A method of producing an inhibitor of 5-lipoxygenase with different heterocyclic systems

 

(57) Abstract:

Described is a method of obtaining the compounds of formula (1.3.0), where

is a group selected from the formulas(1.3.2), (1.3.3), (1.3.4) or (1.3.5), including the formation of a reaction mixture consisting of carboxamide of formula (2.0.0) and the corresponding bicyclic N-heterocycle in an aprotic solvent in the presence of a strong base in solid form selected from the group including sodium hydroxide and potassium hydroxide, and optionally in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, followed by heating the specified reaction mixture in a nitrogen atmosphere, resulting in the target connection. Also disclosed is a method of obtaining one of the specific compounds and the method for mesilate salt compounds. The invention is an improved way of getting known and new inhibitors of 5-lipoxygenase, useful in the treatment of inflammatory diseases and allergies. 4 C. and 4 h.p. f-crystals, 3 PL.

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THE LINK TO WHICH IS IN THE PROCESS OF SIMULTANEOUS CONSIDERATION OF THE APPLICATION

References are in the process of simultaneous consideration is being allocated from the application with registration number 09/020014, submitted February 6, 1998 (the number in the registry attorney PC8708B), now U.S. patent N 5883106, which is a continuation of application serial number 08/809901, filed may 29, 1995 (the number in the registry attorney PC8708A), currently withdrawn; required priority application serial number PCT/JP94/01747, filed October 18, 1994 (the number in the registry attorney PC8708), currently withdrawn; and paragraph 371 of application serial number PCT/IB95/00408, filed may 29, 1995 (with the number in the registry attorney PC8708A), now terminated, and published as WO 96/11911 April 25, 1996, which describes inhibitors of 5-lipoxygenase, used in the treatment of inflammatory diseases and allergies. They describe some of the ways of obtaining inhibitors of 5-lipoxygenase, but nothing that describes would not allow the ordinary person skilled in the art to suggest an improved method according to this invention.

Reference is also made under simultaneous consideration of the application with registration number 60/113221, filed December 22, 1998 (the number in the registry attorney PC10097), which describes a new method of obtaining methylsulfonate amide 4-{3-[4-(2-Mei-1U present invention.

Further references are in the process of simultaneous consideration of the application filed simultaneously with this application, with numbers registry attorney PC10530 and PC10683, which also include methods of obtaining inhibitors of 5-lipoxygenase with different heterocyclic cyclic system, and which have some elements of the methods that are common with the method of this invention.

In WO 96/11911 describes a class of new compounds active as inhibitors of the enzyme 5-lipoxygenase, which is characterized by the following structural formula (1.1.0)

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where Ar1denotes a heterocyclic portion of the molecule, selected from the group comprising imidazolyl; pyrrolyl; pyrazolyl; 1,2,3-triazole; 1,2,4-triazolyl; indolyl; indazoles and benzimidazolyl; associated with X1through the nitrogen atom of the ring and is substituted by 0-2 substituents selected from the group comprising halogen; hydroxy; cyano; amino; (C1-C4) alkyl, (C1-C4) alkoxy; a (C1-C4) alkylthio; (C1-C4) halogen-substituted alkyl, (C1-C4) halogen-substituted alkoxy; a (C1-C4) alkylamino and di(C1-C4) alkylamino;

X1denotes a direct tie the C group, including halogen; hydroxy; cyano; amino; (C1-C4) alkyl, (C1-C4) alkoxy; a (C1-C4) alkylthio; (C1-C4) halogen-substituted alkyl (C1-C4) halogen-substituted alkoxy;

X2denotes-A-X - or-X-A-, where A denotes a direct bond or (C1-C4) alkylene and X is hydroxy; thio; sulfinil or sulfonyl;

Ar3denotes a radical selected from the group comprising phenylene; peridinin; Tianjin; fullen; oxazoline and thiazoline; substituted by 0-2 substituents selected from halogen; hydroxy; cyano; amino; (C1-C4) alkyl, (C1-C4) alkoxy; a (C1-C4) alkylthio; (C1-C4) of halogensubstituted alkyl, (C1-C4) halogen-substituted alkoxy; a (C1-C4) alkylamino and di(C1-C4) alkylamino;

R1and R2denote each (C1-C4) alkyl; or together they form a group of formula: -D1-Z-D2- which together with the carbon atom to which it is attached, forms a cyclic structure with 3-8 carbon atoms, where D1and D2represent a (C1-C4) alkylene and Z denotes a direct bond or hydroxy; thio; sulfonyl; or vinile; and D3)=N-OR4; COOR3; COR3or CSNR3R4; where R3and R4each represent H or (C1-C4) alkyl.

With regard to the above compounds, the preferred value for (C1-C4) of halogensubstituted alkyl is trifluoromethyl and the preferred value for (C1-C4) halogen-substituted alkoxy is triptoreline. A preferred group of the above compounds consists of compounds in which Ar2represents 1,4-phenylene and Ar3represents a 1,3-phenylene or 5-fluoro-1,3-phenylene. In this preferred group of more preferred compounds are compounds in which Ar1is a 2-alkylimidazole; X1represents a direct bond and Y is CONH2; and compounds in which Ar1represents pyrrolyl; X1represents CH2and Y is CONH2.

Particularly preferred variant of the above class of inhibitory compounds is a compound of formula (1.0.0)

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Compounds that inhibit the action of the enzyme lipoxygenase, can be used in the treatment or alleviation of inflammation is armenta lipoxygenase appears as part of arachidonic acid metabolism. Arachidonic acid is the biological precursor of several groups of biologically active endogenous metabolites. Arachidonic acid is first released from the phospholipids of the membranes under the action of phospholipase A2. Then arachidonic acid is metabolized (i) cyclooxygenase with the formation of prostaglandins, including prostacyclin, and thromboxanes; or (ii) lipoxygenases education hydroperoxide acids, which can then be converted into leukotrienes.

Leukotrienes, in turn, are extremely potent and induce a large variety of biological effects, for example, peptidoglycan, LTC4, LTD4and LTE4are important bronchoconstrictors and vasoconstrictors and cause the radiolabeled plasma by increasing capillary permeability. LTB4is a powerful chemotactic agent that enhances infiltration and degranulation of leukocytes at the site of inflammation. I believe that leukotrienes are involved in several pathological States, including asthma, chronic obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, atopic dermatitis, respirati Crown. A tool that actively inhibits lipoxygenase and consequently the production of leukotrienes, will have a significant therapeutic value in the treatment of acute and chronic inflammatory conditions. Cm. Masamune and Melvin, Annual Reports in Medicinal Chemistry 24, 71-80 (1989). Specific lipoxygenase inhibitors have been described in EP 0462830; EP 0505122 and EP 0540165.

A few ways to get lipoxygenase inhibitors described in the aforementioned published application WO 96/39408 here. An example of such a method of obtaining is joining the compounds of formula (1.2.0) and the compounds of formula (1.2.1), which may be represented by the following reaction scheme

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where X1represents thio and Q denotes a substituted group, in the presence of thiourea and a suitable catalyst, for example tetrakis(triphenylphosphine) palladium. References Chem. Lett., 1379-1380 (1986). Indicates that suitable substituted groups Q include halogen or sulfonyloxy.

This invention relates to the field of methods used for synthetic obtain compounds of the type formula (1.0.0), some of which are known compounds, some are new compounds and necatorine, known to date in this area. However, all these compounds have biological activity as inhibitors of 5-lipoxygenase.

As noted above, this area is known that compounds of the type represented in formula (1.0.0) may be obtained by the method in which initially use catalyzed by palladium nucleophilic substitution of aryl halides tooltime anions or by thiols. As in the reaction of Williamson, which is the best General way to obtain asymmetrical and symmetrical ethers, outputs improved by using phase transfer catalysis. In relation to the detailed actions when using phase transfer catalysis in obtaining serosoderjaschei compounds, see, for example, Weber; Gokel, Phase Transfer Catalysis in Organic Synthesis, Springer; New York, 221-233 (1977). Further details regarding the initial stage of the method of the present invention, can be found in Migita et al., Bull. Chem. Soc. Japan 52, 1385-1389 (1980). The specified initial stage can be represented by the following reaction scheme:

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where X is I or Br, and R represents phenyl or (C1-C4) alkyl.

In the literature there are a number of descriptions related to catalyzed by palladium synthesis is ladies, in particular, Pd(PPh3)4the reactions of bifunctional aromatic compounds with terminal alkynes and carbon monoxide, requiring catalysts containing palladium (0) and palladium (II).

Arcadi et al. , Tetrahedron Lett. 34, 2813 (1993) describe the synthesis of 2,3,5-triple-substituted furans from aryl halides and 2-propargyl-1,3-dicarbonyl-compounds in the presence of tetrakis(triphenylphosphine) palladium (0) and K2CO3. The authors observe that the nature of the Foundation strongly affects the course of the reaction.

In McClure and Danishefsky, L. Am. Chem. Soc. 115, 6094-6100 (1993) described the synthesis of compounds of type 1,5-epoxybutene with 90% yield using catalytic tetrakis(triphenylphosphine) palladium (0) in acetonitrile containing triethylamine.

In Nuss et al., J. Am. Chem. Soc. 115, 6991-6992 (1993) described the synthesis of analogues of chromophore neocarzinostatin using catalytic tetrakis(triphenylphosphine) palladium (0) in THF and reagents of alkenylsilanes.

In Paquette and Astles, J. Org. Chem. 58, 165 to 169 (1993) described the synthesis of furanocoumarins with the lengthening of the side chain, mediarray catalyzed by palladium (0) coupling with vinylstyrene held in heated at boiling temperature under reflux benzene or dimethoxyethane. The authors of the solvent chloroform.

The technical literature also contains a number of descriptions relating to the use of other transition metals group, in addition to palladium to catalyze reactions. See, for example, Takagi, Chemistry Letters, 2221-2224 (1987), which describes the use of complexes of Nickel (0) and palladium (0) as catalysts in the synthesis of varisolve from aryl halides and aromatic thiols.

However, none of these references describes not and does not imply any specific methods of obtaining this invention, which are both easy and effective, giving, however, acceptable outputs not achieved before.

