Pyridazinone aldose reductase inhibitors

C - Chemistry – Metallurgy – 07 – D

Patent

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Details

C07D 405/12 (2006.01) C07D 401/12 (2006.01) C07D 403/12 (2006.01) C07D 409/12 (2006.01) C07D 471/04 (2006.01) C07D 491/04 (2006.01) C07D 495/04 (2006.01)

Patent

CA 2442476

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.

L'invention concerne de nouveaux composés pyridazinone, des compositions pharmaceutiques contenant ces composés, des procédés d'utilisation de ces composés, ainsi que des compositions destinées à inhiber l'aldose réductase, a réduire les taux de sorbitol et donc à réduire les taux de fructose, et/ou à traiter ou prévenir des complications diabétiques telles que la neuropathie diabétique, la rétinopathie diabétique, la néphropathie diabétique, la cardiomyopathie diabétique, la microangiopathie diabétique et la macroangiopathie diabétique chez les mammifères. L'invention concerne également des procédés destinés à délivrer une protection cardiaque à des sujets ne souffrant pas de diabète, des compositions et des ensembles pharmaceutiques contenant une combinaison d'un inhibiteur d'aldose réductase (ARI) selon l'invention et d'un inhibiteur de sorbitol déshydrogénase, et des procédés d'utilisation de telles compositions et ensembles pour le traitement ou la prévention desdites complications diabétiques chez les mammifères. L'invention concerne par ailleurs d'autres combinaisons de ARI avec des agonistes d'adénosine, des inhibiteurs de NHE-1, des inhibiteurs de glycogène phosphorylase, des inhibiteurs sélectifs de recaptage de sérotonine, des agonistes de GABA, des agents antihypertension, des inhibiteurs des 3-hydroxy-3-méthylglutaryle coenzyme A réductase, des inhibiteurs de phosphodiestérase-5, ainsi que des agents de réduction de glucose.

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