Thiazole compound and application thereof

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

 

The technical FIELD RELATES TO IZABERETEOF

The present invention relates to a new connection thiazole. The present invention additionally relates to pharmaceutical compositions comprising a compound of thiazole.

The LEVEL of TECHNOLOGY

Recent studies have shown that cyclic adenosine 3',5'-monophosphate (cAMP), which acts as an intracellular second messenger that regulates the activity of cells of the inflammatory infiltrate, such as lymphocytes, neutrophils, eosinophils, mast cells, and so forth. It is known that cAMP is decomposed to 5'-AMP, which does not act as a messenger, under the influence of phosphodiesterase (PDE), and PDE adjusts intramolecular concentration cAMP. Because PDE has such a close relationship with intramolecular concentration cAMP, believe that the regulation of PDE activity is effective for diseases for which it is expected that therapeutic effects are manifested in the regulation increase or decrease cAMP concentration (non-Patent documents 1 and 2).

Known eleven types of PDE isoenzymes (PDEs 1-11), which according to their distribution in vivo is different for different tissues (non-Patent documents 3 and 4). As reported, inhibitors specific to PDE4, inhibit the function of cells of the inflammatory infiltrate, and believe that they are useful when the situation is epitah, asthma and similar inflammatory allergic diseases and multiple sclerosis, rheumatoid arthritis and similar autoimmune diseases (non-Patent documents 5-14).

Up to the present time as a PDE inhibitor for the treatment of asthma used theophylline. However, it is known that theophylline is not specific inhibits different PDE isoenzymes, and therefore inhibits the activity not only PDE4, but also PDE3 and other isoenzymes. Assume that PDE3 causes stimulation of the cardiac activity and/or has a Central action and positive inotropic and chronotropic action on the heart (Patent document 15). Therefore, the use of theophylline as a PDE inhibitor raises the problem of developing side effects.

Describes several compounds with specific inhibitory activity on PDE 4 (Patent documents 1 and 2). However, such PDE4 inhibitors have problems in that they bind the receptor with high affinity to rolipram (HARBS) in the Central nervous system and gastrointestinal tract and produce side effects such as vomiting and nausea, or have drawbacks in that they are insufficient PDE4 inhibitory activity. So famous still PDE4 inhibitors were not used for clinical purposes as therapeutic agents.

Given this known to the achieved level is ehniki the development of compounds that effectively shows no side effects specific inhibitory activity on PDE4 is desirable.

[Patent document 1] Japanese Unexamined Patent Publication No.1975-157360

[Patent document 2] Japanese Unexamined Patent Publication No. 2003-64057

[Non-patent document 1] Trends Pharmacol. Sci. 18: 164-170, 1997

[Non-patent document 2] Immunopharmacology 47: 127-162, 2000

[Non-patent document 3] J. Allergy. Clin. Immunol. 108: 671-680, 2001

[Non-patent document 4] Mol. Pharmacol. 64: 533-546, 2003

[Non-patent document 5] Am. J. Respir. Crit. Care. Med. 157: 351-370, 1998

[Non-patent document 6] Monaldi. Arch. Chest. Dis. 57: 48-64, 2002

[Non-patent document 7] Arzneimittelforschung 44: 163-165, 1994

[Non-patent document 8] Eur. J. Pharmacol. 229: 45-53,1992

[Non-patent document 9] Inflammation 17: 25-31, 1993

[Non-patent document 10] Nat. Med. 1: 244-248, 1995

[Non-patent document 11] J. Neuroimmunol. 79: 54-61, 1997

[Non-patent document 12] Clin. Exp. Immunol. 100: 126-132, 1995

[Non-patent document 13] Clin. Exp. Immunol. 108: 415-419, 1997

[Non-patent document 14] J. Immunol.159: 6253-6259, 1997

[Non-patent document 15] Physiol. Rev. 76: 725-748, 1995

[Non-patent document 16] J. Clin. Pathol. 54: 577-589, 2001

[Non-patent document 17] Curr. Drug Targets Inflamm. Allergy 1: 377-392, 2002

[Non-patent document 18] Curr. Opin. Pharmacol. 3: 449-455, 2003

[Non-patent document 19] J. Infus. Nurs. 26: 319-325, 2003

Description of the INVENTION

Problems to be solved by the invention of

The aim of the present invention is the information and communications technology the above problems of the prior art. In particular, the present invention is to develop a new thiazole compounds, which has a specific inhibitory activity on PDE4, and pharmaceutical compositions comprising this compound. Another objective of the present invention is to develop a PDE4 inhibitor that exhibits specific inhibitory activity for PDE4. An additional objective of the present invention is to develop a preventive or therapeutic agent for atopic dermatitis and treatment of atopic dermatitis.

Solutions to problemsm

The authors of the present invention searched for a new connection, which has a PDE4 inhibitory activity and found that the connection of the thiazole new structure has high PDE4 inhibitory activity, which is highly specific and has no relation to the activity of binding HARBS. The inventors have additionally discovered that the connection thiazole shows the preventive and therapeutic effects in atopic dermatitis because of its PDE4 inhibitory activity.

The inventors have additionally discovered that the connection thiazole also exhibits inhibitory activity in the production of TNF-α inhibitory activity with the production of IL-4. In these chronic inflammatory diseases such as autoimmune for the of Alemania and allergic diseases, cytokines produced by immune cells known as important mediators of inflammation. Among these cytokines, believe that play an important role of tumor necrosis factor (TNF)-α and interleukin (IL)-4 (non-Patent documents 16 to 19). Accordingly, compounds with inhibitory activity to the production of TNF-α or with inhibitory activity for the production of IL-4 are clinically useful.

The present invention was created as a result of further studies based on the above conclusions.

In the present invention are the following compounds thiazole.

1. The compound represented by formula (1), its optical isomer or its salt:

where R1 is CI-C1-6alkoxyphenyl group;

R2 is any one of the following groups (a)-(t):

(a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) phenoxy the Rupp, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6the alkyl group or groups, (a-27) phenyl-C1-6alkoxygroup;

(b) naftilos group;

(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (c-1) hydroxyl groups, (c-2) C1-6alkyl groups, (c-3) C1-6alkoxygroup, (c-4) phenyl-C1-6alkoxygroup and (c-5) C1-6alkoxycarbonyl groups;

(d) shriley group, in which the furan ring may be substituted C1-6alkyl group or groups;

(e) a thienyl group, in which the thiophene ring may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2) C1-6alkyl groups, and (e-3) C1-6alkoxygroup;

(f) isox soleley group, in which isoxazolidine ring may be substituted C1-6alkyl group or groups;

(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups;

(h) pyrrolidino group, in which the pyrrole ring may be substituted C1-6alkyl group or groups;

(i) imidazolidine group, in which the imidazole ring may be substituted C1-6alkyl group or groups;

(j) tetrazolyl group;

(k) personalni group;

(l) tiantianle group;

(m) benzothiazole group;

(n) indolines group, in which the indole ring may be substituted C1-6alkoxygroup or groups;

(o) benzimidazolyl group, in which the benzimidazole ring may be substituted C1-6alkyl group or groups;

(p) indazolinone group;

(q) pinolillo group;

(r) 1,2,3,4-tetrahydroquinoline group, in which 1,2,3,4-tetrahydroquinoline ring may be substituted by oxopropoxy or groups;

(s) khinoksalinona group and

(t) 1,3-benzodioxolyl group and

A is one of the following groups (i)to(vi):

(i) -CO-B-, where B is C1-6 alkalinous group;

(ii) -CO-Ba, where Ba is C2-6alkenylamine group;

(iii) -CH(OH)-B-, where B is defined above;

(iv) the PINES(CR3)-Bb-, where R3 is C1-6alkyl group and Bb is a C1-6alkalinous group and

(v) -Su where Su is C2-6alkalinous group.

2. Connection, optical isomer or salt according to claim 1 wherein in the formula (1) R1 is 3,4-di-C1-6alkoxyphenyl group.

3. Connection, optical isomer or salt according to claim 1 wherein in the formula (1) R1 is 3,4-dimethoxyphenyl group or 3,4-diethoxyaniline group.

4. Connection, optical isomer or salt according to paragraphs 1 to 3, where in the formula (1) R2 is (a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy groups, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-61-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6the alkyl group or groups, (a-27) phenyl-C1-6alkoxygroup;

(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (c-1) hydroxyl groups, (c-2) C1-6alkyl groups, (c-3) C1-6alkoxygroup, (c-4) phenyl-C1-6alkoxygroup, and (c-5) C1-6alkoxycarbonyl groups;

(d) shriley group, in which the furan ring may be substituted C1-6alkyl group or groups;

(e) a thienyl group, in which the thiophene ring may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2) C1-6alkyl groups, and (e-3) C1-6alkoxygroup;

(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C alkoxygroup or groups;

(h) pyrrolidino group, in which the pyrrole ring may be substituted C1-6alkyl group or groups; or

(i) imidazolidine group, in which the imidazole ring may be substituted C1-6alkyl group or groups.

5. Connection, optical isomer or salt according to paragraphs 1 to 3, where in the formula (1), R2 is (a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolidine GRU is p, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6alkyl group or groups, and (a-27) phenyl-C1-6alkoxygroup;

(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (c-1) hydroxyl groups, (c-2) C1-6alkyl groups, (c-3) C1-6alkoxygroup, (c-4) phenyl-C1-6alkoxygroup and (c-5) C1-6alkoxycarbonyl groups; or

(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups.

6. Connection, optical isomer, or salt of items 1-5, where in the formula (1), A is (i) -CO-B-, where B is a methylene group, ethylene group or trimethylene group; (ii) -CO-Ba, where Ba is vinylidene group; (iii) -CH(OH)-B-, where B is a methylene group or ethylene group; (iv) -COCH(CR3)-Bb-, where R3 is a methyl group, ethyl group or tertbutylphenol group and Bb is a methylene group or ethylene group; or (v) -Su where Su is the ethylene group, trimethylene group or tetramethylene group.

7. Connection, optical isomer, or salt of items 1-5, where in the formula (1), A is (i) -CO-B-, where B is an ethylene group; (iii) -CH(OH)-B-, where B is an ethylene group; (iv) -COCH(CR3)-Bb-, where R3 is a methyl group and Bb is a methylene group; or (v) -Su where Su is trimethylene group.

8. Connection, optical isomer or salt according to claim 1 wherein in the formula (1), R1 is 3,4-di-C1-6alkoxyphenyl group; R2 is (a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio is, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6the alkyl group or groups, (a-27) phenyl-C1-6alkoxygroup;

(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (c-1) hydroxyl groups, (c-2) C1-6alkyl groups, (c-3) C1-6alkoxygroup, (c-4) phenyl-C1-6alkoxygroup and (c-5) C1-6alkoxycarbonyl groups;

(d) shriley group, in which the furan ring may be substituted C1-6alkyl group or groups;

(e) a thienyl group, in which the thiophene ring may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2) C1-6alkyl groups, and (e-3) C1-6alkoxygroup;

(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups;

(h) pyrrolidino group, in which the pyrrole ring may be substituted by one or more C1-6alkyl groups;

(i) imidazolidin the th group, in which the imidazole ring may be substituted C1-6alkyl group or groups; and A is (i) -CO-B-, where B is defined above; (ii) -CO-Ba, where Ba is defined above; (iii) -CH(OH)-B-, where B is defined above; (iv) -COCH(CR3)-Bb-, where R3 and Bb defined above; or (v) -Su where Su is defined above.

9. Connection, optical isomer or salt according to claim 1 wherein in the formula (1) R1 is 3,4-di-C1-6alkoxyphenyl group;

R2 is (a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) p is retailing groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6the alkyl group or groups, (a-27) phenyl-C1-6alkoxygroup;

(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (c-1) hydroxyl groups, (c-2) C1-6alkyl groups, (c-3) C1-6alkoxygroup, (c-4) phenyl-C1-6alkoxygroup and (c-5) C1-6alkoxycarbonyl groups;

(d) shriley group, in which the furan ring may be substituted C1-6alkyl group or groups;

(e) a thienyl group, in which the thiophene ring may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2) C1-6alkyl groups, and (e-3) C1-6alkoxygroup;

(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups;

(h) pyrrolidino group, in which the pyrrole ring may be substituted C1-6alkyl group or groups;

(i) imidazolidine group, in which the imidazole ring can b the th substituted C 1-6alkyl group or groups; and

A is (i) -CO-B-, where B is a methylene group, ethylene group or trimethylene group; (ii) -CO-Ba, where Ba is vinylidene group; (iii) -CH(OH)-B-, where B is a methylene group or ethylene group; (iv) -COCH(CR3)-Bb-, where R3 is a methyl group, ethyl group or tertbutylphenol group and Bb is a methylene group or ethylene group; or (v) -G-, where Su is ethylene group, trimethylene group or tetramethylene group.

10. Connection, optical isomer or salt according to claim 1 wherein in the formula (1) R1 is 3,4-di-C1-6alkoxyphenyl group;

R2 is (a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15)C 1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6the alkyl group or groups, (a-27) phenyl-C1-6alkoxygroup;

(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (c-1) hydroxyl groups, (c-2) C1-6alkyl groups, (c-3) C1-6alkoxygroup, (c-4) phenyl-C1-6alkoxygroup and (c-5) C1-6alkoxycarbonyl groups; or

(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups; and

A is (i) -CO-B-, where B is an ethylene group; (iii) -CH(OH)-B-, where B is an ethylene group; (iv) the PINES(CR3)-Bb-, where R3 is a methyl group and Bb is a methylene group; or (v) -Su where Su is trimethylene group.

Now izaberete the s additionally offers the following applications for the above compounds, thiazole.

11. Pharmaceutical composition comprising the compound, an optical isomer or salt according to paragraphs 1 to 10.

12. Inhibitor of phosphodiesterase 4, comprising as active ingredient a compound, an optical isomer or salt according to paragraphs 1 to 10.

13. The inhibitor of the production of IFN-α, comprising as an active ingredient salt, optical isomer or salt according to paragraphs 1 to 10.

14. The inhibitor of IL-4, comprising as an active ingredient salt, optical isomer or salt according to paragraphs 1 to 10.

15. Preventive or therapeutic agent for atopic dermatitis, comprising as an active ingredient salt, optical isomer or salt according to paragraphs 1 to 10.

16. Method for the treatment of atopic dermatitis, including the stage of introduction of the human or animal mammal an effective amount of a compound, optical isomers or salts of items 1-10.

17. Application connections, optical isomer or salt according to paragraphs 1 to 10 to obtain a preventive or therapeutic agent for atopic dermatitis.

18. Application connections, optical isomer or salt according to paragraphs 1 to 10 to obtain an inhibitor of phosphodiesterase 4.

19. Application connections, optical isomer or salt according to paragraphs 1 to 10 for reception of an inhibitor of the production of IFN-α.

20. Application connections, optical isomer, or salt is UNCTAD 1-10 for reception of an inhibitor in the production of IL-4.

The PREFERRED embodiment of the INVENTION

The present invention is described in more detail below.

(I) a Compound represented by the formula (1)

In the formula (1) R1 is CI-C1-6alkoxyphenyl group, that is, phenyl group, substituted with two C1-6linear or branched CNS groups. Specific examples include 2,3-acid, 2,4-acid, 2,5-acid, 2,6-acid, 3,4-acid, 3,5-acid, 2,3-dioxyphenyl, 2,4-dioxyphenyl, 2.5-dioxyphenyl, 2,6-dioxyphenyl, 3,4-dioxyphenyl, 3,5-dioxyphenyl, 2,3-dibromobiphenyl, 2,4-dibromobiphenyl, 2.5-dibromobiphenyl, 2,6-dibromobiphenyl, 3,4-dibromobiphenyl, 3,5-dibromobiphenyl, 2,3-diisopropylphenyl, 2,4-diisopropylphenyl, 2.5-diisopropylphenyl, 2,6-diisopropylphenyl, 3,4-diisopropylphenyl, 3,5-diisopropylphenyl, 2,3-dibutoxy, 2,4-dibutoxy, 2.5-dibutoxy, 2,6-dibutoxy, 3,4-dibutoxy, 3,5-dibutoxy, 2,3-diphenoxyethane, 2,4-diphenoxyethane, 2.5-diphenoxyethane, 2,6-diphenoxyethane, 3,4-diphenoxyethane, 3,5-diphenoxyethane 2,3-thexrooster, 2,4-thexrooster, 2.5-thexrooster, 2,6-thexrooster, 3,4-thexrooster, 3,5-thexrooster and other similar. It is preferable that R1 in the formula (1) was 3,4-di-C1-6alkoxyphenyl group is, more preferably 3,4-di-C1-3alkoxyphenyl group, and particularly preferably 3,4-dimethoxyphenyl group or 3,4-diethoxyaniline group.

In the formula (1) R2 represents (a) phenyl group, (b) naftalina group, (c) pyridyloxy group, (d) follow group, (e) a thienyl group, (f) isoxazolyl group, (g) thiazolidine group, (h) pyrrolidinyl group, (i) imidazolidinyl group, (j) tetrazolyl group, (k) personilnya group, (l) tentionally group, (m) benzothiazoline group, (n) indolenine group, (o) benzimidazolyl group, (p) imidazolidinyl group, (q) pinolillo group, (r) 3,4-dihydrocarbamazepine group (s) khinoksalinona group or (t) of 1,3-benzodioxolyl group.

When R2 is (a) phenyl group, the phenyl ring of the phenyl group may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyl is a system of groups, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups and (a-26) piperazinylcarbonyl groups that may be substituted C1-6alkyl group or groups. When R2 is a substituted phenyl group, the number of substituents is not limited and may be, for example, from 1 to 5 and preferably from 1 to 3.

When R2 is (c) peredelnoj group, pyridine ring peredelnoj group may be substituted by one or more members selected from the group consisting of (c-1) hydroxyl groups, (c-2) C1-6alkyl groups, (c-3) C1-6alkoxygroup and (c-4) phenyl-C1-6alkoxygroup. When R2 is substituted peredelnoj group, the number of substituents is not limited and may be, for example, from 1 to 4, and preferably from 1 to 3.

