11taken together form a double bond;

or R3and R11taken together, constitute

a) (3-8)C-cycloalkyl, substituted with zero to three hydroxy, = N-OH, = O (oxo) or substituted form, or replaced in - position by a group R14: or

b) 5 - or 6-membered saturated ring containing 1 or 2 oxygen atom;

R12is:

a) phenyl, and substituted 0-3 R13or

(b) naphthyl, substituted 0-3 R13;

R13is

a) (1-10)C-alkyl, substituted 0-3 Halogens,

b) hydroxy,

c) hydroxy-(1-5)C-alkyl,

d) -(CH2)n-O-(1-5)C-alkyl, substituted by 0 to 3 hydroxy groups or halogen,

(e) -(CH2)n-O-(2-7)C-alkenyl, substituted 0-3 hydroxy or halogen,

f) halogen,

(g) amino,

h) amino-(1-5)C-alkyl,

(i) mono - or di(1-5)C-alkylamino

j) -C(O)-(1-5)C-alkyl,

k) -CHO,

l) -COOH,

m) -CON(R7)2,

n) -NHCO(1-3)C-alkyl,

o) -NHOH,

p) nitro,

q) -CN,

r) -(CH2)n-phenyl,

s) -COO(1-5)C-alkyl, or

t) -SO2is phenyl, substituted O-3(1-5)C-alkilani,

u) -(CH2)n-X4phenyl, or

v) -(CH2)n-N=N-phenyl, substituted by O or other group N[(1-3)C-alkyl]2;

R14 the keel:

R15represents 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 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, (3-8)C cycloalkyl, or another heterocycle, and substituted 0-3 groups R13:

AA - amino acid residue:

P1is hydrogen or azotaemia group:

m and n independently represent 0 to 5 inclusive:

p = 1-5;

q = 1-5;

and its pharmaceutically acceptable salts.

The present invention is especially such compounds in which R1represents -(CH2)n-CH(R5)-(CH2)m-R4, -C(3-5)C-cycloalkyl-(CH2)n-R4or-CH(R5)-S-(CH2)m-R4, R4aryl, het or (3-7)C-cycloalkyl.

For example, the present invention provides the following connections:

The compounds of formula I, in which

R1- (CH(R5)-R4;

R2is hydrogen,

R3is:

a) (3-8)-alkyl,

b) R4-(CH2)m-CH(R6)-,

c) R4-(CH2)p-,

d) R45is:

a) (2-5)C-alkyl,

b) (2-5)C-alkenyl,

c) cyclopropyl:

R6is

a) (2-5)C-alkyl, or

b) R4-(1-2)C-alkenyl-,

aryl is:

a) phenyl, substituted by 0 to 3 groups of R8or

(b) naphthyl, substituted by 0 to 3 groups of R8,

R8is:

a) halogen, or

b) (1-3)C-alkyloxy;

R10and R11taken together form a double bond;

m = 1 - 3;

p = 1 - 3

More specifically, the present invention provides the following connections:

The compound of the formula I, in which

R1- CH(R5)-R4;

R2is hydrogen;

R3is:

a) (5-8)C-alkyl.

b) R4-(CH2)m-CH(R6)-,

c) R4-(CH2)p-,

d) CH2=CH-(CH2)p- or

e) R4-CH=CH-,

R4- aryl;

R5is:

a) ethyl,

b) ethynyl or

c) cyclopropyl;

R6is:

a) ethyl or

b) R4-CH2-,

aryl is:

a) phenyl, substituted by 0 to 3 groups of R8or

(b) naphthyl, substituted by 0 to 3 groups of R8;

R8is:

a) halogen, or

b) methoxy:

R10and RNedstaal also the following connections:

The compounds of formula I in which:

R1is:

(a) -(CH2)n-CH(R5)-(CH2)m-R4,

b) -CH(aryl)-CH[C(O)-O-(1-6)C-alkyl]2or

c) -C(aryl)=CH-aryl;

R2is hydrogen;

R3is

a) (2-4)C-alkyl,

b) R4-(CH2)p-,

c) aryl, or

d) cyclohexyl;

R4is:

a) aryl, or

b) gets

R5is:

a) ethyl,

b) ethynyl,

c) cyclopropyl,

d) -(CH2)n- aryl, or

(e) -(CH2)n-CH=CH-aryl;

R10represents hydrogen;

R11is:

a) hydrogen,

b) (1-4)C-alkyl,

c) -(CH2)n-aryl, or

d) cyclohexyl;

or R3and R11taken together, constitute

a) (3-8)With cycloalkyl, substituted 0-3 hydroxy, = N-OH, carbonyl groups, or protected form, or replaced in - position -(CH2)n-aryl, or

b) 5 - or 6-membered saturated ring containing 1 or 2 oxygen atom;

aryl is phenyl, substituted by 0 to 3 groups of R8;

gets is:

a) thiophenyl, substituted by 0 to 3 groups of R9or

b) furanyl, substituted by 0 to 3 groups of R9;

R8and R
m = 0

n = 0-3;

p = 1-3;

q = 2.

The compound of the formula I, in which:

R1is:

(a) -(CH2)n-CH(R5)-(CH2)m-R4or

b) -C(3-5)C cycloalkyl-(CH2)n-R4;

R2is

a) hydrogen or

b) halogen;

R3is

a) R4-(CH2)m-CH(R6)-(CH2)n-,

b) R4-(CH2)p-,

c) (3-6)C-alkyl, substituted 0-3 Halogens, or

d) R4-CH(R6)-CH(R6)-;

R4is

a) aryl,

b) gets

c) (3-5)C-cycloalkyl,

d) CH2=CH-,

e) CH3-[O-(CH2)2]q-,

f) halogen,

q) het-O-, or

(h) aryl-(CH2)n-O-C(O)-;

R5is

a) ethyl,

b) cyclopropyl, or

c) -CH2-aryl;

R6is

a) ethyl,

b) propyl,

c) -CH2-cyclopropyl,

d) -CH2-CH=CH2,

(e) -CH2-aryl, or

f) hydroxy:

aryl is phenyl, substituted by 0 to 3 groups of R3;

gets substituted by 0 to 3 groups of R9is:

a) indolyl,

b) tetrahydro-furanyl,

c) thiophenyl,

d) isoxazolyl,

e) tetrahydro-furanyl,
k) piperidinyl,

l) pyrrolidinyl, or

m) pyrrolidinones;

R8is:

a) -X2-(CH2)p-NH-C(O)-O-(1-6)C-alkyl,

b) -(CH2)n-X2-(CH2)n-R12.

c) -(CH2)n-X2-(CH2)n-R15.

d) -(CH2)n-NHC(O)-O-(CH2)p-R12.

e) -NH-C(O)-NH-SO2-R12,

f) -X2-CH(X3)-NHC(O)-O-(1-6)C-alkyl.

q) -X2-(CH2)p-CH[NH-C(O)-O-(CH2)p- R12]-C(O)-O-(CH2)p-R12,

h) -X2-(CH2)p-CH(NH2)(COOH),

i) (1-5)C-alkyl, substituted 0-3 Halogens,

(j) halogen, or

k) (1-5)C-alkyloxy;

R9is:

a) methyl,

b) halogen,

c) -(CH2)n-R12)

d) -SO2-R12,

X2is:

a) -NH-C(O)-, or

b) -NH-C(O)-NH;

X3is:

a) (1-6)alkyl, or

b) -(CH2)p-R15;

R10and R11taken together form a double bond;

R12represents phenyl, substituted 0-3 R13;

R13is:

a) methoxy,

b) halogen,

c) -SO2is phenyl, substituted by 0 or one (1-5)C-alkyl,

d) -CN, or

e) (1-5)C-Ala is) imidazolyl, or

d) chinoline;

m = 0-3;

n = 0 - 2;

p = 1 - 3;

q = 2 or 3.

The present invention is especially such compounds in which R1- -(CH2)n-CH(R5)-(CH2)m-R4or-C(3-5)C-cycloalkyl-(CH2)n-R4, R4- aryl, het or (3-5)C-cycloalkyl.

The compound of the formula I, in which

R1- (CH2)n-CH(R5)-(CH2)m-R4;

R2is hydrogen;

R3- R4-(CH2)m-CH(R6)-(CH2)n-;

R4is:

a) aryl, or

b) gets;

R5- (3-7)C-cycloalkyl;

R6is:

a) (1-10)C-alkyl, or

b) -(CH2)n-(3-7)C-cycloalkyl;

aryl represents phenyl, substituted with zero or one group R8; het represents a 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 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, (3-8)C-cycloalkyl or another heterocycle;

R8is:

(a) -(CH2)n-X2-CH=CH-R12n-R15,

d) -(CH2)n-X2-(1-10)C-alkyl, substituted O or one halogen,

(e) -(CH2)n-X2-(2-5)C-alkenyl,

f) -(CH2)n-X4-N(CH3)2or

g) -(CH2)n-X4-NH-R12;

X2- NHSO2-,

X4- NHSO2-,

R10and R11taken together form a double bond;

R12is:

a) phenyl, substituted by 0 to 3 groups of R13,

(b) naphthyl, substituted by 0 to 3 groups of R13or

c) pergolide;

R13is:

a) (1-10)C-alkyl, substituted 0-3 Halogens,

b) halogen,

c) -O-(1-5)C-alkyl, substituted 0-3 Halogens,

d) -CN.

e) nitro,

f) -COOH.

g) -N(CH3)2,

h) hydroxy,

i) -NHCOCH3,

(j) amino,

k) -NHOH,

l) -CONH2,

m) -CH2-NHCO-phenyl,

n) -SO2-phenyl,

o) -N=N-phenyl, substituted by O-or a group-N(CH3)2or

p) -NHSO2is phenyl;

R15represents 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of these Vism, and substituted by 0-2 groups R13;

m=0 or 1;

n=0 or 1.

The present invention is especially such compounds, in which

R5- cyclopropyl;

R6-(CH2)n-cyclopropyl or ethyl; or is tetrahydropyranyl; and

R15substituted O - two groups of R13is:

a) phthalimide,

b) chinoline,

c) thiophenyl,

d) pyridyl,

e) isoxazolyl,

f) thiophenyl,

g) imidazolyl,

h) benzo(1,2,5)oxadiazolyl,

i) benzo(1,2,5)thiadiazole, or

j) 2-(isoxazol-3-yl)-thiophenyl.

The compounds of formula I, in which

R1is:

(a) -(CH2)n-CH(R5)-(CH2)m-R4or

b) -CH(R5)-S-(CH2)m-R4;

R2is

a) hydrogen, or

b) -(1-6)C alkyl;

R3is

a) R4-(CH2)m-CH(R6)-(CH2)n-;

b) R4-CH(R6)-CH(R6)-,

c) R12-(CH2)m-X2-(CH2)n-(R7)HC or

d) R15-(CH2)m-X2-(CH2)n-(R7)HC-;

R4is:

a) aryl, or

b) gets;

R5is:

a) (1 is, or

c) hydroxy;

R7is:

a) hydrogen, or

b) (1-5)C-alkyl;

aryl is phenyl, substituted by 0 or the two groups R8; gets is:

a) furan-2-yl, substituted by 0, or two R9.

b) furan-3-yl, substituted by 0, or two R9.

c) thiophene-2-yl is substituted by 0, or two R9.

C) thiophene-3-yl, substituted by 0, or two R9.

e) tetrahydrofuran-2-yl, substituted by 0, or two R9.

f) tetrahydrofuran-3-yl, substituted by 0, or two R9.

g) tetrahydropyran-2-yl, substituted by 0, or two R9.

h) tetrahydropyran-3-yl, substituted by 0, or two R9or

i) 8-chinoline;

R8and R9are independently:

a) (1-8)C-alkyl,

b) halogen,

c) hydroxy-(1-4)C-alkyl,

d) -(CH2)n-X2-(CH2)n-R12,

(e) -(CH2)n-X2-(CH2)n-R15,

X2is:

a) -NHSO2-,

b) -SO2NH - or

c) -NHC(O)-;

R10and R11taken together form a double bond;

R12is phenyl, substituted by 0 to 3 groups of R13;

R13is:

a) (1-6)C-alkyl,

b) guide the
a) thiophene-2-yl, substituted by 0 to 3 groups of R13,

b) thiophene-3-yl, substituted by 0 to 3 groups of R13,

c) quinoline-8-yl, substituted by 0 to 3 groups of R13,

d) furan-2-yl, substituted by 0 to 3 groups of R13or

e) furan-3-yl, substituted by 0 to 3 groups of R13;

m = 0 - 4;

n = 0 - 4;

The present invention also provides:

Method of inhibiting retroviruses in mammalian cells infected with the indicated retroviruses, which provides for the treatment of these cells an effective amount of the compounds of formula I in which:

R1is:

(a) -(CH2)n-CH(R5)-(CH2)m-R4;

b) -CH(aryl)-CH[C(O)-O-(1-6)C-alkyl]2.

c) -C(3-5)C-cycloalkyl-(CH2)n-R4.

d) -C(aryl)=CH-aryl.

(e) -CH(R5)-S-(CH2)m-R4or

f) -(CH2)p-aryl;

R2is:

a) hydrogen,

b) halogen,

c) (1-6)C-alkyl-[O-(CH2)2]q-(CH2)n-.

d) (1-6)C-alkyl, or

(e) -(CH2)n-CH(R5)-(CH2)m-R4;

R3is:

a) (1-10)C-alkyl, optionally substituted by 0-5 halides.

b) (2-10)C-alkenyl.

c) R

f) CH2=CH-(CH2)p-.

g) R4(CH2)mX1C(O)(CH2)n-,

h) R4(CH2)mC(O)X1(CH2)n-,

i) aryl,

j) gets

k) (3-7)C-cycloalkyl,

l) (1-6)C-alkyl-O-C(O)-(CH2)n-,

m) (1-6)C-alkyl-[O-(CH2)2]q-(CH2)n-,

n) R4-CH(R6)-CH(R6)-,

p) R12-(CH2)m-X2-(CH2)n- (R7)HC or

q) R15-(CH2)m-X2-(CH2)n- (R7)HC-;

R4is:

a) aryl,

b) gets

c) (3-7)C-cycloalkyl,

d) (2-10)C-alkenyl,

e) (C-6)C-alkyl-[O-(CH2)2]q-(CH2)n-.

f) halogen,

g) het-O-,

h) het-C(O)-,

i) aryl-(CH2)n-O-C(O)-, or

(j) trifluoromethyl;

R5is

a) (1-10)C-alkyl,

b) (2-10)C-alkenyl,

c) (3-7)C-cycloalkyl,

d) -(CH2)n-aryl,

(e) -(CH2)p-gets or

f) -(CH2)n-CH=CH-aryl;

R6is:

a) (1-10)C-alkyl,

b) R4-(1-5)C-alkyl,

(C) -(CH2)n-(3-7)C-cycloalkyl,

d) -(CH2)p-CH=CH2,

(e) -(CH2)p-aryl,

f) -(CH2)p-gets. or

b) (1-5)C-alkyl;

aryl is:

a) phenyl, and substituted 0-3 R8,

(b) naphthyl, substituted 0-3 R8,

c) biphenyl, substituted 0-3 R8or

d) pergolide;

het represents a 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 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, (3-8)C cycloalkyl or another heterocycle;

and, if chemically possible, the nitrogen atoms and sulfur may be in the oxidized forms; and substituted 0-3 groups R9;

R8and R9are independently:

a) (1-8)C-alkyl, substituted 0-3 Halogens,

b) (2-8)C-alkenyl,

c) hydroxy,

(d) hydroxy-(1-5)C-alkyl,

(e) -(CH2)n-O-(1-5)C-alkyl, substituted by 0-3 groups hydroxy,

f) -(CH2)n-O-(2-7)C-alkenyl, substituted 0-3 groups hydroxy,

(g) halogen,

h amino,

i) amino-(1-5)C-alkyl,

(j) a mono - or di(1-5)C-alkylamino,

k) -C(O)-(1-5)C-alkyl,

l) -CHO,

m) -COOH,

n) -COO(1-5)C-alkyl,

o) -CON(R7)2,

p) (3-7)C-cycloalkyl,

q) nitro,

2
-O]q-(1-3)C-alkyl,

w) -(CH2)n-NHC(O)-O-(CH2)p-R12,

x) -(CH2)n-NHC(O)-O-(CH2)p-R15,

y) -(CH2)n-R12,

z) -SO2-R12,

a1) -(CH2)n-X2-(CH2)n-R12,

b1) -(CH2)n-X2-(CH2)n-R15,

c1) -(CH2)n-X2-CH=CH-R12,

d1) -(CH2)n-X2-CH=CH-R15,

e1) -(CH2)n-X2(1-10)C-alkyl, substituted 0-3 Halogens,

f1) -(CH2)n-X2-(2-5)C-alkenyl,

g1) -X2-(CH2)p-CH(NH2)(COOH),

h1) -NHCONH-SO2-R12,

i1) -X2(CH2)p-NH-C(O)-O-(1-6)C-alkyl,

j1) -X2-CH(X3)-NH-C(O)-O-(1-6)C-alkyl,

k1) -X2(CH2)p-CH[NH-C(O)-O)-(CH2)p-R12]-C(O)-O-(CH2)p-R12,

l1) -(CH2)n-X4-N((1-3)C-alkyl)2.

m1) -(CH2)n-X4-OTHER12,

n1) -NH-AA-P1,

o1) -(CH2)p-N3,

p1) -(CH2)p-R12,

q1) -(CH2)p-R15,

r1) -(CH2)n-NHC(SCH3)=CHNO2,

s1) -(CH2)n-NHC(OTHER7)=CHNO2,

t1) -(CH2)n-NHC(SCH3) -,

c)-NH-C(O)-NH-, or

d) -SO2-NH-;

X3is:

a(1-6)C-alkyl, or

b) -(CH2)p-R15;

X4is

a) -NH-C(O)- or

b) -NH-SO2-;

R10is hydrogen;

R11is:

a) hydrogen,

b) (1-6)C-alkyl,

c) -(CH2)n-aryl,

d) -(CH2)n-(3-7)C-cycloalkyl, or

(e) -(CH2)n-gets;

or R10and R11taken together form a double bond;

or R3and R11taken together form:

a) (3-8)C-cycloalkyl, substituted 0-3 groups hydroxy, =NOH, =O(oxo), or protected form, or replaced in - position by a group R14; or

b) 5 - or 6-membered saturated ring containing 1 or 2 oxygen atom;

R12is:

a) phenyl, substituted by 0 to 3 groups of R13or

(b) naphthyl, substituted by 0 to 3 groups of R13;

R13is:

a) (1-10)C-alkyl, substituted 0-3 Halogens,

b) hydroxy,

c) hydroxy-(1-5)C-alkyl,

d) -(CH)n-O-(1-5)C-alkyl, substituted by 0-3 groups hydroxy, or halogen,

(e) -(CH2)n-O-(2-7)C-alkenyl, substituted 0-3 hydroxy or halogen,

f) halogen,

(g) amino,

h) amino-(1-5)C-alkyl,

(i) mono - or R>
o) -NHOH,

p) nitro,

g) -CN,

r) -(CH2)n-phenyl,

s) -COO(1-5)C-alkyl, or

t) -SO2is phenyl, substituted 0-3 (1-5)C-alkilani,

u) -(CH2)n-X4-phenyl, or

v) -(CH2)n-N=N-phenyl, substituted by 0 or 1 group-N[(1-3)C-alkyl]2;

R14is:

(a) -(CH2)n-aryl,

b) -C1-C6alkyl or

c) -(CH2)n-C4-C7-cycloalkyl;

R15represents 5 - or 6-membered saturated or unsaturated ring containing from 1(1) to four (4) heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; and including any bicyclic group in which any of the above heterocyclic rings condensed with a benzene ring, (3-8)C cycloalkyl, or another heterocycle, and substituted by zero (0) to three (3) R13;

AA - amino acid residue;

P1is hydrogen or azotaemia group;

m and n = 0-5;

p = 1-5;

g=1-5; and

pharmaceutically acceptable salts of them.

For example, the present invention provides such a method for compounds of formula I, where

R1- -CH(R5)-R4;

R2is hydrogen;

R3is

a) C34
-CH=CH-,

e) CH2=CH-(CH2)p-,

f) R4-NH-C(O)-CH2-,

R4- aryl;

R5is

a) C2-C5-alkyl

b) C2-C5alkenyl,

c) cyclopropyl,

R6is

a) C2-C5-alkyl, or

b) R4-(1-2)C-alkyl-,

aryl is:

a) phenyl, substituted by 0 to 3 groups of R8or

(b) naphthyl, substituted by 0 to 3 groups of R8;

R8is:

a) halogen, or

b) (1-3)C-alkoxy;

R10and R11taken together form a double bond;

m = 1-3;

p=1-3.