This invention relates to methods of producing, in which a number of end products of these methods are known compounds used as inhibitors of 5-lipoxygenase. This invention relates also to a number of other end products of these methods, which were not known until now, because they were not available synthetically before became available the above mentioned methods of the present invention. These new products can also be used as inhibitors of 5-lipoxygenase, as described in more detail later in this description. All of these methods is a Key intermediate product, used in the methods of obtaining this invention is tetrahydro-4-[3-(4-forfinal)thio]phenyl-2H-Piran-4-carboxamide formula (2.0.0)

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Thus, this invention relates also to a method for obtaining compounds of formula (2.0.0), which can be illustrated by the synthesis scheme (10.0.0) (see the end of the description), providing for (a) the formation of a reaction mixture consisting of (1) tetrahydro-4-(3-bromo - or itfinal)-2H-Piran-4-nitrile of formula (3.0.0)

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where X denotes bromine or iodine, and (2) 4-portifino formula (4.0.0)

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(3) in a solvent consisting of aliphatic alcohol with a straight or branched chain, having generally 2 to 7 carbon atoms, optionally in the form of its aqueous mixture; and more preferably, if the alcohol is a secondary alcohol selected from the group comprising isopropyl alcohol, sec-butyl alcohol, isopentylamine alcohol and 2-heptanol, not necessarily in the form of an aqueous mixture of the specified secondary alcohol, (4) in the presence of a strong base of formula (5.0.0)

M-O-R5,

where M denotes an alkali metal, an element of group 1/Ia selected from the group comprising lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and caesium, Cs; and R5denotes hydrogen, H; or (C1-C43; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; ataxic lithium, LiOCH2CH3; ethoxide sodium, NaOCH2CH3; ataxic potassium KOCH2CH3; ataxic rubidium, RbOCH2CH3; ataxic cesium, CsOCH2CH3; tert-piperonyl lithium, LiOC(CH3)3; tert-piperonyl sodium NaOC(CH3)3; tert-piperonyl potassium KOC(CH3)3; tert-piperonyl rubidium RbOC(CH3)3and tert-piperonyl cesium CsOC(CH3)3including mixtures thereof; and, in addition, (5) in the presence of a catalyst which is a metal of transition group, which includes the complex of palladium metal, which preferably is a representative selected from the group including

tetrakis(triphenylphosphine)palladium (0), [(C6H5)3P]4Pd (0);

tetrakis(methyldiphenylphosphine)palladium (0), [(C6H5)2PCH3]4Pd (0);

TRANS-dichlorobis(methyldiphenylphosphine)palladium (II), [(C6H5)2PCH3]2PdCl2; the adduct dichlorobis[Methylenebis(diphenylphosphine)]dipalladium-dichloromethane;

iodination)dipalladium (0) - chloroform, (C6H5CH=CHCOCH=CHC6H5)3Pd2CHCl3;

bis(dibenzylideneacetone)palladium (0), (C6H5CH=CHCOCH=CHC6H5)2Pd;

[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II), complex with dichloromethane;

bis [1,2-bis(diphenylphosphino)ethane]palladium (0) and

dimer (-allyl)palladium (II) chloride; followed by (b) specified by heating the reaction mixture, preferably by boiling under reflux, preferably during the period from 12 to 36 hours, more preferably from 18 to 24 hours; resulting in the above compound of formula (2.0.0), which does not necessarily produce by conventional methods of separation.

The above method of production, in which 4-carboxamidine part of paranavai part of the molecule is formed during the stage of adding tigraphy, is the preferred method of carrying out this part of the method according to this invention. Applicable alternative provides for the formation of 4-carboxamides part of paranavai part of the molecule at the stage of adding tigraphy. The alternative of this part of the method of the present invention includes a method for obtaining compounds of the form is of the reaction mixture, consisting of (1) tetrahydro-4-(3-bromo - or itfinal)-2H-Piran-4-nitrile of formula (3.0.0)

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where X denotes bromine or iodine, (2) in a solvent consisting of aliphatic alcohol, as defined above, optionally in the form of its aqueous mixture; preferably a secondary alcohol, as defined above; more preferably isopropyl alcohol, optionally in the form of an aqueous mixture of the specified secondary alcohol; (3) in the presence of a strong base of formula (5.0.0)

M-O-R5,

where M and R5have the above values; preferably specified by a strong base is sodium hydroxide, NaOH; potassium hydroxide, KOH; ethoxide sodium, NaOCH2CH3or tert-piperonyl potassium, KOC(CH3)3; followed by (b) specified by heating the reaction mixture preferably by boiling under reflux, preferably for a period of from 3 to 8 hours, more preferably from 5 to 6 hours; resulting in the above compound of formula (3.1.0)

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where X denotes bromine or iodine; and then (c) the formation of a reaction mixture consisting of the compounds of formula (3.1.0) and 4-portifino formula (4.0.0)

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(1) in a solvent consisting of an alcohol, as described above, Italino isopropyl alcohol, not necessarily in the form of an aqueous mixture of the specified secondary alcohol; (2) in the presence of a strong base of formula (5.0.0)

M-O-R5,

where M and R5have the above values; preferably specified in a strong base is sodium hydroxide, NaOH; potassium hydroxide, KOH; ethoxide sodium, NaOCH2CH3or tert-piperonyl potassium, KOC(CH3)3; and, in addition, (3) in the presence of a catalyst which is a metal of transition group, which includes the complex of palladium metal, which is preferably selected from the group including

tetrakis(triphenylphosphine)palladium (0), [(C6H5)3P]4Pd (0);

tetrakis(methyldiphenylphosphine)palladium (0), [(C6H5)2PCH3]4Pd (0);

TRANS-dichlorobis(methyldiphenylphosphine)palladium (II), [(C6H5)2PCH3]2PdCl2; the adduct dichlorobis[Methylenebis(diphenylphosphine)]dipalladium-dichloromethane;

dichlorobis(triphenylphosphine)palladium (II), [(C6H5)3P]2PdCl2;

adduct of Tris(dibenzylideneacetone)dipalladium (0) - chloroform (C6H5CH=CHCOCH=CHC6H5)3Pd2CHCl3;

bis(dibenzylideneacetone)palladium (0), (C6H5CH=CHCO the ohms;

bis [1,2-bis(diphenylphosphino)ethane]palladium (0) and

dimer (-allyl) palladium (II) chloride; and then (d) specified by heating the reaction mixture preferably by boiling under reflux, preferably for a period of 5 to 15 hours, more preferably from 8 to 10 hours; resulting in the above compound of formula (2.0.0).

Further, this invention relates to a method for obtaining compounds of formula (1.3.0)

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which can be illustrated by the synthesis scheme (10.2.0) (see the end of the description), where part of the molecule of the following formula (1.3.1)

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is electrondeficient monocyclic or benzododecinium bicyclic N-heterocyclic group containing two nitrogen atom, of formula(1.3.2), (1.3.3), (1.3.4) or (1.3.5)

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where * is the symbol that represents the attachment point of the molecule of the formula(1.3.2), (1.3.3), (1.3.4) or (1.3.5);

R7and R8independently selected from the group comprising H; (C1-C4) alkyl straight or branched chain, and (C6-C10) aryl; where the groups of the aryl and alkyl substituted by 0-2 substituents selected from the group comprising halogen; hydroxy; cyano; amino; (C1-C4) alkyl, (C1halogen-substituted alkoxy; (C1-C4) alkylamino and di(C1-C4) alkylamino; including (a) the formation of a reaction mixture consisting of (1) tetrahydro-4-[3-(4-forfinal)thio]phenyl-2H-Piran-4-carboxamide of formula (2.0.0)

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and (2) electrodepositing monocyclic or benzododecinium bicyclic N-heterocycle containing two nitrogen atom, of formula(1.3.6), (1.3.7), (1.3.8) or (1.3.9)

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where R7and R8have the above values;

(3) in an aprotic solvent, preferably dimethyl sulfoxide (DMSO);

(4) in the presence of a strong base in solid form selected from the group comprising sodium hydroxide, NaOH, potassium hydroxide, KOH; and (optional) (5) in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, preferably selected from the group comprising cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (-)-N-dodecyl-N-methylephedrine (DMCOH); hexamethylene phosphoric acid (HMPT); cetylpyridinium (NCPB); N-benzylpenicillin (QUIBEC); Tetra-n-butylammonium (TBAB); Tetra-n-butylammonium (TBAC); Tetra-n-butylammonium (TBAH); Tetra-n-butylmethylamine (TBBAB); hexadecyltrimethylammonium (TBHDPB); benzyltriethylammonium (TEBAB); benzyltriethylammonium (TEBA); hexadecyltrimethylammonium (TEHDAC); Tetramethylammonium (TMAC); hexadecyltrimethylammonium (TMHDAC) and octyltrichlorosilane (TMOAC) and more preferably salts of Quaternary ammonium or phosphonium salts of containing representative of the above groups; followed by (b) specified by heating the reaction mixture, preferably by boiling under reflux in a nitrogen atmosphere; the resulting compound of formula (1.3.0).

Further, this invention relates to the above method of obtaining the compounds of formula (1.3.0), in which the indicated compound of formula (1.3.0.) selected from the group including:

tetrahydro-4-{ 3-[4-(2-methyl-1H-imidazol-1-yl)phenyl] thio} phenyl-2H - Piran-4-carboxamide;

tetrahydro-4-{ 3-[4-(1H-imidazol-1-yl)phenyl)thio} phenyl-2H-Piran-4 - carboxamide;

tetrahydro-4-{ 3-[4-(1H-benzoimidazol-1-yl)phenyl)thio}phenyl-2H - Piran-4-carboxamide;

tetrahydro-4-{ 3-[4-(1H-pyrazole-1-yl)phenyl] thio} phenyl-2H - Piran-4-carboxamide and

tetrahydro-4-{ 3-[4-(4-methyl-1H-pyrazole-1-yl)phenyl)thio} - phenyl-2H-Piran-4-carboxamide.

The above final products were not Oswego invention. These new products can also be used as inhibitors of 5-lipoxygenase and selected from the group including:

tetrahydro-4-{ 3-[4-(1H-imidazol-1-yl)phenyl] thio} phenyl-2H-Piran-4 - carboxamide;

tetrahydro-4-{ 3-[4-(1H-benzoimidazol-1-yl)phenyl]thio}phenyl-2H - Piran-4-carboxamide;

tetrahydro-4-{ 3-[4-(1H-pyrazole-1-yl)phenyl] thio} phenyl-2H-Piran-4 - carboxamide and

tetrahydro-4-{ 3-[4-(4-methyl-1H-pyrazole-1-yl)phenyl]thio}phenyl-2H - Piran-4-carboxamide.

This invention relates also to a method for obtaining compounds of formula (1.0.0)

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including (a) the formation of a reaction mixture consisting of

(1) tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide of formula (2.0.0)

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and (2) 2-methylimidazole;

(3) in an aprotic solvent, preferably dimethyl sulfoxide (DMSO);

(4) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH, potassium hydroxide, KOH; and (optional) (5) in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, preferably selected from the group comprising cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-; ethylenedibromide (NCPB); N-benzylpenicillin (QUIBEC); Tetra-n-butylammonium (TBAB); Tetra-n-butylammonium (TBAC); Tetra-n-butylammonium (TBAH); Tetra-n-butylmethacrylate (TBAHS); Tetra-n-butylammonium (TBAI); tetraethylammonium, hydrate (TEAC); tri-n-butylamine (TBA); benzyltrimethylammonium (TBBAB); hexadecyltrimethylammonium (TBHDPB); benzyltriethylammonium (TEBAB); benzyltriethylammonium (TEBA); hexadecyltrimethylammonium (TEHDAC); Tetramethylammonium (TMAC); hexadecyltrimethylammonium (TMHDAC) and octyltrichlorosilane (TMOAC) and more preferably salts of Quaternary ammonium or phosphonium salts of containing the representative of the above groups; followed by (b) specified by heating the reaction mixture, preferably by boiling under reflux, preferably at 115-145oC, more preferably at 125-130oC, in nitrogen atmosphere, preferably for 12 to 30 hours, more preferably for 17-24 hours; resulting in a specified compound of formula (1.3.0).