When R2 is (d) shriley group, furan ring shriley group may be substituted C1-6alkyl group or groups. When R2 is substituted shriley group, the number of mandated the residents is not limited and may be, for example, from 1 to 3 and preferably from 1 to 2.

When R2 is (e) a thienyl group, a thiophene ring thienyl group may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2) C1-6alkyl groups, and (e-3) C1-6alkoxygroup. When R2 is a substituted thienyl group, the number of substituents is not limited and may be, for example, from 1 to 3 and preferably from 1 to 2.

When R2 is (f) isoxazolidine group, isoxazolidine ring isoxazoline group may be substituted C1-6alkyl group or groups. When R2 is substituted isoxazoline group, the number of substituents is not limited and may be, for example, 1 or 2.

When R2 is (g) thiazolidine group, thiazole ring thiazolidine group may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups. When R2 is substituted thiazolidine group, the number of substituents is not limited and may be, for example, 1 or 2.

When R2 is (h) pyrrolidino group, pyrrole ring pyrrolidino group may be substituted C1-6alkyl group or groups. When R2 is substituted pyrrolidino group, the number of substituents is not limited and may be, for example, from 1 to 4, and preferably 1 or 2.

When R2 is (i) imidazolidine group, imidazole ring imidazolidine group may be substituted C1-6alkyl group or groups. When R2 is substituted imidazolidine group, the number of substituents is not limited and may be, for example, from 1 to 3 and preferably 1 or 2.

When R2 is (o) benzimidazolyl group, a benzimidazole ring benzimidazolyl group may be substituted C1-6alkyl group or groups. When R2 is substituted benzimidazolyl group, the number of substituents is not limited and may be, for example, from 1 to 5 and preferably from 1 to 3.

When R2 is a (n) indolines group, indole ring indolines group may be substituted C1-6alkyl group or groups. When R2 is substituted indolines group, the number of substituents is not limited and may be, for example, from 1 to 6 and preferably from 1 to 3.

When R2 is (r) 1,2,3,4-tetrahydroquinoline group, 1,2,3,4-tetrahydroquinoline ring 1,2,3,4-tetrahydroquinoline group may be substituted by oxopropoxy or groups. When R2 is oxazolidines 1,2,3,4-tetrahydroquinoline group, the number of oxoprop is not limited and may be, for example, from 1 to 3 and preferably 1 or 2.

Terms of IP is alzhemier in the description of groups, represented by R2 in the formula (1), are defined as follows.

The halogen atoms include fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, and so on.

C1-6alkyl groups are linear or branched alkyl groups having from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, terbutyl, n-pentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl and so on.

Unsubstituted or halogen-substituted C1-6alkyl groups are linear or branched alkyl groups having from 1 to 6 carbon atoms as defined above, or such alkyl groups substituted by from 1 to 7 halogen atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, terbutyl, n-pentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, dichloromethyl, 2,2,2-triptorelin, pentafluoroethyl, 2-chloroethyl, 3,3,3-cryptochromes, heptafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-tripcomputer, 4,4,4,3,3-PENTACARBONYL, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-tryptophanyl, 5-chloropentyl, 6,6,6-triptorelin, 6-chlorhex and so on.

C1-6CNS groups are groups IFH 1-6alkyl group as defined above, and oxygen. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tributoxy, verboeket, n-pentox, neopentane, n-hexyloxy, isohexane, 3 methylpentane and so on.

Unsubstituted or halogen-substituted C1-6CNS group are C1-6CNS groups defined above, or CNS such groups substituted by from 1 to 7 halogen atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tributoxy, verboeket, n-pentox, neopentane, n-hexyloxy, isohexane, 3 methylpentane, formatosi, deformedarse, triptoreline, chloromethoxy, dichloromethoxy, trichlormethane, bromoethoxy, dibromethane, dichloromethoxy, 2,2,2-triptoreline, pentaborate, 2-chloroethoxy, 3,3,3-cryptocracy, heptafluoropropoxy, heptafluoroisopropoxy, 3 chloropropoxy, 2-chloropropoxy, 3 bromopropane, 4,4,4-triptoreline, 4,4,4,3,3-pentafluorobutane, 4-chloroethoxy, 4-bromoethoxy, 2-chloroethoxy, 5,5,5-triterpenes, 5-chlorphenoxy, 6,6,6-triptoreline, 6-chlorhexidine and so on.

C1-6alkoxy-C1-6CNS group are C1-6CNS groups, substituted from 1 to 7 (C1-6CNS groups defined above. Examples include methoxyethoxy, 2-meth is xiaoxi, 3 methoxypropane, 4-methoxybutyl, 5-methoxyphenoxy, 6-methoxyacetate, ethoxyethoxy, 1 ethoxyethoxy, 2-ethoxyethoxy, 3 ethoxypropane, 2-isopropoxyphenoxy, tributoxyethyl, 2-(tributoxy)ethoxy, 3-(tributoxy)propoxy, 6-(tributoxy)hexyloxy, 4-(tributoxy)butoxy and so on.

Amino-C1-6CNS group which may be substituted C1-6alkyl group or groups are aminoalkoxide groups, in which CNS fragment is C1-6linear or branched CNS group and in which from 1 to 2 C1-6alkyl groups can be substituted on the nitrogen atom. Examples of such aminoalkoxide include aminoethoxy, 2-aminoethoxy, 1 aminoethoxy, 3 aminopropoxy, 4-aminobutoxy, 5-aminopentanoic, 6-aminohexyl, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethyl, 1 ethylaminoethanol, 2-propylaminoethyl, 3 isopropylidenedioxy, 4-isopropylimidazole, 4-butylimidazole, 4-tertbutylbenzene, 5-intellinetics, 6-exelonexelon, dimethylaminoethoxy, 2-diethylaminoethoxy, 2-dimethylaminoethoxy, (N-ethyl-N-propylamino)methoxy, 2-(N-methyl-N-hexylamino)ethoxy and so on.

C1-6alkoxycarbonyl groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl the ilen, butoxycarbonyl, tertbutoxycarbonyl, ventilatsioonile, hexyloxyphenol and other C1-6linear or branched alkoxycarbonyl group.

C1-6alkanoyloxy include, for example, formyloxy, atomic charges, propionyloxy, butyryloxy, isobutyryloxy, pentanoate, tertBUTYLPEROXY, hexanoate, and other C1-6linear or branched alkanoyloxy.

C1-6alcoholnye groups include, for example, formyl, acetyl, propionyl, butyryloxy, isobutyryloxy, pentanoyl, tertbutyloxycarbonyl, hexanoyl and other C1-6linear or branched alcoholnye group.

C1-6alkylcarboxylic groups include, for example, methylcarbamoyl, ethylcarbitol, profilirovannuju, isopropylcarbamate, butylcarbamoyl, tributylammonium, intelceremony, hexylberberine and other C1-6linear or branched alkylcarboxylic group.

Amino group which may be substituted C1-6alkyl group or groups include, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tertbutylamine, pentylamine, hexylamine, dimethylamino, diethylamino, dipropylamino, dibutylamino, diphenhydamine, digoxigenin, N-methyl-N-ethylamino, N-ethyl-N-is propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino and other amino group which may have 1 or 2 C1-6linear or branched alkyl groups as substituents.

C1-6alkanolamine groups include, for example, formylamino, acetylamino, propionamido, bucillamine, isobutylamino, pentanediamine, tributylammonium, exonerating and other C1-6linear or branched alkanolamine group.

C1-6ancilliary include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tributyltin, pentylthio, hexylthio and other C1-6linear or branched ancilliary.

Piperazinylcarbonyl group which may be substituted C1-6alkyl group or groups include, for example, piperazinylcarbonyl, methylpiperidino, ethylpiperidine, propylpiperazine, isopropylaminocarbonyl, isopropylaminocarbonyl, butyldiphenylchlorosilane, tertbutyloxycarbonyl, interpopulational, exelperceirrimageyoy and other piperazinylcarbonyl group which may have a C1-6linear or branched alkyl group or groups as substituents.

Phenyl-C1-6CNS groups include, nab is emer, benzyloxy, penetrate, 3 phenylpropoxy, 4-phenylbutane, 5-phenylpentane, 6-phenylhexanoic and so on.

Preferably, R2 in the formula (1) was (a) phenyl group, (c) peredelnoj group, (d) shriley group, (e) a thienyl group, (g) thiazolidine group, (h) pyrrolidino group or (i) imidazolidine group and more preferably is (a) phenyl group, (c) peredelnoj group, or (g) thiazolidine group.

In the formula (1) is A (i) -CO-B-, where b is a C1-6alkalinous group, (ii) -CO-Ba, where Ba is C2-6alkalinous group, (iii) -CH(OH)-B-, where B is defined above, (iv) the PINES(CR3)-Bb-, where R3 is C1-6alkyl group and Bb is a C1-6alkalinous group, or (v) -Su where Su is C2-6alkalinous group. In A in Formula (1), B, Ba or Bb are associated with a thiazole ring.

The terms used to describe groups represented by A in formula (1), are defined as follows.

C1-6alkylene groups include, for example, methylene, ethylene, trimethylene, 2-methyltrienolone, 2,2-dimethyltrimethylene, 1-methyltrienolone, metilbutilovy, ethylmethylamino, tetramethylene, pentamethylene, hexamethylene and other C1-6linear or branched alkylene group.

C2-6alkylene groups include, for example, ethylene, trimethylene, 2-meth is trimethylene, 2,2-dimethyltrimethylene, 1-methyltrienolone, metilbutilovy, ethylmethylamino, tetramethylene, pentamethylene, hexamethylene and other C2-6linear or branched alkylene group.

C2-6alkenylamine groups include, for example, vinylidene, propylene, butenylamine and other C2-6linear or branched alkenylamine group.

The term "C1-6alkyl group"used in the description of A in the formula (1)has the same meaning as R2.

Preferably, A in the formula (1) was (i) -CO-B-, where B is a methylene group, ethylene group or trimethylene group; (ii) -CO-Ba, where Ba is vinylidene group; (iii) -CH(OH)-B-, where b is a methylene group or ethylene group, (iv) the PINES(CR3)-Bb-, where R3 is a methyl group, ethyl group or tertbutylphenol group and Bb is a methylene group or ethylene group; or (v) -Su where Su is the ethylene group, trimethylene group or tetramethylene group; and more preferably (i) -CO-B-, where B is an ethylene group, (iii) -CH(OH)-B-, where a is ethylene group, (iv) -COCH(CR3)-Bb-, where R3 is a methyl group and Bb is a methylene group or (v) -Su where Su is trimethylene group.

The compound represented by formula (1), covers the following connection is possible (1-1)to(1-3):

The compound (1-1)

The compound in which R1 is 3,4-di-C1-6alkoxyphenyl group, and preferably - 3,4-dimethoxyaniline group or 3,4-diethoxyaniline group;

R2 is (a) phenyl group, (c) peredelnoj group, (d) shriley group, (e) a thienyl group, (g) thiazolidine group, (h) pyrrolidino group or (i) imidazolidine group; and

A is (i) -CO-B-, (ii) -CO-Ba-, (iii) -CH(OH)-B-, (iv) the PINES(CR3)-Bb -, or (v) -Su-.

The compound (1-2)

The compound in which R1 is 3,4-di-C1-6alkoxyphenyl group, and preferably - 3,4-dimethoxyaniline group or 3,4-diethoxyaniline group;

R2 is (a) phenyl group, (c) peredelnoj group, (d) shriley group, (e) a thienyl group, (g) thiazolidine group, (h) pyrrolidino group or (i) imidazolidine group; and

A is (i) -CO-B-, where B is a methylene group, ethylene group or trimethylene group; (ii) -CO-Ba, where Ba is vinylidene group; (iii) -CH(OH)-B-, where b is a methylene group or ethylene group, (iv) the PINES(CR3)-Bb-, where R3 is a methyl group, ethyl group or tertbutylphenol group and Bb is a methylene group or ethylene group; or (v) -G-, where Su is ethylene group, trimethylene group or tetramethylene group.

The compound (1-3)

Connected to the e, in which R1 is 3,4-di-C1-6alkoxyphenyl group, and preferably - 3,4-dimethoxyaniline group or 3,4-diethoxyaniline group;

R2 is (a) phenyl group, (c) peredelnoj group, or (g) thiazolidine group; and

A is (i) -CO-B-, where B is an ethylene group, (iii) -CH(OH)-B-, where a is ethylene group, (iv) the PINES(CR3)-Bb-, where R3 is a methyl group and Bb is a methylene group, or (v) -Su where Su is trimethylene group.

Some compounds represented by the formula (1)have optical isomers. Some compounds represented by the formula (1), and their optical isomers form a salt accession acid or salt attaching the base. The present invention encompasses optical isomers of the compounds represented by formula (1)and salts of compounds represented by formula (1), and their optical isomers.

The method of obtaining the compounds of formula (1)

The compound of formula (1), its optical isomers and its salts can be obtained by different synthetic methods selected in accordance with the basic carbon skeleton, types of substituents, and so forth. Typical methods for obtaining the compounds of formula (1) described below.

<Method 1>

In method 1, the compound of formula (1) is produced by interaction of the compounds of formula (2) with the connection forms of the crystals (3),

where R1, R2 and A are defined above; and X is a halogen atom.

A suitable ratio of the compounds of formula (3) to the compound of formula (2) is usually from 0.5 to 5 mol, and preferably from 0.5 to 3 mol of compound of the formula (3) per mole of the compounds of formula (2).

The reaction of the compound of the formula (2) with the compound of the formula (3) is usually carried out in an appropriate solvent. Can be used various known solvents, unless they do not interfere with the reaction. Examples of solvents include dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile and other aprotic polar solvents; acetone, methyl ethyl ketone and other ketones; benzene, toluene, xylene, tetralin, liquid paraffin and other hydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol, tertbutanol and other alcohols, tetrahydrofuran (THF), dioxane, DIPROPYLENE ether, diethyl ether, dimethoxyethane, diglyme, and other ethers; ethyl acetate, methyl acetate, and other esters; mixtures thereof and so forth. These solvents may contain water.

The reaction of the compound of the formula (2) with the compound of the formula (3) is usually carried out under continuous stirring at a temperature of from -20 to 200°C, and preferably from 0 to 150°C, during the time from 30 minutes to 60 hours, and preferably from 1 to 30 hours.

With the Association of the formula (3), used as a source of reagent, is a known compound. Formula (2) covers the new connection. Ways to obtain the compounds described below.

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound of formula (1).

<Method 2>

In method 2, the compound of formula (4) interacts with the compound of the formula (5) in the presence of a basic compound to obtain the compounds of formula (1), where A is-COCH(COOR3)-Bb- (hereinafter referred to as "compound (1a)"),

where R1, R2, R3 and Bb defined above and R4 is C1-6alkyl group.

The ratio of the compounds of formula (5) to the compound of formula (4) is usually from 0.5 to 5 mol, and preferably from 0.5 to 3 mol of compound of the formula (5) per mole of the compounds of formula (4).

The reaction of the compound of formula (4) with the compound of the formula (5) is usually carried out in an appropriate solvent. Can be used various known solution is teli, if only they do not interfere with the reaction. Examples of solvents include dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-organic (NMP) and other aprotic polar solvents; benzene, toluene, xylene, tetralin, liquid paraffin and other hydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol, tertbutanol and other alcohols, tetrahydrofuran (THF), dioxane, DIPROPYLENE ether, diethyl ether, dimethoxyethane, diglyme, and other ethers; and mixtures thereof, and so forth. These solvents may contain water.

The reaction of the compound of formula (4) with the compound of the formula (5) is usually carried out under continuous stirring at a temperature of from 0 to 200°C, and preferably from room temperature to 150°C, during the time from 30 minutes to 60 hours, and preferably from 1 to 50 hours.

Use a variety of well-known basic compounds, including, for example, alkali metals, metal hydrides, alkoxides of metals, carbonates, hydrogen carbonates and other inorganic basic compounds, acetate and other organic basic compounds, and so forth.

Examples of alkali metals include lithium, sodium, potassium and so on. Examples of metal hydrides include sodium hydride, potassium hydride and so on. Examples of alkoxides of metals include sodium methoxide, ethoxide sodium, tertbutoxide potassium, tertbutoxide sodium is so on. Examples of carbonates include sodium carbonate, potassium carbonate and so on. Examples of carbonates include sodium bicarbonate, potassium bicarbonate, and so on. Inorganic basic compounds include sodium amide, diisopropylamide lithium hexamethyldisilazide lithium hexamethyldisilazide sodium, n-utility, terbutaline, motility and so on.

Examples of acetates include sodium acetate, potassium acetate, and so forth. Other examples of organic basic compounds include triethylamine, trimethylamine, diisopropylethylamine, pyridine, dimethylaniline, 1-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo-[4.3.0]nonan-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 2-tertbutylamine-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-datafactory (BEMP) and so on.

Such a basic compound is used usually in an amount of from 0.1 to 5 mol, and preferably from 0.5 to 3 mol per mol of compound of the formula (5).

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or friend of the mu such that resulting isolate and purify the compound of formula (1a).

<3>

In method 3, the compound of formula (1)in which A is-COCH(COOR3)-Bb- (Compound (1a)), hydrolyzing and decarboxylases with obtaining the compounds of formula (1)in which A is-CO-B- (hereinafter referred to as "compound (1b)"),

where R1, R2, R3, B, and Bb is defined above.

Hydrolysis and decarboxylation of the compound (1a) is carried out in acidic conditions. For example, add the acid to the suspension or solution of the compound (1a) in an appropriate solvent and the resulting mixture is stirred at a temperature of from 0 to 120°C. solvents Used include water, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and so on, acetonitrile, acetone, toluene, DMF, DMSO, acetic acid, triperoxonane acid, mixtures thereof and so forth. Used acids include triperoxonane acid, acetic acid and other organic acids; hydrochloric acid, bromobutyl acid, Hydrobromic acid, sulfuric acid and other inorganic acids and so on. Organic acid, such as triperoxonane acid, acetic acid or similar, can also be used as the reaction solvent. The reaction temperature is usually from 0 to 120°C, preferably from room temperature to 100°C or more is preferably from room temperature to 80°C. the reaction Time is usually from 30 minutes to 24 hours, preferably from 30 minutes to 12 hours, and more preferably from 1 to 8 hours.