The present invention also provides:

The method of prevention or treatment of benign prostatic hypertrophy or hyperplasia, prostate tumors, alopecia, or pattern baldness, excessive body hair growth in women, ordinary acne and sebora, including the appointment of a mammal in need of such prevention or treatment an effective amount of the compounds of formula I in which R1is:

(a) -(CH2)n-CH(R5)-(CH2)m-R4,

b) -CH(aryl)-CH[C(O)-O-(1-6)C-alkyl]2,

c) -C(3-5)C-cycloalkyl-(CH2)n-R4,

d) -C(aryl)=CH-aryl,

e) CH(R5)-S-(CHb) halogen,

c) 1-6)C-alkyl-[O-(CH2)2]q-(CH2)n-,

d) (1-6)C-alkyl, or

(e) -(CH2)n-CH(R5)-(CH2)m-R4;

R3is:

a) (1-10)C-alkyl, optionally substituted by 0-5 halides,

b) (2-10)C-alkenyl,

c) R4-(CH2)m-CH(R6)-(CH2)n-,

d) R4-(CH2)p,

e) R4-CH=CH-,

f) CH2=CH-(CH2)p-,

g) R4(CH2)mX1C(O)(CH2)n-,

h) R4(CH2)mC(O)X1(CH2)n-,

i) aryl,

j) gets

k) (3-7)C-cycloalkyl.

l) (1-6)C-alkyl-O-C(O)-(CH2)n-,

m) (1-6)C-alkyl-[O-(CH2)2]q-(CH2)n-,

n) R4-CH(R6)-CH(R6)-,

p) R12-(CH2)m-X2(CH2)n-(R7)HC-, or

q) R15-(CH2)m-X2-(CH2)n-(R7)HC-;

R4represents: (a) aryl, b) gets

c) (3-7)C-cycloalkyl,

d) (2-10)C-alkenyl,

e) (1-6)C-alkyl-[O-(CH2)2]q-(CH2)n-,

f) halogen,

g) het-O-,

h) het-C(O)-,

i) aryl-(CH2)n-O-C(O)-, or

(j) trifluoromethyl;

R5is:

a) (1-10)C-alkili

f) -(CH2)n-CH=CH-aryl;

R6is:

a) (1-10)C-alkyl,

b) R4-(1-5)C-alkyl,

c) -(CH2)n-(3-7)C-cycloalkyl,

d) -(CH2)p-CH=CH2,

(e) -(CH2)p-aryl,

f) -(CH2)p-gets or

g) hydroxy;

X1represents a group-NR7-;

R7is:

a) hydrogen, or

b) (1-5)C-alkyl;

aryl is:

a) phenyl substituted with 0 to 3 groups of R8,

(b) naphthyl substituted with 0 to 3 groups of R8,

c) biphenyl, substituted by 0 to 3 groups of R8or

d) pergolide;

het represents a 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 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, (3-8)C-cycloalkyl, or another heterocycle; and if chemically possible, the nitrogen atoms and sulfur may be in the oxidized forms; and substituted by 0 to 3 groups of R9;

R8and R9are independently:

a) (1-8)C-alkyl, substituted 0 - 3 Halogens,

b) (2-8)C-alkenyl,

c) hydroxy,

(d) hydroxy-(1-7)C-alkenyl, substituted by 0 to 3 hydroxy,

(g) halogen,

h) amino,

i) amino-(1-5)C-alkyl,

(j) a mono - or di-(1-5)C-alkylamino,

k) -C(O)-(1-5)C-alkyl.

l) -CHO,

m) -COOH,

n) -COO(1-5)C-alkyl,

o) -CON(R7)2,

p) (3-7)C-cycloalkyl,

q) nitro,

r) -CN,

s) -SO3H,

t) -SO2NH2,

u) -O[(CH2)2-O]q-CH3,

v)- (CH2-O]q-(1-3)C-alkyl,

w) -(CH2)n-NHC(O)-O-(CH2)p-R12,

x) -(CH2)n-NHC(O)-O-(CH2)p-R15,

y) -(CH2)n-R12,

z) -SO2-R12,

a1) -(CH2)n-X2-(CH2)n-R12,

b1) CH2)n-X2-(CH2)n-R15,

c1) -(CH2)n-X2-CH=CH-R12,

d1) -(CH2)n-X2-CH=CH-R15,

e1) -(CH2)n-X2-C1-C10-alkyl, substituted 0 - 3 Halogens,

f1) -(CH2)n-X2-C2-C5alkenyl,

g1) -X2-(CH2)p-CH(NH2)(COOH),

h1) -NHCONH-SO2-R12,

i1) -X2-(CH2)p-NH-C(O)-O - C1-C6-alkyl,

j1) -X2-CH(X3)-NH-C(O)-O-C1-C6-alkyl,

k1) -X2-(CH2)p-CH[NH-C(O)-O- (CH2))2,

m1) -(CH2)n-X4-OTHER12,

n1) -NH-AA-P1,

o1) -(CH2)p-N3,

p1) -(CH2)p-R12,

q1) -(CH2)p-R15,

r1) -(CH2)n-NHC(SCH3)=CHNO2,

s1) -(CH2)n-NHC(OTHER7)=CHNO2,

t1) -(CH2)n-NHC(SCH3)=NCN or

u1) -(CH2)n-NHC(OTHER7)=NCN;

X2is

a) -NH-C(O)-,

b) -NH-SO2-,

c) -NH-C(O)-NH - or

d) -SO2-NH-;

X3is

a) (1-6)C-alkyl, or

b) -(CH2)p-R15;

X4is

a) -NH-C(O)-, or

b) -NH-SO2-;

R10is hydrogen,

R11is

a) hydrogen.

b) (1-6)C-alkyl,

c) -(CH2)n-aryl.

d) -(CH2)n-C3-C7-cycloalkyl or

(e) -(CH2)n-gets;

or R10and R11taken together form a double bond;

or R3and R11taken together, constitute

a) (3-8)C-cycloalkyl, substituted 0 - 3 hydroxy, = N-OH, =O (oxo), or substituted in position R14or

b) 5 - or 6-membered saturated ring containing 1-2 oxygen atom;

R12is

a) phenyl substituted with 0 to 3 R
b) hydroxy,

c) hydroxy-C1-C5-alkyl,

d) -(CH2)n-O-C1-C5-alkyl, substituted 0 - 3 hydroxy or halogen atoms,

(e) -(CH2)n-O-C2-C7alkenyl, substituted 0 - 3 hydroxy or halogen atoms,

f) halogen,

(g) amino,

h) amino (1-5)C-alkyl,

(i) mono - or di-C1-C5-alkylamino,

j) -C(O)-C1-C5-alkyl,

k) -CHO,

l) -COOH,

m) -CON(R7)2,

n) -NHCOC1-C3-alkyl,

o) -NHOH,

p) nitro,

q) -CN,

r) -(CH2)n-phenyl,

s) -COOC1-C5-alkyl or

t) -SO2is phenyl, substituted with 0 3 (1-5)C-alkyl,

u) -(CH2)n-X4-phenyl, or

v) -(CH2)n-N=N-phenyl, substituted by 0 or 1 group-N(C1-C3-alkyl)2;

R14is

(a) -(CH2)n-aryl,

b) -(1-6)C-alkyl, or

c) -(CH2)n-C4-C7-cycloalkyl;

R15represents 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic >3
;

AA - amino acid residue;

P1is hydrogen or azotaemia group;

m and n = 0 to 5

p = 1 - 5

q = 1 - 5, and

its pharmaceutically acceptable salts.

The present invention particularly is this the way in which the size of the prostate in mammals the male is reduced or maintained at the same level.

For example, the present invention provides a method for compounds of formula I, in which

R1-(CH2)n-CH(R5) -(CH2)m-R4;

R2is hydrogen;

R3is:

a) R4-(CH2)m-CH(R6) -(CH2)n- or

b) R4-(CH2)p-;

R4is:

a) phenyl, or

b) tetrahydropyranyl;

R5is:

a) propyl, or

b) cyclopropyl;

R6represents ethyl;

m = 0 or 1;

n = 0;

p = 2;

R10and R11taken together form a double bond.

The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of compounds of formula I.

Finally, the present invention give the compound of formula CC-2 in a hydrocarbon solvent, in the presence of trialkylamine at elevated temperatures, allowing the connection of CC-4.

(b) treating compound of formula CC-4 base in a water/alcohol mixture,

c) processing the mixture of stage (b) acid to obtain the compounds of formula CC-5. (See the CC scheme below).

Compounds of the present invention are named according to the nomenclature system IUPAC or CAS.

The content of carbon atoms of the various hydrocarbon-containing fragments is indicated by the index denoting the minimum and maximum number of carbon atoms in the fragment, i.e. the index or prefix (i-j)C shows a fragment, in which the number of carbon atoms is from the integer "i" to the integer "j", inclusive. So, for example, C1-C3-alkyl or (1-3)C-alkyl refers to alkyl with 1 to 3 carbon atoms, inclusive, or, for example, ethyl, stands, propylene and isopropyl.

Examples of alkyl with 1 to 9 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and all their isomeric forms, straight or branched chain.

Examples of alkenyl with 1 to 5 carbon atoms inclusive are ethynyl, propenyl, butenyl, pentenyl and their isomeric forms.

Examples of "kislota" refers to the residue of a natural amino acid, such as: Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamine or Glutamic acid, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, serine, Threonine, Tryptophan, Tyrosine, Valine, Aspartic acid or Asparagine, Glutamic acid or Glutamine; and their synthetic derivatives. These amino acid residues may be L - or D-configuration, and is well known and readily available to specialists in this field. These amino acid residues (or their N-terminal protected form) is connected with the free amino group by C-end or end-atom C.

The compounds of formula I of the present invention inhibit retroviral proteases and thus inhibit the replication of viruses. They are useful for the treatment of patients infected with human immunodeficiency virus (HIV), which leads to the acquired immunodeficiency syndrome (AIDS) and related diseases.

More specifically, the compounds of the present invention are useful as new inhibitors of retroviral protease person. Therefore or consequently, the compounds inhibit the protease and thus inhibit viral replication. They are useful for the treatment of humans, details the viruses leukemia T-cells (HTLV-I or HTLV-II), which result in the acquired immunodeficiency syndrome (AIDS) and/or related diseases.

The capsid and replication enzymes (i.e., protease, reverse transcriptase, integrase) retroviruses are translated from the viral gag and pol genes in the form of polyproteins, which are further processed using the viral protease (PR) in the Mature protein or proteins found in the viral capsid and is required for viral function and replication. If PR is missing or nefunkcionali, the virus cannot replicate. It was found that retroviral PR, such as PR HIV-1, represents aspartic protease with the characteristics of active sites, similar to those that appear more complex aspartic protease, renin.

The term human retrovirus (HRV) includes the human immunodeficiency virus type I, human immunodeficiency virus type II or strains, as well as virus 1 and 2 of leukemia T-cells (HTLV-1 and HTLV-2) or strains, known or understandable to experts in this field, which belong to the same or related families of viruses, and which create similar physiological effects in humans in the form of various human retrovirus the e strains of human retrovirus, that is determined by the presence of any measurable viral antibody or antigen in the serum, and

2) in the case of HIV, with or asymptomatic HIV infection, or defining symptomatic AIDS infection, such as (i) disseminated histoplasmosis, ii) isoporous (Isoporous, which is caused by organisms Isospora belli, parasites via coccidia, is a disease that causes diarrhea, which occurs in patients AIDS when their CD4 count is getting low. If there is, that very few effective drugs for Isospora or Cryptosporidia more common parasite that causes similar chronic diarrhea and exhaustion AIDS patients), iii) bronchial and pulmonary candidias, including Pneumocystis pneumonia, iv) non-Hodgkin lymphoma or v) a Kaposi sarcoma, and with an age of less than sixty years old; or having an absolute CD4+ lymphocyte less than 500/mm3in the peripheral blood. Treatment of these patients is to maintain the inhibitory level of the compounds used according to this invention, patients in all ages, and will continue to until the case or distribution another vital symptomatic AIDS infection will not indicate the need for an alternative treatment is the lack of HIV, also known as HTLV-III or LAV), which is recognized as the cause of acquired immunodeficiency syndrome (AIDS), although a minority expressed the opposite opinion, P. Duesberg, Proc. Natl, Acad. Sci. USA, 86. 755 (1989). HIV contains retroviral encoded protease, HIV-1 protease, which cleaves polypeptides merge into functional proteins of Mature viral particles, E. P. Lillehoj, etc.. J. Virolody, 62: 3053 (1988); C. Debuck and others, Proc. Natl. Acad. Sci., 84: 8903 (1987). This enzyme HIV-1 protease classified as aspirinplease and showed homology with other aspirinplease, such as renin, L. H. Pearl and others, Nature, 329: 351 (1987); I. Katoh and others, Nature, 329: 654 (1987). Inhibition of HIV-1 protease blocks HIV replication and, thus, is useful in the treatment of AIDS in humans, E. D. Clerg, J. Med. Chem., 29: 1561 (1986). Inhibitors of HIV-1 protease useful in the treatment of people with HIV who are asymptomatic or symptomatic in relation to AIDS.

Pepstatin A conventional inhibitor aspartyl-proteases, was discovered as an inhibitor of HIV-1 protease, S. Seelmeier and others, Proc. Natl. Acad. Sci. USA, 85: 8612 (1986). There were also open other inhibitors originating from the substrate containing the recovered associated isostere or statin in the position of cleavage, M. L. Moore and Dene of the present invention are useful for treating diseases, caused by retroviruses, such as acquired immunodeficiency syndrome (AIDS).

These compounds are also useful for treating animals infected with retroviruses, such as cats infected with the virus feline leukemia. Other viruses that infect cats, include, for example, a virus feline infectious peritonitis, caliciviruses, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus) and feline chlamydia. Exact dosages, forms and methods of appointment of the peptides of the present invention to animals understandable to experts in this field, such as veterinarians.

The compounds of formula I of the present invention prepared as described in examples of the preparation, and the examples below, or get them by methods similar to methods that are well known to experts in the field of organic synthesis.

Scheme A.

Getting 6-aryl-4-hydroxy-2-pyrone (such as A-4: X-CH) and 3-alkylated 6-aryl-4-hydroxy-2-pyrone (such as A-5: X = CH, R = ethyl) is shown in scheme A. the Deprotonation of ethylacetoacetate formula A-1, which is industrially available, potassium hydride and n-butyllithium in tetrahydrofuran, followed by debortoli A-3 (where X = CH). Heating the compounds of formula A-3 at 120oC under reduced pressure (1 mm RT. Art., clean) gives 4-hydroxy-6-phenyl-2-pyrone, a compound of formula A-4 (where X = CH). Alkylation of compounds of formula A-4 using the heating with a number corresponding substituted benzylbromide or treatment of compounds of formula A-4 corresponding substituted benzyl alcohols in the presence of a mixture TRIFLUORIDE bordetellosis ether yields the desired product of formula A-5 (where X = CH and R = ethyl), which represents the connection: 3-(alpha-active compounds)-4-hydroxy-6-phenyl-2H-Piran-2-it.

Scheme B.

Obtaining the compounds of formula B-5 (where n = 1), which is the compound: 6-benzyl-3-(alpha-active compounds)-4-hydroxy-2H-Piran-2-it, and the compounds of formula B-5 (where n = 2), which represents the connection: 3-(alpha-active compounds)-6-phenyl-4-hydroxy-2H-Piran-2-he is shown in scheme B. Dianion formula B-1 is obtained using the same conditions, as described for scheme A. Then added or ethylvinylacetate formula B-2 (where n = 1), or acyldihydrazones formula B-3 (where n = 1) or ethyl 7-phenyl-3,5-dioxopentanoate formula B-3 (where n = 2), respectively. The formation of Pyrenophora ring in the compound of formula B-4 (where n = 1 or 2) check the Heating of the compounds of formula B-4 (where n = 1 or 2) with ()-1-bromo-1-phenylpropane or processing ()-1-phenylpropanol in the presence of boron TRIFLUORIDE in dioxane gives the desired products of formula B-5 (where n = 1 or 2, respectively).

Scheme C.

The desired product of formula C-4, which is a combination of: 4-hydroxy-6-phenethyl-3-(alpha-propyl-p-promensil)-2H-Piran-2-it is obtained by heating the pyrone of formula C-3 (obtained according to scheme B in the compounds of formula B-4 (where n = 2) with the compound of the formula C-2 (where R = bromide). The desired compound of formula C-2 (where R = bromide) is obtained by using the two-step sequence of reactions, based on 4-bromobenzaldehyde, the compounds of formula C-1. The process of joining C-1 propylaniline gives 1-(4'-bromanil)-1-butanol, the compound of formula C-2 (in which R = OH). The resulting alcohol compound of formula C-2 (in which R = OH) is then treated with 48% Hydrobromic acid, giving the desired bromide of formula C-2 (where R = bromide).

Scheme D.

On-Allilirovanie 4-hydroxy-6-methyl-2-pyrone, the compounds of formula D-1, zanamivirabdomen is carried out to obtain the compounds of formula D-2. The klaisen rearrangement of the resulting pyrone of formula D-2 is in delegateuser toluene, giving the vinyl analogue of formula D-3. Product Clausen formula D-3 is subjected to catalytic hydrogenation, giving the compound of formula D-4. Treatment of compounds of formula the compounds such as benzylbromide, yields a product of formula D-5, which represents the connection: 3-(alpha-active compounds)-6-phenethyl-4-hydroxy-2H-Piran-2-it. This method is the preferred process for obtaining the connection.

Diagram E.

A wide variety of analogues can be obtained by applying the same conditions that were used to obtain the compounds of formula D-5 according to scheme D. under these conditions, 4-bromobenzylamine, 2-florantyrone or allylbromide introduced into the reaction gianina formula E-1 (obtained according to scheme D in the form of compounds of formula D-4) just giving the compound of formula E-2 (where R = 4 4-bromobenzyl, 2-terbisil or 3-propylene), which are compounds: 6-(p-brominated)-3-(alpha-active compounds)-4-hydroxy-2H-Piran-2-he; 3-(alpha-active compounds)-6-(o-florfenicol)-4-hydroxy-2H-Piran-2-he; and 3-(alpha-active compounds) 4-hydroxy-6-(3-butenyl)-2H-Piran-2-it, respectively. However, the interaction of iodomethane and geneticbased with the compound of the formula E-1 requires stirring the reaction mixture at room temperature for several hours, giving the compound of formula E-2 (in which R = ethyl or phenylethyl), which are respectively the compounds: 3-(alpha-active compounds)-4-hydrox the/P> Treatment of compounds of formula F-1 (derived in the form of compounds of formula D-4 scheme D) 2 equivalents of diisopropylamide lithium and tetrahydrofuran at -40oC followed by the addition of phenylisocyanate gives compound of formula F-2, which is a compound: 3-(alpha-active compounds)-4-hydroxy-6-[[(phenylamino)carbonyl]-methyl]-2H - Piran-2-it.

Diagram G.

Obtaining the compounds of formula G-2, which is the compound: 4-hydroxy-6-phenethyl-3-(alpha-vinylbenzyl)-2H-Piran-2-it is achieved by direct alkylation of compounds of formula G-1 (obtained in the form of compounds of formula D-3 according to scheme D) benzylbromide.

Diagram H.

Industrial available 6-methyl-4-hydroxy-2H-Piran-2-he of the formula H-1 is subjected to reaction with available industrial alpha-ethylbenzylamine alcohol of the formula H-2 with an acid catalyst, giving a compound of the formula H-3.

Treatment of compounds of formula H-3 (can also be in the form of compounds of formula D-4 scheme D) three equivalents of diisopropylamide lithium in tetrahydrofuran followed by successive addition of benzylbromide and ethyliodide, gives compound of formula H-4 (in which R1= benzyl, R2is acelolovia obtained compound of formula H-4 (in which R1= ethyl and R2= ethyl), which represents the connection: 3-(alpha-active compounds)-1-ethylpropyl-4-hydroxy-2H-Piran-2-it, using two equivalents of ethyliodide as electrophilic compounds.

Scheme I.

Alkylation of the anion of methylacetoacetate formula I-1, which is industrially or commercially available, after treatment with sodium hydride, using alpha ethylbenzylamine formula I-2, which is industrially available, gives methyl 2-(alpha-active compounds)-acetoacetate formula I-3. The corresponding dianion, which is formed by sequential treatment with sodium hydride and n-butyllithium, is added to propiophenone formula I-4, which is industrially available, yielding methyl 2-(alpha-active compounds)-5-hydroxy-3-oxo-5-phenyl-heptanoate formula I-5. Methyl ester is then hydrolyzed with sodium hydroxide and after acidification with hydrochloric acid separates the desired substance, 6-ethyl-3-(alpha-active compounds)-6-phenyl-tetrahydropyran-2,4-dione of the formula I-6.

Scheme j

Alkylation of the anion of methylacetoacetate formula J-1 (also used according to scheme 1 as the compounds of formula (I-1): which is industrially available, after obrabotanpri)-acetoacetate formula J-3. The corresponding dianion, which is obtained by sequential treatment with sodium hydride and n-butyllithium, joins 3-pentanone formula J-4, which is industrially available, yielding methyl 2-(3-phenylpropyl)-5-ethyl-5-hydroxy-3-oxo-heptanoate formula J-5. Methyl ester is then hydrolyzed with sodium hydroxide, and after acidification with hydrochloric acid, is allocated the desired substance, 6,6-diethyl-3-(3-phenylpropyl)-tetrahydropyran-2,4-dione of formula J-6.

Scheme K

Scheme K offers an alternative highly effective way of introducing C-3 substituents in the core of 4-hydroxy-alpha-pyrone and 5,6-dihydro-4-hydroxy-2H-Piran-2-it. Allyl carbonates of formula K-2 (a, b and c) and the nucleophilic compound (briefly nucleophile) 5,6-dihydro-4-hydroxy-2-dowels formula K-1 (a, b, and c) treated with palladium acetate and triphenylphosphine in toluene at 50oC, giving the compounds of formula K-3 (a, b and c). Predstavitelnee examples of this reaction is shown in scheme K. you Can also apply allyl carbonates containing substitution in the phenyl ring (scheme K, EQ. a, b). When possible diastereomeric products (scheme K, EQ. a, d), formed chromatographically inseparable mixture. The final products poluchka using successive recrystallization. The mother liquor contains a mixture enriched in the other diastereoisomer, but attempts to purify them further recrystallization may not bring success. Subsequent chemical manipulation of the substituents in the 6-position 5,6-dihydropyran-2-about the rings are held by experts in the field of technology.

Scheme L.

Scheme L describes the General procedure for the synthesis of C-3 alpha-branched substituted 4-hydroxy-2-dowels or 4-hydroxy-5,6-dihydropyran-2-ones. The key reaction involves catalyzed by palladium allylic alkylation of cyclic beta-keeeping the nucleophile of the formula L-1 (in which R11and R3have the meanings given above), using silyl-substituted allyl carbonate of formula L-2. Subsequent disilylgermane and recovery of the compounds of formula L-3 (where R11and R3have the meanings defined above) gives the desired end products, such as the compounds of formula L-4 (in which R11represents phenyl, R3- propyl or cyclohexyl; and R8is hydrogen or hydroxy), which are compounds: 4-hydroxy-6-propyl-6-phenyl-3-(1-phenylpropyl)-2H-Piran-2-he; 4-hydroxy-6-phenyl-6-propyl-3-[1-(2-hydroxyphenyl)-propyl] - 2H-Piran-2-he 4-hydroxy-substituted 5,6-dihydro-2H-Piran-2-ones, such as connection diagrams K and l

Scheme m

Dianion industrial available 4-hydroxy-6-methyl-2-pyrone of the formula M-1 is obtained by deprotonation of two equivalents of diisopropylamide lithium in tetrahydrofuran and hexamethylphosphoramide. Alkylation of benzylbromide gives compound of formula M-2. Then it is treated with two equivalents of diisopropylamide lithium in tetrahydrofuran and hexamethylphosphoramide, with subsequent treatment with ethyliodide, giving the compound of formula M-3. The reaction between the compound of formula M-3 and the compound of the formula O-5, obtained as described in scheme O, in benzene with p-toluensulfonate catalyst in the presence of molecular sieves gives compound of formula M-4, which is 3-(alpha-cyclopropyl-meta-(tert-butyloxycarbonyl)-benzyl)-6- (alpha-ethyl-phenethyl)-4-hydroxy-2H-Piran-2-it.

