MXPA97000644A - Derivatives of substitute campptotecine and process for its preparation - Google Patents

Abstract

The present invention relates to substituted camptothecin derivatives of formula (I) (See Formula) in which the symbol ---- represents a single or double bond, R1, R2 and R3 are as defined under (a) and ( b) below: (a) R1 and R2 are each independently hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C6 phenylalkyl, an optionally substituted phenyl ring, -NR5R6 wherein one of R5 and R6 is hydrogen, C1-C6 alkyl or benzyl and the other is hydrogen, C1-C6 alkanoyl, an optionally substituted C1-C6 alkoxycarbonyl, an optionally substituted benzoyl, a C1-C6 phenylalkanoyl, a C1-C6 alkoxycarbonyl. C6 optionally substituted, an optionally substituted phenoxycarbonyl, an optionally substituted phenoxycarbonyl or a C1-C6 phenylalkoxycarbonyl, or R5 and R6, combined together with the nitrogen atom to which they are attached, form an optionally substituted, saturated, heteromonocyclic ring residue. of 4-7 members; COOR Wherein R 8 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 phenylalkyl, or COR 9 wherein R 9 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 phenylalkyl, optionally substituted phenyl ring or NR 10 R 11 wherein R 10 and R 11 are each independently hydrogen or C 1 -C 6 alkyl, and R 3 is hydrogen, C 1 -C 6 alkyl or an optionally substituted phenyl ring, or (b) R 1 and R3, combined together, form a carbominocyclic ring, optionally substituted with 5-8 members, and R2 is hydrogen, C1-C4 alkyl or C3-C7 cycloalkyl, R3 is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl or C 1 -C 6 phenylalkyl; X is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, C 1 -C 6 alkanoyloxy, benzoyloxy, amino, hydroxy, nitro, halogen or is a methylenedioxy group linked to positions 10 and 11 of the molecule, and pharmaceutically acceptable salts thereof. The compounds according to the invention are useful in therapy as antitumor agents

Description

DERIVATIVES OF SUBSTITUTED CAMPPTOTECINE AND PROCESS FOR ITS PREPARATION The present invention relates to novel substituted camptothecin derivatives having antitumor activity, to a process for their preparation, and to pharmaceutical compositions containing them.

Background of the Invention Camptothecin and some of its analogues exhibit potent antitumor activity due to the inhibition of Topoisomerase I, which is an enzyme involved in some important cellular functions and cell growth (see, for example, Ani et al., J. Med. Chem. 1987, 30, 1774; Hsiang et al., Cancer Res. 1989, 49, 4385; Cancer Res, 1989, 49, 1465). The anticancer activity of camptothecin both in vitro and in vivo is significantly higher for the lactone than the carboxylate form (as described, for example, by WJ Slichenmyer et al., In "The Current State of the Analogs of Camptothecin as Antitumor Agents ", J. Nati. Cancer Inst. 1993, 85, 271-291, and incorporated herein by reference), since a closed a-hydroxy lactone ring is an important structural requirement for both the passive diffusion of drug to cancer cells, as well as for successful interaction REF: 23868 of the drug with the pharmacological target. It has recently been pointed out that, in the presence of biologically relevant levels of human albumin, the biologically active form of camptothecin has a very short half-life (approximately 12 min.), And 2 hours after the addition of the drug to human plasma, a percentage greater than 99% of the drug has been converted to camptothecin carboxylate, the biologically inactive and potentially toxic form of the drug (see Burke, GT; Mi, Z. "The Structural Bases - of the Interactions of Camptothecin with Human Seroalbumin: Impact on Drug Stability ", J. Med. Chem. 1994, 37, 40-46). The same authors also describe the importance of substitution at positions 9 and 7 on the nucleus of camptothecin to improve the stability of the drug in the presence of albumin. Therefore, there is a need to find novel camptothecin derivatives having high intrinsic potency, and at the same time be able to gain stability in the presence of serum albumin.

Description of the invention Accordingly, the present invention relates to the substituted camptothecin derivatives of formula (I) in which the symbol represents a single or double bond; Ri, R2 and R3 are as defined under (a) or (b) below: (a) Ri and R2 are, each independently, '- hydrogen; C? -C4 alkyl; C3-C7 cycloalkyl; phenylalkyl of C? -C6; an optionally substituted phenyl ring; -NR5Rβ wherein one of R5 and Re is hydrogen, C?-C6 alkyl or benzyl and the other is hydrogen, C?-C6 alkanoyl, an optionally substituted C?-C6 alkoxycarbonyl, an optionally substituted benzoyl, phenylalkanoyl Ci-Cβ, an optionally substituted phenoxycarbonyl or C 1 -C 6 phenylalkoxycarbonyl, or R 5 and Re, combined together with the nitrogen atom to which they are attached, form a 4-7 membered, optionally substituted, heteromonocyclic ring residue. , represented by a group (G) wherein W is -C = 0, R is hydrogen or Ci-Ce alkyl and n is an integer from 2 to 5; COOR8 wherein Ra is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl or C? -C6 phenylalkyl; or COR9 wherein R9 is C? -C6 alkyl, C3-C7 cycloalkyl, C? -C6 phenylalkyl, optionally a substituted phenyl ring or NRioRu wherein Ri0 and Ru are, each independently, hydrogen or C? -C6; and R 3 is hydrogen, C 1 -C 6 alkyl or an optionally substituted phenyl ring; or (b) Ri and R3, combined together, form a carbominated cyclic ring, optionally substituted with 5-8 members; and R2 is hydrogen, C1-C4 alkyl or C3-C7 cycloalkyl; R is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl or C? -C6 phenylalkyl; X is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl, C? -C6 alkoxy, C3-C7 cycloalkoxy, Ci-C? Alkanoyloxy, benzoyloxy, amino, hydroxy, nitro, halogen or is a methylenedioxy group linked to positions 10 and 11 of the molecule, and the pharmaceutically acceptable salts of /. the same. In the formulas of the present specification, a dotted line () indicates a substituent below the plane of the ring; a wedge-shaped line i "- ^) indicates a substituent above the plane of the ring When it is in a compound of formula (I) the symbol means a double bond, both the isomers Z as E and a mixture of the Z and E isomers are included within the scope of the present invention. The pharmaceutically acceptable salts according to the invention are the pharmaceutically acceptable salts with acid, both inorganic acids such as, for example, hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid, and organic acids such as, for example, citric acid , fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfdnic, or p-toluenesulfonic. Pharmaceutically acceptable salts of the compounds of formula (I) which contain an acidic group, ie carboxy, with pharmaceutically acceptable bases are also included within the scope of the present invention. The pharmaceutically acceptable bases can be both inorganic bases such as, for example, alkali metal oxides, for example sodium or potassium, or metal alkaline earth metal, for example calcium or magnesium, hydroxides and organic acids such as, for example, alkyl amines, for example methylamine or triethyl, aralkylamines, for example benzylamine, dibenzylamine, a- or b-phenyl-ethylamine, or heterocyclic amines such as, for example, piperidine, 1-methyl-piperidine, piperazine or morpholine. An optionally substituted phenyl ring can be represented by a group wherein Q, linked to the ortho, meta or para position of the phenyl ring, represents hydrogen, C? -C6 alkyl, C? -C6 alkoxy, Ci-C? alkanoyloxy, nitro or halogen. Preferably, it is hydrogen, alkyl C? -C, C1-C4 alkoxy, or halogen. Particularly preferred values of Q are hydrogen, methoxy and chloro. An optionally substituted benzoyl can be represented by a group in which Q is as defined above.

An optionally substituted phenoxycarbonyl can, - be represented by a group -co-o- in which Q is as defined above. An optionally substituted, 5-8 membered carbonominocyclic ring is, when the symbol is used to denote a single bond, for example cyclopentyl or cyclohexyl, or when the symbol is used to denote a double bond, cyclopenten-1-yl or cyclohexen -1-ilo. In the present specification, the hydrocarbon chain of the alkyl, alkoxy, alkanoyl, alkanoyloxy and alkoxycarbonyl groups can be a straight or branched chain. Preferably, C? -C6 alkyl is C? -C4 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or t-butyl. Preferably, the C 1 -C 4 alkyl is methyl, ethyl or propyl. Preferably, the C3-C7 cycloalkyl is C4-C6 cycloalkyl, for example cyclobutyl, cyclopentyl or cyclohexyl. Preferably, the C 1 -C 6 alkoxy is C 1 -C 4 alkoxy, for example methoxy, ethoxy or propoxy.

