Inhibition of matrix metalloproteases by acetylene...

C - Chemistry – Metallurgy – 07 – C

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C07C 59/90 (2006.01) A61K 31/19 (2006.01) C07C 59/84 (2006.01) C07C 69/145 (2006.01) C07C 69/96 (2006.01) C07C 229/34 (2006.01) C07D 209/48 (2006.01)

Patent

CA 2253796

Matrix metalloprotease inhibiting compounds, pharmaceutical compositions thereof and a method of disease treatment using such compounds are presented. The compounds of the invention have the generalized formula: (see formula I) where R15 is selected from the group comprising: HOCH2, (n-Pr)2NCH2, CH3CO2CH2, EtOCO2CH2, HO(CH2)2, CH3CO2(CH2)2, HO2C(CH2)2, OHC(CH2)3, HO(CH2)4, 3-HO-Ph, and PhCH2OCH2; and R16 is (see formula II or III) These compounds are useful for inhibiting matrix metalloproteases and, therefore, combating conditions to which MMP's contribute, such asosteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, corneal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis, bullosa conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempera mandibular joint disease, demyelating diseases of the nervous system, tumor metastasis or degenerative cartilage loss following traumatic joint injury, and coronary thrombosis from athrosclerotic plaque rupture. The present invention also provides pharmaceutical compositions and methods for treating such conditions.

L'invention concerne des composés inhibiteurs de métalloprotéases matricielles, leurs compositions pharmaceutiques et une méthode de traitement de maladies utilisant ces composés. Les composés de l'invention ont la formule générale (I) dans laquelle R<15> est choisi dans le groupe comprenant: HOCH2, MeOCH2, (n-Pr)2NCH2, CH3CO2CH2, EtOCO2CH2, HO(CH2)2, CH3CO2(CH2)2, HO2C(CH2)2, OHC(CH2)3, HO(CH2)4, Ph, 3-HO-Ph, et PhCH2OCH2; et R<16> représente (a) ou (b). Ces composés sont utiles pour inhiber des métalloprotéases matricielles et par conséquent combattre des états auxquels les métalloendo-protéinases matricielles MMP contribuent, tels que, l'arthrose, la polyartrite rhumatoïde, l'arthrite septique, les maladies périodontiques, l'ulcération de la cornée, la protéinurie, les maladies aortiques anévrismales, l'épidermolyse distrophobique, les lésions buleuses, des états conduisant à des réactions inflammatoires, les ostéopénies induites par l'activité de MMP, des maladies des articulations temporomendibulaires, les maladies démiliénisantes du système nerveux, la métastase de tumeurs ou la perte de cartilage dégénérative suivant des lésions articulaires traumatiques, et la thrombose coronaire due à une rupture des plaques athéroscléreuses. La présente invention concerne également des compositions pharmaceutiques et des méthodes de traitement de ces états.

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