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound of formula (1b).

<4>

In method 4, the compound of formula (6) interacts with the compound of the formula (7) to obtain the compound of formula (1)in which A is-CO-B- (hereinafter referred to as "compound (1b)"),

where R1, R2 and B are defined above; R5 is C1-6alkoxygroup or CH3ON(CH3)- M is a lithium atom or MgX; and X is a halogen atom.

The ratio of the compounds of formula (7) to the compound of formula (6) is usually from 0.5 to 5 mol, and preferably from 0.5 to 3 mol of the compounds of formula (7) per mole of the compounds of formula (6).

The reaction of the compound of formula (6) with the compound of the formula (7) is usually carried out in an appropriate solvent, which can be the ü selected from a large number of known solvents, if only the solvent does not interfere with the reaction. Examples of such solvents include benzene, toluene, xylene, tetralin, liquid paraffin and other hydrocarbon solvents; tetrahydrofuran (THF), dioxane, DIPROPYLENE ether, diethyl ether, dimethoxyethane, diglyme and other ethers, mixtures thereof and so forth.

The reaction of the compound of formula (6) with the compound of the formula (7) is usually carried out under continuous stirring at a temperature of from -100 to 200°C, and preferably from -100 to 100°C, during the time from 30 minutes to 60 hours, preferably from 1 to 50 hours.

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization, and/or other similar, resulting isolate and purify the compound of formula (1b).

<5>

In method 5, the compound of formula (1b) is reacted in the presence of a reducing agent to obtain compounds of formula (1)in which A is-CH(OH)-B- (hereinafter referred to as "compound (1C)"),

where R1, R2 and B are as defined above.

Examples of solvents used in privedennoi reaction, include water, methanol, ethanol, isopropanol, butanol, tertbutanol, ethylene and other lower alcohols, ethyl acetate, methyl acetate, and other esters; diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, and other ethers; benzene, toluene, xylene and other aromatic hydrocarbons; dichloromethane, dichloroethane, chloroform, carbon tetrachloride and other halogenated hydrocarbons; mixtures thereof and so forth.

Examples of reducing agents include sodium borohydride, aluminum lithium hydride, the hydride diisobutylaluminum and other reducing agents based hydrides and mixtures of these reducing agents based hydrides.

When the reducing agent on the basis of hydride is used as the reducing agent, the reaction temperature is usually from -80 to 100°C, and preferably from -80 to 70°C, and the reaction ends in a period of time from 30 minutes to 100 hours. The amount of reducing agent on the basis of hydride is usually from 1 to 20 mol, and preferably from 1 to 6 mol per mol of compound (1b). In particular, when in use as a reducing agent lithium hydride aluminum, it is preferable that the solvent used was a simple ether, such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme or similar, or an aromatic hydrocarbon such as benzene, tol is ol, xylene or similar.

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound of formula (1C).

<Method 6>

In method 6, the compound of formula (6) interacts with the compound of the formula (8) to obtain the compounds of formula (1c),

where R1, R2, and M are defined above.

The reaction in method 6 carried out under the same reaction conditions as for the reaction in method 4.

<Method 7>

In method 7, the compound (1c) is reacted in an appropriate solvent in the presence of an oxidant to obtain the compound (1b),

where R1, R2 and B are as defined above.

The solvent for use in the method 7 can be selected from a large number of well-known solvents, if only it does not interfere with the reaction. Examples of solvents include dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-organic (NMP), acetonitrile, and other aprotic polar solvents; Ben is ol, toluene, xylene, tetralin, liquid paraffin and other hydrocarbon solvents; ethyl acetate, methyl acetate, and other esters; tetrahydrofuran (THF), dioxane, DIPROPYLENE ether, diethyl ether, dimethoxyethane, diglyme, and other ethers; dichloromethane, dichloroethane, chloroform, carbon tetrachloride and other halogenated hydrocarbons; mixtures thereof and so forth. These solvents may contain water.

In method 7, the oxidant can be selected from a wide variety of known oxidants. Examples of oxidizing agents include dimethyl sulfoxide (DMSO)-sulfur trioxide-pyridine, dimethyl sulfoxide (DMSO)-oxalicacid-triethylamine, chlorochromate pyridinium (PCC), chromic acid, manganese dioxide, and so forth.

The amount of oxidizing agent is usually from 1 to 20 mol, and preferably from 1 to 6 mol per mol of compound (1C).

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound of formula (1b).

<the manual 8>

In method 8, the compound of formula (8) interacts with the compound of the formula (9) in the presence of a basic compound to obtain the compounds of formula (1)in which A is-CO-Ba- (hereinafter referred to as "compound (1d)"),

where R1, R2 and Ba are defined above; R6 is a hydrogen atom or-PO(OR7)2; Bd is -(CH2)n-; n is an integer from 0 to 4; and R7 is C1-6alkyl group.

The ratio of the compounds of formula (9) to the compound of formula (8) is usually from 0.5 to 5 mol, and preferably from 0.5 to 3 mol of compound of the formula (9) per mole of the compounds of formula (8).

The reaction of the compound of formula (8) with the compound of the formula (9) is usually carried out in an appropriate solvent. Can be used a large number of well-known solvents, unless they do not interfere with the reaction. Examples of solvents include dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-organic (NMP) and other aprotic polar solvents; benzene, toluene, xylene, tetralin, liquid paraffin and other hydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol, tertbutanol and other alcohols, tetrahydrofuran (THF), dioxane, DIPROPYLENE ether, diethyl ether, dimethoxyethane, diglyme, and other ethers; and mixtures thereof, and so forth. These solvents may contain water.

The reaction of the compounds is of formula (8) with the compound of the formula (9) is usually carried out under continuous stirring at a temperature of from 0 to 200°C, and preferably from room temperature to 150°C, during the time from 30 minutes to 60 hours, and preferably from 1 to 50 hours.

Apply a large number of well-known basic compounds, including, for example, alkali metals, metal hydrides, alkoxides of metals, carbonates, hydrogen carbonates and other inorganic basic compounds, acetate and other organic basic compounds, and so forth.

Examples of alkali metals include lithium, sodium, potassium and so on. Examples of metal hydrides include sodium hydride, potassium hydride and so on. Examples of alkoxides of metals include sodium methoxide, ethoxide sodium, tertbutoxide potassium, tertbutoxide sodium and so forth. Examples of carbonates include sodium carbonate, potassium carbonate and so on. Examples of carbonates include sodium bicarbonate, potassium bicarbonate, and so on. Inorganic basic compounds include, in addition to the above amide compounds of sodium, diisopropylamide lithium hexamethyldisilazide lithium hexamethyldisilazide sodium and so forth.

Examples of acetates include sodium acetate, potassium acetate, and so forth. Examples of organic basic compounds, different from those listed above, include triethylamine, trimethylamine, diisopropylethylamine, pyridine, dimethylaniline, 1-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo-[.3.0]nonan-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 2-tertbutylamine-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospholidine (BEMP) and so on.

It is convenient to use such a basic organic compound in an amount of from 0.1 to 5 mol, and preferably from 0.5 to 3 mol per mol of the compound represented by the formula (8).

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound of formula (1d).

<Method 9>

In method 9, the compound (1d) reacts in the presence of a reducing agent to obtain the compound (1b),

where R1, R2, Ba and B defined above.

Examples of reducing agents include reducing agents on the basis of hydrogen in the presence of such catalysts as palladium black, palladium carbon, platinum oxide, platinum black, Raney Nickel, and so forth.

When using a reducing agent based on hydrogen in the presence of a catalyst usually convenient to carry out the reaction in the atmosphere water is kind of at a pressure of from atmospheric to 20 atmospheres, and preferably from atmospheric to 10 atmospheres, or in the presence of a hydrogen donor such as formic acid, muravlensky ammonium, cyclohexene, hydrazine hydrate or other, usually at a temperature of from -30 to 100°C, and preferably from 0 to 60°C. the Reaction is usually complete in a period of time from 1 to 12 hours. A suitable amount of reducing agent based on hydrogen in the presence of a catalyst is usually from 0.1 to 40 parts by weight, and preferably from 1 to 20 parts by weight per 100 parts by weight of the compound (Id).

Examples of solvents used in the reaction in method 9, include water, methanol, ethanol, isopropanol, n-butanol, tertbutanol, ethylene and other lower alcohols, ethyl acetate, methyl acetate, and other esters; dimethyl formamide (DMF), N-organic (NMP) and other aprotic polar solvents; diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, and other ethers; benzene, toluene, xylene and other aromatic hydrocarbons; mixtures thereof and so forth.

The reaction mixture obtained by the above reaction, for example, is cooled and is subjected to the method of separation, such as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, Trad the traditional method of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound of formula (1b).

<Method 10>

In method 10, the compound (1b) is subjected to reduction reaction of obtaining compound of formula (1e) (hereinafter referred to as "compound (1e)"),

where R1, R2 and B are defined above; and g is C2-6alkalinous group.

A large variety of well-known reactions of recovery can be used as a reaction recovery. For example, the reduction may be carried out by heating the compound in the presence of hydrazine and a basic compound in an appropriate solvent.

Examples of solvents include water, methanol, ethanol, isopropanol, butanol, tertbutanol, ethylene glycol, diethylene glycol and other lower alcohols, dimethylformamide (DMF), N-organic (NMP) and other aprotic polar solvents; diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, and other ethers; benzene, toluene, xylene and other aromatic hydrocarbons; mixtures thereof and so forth.

Apply a wide variety of known basic compounds, which includes, for example, metal hydrides, alkoxides of metals, hydroxides, carbonates, bicarbonates and other neorganic the ski basic connectivity and so on.

Examples of metal hydrides include sodium hydride, potassium hydride and so on. Examples of alkoxides of metals include sodium methoxide, ethoxide sodium, tertbutoxide potassium and so on. Examples of the hydroxide include sodium hydroxide, potassium hydroxide and so on. Examples of carbonates include sodium carbonate, potassium carbonate and so on. Examples of carbonates include sodium bicarbonate, potassium bicarbonate, and so on. Inorganic basic compounds include, in addition to the above compounds, sodium amide and the like.

It is convenient to use such a basic compound in an amount of from 0.1 to 2 mol, preferably from 0.1 to 1 mol, and more preferably from 0.1 to 0.5 mol per mol of compound (1b).

A suitable reaction temperature is usually a temperature of from 50 to 250°C, and preferably from 100 to 200°C, and the reaction is complete usually within a time from 30 minutes to 10 hours.

Thus obtained reaction mixture, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound is of ormula (1E).

<Method 11>

In method 11 halogen atom in the compound of formula (If) (hereinafter referred to as "compound (If)") as opposed to langroup with obtaining the compounds of formula (1g) (hereinafter referred to as "compound (1g)"),

where R1, A and X are defined above; R8 is a hydroxyl group, unsubstituted or halogen-substituted C1-6alkyl group, unsubstituted or halogen-substituted C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, phenyl-C1-6alkoxygroup, amino-C1-6alkoxygroup, which may be substituted C1-6alkyl group, methylendioxyphenyl, a carboxyl group, fenoxaprop, C1-6alkoxycarbonyl group, C1-6alkanoyloxy, C1-6alkanoyloxy group, a cyano, a nitro-group, C1-6alkylcarboxylic group, aminosulfonyl group, amino group which may be substituted C1-6alkyl group or groups, C1-6alkanolamines, C1-6alkylthiol, phenyl group, pyrazolidine group, imidazolidine group, triazolines group, morpholinopropan, pyrrolidinyloxy group or piperazinylcarbonyl group which may be substituted C1-6alkyl group or groups; and m is an integer from 0 to 4.

A large variety of izvestnyh substitution reactions can be used as the above-mentioned substitution reactions. For example, the substitution reaction can be carried out by heating the compound with a cyanide in the presence of palladium catalyst in an appropriate solvent.

Examples of palladium catalysts include tetranitropentaerithrite and other similar. The appropriate amount of palladium catalyst is usually from 0.001 to 0.4 mol, and preferably from 0.001 to 0.2 mol per mol of compound (If).

Examples include cyanide cyanide zinc(II) and other similar. Usually it is convenient to use cyanide in an amount of from 0.1 to 5 mol, preferably from 0.5 to 3 mol, and more preferably from 0.5 to 1 mol per mol of compound (If).

The solvent can be selected from a wide variety of known solvents, unless they do not interfere with the reaction. Examples of solvents include dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile and other aprotic polar solvents; acetone, methyl ethyl ketone and other ketones; benzene, toluene, xylene, tetralin, liquid paraffin and other hydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol, tertbutanol and other alcohols, tetrahydrofuran (THF), dioxane, DIPROPYLENE ether, diethyl ether, diglyme, and other ethers; ethyl acetate, methyl acetate, and other esters; mixtures thereof and so forth. These solvents may contain the substance of the water.

The reaction of the compound (If) with cyanide is usually carried out at a temperature of from -100 to 200°C, and preferably from -100 to 100°C, during the time from 30 minutes to 60 hours, and preferably from 1 to 50 hours.

The reaction mixture obtained by the above reaction, for example, cooled and subjected to such method of selection as filtration, concentration, extraction and/or the like for separation of the crude reaction product, which is then subjected, if required, using traditional methods of cleaning, such as column chromatography, recrystallization and/or other similar, resulting isolate and purify the compound of formula (1g).

<Method 12>

In method 12 fragment carboxylic acid compounds of the formula (1h) (hereinafter referred to as "compound (1h)"), subject to the formation of the amide bond with the compound of the formula (10) (hereinafter referred to as "compound 10") with the formation of the compounds of formula (1i) (hereinafter referred to as "compound (1i)"),

where R1, A, and m are defined above; R9 is a hydroxyl group, a halogen atom, unsubstituted or halogen-substituted C1-6alkyl group, unsubstituted or halogen-substituted C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, phenyl-C1-6alkoxygroup, amino-C1-6alkoxygroup the th, which may be substituted C1-6alkyl group or groups; methylendioxyphenyl, fenoxaprop, C1-6alkoxycarbonyl group, C1-6alkanoyloxy, C1-6alkanoyloxy group, a cyano, a nitro-group, C1-6alkylcarboxylic group, aminosulfonyl group, amino group which may be substituted C1-6alkyl group, a C1-6alkanolamines, C1-6alkylthiol, phenyl group, pyrazolidine group, imidazolidine group, triazolines group, morpholinopropan, pyrrolidinyloxy group, or piperazinylcarbonyl group which may be substituted C1-6alkyl group or groups; and m is an integer from 0 to 4; and R10 and R11 are each independently a hydrogen or C1-6alkyl group and may be connected to each other through the adjacent nitrogen atom and carbon atom or atoms or another nitrogen atom with the formation of piperazinovogo ring which may be substituted C1-6alkyl group or groups.

Conditions for known reactions of formation of amide linkages can be used in the formation of the amide bond in method 12. For example, can be used in these reaction methods: (A) method of a mixed anhydride of the acid in which the carboxylic acid (1h) interacts with and what cingulocapsulotomy with the formation of the mixed anhydride of the acid, which is then reacted with compound (10); (B) method, active ester, in which carboxylic acid (1h) is transformed into an activated ester such as phenyl ether, p-nitrophenyloctyl ether, N-hydroxysuccinimidyl ether, 1-hydroxybenzotriazole ether or the like, or an activated amide with benzoxazolyl-2-tion, and the activated ester or amide is reacted with compound (10); (C) a carbodiimide method, in which carboxylic acid (1h) is subjected to the condensation reaction with compound (10) in the presence of an activating agent, such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), carbonyldiimidazole or similar; (D) other methods, for example, a method in which carboxylic acid (1h) is transformed into carbon dioxide when using a dehydrating agent such as acetic anhydride, and carboxylic anhydride then interacts with the compound (10), or a method in which the ether carboxylic acid (1h) with a lower alcohol interacts with compound (10) at high pressure and high temperature, a method in which gelegenheid carboxylic acid (1h), i.e. a carboxylic acid halide, is reacted with compound (10) and so on.

The mixed acid anhydride used in the method (A) mixed acid anhydride can be obtained by means of known reactions of Schotten's-Bauman and obtained mixed acid anhydride, usually not allocated, interacts with the compound (10) obtained compound (1i). The reaction of the Schotten's-Bauman is carried out in the presence of a basic compound. Applied basic compounds include compounds traditionally used in the reaction of Schotten's-Bauman, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiethanolamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonan-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU),

1,4-diazabicyclo[2.2.2]-octane (DABCO) and other organic bases; sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and other carbonates; sodium hydroxide, potassium hydroxide, calcium hydroxide and other metal hydroxides; potassium hydride, sodium hydride, potassium, sodium, sodium amide, alkoxides of metals such as sodium methoxide and ethoxide sodium, and other inorganic bases and so on. The reaction is usually carried out at a temperature from -20 to 100°C, and preferably from 0 to 50°C, usually in a period of time from 5 minutes to 10 hours, and preferably from 5 minutes to 2 hours. The reaction of the obtained mixed acid anhydride with the compound (10) is usually carried out at a temperature of from -20 to 150°C, and preferably from 10 to 50°C, usually in a period of time from 5 minutes to 10 hours, and preferably from 5 minutes to 5 hours. Usually mixed method of angeri is and acid is carried out in a solvent. Apply solvents, which are traditionally used in the methods of the mixed anhydride of the acid. Examples of solvents include chloroform, dichloromethane, dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane and other ethers; methyl acetate, ethyl acetate, isopropylacetate and other esters; N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide and other aprotic polar solvents; mixtures thereof and so forth. Examples of alkylphenolethoxylates used in the method of the mixed anhydride of the acid include methylchloroform, methylbromide, ethylchloride, ethylbromide, isobutylparaben and so on. In this method, the compound (1h), alkylcarboxylic the compound (10) is preferably used in equimolar amounts, but every alkylcarboxylic the compound (1h) can also be used in an amount of from 1 to 1.5 mol per mol of compound (10).

Method [C], in which the condensation reaction is carried out in the presence of an activating agent, can be carried out in an appropriate solvent in the presence or absence of a basic compound. The solvents and basic soy is inane, used in this method include those referred to below as the solvents and basic compounds used in the method in which a halide of carboxylic acid interacts with the compound (10), mentioned above as one of the other methods (D). Appropriate amount of the activating agent is at least 1 mol, and preferably from 1 to 5 mol per mol of compound (10). When using WSC as the activating agent, the addition of 1-hydroxybenzotriazole in the reaction system allows the reaction successfully. The reaction is usually carried out at a temperature from -20 up to 180°C, and preferably from 0 to 150°C and usually end up in a period of time from 5 minutes to 90 hours.

When using a method in which a halide of carboxylic acid interacts with the compound (10), mentioned above as one of the other methods (D), the reaction is carried out in the presence of a basic compound in an appropriate solvent. Used basic compounds include a large variety of well-known of such basic compounds, like the ones used in the reaction of Schotten's-Bauman described above. Used solvents include, in addition to those used in the method of the mixed anhydride of the acid, methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve is, methylcellosolve and other alcohols; acetonitrile; pyridine; acetone; water and so on. The ratio of carboxylic acid halide to the compound (10) is not limited and may be appropriately selected in a wide area. Usually it is convenient to use, for example, at least 1 mol, and preferably from 1 to 5 mol of the carboxylic acid halide per mole of the compound (10). The reaction is usually carried out at a temperature from -20 up to 180°C, and preferably from 0 to 150°C and usually end up in a period of time from 5 minutes to 50 hours.

The reaction of the formation of amide linkages in the method 12 may also be implemented as a result of interaction of the compound (1h) with compound (10) in the presence of phosphorus-containing compounds used as the condensing agent, such as triphenylphosphine, diphenylphosphinite, phenyl-N-phenylphosphinic chloride, diethylphosphate, diethylthiophosphate, azide diphenylphosphinic acid chloride bis(2-oxo-3-oxazolidinyl)phosphinic acid and the like.

The reaction is carried out in the presence of a solvent and basic compound used in the method in which a halide of carboxylic acid interacts with the compound (10), typically at a temperature of from -20 to 150°C, and preferably from 0 to 100°C and usually end up in a period of time from 5 minutes to 30 hours. It is convenient to use each of condensing agents is a and the compound (1h) in amounts at least 1 mol, and preferably 1 to 2 mol per mol of compound (10).

<Method 13>

In method 13 fragment of the carboxylic acid compound (1h) is subjected to the formation of the essential connection with the compound of the formula (11) (hereinafter referred to as "compound (11)") to obtain the compounds of formula (1j) (hereinafter referred to as "compound 1j"),

where R1, R9, A and m are defined above; R12 is C1-6alkyl group; and Y is a hydroxyl group or a halogen atom.

Conditions for known reactions of formation of ether linkages can be used. For example, when Y in the compound (11) is a hydroxyl group, the reaction of formation of the ether bond may be carried out by heating the compound (1h) and the compound (11) in an appropriate solvent in the presence of acid. Examples of solvents include chloroform, dichloromethane, dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and other ethers; methyl acetate, ethyl acetate, isopropylacetate and other esters; N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide and other aprotic polar rest ritali; mixtures thereof and so forth. The compound (11) can also be used as solvent. Examples of acids include triperoxonane acid and other organic acids; hydrochloric acid, bromobutyl acid, Hydrobromic acid, sulfuric acid and other inorganic acids and so on. The reaction is usually carried out at a temperature from 0 to 150°C, and preferably from room temperature to 100°C and usually end up in a period of time from 0.5 to 30 hours.

When Y in the compound (11) is a halogen atom, the reaction in method 13 carried out by reacting compound (11) with compound (1h) in an appropriate solvent in the presence of a basic compound. Examples of solvents include methanol, ethanol, isopropanol, butanol, tertbutanol, ethylene glycol, diethylene glycol and other lower alcohols, chloroform, dichloromethane, dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and other ethers; methyl acetate, ethyl acetate, isopropylacetate and other esters; N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide and other aprotic polar solvents; mixtures thereof and t is to the next.

Examples of basic compounds include triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiethanolamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonan-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and other organic bases; sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and other carbonates; sodium hydroxide, potassium hydroxide, calcium hydroxide and other metal hydroxides; potassium hydride, sodium hydride, potassium, sodium, sodium amide, alkoxides of metals such as sodium methoxide and ethoxide sodium, and other inorganic bases and so on. A suitable ratio of the compound (1h) to the compound (11) is at least 1 mol, and preferably from 1 to 5 mol of compound (1h) mol of compound (11). The reaction is usually carried out at a temperature from 0 to -150°C, and preferably from room temperature to 100°C and usually end up in a period of time from 0.5 hour to 30 hours.

<Method 14>

In method 14 compound of formula (1k) (hereinafter referred to as "compound (1k)") alkylate compound of the formula (12) (hereinafter referred to as "compound (12)") to obtain the compounds of formula (11) (hereinafter referred to as "compound 11"),

where R1, A, and m are defined above; R13 is a halogen atom, nezamedin the th or halogen-substituted C 1-6alkyl group, unsubstituted or halogen-substituted C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, phenyl-C1-6alkoxygroup, amino-C1-6alkoxygroup, which may be substituted C1-6alkyl group, methylendioxyphenyl, a carboxyl group, fenoxaprop, C1-6alkoxycarbonyl group, C1-6alkanoyloxy, C1-6alkanoyloxy group, a cyano, a nitro-group, C1-6alkylcarboxylic group, aminosulfonyl group, amino group which may be substituted C1-6alkyl group or groups, C1-6alkanolamines, C1-6alkylthiol, phenyl group, pyrazolidine group, imidazolidine group, triazolines group, morpholinopropan, pyrrolidinyloxy group, or piperazinylcarbonyl group which may be substituted C1-6alkyl group or groups; R12 is C1-6alkyl group; Y is a hydroxyl group, a halogen atom or-OS2-R13; R13 is C1-6alkyl group or phenyl group where the phenyl ring may be substituted C1-6alkyl group or groups, atoms or halogen atoms or nitro-group or groups; R14 is C1-6alkyl group or a C1-6alkoxy-C1-6alkoxygroup and Ya is a halogen atom.

In method 14 the alkylation reaction can be carried out by the interaction of the compound (Ik) with compound (12), for example, in an appropriate solvent in the presence of a basic compound. Examples of solvents include methanol, ethanol, isopropanol, butanol, tertbutanol, ethylene glycol, diethylene glycol and other lower alcohols, chloroform, dichloromethane, dichloroethane, carbon tetrachloride and other halogenated hydrocarbons; benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and other ethers; methyl acetate, ethyl acetate, isopropylacetate and other esters; N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide and other aprotic polar solvents; mixtures thereof and so forth.

Examples of basic compounds include triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiethanolamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonan-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and other organic bases; sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and other carbonates; metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; potassium hydride, hydride soda which I, potassium, sodium, sodium amide, alkoxides of metals such as sodium methoxide and ethoxide sodium, and other inorganic bases and so on. The corresponding ratio of the compound (12) to the compound (1k) is at least 1 mol, and preferably from 1 to 5 mol of compound (12) per mole of the compound (1k). The reaction is usually carried out at a temperature from 0 to 150°C, and preferably from room temperature to 100°C, and usually end up in a period of time from 0.5 to 30 hours.

The method of obtaining the compounds of formula (2)

The compound of the formula (2) (hereinafter referred to as "compound (2)") to use as the source reagent may be obtained, for example, the following method 15 or 16.

<Method 15>

In method 15 the compound represented by the formula (13) (hereinafter referred to as "compound (13)"), halogenous obtaining compounds (2),

where R2, A and X are defined above. The halogenation reaction of the compound (13) can be carried out in an appropriate solvent in the presence of a halogenation agent. Examples of halogenation agents include bromine, chlorine and other molecular halogen; chloride iodine; sulfurylchloride; bromide of copper and other copper compounds N-bromosuccinimide, N-chlorosuccinimide and other N-halogenated suktinimida; and so on. The examples use the x solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride and other halogenated hydrocarbons; acetic acid; propionic acid and other fatty acids; carbon disulfide and so on. The appropriate amount of halogenation agent is usually from 1 to 10 mol, and preferably from 1 to 5 mol per mol of compound (13). The reaction is usually carried out at a temperature from 0°C to the boiling point of the solvent, and preferably from 0 to 100°C, and is usually completed in a period of time from 5 minutes to 20 hours.

<Method 16>

In method 16, the compound represented by the formula (14) (hereinafter referred to as "compound (14)"), halogenous in the presence of water under acidic conditions to obtain the compound (2),

where R2, A and X are defined above. The halogenation reaction of the compound (14) is carried out in an appropriate solvent in the presence of a halogenation agent. Examples of halogenation agents include bromine, chlorine and other molecular halogen; chloride iodine; sulfurylchloride; N-bromosuccinimide, N-chlorosuccinimide and other N-halogenated suktinimida; and so on. Examples of solvents include water-acetonitrile. Examples of acids include hydrochloric acid, bromobutyl acid, Hydrobromic acid, sulfuric acid and other reorganizes is their acid, and other similar. The appropriate amount of halogenation agent is usually from 1 to 10 mol, and preferably from 1 to 5 mol per mol of compound (14). The reaction is usually carried out at a temperature from 0°C to the boiling point of the solvent, and preferably from 0 to 100°C, and is usually completed in a period of time from 5 minutes to 20 hours.

(II) Medicinal action and application

Compounds represented by formula (1), their optical isomers and their salts (hereinafter referred to together as "the compound of the present invention"), exhibit specific inhibitory activity on PDE4, and can therefore be used as active ingredients PDE4 inhibitors.

The compound of the present invention due to its specific inhibitory activity on PDE4 can be applied as an active ingredient of a pharmaceutical composition for use as a preventive or therapeutic agent for various diseases. Examples of the disease for which preventive or therapeutic effects are manifested on the basis of specific inhibitory activity on PDE4 include acute or chronic (in particular inflammatory and allergen-induced) airway disease (e.g. asthma and chronic obstructive pulmonary disease) razlichnog the origin; dermatoses (especially of proliferative, inflammatory and allergic type) (e.g., psoriasis, toxic and allergic contact eczema, atopic dermatitis, alopecia areata and other proliferative, inflammatory and allergic dermatitis); diseases related to nervous disorders, such as disorders of learning, memory and cognition caused by Alzheimer's disease, Parkinson's disease, and so forth; diseases associated with mental disorders (e.g., manic-depressive psychosis, schizophrenia and anxiety syndrome); systemic or local lesions of the joints (for example, osteoarthritis of the knee and rheumatoid arthritis); diffuse inflammation in the gastrointestinal tract (e.g., Crohn's disease and ulcerative colitis); allergic and/or chronic diseases of the upper respiratory tract (the cavity of the pharynx, nose) and the adjacent areas (colonosopy sinus, eyes)caused false immunological reactions (for example, allergic rhinitis/sinusitis, chronic rhinitis/sinusitis and allergic conjunctivitis); and other diseases. Among them for atopic dermatitis compound of the present invention exhibits particularly high prophylactic or therapeutic action and therefore can be suitably applied to prevent or Les the surveillance of this disease.

When the compound of the present invention is used as a PDE 4 inhibitor or a preventive or therapeutic agent for the above diseases, the connection can be used in the form of a pharmaceutical preparation for oral administration, injection of a medicinal product for external use, or other similar drug.

In oral administration, the compound may be in the form of powder, tablets, granules, capsules, syrup, films, lozenges, liquids, or other similar forms. Drug for oral administration may contain pharmaceutically acceptable base and/or carrier and pharmaceutically acceptable additives such as a binder, a substance that promotes the decomposition, sliding substances, wetting means, buffers, preservatives, flavorings, and so on, if required.

When used in the form of injections connection may be in the form of an aqueous solution or suspension obtained by dissolving or suspendirovanie compounds in saline, aqueous glucose solution, or similar.

When applied externally, the connection can be in the form of liquid oil product, lotion, liniment, milky lotion, suspension, cream, ointment or other similar. The preparation for external use, if required, may contain wear the spruce, basis and/or additives, which are traditionally used in preparations for external use. Examples of additives include water, oils, surfactants, solubilizing components, emulsifiers, colorants (dyes, pigments), flavorings, preservatives, antiseptics, thickeners, antioxidants, chelating agents, pH modifiers, deodorants were examined, and so on.

When the compounds of the present invention is used as a PDE4 inhibitor or a preventive or therapeutic agent for the above diseases, the size of the effective dose and number of doses of the compounds of the present invention varies depending on the connection type, age and weight of the patient, which give the connection, symptom, purpose and other factors, and they cannot in General be determined. For example, for an adult patient per day amount corresponding to from 0.1 to 1000 mg of the compounds of the present invention, can be introduced or applied as a single dose or in two or more divided doses.

Another aspect of the present invention is a method of treatment of the aforementioned diseases, including the stage of introducing an effective amount of the compounds of the present invention to a human or animal mammal.

In addition, the compound of the present invention has inhib the Torno activity with the production of TNF-α inhibitory activity with the production of IL-4 and can therefore be used as active ingredient in the inhibitor of the production of TNF-α inhibitor in the production of IL-4. Form, route of administration, dose, and other similar factors for inhibitor production of TNF-α or inhibitor in the production of IL-4, comprising the compound of the present invention are the same as in the case mentioned above PDE4 inhibitor and a prophylactic or therapeutic agent.

EXAMPLES

The following examples are given to illustrate the present invention, and they do not limit the scope of the invention.

Reference example 1.Getting ethyl-2-benzoyl-4-bromo-4-pentenoate

Sodium hydride (0.26 g, 6.0 mmol) was added under ice cooling to a solution (10 ml) ethylbenzylamine (1.0 ml, 5,77 mmol) in DMF, followed by stirring for 30 minutes and then was added 2,3-dibromopropan (0.63 ml, 5,77 mmol). The resulting mixture was stirred at room temperature for 1.5 hours, was added to the reaction mixture and water was performed three times extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/l). The solvent is kept at reduced pressure, obtaining the result of 1.55 g (yield: 86%) of ethyl-2-benzoyl-4-bromo-4-pentenoate in the form of a colorless oil.

NMR δ ppm (CDCl3); 8,06-of 8.04 (2H, m), 7,63-of 7.60 (1H, m), 7,52-7,49 (2H, m), 5,71 (1H, d, J=1,8 Hz), 5,46 (1H, d, J=1,8 Hz), 4,81-rate 4.79 (2H, m, of 4.16 (2H, square, J=7,1 Hz), 3,15-3,11 (2H, m)of 1.18 (3H, t, J=7,1 Hz).

Reference example 2. Getting ethyl-2-benzoyl-5-bromo-4-oxopentanoate

N-bromosuccinimide (0.95 g, 5.3 mmol) and a drop of Hydrobromic acid was added to a solution of ethyl-2-benzyl-4-bromo-4-pentenoate (1.5 g, 4,82 mmol) in acetonitrile (16 ml) and water (4 ml), followed by stirring at room temperature for 3 hours and 40 minutes. The reaction mixture was diluted with diethyl ether and was added 5% aqueous sodium thiosulfate solution for separating a mixture layers. The organic layer was washed twice with a saturated aqueous solution of sodium bicarbonate, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). The solvent is kept at reduced pressure, obtaining the result of 0.91 g (yield: 58%) of ethyl-2-benzoyl-5-bromo-4-oxopentanoate in the form of a colorless oil.

NMR δ ppm (CDCl3); 8,03-8,01 (2H, m), 7,63-to 7.59 (1H, m), 7,51-of 7.48 (2H, m), is 4.93 (1H, DD, J=6,4 Hz, 7.5 Hz), 4,15 (2K, square, J=7,1 Hz), of 4.05 (2H, DD, J=13,0 Hz, and 21.7 Hz), 3,43 (1H, DD, J=7.5 Hz, 18,1 Hz)to 3.36 (1H, DD, J=6,4 Hz, 18,1 Hz), of 1.16 (3H, t, J=7,1 Hz).

Reference example 3. Getting 4-chloromethyl-2-(3,4-dioxyphenyl)thiazol

3,4-dioxythiophene (30.0 g, 133 mmol) suspended in ethanol (300 ml) was added 1,3-deflorate is n (12,8 ml, 135 mmol) followed by heating under reflux for 4 hours. After cooling to room temperature the solvent is kept under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent is kept under reduced pressure and the residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane, to deliver to 26.9 g (yield: 68%) of 4-chloromethyl-2-(3,4-dioxyphenyl)thiazole in the form of prismatic crystals form a yellow color. Melting point: from 81.5 to 82.3°C.

Reference example 4. Obtain 2-(3,4-dioxyphenyl)thiazole-4-carboxaldehyde

N-methylmorpholin-N-oxide (16.5 g, 141 mmol) was added to a solution (200 ml) of 4-chloromethyl-2-(3,4-dioxyphenyl)thiazole (13,99 g, 47 mmol) in acetonitrile followed by heating under reflux for 1.5 hours. After cooling to room temperature the solvent is kept under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept at igenom pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent is kept at reduced pressure, obtaining the result of 11.2 g (yield: 86%) of 2-(3,4-dioxyphenyl)thiazole-4-carboxaldehyde in a solid yellow color. Melting point: 84,0-87,0°C.

Reference example 5. Obtain 3-[2-(3,4-dioxyphenyl) thiazol-4-yl]propionic acid

Bromine (55 ml, 1.07 mol) was added dropwise under ice cooling to a solution of (1.2 l) dimethylacrylate (200 g, 1.06 mol) in diethyl ether. The resulting mixture was stirred at room temperature overnight, the solvent is kept at reduced pressure. To the residue was added acetic acid (0.4 l) and concentrated hydrochloric acid (0.4 l) and the resulting mixture was stirred at room temperature for 4.5 hours and further at 80°C for 3.5 hours. The solvent is kept under reduced pressure and to the residue was added 3,4-dioxythiophene (215,5 g, 0.96 mol), dimethoxyethane (0.8 l) and water (0.4 l), followed by stirring at 80°C for 1 hour. After cooling to room temperature, precipitated crystals were filtered off, washed with water and dried at 60°C, resulting in the 305,15 g (yield: 83%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionic acid in the form of powder light brown. Melting point: 111,3-113,5°C.

