Pfizer Corporation

Banavara L Mylari

William J Zembrowski

Margaret Y Chu-Moyer

Peter J Oates

Joseph G Lombardino

Eric R Larson

Jerry Anthony Murry

Delvin R Knight, Jr

W Ross Tracey

Todd W Siegel

Thomas A Beyer

E Roy Pettipher

James M McManus

Donald W Landry

Philip Albert Carpino

Andrew Wasmuth

Hermann Faubl

William H Martin

Shi Xian Deng

Ravichandran Ramasamy

The present invention relates to novel pyridazinone compounds, pharmaceutical compositions comprising those compounds and to methods of using such compounds and compositions to inhibit aldose reductase, lower sorbitol levels and, thus, lower fructose levels, and/or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to methods of affording cardioprotection to subjects not suffering from diabetes. This invention also relates to pharmaceutical compositions and kits comprising a combination of an aldose reductase inhibitor (ARI) of this invention and a sorbitol dehydrogenase inhibitor and to methods of using such compositions or kits to treat or prevent the above diabetic complications in mammals. This invention also relates to other combinations with the ARIs of this invention, including combinations with adenosine agonists; NHE-1 inhibitors; glycogen phosphorylase inhibitors; selective serotonin reuptake inhibitors; GABA agonists; antihypertensive agents; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors; phosphodiesterase-5 inhibitors; and to glucose lowering agents.

Pyridazinone aldose reductase inhibitors

This invention is directed to sorbitol dehydrogenase inhibitory compounds of the formula I,wherein R, Rand Rare as defined in the specification. This invention is also directed to pharmaceutical compositions containing those compounds and methods of treating or preventing diabetic complications, particularly diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy and diabetic cardiomyopathy by administering such compounds to a mammal suffering from diabetes and therefore at risk for developing such complications. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of this invention with an aldose reductase inhibitor and to methods of treating or preventing diabetic complications therewith. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of this invention with an NHE-1 inhibitor and to methods of treating cardiomyopathy and other heart-related problems therewith. This invention is also directed to certain intermediates used in the synthesis of the compounds of formula I and to processes for preparing those intermediates.

Sorbitol dehrydrogenase inhibitors

This invention is directed to sorbitol dehydrogenase inhibitory compounds of formula Iwherein R, Rand Rare as defined in the specification. This invention is also directed to pharmaceutical compositions containing these compounds and to methods of treating or preventing diabetic complications, particularly diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy, diabetic cardiomyopathy and foot ulcers. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of the present invention with a second pharmaceutical agent, including an aldose reductase inhibitor, a sodium hydrogen ion exchange inhibitor, a glycogen phosphorylase inhibitor, a selective serotonin reuptake inhibitor, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, an angiotensin converting enzyme inhibitor, a thiazolidinedione antidiabetic agent, an angiotensin II receptor antagonist, a &#x3b3;-aminobutyric acid agonist, a phosphodiesterase type 5 inhibitor, an adenosine agonist, and a CETP inhibitor and to methods of using these compositions.

Triazine compounds useful as sorbitol dehydrogenase inhibitors

This invention relates to therapeutic methods for treatment or prevention of tissue damage resulting from ischemia in mammals.

Therapies for tissue damage resulting from ischemia

This invention is directed to sorbitol dehydrogenase inhibitory compounds of the formula I,wherein R, Rand Rare as defined in the specification. This invention is also directed to pharmaceutical compositions containing those compounds and methods of treating or preventing diabetic complications, particularly diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, diabetic macroangiopathy and diabetic cardiomyopathy by administering such compounds to a mammal suffering from diabetes and therefore at risk for developing such complications. This invention is also directed to pharmaceutical compositions comprising a combination of compound of formula I of this invention with an aldose reductase inhibitor and to methods of treating or preventing diabetic complications therewith. This invention is also directed to pharmaceutical compositions comprising a combination of a compound of formula I of this invention with an NHE-1 inhibitor and to methods of treating cardiomyopathy and other heart-related problems therewith. This invention is also directed to certain intermediates used in the synthesis of the compounds of formula I and to processes for preparing those intermediates.

Sorbitol dehydrogenase inhibitors

Sulfonyl pyridazinone compounds useful as aldose reductase inhibitors

This invention relates to pharmaceutical compositions comprising combinations of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug, kits containing such combinations and methods of using such combinations to treat mammals, including humans, suffering from diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers.

Combination of gaba agonists and aldose reductase Inhibitors

The present invention relates to novel pyridazinone compounds, pharmaceutical compositions comprising those compounds and to methods of using such compounds and compositions to inhibit aldose reductase, lower sorbitol levels and, thus, lower fructose levels, and/or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to methods of affording cardioprotection to subjects not suffering from diabetes. This invention also relates to pharmaceutical compositions and kits comprising a combination of an aldose reductase inhibitor (ARI) of this invention and a sorbitol dehydrogenase inhibitor and to methods of using such compositions or kits to treat or prevent the above diabetic complications in mammals. This invention also relates to other combinations with the ARIs of this invention, including combinations with adendsine agonists; NHE-1 inhibitors; glycogen phosphorylase inhibitors; selective serotonin reuptake inhibitors; GABA agonists; antihypertensive agents; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors; phosphodiesterase-5 inhibitors; and to glucose lowering agents.

This invention relates to &lsqb;4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl&rsqb;-acetic acid ethanolamine salt, pharmaceutical compositions thereof and methods of treating diabetic complications in mammals comprising administering to said mammals said salt and said compositions. This invention is also directed to combinations of said diethylamine salt with NHE-1 inhibitors, selective serotonin retuptake inhibitors (SSRIs), glycogen phosphorylase inhibitors (GPIs), sorbitol dehydrogenase inhibitors (SDIs) and antihypertensive agents. Said combinations are useful in treating diabetic complications in mammals.

Salts of zopolrestat

This invention is directed to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a selective COX-2 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug. This invention further relates to methods of using those pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy.

Combinations of aldose reductase inhibitors and selective cyclooxygenase-2 inhibitors

This invention relates to pharmaceutical compositions comprising combinations of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, kits containing such combinations and methods of using such combinations to treat mammals, including humans, suffering from diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers.

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Waterford, CT, United States of America

Banavara L Mylari