The hydrogenolysis of compounds of formula M-4 in methanol with hydrogen and palladium on charcoal gives the free amine of formula M-5. Condensation of this compound of formula M-5 with tert-butyloxycarbonyl-beta-alanine in dichloromethane using diisopropylcarbodiimide gives compound of formula M-6, which is N-(3-cyclopropyl-[6-(1-ID. Amin M-5 is subjected to reaction with alkylsulfonamides or arylsulfonamides in the presence of pyridine, giving the compound of formula M-7, in which R1is aryl, for example phenyl, 3-(alpha - cyclopropylmethyl(phenylcarbonylamino)-benzyl)-6-(alpha - ethylphenyl)-4-hydroxy-2H-Piran-2-it.

Scheme n

Processing industrial available 4-hydroxy-6-methyl-2-pyrone of the formula N-1 three equivalents of diisopropylamide lithium in tetrahydrofuran and hexamethylphosphoramide, followed by treatment with bromelicola, giving the compound of the formula N-2. The reaction between the compound of the formula N-2 and the compound of the formula O-5, obtained as described in scheme O, in benzene with p-toluensulfonate catalyst in the presence of molecular sieves gives compound of the formula N-3, which is 3-(alpha-cyclopropyl-meta-(tert-butyloxycarbonyl)benzyl)-6 - alpha-cyclopropylmethyl)-4-hydroxy-2H-Piran-2-it.

The hydrogenolysis of compounds of formula N-3 in methanol with hydrogen and palladium on charcoal gives the free amine of the formula N-4. Condensation of the compounds of formula N-4 from 3-(1-indolyl)-propionic acid in dichloromethane and dimethylformamide using diisopropylcarbodiimide gives coedine-5,6-dihydro-2H-Piran-3-yl]methyl}phenyl)-3-indol-1-yl - propionamide.

Scheme O.

Nitration industrially available cyclopropylacetylene formula O-1 fuming nitric acid gives compound of the formula O-2. The recovery of the compounds of formula O-2 in methanol hydrogen, catalyzed by platinum on charcoal, gives the amine of the formula O-3. Connection O-3 is processed by benzylchloride and diisopropylethylamine in dichloromethane, giving the compound of the formula O-4. The recovery of the compounds of formula O-4 with sodium borohydride in tetrahydrofuran and ethanol gives compound of the formula O-5.

Scheme P.

The reaction between 5-bromo-4-hydroxy-6-methyl-Piran-2-one of formula P-1 (obtaining the substance described in Syn. Comm. 1984, 14, 521) and commercially available 1-phenyl-1-propanol in benzene catalyzed by p-toluensulfonate acid gives compound of formula P-2. Treatment of compounds of formula P-2 diisopropylamide lithium and industrial available (methyl bromide)cyclopropane gives compound of formula P-3, which is 5-bromo-6-(2-cyclopropyl-cyclopropylmethyl-ethyl)-4-hydroxy-3- (1-phenyl-propyl)-Piran-2-it.

Scheme q

Treatment of 3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6-methyl-Piran-2-one of formula Q-1 example 20 diisopropylamide lithium, and then 2-(2-methoxy-ethoxy)-tiltability network with the exclusion of the General formula Q-3, which is 3-(cyclopropyl-phenyl-methyl)-4-hydroxy-5-(2-(2-methoxy-ethoxy)- ethyl)-6-propyl-Piran-2-it.

Scheme R.

The reaction industrially available 1,3-diphenylacetone formula R-1 with the anion of tert-butyl P, P-diethylphosphonoacetate gives compound of the formula R-2, which hydrogenolysis in ethyl acetate with hydrogen under a pressure of 50 lb. square inch (3. 515 kg/sq. cm) using platinum on an angle, giving the compound of formula R-3. Treatment of compounds of formula R-3 diisopropylamide lithium, and then diketene, gives compound of the formula R-4, which is processed triperoxonane acid, and then acetic anhydride, giving the compound of the formula R-5. Treatment of compounds of formula R-5 diisopropylamide lithium, and then(methyl bromide)cyclopropane gives compound of the formula R-6, which is 3-(1-benzyl-2-phenyl-ethyl)-6-(2-cyclopropyl-1-cyclopropylmethyl-ethyl) -4-hydroxy-Piran-2-it.

Scheme S.

The compound of formula S-1 obtained by the method of the authors Y. S. Zapryagaev, N. A. Don and R. Y. Lovina. Journal of General chemistry, 33: 3434 (1963) (SA:s). The compound of formula S-3 is obtained from the compounds S-1 and S-2 (M-2) using the procedure described in example 1 below. The target compound of formula S-4, which is 4-hydroxy-3-(1-fmera 6.

Scheme T.

The compound of formula T-5, which represents a 4-hydroxy-3-(1-phenyl-2-propenyl)-1-oxaspiro[5.7] tridec-3-EN-2-it is obtained from cyclooctanone (compound T-1) using the procedures described in the receive 16A, 16B and 16C below. The compound of formula T-6, which is 4-hydroxy-3-(1-phenylpropyl)-1-oxaspiro[5.7] tridec-3-EN-2-it is obtained from the connection T-5 using the procedure described in obtaining 16D below.

Scheme U.

Unsaturated amide U-1 (Chemistry Letters (1981, 913 - 916)) is processed by ethylmagnesium in diethyl ether at -40oC, giving the connection of the U-2. Acid hydrolysis of compounds of the U-2 provides an intermediate connection U-3. In the manner similar to that described above, the process of joining U-4 phenylmagnesium in diethyl ether gives compound U-5, which, after treatment with acid to give the intermediate compound U-6. The compounds of formula U-3 and U-6, in which phenyl substituted, for example, halogen, trifluoromethyl group,- NHBOC, -NHCBZ, NHSO2Ph, or N-(1,1,4,4-tetramethyl-1,4-bidirectional) (for example, see formula BBB-5 in the diagram BBB), or in which the substituted phenyl optionally substituted by heterocycles, for example, furan and thiophene, are obtained by following the procedure as described above.

Shevii copper catalyst in tetrahydrofuran, giving compound V-2. Hydrolysis of V-2 gives compound V-3 (same as V-6).Similarly, the V-4 is transformed into V-5 and finally in the V-6 (same as V-3). The compounds of formula V-3 and V-6, in which phenyl substituted, for example, halogen, trifluoromethyl, -NHBOC or-NHCBZ, or in which the substituted phenyl, optionally substituted heterocycle, for example, furan and thiophene, are obtained using the above procedure. Using the procedure of this scheme, proceeding from compounds of formula V-7 and V-8 are obtained the compounds of formula V-3 and V-6, in which the ethyl group is replaced by cyclopropyl.

Scheme W.

[4S, 5R]-(+)-4-Methyl-5-phenyl-2-oxazolidinone, which is industrially available, dissolved in THF and cooled to -78oC. For 5 minutes, add the p-utility, and stirring is continued for 1 hour. One portion is added butyrylcholine, giving the compound W-1 after water treatment. Compound W-1 is processed by diisopropylamide lithium (LDA) and subjected to reaction with W-2, which is industrially available (or other benzylchloride, substituted, e.g. by halogen, alkoxy, -CN, nitro or trifluoromethyl, to obtain the substituted compounds corresponding to the following below),the ode in a mixture of THF/water gives compound W-4 (R), which is then introduced into reaction with methyllithium in ethyl ether, yielding the ketone W-5. The carboxylation W-5 is beta-ketoacid W-6 (see Hogeveen, Menge Tetrahedron Letters (1986) 2767), which is treated with acetic anhydride and acid in the presence of acetone, giving 1,3-dioxin-4-about the derived W-7.

Connection W-4 is treated with oxalylamino, giving connection W-8. W-8 is subjected to reaction with analita lithium obtained from tert-butyl acetate (W-9; adalat formed in THF using diisopropylamide lithium at -78oC) giving - ketoester W-10. The process of joining W-10 in a mixture of sulfuric acid/acetic anhydride/acetone then gives a connection W-7. (Kaneko, Sato, Sakaki, Abe J. Heterocyclic Chem. (1990) 27 : 25).

Scheme X.

[4R,5S]-(-)-4-Methyl-5-phenyl-2-oxazolidinone, which is industrially available, dissolved in THF and cooled to -78oC. For 5 minutes, add the n-utility, and stirring is continued for one hour. One portion is added butyrylcholine, giving X-1 after water treatment. Compound X-1 is processed by diisopropylamide lithium (LDA) and subjected to reaction with X-2, which is industrially available (or other benzylchloride, substituted, for example, Galaga X-3 as a single diastereoisomer. The treating compound X-3 by lithium hydroxide and hydrogen peroxide in a mixture of THF/water gives X-4 (S), which then undergoes reaction with methyllithium in ethyl ether, yielding the ketone X-5. The carboxylation of the compound X-5 is beta-ketoacid X-6 (see Hogeveen, Menge Tetrahedron Letters (1986) 2767), which is treated with acetic anhydride and acid in the presence of acetone, giving 1,3-dioxin-4-about-derived compounds X-7.

X-4 is treated with auxiliaries, giving X-8. Connection X-8 is subjected to reaction with liciense tert-butyl acetate (X-9), as in the example above, giving X-10. Processing X-10 a mixture of sulfuric acid/acetic anhydride/acetone then gives X-7. (Kaneko, Sato, Abe J. Heterocyclic Chem. (1990) 27: 25).

Scheme y

Processing Y-1, which is industrially available, oxalylamino in methylene chloride gives the acid chloride of the acid Y-2. The processing mixture of compound Y-2 and 2,2,6-trimethyl-4H-1,3-dioxin-4-it (Y-3), which is industrially available, triethylamine (tea) in toluene at elevated temperature gives Piron Y-4. The process of joining Y-4 with sodium carbonate in methanol gives hydroxypyrene Y-5 (3-methylbenzyl-4-hydroxy-6-methyl-2H-Piran-2-one) and an ester of Y-6.

Scheme z

The process of joining Z-1 (which yavleniya Z-2 and a commercially or industrially available 2,2,6-trimethyl-4H-1,3-dioxin-4-it (Z-3) (which is the same, as Y-3) triethylamine (tea) in toluene at elevated temperature gives Piron Z-4. W-4 with sodium carbonate in methanol gives hydroxypyrene Z-5 (3-[(R) -- active compounds-4-hydroxy-6-methyl-2H-Piran-2-one) and an ester of Z-6.

Scheme AA.

The process of joining AA-1 (which is the same as U-3) oxalylamino in methylene chloride gives the acid chloride acid AA-2. Treatment of a mixture of (S)-3-phenylalaninamide (AA-2) (which is the same as Z-2) and (R)-2,2-dimethyl-6- - ethylphenyl)-4H-1,3-dioxin-4-it (AA-3) (which is the same connection as W-7) triethylamine (tea) in toluene at elevated temperature gives Piron AA-4. Basic hydrolysis of AA-4 in methanol gives the final hydroxypyrene AA-5 (3-([R] -- ethylphenyl)-2H-Piran-2-one) and an ester of AA-6 (which is the same as Z-6).

Scheme BB.

The process of joining BB-1 (which is the same as U-3) oxalylamino in methylene chloride gives the acid chloride acid BB-2. Treatment of a mixture of (S)-3-phenylalaninamide (BB-2) (which is the same as Z-2) and (S)-2,2-dimethyl-6-( - ethylphenyl)-4H-1,3-dioxin-4-it (BB-3) (which is the same as X-7) triethylamine (tea) in toluene at elevated temperatures gives Piron BB-4. Basic hydrolysis of compound BB-4 in methanol gives konecne what is the same, Z-6).

Scheme CC

Treatment of compound CC-1 (which is the same as U-6) oxalylamino in methylene chloride gives the acid chloride acid CC-2. Treatment of a mixture of (R)-3-phenylalaninamide (CC-2) and (R)-2,2-dimethyl-6-( - ethylphenyl)-4H-1,3-dioxin-4-it (CC-3) (which is the same as W-7) trialkylamines, for example, triethylamine (tea) in a hydrocarbon solvent, for example toluene, at elevated temperatures (for example, 100oC) gives Piron CC-4. Basic hydrolysis CC-4 using, for example, sodium carbonate, in a mixture of water/alcohol/ (e.g., methanol) (about 1:9), followed by treatment with an acid, for example 1 standards. hydrochloric acid, gives the final hydroxypyrene CC-5 (3-[S] -- active compounds)-4-hydroxy-6-([R] -- ethylphenyl)-2H-Piran-2-he and ester CC-6.

Removal of triethylamine hydrochloride by filtration adding a molar equivalent of sodium hydroxide (methanol) to a toluene solution of compound CC-4 also gives the sodium salt of compound CC-5 in the form of sediment. The collection of this sediment is carried out using standard procedures.

Diagram DD

The process of joining the DD-1 (which is what and U-6) oxalylamino in methylene chloride gives the acid chloride acid DD-2. Treatment of a mixture of (R)-3-Feeney is the same, that and X-7) triethylamine (TEA) in toluene at elevated temperatures gives Piron DD-4. Basic hydrolysis DD-4 in methanol gives the final hydroxypyrene DD-5 (3-([S] -- active compounds)-4-hydroxy-6-([S] -- ethylphenyl)-2H-Piran-2-one) and ester DD-6 (which is the same as CC-6).

The synthesis of all four diastereomers of 3-( - active compounds)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it is preferably carried out by the procedures of schemes AA, BB, CC and DD.

Scheme EE

(R)-3-Fenilalanina acid (EE-1) (which is the same as U-3) is transformed into the corresponding methyl ester with thionyl chloride in methanol, giving EE-2 (which is the same as Z-6), EE-2 is processed in a strong base, such as diisopropylamide lithium, and then trimethylsilylpropyne, giving EE-3. The mixture EE-3, EE-4 (W-7) is heated in an organic solvent, such as toluene, followed by treating the reaction mixture with acid to yield the final product EE-5 (which is what and AA-5) (3-([R]- -- active compounds)-4-hydroxy-6-([R]- - ethylphenyl)-2H-Piran-2-one).

Diagram FF

Mix FF-1 (which is the same as EE-3 and is obtained from (S)-3-phenylalaninol acid (U-3) and FF-2 (which is the same as X-7 in the schema X) is heated in Organicheskaya the same, that and BB-5) (3-([R] -- methylbenzyl)-4-hydroxy-6-([S] -- ethylphenyl)-2H-Piran-2-one).

Scheme GG

(R)-3-fenilalanina acid (GG-1) (which is the same as U-6) is transformed into the corresponding methyl ester with thionyl chloride in methanol, giving GG-2 (which is the same as CC-6). GG-2 is processed in a strong base, such as diisopropylamide lithium, followed by treatment with trimethylsilylpropyne, giving GG-3. A mixture of GG-3 GG-4 (W-7) is heated in an organic solvent, such as toluene, followed by treating the reaction mixture with acid to yield the final product (GG-5) (which is the same as CC-5) (3-([S] -- methylbenzyl-4-hydroxy-6-([R] -- ethylphenyl)-2H-Piran-2-one).

The scheme HH.

A mixture of compound HH-1 (which is the same as GG-3 GG and HH-2 (X-7) is heated in an organic solvent, such as toluene, followed by treating the reaction mixture with acid to yield the final product HH-3 (which is the same as the DD-5) (3-([S] -- methylbenzyl)-4-hydroxy-6([S] -- ethylphenyl)-2H-pyrone-4-one).

Scheme II

Furfuryl alcohol (II-1), which is industrially available, processed chloromethylation ether in the presence of diisopropylethylamine in organic restorel for several hours followed by the addition of cyclopropanecarboxaldehyde, which is industrially available, giving the alcohol II-3. The mixture of alcohol II-3 and Piron II-4, which is industrially available, is treated with a catalytic amount of triperoxonane acid in methylene chloride, giving II-5. Compound II-5 is treated with 2.2 equivalents of LDA, and then ethyliodide, giving II-6. Processing II-6 of 2.2 equivalents of LDA, and then benzylbromide gives the final product (II-7, which is processed by a soft acid, giving the final product II-8 (3 - cyclopropyl-((5-hydroxymethyl)furfural-2-yl))-4-hydroxy-6-( - ethylphenyl)-2H-pyrone-4-one. In accordance with the above procedure instead of cyclopropanecarboxaldehyde used other ancillarity, giving alkyl compounds corresponding to the compound II-3. Other alkyl or cycloalkylcarbonyl also used instead of ethyliodide to produce compounds corresponding to compound II-6, and instead of benzylbromide used other benzylchloride, substituted, for example, a halogen trifluoromethyl, -CN, nitro or alkoxy group, to obtain the substituted compounds corresponding to compound II-7.

Scheme JJ.

Processing II-8 methanesulfonamido in the presence of a base, such as pyridine, gives the sulfonate JJ-1. Education is logical solvent gives the final product, azide JJ-3, which is reduced by hydrogen (Pd/charcoal), yielding the final product JJ-4. Connection JJ-4 alleroed acetylchloride in the presence of triethylamine in chloroprene or ether solvent, or in pyridine without additional grounds, giving the final product JJ-5, or subjected to reaction with alkyl - or arylsulfonate, giving the final product sulfonate JJ-6. Connection JJ-3 is subjected to reaction with methylpropionate in an organic solvent at elevated temperatures, giving the final product JJ-7. Other alkalemia alcohols are used instead of methanol, which is used when receiving JJ-2 JJ-1, giving the corresponding alkyl analogs of compounds JJ-2. Other acid anhydrides are used instead of acetylchloride, which is used when receiving JJ-5 JJ-4, giving the corresponding analogue connections JJ-5. Other acetylene, substituted alkyl and aryl groups are used instead of methylpropionate, which is used when obtaining the JJ-7 from JJ-3, giving a corresponding analogue connections JJ-7. Aryl or heterocycle-substituted sulphonylchloride used in obtaining the appropriate analogues of the compounds JJ-6.

Scheme KK.

KK-1 (JJ-4) is subjected to Rea the Le, giving the final product KK-3. The reaction KK-3 with the equivalent of a primary or secondary amine gives the final product KK-4. Similarly KK-1 (JJ-4) is subjected to reaction with dimethyl N-zanamiviraberration (KK-5), which is industrially available, giving the final product KK-6, which undergoes reaction with a primary or secondary amine, giving the final product KK-7. Other amines, such as primary and secondary amines, are used instead of Isopropylamine to obtain the appropriate analogues of compound KK-4 and KK-7.

Circuit LL.

Compound LL-1, which is industrially available, is added to saturated sodium bicarbonate solution. To the suspension is added benzylchloride, giving the compound LL-2. LL-2 is dissolved in methylene chloride and cooled to 0oC. is Added the acid chloride cyclopropylboronic acid, which is derived from a commercially available cyclopropanecarbonyl acid using oxalicacid, with the subsequent addition of an excess of AlCl3. The reaction mixture is poured into ice water, giving LL-3. Reconnection LL-3 with sodium borohydride in a mixture of THF and ethanol gives LL-4. Treatment of a solution of LL-4 and Piron LL-5 (which is the same as M-3) in methyl shall chlorophil)(5-aminomethyl)furfur-2-yl))-4-hydroxy-6-( - ethylphenyl)-2H-Piran-2-one) (which is the same as JJ-4). The acid chlorides of other alkyl-acids are used instead of the acid chloride cyclopropylboronic acid, which is used when receiving LL-3 LL-2, giving the following relevant counterparts.

Diagram MM.

MM-1, which is industrially available, is added to saturated sodium bicarbonate solution. To this suspension is added benzylchloride, giving MM-2. MM-2 is dissolved in methylene chloride and cooled to 0oC. the acid chloride cyclopropylboronic acid derived from industrially available cyclopropanecarbonyl acid using oxalicacid, is added followed by the addition of excess AlCl3. The reaction mixture is poured into ice water, giving MM-3. Restoration MM-3 with sodium borohydride in a mixture of THF and ethanol gives the MM-4. Processing solution MM-4 and Piron MM-5 (which is the same as M-3) in methylene chloride triperoxonane acid gives the final product MM-6. Hydrogenation MM-6 gives the final product MM-7 (3-( - cyclopropyl((5-aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6( - ethylphenyl)-2H-Piran-2-one). Treatment of MM-7 phenylsulfonylacetate gives the final product MM-8. To obtain analogues corresponding to Merolli. To obtain analogues of the corresponding MM-8, instead of phenylsulfonylacetate use other substituted arylsulfonate.

Scheme NN.

A mixture of compound NN-1, which is industrially available, and the acid chloride cyclopropylboronic acid, which is derived from industrially available cyclopropanecarbonyl acid is processed by a Lewis acid, such as AlCl3in methylene chloride at 0oC, giving the connection is NN-2. Processing NN-2 with sodium borohydride in an alcohol solvent gives NN-3. Processing the mixture NN-3, NN-4 (which is what, and M-3) in methylene chloride or toluene anhydrous acid, such as triperoxonane acid or p-toluensulfonate, gives the final product NN-5. Processing NN-5 isosulfan (NN-6). S. K. Gupta, Synthesis, page 39 (1977), then gives the final product NN-7. Similarly the process of joining NN-5 chlorosulfonic acid followed by the addition of aniline gives NN-7 in two stages. Anilines, substituted by one or more substituents: halogen, alkoxy, trifluoromethyl, alkyl, nitro and -- CN, are also used in this process, giving the substituted analogues compounds NN-7.

Scheme OO

Thiophene-2-ylmethanol (OO-1), which is industrially available, processing esidency alcohol OO-2, OO-2 is processed by n-butyllithium at low temperature in an ethereal solvent for several hours followed by the addition of cyclopropanecarboxaldehyde, giving alcohols OO-3 OO-3a. The mixture of alcohol OO-3 and Piron OO-4 (which is the same as D-1) is treated with a catalytic amount of triperoxonane acid in methylene chloride, giving OO-5. OO-5 is treated with 2.2 equivalents of LDA, followed by treatment with ethyliodide, giving OO-6. Processing OO-6 with 2.2 equivalents of LDA, and then benzylbromide gives the final product OO-7, which is processed moderately acid to yield the final product OO-8 (3-( - cyclopropyl((5-hydroxymethyl) thiophene-2-yl))-4-hydroxy-6-( - ethylphenyl)-2H-pyrone-4-one). By the above procedure uses other ancillarity instead of cyclopropanecarboxaldehyde, giving alkyl connection corresponding to the connection OO-3. Other alkyl - or cycloalkyl-halides are used instead of ethyliodide, giving compounds corresponding OO-6, and other benzylchloride, substituted, e.g. by halogen, trifluoromethyl, -CN, nitro or alkoxy, are used instead of benzylbromide, giving substituted compounds corresponding OO-7.

Diagram PP.

