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Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids

a technology of pyrrolo[1,1-c] [1,4] and hybrids, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of poor water solubility and hinder the clinical efficacy of these antibiotics

Active Publication Date: 2005-10-06
COUNCIL OF SCI & IND RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a new pyrrolo[2,1-c][1,4]benzodiazepine hybrid compound that can be used as an antitumour agent. The invention also provides a process for preparing these new compounds. These compounds have DNA binding and anticancer activity, and can be used to treat tumours in humans. The invention provides a new method for treating cancer that is effective and safe.

Problems solved by technology

However, the clinical efficacy for these antibiotics is hindered by several limitations, such as poor water solubility, cardiotoxicity, development of drug resistance and metabolic inactivation.

Method used

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  • Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids
  • Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids
  • Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids

Examples

Experimental program
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Effect test

example 1

[0029] Compound 4-[1H-benzo[d]imidazol-2-yl]phenol I (210 mg, 1 mmol) and (2S)-N-4-(3-bromobutyloxy)-5-methoxy-2-nitrobenzoyl]pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (521 mg, 1 mmol) was taken in dry DMF (10 mL). K2CO3 (690 mg, 5 mmol) was added and the mixture was stirred for 12 to 24 hrs. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHCl3 (50 mL), then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was chromatographed over silica gel using chloroform / methanol (8:2) solvent to give compound (2S)-N-{3-(4-(1H-benzo[d]imidazol-2-yl]phenoxy)propoxy-5-method-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal VII as a sticky solid.

[0030] The compound (2S)-N-{3-(4-(1H-benzo[d]imidazol-2-yl]phenoxy)propoxy-5-method-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.649 ...

example 2

[0033] Compound 4-(1H-benzo[d]imidazol-2-yl]phenol I (210 mg, 5 mmol) and (2S)-N-[4-(4-bromobutyloxy)-5-methoxy-2-nitrobenzoyl]pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (535 mg, 1 mmol) was taken in dry DMF (10 mL). K2CO3 (690 mg, 5 mmol) was added and the mixture was stirred for 12 to 24 hrs. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHCl3 (50 mL). Then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was chromatographed over silica gel using chloroform / methanol (8:2) solvent to give compound (2S)-N-{3-(4-(1H-benzo[d]imidazol-2-yl]phenoxy)propoxy]butoxy-5-method-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III as a sticky solid.

[0034] The compound (2S)-N-{4-(4-(1H-benzo[d]imidazol-2-yl]phenoxy)-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (633 ...

example 3

[0037] Compound 4-[1H-benzo[d]imidazol-2-yl]phenol I (210 mg, 1 mmol) and (2S)-N-[4-(5-bromobutyloxy)-5-methoxy-2-nitrobenzoyl]pyrrolidin-2-carboxaldehyde diethyl thioacetal of formula II (549 mg, 5 mmol) was taken in dry DMF (10 mL), K2CO3 (690 mg, 5 mmol) was added and the mixture was stirred for 12-24th. The reaction mixture was poured in to ice-water then solid was formed and it was filtered and aqueous media was extracted with EtOAc and CHCl3 (50 mL). Then the extracted solution was evaporated in vacuum to obtain the solid compound. Two solids were combined and the crude material was chromatographed over silica gel using chloroform / methanol (9:1) solvent to give compound (2S)-N-{5-(4-(1H-benzo-[d]imidazol-2-yl]phenoxy)pentyloxy-5-method-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III as a sticky solid.

[0038] The compound (2S)-N-{5-(4-(1H-benzo[d]imidazol-2-yl]phenoxy)pentyloxy-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (0.64...

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Abstract

Novel pyrrolo[2,1-c][1,4]benzodiazepine hybrids as well as processes for the preparation of novel pyrrolo[2,1-c][1,4]benzodiazepine hybrids are dislcosed. More particularly, present invention relates to a process for the preparation of novel pyrrolo[2,1-c][1,4]benzodiazepine hybrids as DNA sequence selective agents which are useful as potential antitumour agents. In particular, the present invention relates to a process for the preparation of new pyrrolo [2,1-c][1,4]benzodiazepine hybrids as potential antitumour agents. These compounds have the formula XIV shown below:

Description

FIELD OF THE INVENTION [0001] The present invention relates to novel pyrrolo[2,1-c][1,4]benzodiazepine hybrids as well as processes for the preparation of novel pyrrolo[2,1-c][1,4benzodiazepine hybrids. More particularly, present invention relates to a process for the preparation of novel pyrrolo[2,1-c][1,4]benzodiazepine hybrids as DNA sequence selective agents which are useful as potential antitumour agents. In particular, the present invention relates to a process for the preparation of new pyrrolo[2,1-c][1,4benzodiazepine hybrids as potential antitumour agents. BACKGROUND OF THE INVENTION [0002] Pyrrolo[2,1-c][1,4]benzodiazepine antitumour antibiotics are commonly known as anthramycin class of compounds. In the last few years, a growing interest has been shown in the development of new pyrrolo[2,1-c]benzodiazepines (PBDs). These antibiotics react covalently with DNA to form an N2-guanine adduct that lies within the minor groove of duplex DNA via an acid-labile aminal bond to the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/55A61K31/551A61P35/00C07D487/00C07D487/02C07D487/04
CPCA61P35/00C07D487/04
Inventor KAMAL, AHMEDPODDUTOORI, RAMULUOLEPU, SRINIVAS
Owner COUNCIL OF SCI & IND RES
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