PREPARATION PROCESS OF N2-ARYLSULFONYL-L-ARGINIAMIDES AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

摘要

New N2-arylsulphonyl-L-argininamide derivs are cpds. of the formula HN=C(NH2)-NH-CH2CH2CH(COR)-NH-SO2-Ar (I) and their salts with acids or bases. In (I), R is NR1-(CH2)n-COOR2, -NR3-CHR4-(CH2)m-COOR5, or (Ia), (Ib), (Ic) or (Id). R1 and R3 are 2-10C alkyl, 3-10C alkenyl, or alkynyl, 2-10C alkoxy- alkyl, 2-10C alkylthio-alkyl, 2-10C alkylsulphinylalkyl, 1-10C hydroxyalkyl, 2-10C carboxyalkyl, 3-10C alkoxy-carbonylalkyl, 3-10C alkylcarbonyl, 1-10C haloalkyl, 7-15C aralkyl, 8-15, alpha-carboxyaralkyl, 3-10C cycloalkyl, 4-10C cycloalkyl, 4-10C cycloalkylalkyl, furfuryl, opt. substd. tetrahydrofurfuryl 3-furylmethyl, opt. substd. tetrahydro-3-furylmethyl tetrahydro-2(3- or 4-)-pyranylmethyl opt. substd. 1, 4-dioxa-2-cyclohexylmethyl or opt. 2- or 3-thenyl or tetrahydro-2- or 3-thenyl. R2 is H, 1-10C alkyl, 6-10C aryl, 7-12C aralkyl or 5-indanyl. n is 1,2 or 3. R4 is 1-10C alkyl, COOH, 2-10C alkoxycarbonyl, opt. substd. phenyl 7-12C aralkyl, or benzyl nuclear-substd. by 1-5C alkyl or alkoxy. R5 is H, 1-10C alkyl, 6-10C aryl, 7-12C aralkyl or 5-indanyl. m is 0, 1 or 2. R6 is -COOR8 in the 2- or 3- position, R8 being H, 1-10C alkyl, 6-10C aryl, 7-12C aralkyl or 5-indanyl R7, which is in the 2-, 3- 5- and/or 6-position is H, 1-10C alkyl, phenyl, 1-5C alkoxy or COOH. p is 1-3. The (Ib) is opt. substd. by 1 1-5C alkyl and/or alkoxy residue; R9 is H, 1-10C alkyl, 6-10C aryl, 7-12C aralkyl or 5-indanyl and r is 1,2,3 or 4. R10 is H, 1-10C alkyl, 6-10C aryl, 7-12C aralkyl or 5-indanyl, Z is O, S or SO. q is 0 or 1. R11 is H, 1-10C alkyl, 6-10C aryl, 7-12C aralkyl or 5-indanyl. i is 0,1 or 2 and j is 0,1 or 2 i + j being 1 or 2. Ar is opt. substd. naphthyl; opt. substd. 5,6,7,8-tetrahydronaphthyl 1-5C opt. substd. 7-12C aralkyl; or an oxygen contg. fused ring heterocyclic cpd. (I) are highly specific thrombin inhibitors. They are suitable for the prophylaxis and therapy of thromboses. Their toxicity is low. (I) are also useful as inhibitors of thrombocyte aggregation. Specific cpds. (I) include N2-(6, 7-dimethoxy-2-naphthylsulphonyl) L-arginyl-N-butyl-glycine. In an example, this spd. is prepd. in 4 stages from L-arginine.