Antitumoral derivatives of ET-743

1. A compound of the general formula Ia:

wherein R 1 is C(═O)R′, C(═O)OR′, P═O(OR′) 2 , substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 2 -C 18 alkenyl, substituted or unsubstituted C 2 -C 18 alkynyl, substituted or unsubstituted aryl, with the proviso that R 1 is not acetyl;

wherein R 2 , R 4 , R 5 are each independently selected from H, C(═O)R′, C(═O)OR′, P═O(OR′) 2 , substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 2 -C 18 alkenyl, substituted or unsubstituted C 2 -C 18 alkynyl, substituted or unsubstituted aryl;

wherein R 6 and R 7 are both ═O and the dotted lines indicate a quinone ring, or R 6 is —OR 3 , where R 3 is H, C(═O)R′, C(═O)OR′, substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 2 -C 18 alkenyl, substituted or unsubstituted C 2 -C 18 alkynyl, substituted or unsubstituted aryl, R 7 is H, and the dotted lines indicate a phenyl ring;

wherein X 2 , X 3 , X 4 , X 5 , X 6 are independently selected from H, OH, OR′, SH, SR′, SOR′, SO 2 R′, C(═O)R′, C(═O)OR′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHC(O)R′, CN, halogen, unsubstituted C 1 -C 24 alkyl, unsubstituted C 2 -C 18 alkenyl, unsubstituted C 2 -C 18 alkynyl, unsubstituted C 6 -C 18 carbocyclic aryl, and unsubstituted heteroaromatic selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl tetrahyrdrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrolindinyl;

wherein X 1 is selected from hydrogen, hydroxy and cyano;

wherein when R 1 , R 2 , R 3 , R 4 , and R 5 are substituted, the substituents are each independently selected from the group consisting of OH, OR′, SH, SR′, SOR′, SO 2 R′, C(═O)R′, C(═O)OR′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHC(O)R′, CN, halogen, ═O, unsubstituted C 1 -C 18 alkyl, unsubstituted C 2 -C 18 alkenyl, unsubstituted C 2 -C 18 alkynyl, unsubstituted C 6 -C 18 carbocyclic aryl, and unsubstituted heterocyclic selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrolindinyl;

wherein each of the R′ groups is independently selected from the group consisting of H, OH, NO 2 , NH 2 , SH, CN, halogen, C(═O)H, C(═O)CH 3 , CO 2 H, substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 2 -C 18 alkenyl, substituted or unsubstituted C 2 -C 18 alkynyl, and substituted or unsubstituted C 6 -C 18 carbocylic aryl; and

wherein when R′ is substituted, the substituents are each independently selected from the group consisting of halogen, cyano, hydroxyl, nitro, azido, unsubstituted C 1 -C 6 alkanoyl, carboxamido, unsubstituted C 1 -C 12 alkyl, unsubstituted C 2 -C 12 alkenyl, unsubstituted C 2 -C 12 alkynyl, unsubstituted C 1 -C 12 alkoxy, unsubstituted C 6 -C 18 carbocyclic aryloxy, unsubstituted C 1 -C 12 alkylthio, unsubstituted C 1 -C 12 alkylsulfinyl, unsubstituted C 1 -C 12 alkylsulfonyl, unsubstituted C 1 -C 12 aminoalkyl, unsubstituted C 6 -C 18 carbocyclic aryl, unsubstituted aralkyl and unsubstituted heterocyclic group which is selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl,pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrolindinyl.

2. A compound according to claim 1 , wherein:

R 3 and R 4 are independently selected from hydrogen, C 1 -C 18 alkyl, C 2 -C 18 alkenyl, C═OR′, and COOR′, where R′ is optionally substituted C 1 -C 18 alkyl or optionally substituted C 2 -C 18 alkenyl, the optional substituents being chosen from halo, amino, amino derived from amino acid, unsubstituted C 6 -C 18 carbocyclic aryl or unsubstituted heterocyclic, which is selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahvdropyranyl, piperidinyl, morpholinyl and pyrolindinyl;

R 2 is hydrogen, C 1 -C 18 alkyl or C(═O)OR′, where R′ is C 1 -C 18 alkyl;

R 5 is hydrogen, C 1 -C 18 alkyl or C(═O)OR′, where R′ is C 2 -C 18 alkenyl;

X 2 , X 4 and X 5 are hydrogen;

X 3 is OR′, where R′ is C 1 -C 18 alkyl;

X 6 is hydrogen or unsubstituted C 1 -C 24 alkyl;

R 6 is OR 3 ;

R 7 is hydrogen; and

the dotted lines indicate a phenyl ring.

