Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-27
2003-07-15
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...
C514S226200, C514S291000, C514S365000, C514S374000, C514S375000, C514S378000, C514S393000, C514S404000, C514S406000, C514S411000, C514S416000, C514S419000, C514S423000, C514S427000, C514S428000, C514S431000, C514S448000, C514S450000, C514S532000, C514S539000, C514S545000, C514S621000, C514S640000, C514S658000, C514S676000, C514S709000, C514S719000
Reexamination Certificate
active
06593347
ABSTRACT:
FIELD OF INVENTION
The present invention describes novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory drugs, and novel compositions comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory drug, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The present invention also provides methods for treating, preventing and/or reducing inflammation, pain, and fever; decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflanmatory compounds; treating and/or preventing gastrointestinal disorders; treating inflammatory disease states and disorders; and treating and/or preventing ophthalmic diseases or disorders.
BACKGROUND OF THE INVENTION
The chemistry and pharmacology of nitroxybutylester ((CH
2
)
4
—ONO
2
) derivatives of several aryl propionic acid nonsteroidal antiinflammatory compounds, including ketoprofen, flurbiprofen, suprofen, indobufen and etodolac, was described in PCT Application No. WO 94/12463. 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. U.S. Pat. No. 5,703,073 describes nonsteroidal antiinflammatory compounds containing a nitrogen monoxide group indirectly linked to the nonsteroidal antiinflammatory compound and their protection against gastrointestinal, renal and other toxicities normally induced by nonsteroidal antiinflammatory compounds. The compounds described in U.S. Pat. No. 5,703,073 all contain a heteroatom flanked by a carbonyl group in the form of an ester, amide or thioester in the main chain of the linker.
The use of nonsteroidal antiinflammatory compounds for the treatment and/or prevention of ophthalmic diseases or disorders such as glaucoma, inflammations of the eye and elevation of intraocular pressure has been described. For example, U.S. Pat. No. 5,474,985 describes the use of nonsteroidal antiinflammatory compounds to treat or prevent non-inflammatory induced, elevated intraocular pressure associated with the administration of corticosteroids; U.S. Pat. Nos. 5,674,888 and 5,599,535 describe the use of nonsteroidal antiinflammatory compounds to treat loss of trabecular meshwork resulting from aging, exposure to toxic substances, environmental stresses, such as oxidative or phagocytic injury, or glucocorticoid exposure; U.S. Pat. No. 5,814,655 describes topical ophthalmic compositions comprising nonsteroidal antiinflammatory compounds; Wiederholt et al.,
Invest. Opthalmol. Vis. Sci.,
2515-2520 (1994) describes the use of nitric oxide donors to relax trabecular meshwork and ciliary muscle; Behar-Cohen et al.,
Invest. Opthalmol. Vis. Sci
., describes the use of nitric oxide donors to decrease intraocular pressure.
There is a need in the art for nonsteroidal antiinflammatory compounds that do not have the adverse side effects associated with prior art compounds. There is also a need for new and improved treatments of inflammatory disease states and disorders; and ophthalmic diseases and disorders. The present invention is directed to these, as well as other important ends.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that it is possible to link a nitrogen monoxide group (NO), and/or a nitrogen dioxide group (NO
2
) (i.e., nitrosylated and/or nitrosated group, respectively) to a nonsteroidal antiinflammatory compound and that the resulting compounds have good bioavailibility, possess potent analgesic and antiinflammatory properties and have an unexpectedly reduced potential for producing gastrointestinal lesions (ulcers). The novel compounds also have unexpected properties in the treatment and/or prevention of ophthalmic diseases and disorders.
The present invention is also based on the discovery that it is possible to administer at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound (NSAID) and at least one nitric oxide donor to prevent, reduce, or reverse gastrointestinal, renal, and other toxicities induced by the NSAID. NSAIDs are antiinflammatory, analgesic and antipyretic compounds that act at cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid 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 releases or chemically transfers nitric oxide to another molecule. Nitric oxide donors include, for example, S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, and substrates of the various isozymes of nitric oxide synthase.
One aspect of the present invention provides novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds. The nonsteroidal antiinflammatory compound can be nitrosated and/or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and/or nitrogen. The nonsteroidal antiinflammatory compound can be, for example, an aryl propionic acid, an aryl acetic acid or an enolic anilide. The present invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
Another aspect of the invention provides compositions comprising a therapeutically effective amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound and at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO
+
) or nitroxyl (NO−), or as the neutral species, nitric oxide (NO·), and/or stimulates endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds can be, for example, aryl propionic acids, aryl acetic acids, or enolic anilides. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
Yet another aspect of the present invention provides kits comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO
+
) or nitroxyl (NO−), or as the neutral species, nitric oxide (NO·), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated NSAID and the nitric oxide donor can be separate components in the kit or can be in the form of a composition.
The present invention also provides methods for treating and/or preventing inflammation, pain and fever; decreasing and/or reversing gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory compounds; and treating and/or preventing gastrointestinal disorders in a patient in need thereof which comprises administering to the patient a therapeutically effective amount of at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO
+
) or nitroxyl (NO−), or as the n
Bandarage Upul K.
Dong Qing
Fang Xinqin
Garvey David S.
Mercer Gregory J.
Hale and Dorr LLP
NitroMed Inc.
Raymond Richard L.
LandOfFree
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