Indolyl-derivatives, method for their preparing, pharmaceutical composition, method of treatment and/or prophylaxis of diseases

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel indolyl-derivatives of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkyl substituted with from one to three halogen atoms; R2 means hydrogen atom, (C1-C8)-alkyl; R3 means (C1-C8)-alkoxy-group; R4 means hydrogen atom; A means oxygen atom or sulfur atom; n = 1,2 or 3. Synthesized compounds possess agonistic activity with respect to PPARα- and/or PPARγ-receptors. Also, invention relates to methods for their synthesis, a pharmaceutical composition based on thereof and their using for preparing medicinal agents, and to a method for treatment and/or prophylaxis of diseases.

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

29 cl, 1 tbl, 7 sch, 17 ex

 

The text descriptions are given in facsimile form.

1. The compounds of formula

where R1means phenyl, optionally substituted from one to three substituents independently selected from halogen, C1-8-alkyl, C1-8-alkoxy and C1-8of alkyl, substituted from one to three halogen atoms,

R2means hydrogen, C1-8-alkyl,

R3means C1-8-alkoxy,

R4means hydrogen,

A represents oxygen or sulphur,

n is 1, 2 or 3,

and their pharmaceutically acceptable salts and esters.

2. Compounds according to claim 1, where R1means phenyl, acid, isopropylphenyl, forfinal, chlorophenyl, were, triptoreline, methylphosphinyl or isopropoxyphenyl.

3. Compounds according to claim 1, where R2means hydrogen, methyl or ethyl.

4. Compounds according to claim 3, where R2means methyl.

5. Compounds according to claim 1, where R3means methoxy or ethoxy.

6. Compounds according to claim 1, where R4means hydrogen.

7. Compounds according to claim 1, where n is 1 or 3.

8. Compounds according to claim 1, where a represents oxygen.

9. Compounds according to claim 1, selected from the range

rat-3-{1-[2-(3,5-acid)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}-2-ethoxypropionate acid,

rat-2-ethoxy-3-{1-[2-(4-isopropy is phenyl)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}propionic acid,

rat-2-ethoxy-3-{1-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1H-indol-4-yl}propionic acid,

rat-2-ethoxy-3-{1-[2-(5-methyl-2-phenyloxazol-4-yl)ethyl]-1H-indol-4-yl}propionic acid,

rat-2-ethoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-4-yl]propionic acid,

rat-2-ethoxy-3-{1-[2-(2-forfinal)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}propionic acid,

rat-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}-2-ethoxypropionate acid,

rat-2-ethoxy-3-[1-(5-methyl-2-ortho-tolyloxy-4-ylmethyl)-1H-indol-4-yl]propionic acid,

rat-3-{1-[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}-2-ethoxypropionate acid,

rat-2-ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-4-yl}propionic acid,

rat-2-ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}propionic acid,

rat-2-ethoxy-3-{1-[2-(4-isopropoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}propionic acid and

rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)thiazole-4-ylmethyl]-1H-indol-4-yl}propionic acid.

10. Compounds according to claim 9, selected from a number of

rat-3-{1-[2-(3,5-acid)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}-2-ethoxypropionate acid,

rat-2-ethoxy-3-{1-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1H-indol-4-yl}propionic acid and

RA is-2-ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-4-yl}propionic acid.

11. A method of obtaining a compound according to any one of claims 1 to 10, comprising the reaction of interaction of the compounds of formula

with the compound of the formula

where R1-R4And n have the meanings indicated in claim 1, X is halogen or CH3SO3, R is C1-8-alkyl, phenyl or naphthyl, alkyl or cycloalkyl, in which one or more hydrogen atoms replaced by a phenyl group or naftalina group.

12. A method of obtaining a compound according to any one of claims 1 to 10, comprising the hydrogenation of the compounds of formula

where R1-R4And n have the meanings indicated in claim 1.

13. Compounds according to any one of claims 1 to 10, with agonistic activity in respect of PPARα and/or PPARγ-receptors.

14. Compounds according to any one of claims 1 to 10 to obtain drugs for the prevention and/or treatment of diseases which are modulated by PPAR agonistsα and/or PPARγ.

15. Pharmaceutical composition having agonistic activity in respect of PPARα and/or PPARγreceptors, comprising the compound according to any one of claims 1 to 12 and a therapeutically inert carrier.

16. The pharmaceutical composition according to item 15, which includes, in addition, a therapeutically effective amount and is of hibitor lipase.

17. The pharmaceutical composition according to clause 16, where the lipase inhibitor means orlistat.

18. The use of compounds according to any one of claims 1 to 10 to obtain drugs intended for the treatment and/or prevention of diseases which are modulated by PPAR agonistsα and/or PPARγ.

19. The compound according to any one of claims 1 to 10, obtained by the methods of 11, 12.

20. The method of treatment and/or prevention of diseases which are modulated by PPAR agonistsα and/or PPARγincluding the introduction of an effective amount of a compound according to any one of claims 1 to 10.

21. The method according to claim 20, additionally comprising the administration to a human a therapeutically effective amount of a lipase inhibitor,

22. The method according to item 21, where the lipase inhibitor means orlistat.

23. The method according to item 21 simultaneous, separate or sequential administration.

24. The use of compounds according to any one of claims 1 to 10 to obtain drugs intended for the treatment and/or prevention of diseases which are modulated by PPAR agonistsα and/or PPARγ, in a patient who, in addition, is undergoing treatment for a lipase inhibitor.