Processing OO-8 methanesulfonanilide gives the final product PP-2. Processing of PP-1 with sodium azide in an organic solvent gives the final product azide PP-3, which is reduced by hydrogen (Pd/charcoal), yielding the final product PP-4. PP-4 alleroed acetylchloride in the presence of triethylamine in chloropercha or ethereal solvent, or in pyridine without additional grounds, giving the final product PP-5, or subjected to reaction with alkyl - or aryl-sulphonylchloride, giving the final product, sulfonate PP-6 (N-(5-(1-cyclopropyl)-1-(4-hydroxy-6-( - ethylphenyl)-2H-pyrone-4-one-3-yl))methyl)thiophene-2-ylphenyl-sulfonamide). PP-3 is introduced into the reaction methylpropionate in an organic solvent at elevated temperatures, giving the final product PP-7. Other alkalemia alcohols are used instead of methanol, which is used when receiving PP-2 PP-1, giving the corresponding alkyl analogs of compounds PP-2. Instead of acetylchloride, which is used when receiving PP-5 PP-4, used other anhydrides of acids, giving the corresponding analogs of compounds PP-5. Other acetylene, substituted alkyl and aryl groups are used instead of methylpropionate, which is used when receiving PP-7 PP-3, giving the corresponding analogs of compounds PP-7. Aryl or heterocycle-substituted cf CLASS="ptx2">

The mixture of compounds QQ-1 (OO-3a of the circuit OO and QQ-2 (which is the same as D-1) in methylene chloride is treated with a catalytic amount of triperoxonane acid that gives QQ-3, QQ-3 is treated with 3.3 equivalents of diisopropylamide lithium (LDA) in an ether solvent below room temperature followed by the addition of ethyliodide, giving the final product QQ-4. Processing QQ-4 and 3.3 equivalents of LDA in ethereal solvent followed by the addition of benzylbromide gives the final product QQ-5 (which is the same as OO-8).

The RR scheme.

RR-1 (PP-4) is introduced into the reaction with 1,1-bis(methylthio)-2-nitroethylene (RR-2), which is commercially available in an organic solvent, giving the final product RR-3. The reaction RR-3 with the equivalent of a primary or secondary amine gives the final product RR-4. Similarly, RR-1 undergoes reaction with dimethyl N-zanamiviraberration (RR-5), which is industrially available, giving the final product RR-6, which undergoes reaction with a primary or secondary amine, giving the final product RR-7. Other amines, such as primary and secondary amines, are used instead of Isopropylamine to obtain the appropriate analogues of the compounds RR-4 RR-7.

Schemata, which is derived from industrially available cyclopropanecarbonyl acid is processed by a Lewis acid, such as AlCl3in methylene chloride at 0oC, giving SS-2. Processing SS-2 with sodium borohydride in an alcohol solvent gives SS-3. Processing the mixture of SS-3 and SS-4 (which is the same as M-3) in methylene chloride or toluene anhydrous acid, such as triperoxonane acid or p-toluensulfonate acid, gives the final product SS-5. Process connection SS-5 isosulfan SS-6, S. K. Gupta Synthesis page 39 (1977), then gives the final product SS-7. Similarly, the processing SS-5 chlorosulfonic acid followed by the addition of aniline gives SS-7 in two stages. To obtain substituted analogues of compound SS-7 in this process are also used aniline compounds substituted by one or more halogen, alkoxy, trifluoromethyl, alkyl, nitro and -- CN.

Diagram of the TT.

Piron TT-1 (which is the same as Q-1) is treated with two equivalents of diisopropylamide lithium in ether solvent. At low temperature aryl halides is added, and the reaction mixture is abruptly cooled by the addition of saturated solution of ammonium chloride. This gives the final product TT-2. Additionally, TT-1 om ethyliodide, giving TT-3. To this solution is added one equivalent of LDA, and then benzaldehyde, giving the final product TT-4.

Scheme UU.

Carboxylic acid UU-1 and UU-7 obtained by the method described in J. Amer. Chem. Soc. (1981) 103: 2127, and Tetrahedron Letters (1986) 27:897. Beta-hydroxyl group as in UU-1 and UU-7, is secured by the reaction of hydroxy acids with tert-butyldimethylsilyloxy in DMF in the presence of imidazole (or 2,6-lutidine, ethyldiethanolamine) followed by treatment of the aqueous base, giving a free carboxylic acid. Carboxylic acid is processed by oxalylamino (or alternative reagent), giving the acid anhydrides UU-2 and UU-8. If necessary, use another which is the silyl derivative of a protective group such as tert-butyldiphenylsilyl group, or some other suitable alcohol protecting group. As UU-2 and UU-8, are subjected to reaction with anastom lithium produced from tert-butyl acetate (LDA/THF/-78oC) giving beta-ketoesters UU-3 and UU-9. Connection handling UU-3 and UU-9 a mixture of sulfuric acid/acetic anhydride/acetone gives UU-4 and UU-10 (Kaneko, Sato, Sakaki, Abe J. Heterocyclic Chem. (1990) 27:25), both of which interact with the acid chloride of the acid UU-5 in hot toluene in the presence of trial end products UU-12 and UU-14, both of which when processed by sodium borohydride (or other hydride reagents) to give a mixture of diastereoisomers. Recovery UU-12 gives UU-11 and UU-15 in the form of a separable mixture of diastereomers. Reconnection UU-14 gives UU-11 and UU-15 in the form of a separable mixture of diastereomers. Other diastereomer products obtained using the same methodology, but using (S)-carboxylic acid UU-16 instead of UU-5.

Scheme VV.

Scheme VV is a modified version of the scheme L, described above. This scheme describes catalyzed by palladium allylic alkylation of cyclic - keeeping the nucleophile of formula VV-1 (in which, for example, R1-phenyl, phenethyl or phenylmethyl; R2-phenylmethyl or propyl) using silyl-substituted allyl carbonate of formula VV-2. Disilylgermane results in a compound of formula VV-4 (in which, for example, R1-phenyl, phenethyl or phenylmethyl; R2-phenylmethyl or propyl) and subsequent recovery results in the compound of formula VV-5 (in which, for example, R1represents phenyl, phenethyl or phenylmethyl; R2-phenylmethyl or propyl).

Scheme WW.

This diagram describes the General procedure SOEDINENIYa formula WW-1 (which, for example, R1represents phenyl, phenethyl or phenylmethyl; R2-propyl, phenylmethyl or 2-methylpropyl), catalyzed by efratom boron TRIFLUORIDE with 1.3 diphenylethylene alcohol (WW-2) gives compound of formula WW-3 (in which, for example, R1-phenyl, phenethyl or phenylmethyl; R2-propyl, phenylmethyl or 2-methylpropyl). Subsequent hydrogenation catalyzed by palladium on charcoal, gives compound of formula WW-4 (in which, for example, R1represents phenyl, phenethyl or phenylmethyl; and R2-propyl, phenylmethyl or 2-methylpropyl).

Scheme XX

This scheme is a variation of the scheme WW. The only change is that the TRANS-stilbenoid replaces 1,3-defenitally alcohol. This diagram describes the General procedure for the synthesis of C-3 - branched 5,6-dihydropyrones by alkylation of TRANS-stilbenoid. So, catalyzed by efratom boron TRIFLUORIDE, the reaction of the compound of formula XX-1 (in which, for example, R1-phenethyl; R2-propyl) transstilbene (XX-2) gives compounds of formula XX-3 (where, for example, R1-phenethyl, R2-propyl). Subsequent hydrogenation catalyzed by palladium on charcoal, gives compound of formula XX-4 (in which, for example, R1-phenethyl, R2oC then gives the pure (R)-3-phenylpentane acid YY-7 (which is the same as CC-1). (S)-3-phenylpentane acid is produced using the above procedures, if (R) --methylbenzylamine is used for the formation of diastereomeric amides racemic acid YY-4.

Scheme ZZ

Diethylmalonate (ZZ-1) alkiliruya ethyliodide, giving the compounds of formula ZZ-2, which is further alkiliruya benzylbromide, giving the compound of formula ZZ-3 (Procedures in Organic Synthesis, Coll VI:250). Hydrolysis of compounds ZZ-3 gives racemic acid ZZ-4. Optically active acid. ZZ-5 (which is the same as W-4) and ZZ-6 (which is what ivesiana.

The AAA scheme.

This diagram illustrates catalyzed by Lewis acid reaction connection between 5,6-dihydro-6,6-disubstituted-2H-Piran-2-areas (AAA-1, in which, for example, R1-2-methylpropyl, R2-phenylethyl) and benzhydrol (AAA-2), giving 3-diphenylethylene derivatives (AAA-3, where, for example, R1-phenylethyl, R2-2-methylpropyl).

Scheme BBB.

Acetic acid (BBB-1) is treated with two equivalents of diisopropylamide lithium in tetrahydrofuran. To this solution is added cyclopropanecarboxaldehyde (industrial available). After water treatment is allocated racemic BBB-2. (R) BBB-2b and (S) BBB-2a obtained using fractional crystallization of racemic acid or R - or S-measurement - methylbenzylamine, ephedrine, brucine, strychnine, quinine, cinchonidine, quinidine or cinchonine. Alternative andolina condensation using the method of Evans (J. Amer. Chem. Soc. (1981) 103, 2127) also gives the pure enantiomers BBB-2a and BBB-2b. BBB-2a is processed by triethylorthoformate, giving BBB-3 (Helv. Chim, Actd. (1987) 70, 1320). After thermolysis BBB-3 is BBB-4. (Helv. Chim. Actd. (1987) 70, 1320). The process of joining the BBB-4 connection BBB-5 in the presence of copper iodide (Tetrahedron Letters 1253 (1984)) gives BBB-6. The process of joining BBB-6 Oxalis-7 is added to the toluene solution of triethylamine and BBB-8. The reaction mixture is heated for several hours, and the solvent is removed by evaporation, when thin layer chromatography (silica gel, ethyl acetate) shows complete consumption of the BBB-8. The crude reaction mixture is diluted with a 10/1 mixture of methanol/ water followed by the addition of sodium carbonate. This procedure then gives BBB-9. Handling BBB-9 catalytic amount of p-toluenesulfonic acid and several equivalents of methanol gives BBB-10. Processing methylenechloride solution BBB-10 p-cyanobenzenesulfonyl in the presence of triethylamine gives BBB-11.

Alternative treatment BBB-3 connection BBB-5 in the presence of copper iodide (Tetrahedron Letters 1253 (1984) gives BBB-12, which is the enantiomer of the compound BBB-6, and when the process is carried out using similar stages, BBB-6 gives BBB-13.

In addition, to obtain the corresponding ethyl stereoisomers BBB-4 and BBB-3 substituted compounds BBB-14 and BBB-15.

Scheme CCC.

Ketone CCC-1 is processed (carletonville)triphenylphosphorane, giving unsaturated ester CCC-2. Regulation (Red-Al/CuBr, DIBAH/MeCu; NaBH4/resin; NaBH4/Cu2Cl2link Reduction By the Alumino and Borohydrides in Organic Synthesis, J. Seyden-Penne, VCH. Publisher using fractional crystallization of racemic acid CCC-3 or R - or S - isomer - methylbenzylamine, ephedrine, brucine, strychnine, quinine, cinchonidine, quinidine or cinchonine. Alternative CCC-4a and CCC-4b are obtained using asymmetric recovery (Angew. Chem. Int. Ed. Engl. (1989) 28, 60) with the subsequent basic hydrolysis. Following the procedure described in scheme BBB receive CCC-6.

Scheme DDD.

2-Tienamin-DDD-1 (industrial available) is treated with 2 equivalents of n-utillity simple ether at -78oC. After stirring at -73oC for 30 minutes, the reaction temperature rises to 0oC for 30 minutes followed by the addition of sulfur (fine powder). After water treatment is allocated DDD-2 (J. Amer. Chem. Soc. (1955) 77, 5357, 5446, Org. Syn. Vol. VI. 979 (1988). DDD-2 processed p-fortuneloungecasino in methylene chloride in the presence of triethylamine, giving DDD-3. DDD-3 can also be obtained with the cooperation of the first DDD-1 with p-forbindelsesfanebladet, and then processing the intermediate product 2 equivalents of n-utillity simple ether followed by the addition of sulfur. Processing the mixture DDD-3 and DDD-4 simple ether-triethylamine gives the DDD-5 (U.S. patent 4968815). Using the same procedure as described in scheme BBB, compound DD-5 is converted to the acid chloride acid and subjected to Rea the second area, compounds of the present invention can be in several diastereoisomeric forms, depending on the configuration at the asymmetric carbon atoms. All such diastereomeric forms included in the scope of the present invention. Compounds of the present invention may also exist in several tautomeric forms, including the specific enol form shown in the drawings formulas the following formula I, and keto form of the formula II, and mixtures thereof. (For formulas I and II, the dotted line indicates that a double bond may be present or absent). All such tautomeric forms are included within the scope of the present invention. For compounds of the present invention, which are 4-hydroxy-Piran-2-ones of formula IV in scheme formulas below, prevails enol form. For compounds of the present invention, which is 5,6-dihydro-4-hydroxy-Piran-2-ones of the formula III in scheme formulas below, it is generally assumed mixture of enol and keto forms.

Compounds of the present invention can be either in free form or in protected form at one or more of the remaining (not previously protected) carboxyl, amino, hydroxy or other reactive groups. Protecting groups may be any of try, Plenum Press (1973) and J. Fuhrhop and G. Benzilin, Organic Synthesis, Verlang Chemie (1983). Among the protective groups of the nitrogen are tert-butoxycarbonyl (BOC), benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and similar. The number of protective groups of the ketone include 1,3-dioxolan.

The present invention provides compounds of formula I or their pharmacologically acceptable salts and/or hydrates. To pharmacologically acceptable salts include those salts, which, as it is clear to experts in the field of manufacturing pharmaceutical products, equivalent to the properties of the original or basic compound, such as stability, acceptability to patients and bioavailability. Examples of compounds of the present invention include acidic salts such as sodium and potassium salts of compounds of formula I, and basic salts such as chlorhydrate salt compounds of the formula I in which the R substituents contain the primary fragment.

Compounds of the present invention are useful for the treatment of patients infected with human immunodeficiency virus (HIV), which leads to the acquired immunodeficiency syndrome (AIDS) and related diseases. For this treatment, these compounds can be assigned to receive ornatipinnis) ways in doses of 0.1 mg to 100 mg/kg of body weight per day.

Professionals in this field know how to prepare formulations of compounds of the present invention using pharmaceutically acceptable carriers by converting them in the form of appropriate pharmaceutical dosages. Examples of dosage forms include oral ready preparative forms, such as tablets or capsules, or parenteral preparations, such as sterile solutions.

When the compounds of this invention are assigned to receive oral route, an effective amount is from about 0.1 mg to 100 mg per kg of body weight per day. For oral assignments can be prepared or solid, or liquid dosage forms. Solid compositions are prepared by displacement of the compounds of this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminosilicate, calcium sulfate, starch, lactose, gum acacia, methylcellulose, or a similar functional relationship diluents and carriers. Capsules are prepared by mixing the compounds of this invention with an inert pharmaceutically diluent or carrier and placing the mixture into hard gelatin capsules of appropriate size is m equipment suspensions of the compounds of this invention with acceptable inert oil, such as vegetable oil or light liquid petrolatum (vaseline). Syrups are prepared by dissolving the compounds of this invention in an aqueous medium and adding sugar, aromatic flavoring agents and preservatives. Elixirs are prepared using hydrocellulose media, such as ethanol, suitable classtitle, such as sugar or saccharin, and aromatic flavoring agent. Suspensions prepared with water media and suspenders agent such as gum acacia, tragakant or methylcellulose.

When the compounds of this invention are assigned parenteral, they can be administered by injection or intravenous infusion. The effective amount is from about 0.1 to 100 mg per kg of body weight per day. Parenteral solutions are prepared by dissolving the compounds of this invention in aqueous media and sterilization on the filter solution before placing it in the appropriate zapaivanie vessels or vials. Parenteral suspensions are prepared essentially in the same way, except that you use sterile suspension media, and the compounds of this invention are sterilized by ethylene oxide or by whom state reception can be easily determined by experts in the field and depend on age, weight, General physical condition, or other clinical symptoms that are specific to being treated patient.

Patients to be treated, are the following individuals: 1) infected with one or more than one strain of HIV that is determined by the presence or measurable viral antibody or antigen in the serum and 2) having or asymptomatic HIV infection or symptomatic infection that defines AIDS, such as (i) disseminated histoplasmosis, ii) isosporous, iii) bronchial or pulmonary candidates, including Pneumocystis pneumonia, iv) lymphoma non-Hodgkin, or v) a Kaposi sarcoma, and with an age of less than sixty years; or having the absolute number of CD4+ lymphocytes less than 500/cu mm in the peripheral blood. Treatment consists of maintaining an inhibition level of the compounds of this invention in patients during all periods of time and will continue to until finding another symptomatic infection, defining AIDS, will not show that you need an alternative treatment.

The utility of the representative compounds of the present invention in relation to HIV protease has been demonstrated in biological experience, described below.

Analno the substrate, which can be chipped off from the unlabeled product decomposition with the use of avidin-polystyrene particles, 0.7 to 0.9 μm. The substrate biotinylated by amino-terminal arginine and fluorescently labeled by isothiocyanato fluorescein (FITC) at the carboxyl-terminal lysine. This analysis was used to determine the new ones inhibitors of HIV-1 protease. The substrate (20 μl of a concentration of 0.2 μm), the sample or the sample (10 ál of the desired concentration) and the enzyme (10 μl of a concentration of 0.1 μm) are added to 96-well pandex-tablet. The analysis is carried out in 0.1 M nitroacetate buffer at pH 5.5 in the presence of 1.0 M sodium chloride and 0.05% NP-40, and the mixture incubated in the dark for one hour at room temperature. Added covered Avidya polystyrene beads (40 μl of 0.1% weight/volume), and the incubation continued in the dark for additional half an hour. The labeled cleavage product is separated from unreacted substrate by filtration, and is reading at Idexx Screen device. The data is analyzed using appropriate computer algorithms for the assessment of the values of inhibition in percent.

Values of % inhibition and in some cases the value of the IC50or Kithe present invention, such as 3-(alpha-active compounds)-6-(alpha-ethylphenidate)-4-hydroxy-2H-Piran-2-he was tested by the well-known lines of human cells, such as line of T-cells, such as MT4 and H9, which were infected with HIV-1SWand some of the compounds were additionally tested on managernew peripheral blood cells (RVMS), which were infected with HIV-1JRCSF(clinical isolate). It was found that these compounds inhibit the replication of retroviruses.

Quite surprisingly and unexpectedly, it was also found that the compounds of the present invention reduce the size and weight of the prostate gland in mammals the male sex. This is particularly unexpected in view of the fact that these compounds are structurally quite similar to any known inhibitors of testosterone 5 - reductase. Compounds of the invention can also find a number of other applications, as described in more detail below.

Thus, the present invention provides the use of compounds such as 3-(alpha-active compounds)-6-(alpha-ethylphenyl)-4 - hydroxy-2H-Piran-2-it, for the prevention and treatment of androgen-dependent diseases, including the prevention and treatment of injuries of the prostate in humans and animals, t is m, for example, maintain and reduce the size of the prostate gland and prostate cancer in mammals the male sex. The present invention also provides the use of these compounds for the prevention and treatment of androgen-dependent skin diseases, such as alopecia, hirsutism, especially hair growth in women, common acne and seborrhea, in mammals.

The term "prevention" refers to the avoidance of cases.

The term "treatment" refers to alleviating or improvement or elimination of the effect of the disease.

The term "maintenance" means the preservation of the existing situation.

Under "mammals" refers to a warm-blooded vertebrate animals of the class Mammalia, including humans and all other animals that feed their offspring with milk secreted by mammary glands and have the skin usually more or less covered with hair or wool. Among them especially includes people, dogs and rats.

The term "hypertrophy" refers to increased or excessive growth of an organ or part due to the increase in size of its constituent cells.

The term "hyperplasia" refers to abnormal mulvenna, the present invention also relates to providing a method of prophylaxis or treatment of androgen-dependent disorders, alopecia (baldness), hirsutism (excessive hair growth in women), common acne and seborrhea with local or topical application, and method of prevention or treatment of the above conditions as well as benign hypertrophy of prostate cancer and prostate cancer with topical or parenteral purpose of the compounds of the present invention. Thus, the present invention relates to the provision of appropriate topical and parenteral pharmaceutical finished preparative forms for use in the new methods of treatment of the present invention.

For information in the description of the feature included a variety of therapeutic dosage forms for different ways to assign and retrieve known from the following sources: U.S. patent 4377584, No. 10, line 52 to column 11, line 31; U.S. patent 4760071, No. 6, line 62 to column 7, line 42; and U.S. patent 5017568, No. 28, line 3-39. The amount of the compounds of formula I which is effective for the treatment of the above conditions is in the range from 1 to 1000 mg/kg/day, preferably t is, the method and frequency assignment for intake and dose can easily be determined by experts in the field and depend on age, weight, General physical condition, or other clinical symptoms that are specific to the patient, humans and other mammals being treated.

By analyzing in vitro for inhibition of testosterone 5 - reductase was tested the following five (5) compounds of the present invention:

3-( - active compounds)-6-( - ethylenebutylene)-4-hydroxy-2H - Piran-2-he;

6-(1-benzyl-propyl)-3-(cyclopropyl-phenyl-methyl)-4-hydroxyfuran - 2-he;

3-( - active compounds)-6-( - active compounds)-4-hydroxy-2H-Piran - 2-he;

3-( - active compounds)-6-phenethyl-4-hydroxy-2H-Piran-2-he;

4-hydroxy-3-(1-phenylpropyl)-6-[1-[(tetrahydro-2H-Piran-3- -yl)methyl]-propyl]-2H-Piran-2-it.

This analysis is very similar to those described in the following sources, except prostate dogs and rats, instead of the prostate glands person: Proc. Natl. Acaf. Sci USA, vol. 90: 5277-5281 (1993); J. Steroid. Biochem. Molec. Biol. volume 44, No. 2, pp. 121-131 (1993). All five compounds showed activity in this assay at a dose of at least 0.1 mm.

Therefore, no measurement to be limited to any particular mechanism of action, are made for the prevention or the prevention or treatment of androgen-dependent diseases, such as those described above.

The usefulness of typical representatives of the compounds of the present invention was demonstrated in the biological tests described below:

3-( - active compounds)-6-( - ethylphenidate)-4-hydroxy-2H-Piran - 2-he - was further tested in vivo using a four-week study of the safety and toxicity oral drug drug hound dogs, described in example 208 below. It was found that during the evaluation of the results of this study in post-dosing (medication after onset) was observed in a dose-related reduction in the size of the prostate and its weight in male dogs. The average weight of prostate (n=3, 3 dogs in each of groups 1-5) is given in table IV below. Check under the microscope of the adrenal gland and the hypophysis in the application of high doses and the results of control tests did not show associated with medication changes.

When you study (groups 6 and 7, from 4 dogs each), the results of which are given in table IV, 2 of 4 dogs at the high dose had lower absolute and relative weight of the prostate than those in the control experiments, but significant reduction was one of 4 dogs.

As is to reduce the size and weight of the prostate, especially without significant effects on the test and other endocrine glands, indicates that this compound and related compounds of the present invention are useful for prevention for the treatment of androgen-dependent diseases, such as mentioned above, especially benign prostatic hypertrophy and hyperplasia in mammals the male sex.

Preferred are the following compounds of the present invention:

3-(alpha-active compounds)-6-(alpha-ethylphenyl)-4-hydroxy-2H-Piran - 2-he;

3-([R] -- active compounds)-4-hydroxy-6-([R] -- ethylphenyl)-2H - Piran-2-he;

3-([R] -- active compounds)-4-hydroxy-6-([S] -- ethylphenyl)-2H - Piran-2-he;

3-([S] -- active compounds)-4-hydroxy-6-([R] -- ethylphenyl)-2H - Piran-2-he;

3-([S] -- active compounds)-4-hydroxy-6-([S] -- ethylphenyl)-2H - Piran-2-he;

4-oxide of sodium (3S, 6R) 3-( - active compounds)-6-( - ethylphenyl)-2H-Piran-2-it;

N-(3-cyclopropyl-[6-(1-ethyl-phenethyl)-4-hydroxy-2-oxo-2H - Piran-3-yl)] -methyl)phenyl)-3-(tert-butyloxycarbonyl)-propionamide;

3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6-(1-(tetrahydro-furan - 3-ylmethyl)-propyl)-Piran-2-he;

6-(1-(5-chloro-thiophene-2-ylmethyl-propyl)-3-(1-(cyclopropyl-phenyl - methyl)-4-hydroxy-Piran-2-he;

3-(cyclopropyl-phenyl-methyltricyclo-furan - 4-ylmethyl)-propyl)-Piran-2-he;

3-(cyclopropyl-phenyl-methyl)-6-(1-furan-2-ylmethyl-propyl)- 4-hydroxy-Piran-2-he;

3-(cyclopropyl-phenyl-methyl)-6-(1-(1,3)dioxolane-2-ylmethyl-propyl)- 4-hydroxy-Piran-2-he;

3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6-(1-(tetrahydro-Piran - 2-ylmethyl)-propyl)-Piran-2-he;

6-(4-chloro-1-ethyl-butyl)-3-(cyclopropyl-phenyl-methyl)-4-hydroxy - Piran-2-he;

6-(3-chloro-1-ethyl-propyl)-3-(cyclopropyl-phenyl-methyl)-4-hydroxy - Piran-2-he;

3-(cyclopropyl-phenyl-methyl)-6-(1-ethyl-3-thiophene-3-yl-propyl)-4 - hydroxy-Piran-2-he;

3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6-(1-(tetrahydro-Piran - 3-yl-methyl)-butyl)-Piran-2-he;

3-(1-benzyl-2-phenyl-ethyl)-6-(2-cyclopropyl-1 - cyclopropylmethyl)-4-hydroxy-Piran-2-it,

6-(2-cyclopropylmethyl-ethyl)-3-(cyclopropyl-phenyl-methyl)-4 - hydroxy-Piran-2-it,

3-(cyclopropyl-phenyl-methyl)-6-(1-ethyl-3-(2-methoxy-ethoxy)- propyl)-4-hydroxy-Piran-2-it,

6-(1-benzyl-3-(2-methoxy-ethoxy)-propyl)-3-(cyclopropyl-phenyl - methyl)-4-hydroxy-Piran-2-it,

3-(cyclopropylmethyl)-4-hydroxy-6-[2-methyl-1-(phenylmethyl)- propyl] -2H-Piran-2-it,

3-(cyclopropylmethyl)-4-hydroxy-6-[2-methyl-1[(tetrahydro - 2H-Piran-3-yl)methyl]propyl-2H-Piran-2-it,

4-hydroxy-3-(1-phenylpropyl)-6-[1-[(tetrahydro-2H-Piran-3-yl)- methyl] propyl]-2H-Piran-2-it,
the Roxy-6-( - ethyl-p - bromperidol)-2H-Piran-2-it,

3-(1,3-diphenyl-2-propenyl)-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)- 6-propyl, (E)-2H-Piran-2-it,

3-(1,3-diphenyl-2-propyl)-5,6-dihydro-4-hydroxy-6-(2-phenethyl)- 6-propyl, (E)-2H-Piran-2-it,

5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-3-(1-phenyl-2-propenyl)-6 - propyl-2H-Piran-2-it,

5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-3-(1-phenylpropyl)-6 - propyl-2H-Piran-2-it,

3-( - cyclopropylmethyl)-4-hydroxy-6-( - ethyl-p - florfenicol)-2H-Piran-2-it,

3-( - cyclopropylmethyl)-4-hydroxy-6-( - ethyl-hydroxyphenethyl)-2H-Piran-2-it,

3-( - cyclopropyl-meta(phenylcarbonylamino)benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(propylsulfonyl)benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta((E-2-phenylacetylamino)- benzyl-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(4-bromophenylacetonitrile)benzyl)- 6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(4-sanofisynthelabo)benzyl)- 6-( - ethyl-phenethyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(4-methoxyphenylacetylene)benzyl)- 6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-(alpha-cyclopropylmethyl)-6-(1-propinball)-4-hydroxy-2H-earn - 2-it,

5,6-di is propyl)-6-(2-phenylethyl)-3-(1 - phenyl-2-propenyl)-2H-Piran-2-it,

3-( - cyclopropyl-meta-(tert-butyloxycarbonyl -- alaninemia)benzyl)-6-( - ethylphenyl)-4-nitroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta-(N-tert-butyloxycarbonyl-N-im-p - toluensulfonyl-L-histidine)-benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(4-chlorophenylsulfonyl)benzyl - 6-( - ethyl-phenethyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta-(N-tert-butyloxycarbonyl-L - histidine)-benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( -- cyclopropyl-meta(ethylsulfonyl)benzyl)-6-[1 - cyclopropyl-methyl-2-(tetrahydropyran-3-yl)ethyl]-4-hydroxy-2H-Piran - 2-it,

3-( - cyclopropyl-meta(4-methylphenylsulfonyl)-benzyl)- 6-[1-cyclopropylmethyl-2-(tetrahydropyran-3-yl)ethyl]-4-hydroxy-2H - Piran-2-it,

3-( - cyclopropyl-meta(4-methylphenylsulfonyl)-benzyl)- 6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(ethylsulfonyl)benzyl)-6-( - ethyl-phenethyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-[5-(methoxyethoxy-methyl)-thiophene-2-yl]- methyl)-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-2H-Piran-2-it, and

5,6-dihydro-3-diphenylmethyl-4-hydroxy-6-(3-phenylpropyl)-6 - propyl-2H-Piran-2-it.

The most preferred compounds of this izaberete ensil)-4-hydroxy-6-([R] -- ethylphenyl)- 2H-Piran-2-it,

4-oxide of sodium (3S, 6R)-3-( - active compounds)-6-( - ethylphenyl)- 2H-Piran-one,

3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6-(1-tetrahydro-furan-2 - ylmethyl)-propyl)-Piran-2He,

3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6-[1-(tetrahydro-Piran-3 - ylmethyl)-propyl)-Piran-2He,

3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6-[1-(tetrahydro-Piran-3 - ylmethyl)-butyl)-Piran-2He,

3-(1-benzyl-2-phenyl-ethyl)-6-(2-cyclopropyl-1-cyclopropylmethyl - ethyl)-4-hydroxy-Piran-2-it,

6-(2-cyclopropyl-methyl-ethyl)-3-(cyclopropyl-phenyl-methyl)-4 - hydroxy-Piran-2-it,

3-(cyclopropylmethyl)-4-hydroxy-6-[2-methyl-1-[(tetrahydro - 2H-Piran-3-yl)methyl]propyl]-2H-Piran-2-it,

3-(1,3-diphenyl-2-propyl)-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)- 6-propyl, (E)-2H-Piran-2He,

5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-3-(1-phenyl-2-propenyl)-6 - propyl-2H-Piran-2-it,

5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-3-(1-phenylpropyl)-6 - propyl-2H-Piran-2-it,

3-( - cyclopropylmethyl)-4-hydroxy-6-( - ethyl-hydroxyphenethyl)-2H-Piran-2-it,

3-( - cyclopropyl-meta(phenylcarbonylamino)benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-methyl-((E)-2-phenylacetylamino)- benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(4-bromophenylacetonitrile)-benzyl)- 6-( Anatel)-4-nitroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta 4-(4-methoxyphenylacetylene)- benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-3- (1-phenyl-2-propenyl)-2H-Piran-2-it,

5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-3- (1-phenylpropyl)-2H-Piran-2-it,

3-( - cyclopropyl-meta-(tert-butyloxycarbonyl-L-alaninemia)- benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta-(N-tert-butyloxycarbonyl-N-im-n - toluensulfonyl-L-histidine)-benzyl)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl meta-(4-chlorophenylsulfonyl)-benzyl)- 6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta-(N-tert-butyloxycarbonyl-L - histidine)-benzyl)-6- - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(ethylsulfonyl)benzyl-6-[1 - cyclopropyl - methyl-2-(tetrahydropyran-3-yl)ethyl]-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(4-methylphenylsulfonyl)-benzyl)- 6-[1-cyclopropylmethyl-2-(tetrahydropyran-3-yl)ethyl]-4-hydroxy-2H - Piran-2-it,

3-( - cyclopropyl-meta(4-methylphenylsulfonyl)-benzyl)- 6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it,

3-( - cyclopropyl-meta(ethylsulfonyl)benzyl)-6-( - ethyl-phenethyl)-4-hydroxy-2H-Piran-yl-2H-Piran-2-it, and

5,6-dihydro-3-diphenylmethyl-4-hydroxy-6-(3-phenylpropyl)-6 - propyl-2H-Piran-2-it.

For the treatment of androgen-dependent diseases preferred are the following compounds of the present invention:

3-( - active compounds)-6-( - ethylphenyl)-4-hydroxy-2H - Piran-2-it,

6-(1-benzyl-propyl)-3-(cyclopropyl-Hairdryer-methyl)-4-hydroxyfuran - 2-it,

3-( - active compounds)-6-( - active compounds)-4-hydroxy-2H-Piran - 2-it,

3-( - active compounds)-6-phenethyl-4-hydroxy-2H-Piran-2He, and

4-hydroxy-3-(1-phenylpropyl-6-[(tetrahydro-2H-Piran-3-yl)- methyl] propyl-2H-Piran-2He.

The most preferred compound of this invention for this use is 3-( - active compounds)-6-( - ethylphenyl)-4-hydroxy-2H-Piran-2-it.

Description of the preferred embodiments

In the receiving and the following examples and throughout this specification uses the following symbols and abbreviations:

oC - degrees Celsius

M - molar (concentration)

N or norms. - normal (concentration)

ml - milliliters

mg - milligrams

mm RT. senior - millimeters of mercury

1H-NMR spectrum of the proton nuclear magnetic resonance

13C-NMR - spectrum of carbon nuclear magnetic is R>
CD3OD - deuterio-methanol

FAB MC - mass spectroscopy rapid bombardment of atoms

HPMC - mass spectroscopy, high-resolution

Anal. analytical data.

Pd/C is palladium on charcoal

THF is tetrahydrofuran.

Following receipt and examples illustrate the present invention:

Obtaining 1. Ethyl-5-phenyl-3,5-dioxopentanoate (formula A-3: X represents CH). Cm. scheme A.

130 mg of Ethylacetoacetate added dropwise at 0oC to a suspension of 50 mg of potassium hydride in 1 ml of dry tetrahydrofuran, and then was added 0.7 ml of 1.6 M solution of n-butyl lithium-hexane. To the resulting yellow reaction mixture is then added 150 mg of etilbenzene (A-2: X is CH and all of this is stirred for a further 5 minutes. The reaction mixture was extinguished 0.5 ml of glacial acetic acid and then diluted with 1 ml water. The tetrahydrofuran is removed under reduced pressure and the aqueous layer was extracted with methylene chloride (2 x 5 ml). The combined organic layers are washed with water (2 ml), dried (magnesium sulfate) and then concentrated. The residue is purified using instant chromatography (0-30% ethyl acetate in hexane) to give 201 mg SUB>3
) 1,29, 3,48, 4,22, 6,30, 7,47, 7,87, 15,81.

13C-NMR (CDCl3) 13,8, 45,6, 61,2, 96,5, 126,8, 128,4, 132,4, 133,8, 167,3, 182,3, 189,1.

Getting 2. 4-Hydroxy-6-phenyl-2-pyrone (formula A-4: X is CH). Cm. scheme A.

Target product yield 1 (700 mg) is heated at 120oC under reduced pressure (1 mm Hg) for 10 hours. The resulting brown cake washed with diethyl ether, dried under reduced pressure, giving the 411 mg of the target compound as a white solid.

Physical features:

1H-NMR (CDCl3) 5,40, 6,78, 7,53, 7,85.

(see the following text after the claims).

1. Paramonovo compound of General formula I

< / BR>
in which R1represents: (a) -(CH2)n-CH(R5)-(CH2)m- R4b) -C(C3- C5-cycloalkyl)-(CH2)n- R4or c) -C(aryl)=CH-aryl;

R2is: a) hydrogen, b) halogen, c) C1- C6-alkyl-[O-(CH2)2]q-(CH2)n-;

R3is: a) C2- C10-alkyl, optionally substituted by 0 to 5 Halogens, (b) C2- C10alkenyl, c) R4-(CH2)m-CH(R6)-(CH2)n-, d) R4-(CH2)p1(CH2)n-, i) aryl, (k) C3- C7-cycloalkyl, l) C1- C6-alkyl-O-C(O)-(CH2)n-, m) C1- C6-alkyl-[O-(CH2)2]q-(CH2)nor n) R4-CH(R6)-CH(R6)-;

R4represents: (a) aryl, b) gets c) C3- C7-cycloalkyl, d) C2- C10alkenyl, e) C1- C6-alkyl-[O-(CH2)2]q-(CH2)n- , (f) halogen, (g), het-O-, h) het-C(O) -, (i) aryl-(CH2)n-O-C(O) -, or (j) trifluoromethyl;

R5is: a) C1- C10-alkyl, b) C3- C7-cycloalkyl, c), (CH2)n-aryl or (f) (CH2)n-CH=CH-aryl;

R6is: a) C1- C10-alkyl, b) -(CH2)n-C3- C7-cycloalkyl, c) -(CH2)p-CH=CH2d) (CH2)p-aryl or (e) hydroxy;

X1is-NR7;

R7is: a) hydrogen or b) C1- C5-alkyl;

aryl represents: (a) phenyl substituted with 0 to 3 groups of R8,

het is a 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and including any bicyclic group in which any of the above and, if it is chemically possible, the nitrogen atoms and sulfur can be oxidized form; and substituted by 0 to 3 groups of R9;

R8and R9are independently: (a) C1- C8-alkyl, substituted by 0 to 3 groups of halogen, (b) C2- C8alkenyl, (c) hydroxy, (d) hydroxy-C1- C5-alkyl, (e) -(CH2)n-O-C1- C5-alkyl, substituted 0 - 3 hydroxy groups, (f) halogen, (g) amino, (h) amino-C1- C5-alkyl, i) mono - or di-C1- C5-alkylamino, j) -C(O)-C1- C5-alkyl, k) -COOC1- C5-alkyl, l) -CON(R7)2, m) C3- C7-cycloalkyl, n) -CN, (o) -SO2NH2p) -(CH2)n-NHC(O)-O-(CH2)p-R12, q) -(CH2)n-R12, r-SO2-R12, s) -(CH2)n-X2-(CH2)n-R12, t) -(CH2)n-X2-(CH2)n-R15, u) -(CH2)n-X2-CH=CH-R12, v) -(CH2)n-X2-C1- C10-alkyl, substituted by 0 to 3 atoms of halogen, w) -X2-(CH2)p-NH-C(O)-O-C1- C6-alkyl, x) -(CH2)p-N3, y) -(CH2)n-NHC(SCH3)=NCN, or z) -(CH2)n-NHC(OTHER7)=NCN;

X2represents: (a) -NH-C(O)- or b) -NH-SO2;

R10- What SUB>)nC3- C7-cycloalkyl,

or R10and R11taken together form a double bond;

or R3and R11taken together, constitute: (a) C3- C8-cycloalkyl, substituted 0 - 3 hydroxy, =N-OH, =O(oxo) or a protected form his or substituted in position by a group R14;

R12is phenyl, substituted by 0 to 3 groups of R13;

R13is: a) C1- C10-alkyl, substituted 0 - 3 Halogens, (b) (CH2)n-O-C1- C5-alkyl, substituted 0 - 3 hydroxy or halogen, (c) halogen or (d) -CN;

R14represents: (a) -(CH2)nis aryl, b) C1- C6-alkyl or c) -(CH2)n-C4- C7cycloalkyl;

R15- 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 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, C3- C8-cycloalkyl or another heterocycle and substituted by 0 to 3 groups of R13;

m and n independently represent from 0 to 5;

p = 1 - 5;

q = 1 to 5;

provided that when R1- -CHR4R5, phenyl, which may be substituted by at least one alkyl, or hydroxyalkyl, or halogen at position 2 or 4, R5- C1-10is alkyl or aryl, and R10and R11taken together form a double bond, then R3is not alkyl or halogenation,

and its pharmaceutically acceptable salts.

2. Connection on p. 1, which provided that when R1group -(CH2)n-CH(R5)-(CH2)m- R4or C(C3- C5-cycloalkyl)-(CH2)n- R4, R4represents aryl, het or C3- C7-cycloalkyl.

3. Connection on p. 1, in which R1- -CH(R5)-R4; R2is hydrogen; R3is: a) C3- C8-alkyl, b) R4-(CH2)m-CH(R6), c) R4-(CH2)p- , (e) CH2= CH-(CH2)p-, f) R4-NH-C(O)-CH2-, R4- aryl; R5is: a) C2- C5-alkyl, b) C2- C5alkenyl, c) cyclopropyl; R6is: a) C2- C5-alkyl, b) R4-(1-2)C-alkyl, aryl represents (a) phenyl substituted with 0 to 3 groups of R8, R8represents: (a) halogen, or (b) C - C3alkoxy; R10and R11taken together form a double SUB> is: a) C5- C8-alkyl, b) R4-(CH2)m-CH(R6), c) R4-(CH2)p-, d) CH2= CH-(CH2)por e) R4-CH=CH-; R4- aryl; R5represents: (a) ethyl, (b) ethynyl or (c) cyclopropyl; R6represents: (a) ethyl or (b) R4-CH2-; aryl represents (a) phenyl substituted with 0 to 3 groups of R8, R8represents: (a) halogen, or (b) methoxy; R10and R11taken together form a double bond; m = 1 or 2; p = 2 or 3.

5. Connection on p. 3, selected from the group consisting of the following compounds:

3-(alpha-active compounds)-4-hydroxy-6-phenyl-2H-Piran-2-it, 6-benzyl-3-(alpha-active compounds)-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-6-phenethyl-4-hydroxy-2H-Piran-2-he;

4-hydroxy-6-phenethyl-3-(alpha-propyl-p-bromobenzyl)-2H-Piran-2-he;

6(p-bromophenetole)-3-(alpha-active compounds)-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-6-(o-florfenicol)-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(3-phenylpropyl)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-propyl-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(3-butenyl)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-[[(phenylamino) carbonyl] methyl]-2H-Piran-2-he;

4-hydroxy-6-Veneti is-([R] --active compounds)-4-hydroxy-6-([R] --ethylphenyl)-2H-Piran-2-he;

3-([R] --active compounds)-4-hydroxy-6-([R]--ethylphenyl)-2H-Piran-2-he;

3-([S]--active compounds)-4-hydroxy-6-([R]--ethylphenyl)-2H-Piran-2-he;

3-([S]--active compounds)-4-hydroxy-6-([S]--ethylphenyl)-2H-Piran-2-he;

sodium(3S,6R)-3-(-active compounds)-6-(-ethylphenyl)-2H-Piran-2-4 oxide;

3-(alpha-active compounds)-1-ethylpropyl-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(p-methoxytrityl)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(2-naphthas-2-retil)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(1-ethyl-2-naphthas-2-retil)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(2-naphthas-1-retil)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(1-ethyl-2-naphtalate)-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-4-hydroxy-6-(3-phenylpropyl)-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-6-(1-ethylpropyl)-4-hydroxy-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-6-(alpha-benzoylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-4-hydroxy-6-phenethyl-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-6-(1-propinball)-4-hydroxy-2H-Piran-2-it.

6. Connection on p. 1, in which R1represents: (a) -(CH2)n-CH(R5)-(CH2)m- R4or b) -C(aryl)=CH-aryl; R2is hydrogen; R3is: a) C2- C2)n-aryl or (e) (CH2)n-CH=CH-aryl; R10is hydrogen; R11is: a) hydrogen, b) C1- C4-alkyl, c) -(CH2)n-aryl or (d) cyclohexyl; or R3and R11taken together, constitute: (a) C3- C8-cycloalkyl, substituted by 0 to 3 hydroxy groups, =N-OH), a carbonyl group or a protected form or substituted in position (CH2)nthe aryl or b) 5 - or 6-membered saturated ring containing 1 or 2 oxygen atoms; aryl is phenyl, substituted by 0 to 3 groups of R8; het represents: (a) thiophenyl, substituted by 0 to 3 groups of R9or (b) furanyl, substituted by 0 to 3 groups of R9, R8and R9independently represent: a) hydroxy, (b) methyl, or (c)- (CH2-O]q- C1- C3-alkyl; m = 0; n = 0 - 3; p = 1 to 3; q = 2.

7. Connection under item 6, selected from the group consisting of the following compounds:

dimethyl-3- [(4-hydroxy-2-oxo-6-phenyl-2H-1-Piran-3-yl)] (4-nitrophenyl)-1,3-propandiol;

dimethyl-3- [(4-hydroxy-2-oxo-6-phenyl-2H-1-Piran-3-yl)] -(3-nitrophenyl)-1,3-propandiol;

6-ethyl-3-(-active compounds)-6-vinyltetrahydrofuran-2,4-dione;

5,6-dihydro-4-hydroxy-6-cyclohexyl-6-phenyl-3-[1-(3-hydroxyphenyl)propyl]-2H-Piran-2-he;
rehydration-2,4-dione;

digido-6-methyl-6-phenyl-3-(1-phenyl-2-propenyl)-2H-Piran-2,4-(3H)-dione;

dihydro-3-[1-(3-hydroxyphenyl)propyl] -3-phenyl-6-propyl-2H-Piran-2,4(3H)-dione;

5,6-dihydro-4-hydroxy-6-phenyl-6-propyl-3-(1-phenylpropyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6-phenyl-6-propyl-3-[1-(3-hydroxyphenyl)propyl] -2H-Piran-2-he;

12-hydroxy-11-(1-phenyl-allyl)-1,4,9-trioxa-despero[4.2.5.2] pentadec-11-EN-10-he;

12-hydroxy-11-(1-phenyl-propyl)-1,4,9-trioxa-despero-[4.2.5.2] pentadec-11-EN-10-he;

4-hydroxy-3-(1-phenylpropyl)-1-oxa-Spiro[5.5]undec-3-ene-2,9-dione;

6,6-dibenzyl-4-hydroxy-3-(1-phenylpropyl)-5,6-dihydropyran-2-he;

4-hydroxy-3-(1-phenylalkyl)-1,9-dioxa-Spiro[5.5]undec-3-EN-2-he;

4,9-dihydroxy-3-(1-phenylpropyl)-1-oxa-Spiro[5.5]undec-3-EN-2-he;

5,6-dihydro-4-hydroxy-6-phenyl-6-(phenylmethyl)-3-(1-phenyl-2-propenyl)-2H-pyrene-2-he;

5,6-dihydro-4-hydroxy-6-phenyl-6-(phenylmethyl)-3-(1-phenylpropyl-2H-Piran-2-he;

3-(1,3-diphenyl-2-propenyl)-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl, (E)-2H-Piran-2-he;

3-(1,3-diphenyl-2-propyl)-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-, (E)-2H-Piran-2-he;

3-(1,3-diphenyl-2-propenyl)-5,6-dihydro-4-hydroxy-6-phenyl-6-(phenylmethyl)-2H-Piran-2-he;

3-(1,2-diphenylethane)-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-, (E)-2H-Piran-2-he;

5,6-dihydr eliprodil)-6-propyl-2H-Piran-2-he;

3-(1,3-diphenyl-2-propenyl)-5,6-dihydro-4-hydroxy-6-(phenylmethyl-6-propyl-2H-Piran-2-he;

3-(1,3-diphenylpropyl)-5,6-dihydro-4-hydroxy-6-(phenylmethyl)-6-propyl-2H-Piran-2-he;

4-hydroxy-3-(1-phenylalkyl)-1-oxaspiro[5.6]dodec-3-EN-2-he;

4-hydroxy-3-(1-phenylalkyl)-1-oxaspiro[5.4]Dec-3-EN-2-he;

7-benzyl-4-hydroxy-3-(1-phenylalkyl)-1-oxaspiro[5.5]undec-3-EN-2-he;

4-hydroxy-3-(1-phenylpropyl)-1-oxaspiro[5.4]Dec-3-EN-2-he;

4-hydroxy-3-(1-phenyl-2-propenyl)-1-oxaspiro[5.7]-tridec-3-EN-2-he;

4-hydroxy-3-(1-phenylpropyl)-1-oxaspiro[5.7]-tridec-3-EN-2-he;

6-butyl-5,6-dihydro-3-(1,3-diphenyl-2-propenyl)-4-hydroxy-6-phenylmethyl-2H-Piran-2-he;

6-butyl-5,6-dihydro-3-(1,3-diphenylpropyl)-4-hydroxy-phenylmethyl-2H-Piran-2-he;

6-butyl-5,6-dihydro-4-hydroxy-6-phenylmethyl-3-(1-phenyl-2-propenyl)-2H-Piran-2-he;

6-butyl-5,6-dihydro-4-hydroxy-6-phenylmethyl-3-(1-phenylpropyl)-2H-Piran-2-he;

3-(-cyclopropyl-[5-(methoxyethoxy-methyl)-thiophene-2-yl] methyl)-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-3-(1-phenyl-2-propenyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-3-(10-phenylpropyl)-2H-Piran-2-he;

5,6-dihydro-3-diphenylmethyl-4-hydroxy-6,6-di-(2-phenylethyl)-2H-feast of the si-6,6-di-(2-phenylethyl)-3-(1,3-diphenylpropyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-3-(1,3-diphenyl-2-propenyl)-6-(3-phenylpropyl)-6-propyl-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-3-(1,3-diphenylpropyl)-6-(3-phenylpropyl)-6-propyl-2H-Piran-2-he;

3-(-cyclopropyl-[5-(methoxyethoxymethyl)thiophene-2-yl] methyl)-5,6-dihydro-4-hydroxy-6-(2-phenylethyl)-6-propyl-2H-Piran-2-he;

3-(-cyclopropyl-[5-(methoxyethoxymethyl)thiophene-2-yl] methyl)-5,6-dihydro-4-hydroxy-6-(3-phenylpropyl)-6-propyl-2H-Piran-2-he;

5,6-dihydro-3-diphenylmethyl-4-hydroxy-6-(3-phenylpropyl)-6-propyl-2H-Piran-2-he;

3-diphenylmethyl-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-he;

3-(1,3-diphenyl-2-propenyl)-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-he

3-(1,3-diphenyl-2-propyl)-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-it.

8. Connection on p. 1, in which R1represents: (a) -(CH2)n-CH(R5)-(CH2)m-R4or b) -C(C3-C5-cycloalkyl)-(CH2)n-R4; R2is hydrogen or halogen; R3represents: (a) R4-(CH2)m-CH(R6)-(CH2)n-, b) R4-(CH2)p-, c) C3-C6-alkyl, substituted 0-3 halogen, or d) R4-CH(R6)-CH(R6)-; R4represents: (a) aryl, b) gets c) C3<>)n-O-C(O)-; R5represents: (a) ethyl, (b) cyclopropyl or c) -CH2-aryl; R6represents: (a) ethyl, (b) propyl, c) -CH2-cyclopropyl, d) -CH2-CH=CH2e) -CH2-aryl or (f) hydroxy; aryl is phenyl, substituted by 0 to 3 groups of R8; gets substituted by 0 to 3 groups of R9that is: a) indolyl, (b) tetrahydrofuranyl, c) thiophenyl, d) isoxazolyl, e) tetrahydrofuranyl, f) tetrahydropyranyl, g) furanyl, h) (1,3)dioxolane, i) pyridinyl, (j) morpholinyl, k) piperidinyl, j) pyrrolidinyl or m) of pyrrolidinyl; R8is: a) -X2-(CH2)p-NH-C(O)-O-C1C6-alkyl, b) -(CH2)n-X2-(CH2)n-R12c) -(CH2)n-X2-(CH2)n-R15d) -(CH2)n-NHC(O)-O-(CH2)p-R12e) C1-C5-alkyl, substituted 0-3 Halogens, (f) halogen or (g) C1-C5-alkyloxy; R9is; a) methyl, b) halogen, c) -(CH2)n-R12d) -SO2-R12; X2represents: (a) -NH-C(O)-; R10and R11taken together form a double bond; R12is phenyl, substituted by 0 to 3 groups of R13; R13represents: (a) methoxy, (b) halogen, c) -CN, or d) C1-C5-alkyl; R15replaced by 0 or 1 ptx2">

9. Connection on p. 8, provided that when R1- -(CH2)n-CH(R5)-(CH2)m-R4or C(C3-C5-cycloalkyl)-(CH2)n-R4, R4-aryl, het or C3-C5-cycloalkyl. 10. Connection on p. 9, selected from the group consisting of the following compounds:

N-(3-cyclopropyl[6-(1-ethylphenyl)-4-hydroxy-2-oxo-2H-Piran-3-yl] methyl)phenyl)-3-(tert-butyloxycarbonyl)-propionamide;

N-(3-{ cyclopropyl[6-(2-cyclopropyl-1-cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-3-yl]methyl}phenyl)-3-indol-1-yl-propionamide;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-tetrahydrofuran-3-yl-methyl)propyl)Piran-2-he;

6-(1-(5-chlorothiophene-2-ylmethyl)propyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-6-(1-(3,5-dimethylisoxazol-4-ylmethyl)propyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)propyl)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-(thiophene-2-iletileri)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)Piran-2-he;

3-(cyclopropylmethyl)-6-(1-furan-2-iletileri)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-6-(1-(1,3)-dioxolane-2-filing)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)propyl)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-pyridin-2-iletileri)Piran-2-he;

6-(4-chloro-1-ethylbutyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

6-(3-chloro-1-ethylpropyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-6-[ethyl-3-(tetrahydropyran-2-yloxy)propyl] -4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-pyridine-3-iletileri)Piran-2-he;

3-(cyclopropylmethyl)-6-(1-ethyl-3-thiophene-3-yl-propyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-[1-(tetrahydropyran-3-ylmethyl)butyl]Piran-2-he;

5-bromo-6-(2-cyclopropanecarboxylate)-4-hydroxy-3-(1-phenylpropyl)Piran-2-he;

3-(1-benzyl-2-phenylethyl)-6-(2-cyclopropyl-1-cyclopropylmethyl)-4-hydroxyfuran-2-he;

6-(2-cyclopropylethyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

6-(1-halibut-3-enyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-6-(1-ethyl-3-(2-methoxyethoxy)propyl)-4-hydroxyfuran-2-he;

6-(1-benzyl-3-(2-methoxyethoxy)propyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl--hydroxyine epibenthic)-4-hydroxy-6-(hydroxy-p-florfenicol)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(hydroxy-p-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-hydroxy-m-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-hydroxy-o-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(2-(furan-3-yl)-2-hydroxyethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(2-thiophene-3-yl)-2-hydroxyethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-florfenicol)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-o-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-bromophenetole)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-brominated)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-triptoreline)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-triptoreline)-2H-Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(-ethyl-o-triptoreline)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-methoxyphenethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-methoxyphenethyl)-2H-Eoxy-6-(p-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(p-bromophenetole)-2H-Piran-2-he;

3-(cyclopropylmethyl)-6-[1-ethyl-3-(4-morpholinyl)-propyl] -4-hydroxy-2H-Piran-2-he;

3-(cyclopropylmethyl)--ethyl-4-hydroxy-2-oxo-, fenilmetilovy ether-2H-Piran-6-propanoic acid;

3-(cyclopropylmethyl)-4-hydroxy-6-[2-methyl-1-(phenylmethyl)propyl] -2H-Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-[2-methyl-1-[(tetrahydro-2H-Piran-3-yl)methyl]propyl]-2H-Piran-2-he;

4-hydroxy-3-(1-phenylpropyl)-6-[1-[(tetrahydro-2H-Piran-3-yl)methyl] propyl]-2H-Piran-2-he;

3-(cyclopropylmethyl)-6-(1-ethyl-4,4,4-trifloromethyl)-4-hydroxy-2H-Piran-2-he;

3-[2-[3-(cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl] -1-[(4-were)sulfonyl] piperidine;

2-[2-[3-(cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl] -1-[(4-were)sulfonyl] pyrrolidin;

3-(cyclopropylmethyl)-4-hydroxy-6-(3,3,3-cryptochromes)-2H-Piran-2-he;

2-[2-[3-(cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl] -1-[(4-were)sulfonyl]piperidine;

4-[2-[3-(cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl-1-[(4-were)sulfonyl]piperidine;

4-[2-[3-(cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl-1-(phenylmethyl)-2-pyrrolidin what-hydroxy-6-[(tetrahydro-2H-Piran-4-yl)methyl] -2H-Piran-2-he;

3-(cyclopropylmethyl)-6-(3-forproper)-4-hydroxy-2H-Piran-2-he;

4-hydroxy-3-(1-phenylcyclohexyl)-6-[1-(phenylmethyl) propyl]-2H-Piran-2-he;

3-(-active compounds)-6-(-active compounds)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-[(phenylamine carbonyl)amino]benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-[(4-methoxyphenylacetyl)-amino] benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-[(benzylaminocarbonyl)amino]-benzyl)-6-(-cyclopropyl-meta-[(4-brompheniramineodeine)amino] benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-[(vinylsulfonylacetamido)amino] benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-(N-tert-butyloxycarbonyl-N-p-toluensulfonyl-L-histidine)benzyl)-6-(-cyclopropyl-meta-(tert-butyloxycarbonyl-L-alaninemia)benzyl)-6-(-cyclopropyl-meta(4-brompheniramine)benzyl-6-(-cyclopropyl-meta-(N-tert-butyloxycarbonyl-L-histidine)benzyl)-6-(-cyclopropyl-meta-(N-benzyloxycarbonyl-0--ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(4-cyanobenzylidene)benzyl)-6-(-cyclopropyl-meta-(L-glutamine)benzyl)-6-(-cyclopropyl-meta-(3-(1-indolyl)propanolamine)-benzyl)-6-(-cyclopropyl-Roxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-(3-pyridylamino)benzyl)-6-(-cyclopropyl-meta(4-pyridylamino)benzyl)-6-(-cyclopropyl-meta(phenylcarbonylamino)benzyl)-6-(-cyclopropyl-meta(propylsulfonyl)benzyl)-6-(-cyclopropyl-meta-( (E)-2-phenylethylenediamine)benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;< / BR>
3-(-cyclopropyl-meta(4-bromophenylacetonitrile)benzyl)-6-(cyclopropyl-meta-(2,5-dichlorophenylamino)-benzyl)-6-(-cyclopropyl-meta-(4-tert-butylphenylphosphine)-benzyl)-6-(-cyclopropyl-meta(4-sanofisynthelabo)-benzyl)-6-(-cyclopropyl-meta(4-methoxyphenylacetylene)-benzyl)-6-(-cyclopropyl-meta(4-chlorophenylsulfonyl)benzyl)-6-(-cyclopropyl-meta-(8-chinaincorporated)benzyl)-6-(-cyclopropyl-meta(ethylsulfonyl)benzyl)-6-[1-cyclopropylmethyl-2(tetrahydropyran-3-yl)ethyl]-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(4-methylphenylsulfonyl)-benzyl)-6-(-cyclopropyl-meta(4-methylphenylsulfonyl)benzyl-6-[1-cyclopropylmethyl-2-(tetrahydropyran-3-yl)ethyl]-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(ethylsulfonyl)benzyl)-6-(-cyclopropyl-meta(4-fortunaltely)benzyl)-6-(-cyclopropyl-meta(benzothiazolylsulfenamide)-benzyl)-6-(-cyclopropyl-meta(Ben is propyl-meta-((pyridin-3-yl) sulfonylamino)-benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-(5-(pyridin-2-yl)-thiophene-2-yl-sulfonylamino)benzyl)-6-(-cyclopropyl-meta(4-hydroxymethanesulfinic)benzyl)-6-(-cyclopropyl-meta(4-dimethylaminopropylamine)benzyl)-6-(-cyclopropyl-meta-3-aminophenylacetylene)benzyl)-6-(-cyclopropyl-meta(4-aminocarbonylmethyl)benzyl)-6-(-cyclopropylmethyl)-6-(-ethylphenethylamine)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropylmethyl)-6-(1-ethyl-2-phenylcarbonylamino)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(4-fortunaltely)-benzyl)-6-(-cyclopropyl-meta(phenylcarbonylamino)benzyl)-6-(-cyclopropyl-meta-(2,5-dichlorophenylamino)benzyl)-6-(-cyclopropyl-meta(4-sanofisynthelabo)-benzyl)-6-(-cyclopropyl-meta-(quinoline-8-ylsulphonyl)-benzyl)-6-(-cyclopropyl-meta-((2-phenylethenyl)sulfonylamino)-benzyl)-6-(-cyclopropyl-meta-((1-methylimidazol-4-yl)-sulfonylamino)-benzyl)-6-(-cyclopropyl-meta-(pyridine-3-ylsulphonyl)-benzyl)-6-(-cyclopropyl-meta(4-dimethylaminopropylamine)benzyl)-6-(-cyclopropyl-meta(4-fortunaltely)-benzyl)-6-(1-ethyl-2-phenylsulfonylacetate)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(phenylcarbonylamino)-benzyl)-6-(1-ethyl-2-phenylsulfonyl sulfonylamino)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(4-sanofisynthelabo)-benzyl)-6-(1-ethyl-2-phenylcarbonylamino)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-(quinoline-8-yl-sulfonylamino)-benzyl)-6-(1-ethyl-2-phenylcarbonylamino)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-((2-phenylethenyl)sulfonylamino)-benzyl)-6-(1-ethyl-2-phenylcarbonylamino)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-((1-methylimidazol-4-yl)sulfonylamino)-benzyl)-6-(1-ethyl-2-phenylcarbonylamino)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-(pyridin-3-yl-sulfonylamino)-benzyl)-6-(1-ethyl-2-phenylcarbonylamino)-4-hydroxy-2H-Piran-2-he

3-(-cyclopropyl-meta(4-dimethylaminopropylamine)-benzyl)-6-(1-ethyl-2-phenylcarbonylamino)-4-hydroxy-2H-Piran-2-it.

14. Connection on p. 1, in which R1-(CH2)n- CH(R5) - (CH2)m- R4; R2is hydrogen or C1- C6-alkyl; R3is (a) R4- (CH2)m- CH(R6) - (CH2)n-, b) R4CH(R6) - CH(R6), c) R12-(CH2)m-X2-(CH2)n-(R7)HC - d) R15-(CH2)m-X2-(CH2)n-(R7)HC-; R4is aryl or het; R5- C1-C4-hell or1-C5is alkyl, aryl is phenyl, unsubstituted or substituted by two groups of R8; het represents: (a) furan-2-yl, unsubstituted or substituted 2 groups of R9; (b) furan-3-yl, unsubstituted or substituted 2 groups of R9; (c) thiophene-2-yl, unsubstituted or substituted 2 groups of R9; d) thiophene-3-yl, unsubstituted or substituted 2 groups of R9; (e) tetrahydrofuran-2-yl, unsubstituted or substituted 2 groups of R9; f) tetrahydrofuran-3-yl, unsubstituted or substituted 2 groups of R9; g) tetrahydropyran-2-yl, unsubstituted or substituted 2 groups of R9; (h) tetrahydropyran-3-yl, unsubstituted or substituted 2 groups of R9or i) chinoline; R8and R9is independently: (a) C1-C8-alkyl, b) halogen, c) hydroxy - C1-C4-alkyl, d) -(CH2)n-X2-(CH2)n-R12e) -(CH2)n-X2-(CH2)n-R15X2is: a) -NHSO2-, b) -SO2NH - or c) -NHC(O)-; R10and R11taken together form a double bond; R12is phenyl, substituted by 0 to 3 groups of R13, R13represents: (a)- (C1-C6-alkyl, (b) hydroxy, (c) hydroxy-C1-C5-alkyl, d) halogen, e) -CN or f) amino; R15presents: alseny 0 - 3 groups of R13d) furan-2-yl, substituted by 0 to 3 groups of R13or e) furan-3-yl, substituted by 0 to 3 groups of R13m = 0 - 4; n = 0 - 4.

15. Connection on p. 14, selected from the group consisting of:

N-[5-[[R] cyclopropyl--[6-[R] -ethyl-[S] -tetrahydrofuran-2-yl methyl)methyl-4-hydroxy-2-Piran-3-yl] -methyl] thiophene-2-ylmethyl] -n-cyanophenylacetic;

N-[5-[-[R] cyclopropyl-[6-[R] -ethyl-[R] -tetrahydrofuran-2-ylmethyl)methyl-4-hydroxy-2-Piran-3-yl] -methyl] thiophene-2-ylmethyl] -n-cyanophenylacetic;

N-[5-[[R] cyclopropyl--[6-[R] -ethyl-[S] -tetrahydrofuran-2-ylmethyl)methyl-4-hydroxy-2-Piran-3-yl] -methyl] thiophene-2-ylmethyl] -n-fortunaltely;

N-[5-[[R] cyclopropyl--[6-[R] -ethyl--[R] -tetrahydrofuran-2-ylmethyl)methyl-4-hydroxy-2-Piran-3-yl] -methyl] thiophene-2-ylmethyl] -n-fortunaltely;

N-[5-[[R] cyclopropyl--[6-(I[S] -ethyl-2[R] -hydroxy-2[S]tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -n-cyanophenylacetic;

N-[5-[-[R] cyclopropyl--[6-(I[S] -ethyl-2[R] -hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]methyl]thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[R] -cyclopropyl--[6-(I[R] -ethyl-2[S] -hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]methyl]-thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-the l] -n-cyanophenylacetic;

N-[5-[[R] -cyclopropyl--[6-(I[S] -ethyl-2[S] -hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]methyl]thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[R] -cyclopropyl--[6-(I[S] -ethyl-2[S] -hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]-methyl]thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[R] -cyclopropyl--[6-(I[R] -ethyl-2[R] -hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]methyl]-thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[R] -cyclopropyl--[6-(I[R] -ethyl-2[R] -hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]-methyl]thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[S] -cyclopropyl--[6-(I[S] -ethyl-2[R]-hydroxy-2[S]tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl]-thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[S] -cyclopropyl--[6-(I[S] -ethyl-2[R]-hydroxy-2[R]tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] -methyl]thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[S] -cyclopropyl--[6-(I[R] -ethyl-2[S] hydroxy-2[S]tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] -methyl] thiophene-2-ylmethyl] -n-cyanophenylacetic;

N-[5-[[S] -cyclopropyl--[6-(I[R] -ethyl-2[S]-hydroxy-2[R]tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl]-thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[S] -cyclopropyl[6-(I[S] -ethyl-is;

N-[5-[-[S] -cyclopropyl--[6-(I[S] -ethyl-2[S]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]-methyl]thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[-[S] -cyclopropyl--[6-(I[R] -ethyl-2[R]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]-methyl]thiophene-2-ylmethyl]-n-cyanophenylacetic;

N-[5-[[S] -cyclopropyl--[6-(I[R] -ethyl-2[R]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl]methyl]-thiophene-2-ylmethyl]-n-cyanophenylacetic;

3-([S] -cyclopropyl-(5-(2-hydrocity)thiophene-2-ylmethyl)-6-(I[R] -ethyl-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2H-Piran-2-he;

3-([S]-cyclopropyl-(5-(2-hydroxyethyl)-thiophene-2-ylmethyl)-6-[[S] -cyclopropyl-(5-(2-hydroxyethyl)thiophene-2-ylmethyl)-6-([R] -ethyl-meta-hydroxymethylene)-4-hydroxy-2H-Piran-2-he;