3. A compound according to claim 1 , wherein R 1 is: C 1 -C 18 alkyl;

C(═O)R′, where R′ is optionally substituted C 1 -C 18 alkyl, the optional substituents being chosen from halogen, amino, unsubstituted C 6 -C 18 carbocyclic aryl or unsusbtituted heterocyclic, which is selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrolindinyl; optionally substituted C 2 -C 18 alkenyl, the optional substituents being chosen from unsubstituted C 6 -C 18 carbocyclic aryl; or C(═O)OR′, where R′is C 1 -C 18 alkyl or C 2 -C 18 alkenyl.

4. A compound according to claim 1 , wherein R 2 is hydrogen, methyl, or alkoxycarbonyl.

5. A compound according to claim 1 , wherein R 3 is:

hydrogen;

C 1 -C 18 alkyl;

(C═O)R′, where R′ is optionally substituted C 1 -C 18 alkyl, the optional substituents being chosen from halogen, unsubstituted C 6 -C 18 carbocyclic aryl or unsusbtituted heterocyclic, which is selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrolindinyl; optionally substituted C 2 -C 18 alkenyl, the optional substituents being chosen from unsubstituted C 6 -C 18 carbocyclic aryl; or

(C═O)OR′, where R′ is C 1 -C 18 alkyl; optionally substituted C 2 -C 18 alkenyl, the optional substituents being chosen from unsubstituted C 6 -C 18 carbocyclic aryl.

6. A compound according to claim 1 , wherein R 4 is:

C(═O)R′, where R′ is optionally substituted C 1 -C 18 alkyl, the optional substituents being chosen from halogen, amino, unsubstituted C 6 -C 18 carbocyclic aryl or unsusbtituted heterocyclic, which is selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrolindinyl; optionally substituted C 2 -C 18 alkenyl, the optional substituents being chosen from unsubstituted C 6 -C 18 carbocyclic aryl; or

C(═O)OR′, where R′ is optionally substituted C 1 -C 18 alkyl or optionally substituted C 2 -C 18 alkenyl, the optional substituents being chosen from unsubstituted C 6 -C 18 carbocyclic aryl; or

P═O(OR′) 2 , where R′ is benzyl.

7. A compound according to claim 1 , wherein R 5 is:

hydrogen;

C 1 -C 18 alkyl; or

(C═)OR′ , where R′ is C 2 -C 18 alkenyl.

8. A compound according to claim 1 , wherein X 2 is hydrogen.

9. A compound according to claim 1 , wherein X 3 is OR′, where R′ is C 1 -C 18 alkyl.

10. A compound according to claim 1 , wherein X 4 is hydrogen.

11. A compound according to claim 1 , wherein X 5 is hydrogen.

12. A compound according to claim 1 , wherein X 6 is hydrogen or unsubstitited C 1 -C 24 alkyl.

13. A compound according to claim 1 , wherein R 1 is C(═O)R′, where R 1 is optionally substituted C 4 -C 18 alkyl or optionally substituted C 2 -C 18 alkenyl.

14. A compound according to claim 13 , wherein the optional substituent of R 1 is unsubstituted C 6 -C 18 carbocyclic aryl or unsubstituted heterocyclic group which is selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrolindinyl; or R′ is derived from an optionally protected amino acid.

15. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutical carrier.

16. A compound according to claim 1 , wherein R 3 is:

hydrogen;

C 1 -C 6 alkyl;

cinnamoyl;

(C═O)R′ where R′ is C 1 -C 18 alkyl, perfluoro C 1 -C 4 alkyl, heterocyclicalkyl containing an alkyl of 1 to 6 carbon atoms with a ω-heterocyclic substituent; or

(C═O)OR′ where R′ is C 1 -C 6 alkyl, vinyl, allyl or benzyl.

17. A compound according to claim 1 , wherein R 4 is:

cinnamoyl;

(C═O)R′ where R′ is C 1 -C 18 alkyl, ω-chloro- or perfluoro-C 1 -C 4 alkyl, phenethyl, aminoacid, heterocyclicalkyl containing an alkyl of 1 to 6 carbon atoms with a ω-heterocyclic substituent;

(C═O)OR′, where R′ is C 1 -C 6 alkyl, vinyl, allyl, benzyl; or

P═O(OR′) 2 where R′ is benzyl.

18. A compound according to claim 1 , wherein R 1 is:

C 1 -C 6 alkyl;

cinnamoyl;

C(═O)R′ where R′ is C 2 -C 18 alkyl, ω-chloro- or perfluoro-C 1 -C 4 alkyl, heterocyclicalkyl containing an alkyl of 1 to 6 carbon atoms with a ω-heterocyclic substituent; aminoalkyl of 1 to 6 carbon atoms with a ω-amino group optionally protected, vinyl, allyl, benzyl; or C(═O)OR′ where R′ is C 1 -C 6 alkyl, or allyl.