Patent NZ-504218-A (NZ)
Title: Thrombin receptor antagonists
Inventor: CHACKALAMANNIL SAMUEL
IPC: A61K31/506
Filed: 1998-11-23
Abstract: A compound of formula (I) wherein: the single dotted line represents an optional double bond; the double dotted line represents an optional single bond; n is 0-2; Q is a group of formula (II) wherein n1 and n2 are independently 0-2; or when the double bond is not present, Q is also fused R-substituted aryl or R-substituted heteroaryl; R is 1 to 3 substituents independently selected from the group consisting of H, alkyl, halogen, hydroxy, amino, alkylamino, dialkylamino, alkoxy,-COR16,-COOR17,-SOR16, -SO2R16,-NR16COR16a, -NR16COOR16a,-NR16CONR4R5, fluoralkyl, difluoro alkyl, trifluoroalkyl, cycloalkyl, alkenyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl and thioalkyl; R1 and R2 are independently selected from the group consisting of H, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl and thioalkyl; or R1 and R2 together form a =O group; R3 is H, hydroxy, alkoxy, -SOR16, -SO2R17, -C(O)OR17, -C(O)NR13R19, alkyl, halogen, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, alkenyl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, aminoalkyl, aryl or thioalkyl; Het is a mono-, bi-or tricyclic heteroaromatic group of 5 to 14 atoms comprise of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein a ring nitrogen can form an N-oxide or a quaternary group with an alkyl group; wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by 1 to 4 substituents W; Each W is independently selected from the group consisting of H, alkyl, fluoroalkyl, difluoroalkyl, trifluoroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted by alkyl or alkenyl, alkenyl, R21-arylalkyl, R21-aryalkenyl, heteroarylalkyl, heteroarylalkenyl, hydroxyalkyl, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, thioalkyl, alkoxy, alkenyloxy, halogen, -NR4R5,-CN,-OH,-COOR17, -COR16 ,-OSO2CF3,-CH2OCH2CF3, alkylthio,-C (O) NR4R5, -OCHR6-phenyl, -NHSO2R16,-NHCOR16, biphenyl, -OC(R6)2COOR7,-OC(R6)2C(O)NR4R5, alkoxy, alkoxy substituted by alkyl, amino,-OH, COOR17, -NHCOOR17, -CONR4R5, aryl, aryl substituted by 1 to 3 substituents independently selected from the group consisting of halogen,-CF3, alkyl, alkoxy and-CoOR17, aryl wherein adjacent carbons form a ring with a methylenedioxy group,-C(O)NR4R5 and heteroaryl; R21 is aryl, aryl wherein adjacent carbons form a ring with a methylenedioxy group, heteroaryl, heteroaryl substituted by 1 to 4 substituents selected from the group consisting of halogen, alkoxy alkyl, alkylamino, dialkylamino,-OCF3,-NO2, hydroxyalkyl,-CHO and phenyl, and heteroaryl wherein adjacent carbon atoms form a ring with an alkylene group or a methylenedioxy group; R4 and R5 are independently selected from the group consisting of H, alkyl, phenyl, benzyl and cycloalkyl, or R4 and R5 together are -(CH2)4-, -(CH2)5- and- (CH2)2NR7(CH2)2- and form a ring with the nitrogen to which they are attached; R6 is independently selected from the group consisting of H, alkyl and phenyl; R7 is H or alkyl; R8, R10 and R11 are independently selected from the group consisting of R1 and -OR1, provided that when the optional double bond is present, R10 is absent, and when ring Q is aromatic, R10 and R11 are absent; R9 is H, OH, alkoxy, halogen or haloalkyl; B is -(CH2)n3-, -CH2-O-, -CH2S-, -CH2-NR6-, -C(O)NR6-,  -NR6C(O)-, -CH-(CH2)-CH-,  cis or trans -(CH2)n4CR12=CR12a(CH2)- or (CH2)n4C=C(CH2)-  wherein n3 is 0-5 , n4 and n5 are independently 0-2 and R12 and R12a are independently selected from the group consisting of H, alkyl and halogen; X is -O- or -NR6- when the double dotted line represents a single bond, or X is-OH or -NHR20 when the bond is absent; Y is =O, =S, (H, H), (H, OH) or (H, alkoxy) when the double dotted line represents a single bond, or when the bond is absent, Y is =O, (H, H), (H, OH), (H, SH) or (H, alkoxy); R15 is absent when the double dotted line represents a single bond and is H, alkyl, -NR13R19, or-OR17 when the bond is absent, or Y is -OCH2-CH2O- or -SCH2-CH2S- and R15 is H or alkyl; R16 and R16a are independently selected from the group consisting of lower alkyl, phenyl or benzyl; R17, R18 and R19 are independently selected from the group consisting of H, alkyl, phenyl, benzyl; R20 is H, alkyl, phenyl, benzyl, -C(O)R6 or -SO2R6; R21 is 1 to 3 substituents independently selected from the group consisting -OCF3, -CF3, alkyl, alkoxy, -NO2, alkylamino, di-alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,  -COR17, -NHCOR16, -NHSO2R16, -COOR-17, -NHSO2CH2CF3; Z is -O-, -S(O)0-2-, -NR22-, -C(O)-, -C(=NOR17)- or -CH2-, -C(R13R14)-, wherein R13 and R14, together with the carbon to which they are attached, form a spirocycloalkyl group of 3 to 6 carbons, or a spiroheterocycloalkyl group of 3 to 6 members comprised of 2 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of O, S and N, and R22 is H, alkyl, phenyl, benzyl,-COR16 or-CONR18R19. The compounds are useful for inhibiting thrombin receptors and therefore in treating thrombosis, atherosclerosis, restinosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, inflammation disorders, cerebral ischemia and cancer.