Further, this invention relates to a method for obtaining essentially pure mesilate salt of formula (1.0.1)

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which may be instantiated with trialsee (1) formation of a reaction mixture, consisting of (i) tetrahydro-4-(3-bromophenyl)-2H-Piran-4-nitrile of the formula (3.2.0)

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and (ii) 4-portifino formula (4.0.0)

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(iii) in a solvent selected from the group consisting of isopropyl alcohol, sec-butyl alcohol, isopentanol alcohol and 2-heptanol, preferably isopropyl alcohol, optionally in the form of the aqueous mixture; (iv) in the presence of a strong base selected from the group consisting of sodium hydroxide, NaOH, potassium hydroxide, KOH; and, in addition, (v) in the presence of a catalyst containing a transition metal of groups, including independently selected from the group consisting of metal complexes of palladium; preferably such a complex of palladium metal is a member selected from the group including

tetrakis(triphenylphosphine) palladium (0), [(C6H5)3P]4Pd (0);

tetrakis(methyldiphenylphosphine)palladium (0), [(C6H5)2PCH3]4Pd (0);

TRANS-dichlorobis(methyldiphenylphosphine) palladium (II), [(C6H5)2PCH3]2PdCl2; the adduct dichlorobis[Methylenebis(diphenylphosphine)]dipalladium-dichloromethane;

dichlorobis(triphenylphosphine)palladium (II), [(C6H5)3P]2PdCl2;

adduct of Tris(dibenzo/BR> bis(dibenzylideneacetone)palladium (0), (C6H5CH=CHCOCH=CHC6H5)2Pd;

[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II), complex with dichloromethane;

bis[1,2-bis(diphenylphosphino)ethane]palladium (II) and

dimer (-allyl)palladium (II) chloride; and then (2) heating this mixture while boiling under reflux at 80-84oduring the period from 18 to 30 hours, preferably 24 hours; resulting in the above compound of formula (2.0.0);

(b) formation of a reaction mixture consisting of the compounds of formula (2.0.0) and the compounds of formula (1.3.10)

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(1) in an aprotic solvent, preferably dimethyl sulfoxide (DMSO);

(2) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH, potassium hydroxide, KOH; and optionally (3) in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, preferably selected from the group comprising cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (-)-N-dodecyl-N-methylephedrine (DMCOH); hexamethylene phosphoric acid (HMPT); pyridinium-n-butylaminoethyl (TBAH); Tetra-n-butylmethacrylate (TBAHS); Tetra-n-butylammonium (TBAI); tetraethylammonium, hydrate (TEAC); tri-n-butylamine (TBA); benzyltrimethylammonium (TBBAB); hexadecyltrimethylammonium (TBHDPB); benzyltriethylammonium (TEBAB); benzyltriethylammonium (TEBA); hexadecyltrimethylammonium (TEHDAC); Tetramethylammonium (TMAC); hexadecyltrimethylammonium (TMHDAC) and octyltrichlorosilane (TMOAC) and more preferably salts of Quaternary ammonium or phosphonium salts of containing the representative of the above groups; and then (c) by heating the reaction mixture at the specified boiling under reflux in a nitrogen atmosphere; resulting in a specified compound of formula (1.0.0)

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then (d) the formation of a concentrated solution in methanol of the compounds of formula (1.0.0), which is then preferably filtered through activated charcoal, then add to the filtrate methansulfonate acid, MeSO3H; followed by an additional concentration and addition of ethyl acetate ad seriatim to the selection of crystalline product containing essentially pure mesilate salt of formula (1.0.1)

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or alternate with the subsequent add methansulfonate acid, MeSO3H; with subsequent filtration of this mixture preferably through activated charcoal, followed by further concentration and adding ethyl acetate ad seriatim to the selection of crystalline product containing essentially pure mesilate salt of formula (1.0.1)

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This invention relates to an improved process for the preparation of known compounds, demonstrated the possibility of their use as inhibitors of 5-lipoxygenase, and, in particular, the compounds of formula (1.0.0)

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Further, this invention relates to the production of other compounds, which were not known up to the present time, as they were synthetically inaccessible before the availability of the improved method of this invention. These new compounds can also be used as inhibitors of 5-lipoxygenase and include, among other compounds, the following compounds of the formula(1.1.1); (1.1.2); (1.1.3) and (1.1.4):

Tetrahydro-4-{ 3-[4-(1H-imidazol-1-yl)phenyl] thio} phenyl-2H-Piran-4 - carboxamid

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Tetrahydro-4-{ 3-[4-(1H-benzoimidazol-1-yl)phenyl]thio}phenyl-2H - Piran-4-carboxamid

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Tetrahydro-4-{ 3-[4-(1H-pyrazole-1-yl)phenyl] thio} phenyl-2H-Piran-4 - carboxamid

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Tetrahydro-4-{ 3-[4-(4-methyl is l (1.1.1)-(1.1.4) and similar compounds of this type it is preferable to use the following method of this invention for obtaining the compounds of formula (1.3.0)

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where part of the molecule of formula (1.3.1)

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is the electron monocyclic benzododecinium bicyclic N-heterocyclic group containing two nitrogen atom, of formula(1.3.2), (1.3.3), (1.3.4) or (1.3.5)

< / BR>
< / BR>
where * denotes the symbol that represents the attachment point of the molecule of the formula(1.3.2), (1.3.3), (1.3.4) or (1.3.5);

R7and R8independently selected from the group comprising H; (C1-C4)

alkyl straight or branched chain, and (C6-C10) aryl; where the groups of the aryl and alkyl substituted by 0-2 substituents selected from the group comprising halogen; hydroxy; cyano; amino; (C1-C4) alkyl, (C1-C4) alkoxy; a (C1-C4) alkylthio; (C1-C4) halogen-substituted alkyl, (C1-C4) halogen-substituted alkoxy; a (C1-C4) alkylamino and di (C1-C4) alkylamino.

The above variant of the method of this invention can be illustrated by the synthesis scheme (10.2.0) (see the end of the description), where the reacting substance of formula (1.4.0)

< / BR>
is the electron monocyclic benzododecinium bicyclic N-heterocycle containing two nitrogen atom, the persons present invention, illustrated in the synthesis scheme (10.2.0), may be conducted by:

(a) form a reaction mixture, consisting of

(1) tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide of formula (2.0.0)

< / BR>
and (2) electron monocyclic or benzododecinium bicyclic N-heterocycle containing two nitrogen atom, of formula(1.3.6), (1.3.7), (1.3.8) or (1.3.9)

< / BR>
< / BR>
where R7and R8have the above values;

(3) in an aprotic solvent, preferably selected from the group comprising mainly hexane; 1,4-dioxane; carbon tetrachloride; benzene; toluene; xylenes; diethyl ether; chloroform; ethyl acetate; tetrahydrofuran (THF), methylene chloride; hexamethylene phosphoric acid (HMPT); nitromethane; N, N-dimethylformamide (DMF); acetonitrile; sulfolane and dimethyl sulfoxide (DMSO); more preferably dimethyl sulfoxide (DMSO);

(4) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH, potassium hydroxide, KOH; and (optional) (5) in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, preferably selected from the group consisting of setitimer minibrain (DMCOH); hexamethylene phosphoric acid (HMPT); cetylpyridinium (NCPB); N-benzylpenicillin (QUIBEC); Tetra-n-butylammonium (TBAB); Tetra-n-butylammonium (TBAC); Tetra-n-butylammonium (TBAH); Tetra-n-butylmethacrylate (TBAHS); Tetra-n-butylammonium (TBAI); tetraethylammonium, hydrate (TEAC); tri-n-butylamine (TBA); benzyltrimethylammonium (TBBAB); hexadecyltrimethylammonium (TBHDPB); benzyltriethylammonium (TEBAB); benzyltriethylammonium (TEBA); hexadecyltrimethylammonium (TEHDAC); Tetramethylammonium (TMAC); hexadecyltrimethylammonium (TMHDAC) and octyltrichlorosilane (TMOAC), and more preferably salts of Quaternary ammonium or phosphonium salts of containing the representative of the above groups; followed by (b) specified by heating the reaction mixture preferably by boiling under reflux in a nitrogen atmosphere; resulting in the above compound of formula (1.3.0).

As it is clear to the average expert in the field of preparation of organic compounds of the type with which deals the invention, the substitution halftoned in the presence of base nitrogen-containing heterocycle with a lack of electrons is relatively the present time as a way which can be used to obtain the types of the considered compounds. Usually strong dilatory electron group, such as nitro, located in the para - or orthopaedie relatively fluorine atom, is required to achieve an acceptable level of substitution of the nitrogen nucleophile in the presence of a base. Such substitution reactions usually give only low yields, often require high temperatures and long reaction periods and result in products that require additional purification. See, for example, Morgan et al. , J. Med. Chem., 33, 1091-1097 (1990), which describes a method of obtaining, in which the methyl or ethyl ester of 4-fermenting acid interacts with the appropriate imidazole in DMSO using a base, such as K2CO3, NaOH or NaH. Connection ethyl ester 4-(2-methyl-1H-imidazol-1-yl) benzoic acid was obtained with only 33% yield supercriticalities product. In contrast, the methods of this invention give high outputs, the result is completely unexpected, since the reactant eilperin in the methods of the present invention is not dilatory electrons of the substituents attached to the aryl ring.

The most preferred Rastro), although any suitable aprotic solvent, and solvents listed above, are preferred. In another preferred variant of the method of solid sodium hydroxide, NaOH, is used in the reaction mixture, and the solvent is DMSO. A strong Foundation in solid form, which is used in this stage of the method of this invention, are selected from sodium hydroxide, NaOH, potassium hydroxide, KOH. The term "solid" as used in this context, refers to the phase in which the strong base is present, should be detected in this reaction mixture. Preferably specified solid substance use fragmented and not as a whole, thereby providing a wider surface area on which other reactive substances capable of contact with a strong base during this stage of the method. So, a strong Foundation in solid form may be used in powder form or in the form of pellets (granules). On the other hand, is not mandatory that this solid form a strong base has been finely ground. Solid forms of a strong base, preferably used in the methods of this invention are commercially readily available.

2CO3or phase transfer catalyst (PTC). The amount used can vary between 0.5% and 10 mol% mol, i.e., mol. %, but preferably between 1 mol.% and 5 mol.%. The amount of catalyst that is suitable for use in the methods of the present invention, can be expressed as being in the range of 0.005 to 0.5 equivalents, preferably from 0.01 to 0.1 equivalents, and more preferably about 0.05 equivalents relative to other compounds participating in the reaction.