25. The application of paragraph 24, where the lipase inhibitor means orlistat.

26. Use PP and 24, where the disease means mellitus, insulin-independent diabetes, high blood pressure, elevated lipids and cholesterol is, atherosclerotic disease or metabolic syndrome.

27. Use p, where the disease means insulin-independent diabetes mellitus.

28. The method according to p-23, where the disease means mellitus, insulin-independent diabetes, high blood pressure, elevated lipids and cholesterol, atherosclerotic diseases, or metabolic syndrome.

29. The method according to p, where the disease means insulin-independent diabetes mellitus.



 

Same patents:

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means substituted or unsubstituted thiazolinyl or oxazolinyl residue; each R5 and R6 means independently hydrogen atom or protective group; X means oxygen (O), sulfur atom (S) or -NR7 wherein in each case R7 means hydrogen atom or lower alkyl; RB means in each case independently hydrogen atom, (C1-C6)-alkyl, -CY3, -CHY2 or -CH2Y wherein Y means F, Br, Cl or J. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I) and possessing cytotoxic activity, and using this compound in treatment of malignant tumor with multiple drug resistance.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

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EFFECT: valuable biochemical and medicinal properties of compounds and pharmaceutical compositions.

20 cl, 6 sch, 3 tbl, 153 ex

FIELD: organic chemistry, pharmacy.

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EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, medicine.

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EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry, pharmaceuticals.

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18 cl, 388 ex, 68 tbl, 3 dwg

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

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

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EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R means -C(O)R1 wherein R1 is chosen from the series: (C1-C6)-alkyl, -C=CH-COOH, -NHCH2-CH2R2, -N(CH2-CH2OH)CH2-CH2OH, -N(CH3)CH2-CH2-NHCH3, -N(CH3)CH2-CH2N(CH3)CH3, saturated 4-, 5- and 6-membered cycles and saturated and unsaturated 5- and 5-membered cycles comprising at least one heteroatom from a series sulfur (S), nitrogen (N) and oxygen (O), and optionally substituted with a group chosen from the series: (C1-C6)-alkyl, -C=O-R5, -OH, (C1-C6)-alkyl substituted with hydroxy-group optionally, (C1-C6)-alkyl substituted optionally with a group of the series: -NH2, -N-(C1-C6)-alkyl, -SO2CH3, =O, and 5- and 6-membered saturated cycles comprising at least one heteroatom chosen from N and O, and wherein R5 is chosen from the series: hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkyl substituted with hydroxy-group optionally, and (C1-C6)-alkyl substituted with NH2-group optionally; R2 is chosen from the series: -N(CH3)CH3, -NH2, morpholinyl and piperazinyl; X1, X2 and X3 are chosen independently from the series: -OH, (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CH2OCH3 and -CH2OCH2CH3, or one among X1, X2 or X3 means hydrogen atom, and two others are chosen independently from the series: hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2-CH2R3, -OCH2-CF3 and -OR4, morpholylmethyl, -N(CH3)CH3, -CH2OH, -COOH, or one among X1, X2 or X3 means hydrogen atom, and two others in common with two carbon atoms including bonds between them in benzene cycle to which they are bound optionally form 5- or 6-membered saturated cycle comprising at least one heteroatom chosen from S, N and O, and wherein R3 is chosen from the series: -F, -OCH3, -N(CH3)CH3, saturated 5-membered cycle comprising at least one heteroatom N; R4 means 3-5-membered saturated cycle, and each Y1 and Y2 is chosen independently from the series: -Cl, -Br, -NO2,-C≡N and C≡N, and compound of the formula (II) also given in the invention description. Also, invention relates to a pharmaceutical composition possessing anti-proliferative activity and based on these compounds. Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 39 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine.

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

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel carboxylic acid amides of the general formula (I):

wherein R1 represents hydrogen atom (H); R2 represents a linear or branched (C1-C8)-alkyl possibly substituted with phenyl; or R1 and R2 in common with nitrogen atom (N) represent a 5-membered heterocyclic residue or a 6-membered heterocyclic residue comprising oxygen atom additionally; n = 0, 1. Method involves heating a mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid ester of the general formula (II):

wherein R3 represents (C1-C4)-alkyl group; n = 0, 1, amine of the general formula (III):

wherein R1 and R2 have value given above and tertiary aliphatic amine of the formula (IV) given in the invention description at temperature 70-130°C wherein components are taken in the ratio (II) : (III) : (IV) = 1.0:(1.1-2.5):(1.0-3.0), respectively. Method provides decreasing the cost of compounds of the formula (I) based on using the more inexpensive raw, reducing duration of the process and enhancing safety of the process. Synthesized compounds can be used in synthesis of biologically active substances and dyes.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pentafluorosulfanylbenzoylguanidines of the formulae (I) and (II) , wherein R1 means hydrogen atom, alkyl with 1-4 carbon atoms, F, Cl, Br or J; R2 means hydrogen atom or -O-phenyl that is unsubstituted or substituted with F, Cl, Br or J; each R3 and R4 means hydrogen atom, and to their pharmaceutically acceptable salts. Using compounds of formulae (I) and (II) provides inhibition of cellular sodium-proton pump and they can be used as anti-arrhythmic medicinal agents with cardioprotective effect for prophylaxis and treatment of infarction and stenocardia. Invention describes a method for synthesis of compounds, medicinal agent based on thereof and using in preparing medicinal agents.

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

10 cl, 6 ex

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