Water-soluble SHPs as novel alkylating agents

1. A compound or its pharmaceutically acceptable salt of the structure:

Where

R is —CH 3 or —CH 2 CH 2 Cl;

R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl; one of R 2 or R 4 , but not both, is selected from OPO 3 H 2 , NO 2 , OCO(Glu), NHCO(Glu) and NHR 7 and the other of R 2 or R 4 which is unassigned, and R 3 , R 5 and R 6 , are, independently selected from H, F, Cl, Br, I, OH, OPO 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SF 5 , NHR 8 , N(R 9 ) 2 and C 1 -C 7 alkyl,

with the proviso that at least two of R 2 , R 3 , R 4 , R 5 and R 6 are H;

R 7 is H, glutamyl or a polyglutamic acid polypeptide residue —OCH(NHR 7a )CH 2 CH 2 CO 2 H where R 7a is glutamyl or a polyglutamic acid polypeptide residue having from 1 to 50 peptide linkages;

R 8 is H or C 1 -C 7 alkyl; and

R 9 is CH 3 or CH 2 CH 3 .

2. The compound according to claim 1 wherein R is —CH 2 CH 2 Cl.

3. The compound according to claim 1 wherein said R′ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or substituted hexyl.

4. The compound according to claim 3 wherein R′ is methyl.

5. The compound according to claim 1 wherein R 2 is a OPO 3 H 2 group or its pharmaceutically acceptable salt.

6. The compound according to claim 1 wherein R 4 is F, Cl or OCH 3 when R 3 , R 5 and R 6 are each H.

7. The compound according to claim 1 wherein R 5 is F, Cl, OCH 3 or OCF 3 when R 3 , R 4 and R 6 are each H.

8. The compound according to claim 1 wherein two of R 3 , R 4 , R 5 or R 6 are independently F or Cl.

9. The compound according to claim 8 wherein R 4 and R 5 are independently F or Cl.

10. The compound according to claim 8 wherein R 5 and R 6 are independently F or Cl.

11. The compound according to claim 9 wherein R 4 and R 5 are Cl.

12. The compound according to claim 10 wherein R 5 and R 6 are Cl.

13. The compound according to claim 1 wherein R 5 is a OPO 3 H 2 group or its pharmaceutically acceptable salt.

14. The compound according to claim 1 wherein R 2 is NO 2 and R 3 , R 4 and R 6 are each H.

15. The compound according to claim 1 wherein R 4 is NO 2 and R 2 , R 3 and R 6 are each H.

16. The compound according to claim 1 wherein R 4 is OCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.

17. The compound according to claim 16 wherein OCO(Glu) is in the form of a pharmaceutically acceptable salt.

18. The compound according to claim 1 wherein R 4 is NHCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.

19. The compound according to claim 18 wherein NHCO(Glu) is in the form of a pharmaceutically acceptable salt.

20. The compound according to claim 1 wherein R 4 is NHR 7 and R 2 , R 3 , R 5 and R 6 are each H.

21. The compound according to claim 20 wherein R 7 is H, a α-glutamyl or a pharmaceutically acceptable salt thereof or a polyglutamic acid polypeptide residue having from 1 to 50 peptide linkages or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 21 wherein R 7 is α-glutamyl or a pharmaceutically acceptable salt thereof or a polyglutamic acid polypeptide residue having from 2 to 10 peptide linkages or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising an effective amount for treating a tumor of a compound or its pharmaceutically acceptable salt according to the structure:

Where

R is —CH 3 or —CH 2 CH 2 Cl;

R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl;

one of R 2 or R 4 , but not both, is selected from OPO 3 H 2 , NO 2 , OCO(Glu), NHCO(Glu) and NHR 7 and the other of R 2 or R 4 which is unassigned, and R 3 , R 5 and R 6 , are, independently selected from H, F, Cl, Br, I, OH, OPO 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SF 5 , NHR 8 , N(R 9 ) 2 and C 1 -C 7 alkyl, with the proviso that at least two of R 2 , R 3 , R 4 , R 5 and R 6 are H;

R 7 is H, glutamyl or a polyglutamic acid polypeptide residue (—COCH(NHR 7a )CH 2 CH 2 CO 2 H where R 7a is glutamyl or a polyglutamic acid polypeptide residue having from 1 to 50 peptide linkages;

R 8 is H or C 1 -C 7 alkyl; and

R 9 is CH 3 or CH 2 CH 3 ; optionally, in combination with a pharmaceutically acceptable additive, carrier, or excipient.