It was found that the carbonate, cesium, Cs2CO3, a substance that is used as a catalyst in the polymerization of ethylene oxide and other conducted with catalyst reactions, can be used as an alternative catalyst relative to the phase transfer catalyst as described here.

The concentration of the reacting substances in the same phase during this stage can be lower than optimal for achieving a convenient reaction rate, and, consequently, the use of the phase transfer catalyst can often be advantageous to reduce the temperature and reaction time. For example, when using the phase transfer catalyst floor is 130oC and the use of the phase transfer catalyst, the reaction time is reduced to 2-4 hours, while required 3-4 hours in the absence of a phase transfer catalyst. However, it should be clear that the invention assumes that solid NaOH or KOH can be used alone, i.e. without the use of phase transfer catalyst.

There are two main types of phase transfer catalysts on the basis of their mode of action. The first type includes salts of Quaternary ammonium or phosphonium, while the second type includes crown-ethers and other cryptand. Salts of Quaternary ammonium compounds may include, in addition to more typical aliphatic configurations, connections quaternionic the nitrogen atom is part of a cyclic heterocyclic system, for example pyridinium salt or salt chinine. The first type of phase transfer catalyst, i.e., salts of Quaternary ammonium or phosphonium salts of, is preferred for use as the phase transfer catalyst in the methods of this invention. Among the catalysts of this type are more preferred are salts of Quaternary ammonium compounds, and among them the most prediposed (TBAB); Tetra-n-butylammonium (TBAC); Tetra-n-butylammonium (TBAH); Tetra-n-butylammonium (TBAI) and hydrate tetraethylammonium.

It should be clear that, despite the above preferences for specific phase transfer catalysts, which are selected for use in the methods of production according to this invention, there is a significant amount of phase transfer catalysts known in this field and is suitable for use in this invention. Specialist well-known identity of such phase transfer catalysts and suitable stage, which can be demonstrated their effectiveness in the methods of this invention. For example, among the phase transfer catalysts known in this field, the following catalysts suitable for use in the methods of this invention include cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (- )-N-dodecyl-N-methylephedrine (DMCOH); hexamethylene phosphoric acid (HMPT); cetylpyridinium (NCPB); N-benzylpenicillin (QUIBEC); Tetra-n-butylammonium (TBAB); Tetra-n-butylammonium (TBAC); the Rath of tetraethylammonium (TEAC); tri-n-butylamine (TBA); benzyltrimethylammonium (TBBAB); hexadecyltrimethylammonium (TBHDPB); benzyltriethylammonium (TEBAB); benzyltriethylammonium (TEBA); hexadecyltrimethylammonium (TEHDAC); Tetramethylammonium (TMAC); hexadecyltrimethylammonium (TMHDAC) and octyltrichlorosilane (TMOAC).

The main mechanism of action systems catalysts phase transfer is a continuous formation of lipophilic ion pairs of the desired anions with lipophilic cations provided by these catalysts. As a result, these anions can enter into non-polar organic medium, which may be desirable reaction. Typical sources of lipophilic cations, which can act as catalysts in such systems are tetraalkylammonium or other onevia salts, crown ethers, cryptand, ethers of polyethylene glycol, etc. the Fundamental nature of interfacial catalysis is the formation of lipophilic ion pairs, which can be detected in non-polar environments. With vysokolikvidnymi cations even small inorganic anions form such ion pairs. Interfacial catalysis can only operate in a heterogeneous, mostly on the ATOR, for example lipophilic tetraalkylammonium, while water, or in General inorganic phase contains a salt of the desired anion or base, which can form organic anions from the corresponding precursors, localized in the organic phase.

In these systems, catalysis consists of transfer of anions of the inorganic phase or alternative organic anions formed on the surface of the partition to the organic phase, where they enter in the desired reaction, while the released catalyst may bring another anion in the organic phase. By continuous repetition of this action 1 mol of the catalyst can promote the transformation of 100 moles of the reacting substances. Depending on the state of aggregation, types of anions and some other factors is possible to distinguish several variants of the above-described interfacial catalytic process. Despite this, the person skilled in the art can easily adapt the basic requirements for conducting interfacial catalysis to methods for this invention.

Now let us return to the description of the methods of this invention. After the formation of the above mixture, it is heated to mperature boiling under reflux this reaction mixture will be in the range from 120 to 140oC, usually from 125oC to 135oC and most often 130oC.

The reaction mixture must be heated at lower of these temperatures for a considerable period of time, from 12 to 30 hours, preferably from 16 to 24 hours, most preferably from 18 to 20 hours. However, these high temperatures the reaction proceeds more quickly, and it is necessary to heat the reaction mixture for more than short periods of time, from 1/2 to 4 hours, typically from 3/4 to 3 hours, and most typically from 1 to 2 hours.

The selection of the suitable temperature and time for the reaction to completion is within the skill of a specialist who is familiar with the methods of organic synthesis. The selection of the product from the above process, such as vacuum filtration, washing with water and drying in a vacuum thermostat, carried out using conventional procedures, which are also within the ordinary skill in this field. As an additional guide for professionals here given table. 1 values showing different results output method, which can be obtained with indirect solid sodium hydroxide overrides allfor the key reactant is a compound of formula (2.0.0)

< / BR>
This connection is also a new intermediate product of the present invention, tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide. For carrying out the above method according to this invention it is necessary, therefore, to develop a method with which can be obtained very new reactive substance/intermediate product. Thus, what follows is a description of another method of the present invention, by which can be obtained compound of formula (2.0.0).

This invention relates further to a method for obtaining compounds of formula (2.0.0)

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One of the preferred methods of the present invention to obtain a new intermediate product of formula (2.0.0) may be illustrated by the following synthesis scheme (10.0.1) (see the end of the description), where X, M and R5have mentioned elsewhere in the description.

Thus, the above method according to this invention, illustrated in the synthesis scheme (10.0.1), may be performed by (a) form a reaction mixture, consisting of

(1) tetrahydro-4-(3-bromo - or itfinal)-2H-Piran-4-nitrile of formula (3.0.0)

< / BR>
where X denotes bromine or iodine; and (2) 4-portifino formula (4.0.0)


(4) in the presence of a strong base of formula (5.0.0):

M-O-R5,

where M denotes an alkali metal, an element of group 1/Ia selected from the group consisting of lithium, Li; sodium, Na; potassium. K; rubidium, Rb; and cesium Cs; and

R5denotes hydrogen, H; or (C1-C4) alkyl straight or branched chain; preferably representative selected from the group comprising lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; ataxic lithium, LiOCH2CH3; ethoxide sodium, NaOCH2CH3; ataxic potassium KOCH2CH3; ataxic rubidium, RbOCH2CH3; ataxic cesium, CsOCH2CH3; tert-piperonyl lithium, LiOC(CH3)3; tert-piperonyl sodium NaOC(CH3)3; tert-piperonyl potassium KOC(CH3
tetrakis(triphenylphosphine)palladium (0), [(C6H5)3P]4Pd (0);

tetrakis(methyldiphenylphosphine)palladium (0), [(C6H5)2PCH3]4Pd (0);

TRANS-dichlorobis(methyldiphenylphosphine)palladium (II), [(C6H5)2PCH3]2PdCl2; adduct(dichlorobis[Methylenebis(diphenylphosphine)]dipalladium-dichloromethane;

dichlorobis(triphenylphosphine)palladium (II), [(C6H5)3P]2PdCl2;

adduct of Tris(dibenzylideneacetone)dipalladium (0) - chloroform (C6H5CH=CHCOCH=CHC6H5)3Pd2CHCl3;

bis(dibenzylideneacetone)palladium (0), (C6H5CH=CHCOCH=CHC6H5)2Pd;

[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II), complex with dichloromethane;

[1,2-bis(diphenylphosphino)ethane]palladium (II) and

dimer (-allyl)palladium (II) chloride; followed by (b) specified by heating the reaction mixture, preferably by boiling under reflux, preferably during the period from 12 to 36 hours, more prebaseline produce using conventional methods of separation.

The above method is a method that gives asymmetrically substituted dailoy simple ether. At the same time, the reaction that occurs leads to the hydrolysis of the nitrile substituent to the corresponding carboxamides Deputy. It was found that several factors are important in guaranteeing the completion of the above process with acceptable outputs the new intermediate product of formula (2.0.0).

One such factor is the solvent in which the conduct of the considered reaction. The solvent consists of an aliphatic alcohol with a straight or branched chain, having in General from 2 to 7 carbon atoms. The alcohol solvent may also be used in mixture with water, i.e., in the form of an aqueous mixture of alcohol in suitable proportions. Although alcohol and water are miscible in almost all relationships, it was found that it is desirable to maintain the ratio of the volume:the volume of alcohol to water, respectively, in the range from 25:1 to 3:1, preferably in the range of from 10:1 to 5:1.

It was found that the most suitable aliphatic alcohol with a straight or branched chain, having in General from 2 to 7 carbon atoms, for use as rusty alcohol, sec-butyl alcohol, isopentylamine alcohol and 2-heptanol. Of these preferred secondary alcohols are most preferred is isopropyl alcohol. The above secondary alcohols used optionally in the form of an aqueous mixture, as described in detail above.

It should be clear that the reaction temperature used in the above method of the present invention, can be adjusted by selection of an alcoholic solvent based, in turn, on the degree of reactivity of the substrate. For example, the reacting substances of the formula (3.0.0), where X is iodine, it was found that this reaction can be conducted under mild conditions in isopropyl alcohol by boiling under reflux. For the reacting substances of the formula (3.0.0), where X denotes bromine, it was found that this reaction can be conducted under mild conditions in sec-butyl alcohol boiling under reflux. It should be clear that the reaction involving arylated in the above-described method of the present invention, i.e., when X is iodine reacting substance of formula (3.0.0), is very easy and can be completed within a period of several hours. On the other hand, the reaction with the participation of eacce involving arriagada, and to complete the reaction required heating of the reaction mixture over a much longer period of time, more than 10 hours. However, prolonged heating of the reaction mixture in the case of any reaction has no adverse effect on the yield of the obtained guiltiafre, i.e. diaryland.

Another such factor is the use of strong bases of formula (5.0.0)

M-O-R5,

where M denotes an alkali metal, an element of group 1/Ia selected from the group comprising lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and caesium, Cs; and R5denotes hydrogen, H; or (C1-C4)alkyl straight or branched chain. Preferred strong bases include a representative selected from the group comprising lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; ataxic lithium, LiOCH2CH3; ethoxide sodium, NaOCH2CH3; ataxic potassium KOCH2CH3; ataxic rubidium, RbOCH2CH3; ataxic cesium, CsOCH2CH3; tert-piperonyl lithium, LiOC(CH33
)3and tert-piperonyl cesium CsOC(CH3)3.

