Patent ID: 6489475
Filing Date: 2002-12-03
Classification: A61K,A61P,C07D,Y10S

Abstract:
A method of preparing a compound of the formula whereinR1 and R3 are methyl, R2 is hydrogen, R4 is â€”NHCOâ€”R6, R6 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, naphthyl C1-C4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 alkyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, pyridyl C1-C8 alkyl (wherein any of the foregoing is unsubstituted or substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, carboxy(C1-C4)alkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), â€”RASO3A, and â€”RBPO3B where RA and RB are each C1-C8 alkylene and A and B are each alkali metal or hydrogen atom, â€”NR7R8 where R7 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, and naphthyl C1-C4 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, carboxy(C1-C4)alkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), and R8 is hydrogen atom or C1-C4 alkyl, or â€”R9â€”OCOR10 where R9 is C1-C8 alkylene and R10 is selected from the group consisting of C1-C12 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 alkyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, and pyridyl C1-C8 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, carboxy(C1-C4)alkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), R5 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, naphthyl C1-C4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 alkyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, pyridyl C1-C8 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, carboxy(C1-C4)alkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, di(C1-C8)alkylamino(C2-C5)acyloxy(C1-C8)alkyl, â€”RDSO3D, and â€”REPO3E where RD and RE are each C1-C8 alkylene and D and E are each alkali metal or hydrogen atom, and m is 1, said method comprising: providing 1-acetyl-5-bromo-4,6-dimethylindoline; introducing a nitro substituent to the 7- position of said 1-acetyl-5-bromo-4,6-dimethylidoline; reducing said nitro substituent to an amino substituent; converting said amino substituent to an amide group of the formula R6C(O)â€”, wherein R6 is as defined above; reductively removing the bromine atom at the 5-position; and removing the acetyl substituent at the 1- position and thereafter covalently bonding R5 to the indoline nitrogen at the 1-position.