Preferably, the C alca-C6 alkanoyl is C1-C4 Icanoyl, for example methanoyl, ethanoyl or propanoyl. Preferably, the C? -C6 alkanoyloxy is C? -C4 alkanoyloxy, for example methanoyloxy, ethanoyloxy or propanoyloxy. Preferably, the C 1 -C 6 alkoxycarbonyl is C 1 -C 4 alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl. Preferably, an optionally substituted C 1 -C 6 alkoxycarbonyl is trichloroethoxycarbonyl. The preferred meanings of the heteromonocyclic ring residue represented by the group defined above (G) are A preferred class of compounds according to this invention is represented by the compounds of the formula (I) above where the symbol represents a single or double bond; Ri and R2 are, each independently, hydrogen; -NR5R6 wherein one of R5 and Re is hydrogen, and the other is hydrogen, C? -C6 alkanoyl, a benzoyl optionally substituted, C? -C6 phenylalkanoyl, a? -C6 alkoxycarbonyl, phenoxycarbonyl or Ci-Ce phenylalkoxycarbonyl; COOR8 wherein Re is hydrogen or C? -C6 alkyl; or COR9 wherein R9 is C? -C6 alkyl, unsubstituted phenyl or NR10R11 wherein Rio and Rn are both hydrogen; R3 is hydrogen; R 4 is hydrogen or C 6 -C 6 alkyl; X is hydrogen, hydroxy, amino, C? -C6 alkoxy or is a methylenedioxy group linked to positions 10 and 11 of the molecule, and pharmaceutically acceptable salts thereof. Examples of specific compounds preferred under the invention are the following: 9-vinyl camptothecin (1); (E) -9- (2-methoxycarbonyl-ethenyl) camptothecin (2); 9- (2-hydroxycarbonyl-ethenyl) camptothecin (3); (Z) -9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (4); B- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (5); 9- (3-oxo-but-l-enyl) camptothecin (6); 9- (3-oxo-3-phenyl-propenyl) camptothecin (7); 9- (2-aminocarbonyl-ethenyl) camptothecin (8); 7-ethyl-9-vinyl camptothecin (9); 7-ethyl-9- (2-methoxycarbonyl-ethenyl) camptothecin (10); 7-ethyl-9- (2-hydroxycarbonyl-ethenyl) camptothecin (11); 7-ethyl-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin. 12); 7-ethyl-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (13); 7-ethyl-9- (3-oxo-but-l-enyl) camptothecin (14); 7-ethyl-9- (3-oxo-3-phenyl-propenyl) camptothecin (15); 7-ethyl-9- (2-aminocarbonyl-ethenyl) camptothecin (16); 10-vinyl camptothecin (17); (E) -10- (2-methoxycarbonyl-ethenyl) camptothecin (18); 10- (2-hydroxycarbonyl-ethenyl) camptothecin (19); 10- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (20); - (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (21); - (3-oxo-but-l-enyl) camptothecin (22); 10- (3-oxo-3-phenyl-propenyl) camptothecin (23); 10- (2-aminocarbonyl-ethenyl) camptothecin (24); 7-ethyl-10-vinyl camptothecin (25); 7-ethyl-10- (2-methoxycarbonyl-ethenyl) camptothecin (26); 7-ethyl-10- (2-hydroxycarbonyl-ethenyl) camptothecin (27); 7-ethyl-10- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (28); 7-ethyl-10- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (29); 7-ethyl-10- (3-oxo-but-l-enyl) camptothecin (30); 7-ethyl-10- (3-oxo-3-phenyl-propenyl) camptothecin (31); 7-ethyl-10- (2-aminocarbonyl-ethenyl) camptothecin (32); -hydroxy-9-vinyl camptothecin (33); - - 0-hydroxy-9- (2-methoxycarbonyl-ethenyl) camptothecin (34); 10-hydroxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (35); 10-hydroxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (36); 10-hydroxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (37); 10-hydroxy-9- (3-oxo-but-l-enyl) camptothecin (38); 10-hydroxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (39); 10-hydroxy-9- (2-aminocarbonyl-ethenyl) camptothecin (40); 10, 11-methylenedioxy-9-vinyl camptothecin (41); 10, 11-methylenedioxy-9- (2-methoxycarbonyl-ethenyl) camptothecin (42); 10, 11-methylenedioxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (43); 10, 11-methylenedioxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (44); 10, 11-methylenedioxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (45); 10, 11-methylenedioxy-9- (3-oxo-but-l-enyl) camptothecin (46); , 11-methylenedioxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (47); 10, 11-methylenedioxy-9- (2-aminocarbonyl-ethenyl) camptothecin (48); 10-methoxy-9-vinyl camptothecin (49); -methoxy-9- (2-methoxycarbonyl-ethenyl) camptothecin (50); 0-methoxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (51); 10-methoxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (52); 10-methoxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (53); 10-methoxy-9- (3-oxo-but-l-enyl) camptothecin (54); 10-methoxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (55); 10-methoxy-9- (2-aminocarbonyl-ethenyl) camptothecin (56); 11-vinyl camptothecin (57); 11- (2-methoxycarbonyl-ethenyl) camptothecin (58); 11- (2-hydroxycarbonyl-ethenyl) camptothecin (59); 11- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (60); 11- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (61); 11- (3-oxo-but-l-enyl) camptothecin (62); 11- (3-oxo-3-phenyl-propenyl) camptothecin (63); 11- (2-aminocarbonyl-ethenyl) camptothecin (64); 12-vinyl camptothecin (65); (E) -12- (2'-methoxycarbonyl-ethenyl) camptothecin (66); 12- (2-hydroxycarbonyl-ethenyl) camptothecin (67); (Z) -12- (2-Acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (68); 12- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (69); 12- (3-oxo-but-l-enyl) camptothecin (70); 12- (3-oxo-3-phenyl-propenyl) camptothecin (71); 12- (2-aminocarbonyl-ethenyl) camptothecin (72); ^ -amino-10-vinyl camptothecin (73); 9-amino-10- (2-methoxycarbonyl-ethenyl) camptothecin (74); 9-amino-10- (2-hydroxycarbonyl-ethenyl) camptothecin (75); 9-amino-10- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (76); 9-amino-10- (2-acetylamino-2-hydroxycarbonyl-1-ethenyl) camptothecin (77); 9-amino-10- (3-oxo-but-l-enyl) camptothecin (78); 9-amino-10- (3-oxo-3-phenyl-propenyl) camptothecin (79); 9-amino-10- (2-aminocarbonyl-ethenyl) camptothecin (80); 7-ethyl-9-amino-10-vinyl camptothecin (81); 7-ethyl-9-amino-10- (2-methoxycarbonyl-ethenyl) camptothecin (82); 7-ethyl-9-amino-10- (2-hydroxycarbonyl-ethenyl) camptothecin (83); 7-ethyl-9-amino-10- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (84); 7-ethyl-9-amino-10- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (85); 7-ethyl-9-amino-10- (3-oxd-but-l-enyl) camptothecin (86); 7-ethyl-9-amino-10- (3-oxo-3-phenyl-propenyl) camptothecin (87); 7-ethyl-9-amino-10- (2-aminocarbonyl-ethenyl) camptothecin (88); 9-ethyl camptothecin (1 ') / 9- (2-methoxycarbonyl-ethyl) camptothecin (2'); 9- (2-hydroxycarbonyl-ethyl) camptothecin (3 '); 9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (4 '); r ^ 9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (5 '); 9- [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (6 '); 9 - [(2-Acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (7 '); 9- (3-oxo-butyl) camptothecin (8 '); 9- (3-oxo-3-phenyl-propyl) camptothecin (9 '); 9- (2-aminocarbonyl-ethyl) camptothecin (10 '); 7-ethyl-9-ethyl camptothecin (11 '); 7-ethyl-9- (2-methoxycarbonyl-ethyl) camptothecin (12 '); "" 7-ethyl-9- (2-hydroxycarbonyl-ethyl) camptothecin (13 '); 7-ethyl-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (14 '); 7-ethyl-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (15 '); 7-ethyl-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (16 '); 7-ethyl-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (17 '); And * "7-ethyl-9- (3-oxo-butyl) camptothecin (18 '); 7-ethyl-9- (3-oxo-3-phenyl-propyl) camptothecin (19'); 7-ethyl-9 - (2-aminocarbonyl-ethyl) camptothecin (20 '), 10-ethyl camptothecin (21'), 10- (2-methoxycarbonyl-ethyl) camptothecin (22 '), 10- (2-hydroxycarbonyl-ethyl) camptothecin (23) '); 10 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (24'); - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (25 '); [(2-amino-2-hydroxycarbonyl] -ethyl) camptothecin (26 '); 10 - [(2-Acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (27 '); 10- (3-oxo-butyl) camptothecin (28 '); 10- (3-oxo-3-phenyl-propyl) camptothecin (29 '); 10- (2-aminocarbonyl-ethyl) camptothecin (30 '); 7-ethyl-10-ethyl camptothecin (31 '); 7-ethyl-10- (2-methoxycarbonyl-ethyl) camptothecin (32 '); 7-ethyl-10- (2-hydroxycarbonyl-ethyl) camptothecin (33 '); 7-ethyl-10 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (34 '); 7-ethyl-10 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (35 '); 7-ethyl-10 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (36 '); 7-ethyl-10 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (37 '); 7-ethyl-10- (3-oxo-butyl) camptothecin (38 '); 7-ethyl-10- (3-oxo-3-phenyl-propyl) camptothecin (39 '); 7-ethyl-10- (2-aminocarbonyl-ethyl) camptothecin (40 '); 11-ethyl camptothecin (41 '); 11- (2-methoxycarbonyl-ethyl) camptothecin (42 '); 11- (2-hydroxycarbonyl-ethyl) camptothecin (43 '); 11 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (44 '); 11 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (45 '); 11 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (46 '); 11 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (47 '); and * -l- (3-oxo-butyl) camptothecin (48 '); 11- (3-oxo-3-phenyl-propyl) camptothecin (49 '); 11- (2-aminocarbonyl-ethyl) camptothecin (50 '); 9-amino-12-ethyl camptothecin (51 '); 9-amino-12- (2-methoxycarbonyl-ethyl) camptothecin (52 '); 9-amino-12- (2-hydroxycarbonyl-ethyl) camptothecin (53 '); 9-amino-12 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (54 '); 9-amino-12 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (55 '); 9-amino-12 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (56 '); 9-amino-12 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (57 '); 9-amino-12- (3-oxo-butyl) camptothecin (58 '); 9-amino-12- (3-oxo-3-phenyl-propyl) camptothecin (59 '); 9-amino-12- (2-aminocarbonyl-ethyl) camptothecin (60 '); 10-amino-9-ethyl camptothecin (61 '); 10-amino-9- (2-methoxycarbonyl-ethyl) camptothecin (62 '); 10-amino-9- (2-hydroxycarbonyl-ethyl) camptothecin (63 '); 10-amino-9 - [(2-acetylamino-2-methoxycarbonyl) -ethyl] camptothecin (64 '); 10-amino-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (65 '); -amino-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (66 '); -amino-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] -r amptothecin (67 '); 10-amino-9- (3-oxo-butyl) camptothecin (68 '); 10-amino-9- (3-oxo-3-phenyl-3-one-propyl) camptothecin (69 '); 10-amino-9- (2-aminocarbonyl-ethyl) camptothecin (70 '); 12-ethyl camptothecin (71 '); 12- (2-methoxycarbonyl-ethyl) camptothecin (72 '); 12- (2-hydroxycarbonyl-ethyl) camptothecin (73 '); 12- [(2R, S,) (2-acetylamino-2-methoxycarbonyl) -ethyl] f 'camptothecin (74'); 12 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (75 '); 12 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (76 '); 12- [(2-Acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (77 '); 12- (3-oxo-butyl) camptothecin (78 '); 12- (3-oxo-3-phenyl-propyl) camptothecin (79 '); 12- (2-aminocarbonyl-ethyl) camptothecin (80 '); 10-hydroxy-9-ethyl camptothecin (81 '); 10-hydroxy-9- (2-methoxycarbonyl-ethyl) camptothecin (82 '); 10-hydroxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (83 '); -hydroxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (84 '); 10-hydroxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (85 '); -hydroxy-9 - [(2-amino-2-hydroxycarbonyl] -ethyl) camptothecin,. (86 '); 10-hydroxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (87 '); 10-hydroxy-9- (3-oxo-butyl) camptothecin (88 '); 10-hydroxy-9- (3-oxo-3-phenyl-3-one-propyl) camptothecin (89 '); -hydroxy-9- (2-aminocarbonyl-ethyl) camptothecin (90 '); 10, 11-methylenedioxy-9-ethyl camptothecin (91 '); 10, 11-methylenedioxy-9- (2-methoxycarbonyl-ethyl) camptothecin, • (92 '); 10, 11-methylenedioxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (93 '); 10, 11-methylenedioxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (94 '); 10, 11-methylenedioxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (95 '); 10, 11-methylenedioxy-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (96 '); 10, 11-methylenedioxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (97 '); 10, 11-methylenedioxy-9- (3-oxo-butyl) camptothecin (98 '); 10, 11-methylenedioxy-9- (3-oxo-3-phenyl-propyl) camptothecin (99 '); 10, 11-methylenedioxy-9- (2-aminocarbonyl-ethyl) camptothecin (100 '); -methoxy-9-ethyl camptothecin (101 '); 10-methoxy-9- (2-methoxycarbonyl-ethyl) camptothecin (102 '); 10-methoxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (103 '); 10-methoxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) 'camptothecin (104'); 10-methoxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (105 '); 10-methoxy-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (106 '); 10-methoxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (107 '); 10-methoxy-9- (3-oxo-butyl) camptothecin (108 '); 10-methoxy-9- (3-oxo-3-phenyl-propyl) camptothecin (109 '); 10-methoxy-9- (2-aminocarbonyl-ethyl) camptothecin (110 '); and, wherein a salifiable substituent on the backbone of the molecule is present, its pharmaceutically acceptable salts. The structural formula of the compounds listed above is illustrated in the following Table 1 with reference to the above formula (I) wherein the symbol represents a double bond, and Table 2 with reference to the above formula (I) wherein the symbol represents a simple link.