Reference example 6.Obtaining methyl-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propyn is that

The solution of (2.3 l) 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionic acid (254,5 g) in methanol was cooled on ice and was added dropwise 58 ml of thionyl chloride. After adding the resulting mixture was heated under reflux for 2 hours and cooled to room temperature. The solvent is kept under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent is kept under reduced pressure and the residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane, resulting in the 219,35 g (yield: 68%) of methyl-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionate in the form of a white powder. Melting point: 58,1 is 58.3°C.

Reference example 7.Obtain 3-[2-(3,4-dioxyphenyl)]-thiazol-4-yl]-N-methoxy-N-methylpropionamide

1-hydroxybenzotriazole (22,91 g, 149,6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (28,68 g, 149,6 mmol), N,O-dimethylhydroxylamine hydrochloride (13,93 g, 136 mmol) and triethylamine (41.7 ml, 299,2 mmol) was added to solution (1.0 l) 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionic acid (43,71 g, 136 mmol) in dichloroethane is followed by stirring at room temperature for 4 hours. To separate the reaction mixture into layers were added water and the aqueous layer was then subjected to extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent is kept under reduced pressure and the residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane, resulting in the 42,4 g (yield: 68%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-N-methoxy-N-methylpropionamide in the form of colourless crystals of prismatic shape. Melting point: 72,0-73,0°C.

Example 1.Obtaining (E)-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)propenone

2-methoxyacetophenone (0.16 ml, 1.2 mmol) was added to a solution (5 ml) of 2-(3,4-dioxyphenyl)thiazole-4-carboxaldehyde (310.5 mg, 1.12 mmol) in ethanol at room temperature. Then was added dropwise 1M aqueous solution of potassium hydroxide (2,24 ml, 2,24 mmol) at the same temperature. After stirring at room temperature for 1 hour to the reaction mixture was added water, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was recrystallized from a mixture of ethyl acetate/n-hexane, receiving 400 mg (yield: 94%) (E)--[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)propenone in the form of a yellow powder. Melting point: 130-131°C.

Example 2.Obtaining (E)-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)propenone

Sodium hydride (353,3 mg, 8,83 mmol) was added to a solution (80 ml) of diethyl-[2-(2-methoxyphenyl)-2-oxoethyl]phosphonate (2.30 g, 8,03 mmol) in THF at room temperature. After stirring at the same temperature for 30 minutes was added 2-(3,4-dioxyphenyl)thiazole-4-carboxaldehyde (2.15 g, of 7.75 mmol)and the resulting mixture was stirred at room temperature for 22 hours. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1 to 2/1). The solvent is kept under reduced pressure and the residue was recrystallized from a mixture of ethyl acetate/n-hexane, obtaining the result of 1.62 g (yield: 51%) of (E)-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)propenone in the form of prismatic crystals form a yellow color. Melting point: 130-131°C.

Example 3.Obtaining (E)-3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-diacetoxybiphenyl)propenone

2-(3,4-acid)thiazole-4-carboxaldehyde (450 mg, is 1.81 mmol) and (3,4-diacetoxybenzoic)triphenylphosphorane (900 mg, is 1.81 mmol) suspended in THF (25 ml) and the suspension was heated under reflux for 20 hours. After cooling, the solvent is kept under reduced pressure, and the residue on the imali on silica gel column chromatography (eluent: dichloromethane). The solvent is kept under reduced pressure and the residue was recrystallized from a mixture of ethyl acetate/n-hexane, to deliver 380 mg (yield: 44.9 percent) (E)-3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-diacetoxybiphenyl)propanone in the form of a yellow powder. Melting point: 163-164°C.

Examples 4-34

In accordance with the method of obtaining from example 1 the following compounds of examples 4-34 were obtained (table 1). In

table 1 also shows the melting points of these compounds.

-N -OS2H5
[Table 1]
ExampleRaRbrcRdReRfRgThe pace. melting point (°C)Sol
4-C2H5-C2H5-Och2Och3-N-OCH2OCH3-N-HE140,3-143 -
5-C2H5-C2H5-N-N-OCH2OCH3-OCH2OCH3-N89,8 is 91.5-
6-CH3-CH3-N-HE-N-HE-N164-168hydrochloride
(Razlog.)
7-CH3-CH3-N-HE-HE-N-N162 to 165hydrochloride
8-C2H5-C2H5-N-NOSON3OSON3-N139-140-
9-C2H5-C2H6-HE-N-HE-N-HE188-189-
10-C2H5-C2H5-N-N-HE-N-N133-134-
11-C2H5-C2H5-N-Och3-Och3-Och3-N 155-156-
12-C2H5-C2H5-N-Cl-NH2-Cl-N165-168hydrochloride
13-C2H5-C2H5-N-N-Och3-Och3-N152-153-
14-C2H5-C2H5-N-N-N-N-N129-130-
15-C2H5-C2H6-HE-N-N-N -N126-127hydrochloride
16-C2H5-C2H5-N-N-N-HE-N144,5-146-
17-C2H5-C2H5-N-N-CO2CH3-N-N150-151-
18-C2H5-C2H5-N-N-CN-N-N164-167-
19-C2H5-C2H5-N-N-HE-CO 2H-N195-196-
20-C2H5-C2H5-N-N-HE-CO2CH3-N161,3-162,8-
21-C2H5-C2H5-N-N-Cl-N-N131-133-
22-CH2-CH3-N- (CH3)3-HE- (CH3)3-N228-230-
23-C2H5-C2H5-N-N-N-N128-129-
24-C2H5-C2H5-N-N-N-NO2-N125-126-
25-C2H5-C2H5-N-N-F-N-N116-121-
26-C2H5-C2H5-N-N-CH3-N-N124-125,5-
27-C2H5-C2H5-N-N-N-NO2142-143-
28-C2H5-C2H5-N-N-NHCOCH3-N-N199,5-201,5-
29-C2H5-C2H5-N-N-Cl-Cl-N138-139-
30-C2H5-C2H5-N-N-NH2-N-N148-150-
31-C2H5-C2H5-N-N-N-N130-135-
32-C2H5-C2H5-N-N-NO2-N-N125-127-
33-C2H5-C2H5-N-N-N-N-CO2CH3132-133-
34-C2H5-C2H5-H-H-CON(CH3)2-H-H110-112-

Examples 35-36.

In accordance with the method of obtaining from example 1 the following compounds of examples 35 and 36 were obtained (table 2). In table 2 that the same is given physico-chemical characteristics of these compounds.

[Table 2]
ExampleRaRbRCRdReRfRgNMR δ ppm (CDCl3)
35-C2H5C2H5-OCH2OCH3-H-OCH2OCH3-H-OCH2OCH37,58 (1H, d, 2.0 Hz), 7,47 (1H, DD, J=2.0 a, and 8.4 Hz), 7,35-7,33 (3H, m), 6,92 (1H, J=8,4 Hz), to 6.57 (2H, s), 5,19 (2H, s), 5,13 (4H, s), is 4.21 (2H, square, J=7,0 Hz), 4,13 (2H, square, J=7,0 Hz), 3,51 (3H, s)to 3.41 (6H, )and 1.51 (3H, t, J=7.0 Hz), for 1.49 (3H, J=7,0 Hz).
36-CH3-CH3-H-H-OH-CO2CH3-Hto 11.28 (1H, s), 8,67 (1H, d, J=2.2 Hz), of 8.28 (1H, DD, J=2,4, 8,8 Hz), 8,00(1 H, d, J=15,0 Hz), 7,79 (1H, d, J=15,0 Hz), to 7.61 (1H, d, J=2.4 Hz), to 7.59 (1H, DD, J=2,2, 8,2 G is), 7,49 (1H, s), 7,13 (1H, d, J=8,8 Hz), 6,97 (1H, d, J=8,2 Hz), a 4.03 (3H, s), was 4.02 (3H, s), of 3.97 (3H, s).

Examples 37-42

In accordance with the method of obtaining from example 1 the following compounds of examples 37-42 were obtained (table 3). Table 3 also shows the physico-chemical characteristics of these compounds.

[Table 3]
If-
measures
RaRbRCRdReRfRgMelting point (°C)Sol
37-CH3-CH3-H-H-OH-H-H174-177-
38-CH3-CH3-H-H- (CH2)2N(C2H5)2 -H-H178-183trihydro-chloride
39-CH3-CH3-H-H-OH-CO2H-H227,4-228-
40-C2H5-C2H5-OCH3-H-H-OCH3-H79-82-
41-CH3-CH3-H-H-H-H165-166-
42-C2H5-C2H5-H-H -H-H135
(decomposition)
dihydro-chloride

Examples 43-57

In accordance with the method of obtaining from example 1 the following compounds of examples 43-57 were obtained (table 4). Table 4 also shows the physico-chemical characteristics of these compounds.

[Table 4]
ExampleRaRbRhMelting point (°C)Sol
43-CH3-CH3-4-PYRIDYL167-168-
44-CH3-CH3-3-PYRIDYL168-169-
45-CH3-CH3-2-PYRIDYL137-139 -
46-CH3-CH3-2-FURYL154-156-
47-CH3-CH3-2-THIENYL157-158-
48-CH3-CH3-3-THIENYL178-179-
49-C2H5-C2H5-2-PYRIDYL92,2-93,8-
50-CH3-CH3175-177-
51-CH3-CH3152-153-
52 -CH3-CH3176-177-
53-CH3-CH3197-199-
54-CH3-CH3146-147-
55-C2H5-C2H5116-117-
56-CH3-CH3147-149the dihydrochloride
57-CH3-CH3222-224
(decomposition)
-

Example 58. Obtaining methyl-2-[2-(3,4-dioxyphenyl)thiazole-4-ylmethyl]-3-(3-ethoxypyridine-2-yl)-3-oxopropionate

Sodium hydride (239 mg, 6.0 mmol) and a drop of methanol was added to a solution (10 ml) of methyl-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionate (1.0 g, 3.0 mmol) and methyl-3-ethoxypyridine-2-carboxylate (702 mg, 3.9 mmol) in dimethoxyethane followed by heating under reflux for 2 hours. After cooling to room temperature, to the reaction mixture were added saturated aqueous solution of ammonium chloride and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/3). The solvent is kept at reduced pressure, obtaining the result of 740 mg (yield: 51%) of methyl 2-[2-(3,4-dioxyphenyl)thiazole-4-ylmethyl]-3-(3-ethoxypyridine-2-yl)-3-oxopropionate in the form of a yellow oil.

1H-NMR δ ppm (CDCl3); by 8.22 (1H, DD, J=1.3 Hz, 4.3 Hz), 7,44 (1H, d, J=2.1 Hz), between 7.4 to 7.2 (3H, m), 6,92 (1H, s), 6,85 (1H, d, J=8,4 Hz), from 5.29 (1H, t, J=7.4 Hz), 4,2-4,0 (6H, m), the 3.65 (3H, s), 3,6-3,4 (2H, m), 1,5-1,4 (9H, m).

Example 59.Getting ethyl-2-[2-(3,4-dioxyphenyl)thiazole-4-ylmethyl]-3-oxo-3-phenylpropionate

3,4-dioxythiophene (to 0.63 g, 2.8 mmol) was added to the races the thief (20 ml) of ethyl-2-benzoyl-5-bromo-4-oxopentanoate (0,90 g, 2.8 mmol) in ethanol followed by heating under reflux for 1.5 hours. After cooling to room temperature the solvent is kept under reduced pressure and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure, obtaining the result of 1.43 g (yield: 65%) of ethyl-2-[2-(3,4-dioxyphenyl)thiazole-4-ylmethyl]-3-oxo-3-phenylpropionate in the form of a yellow oil.

NMR δ ppm (CDCl3); 8,06-with 8.05 (2H, m), 7,58-of 7.55(1H, m), 7,47-7,44 (2H, m), 7,40 (1H, d, J=2.0 Hz), was 7.36 (1H, DD, J=2.0 Hz, 8,4 Hz), make 6.90 (1H, s)6,86 (1H, d, J=8,4 Hz), 5,06-to 5.03 (1H, m), 4,17-4,07 (6H, m), 3,50-to 3.49 (2H, m,), to 1.47(6H, t, J=7,0 Hz)and 1.15 (3H, t, J=7.2 Hz).

Examples 60-66

In accordance with the method of obtaining from example 58, the following compounds of examples 60-66 were obtained (table 5). Table 5 also shows the physico-chemical characteristics of these compounds.

[Table 5]
If-
measures
RaRbRcRdReRf RgRiNMR δ ppm (CDCl3)
60-C2H5-C2H5-H-H-Cl-H-OCH3-CH37,71 (1H, d, J=8,3 Hz), 7,41 (1H, d, J=2.0 Hz), 7,35 (1H, DD, J=2.0 Hz, 8,3 Hz), 6,98 (1H, DD, J=1,8 Hz and 8.4 Hz), 6,92(1H, d, J=1,8 Hz)and 6.9 to 6.8 (2H, m), of 4.95 (1H, DD, J=6,5 Hz, 7.8 Hz), 4,2-4,0 (4H, m), 3,85 (3H, s), of 3.69 (3H, s), 3,6-3,3 (2H, m), 1,5-1,4 (6H, m).
61-C2H5-C2H5-H-H-H-Cl-OCH3-CH3of 7.5 to 7.3 (4H, m),? 7.04 baby mortality (1H, t, J=7.9 Hz), 6.89 in (1H, s), 6,85 (1H, d, J=8,4 Hz), 5,09 (1H, DD, J=6,6 Hz, 8.0 Hz), 4,2-4,0 (4H, m), of 3.84 (3H, s), 3,70 (3H, s), 3,5-3,4 (2H, m), 1,5-1,4 (6H, m).
62-C2H5-C2H5-H-H-H-H-OC2H5 -C2H5to 7.68 (1H, DD, J=1,8 Hz, 7.7 Hz), 7.5 to to 7.3 (3H, m), 7,0-6,8 (4H, m), 5,14 (1H, t, J=7,3 Hz), 4,2-4,0 (8H, m), 3,6-3,3 (2H, m), 1,5-1,3 (9H, m)of 1.13 (3H, t, J=7,1 Hz).
63-C2H5-C2H5-H-H-H-H-N(CH3)2-C(CH3)37,49 (1H, d, J=1.9 Hz), 7,43-of 7.2 (3H, m), 7,0-6,8 (4H, m), 5,28 (1H, 1, J=7,1 Hz), from 4.2 to 4.1 (4H, m)to 3.36 (2H, DD, J=2.2 Hz and 7.1 Hz), 2,69 (6H, s), 1,5-1,4 (6H, m)of 1.27 (9H, s).
64-C2H5-C2H5-H-H-H-H-OCH2OCH3-CH3of 7.69 (1H, DD, J=7.8 Hz), 7.5 to to 7.3 (3H, m), 7,19 (1H, d, J=8,4 Hz), 7,1-a 7.0 (1H, m), to 6.88 (1H, s), 6,85 (1H, d, J=8,4 Hz), with 5.22 (2H, s), 5,1-5,0 (1H, m), 4,2-4,0(4H, m), 3,68 (3H, s), 3,6-3,3 (5H, m), 1,5-1,4 (6H, m).
65-C2H5-C2H5-H-H -H-H-OC6H5-CH37,80 (1H, DD, J=1,8 Hz, 7.8 Hz), between 7.4 to 7.2 (5H, m), a 7.2 to 6.9 (4H, m), 6,9-6,8 (3H, m), 5,13 (1H, DD, J=6.2 Hz, 8,3 Hz), 4,2-4,0 (4H, m), which is 3.7 and 3.3 (5H, m), 1,5-1,4 (6H, m).
66-C2H5-C2H5-H-H-H-H-OCH3-CH37,74 (1H, DD, J=1,8 Hz, 7.7 Hz), 7,5 to 7.4 (2H, m), of 7.36 (1H, DD, J=2.1 Hz, 8,3 Hz), 7,1-6,8 (4H, m), equal to 4.97 (1H, t, J=7.2 Hz), 4,2-4,0 (4H, m), 3,85 (3H, s), of 3.69 (3H, s), 3,6-3,3 (2H, m), 1,5-1,4 (6H, m).

Examples 67-71

In accordance with the method of obtaining from example 58, the following compounds of examples 67-71 were obtained (table 6). Table 6 also shows the physico-chemical characteristics of these compounds.

[Table 6]
ExampleRaRbRCRdReRfRg RiMS (M+1)
67-C2H5-C2H5-H-H-H-H-CN-CH3465
68-C2H5-C2H5-H-H-H-H-OC2H5-CH3484
69-C2H5-C2H5-H-H-H-H-Cl-CH3474
70-C2H5-C2H5-H-Cl-H-H-OCH3 -CH3504
71-C2H5-C2H5-H-H-H-H-CH3-CH3454

Examples 72-75

In accordance with the method of obtaining from example 58, the following compounds of examples 72-75 were obtained (table 7). Table 7 also shows the physico-chemical characteristics of these compounds.

[Table 7]
ExampleRaRbRhRjMS (M+1)
72-C2H5-C2H5-2-PYRIDYL-CH3441
73-C2H5-C2H5 -3-PYRIDYL-CH3441
74-C2H5-C2H5-CH3443
75-C2H5-C2H5-CH3455

Examples 76-82

In accordance with the method of obtaining from example 58, the following compounds of examples 76-82 were obtained (table 8). Table 8 also shows the physico-chemical characteristics of these compounds.

[Table 8]
ExampleRaRbRhRjNMR δ ppm (CDCl3)
76-C2H5-C2H5-2-FURYL-CH3 of 7.60 (1H, d, J=1.6 Hz), the 7.43 (1H, d, J=2.0 Hz), between 7.4 and 7.3 (2H, m), 6.89 in (1H, s)6,86 (1H, d, J=8,4 Hz), of 6.52 (1H, DD, J=1.7 Hz, 3.6 Hz), to 4.81 (1H, t, J=7.4 Hz), 4,2-4,0 (4H, m), 3,71 (3H, s), 3,48 (2H, d, J=7,4 Hz), 1,5-1,4 (6H, m).
77-C2H5-C2H5-4-PYRIDYL-CH38,8-8,7 (2H, m), 7,9-7,8 (2H, m), 7,32 (1H, d, J=1.9 Hz), and 7.3 to 7.2 (1H, m), 6.90 to (1H, s), 6,83 (1H, d, J=8,3 Hz), of 5.05 (1H, DD, J=6,6 Hz, 8.0 Hz), 4,2-4,0 (4H, m), 3,70 (3H, s), 3,6-3,4 (2H, m), 1.5 to 1,4 (6H, m).
78-C2H5-C2H5-CH38,23 (1H, DD, J=1.2 Hz, 4.4 Hz), 7.5 to to 7.3 (4H, m), 6,92 (1H, s), 6,85 (1H, d, J=8,4 Hz), and 5.30 (1H, DD, J=6,9 Hz, 7.8 Hz), 4,2-4,0 (4H, m)to 3.89 (3H, s), the 3.65 (3H, s), 3,6-3,4 (2H, m), 1,5-1,4 (6H, m).
79-C2H5-C2H5-CH38,21 (1H, DD, J=1.7 Hz, 4.0 Hz), was 7.45 (1H, d, J=1.9 Hz), between 7.4 to 7.2 (3H, m), 6,92 (1H, s), 6,85 (1H, d, J=8,4 Hz), 5,28 (1H, t, J=7,3 Hz), 4.6 to 4.5 (1H, m), 4,2-4,0 (4H, m), the 3.65 (3H, s), 3,6-3,4 (2H, m), 1,5-1,4 (6H, m)to 1.37 (3H, s)of 1.35(3H, s).
80 -C2H5-C2H5-CH37,89 (1H, d, J=8.1 Hz), 7.5 to to 7.3 (4H, m), 7,19 (1H, DD, J=2.1 Hz, 8,4 Hz), to 6.95 (1H, s), 6,74(1H, d, J=8,4 Hz), 5,59 (1H, DD, J=6,0 Hz and 8.9 Hz), 4.2 ñ 3.9 (7H, m), 3,71 (3H, s), 3,7-3,4 (2H, m), 1,5-1,3 (6H, m).
81-C2H5-C2H5-CH39,27 (1H, d, J=1.5 Hz), 8,73 (1H, d, J=2.5 Hz), to 8.62 (1H, DD, J=1.5 Hz, 2.4 Hz), 7,31 (1H, d, J=2.1 Hz), and 7.3 to 7.2 (1H, m)6,91 (1H, s), for 6.81 (1H, d, J=8,4 Hz), 5,38 (1H, DD, J=5,8 Hz and 8.9 Hz), 4,2-4,0 (4H, m)to 3.67 (3H, s), 3,6-3,4 (2H, m), 1,5-1,4 (6H, m).
82-C2H5-C2H5-CH3of 8.27 (1H, d, J=8.5 Hz), and 8.2 to 8.1 (2H, m), of 7.9 and 7.6 (3H, m), 7,37 (1H, d, J=2.0 Hz), 7,29 (1H, DD, J=2.1 Hz, 8,4 Hz), 6,93 (1H, s), to 6.80 (1H, d, J=8,3 Hz), the ceiling of 5.60 (1H, DD, J=6.3 Hz, 8,3 Hz), 4,2-4,0 (4H, m), of 3.7 and 3.5 (5H, m), 1,5-1,3 (6H, m).

Examples 83-86

In accordance with the method of obtaining from example 58, the following compounds of examples 83-86 were obtained (table 9). Table 9 also shows the physico-chemical characteristics of these compounds is of deposits.

[Table 9]
ExampleRaRbRhRjNMR δ ppm (CDCl3)
83-C2H5-C2H5-CH38,5 an 8.4 (1H, m), 7,56 (1H, d, J=7.8 Hz), 7,41 (1H, d, J=2.0 Hz), between 7.4 to 7.2 (2H, m)6,91 (1H, s), at 6.84 (1H, d, J=8,4 Hz), to 5.35 (1H, DD, J=6,6 Hz, 8.1 Hz), 4,2-4,0 (4H, m), 3,66 (3H, s), 3,6-3,3 (2H, m), of 2.56 (3H, s), 1,5-14 (6H, m)
84-C2H5-C2H5-CH3of 8.3 to 8.2 (1H, m), 7.5 to to 7.3 (9H, m)6,91 (1H, s), PC 6.82(1H, d, J=8,4 Hz), 5,32 (1H, t, J=7.4 Hz), to 5.17 (2H, s), 4,2-4,0 (4H, m), the 3.65 (3H, s), 3,6-3,4 (2H, m), 1,5-1,4 (6H, m)
85-C2H5-C2H5-CH3of 9.02 (1H, s), 8,51 (1H, d, J=5,0 is C), 74-7,3 (2H, m), to 7.15 (1H, d, J=5,0 Hz), 6,91 (1H, s), 6,85 (1H, d, J=8,3 Hz), 5,1-5,0 (1H, m), 4,2-4,0 (4H, m), 3,70 (3H, s), 3,6-3,4 (2H, m), 2,43 (3H, s), 1,5-1,4 (6H, m)
86-C2H5-C2H5-C(CH3)3of 7.48 (1H, d, J=2.1 Hz), 7,40 (1H, DD, J=2.1 Hz, 8,3 Hz), 7,14 (1H, DD, J=1.7 Hz and 4.2 Hz), 6,9-6,8 (3H, m), 6,11 (1H, DD, J=2.5 Hz and 4.2 Hz), with 4.64(1H, t, J=7,3 Hz), from 4.2 to 4.1 (4H, m)to 3.92 (3H, s)to 3.41 (2H, d, J=7.4 Hz), 1,5-14 (6H, m)to 1.37 (9H, s)

Example 87.Obtain 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-ethoxypyridine-2-yl)-1-propanone

Methyl-2-[2-(3,4-dioxyphenyl)thiazole-4-ylmethyl]-3-(3-ethoxypyridine-2-yl)-3-oxopropionate (730 mg, 1.5 mmol) was added to a mixture of acetic acid (4.5 ml) and hydrochloric acid (1.5 ml) followed by heating with stirring at a temperature of from 100 to 110°C for 6 hours. After cooling to room temperature the reaction mixture was added to aqueous solution of sodium carbonate (5.3 g, 0.05 mol) and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/4). The solvent is about what drove under reduced pressure and the residue was recrystallized from ethanol, receiving a result of 475 g (yield: 74%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-ethoxypyridine-2-yl)-1-propanone in the form of colorless needle-like crystals. Melting point: 66,7-68,2°C.

Example 88.Obtain 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanone

The triethylamine (0,19 ml of 1.36 mmol) and pyridine complex with sulfur trioxide (0.11 g, of 0.68 mmol) was added to a solution (5 ml) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propane-1-ol (0.14 g, 0.34 mmol) in DMSO, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water and was performed three times extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel thin-layer column chromatography (eluent: dichloromethane /methanol=10/1). The solvent is kept at reduced pressure, obtaining 120 mg (yield: 86%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanone in the form of a colorless oil. The oil was recrystallized from anhydrous ethanol, resulting in the 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanone in the form of needle crystals yellow. Melting point: 7,2-79,7°C.

Example 89.Obtain 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)-1-propanone

(E)-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)propenone (1,62 g, 4.0 mmol) was dissolved in a mixed solvent of ethyl acetate (40 ml), methanol (10 ml) and DMF (10 ml) and was added 400 mg of 10% palladium/carbon for carrying out catalytic reduction in a hydrogen atmosphere at room temperature and atmospheric pressure for 4 hours. The reaction mixture was filtered, the solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/2-1/1). The solvent is kept under reduced pressure and the residue was recrystallized from diethyl ether, to deliver 750 mg (yield: 46%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)-1-propanone in the form of colourless crystals of prismatic shape. Melting point: 68,9-69,3°C.

Example 90.Obtain 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-thiazol-2-yl-1-propanone

Solution (2 ml) thiazole (129 mg, 1.5 mmol) in THF was cooled to -70°C was added n-utility (2,44M solution in hexane) (0,62 ml, 1.5 mmol) and the resulting mixture was stirred at -70 ° C for 30 minutes. To the reaction mixture solution was added (4 ml) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-N-methoxy-N-methylpropionamide (500 mg, 1.4 mmol) in THF, followed by stirring at -70°C for 3 hours. After heating to room temperature, to the reaction mixture were added nasy the military aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). The solvent is kept under reduced pressure and the residue was recrystallized from ethanol, to deliver 350 mg (yield: 66%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-thiazol-2-yl-1-propanone in the form of colorless needle-like crystals. Melting point: br93.1-94,4°C.

Examples 91-108

In accordance with the method of obtaining from example 87, the following compounds of examples 91-108 were obtained (table 10). Table 10 also shows the physico-chemical characteristics of these compounds.

-OCH3
[Table 10]
ExampleRaRbRCRdReRfRgMelting point (°C)Sol
91-C2H5-C2H5 -H-H-H-H113,3-113,6-
92-C2H5-C2H5-H-H-OH-OH-H153,2-153,8hydrochloride
93-CH3-CH3-H-H-OC2H5-OC2H5-H141,3-142,4-
94-CH3-CH3-H-H-OCOCH3-OCOCH3-H128-128,5-
95-C2H5-C2H5-H-H-OCH3-Hof 97.8-98,5-
96-C2H5-C2H5-H-H-H-H-OCH368,9-69,3-
97-C2H5-C2H5-H-H-H-H-OC6H5118,2-119-
98-C2H5-C2H5-OH-H-H-H-H113,7-USD 114.9-
99-C2H5-C2H5 -CF3-H-H-H-H91,7-93-
100-C2H5-C2H5-OC2H5-H-H-H-H84,3-86,1-
101-C2H5-C2H5-F-H-H-H-H82,5-to 83.5-
102-C2H5-C2H5-CN-H-H-H-H113,7-114,8-
103-C2H5-C2 H5-Br-H-H-H-H66,1-67,9-
104-C2H5-C2H5-Cl-H-H-H-H64,4 from 65.1-
105-C2H5-C2H5-H-H-H-H-CO2CH391,7-92,9-
106-C2H5-C2H5-OCH3-H-Cl-H-H102,8-104,2-
107-C2H5 -C2H5-CH3-H-H-H-H107,1-107,4-
108-C2H5-C2H5-OCH3-H-H-CI-H90,2-92-

Examples 109-114.

In accordance with the method of obtaining from example 87, the following compounds of examples 109-114 were obtained (table 11). Table 11 also shows the physico-chemical characteristics of these compounds.

[Table 11]
ExampleRaRbRcRdReRfRgNMR δ ppm (CDCl3)
109-C2H5-OCH3-Cl-H-H-Hof 7.6 to 7.3 (4H, m), 7,10 (1H, t, J=7,8gts), the 6.9 to 6.8 (2H, m), 4,2-4,0 (4H, m), a 3.87 (3H, s), of 3.46 (2H, t, J=7,1 Hz), 3,21 (2H, t, J=7,1 Hz), 1,5-1,4 (6H, m)
110-C2H5-C2H5-N(CH3)2-H-H-H-H7,49 (1H, d, J=2.0 Hz), 7,43-of 7.3 (3H, m), 7,0-6,8 (4H, m), from 4.2 to 4.1 (4H, m), of 3.48 (2H, t, J=7,3 Hz), 3,18 (2H, t, J=7,3 Hz), 2,73 (6H, s), 1,5-1,4 (6H, m)
111-C2H5-C2H5-H-H-H-H-CON(CH3)27,88 (1H, d, J=7,4 Hz), of 7.6 to 7.3 (4H, m), and 7.3 to 7.2 (1H, m), 6,9-6,8 (2H, m), from 4.2 to 4.1 (4H, m), of 3.45 (2H, t, J=7,3 Hz), 3,20 (2H, t, J=7.2 Hz), 3,14 (3H, s), was 2.76 (3H, s), 1,5-1,4 (6H, m)
112-C2H5-C2H5-H-H -H-H-CO2H10,08 (1H, W), 7,87 (1H, d, J=7,1 Hz), 7,7-of 7.3 (5H, m), 6,92 (1H, s), 6.89 in (1H, d, J=8,3 Hz), 4,2-4,0 (4H, m), 3,6-3,4 (1H, m), and 3.1 to 3.0 (1H, m), 2,6-2,2 (2H, m), 1,5-1,4 (6H, m)
113-C2H5-C2H5-H-H-H-H-C2H5of 7.5 to 7.3 (11H, m), 6.87 in (1H, d, J=8,4 Hz), 6,63 (1H, s), 4,2-4,0 (4H, m), of 3.0 and 2.9 (2H, m), 2,8-2,7 (2H, m), 1,5-1,4 (6H, m)
114-C2H5-C2H5-OCH2OCH3-H-H-H-Hof 7.69 (1H, DD, J=7.8 Hz), 7.5 to to 7.3 (3H, m), 7,19 (1H, d, J=8,4 Hz), 7,1-a 7.0 (1H, m), to 6.88 (1H, s), 6,85 (1H, d, J=8,4 Hz), with 5.22 (2H, s), 5,1-5,0 (1H, m), 4,2-4,0 (4H, m), 3,68 (3H, s), 3,6-3,3 (5H, m), 1,5-1,4 (6H, m)

Examples 115-147.

In accordance with the method of obtaining from example 87, the following compounds of examples 115-147 were obtained (table 12). Table 12 also shows the physico-chemical characteristics of these compounds.

[Table 12]
ExampleRaRbRCRdReRfRgMS (M+1)
115-C2H5-C2H5-Cl-H-Cl-SO2NH2-H529
116-C2H5-C2H5-OCH3-H-H-SO2NH2-H491
117-C2H5-C2H5-H-H-CN-H-H407
118-C2Hsub> 5-C2H5-H-OCH3-H-OCH3-H442
119-C2H5-C2H5-H-H-H-CH3-H396
120-C2H5-C2H5-H-H-CH3-H-H396
121-C2H5-C2H5-H-H-N(CH3)2-H-H425
122-C2H5-C2H5-H -H-H-N(CH3)2-H425
123-C2H5-C2H5-H-H-H-Br-H460
124-C2H5-C2H5-H-H-F-H-H400
125-C2H5-C2H5-H-H-OCH3-CN-H437
126-C2H5-C2H5-H-H-CH3-OCH3-H 426
127-C2H5-C2H5-H-H-H-H-OCF3466
128-C2H5-C2H5-H-H-H-Cl-H416
129-C2H5-C2H5-H-H-Cl-H-H416
130-C2H5-C2H5-H-H-OCH3-OCH3-H442
131-C2H5 -C2H5-H-H-OCH3-H-H412
132-C2H5-C2H5-H-H-H-CF3-H450
133-C2H5-C2H5-H-H-H-Cl-Cl450
134-C2H5-C2H5-H-H-H-H-SCH3428
135-C2H5-C2H5-H-H-OC4/sub> H9-H-H454
136-C2H5-C2H5-H-H-H-F-H400
137-C2H5-C2H5-H-Cl-H-H-Cl450
138-C2H5-C2H5-H-H-H-OCH3-H412
139-C2H5-C2H5-H-H-C6H5-H-H458
140-C2H5-C2H5-H-H-H-OC2H5-H426
141-C2H5-C2H5-H-H-OC2H5-H-H426
142-C2H5-C2H5-H-H-OCH2C6H5-H-H488
143-C2H5-C2H5-H-H-H-OCF3-H466
144-C2H5 -C2H5-H-H-CF3-H-H450
145-C2H5-C2H5-H-H-C4H9-H-H438
146-C2H5-C2H5-H-H-H-H-OCH2C6H5488
147-C2H5-C2H5-H-H-OH-H-H398

Examples 148-152.

In accordance with the method of obtaining from example 87, the following compounds of examples 149-152 were obtained (table 13). Table 13 also shows the physical-chemical the definition of the characteristics of these compounds.

[Table 13]
ExampleRaRbRCRdReRfRgMS (M+1)
148-C2H5-C2H5-H-H-H-H448
149-C2H5-C2H5-H-H-H-H449
150-C2H5-C2H5-H-H-H -H448
151-C2H5-C2H5-H-H-H-H449
152-C2H5-C2H5-H-H-H-H467

Examples 153-157

In accordance with the method of obtaining from example 87, the following compounds of examples 153-157 were obtained (table 14). Table 14 also shows the physico-chemical characteristics of these compounds.

[Table 14]
ExampleRaRbRhMelting point (°C)
153-C2H5 2H5-2-PYRIDYL92,9-93
154-C2H5-C2H5-2-FURYL110,8-112,5
155-C2H5-C2H5-2-THIENYL106,5-107,4
156-C2H5-C2H5-4-PYRIDYL90,6-to 91.1
157-C2H5-C2H5-3-PYRIDYL107,5-108,0

Examples 158-167.

In accordance with the method of obtaining from example 87, the following compounds of examples 158-167 were obtained (table 15). Table 15 also shows the physico-chemical characteristics of these compounds.

[Table 15]
ExampleRaRb RhMelting point (°C)
158-C2H5-C2H559,5 is 60.5
159-C2H5-C2H5118,7-119,6
160-C2H5-C2H5109,1-110,5
161-C2H5-C2H581,7-83,1
162-C2H5-C2H587,0-87,6
163-C2H5-C2H5 to 92.1-br93.1
164-C2H5-C2H5117,9-119,2
165-C2H5-C2H580,3-81,9
166-C2H5-C2H5to 107.7-108,5
167-C2H5-C2H592,8-94,2

Example 168.

In accordance with the method of obtaining from example 87, the following compound of example 168 was obtained (table 16). Table 16 also shows the physico-chemical characteristics of the compound.

[Table 16]
ExampleRaRb RhNMR δ ppm (DMSO-d6)
168-C2H5-C2H58,31-8,29 (1H, m), of 8.00 (1H, d, J=8.7 Hz), 7,8-in 7.7 (1H, m), 7,53 (1H, d, J=2.1 Hz), 7,44 (1H, DD, J=2.1 Hz, 8,4 Hz), was 7.36 (1H, s), 7,03 (1H, d, J=8.5 Hz), the 4.9 to 4.7 (1H, m), 4,1-4,0 (4H, m), 3,50 (2H, t, J=7,2 Hz), 3,11 (2H, t, J=7.2 Hz), 1,4-1,2 (12H, m)

Examples 169-178.

In accordance with the method of obtaining from example 87, the following compounds of examples 169-178 were obtained (table 17). Table 17 also shows the physico-chemical characteristics of these compounds.

[Table 17]
ExampleRaRbRhMS (M+1)
169-C2H5-C2H5451
170-C2H5-C2H5 451
171-C2H5-C2H5422
172-C2H5-C2H5386
173-C2H5-C2H5397
174-C2H5-C2H5418
175-C2H5-C2H5386
176-C2H5-C2H5413
177-C2 H5-C2H5432
178C2H5C2H5387

Examples 179-185.

In accordance with the method of obtaining from example 87, the following compounds of examples 179-185 were obtained (table 18). Table 18 also shows the physico-chemical characteristics of these compounds.

[Table 18]
ExampleRaRbRhMS (M+1)
179-C2H5-C2H5438
180-C2H5-C2H5418
181 -C2H5-C2H5444
182-C2H5-C2H5432
183-C2H5-C2H5426
184-C2H5-C2H5434
185-C2H5-C2H5433

Example 186.Obtain 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)-1-propanol

Sodium borohydride (20 mg, of 0.53 mmol) was added to a mixed solution of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)-1-propanone (458 mg, 1.11 mmol) in THF (10 ml) and methanol (10 ml) at room temperature and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). The solvent is kept under reduced pressure and the residue was recrystallized from a mixed solvent of diethyl ether/n-hexane, to deliver 336 mg (yield: 73%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)-1-propanol in the form of a white powder. Melting point: 78,2-79°C.

Example 187.Obtain 3-[2-(3, 4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol dihydrochloride.

In accordance with the method of obtaining of example 186 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol the dihydrochloride was obtained. Melting point: 161,0-161,5°C.

Example 188.Obtain 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol

A solution of 2-bromo-3-methoxypyridine (1.65 g, 8,78 mmol) in THF was cooled to -78°C and added dropwise 5,23 ml (8.16 mmol) of 1.57 n solution of n-utility in n-hexane. The resulting mixture was stirred at the same temperature for 45 minutes and was added dropwise a solution (15 ml) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]Propionaldehyde (1,34 g, 4,39 IMO the ü) in THF. After stirring at the same temperature for 30 minutes, the temperature of the mixture was raised to -30°C for 30 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). The solvent is kept under reduced pressure and the residue was purified preparative thin-layer column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/2)). The solvent is kept at reduced pressure, obtaining the result of 470 mg (yield: 26%) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol in the form of a yellow oil.

Examples 189-208.

In accordance with the method of obtaining of example 186, the following compounds of examples 189-208 were obtained (table 19). In table 19 also shows the physico-chemical characteristics of these compounds.

[Table 19]
ExampleRaRbRCRdRe RfRgMS (M+1)
189-C2H5-C2H5-H-H-H-H-H384
190-C2H5-C2H5-H-H-CN-H-H409
191-C2H5-C2H5-H-OCH3-H-OCH3-H444
192-C2H5-C2H5-H-H-H-CH3-H398
193 -C2H5-C2H5-H-H-CH3-H-H398
194-C2H5-C2H5-H-H-N(CH3)2-H-H426(M+)
195-C2H5-C2H5-H-H-HN(CH3)2-H427
196-C2H5-C2H5-H-H-H-H-Br462
197-C2H5-C2H5-H -H-H-H-OC2H5428
198-C2H5-C2H5-H-H-H-Br-H462
199-C2H5-C2H5-H-H-F-H-H402
200-C2H5-C2H5-H-H-OCH3-CN-H439
201-C2H5-C2H5-H-H-CH3-OCH3 -H428
202-C2H5-C2H5-H-H-H-H-OCF3468
203-C2H5-C2H5-H-H-H-H-OCH3414
204-C2H5-C2H5-H-H-Cl-H-H418
205-C2H5-C2H5-H-H-H-H-Cl418
206-C2H5 -C2H5-H-Cl-H-H-OCH3448
207-C2H5-C2H5-H-H-H-CF3-H452
208-C2H5-C2H5-H-OCH3-H-H-OCH3444

Examples 209-225.

In accordance with the method of obtaining of example 186, the following compounds of examples 209-225 were obtained (table 20). Table 20 also shows the physico-chemical characteristics of these compounds.

[Table 20]
ExampleRaRbRC RdReRfRgMS (M+1)
209-C2H5-C2H5-H-H-H-Cl-Cl452
210-C2H5-C2H5-H-H-H-H-SCH3430
211-C2H5-C2H5-H-H-H-F-H402
212-C2H5-C2H5-H-Cl-H-H-Cl452
213-C2H5-C2H5-H-H-H-OCH3-H414
214-C2H5-C2H5-H-H-C6H5-H-H460
215-C2H5-C2H5-H-H-H-OC2H5-H428
216-C2H5-C2H5-H-H-H-H-F402
217-C2H5 -C2H5-H-H-H-OCF3-H468
218-C2H5-C2H5-H-H-CF3-H-H452
219-C2H5-C2H5-H-H-H-H-CF3452
220-C2H5-C2H5-H-H-C4H9-H-H440
221-C2H5-C2H5-H-H -H-H-CN409
222-C2H5-C2H5-H-H-OCH3-OCH3-H444
223-C2H5-C2H5-H-H-OCH3-H-H414
224-C2H5-C2H5-H-H-OC4H9-H-H456
225-C2H5-C2H5-H-H-OC2H5-H-H 428

Examples 226-237.

In accordance with the method of obtaining of example 186, the following compounds of examples 226-237 were obtained (table 21). Table 21 also shows the physico-chemical characteristics of these compounds.

[Table 21]

Example 238.

Getting 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propyl}-3-methoxypyridine dihydrochloride

The hydrazine hydrate (of 0.18 ml, 3.6 mmol) and potassium hydroxide (136 mg, 2.4 mmol) was added to a solution (5 ml) of 3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanone (500 mg, 1.2 mmol) in diethylene glycol and the resulting mixture was heated to 150°C and was stirred for 1 hour. After cooling to room temperature, to the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/4). The solvent is kept under reduced pressure and the residue was dissolved in 4 ml of ethanol. Added 1 n hydrochloric acid in ethanol (1.6 ml), the solvent is kept at igenom pressure and the residue was recrystallized from a mixed solvent of ethanol/ethyl acetate, getting in the 320 mg (yield: 73%) of 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propyl}-3-methoxypyridine dihydrochloride in the form of a white powder. Melting point: 169,4 of 171.2°C.

Example 239.Getting 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}benzonitrile

Cyanide zinc(II) (purity 60%) (140 mg, 0.7 mmol) and tetrakis(triphenylphosphine)palladium (19 mg, to 0.016 mmol) was added to solution (1 ml) of 1-(2-bromophenyl)-3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propane-1-she (150 mg, 0.33 mmol) in DMF and the mixture was stirred while heating in an argon atmosphere at 100°C for 2 hours. After cooling to room temperature, to the reaction mixture were added water and ethyl acetate, the resulting mixture was filtered through celite and the filtrate was divided into layers. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/4. The solvent is kept under reduced pressure and the residue was recrystallized from ethanol, resulting in the 70 mg (yield: 53%) of 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}benzonitrile in the form of colorless policytech crystals. Melting point: 113,7-114,8°C.

Example 240.Obtaining methyl-2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}benzoate

Hydrogen h is Tria (79 mg, to 0.94 mmol) and methyliodide (0,04 ml of 0.56 mmol) was added to a solution (4 ml) of 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}benzoic acid (200 mg, 0.47 mmol) in DMF, followed by stirring at room temperature over night. To the reaction mixture were added water and extraction was performed with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent is kept under reduced pressure and the residue was recrystallized from ethanol, to deliver 190 mg (yield: 92%) of methyl 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}benzoate as a colourless policytech crystals. Melting point: 91,7-of 92.9°C.

Example 241.Getting 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}-N,N-dimethylbenzamide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) (54 mg, 0.29 mmol), 1-hydroxybenzotriazole (HOBT) (43 mg, 0.29 mmol) and 50% aqueous solution of dimethylamine (0,025 ml, 0.29 mmol) was added at room temperature to a solution (2 ml) of 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}benzoic acid (100 mg, 0.24 mmol) in DMF, followed by stirring at the same temperature for 2 hours. To the reaction mixture were added water and extraction was performed atilas what tatom. The organic layer was washed with a saturated solution of sodium bicarbonate, water and saturated saline solution in this order and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and the residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3)). The solvent is kept under reduced pressure, to deliver 65 mg (yield: 61%) of 2-{3-[2-(3,4-dioxyphenyl)thiazol-4-yl]propionyl}-N,N-dimethylbenzamide in the form of a colorless oil.

NMR δ ppm (CDCl3); 7,88 (1H, d, J=7,4 Hz), of 7.6 to 7.3 (4H, m), and 7.3 to 7.2 (1H, m), 6,9-6,8 (2H, m), from 4.2 to 4.1 (4H, m), of 3.45 (2H, t, J=7,3 Hz), 3,20 (2H, t, J=7.2 Hz), 3,14 (3H, s), was 2.76 (3H, s), 1,5-1,4 (6H, m).

Example 242.Obtain 3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-diacetoxybiphenyl)propanone

Acetic anhydride was added dropwise (2 ml, 20 mmol) at room temperature to a solution (4 ml) of 3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-dihydroxyphenyl)propanone (320 mg, 0.78 mmol) in pyridine at room temperature, followed by stirring at the same temperature for 1 hour. To the reaction mixture were added methanol (10 ml)was stirred at room temperature for 1 hour and the solvent is kept at reduced pressure. Then add water and extraction was performed with ethyl acetate. The residue was purified on silica gel column chromatography (eluent: ethyl acetate). The solvent of othona and under reduced pressure and the residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane, getting in the 195 mg (yield: 54%) of 3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-dihydroxyphenyl) propanone in the form of colorless policytech crystals. Melting point: 128-128,5°C.

Example 243.Obtain 3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-dioxyphenyl)propanone

Ethyliodide (of 0.48 ml, 6.0 mmol) and potassium carbonate (of 0.62 g, 4.5 mmol) was added at room temperature to a solution (7 ml) of 3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-dihydroxyphenyl) propanone (of 0.58 g, 1.5 mmol) in DMF, followed by stirring at 60°C for 1 hour. After cooling to room temperature, to the reaction mixture was added ethyl acetate, the resulting mixture was filtered and the solvent is kept at reduced pressure. The residue was purified on silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent is kept under reduced pressure and the residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane, to deliver 290 mg (yield: 44%) of 3-[2-(3,4-acid)thiazol-4-yl]-1-(3,4-dioxyphenyl) propanone in the form of a white powder. Melting point: 141, 3mm-142,4°C.

Examples 244-247.

In accordance with the method of obtaining of example 186, the following compounds of examples 244-247 were obtained (table 22).

[Table 22]
ExampleConnectionMS (M+1)
2443-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-naphthalene-1-yl-1-propanol434
2453-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-naphthalene-2-yl-1-propanol434
2463-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-cinoxacin-6-yl-1-propanol436
2471-benzo[1,3]dioxol-5-yl-3-[2-(3,4-dioxyphenyl) thiazol-4-yl]-1-propanol428

Example 248.

In accordance with the method of obtaining from example 58, the following compound was obtained.

Methyl-2-[2-(3,4-dioxyphenyl)thiazole-4-ylmethyl]-2-(3-ethoxypyridine-2-yl)-3-oxybutyrate.

NMR δ ppm (CDCl3); by 8.22 (1H, DD, J=1.4 Hz, 4.3 Hz), 7.5 to to 7.3 (4H, m), 6,9-6,8 (2H, m),4,8-4,6 (1H, m), 4,2-4,0 (4H, m), 3,90 (3H, s), the 3.65 (3H, s), 3,0-2,8 (2H, m), 2,6-2,3 (2H, m), 1,5-1,4 (6H, m).

Example 249.

In accordance with the method of obtaining from example 87, the following compound was obtained.

3-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(3-ethoxypyridine-2-yl)-1-butanone.

NMR δ ppm (CDCl3); 8,30-to 8.20 (1H, m), 7,51 (1H, d, J=1,8 Hz), 7.5 to to 7.3 (3H, m), 6,9-6,8 (2H, m), from 4.3 to 4.1 (4H, m)to 3.89 (3H, s), 3,20 (2H, t, J=7,3 Hz), only 2.91 (2H, t, J=7.5 Hz), 22-2,1 (2H, m), 1,5-1,4 (6H, m).

Example 250.

In accordance with the method of obtaining from example 90, the following compound was obtained.

2-[2-(3,4-dioxyphenyl)thiazol-4-yl]-1-(2-methoxyphenyl)-Etalon.

NMR δ ppm (CDCl3); 7,79 (1H, DD, of 1.8, 7.7 Hz), 7,49 (1H, d, J=2.1 Hz), 7,49-7,46 (1H, m), 7,42 (1H, DD, J=2,1, 8,4 Hz), 7,06 (1H, s), 7.03 is-7,00 (1H, m), 6,98 (1H, d, J=8,4 Hz), to 6.88 (1H, d, J=8,4 Hz), 4,55 (2H, s), 4,18 (2H, square, J=7,0 Hz), 4,14(2H, square, J=7,0 Hz)to 3.92 (3H, s)to 1.48 (3H, t, J=7.0 Hz), of 1.47(3H, t, J=7,0 Hz).

Test example 1.Test for inhibitory activity of the phosphodiesterase (PDE)4.

Using the compounds of examples 1, 78, 87, 88, 99, 100, 106, 107, 158, 162, 165, 167, 174, 175, 187, 227, 238 and 239 as the test compounds, the following test was conducted to evaluate their inhibitory activity on phosphodiesterase (PDE)4.

(1) Preparation of the masses plasmids

Plasmids containing the genes encoded for human PDE4D (HPDE4D) (stored at Otsuka America Pharmaceutical, Inc., Maryland Research Laboratories), transformed into Escherichia coli and mass cultured. Plasmids were then purified using the kit EndoFreeTMPlasmid Mxi Kit (Qiagen).

(2) the Expression of mass and purification of PDE4D

Line COS-7 cells derived from the kidney of African green monkeys (RCB 0539), perceivable in DMEM containing 100 units/ml penicillin, 100 μm/ml streptomycin and 10% FBS. The plasmid prepared in (1), transferrable in cells using LipofetAMINETM2000 Reagent (hereinafter referred to is as "LF2000", the product of the company Invitroge) in accordance with the attached Protocol. For comparison, pcDNA3.1 was transferrable as a control vector. COS-7 cells were seeded in Petri dishes 10 cm in diameter, the day before transfection so that the cells reached 90% of confluently the day of the transfection. Twelve micrograms of the plasmid diluted with 0.9 ml of OPTI-MEM I (Invitrogen), (solution plasmids; solution A)and 30 ál of LF2000, diluted with 0.9 ml of OPTI-MEM I (LF2000 solution; solution B)was obtained on the Petri dish and kept at room temperature for 5 minutes. Solutions A and B were then mixed together and kept at room temperature for 20 minutes. The mixture was added to cultured cells and incubated over night at 37°C in an atmosphere of 5% CO2. Culture medium was changed the next day, the incubation was continued during the night and collected cells using the following methodology. First, cells were washed once with PBS (Sigma) and added to a Petri dish with 2 ml Trypsin-EDTA (Sigma), distributed by the Cup and removed. Then kept the cells at 37°C for 2 to 3 minutes, chose them from the Petri dishes and suspended in the medium. The suspension was placed in a centrifuge tube, and centrifuged at 200g and 4°C for 5 minutes. The supernatant was then removed. Cells then were washed in PBS and stored at -80°C. To the saved cells were added KHEM buffer (50 mm Hepes 50 mm KCl, 10 mm EGTA, 1,92 mm MgCl2pH of 7.2)containing 1 mm DTT, 40 μg/ml PMST, 156 µg/ml of benzamidine, 1 μg/ml Aprotinin, 1 μg/ml leupeptin, 1 μg/ml of pepstatin A, and 1 μg/ml antipain, and the resulting mixture was placed in a glass homogenizer and homogenized on ice. The cell suspension was centrifuged at 100g and 4°C for 5 minutes, and the supernatant was then centrifuged at 100000g for 1 hour. Then the supernatant was transferred into a new tube as a solution of the enzyme PDE4D and kept in the freezer for very low temperatures. Then measured the concentration of protein in solution PDE4D enzyme.

(3) determination of the dilution factor of the solution of enzyme PDE4D

The solution of PDE4D enzyme prepared in (2), was diluted in 10, 25, 50, 100, 200, 400 and 800-fold with 20 mm Tris-HCl (pH 7,4) and measured PDE4D activity of dilute solutions of the enzyme by the method described in (4), to determine the optimal dilution factor and reconstitution of the enzyme PDE4D, which disintegrated cAMP ranged from 10% to 30% of the total cAMP.

(4) Measurement of inhibitory activity on PDE4D.

