Vinca derivatives

1. A compound of Formula (I) as follows:

where:

R 1 is:

alkenyl;

alkynyl;

aryl;

heterocyclyl;

halogen;

CN;

CH(O);

COR 5 ;

C(O)NR 5 R 6 ;

C(O)NHR 5 ;

C(O)NH 2 ;

C(O)NHNH 2 ;

C(O)NR 5 NH 2 ;

C(O)NR 5 NHR 6 ;

C(O)NR 5 NR 6 R 7 ;

C(O)NHNHR 5 ;

C(O)NHNR 5 R 6 ;

C(O)NHOH;

SO 2 NHNH 2 ;

SO 2 NR 5 NH 2 ;

SO 2 NR 5 NHR 6 ;

SO 2 NR 5 NR 6 R 7 ;

SO 2 NHNHR 5 ;

SO 2 NHNR 5 R 6 ;

CO 2 R 5 ;

SR 5 ;

SSR 5 ;

SO 2 NHR 5 ;

SO 2 NR 5 R 6 ;

B(OR 5 ) 2 ;

CF 3 ;

SH;

SO 2 NH 2 ;

NH 2 ;

NHR 5 ;

NHSO 2 R 5 ;

NR 5 R 6 ;

NHCOR 5 ;

NR 5 COR 6 ; or

NR 5 SO 2 R 6 ;

SOR 5 ;

SO 2 R 5 ;

OR 7 ; or

R 2 =alkyl or CH(O);

R 3 =hydrogen, alkyl, or C(O)R 5 ;

R 4 =hydrogen or C(O)R 5 ;

R 5 , R 6 , and R 7 each are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;

R 8 =hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, or thioalkyl;

R 5 and R 6 could form a ring or R 6 and R 7 could form a ring;

X=OR 5 , NR 5 R 6 , NHNH 2 , NHNHC(O)R 5 , OH, NHR 5 , NH 2 , or NHNHC(O)H;

R 4 and X may be linked together with intervening atoms to form a ring; R 1 and R 8 may be linked together; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched, straight, unsubstituted, and/or substituted and wherein the aryl, alkynyl, and heterocyclyl groups are substituted or unsubstituted.

2. The compound according to claim 1 , wherein R 3 =acetyl.

3. The compound according to claim 1 , wherein R 4 =hydrogen.

4. The compound according to claim 1 , wherein X=OMe.

5. The compound according to claim 1 wherein R 3 =acetyl, R 4 =hydrogen, and X=OMe.

6. The compound according to claim 1 , wherein R 2 =CH(O).

7. The compound according to claim 1 , wherein R 2 =alkyl.

8. A compound of Formula II as follows:

where:

R 1 is

alkyl;

alkenyl;

alkynyl;

CN;

SR 5 ;

CF 3 ;

OR 7 ;

R 2 =alkyl or CH(O);

R 5 and R 7 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched, straight, unsubstituted, and/or substituted and wherein the aryl, alkynyl, and heterocyclyl groups are substituted or unsubstituted.

9. A compound of Formula III as follows:

where:

R 1 is:

SR 5 ;

OR 7 ;

R 5 and R 7 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched, straight, unsubstituted, and/or substituted and wherein the aryl, alkynyl, and heterocyclyl groups are substituted or unsubstituted.

10. A compound of Formula V as follows:

where:

R 5 =alkyl; or a pharmaceutically acceptable salt thereof, wherein the alkyl group may be branched, straight, unsubstituted, and/or substituted.

