Taxane derivatives and processes for the preparation thereof

Abstract

A novel taxane derivative with anticancer activity, a process for its preparation and a process for the preparation of 14-β-hydroxy-1,14-carbonate-baccatine III and V derivatives 13-substituted by an isoserine residue.

1. A compound of Formula I, 
                 
 
     
     
       2. A process for preparing a compound of Formula I, 
                 
 
       comprising reacting 13-(N-Boc-β-isobutylisoserinyl)-14β-hydroxy-baccatine III 1,14-carbonate with diazabicyclo[5,4,0]7-undecene in methanol or THF. 
     
     
       3. A method of treating cancer selected from the group consisting of breast, ovarian and colon cancer  in a patient in need thereof comprising administering to said  a patient having breast, ovarian, or colon cancer a therapeutically effective amount of a compound of  claim 1 . 
     
     
       4. The method of  claim 3 , wherein the compound is administered in an amount of  from 50 to 500 mg/m 2 . 
     
     
       5. A pharmaceutical composition comprising the compound of  claim 1  and one or more pharmaceutically acceptable carriers and/or excipients. 
     
     
       6. The method of  claim 3  wherein the cancer is breast cancer. 
     
     
       7. The method of  claim 3  wherein the cancer is ovarian cancer. 
     
     
       8. The method of  claim 3  wherein the cancer is colon cancer. 
     
     
       9. A process for preparing a compound of Formula I, 
                   
         comprising preparing  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid, comprising the steps of:      a. protecting the amino group of a leucinol with Boc to form N - Boc - L - leucinol;        b. converting the N - Boc - L - leucinol into N - Boc - L - leucinal;        c. preparing a cyanhydrin nitrile from the N - Boc - L - leucinal;        d. transforming the cyanhydrin nitrile into a carboxylic acid;        e. forming a methyl ester of the carboxylic acid;        f. purifying the methyl ester of the carboxylic acid;        g. condensing the product of step  ( f )  with  2 , 4   - dimethoxybenzaldehyde dimethyl acetal to form  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester;        h. transforming the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester into the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid; and        i. using the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid to prepare the compound of Formula I.     
     
     
       10. The process of  claim 2 , wherein the  13 -( N - Boc -β- isobutylisoserinyl )-   14   β- hydroxy - baccatine III  1 , 14   - carbonate is prepared by a process comprising the steps of:      a. reacting  14   β- hydroxy -   10   - deacetylbaccatine III with a silylating agent to provide a  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III;        b. reacting the  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III with phosgene to provide a  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III;        c. reacting the  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III with a LiHMDS to provide a lithium salt of the  10   - hydroxyl group of the  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III;        d. reacting the lithium salt of the  10   - hydroxyl group of the  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III with an acetylating agent to acetylate the  10   - hydroxyl group to provide a  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - acetylbaccatine III;        e. reacting the  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - acetylbaccatine III with  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid to form a C -   13  esterified  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - acetylbaccatine III; and        f. removing the  7   - triethylsilyl group from the C -   13  esterified  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - acetylbaccatine III to provide a C -   13  esterified  1 , 14  carbonate  7   - hydroxy  14   β- hydroxy -   10   - acetylbaccatine III; and        g. removing a dimethoxybenzylidene group from the C -   13  esterified  1 , 14  carbonate  7   - hydroxy  14   β- hydroxy -   10   - acetylbaccatine III to provide  13   -( N - Boc -β- isobutylisoserinyl )-   14   β- hydroxy - baccatine III  1 , 14   - carbonate.     
     
     
       11. The process of  claim 10 , wherein the silylating agent is triethyl chlorosilane. 
     
     
       12. The process of  claim 10 , wherein the  7 - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III is reacted with phosgene by dissolving the  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III in a methylene chloride/pyridine mixture in a  3 : 1  ratio and then adding a toluene solution containing phosgene to the methylene chloride/pyridine mixture under a nitrogen atmosphere.   
     
     
       13. The process of  claim 10 , wherein the  1 , 14  carbonate  7 - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III is reacted with LiHMDS in anhydrous THF.   
     
     
       14. The process of  claim 10 , wherein the lithium salt of the  10 - hydroxyl group of the  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - deacetylbaccatine III is acetylated with acetyl chloride.   
     
     
       15. The process of  claim 10 , wherein the  1 , 14  carbonate  7 - triethylsilyl  14   β- hydroxy -   10   - acetylbaccatine III is reacted with the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid in an anhydrous apolar organic solvent in the presence of a base and of a condensing agent.   
     
