Patent IL-103252-A (IL)
Title: CYCLIC COMPOUNDS USEFUL AS INHIBITORS OF PLATELET GLYCOPROTEIN IIb/IIIa AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
IPC: C07K7/56
Filed: 1992-09-23
Abstract: Compounds having anti- thromboembolic activity of the formula JKLMNR2 O=C (R22 (R23) C)n" R31 (C (R21)R1)n( (I) or pharmaceutically acceptable salt or prodrug forms thereof wherein: R31 is a C6-C14 saturated, partially saturated, or aromatic carbocyclic ring system substituted with 0-2 R10; or n" and n( are independently 0-3; R1 and R22 are independently selected from the following groups: hydrogen, C1-C8 alkyl substituted with 0-2 R11, C1-C8 alkenyl substituted with 0-2 R11, C1-C8 alkynyl substituted with 0-2 R11, C1-C8 cycloalkyl substituted with 0-2 R11, C6-C10 bicycloalkyl substituted with 0-2 R11, aryl substituted with 0-2 R12, a heterocylic ring system substituted with 0-2 R12, composed of 5-10 atoms including 1-3 N, S, or O heteroatoms, =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C (=O) NR13R14, -CHO, -CH2OR13, -OC(=O)R13, -OC(=O)OR13, - OR13, -OC(=O)NR13R14, -NR14C (=O) R13, -NR14C(=O) OR13, -NR13C (=O) NR13R14, -NR14 SO2 NR13R14, -NR14 SO2R13, -SO3H, -SO2R13, -SR13, -S(=O)R13, -SO2NR13 R14, -NR13 R14, -NHC(=NH) NHR13, -C(=NH) NHR13, =NOR14, NO2, -C(=O) NHOR13, -C(=O) NHNR13 R14, oxime, boronic acid, -OCH2CO2H, 2-(1-morpholino) ethoxy; R1 and R21 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R12; R22 and R23 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R12; R1 and R2, where R21 is H, can alternatively join to form a 5-8 membered carbocyclic ring substituted with 0-2 R12; R11 is selected from one or more of the following: =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C (=O) NR13R14, -CHO, -CH2OR13, -OC(=O)R13, -OC(=O) OR13, -OR13, -OC(=O)NR13R14, -NR14C (=O) R13, -NR14C(=O) OR13, -NR13C (=O) NR13R14, -NR14SO2 NR13R14, -NR14 SO2R13, -SO3H, -SO2R13, -SR13, -S(=O)R13, -SO2NR13R14, -NR13R14, -NHC(=NH) NHR13, -C(=NH) NHR13, =NOR14, NO2, -C(=O) NHOR13, -C(=O) NHNR13R14, oxime, boronic acid, -OCH2CO2H, 2-(1-morpholino) ethoxy; C1-C5 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6 alkoxyalkyl, C3-C6 cycloalkoxy, C1-C4 alkyl (substituted with -NR13R14, -CF3, NO2, -SO2R13a,  or -S(=O) R13a), aryl substituted with 0-2 R12, a heterocylic ring system substituted with 0-2 R12, composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms; R10 and R12 are selected from one or more of the following: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R13, -C (=O) NHOR13, -C (=O) NHNR13R14, oxime, boronic acid, C3-C6 cycloalkoxy, -OC (=O)R13, -C(=O)R13, -OC (=O)OR13, -OR13, -CH2OR13, -NR13R14, -OC(=O)NR13R14, -NR14C(=O)R13, -NR14C(=O)OR13, -NR13C (=O) NR13R14, -NR14SO2NR13R14, -NR14SO2R13a, -SO3H, -SO2R13a, -S(=O) R13a, -SR13, -SO2NR13R14, C2-C6 alkoxyalkyl, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, alkylcarbonyl, C1-C4 