11. The compound according to claim 10 , herein the compound has the following chemical formula:

12. The compound according to claim 10 , wherein the compound has the following chemical formula:

13. A process for preparation of a derivative product compound of Formula (I) as follows:

where:

R 1 is:

alkyl;

alkenyl;

alkynyl;

aryl;

heterocyclyl;

CN;

CH(O);

COR 5 ;

C(O)NR 5 R 6 ;

C(O)NHR 5 ;

C(O)NH 2 ;

C(O)NHNH 2 ;

C(O)NR 5 NH 2 ;

C(O)NR 5 NHR 6 ;

C(O)NR 5 NR 6 R 7 ;

C(O)NHNHR 5 ;

C(O)NHNR 5 R 6 ;

C(O)NHOH;

SO 2 NHNH 2 ;

SO 2 NR 5 NH 2 ;

SO 2 NR 5 NHR 6 ;

SO 2 NR 5 NR 6 R 7 ;

SO 2 NHNHR 5 ;

SO 2 NHNR 5 R 6 ;

CO 2 R 5 ;

SR 5 ;

SSR 5 ;

SO 2 NHR 5 ;

SO 2 NR 5 R 6 ;

B(OR 5 ) 2 ;

CF 3 ;

SH;

SO 2 NH 2 ;

NH 2 ;

NHR 5 ;

NHCOR 5 ;

NHSO 2 R 5 ;

NR 5 R 6 ;

NHCOR 5 ;

NR 5 COR 6 ; or

NR 5 SO 2 R 6 ;

SOR 5 ;

SO 2 R 5 ;

OR 7 ; or

R 2 =alkyl or CH(O);

R 3 =hydrogen, alkyl, or C(O)R 5 ;

R 4 =hydrogen or C(O)R 5 ;

R 5 , R 6 , and R 7 each are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;

R 8 =hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, or thioalkyl;

R 5 and R 6 can form a ring or R 6 and R 7 can form a ring;

X=OR 5 , NR 5 R 6 , NHNH 2 , NHNHC(O)R 5 , OH, NHR 5 , NH 2 , or NHNHC(O)H;

R 4 and X may be linked together with intervening atoms to form a ring; R 1 and R 8 may be linked together; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched, straight, unsubstituted, and/or substituted and wherein the aryl, alkynyl, and heterocyclyl groups are substituted or unsubstituted, said process comprising:

converting an intermediate compound of formula:

wherein Y 1 is a halogen and Y 2 is a halogen or hydrogen,

under conditions effective to produce the product compound of Formula (I).

14. The process of claim 13 further comprising:

reacting a starting material compound of formula:

under conditions effective to form the intermediate compound.

15. The process of claim 14 , wherein the conditions effective to form the intermediate compound include using a halogenating agent selected from the group consisting of N-bromosuccinimide, N-iodo-succinimide, and iodine monochloride.

16. The process of claim 14 , wherein said converting comprises:

reacting the intermediate compound with a palladium catalyst reagent to produce the product of Formula (I).

17. The process of claim 16 , wherein the palladium catalyst reagent is selected from the group consisting of palladium acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), tetrakis(triphenylphosphine)palladium, and bis(triphenylphosphine) palladium(II)dichloride.

18. A process for preparation of a derivative product compound of Formula (I) as follows:

where:

R 1 is:

halogen;

R 2 =alkyl or CH(O);

R 3 =hydrogen, alkyl, or C(O)R 5 ;

R 4 =hydrogen or C(O)R 5 ;

R 5 , R 6 , and R 7 each are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;

R 8 =hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, or thioalkyl;

R 5 and R 6 can form a ring or R 6 and R 7 can form a ring;

X=OR 5 , NR 5 R 6 , NHNH 2 , NHNHC(O)R 5 , OH, NHR 5 , NH 2 , or NHNHC(O)H;

R 4 and X may be linked together with intervening atoms to form a ring; R 1 and R 8 may be linked together; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched, straight, unsubstituted, and/or substituted and wherein the aryl, alkynyl, and heterocyclyl groups are substituted or unsubstituted, said process comprising:

reacting a starting material compound of formula:

under conditions effective to form the derivative product compound.

19. The process of claim 18 , wherein the conditions effective to form the intermediate compound include using a halogenating agent selected from the group consisting of N-bromosuccinimide, N-iodo-succinimide, and iodine monochloride.

