PROCEDURE FOR THE RESOLUTION OF 2,4-DIAMINO-3,6-DIHYDRID-1,3,5-TRIAZINS, USEFUL FOR THE TREATMENT OF DISORDERS ASSOCIATED WITH THE INSULIN RESISTANCE SYNDROME.

摘要

Procedure for the resolution of a racemic compound of the following formula (I): in which: R1, R2, R3 and R4 are independently selected from the following groups: - H; - alkyl (with 1 to 20 carbon atoms), optionally substituted by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms) or by cycloalkyl (with 3 to 8 atoms of carbon); - alkylene with (2 to 20 carbon atoms), optionally substituted by halogen, by alkyl (with 1 to 5 carbon atoms) or by alkoxy (with 1 to 5 carbon atoms); - alkyne (with 2 to 20 carbon atoms), optionally substituted by halogen, by alkyl (with 1 to 5 carbon atoms) or by alkoxy (with 1 to 5 carbon atoms); - cycloalkyl (with 3 to 8 carbon atoms), optionally substituted by alkyl (with 1 to 5 carbon atoms) or by alkoxy (with 1 to 5 carbon atoms); - heterocycloalkyl (with 3 to 8 carbon atoms), which carries one or more heteroatoms chosen from N, O and S and optionally substituted by alkyl (with 1 to 5 carbon atoms) or by alkoxy (with 1 to 5 carbon atoms ); - aryl (with 6 to 14 carbon atoms) alkyl (with 1 to 20 carbon atoms), optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), for alkylthio (with 1 to 5 carbon atoms), for alkylamino (with 1 to 5 carbon atoms), for aryl (with 6 to 14 carbon atoms) oxy, for aryl ( with 6 to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), per cyano, trifluoromethyl, carboxy, carboxymethyl or carboxy ethyl; - aryl (with 6 to 14 carbon atoms), optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), by alkylamino (with 1 to 5 carbon atoms), by aryl (with 6 to 14 carbon atoms) oxy, by aryl (with 6 to 14 carbon atoms) alkoxy ( with 1 to 5 carbon atoms), per cyano, trifluoromethyl, carboxy, carboxymethyl or carboxy ethyl; o - heteroaryl (with 1 to 13 carbon atoms) bearing one or more heteroatoms chosen from N, O and S and optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms ), by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), by alkylamino (with 1 to 5 carbon atoms), by aryl (with 6 to 14 carbon atoms) oxy , by aryl (with 6 to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), by cyano, by trifluoromethyl, by carboxy, by carboxymethyl or by carboxy-ethyl; R1 and R2, on the one hand, and R3 and R4, on the other hand, optionally form with the nitrogen atom a ring with n members (n between 3 and 8) comprising, if appropriate, one or more heteroatoms chosen from N, O and S and which is substituted, if appropriate, by one of the following groups: amino, hydroxyl, thio, halogen, alkyl (with 1 to 5 carbon atoms), alkoxy (with 1 to 5 carbon atoms) , alkylthio (with 1 to 5 carbon atoms), alkylamino (with 1 to 5 carbon atoms), aryl (with 6 to 14 carbon atoms) oxy, aryl (with 6 to 14 carbon atoms) alkoxy (with 1 to 5 5 carbon atoms), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxy ethyl; R6 is selected from the following groups: - alkyl (with 1 to 20 carbon atoms), optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), for alkylthio (with 1 to 5 carbon atoms), for alkylamino (with 1 to 5 carbon atoms), for aryl (with 6 to 14 carbon atoms) oxy, for aryl (with 6 up to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), per cyano, trifluoromethyl, carboxy, carboxymethyl or carboxy ethyl; - alkylene with (2 to 20 carbon atoms), optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), by alkylamino (with 1 to 5 carbon atoms), by aryl (with 6 to 14 carbon atoms) oxy, by aryl (with 6 to 14 carbon atoms) alkoxy ( with 1 to 5 carbon atoms), per cyano, trifluoromethyl, carboxy, carboxymethyl or carboxy ethyl; - alkyne (with 2 to 20 carbon atoms), optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), by alkylamino (with 1 to 5 carbon atoms), by aryl (with 6 to 14 carbon atoms) oxy, by aryl (with 6 to 14 carbon atoms) alkoxy ( with 1 to 5 carbon atoms), per cyano, trifluoromethyl, carboxy, carboxymethyl or carboxy ethyl; - cycloalkyl (with 3 to 8 carbon atoms) optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), for alkylamino (with 1 to 5 carbon atoms), for aryl (with 6 to 14 carbon atoms) oxy, for aryl (with 6 to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), per cyano, for trifluoromethyl, for carboxy, for carboxymethyl or for carboxy ethyl; - heterocycloalkyl (with 3 to 8 carbon atoms) bearing one or more heteroatoms chosen from N, O and S and optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms) , by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), by alkylamino (with 1 to 5 carbon atoms), by aryl (with 6 to 14 carbon atoms) oxy, by aryl (with 6 to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), by cyano, by trifluoromethyl, by carboxy, by carboxymethyl or by carboxy-ethyl; - aryl (with 6 to 14 carbon atoms) optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), for alkylamino (with 1 to 5 carbon atoms), for aryl (with 6 to 14 carbon atoms) oxy, for aryl (with 6 to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), per cyano, for trifluoromethyl, for carboxy, for carboxymethyl or for carboxy ethyl; - heteroaryl (with 1 to 13 carbon atoms) bearing one or more heteroatoms chosen from N, O and S and optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms) , by alkoxy (with 1 to 5 carbon atoms), by alkylthio (with 1 to 5 carbon atoms), by alkylamino (with 1 to 5 carbon atoms), by aryl (with 6 to 14 carbon atoms) oxy, by aryl (with 6 to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), by cyano, by trifluoromethyl, by carboxy, by carboxymethyl or by carboxy-ethyl; o-aryl (with 6 to 14 carbon atoms) alkyl (with 1 to 5 carbon atoms) optionally substituted by amino, by hydroxyl, by thio, by halogen, by alkyl (with 1 to 5 carbon atoms), by alkoxy (with 1 to 5 carbon atoms), for alkylthio (with 1 to 5 carbon atoms), for alkylamino (with 1 to 5 carbon atoms), for aryl (with 6 to 14 carbon atoms) oxy, for aryl ( with 6 to 14 carbon atoms) alkoxy (with 1 to 5 carbon atoms), per cyano, trifluoromethyl, carboxy, carboxymethyl or carboxy ethyl; comprising the steps consisting of: a) the reaction of the racemic compound of the formula (I) with a chiral acid, the chiral acid being chosen from the group consisting of (-) - di-O, O '' - p -tolyl-L-tartaric, R (-) - 1,1 '' - binaphthalene-2,2 '' - diyl hydrogen phosphate, S (+) - 1,1 '' - 2,2-binaphthalene-hydrogen phosphate '' -diyl, to form the corresponding diastereomeric sa and b) purification of the diastereomeric salt obtained in this way; c) the release of said diastereomeric salt as one of the two enantiomers of the formula (I) in the form of a pharmaceutically acceptable salt.