Chemical compounds

• US 20060142238A1
• Filed: 07/20/2004
• Published: 06/29/2006
• Est. Priority Date: 07/21/2003
• Status: Active Grant

• Current Assignee: NuCana Plc
• Original Assignee: Cardiff Protides Limited (Morvus Technology Limited)
• Inventors: McGuigan, Christopher
• Granted Patent: US 7,951,787 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The a-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.

Claims

1. A chemical compound having formula I:

2. A compound according to claim 1 wherein R is selected from the group comprising a C_1-16 primary or secondary alkyl group, a C_5-7 carbocyclic aryl group or a C_1-16alkylC_5-11 aryl group.

3. A compound according to claim 2 wherein R is selected from the group comprising methyl (—

CH₃), ethyl (—

C₂H₅) and benzyl (—

CH₂C₆H₅).

4. A compound according to claim 3 wherein R is benzyl.

5. A compound according to claim 1 wherein Ar is an optionally substituted C₆ monocyclic aromatic ring moiety.

6. A compound according to claim 5 wherein Ar is selected from the group comprising —

C₆H₅, pCF₃C₆H₄—

, pFC₆H₄—

, pNO₂C₆H₄—

, PClC₆H₄—

.

8. A compound according to claim 1 wherein R′

and R″

are, independently, selected from the group comprising H, C_1-6 primary, secondary and tertiary alkyl, C_1-3alkylC_5-7 aryl, or, when together they form an alkylene chain, they provide, together with the C atom to which they are attached, a C_3-8 carbocyclic aliphatic ring.

9. A compound according to claim 8 wherein R′

and R″

are, independently, selected from the group comprising H, methyl, benzyl and —

CH₂CH(CH₃)₂, or, R′ and

R″

together with the C atom to which they are attached, provide a C_5-6 ring.

10. A compound according to claim 9 wherein R′

and R″

are each methyl.

11. A compound according to claim 9 wherein one of R′

and R″

is H and one of R′ and

R″

is methyl.

12. A compound according to claim 9 wherein the carbocyclic ring is a pentyl ring.

13. A compound according to claim 1 wherein R′

and R″

correspond to the side chains of a naturally occurring amino acid.

14. A compound according to claim 1 wherein Z is selected from the group comprising H, C_1-6alkyl, substituted C_1-6alkyl, C_1-6alkenyl, substituted C_1-6alkenyl, C_1-6alkynyl, and halogen.

15. A compound according to claim 1 wherein Q is O.

16. A compound according to claim 1 wherein when n is 1, each of X and Y is H.

17. A compound according to claim 1 wherein when n is 0, each of X and Y is F.

18. A compound according to claim 1 wherein when n is 0, X is OH and Y is H.

19. A compound according to claim 1 wherein when n is 0, X is H and Y is OH.

21. A compound according to claim 1 for use in a method of treatment, preferably in the prophylaxis or treatment of cancer, with the proviso that when n is 1, X and Y are both H, one of R′

and R″

is H and one of R′ and

R″

is methyl (CH₃), R is 2-Bu(—

CH₂—

CH—

(CH₃)₂) or R is benzyl (—

CH₂C₆H₅), then Ar can be unsubstituted phenyl (—

C₆H₅).

22. Use of a compound according to claim 1 in the manufacture of a medicament for the prophylaxis or treatment of cancer, with the proviso that when n is 1, X and Y are both H, one of R″

and R″

is H and one of R′ and

R″

is methyl (CH₃), R is 2-Bu(—

CH₂—

CH—

(CH₃)₂) or R is benzyl (—

CH₂C₆H₅), then Ar can be unsubstituted phenyl (—

Ca₆H₅).

23. A method of prophylaxis or treatment of cancer comprising administration to a patient in need of such treatment an effective dose of a compound according to claim 1 with the proviso that when n is 1, X and Y are both H, one of R′

and R″

is H and one of R′ and

R″

is methyl (CH₃), R is 2-Bu(—

CH₂—

CH—

(CH₃)₂) or R is benzyl (—

CH₂C₆H₅), then Ar can be unsubstituted phenyl (—

C₆H₅).

24. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient.

25. A method of preparing a pharmaceutical composition comprising the step of combining a compound according to claim 1 with a pharmaceutically acceptable excipient, carrier or diluent.

26. A process for the preparation of a compound of formula I according to claim 1, the process comprising reacting of a compound of formula (III):

7. A chemical compound having formula II:

27. A compound according to claim 7 wherein R′

and R″

are, independently, selected from the group comprising H, C_1-6 primary, secondary and tertiary alkyl, C_1-3alkylC_5-7 aryl, or, when together they form an alkylene chain, they provide, together with the C atom to which they are attached, a C_3-8 carbocyclic aliphatic ring.

28. A compound according to claim 27 wherein R′

and R″

are, independently, selected from the group comprising H, methyl, benzyl and —

CH₂CH(CH₃)₂, or, R′ and

R″

together with the C atom to which they are attached, provide a C_5-6 ring.

29. A compound according to claim 28 wherein R′

and R″

are each methyl.

30. A compound according to claim 28 wherein one of R′

and R″

is H and one of R′ and

R″

is methyl.

31. A compound according to claim 28 wherein the carbocyclic ring is a pentyl ring.

32. A compound according to claim 7 wherein R′

and R″

correspond to the side chains of a naturally occurring amino acid.

33. A compound according to claim 7 wherein Z is selected from the group comprising H, C_1-6alkyl, substituted C_1-6alkyl, C_1-6alkenyl, substituted C_1-6alkenyl, C_1-6alkynyl, and halogen.

34. A compound according to claim 7 wherein Q is O.

35. A compound according to claim 7 wherein when n is 1, each of X and Y is H.

36. A compound according to claim 7 wherein when n is 0, each of X and Y is F.

37. A compound according to claim 7 wherein when n is 0, X is OH and Y is H.

38. A compound according to claim 7 wherein when n is 0, X is H and Y is OH.

39. A pharmaceutical composition comprising a compound according to claim 7 in combination with a pharmaceutically acceptable carrier, diluent or excipient.

40. A method of preparing a pharmaceutical composition comprising the step of combining a compound according to claim 7 with a pharmaceutically acceptable excipient, carrier or diluent.

20. A compound selected from the group comprising:

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(ethoxy-L-alaninyl)]-phosphate (CPF

     3)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF

     2)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-fluorophenyl-(methoxy-L-alaninyl)]-phosphate (CPF

     5)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-fluorophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF

     6)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-fluorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF

     7)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-nitrophenyl-(methoxy-L-alaninyl)]-phosphate (CPF

     10)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-nitrophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF

     9)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-nitrophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF

     8)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[para-(trifluoromethyl)-phenyl-(methoxy-L-alaninyl)]-phosphate (CPF

     15)

(E)-5-(2-bromoyinyl)-2′

-deoxyuridine-5′

-[para-(trifluoromethyl)-phenyl-(ethoxy-L-alaninyl)]-phosphate (CPF

     25)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-trifluorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF

     4)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-chlorophenyl-(methoxy-L-alaninyl)]-phosphate (CPF

     13)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-chlorophenyl-(ethoxy-L-alaninyl)]-phosphate (CPF

     12)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-chlorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF

     12)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(methoxy-ana-dimethylglycinyl)]-phosphate (CPF

     26)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(ethoxy-a,a-dimethylglycinyl)]-phosphate (CPF

     27)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(benzoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     14)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-nitrophenyl-(methoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     45)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-nitrophenyl-(ethoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     46)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-nitrophenyl-(benzoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     47)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-chlorophenyl-(methoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     42)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-chlorophenyl-(ethoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     43)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[4-chlorophenyl-(benzoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     44)

(E)-5-(2-bromovinyl)-2′

-deoxyuridine-5′

-[para-(trifluoromethyl)-phenyl-(benzoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     48)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(methoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     16)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(ethoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     17)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(benzoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     18)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-nitrophenyl-(methoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     19)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-nitrophenyl-(ethoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     20)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-nitrophenyl-(benzoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     21)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-fluorophenyl-(methoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     22)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-fluorophenyl-(ethoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     23)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-fluorophenyl-(benzoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     24)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-chlorophenyl-(methoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     32)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-chlorophenyl-(ethoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     33)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(methoxy-L-phenylalaninyl)]-phosphate (CPF

     36)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-chlorophenyl-(benzoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     34)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-trifluorophenyl-(methoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     28)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-trifluorophenyl-(ethoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     29)

(E)-5 -(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-trifluorophenyl-(benzoxy-α

,α

-cycloleucinyl)]-phosphate (CPF

     30)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(methoxy-L-phenylalaninyl)]-phosphate (CPF

     36)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(methoxy-L-leucinyl)]-phosphate (CPF

     35)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(benzoxy-L-leucinyl)]-phosphate (CPF

     37)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-nitrophenyl-(benzoxy-L-leucinyl)]-phosphate (CPF

     38)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[para-chlorophenyl-(benzoxy-L-leucinyl)]-phosphate (CPF

     39)

(E)-5-(2-Bromovinyl)-2′

-deoxyuridine-5′

-[phenyl-(2-butyl-L-alaninyl)]-phosphate

Gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF

     31)

Gemcitabine-[para-chlorophenyl-(benzoxy-L-alaninyl)]-phosphate (CPF

     40) and

Gemcitabine-[para-chlorophenyl-(benzoxy-α

,α

-dimethylglycinyl)]-phosphate (CPF

     41).