IP Library › Granted Patent US 8,338,414

Granted Patent B2

US 8,338,414 · App. 12/785,683 · Granted Dec 25, 2012

Immunosuppressive agent and anti-tumor agent comprising heterocyclic compound as active ingredient

Assignee: Zenyaku Kogyo KabushikiKaisha

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Patent No.: US 8,338,414
App. No.: 12/785,683
Granted: Dec 25, 2012
Kind: B2

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Abstract

A novel method for immunosuppressive in a mammal suffering from an immune disease, including administering to the mammal a therapeutically effective amount of a heterocyclic compound represented by the general formula (I) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof is disclosed. A novel heterocyclic compound represented by the general formula (II) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof is also disclosed.

Claims (262)

1. A heterocyclic compound represented by the general Formula (II):

wherein,

n represents 0-2;

X represents a nitrogen atom or CH;

Y represents -(CH 2 )n 1 -, wherein n 1 is 1-2;

R 1 and R 2 , both or either, represent a hydrogen atom, a hydroxyl group, a halogen, an amino group, a C 1 -C 6 alkylamino group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, or a cyano group;

R 3 represents a difluoromethyl group, a C 1 -C 6 alkylamino group or a hydroxymethyl group;

R 4 and R 5 represent a hydrogen, or a C 1 -C 6 alkyl group;

R 7 represents a hydrogen atom, a C 1 -C 6 alkyl group, a formyl, a C 1 -C 6 hydroxyalkyl, a C 1 -C 6 alkoxycarbonyl, a C 1 -C 6 oxoalkyl, an aromatic carbonyl, a benzylcarbonyl, or a substituted carbamoyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein the heterocyclic compound is selected from the group consisting of: A heterocyclic compound selected form the group consisting of:

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)-1,3,5-triazine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(trans-2,3-dimethylmorpholino)-1,3,5-triazine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(2,2-dimethylmorpholino)-1,3,5-triazine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetylpiperazin-1-yl)-2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholinopyrimidine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)pyrimidine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(trans-2,3-dimethylmorpholino)pyrimidine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(2,2-dimethylmorpholino)pyrimidine;

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6-morpholinopyrimidine;

4-(4-acetylpiperazin-1-yl)-2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-6-morpholinopyrimidine;

4-(4-acetylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-(cis-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N- dimethylcarbamoyl)piperazin-1-yl]-6-(trans-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-(2,2-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-(cis-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-(trans-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-(2,2-dimethylmorpholino)pyrimidine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-[4-(N,N-dimethylcarbamoyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-(cis-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-(trans-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-(2,2-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

4-[4-(2-furoyl)piperazin-1-yl]-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-(cis-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-(trans-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-(2,2-dimethylmorpholino)pyrimidine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(2-furoyl)piperazin-1-yl]-6-morpholinopyrimidine;

4-[4-(2-furoyl)piperazin-1-yl]-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholinopyrimidine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-ditnethylmorpholino)-1,3,5-triazine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(trans-2,3-dimethylmorpholino)-1,3,5-triazine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(2,2-dimethylmorpholino)-1,3,5-triazine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetonylpiperazin-1-yl)-2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholinopyrimidine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)pyrimidine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(trans-2,3-dimethylmorpholino)pyrimidine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-(2,2-dimethylmorpholino)pyrimidine;

4-(4-acetonylpiperazin-1-yl)-2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-6-morpholinopyrimidine;

4-(4-acetonylpiperazin-1-yl)-2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-6-morpholinopyrimidine;

4-(4-acetonylpiperazin-1-yl)-2-(2-hydroxymethylbenzimidazol-1-yl)-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-(4-propionylpiperazin-1-yl)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-(4-propionylpiperazin-1-yl)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-(4-propionylpiperazin-1-yl)-1,3,5-triazine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)-1,3,5-triazine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)-1,3,5-triazine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(cis-2,3-dimethylmorpholino)-6-(4-propionylpiperazin-1-yl)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(trans-2,3-dimethylmorpholino)-6-(4-propionylpiperazin-1-yl)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(2,2-dimethylmorpholino)-6-(4-propionylpiperazin-1-yl)pyrimidine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)pyrimidine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)pyrimidine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-morpholino-6-(4-propionylpiperazin-1-yl)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-(cis-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-(trans-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-(2,2-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-(cis-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-(trans-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-(2,2-dimethylmorpholino)pyrimidine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxyacetylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyppiperazin-1-yl]-6-(cis-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-(trans-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-(2,2-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-(cis-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-(trans-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-(2,2-dimethylmorpholino)pyrimidine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(cis-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(trans-2,3-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(2,2-dimethylmorpholino)-1,3,5-triazine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholino-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(cis-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(trans-2,3-dimethylmorpholino)pyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-(2,2-dimethylmorpholino)pyrimidine;

2-(2-difluoromethyl-4-hydroxybenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(2-hydroxymethylbenzimidazol-1-yl)-4-(4-methoxycarbonylpiperazin-1-yl)-6-morpholinopyrimidine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(5-oxo-1,4-diazepan-1-yl)-1,3,5-triazine;

2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(3-oxopiperazin-1-yl)-1,3,5-triazine; and

2-(2-difluoromethylbenzimidazol-1-yl)-6-(3,5-dioxopiperazin-1-yl)-4-morpholino-1,3,5-triazine.

3. A method for immunosuppression in a mammal suffering from an immune disease, comprising administering to the mammal a therapeutically effective amount of the heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein said immune disease is atopic dermatitis or rheumatoid arthritis.

4. The method according to claim 1 , wherein either of R 1 or R 2 is a hydroxyl group.

5. The method according to claim 1 , wherein either of R 1 or R 2 is a hydroxyl group, and R 3 is a difluoromethyl.

6. The method according to claim 1 , wherein both of R 1 and R 2 are hydrogens, and R 3 is a difluoromethyl.

7. The method according to claim 1 , wherein n 1 is 1, n is 0, and R 7 is acetyl.

8. The method according to claim 1 , wherein the heterocyclic compound is selected from the group consisting of:

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholinopyrimidine; and

4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine.

9. The method according to claim 1 , wherein said immune disease is an atopic dermatitis.

10. The method according to claim 1 , wherein said immune disease is an rheumatoid arthritis.

11. A method for immunosuppression in a mammal suffering from an immune disease, comprising administering to the mammal a therapeutically effective amount of a heterocyclic compound, wherein said immune disease is atopic dermatitis or rheumatoid arthritis and the heterocyclic compound is selected form the group consisting of: