Patent RU-2273642-C2 (RU)
Inventor: TSZJAN TAO
IPC: C07F9/6558
Filed: 2000-12-22
Granted: 2006-04-10
Abstract: FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy. 
     SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA):   wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO 3 H 2  that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R 5 -X- wherein R 5  is chosen from a group consisting of compounds of the formula   or   wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR 4   2 , -CONR 4   2 , -CO 2 R 3 , halide, -S(O)R 3 , -SO 2 R 3 , alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH 2 OH, -CH 2 NR 4   2 , -CH 2 CN, -CN, -C(S)NH 2 , -OR 2 , -SR 2 , -N 3 , -NHC(S)NR 4   2 , -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R 11 , -C(O)SR 11 , -SO 2 R 11 , -S(O)R 3 , -CN, -NR 9   2 , -OR 3 , -SR 3 , perhaloidalkyl, halide, -NO 2 , or absent and all groups except for -H, -CN, perhaloidalkyl, -NO 2  and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR 3 , -CONR 4   2 , -CN, -NR 9   2 , -NO 2 , -OR 3 , -SR 3 , perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R 5  with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R 5  and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR 2 , -SO 3 H or -PO 3 R 2   2 ; n means a whole number from 1 to 3; R 2  is taken among the group -R 3  and -H; R 3  is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R 4  is chosen independently from the group consisting of -H and alkyl, or R 4  and R 4  form cycloalkyl group; each R 9  is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R 9  and R 9  form in common cycloalkyl group; R 11  is chosen from the group consisting of alkyl, aryl, -NR 2   2  and -OR 2 ; each R 12  and R 13  is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R 12  and R 13  in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R 14  is chosen independently from the group consisting of -OR 17 , -N(R 17 ) 2 , -NHR 17 , -NR 2 OR 19  and -SR 17 ; R 15  is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R 16  is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R 16  is chosen from the group consisting of -(CR 12 R 13 ) n -C(O)-R 14 , -H, lower alkyl, lower aryl, lower aralkyl, or in common with R 15  is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R 17  is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R 17  and R 17  at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R 18  is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R 12  is bound through 1-4 carbon atoms forming cyclic group; each R 19  is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR 3 ; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA). 
     EFFECT: valuable medicinal and biochemical properties of compounds. 
     69 cl, 7 tbl, 64 ex