Table 1 Table 1 (continued) Table 1 (continued) Table 1 (continued) Table 2 Table 2 (continued) Table 2 (continued) Table 2 (continued) Table 2 (continued) Table 2 (Continued) Table 2 (continued) In Tables 1 and 2, the symbols Et and Ph refer respectively to ethyl and phenyl. The present invention also includes in its scope a process for preparing the compounds of formula (I) as defined above, the process comprising 1) reacting a compound of formula (II) wherein Rn is a halogen atom, -OS02R? 2 in which Ri2 is alkyl C1-C5 unsubstituted or substituted at the terminal carbon atom by one, two or three halogen atoms or an optionally substituted phenyl ring; R < is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl or C? -C6 phenylalkyl; and X is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl, C? -C6 alkoxy, C3-C7 cycloalkoxy, C? -C6 alkanoyloxy, benzyloxy, amino hydroxy, nitro, halogen or is a group ^ methylenedioxy linked to positions 10 and 11 of the molecule, with a compound of formula (III) in which Ri, R2 and R3 are as defined under (a) or (b) below: (a) Ri and R2 are each independently hydrogen; • "C" -C4 alkyl, C3-C7 cycloalkyl, Ci-Cβ phenylalkyl, an optionally substituted phenyl ring, -NR5R6 in which one of R5 and Re is hydrogen, i-Cß alkyl or benzyl and the other is hydrogen, Ci-Cß alkanoyl, an optionally substituted benzoyl, C?-C6 phenylalkanoyl, an optionally substituted C?-C6 alkoxycarbonyl, an optionally substituted phenoxycarbonyl or C?-C6 phenylalkoxycarbonyl, or R5 and Re, combined together with a nitrogen atom to which they are bound, they form a heteromonocyclic, optionally substituted, saturated ring of 4-7 members, represented by a group (G) wherein W is -C = 0, R7 is hydrogen or C? -C6 alkyl and n is an integer from 2 to 5; COOR8 in which R8 is C? -C6 alkyl, C3-C7 cycloalkyl or C? -C6 phenylalkyl; or COR9 in which R9 is C? -C6, C3-C7 cycloalkyl, C? -C6 phenylalkyl, a phenyl ring optionally substituted, RioRp in which Rio and Rp are each ~ ~ independently hydrogen or Ci-Ce alkyl; and R 3 is hydrogen, C 1 -C 6 alkyl or an optionally substituted phenyl; or (b) Rx and R, combined together, form an optionally substituted, 5-8 membered carbon monocyclic ring; and R 2 is hydrogen, C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl; thereby obtaining a compound of formula (I) in which the symbol represents a double bond; and, if desired, 2) reducing a compound of formula (I) as obtained under step 1) into a corresponding compound of formula (I) in which the symbol represents a single bond, and / or if desired, salifying a compound of formula (I). The starting compounds of formula (II) have a configuration (S), which is retained through the process leading to the compounds of formula (I). The compounds of formula (II) are typically free of the corresponding isomers (R). However, the process can be applied to a racemic mixture of a compound of formula (II) and a corresponding 20 (R) isomer. In that case, a racemic mixture of a compound of formula (I) and a 20 (R) isomer of a compound is obtained of formula (I). When one or more new stereogenic centers are created in one of the steps mentioned above, all possible isomers, diastereomers, epimers and geometrical isomers are included in the present description. The reaction reported under step 1) can be carried out in a stable solvent, in the presence of catalytic amounts, ie from 0.0001 to 0.2 molar equivalents, of a compound of the formula MLqL'r in which M represents Palladium, Nickel or Platinum. L and L ', which may be the same or different, represent an anion such as, for example, a halide or an acetate or a neutral molecule, such as, for example, a solvent molecule, a phosphine, a phosphite or a diamine; and qyr may vary from 0 to 4, provided that q + r is at least 1, at a temperature of from about -20 ° C to about 200 ° C, preferably from about 20 ° C to about 100 ° C, for a time which may vary from a few minutes to several days, such as, for example, from 5 minutes to 3 days, preferably from approximately one hour to approximately one day, optionally in the presence of a suitable organic or inorganic base, and optionally in the presence of lithium halides, such as, for example, LiCl, or LiBr. Suitable solvents include, for example, dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO), CHC13, dioxane, tetrahydrofuran (THF) and mixtures thereof. Suitable inorganic bases include, for example, salts with alkali or alkaline earth metals, such as, for example, NaHCO 3, Na 2 CO 3, or NaOAc. Suitable organic bases may be, for example, trialkylamines, such as, for example, triethylamine or diisopropylethylamine; or heteroaromatic bases such as, for example, pyridine, or pyridines substituted at the 2,6-positions, with C 1 -C 6 alkyl, such as, for example, 2,6-lutidine. Preferred groups that L and / or L 'may represent are halides; acetates; phosphines such as, for example, triphenylphosphine or chelating diphosphines such co or, for example, bis (diphenylphosphino) methane, 1,2- and 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) -butane or 1, 1'-bis (diphenylphosphino) ferrocene (DPPF). The molar ratio of the transition metal atom and / or is generally from 1: 1 to 1: 4.

The reduction reported under point 2) may -effecting by reacting a compound of formula (I) as above under point 1) by the use of suitable reducing agents, in the presence of suitable catalysts. Suitable catalysts for the aforementioned reduction are metals known to effect the reduction of multiple bonds such as, for example, Palladium, Platinum oxide, Platinum, Rhodium, Nickel or Ruthenium. Suitable reducing agents for the reduction mentioned above are those of molecular hydrogen or hydrogen sources such as, for example, triethylammonium formate, formic acid, tributyltin hydride, cyclohexadiene, etc., in a suitable solvent such as, for example, dimethylformamide (DMF), CH3OH, acetic acid, CHC13, dioxane, or mixtures thereof, at a temperature from about 0 ° C to about 100 ° C, for a time of 1 hour to 3 days, at a pressure of about 1 atm to approximately 100 atm. The starting materials used in this description are known compounds or can be obtained following the known methods. For example, 9-halogen camptothecin, 10-halogen camptothecin, 11-halogen camptothecin, and 12-halogen camptothecin can be prepared from a-'ierdo a Sawada, S., et al., Chem. Pharm. Bull. 39, 3183- •• ^ 188 (1991). For example, 10-hydroxy-9-halogen camptothecin, 10-methoxy-9-halogen camptothecin, and 10, 11-methylenedioxy-9-halogen camptothecin can be prepared starting from the 9-amino-substituted derivatives at positions 10 or 10, 11, prepared by the known procedures (see, for example, Wall et al., J. Med. Chem. 1993, 36.2689-2700, or Wani et al., J. Med. Chem. 1986, 29, 2358-2363. ), and then following the cited reference. For example, the 9-trifluoromethanesulfonyloxy camptothecin, 10-trifluoromethansulfonyloxy camptothecin, 11- trifluoromethanesulfonyloxy camptothecin, 12-trifluoromethansulfonyloxy camptothecin, 10-hydroxy-9-trifluoromethansulfonyloxy camptothecin, 10-methoxy-9-trifluoromethansulfonyloxy camptothecin, 10, ll -methylene-dioxy-9-trifluoro- methanesulfonyloxy camptothecin, 10-p-toluenesulfonyloxy camptothecin, 11-p-toluenesulfonyloxy camptothecin, 12-p- toluenesulfonyloxy camptothecin, 10-hydroxy-9-toluenesulfonyloxy camptothecin, 10-methoxy-9- toluenesulfonyloxy camptothecin and 10, ll-methylenedioxy-9-p-toluenesulfonyloxy camptothecin were prepared from derivatives corresponding hydroxy obtained, in turn, as described in the references cited above, and treatment with suitable sulfonylating agents.

The compounds of the present invention are labeled with antitumor activity, for example against leukemia and solid tumors, such as, for example, colon and rectal tumors. The antitumor activity of the compounds of the present invention are shown, for example, by the fact that they have been found to possess antileukemic activity when tested according to the method described in: J. Med.

Chem 1993, 36, 2689, using the murine lymphoid leukemia model of L1210. As an example, the activity of (E) -9- (2-methoxycarbonyletenyl) camptothecin (internal code FCE 28681) and 9- (2-methoxycarbonyl-ethyl) camptothecin (internal code FCE 29559) was tested according to the following method (to) . The compounds were dissolved in dimethylsulfoxide (DMSO) at a final concentration of 0.5%. The percentage of the DMSO solution does not affect cell growth.

Method (a): evaluation of cytotoxic activity Murine leukemia cells were grown L1210 in vitro as floating cells in RPMI 1640 medium supplemented with 10% fetal sheep serum, 1% 200 mM L-glutamine, 1% 1 mM B-mercaptoethanol, 100 IU / ml penicillin and 100 μg of streptomycin. To test the cytotoxicity, exponentially growing cells were seeded to the concentration of 5 × 10 04 cells / ml and exposed to graded doses with the compounds under evaluation for 48 h at 37 ° C in a modified atmosphere of 5% C02. The number of surviving cells was determined with a Coulter Counter; the results were expressed as IC 50 (doses that cause 50% inhibition of cell growth in the treated cultures in relation to the untreated controls after 48 h of treatment) in this test the (E) -9- (2-methoxycarbonyl -etenil) camptothecin (internal code FCE 28681) and 9- (2-methoxycarbonyl-ethyl) camptothecin (internal code FCE 29559) and the results obtained are reported in Table 1 below.

-' Table 1 A human or animal body can be treated in this way by a method comprising the administration thereto of a pharmaceutically effective amount of a compound of formula (I) or a salt thereof. The conditions of the human or ^ -imal can therefore be improved. Pharmaceutical compositions containing the novel camptothecin analogs according to the invention are also within the scope of the present invention. These pharmaceutical compositions may contain any amount of a camptothecin analog that is effective to exhibit any antitumor activity in vivo. Mammals such as humans are treatable with the compositions of the invention. Typical doses in vivo within the scope of the invention are 0.1-60 mg of camptothecin analog per kg body weight. A particularly preferred range is 1-40 mg / kg. The composition may also include binder, and / or pharmaceutically compatible adjuvant materials as part of the composition. The active materials can also be mixed with other active materials that do not impart the desired action and / or supplement the desired action. The active materials according to the present invention can be administered by any route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically. In liquid or solid form. A preferred mode of administration of the compounds of the invention is oral.

The oral compositions will generally include a * -enable or inert edible carrier. They can be embedded in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, the aforementioned compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, syrups and the like. These preparations should contain at least 0.1% active compound but may vary depending on the particular form. The tablets, dragees, capsules, troches and the like may contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin, an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like, a lubricant such as magnesium stearate or Sterotes, a lubricating agent such as colloidal silicon dioxide, an agent and sweetener such as sucrose or saccharin or a flavoring agent such as peppermint may be added , methyl salicylate, or orange flavor When the unit dosage form is a capsule it may contain, in addition to the material of the above type, a liquid carrier such as a fatty oil Other dosage unit forms may contain other different materials which they modify to the physical form of the dose unit, for example, how coatings. In this way tablets or coated tablets can be coated with a stamp of sugar or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as an adulterating agent and certain preservatives, dyes and dyes and flavorings. The material used to prepare these different compositions should be pharmaceutically pure and non-toxic in the amount used. For the purpose of parenteral therapeutic administration, the active ingredient can be incorporated into a solution or suspension. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium disulphate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral preparation can be contained in ampoules, disposable syringes or multi-dose vials made of glass or plastic.

The dose values will vary with the specific severity of the condition of the disease to be alleviated.

Good results are achieved when the compounds described herein are administered to a subject that requires such treatment as an effective oral, parenteral or intravenous dose. It should be understood that for any particular subject, specific dosage regimens should be adjusted for the individual needs and professional judgment that administers and supervises the administration of the above mentioned compound. It should further be understood that the doses set forth herein are exemplary only and do not limit the scope or practice of the invention. The doses may be administered once, or they may be divided into a number of small doses to be administered at varying time intervals. The following examples illustrate but do not limit the invention. The number reported in brackets before the chemical name of the compounds prepared according to the following examples corresponds to a given number to the preferred compounds listed on pages 6-18 of the present specification.

Preparation of starting materials Method A: 9-bromo camptothecin 2.15 g of NaN02 in 40 mL of H20 at 5 ° C were dripped into a solution of 9 g of 9-amino-camptothecin in 850 mL of 16% HBr. 1 hr after t.a. the solution was dripped into a flask containing 19 g of CuBr in 200 mL of 16% HBr at 70 ° C. The / - reaction was allowed to stand at 70 ° C for 2 hr, then poured into cold water. The filtrate was precipitated and the • mother liquors were extracted with CH2C12; The dried and evaporated organic extract was combined with the precipitate and purified by flash chromatography (eluent: CH2C12 / CH30H = 95/5) to give 8.19 g of the title product. (assay by CLAP: 97.3%) * "^ -RN 400 MHz (DMSO-d6): d = 8.87 (s, 1H), 8.20 (d, J = 8.5, iH), 8.06 (d, J = 7.32, 1H ), 7.81-7.75 (m, 1H), 7.35 (s, 1H), 6. 53 (s, 1H), 5.42 (s, 2H), 5.32 (s, 2H) 1.89-1.82 (m, 2H), 0.87 (t, J = 7.32, 3H). MS (FD): M + = 427. By analogy starting from the corresponding amino derivatives, the following bromine derivatives were prepared: 10-bromo camptothecin; 11-bromine camptothecin; 2-bromo camptothecin; 10-hydroxy-9-bromo camptothecin; 10-methoxy-9-bromo camptothecin; and 10, 11-methylenedioxy-9-bromo camptothecin, Method B: 10-trifluoromethanesulfonyloxy camptothecin r- 1.25 g of 10-hydroxy camptothecin were dissolved in 35 mL of DMF and 2 L of Et3N and 1.5 g of N, N-Bis- (trifluoromethanesulfonyl) -aniline were added. The solution was heated at 50 ° C for 1 hr, then poured into water; the precipitate was filtered and the mother liquors were extracted with CH2C12. The organic extract, dried (Na2SO4) and evaporated, was , was combined with the precipitate and purified by flash chromatography (eluent: CH2C12 / CH30H = 98/2). 1 g of the title product was obtained (assay by CLAP: 97%) XH-NMR 400 MHz (DMSO-d6): d = 8.81 (s, 1H), 8.43-8.32 (m, 2H), 7.99-7.94 (m , 1H), 7.36 (s, 1H), 6.54 (s, 1H), 5.42 (s, 2H), 5.32 (s, 2H), 1.90-1.81 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). MS (FD): M * = 496 By analogy starting from the corresponding nitro and amino derivatives, the following sulfonyl derivatives were prepared: 9-trifluoromethanesulfonyloxy camptothecin; or 10-trifluoromethanesulfonyloxy camptothecin; 12-trifluorome ansulfonyloxy camptothecin 10, 11-methylenedioxy-9-trifluoromethanesulfonyloxy camptothecin 10-p-toluenesulfonyloxy camptothecin; 11-p-toluenesulfonyloxy camptothecin; j 0 12-p-toluenesulfonyloxy camptothecin; 10-methoxy-9-p-toluenesulfonyloxy camptothecin; and 10, 11-methylenedioxy-9-p-toluenesulfonyloxy camptothecin.

Example 5 12-vinyl camptothecin (65) / 1 g of 12-Br-camptothecin was dissolved in 20 mL of DMF; in an atmosphere of Ar, they were added in a Sequential 0.72 mL of Et3N, 3.61 mL of vinyltrimethylsilane, 0.071 g of DPPF and 0.026 g of Pd (OAc) 2. The reaction mixture was heated at 100 ° C for 1 hr and then treated with CH2C12 and water. The aqueous phase was extracted twice with CH2C12 and the organic extracts were collected, dried (Na2SO4), and evaporated. The residue was dissolved in 20 L of CH2C12 mL of CF3COOH were added and the solution was left at t.a. arante 24 hr. The reaction was worked up as above and the product was purified by flash chromatography (eluent : CH2C12 / CH30H = 95/5) to give 0.59 g of the title product (trial by CLAP: 97%). ^ -RMN 400 MHz (DMSO-d6): d = 8.67 (s, 1H), 8.14-8.00 (m, 3H), 7.69 (t, J = 7.9Hz, 1H), 7.36 (s, 1H), 6.54 (s, 1H), 6.14 (dd, J = 1.2, 17.9Hz, 1H), 5.57 (d, J = 12.3Hz, 1H), 5.42 (s, 2H), 5.28 (s, 2H) 1.94-1.80 (m, 2H), 0.88 (t, J = 7.0Hz, 3H). MS (FD): Mh = 374. By analogy the following compounds were obtained (Table 1): 9-vinyl camptothecin (1); 7-ethyl-9-vinyl camptothecin (9); 10-vinyl camptothecin (17); 7-ethyl-10-vinyl camptothecin (25); , 10-hydroxy-9-vinyl camptothecin (33); 10, 11-methylenedioxy-9-vinyl camptothecin (41); 10-methoxy-9-vinyl camptothecin (49); 11-vinyl camptothecin (57); 9-amino-10-vinyl camptothecin (73); and 7-ethyl-9-amino-10-vinyl camptothecin (81); Example 2 Z) -12- (2-Acetylamino-2-methoxycarbonyl-eteni1) camptothecin (68) 2 g of 12-Br-camptothecin were dissolved in 40 mL of DMF; in an atmosphere of Ar, 0.72 mL of Et3N, 3.32 g of 2-acetamidoacrylate of Methyl, 0.14 g of DPPF and 0.052 g of Pd (OAc) 2 were added sequentially. The reaction mixture was heated at 100 ° C for 24 hr. The reaction mixture was cooled to room temperature, diluted with CH2C12 and washed with water. The organic extracts dried (Na2SO4), and the solvent was removed under vacuum. The pure product was purified by flash chromatography (eluent: CH2C12 / CH30H = 98/2) to give 1.72 g of the title product (assay by CLAP: 97.4%) XH-NMR 400 MHz (DMSO-d6): d = 9.79 (s, 1H), 8.78 (s, 1H) , • "8.32 (s, 1H), 8.18 (d, J = 7.03 Hz, 1H), 8.15 (d, J = 7.91 Hz, 1H), 7.75 (t, J = 7.62 Hz, 1H) 7.34 (s, 1H), 6.56 (s, 1H), 5.43 (s, 2H), 5.43 (s, 2H), 3.78 (s, 3H), 1.98 (s, 3H), 1.88 (m, 2H), 0.88 (t, J = 7.3Hz, 3H). MS (FD): M + - 489. When a solution of (Z) -12- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin was allowed to stand at room temperature for 2 weeks, a 50/50 mixture of isomers was obtained E and Z.