24. The composition according to claim 23 wherein R is —CH 2 CH 2 Cl.

25. The composition according to claim 23 wherein said R′ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or substituted hexyl.

26. The composition according to claim 25 wherein R′ is methyl.

27. The composition according to claim 23 wherein R 2 is OPO 3 H 2 or its pharmaceutically acceptable salt.

28. The composition according to claim 23 wherein R 4 is F, Cl or OCH 3 when R 3 , R 5 and R 6 are each H.

29. The composition according to claim 23 wherein R 5 is F, Cl, OCH 3 or OCF 3 when R 3 , R 4 and R 6 are each H.

30. The composition according to claim 23 two of R 3 , R 4 , R 5 or R 6 are independently F or Cl.

31. The composition according to claim 30 wherein R 4 and R 5 are independently F or Cl.

32. The composition according to claim 30 wherein R 5 and R 6 are independently F or Cl.

33. The composition according to claim 31 wherein R 4 and R 5 are Cl.

34. The composition according to claim 32 wherein R 5 and R 6 are Cl.

35. The composition according to claim 23 wherein R 5 is OPO 3 H 2 or its pharmaceutically acceptable salt.

36. The composition according to claim 23 wherein R 2 is NO 2 when R 3 , R 4 and R 6 are each H.

37. The composition according to claim 23 wherein R 4 is NO 2 and R 2 , R 3 and R 6 are each H.

38. The composition according to claim 23 wherein R 4 is OCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.

39. The composition according to claim 38 wherein Glu is in the form of a pharmaceutically acceptable salt.

40. The composition according to claim 23 wherein R 4 is NHCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.

41. The composition according to claim 40 for wherein Glu is in the form of a pharmaceutically acceptable salt.

42. The composition according to claim 23 wherein R 4 is NHR 7 and R 2 , R 3 , R 5 and R 6 are each H.

43. The composition according to claim 42 for wherein R 7 is α-glutamyl or a pharmaceutically acceptable salt thereof.

44. The composition according to claim 43 wherein R 7 is H, α-glutamyl or a pharmaceutically acceptable salt thereof or a polyglutamic acid polypeptide residue or a pharmaceutically acceptable salt thereof.

45. A method of treating a tumor in a patient in need of therapy comprising administering to said patient an effective amount of a compound or its pharmaceutically acceptable salt according to the structure:

Where

R is —CH 3 or —CH 2 CH 2 Cl;

R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl;

one of R 2 or R 4 , but not both, is selected from OPO 3 H 2 , NO 2 , OCO(Glu), NHCO(Glu) and NHR 7 and the other of R 2 or R 4 which is unassigned, and R 3 , R 5 and R 6 , are, independently selected from H, F, Cl, Br, I, OH, OPO 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SF 5 , NHR 9 , N(R 9 ) 2 and C 1 -C 7 alkyl, with the proviso that at least two of R 2 , R 3 , R 4 , R 5 and R 6 are H;

R 7 is H, glutamyl or a polyglutamic acid polypeptide residue —COCH(NHR 7a )CH 2 CH 2 CO 2 H where R 7a is glutamyl or a polyglutamic acid polypeptide residue having from 1 to 50 peptide linkages;

R 8 is H or C 1 -C 7 alkyl; and

R 9 is CH 3 or CH 2 CH 3 ;

optionally, in combination with a pharmaceutically acceptable additive, carrier, or excipient.

46. The method according to claim 45 wherein R is —CH 2 CH 2 Cl.

47. The method according to claim 45 wherein said R′ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or substituted hexyl.

48. The method according to claim 47 wherein R′ —CH 3 .

49. The method according to claim 45 wherein R 2 is OPO 3 H 2 or a pharmaceutically acceptable salt thereof.

50. The method according to claim 45 wherein R 4 is F, Cl or OCH 3 and R 3 , R 5 and R 6 are each H.

51. The method according to claim 45 wherein R 5 is F, Cl, OCH 3 or OCF 3 and R 3 , R 4 and R 6 are each H.

52. The method according to claim 45 wherein two of R 3 , R 4 , R 5 or R 6 are independently F or Cl.

53. The method according to claim 52 wherein R 4 and R 5 are independently F or Cl.

54. The method according to claim 52 wherein R 5 and R 6 are independently F or Cl.

55. The method according to claim 53 wherein R 4 and R 5 are Cl.

56. The method according to claim 54 wherein R 5 and R 6 are Cl.

57. The method according to claim 45 wherein R 5 is OPO 3 H 2 or a pharmaceutically acceptable salt thereof.

58. The method according to claim 45 wherein R 2 is NO 2 and R 3 , R 4 and R 6 are each H.

59. The method according to claim 45 wherein R 4 is NO 2 and R 2 , R 3 and R 6 are each H.

60. The method according to claim 45 wherein R 4 is OCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.

61. The method according to claim 60 wherein Glu is in the form of a pharmaceutically acceptable salt.

62. The method according to claim 45 wherein R 4 is NHCO(Glu) and R 2 , R 3 , R 5 and R 6 are each H.

63. The method according to claim 62 wherein Glu is in the form of a pharmaceutically acceptable salt.

64. The method according to claim 45 wherein R 4 is NHR 7 and R 2 , R 3 , R 5 and R 6 are each H.

65. The method according to claim 64 wherein R 7 is a α-glutamyl or a pharmaceutically acceptable salt thereof.

66. The method according to claim 64 wherein R 7 is H, a α-glutamyl or a pharmaceutically acceptable salt thereof or a polyglutamic acid polypeptide residue or a pharmaceutically acceptable salt thereof.

67. The method according to claim 45 wherein said cancer is selected from the group consisting of stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder, renal, brain/CNS, head and neck, throat, multiple myeloma, melanoma, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' Tumor, neuroblastoma, mouth/pharynx, oesophagus, larynx, kidney or lymphoma.

68. The method according to claim 67 wherein said lymphoma is Hodgkin's disease or non-Hodgkin's lymphoma.

69. A method of treating a drug-resistant a tumor in a patient in need thereof, said method comprising administering to said patient an effective amount of a compound according to any of claims 1 - 22 .

70. A method of treating a tumor in a patient in need thereof said method comprising administering to said patient an effective amount of a compound according to any of claims 1 - 22 in combination with at least one additional anti-tumor agent.

71. A method of treating a tumor in a patient in need thereof said method comprising administering to said patient an effective amount of a compound according to any of claims 1 - 22 in combination with at least one additional anti-tumor agent selected from the group consisting of antimetabolites, Ara C, etoposide, doxorubicin, taxol, hydroxyurea, vincristine, cytoxan, mitomycin C, adriamycin, topotecan, campothecin, irinotecan, gemcitabine and cis-platin.

72. A pharmaceutical composition comprising an effective amount of a compound according to any of claims 1 - 22 in combination with at least one additional anti-tumor agent.

73. A pharmaceutical composition comprising an effective amount of a compound according to any of claims 1 - 22 in combination with at least one additional anti-tumor agent selected from the group consisting of antimetabolites, Ara C, etoposide, doxorubicin, taxol, hydroxyurea, vincristine, cytoxan, mitomycin C, adriamycin, topotecan, campothecin, irinotecan, gemcitabine, campothecin and cis-platin.