Antineoplastic combinations

Abstract

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.