HYDROGEN SULFIDE DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

• US 20100210607A1
• Filed: 02/11/2010
• Published: 08/19/2010
• Est. Priority Date: 05/27/2005
• Status: Active Grant

• Current Assignee: Antibe Therapeutics, Inc.
• Original Assignee: Antibe Therapeutics, Inc.
• Inventors: WALLACE, JOHN, CALIENDO, GIUSEPPE, CIRINO, GIUSEPPE, SANTAGADA, VINCENZO
• Granted Patent: US 8,541,398 B2
• Time in Patent Office: Days
• US Class Current: 514/165
• 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: C07C 219/14 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 327/48 having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/32 Oxygen atoms
• CPC Class Codes: C07D 309/30 Oxygen atoms, e.g. delta-lactones
• CPC Class Codes: C07D 339/04 having the hetero atoms in positions 1 and 2, e.g. lipoic acid
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) having improved anti-inflammatory properties useful in the treatment of inflammation, pain and fever. More particularly, NSAIDs are derivatized with a hydrogen sulfide (H₂S) releasing moiety to produce novel anti-inflammatory compounds having reduced side effects.

Claims

1. A compound of the formula:

A-Y—

X 

 

(Formula I)

wherein A is an NSAID radical, Y is selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

C(O)OC(O)—

, —

C(O)NHCH₂C(O)—

, or zero, and X is selected from the group consisting of;

or a salt thereof;

whereby when Y is zero, the compound may be a salt of A and X.

3. The compound according to claim 1, wherein the NSAID is selected from the group consisting of acetylsalicylic acid (ASA), diclofenac, naproxen, indomethacin, flurbiprofen, sulindac, ibuprofen, aceclofenac, acemetacin, benoxaprofen, benzofenac, bromfenac, bucloxic acid, butibufen, carprofen, celecoxib, cicloprofen, cinmetacin, clidenac, clopirac, diflusinal, etodolac, etoricoxib, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, furobufen, furafenac, ibufenac, indoprofen, isoxepac, ketoprofen, ketorolac, loxoprofen, lonazolac, lumiracoxib, metiazinic, mefenamic acid, meclofenamic acid, meloxicam, nabumetone, piromidic acid, salsalate, miroprofen, oxaprozin, oxepinac, paracoxib, phenylbutazone, pirprofen, piroxicam, pirozolac, protizinic acid, rofecoxib, sodium salicylate, suprofen, tiaprofenic acid, tolmetin, valdecoxib, and zomepirac.

5. The compound according to claim 1, wherein the NSAID is selected from the group consisting of acetylsalicylic acid, naproxen, indomethacin, flurbiprofen, ibuprofen, aceclofenac, acemetacin, benoxaprofen, benzofenac, bromfenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinmetacin, clidenac, clopirac, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, furobufen, furafenac, ibufenac, indoprofen, isoxepac, loxoprofen, lonazolac, lumiracoxib, metiazinic, mefenamic acid, nabumetone, piromidic acid, salsalate, miroprofen, oxaprozin, oxepinac, phenylbutazone, pirprofen, pirozolac, protizinic acid, suprofen, tiaprofenic acid, and tolmetin.

6. The compound according to claim 1, wherein the NSAID is selected from the group consisting of acetylsalicylic acid, indomethacin, lumiracoxib, naproxen, ibuprofen, and flurbiprofen;

Y is —

C(O)O—

; and

X is

or a salt thereof.

7. The compound according to claim 1, wherein the NSAID is selected from the group consisting of acetylsalicylic acid, diclofenac, indomethacin, lumiracoxib, naproxen, ibuprofen, ketoprofen and flurbiprofen;

Y is —

C(O)O—

; and

X is

or a salt thereof.

8. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

9. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

10. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

11. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

12. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

13. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

14. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

15. Compound of claim 1 where the compound is

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable excipient or carrier.

17. The compound according to claim 1, wherein the NSAID is selected from the group consisting of acetylsalicylic acid (ASA), naproxen, indomethacin, flurbiprofen, ibuprofen, aceclofenac, acemetacin, benoxaprofen, benzofenac, bromfenac, bucloxic acid, butibufen, carprofen, celecoxib, cicloprofen, cinmetacin, clidenac, clopirac, etodolac, etoricoxib, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, furobufen, furafenmac, ibufenac, indoprofen, isoxepac, loxoprofen, lonazolac, lumiracoxib, metiazinic, mefenamic acid, meclofenamic acid, meloxicam, nabumetone, piromidic acid, salsalate, miroprofen, oxaprozin, oxepinac, paracoxib, phenylbutazone, pirprofen, piroxicam, pirozolac, protizinic acid, rofecoxib, sodium salicylate, suprofen, tiaprofenic acid, tolmetin, valdecoxib, and zomepirac.

2. A compound of the formula:

B—

C(O)O—

X 

 

(Formula II)

where B—

C(O)O—

is derived from an NSAID having a free carboxyl group or a carboxy-substituted NSAID and X is selected from the group consisting of;

or a salt thereof.

4. The compound according to claim 2, wherein the NSAID is selected from the group consisting of acetylsalicylic acid, naproxen, indomethacin, flurbiprofen, ibuprofen, aceclofenac, acemetacin, benoxaprofen, benzofenac, bromfenac, bucloxic acid, butibufen, carprofen, celecoxib, cicloprofen, cinmetacin, clidenac, clopirac, etodolac, etoricoxib, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, furobufen, furafenac, ibufenac, indoprofen, isoxepac, loxoprofen, lonazolac, lumiracoxib, metiazinic, mefenamic acid, meclofenamic acid, meloxicam, nabumetone, piromidic acid, salsalate, miroprofen, oxaprozin, oxepinac, paracoxib, phenylbutazone, pirprofen, piroxicam, pirozolac, protizinic acid, rofecoxib, sodium salicylate, suprofen, tiaprofenic acid, tolmetin, valdecoxib, and zomepirac.

18. The compound according to claim 2, wherein the NSAID is selected from the group consisting of acetylsalicylic acid, diclofenac, indomethacin, lumiracoxib, naproxen, ibuprofen, ketoprofen and flurbiprofen.