Novel thiophene derivatives as s1p1/edg1 receptor agonists

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I) where A denotes *-CO-CN=CH-, *-CO-CH2CH2-, or where the sign * indicates the thiophene bonding site in formula (I), R1 denotes hydrogen or methyl, R2 denotes n-propyl or isobutyl, R3 denotes hydrogen, methyl, ethyl, n-propyl, isopropyl or isobutyl, R4 denotes hydrogen or methoxy, R5 denotes hydrogen, C1-C4alkyl, C1-C4alkoxy or hydrogen, R6 denotes -(CH2)k-(CHR65)p-CHR66-CONR61R62 hydroxy, hydroxy(C2-C4)alkoxy, di(hydroxy(C1-C4)alkyl)(C1-C4)alkoxy, 2,3-dihydroxypropoxy, -OCH2-(CH2)m-NHCOR64, -OCH2-CH(OH)-CH2-NR61R62, -OCH2- CH(OH)-CH2-NHCOR64 or -OCH2-CH(OH)-CH2-NHSO2R63, R61 denotes hydrogen, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, carboxymethyl or C1-C4alkylcarboxymethyl, R62 denotes hydrogen, R63 denotes methyl or ethyl, R64 denotes hydroxymethyl, methyl aminomethyl or 2-methyl aminoethyl, R65 denotes hydrogen, R66 denotes hydrogen, m equals 1 or 2, k equals 0, p equals 1, R67 denotes hydrogen, C1-C4alkyl or halogen, and to a salt thereof. The invention also relates to a pharmaceutical composition for preventing or treating diseases or disorders associated with an activated immune system based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as immunodepressants.

31 cl, 2 tbl, 114 ex

 

The text descriptions are given in facsimile form.

1. A compound selected from the group comprising derivatives of thiophene of the formula (I),

where a represents *-CO-CH=CH-, *-CO-CH2CH2-,
,or,
where the asterisk ( * ) indicates place of joining the thiophene in the formula (I),
R1means hydrogen or methyl,
R2means n-propyl or isobutyl,
R3means hydrogen, methyl, ethyl, n-propyl, isopropyl or isobutyl,
R4means hydrogen or methoxy,
R5means hydrogen, C1-C4alkyl, C1-C4alkoxy or halogen,
R6means -(CH2)k-(CHR65)p-CHR66-CONR61R62, hydroxy, hydroxy(C2-C4)alkoxy, di(hydroxy(C1-C4)alkyl)(C1-C4)alkoxy, 2,3-dihydroxypropane, -OCH2-(CH2)m-NHCOR64, -OCH2-CH(OH)-CH2-NR61R62, -OCH2-CH(OH)-CH2-NHCOR64or-och2-CH(OH)-CH2-NHSO2R3 ,
R61means hydrogen, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylation, carboxymethyl or1-C4alkylcarboxylic,
R62means hydrogen,
R63means methyl or ethyl,
R64means hydroxymethyl, methylaminomethyl or 2-methylaminomethyl,
R65means hydrogen,
R66means hydrogen,
m is an integer 1 or 2,
k is 0,
p is 1,
R7means hydrogen, C1-C4alkyl or halogen,
and its salts.

2. The compound according to claim 1, where R6means -(CH2)k-(CHR65)p-CHR66-CONR61R62, hydroxy, hydroxy(C2-C4)alkoxy, di(hydroxy(C1-C4)alkyl)(C1-C4)alkoxy, -OCH2-(CH2)m-NHCOR64, -OCH2-CH(OH)-CH2-NR61R62, -Och2-CH(OH)-CH2-NHCOR64or-OCH2-CH(OH)-CH2-NHSO2R63.

3. The compound according to claim 1 or 2, where a represents *-CO-CH2-CH2-,
or
where the asterisk ( * ) indicates the place of attachment to the group of thiophene in the formula (I).

4. The compound according to claim 1 or 2, where a represents *-CO-CH2-CH2-where the asterisk ( * ) indicates the place of attachment to the group of thiophene in the formula (I).

5. The compound according to claim 1 or 2, And where means
,
where the asterisk indicates where p is soedineniya to the group of thiophene in the formula (I).

6. The compound according to claim 1 or 2, And where means

7. The compound according to claim 1 or 2, where R1means hydrogen.

8. The compound according to claim 1 or 2, where R1means methyl.

9. The compound according to claim 1 or 2, where R2means isobutyl.

10. The compound according to claim 1 or 2, where R3means methyl, ethyl, n-propyl or isobutyl.

11. The compound according to claim 1 or 2, where R3means methyl.

12. The compound according to claim 1 or 2, where R4means methoxy, and R5and R7mean hydrogen, or R4means hydrogen, R5means methyl, ethyl or methoxy, and R7means methyl, ethyl or halogen.

13. The compound according to claim 1 or 2, where R4means methoxy, and R5and R7mean hydrogen.

14. The compound according to claim 1 or 2, where R4means hydrogen, and R5and R7means methyl.

15. The compound according to claim 1 or 2, where R4means hydrogen, and R5and R7means ethyl.

16. The compound according to claim 1 or 2, where R4means hydrogen, R5means methyl, and R7means ethyl.

17. The compound according to claim 1 or 2, where R4means hydrogen, R5means methoxy, and R7means chlorine.

18. The compound according to claim 1 or 2, where R4means hydrogen, R5means methyl, and R7means chlorine.

19. The compound according to claim 1 or 2, where R6means -(CH2)k-(CHR65) -CHR66-CONR61R62.

20. The compound according to claim 1 or 2, where R6means-och2-CH(OH)-CH2-NHCOR64.

21. The compound according to claim 1 or 2, where R6means-och2-CH(OH)-CH2-NHCOR64where R64means hydroxymethyl.

22. The compound according to claim 1, where R62,3-dihydroxypropane.

23. The compound according to claim 1, where
R5means hydrogen, C1-C4alkyl or C1-C4alkoxy,
R6means hydroxy, hydroxy(C2-C4)alkoxy, 2,3-dihydroxypropane, -OCH2-(CH2)m-NHCOR64, -OCH2-CH(OH)-CH2-NR61R62, -Och2-CH(OH)-CH2-NHCOR64, -OCH2-CH(OH)-CH2-NHSO2R63or-CH2-CH2-CONHR',
where R' represents 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylation, hydroxycarbonylmethyl or methoxycarbonylmethyl,
R61means hydrogen, and
R63means methyl.

24. The compound according to claim 1 or 2, where R2means isobutyl, R3means hydrogen or methyl, R4means hydrogen, R5and R7mean1-C4alkyl, R6means-OCH2-CH(OH)-CH2-NHCOR64, a a means,or,
where the stars indicate the place of connection to the group of thiophene in the formula (I).

25. The compound according to claim 1, select the Noah group, including
3-(4-hydroxy-3, 5dimethylphenyl)-1-(4-isobutyl-3-propylthiophene-2-yl)propenone,
1-(3,4-diisobutyrate-2-yl)-3-(4-hydroxy-3, 5dimethylphenyl)propane,
1-(3,4-diisobutyrate-2-yl)-3-(4-hydroxy-3, 5dimethylphenyl)-propane-1-he,
3-[4-((S)-2,3-dihydroxypropane)for 3,5-dimetilfenil]-1-(4-isobutyl~3-propylthiophene-2-yl)propane-1-he,
3-[4-((S)-2,3-dihydroxypropane)for 3,5-dimetilfenil]-1-(4-isobutyl-3,5-dimethylthiophene-2-yl)propane-1-he,
2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-(3-{2-ethyl-4-[5-(4-isobutyl-5-methylthiophene-2-yl)[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-[-(3-{2-ethyl-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
2-hydroxy-N-(2-hydroxy-3-{4-[3-(4-isobutyl-3-propylthiophene-2-yl)-3-oxopropyl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-(3-{4-[3-(3,4-diisobutyrate-2-yl)-3-oxopropyl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)-2-methylaminoethanol,
2-hydroxy-N-(3-{4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy)}propyl)acetamide", she
3-{4-[5-(4-isobutyl-3-metaltype the-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol,
3-{4-[5-(3-ethyl-4-isobutylidene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}-propane-1,2-diol,
3-{4-[5-(4-isobutyl-3-propylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propane-1,2-diol,
3-{4-[5-(3,4-diisobutyrate-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy} propane-1,2-diol,
2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-(3-{4-[5-(3-ethyl-4-isobutylidene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-propylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-(3-{4-[5-(3,4-diisobutyrate-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
3-{4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-3-methoxyphenoxy}propane-1,2-diol,
2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-3-methoxyphenoxy}propyl)ndimethylacetamide and
2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3,5-dimethylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
and salts of such compounds.

26. The compound according to claim 1, selected from the group including
N-((S)-3-{2,6-diethyl-4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((S)-3-{2-chloro-4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((R)-3-{2-chloro-4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
3-{2-ethyl-4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxyethyl)propionamide,
2-hydroxy-N-((S)-2-hydroxy-3-{4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
2-hydroxy-N-((R)-2-hydroxy-3-{4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-((R)-3-{2-ethyl-4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((S)-3-{2-ethyl-4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,3,4]-oxadiazol-2-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-(2-hydroxy-1-hydroxymethylene)-3-{4-[5-(4-isobutyl-5-methylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimetilfenil}propionamide,
2-hydroxy-N-((S)-2-hydroxy-3-{4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
2-hydroxy-N-((R)-2-hydroxy-3-{4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-((S)-3-{2-ethyl-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((R)-3-{2-ethyl-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((S)-3-{2-chloro-4-[5-(4-isobutyl-3-metaltype the-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((R)-3-{2-chloro-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((S)-3-{2,6-diethyl-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((R)-3-{2,6-diethyl-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]phenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((S)-3-{2-ethyl-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((R)-3-{2-ethyl-4-[5-(4-isobutyl-3-methylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
2-hydroxy-N-((S)-2-hydroxy-3-{4-[3-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-5-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
2-hydroxy-N-((R)-2-hydroxy-3-{4-[3-(4-isobutyl-3-methylthiophene-2-yl)-[1,2,4]oxadiazol-5-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
2-hydroxy-N-((S)-2-hydroxy-3-{4-[3-(4-isobutyl-3,5-dimethylthiophene-2-yl)-3-oxopropyl]-2,6-dimethylphenoxy}propyl)acetamide", she
2-hydroxy-N-((R)-2-hydroxy-3-{4-[3-(4-isobutyl-3,5-dimethylthiophene-2-yl)-3-oxopropyl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-((S)-3-{2-ethyl-4-[3-(4-isobutyl-3,5-dimethylthiophene-2-yl)-3-oxopropyl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((R)-3-{2-ethyl-4-[3-(4-isobutyl-3,5-dimethylthiophene-2-yl)-3-oxopropyl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((S)-3-{2-chloro-4-[5-(4-isobutyl-3,5-dimethylthiophene-2-is)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((R)-3-{2-chloro-4-[5-(4-isobutyl-3,5-dimethylthiophene-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
2-hydroxy-N-((S)-2-hydroxy-3-{4-[5-(4-isobutyl-3,5-dimethylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
2-hydroxy-N - ((R)-2-hydroxy-3-{4-[5-(4-isobutyl-3,5-dimethylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-((R)-3-{2-ethyl-4-[5-(4-isobutyl-3,5-dimethylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido and
N-((S)-3-{2-ethyl-4-[5-(4-isobutyl-3,5-dimethylthiophene-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
and salts of such compounds.