alkylcarbonylamino, -OCH2CO2H, 2-(1-morpholino) ethoxy, C1-C4 alkyl (substituted with -NR13R14, -CF3, NO2, or -S(=O)R13a); R13 is H, C1-C7 alkyl, aryl, -(C1-C6 alkyl) aryl, or C3-C6 alkoxyalkyl; R13 is C1-C7 alkyl, aryl, -(C1-C6 alkyl) aryl, or C3-C6 alkoxyalkyl; R14 is OH, H, C1-C4 alkyl, or benzyl; R21 and R23 are independently selected from: hydrogen; C1-C4 alkyl, optionally substituted with halogen; C1-C2 alkoxy; benzyl; R2 is H or C1-C8 alkyl; J is b-Ala or an L-isomer or D-isomer amino acid of structure -N(R3)C(R4)(R5)C(=O)-, wherein: R3 is H or C1-C8 alkyl; R4 is H or C1-C3 alkyl; R5 hydrogen, C1-C8 alkyl substituted with 0-2 R11, C2-C8 alkenyl substituted with 0-2 R11, C2-C8 alkynyl substituted with 0-2 R11, C3-C8 cycloalkyl substituted with 0-2R11, C6-C10 bicycloalkyl substituted with 0-2 R11, aryl substituted with 0-2 R12, a heterocylic ring system substituted with 0-2 R12, composed of 5-10 atoms including 1-3 N, S, or O heteroatoms, =O, F, Cl, Br, I, -CF3, -CN, -CO2R13, -C(=O)R13, -C (=O) NR13R14, -, -CH2OR13, -OC(=O)R13, -OC(=O)OR13, -OR13, -OC(=O)NR13R14, -NR14C (=O) R13, -NR14C(=O) OR13, -NR13C (=O) NR13R14, -NR14SO2 NR13R14, -NR14 SO2R13a, -SO3H, -SO2R13a, -S(=O)R13a, -SO2NR13R14, -NR13R14, -NHC(=NH) NHR13, -C(=NH) NHR13, =NOR14, NONO2, -C(=O) NHOR13, -C(=O) NHNR13R14, oxime, boronic acid, -OCH2CO2H, 2-(1-morpholino) ethoxy; -SC(=NH) NHR13, N3, -Si(CH3)3, (C1-C5 alkyl) NHR16; -(C0-C6 alkyl) X; (CH2) q (CH2) q -X ,where q is independently 0, 1; CH2 CH2X ; -(CH2)mS (CH2)2X, where m = 1, 2; and wherein X is defined below; R3 with R4 and R6 with R7 may also be taken together to form (CH2)nX -CH2CHCH2-, where NHCNR13 N(R13) R13; n = 0, 1 and X is R3 and R5 can also be taken together to form -(CH2)t- (t = 2-4) or -CH2SC(CH3)2-; or R4 and R5 can also be taken together to form -(CH2)u-, where u = 2-5; R16 is selected from: an amine protecting group; 1-2 amino acids; 1-2 amino acids substituted with an amine protecting group; K is a D-isomer or L-isomer amino acid of structure -N(R6) CH(R7) C (=O) -, wherein: R6 is H or C1-C8 alkyl; R7 is selected from: -(C1-C7 alkyl) X; (CH2)q (CH2)q X, where q is independently 0, 1; CH2CH2X ; -(C1-C6 alkyl) NH0-3 -(CH2)mO- (C1-C4 alkyl) -X, where m - 1, 2; -(CH2)mS- (C1-C4 alkyl) -X, where m - 1, 2; and X is selected from: NR13 NHC N (R13)R13, -N(R13)R13, -C(=NH) (NH2), -SC(NH) - NH2; L is -Y (CH2)vC (=O)-, wherein: Y is NH, N(C1-C3 alkyl), O, or S; and v = 1, 2; M is a D-isomer or L-isomer amino acid of structure -NR17-CH(R8)C(=O)-, wherein: R17 is H, C1-C3 alkyl; R8 is -CH2CO2R13, -CH2SO3R13a, -CH(CH3) CO2R13 -SO2NR13R14, -CH2-boronic acid, -CH2-tetrazole, -NHSO2CF3, -CONHNHSO2CF3, -PO(OR13)2, -PO(OR13)R13, -CONHOR13, -SO2NH- heteroaryl, CH2SO2NH-heteroaryl, -SO2NHCOR13, -CH2SO2NHCOR13, -CONHSO2R13a, -CH2CONHSO2R13a, -NHSO2NHCOR13a, -NHCONHSO2R13, -SO2NHCONR13.