3-([S] -cyclopropyl(5-(2-hydroxyethyl)thiophene-2-ylmethyl)-6-([R]-ethyl-ortho-hydroxymethylene)-4-hydroxy-2H-Piran-2-he;

3-([S] -cyclopropyl(5-(1,2-dihydroxyethyl))thiophene-2-ylmethyl)-6-(1[R]-ethyl-2[R]tetrahydrofuran-2-yl)ethyl-4-hydroxy-2H-Piran-2-he;

3-([S] -cyclopropyl(5-(1,2-dihydroxyethyl))thiophene-2-ylmethyl)-6-([S] -cyclopropyl(5-(1,2-dihydroxyethyl))thiophene-2-ylmethyl)-6-([S] -cyclopropyl(5-(1,2-dihydroxyethyl))thiophene-2-ylmethyl)6-([S]-cyclopropyl)-meta(4-sanofisynthelabo)-benzyl-6-([S]-cyclopropyl)ropyl)-meta(4-sanofisynthelabo)-benzyl-6-([R] -cyclopropylmethyl) (5-N-(p-perpenicular)-methyl)-tiermarkt-2-yl]-6-([R] -ethyl--[6-[R] -ethyl-[S]-tetrahydrofuran-2-ylmethyl)methyl-4-hydroxy-2-Piran-3-yl]methyl]thiophene-2-ylmethyl]-p-cyanobenzylidene;< / BR>
N-[5-[[R] -ethyl--[6-[R]-ethyl-[R]-tetrahydrofuran-2-ylmethyl)methyl-4-hydroxy-2-Piran-3-yl]methyl]thiophene-2-ylmethyl-p-cyanobenzylidene;

N-[5-[[R] -ethyl--[6-[R]-ethyl-[S]-tetrahydrofuran-2-ylmethyl)methyl-4-hydroxy-2-Piran-3-yl]methyl]thiophene-2-ylmethyl-p-fortunaltely;

N-[5-[[S] -ethyl--[6-[R]-ethyl-[R]-tetrahydrofuran-2-ylmethyl)methyl-4-hydroxy-2-Piran-3-yl]methyl]thiophene-2-ylmethyl]-p-fortunaltely;

N-[5-[[R] -ethyl--[6-(1-[S]-ethyl-2[R]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] -thiophene-2-ylmethyl]-p-cyanobenzylidene;

N-[5-[[R] -ethyl--[6-(1[S] -ethyl-2[R]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[R] -ethyl--[6-(1[R] -ethyl-2[S]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[R] -ethyl--[6-(1[R]-ethyl-2[S]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[R] -ethyl--[6-(1[S] -ethyl-2[S]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[R] -ethyl--[6-(1[S] -ethyl-2[S]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-C-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[R] -ethyl--[6-(1[R] -ethyl-2[R]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[S] -ethyl--[6-(1[S] -ethyl-2[R]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[-[S] -ethyl--[6-(1[S]-ethyl-2[R]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[S] -ethyl--[6-(1[R] -ethyl-2[S]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[S] -ethyl--[6-(1[R] -ethyl-2[S]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[S] -ethyl--[6-(1[S] -ethyl-2[S]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[S] -ethyl--[6-(1[S] -ethyl-2[S]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene;

N-[5-[[S] -ethyl--[6-(1[R] -ethyl-2[R]-hydroxy-2[S]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-Piran-3-yl] methyl] thiophene-2-ylmethyl] -p-cyanobenzylidene and

N-[5-[[S] -ethyl--[6-(1[R] -ethyl-2[R]-hydroxy-2[R]-tetrahydrofuran-2-yl)ethyl-4-hydroxy-2-periostea of the following:

3-(-cyclopropyl-meta(benzyloxycarbonylamino)benzyl)-6-(-cyclopropyl-meta-(tert-butyloxycarbonyl)-benzyl-6-(-active compounds)-4-hydroxy-6-([R]--ethylphenyl)-2H-Piran-2-he;

3-([R]--active compounds)-4-hydroxy-6-([S]--ethylphenyl)-2H-Piran-2-he;

3-([S]--active compounds)-4-hydroxy-6-([R]--ethylphenyl)-2H-Piran-2-he;

3-([S]--active compounds)-4-hydroxy-6-([S]--ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl)(5-methoxyethoxymethyl ether)-furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((5-hydroxymethyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-methoxymethyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((-5-azidomethyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-aminomethyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-[N-acetyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((-5-[N-phenylsulfonyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((5-[N-(o-fluoro)phenylsulfonyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(cyclopropyl((5-[N-(p-fluoro)phenylsulfonyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((-5-[N-(m-fluoro)phenylsulfonyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(- ecoprofile((-4-[N-(cyano)phenylsulfonyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((5-[N-(p-cyano)phenylsulfonyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((5-[N-(m-cyano)phenylsulfonyl] aminomethyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((5-(N-carbomethoxy-1,2,3-triazole-1-yl)-methyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-(4-carboxy-1,2,3-triazole-1-yl)methyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-(N-(1-nitro-2-methylthioethyl-2-yl)aminomethyl)furfur-2-yl))-4-hydroxy-6-(-cyanopropyl((5-(N-(1-nitro-2-N-isopropyl/)-ethen-2-yl)aminomethyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-(N-(N-cyano, methylthionine)amino)methyl)furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((5-(N - (N-cyano N'-isopropylaniline)-aminomethyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-(N-benzylcarbamoyl)aminomethyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-(N-benzylcarbamoyl)aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-(N-phenylsulfonyl)-aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropylmethyl-2-yl)-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-cyclopropyl((5-N-phenylsulfonyl)furfur-2-yl))-4-hydroxy-6-(-cyclopropyl((5-methoxyethoxymethyl ether)thiophene-2-ylmethyl))-4-hydroxy-6-(-this is imethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-azidomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-[N-acetyl]-aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-[N-phenylsulfonyl] aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;< / BR>
3-(-cyclopropyl((5-(4-carboethoxy-1,2,3-triazole-1-yl)methyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-(4-carboxy-1,2,3-triazole-1-yl)methyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-(N-(1-nitro-2-methylthioethyl-2-ylmethyl)aminomethyl)thiophene-2-yl))-4-hydroxy-6-(-cyclopropyl((5-(N-(1-nitro-2-[N-isopropyl]ethen-2-yl)aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-(N-(N-cyanoethylidene)aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl((5-(N-(N-cyano-N'-isopropylaniline)aminomethyl)thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropylidene-2-ylmethyl)-4-hydroxy-6-(-cyclopropyl((5-N-phenylsulfonyl)thiophene-2-ylmethyl))-4-hydroxy-6-([S] -active compounds)-4-hydroxy-6-([R] -ethyl-[S]-hydroxyphenethyl)-2H-Piran-2-he;

3-([S] -active compounds)-4-hydroxy-6-([S] -ethyl-[R]-hydroxyphenethyl)-2H-Piran-2-he;

3-([S] -active compounds)-4-hydroxy-6-([R] -ethyl-[R]-hydroxyphenethyl)-2H-Piran-2-he;

3-([S] -active compounds)-4-hydroxy-6-([S] -ethyl-[S]-hydroxyphenethyl)-2H-Piran-2-he;

3-([R] -active compounds)-4-hydroxy-6-([R] -ethyl-[S]-hydroxyphenethyl)-2H-Piran-2-he;

3-([R] -active compounds)-4-hydroxy-6-([S] -ethyl-[R]-hydroxyphenethyl)-2H-Piran-2-he;

3-([R] -active compounds)-4-hydroxy-6-([R] -ethyl-[R]-hydroxyphenethyl)-2H-Piran-2-he;

3-([R] -active compounds)-4-hydroxy-6-([S] -ethyl-[S]-hydroxyphenethyl)-2H-Piran-2-he;

3-([S] -cycloprop the Il-[R] -hydroxyphenethyl)-2H-Piran-2-he;

3-([S] -cyclopropylmethyl)-4-hydroxy-6-([R] -ethyl-[R] -hydroxyphenethyl)-2H-Piran-2-he;

3-([S] -cyclopropylmethyl)-4-hydroxy-6-([S] -ethyl-[S] -hydroxyphenethyl)-2H-Piran-2-he;

3-([R] -cyclopropylmethyl)-4-hydroxy-6-([R] -ethyl-[S] -hydroxyphenethyl)-2H-Piran-2-he;

3-([R] -cyclopropylmethyl)-4-hydroxy-6-([S] -ethyl-[R] -hydroxyphenethyl)-2H-Piran-2-he;

3-([R] -cyclopropylmethyl)-4-hydroxy-6-([R] -ethyl-[R]-hydroxyphenethyl)-2H-Piran-2-he

3-([R] -cyclopropylmethyl)-4-hydroxy-6-([S] -ethyl-[S] -hydroxyphenethyl)-2H-Piran-2-it.

18. Connection on p. 1, selected from the group consisting of the following:

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethyl[p-florfenicol] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethyl[p-chlorphenyl] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethyl[p-bromophenetole] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethyl[p-methylphenethyl] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethyl[p-methoxyphenethyl] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethyl[p-hydroxyphenethyl] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-ethyl[p-triptoreline] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropylmethyl[p-R> 3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropylmethyl[p-bromophenetole] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropylmethyl[p-methylphenethyl] )-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropylmethyl[p-methoxyphenethyl])-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl ))-4-hydroxy-6-(-cyclopropylmethyl[p-hydroxyphenethyl])-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropylmethyl[p-triptoreline])-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-3-elmet the methyl-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(furan-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(furan-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(furan-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(furan-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(- the N-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl)-furfur-2-yl))-4-hydroxy-6-(1-(furan-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl)(furfur-2-yl))-4-hydroxy-6-(1-(furan-3-ylmethyl) propyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl) propyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-3-ylmethyl)-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(furan-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(furfur-2-yl))-4-hydroxy-6-(1-(thiophene-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl((furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl((furfur-2-yl)))-4-hydroxy-6-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)C)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(furan-2-ylmethyl) propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(furan-3-ylmethyl) propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(thiophene-2-ylmethyl) propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(thiophene-3-ylmethyl) propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl-(furfur-2-yl)))-4-hydroxy-6-(1-(furan-2-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(furan-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(thiophene-2-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(thiophene-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-about the Il(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(furan-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(furan-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(thiophene-2-yl) - Rev. RAS-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(furan-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(furan-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl(furfur-2-yl)))-4-hydroxy-6-(1-(thiophene-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethylphenyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethyl-[n-florfenicol] )-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethyl-[n-chlorphenyl] )-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethyl-[n-brominated] )-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethyl-[n-methylphenethyl] )-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethyl-[n-methoxyphenethyl] )-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethyl-[n-hydroxyphenethyl] )-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-ethyl-[n-triptoreline])-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropylmethyl [p-florfenicol])-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(cyclopropylmethyl [p-chlorphenyl])-2H-Piran-open-3-ylmethyl))-4-hydroxy-6-(-cyclopropylmethyl [p-methylphenethyl])-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropylmethyl [p-methoxyphenethyl])-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropylmethyl [p-hydroxyphenethyl])-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropylmethyl [p-triptoreline])-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydrofuran-2-yl-methyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydro-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-4-Iran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(furan-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl) propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(thiophene-3-ylmethyl) propyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(furan-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(furan-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(thiophene-3-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(-cyclopropyl(thiophene-2-ylmethyl))-4-guide is n-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(furan-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(furan-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(ylmethyl))-4-hydroxy-6-(1-(furan-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(furan-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)cyclopropylmethyl)-2-Piran-2-he;

3-(-cyclopropyl(thiophene-2-ylmethyl))-4-hydroxy-6-(1-(thiophene-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl) cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(furan-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(furan-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(thiophene-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(furan-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(furan-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-ethyl(5-methyl - (thiophene-2-ylmethyl)))-4-(1-(thiophene-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(ethyl[p-methylphenethyl])-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)propyl)-2H-Piran-2-he;< / BR>
3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydrofuran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydrofuran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydrofuran-3-ilman-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(tetrahydropyran-4-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(furan-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-3-ylmethyl)))-4-hydroxy-6-(1-(furan-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(thiophene-2-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(thiophene-3-ylmethyl)propyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(furan-2-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroxy-6-(1-(furan-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

3-(-cyclopropyl(5-methyl - (thiophene-2-ylmethyl)))-4-hydroc-(1-(thiophene-3-ylmethyl)cyclopropylmethyl)-2H-Piran-2-he;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]phenylsulfonyl;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]vinylsulfonate;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-n-fortunaltely;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-p-fortunaltely;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-n-chlorophenylsulfonyl;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-p-chlorophenylsulfonyl;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-3,4-dichlorobenzenesulfonate;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-3,4-dichlorobenzenesulfonate;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-ylmethyl]-p-cyanobenzylidene;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-p-cyanobenzylidene;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-n-triftormetilfullerenov;

N-[5-[(-cyclopropyl--(6-(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-fortunaltely;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-fortunaltely;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-chlorophenylsulfonyl;

N-[5-[(cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-chlorophenylsulfonyl;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-cyanophenylacetic;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-cyanophenylacetic;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-triftormetilfullerenov;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-triftormetilfullerenov;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-o-fortunaltely;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-o-fortunaltely;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-o-chlorophenylsulfonyl;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-o-chlorophenylsulfonyl;

N-[5-[(-cyclo is l--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-o-cyanophenylacetic;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-o-triftormetilfullerenov;

N-[5-[(-cyclopropyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-p-triftormetilfullerenov;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3)methyl] furfur-2-yl]phenylsulfonyl;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]vinylsulfonate;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-n-fortunaltely;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-p-fortunaltely;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-n-chlorophenylsulfonyl;

N-[5-[(ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-p-chlorophenylsulfonyl;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-yl)methyl] furfur-2-yl]-3,4-dichlorobenzenesulfonate;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-3,4-dichlorobenzenesulfonate;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-n-cyanophenylacetic;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-p-cyanobenzylidene;
N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-fortunaltely;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-fortunaltely;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-chlorophenylsulfonyl;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-chlorophenylsulfonyl;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-cyanophenylacetic;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-cyanophenylacetic;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-m-cryptoperidiniopsoid;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-m-triftormetilfullerenov;

N-[5-[-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-o-fortunaltely;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-o-fortunaltely;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-o-chlorophenylsulfonyl;

N-[5-[(-ethyl(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-o-chlorophenylsulfonyl;

N-[5-[-Anatel)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-o-cyanophenylacetic;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] furfur-2-yl]-o-triftormetilfullerenov;

N-[5-[(-ethyl--(6-(-ethylphenyl)-4-hydroxy-2-Piran-3-yl)methyl] thiophene-2-ylmethyl]-o-triftormetilfullerenov;

3-(/S/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-he;

3-(/S/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-he;

3-(/S/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-he;

3-(/S/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-he;

3-(/R/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-he;

3-(/R/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-he;

3-(/S/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-he

3-(/R/-cyclopropyl-(m-terbisil))-4-hydroxy-6-(-tetrahydropyran-4-yl)ethyl-2H-Piran-2-it.

19. The compound of the formula I

< / BR>
or its pharmaceutically acceptable salt according to p. 1,

useful for getting medicines for inhibiting retroviruses in mammalian cells infected with the indicated retrovirus, where R1represents: (a) (CH2)n-(The Il)=CH-aryl, d) -(CH2)p-aryl;

R2is: a) hydrogen, b) halogen, C), (1-6C alkyl-[O-(CH2)2]g-(CH2)n-, d) -(CH2)n-(CH(R5)-(CH2)m- R4;

R3is: a)1-C10-alkyl, optionally substituted by 0-5-halogen, b)2-C10alkenyl, C) R4-(CH2)m-CH(R6) - (CH2)n-, d) R4-(CH2)p- , (e) R4-CH=CH -, f) R4(CH2)mX1C(O)(CH2)n- , (g) aryl, (h)3-C7-cycloalkyl, i)1-C6-alkyl-O-C(O)-(CH2)n-, j)1-C6-alkyl -[O-(CH2)2]g-(CH2)n- or) R4-CH(R6-CH(R6)-;

R4represents: (a) aryl, b) gets C)3-C7-cycloalkyl, d)2-C10alkenyl, e)1-C6-alkyl-[O-(CH2)2]g-(CH2) n- , (f) halogen, (g), het-O-, h) het-C(O) -, (i) aryl-(CH2)n-O-C(O) -, or (j) trifluoromethyl,

R5is: a)1-C10-alkyl, (b) (C3-C7-cycloalkyl, C) -(CH2)n-aryl, or (d) -(CH2)n-CH=CH-aryl;

R6is: a)1-C10-alkyl, b) -(CH2)
X1- NR7-;

R7is hydrogen or C1-C5-alkyl;

aryl represents phenyl, substituted by 0 to 3 groups of R8;

het is a 5 - or 6-membered saturated or unsaturated ring containing from 1 to 4 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, C3-C8-cycloalkyl or another heterocycle, and if it is chemically possible, the nitrogen atoms and sulfur can be oxidized form; and substituted 0-3 groups R9;

R8and R9are independently: (a)1-C8-alkyl, substituted 0-3-halogen, b)2-C8alkenyl, (C) hydroxy, (d) hydroxy-C1-C5-alkyl, (e) -(CH2)n-O-C1-C5-alkyl, substituted by 0-3 groups hydroxy, (f) halogen, (g) amino, (h) amino1-C5-alkyl, i) mono - or di-C1-C5-alkylamino, j) -C(O)-C1-C5-alkyl, K) -SOOS1-C5-alkyl, I) -SOP (R7)2, m)3-C7-cycloalkyl, n) -CN, on) -SO2N N2, R) -(CH2)n-NHC(O)-O-(CH2)p- R12, g) -(CH2)n- R122-(CH2)n- R15, u) -(CH2)n-X2-CH=CH - R12, v) -X2-(CH2)p-NH-C(O)-O-C1-C6alkyl, w) -(CH2)p-N3x) -(CH2)n-NHC(S CH3)=NCH, or) -(CH2)n-NHC(N HR7)=NCN;

X2represents: (a) -NH-C(O)-, or: b) -NH - SO2-; R10is hydrogen; R11is: a) hydrogen, b)1-C6-alkyl, C) -(CH2)n-aryl or (d) -(CH2)n-C3-C7cycloalkyl; or R10and R11taken together form a double bond; or R3and R11taken together, constitute: (a)3-C8cycloalkyl, substituted 0-3 groups hydroxy, =N-OH, =O (oxo) or protected form, or replaced in - position by a group R14or b) 5 - or 6-membered saturated ring containing 1 or 2 oxygen atom;

R12is phenyl, substituted by 0 to 3 groups of R13or naphthyl, substituted by 0 to 3 groups of R13;

R13is: a)1-C10-alkyl, substituted 0-3 halogen, b) -(CH2)n-O-C1-C5-alkyl, substituted 0-3 hydroxy or halogen, (C) halogen, or (d) -CN;

R14represents: (a) -(CH2)n-aryl, (b) (C1-C6-alkyl, or OE ring, containing from 1 to 4 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, C3-C8-cycloalkyl or another heterocycle, and substituted 0-3 groups R13;

m and n = 0-5 independently;

p = 1-5;

g = 1-5.

20. Connection on p. 19, in which R1-CH(R5)- R4; R2is hydrogen; R3is: a)3-C8-alkyl, b) R4-(CH2)m-CH(R6)-, C) R4-(CH2)p-, d) R4-CH= CH -, (e) CH2=CH-(CH2)p-, f) R2-NH-C(O)-CH2-; R4- aryl; R5is: a)2-C5alkyl, (b) (C2-C5alkenyl,) cyclopropyl; R6- C2-C5-alkyl, or R4-C1-C2-alkyl-; aryl is phenyl, substituted by 0 to 3 groups of R8; R8- halogen or C1-C3-alkoxy; R10and R11taken together form a double bond; m = 1-3; p = 1-3.

21. Connection on p. 20, selected from the group consisting of the following:

3-(alpha-active compounds)-4-hydroxy-6-phenyl-2H-Piran-2-he;

6-benzyl-3-(alpha-active compounds)-4-hydroxy-2H-Piran-2-about the ZIL)-2H-Piran-2-he;

6-(p-bromophenetole)-3-(alpha-active compounds-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-6-(o-florfenicol)-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(3-phenylpropyl)-2-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-propyl-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(3-butenyl)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-[[(phenylamino)-carbonyl] methyl] -2H-Piran-2-he;

4 hydroxy-6-phenethyl-3-(alpha-vinylbenzyl)-2H-Piran-2-he;

3-(alpha-active compounds)-6-(alpha-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-1-ethylpropyl-4-hydroxy-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(p-methoxytrityl)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(2-naphthas-2-retil)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(1-ethyl-2-naphthas-2-retil)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(2-naphthas-1-retil)-2H-Piran-2-he;

3-(alpha-active compounds)-4-hydroxy-6-(1-ethyl-2-naphthas-1-yl-ethyl)-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-4-hydroxy-6-(3-phenylpropyl)-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-6-(1-ethylpropyl)-4-hydroxy-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-6-(alpha-benzoylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(alpha-cyclopropylmethyl)-4-hydroxy-6-phenethyl-2H-Piran-2--hydroxy-6-methyl-2H-Piran-2-he

4-hydroxy-6-methyl-3-(3-phenylprop-2-enyl)-2H-Piran-2-it.

