Antiviral phosphonate analogues and process for preparation thereof

Patent metadata

Field	Value
Publication number	US-9227990-B2
Application number	US-201314439578-A
Country	US
Kind code	B2
Filing date	Oct 29, 2013
Priority date	Oct 29, 2012
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The present invention provides a compound of the Formula (I)

wherein R is 9-isopropyl-9H-purin-6-amine; 2-amino-9-isopropyl-1H-purin-6(9H)-one; 4-amino-1-isopropyl pyrimidin-2(1H)-one; or 1-isopropyl-5-methylpyrimidine-2,4(1H,3H)-dione, R′ is —CH 2 OC(O)R″, and R″ is —C(CH 3 ) 3 or —CH(CH 3 ) 2 including pharmaceutically acceptable salts thereof. The present invention also provides a process for preparing a compound of formula (Ia) and a compound of formula (I) for use in treating a viral infection.

First claim

The invention claimed is:

1. A compound of Formula (Ia)

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound according to claim 1 , wherein the pharmaceutically acceptable acid addition salt is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, acetic acid, lactic acid, citric acid, oxalic acid, glutaric acid, malic acid, tartaric acid, fumaric acid, mandelic acid, maleic acid, benzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid.

3. A compound of formula

4. The compound according to claim 1 , wherein the compound is in the form of the R,R-diastereomer.

5. The compound according to claim 4 , wherein the compound in the form of the R,R-diastereomer has a chiral purity of at least 95%.

6. A method of preparing a compound of Formula (Ia) as defined in claim 1 , the method comprising reacting a compound of Formula (IIa) with a compound of Formula (IIIa) to obtain a compound of Formula (Ia)

7. The method according to claim 6 , wherein the compound of Formula (Ia) is:

and the method comprises reacting the compound of Formula (IIa) with the compound of Formula (IIIa) to obtain the free base of the compound of Formula (Ia), and reacting the free base of the compound of formula (Ia) with fumaric acid to obtain the fumaric acid salt thereof.

8. The method according to claim 6 , wherein the compound of formula (Ia) is in the form of the R-enantiomer, and the method comprises a chiral resolution step.

9. A pharmaceutical composition comprising a compound as defined in claim 1 together with a pharmaceutically acceptable carrier.

10. A method of treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1 .

11. L-tartrate salt of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy)phosphoryloxy)methyl pivalate.

12. A method of treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition as defined in claim 9 .

13. The compound according to claim 3 , wherein the compound is in the form of the R,R-diastereomer.

14. The compound according to claim 13 , wherein the compound in the form of the R,R-diastereomer has a chiral purity of at least 95%.

15. The method according to claim 7 , wherein the compound of formula (Ia) is in the form of the R-enantiomer, and the method comprises a chiral resolution step.

16. A pharmaceutical composition comprising a compound as defined in claim 3 together with a pharmaceutically acceptable carrier.

Assignees

• Cipla Ltd

Inventors

• Phull Manjinder Singh
• Kankan Rajendra Narayanrao
• Rao Dharmaraj Ramachandra

Classifications

• A61P31/12

  Antivirals · CPC title

• C07F9/65616 Primary

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title