The above strong bases can be used in the form of their mixtures, but it is preferable to use only one strong base. More preferred among the above-mentioned strong bases are sodium hydroxide, NaOH; potassium hydroxide, KOH; ethoxide sodium, NaOCH2CH3and tert-piperonyl potassium KOC(CH3)3.

Another factor in achieving satisfactory completion of the above-described method according to this invention is the use as catalyst of a transition metal of the group comprising the metal complexes of palladium. Among the metal complexes of palladium, which are preferred for use in the method of the present invention are more preferred types of catalysts used in the above process. These preferred species selected from the group comprising tetrakis(triphenylphosphine)palladium (0), [(C6H5)3P]4Pd (0);

tetrakis (methyldiphenylphosphine) palladium (0), [(C6H5)2PCH3]4Pd (0);

TRANS-dichlorobis(methyldiphenylphosphine) palladium (II), [(C6H5)2)

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dichlorobis(triphenylphosphine)palladium (II), [(C6H5)3P]2PdCl2;

adduct of Tris(dibenzylideneacetone)dipalladium (0) - chloroform: (C6H5CH= CHCOCH=CHC6H5)3Pd2CHCl3;

bis(dibenzylideneacetone)palladium (0): (C6H5CH=CHCOCH=CHC6H5)2Pd;

[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II), complex with dichloromethane, formula (6.1.0)

< / BR>
bis[1,2-bis(diphenylphosphino)ethane]palladium (II) formula (6.2.0)

< / BR>
dimer (-allyl) palladium (II) chloride of the formula (6.3.0)

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Of the metal complexes of palladium, as described above, the most preferred is tetrakis(triphenylphosphine)palladium (0), [(C6H5)3P]4Pd (0). This is the preferred catalyst may be used with the ligand, or no ligand. When the ligand with [(C6H5)3P]4Pd (0) preferred ligands are triphenylphosphine (TPP), ethylenebis (diphenylphosphine) and three(2-tolyl)phosphine. The preferred ratio of the catalyst to the ligand is about 1: 2 mol. EQ. but expert it is clear that the use of excess amounts of the ligand can lead to a reduction in overall yield of the reaction in which ispolzov in the methods of the present invention, use as a ligand, or no ligand. The ligand can affect the yield of the final product, i.e. the compounds of formula (2.0.0), as illustrated by table. 2 quantities directly after specifying the outputs from the above-described process of the present invention, where use of various complexes of palladium metal without ligand or one of a variety of ligands.

The above-described ligands, as well as other ligands, are well known in this field can be used with the metal complexes of palladium used as catalysts in the method of this invention.

As clearly outlined above, a particular advantage of the method described above is that in the course of carrying out the reaction in the above-described conditions, which are suitable or preferred nitrile group of the molecule of the compounds of formula (3.0.0) is hydrolyzed to the corresponding carboxamide group, which is formed in the final product, the compound of formula (1.0.0). However, this invention also provides an alternative way to obtain a new intermediate product, the compounds of formula (2.0.0), in which the specified shape of the molecule is first hydrolyzed to sootvetstvenno compound of formula (3.1.0) reacts with fortifying compound of formula (4.0.0) with the formation of the above new intermediate product of formula (2.0.0).

Additionally it should be noted that the second stage of the above-mentioned alternative method is carried out essentially in the same manner as illustrated in scheme 2 above.

Therefore, this invention also relates to an alternative method of obtaining the compounds of formula (2.0.0)

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which can be illustrated by the synthesis scheme (10.1.0) (see the end of the description), where X, M and R5all are defined elsewhere in the description.

An alternative method of the present invention, shown in the synthesis scheme (10.1.0), may be performed by (a) form a reaction mixture comprising (1) tetrahydro-4-(3-bromo - or itfinal)-2H-Piran-4-nitrile of formula (3.0.0)

< / BR>
where X denotes bromine or iodine; (2) in a solvent consisting of aliphatic alcohol with a straight or branched chain, having generally 2 to 7 carbon atoms, optionally in the form of its aqueous mixture; and more preferably, if the alcohol is a secondary alcohol selected from the group consisting of isopropyl alcohol, sec-butyl alcohol, isopentanol alcohol and 2-heptanol, not necessarily in the form of an aqueous mixture of the specified secondary alcohol; (3) in the presence of a strong base of formula (5.0.0)

M-O-RRiya, Na; potassium, K; rubidium, Rb; and cesium Cs; and R5denotes hydrogen, H; or (C1-C4)alkyl straight or branched chain; preferably representative selected from the group comprising lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; ataxic lithium, LiOCH2CH3; ethoxide sodium, NaOCH2CH3; ataxic potassium KOCH2CH3; ataxic rubidium, RbOCH2CH3; ataxic cesium, CsOCH2CH3; tert-piperonyl lithium, LiOC(CH3)3; tert-piperonyl sodium NaOC(CH3)3; tert-piperonyl potassium KOC(CH3)3; tert-piperonyl rubidium RbOC(CH3)3and tert-piperonyl cesium CsOC(CH3)3including mixtures thereof; and then (b) specified by heating the reaction mixture, preferably by boiling under reflux, preferably for a period of from 3 to 8 hours, more preferably from 5 to 6 hours; resulting in the above compound of formula (3.1.0)

< / BR>
where X denotes bromine or iodine; and then (c) the formation of the reaction mixture, the aliphatic alcohol with a straight or branched chain, having generally 2 to 7 carbon atoms, optionally in the form of its aqueous mixture; and more preferably, if the alcohol is a secondary alcohol selected from the group consisting of isopropyl alcohol, sec-butyl alcohol, isopentanol alcohol and 2-heptanol, not necessarily in the form of an aqueous mixture of the specified secondary alcohol; (2) in the presence of a strong base of formula (5.0.0)

M-O-R5,

where M denotes an alkali metal, an element of group 1/Ia selected from the group consisting of lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium Cs; and R5denotes hydrogen, H; or (C1-C4) alkyl straight or branched chain; preferably representative selected from the group comprising lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; ataxic lithium, LiOCH2CH3; ethoxide sodium, NaOCH2CH3; ataxic potassium KOCH2CH3; ataxic rubidium, RbOCH2CH3; ataxic cesium, CsOCH2CH3; tert-piperonyl lithium, LiOC(CH3)3; tert-piperonyl sodium NaOC(CH3)3; tert-is B>)3including mixtures thereof; and, in addition, (3) in the presence of a catalyst which is a metal of transition group, which includes the representative, is independently selected from the group comprising a complex of palladium metal, which is preferably selected from the group comprising tetrakis(triphenylphosphine) palladium (0), [(C6H5)3P]4Pd (0); tetrakis(methyldiphenylphosphine)palladium (0), [(C6H5)2PCH3]4Pd (0); TRANS-dichlorobis(methyldiphenylphosphine)palladium (II), [(C6H5)2PCH3]2PdCl2; the adduct dichlorobis[Methylenebis(diphenylphosphine)]dipalladium-dichloromethane; dichlorobis(triphenylphosphine)palladium (II), [(C6H5)3P]2PdCl2; adduct of Tris(dibenzylideneacetone)dipalladium (0) - chloroform (C6H5CH= CHCOCH= CHC6H5)3Pd2CHCl3; bis(dibenzylideneacetone) palladium (0), (C6H5CH=CHCOCH= CHC6H5)2Pd; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane; bis[1,2-bis(diphenylphosphino)ethane] palladium (II) dimer (-allyl)palladium (II) chloride; and then (d) specified by heating the reaction mixture, preferably by boiling under reflux, preferably in the amount of compound of formula (2.0.0).

One of the key aspects of the methods of obtaining this invention is an improved method of obtaining well-known inhibition of 5-lipoxygenase compounds of formula (1.0.0)

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This improved method comprises the most preferred variants of the present invention and may be illustrated by the synthesis scheme (10.3.1) (see the end of the description).

It is expected that this improved method of this invention, shown in the synthesis scheme (10.3.0), includes, in General, six variants of the present invention. The first option is a stage, which is the first stage, shown in the synthesis scheme (10.3.0), and is a way to get a new intermediate product of the present invention of formula (2.0.0). The second option is to stage b, which is the second or middle stage, shown in the synthesis scheme (10.3.0), and is a method of obtaining the known inhibition of 5-lipoxygenase compounds of formula (1.0.0) as compounds per se. The third option is to stage c or stage d, which is the last stage in the synthesis scheme (10.3.0) and is a method of obtaining mesilate salt specified known compounds f the Estai option is to phase a + phase b + phase c or d.

For brevity, only the second and sixth options are described in detail below. Thus, the second above-mentioned variant, stage b in the scheme of the synthesis of (10.3.1), carried out as follows: (a) formation of a reaction mixture consisting of (1) tetrahydro-4-[3-(4-forfinal)thio]phenyl-2H-Piran-4-carboxamide of formula (2.0.0)

< / BR>
and (2) 2-methylimidazole;

(3) in an aprotic solvent, preferably selected from the group comprising mainly hexane; 1,4-dioxane; carbon tetrachloride; benzene; toluene; xylenes; diethyl ether; chloroform; ethyl acetate; tetrahydrofuran (THF), methylene chloride; hexamethylene phosphoric acid (NMRT); nitromethane; N, N-dimethylformamide (DMF); acetonitrile; sulfolane and dimethyl sulfoxide (DMSO); more preferably dimethyl sulfoxide (DMSO);

(4) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH, potassium hydroxide, KOH; and (optional)

(5) in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, preferably selected from the group comprising cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (-)-N-dodecyl-N-metered (QUIBEC);

butylammonium (TBAC); Tetra-n-butylammonium (TBAH); Tetra-n-butylmethacrylate (TBAHS); Tetra-n-butylammonium (TBAI); hydrate tetraethylammonium, (TEAC); tri-n-butylamine (TBA); benzyltrimethylammonium (TBBAB); hexadecyltrimethylammonium (TBHDPB); benzyltriethylammonium (TEBAB); benzyltriethylammonium (TEBA); hexadecyltrimethylammonium (TEHDAC); Tetramethylammonium (TMAC); hexadecyltrimethylammonium (TMHDAC) and octyltrichlorosilane (TMOAC) and more preferably salts of Quaternary ammonium or phosphonium salts of, containing the representative of the above groups; followed by (b) specified by heating the reaction mixture, preferably by boiling under reflux, preferably at 115-145oC, more preferably at 125-130oC, in nitrogen atmosphere, preferably for 12 to 30 hours, more preferably for 17-24 hours; resulting in a specified compound of formula (1.3.0).

The above-mentioned sixth variant, the phase a + phase b + phase c circuit synthesis (10.3.0) this invention is a method of obtaining essentially pure mesilate salt of formula (1.0.1)

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providing (a) obtaining soedineniya-4-(3-bromophenyl)-2H-Piran-4-nitrile of the formula (3.2.0)

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and (ii) 4-portifino formula (4.0.0)

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(iii) in a solvent selected from the group consisting of isopropyl alcohol, sec-butyl alcohol, isopentanol alcohol and 2-heptanol, not necessarily in the form of its aqueous mixtures;

(iv) in the presence of a strong base selected from the group consisting of sodium hydroxide, NaOH, potassium hydroxide, KOH; and, in addition, (v) in the presence of a catalyst containing representative, is independently selected from the group including the following complexes of palladium metal:

tetrakis(triphenylphosphine)palladium (0), [(C6H5)3P]4Pd (0);

tetrakis(methyldiphenylphosphine)palladium (0), [(C6H5)2PCH3]4Pd (0);

TRANS-dichlorobis(methyldiphenylphosphine)palladium (II), [(C6H5)2PCH3]2PdCl2; the adduct dichlorobis[Methylenebis(diphenylphosphine)]dipalladium-dichloromethane;

dichlorobis(triphenylphosphine)palladium (II), [(C6H5)3P]2PdCl2;

adduct of Tris(dibenzylideneacetone)dipalladium (0) - chloroform (C6H5CH=CHCOCH-CHC6H5)3Pd2CHCl3;

bis(dibenzylideneacetone)palladium (0), (C6H5CH=CHCOCH=CHC6H5)2Pd;

[1,1'-bis(defenisve the

dimer (-allyl)palladium (II) chloride; followed by (2) specified by heating the reaction mixture at the boiling temperature under reflux 80 to 84oC during the period from 18 to 30 hours, preferably 24 hours; resulting in the above compound of formula (2.0.0),

(b) formation of a reaction mixture consisting of the compounds of formula (2.0.0) and the compounds of formula (1.3.10)

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(1) in an aprotic solvent selected from the group consisting mostly of tetrahydrofuran (THF), methylene chloride; N, N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO); more preferably in dimethyl sulfoxide (DMSO);

(2) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH, potassium hydroxide, KOH; and (optional) (3) in the presence of catalytic amounts of carbonate sesia, Cs2CO3or phase transfer catalyst, preferably a member selected from the group comprising cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (-)-N-dodecyl-N-methylephedrine (DMCOH); hexamethylene phosphoric acid (HMPT); cetylpyridinium (NCPB); N-benzylpenicillin (QUIBEC); those whom lammikivitalot (TBAHS); Tetra-n-butylammonium (TBAI); tetraethylammonium, hydrate (TEAC); tri-n-butylamine (TBA); benzyltrimethylammonium (TBBAB); hexadecyltrimethylammonium (TBHDPB); benzyltriethylammonium (TEBAB); benzyltriethylammonium (TEBA); hexadecyltrimethylammonium (TEHDAC); Tetramethylammonium (TMAC); hexadecyltrimethylammonium (TMHDAC) and octyltrichlorosilane (TMOAC) and more preferably salts of Quaternary ammonium or phosphonium salts of containing the representative of the above groups; and then (c) heating the reaction mixture at the specified boiling under reflux in a nitrogen atmosphere; with the obtained compounds of formula (1.0.0)

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then (d) the formation of a concentrated solution in methanol of the compounds of formula (1.0.0), which is then preferably filtered through activated charcoal, then add to the filtrate methansulfonate acid, MeSO3H; followed by an additional concentration and addition of ethyl acetate ad seriatim to the selection of crystalline product containing essentially pure mesilate salt of formula (1.0.1)

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or alternate with subsequent (e) the formation of a concentrated solution in metascheduler filtering the mixture, preferably through activated charcoal, followed by further concentration and adding ethyl acetate ad seriatim to the selection of crystalline product containing essentially pure mesilate salt of formula (1.0.1).

The preferred method of education mesilate salt is a method of forming a concentrated solution in methanol of the compounds of formula (1.0.0), which also contains methansulfonate acid, MeSO3H, followed by filtration. It was found that this method leads to a significant reduction in the way and reduce the amount of residual palladium in the final product. The primary purposes of the above recrystallization in methanol in education mesilate salt of formula (1.0.1) is the removal of all residual palladium from the final product, which was not removed during the stage filtration carried out preferably by using activated charcoal.

Note that the above method of obtaining mesilate salts of the compounds of formula (1.0.0) may be easily adapted using the skills and knowledge available in this field, to obtain other similar Sultanov

Ways, new intermediate products and new final products of this invention will be more readily understandable from their illustrations in the form of working examples illustrating the details of their conduct. However, examples of preferred variants of the present invention which follow, are intended only for illustration purposes and should not be construed as limiting in any way the scope of the present invention, and for purposes of limitation is only appended claims.

Example 1. Synthesis of tetrahydro-4-(3-bromophenyl)-2H-Piran-4-nitrile

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3-Bromophenylacetonitrile (20,0 g, 102 mmol, 1 EQ.), from the firm Aldrich Chemical Co. Milwaukee, WI, tetrahydrofuran (120 ml), 40% aqueous sodium hydroxide solution (180 ml, mmol, equiv.) the tetrabutylammonium hydrosulfate (of 3.46 g, mmol, 0.1 EQ.) was stirred reaction install flask to boil at the boiling point under reflux. After this was added 2,2'-dichloromethylene ether (of 13.75 ml, 117 mmol, 0.1 EQ.) with stirring at room temperature, 20-25oC. the reaction mixture is boiled under reflux for 5-8 h at approximately 64oC. the Reaction mixture was cooled to ambient temperature and was added ethyl acetate is isopropanol (100 ml) and water (10 ml) and stirred at 0oC during the night with obtaining crystalline suspension. The crystal suspension was filtered under vacuum, washed with isopropanol (2 × 20 ml). The white crystalline solid was dried in vacuum at 40-45oC. Output a 18.57 g (68,4%): so pl. 82-85oC; m/z 267 (m+1);

1H-NMR (300 MHz, DMSO) of 7.75 (s, 1H), 7,6 (m, 2H), 7,44 (t, 1H), was 4.02 (m, 2H), 3,66 (m, 2H), and 2.14 (m, 4H).

Example 2. Synthesis of tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide

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Propane-2-ol (311 ml), tetrahydro-4-(3-bromophenyl)-2H-Piran-4-nitrile (51,91 g, of € 0.195 mol, 1 EQ.), potassium hydroxide (25,16 g to 0.39 mol, 2 equiv.) water (4 ml to 0.39 mol, 2 equiv.) tetrakis(triphenylphosphine)palladium (0) (of 2.26 g, 0,00195 mol, 0.01 EQ. 4-portifino (25 g, of € 0.195 mol, 1 EQ.) was added to the reaction install flask to boiling under reflux in a nitrogen atmosphere. The reaction mixture is boiled under reflux for 20-24 h at approximately 82oC. the Reaction mixture was cooled to ambient temperature, 20-25oC, was added water (315 ml) to give a suspension. The crude product was isolated by filtration and washed with a mixture of 1:1 water:propane-2-ol (125 ml) and was aspirated to dryness. The crude dry product was dissolved in methanol (1900 ml), treated with activated carbon, Da 60oC for 20 minutes, and was filtered product that does not contain activated carbon and accelerator filtering. The filter cake was washed with hot methanol (200 ml) and the washing solution was combined with the main filtrate. The product containing the combined filtrate and wash solution was concentrated by distillation to a volume of approximately 700 ml of the Concentrate was cooled to 10-0owas grained in this temperature range for 1-3 hours to obtain crystals. The crystalline product was isolated by filtration, washed with cold methanol (125 ml) and dried under vacuum at 40-45oC. Output 40,2 g (62.2 per cent): so pl. 175-178oC; m/z 332 (m+1);1H-NMR (300 MHz, DMSO) 7,37 (m, 8H), 7,11 (m, 2H), 3,60 (m, 2H), 2,30 (m, 2H), 2.40 a (m, 2H), 1.77 in (m, 2H); IR (offset) vmax3394, 3198, 3078, 3014, 2970, 2931, 2880, 2824, 1681, 1664, 1664, 1623, 1588, 1569.

Example 3. Synthesis of tetrahydro-4-{3-[4-(2-methyl-1H-imidazol-1 - yl)phenyl] thio}phenyl-2H-Piran-4-carboxamide using solid NaOH and Cs2CO3< / BR>
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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamid (25,0 g, 75,4 mmol, 1 EQ. ), dimethyl sulfoxide (250 ml, 10 vol.), 2-Mei (KZT 12.39 g, 150,9 mmol, 2.0 equiv.) sodium hydroxide (6,03 g, 150,9 mmol, 2.0 equiv. ) and cesium carbonate (1.23 g, 0.38 mmol, 0.005 EQ.) was added to the reaction setup is SUP>C for 17-24 h in nitrogen atmosphere. Upon completion the reaction was cooled (<30C) and extinguished with water (250 ml, 10 vol.), which led to the formation of a precipitate. During the addition of water was observed to ectothermy 10-15oC. Formed in this way, the suspension was cooled to room temperature (15-25oC) and then granulated for 1 hour. The product was isolated by filtration under vacuum and washed with water (140 ml, about 5,6. ). The product was dried overnight in a vacuum thermostat at 40-45oC. the Amount of the obtained product was of 29.4 g, which corresponds to a yield of 99%. Analytical data for the product the following: I. pl. 198-200oC; m/z 396 (m+1);1H-NMR (300 MHz, DMSO) 7,41 (m, 10H), 7,12 (s, 1H), 6,93 (d, 1H, in), 3.75 (m, 2H), 3,48 (t, 2H), 2,48 (d, 2H), 2,3 (s, 3H), of 1.75 (m, 2H); IR (offset) vmax3402, 3301, 3123, 3096, 2971, 2930, 2880, 1680, 1663, 1622, 1593, 1569, 1528.

Example 4. Synthesis of tetrahydro-4-{3-[4-(2-methyl-1H-imidazol-1 - yl)phenyl] thio} phenyl-2H-Piran-4-carboxamide using solid NaOH and the phase transfer catalyst

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamid (25,0 g, 75,4 mmol, 1 EQ. ), dimethyl sulfoxide (250 ml, 10 vol.), 2-Mei (KZT 12.39 g, 150,9 mmol, 2.0 equiv.) sodium hydroxide (6,03 g, 150,9 mmol, 2.0 equiv. ) and Tetra-n-butylammonium (TBAC) (0,210 g, 0.75 mmol, 0.05 to EQ. is ion mixture was heated at 125-130oC for 17-24 h in nitrogen atmosphere. Upon completion the reaction was cooled (<30C) and extinguished with water (250 ml, 10 vol.), which led to the formation of a precipitate. In the process of adding water observed ectothermy 10-15oC. Formed in this way, the suspension was cooled to room temperature (15-25oC) and then granulated for 1 hour. The product was isolated by filtration under vacuum and washed with water (140 ml, about 5,6.). The product was dried overnight in a vacuum thermostat at 40-45oC. the Amount of the obtained product was 27,6 g, which corresponds to the output 93,0%. Analytical data for the product were as follows: I. pl. 198-200oC; m/z 396 (m+1);1H-NMR (300 MHz, DMSO) 7,41 (m, 10H), 7,12 (s, 1H), 6,93 (d, 1H, in), 3.75 (m, 2H), 3,48 (t, 2H), 2,48 (d, 2H), 2,3 (s, 3H), of 1.75 (m, 2H); IR (offset) vmax3402, 3301, 3123, 3096, 2971, 2930, 2880, 1680, 1663, 1622, 1593, 1569, 1528.

Example 5. Synthesis of tetrahydro-4-{3- [4-(2-methyl-1H-imidazol-1 - yl)phenyl] thio}phenyl-2H-Piran-4-carboxamide using only solid NaOH

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamid (6.5 g, a 19.6 mmol, 1 EQ. ), dimethyl sulfoxide (65 ml, 10 vol.), 2-Mei (3,22 g, 39,23 mmol, 2.0 EQ.) and sodium hydroxide (1,57 g, 39,23 mmol, 2.0 equiv. ) was added to the reaction install flask for boiling reverse the and. Upon completion the reaction was cooled (<30C) and extinguished with water (65 ml, 10 vol.), which led to the formation of a precipitate. In the process of adding water observed ectothermy 10-15oC. Formed in this way, the suspension was cooled to room temperature (15-25oC) and then granulated for 1 hour. The product was isolated by filtration under vacuum and washed with water (80 ml, 12,3 about.). The product was dried overnight in a vacuum thermostat at 40-45oC. the Amount of the obtained product was 6,98 g, which corresponded to the output 90,4%. Analytical data for the product the following: I. pl. 198-200oC; m/z 396 (m+1);1H-NMR (300 MHz, DMSO) 7,41 (m, 10H), 7,12 (s, 1H), 6,93 (d, 1H, in), 3.75 (m, 2H), 3,48 (t, 2H), 2,48 (d, 2H), 2,3 (s, 3H), of 1.75 (m, 2H); IR (offset) vmax3402, 3301, 3123, 3096, 2971, 2930, 2880, 1680, 1663, 1622, 1593, 1569, 1528.

Example 6. Education mutilates tetrahydro salt-4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenyl]thio}phenyl-2H - Piran-4-carboxamide

Methanol (640 ml, 40 vol.), tetrahydro-4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenyl] thio}phenyl-2H - Piran-4-carboxamide obtained by the method of example 3 (16.0 g, up 40.7 mmol, 1.0 EQ.), activated carbon, DARCO KB-B (0,80 g) and the accelerator filtering, celite (2.4 g) was added to the reaction install flask to boiling under reflux. A mixture of agrawalla temperature in the range of 55-60oC and coal and accelerator filtering was removed by filtration in the temperature range of 55-60oC. the Residue was washed with methanol (50 ml) and washing solutions were combined with the original filtrate. Thus obtained transparent combined filtrate and wash solutions were concentrated by distillation at atmospheric pressure to a volume of approximately 700 ml To the concentrated solution in methanol was added methanesulfonyl acid (4.1 g, and 42.7 mmol, of 1.05 EQ.). The resulting solution was further concentrated by distillation at atmospheric pressure to a volume of approximately 250 ml was added ethyl acetate (500 ml) in two aliquot, the total volume was reduced by distillation to 250 ml after each addition of ethyl acetate. The resulting crystalline suspension was cooled to room temperature 15-25oC and grained 4-16 h in the temperature range of 15-25oC. the White crystalline product was isolated by filtration and washed with ethyl acetate (135 ml) and dried in vacuum at 45-50oC. Output 18,39 g, 92.3 per cent. Thus obtained Sol was characterized pattern of x-ray diffraction powder with the main peaks are presented in table 3.

Example 7. Recrystallization tetrahydro-4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenyl] thio}phenyl-2H - Piran-4-carboxamid, obtained by the method of example 3 (an 80.2 g), activated carbon, DARCO KB-B (4.0 g) and the accelerator filtering, celite, (10 g) was added to the reaction install flask to boiling under reflux. The mixture was heated to boiling, approximately 66oC, for the dissolution of the organic substrate. The contents of the flask were cooled to a temperature in the range of 55-60oC and coal and accelerator filtering was removed by filtration in the temperature range of 55-60oC. the Residue was washed with methanol (300 ml) and washing solutions were combined with the original filtrate. Thus obtained transparent combined filtrate and wash solutions were concentrated by distillation at atmospheric pressure to a volume of about 1000 ml of thus Obtained methanolic concentrate was cooled to a temperature range 3-7oC to obtain crystallization of the product and granulated within 6-24 hours in this temperature range. White crystals of product were isolated by filtration and stosil in vacuum at 40-45oC. the Output is 70.3 g, 87.7 per cent, so pl. 198-200oC; m/z 396 (m+1); spectral data identical to the data of example 3.

Example 8. Synthesis of tetrahydro-4-(3-bromophenyl)-2H-Piran-4-carboxamide

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Propane-2-ol (100 ml), tetrahedron installation flask to boiling under reflux in a nitrogen atmosphere, and the reaction mixture was heated under stirring while boiling under reflux, approximately 82oC for 5-6 hours in a nitrogen atmosphere. Upon completion of the reaction the mixture was cooled (to <30C) and extinguished with water (100 ml). The resulting suspension was filtered and the residue product was washed with water (30 ml) and dried in vacuum at 45-50oC to obtain a white solid. Output 19,05 g, 89.2% of, so pl. 245-247oC; m/z 285 (m+1);1H-NMR (300 MHz, DMSO) the 7.43 (m, 5H), 7,14 (s, 1H), 3,76 (d, 2H), 3,47 (t, 2H), 2,44 (d, 2H), 1,79 (m, 2H); IR (offset) vmax3363, 3174, 3062, 2973, 2935, 2879, 2828, 1685, 1631, 1588.

Example 9. Synthesis of tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide

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Butane-1-ol (8 ml), tetrahydro-4-(3-bromophenyl)-2H-Piran-4-carboxamid (2,97 g, 10,45 mmol, 1 EQ.) tert-piperonyl potassium (2,34 g of 20.9 mmol, 2 EQ. ), water (4 ml to 0.39 mol, 1 EQ.), tetrakis(triphenylphosphine)palladium (0) (0,242 g, 0,209 mmol, 0.02 EQ.) and 4-portifino (1,34 g, 10,45 mmol, 1 EQ. ) was added to the reaction install flask to boiling under reflux in a nitrogen atmosphere. The resulting reaction mixture was heated at approximately 100oC for 8-10 h to complete the reaction. The reaction mixture was cooled to ambient temperature, 20-25oC, was added butane-1-ol (sivali dry. The crude dry product was stirred in methanol (15 ml), the resulting suspension was filtered and the filter residue (product) was washed with methanol (5 ml) and dried in vacuum at 40-45oC. the Partially purified product was heated to boiling under reflux in a propane-2-OLE (45 ml) for 30 minutes, cooled, and the resulting suspension was filtered and the filter residue (product) was washed with propan-2-I (5 ml) and dried in vacuum at 40-45oC. the Obtained solid (3,22 g) was further purified by stirring in tetrahydrofuran (240 ml) at 20-25oC. the Insoluble solids were removed by filtration and containing the product, the filtrate was concentrated to 20 ml and was treated with heptane (20 ml). The resulting slurry product was filtered and the filter cake was washed with heptane (8 ml) and dried in vacuum at 40-45oC. Yield of 1.62 g (46,8%): so pl. 175-178oC; m/z 332 (m+l); spectral data identical with the data of example 2.

Example 10. Synthesis of tetrahydro-4-{3-[4-(1H-pyrazole-1-yl)phenyl]thio}phenyl-2H-Piran-4-carboxamide using solid NaOH and the phase transfer catalyst

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ.), DMSO (50 ml, 10 vol.), pyrazole (2,05 g, 30,17 mm is stirred at 140oC in nitrogen atmosphere for 2 to 6 hours. Upon completion the reaction was cooled (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ectothermy 20-25oC. Quenched the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6. ) to obtain the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). The white solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 5,42 g, which gave a yield of 95%. Analysis of the product confirmed its proposed structure.

Example 11. Synthesis of tetrahydro-4-{3-[4-(1H-imidazol-1 - yl)phenyl]thio}phenyl-2H-Piran-4-carboxamide using solid NaOH and the phase transfer catalyst

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ.), DMSO (50 ml, 10 vol.), the imidazole (2,05 g, 30,17 mmol, 2.0 equiv. ), sodium hydroxide (1,21 g, 30,17 mmol, 2.0 EQ.) and tetrabutylammonium (0,042 g, 0,151 mmol, 0.01 EQ.) was stirred at 140oC in nitrogen atmosphere is OK and ectothermy 20-25oC. Quenched the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6. ) to obtain the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). The white solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 5.35 g, which gave a yield of 93%. Analysis of the product was consistent with its proposed structure.

Example 12. Synthesis of tetrahydro-4-{3-[4-(1H-benzoimidazol-1 - yl)phenyl]thio} phenyl-2H-Piran-4-carboxamide using solid KOH and the phase transfer catalyst

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ. ), DMSO (50 ml, 10 vol.), benzoimidazol (of 3.56 g, 30,17 mmol, 2.0 equiv. ), potassium hydroxide (KOH contained 12% water) (1,96 g, 30,17 mmol, 2.0 EQ.) and tetrabutylammonium (0,042 g, 0,151 mmol, 0.01 EQ.) was stirred at 140oC in nitrogen atmosphere for 2 to 6 hours. Upon completion of the reaction the mixture was cooled (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ek hours, was filtered under vacuum and washed with water (28 ml, about 5,6.) with the receipt of the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). The white solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 6,34 g, which gave a yield of 98%. Analysis of the product is consistent with its proposed structure.

Example 13. Synthesis of tetrahydro-4-{3-[4-(1H-pyrazole-1-yl)phenyl]thio}phenyl-2H-Piran-4-carboxamide using only solid KOH

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ.), DMSO (50 ml, 10 vol.), pyrazole (2,05 g, 30,17 mmol, 2.0 equiv. ) and potassium hydroxide (KOH contained 12% water) (1,96 g, 30,17 mmol, 2.0 EQ.) was stirred at 140oC in nitrogen atmosphere for 22-24 hours. Upon completion of the reaction the mixture was cooled (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ectothermy 20-25oC. Then the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6.) with the receipt of the product. Then room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6. ). The white solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 5.53 g, which gave a yield of 97%. Analysis of the product confirmed its proposed structure.

Example 14. Synthesis of tetrahydro-4-{ 3-[4-(1H-imidazol-1-yl)phenyl]thio}phenyl-2H-Piran-4-carboxamide using only solid NaOH

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ.), DMSO (50 ml, 10 vol.), the imidazole (2,05 g, 30,17 mmol, 2.0 equiv. ) and sodium hydroxide (1,21 g, 30,17 mmol, 2.0 EQ.) was stirred at 140oC in nitrogen atmosphere for 22-24 hours. Upon completion of the reaction the mixture was cooled (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ectothermy 20-25oC. Then the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6.) with the receipt of the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). The white solids were placed in sakurazuka is consistent with its proposed structure.