By analogy the following were obtained, "Compounds (Table 1): 10- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (20); 10- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (21); 7-ethyl-1-10- (2-acetylamino-2-methoxycarbonyl-1-ethenyl) camptothecin (28); 7-ethyl-10- (2-acetylamino-2-hydroxycarbonyl-1-ethenyl) camptothecin (29); 10-hydroxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (36); 10-hydroxy-9- (2-acetylamino-2-hydroxycarbonyl-1-ethenyl) camptothecin (37); 10, 11-methylenedioxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (44); 10, 11-methylenedioxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (45); 10-methoxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (52); 10-methoxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (53); 11- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (60); 11- (2-Acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (61); 12- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin - "" 69); 9-amino-10- (2-acetylamino-2-methoxycarbonyl-1-ethenyl) camptothecin (76); 9-amino-10- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (77); 7-ethyl-9-amino-10- (2-acetylamino-2-methoxycarbonyl-1-ethenyl) camptothecin (84); and 7-ethyl-9-amino-10- (2-acetylamino-2-hydroxycarbonyl-ethenyl) 'camptothecin (85).

Example 3 (E) -12- (2-methoxycarbonyl-ethenyl) captptothecin (66) g of 12-Br-camptothecin were dissolved in 50 mL _-- of DMF; in an Ar atmosphere, 1.5 mL of Et3N, 4.6 g of Methyl acrylate, 0.28 g of DPPF and 0.11 g of Pd (OAc) 2 were added sequentially. The reaction mixture was heated at 100 ° C for 18 hr then worked up by diluting with CH2C12 and washing twice with water. The organic phase was dried (Na2SO4), evaporated and the residue was purified by flash chromatography (eluent: CH2C12 / CH30H = 98/2) to give 4.1 g of the title product (assay by CLAP: 93.34%) ^ -RMN 400 MHz (DMSO-d6): d = 8.94, (d, J = 16.2 Hz, 1H), • .73 (s, 1H), 8.39 (d, J = 6.7 Hz, 1H), 8.21 (d , J = 8.2 Hz, 1H), 7.75 (t, J = 7.6, 1H), 7.36 (s, 1H), 7.00 (d, J = 16.2 Hz, 1H), 6.59 (s, 1H), 5.43 (s, 2H), 5.30 (s, 2H), 3.80 (s, 3H), 1.88 (m, 2H), 0.89 (t, 3H). MS (FD): M + = 432. By analogy, the. following compounds (Table 1): 11- (2-methoxycarbonyl-ethenyl) camptothecin (58); Y 11- (2-hydroxycarbonyl-ethenyl) camptothecin (59); 11- (3-oxo-but-l-enyl) camptothecin (62); 11- (3-oxo-3-phenyl-propenyl) camptothecin (63); 11- (2-aminocarbonyl-ethenyl) camptothecin (64); 12- (2-hydroxycarbonyl-ethenyl) camptothecin (67); 12- (3-oxo-but-l-enyl) camptothecin (70); 12- (3-oxo-3-phenyl-propenyl) camptothecin (71); 12- (2-aminocarbonyl-ethenyl) camptothecin (72); 9-amino-10- (2-methoxycarbonyl-ethenyl) camptothecin (74); 9-amino-10- (2-hydroxycarbonyl-ethenyl) camptothecin (75); 9-amino-10- (3-oxo-but-l-enyl) camptothecin (78); 9-amino-10- (3-oxo-3-phenyl-propenyl) camptothecin (79); 9-amino-10- (2-aminocarbonyl-ethenyl) camptothecin (80); 7-Ethyl-9-amino-10- (2-methoxycarbonyl-ethenyl) camptothecin (82); 7-ethyl-9-amino-10- (2-hydroxycarbonyl-ethenyl) camptothecin "'83); 7-ethyl-9-amino-10- (3-oxo-but-l-enyl) camptothecin (86); -ethyl-9-amino-10- (3-oxo-3-phenyl-propenyl) camptothecin (87); and 7-ethyl-9-amino-10- (2-aminocarbonyl-ethenyl) camptothecin (88); Example 4 f '12- (2-methoxycarbonyl-ethyl) camptothecin (52') 1 g of 12- (2-methoxycarbonyl-ethenyl) camptothecin was dissolved in 20 mL of DMF and hydrogenated in the presence of 0.1 g of Pd / C at t.a. under 1 atm of H2. The reaction mixture was filtered through a pad of celite by curing the celite perfectly with DMF, the solvent was evaporated and the "Residue was purified by flash chromatography (eluent: CH2C12 / CH30H = 98/2) to give 0.82 g of the title product.

XH-NMR 400 MHz (DMSO-d6): d = 8.60 (s, 1H), 7.92 (dd, J = 1.5, 8.2 Hz, 1H), 7.66 (dd, J = 1.5, 7 Hz, 1H), 7.54 ( dd, J = 7, 8.2 Hz, 1H), 7.31 (s, 1H), 6.54 (s, 1H), 5.41 (s, 2H), 5.20 (m, 2H), 3.57 (s, 3H), 3.52-3.49 (, 2H), 2.84-2.81 (m, 2H), 1.88-1.84 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). MS (FD): M + = 434.

By analogy the following compounds were obtained (Table 2): 11-ethyl camptothecin (41 '); 11- (2-methoxycarbonyl-ethyl) camptothecin (42 '); 11- (2-hydroxycarbonyl-ethyl) camptothecin (43 '); 11- (3-oxo-butyl) camptothecin (48 '); 11- (3-oxo-3-phenyl-propyl) camptothecin (49 '); 11- (2-aminocarbonyl-ethyl) camptothecin (50 '); 9-amino-12-ethyl camptothecin (51 '); / 9-amino-12- (2-methoxycarbonyl-ethyl) camptothecin (52 '); 9-amino-12- (2-hydroxycarbonyl-ethyl) camptothecin (53 '); 9-amino-12- (3-oxo-butyl) camptothecin (58 '); 9-amino-12- (3-oxo-3-phenyl-propyl) camptothecin (59 '); 9-amino-12- (2-aminocarbonyl-ethyl) camptothecin (60 '); 10-amino-9-ethyl camptothecin (61 '); 10-amino-9- (2-methoxycarbonyl-ethyl) camptothecin (62 '); 10-amino-9- (2-hydroxycarbonyl-ethyl) camptothecin (63 '); 10-amino-9- (3-oxo-butyl) camptothecin (68 '); 10-amino-9- (3-oxo-3-phenyl-3-one-propyl) camptothecin (69 '); 10-amino-9- (2-aminocarbonyl-ethyl) camptothecin (70 '); 12-ethyl camptothecin (71 '); 12- (2-hydroxycarbonyl-ethyl) camptothecin (73 '); 12- (3-oxo-butyl) camptothecin (78 '); 12- (3-oxo-3-phenyl-propyl) camptothecin (79 '); 12- (2-aminocarbonyl-ethyl) camptothecin (80 '); -hydroxy-9-ethyl camptothecin (81 '); '"0-hydroxy-9- (2-methoxycarbonyl-ethyl) camptothecin (82'); 10-hydroxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (83 '); 10-hydroxy-9- (3-oxo) -butyl) camptothecin (88 '); 10-hydroxy-9- (3-oxo-3-phenyl-3-one-propyl) camptothecin (89'); -hydroxy-9- (2-aminocarbonyl-ethyl) camptothecin (90 '); 10-methoxy-9-ethyl camptothecin (101 '); 10-methoxy-9- (2-methoxycarbonyl-ethyl) camptothecin (102 '); 10-methoxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (103 '); 10-methoxy-9- (3-oxo-butyl) camptothecin (108 '); 10-methoxy-9- (3-oxo-3-phenyl-propyl) camptothecin (109 '); Y -methoxy-9- (2-aminocarbonyl-ethyl) camptothecin (110 ').

Example 5 12- [(2R, S) (2-Acetylamino-2-methoxycarbonyl) ethyl] captptothecin (7 ') 1 g of (Z) -12- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin was dissolved in DMF. After the addition of 0.15 g of Pd / C the product was hydrogenated at a.t. for 28 hr. The reaction mixture was filtered through a pad of celite and evaporated; the residue was purified by flash chromatography (eluent: CH2C12 / CH30H) to give 0.89 g of the title product, (assay '^ "or CLAP: 96.7%) ^ -RMN 400 MHz (DMSO-d6): d = 8.66 (s, 1H), 8.49-8.43 (m, 1 HOUR) 7. 99 (d, J = 7.33 Hz, 1H), 7.63-7.60 (m, 2H), 7.42 (s, 1 / 2H) 5 7.40 (s, 1 / 2H), 6.56 (s, 1 / 2H) 6.54 (s) , 1 / 2H), 5.42 (s, 2H), . 30 (s, 2H), 4.75-4.66 (m, 1H), 3.96-3.88 (, 1H), 3.55 (s, 1. 5H), 3.49 (s, 1.5H), 3.36-3.31 (m, 1H), 1.81-1.87 (m, 2H) 1. 77 (s, 1.5H), 1.75 (s, 1.5H), 0.92-0.94 (m, 3H). MS (FD): M + = 491? 0 By analogy the following compounds were obtained (Table 2): 9- [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (4 '); 9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (5 '); 9- [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (6 '); .5 9- [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (7 '); 7-ethyl-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin Y . (14 '>' * 7-ethyl-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (15 '); 7-ethyl-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin 20 (16 '); 7-ethyl-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (17 '); 10 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (24 '); 10- [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (25 '); - [(2-amino-2-hydroxycarbonyl] -ethyl) camptothecin (26 '); , 0 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (27 '); 7-ethyl-10 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (34 '); 7-ethyl-10 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (35 '); 7-ethyl-10 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (36 '); 7-ethyl-10 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (37 '); / - 11 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (44 '); 11 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (45 '); 11 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (46 '); 11 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (47 '); 9-amino-12 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (54 '); 9-amino-12 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (55 '); / .9-amino-12 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (56 '); 9-amino-12 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (57 '); 10-amino-9 - [(2-acetylamino-2-methoxycarbonyl) -ethyl] camptothecin (64 '); 10-amino-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (65 '); -amino-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (66 '); -amino-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] f - amphotericin (67 '); 12 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (75 '); 12 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (76 '); 12- [(2-Acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (77 '); 10-hydroxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (84 '); 10-hydroxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (85 '); 10-hydroxy-9 - [(2-amino-2-hydroxycarbonyl] -ethyl) camptothecin (86 '); 10-hydroxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (87 '); 10, 11-methylenedioxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (94 '); 10, 11-methylenedioxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (95 '); 10, 11-methylenedioxy-9- t (2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (96 '); 10, 11-methylenedioxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (97 '); 10-methoxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (104 '); -methoxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin ", 105 '); 10-methoxy-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (106') and 10-methoxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (107 ').