     
       16. The process of  claim 15 , wherein the condensing agent is dicyclohexylcarbodiimide. 
     
     
       17. The process of  claim 10 , wherein the  7 - triethylsilyl group is removed from the C -   13  esterified  1 , 14  carbonate  7   - triethylsilyl  14   β- hydroxy -   10   - acetylbaccatine III with pyridinium fluoride in an acetonitrile/pyridine solution under nitrogen, and the dimethoxybenzylidene group is removed from the C -   13  esterified  1 , 14  carbonate  7   - hydroxy  14   β- hydroxy -   10   - acetylbaccatine III in a methylene chloride solvent by addition of methanolic HCl followed by addition of NaHCO   3 . 
     
     
       18. The process of  claim 10 , wherein the (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid is prepared by the process comprising the steps of:      a. protecting the amino group of a leucinol with Boc to form N - Boc - L - leucinol;        b. converting the N - Boc - L - leucinol into N - Boc - L - leucinal;        c. preparing a cyanhydrin nitrile from the N - Boc - L - leucinal;        d. transforming the cyanhydrin nitrile into a carboxylic acid;        e. forming a methyl ester of the carboxylic acid;        f. purifying the methyl ester of the carboxylic acid;        g. condensing the product of step  ( f )  with  2 , 4   - dimethoxybenzaldehyde dimethyl acetal to form  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )    4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester; and        h. transforming the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester into the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid.     
     
     
       19. The process of  claim 2 , wherein the  13 -( N - Boc -β- isobutylisoserinyl )-   14   β- hydroxy - baccatine III  1 , 14   - carbonate is prepared by a process comprising the steps of:      a. acetylating the C -   10  hydroxyl of  14   β- hydroxy -   10   - deacetylbaccatine III to provide  14   β- hydroxy -   10   - acetylbaccatine III:        b. reacting  14   β- hydroxy -   10   - acetylbaccatine III with phosgene to provide a  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III;        c. silylating the C -   7  hydroxyl of the  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III to provide a  7   - silyl  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III;        d. reacting the  7   - silyl  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III with  (   4 S, 5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid to provide a C -   13  esterified  7   - silyl  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III;        e. removing the  7   - silyl group from the C -   13  esterified  7   - silyl  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III to provide a C -   13  esterified  7   - hydroxy  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III; and        f. removing a dimethoxybenzylidene group from the C -   13  esterified  7   - hydroxy  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III to provide  13   -( N - Boc -β- isobutylisoserinyl )-   14   β- hydroxy - baccatine III  1 , 14   - carbonate.     
     
     
       20. The process of  claim 19 , wherein the C-   10  hydroxyl of  14   β- hydroxy -   10   - deactylbaccatine III is acetylated with acetic anhydride in the presence of a cerium, scandium, or ytterbium salt.   
     
     
       21. The process of  claim 20 , wherein the salt is CeCl 3 .H 2 O. 
     
     
       22. The process of  claim 19 , wherein  14 β- hydroxy -   10   - acetylbaccatine III is reacted with phosgene by dissolving the  14   β- hydroxy -   10   - acetylbaccatine III in a methylene chloride/pyridine mixture in a  3 : 1  ratio and then adding a toluene solution containing phosgene to the methylene chloride/pyridine mixture under a nitrogen atmosphere.   
     
     
       23. The process of  claim 19 , wherein the C-   10  hydroxyl of  14   β- hydroxy -   10   - deacetylbaccatine III is acetylated with acetyl chloride.   
     
     
       24. The process of  claim 19 , wherein the  7 - silyl  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III is reacted with  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid in an anhydrous apolar organic solvent in the presence of a base and a condensing agent.   
     
     
       25. The process of  claim 24 , wherein the condensing agent is dicyclohexylcarbodiimide. 
     
     
       26. The process of  claim 19 , wherein the silyl protective group is removed from the C-   13  esterified  7   - silyl  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III with pyridinium fluoride in a acetonitrile/pyridine solution under nitrogen, and the dimethoxybenzylidene group is removed from the C -   13  esterified  7   - hydroxy  1 , 14  carbonate derivative of  14   β- hydroxy -   10   - acetylbaccatine III in a methylene chloride solvent by addition of methanolic HCl followed by addition of NaHCO   3 . 
     
     
       27. The process of  claim 19 , wherein the (   4 S, 5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid is prepared by the process comprising the steps of:      a. protecting the amino group of a leucinol with Boc to form N - Boc - L - leucinol;        b. converting the N - Boc - L - leucinol into N - Boc - L - leucinal;        c. preparing a cyanhydrin nitrile from the N - Boc - L - leucinal;        d. transforming the cyanhydrin nitrile into a carboxylic acid;        e. forming a methyl ester of the carboxylic acid;        f. purifying the methyl ester of the carboxylic acid;        g. condensing the product of step  ( f )  with  2 , 4   - dimethoxybenzaldehyde dimethyl acetal to form  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )    4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester; and        h. transforming the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester into the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid.     
     
