Derivatives of pyrrole, pharmaceutical compositions and method of treatment

 

(57) Abstract:

Describes the new derived pyrrole of the formula (I-1) or (I-3) or its pharmacologically acceptable salt, ester or amide derivative, where R1, R2such as described in the claims, R3is Hinkley-2-EN-C-ilen group, 8-methyl-8-azabicyclo[3.2.1] Oct-2-EN-3-ilen group, 8-azabicyclo[3.2.1]Oct-2-EN-3-ilen group or a group of the following formula (II), where m = 0 or 1, n = 1 or 2 and R5, R7, R6, R8, R9, D, E, R10, R11, R12such as they are described in the claims. The new compounds possess inhibitory activity against the production of inflammatory cytokines. Also describes pharmaceutical compositions and method of treatment or prevention of diseases. 4 C. and 27 C. p. F.-ly, 3 PL.

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Description text in facsimile form. T T T T T T T The

1. Derived pyrrole of the formula (I-1) or (I-3) or its pharmacologically acceptable salt, ester or amide derivative

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where R1represents a phenyl group which may be optionally substituted by at least one Deputy, selected from the group comprising atoms kalilou or pyrimidinyl group, moreover, this group optionally substituted by at least one Deputy of the formula-NRcRdwhere Rcand Rdthe same or different, and each independently selected from the group comprising hydrogen atoms and alkyl groups containing from 1 to 6 carbon atoms, which optionally can be substituted by phenyl group;

R3is Hinkley-2-EN-3-ilen group, 8-methyl-8-azabicyclo[3.2.1]Oct-2-EN-3-ilen group, 8-azabicyclo[3.2.1]Oct-2-EN-3-ilen group or a group of the following formula (II):

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where m=0 or 1;

n=1 or 2;

one of R5and R7together with R6represents a single bond and the other represents a Deputy selected from the group comprising hydrogen atoms, hydroxy-group, alkyl groups containing from 1 to 6 carbon atoms, which optionally can be substituted phenyl group, and alkeneamine group containing from 2 to 6 carbon atoms;

R8and R9can be the same or different from each other, and each is selected from the group comprising hydrogen atoms, hydroxy-group, alkyl groups containing from 1 to 6 carbon atoms, which optionally can be substituted phenyl group, and alkeneamine group, 10 selected from the group comprising hydrogen atoms and alkyl groups containing from 1 to 6 carbon atoms, which optionally can be substituted by phenyl group or a nitro-group and the other represents a group of formula >CR11R12where R11and R12the same or different from each other, and each is selected from the group comprising hydrogen atoms, alkyl groups containing from 1 to 6 carbon atoms, which optionally can be substituted phenyl group, and alkeneamine group containing from 2 to 6 carbon atoms; or R10and R11together, they form a straight or branched alkylenes group containing 3 or 4 carbon atoms, which is unsubstituted.

2. Connection on p. 1 or its pharmacologically acceptable salt, ester or amide derivative, where R1selected from the group comprising phenyl group, 4-forfinal, 3-forfinal, 3-chlorophenyl, 3,4-differenl, 3,4,5-tryptophanyl, 3-chloro-4-forfinal and 3-triptoreline.

3. Connection on p. 1 or 2 or its pharmacologically acceptable salt, ester or amide derivative, where R2is a 4-pyridyloxy or 4-pyrimidinyl group which may be optionally substituted by at least one zamestitel 2 or its pharmacologically acceptable salt, ester or amide derivative, where R2is a 4-pyridyloxy or 4-pyrimidinyl group which may be optionally substituted in position 2 by a Deputy of the formula-NRcRdwhere Rcand Rdsuch as specified in paragraph 1.

5. Connection on p. 1 or 2 or its pharmacologically acceptable salt, ester or amide derivative, where R2is a 4-pyridyloxy or 4-pyrimidinyl group which may be optionally substituted in position 2 by a Deputy selected from the group comprising amino, methylamino and benzylamino.

6. The compound according to any one of paragraphs.1-5 or its pharmacologically acceptable salt, ester or amide derivative, where m=1 and n=1.

7. The compound according to any one of paragraphs.1-6, or its pharmacologically acceptable salt, ester or amide derivative, where E represents a group of formula >NR10and D denotes a group of formula >CR11R12.

8. The compound according to any one of paragraphs.1-7 or its pharmacologically acceptable salt, ester or amide derivative, where R10and R11together form unsubstituted alkylenes group with a straight chain containing 3 or 4 carbon atoms.

9. The compound according to any one of paragraphs.1-8 Il is UP> represents a hydrogen atom, and R10and R11together form unsubstituted alkylenes group with a straight chain having 3 or 4 carbon atoms.

10. Connection on p. 1 or its pharmacologically acceptable salt, ester or amide derivative, where R1matter specified in paragraph (1; R2means pyridyloxy or pyrimidinyl group which may be optionally substituted by at least one Deputy of the formula-NRcRdwhere Rcand Rdsuch as specified in paragraph 1; and R3denotes a group of formula (II) as defined in paragraph 1.

11. Connection on p. 1 or its pharmacologically acceptable salt, ester or amide derivative, where R1matter specified in paragraph (1; R2is a 4-pyridyloxy or 4-pyrimidinyl group which may be optionally substituted by at least one Deputy of the formula-NRcRdwhere Rcand Rdsuch as specified in paragraph 1; and R3represents a group of formula (II) as defined in paragraph 1, where m=1 and n=1.

12. Connection on p. 1 or its pharmacologically acceptable salt, ester or amide derivative, where R1matter specified in paragraph (1; R2is a 4-parietale formula-NRcRdwhere Rcand Rdsuch as specified in paragraph 1; and R3represents a group of formula (II) as defined in paragraph 1, where E represents a group of formula >NR10where R10matter specified in paragraph 1, and D represents a group of formula >CR11R12where R11and R12such as specified in paragraph 1.

13. The compound of formula (I) under item 1 or its pharmacologically acceptable salt, ester or amide derivative, where R1matter specified in paragraph (1; R2is a 4-pyridyloxy or 4-pyrimidinyl group which may be optionally substituted in position 2 by a Deputy of the formula-NRcRdwhere Rcand Rdsuch as specified in paragraph 1; and R3represents a group of formula (II) as defined in paragraph 1.

14. The compound of formula (I) under item 1 or its pharmacologically acceptable salt, ester or amide derivative, where R1selected from the group comprising phenyl, 4-forfinal, 3-forfinal, 3-chlorophenyl, 3,4-differenl, 3,4,5-tryptophanyl, 3-chloro-4-forfinal and 3-triptoreline; R2is a 4-pyridyloxy or 4-pyrimidinyl group which may be optionally substituted in position 2 by a Deputy, selected from the group on paragraph 1, where R10and R11together form unsubstituted alkylenes group with a straight chain having 3 or 4 carbon atoms.

15. The compound of formula (I) under item 1 or its pharmacologically acceptable salt, ester or amide derivative, where R1selected from the group comprising phenyl, 4-forfinal, 3-forfinal, 3-chlorophenyl, 3,4-differenl, 3,4,5-tryptophanyl, 3-chloro-4-forfinal and 3-triptoreline; R2denotes 4-pyridyloxy or 4-pyrimidinyl group which may be optionally substituted in position 2 by a Deputy selected from the group comprising amino, methylamino and benzylamino; and R3denotes a group of formula (II) as defined in paragraph 1, where each of R7, R8and R9represents a hydrogen atom, and R10and R11together form unsubstituted alkylenes group with a straight chain having 3 or 4 carbon atoms.

16. The compound of formula (I) under item 1, selected from the following group of compounds, or a pharmacologically acceptable salt, ester or amide derivative:

4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-3-(pyridin-4-yl)-4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1-methyl-1,2,3,6-tetrahedron-4-yl)-lH-pyrrol,

2-(4-forfinal)-4-(2-methyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(6-methyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1-isopropyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1-phenethyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,2,3,5,8,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1,2-dimethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1-ethyl-6-methyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1-ethyl-2-methyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

4-(6-allyl-1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

4-(2-allyl-1-methyl-1,2,3,6-tetrahydropyridine-4-yl) - Rev. Jn-4-yl)-1H-pyrrol,

4-(2-benzyl-1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(6-methyl-1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(2-methyl-1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,3,4,6,7,9-hexahydro-2H-chinolin-8-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,3,4,6,9,9 and hexahydro-2H-chinolin-8-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,2,3,5,8,8 and-hexahydroquinoline-7-yl)-3-(2-methylaminopropyl-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(2-methylaminopropyl-4-yl)-1H-pyrrol,

2-(3,4-differenl)-4-(1,2,3,5,8,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(3,4-differenl)-4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1,2,3,5,8,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-2-(3-triptoreline)-1H-pyrrol,

4-(1,2,3, 5,6,8-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-2-(3-triptoreline)-1H-pyrrol,

2-(3-forfinal)-4-(1,2,3,5,8,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(3-forfinal)-4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(3-chlorophenyl)-4-(1,2,3,5,8,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(3-chlorophenyl)-4-(1, the DIN-4-yl)-1H-pyrrole and

4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-2-phenyl-3-(pyridin-4-yl)-1H-pyrrole.

17. The compound of formula (I) under item 1, selected from the following group of compounds, or a pharmacologically acceptable salt, ester or amide derivative:

2-(4-forfinal)-3-(pyridin-4-yl)-4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(6-methyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1-isopropyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1-phenethyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1,6-dimethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1,2-dimethyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-lH-pyrrol,

4-(1-ethyl-6-methyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

4-(1-ethyl-2-methyl-1,2,3,6-tetrahydropyridine-4-yl)-2-(4-forfinal)-3-(pyridin-4-yl)-1H-pyrrol,

2-(4-forfinal)-4-(6-methyl-1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-p is nil)-4-(1,3,4,6,7,9-hexahydro-2H-chinolin-8-yl)-3-(pyridin-4-yl)-1H-pyrrol,

2-(3,4-differenl)-4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrole and

4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-2-(3-triptoreline)-1H-pyrrole.

18. Connection on p. 1, selected from 2-(4-forfinal)-4-(1-phenethyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrole and its pharmacologically acceptable salts, esters and other derivatives.

19. Connection on p. 1, selected from 2-(4-forfinal)-4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-1H-pyrrole and its pharmacologically acceptable salts, esters and other derivatives.

20. Connection on p. 1, selected from 2-(4-forfinal)-4-(6-methyl-1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrole and its pharmacologically acceptable salts, esters and other derivatives.

21. Connection on p. 1, selected from 2-(4-forfinal)-4-(2-methyl-1-propyl-1,2,3,6-tetrahydropyridine-4-yl)-3-(pyridin-4-yl)-1H-pyrrole and its pharmacologically acceptable salts, esters and other derivatives.

22. Connection on p. 1, selected from 2-(4-forfinal)-4-(1,3,4,6,7,9-hexahydro-2H-chinolin-8-yl)-3-(pyridin-4-yl)-1H-pyrrole and its pharmacologically acceptable salts, esters and other derivatives.

23. Connection on p. 1, selected from 2-(3,4-differenl)-4-(1,2,3,5, is derived.

24. Connection on p. 1, selected from 4-(1,2,3,5,6,8 and-hexahydroquinoline-7-yl)-3-(pyridin-4-yl)-2-(3-triptoreline)-1H-pyrrole and its pharmacologically acceptable salts, esters and other derivatives.

25. The compound of formula (I) according to any one of paragraphs.1-24 or its pharmacologically acceptable salt, ester or amide derivative as an active ingredient of a medicinal product for the treatment or prevention of diseases selected from the group including psoriasis, Crohn's disease, diabetes, hepatitis, chronic rheumatoid arthritis or osteoarthritis in a mammal, which may be the man.

26. The compound of formula (I) according to any one of paragraphs.1-24 or its pharmacologically acceptable salt, ester or amide derivative as an active ingredient of a medicinal product for the treatment or prevention of diseases selected from the group comprising chronic rheumatoid arthritis or osteoarthritis.

27. Pharmaceutical composition for inhibiting the production of inflammatory cytokines in a mammal, which may be human, containing an effective amount of the pharmacologically active compound together with a carrier or diluent, where the aforementioned pharmacologically Ealy, ester or other derivative.

28. Pharmaceutical composition for treatment or prevention of a disease in a mammal, which may be people, where the disease is selected from the group comprising chronic rheumatoid arthritis or osteoarthritis, containing an effective amount of the pharmacologically active compound together with a carrier or diluent, where the aforementioned pharmacologically active compound is a compound of formula (I) according to any one of paragraphs.1-24 or its pharmacologically acceptable salt, ester or other derivative.

29. Method for the treatment or prevention of diseases selected from the group including psoriasis, Crohn's disease, diabetes, hepatitis, chronic rheumatoid arthritis or osteoarthritis in a mammal, which may be people, introducing to a mammal suffering from such disease an effective amount of the compounds of formula (I) according to any one of paragraphs. 1-25 or its pharmacologically acceptable salt, ester or other derivative.

30. The method of treatment or prophylaxis for p. 29, where the disease is chronic rheumatoid arthritis.

31. The method of treatment or prophylaxis for p. 29, where the disease

 

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