pyridinium series compound, process for preparing it, use thereof, pharmaceutical composition for treating diabetic complications and aging-related diseases, and method for preparing a parenteral formulation.

摘要

Pyridinium derivatives (I) and their salts are new. Pyridinium derivatives of formula (I) and their salts are new: [Image] R 1R 4R 5 or N(R 7)N(R 7)R 9; R 4N(R 7)R 6O, N(R 7)R 6N(R 7), OR 6O, or OR 6N(R 7); R 6alkyl; R 5alkyl, aryl, heteroaryl, COR 7, SO 2R 7, C(S)NHR 7, C(NH)NHR 7, C(O)R 1 0, C(O)NHR 7, or N(R 7)N=C(R 7)R 1 0; R 7,R 1 0H, alkyl, aryl or heteroaryl (provided that the N of the heteroaryl, when present, of R 1 0 is optionally quarternized with compounds such as X-CH 2C(O)R 3; R 2F, Cl, Br, I, OR 7, NO 2, alkyl, aryl, heteroaryl, formyl, acyl, C(O)NR 7R 1 0, CO 2R 7, NR 7R 1 0, N=C(R 7)R 1 0, SR 7, SO 2NH 2, SO 2-alkyl or SO 2-aryl; m : 0-2; R 3R 7, OR 7, NR 7R 1 0, N=C(R 7)R 1 0, N(R 7)NR 7R 1 0, N(R 7)N=C(R 7)R 1 0 or CH(R 7)C(O)R 8; R 8R 7, OR 7 or NR 7R 1 0; R 9H, alkyl, aryl, heteroaryl, C(O)R 1 0, SO 2R 1 0, C(S)NHR 1 0, C(NH)NHR 1 0, or C(O)NHR 1 0; and X : halide, acetate, perchlorate, sulfate, oxalate, citrate, tosylate, maleate, mesylate, carbonate, sulfite, phosphoric hydrogen, phosphonate, phosphate, BF 4 - or PF 6 - (provided that when 2 alkyl groups are present on the same C or N, they may link together to form a cycloalkyl group). Independent claims are also included for: (a) a process for the preparation of (I) comprising preparing the properly substituted pyridine derivative followed by quarternization; (b) the use of (I) in the manufacture of a medicament for diabetic complications and aging-related diseases including kidney disease, nerve damage, retinopathy, artherosclerosis, microangiopathy, endothelial dysfunctions, dermatological conditions, discoloration of teeth and other organ dysfunctions; (c) a method for treating a diabetic patient by breaking preformed advanced glycation end products (AGE) comprising administration of (I) either singly or in combination with another drug. ACTIVITY : Antidiabetic; nephrotropic; neuroprotective; ophthalmological; antiarteriosclerotic; dermatological; dental. Tests were performed to study the efficacy of (I) in the inhibition of advanced glycation end products (AGE) breaker activity. Bovine serum albumin (160 mg/ml) and glucose sugar (1.6 M) were dissolved in phosphate buffered saline. Sodium azide was added at 0.2 % concentration. The solution was filtered and kept for aging at 37 [deg] C for 16 weeks. After 16 weeks the solution was dialyzed against PBS, aliquoted and stored at -20 [deg] C. The AGE breaking activity of N,N'-bis[3-carbonyl-1-(2-phenyl-2-oxoethyl)pyridinium]hydrazine dibromide (Ia) at 5 mM was tested, and found to be 13 %. MECHANISM OF ACTION : None given.