Therapeutic nucleosides

• US 5,034,394 A
• Filed: 12/22/1989
• Issued: 07/23/1991
• Est. Priority Date: 06/27/1988
• Status: Expired due to Term

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Burroughs Wellcome and Co.
• Inventors: Daluge, Susan M.
• Primary Examiner(s): Shen, Cecilia
• Application Number:
  US07/455,201
• Time in Patent Office: 578 Days
• Field of Search: 544/277, 544/244, 514/81, 514/261
• US Class Current: 514/263.4
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07C 215/42 having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 2601/10 the ring being unsaturated
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 239/50 Three nitrogen atoms
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

The present invention relates to 6-substituted purine carbocyclic nucleosides and their use in medical therapy particularly in the treatment of HIV and HBV infections. Also provided are pharmaceutical formulations and processes for the preparation of compounds according to the invention.

Claims

1. A compound of formula (I):

##STR4## wherein R³ represents hydrogen or C_1-6 alkyl;

R⁶ represents C_3-8 cycloalkyl, and R⁷ represents a hydrogen atom or a branched or straight chain C_1-6 alkyl;

or a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof.

2. A compound, ester or salt of formula (I) according to claim 1 in which R³ is hydrogen, R⁶ is C_3-6 cycloalkyl and R⁷ is methyl or hydrogen.

3. A compound according to claim 2 in which R⁶ is cyclopropyl.

4. A compound of formula (I) according to claim 1 selected from:

(-)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and

(-)-cis-4-[2-amino-6-(cyclopropylmethylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol or

racemic or partially resolved mixtures with the (+)-cis enantiomers thereof.

5.

9. A compound of formula (I) according to claim 1 wherein the pharmaceutically acceptable ester is a mono-, di-, or tri-phosphate ester or a pharmaceutically acceptable salt thereof.

10. A compound of formula (I) according to claim 1 wherein the pharmaceutically acceptable ester is the L-valinate or a salt thereof.

11. A compound, ester or salt of claim 3, in which the pharmaceutically acceptable ester is a mono-, di, or tri-phosphate ester or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical formulation comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

19. A formulation according to claim 18 wherein the compound of formula (I) is selected from:

(-)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and

(-)-cis-4-[2-amino-6-(cyclopropylmethylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol or

racemic or partially resolved mixtures with the (+)-cis enantiomers thereof.

5. (±

)-cis-4-[2-amino-6-(cyclopropylamino-9H-purin-9-yl]-2-cyclopentene-1-methanol.

7. A pharmaceutically acceptable salt of a compound according to claims 5 or 6.

8. A pharmaceutically acceptable ester of a compound according to claims 5 or 6.

20. A tablet or capsule containing 50 to 700 mg of a compound according to claims 5 or 6 or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof.

6. (-)-cis-4-[2-amino-6-(cyclopropylamino-9H-purin-9-yl]-2-cyclopentene-1-methanol.

12. A compound of the formula (I):

R1 ? ? ##STR5## wherein R⁷ is hydrogen, R⁶ is cyclopropyl and R³ is hydrogen or a pharmaceutically acceptable salt thereof.

14. A tablet or capsule containing the compound of claim 12.

13. A compound of the formula (I):

##STR6## wherein R⁷ is methyl, R⁶ is cyclopropyl and R³ is hydrogen or a pharmaceutically acceptable salt thereof.

15. A tablet or capsule containing the compound of claim 13.

16. (±

)-cis-4-[2-amino-6-(cyclopropylmethylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol.

17. (-)-cis-4-[2-amino-6-(cyclopropylmethylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol.