Novel ester derivatives of buprenorphine and their preparation processes, and long acting analgestic pharmaceutical compositions

• US 20050075361A1
• Filed: 08/22/2003
• Published: 04/07/2005
• Est. Priority Date: 11/12/2002
• Status: Abandoned Application

• Current Assignee: Chi Mei Foundation Hospital
• Original Assignee: Chi Mei Foundation Hospital
• Inventors: Wang, Jhi-Joung
• Application Number:
  US10/645,557
• Publication Number:
  US 20050075361A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 489/12 the bridge containing only two carbon atoms

Abstract

Disclosed herein are novel buprenorphine monocarboxylic ester derivatives and dibuprenorphine dicarboxylic ester derivatives which exert a longer analgesic effect as compared to buprenorphine hydrochloride. Also disclosed are the processes for synthesizing the novel ester derivatives of buprenorphine, and long-acting analgesic pharmaceutical compositions containing a compound selected from buprenorphine base and the novel ester derivatives of buprenorphine.

Claims

1. A dibuprenorphine dicarboxylic ester derivative of formula (II):

2. The dibuprenorphine dicarboxylic ester derivative as claimed in claim 1, wherein R₁ is an alkylene group having 1 to 40 carbon atoms.

3. The dibuprenorphine dicarboxylic ester derivative as claimed in claim 2, wherein R₁ is an alkylene group having 1 to 20 carbon atoms.

4. The dibuprenorphine dicarboxylic ester derivative as claimed in claim 1, which is selected from dibuprenorphine pimelate and dibuprenorphine sebacoyl ester.

5. An analgesic pharmaceutical composition for intramuscular or subcutaneous administration, comprising

a therapeutically effective amount of a compound selected from the group consisting of buprenorphine base of formula (A)

a buprenorphine monocarboxylic ester derivative of formula (I)

wherein R is selected from the group consisting of a straight-chain or branched saturated or unsaturated aliphatic group optionally substituted with an aryl group, and an aryl group optionally substituted with a straight-chain or branched saturated or unsaturated aliphatic group, with the proviso that R is not selected from methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl and isopropyl;

and

a buprenorphine dicarboxylic ester derivative of formula (II)

wherein R₁ is a divalent moiety of a saturated or unsaturated aliphatic group optionally substituted with a phenyl group; and

a pharmaceutically acceptable oil carrier.

6. The analgesic pharmaceutical composition as claimed in claim 5, wherein said compound is said buprenorphine dicarboxylic ester derivative of formula (II), wherein R₁ is an alkylene group having 1 to 40 carbon atoms.

7. The analgesic pharmaceutical composition as claimed in claim 5, wherein said compound is said buprenorphine dicarboxylic ester derivative of formula (II), wherein R₁ is an alkylene group having 1 to 20 carbon atoms.

8. The analgesic pharmaceutical composition as claimed in claim 5, wherein said compound is said buprenorphine monocarboxylic ester derivative of formula (I), wherein R is an alkyl group optionally substituted with a phenyl group.

9. The analgesic pharmaceutical composition as claimed in claim 5, wherein said compound is said buprenorphine monocarboxylic ester derivative of formula (I), wherein R is an alkyl group having 2 to 40 carbon atoms.

10. The analgesic pharmaceutical composition as claimed in claim 5, wherein said compound is said buprenorphine monocarboxylic ester derivative of formula (I), wherein R is an alkyl group having 5 to 20 carbon atoms.

11. The analgesic pharmaceutical composition as claimed in claim 5, wherein said compound is said buprenorphine monocarboxylic ester derivative of formula (I), wherein R is selected from the group consisting of a straight-chain alkyl group optionally substituted with a phenyl group, a branched alkyl group optionally substituted with a phenyl group, a phenyl group optionally substituted with a straight-chain aliphatic group, and a phenyl group optionally substituted with a branched aliphatic group.

12. The analgesic pharmaceutical composition as claimed in claim 5, wherein said compound is selected from the group consisting of dibuprenorphine pimelate, dibuprenorphine sebacoyl ester, buprenorphine pivalate, buprenorphine benzoate, buprenorphine decanoate and buprenorphine palmitate.

13. The analgesic pharmaceutical composition as claimed in claim 5, wherein said oil carrier is selected from the group consisting of sesame oil, castor oil, cotton seed oil, soybean oil, peanut oil or ethyl ester of peanut oil, and a combination thereof.

14. A method of providing a prolonged analgesia to an animal or human comprising administering intramuscularly or subcutaneously to an animal or human in need of such treatment an effective amount of the composition of claim 5.