The required number of each of the tested compounds were weighed and dissolved in 100% DMSO and obtaining a concentration of 10 mm. The resulting solutions were stored in the freezer as initial solutions of the tested compounds. Before measuring inhibitory activity : the derivative solutions were thawed, was diluted two times with 100% DMSO to a concentration of 5 mm and then diluted using 100% DMSO to obtain solutions of the tested substances with concentrations decreasing consistently 10 times. Each solution of the test substance was added 1.2 ml tube containing 23 μl of 20 mm Tris-HCl (pH 7,4). Was added while cooling on ice twenty-five microlitres solution of PDE4D enzyme at optimal dilution factor defined in (3), and add 50 µl of substrate solution containing 2 μm [3H]cAMP, obtained by dilution with 20 mm Tris-HCl (pH 7,4)containing 10 mm MgCl2. The final concentration of DMSO in the reaction mixture was 2%. After mixing, the mixture is incubated at 30°C for 10 minutes. After incubation, the tubes were placed in a boiling water bath for 3 minutes to terminate the reaction. The tubes were cooled on ice and added 25 μl of 0.2 μg/ml snake venom. After mixing, incubation was performed at 30°C for 10 minutes. After incubation, was added 0.4 ml of a solution of resin Dowex 1x8, prepared using a mixture of EtOH:H2O (1:1). After mixing, the mixture was stirred at room temperature for at least 1 hour. Fifty microlitres each of the supernatant liquid in the test tubes were placed in the hole of the tablet Topcount and the plate was dried for 3 but is her. The radioactivity of [3H] (cpm) was measured using a Topcount. Determining the radioactivity of [3H] as X cpm, the radioactivity of [3H]cAMP added to the reaction system, as T cpm, and the protein concentration in the reaction mixture as Y mg/ml, the activity of PDE4D in the reaction mixture were found from the following equation:

To find the inhibitory activity of PDE4D of the tested substances, cpm in the absence of the tested substances, from which the priest cpm in the absence of enzyme was taken as 100% and the degree of inhibition of the tested substances was expressed as percent of control values. Then calculate the value of the IC50(the concentration at which the inhibition of PDE4 activity by 50%) of each test substance.

The results are shown in table 23. These results show that the compounds represented by formula (1), have excellent inhibitory activity on PDE4.

[Table 23]
The substance to be testedThe value of the IC50(µm)
Connection example 10,0236
The compound of example 780,0100
Connection use the and 87 is 0.0002
The compound of example 880,0004
The compound of example 990,0290
The compound of example 1000,0023
The compound of example 1060,0057
The compound of example 1070,0058
The compound of example 1580,0057
The compound of example 1620,0016
The compound of example 1650,0150
The compound of example 1670,0100
The compound of example 1740,0100
The compound of example 1750,0330
The compound of example 1870,0066
The compound of example 2270,0290
The compound of example 2380,0072
The compound of example 2390,097

Test example 2. Measurement of inhibitory activity of production of TNF-α

To evaluate inhibitory activity production of TNF-α was performed the following tests.

(1) Isolation of mononuclear cells in human peripheral blood.

A sample of peripheral blood was obtained from healthy adult donor who has given official consent. Thirty milliliters of pre-heparinised blood sample was placed in a Leucosep tube (Greiner)containing 16 ml of solution for isolation of lymphocytes (Nakarai Chemical co., Ltd.) under the filter wall, and was centrifuged at 1000g for 15 minutes.

Collected intermediate layer, corresponding to the fraction of mononuclear cells in 50 ml centrifuge tube and washed twice with RPMI medium 1640. After staining Trifanova blue determined the number of viable microorganisms and brought up to cocentrate 2×106cells/ml with RPMI medium 1640.

(2) inducing the production of TNF-α

LPS E. coli E. coli (Serotype 055:B5), which was dissolved in medium RPMI 1640 to a concentration of 5 mg/ml, sterilized by filtration and stored in the freezer was thawed and diluted with RPMI medium 1640 to 10 μg/ml compound was dissolved in DMSO to obtain solutions with concentrations 50 times higher concentration of end use. One microliter of each and the solutions with graded concentrations of the test substance, 149 μl of medium RPMI 1640, 50 μl of the solution of LPS (final concentration: 1 μg/ml), 50 μl of fetal bovine serum and 50 ml suspension of mononuclear peripheral blood cells were placed in each well of a 48-hole tablet, and incubated at 37°C for 24 hours.

(3) Measurement of the concentration of TNF-α

After incubation of each well was collected culture supernatant and measured the concentration of TNF-α in the supernatant using ELISA method (Human TNF-α Eli-pair, Diaclone). The concentration of TNF-α caused by LPS stimulation in the absence of the tested compounds was taken as 100% and the degree of inhibition of the test compounds was expressed as percent of control values and calculated size IC50(the concentration at which the inhibition of production of TNF-α at 50%) for each of the test compounds.

The results are shown in table 24. These results showed that the compounds represented by formula (1)have inhibitory activity on the production of TNF-α.

[Table 24]
The substance to be testedThe value of the IC50(µm)
Connection example 10,008
The compound of example 48 0,25
The compound of example 510,8
The compound of example 520,13
The compound of example 560,16
The compound of example 890,007
The compound of example 910,543
The compound of example 1530,183

Test example 3.Measurement of inhibitory activity of IL-4

To assess the inhibitory activity of IL-4 conducted the following tests.

(1) Isolation of spleen cells of the mouse

In the abdominal cavity of male mice of BALB/c mice aged six to ten weeks had made the cut with the use of anesthesia with ether, and removed the spleen. The spleen was divided into pieces, Prodanova through the mesh using a glass pestle, and spleen cells suspended in RPMI medium 1640. The suspension was filtered through a Cell Strainer and centrifuged at 100g for 10 minutes. Debris suspended in a solution of red blood cells (0,75% ammonium chloride, 17 mm, the buffer Tris-hydrochloric acid) and centrifuged. Then for resuspendable cells to the debris was added to the medium RPMI 1640. After the penny is fugiranje cells were twice washed and the number of viable microorganisms was determined by staining Trifanova blue and brought to a concentration of 2×10 6cells/ml with RPMI medium 1640.

(2) inducing the production of IL-4

ConA dissolved in a solution of cell culture medium RPMI 1640 containing 10% fetal bovine serum) to a concentration of 5 mg/ml, sterilized by filtration and stored in the freezer was thawed and diluted with a solution of cell culture to 50 μg/ml compound was dissolved in DMSO to obtain solutions with concentrations 10 times higher concentration of end use. Fifty microlitres each of the solutions with graded concentrations of the test substance, 150 μl of a solution of cell culture, 50 μl of ConA solution (final concentration: 5 μg/ml) and 20 μl of cell suspension of the spleen of the mouse was placed in each well of a 48-hole tablet, and incubated at 37°C for 48 hours.

(3) Measurement of the concentration of IL-4

After incubation of each well was collected culture supernatant and measured the concentration of IL-4 in the supernatant using ELISA method (mouse IL-4 EIA kit, BD Pharmingen). The concentration of IL-4 caused by ConA stimulation in the absence of the tested compounds was taken as 100% and the degree of inhibition of the test compounds was expressed as percent of control values and calculated size IC50for each of the test compounds as the concentration of the test compound, at which ingibirovanie production of IL-4 by 50%.

An example of the dosage form 1. Ointment

One gram of the compound of the present invention has dispersible in 10 g of liquid paraffin to obtain the dispersion. The base was prepared by heating and mixing 3 g of paraffin, 5 g white beeswax and 81 g medical vaseline and cooled, and then, when the base was cooled to 60°C., was added to the above dispersion. After mixing, the mixture was cooled to obtain a cream.

An example of the dosage form 2.Cream

One gram of the compound of the present invention has dispersible in an aqueous solution containing 10 g of purified water and 1 g polyoxyethylene hydrogenated castor oil 60, to obtain the dispersion. Was prepared by heating the emulsion base comprising 25 g medical vaseline, 20 g of stearyl alcohol, 12 g of propylene glycol, 3 g polyoxyethylene hydrogenated castor oil 60, 1 g glycerylmonostearate, 0.1 g of methylparahydroxybenzoate, 0.1 g of propylparabens and 26.8 g of purified water. The obtained emulsion base was cooled, and then, when the base was cooled to 60°C., was added to the above dispersion. After mixing, the mixture was cooled to obtain a cream.

[Industrial use]

The compound of the present invention exhibits a specific inhibitory activity on D4 and can therefore be used as active ingredient is and inhibitor D4.

In addition, the compound of the present invention due to its specific inhibitory activity on D4 can be used as a preventive or therapeutic agent for atopic dermatitis, and many other diseases.

1. The compound represented by formula (1), its optical isomer, or its pharmaceutically acceptable salt

where R1 is CI-C1-6alkoxyphenyl group;
R2 is any one of the following groups (a)-(t):
(a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or is a group (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6the alkyl group or groups, (a-27) phenyl-C1-6alkoxygroup;
(b) naftilos group;
(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (1) hydroxyl groups, (C-2) C1-6alkyl groups, (C-3) C1-6alkoxygroup, (C-4) phenyl-C1-6alkoxygroup, and (C-5) C1-6alkoxycarbonyl groups;
(d) shriley group, in which the furan ring may be substituted C1-6alkyl group or groups;
(e) a thienyl group, in which the thiophene ring may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2) C1-6alkyl groups, and (e-3)1-6alkoxygroup;
(f) isoxazolidine group where isoxazolidine ring may be substituted With1-6alkyl group or groups;
(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl which groups, which may be substituted C1-6alkoxygroup or groups;
(h) pyrrolidino group, in which the pyrrole ring may be substituted C1-6alkyl group or groups;
(i) imidazolidine group, in which the imidazole ring may be substituted C1-6alkyl group or groups;
(j) tetrazolyl group;
(k) personalni group;
(l) tiantianle group;
(m) benzothiazole group;
(n) indolines group, in which the indole ring may be substituted C1-6alkoxygroup or groups;
(o) benzimidazolyl group, in which the benzimidazole ring may be substituted C1-6alkyl group or groups;
(R) indazolinone group;
(q) pinolillo group;
(r) 1,2,3,4-tetrahydroquinoline group, in which 1,2,3,4-tetrahydroquinoline ring may be substituted by oxopropoxy or groups;
(s) khinoksalinona group; and
(t) 1,3-benzodioxolyl group; and
And is one of the following groups (i)to(vi):
(i) -CO-B-, where b is a C1-6alkalinous group;
(ii) -CO-VA, where VA is C2-6alkenylamine group;
(iii) -CH(OH)-B-, where a is defined above;
(iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and b is
C1-6alkalinous group.

2. Connection, optical isomer, or pharmaceutically acceptable salt, n is 1, where in the formula (1) R1 is 3,4-di-C1-6alkoxyphenyl group.

3. Compound, an optical isomer or pharmaceutically acceptable salt according to claim 1, where in formula (1) R2 is (a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6alkyl group and the and groups, and (a-27) phenyl-C1-6alkoxygroup;
(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (1) hydroxyl groups, (C-2)1-6alkyl groups, (C-3) C1-6alkoxygroup, (C-4) phenyl-C1-6alkoxygroup, and (C-5) C1-6alkoxycarbonyl groups;
(d) shriley group, in which the furan ring may be substituted C1-6alkyl group or groups;
(e) a thienyl group, in which the thiophene ring may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2)
C1-6alkyl groups, and (e-3) C1-6alkoxygroup;
(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups;
(h) pyrrolidino group, in which the pyrrole ring may be substituted C1-6alkyl group or groups; or
(i) imidazolidine group, in which the imidazole ring may be substituted C1-6alkyl group or groups.

4. Connection, optical isomer, or pharmaceutically acceptable salt according to claim 1, where in formula (1) And is (i) -CO-B-, where b is a methylene group is Oh, ethylene group or trimethylene group; (ii) -CO-VA, where VA is vinylidene group; (iii) -CH(OH)-B-, where b is a methylene group or ethylene group; (iv) -COCH(COOR3)-Bb-, where R3 is a methyl group, ethyl group or tertbutylphenol group and Bb is a methylene group or ethylene group.

5. Connection, optical isomer, or pharmaceutically acceptable salt according to claim 1, where in formula (1) R1 is 3,4-di-C1-6alkoxyphenyl group;
R2 is (a) phenyl group where the phenyl ring may be substituted by one or more members selected from the group consisting of (a-1) hydroxyl groups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substituted C1-6alkyl groups, (a-4) unsubstituted or halogen-substituted C1-6alkoxygroup, (a-5) C1-6alkoxy-C1-6alkoxygroup, (a-6) amino-C1-6alkoxygroup, which can be substituted C1-6alkyl group or groups, (a-7) methylenedioxy, (a-8) carboxyl groups, (a-9) fenoxaprop, (a-10) C1-6alkoxycarbonyl groups, (a-11) C1-6alkanoyloxy, (a-12) C1-6alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C1-6alkylcarboxylic groups, (a-16) aminosulfonyl groups, (a-17) amino group which may be substituted C1-6alkyl group or groups, (a-18) C 1-6alkanolamines, (a-19) C1-6alkylthio, (a-20) phenyl groups, (a-21) pyrazolidine groups, (a-22) imidazolinium groups, (a-23) triazolyl groups, (a-24) morpholinopropan, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groups that may be substituted C1-6the alkyl group or groups, (a-27) phenyl-C1-6alkoxygroup;
(c) peredelnoj group, in which the pyridine ring may be substituted by one or more members selected from the group consisting of (1) hydroxyl groups, (C-2) C1-6alkyl groups, (C-3) C1-6alkoxygroup, (C-4) phenyl-C1-6alkoxygroup, and (C-5) C1-6alkoxycarbonyl groups;
(d) shriley group, in which the furan ring may be substituted C1-6alkyl group or groups;
(e) a thienyl group, in which the thiophene ring may be substituted by one or more members selected from the group consisting of (e-1) halogen atoms, (e-2)
C1-6alkyl groups, and (e-3) C1-6alkoxygroup;
(g) thiazolidine group, in which the thiazole ring may be substituted by one or more members selected from the group consisting of (g-1) C1-6alkyl groups, and (g-2) phenyl groups which may be substituted C1-6alkoxygroup or groups;
(h) pyrrolidino group, in which the pyrrole ring may be substituted C-6 alkyl group or groups;
(i) imidazolidine group, in which the imidazole ring may be substituted C1-6alkyl group or groups; and
And is (i) -CO-B-, where a is defined above; (ii) -CO-Ba, where BA is defined above; (iii) -CH(OH) -, where a is defined above; (iv) the PINES (COOR3)-Bb-, where R3 and Bb defined above.

6. Pharmaceutical composition having the properties of an inhibitor of phosphodiesterase PDE4, including connection, optical isomer, or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier.

7. Inhibitor of phosphodiesterase 4, comprising as active ingredient a compound, an optical isomer or pharmaceutically acceptable salt according to claim 1.

8. Preventive or therapeutic agent for atopic dermatitis, comprising as active ingredient a compound, an optical isomer or pharmaceutically acceptable salt according to claim 1.



 

Same patents:

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I)

, where R is selected from ethyl, n-propyl, iso-propyl, n-butyl and allyl; R' is selected from hydrogen, straight, branched or cyclic C1-C4alkyl; straight, branched or cyclic C1-C3alkoxy; fluorine, chlorine, bromine, trifluoromethyl and OCHxFy, where x=0, 1, 2, y=1, 2, 3 under the condition that, x+y=3; R" is selected from hydrogen, fluorine and chlorine, with the condition that, R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine; R3 is selected from hydrogen and straight, branched or cyclic C1-C5alkyl; R4 is selected from hydrogen, CH2OCOC(CH3)3, pharmaceutically acceptable inorganic or organic cations, and COR4', where R' is straight, branched or cyclic C1-C5alkyl, phenyl, benzyl or phenethyl; R7 is selected from methyl and ethyl; one of A and B is sulphur, and the other is C-R2; when A is S, R2 is selected from hydrogen and methyl, with the condition that R2 is methyl only when R3 is not hydrogen; and when B is S, R2 is hydrogen; and to any tautomer thereof, as well as to a pharmaceutical composition which contains formula (I) compound, to a method of producing said compounds and to a method of treating diseases which are a result of autoimmune response or pathologic inflammation.

EFFECT: new compounds are disclosed, which can be used in treating diseases which are a result of autoimmune response or pathologic inflammation.

35 cl, 2 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: medicine.

SUBSTANCE: invention relates to the method for production of the compound of the formula (1a), being an inhibitor of thrombocyte aggregation (1a), where X is halogen atom. The method includes interaction of compounds of the formula (II), (II), where X has above mentioned value and Y and Z independently from each other are leaving groups, with optically active alkamine with formation of diastereoisomers admixture.

EFFECT: development of the new advantageous method for production of the bioactive compound.

48 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the method for preparation of hexachloroantimonates of 2,3-dihydro[1,3]thiazolium of general formula wherein R1 is alkyl or phenyl, R2 is alkyl, phenyl or hydrogen, R1+R2 is cycloalkyl by the interreaction of 4,6-dimethyl-2-pyrimidinsulfenyl chloride with corresponding olefine in presence of antimony pentachloride in equimolar ratio in the media of methylene chloride.

EFFECT: claimed compounds can be used in production of pharmaceutical preparations and biologically active substances.

2 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

Thienopyrazoles // 2358978

FIELD: chemistry.

SUBSTANCE: description is given of thienopyrazol of formula I its pharmaceutically acceptable salts or esters, in which X represents N or C-R7; X1 represents N or C-R1; R1, R2, R3, R4, R5 and R6 are independently chosen from a group which contains hydrogen, possibly substituted acyl, alkyl, alkoxy group, acylaminogroup, alkoxyalkyl, (Y1)(Y2)NC(=O)-, alkoxycarbonyl, aryl, halogen, carboxy group; or R5 and R6 together with two carbon atoms with a double bond, with they are bonded, form a benzene ring; R7 is a hydrogen atom, halogen or alkyl; and Y1 and Y2 are independently a hydrogen atom, alkyl, aryl or heteroaryl, or Y1 and Y2 together with a nitrogen atom, with which they are bonded, form a heteroaryl group or heterocycloalkyl group. The invention also relates to pharmaceutical compositions, containing these compounds. Thienopyrazoles can be used for treating diseases, which can be affected by protein kinase inhibition, particularly, interleukin-2-induced tyrosine kinase.

EFFECT: wider field of application of the compounds.

14 cl, 1 tbl, 98 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

7 cl, 1 tbl, 144 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

Up!