WO1996013512B1 - L-ribofuranosyl nucleosides - Google Patents

Abstract

This invention relates to α and β L-ribofuranosyl nucleosides, processes for their preparation, pharmaceutical compositions containing them, and methods of using them to treat various diseases in mammals.

Claims

AMENDED CLAIMS

[received by the International Bureau on 28 February 1997 (28.02.97);

original claims 1-16 replaced by amended claims 1-16 (4 pages)]

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof;

wherein:

R is H, COR₅, P(O)_nR₆R₇, or SO₃H wherein R₅ is alkyl of 1-5 carbon atoms or an aromatic ring structure, R₆ and R₂ are each H or alkyl of 1-5 carbon atoms and n is 2 or 3;

R₁ and R₂ are independently H, halogen, mono- or di-difluro or OR₈ wherein R₈ is H, COR₉, P(O)_mR₁₀R₁₁ wherein R₉ is H₂, substituted or unsubstituted alkyl of 1-5 carbon atoms or a substituted or unsubstituted aromatic ring structure, R₁₀ and R₁₁ are each H or alkyl of 1-5 carbon atoms and m is 2 or 3, provided that when R₂ is OH, R₂ and B can combine to form a 5- membered cyclic ring structure;

R₃ and R₄ are independently B, H or OR₁₂ where R₁₂ is H, COR₁₃, P(O)_pR₁₄R₁₅ wherein R₁₃ is substituted or unsubstituted alkyl of 1-5 carbon atoms or a substituted or unsubstituted aromatic ring structure, R₁₄ and R₁₅ are each H or alkyl of C1-C5 carbon atoms and p is 2 or 3;

B is a naturally-occurring nucleobase or a modified base consisting of one or more substituents selected from the group consisting of H, halogen, C1- C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl-C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkylthio, C1-C6 alkylthio. a substituted amino group, an aryl, aralkyl, aryloxy, aralkoxy, arylthio, aralkylthio, a heterocyclic ring and an amino group, provided that when the base is a pyrimodine. the atom at position 4 of the base can be sulfur and further provided that when the base is a purine, the atom at position 6 of the base may be sulfur;

provided that

only one of R₃ or R₄ can be B and there is only one B ; R₁ and R₂ are independently H, halogen, mono- or di-difluro or OR₈ (wherein R₈ is H, COR₉, P(O)_mR₁₀R₁₁ (wherein R₉ is H₂, substituted or unsubstituted alkyl of 1-5 carbon atoms or a substituted or unsubstituted aromatic ring structure, R₁₀ and R₁₁ are each H or alkyl of 1-5 carbon atoms and m is 2 or 3)), provided that when R₂ is OH, R₂ and B can combine to form a 5-membered cyclic ring structure;

R₃ and R₄ are independently B, H or OR₁₂ (where R₁₂ is H, COR₁₃, P(O)_pR₁₄R₁₅ (wherein R₁₃ is substituted or unsubstituted alkyl of 1-5 carbon atoms or a substituted or unsubstituted aromatic ring structure, R₁₄ and R₁₅ are each H or alkyl of C1-C5 carbon atoms and is 2 or 3));

B is a naturally-occurring nucleobase or a modified base consisting of one or more substituents selected from the group consisting of H, halogen, C1- C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C6 cycloalkyl-C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 cycloalkylthio, C1-C6 alkylthio, a substituted amino group, an aryl, aralkyl, aryloxy, aralkoxy, arylthio, aralkylthio, a heterocyclic ring and an amino group, provided that when the base is a pyrimidine, the atom at position 4 of the base can be sulfur and further provided that when the base is a purine, the atom at position 6 of the base may be sulfur;

14. A method of treating cancer in a mammal, the method comprising administering to &

mammal bearing a cancer, a cancer-inhibiting amount of a compound of Claim 10.

15. An anhydride derivative of a compound of Claim 1, selected from the group consisting of 2- amino-a-L-ribofurano [1 ',2':4,5]oxazoline, and O²,O³-anhydro-1-a-L-ribofurano- syluracil.

16. A method of treating cancer in a mammal, the method comprising administering to a

mammal bearing a cancer, a cancer-inhibiting amount of a compound selected from the group consisting of 2-amino-a-L-ribofurano[1',2':4,5] oxazoline, O²,O²-anhydro-1-a-L- ribofuranosyluracil and O²,O^2'-anhydro-1-a-L-ribofuranosyl uracil.

7. A compound of Claim 6 wherein R₂ is OH and combines with B to form a 5-membered cyclic ring.

8. A compound of Claim 1 wherein R₃ is B; B is a nucleobase selected from the group

consisting of C, T, U, G, A, hypoxanthine, 6-thioguanine, 4-thiouracil and 5-fluorouracil; R is H; R₁ and R₂ are each independently H or OH; and R₄-Η.

9. A compound of Claim 1 wherein R₄ is B; B is a nucleobase selected from the group

consisting of C, T, U, G, A, hypoxanthine, 6-thioguanine, 4-thiouracil and 5-fluorouracιl; R is H; R₁ and R₂ are each independently H or OH, and R₃=H

10. The compound of Claim 1 which is selected from the group consisting of a-L- ribofuranosyluracil, 1-(2,3,5-tri-O-benzoyl-a-L-ribofuranosyl)-4-thiouracιl; a-L- ribofuranosyl-4-thiouracil; 1-(3,5-di-O-benzoyl-2-deoxy-b-L-ribofuranosyl)-4-thιiouracil; 2'-b- L-deoxyribofuranosyl-4-thiouracil; a-L-ribofuranosyl-5-fluorouracil; b-L- ribofuranosylguanine; b-L-ribofuranosyl-6-thioguanine; or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a

therapeutically effective amount of one or more of the compounds of Claim 1.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a

therapeutically effective amount of one or more of the compounds of Claim 10,

13. A method of treating cancer in a mammal, the method comprising administering to a

mammal bearing a cancer, a cancer-inhibiting amount of a compound of the formula.

or a pharmaceutically acceptable salt thereof,

wherein:

R is H₂ COR₅, P(O)_nR₆R₇ or SO₃H (wherein R₅ is alkyl of 1-5 carbon atoms or an aromatic ring structure, R₆ and R₇ are each H or alkyl of 1-5 carbon atoms and n is 2 or 3);