Connection piperazine, an inhibitor of the production of tnf-and /or promoter of the production of il-10 and agent for the prevention or treatment of diseases based on it

 

(57) Abstract:

Describes the connection piperazine of General formula I or its pharmaceutically acceptable salt, where R1and R2are the same or different and each denotes hydrogen, halogen, lower alkyl, amino, amino, monosubstituted lower acyl; nitro, R3, R4and R5-same or different and each denotes hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy, amino, mono - or disubstituted by a group which is selected from the group comprising lower alkyl or lower acyl; R6and R7- same or different and each denotes hydrogen, acyl, R8and R9- same or different and each denotes hydrogen or lower alkyl, Y represents the

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where R10and R11denote hydrogen, R12and R13- same or different and each denotes hydrogen or lower alkyl, or R12and R13together form alkylene, R14and R15denote hydrogen, m is an integer of 0-2, n is an integer of 0 to 2 and 0m+n2; cycle And denotes phenyl, pyrimidinyl, thiazolyl, pyridyl, pyrazolyl or imidazolyl. Also described inhibitor of the production of TNF - and/or promoter of the production of IL-10, aderiva for the prevention or treatment of disease, caused by abnormal production of TNF-, disease-mediated TNF-, or diseases treatable IL-10, containing as active ingredient a compound of formula I or its pharmaceutically acceptable salt. 3 S. and 19 C.p. f-crystals, 2 PL.

Description text in facsimile form (see graphic part).

1. Connection piperazine of the formula

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where R1and R2are the same or different and each denotes hydrogen, halogen, lower alkyl, amino, amino, monosubstituted lower acyl; nitro;

R3, R4and R5are the same or different and each denotes hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino, mono - or disubstituted by a group which is selected from the group comprising lower alkyl and lower acyl;

R6and R7are the same or different and each denotes hydrogen, acyl;

R8and R9are the same or different and each denotes hydrogen or lower alkyl;

Y denotes a group of the formula

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where R10and R11denote hydrogen, R12and R13are the same or different and each denotes hydrogen or lower alkyl, Isla 0-2, n denotes an integer of 0-2 and 0m+n2;

cycle And denotes phenyl, pyrimidinyl, thiazolyl, pyridyl, pyrazolyl or imidazolyl,

or its pharmaceutically acceptable salt.

2. Connection piperazine under item 1, having the following formula:

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where R1and R2are the same or different and each denotes hydrogen, halogen, lower alkyl, amino, amino, monosubstituted lower acyl; nitro;

R3, R4and R5are the same or different and each denotes hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino, monosubstituted by acyl;

R6and R7are different and each denotes hydrogen, acyl;

Y1denotes a group of the formula

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where R12and R13are the same or different and each denotes hydrogen or lower alkyl, or R12and R13together form alkylene,

or its pharmaceutically acceptable salt.

3. Connection piperazine under item 1, having the following formula:

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where R1and R2represent hydrogen;

R3, R4and R5are the same or different and each represents halogen;

R6and R7is the group of the formula

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where R12and R13are the same or different and each denotes hydrogen or lower alkyl, or R12and R13together form alkylene,

or its pharmaceutically acceptable salt.

4. Connection piperazine under item 3, where R8adenotes methyl and its pharmaceutically acceptable salt.

5. Connection piperazine under item 1, having the following formula:

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where R1and R2represent hydrogen;

R3, R4and R5are the same or different and each denotes hydrogen, halogen;

R6and R7are different and each denotes hydrogen, acyl;

R8aand R9aare the same and each represents lower alkyl;

Y1denotes a group of the formula

< / BR>
where R12and R13denote hydrogen,

or its pharmaceutically acceptable salt.

6. Connection piperazine under item 5, where R8aand R9aboth denote methyl, or its pharmaceutically acceptable salt.

7. Connection piperazine according to any one of paragraphs.1-6, where R3, R4and R5are the same or different and each denotes hydrogen, halogen, or its pharmaceutically acceptable salt is appoints hydrogen;

cycle A' signifies a group of the formula

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< / BR>
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< / BR>
< / BR>
or

< / BR>
where R16and R17are the same or different and each denotes hydrogen, halogen, lower alkyl, lower alkoxy or amino, disubstituted by lower alkyl, R18denotes lower alkyl;

R6and R7are the same or different and each denotes hydrogen, acyl;

Y1denotes a group of the formula

< / BR>
where R12and R13are the same or different and each denotes hydrogen or lower alkyl, or R12and R13together form alkylene,

or its pharmaceutically acceptable salt.

9. Connection piperazine under item 1, having the following formula:

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where R1and R2represent hydrogen;

cycle A' signifies a group of the formula

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< / BR>
or

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where R16and R17are the same or different and each denotes hydrogen, halogen, R18denotes lower alkyl;

R6and R7are different and each denotes hydrogen, acyl;

R8adenotes lower alkyl;

Y1denotes a group of the formula

< / BR>
where R12and R13are the same who think,

or its pharmaceutically acceptable salt.

10. Connection piperazine under item 9, where R8adenotes methyl, and pharmaceutically acceptable salt.

11. Connection piperazine according to any one of paragraphs.1-10, where one of R6and R7denotes hydrogen and the other denotes acyl, or its pharmaceutically acceptable salt.

12. Connection piperazine according to any one of paragraphs.1-11, where R12and R13are the same or different and each denotes hydrogen or methyl, or R12and R13together form ethylene, or its pharmaceutically acceptable salt.

13. Connection piperazine according to any one of paragraphs.1, 2, 7, 11, or 12, which is a member selected from the group including

N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)ndimethylacetamide,

N-(4-((4-(4-forfinal)piperazine-1-yl)methyl)phenylmethyl)-ndimethylacetamide,

N-(4-((4-(2-forfinal)piperazine-1-yl)methyl)phenylmethyl)-ndimethylacetamide,

N-(4-((4-(2,4-differenl)piperazine-1-yl)methyl)phenylmethyl)ndimethylacetamide,

N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide", she

N-(2-(4-((4-(4-forfinal)piperazine-1-yl)methyl)phenyl)ethyl)-acetamide", she

N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide", she

N-(1-(4-((4-(4-forfinal)piperazine-1-yl)methyl)phenyl)ethyl)-ndimethylacetamide,ethyl)phenyl)-1-methylethyl)ndimethylacetamide,

N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)ndimethylacetamide and

N-(1-(4-((4-(4-forfinal)piperazine-1-yl)methyl)phenyl)-cyclopropyl)ndimethylacetamide,

or its pharmaceutically acceptable salt.

14. Connection piperazine according to any one of paragraphs.1, 3, 4, 7, 11 or 12, which is a member selected from the group including

N-(4-(1-(4-phenylpiperazin-1-yl)ethyl)phenylmethyl)ndimethylacetamide,

N-(4-(1-(4-(4-forfinal)piperazine-1-yl)ethyl)phenylmethyl)ndimethylacetamide and

N-(4-(1-(4-(2,4-differenl)piperazine-1-yl)ethyl)phenylmethyl)ndimethylacetamide,

or its pharmaceutically acceptable salt.

15. Connection piperazine according to any one of paragraphs.1, 5-7, 11, or 12, which is N-(4-(1-(4-(4-forfinal)piperazine-1-yl)-1-methylethyl)phenylmethyl)ndimethylacetamide, or its pharmaceutically acceptable salt.

16. Connection piperazine according to any one of paragraphs.1, 7, 8, 11, or 12, which is a member selected from the group including

N-(4-((4-(pyrimidine-2-yl)piperazine-1-yl)methyl)phenylmethyl)ndimethylacetamide,

N-(1-(4-((4-(pyrimidine-2-yl)piperazine-1-yl)methyl)phenyl) ethyl)acetamide", she

N-(1-(4-((4-(pyrimidine-2-yl)piperazine-1-yl)methyl)phenyl)-cyclopropyl)ndimethylacetamide,

N-(4-((4-(pyrimidine-2-yl)piperazine-1-yl)methyl)phenylmethyl)formamid,

N-(4-((4-(pyrimidine-2-yl)piperazine-1-yl)methyl)phenylmethyl)propionamide,
ylmethyl)-ndimethylacetamide,

or its pharmaceutically acceptable salt.

17. Connection piperazine according to any one of paragraphs.1, 7, 9, 10, 11 or 12, which is N-(1-(4-(1-(4-(pyrimidine-2-yl)piperazine-1-yl)ethyl)phenyl)cyclopropyl)ndimethylacetamide, or its pharmaceutically acceptable salt.

18. The inhibitor of the production of TNF - and/or promoter of the production of IL-10, containing as active ingredient a compound of piperazine according to any one of paragraphs.1-17 or its pharmaceutically acceptable salt.

19. Agent for the prevention or treatment of diseases caused by abnormal production of TNF-, disease-mediated TNF-, or diseases treatable IL-10, containing as active ingredient a compound of piperazine according to any one of paragraphs.1-17 or its pharmaceutically acceptable salt.

20. Means on p. 19, where the disease is an inflammatory disease.

21. Means on p. 19, where the disease is an autoimmune disease.

22. Means on p. 19, where the disease is a rheumatoid arthritis.

Priorities on items and features:

14.10.1997 - PP.1-3, 5, 7, 12, 18-22 - when all these values of R1, R2, R6, R7, R8, Y, R10, R11, R14, R15, m, n; PI hydroxy; when R5and R9is hydrogen; when R12and R13- same or different and each denotes hydrogen or lower alkyl; when the cycle And denotes phenyl; p. 4, 11, under item 13 - for all these compounds, except the last two in the course of the narrative; p. 14 and 15;

16.09.1998 - PP.1-3, 5, 7, 12, 18-22 - when R3and R4- same or different and each denotes a nitro, amino, mono - or disubstituted by a group which is selected from the group comprising lower alkyl and lower acyl; R5- halogen, lower alkoxy, nitro, amino, hydroxy, amino, mono - or disubstituted by a group which is selected from the group comprising lower alkyl and lower acyl; R9is lower alkyl; R12and R13together - alkylen; when the loop And indicates pyrimidinyl, thiazolyl, pyridyl, pyrazolyl or imidazolyl; p. 6; 8-10; p. 13 - for the last two during the presentation compounds; PP.16 and 17.

 

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