Antineoplastic combinations
View Patent ↗This invention provides the use of a combination of CCI-779 and EKB-569 in the treatment of neoplasms.
1. A method of treating a neoplasm in a mammal in need thereof, which comprises providing to said mammal synergistically effective amount of a combination comprising CCI-779 and EKB-569.
2. The method according to claim 1 , wherein the neoplasm is renal cancer.
3. The method according to claim 1 , wherein the neoplasm is soft tissue sarcoma.
4. The method according to claim 1 , wherein the neoplasm is breast cancer.
5. The method according to claim 1 , wherein the neoplasm is a neuroendocrine tumor of the lung.
6. The method according to claim 1 , wherein the neoplasm is cervical cancer.
7. The method according to claim 1 , wherein the neoplasm is uterine cancer.
8. The method according to claim 1 , wherein the neoplasm is a head and neck cancer.
9. The method according to claim 1 , wherein the neoplasm is glioma.
10. The method according to claim 1 , wherein the neoplasm is non-small cell lung cancer.
11. The method according to claim 1 , wherein the neoplasm is prostate cancer.
12. The method according to claim 1 , wherein the neoplasm is pancreatic cancer.
13. The method according to claim 1 , wherein the neoplasm is lymphoma.
14. The method according to claim 1 , wherein the neoplasm is melanoma.
15. The method according to claim 1 , wherein the neoplasm is small cell lung cancer.
16. The method according to claim 1 , wherein the neoplasm is ovarian cancer.
17. The method according to claim 1 , wherein the neoplasm is colon cancer.
18. The method according to claim 1 , wherein the neoplasm is esophageal cancer.
19. The method according to claim 1 , wherein the neoplasm is gastric cancer.
20. The method according to claim 1 , wherein the neoplasm is leukemia.
21. The method according to claim 1 , wherein the neoplasm is colorectal cancer.
22. The method according to claim 1 , wherein the neoplasm is unknown primary cancer.
23. A method of treating a neoplasm in a mammal in need thereof, which comprises providing to said mammal an effective amount of a synergistic combination comprising CCI-779 and EKB-569, wherein either CCI-779, EKB-569, or both are provided in subtherapeutically effective amounts.
24. The method according to claim 23 in which CCI-779 is provided in a subtherapeutically effective amount.
25. The method according to claim 23 in which EKB-569 is provided in a subtherapeutically effective amount.
26. The method according to claim 23 in which both CCI-779 and EKB-569 are provided in subtherapeutically effective amounts.
27. An antineoplastic combination which comprises an antineoplastic effective amount of a synergistic combination of CCI-779 and EKB-569.
28. A process for the preparation of 4 - dimethylamino - but - 2 - enoic acid [ 4 -( 3 - chloro - 4 - fluoro - phenylamino )- 3 - cyano - 7 - ethoxy - quinolin - 6 - yl] - amide comprising:
( a ) forming a mixture containing ( 4 - [ 3 - chloro - 4 - fluoro - phenyl]amino - 6 - amino - 3 - cyano - 7 - ethoxy - quinoline ) , 4 - N,N - dimethylaminocrotonoyl chloride hydrochloride, and N - methylpyrrolidinone at a temperature of 0 to 10 ° C.;
( b ) holding the mixture until the concentration of the ( 4 - [ 3 - chloro - 4 - fluoro - phenyl]amino - 6 - amino - 3 - cyano - 7 - ethoxy - quinoline ) is equal to or less than 2 %;
( c ) adding sodium bicarbonate to the suspension in step ( b ) until a solution is obtained;
( d ) collecting the product of step ( c ) to yield the compound 4 - dimethylamino - but - 2 - enoic acid [ 4 -( 3 - chloro - 4 - fluoro - phenylamino )- 3 - cyano - 7 - ethoxy - quinolin - 6 - yl] - amide.
29. The process according to claim 28 wherein the collecting step comprises filtering, washing and drying the product of step ( c ).
30. The process according to claim 28 , further comprising the step of preparing the 4 - N,N - dimethylaminocrotonoyl chloride hydrochloride, said step further comprising:
( i ) adding oxalyl chloride to a combination of the compound
( ii ) stirring the combination in step ( i ) at 20 to 25 ° C.;
( iii ) cooling the combination of step ( ii ).
31. The process according to claim 30 , wherein the combination in ( i ) is at 0 ° C.
32. The process according to claim 30 , wherein the cooling is to 0 ° C.
33. The process according to claim 30 , wherein the product of ( iii ) is washed with tetrahydrofuran ( THF ) and dried to yield 4 - N,N - dimethylaminocrotonoyl chloride hydrochloride.
34. The process according to claim 28 , wherein the 4 - N,N - dimethylaminocrotonoyl chloride hydrochloride is prepared in CH 3 CN.
35. The process according to claim 28 , wherein the 4 - N,N - dimethylaminocrotonoyl chloride hydrochloride is prepared in tetrahydrofuran with dimethylformamide.