Hexafluoroisopropanol-substituted ether derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

 

The text descriptions are given in facsimile form.

1. The compounds of formula (I)

in which
R1is hydrogen, lower alkyl or halogen,
one of the groups R2and R3is hydrogen, lower alkyl or halogen, and the second of the groups R2and R3is-O-CHR4-(CH2)m-(CHR5)n-R6,
R4is hydrogen, lower alkyl, phenyl, phenyl(ness.)the alkyl,
5is hydrogen or phenyl,
R6is phenyl, where phenyl optionally substituted by 1-3 substituents selected from the group comprising R8-O-C(O)R11-O-C(O)-(ness.)alkyl,
or R6is a 5-membered monocyclic heteroaryl, including 2 or 3 heteroatoms selected from the group consisting of nitrogen and oxygen, which is substituted by 1-3 substituents selected from the group comprising lower alkyl and phenyl, where phenyl optionally substituted by 1-3 substituents selected from the group comprising halogen, lower alkyl, fluorine(ness.)alkyl, hydroxy(ness.)alkyl, R9R10NC(O)-,
or R6is-O-R7or (ness.)alkyl-or SIG7,
R7is phenyl, which is substituted by 1-3 substituents selected from the group comprising hydroxy(ness.)alkyl, R8-O-C(O)-, R11-O-C(O)-(ness.)alkyl, R12R13NC(O)-(ness.)alkyl,
or R7is 9-membered bicyclic-heteroaryl, containing two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which is substituted by 1-3 substituents selected from the group comprising lower alkyl, fluorine(ness.)alkyl and phenyl, where phenyl is substituted by 1-3 substituents selected from halogen,
R8, R9, R10, R11, R12and R13independently from each other are hydrogen or lower alkyl,
m takes values from up to 3,
n takes on the values 0 or 1,
and their pharmaceutically acceptable salts and esters.

2. Compounds according to claim 1, in which R1is hydrogen, chlorine or stands.

3. Compounds according to claim 1, in which one of R2and R3is hydrogen or lower alkyl and the other of R2and R3is-O-CHR4-(CH2)m-(CHR5)n-R6where R4, R5, R6, m and n have the meanings given in claim 1.

4. Compounds according to claim 1, in which R2is-O-CHR4-(CH2)m-(CHR5)n-R6and R3is hydrogen, where R4, R5, R6, m and n have the meanings given in claim 1.

5. Compounds according to claim 1, in which R4is hydrogen, lower alkyl or phenyl(ness.)the alkyl.

6. Compounds according to claim 1, in which R4is hydrogen, stands or benzyl.

7. Compounds according to claim 1, in which n is 1 and R5is phenyl.

8. Compounds according to claim 1, in which R6is phenyl, which is optionally substituted by R8-O-C(O)-, or R6is a 5-membered monocyclic heteroaryl, including 2 or 3 heteroatoms selected from the group consisting of nitrogen and oxygen, which is substituted by 1-3 substituents selected from the group comprising lower alkyl and phenyl, where phenyl optionally substituted by 1-3 substituents selected from g is uppy, including halogen, lower alkyl, fluorine(ness.)alkyl, hydroxy(ness.)alkyl, and R9R10NC(O)-, where R8, R9and R10have the meanings defined in claim 1.

9. Compounds according to claim 1, in which R6is phenyl, or R6is oxazolium, and oxazolyl substituted lower alkyl or phenyl, where phenyl substituted with halogen, fluorine(ness.)the alkyl or hydroxy(ness.)the alkyl.

10. Compounds according to claim 1, in which R6is phenyl, 2-(3-chlorophenyl)-5-methoxazole-4-yl, 5-methyl-2-(3-triptoreline)oxazol-4-yl or 2-(3-hydroxymethylene)-5-methoxazole-4-yl.

11. Compounds according to claim 1, in which R6is a group-O-R7in which R7is phenyl, substituted by one Deputy, selected from the group comprising hydroxy(ness.)alkyl, R11-O-C(O)-(ness.)alkyl, and R12R13NC(O)-(ness.)alkyl, or R7is heteroaryl selected from the group including benzo[d]isothiazole and benzo[d]isoxazolyl, which is substituted by one or two substituents selected from the group comprising lower alkyl, fluorine(ness.)alkyl and phenyl, where phenyl substituted with halogen, and R11, R12and R13defined in claim 1.

12. Compounds according to claim 11, in which R7is phenyl, substituted (ness.)alkoxycarbonyl group or (ness.)alkoxycarbonyl(ness.)the alkyl.

13. Connection is .12, in which R7is a 3-methoxycarbonylmethylene, 4-methoxycarbonylmethylene or 4-ethoxycarbonylphenyl.

14. Compounds according to claim 1, in which m takes values from 0 to 2.

15. Compounds according to claim 1, in which m takes on the values 0 or 1.

16. Compounds according to claim 1, in which n is equal to 0.

17. Compounds according to claim 1, selected from the group comprising 2-(4-{3-[3-(4-bromophenyl)benzo[d]isothiazol-6-yloxy]propoxy}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
ethyl ester of 3-(3-{3-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl) propionic acid,
rat methyl ester (4-{1-phenyl-2-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
rat (4-{1-phenyl-2-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
rat methyl ester 4-{1-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}benzoic acid,
methyl ester of 4-{2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}benzoic acid,
2-(4-benzyloxy-3-chlorophenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-benzyloxy-3-were)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(3-benzyloxyphenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-benzyloxy-3, 5dimethylphenyl)-1,1,1,3,3,3-hexaferrite-2-ol
2-(4-benzyloxyphenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
methyl ester of (4-{3-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)is enocsi]propoxy}phenyl)acetic acid,
methyl ester of 4-{3-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}benzoic acid,
methyl ester of 3-(4-{3-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl) propionic acid,
methyl ester of (4-{3-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
methyl ester of 4-{3-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}benzoic acid,
methyl ester of (4-{3-[2,6-dimethyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
methyl ester of 4-{3-[2,6-dimethyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy] propoxy}benzoic acid,
4-{3-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}benzoic acid,
(4-{3-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
(4-{3-[2,6-dimethyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
4-{3-[2,6-dimethyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}benzoic acid,
methyl ester of 4-{2-[2,6-dimethyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}benzoic acid,
methyl ester of 3-(4-{(S)-2-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]-3-phenylpropoxy}phenyl)propionic acid,
methyl ester of (4-{S)-2-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]-3-phenylpropoxy}phenyl)acetic acid,
methyl ester of 4-{(S)-2-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]-3-phenylpropoxy}benzoic acid,
methyl ester of (4-{(S)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
methyl ester of 4-{(S)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}benzoic acid,
(4-{(S)-2-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]-3-phenylpropoxy}phenyl)acetic acid,
4-{(S)-2-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]-3-phenylpropoxy}benzoic acid,
(4-{(S)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
4-{(S)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}benzoic acid,
rat 1,1,1,3,3,3-hexamer-2-{4-[2-(4-hydroxymethylene)-1-phenylethane]phenyl}propan-2-ol,
1,1,1,3,3,3-hexamer-2-(3-methyl-4-phenylacetonitrile)propan-2-ol,
rat 1,1,1,3,3,3-hexamer-2-[3-methyl-4-(1-phenylethane)phenyl]propan-2-ol,
2-{4-[2-(3-chlorophenyl)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-[4-(3,5-dimethylisoxazol-4-ylethoxy)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-hexamer-2-[4-(5-methylisoxazol-3-ylethoxy)phenyl]propan-2-ol,
1,1,1,3,3,3-hexamer-2-[4-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-ylethoxy)phenyl]propan-2-ol,
1,1,1,3,3,3-hexamer-2-[4-(5-methyl-3-phenylisoxazol-4-illcox is)phenyl]propan-2-ol,
methyl ester of 3-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxymethyl]benzoic acid
4-{(S)-2-[2-methyl-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]-3-phenylpropoxy}benzoic acid,
(4-{(S)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
methyl ester of 3-(4-{(R)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)propionic acid,
methyl ester of (4-{(R)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
methyl ester of 4-{(R)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy} benzoic acid,
3-(4-{(R)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl) propionic acid,
(4-{(R)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
4-{(R)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}benzoic acid,
2-{4-[2-(3-chlorophenyl)-5-methoxazole-4-ylethoxy]-3-were}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{3-chloro-4-[2-(3-chlorophenyl)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-hexamer-2-(4-phenylacetonitrile)propan-2-ol,
2-(3,5-dimethyl-4-phenylacetonitrile)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(3-chloro-4-phenylacetonitrile)-1,1,1,3,3,3-hexaferrite-2-ol,
rat 1,1,1,3,3,3-hexaf the PR-2-[4-(1-phenylethane)phenyl]propan-2-ol,
1,1,1,3,3,3-hexamer-2-[3-methyl-4-(5-methyl-2-m-teleological-4-ylethoxy)phenyl]propan-2-ol,
2-{4-[2-(2-chlorophenyl)-5-methoxazole-4-ylethoxy]-3-were}-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-hexamer-2-[3-methyl-4-(5-methyl-2-o-tolyloxy-4-ylethoxy)phenyl]propan-2-ol,
1,1,1,3,3,3-hexamer-2-{3-methyl-4-[5-methyl-2-(3-triptoreline)oxazol-4-ylethoxy]phenyl}propan-2-ol,
1,1,1,3,3,3-hexamer-2-{4-[2-(4-fluoro-3-were)-5-methoxazole-4-ylethoxy]-3-were}propan-2-ol,
2-{3-chloro-4-[5-methyl-2-(4-triptoreline)-oxazol-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-[3-chloro-4-(5-methyl-2-m-tolyloxy-4-ylethoxy)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
2-{3-chloro-4-[2-(2-chlorophenyl)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-[3-chloro-4-(5-methyl-2-o-tolyloxy-4-ylethoxy)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
2-{3-chloro-4-[5-methyl-2-(3-triptoreline)oxazol-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{3-chloro-4-[2-(4-fluoro-3-were)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{3-[2-(3-chlorophenyl)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-hexamer-2-[3-(5-methyl-2-o-tolyloxy-4-ylethoxy)phenyl]propan-2-ol,
1,1,1,3,3,3-hexamer-2-{3-[5-methyl-2-(3-triptoreline)oxazol-4-ylethoxy]phenyl}propan-2-ol,
2-{3-[2-(2-chlorophenyl)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-g is xafter-2-[3-(5-methyl-2-m-tolyloxy-4-ylethoxy)phenyl]propan-2-ol,
methyl ester of 3-{4-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxymethyl]-5-methoxazole-2-yl}benzoic acid,
2-{3-chloro-4-[2-(3-hydroxymethylene)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
methyl ester of 4-{5-methyl-4-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxymethyl]oxazol-2-yl}benzoic acid,
4-{5-methyl-4-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxymethyl]oxazol-2-yl}benzoic acid,
N,N-dimethyl-4-{5-methyl-4-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxymethyl]oxazol-2-yl}benzamide,
methyl ether (3-{2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
methyl ester of (4-{2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
methyl ether (3-{2-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
(3-{2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
(4-{2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy} phenyl)acetic acid,
rat methyl ether (3-{1-phenyl-2-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
rat (3-{1-phenyl-2-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
rat N,N-dimethyl-2-(3-{1-phenyl-2-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)Fe is hydroxy]ethoxy}phenyl)acetamide", she
2-(4-{2-[3-(4-bromophenyl)benzo[d]isothiazol-6-yloxy]ethoxy}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-hexamer-2-{4-[3-(7-propyl-3-triptorelin[d]isoxazol-6-yloxy)propoxy]phenyl}propane-2-ol,
1,1,1,3,3,3-hexamer-2-{3-[3-(7-propyl-3-triptorelin[d]isoxazol-6-yloxy)propoxy]phenyl}propane-2-ol,
methyl ester of (4-{3-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
methyl ether (3-{3-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
methyl ester of 3-(4-{3-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)propionic acid and
3-(4-{3-[3-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl) propionic acid,
and their pharmaceutically acceptable salts and esters.

18. Compounds according to claim 1, selected from the group comprising methyl ether (3-{2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy}phenyl)acetic acid,
rat methyl ester 4-{1-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]ethoxy} benzoic acid,
2-(4-benzyloxy-3-chlorophenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
methyl ester of (4-{(S)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
1,1,1,3,3,3-hexamer-2-(3-methyl-4-phenylacetonitrile)propan-2-ol,
rat 1,1,1,3,3,3-hexamer-2-[3-methyl-4-(1-phenylethane)FeNi is]propan-2-ol,
2-{4-[2-(3-chlorophenyl)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
methyl ester of (4-{(R)-3-phenyl-2-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenoxy]propoxy}phenyl)acetic acid,
2-{3-chloro-4-[2-(3-chlorophenyl)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-(3-chloro-4-phenylacetonitrile)-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-hexamer-2-{3-methyl-4-[5-methyl-2-(3-triptoreline)oxazol-4-ylethoxy]phenyl}propan-2-ol,
2-{3-chloro-4-[5-methyl-2-(3-triptoreline)oxazol-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol and
2-{3-chloro-4-[2-(3-hydroxymethylene)-5-methoxazole-4-ylethoxy]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
and their pharmaceutically acceptable salts and esters.

19. Compounds according to any one of claims 1 to 18, having the ability to bind to LXR-alpha and/or LXR-beta.

20. Compounds according to any one of claims 1 to 18, designed for the manufacture of drugs for therapeutic and/or prophylactic treatment of diseases modulated by agonists of LXR-alpha and/or LXR-beta, such as increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia.