27. Pharmaceutical composition for prevention or treatment of diseases or disorders associated with an activated immune system, including a connection according to any one of claims 1 to 26 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

28. The compound according to any one of claims 1, 2, 22, 23, 25 and 26 or its pharmaceutically acceptable salt or pharmaceutical composition according to item 27, used for prevention or treatment of diseases or disorders associated with an activated immune system.

29. The use of compounds according to any one of claims 1 to 26, or its pharmaceutically acceptable salts, pharmaceutical compositions intended for the profile is ctice or treatment of diseases or disorders, associated with an activated immune system.

30. A compound selected from the group including tifany formula (II)

where R1and R3have the meanings indicated in claim 1, a R8means-COOH, -COON3-SOON2CH3or-CN, and their salts.

31. A compound selected from the group including tifany formula (III)

where A, R1, R2, R3, R4, R5, R65, R66, R7, k and p have the meanings indicated in claim 1, and their salts.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 1H-quinazoline-2,4-diones of formula and to their pharmaceutically acceptable salts where R1 and R2 have the values specified in cl. 1 of the patent claim. The specified compounds exhibit antagonistic activity with respect to the AMPA receptor.

EFFECT: reception of a pharmaceutical composition for preparing a preparation used for treating a condition mediated by the AMPA receptor and first of all for treating epilepsy or schizophrenia.

8 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), where A1, A2, A3, A4, A5 ad A6 are independently selected from a group comprising CR3 and N; provided that the biggest one of A1, A2, A , A4, A5 and A6 denotes N; B1, B2 and B3 are independently selected from a group comprising CR2 and N; each R3 independently denotes H or C1-C6 alkyl; and R1, R2, R4, R5, W and n are as given in the description, or salts thereof which are suitable for use in agriculture. The invention also relates to compositions containing compounds of formula (1), and insect-pest control methods which involve contact between the pest or habitat thereof with a biologically effective amount of the compound or composition according to the present invention, as well as to methods of protecting seeds and animals from insects-pests.

EFFECT: high effectiveness of the obtained compounds in insect-pest control.

29 cl, 12 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: described are novel benzofuroxanes of general formula

, where R is phenylamino-, N-[4-methoxyphenyl]amino-, N-piperidyl-, which have fungicidal and bactericidal activity and which can be used in veterinary, medicine and agriculture.

EFFECT: high efficiency of the compositions.

2 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof , where D denotes phenyl; n equals 0; A, B and Q denote hydrogen; Z is selected from a group comprising a bond, straight C1-3alkylene; R1 is selected from a group comprising hydrogen, C1-10alkyl, C3-8cycloalkyl, benzyl, a 6-member monocyclic, 9-10-member bicyclic aromatic carbon-containing ring system and a spiro-ring system of formula (V): where X1 and X3 denote O; and where the said alkyl, cycloalkyl or benzyl from the R1 group is optionally substituted with 1-3 substitutes selected from a group comprising C1-3alkyl, cyano, phenyl, wherein the said phenyl is optionally substituted with 1-3 substitutes selected from halogen. The invention also relates to compounds of formulae .

Values of radicals of the said compounds are given in the claim. The invention also relates to a pharmaceutical composition having ORL1 receptor or µ opioid receptor inhibiting properties, containing an effective amount of the disclosed compound, a method of curing pain and a method of modulating pharmacological response from the opioid receptor, including the ORL1 or µ opioid receptor.

EFFECT: improved method.

41 cl, 5 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - arylamidrazone derivatives of formula ,

where R1 is a C2-C8 alkyl group or a C2-C8 alkoxy group, which can be substituted with a halogen or a C1-C8 alkoxy group; a 5-7-member aromatic heterocycle containing 1 or 2 oxygen, nitrogen or sulphur atoms, or phenyl, which can be substituted with a halogen, a C1-C8 alkyl group, a haloC1-C8alkyl group or a C1-C8alkoxy group; or NR4R5; R2 and R3 are identical or different, and each is a hydrogen atom, a halogen atom, a halogenC1-C8alkyl group, a C1-C8alkyl group, a C2-C6alkynyl group, a C1-C8alkoxy group, a cyano group, a C2-C6alkanoyl group or a C1-C8alkylsulphonyl group; A is a benzene, pyridine, quinoline or isoquinoline ring; D is a single bond or methylene; m assumes values from 1 to 3 and n assumes values from 1 to 5, having antagonistic effect on S1P3 receptors, as well as to medicinal agents and pharmaceutical compositions containing such compounds as an active ingredient.