Example 15. Synthesis of tetrahydro-4-{3-[4-(1H-benzoimidazol-1 - yl)phenyl]thio} phenyl-2H-Piran-4-carboxamide using only solid NaOH

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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ. ), DMSO (50 ml, 10 vol.), benzoimidazol (of 3.56 g, 30,17 mmol, 2.0 equiv. ) and sodium hydroxide (1,21 g, 30,17 mmol, 2.0 EQ.) was stirred at 140oC in nitrogen atmosphere for 22-24 hours. Upon completion the reaction was cooled (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ectothermy 20-25oC. Slaked the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6.) with the receipt of the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). Light brown solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 6,27 g, which gave a yield of 97%. It was shown that the analysis of the product is consistent with its proposed structure.

Example 16. Synthesis of tetrahydro-4-{3-[4-(1H-pyrazole-1-yl)Hairdryer Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ.), DMSO (50 ml, 10 vol.), pyrazole (2,05 g, 30,17 mmol, 2.0 equiv.) sodium hydroxide (1,21 g, 30,17 mmol, 2.0 EQ.) and cesium carbonate (catalyst) (0,246 g, 0,754 mmol, of 0.05 EQ.) was stirred at 140oC in nitrogen atmosphere for 4-6 hours. Upon completion the reaction was cooled (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ectothermy 20-25oC. Then the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6.) with the receipt of the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). The white solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 5.53 g, which gave a yield of 97%. Analysis of the product confirmed its proposed structure.

Example 17. Synthesis of tetrahydro-4-{ 3-[4-(1H-imidazol-1-yl)phenyl]thio}phenyl-2H-Piran-4-carboxamide using solid KOH and catalyst Cs2CO3< / BR>
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Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ.), DMSO (50 m is cesium (catalyst) (0,246 g, 0,754 mmol, of 0.05 EQ.) was stirred at 140oC in nitrogen atmosphere for 4-6 hours. Upon completion of the reaction the mixture was cooled (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ectothermy 20-25oC. Then the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6.) with the receipt of the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). The white solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 5.29 g, which gave a yield of 92%. Analysis of the product was consistent with its proposed structure.

Example 18. Synthesis of tetrahydro-4-{3-[4-(1H-benzoimidazol-1 - yl)phenyl]thio} phenyl-2H-Piran-4-carboxamide using solid NaOH and catalyst Cs2CO3< / BR>
< / BR>
Tetrahydro-4-[3-(4-forfinal)thio] phenyl-2H-Piran-4-carboxamide (5.0 g, 15,09 mmol, 1 EQ. ), DMSO (50 ml, 10 vol.), benzoimidazol (of 3.56 g, 30,17 mmol, 2.0 equiv. ), sodium hydroxide (1,21 g, 30,17 mmol, 2.0 EQ.) and cesium carbonate (catalyst) (0,246 g, 0,754 was ladli (<30C) and extinguished with water (50 ml, 10 vol). This gave a residue and ectothermy 20-25oC. Then the reaction mixture was cooled to room temperature and granulated for 1 hour, filtered under vacuum and washed with water (28 ml, about 5,6.) with the receipt of the product. The product is then again suspended in water (55 ml, about 11.) at 60oC for 1 hour. The suspension was allowed to cool to room temperature and was stirred for 1 hour, then filtered under vacuum and washed with water (28 ml, about 5,6.). The white solids were placed in a vacuum thermostat at 40oC for 24-48 hours, the Number of the obtained product was 6,27 g, which gave a yield of 97%. Analysis of the product was consistent with its proposed structure.

1. The method of obtaining the compounds of formula (1.3.0)

< / BR>
where part of the molecule of formula (1.3.1)

< / BR>
is the electron monocyclic or benzododecinium bicyclic N-heterocyclic group containing two nitrogen atom, of formula(1.3.2), (1.3.3), (1.3.4) or (1.3.5):

< / BR>
< / BR>
where * is the symbol that represents the attachment point of the molecule of the formula(1.3.2), (1.3.3), (1.3.4) or (1.3.5);

R7and R8independently selected from the group comprising H; (C1-C4)alkyl straight or razvetvleniya-4-[3-(4-forfinal)thio]phenyl-2H-Piran-4-carboxamide of formula (2.0.0)

< / BR>
and (2) having a shortage of electrons monocyclic or benzododecinium bicyclic N-heterocycle containing two nitrogen atom, of formula(1.3.6), (1.3.7), (1.3.8) or (1.3.9):

< / BR>
< / BR>
where R7and R8have the above values;

(3) in an aprotic solvent (4) in the presence of a strong base in solid form selected from the group including sodium hydroxide and potassium hydroxide, and (optional) (5) in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, followed (b) specified by heating the reaction mixture under nitrogen atmosphere, resulting in a compound of formula (1.3.0).

2. The compound obtained by the method of p. 1, which is selected from the group including

tetrahydro-4-{ 3-[4-(1H-imidazol-1-yl)phenyl] thio} phenyl-2H-Piran-4-carboxamide;

tetrahydro-4-{ 3-[4-(1H-benzoimidazol-1-yl)phenyl] thio}phenyl-2H-Piran-4-carboxamide;

tetrahydro-4-{ 3-[4-(1H-pyrazole-1-yl)phenyl] thio}phenyl-2H-Piran-4-carboxamide and

tetrahydro-4-{3-[4-(4-methyl-1H-pyrazole-1-yl)phenyl]thio}

phenyl-2H-Piran-4-carboxamide.

3. The method of obtaining the compounds of formula (1.0.0)

< / BR>
includes (a) creating reacts/BR> and (2) 2-methylimidazole, (3) in an aprotic solvent, (4) in the presence of a strong base in solid form selected from the group including sodium hydroxide and potassium hydroxide, and (optional) (5) in the presence of catalytic amounts of carbonate, cesium, Cs2CO3or phase transfer catalyst, followed (b) specified by heating the reaction mixture under nitrogen atmosphere, resulting in a specified compound of formula (1.3.0).

4. The method of obtaining essentially pure mesilate salt of formula (1.0.1)

< / BR>
comprising (a) obtaining the compounds of formula (2.0.0)

< / BR>
providing (1) formation of a reaction mixture comprising (i) tetrahydro-4-(3-bromophenyl)-2H-Piran-4-nitrile of the formula (3.2.0)

< / BR>
(ii) 4-portifino formula (4.0.0)

< / BR>
(iii) in a solvent selected from the group comprising isopropyl alcohol, sec-butyl alcohol, isopentylamine alcohol and 2-heptanol, not necessarily in the form of its aqueous mixture, (iv) in the presence of a strong base selected from the group including sodium hydroxide and potassium hydroxide, and, in addition, (v) in the presence of a catalyst containing a metal of the transition series, including independently selected from the group consisting of the sets the formula (2.0.0) (b) formation of a reaction mixture, consisting of the compounds of formula (2.0.0) and the compounds of formula (1.3.10)

< / BR>
(1) in an aprotic solvent, (2) in the presence of a strong base in solid form selected from the group including sodium hydroxide and potassium hydroxide, and (optional) (3) in the presence of catalytic amount of cesium carbonate or the phase transfer catalyst with subsequent (s) specified by heating the reaction mixture in nitrogen atmosphere with the formation of the compounds of formula (1.0.0)

< / BR>
then (d) the formation of a concentrated solution in methanol of the compounds of formula (1.0.0) contained in the specified heated reaction mixture, (1) filtering the specified solution in methanol still in a hot state and then by concentration of the obtained solution of the filtrate, (2) processing the specified solution filtrate methanesulfonic acid, (3) inducing crystallization of the compounds of formula (1.0.0) from the solution of the filtrate by displacing the residual methanol in the specified solution of the filtrate with ethyl acetate, and (4) removing after that, essentially, pure mesilate salt of formula (1.0.1) in crystalline form.

5. The method according to p. 4, where the specified complex of palladium metal on a hundred)3R]4Pd (0);

tetrakis(methyldiphenylphosphine)palladium (0), [(C6H5)2RSN3]4Pd (0);

TRANS-dichlorobis(methyldiphenylphosphine)palladium (II), [(C6H5)2RSN3]2dl2; the adduct dichlorobis[Methylenebis(diphenylphosphine)]dipalladium-dichloromethane;

dichlorobis(triphenylphosphine)palladium (II), [(C6H5)3R]2PdCl2;

adduct of Tris(dibenzylideneacetone)dipalladium (0)-chloroform, (C6H5SN=SSON= SNA6H5)2PD2l3;

bis(dibenzylideneacetone)palladium (0), (C6H5SN=SSON=SNA6H5)2Pd;

[1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II), complex with dichloromethane;

bis[1,2-bis(diphenylphosphino)ethane]palladium (II) and

dimer (-allyl)palladium (II) chloride.

6. The method according to p. 4, where at stage (b) (1) specified aprotic solvent is dimethylsulfoxide.

7. The method according to p. 4, where at stage (b) (2) indicated a strong Foundation in solid form is sodium hydroxide in powder form.

8. The method according to p. 4, where the specified phase transfer catalyst is a Tetra-n-butylammonium (TWAS).

 

Same patents:

The invention relates to substituted chromalusion (thio)ureas of the formula (I):

< / BR>
where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;

R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;

R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

R (2c) and R (2e), which are identical or different, denote hydrogen or alkyl with 1 or 2 C-atoms;

R (3) denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, CH2-cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, or CF3;

Q represents (CH2)n;

where n = 1 or 2;

Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

or

A denotes the residue of a saturated or unsaturated lactam of the formula:

< / BR>
where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;

or

A denotes the residue of a bicyclic system of the formula:

< / BR>
< / BR>
< / BR>
< / BR>
and their physiologically acceptable salts

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis

-alaninemia and their derivatives, method for the treatment glycolipoprotein diseases, the prevention of ischemic myocardial damage, the pharmaceutical composition" target="_blank">

The invention relates to derivatives of indole-2-carboxamide that can be used as inhibitors of glycogen phosphorylase, and to methods of treatment of glycogenolysis-dependent diseases or conditions using these compounds and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of chromone General formula 1, in which ring a is unsubstituted or one-deputizing halogen, and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts, also describes a method of production thereof and pharmaceutical composition based on compounds of the formula I, which has antagonistic activity against neirokinina 1

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: bioactive compounds.

SUBSTANCE: invention relates to new 3-phenyl-1,2,4-benzotriazines and their derivatives of general formula 1

wherein R1 and R2 are independently fluorine or C1-C4-alkoxy, optionally substituted with halogen or tetrahydrofuryl. Compounds of present invention are useful in treatment and prophylaxis of diseases, induced by pathogenic for human and animals viruses including pathogenic for human orthopoxviruses, as well as postvaccinal sequelae.

EFFECT: compounds with improved antiviral activity.

1 cl, 12 ex, 7 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

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