21. Pharmaceutical composition having the ability in order to communicate with LXR-alpha and/or LXR-beta, containing the compound according to any one of claims 1 to 18 as an active ingredient and a pharmaceutically acceptable carrier and/or adjuvant.

22. The pharmaceutical composition according to item 21, intended for manufacturing of medicines for therapeutic and/or prophylactic treatment of diseases modulated by agonists of LXR-alpha and/or LXR-beta, such as increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia.



 

Same patents:

The invention relates to new chemical compounds derived from anthra[2,1-d]isothiazol-3,6,11-trione General formula I, where a is the lowest alkylene, R1and R2(independent) - lower alkyl, or R1and R2together with the nitrogen atom form a six-membered saturated, a heterocycle, which may optionally contain a heteroatom such as oxygen atom, and their pharmaceutically acceptable salts

The invention relates to a method for producing 2-alkylbenzoates, which includes the interaction bisimide formula 2 in water or water-containing organic liquid bisulfite or allocating the bisulfite agent with the formation of salts of the Rebellion and the transformation of the salt Riot in alkaline conditions in the 2-alkyl-BIT

The invention relates to a method for producing 6-fluoro-1,2-benzisothiazole formula

(I) where R is a hydrogen atom, a lower alkyl or a group of the formula

orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

(III)where R and R3have the specified values, which are subjected to interaction with a halogenation agent to obtain the corresponding sulfanilamide formula

(IV)Subjected to interaction obtained sulfanilamide with ammonia in the compounds of the formula

(I)

Polucheniya pharmaceutically active compounds, which can be used, for example, as antipsychotic agents and as inhibitors of reuptake of serotonin

FIELD: chemistry.

SUBSTANCE: invention relates to versions of the method of producing chiral non-racemic compound of formula I where R1 represents . Values of the rest of the radicals are given in the formula of invention. Formula I compound is obtained in several steps. The starting material used is cis-1,3-cyclohexanediol. One of the key steps is enzymatic formation of ester or enzymatic splitting of ester.

EFFECT: method is described for production of enantiomeric forms of derivatives of 1,3-cyclohexanedio in cis orientation.

8 cl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula and their pharmaceutically acceptable salts used as inhibiting agent in the relation of fermentative beta-secretase and it also relates to pharmaceutical compositions based on the formula. In general formula one of RN and RN' represents hydrogen, and another represents - C(=O)-(CRR')0-6R100, or where R4 is chosen from the group including H; NH2; -NR50CO2R51; -(C1-C4)-alkyl-NR50CO2R51; where n7 is equal to 0, 1, 2 or 3; R50 represents H or C1-C6alkyl; R51 is chosen from the group including phenyl-(C1-C4)-alkyl and (C1-C6)-alkyl; X is chosen from the group including -(C1-C6)-alkylidenyl optionally substituted with 1, 2 or 3 metal groups; Z is chosen from the group including bond, SO2, SO and S; Y stands for (C1-C10)-alkyl; R1 represents -(C1-C6)-alkylphenyl where phenyl ring is optionally substituted by 1, 2, 3 or 4 halogen atoms; R and R' independently represent hydrogen or (C1-C6)-alkyl; R2 represents hydrogen; R3 represents hydrogen; Rc represents - (CR245R250)0-4-aryl; where aryl is optionally substituted by 1, 2 or 3 R200; R200 is chosen from the group including (C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups R205; halogen; C=N; R205 stands for halogen; R245 and R250 in each case stands for H; either R245 or R250 are taken together with carbon atom whereto attached to form carbocycle from 3, 4, 5, 6 or 7 carbon atoms; R100 represents 5-6-merous heteroaryl with 1-2 heteroatoms chosen from nitrogen and sulphur, -phenyl-W-heteroaryl where heteroaryl is 5-6-merous ring containing 1-2 heteroatoms, chosen from nitrogen and oxygen and where cyclic parts of each group are optionally substituted by 1, 2 or 3 groups independently chosen among C1-C6alkyl, -(CH2)0-4-CO2-NR105R'105, -(CH2)0-4-SO2-NR105R'105, -(CH2)0-4-N(R150)-CO-R105, -(CH2)0-4-N(R150)-SO2-R105; W represents -(CH2)0-4; R105 and R'105 independently represent (C1-C6)-alkyl optionally substituted with -NH2 or halogen; R150 represents hydrogen.

EFFECT: compounds can be applied to prevent and treat diseases mediated by excess activity of beta-secretase such as Alzheimer's disease.