Example 7 (Z) -9- (2-Acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (4) g of 9-Br-camptothecin were dissolved in 50 mL of DMF; in an Ar atmosphere, 1.8 mL of Et3N, 8.3 g of Methyl 2-acetamidoacrylate, 0.35 g of DPPF and 0.13 g of Pd (OAc) 2 were added sequentially. The reaction mixture was heated at 100 ° C for 7 hr and then extracted with CH2C12 and water. The organic extract was dried (Na2SO4), the solvent was evaporated and the residue was purified by flash chromatography (eluent: CH2C12 / CH30H = 98/2) to give 4.89 g of the title product, (assay by CLAP: 98.7%) ^ -NMR 400 MHz (DMSO-d6): d = 9.63 (s, 1H), 8.73 (s, 1H), 8.16 (d, J = 8.54 Hz, 1H), 7.89-7.85 (m, 1H), 7.77 (d , J = 7.26 Hz, 1H), 7.62 (s, 1H), 7.34 (s, 1H), 6.52 (s, 1H), 5.41 (s, 2H), 5.25 (s, 2H), 3.76 (s, 3H), 1.87-1.83 (m, 5H), 0.86 f t, J = 7.26, 3H). MS (FD): M + = 489 When a solution of (Z) -9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin was allowed to stand at t.a. for two weeks, a 50/50 mixture of the E and Z isomers was obtained. The XH-NMR spectrum of (E) -9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin is: d = 10.32 (s) , 1H), 8.74 (s, 1H), 8.09 (d, J = 8.79, 1H), 7.80-7.76 (m, 1H), 7.63 (s, 1H), 7.37-7.34 (m, 2H), 6.53 (s) , 1H), 5.42 (s, 2H), 5.28 (s, 2H), 3.42 (s, 3H), 2.02 (s, 3H), 1.89-1.82 (, 2H), 0.87 (t, J = 7.26, 3H) . By analogy the following compounds were prepared (Table 1): 9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (5); 7-Ethyl-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (12); and 7-ethyl-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (13) Example 8 (E) -9- (2-methoxycarbonyl-ethenyl) camptothecin (2) 1 g of 9-Br-camptothecin was dissolved in 11 mL of DMF; 0.3 mL of Et3N, 0.92 was added sequentially L of methyl acrylate, 0.056 g of DPPF, 0.022 g of '"" "' d (OAc) 2 under an Ar atmosphere. The reaction mixture was heated at 100 ° C for 3 hr after the reaction was finished and was present a yellowish white precipitate.The precipitate was filtered and washed twice with DMF and twice with Et20.The product was crystallized (CHC13 / DMF) to give 0.58 g of the title product (assay by CLAP: 95.59%) XH-NMR 400 MHz (DMSO-d6): d = 9.07 (s, 1H), 8.45 (d, J = 15.5 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 7.1, 1H), 7.88 (dd, J - 7.6 Hz, J '= 8.2 Hz, 1H), 7.34 (s, 1H), 6.80 (d, J = 15.8 Hz, 1H), 6.53 (s, 1H), 5.42 (s, 2H), 5.27 (s, 2H), 3.79 (s, 3H), 1.86 (m, 2H), 0.87 (t, 3H). MS (FD): M + = 432. By analogy the following compounds were prepared (Table 1): 9- (2-hydroxycarbonyl-ethenyl) camptothecin (3); , 9- (2-aminocarbonyl-ethenyl) camptothecin (8); 9- (3-oxo-but-l-enyl) camptothecin (6); 9- (3-oxo-3-phenyl-propenyl) camptothecin (7); 7-ethyl-9- (2-methoxycarbonyl-ethenyl) camptothecin (10); 7-ethyl-9- (2-hydroxycarbonyl-ethenyl) camptothecin (11); 7-ethyl-9- (3-oxo-but-l-enyl) camptothecin (14); 7-ethyl-9- (3-oxo-3-phenyl-propenyl) camptothecin (15); 7-ethyl-9- (2-aminocarbonyl-ethenyl) camptothecin (16); , 11-methylenedioxy-9- (2-methoxycarbonyl-ethenyl) camptothecin 42); 10, 11-methylenedioxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (43); 10, 11-methylenedioxy-9- (3-oxo-but-l-enyl) camptothecin (46); 10, 11-methylenedioxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (47); 10, 11-methylenedioxy-9- (2-aminocarbonyl-ethenyl) camptothecin (48); 10-methoxy-9- (2-methoxycarbonyl-ethenyl) camptothecin (50); 10-methoxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (51); 10-methoxy-9- (3-oxo-but-l-enyl) camptothecin (54); 10-methoxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (55); Y -methoxy-9- (2-aminocarbonyl-ethenyl) camptothecin (56).

Example 9 9- (2-m-toxicarbonyl-ethyl) camptothecin (2 ') 1.4 g of (E) -9- (2-methoxycarbonyl-ethenyl) camptothecin were dissolved in 400 L of DMF, 0.3 g of Pd / C were added and the mixture was hydrogenated at t.a. (1 atm of H2) for 3hr. The reaction mixture was filtered and the solvent was evaporated. The residue was purified by flash chromatography (eluent: CH2C12 / CH30H = 98/2) to give 1.2 g of the product "** <titre. lH-NMR 400 MHz (DMSO-d6): d = 8.89 (s, 1H), 8.03 (d, J = 8.49 Hz, 1H), 7.79-7.73 (, 1H), 7.55 (d, J = 7.03, 1H), 7.33 (s, 1H), 6.51 (s, 1H), 5.42 (s, 2H), 5.28 (s, 2H) ), 3.59 (s, 3H), 3. 42-3.36 (m, 2H), 2.88-2.77 (m, 2H), 1.91-1.80 (m, 2H), 0.87 (t, J = 7.33, 3H). MS (FD): M + = 434. By analogy the following compounds were prepared (Table 2): 9-ethyl camptothecin (1 '); 9- (2-hydroxycarbonyl-ethyl) camptothecin (3 '); 9- (3-oxo-butyl) camptothecin (8 '); 9- (3-oxo-3-phenyl-propyl) camptothecin (9 '); 9- (2-aminocarbonyl-ethyl) camptothecin (10 '); 7-ethyl-9-ethyl camptothecin (11 '); 7-ethyl-9- (2-methoxycarbonyl-ethyl) camptothecin (12 '); 7-ethyl-9- (2-hydroxycarbonyl-ethyl) camptothecin (13 '); 7-ethyl-9- (3-oxo-butyl) camptothecin (18 '); 7-ethyl-9- (3-oxo-3-phenyl-propyl) camptothecin (19 '); 7-ethyl-9- (2-aminocarbonyl-ethyl) camptothecin (20 '); 10-ethyl camptothecin (21 '); 10- (2-methoxycarbonyl-ethyl) camptothecin (22 '); 10- (2-hydroxycarbonyl-ethyl) camptothecin (23 '); 10- (3-oxo-butyl) camptothecin (28 '); - (3-oxo-3-phenyl-propyl) camptothecin (29 '); "*" 0- (2-aminocarbonyl-ethyl) camptothecin (30 '); 7-ethyl-10-ethyl camptothecin (31 '); 7-ethyl-10- (2-methoxycarbonyl-ethyl) camptothecin (32 '); 7-ethyl-10- (2-hydroxycarbonyl-ethyl) camptothecin (33 '); 7-ethyl-10- (3-oxo-butyl) camptothecin (38 '); 7-ethyl-10- (3-oxo-3-phenyl-propyl) camptothecin (39 '); 7-ethyl-10- (2-aminocarbonyl-ethyl) camptothecin (40 '); 10, 11-methylenedioxy-9-ethyl camptothecin (91 '); 10, 11-methylenedioxy-9- (2-methoxycarbonyl-ethyl) camptothecin (92 '); 10, 11-methylenedioxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (93 '); 10, 11-methylenedioxy-9- (3-oxo-butyl) camptothecin (98 '); 10, 11-methylenedioxy-9- (3-oxo-3-phenyl-propyl) camptothecin (99 '); and 10, 11-methylenedioxy-9- (2-aminocarbonyl-ethyl) camptothecin (100 ').

Example 10 (E) -10- (2-methoxycarbonyl-ethenyl) camptothecin (18) 1 g of 10-trifluoromethanesulfonyloxy camptothecin was dissolved in 10 mL of DMF; in an atmosphere of Ar, it sequentially added 0.31 mL of Et3N, 0.91 mL of 'Methyl acrylate, 0.062 g of DPPF and 0.023 g of Pd (OAc) 2. The reaction was heated at 80 ° C for 24 hr and then worked up by diluting with CH2C12 and washing twice with brine. The organic phase was dried (Na 2 SO 4), evaporated and the residue was purified by flash chromatography (eluent: CH2C12 / CH30H = 99/1) to give 0.5 g of the title product. (assay by CLAP: 97%) ^ -RMN 400 MHz (DMSO-d6): d = 8.65 (s, 1H), 8.42 (s, 1H), 8.24 (d, J = 9.0 Hz, 1H), 8.14 (d , J - 9.0 Hz, 1H), 7.86 (d, J = 16.1 Hz, 1H), 7.34 (s, 1H), 6.87 (d, J = 16.1 Hz, 1H), .6.53 (s, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 3.76 (s, 3H), 1.88-1.82 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). MS (FD): M + - 432. By analogy the following compounds were prepared (Table 1):,. 10- (2-hydroxycarbonyl-ethenyl) camptothecin (19); 10- (3-oxo-but-l-enyl) camptothecin (22); 10- (3-oxo-3-phenyl-propenyl) camptothecin (23); 10- (2-aminocarbonyl-ethenyl) camptothecin (24); 7-ethyl-10- (2-methoxycarbonyl-ethenyl) camptothecin (26); 7-ethyl-10- (2-hydroxycarbonyl-ethenyl) camptothecin (27); 7-ethyl-10- (3-oxo-but-l-enyl) camptothecin (30); 7-ethyl-10- (3-oxo-3-phenyl-propenyl) camptothecin (31); 7-ethyl-10- (2-aminocarbonyl-ethenyl) camptothecin (32); -hydroxy-9- (2-methoxycarbonyl-ethenyl) camptothecin (34); "j-hydroxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (35); 10-hydroxy-9- (3-oxo-but-l-enyl) camptothecin (38); 10-hydroxy-9- (3-) oxo-3-phenyl-propenyl) camptothecin (39); and 10-hydroxy-9- (2-aminocarbonyl-ethenyl) camptothecin (40).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (6)