EFFECT: improved properties.

13 cl, 161 ex, 19 tbl

FIELD: chemistry.

SUBSTANCE: present invention describes novel compounds of formula (I), where substitutes R1, R2, R3, Ar and A are described in the formula of invention, having histone deacetylase inhibiting activity, use thereof and methods for synthesis of said compounds.

EFFECT: improved composition properties.

15 cl, 72 ex, 9 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: present invention is related to thiophen amidines of general formula I or their solvate, hydrate or pharmaceutically acceptable salt, where Z stands for -S(O2)-; R1 - halogen, amino, C1-6alkylthio; Ar - phenyl, piridyl, thiazolyl, phuranyl, benzothiazolyl, benzimidazolyl, every of which is not necessarily substituted; R2, R3, R4 and R7- hydrogen Compounds may be used for inhibition of ferment Cls, protease of classical pathway of complement system. Pharmaceutical compositions are also described on the basis of formula I compounds.

EFFECT: compounds may find application for treatment of certain acute and chronic immunological diseases, some neurogenerative diseases.

24 cl, 1 tbl, 337 ex

The invention relates to novel 2,5-disubstituted tetrahydrofuran or tetrahydrothiophene formula I

< / BR>
where Ar is phenyl, which is optionally substituted by at least one group selected from halo (including, but not limited to, fluorine), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), cyano, or R3;

m = 1;

W is independently - AN(OM)C(O)N(R3R4, -AN(R3)C(O)N(OM)R4, -AN(OM)C(O)R4AC(O)N(OM)R4, -C(O)N(OM)R4or-C(O)NHA;

A - lower alkyl, lower alkenyl or lower quinil, in which one or more carbons optionally may be replaced by O, N or S;

M is hydrogen, a pharmaceutically acceptable cation;

X IS O,S;

Y is O, S, hydrogen, lower alkyl, lower alkenyl, lower quinil, alkaryl;

R1and R2independently is hydrogen, lower alkyl, halo, or-COOH;

R3and R4independently is hydrogen, alkyl, alkenyl, quinil,1-6alkoxy-C1-C10alkyl or C1-6alkylthio-C1-10alkyl,

which possess anti-inflammatory activity through inhibition of 5-lipoxygenase as PAF receptor antagonists and are dual activity, t

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula (I), where R represents hydrogen atom or P(=O)(OH)2, X represents oxygen atom or sulphur atom, Y represents CH2CH2 or CH=CH, R1 represents trifluoromethyl, difluoromethyl or cyano, R2 represents alkyl, which has 1-4 carbon atoms, and optionally substituted with hydroxyl group (groups) or halogen atom (atoms), R3 and R4 can be similar or different, and each represents hydrogen atom or alkyl, which has 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid-additive salt. Invention also relates to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propan-1,3-diol or its hydrochloride and pharmaceutical composition, containing said compounds.

EFFECT: elaboration of pharmaceutical composition, applied for treatment or prevention of autoimmune diseases, prevention or suppression of resistance or acute rejection or chronic rejection of organ or tissue transplant; treatment or prevention of graft-versus-host disease (GvH) resulting from transplantation of bone marrow; or treatment or prevention of allergic diseases.

16 cl, 39 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to stents and bag catheters with improved rapamycin release coating, and also to methods for producing such coatings.

EFFECT: production of stents and bag catheters with improved rapamycin release coating.

10 dwg, 24 ex

Up!