GB1299198A - Pyrrolobenzodiazepinone derivatives - Google Patents

Abstract

1299198 Antibiotic pyrrolobenzodiazepinone derivatives FUJISAWA PHARMACEUTICAL CO Ltd 24 Dec 1969 [30 Dec 1968 26 June 1969] 62863/69 Heading C2A Novel pyrrolobenzodiazepinone derivatives having the Formula (I) wherein R 1 is H, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, aryl-C 1 -C 6 alkylcarbonyl, or arylcarbonyl; Y is -N=CH- or -NH-CHR- and R is C 1 -C 6 alkoxy, aryl-C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, aryl-C 1 -C 6 alkylthio, or di(C 1 -C 6 alkyl)amino, are prepared from a new compound of unknown chemical structure obtained by aerobically cultivating Streptomyces achromogenes var. tomaymyceticus (ATCC 21353) by treating said compound as follows: (a) reacting with an alcohol of formula R<SP>1</SP>H to give a compound of Formula (A) wherein R<SP>1</SP> is C 1 to C 6 alkoxy; (b) dissolving the compound (A) in a non-alcoholic organic solvent to convert it into a compound of Formula (B) (c) reacting the compound (A) or the compound (B) with an acylating agent to form a compound of Formula (C) wherein R<SP>1</SP> 1 is C 1 -C 6 alkylcarbonyl, aryl- C 1 -C 6 alkylcarbonyl or arylcarbonyl, and Y is -N=CH- or -NH-CHR<SP>1</SP> and R<SP>1</SP> is as defined in (a) above; (d) reacting the compound (A) or the compound (B) with an alkylating agent to give a compound of Formula (D) wherein R<SP>11</SP> 1 is C 1 -C 6 alkyl and Y is -N = CH- or -NH-CHR<SP>1</SP> and R<SP>1</SP> is as defined in (a) above; (e) dissolving the compound (C) in which Y is -NH-CHR<SP>1</SP>- in a non-alcoholic organic solvent to convert it into a compound of Formula (E) wherein R<SP>1</SP> 1 is as defined in (c) above; (f) reacting the compound (B) or (E), or the compound (C) or (D) in which Y is -N=CH-, with an alcohol, thioalcohol or dialkylamine to give a compound of Formula (I) wherein R is C 1 -C 6 alkoxy, aryl-C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, aryl-C 1 -C 6 alkylthio, or di(C 1 -C 6 alkyl)- amino. The initial fermentation is carried out under conventional conditions for the culture of a Streptomycete. The said new compound may be subjected to the aforesaid treatment either in the fermentation broth (preferably filtered) or after isolation. Such isolation may be by extraction with a water-immiscible solvent (e.g. ethyl acetate or chloroform) or by adsorption on e.g. diatomaceous earth, activated carbon or alumina, silica gel or silicic acid, followed by elution with a polar organic solvent or aqueous such solvent. The compound may be purified by fractional chromatography and isolated by evaporation of the solvent or precipitation by adding a non-solvent. When an alcohol is used in the preparative procedure, the product is the alcohol-reaction compound (A) instead of the said new compound. The inventive compounds (I) variously have activity against gram-positive and gram-negative bacteria, phages, viruses and tumours. Pharmaceutical compositions having such activity comprise a compound of Formula I together with a physiologically acceptable carrier or diluent; they may be in forms suitable for injection or oral administration.