Certain N-deacetylcolchicine and N-deacetylthiocolchine derivatives are described wherein the 7-N position on the B ring is substituted with the group --C(O)--(CHR.sub.4).sub.m --AR, wherein m is an integer of 0-10, A is S, O, N or a covalent bond; R.sub.1 is substituted phenyl or substituted benzoyl; optionally substituted cycloalkyl of 3-7 carbons; optionally substituted naphtyl; an optionally substituted imide ring; an optionally substituted 5 or 6 member heterocycle with at least one N, S, or O in the ring; or an optionally substituted fused heterocyclic or fused carboxyclic ring system; R.sub.2 (at the 2-position of the A ring) is methoxy, hydroxy, or methylenedioxy when taken together with R.sub.3 ; R.sub.3 (at the 3-position of the A ring) is methoxy, hydroxy, a monosaccharide radical, or is methylenedioxy when taken together with R.sub.2 ; and R.sub.4 is H or is H or methyl when m is 1. Also dimers of such compounds are disclosed. When combined with suitable pharmaceutical excipients, these compounds are useful for treating various types of cancer.

The invention related to colchinol derivatives of the formula (I): Wherein: R.sup.1, R.sup.2 and R.sup.3 are each independently hydroxy, phosphoryloxy (--OPO.sub.3 H.sub.2), C.sub.1-4 alkoxy or an in vivo hydrolysable ester of hydroxy, with the proviso that at least 2 of R.sup.1, R.sup.2 and R.sup.3 are C.sub.1-4 alkoxy; A is --CO--, --C(O)O--, --CON(R.sup.8)-- (wherein R.sup.8 is hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxyC.sub.1-3 alkyl, aminoC.sub.1-3 alkyl or hydroxyC.sub.1-3 alkyl); a is an integer from 1 to 4 inclusive; R.sup.a and R.sup.b are independently selected from hydrogen, hydroxy and amino; B is --O--, --CO--, N(R.sup.9)CO--, --CON(R.sup.9)--, --N(R.sup.9)C(O)O--, --N(R.sup.9)CON(R.sup.10)--, --N(R.sup.9)SO.sub.2 --, --SO.sub.2 N(R.sup.9)-- or a direct single blond (wherein R.sup.9 and R.sup.10 are independently selected from hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxyC.sub.1-3 alkyl, aminoC.sub.1-3 alkyl and hydroxyC.sub.1-3 alkyl); b is 0 or an integer from 1 to 4 inclusive, (provided that when b is 0, B is a single direct bond); D is carboxy, sulpho, tetrazolyl, imidazolyl, phosphoryloxy, hydroxy, amino, N--(C.sub.1-4 alkyl)amino, N,N-di(C.sub.1-3 alkyl)amino, or of the formula --Y.sup.1 (CH.sub.2).sub.0 R.sup.11 or --NHCH(R.sup.12)COOH; [wherein Y.sup.1 is a direct single bond, --O--, --C(O)--, --N(R.sup.13)C(O)-- or --C(O)N(R.sup.13)-- (wherein R.sup.13 is hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxyC.sub.2-3 alkyl, aminoC.sub.2-3 alkyl or hydroxyC.sub.2-3 alkyl); e is 0 or an integer from 1 to 4 inclusive.

The invention related to colchinol derivatives of the formula (I): Wherein: R.sup.1 ; R.sup.2 and R.sup.3 are each independently hydroxy, phosphoryloxy (--OP.sub.3 H.sub.2), C.sub.1-4 alkoxy or an in vivo hydrolysable ester of hydroxy, with the proviso that at least 2 of R.sup.1, R.sup.2 and R.sup.3 are C.sub.1-4 alkoxy; A is --CO--, --C(O)O--, --CON(R.sup.8)-- (wherein R.sup.8 is hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxyC.sub.1-3 alkyl, aminoC.sub.1-3 alkyl or hydroxyC.sub.1-3 alkly); a is an integer from 1 to 4 inclusive; R.sup.a and R.sup.b are independently selected from hydrogen, hydroxy and amino; B is --O--, --CO--, N(R.sup.9)CO--, --CON(R.sup.9)--, --N(R.sup.9)C(O)O--, --N(R.sup.9)CON(R.sup.10)--, --N(R.sup.9)SO.sub.2 --, --SO.sub.2 N(R.sup.9)-- or a direct single blond (wherein R.sup.9 and R.sup.10 are independently selected from hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxyC.sub.1-3 alkyl, aminoC.sub.1-3 alkyl and hydroxyC.sub.1-3 alkyl); b is O or an integer from 1 to 4 inclusive, (provided that when b is O, B is a single direct bond); D is carboxy, sulpho, tetrazolyl, imidazolyl, phosphoryloxy, hydroxy, amino, N-(C.sub.1-4 alkyl)amino, N,N-di(C.sub.1-3 alkyl)amino, or of the formula --Y.sup.1 (CH.sub.2).sub.0 R.sup.11 or --NHCH(R.sup.12)COOH; [wherein Y.sup.1 is a direct single bond, --O--, --C(O)--, --N(R.sup.13)C(O)-- or --C(O)N(R.sup.13)-- (wherein R.sup.13 is hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxyC.sub.2-3 alkyl, aminoC.sub.2-3 alkyl or hydroxyC.sub.2-3 alkyl); e is O or an integer from 1 to 4 inclusive.

Colchinol derivatives of formula ##STR1## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.6 are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, alkanoyl, PO.sub.3 H.sub.2 ; X is carbonyl (CO), thiocarbonyl (CS), methylene (CH.sub.2) or a group CHR.sub.4 ; R.sub.4 is OH, O-alkyl or NR.sub.8 R.sub.9 ; R.sub.5 and R.sub.7 are each independently H, alkyl, halogen, hydroxy, alkoxy, nitro or amino; R.sub.8 is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl; and R.sub.9 is H, alkyl or cycloalkyl; and the pharmaceutically acceptable salts, solvates, and hydrates thereof have been found to be useful for treatment of diseases involving angiogenesis. Some of these compounds are novel. Particularly preferred are those compounds in which R.sub.6 is PO.sub.3 H.sub.2.

The invention relates to the use of compounds of formula (I): wherein X is --C(O)--, --C(S)--, --C.dbd.NOH, or --CH(R.sup.7)-- wherein R.sup.7 is hydrogen, hydroxy, C.sub.1-7alkoxy, --OR.sup.8 or --NR.sup.8R.sup.9 (wherein R.sup.8 is a group --Y.sup.1R.sup.10 (wherein Y.sup.1 is a direct bond, --C(O)--, --C(S)--, --S--, --C(O)O, --C(O)NR.sup.11--, --SO.sub.2-- or --SO.sub.2NR.sup.12-- (wherein R.sup.11 and R.sup.12, which may be the same or different, each independently represents hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.10 is as defined herein, and R.sup.9 includes hydrogen; R.sup.1, R.sup.2 and R.sup.3 are as defined herein and are preferably methyl; R.sup.4, R.sup.5 and R.sup.6 are as defined herein with the proviso that R.sup.5 is not hydroxy, alkoxy, substituted alkoxy, --OPO.sub.3H.sub.2, --O--C.sub.1-7alkanoyl or benzyloxy; and salts thereof in the manufacture of a medicament for use in the production of a vascular damaging effect in warm-blooded animals such as humans. The present invention further relates to compounds of the formula (I), pharmaceutical compositions containing them, processes for their preparation and to a method of treatment using the compounds to produce a vascular damaging effect in a warm-blooded animal such as a human. The compounds of formula (I) and the pharmaceutically acceptable salts thereof may be useful in the treatment of a number of disease states including cancer and rheumatoid arthritis. ##STR00001##