22. Connection on p. 19, selected from the group consisting of:

dimethyl 3-[(4-hydroxy-2-oxo-6-phenyl-2H-1-Piran-3-yl)-(4-nitrophenyl)] -1,3-propandiol;

dimethyl 3-[(4-hydroxy-2-oxo-6-phenyl-2H-Piran-3-yl)-(3-nitrophenyl)] -1,3-propandiol;

6-ethyl-3-(alpha-active compounds)-6-phenyl-tetrahydrofuran-2,4-dione;

5,6-dihydro-4-hydroxy-6-cyclohexyl-6-phenyl-3-[1-(3-hydroxyphenyl)propyl]-2H-Piran-2-he;

4-hydroxy-1-oxa-3-(1-phenylpropyl) Spiro[5.5]undec-3-EN-2-she sodium salt;

6,6-diethyl-3(3-phenylpropyl)tetrahydrofuran-2,4-dione;

dihydro-6-methyl-6-phenyl-3-(1-phenyl-2-propenyl)-2H-Piran-2,4(3H)-dione;

dihydro-3-(1-(3-hydroxyphenyl)propyl)-6-phenyl-6-propyl-2H-Piran-2,4(3H)-dione;

5,6-dihydro-4-hydroxy-6-phenyl-6-propyl-3-(1-phenylpropyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6-phenyl-6-propyl-3-[1-(3-hydroxyphenyl)propyl] -2H-Piran-2-he;

12-hydroxy-11-(1-phenylalkyl)-1,4,9-trioxadecyl[4.2.5.2] pentadec-11-EN-10-he;

12-hydroxy-11-(1-phenylpropyl)-1,4,9-trioxadecyl[4.2.5.2] pentadec-11-EN-10-he;

4-hydroxy-3-(1-phenylpropyl)-1-oxaspiro[5.5]undec-3-ene-2,9-dione;

6,6-dibenzyl-4-hydroxy-3-(1-phenylpropyl)-5,6-dihydropyran-2-he;

4-hydroxy-3-(1-phenylalkyl)-1,9-dioxaspiro[5,5]undec-3-EN-2-he;-2-oxo-5,6-dihydro-2H-Piran-3-yl/methyl/phenyl/-3-(tert-butyloxycarbonyl)propionamide;

N-(3-{ cyclopropyl[6-(2-cyclopropyl-1-cyclopropylmethyl)-4-hydroxy-2-oxo-5,6-dihydro-2H-Piran-3-yl]methyl}-phenyl)-3-indol-1-ylpropionic;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-tetrahydrofuran-3-ylmethyl)propyl)Piran-2-he;

6-(1-(5-chlorothiophene-2-ylmethyl)propyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-6-(1-(3,5-dimethylisoxazol-4-ylmethyl)propyl-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-tetrahydrofuran-2-ylmethyl)propyl)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-thiophene-2-iletileri)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-tetrahydropyran-4-ylmethyl)propyl)Piran-2-he;

3-(cyclopropylmethyl)-6-(1-furan-2-iletileri)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-6-(1-(1,3)dioxolane-2-iletileri)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-tetrahydropyran-3-ylmethyl)propyl)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-tetrahydropyran-2-ylmethyl)propyl)Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(1-pyridin-2-iletileri)Piran-2-he;

6-(4-chloro-1-ethylbutyl)-3-(cyclopropylmethyl-)-4-hydroxyfuran-2-he;

6-(3-chloro-1-ethylpropyl)-3-(cyclopropylmethyl)-4-Ki is

3-(cyclopropylmethyl)-4-hydroxy-6-(1-pyridine-3-iletileri)Piran-2-he;

3-(cyclopropylmethyl)-6-(1-ethyl-3-thiophene-3-ylpropyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-[1-(tetrahydropyran-3-ylmethyl)butyl]Piran-2-he;

5-bromo-6-(2-cyclopropanecarbonyl-ethyl)-4-hydroxy-3-(1-phenylpropyl)Piran-2-he;

3-(1-benzyl-2-phenylethyl)-6-(2-cyclopropyl-1-cyclopropylmethyl)-4-hydroxyfuran-2-he;

6-(2-cyclopropylethyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

6-(1-halibut-3-enyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

3-(cyclopropylmethyl)-6-(1-ethyl-3-(2-methoxyethoxy)propyl)-4-hydroxyfuran-2-he;

6-(1-benzyl-3-(2-methoxyethoxy)propyl)-3-(cyclopropylmethyl)-4-hydroxyfuran-2-he;

3-(-cyclopropylmethyl(benzyloxycarbonylamino)benzyl)-6-(-cyclopropyl-meta-(tert-butyloxycarbonyl)benzyl)-6-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-hydroxyphenethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(hydroxy-p-methylphenethyl)-2H-Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-(hydroxy-p-florfenicol)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(hydroxy-p-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-hydroc
3-(-cyclopropylmethyl)-4-hydroxy-6-(2-(furan-3-yl)-2-hydroxyethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(2-(thiophene-3-yl)-2-hydroxyethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-florfenicol)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-o-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-bromophenetole)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-brominated)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-triptoreline)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-triptoreline)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-o-triptoreline)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-p-methoxyphenethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-ethyl-m-methoxyphenethyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(-p-florfenicol)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(p-chlorphenyl)-2H-Piran-2-he;

3-(-cyclopropylmethyl)-4-hydroxy-6-(p-bromophenetole)-2H-Piran-2-he;

3-(cycle-4-hydroxy-2-oxo-, fenilmetilovy ether-2H-Piran-6-propanoic acid;

3-(cyclopropylmethyl)-4-hydroxy-6-[2-methyl-1-[(phenylmethyl)propyl] -2H-Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-[2-methyl-1-[(tetrahydro-2H-Piran-3-yl)methyl]propyl]-2H-Piran-2-he;

4-hydroxy-3-(1-phenylpropyl)-6-[1-[(tetrahydro-2H-Piran-3-yl)methyl] propyl]-2H-Piran-2-he;

3-(cyclopropylmethyl)-6-(1-ethyl-4,4,4-trifloromethyl)-4-hydroxy-2H-Piran-2-he;

3-[2-[3-cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl]-1-[(4-were)sulfonyl]piperidine;

2-[2-[3-cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl]-1-[(4-were)sulfonyl]pyrrolidin;

3-(cyclopropylmethyl)-4-hydroxy-6-(3,3,3-cryptochromes)-2H-Piran-2-he;

2-[2-[3-cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl/butyl/-1-/(4-were)sulfonyl/piperidine;

4-[2-[3-cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl]-1-[(4-were)sulfonyl]piperidine;

4-[2-[3-cyclopropylmethyl)-4-hydroxy-2-oxo-2H-Piran-6-yl] butyl]-1-(phenylmethyl)-2-pyrrolidinone;

6-(zielorientierte)-3-(cyclopropylmethyl)-4-hydroxy-2H-Piran-2-he;

3-(cyclopropylmethyl)-4-hydroxy-6-[(tetrahydro-2H-Piran-4-yl)methyl] -2H-Piran-2-he;

3-(cyclopropylmethyl)-6-(3-fluoro the active compounds)-6-(-active compounds)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(phenylcarbonylamino)benzyl)-6-(-cyclopropyl-meta(propylsulfonyl)benzyl)-6-(-cyclopropyl-meta((E-2-phenylacetylamino)-benzyl)-6-(-cyclopropyl-meta(4-bromophenylacetonitrile)benzyl-6-(-cyclopropyl-meta-(2,5-dichlorophenylamino)benzyl)-6-(-cyclopropyl-meta-(4-tert-butylphenylphosphine)benzyl)-6-(-cyclopropyl-meta(4-sanofisynthelabo)benzyl)-6-(cyclopropyl-meta(4-methoxyphenylacetylene)benzyl)-6-(-cyclopropyl-[5-methoxyethoxymethyl)thiophene-2-yl] -methyl)-5,6-dihydro-4-hydroxy-5-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-3-(1-phenyl-2-propenyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-3-(1-phenylpropyl)-2H-Piran-2-he;

5,6-dihydro-3-diphenylmethyl-4-hydroxy-6,6-di(2-phenylethyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6,6-di-(2-phenylethyl)-3-(1,3-diphenyl-2-propenyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-6,6-di-(2-phenylethyl)-3-(1,3-diphenylpropyl)-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-3-(1,3-diphenyl-2-propenyl)-6-(3-phenylpropyl)-6-propyl-2H-Piran-2-he;

5,6-dihydro-4-hydroxy-3-(1,3-diphenylpropyl)-6-(3-phenylpropyl)-6-propyl-2H-Piran-3-one;

3-(-cyclopropyl-[5-(methoxyethoxymethyl)thiophene-2-yl] -methyl)-5,6-methyl)-5,6-dihydro-4-hydroxy-6-(3-phenylpropyl)-6-propyl-2H-Piran-2-he;

5,6-dihydro-3-diphenylmethyl-4-hydroxy-6-(3-phenylpropyl)-6-propyl-2H-Piran-2-he;

3-diphenylmethyl-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-he;

3-(1,3-diphenyl-2-propenyl)-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-he;

3-(1,3-diphenyl-2-propyl)-5,6-dihydro-4-hydroxy-6-(2-methylpropyl)-6-(2-phenylethyl)-2H-Piran-2-he;

3-(-cyclopropyl-meta-[(phenylenecarbonyl)amino]benzyl)-6-(-cyclopropyl-meta-[(4-methoxyphenylacetyl)-amino] benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-[(benzylaminocarbonyl)amino]benzyl)-6-(-cyclopropyl-meta-[(4-brompheniramineodeine)amino] benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-[(vinylsulfonylacetamido)amino] benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-(N-tert-butyloxycarbonyl-N-p-toluensulfonyl-L-histidine)benzyl)-6-(-cyclopropyl-meta-(tert-butyloxycarbonyl-L-alaninemia)benzyl)-6-(-cyclopropyl-meta(4-brompheniramine)benzyl)-6-(-cyclopropyl-meta-(N-tert-butyloxycarbonyl-L-histidine)benzyl)-6-(-cyclopropyl-meta-(N-benzyloxycarbonyl-O--ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(4-cyanobenzylidene-benzyl)-6-(-CEC is a-(2-pyridylamino)-benzyl)-6-(-cyclopropylmethyl)-6-/1-cyclopropylmethyl-2-(tetrahydropyran-3-yl)ethyl/-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta-(3-pyridylamino)benzyl)-6-(-cyclopropyl-meta(4-pyridylamino)benzyl)-6-(-cyclopropyl-meta(4-chlorophenylsulfonyl)benzyl)-6-(-cyclopropyl-meta-(8-chinaincorporated)benzyl-6-(-cyclopropyl-meta(ethylsulfonyl)benzyl-6-/1-cyclopropylmethyl-2-(tetrahydropyran-3-yl)ethyl/-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(4-methylphenylsulfonyl)benzyl-6-(-cyclopropyl-meta(4-methylphenylsulfonyl)benzyl-6-[1-cyclopropylmethyl-2-(tetrahydrofuran-3-yl)ethyl]-4-hydroxy-2H-Piran-2-he;

3-(-cyclopropyl-meta(ethylsulfonyl)benzyl-6-(-active compounds)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

(3S,6S)-3-(-active compounds)-6-(ethylphenyl)-4-hydroxy-2H-Piran-2-he;

sodium(3S,6R)-3-(-active compounds)-6-(-ethylphenyl)-2H-Piran-2-4-oxide;

(3R,6R)-3-(-active compounds)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he

(3R,6S)-3-(-active compounds)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-it.

23. The pharmaceutical composition exhibiting inhibitory activity against HIV-protease, comprising a pharmaceutically acceptable carrier and an effective amount of the compounds of formula I under item 1.

24. Connection on p. 5, selected from the group consisting of the following:

(3S,6R)3-(-active compounds)-6-(-ethylphenyl)benzyl)-6-(-ethylphenyl)-2H-Piran-2-4-oxide;

(3R,6R)3-(-active compounds)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

(3R,6S)3-(-active compounds)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-it.

25. Connection on p. 1, selected from the group consisting of the following:

(3S,6R)3-(-ethyl-4-hydroxybenzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R)3-(-active compounds)-6-(-ethyl-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R)3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R,6R)3-(-active compounds)-6-(-ethyl-hydroxyphenethyl-4-hydroxy-2H-Piran-2-he;

(3S,6R,6S)3-(-active compounds)-6-(-ethyl-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R,6R)3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R,6S)3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R,6R)3-(-active compounds)-6-(-ethyl-hydroxy-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R,6S)-3-(-active compounds)-6-(-ethyl-hydroxy-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R,6R)3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-hydroxy-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6R,6S) 3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-hydroxy-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

(3S, 6R) 3-(-(1[R] -hydroxyethyl)benzyl)-6-(ethylphenyl)-4-hydroxy-2H-Piran-2-he;

(3S, 6R) 3-(-(1[R] -hydroxyoxy-2H-Piran-2-he;

(3S, 6S) 3-(-active compounds)-6-(-(1[S]-hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6S) 3-(-(1-[R]-hydroxyethyl)benzyl)-6-(-(1[R]-hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-he;

(3S, 6R) 3-(-(1-[S] ethyl)benzyl)-6-(-(1[S] -hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-he;

(3S,6S) 3-(-(1-[R]-hydroxyethyl)benzyl)-6-(-(1[S]-hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-he;

(3S, 6S) 3-((1-[S] ethyl)benzyl)-6-(-(-(1[R]-hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-he;

(3S, 6R) 3-(-(2-hydroxyethyl)benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

(3S, 6R) 3-(-active compounds)-6-(-(2-hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-he;

(3S, 6R) 3-(-(2-hydroxyethyl)benzyl)-6-((2-hydroxyethylene)-4-hydroxy-2H-Piran-2-he;

3-(-ethyl-4-hydroxybenzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-active compounds)-6-(-ethyl-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

3-(-active compounds)-6-(-ethyl-hydroxy-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

3-(-ethyl-4-hydroxybenzyl)-6-(-ethyl-hydroxy-4-hydroxyphenethyl)-4-hydroxy-2H-Piran-2-he;

3-(-(1-hydroxyethyl)benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-active compounds-6-(-(1-GII-2H-Piran-2-he;

3-(-(2-hydroxyethyl)benzyl)-6-(-ethylphenyl)-4-hydroxy-2H-Piran-2-he;

3-(-active compounds-6-(2-hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-he

3-(-(2-hydroxyethyl)benzyl)-6-(-(2-hydroxyethyl)phenethyl)-4-hydroxy-2H-Piran-2-it.

Priority points:

13.11.92 under item 1, where R1- (CH2)nCH(R5)(CH2)m-R4, R2-H; PP.2 - 22, 24 - 25, where the values of R1and R2specified above;

13.07.93 under item 1, where R1- (CH2)n(CH(R5)(CH2)mR4; R2- halogen, C1-C6-alkyl [O-(CH2)2)]q-(CH2)n; PP.2 - 22, 25 - 25, where the values of the radicals specified above;

01.10.93 under item 1, where R1- other values, PP.2 - 22, 24 and 25, where R1- other values.

 

Same patents:

The invention relates to a new catalytic method for obtaining optically active compounds of General formula (I),

< / BR>
where R1and R2denote alkyl, which can be broken by oxygen atom in a different position thanor- position, or optionally substituted benzyl;

R3denotes hydrogen, lower alkyl, optionally substituted benzyl, -CO R4, -COOR4or-CONR24;

R4denotes lower alkyl or aryl,

asymmetric hydrogenation of compounds of formula (II)

< / BR>
where R1, R2, R3have the above values,

asimetricna hydronaut in the presence of a complex of optically active, preferably atropoisomeric of lifestyleand with the metal of group VIII

The invention relates to medicine, more specifically to a method of normalizing the physiological state by drug therapy and physiotherapy, and can be used for the prevention and treatment of a wide range of diseases

The invention relates to the field of macrolides

FIELD: medicine, cosmetology.

SUBSTANCE: one should apply acid composition onto patient's skin scar, moreover, this composition consists of the following ratio of components, weight%: alpha-hydroacid 0.1-70; gamma-lactone of 2,3-dehydro-L-gulonic acid 0.1-10; 1,2,3-propanetriol 1-10; strontium nitrate 0.5-10, water - the rest. Moreover, for steady penetration of this composition for desired depth against scars and surrounding skin one should treat them with alcoholic solution of beta-hydroxyacid for 3-7 d, and for improved regeneration one should lubricate it with an ointment supplemented with hydroxyacid for 7 d.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.

EFFECT: valuable medicinal properties of compounds.

21 cl, 1 dwg, 1 tbl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises a medicine orlistat and sucrose fatty acid ester wherein fatty acid moiety in fatty acid di-, tri- or tetra-ester means a mixture of two or some fatty acids. Also, invention relates to a method for treatment of obesity by using the claimed composition. Invention provides enhancing effectiveness of treatment.

EFFECT: enhanced and valuable properties of composition.

36 cl, 5 dwg, 7 tbl, 19 ex

FIELD: pharmacy, chemical technology.

SUBSTANCE: invention relates to methods for preparing simvastatin of high purity degree from lovastatin by the following stages: (a) opening lactone ring in addition of lovastatin in reaction with amine for formation of amide; (b) protection of 1,3-diol moiety by a protecting group; (c) removal of 2-methylbutyryl group joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining of 2,2-dimethylbutyrate group by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and lactone ring closure resulting to formation of simvastatin. Semi-synthetic statin is prepared from statin by carrying out the following steps: (a) opening lactone ring by reaction of statin with amine resulting to formation of amide; (b) protection of 1,3-diol moiety by using the protecting group; (c) removal of group R1 joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining group R2 by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and (g) lactone ring closure with formation of semi-synthetic statin. Invention provides enhancing purity degree of the product.

EFFECT: improved preparing methods of statins.

17 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of discodermolid and its analogs of the formula (V): At the first step method involves the coupling reaction of ketone compound of the formula (I): with aldehyde compound of the formula (II): in the presence of dialkylboron halide or triphlate, amine base and polar organic solvent to yield β-hydroxyketone of the formula (III): at the second step method involves reduction of ketone compound synthesized at the first step by its treatment with boron hydride reagent in polar organic solvent medium and proton solvent to yield 1,3-diol of the formula (IV): at the third step method involves lactonization and removal of free acid-labile hydroxyl protective group of 1,3-diol synthesized at the second step by its treatment with hydrogen halide dissolved in polar solvent or mixture of solvents to yield the end compound of the formula (V) wherein R1 means (C1-C6)-alkyl; R2 means (C1-C6)-alkyl; R3 means hydrogen atom or acid-labile hydroxyl protective group; R3'' means acid-labile hydroxyl protective group; R4 means hydrogen atom or methyl group; X means oxygen atom (O) under condition that when X means O and R3 means acid-labile hydroxyl protective group of compound of the formula (I) then residue -X-R3 in compound of the formula (V) represents hydroxyl group (-OH). Also, invention relates to novel intermediate compounds of formulae (I), (III) and (IV) and to a method for synthesis of compound of the formula (I). Invention provides a new method for synthesis of the valuable compound discodermolid and its analogs with the satisfied yields.

EFFECT: improved method of synthesis.

16 cl, 4 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: pharmacology, in particular composition and methods for obesity treatment.

SUBSTANCE: claimed composition contains lipase inhibitor, namely orlistat and koniac or glucomannan and pharmaceutically acceptable excipients.

EFFECT: composition preventing gastrointestinal disturbances associated with administration of lipase inhibitor orlistat.

35 cl, 10 ex, 3 dwg

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the general formula (I) wherein R1 and R2 mean independently of on another hydrogen atom (H) or fluorine atom (F); R3 means -CH3 or -CF3 ; Ar means structural formulae (a) or (b) Invention relates also to a pharmaceutical composition possessing the modulating activity with respect to progesterone receptor and containing compound of the formula (I), adjuvants, carriers and excipents. Compounds of the formula (I) are used in preparing a medicinal agent designated for selective modulation of processes in organ-targets mediated by progesterone receptor, such as uterus/breast and for selective activation of transcription of progesterone receptor isoform A as compared with transcription of progesterone receptor isoform B, selective enhancing processes mediated by progesterone receptor isoform A as compared with processes mediated by progesterone receptor isoform B and as a contraceptive. Invention provides a compound using as a medicinal agent in hormone-substitution therapy and for control of reproductive function.

EFFECT: valuable medicinal and biological properties of compound and pharmaceutical composition.

45 cl, 4 dwg, 5 tbl, 6 ex

FIELD: medicine, experimental cardiology.

SUBSTANCE: the present innovation deals with restricting the necrosis area in the course of experimental coronary occlusion myocardial infarction due to intragastric introduction of roxytromycin at the dosage of 30 mg/kg 15 min before coronary occlusion. The innovation provides significant decrease of the necrosis area due to cardioprotector action of roxytromycin.

EFFECT: higher efficiency.

1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydropyran-2-one of formula

, where R1 is selected from hydrogen, ORa, OCORa, OCOORa, NRaRb, NRaCORb and NRaC(NRa)NRaRb; each R2 and R3 are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl; each R41, R42, R43, R44, R45, R46, R47 and R48 are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl; each R5, R6 and R7 are optionally selected from hydrogen, CORa, COORa, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl, or R5 and R48 together with coupled atom N and atom C whereto attached can form substituted or unsubstituted heterocyclic group; each Ra and Rb are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and each dashed line means an optional additional bond; to its pharmaceutically acceptable salts, tautomers or stereoisomers.

EFFECT: development of the method for preparing an anticancer composition, and the method of treating cancer.

46 cl, 10 tbl, 12 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to compounds of general formula I, having cytostatic or cytotoxic activity, its pharmaceutically acceptable salts, tautomers or stereoisomers, a pharmaceutical composition on their basis. Compounds may be used for treatment of cancerous diseases. In the general formula I

Y is selected from the group comprising -CHRay- and -CHRay-CRby-CRcy-; each Ray, Rby and Rcy are independently selected from hydrogen and non-substitute C1-C12-alkyl; each R1, R2, R3, R4 and R5 are independently selected from hydrogen and non-substitute C1-C12-alkyl; R6 is selected from NR8R9 and OR10; A means , W means NR7; R7 means hydrogen; R8 means hydrogen; R10 means non-substitute C2-C12-alkenyl; each dotted line means unnecessary additional link, but when there is a triple link between atoms of carbon, to which R1 and R2 are attached, then R1 and R2 are absent, and when there is a triple link between carbon atoms, to which R3 and R4 are attached, then R3 and R4 are absent; R9 is selected from substitute C2-C12-alkenyl and substitute C4-C|2-alkenylyl, where substitutes are selected from the group, consisting of: halogen, OR', OCONHR' and OH, protected with a simple silyl ether; where R' means hydrogen; provided that whenever Y means -CHRay-CRby=CRcy- and there is a single or double link between atoms of carbon, to which R3 and R4 are attached, then R9 means substitute C4-C12-alkenylyl; and each R16, R17 and R18 are independently selected from hydrogen and ORa; each Ra is selected from hydrogen or non-substitute C1-C12-alkyl.

EFFECT: higher efficiency of compound application.

FIELD: biochemistry.

SUBSTANCE: group of inventions relates to biochemistry. Disclosed is a method of detecting luciferase in biological samples using 3-hydroxy hispidin or 3-hydroxy bisnoriangonin as luciferin. Proposed compound for implementing said method represents a 3-hydroxy hispidin. Besides, disclosed is a method of detecting luciferase in the presence of hispidin-3-hydroxylase in biological samples using hispidin or bisnoriangonin as luciferin precursor and NADP. Also disclosed is a reagents kit for implementing said method, including hispidin or bisnoriangonin and NADP.

EFFECT: group of inventions enables detecting luciferase fungi in biological samples and can be used in a wide spectrum of the bioluminescent analyses in vivo and in vitro.

4 cl, 19 dwg, 1 tbl, 5 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

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