     
       28. The process of  claim 2 , wherein the  13 -( N - Boc -β- isobutylisoserinyl )-   14   β- hydroxy - baccatine III  1 , 14   - carbonate is prepared by a process comprising the steps of:      a. transforming  14   β- hydroxy -   10   - deacetylbaccatine III into a triethylsilylated derivative at the  7   - position;        b. preparing a  1 , 14  carbonate derivative from the product of step  ( a );      c. selectively acetylating the  10   - hydroxyl;        d. reacting the product of step  ( c )  with  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid;        e. cleaving the triethylsilyl and dimethoxybenzylidene protective groups from the product of step  ( d ).   
     
     
       29. The process of  claim 28 , wherein the silylating agent of step ( a )  is triethyl chlorosilane; the  1 , 14  carbonate derivative in step  ( b )  is prepared using phosgene in toluene in a  3 : 1  methylene chloride/pyridine solution under nitrogen atmosphere; step  ( c )  is carried out with LiHMDS in anhydrous THF, and the resulting  10   - hydroxy derivative is subsequently acetylated with acetyle chloride; step  ( d )  is carried out in anhydrous apolar organic solvent, in the presence of a base and the condensing agent dicyclohexylcarbodiimide  ( DCC );  the triethylsilyl protective group in step  ( e )  is removed with pyridinium fluoride in acetonitrile/pyridine solution under nitrogen, and the dimethoxybenzylidene protective group is removed in methylene chloride solvent by addition of HCl in methanol and subsequently addition of NaHCO   3 . 
     
     
       30. The process of  claim 28 , wherein the (   4 S, 5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid is prepared by the process comprising the steps of:      a. protecting the amino group of a leucinol with Boc to form N - Boc - L - leucinol;        b. converting the N - Boc - L - leucinol into N - Boc - L - leucinal;        c. preparing a cyanhydrin nitrile from the N - Boc - L - leucinal;        d. transforming the cyanhydrin nitrile into a carboxylic acid;        e. forming a methyl ester of the carboxylic acid;        f. purifying the methyl ester of the carboxylic acid;        g. condensing the product of step  ( f )  with  2 , 4   - dimethoxybenzaldehyde dimethyl acetal to form  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )    4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester; and        h. transforming the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester into the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid.     
     
     
       31. The process of  claim 2 , wherein the  13 -( N - Boc -β- isobutylisoserinyl )-   14   β- hydroxy - baccatine III  1 , 14   - carbonate is prepared by a process comprising the steps of:      a. selectively acetylating the hydroxyl at the C -   10  of  14   β- hydroxy -   10   - deacetylbaccatine III;        b. preparing a  1 , 14  carbonate derivative from the product of step  ( a );      c. silylating the hydroxyl at C -   7 ;        d. reacting the product of step  ( c )  with  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid;        e. cleaving the triethylsilyl and dimethoxybenzylidene protective groups from the product of step  ( d ).   
     
     
       32. The process of  claim 31 , wherein step ( a )  is carried out with acetic anhydride in the presence of a cerium, scandium or ytterbium salt, the  1 , 14  carbonate derivative in step  ( b )  is prepared using phosgene in toluene in a  3 : 1  methylene chloride/pyridine solution under nitrogen atmosphere; step  ( c )  is carried out with LiHMDS in anhydrous THF, and the resulting  10   - hydroxy derivative is subsequently acetylated with acetyle chloride; step  ( d )  is carried out in anhydrous apolar organic solvent, in the presence of a base and the condensing agent dicyclohexylcarbodiimide  ( DCC );  the triethylsilyl protective group in step  ( e )  is removed with pyridinium fluoride in acetonitrile/pyridine solution under nitrogen, and the dimethoxybenzylidene protective group is removed in methylene chloride solvent by addition of HCl in methanol and subsequently addition of NaHCO   3 . 
     
     
       33. The process of  claim 32 , wherein the cerium salt comprises CeCl 3     7 H   2   O.   
     
     
       34. The process of  claim 31 , wherein the (   4 S, 5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid is prepared by the process comprising the steps of:      a. protecting the amino group of a leucinol with Boc to form N - Boc - L - leucinol;        b. converting the N - Boc - L - leucinol into N - Boc - L - leucinal;        c. preparing a cyanhydrin nitrile from the N - Boc - L - leucinal;        d. transforming the cyanhydrin nitrile into a carboxylic acid;        e. forming a methyl ester of the carboxylic acid;        f. purifying the methyl ester of the carboxylic acid;        g. condensing the product of step  ( f )  with  2 , 4   - dimethoxybenzaldehyde dimethyl acetal to form  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )    4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester; and        h. transforming the  (   4 S, 5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid methyl ester into the  (   4 S,  5 R )- N - Boc -   2   -(   2 , 4   - dimethoxyphenyl )-   4   - isobutyl -   1   - oxazolidine -   5   - carboxylic acid.