Pyrrolo-benzodiazepine compounds and anti-tumor composition thereof
AssigneeThe Green Cross Corporation
InventorsYasuo Ueda, Yoshio Kagitani, Eiji Sako, Tadakazu Suyama, Nobuhiko Komatsu, Daisuke Satoh
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Abstract
Novel 5,10,11,11a-tetrahydro-8-methyl-11-sulfo or sulfino-1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamides which have antitumor activity and low toxicity are prepared by reacting corresponding 11-reactive compound with a reactive sulfur compound to form 11-sulfino compounds and, if desired, oxidizing the 11-sulfino compounds to obtain 11-sulfo compound.
Claims28
A 1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide compound represented by the formula ##STR6## wherein R.sub.1 represents a hydrogen atom, alkanoyl group having 1 to 6 carbon atoms, benzoyl group, phenylcarbamyl group, alkyl carbamyl group having 1 to 6 carbon atoms, or alkoxycarbonyl group wherein the alkoxy portion has 1 to 6 carbon atoms, R.sub.2 represents a hydrogen atom, an alkanoyl group having 1 to 6 carbon atoms or a benzoyl group, and R.sub.3 represents a sulfinic acid residue, SO.sub.2 X, or sulfonic acid residue, SO.sub.3 X, wherein X is hydrogen or a pharmaceutically acceptable cation.
5,10,11,11a-Tetrahydro-10-acetyl-9-hydroxy-8-methyl-5-oxo-11-s ulfo-1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-acetoxy-10-acetyl-8-methyl- 5-oxo-11-sulfo-1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-10-acetyl-9-carbamyloxy-8-methyl-5-oxo- 11-sulfo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-hydroxy-8-methyl-5-oxo-11-sulf o-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-acetoxy-8-methyl-5-oxo- 11-sulfo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-carbamyloxy-8-methyl-5-oxo-11 -sulfo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-10-acetyl-9-hydroxy-8-methyl- 5-oxo-11-sulfino-1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-acetoxy-10-acetyl-8-methyl-5-oxo-11-su lfino-1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-10-acetyl-9-carbamyloxy-8-met hyl-5-oxo-11-sulfino-1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-hydroxy-8-methyl-5-oxo-11-sulfino-1H-pyrrolo[2 ,1-c][1,4]benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-acetoxy- 8-methyl-5-oxo-11-sulfino-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-9-carbamyloxy-8-methyl-5-oxo-11-sulfino-1H-pyrro lo[2,1-c][1,4]benzodiazepin-2-acrylamide.
5,10,11,11a-Tetrahydro-8-methyl-9-met hoxycarbonyloxy-5-oxo-11-sulfo-1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acryl amide.
A process for producing a 1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamide compound represented by the formula ##STR7## wherein R.sub.1 represents a hydrogen atom, alkanoyl group having 1 to 6 carbon atoms, benzoyl group, phenylcarbamyl group, alkylcarbamyl group having 1 to 6 carbon atoms, or alkoxycarbonyl group wherein the alkoxy portion has 1 to 6 carbon atoms, R.sub.2 represents a hydrogen atom, an alkanoyl group having 1 to 6 carbon atoms or a benzoyl group, and R.sub.3 represents a sulfinic acid residue, SO.sub.2 X, wherein X is hydrogen or a pharmaceutically acceptable cation, which comprises allowing a reactive sulfur compound to react with a compound of the formula ##STR8## wherein R.sub.1 and R.sub.2 are the same as those described above and Y represents a hydrogen atom, an alkyl group or a phenyl(lower)alkyl group.
A process for producing a 1H-pyrrolo[2,1-c][1,4]-benzodiazepin-2-acrylamide compound represented by the formula ##STR9## wherein R.sub.1 represents a hydrogen atom, alkanoyl group having 1 to 6 carbon atoms, benzoyl group, phenylcarbamyl group, alkylcarbamyl group having 1 to 6 carbon atoms, or alkoxycarbonyl group wherein the alkoxy portion has 1 to 6 carbon atoms, R.sub.2 represents a hydrogen atom, an alkanoyl group having 1 to 6 carbon atoms or a benzoyl group, and R.sub.3 represents a sulfonic acid residue, SO.sub.3 X, wherein X is hydrogen or a pharmaceutically acceptable cation, which comprises oxidizing a compound or pharmaceutically acceptable salt thereof represented by the formula ##STR10## wherein R.sub.1 and R.sub.2 are the same as those defined above.
A process for producing a 1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide compound represented by the formula ##STR11## wherein R.sub.1 represents a hydrogen atom, alkanoyl group having 1 to 6 carbon atoms, benzoyl group, phenylcarbamyl group, or alkoxycarbonyl group wherein the alkoxy portion has 1 to 6 carbon atoms, and a pharmaceutically acceptable salt thereof, which comprises allowing a reactive sulfur compound to react with a compound of the formula ##STR12## wherein R.sub.1 is the same as those defined above.
A anti-tumer composition comprising a carrier and an anti-tumer effective amount of a 1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-acrylamide compound represented by the formula ##STR13## wherein R.sub.1 represents a hydrogen atom, alkanoyl group having 1 to 6 carbon atoms, benzoyl group, phenylcarbamyl group, alkylcarbamyl group having 1 to 6 carbon atoms, or alkoxycarbonyl group wherein the alkoxy portion has 1 to 6 carbon atoms, R.sub.2 represents a hydrogen atom, an alkanoyl group having 1 to 6 carbon atoms or a benzoyl group, and R.sub.3 represents a sulfinic acid residue, SO.sub.2 X, or sulfonic acid residue, SO.sub.3 X, wherein X is hydrogen or a pharmaceutically acceptable cation.
Dependencies are inferred from the claim text.