PT95324A - Process for preparation of 20(S) or 20(RS)-camptothecins, the salts thereof, and pharmaceutical compositions that contain them, and for inhibition of the enzyme topoisomerase I - Google Patents

Abstract

The present invention relates to the process for preparation of a 20(S) or 20(RS) camptothecin having the structure shown below <IMAGE> in which Z is H or C1-8 alkyl and R is NO2, NH2, N3, H, halogen, COOH, OH, C1-3 O-alkyl, SH, C1-3 S-alkyl, CN, CH2NH2, C1-3 NH-alkyl, C1-3 CH2-NH-alkyl, N-(C1-3 alkyl)2, CH2N(C1-3 alkyl)2, O-, NH- or S-CH2CH2N(CH2CH2OH)2, O-, NH- or S-CH2CH2CH2N(CH2CH2OH)2, O-, NH- or S-CH2CH2N(CH2CH2CH2OH)2, O-, -NH- or S-CH2CH2CH2N(CH2CH2CH2OH2)2, O-, NH- or S-CH2CH2N(C1-3 alkyl)2, O-, NH- or S-CH2CH2CH2N(C1-3 alkyl)2, CHO, C1-3 alkyl or NHCOCHR1NR2R3, in which R1 is a side chain of an α-amino acid and R2 and R3 are, independently of each other, hydrogen or a lower alkyl group or R3 is a peptide unit containing l-3 amino acid units bound to nitrogen, via a peptide bond; NHCO-alkyleno-C2-8-X or NHCO-alkenyleno-C2-8-X, in which X is COOH, CONR2-(CH2)n- NR2R3, where n = 1-10 and R2 and R3 are defined as above; NHCO-B-(CH2)n-NR2R3, where B = oxygen or NH; or <IMAGE> where m + y = 3-6. The process involves, when appropriate: diazotizing a 9-amino-10,11-methylenedioxy-20(S)- or 20(RS)-camptothecin and displacing the diazo group with a corresponding nucleophil, or reducing the group R = CN; or alkylating the group R = OH, SH, NH2 or CH2NH2 with an alkylating agent; or reacting 10,11-methylenedioxy-20(S) or 20(RS)- camptothecin with a mixture of concentrated sulphuric and nitric acid; or nitrating 10,11-methylenedioxy-20(S)- or 20(RS)- camptothecin in order to obtain 9-nitro-10,11- methylenedioxy-20(S) or 20(RS)-camptothecin and then reducing the 9-nitro group; or reacting 9-amino or 9-amino-7-alkyl C1-8-10,11- methylenedioxy-20(S)- or 20(RS)-camptothecin with an amino acid with a protected amino group or peptide containing 1-4 amino acid units, a saturated or unsaturated C4-10 carboxylic acid anhydride or phosgene, and then with a primary or secondary straight, branched- chain or cyclic diamine, or with a tertiary amino- alcohol. The invention also relates to the process for preparation of salts of the abovementioned compounds, as well as the process for preparation of pharmaceutical compositions containing the compounds or salts.