SUBSTITUTED PHENYL AMIDINES AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

摘要

1478671 N - (substituted phenyl) - amidines SCHERICO Ltd 17 June 1974 [20 June 1973] 26773/74 Heading C2C Novel compounds and their acid addition salts I in which M is [where R1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, OH, C 1-6 alkoxy, C 3-6 cycloalkoxy or phenyl (optionally substituted by NO 2 , CF 3 or Hal), R2 is H, C 1-6 alkyl or C 3-6 cycloalkyl or R1 and R2 together are C 3-7 alkylene or -(CH 2 ) 2# (CH 2 ) 2 - (where #is >O, >S, >NH or >N C 1-6 alkyl) and R8 is H or C 1-6 alkyl], X is N0 2 , CF 3 , Cl, Br or I, Y is H, Hal, NO 2 , amino optionally mono- or di-C 1-6 alkylated, C 1-6 alkyl, C 1-6 alkoxy, polyfluoro C 1-6 alkoxy, polyfluoro C 1-6 alkyl, polyfluoro C 1-6 alkylthio, NR3COR5 or NR3SO 2 R4 (where R3 is H or C 1-6 alkyl, R4 is C 1-6 alkyl, aralkyl or aryl and R5 is C 1-6 alkoxy, aralkoxy, aryloxy, C 1-6 alkyl, aralkyl or aryl), R is a divalent alkane or alkene radical in which at least one C atom has more than two C atoms bonded to it and any double bond in the alkene moiety is not conjugated with the amidine group and Z is H, OH, C 1-6 alkoxy, aryl C 1-6 alkoxy, C 1-6 alkanoyloxy, aryl C 1-6 alkanoyloxy carbamoyloxy or thiocarbamoyloxy both optionally mono- or di-C 1-6 alkylated with the proviso that when X is Cl, Br or I at least one of R1, R2, R8 or Z is other than H are prepared by (1) reacting a compound II in which A- is an anion, Q4 is Hal or an alkoxy or aralkoxy radical and Z is as above other than hydroxy with an appropriate amine R1R2NH to form a compound I (Z # OH); (2) condensing an aniline IV or a reactive derivative thereof with an appropriate imidate or the corresponding free base, in which Q2 is Hal, alkoxy or alkylthio to form a compound I (Z # OH); (3) condensing an amide or thioamide X=C(NR1R2)-R-Z (where X is O or S) with an appropriate amine VI or a reactive derivative thereof or an amide or thio amide VIII with an appropriate amine R1R2NH or reactive derivative thereof to produce a compound I (Z # OH); (4) the Beckmann rearrangement of a compound X in which T is an acyl radical in the presence of an amine R1R2NH to form a compound I [M = -N=C(NR1R2)-]; (5) reacting an amine VI or a salt thereof with a nitrile Z-R-CN optionally in the presence of compounds capable in a manner known per se of introducing groups R1a and R2a, where R1a is C 1-6 alkyl, C 3-6 cycloalkyl or phenyl (optionally substituted by NO 2 , CF 3 or Hal), R2a is C 1-6 alkyl or C 3-6 cycloalkyl or R1a and R2a are as defined for R1 and R2 together to form a compound I (R1 = H or R1a, R2 = H or R2a); (6) converting X=NH 2 to X=C1, Br or I using the Sendmeyer reaction in compounds I (Y is other than amino) ; (7) eliminating NH2 from a compound equivalent to a compound I. (except that Y is not amino) and containing such a group; (8) reducing a compound XV in which Q5 is a double bond conjugated with the amidine double bond to form a compound I (R = alkylene; Z = H); (9) hydrolysing a compound XIX to form a compound I (Z = OH); (10) alkylating a compound I (M = to replace the N-hydrogen atom with C 1-6 alkyl ; (11) alkylating a compound I (R1 = H, OH and/or R2 = H) to give a compound I (B1 = C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy and/or R2 = C 1-6 alkyl or C 1-6 cycloalkyl); (12) converting Y = NH 2 to mono- or di-C 1-6 alkylamino, halogen or NR3COR5 (where R3 is H or C 1-6 alkyl, R5 is C 1-6 alkyl, aralkyl (or aryl) by methods known per se in compounds I; (13) hydrolysing Y = acylamino or reducing Y=NO 2 to NH 2 in compounds I; (14) subjecting a compound I (Z = C 1-6 alkoxy or aryl C 1-6 alkoxy) to ether cleavage to produce compounds I (Z = OH); (15) acylating or etherifying a compound I (Z=OH) to form a compound I (Z = C 1-6 alkoxy, aryl C 1-6 alkoxy- C 1-6 alkanoyloxy, aryl-C 1-6 alkanoyloxy or di- C 1-6 alkylcarbamoyloxy; (16) reducing an alkenyline group R to the corresponding alkylene group; or (17) forming a salt by salification of a compound I. Compounds I are anti-androgenic agents and form with a carrier or excipient a pharmaceutical or veterinary composition which may be administered orally, parenterally or rectally. They may also be admixed with animal feedstuff.