Bisulfate of janus kinase (JAK) inhibitor and preparation method therefor

Patent metadata

Field	Value
Publication number	US-9422300-B2
Application number	US-201414895117-A
Country	US
Kind code	B2
Filing date	May 5, 2014
Priority date	Jun 7, 2013
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The present invention relates to a bisulfate of a Janus kinase (JAK) inhibitor and a preparation method therefor. More specifically, the present invention relates to a (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazole-5-group)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-group)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-formamide bisulfate shown in the formula (I), a preparation method therefor, and an application thereof. The bisulfate shown in the formula (I) can be well suitable as a Janus kinase (JAK) inhibitor in clinical work for treating rheumatism or rheumatoid arthritis.

First claim

What is claimed is:

1. (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide bisulfate of formula (I)

2. (3 aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide bisulfate of formula (I) according to claim 1 , wherein a stoichiometric ratio of a compound of formula (IV) to sulfuric acid is 1:1:

3. A preparation method, of (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide bisulfate of formula (I) according to claim 1 , comprising a step of reacting a compound of formula (IV) with sulfuric acid, thereby forming a salt of formula (I)

4. The preparation method according to claim 3 , wherein the salt-forming reaction is carried out in a solvent, and the solvent is a mixed solvent of haloalkanes and alcohols having less than or equal to 3 carbon atoms.

5. The preparation method according to claim 4 , wherein the reaction temperature of the salt-forming reaction is 10-30° C., and the reaction time is 0.5-4 hours.

6. A pharmaceutical composition comprising the (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide bisulfate of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.

7. The preparation method according to claim 4 , wherein the solvent is a mixed solvent of dichloromethane and methanol.

8. A method of treating rheumatism or rheumatoid arthritis in a subject in need thereof, the method comprising administering to the subject (3aR,5s,6aS)—N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide bisulfate of formula (I) according to claim 1 .

9. A method of treating rheumatism or rheumatoid arthritis in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 6 .

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Sun Piaoyang
• Wu Guaili
• Gao Xiaohui
• Shen Lingjia

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title