Patent ID: 6790960
Filing Date: 2004-09-14
Classification: A61K,A61P,C07D

Abstract:
A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:X is NHCH2; R1 is selected from the group consisting of: (a) H, (b) C1-C6 alkyl, (c) C1-C6 alkenyl, (d) CH2OH, (e) halogen, and (f) thiocyano; R2 is selected from the group consisting of: (a) C1-C6 alkyl, (b) hydroxyalkyl, (c) C1-C6 alkoxy C1-C6 alkyl, (d) hydroxy C1-C6 alkoxy C1-C6 alkyl, (e) C1-C6 alkylthio C1-C6 alkyl, (f) cyano C1-C6 alkyl, (g) halogenated C1-C6 alkyl, and (h) aminocarbonyl C1-C6 alkyl; R3 is selected from the group consisting of: (a)H, (b) C1-C6 alkoxy, (c) C1-C6 alkyl, (d) halogen, (e) hydroxy C1-C6 alkyl, (f) hydroxy C1-C6 alkoxy, (g) C1-C6 alkoxy C1-C6 alkyl, (h) C1-C6 alkoxy C1-C6 alkoxy, (i) C1-C6 alkoxycarbonyl, (j) C1-C6 alkanoyl, (k) halogenated C1-C6 alkyl, (l) NO2, (m) CN, (n) C1-C6 sulfonyl, (o) C1-C6 sulfinyl, (p) C1-C6 alkylthio, (q) C1-C6 alkylaminosulfonyl, (r) C1-C6 (alkyl)2aminosulfonyl, (s) aminosulfonyl, (t) C1-C6 alkylsulfonylamino, (u) C1-C6 (alkylsulfonyl)2amino, (v) trifluoromethylsulfonylamino, (x) C1-C6 alkylcarbonylamino, (y) C1 -C6 alkoxycarbonylamino, and (z) C1-C6 aminocarbonylamino, optionally substituted by one or two C1-C6 alkyl groups; R4 is selected from the group consisting of: (a) H, (b) C1-C6 alkyl, (c) halogenated C1-C6 alkyl, (d) C1-C6 alkoxy, and (e) halogen; Ar is a phenyl, thienyl, furanyl, naphthyl, or pyridyl group substituted with one or more substituents selected from the group consisting of R5, R6, and R7, wherein: R5 is selected from the group consisting of: (a) H, (b) C1-C6 alkyl, (c) C1-C6 alkyl, (d) hydroxy, (e) hydroxy C1-C6 alkyl, (f) hydroxy C1-C6 alkoxy, (g) halogenated C1-C6 alkyl, (h) halogenated C1-C6 alkoxy, (i) C1-C6 alkoxy C1-C6 alkyl, (j) halogen, (k) hydroxy C1-C6 alkoxy C1-C6 alkyl, (l) CN, (m) C1-C6 alkoxycarbonyl, (n) C1-C6 alkoxycarbonyloxy, (o) C1-C6 alkylsulfonyloxy, (p) trifluoromethylsulfonyloxy, (q) C1-C6 acyloxy C1-C6 alkyl, (r) C1-C6 alkylsulfonyl C1-C6 alkyl, (s) C1-C6 alkylsulfonyl C1-C6 alkyl, (t) C1-C6 alkylthio C1-C6 alkyl, (u) C1-C6 alkoxycarbonylamino C1-C6 alkyl, (v) aryl, (x) amino C1-C6 alkyl, (y) NHC&boxH;OR12, (z) H or C1-C4 alkyl substituted â€ƒgroup, (aa) H or C1-C4 alkyl substituted â€ƒgroup, and (ab) C1-C6 alkyl sulfonyl amino; R6 is selected from the group consisting of: (a) H, (b) C1-C6 alkyl, (c) halogen, (d) hydroxy C1-C6 alkyl, (e) halogenated C1-C6 alkyl, (f) halogenated C1-C6 alkoxy, (e) C1-C6 alkoxy C1-C6 alkyl, and (f) CN; R7 is selected from the group consisting of: (a) H, (b) C1-C6 alkyl, (c) C1-C6 alkoxy, (d) halogen, (e) NO2, (f) halogenated C1-C6 alkyl, (g) halogenated C1-C6 alkoxy, (h) aryloxy, and (i) CN; R8 is selected from the group consisting of: (a) H and (b) C1-C6 alkyl; and R12 is selected from the group consisting of: (a) C1-C6 alkoxy, (b) C1-C6 alkoxy C2-C4 alkoxy, (c) NH2, (d) hydroxy C2-C4 alkoxy, (e) C1-C6 alkyl carbonyloxy C2-C4 alkoxy, (f) halogenated C2-C4 alkoxy, (g) halogenated C1-C4 alkyl, (h) hydroxy C1-C4 alkyl, (i) C1-C6 alkyl carbonyloxy C1-C4 alkyl, (j) aryl, (k) aryl C1-C4 alkyl, (l) C1-C4 sulfanyl C2-C4 alkoxy, (m) C1-C4 sulfinyl C2-C4 alkoxy, and (n) C1-C4 sulfonyl C2-C4 alkoxy; wherein: R5 and R6 are in the ortho positions relative to X, R7 is in the meta or para position relative to X, and R5 and R6 may together form a hydroxy- or alkoxy-substituted 5- or 6- membered ring, provided that one of R3 and R4 is not H or halogen, provided also that at least one of R5, R6 and R7 is not H, provided also that when R5=(y),(z),(aa) or (ab), then one of R3 and R4 is not H, provided also that when R1=H, then R7 is not CH3, and provided also that when R2=CH2OH or CH2CN, then one of R5 and R6 is not H, the process comprising: a) reacting a compound of Formula IV, wherein R1, R2, R3 and R4 are as defined for Formula I, with a compound of Formula V, wherein Ar is as defined for Formula I, in an inert solvent in the presence of a Lewis acid under standard conditions, to give a compound of Formula VI, wherein R1, R2, R3, R4 and Ar are as defined for Formula I; and b) treating the compound of Formula VI, wherein R1, R2, R3, R4 and Ar are as defined for Formula I, with sodium borohydride or sodium cyanoborohydride under standard conditions in a solvent to give a compound of Formula I, wherein X is NHCH2.