11 cl, 12 tbl, 3 dwg, 1729 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-. The invention also relates to the method of obtaining these compounds. The method involves reacting dimethylbenzoic acid ester with formula where R assumes values given above, with a chlorinating agent in an inert solvent or without a solvent at temperature above 40°C, and then cleaning, if necessary. Formula (I) compounds are essential intermediate products during synthesis of PPAR agonists with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-; Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl; R' represents H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl; CF3; obtained from reaction of compounds with formula with formula (I) compounds in toluene, N-methylpyrrolidone or other aprotic solvents, in the presence of a suitable base, at temperature lying in the -78°C - +50°C interval, with subsequent extractive processing and, if necessary, crystallisation of the end product.

EFFECT: obtaining new compounds.

8 cl, 5 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a compound of the formula (I) where A ring is (C3-C8)-cycloalkyl or (C3-C8)-cycloalkenyl where two carbon atoms in the cycloalkyl ring can be substituted by oxygen atoms; R1, R2 are H, F, Cl, Br, OH, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl independently from each other; R3 is H or (C1-C6)-alkyl; R4, R5 are H, (C1-C6)-alkyl independently from each other; X is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; Y is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; and its pharmaceutically acceptable salts. The invention also concerns such compounds as (+)-cis-2-(3-(2-(4-fluorphenyl)oxazole-4-ylmethoxy)cyclohexyloxymethyl)-6-methylbenzoic acid of the formula 6b , 2-{3-[2-(3-methoxyphenyl)-5-methyloxazole-4-ylmethoxy]cyclohexyl-oxymethyl}-6-methylbenzoic acid of the formula 53 and 2-methyl-6-[3-(5-methyl-2-n-tolyloxazole-4-ylmethoxy)cyclohexylomethyl]benzoic acid of the formula 70 , or their enantiomers. The invention also concerns pharmaceutical composition exhibiting PPARα agonist effect, including one or more compounds of the formula (I) as an active component together with a pharmaceutically acceptable carrier. The pharmaceutical composition is obtained by mixing of active compound of the formula (I) with a pharmaceutically acceptable carrier and rendering it a form viable for introduction.

EFFECT: obtaining of diarylcycloalkyl derivatives applicable as PPAR-activators.

9 cl, 2 tbl, 67 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the method of obtaining the derivatives 3-aroilanra-(1,9-cd)isoxazole-6-one of the general formula where X - hydrogen, halogen or the lowest alkyl, which are used as intermediate products in synthesis of derivatives 7,8-phthalylclaridone used as dyes for various polymeric materials and polyester fibres. The essence of the method lies in boiling 1(triazene-N-sulfonate)-2-aroihtranquonine in spirit solution of alkali with the subsequent neutralisation by acetic acid.

EFFECT: simpler technology and safer process.

1 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the method of obtaining the derivatives of 3-aroilantra(1,9-cd)isoxazol-6-one with the general formula of where X - hydrogen, halogen or the lowest alkyl, which are used as intermediate products in synthesis of derivatives 7,8-phthalylclaridone, used as dyes for the polyester fibres. The essence of the method lies in heating 1-hydroxytriazone-2-aroilantraquinone in acetic anhydride.

EFFECT: simpler technology and safer process.

1 cl, 2 tbl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-phenylsulfonylanthra-[1,9-cd]-isoxazole-6-one of the general formula: wherein X means hydrogen, halogen atom or lower alkyl; Y means hydrogen atom or hydroxy-group. Method involves heating derivative of 2-phenylsulfonylanthraquinone in organic solvent wherein 1-(triazene-N-sulfonate)-2-phenylsulfonylanthraquinone of the general formula: wherein X and Y have above given values is used as derivative of 2-phenylsulfonylanthraquinone that is boiled in alkali alcoholic solution followed by neutralization with acetic acid. Invention provides simplifying technology of the process and expanding assortment of the end products.

EFFECT: improved preparing method.

2 tbl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-phenylsulfonylanthra-[1,9-cd]-isoxazole-6-one of the general formula: wherein X means hydrogen, halogen atom or lower alkyl; Y means hydrogen atom or hydroxy-group. Method involves heating 1-substituted derivative of 2-phenylsulfonylanthraquinone in organic solvent wherein 1-hydroxytriazeno-2-phenylsulfonylanthraquinone of the general formula: wherein X and Y have above given values is used as 1-substituted derivative of 2-phenylsulfonylanthraquinone, and acetic anhydride is used as an organic solvent. Invention provides simplifying technology of the process and expanding assortment of the end products.

EFFECT: improved preparing method.

2 tbl, 5 ex

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