Heterocyclic derivatives, method of production thereof and pharmaceutical use thereof

A method of preparing a compound of the formula ##STR43## wherein R.sup.1 and R.sup.3 are methyl, R.sup.2 is hydrogen, R.sup.4 is --NHCO--R.sup.6, R.sup.6 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1 -C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, naphthyl C.sub.1 -C.sub.4 alkyl, pyriolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 allyl, morpholino C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1 -C.sub.8 alkyl (wherein any of the foregoing is unsubstituted or substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, di(C.sub.1 -C.sub.4)alkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1 -C.sub.4)alkylamino), --R.sup.A SO.sub.3 A, --R.sup.B PO.sub.3 B where R.sup.A and R.sup.B are each alkylene and A and B are each alkali metal or hydrogen atom, --NR.sup.7 R.sup.8 where R.sup.7 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1 -C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, and naphthyl C.sub.1 -C.sub.4 alkyl (wherein any of the foregoing is optionally substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, di(C.sub.1 -C.sub.4)alkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl (C.sub.1 -C.sub.4)dialkylamino), and R.sup.8 is hydrogen atom or C.sub.1 -C.sub.4 alkyl, or --R.sup.9 --OCOR.sup.10 where R.sup.9 is alkylene and R.sup.10 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 alkyl, morpholino C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1 -C.sub.8 alkyl (wherein any of the foregoing is optionally substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, C.sub.1 -C.sub.4 dialkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1 -C.sub.4)alkylamino), and the remaining three of R.sup.1, R.sup.2, R.sup.3, or R.sup.4 may be the same or different and each is independently a hydrogen atom, a C.sub.1 -C.sub.4 alkyl or a C.sub.1 -C.sub.4 alkoxy, R.sup.5 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1 -C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, naphthyl C.sub.1 -C.sub.4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 alkyl, morpholino C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1 -C.sub.8 alkyl (wherein any of the foregoing is optionally substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, C.sub.1 -C.sub.4 dialkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1 -C.sub.4)alkylamino), an alkenyl, an alkynyl, a dialkylaminoacyloxyalkyl, --R.sup.D SO.sub.3 D or --R.sup.E PO.sub.3 E where R.sup.D and R.sup.E are each alkylene and D and E are each alkali metal or hydrogen atom, and m is 1, said method comprising: providing 1-acetyl-5-bromo4,6dimethylindoline; introducing a nitro substituent to the 7- position of said 1-acetyl-5-bromo-4,dimethylindoline; reducing said nitro substituent to an amino substituent; converting said amino substituent to an amide group of the formula R.sup.6 C(O)--, wherein R.sup.6 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 R.sup.5 to the indoline nitrogen at the 1-position.

A method of preparing a compound of the formula ##STR44## wherein R.sup.1 and R.sup.3 are methyl, R.sup.2 is hydrogen, R.sup.4 is --NHCO--R.sup.6, R.sup.5 is acetyl, R.sup.6 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1 -C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, naphthyl C.sub.1 -C.sub.4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 alkyl, morpholino C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1 -C.sub.8 alkyl (wherein any of the foregoing is unsubstitated or substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, di(C.sub.1 -C.sub.4)alkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1 -C.sub.4)alkylamino), --R.sup.A SO.sub.3 A, --R.sup.B PO.sub.3 B where R.sup.A and R.sup.B are each alkylene and A and B are each alkali metal or hydrogen atom, --NR.sup.7 R.sup.8 where R.sup.7 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl, cyclo C.sub.3 -C.sub.6 alkyl, cyclo C.sub.3 -C.sub.6 alkyl C.sub.1 -C.sub.3 alkyl, phenyl, naphthyl, phenyl C.sub.1 -C.sub.4 alkyl, and naphthyl C.sub.1 -C.sub.4 alkyl (wherein any of the foregoing is optionally substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, di(C.sub.1 -C.sub.4)alkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl (C.sub.1 -C.sub.4)dialkylamino), and R.sup.8 is hydrogen atom or C.sub.1 -C.sub.4 alkyl, or --R.sup.9 --OCOR.sup.10 where R.sup.9 is alkylene and R.sup.10 is selected from the group consisting of C.sub.1 -C.sub.12 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C.sub.1 -C.sub.8 alkyl, piperidyl C.sub.1 -C.sub.8 alkyl, piperidino C.sub.1 -C.sub.8 alkyl, morpholinyl C.sub.1 -C.sub.8 alkyl, morpholino C.sub.1 -C.sub.8 alkyl, piperazinyl C.sub.1 -C.sub.8 alkyl, pyrrolyl C.sub.1 -C.sub.8 alkyl, imidazolyl C.sub.1 -C.sub.8 alkyl, pyridyl C.sub.1 -C.sub.8 alkyl (wherein any of the foregoing is optionally substituted with a C.sub.1 -C.sub.4 alkyl, amino, hydroxy, C.sub.1 -C.sub.4 dialkylamino, C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkoxy, carboxyl, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 carboxyalkyl, C.sub.2 -C.sub.5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C.sub.1 -C.sub.4)alkylamino), and the remaining three of R.sup.1, R.sup.2, R.sup.3, or R.sup.4 may be the same or different and each is independently a hydrogen atom, a C.sub.1 -C.sub.4 alkyl or a C.sub.1 -C.sub.4 alkoxy, and m is 1, said method comprising: providing 1-acetyl-5-bromo4,6-dimethylindoline; introducing a nitro substituent to the 7-position of said 1-acetyl-5-bromo4,6-dimethylindoline; reducing said nitro substituent to an amino substituent; converting said amino substituent to an amide group of the formula R.sup.6 C(O)--, wherein R.sup.6 is as defined above; and reductively removing the bromine atom at the 5-position.