Camptothecin derivatives with antitumor activity

1. Compounds of general formula I:

wherein:

R is F, Cl, Br, I, —N3, NH2, —NR′R″, —COOR′, —CONR′R″, —NHR″′-NR′R″ in which R′, R″ and R″′ can be H, alkyl, aryl, arylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl;

R1 is alkyl, aminoalkyl, hydroxyalkyl, nitrite, alkoxymino, aryloxymino, silylalkyl;

R2 is hydrogen, hydroxyl, alkoxy, aminoalkyl;

R3 is hydrogen, optionally protected hydroxyl, alkoxy, aminoalkyl,

wherein the alkyl groups, acyl, alkoxy, aminoalkyl or alkoxymino can contain 1 to 8 carbon atoms, in a straight or branched chain, and the groups aryl and aryloxy can contain 5 to 10 carbon atoms;

the pharmaceutically acceptable salts, isomers, enantiomers, diastereomers thereof and corresponding mixtures.

2. A compound of formula (I) which is selected from the group consisting of:

a) thio-camptothecin;

b) thio-homocamptothecin;

c) thioSN38;

d) thio-topotecan;

e) thioirinotecan; and

f) thiogimatecan.

3. A process for the preparation of compounds of formula (I), substantially comprising the steps shown in Scheme I, wherein:

a) protection of hydroxy precursor groups;

b) conversion of the pyridone ring to thiopyridone ring;

c) removal of the protective groups;

wherein PG is an OH-protecting group, and wherein

R is F, Cl, Br, I, —N3, NH2, —NR′R″, —COOR′, —CONR′R″, —NHR″ζ-NR′R″ in which R′, R″ and R″′ can be H, alkyl, aryl, arylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl;

R1 is alkyl, aminoalkyl, hydroxyalkyl, nitrite, alkoxymino, aryloxymino, silylalkyl;

R2 is hydrogen, hydroxyl, alkoxy, aminoalkyl;

R3 is hydrogen, optionally protected hydroxyl, alkoxy, aminoalkyl,

wherein the alkyl groups, acyl, alkoxy, aminoalkyl or alkoxymino can contain 1 to 8 carbon atoms, in a straight or branched chain, and the groups aryl and aryloxy can contain 5 to 10 carbon atoms.

4. A process for the preparation of the compounds of formula (I), substantially comprising the steps shown in Scheme II, wherein:

a) protection of the precursor hydroxy groups;

b) derivatization at 5 through formation of a carbanion and reaction with an electrophilic reagent;

c) transformation of the 16a carbonyl into thiocarbonyl;

d) deprotection of the hydroxy groups;

in which steps b) and c) can be reversed:

wherein PG is an OH-protecting group, and wherein

R is F, Cl, Br, I, —N3, NH2, —NR′R″, —COOR′, —CONR′R″, —NHR″′-NR′R″ in which R′, R″ and R″′ can be H, alkyl, aryl, arylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl;

R1 is alkyl, aminoalkyl, hydroxyalkyl, nitrite, alkoxymino, aryloxymino, silylalkyl:

R2 is hydrogen, hydroxyl, alkoxy, aminoalkyl;

R3 is hydrogen, optionally protected hydroxyl, alkoxy, aminoalkyl,

wherein the alkyl groups, acyl, alkoxy, aminoalkyl or alkoxymino can contain 1 to 8 carbon atoms, in a straight or branched chain, and the groups aryl and aryloxy can contain 5 to 10 carbon atoms.

5. A pharmaceutical composition containing a compound of formula (I) together with pharmaceutically acceptable carriers and excipients.

6. A pharmaceutical composition as claimed in claim 5 , which is in a form suited to the oral or parenteral administration.

7. A method for the treatment of a tumor or leukemia, comprising administering a compound of claim 1 to a subject in need thereof.

8. The method of claim 7 , wherein the tumor or leukemia is selected from the group consisting of: tumors of the lung, ovary, breast, stomach, liver, prostate, soft tissues sarcomas, esophagus, pancreas, head and neck, glioblastoma, and chronic and acute myelocytic leukemias.

9. A method for the treatment of a tumor or leukemia, comprising administering the pharmaceutical composition of claim 5 to a subject in need thereof.

10. The method of claim 9 , wherein the tumor or leukemia is selected from the group consisting of: tumors of the lung, ovary, breast, stomach, liver, prostate, soft tissues sarcomas, esophagus, pancreas, head and neck, glioblastoma, and chronic and acute myelocytic leukemias.

11. The compounds of claim 1 , wherein R3 is hydrogen, optionally protected hydroxyl, alkoxy, aminoalkyl, wherein the alkyl groups, acyl, alkoxy, aminoalkyl or alkoxymino can contain 1 to 4 carbon atoms, in a straight or branched chain, and the groups aryl and aryloxy can contain 5 to 10 carbon atoms.

12. The pharmaceutical composition of claim 5 , wherein R3 is hydrogen, optionally protected hydroxyl, alkoxy, aminoalkyl, wherein the alkyl groups, acyl, alkoxy, aminoalkyl or alkoxymino can contain 1 to 4 carbon atoms, in a straight or branched chain, and the groups aryl and aryloxy can contain 5 to 10 carbon atoms.