20. A process for preparation of a derivative product compound of Formula (I) as follows:

where:

R 1 is:

alkenyl;

alkynyl;

aryl;

heterocyclyl;

CN;

CH(O);

COR 5 ;

C(O)NR 5 R 6 ;

C(O)NHR 5 ;

C(O)NH 2 ;

C(O)NHNH 2 ;

C(O)NR 5 NH 2 ;

C(O)NR 5 NHR 6 ;

C(O)NR 5 NR 6 R 7 ;

C(O)NHNHR 5 ;

C(O)NHNR 5 R 6 ;

C(O)NHOH;

SO 2 NHNH 2 ;

SO 2 NR 5 NH 2 ;

SO 2 NR 5 NHR 6 ;

SO 2 NR 5 NR 6 R 7 ;

SO 2 NHNHR 5 ;

SO 2 NHNR 5 R 6 ;

CO 2 R 5 ;

SR 5 ;

SSR 5 ;

SO 2 NHR 5 ;

SO 2 NR 5 R 6 ;

B(OR 5 ) 2 ;

CF 3 ;

SH;

SO 2 NH 2 ;

NH 2 ;

NHR 5 ;

NHCOR 5 ;

NHSO 2 R 5 ;

NR 5 R 6 ;

NHCOR 5 ;

NR 5 COR 6 ;

NR 5 SO 2 R 6 ;

SOR 5 ;

SO 2 R 5 ; or

OR 7 ;

R 2 =alkyl or CH(O);

R 3 =hydrogen, alkyl, or C(O)R 5 ;

R 4 =hydrogen or C(O)R 5 ;

R 5 , R 6 , and R 7 each are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;

R 8 =hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, or thioalkyl;

R 5 and R 6 can form a ring or R 6 and R 7 can form a ring;

X=OR 5 , NR 5 R 6 , NHNH 2 , NHNHC(O)R 5 , OH, NHR 5 , NH 2 , or NHNHC(O)H;

R 4 and X may be linked together with intervening atoms to form a ring; R 1 and R 8 may be linked together; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched, straight, unsubstituted, and/or substituted and wherein the aryl, alkynyl, and heterocyclyl groups are substituted or unsubstituted, said process comprising:

fluorinating an intermediate compound of formula:

under conditions effective to produce the product compound of Formula (I).

21. The process of claim 13 further comprising:

converting a starting material compound of formula:

under conditions effective to form the intermediate compound.

22. The process of claim 21 , wherein the conditions effective to form the intermediate compound include using a halogenating agent selected from the group consisting of N-bromosuccinimide, N-iodo-succinimide, and iodine monochloride.

23. A composition of matter comprising the compound of claim 1 and one or more pharmaceutical excipients.

24. The composition according to claim 23 , wherein R 3 =acetyl.

25. The composition according to claim 23 , wherein R 4 =hydrogen.

26. The composition according to claim 23 , wherein X=OMe.

27. The composition according to claim 23 , wherein R 3 acetyl, R 4 =hydrogen, and X=OMe.

28. The composition according to claim 23 , wherein R 2 =CH(O).

29. The composition according to claim 23 , wherein R 2 =alkyl.

30. A method for treating a condition selected from the group consisting of breast cancer, Hodgkin's disease, and small cell lung cancer in mammals, said method comprising:

administering a therapeutically effective amount of the compound of claim 1 to the mammal.

31. The method according to claim 30 , wherein R 3 =acetyl.

32. The method according to claim 30 , wherein R 3 =acetyl, R 4 =hydrogen, and X=OMe.

33. The method according to claim 30 , wherein R 2 =CH(O).

34. The method according to claim 30 , wherein R 2 =alkyl.

35. The method of claim 30 , wherein the mammal is human.

36. A method for treating a condition selected from the group consisting of Non-Hodgkin's lymphoma, chronic myeloid leukemia, melanoma, squamous cell cervical cancer, and Kaposi's sarcoma in mammals, said method comprising:

administering a therapeutically effective amount of the compound of claim 1 to the mammal.

37. The method according to claim 36 , wherein R 3 =acetyl.

38. The method according to claim 36 , wherein R 3 =acetyl, R 4 =hydrogen, and X=OMe.

39. The method according to claim 36 , wherein R 2 =CH(O).

40. The method according to claim 36 , wherein R 2 =alkyl.

41. The method of claim 36 , wherein the mammal is human.