| 摘要 |
Piperidinyl- or piperazinyl-substituted linear or cyclic urea derivatives (or analogs) (I) are new. Piperidine or piperazine derivatives of formula (I) and their isomers, hydrates, solvates and acid addition salts are new. [Image] V, M : direct bond or linear or branched 1-6C alkylene; A, E : N or CH, provided that at least one is N; W : diaza-cyclic group of formula (a) or bicyclic group of formula (b), or may also be a bicyclic group of formula (c) if V = direct bond and A = N; [Image] * : attachment point; X : CO, SO or SO 2; G 12-4C n-alkylene (optionally containing a double bond and/or substituted by OH); G 2direct bond; and G 32-3C n-alkylene (optionally containing a double bond); or G 2CH 2; and G 31-2C n-alkylene (optionally containing a double bond); T : fused benzene or pyridine ring; R 1H, alkyl, Ar or Ar-alkyl; R 2 a, R 2 bH, halo, alkyl, OH, alkoxy, SH, alkylthio, trihaloalkyl, CN, NO 2, NH 2, mono- or dialkylamino, trihaloalkoxy, Ar-alkoxy, alkylsulfonate, trihaloalkylsulfonate or alkylsulfonyl; or R 2 a + R 2 bOCH 2O, O(CH 2) 2O, O(CH 2) 3O or CH 2CH 2 (optionally substituted by CN, CH 2OH, alkoxycarbonyl, ArOCO, or Ar-alkoxycarbonyl); R 3Ar or Het 1 (both optionally substituted by one or more R 2 a); Y : OAr, OHet 1 or Het 2 (all optionally substituted by one or more R 2 a); Ar : phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or benzocyclobutyl; Het 15-12 membered mono- or bicyclic aromatic system containing 1 or 2 of O, S and N as heteroatom(s), where in the case of bicyclic systems one of the rings may be partially hydrogenated; and Het 25-12 membered mono- or bicyclic aromatic system containing 1-3 of O, S and N as heteroatom(s). alkyl moieties have 1-6C unless specified otherwise; provided that: (i) if V = direct bond, W = (a) and R 3 = Ph, then Y cannot be 3-indolyl; (ii) if M = direct bond, W = (a) and Y = bicyclic Het 2 in which one ring is a benzene ring, then Y cannot be bonded to M via this benzene ring; and (iii) if M = direct bond, V = CH 2CH 2, W = (a) and R 3 = Ph, then Y cannot be 1,2-benzisoxazol-3-yl. An independent claim is included for the preparation of (I). ACTIVITY : Vasotropic; antiarteriosclerotic; cardiant; hypotensive. MECHANISM OF ACTION : Endothelial nitrogen monoxide (NO) synthase inhibitor antagonist; superoxide antagonist; antioxidant. (I) reduce endothelial dysfunction and reduction in vascular NO availability induced by inhibition of endothelial NO synthase or by oxidative stress associated with production of superoxide anion. In tests in rat aortic rings, N-(2-(4-(phenoxymethyl)-1-piperidinyl)-ethyl)-1-indoline-carboxamide (Ia) at a concentration of 30 nM gave 26 % inhibition of endothelial dysfunction induced by the NO synthase inhibitor N(G)-nitro-L-arginine. |
