Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-30
2002-11-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S002600, C514S019300, C514S023000, C514S159000, C514S162000, C514S165000, C514S166000, C514S226500, C514S364000, C514S374000, C514S393000, C514S411000, C514S412000, C514S416000, C514S419000, C514S448000, C514S513000, C514S539000, C514S546000, C514S567000, C514S611000, C514S619000, C514S622000, C514S681000, C514S727000
Reexamination Certificate
active
06482846
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of “aspirin-like” or nonsteroidal antiinflammatory drug compounds and compositions that prevent, reduce or reverse the gastrointestinal, renal, and other toxicities associated with nonsteroidal antiinflammatory drugs.
BACKGROUND OF THE INVENTION
Arena et al., WO94/12463, discloses the chemistry and pharmacology of nitroxybutylester[(CH2)
4
—ONO
2
] derivatives of several aryl propionic acid non-steroidal antiinflammatory drugs including ketoprofen, flurbiprofen, suprofen, indobufen and etodolac. Studies on nitroxybutylester derivatives of flurbiprofen and ketoprofen are also reported in Wallace et al.,
Gastroenterology
, 107:173-179 (1994). See, also, Cuzzolin et al.,
Pharmacol. Res
., 29(1):89-97 (1994); Reuter et al.,
Life Sci
. (USA), 55/1(PL1-PL8(1994); Reuter et al.,
Gastroenterology
, 106(4):Suppl. A759 (1994); Wallace et al.,
Eur. J. Pharmacol.
., 257(3):249-255 (1994); Wallace et al.,
Gastroenterology
, 106(4):Suppl. A208 (1994); and Conforti et al.,
Agents
-
Actions
, 40(3-4):176-180 (1993). These publications uniformly examine and rely upon the use of indirectly linked nitrogen dioxide substitutions.
SUMMARY OF THE INVENTION
The present invention is based on the discovery by the inventors that it is possible to link a nitrogen monoxide group, nitric oxide (NO), to a non-steroidal antiinflammatory agent and that the resulting compounds not only possess potent analgesic/antiinflammatory properties but has a much reduced potential for producing gastrointestinal lesions (ulcers).
The present invention is further based on the discovery by the inventors that it is possible to coadminister a nonsteroidal antiinflammatory drug (NSAID) and a compound that directly donates, releases or transfers nitrogen monoxide(preferably as a charged species, particularly nitrosonium) to prevent, reduce, or reverse the gastrointestinal, renal, and other toxicities induced by the NSAID. NSAIDs are antiinflammatory, analgesic and antipyretic compounds that act as cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoids, inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase-1 and -2) and as inhibitors of both cyclooxygenase and lipoxygenase. A nitric oxide donor is a compound that contains a nitric oxide moiety and which directly releases or directly chemically transfers nitrogen monoxide (nitric oxide), preferably in its positively charged nitrosonium form, to another molecule. Nitric oxide donors include but are not limited to S-nitrosothiols, nitrites, Noxo-N-nitrosamines, and substrates of various forms of nitric oxide synthase.
In one aspect the present invention provides a compound comprising a non-steroidal antiinflammatory agent to which is directly or indirectly linked at least one NO group. The non-steroidal antiinflammatory agent can, for example, be an aryl propionic acid or an enolic anilide. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
In another aspect the invention provides a composition comprising a mixture of a therapeutically effective amount of a nonsteroidal antiinflammatory agent and an NSAID toxicity reducing amount of a compound that donates, transfers or releases nitric oxide.
In another aspect the present invention provides a composition comprising a non-steroidal antiinflammatory agent to which is directly or indirectly linked at least one NO group and a compound that donates, transfers or releases nitric oxide. The non-steroidal antiinflammatory agent can, for example, be an aryl propionic acid or an enolic anilide. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
In another aspect the invention provides a method for treating inflammation, pain and/or fever in an individual in need thereof which comprises administering to the individual a nonsteroidal antiinflammatory agent, which may optionally be substituted with at least one NO group, and a compound that donates, transfers or releases nitric oxide. The NSAID or NSAID directly or indirectly linked to at least one NO group, and nitric oxide donor can be administered separately or as components of the same composition.
In another aspect the invention provides a method of treating inflammation, pain and/or fever in an individual in need thereof which comprises administering to the individual a composition comprising a therapeutically effective amount of an NSAID, which may optionally be substituted with at least one NO group, and an NSAID toxicity reducing amount of a nitric oxide donor in a pharmaceutically acceptable carrier. Such compositions are discussed in more detail below.
In another aspect the invention provides a method to decrease or reverse the gastrointestinal toxicity of nonsteroidal antiinflammatory drugs administered to an animal, particularly a human, by co-administering to said animal a nitric oxide donor. The NSAID and nitric oxide donor can be administered separately or as components of the same composition.
In another aspect the invention provides a method to decrease or reverse the renal toxicity of nonsteroidal antiinflammatory drugs administered to an animal, particularly a human, by co-administering to said animal a nitric oxide donor. The NSAID and nitric oxide donor can be administered separately or as components of the same composition.
In another aspect the invention provides a method to accelerate gastrointestinal tissue repair in an animal, particularly a human, by administering to said animal a nitric oxide donor. The NSAID and nitric oxide donor can be administered separately or as components of the same composition.
DETAILED DESCRIPTION OF THE INVENTION
The compounds and compositions of the present invention are novel and can be utilized to treat numerous inflammatory disease states and disorders. For example, reperfusion injury to an ischemic organ, e.g., reperfusion injury to the ischemic myocardium, myocardial infarction, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, organ transplant rejections, organ preservation, impotence, radiation-induced injury, asthma, atherosclerosis, thrombosis, platelet aggregation, metastasis, influenza, stroke, bums, trauma, acute pancreatitis, pyelonephritis, hepatitis, autoimmune diseases, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, Alzheimer's disease, adult and infantile respiratory diseases, carcinogenesis and hemorrhages in neonates.
The NSAID can be nitrosylated through sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and nitrogen.
The term “lower alkyl” herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
The term “alkoxy” herein refers to RO-wherein R is lower alkyl as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
The term “alkoxyalkyl” herein refers to an alkoxy group as previously defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
The term “alkenyl” herein refers to a branched or straight chain C
2
-C
10
hydrocarbon which also comprises one or more carbon-carbon double bonds.
The term “amino” herein refers to —NH
2
.
The term “cyano” herein refers to —CN.
The term “hydroxy” herein refers to —OH.
The term “alkylsulfinyl” herein refers to R
50
—S(O)
2
— wherein R
50
is a branched or unbranched lower alkyl of up to four carbons.
The term “carboxamido” herein refers to —C(O)NH
2
.
The term “carbamoyl” herein refers to —O—C(O)NH
2
.
The term “carboxyl” herein refers to —CO
2
H.
The term “alkylamino” herein refers to R
51
NH-wherein R
51
is a lower alkyl group, for example, methylamino, ethylamino,
Garvey David S.
Letts L. Gordon
Renfroe H. Burt
Tam Sang William
Hale and Dorr LLP
NitroMed Inc.
Raymond Richard L.
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