1. The substituted camptothecin derivatives of formula (I) characterized because the symbol represents a single or double bond; Ri, R2 and R3 are as defined under (a) or (b) below: (a) Ri and R2 are, each independently, hydrogen; C? -C4 alkyl; C3-C7 cycloalkyl; phenylalkyl of C? -C6; an optionally substituted phenyl ring; -NR5R6 wherein one of R5 and Re is hydrogen, C? -C6 alkyl or benzyl and the other is hydrogen, C? -C6 alkanoyl, an optionally substituted C? -C6 alkoxycarbonyl, an optionally substituted benzoyl, phenylalkanoyl C? -C6, an optionally substituted phenoxycarbonyl or C? -C6 phenylalkoxycarbonyl, or R5 and R6, combined together with the nitrogen atom to which they are bound, they form a residue of 4-7 membered, optionally substituted, heteromonocyclic ring, represented by a group (G) wherein W is -C = 0, R; is hydrogen or C? -C6 alkyl and n is an integer from 2 to 5; COOR8 wherein R8 is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl or C? -C6 phenylalkyl; or CORg wherein R9 is C? -C6 alkyl, C3-C7 cycloalkyl, C? -C6 phenylalkyl, an optionally substituted phenyl ring or R? 0Rn wherein Rio and Rp are, each independently, hydrogen or alkyl from C? -C6; and R 3 is hydrogen, C 1 -C 6 alkyl or an optionally substituted phenyl ring; or (b) Ri and R3, combined together, form a carbominated cyclic ring, optionally substituted with 5-8 members; and R 2 is hydrogen, C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl; R 4 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 phenylalkyl; X is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl, C? -C6 alkoxy, C3-C7 cycloalkoxy, Ci-Ce alkanoyloxy, benzoyloxy, amino, hydroxy, nitro, halogen or is a methylenedioxy group linked to positions 10 and 11 of the molecule, and pharmaceutically acceptable salts thereof.

2. The compound of formula (I), according to claim 1, characterized in that the symbol represents a single or double bond; Ri and R2 are, each independently, hydrogen; -NR 5 R 6 wherein one of R 5 and e is hydrogen and the other is hydrogen, C?-C6 alkanoyl, an optionally substituted benzoyl, C?-C6 phenylalkanoyl, a C?-C6 alkoxycarbonyl, phenoxycarbonyl or C fen-phenylalkoxycarbonyl C6; , COOR8 wherein Rβ is hydrogen or C? -C6 alkyl; or COR9 wherein R9 is C? -C6 alkyl, unsubstituted phenyl or NR10R11 wherein Ri0 and Rn are both hydrogen; R3 is hydrogen; R 4 is hydrogen or Ci-Cß alkyl; X is hydrogen, hydroxy, amino, C? -C6 alkoxy or is a methylenedioxy group linked to positions 10 and 11 of the molecule, and pharmaceutically acceptable salts thereof.

3. A compound, characterized in that it is taught of: 9-vinyl camptothecin (1); (E) -9- (2-methoxycarbonyl-ethenyl) camptothecin (2); 9- (2-hydroxycarbonyl-ethenyl) camptothecin (3); (Z) -9- (2-Acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (4); 9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (5); 9- (3-oxo-but-l-enyl) camptothecin (6); 9- (3-oxo-3-phenyl-propenyl) camptothecin (7); 9- (2-aminocarbonyl-ethenyl) camptothecin (8); 7-ethyl-9-vinyl camptothecin (9); 7-ethyl-9- (2-methoxycarbonyl-ethenyl) camptothecin (10); 7-ethyl-9- (2-hydroxycarbonyl-ethenyl) camptothecin (11); 7-Ethyl-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (12); 7-ethyl-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (13); 7-ethyl-9- (3-oxo-but-l-enyl) camptothecin (14); 7-ethyl-9- (3-oxo-3-phenyl-propenyl) camptothecin (15); 7-ethyl-9- (2-aminocarbonyl-ethenyl) camptothecin (16); 10-vinyl camptothecin (17); (E) -10- (2-methoxycarbonyl-ethenyl) camptothecin (18); 10- (2-hydroxycarbonyl-ethenyl) camptothecin (19); 10- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (20); 10- (2-Acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (21); •, 0- (3-oxo-but-l-enyl) camptothecin (22); 10- (3-oxo-3-phenyl-propenyl) camptothecin (23); 10- (2-aminocarbonyl-ethenyl) camptothecin (24); 7-ethyl-10-vinyl camptothecin (25); 7-ethyl-10- (2-methoxycarbonyl-ethenyl) camptothecin (26); 7-ethyl-10- (2-hydroxycarbonyl-ethenyl) camptothecin (27); 7-ethyl-10- (2-acetylamino-2-methoxycarbonyl-1-ethenyl) camptothecin (28); 7-ethyl-10- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (29); 7-ethyl-10- (3-oxo-but-l-enyl) camptothecin (30); 7-ethyl-10- (3-oxo-3-phenyl-propenyl) camptothecin (31); 7-ethyl-10- (2-aminocarbonyl-ethenyl) camptothecin (32); 10-hydroxy-9-vinyl camptothecin (33); 10-hydroxy-9- (2-methoxycarbonyl-ethenyl) camptothecin (34); f ... 10-hydroxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin '(35); 10-hydroxy-9- (2-acetylamino-2-methoxycarbonyl-1-ethenyl) camptothecin (36); 10-hydroxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (37); 10-hydroxy-9- (3-oxo-but-l-enyl) camptothecin (38); 10-hydroxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (39); 10-hydroxy-9- (2-aminocarbonyl-ethenyl) camptothecin (40); 10, 11-methylenedioxy-9-vinyl camptothecin (41); 10, 11-methylenedioxy-9- (2-methoxycarbonyl-ethenyl) camptothecin < 42); 10, 11-methylenedioxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (43); 10, 11-methylenedioxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (44); 10, 11-methylenedioxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (45); 10, 11-methylenedioxy-9- (3-oxo-but-l-enyl) camptothecin (46); r "10 10, 11-methylenedioxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (47); 10, 11-methylenedioxy-9- (2-aminocarbonyl-ethenyl) camptothecin (48); -9-vinyl camptothecin (49); IZ 10-methoxy-9- (2-methoxycarbonyl-ethenyl) camptothecin (50); 10-methoxy-9- (2-hydroxycarbonyl-ethenyl) camptothecin (51); -.10- methoxy-9- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (52); 10-methoxy-9- (2-acetylamino-2-hydroxycarbonyl-ethenyl) 20 camptothecin (53); 10-methoxy-9- ( 3-oxo-but-l-enyl) camptothecin (54); 10-methoxy-9- (3-oxo-3-phenyl-propenyl) camptothecin (55); 10-methoxy-9- (2-aminocarbonyl-ethenyl) camptothecin (56); 11-vinyl camptothecin (57); 11- (2-methoxycarbonyl-ethenyl) camptothecin (58); 11- (2-hydroxycarbonyl-ethenyl) camptothecin (59); '"" 1- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (60); 11- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (61); 11- (3-oxo-but-l-enyl) camptothecin (62); 11- (3-oxo-3-phenyl-propenyl) camptothecin (63); 11- (2-aminocarbonyl-ethenyl) camptothecin (64); 12-vinyl camptothecin (65); (E) -12- (2-methoxycarbonyl-ethenyl) camptothecin (66); 12- (2-hydroxycarbonyl-ethenyl) camptothecin (67); (Z) -12- (2-Acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (68); 12- (2-acetylamino-2-hydroxycarbonyl-ethenyl) camptothecin (69); 12- (3-oxo-but-l-enyl) camptothecin (70); 12- (3-oxo-3-phenyl-propenyl) camptothecin (71); 12- (2-aminocarbonyl-ethenyl) camptothecin (72); 9-amino-10-vinyl camptothecin (73); 9-amino-10- (2-methoxycarbonyl-ethenyl) camptothecin (74); 9-amino-10- (2-hydroxycarbonyl-ethenyl) camptothecin (75); 9-amino-10- (2-acetylamino-2-methoxycarbonyl-1-ethenyl) camptothecin (76); 9-amino-10- (2-acetylamino-2-hydroxycarbonyl-1-ethenyl) camptothecin (77); 9-amino-10- (3-oxo-but-l-enyl) camptothecin (78); 9-amino-10- (3-oxo-3-phenyl-propenyl) camptothecin (79); 9-amino-10- (2-aminocarbonyl-ethenyl) camptothecin (80); 7-ethyl-9-amino-10-vinyl camptothecin (81); • "ir-. / -ethyl-9-amino-10- (2-methoxycarbonyl-ethenyl) camptothecin (82); 7-Ethyl-9-amino-10- (2-hydroxycarbonyl-ethenyl) camptothecin (83); 7-ethyl-9-amino-10- (2-acetylamino-2-methoxycarbonyl-ethenyl) camptothecin (84); 7-ethyl-9-amino-10- (2-acetylamino-2-hydroxycarbonyl-1-ethenyl) camptothecin (85); 7-ethyl-9-amino-10- (3-oxo-but-l-enyl) camptothecin (86); 7-ethyl-9-amino-10- (3-oxo-3-phenyl-propenyl) camptothecin (87); 7-ethyl-9-amino-10- (2-aminocarbonyl-ethenyl) camptothecin (88); 9-ethyl camptothecin (1 '); 9- (2-methoxycarbonyl-ethyl) camptothecin (2 '); 9- (2-hydroxycarbonyl-ethyl) camptothecin (3 '); 9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (4 '); 9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (5 '); 9- [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (6 '); 9 - [(2-Acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (7 '); 9- (3-oxo-butyl) camptothecin (8 '); 9- (3-oxo-3-phenyl-propyl) camptothecin (9 '); 9- (2-aminocarbonyl-ethyl) camptothecin (10 '); 7-ethyl-9-ethyl camptothecin (11 '); 7-ethyl-9- (2-methoxycarbonyl-ethyl) camptothecin (12 '); 7-ethyl-9- (2-hydroxycarbonyl-ethyl) camptothecin (13 '); 7-ethyl-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin .14 '); 7-ethyl-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (15 '); 7-ethyl-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (16 '); 7-ethyl-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (17 '); 7-ethyl-9- (3-oxo-butyl) camptothecin (18 '); 7-ethyl-9- (3-oxo-3-phenyl-propyl) camptothecin (19 '); 7-ethyl-9- (2-aminocarbonyl-ethyl) camptothecin (20 '); 10-ethyl camptothecin (21 '); 10- (2-methoxycarbonyl-ethyl) camptothecin (22 '); 10- (2-hydroxycarbonyl-ethyl) camptothecin (23 '); 10 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (24 '); 10 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (25 '); 10 - [(2-amino-2-hydroxycarbonyl] -ethyl) camptothecin (26 '); 10 - [(2-Acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (27 '); 10- (3-oxo-butyl) camptothecin (28 '); 10- (3-oxo-3-phenyl-propyl) camptothecin (29 '); 10- (2-aminocarbonyl-ethyl) camptothecin (30 '); 7-ethyl-10-ethyl camptothecin (31 '); 7-ethyl-10- (2-methoxycarbonyl-ethyl) camptothecin (32 '); 7-ethyl-10- (2-hydroxycarbonyl-ethyl) camptothecin (33 '); 7- 'til-10- [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (34'); 7-ethyl-10 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (35 '); 7-ethyl-10-L (2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (36 '); 7-ethyl-10 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (37 '); 7-ethyl-10- (3-oxo-butyl) camptothecin (38 '); 7-ethyl-10- (3-oxo-3-phenyl-propyl) camptothecin (39 '); 7-ethyl-10- (2-aminocarbonyl-ethyl) camptothecin (40 '); 11-ethyl camptothecin (41 '); 11- (2-methoxycarbonyl-ethyl) camptothecin (42 '); 11- (2-hydroxycarbonyl-ethyl) camptothecin (43 '); 11 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (44 '); 11 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (45 '); 11 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (46 '); 11 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (47 '); 11- (3-oxo-butyl) camptothecin (48 '); 11- (3-oxo-3-phenyl-propyl) camptothecin (49 '); 11- (2-aminocarbonyl-ethyl) camptothecin (50 '); 9-amino-12-ethyl camptothecin (51 '); 9-amino-12- (2-methoxycarbonyl-ethyl) camptothecin (52 '); 9-amino-12- (2-hydroxycarbonyl-ethyl) camptothecin (53 '); 9-amino-12 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (54 '); 9-amino-12 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (55 '); 9-amino-12 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin 06 '); 9-amino-12 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (57 '); 9-amino-12- (3-oxo-butyl) camptothecin (58 '); 9-amino-12- (3-oxo-3-phenyl-propyl) camptothecin (59 '); 9-amino-12- (2-aminocarbonyl-ethyl) camptothecin (60 '); 10-amino-9-ethyl camptothecin (61 '); 10-amino-9- (2-methoxycarbonyl-ethyl) camptothecin (62 '); '10-amino-9- (2-hydroxycarbonyl-ethyl) camptothecin (63'); 10-amino-9 - [(2-acetylamino-2-methoxycarbonyl) -ethyl] camptothecin (64 '); 10-amino-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (65 '); 10-amino-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (66 '); 10-amino-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (67 '); 10-amino-9- (3-oxo-butyl) camptothecin (68 '); < - 10-amino-9- (3-oxo-3-phenyl-3-one-propyl) camptothecin (69 '); 10-amino-9- (2-aminocarbonyl-ethyl) camptothecin (70 '); 12-ethyl camptothecin (71 '); 12- (2-methoxycarbonyl-ethyl) camptothecin (72 '); 12- (2-hydroxycarbonyl-ethyl) camptothecin (73 '); 12 - [(2R, S,) (2-acetylamino-2-methoxycarbonyl) -ethyl] camptothecin (74 '); 12 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (75 '); .2- [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (76 '); 12- [(2-Acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (77 '); 12- (3-oxo-butyl) camptothecin (78 '); 12- (3-oxo-3-phenyl-propyl) camptothecin (79 '); 12- (2-aminocarbonyl-ethyl) camptothecin (80 '); 10-hydroxy-9-ethyl camptothecin (81 '); 10-hydroxy-9- (2-methoxycarbonyl-ethyl) camptothecin (82 '); 10-hydroxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (83 '); 10-hydroxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (84 '); 10-hydroxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (85 '); 10-hydroxy-9 - [(2-amino-2-hydroxycarbonyl] -ethyl) camptothecin (86 '); 10-hydroxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (87 '); 10-hydroxy-9- (3-oxo-butyl) camptothecin (88 '); 10-hydroxy-9- (3-oxo-3-phenyl-3-one-propyl) camptothecin (89 '); 10-hydroxy-9- (2-aminocarbonyl-ethyl) camptothecin (90 '); 10, 11-methylenedioxy-9-ethyl camptothecin (91 '); 10, 11-methylenedioxy-9- (2-methoxycarbonyl-ethyl) camptothecin (92 '); 10,11-methylenedioxy-9- (2-hydroxycarbonyl-ethyl) camptothecin "'*", 93'); 10, 11-methylenedioxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl-camptothecin (94 ') ); 10, 11-methylenedioxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (95 '); 10, 11-methylenedioxy-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (96 '); 10, 11-methylenedioxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] camptothecin (97'); 10, 11-methylenedioxy-9- (3-oxo-butyl) camptothecin ( 98 '); 10, 11-methylenedioxy-9- (3-oxo-3-phenyl-propyl) camptothecin (99 '); 10, 11-methylenedioxy-9- (2-aminocarbonyl-ethyl) camptothecin (100 '); 10-methoxy-9-ethyl camptothecin (101 '); 10-methoxy-9- (2-methoxycarbonyl-ethyl) camptothecin (102 '); 10-methoxy-9- (2-hydroxycarbonyl-ethyl) camptothecin (103 '); 10-methoxy-9 - [(2-acetylamino-2-methoxycarbonyl] -ethyl) camptothecin (104 '); 10-methoxy-9 - [(2-amino-2-methoxycarbonyl] -ethyl) camptothecin (105 '); 10-methoxy-9 - [(2-amino-2-hydroxycarbonyl) -ethyl] camptothecin (106 '); 10-methoxy-9 - [(2-acetylamino-2-hydroxycarbonyl) -ethyl] .amptothecin (107 '); 10-methoxy-9- (3-oxo-butyl) camptothecin (108 '); 10-methoxy-9- (3-oxo-3-phenyl-propyl) camptothecin (109 '); 10-methoxy-9- (2-aminocarbonyl-ethyl) camptothecin (110 '); and, wherein a salifiable substituent is present on the backbone of the molecule, its pharmaceutically acceptable salts.

4. A process for preparing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the process is characterized or comprising: 1) reacting a compound of formula (I) wherein Rn is a halogen atom, -OS02R? 2 wherein Ri2 is C? -C5 alkyl unsubstituted or substituted at the terminal carbon atom by one, two or three halogen atoms or an optionally substituted phenyl ring; R is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl or C? -C6 enylalkyl; and X is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl, C1-C5 alkoxy, C3-C7 cycloalkoxy, C? -C6 alkanoyloxy, benzoyloxy, amino hydroxy, nitro, halogen or is a methylenedioxy group linked to positions 10 and 11 of the molecule, with a compound of formula (III) wherein Ri, R2 and R3 are as defined under (a) or (b) below: (a) Ri and R2 are each independently hydrogen; C? -C4 alkyl; C3-C7 cycloalkyl; phenylalkyl of Ci-Ce; an optionally substituted phenyl ring; -NR5R6 wherein one of R5 and R6 is hydrogen, Ci-Cs alkyl or benzyl and the other is hydrogen, C?-C6 alkanoyl, an optionally substituted benzoyl, C?-C6 phenylalkanoyl, a C-hydroxycarbonyl; C6 optionally substituted, an optionally substituted phenoxycarbonyl or phenylalkoxycarbonyl of C? -C6, or R5 and Re, combined together with the nitrogen atom to which they are attached, form a heteromonocyclic ring, optionally substituted, saturated, 4-7 members, represented by a group (G) wherein W is -C = 0, R7 is hydrogen or C? -C6 alkyl and n is an integer from 2 to 5; COORß wherein R8 is C? -C6 alkyl, cycloalkyl C3-C7 or phenylalkyl of C? -Cc; or COR9 wherein R9 is C? -C alkyl, cycloalkyl C3-C7, C? -C6 phenylalkyl, an optionally substituted phenyl ring, NRio p wherein Rio and Ru are each independently, hydrogen or alkyl C? -C6; and R 3 is hydrogen, C 1 -C 6 alkyl or an optionally substituted phenyl; or '"' - (b) Ri and R, combined together, form an optionally substituted 5-8 membered carbocyclic carbo ring, and R 2 is hydrogen, C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl; thereby obtaining a compound of formula (I) in which the symbol represents a double bond; and, if desired, 2) optionally producing a compound of formula (I) (as obtained under step 1) in a corresponding compound of formula (I) wherein the symbol represents a single bond, and / or if desired, salifying a compound of formula (I).

5. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier and / or diluent.

6. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is used as an antitumor agent. SUMMARY OF THE INVENTION The present invention relates to substituted camptothecin derivatives of formula (I) in which the symbol represents a single or double bond; Ri, R2 and R3 are as defined under (a) or (b) below: (a) Ri and R2 are, each independently, hydrogen; C? -C4 alkyl; C3-C7 cycloalkyl; phenylalkyl of C? -C6; an optionally substituted phenyl ring; -NR5Re wherein one of R5 and Re is hydrogen, alkyl of Ci-Ce or benzyl and the other is hydrogen, C?-C6 alkanoyl, an optionally substituted C?-C6 alkoxycarbonyl, an optionally substituted benzoyl, a C?-C6 phenylalkanoyl, a C?-C6 alkoxycarbonyl optionally substituted, an optionally substituted phenoxycarbonyl or phenylalkoxycarbonyl of C? -C6, or R5 and R6, combined together with the nitrogen atom to which they are attached, form a 4-7 membered, optionally substituted, heteromonocyclic ring residue; COOR8 wherein R8 is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl or C? -C6 phenylalkyl; or COR9 wherein R9 is C? -C6 alkyl, C3-C7 cycloalkyl, C? -C6 phenylalkyl, an optionally substituted phenyl ring or NRioRu wherein Rio and Rn are, each independently, hydrogen or C-alkyl; ? -C6; and R 3 is hydrogen, C 1 -C 6 alkyl or an optionally substituted phenyl ring; or (b) Ri and R3, combined together, form a carbominated cyclic ring, optionally substituted with 5-8 * * - members; and R2 is hydrogen, C? -C alkyl or C3-C7 cycloalkyl; R 4 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 phenylalkyl; X is hydrogen, C? -C6 alkyl, C3-C7 cycloalkyl, C? -C6 alkoxy, C3-C7 cycloalkoxy, C? -C6 alkanoyloxy, benzoyloxy, amino, hydroxy, nitro, halogen or is a group methylenedioxy linked to positions 10 and 11 of the molecule, and the pharmaceutically acceptable salts of < ?---_ the same. The compounds according to the invention are useful in therapy as antitumor agents.