2-Aroyl-4-acyl paclitaxel (taxol) analogs

Abstract

2-debenzoyl-4-deacetyl paclitaxel, antineoplastic analogs thereof and intermediates are taught, as well as the formation of the compound, analogs and intermediates. The compound, analogs and intermediates may be used to form pharmaceutical compositions having anti-neoplastic activity. Further, the compound, analogs and intermediates may be used to treat cancer when applied in an effective amount by means such as a pharmaceutical composition.

1 . An antineoplastic analog of paclitaxel, or a pharmaceutically acceptable salt thereof, comprising the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 6  is a substituted benzoyloxy group and R 5  is selected from the group consisting of an acyloxy group, an S-alkyl and S-aryldithiocarboxyoxy group, wherein the acyloxy group is not acetyloxy.  
     
     
         2 . The analog of  claim 1 , wherein said substituents on the benzoyloxy group are independently selected from the group consisting of hydrogen, hydroxyl, halogens, alkyls, alkoxys, nitro, cyano, azido, thiol, alkyl thiols, acyls, acyloxy, alkoxycarbonyloxys, diatomics, and linear triatomics.  
     
     
         3 . The analog of  claim 1 , wherein said acyloxy group is selected from the group consisting of alkylcarbonyloxy, arylcarbonyloxy, substituted arylcarbonyloxy, cycloalkylcarbonyloxy, heterocycloalkylcarbonyloxy, and alkoxycarbonyloxy.  
     
     
         4 . The analogs of  claim 1 , wherein the alkyl group of said S-alkyldithiocarboxyoxy group is selected from the group consisting of alkyl, cycloalkyl, and heterocycloalkyl.  
     
     
         5 . The analog of  claim 1 , wherein the aryl group of said S-aryldithiocarboxyoxy group is selected from the group consisting of phenyl, substituted phenyl, and heteroaryl.  
     
     
         6 . An antineoplastic compound, or a pharmaceutically acceptable salt thereof, comprising the general formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is an aryl or substituted aryl; R 2  is an aryl or substituted aryl; R 3  is selected from the group consisting of H, OH, and OC(O)R a , R 4  is selected from the group consisting of H, OH, oxyprotecting group (i.e. triethylsiloxy), OR b , and OC(O)R c , and wherein R a , R b , and R c  are independently selected from the group consisting of alkyls, aryls, and substituted aryls; R 5  is selected from the group OH, OC(O)R d , OC(O)OR e  and OC(S)SR f ; and R 6  is selected from the group H and OC(O)R g , where R d , R e , R f  and R g  are independently selected from the group consisting of alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls, alkynyls, aryls, and substituted aryls.  
     
     
         7 . The compound of  claim 6 , wherein R 4  is OH and R 3  is OC(O)CH 3 .  
     
     
         8 . The compound of  claim 7 , wherein R 5  is OC(O)R d .  
     
     
         9 . The compound of  claim 8  wherein R d  is selected from the group consisting of alkyl, cycloalkyl and alkoxy.  
     
     
         10 . The compound of  claim 8 , wherein R 6  is OC(O)R g .  
     
     
         11 . The compound of  claim 10  wherein R g  is an aryl or substituted aryl.  
     
     
         12 . The compound of  claim 7 , wherein R 1  and R 2  are both phenyl.  
     
     
         13 . The compound of  claim 12 , wherein R 5  is cyclopropylcarbonyloxy.  
     
     
         14 . The compound of  claim 13 , wherein R 6  is selected from the group consisting of m-azidobenzoyloxy, m-methoxybenzoyloxy, m-chlorobenzoyloxy, 3,5-dichlorobenzoyloxy, 3,5-difluorobenzoyloxy, and 2,5-dimethoxybenzoyloxy.  
     
     
         15 . The compound of  claim 12 , wherein R 5  is methoxycarbonyloxy.  
     
     
         16 . The compound of  claim 15 , wherein R 6  is selected from the group consisting of m-methylbenzoylozxy, m-methoxybenzoyloxy, and m-chlorobenzoyloxy.  
     
     
         17 . The compound of  claim 10 , wherein R 5  is S-methyldithiocarboxyoxy.  
     
     
         18 . The compound of  claim 17 , wherein R 6  is selected from the group consisting of m-methoxybenzoyl, m-chlorobenzoyloxy, and m-azidobenzoyloxy.  
     
     
         19 . A pharmaceutical composition, comprising an effective amount of the analog of  claim 1 .  
     
     
         20 . A pharmaceutical composition comprising an effective amount of the compound of  claim 6 .  
     
     
         21 . A method for treating cancer, comprising administering an effective amount of the analog of  claim 1 .  
     
     
         22 . A method of treating cancer comprising administering an effective amount of the compound of  claim 6 .  
     
     
         23 . A first paclitaxel analog compound having a protecting group at each of the positions C-2′ and C-7 and having OH groups at positions C-2 and C-4, wherein said analog has the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently selected from the group consisting of aryl, substituted aryl and heteroaryl; R 3  is hydroxy or acyloxy; R 4  is trialkylsilyl; and R 7  is trialkylsilyl.  
     
     
         24 . An intermediate of  claim 23  wherein R 1  and R 2  are phenyl, R 3  is acetoxy, R 4  is triethylsilyl, and R 7  is t-butyldimethylsilyl.  
     
     
         25 . A method of making the first paclitaxel analog compound of  claim 23 , comprising reacting 2′-t-butyldimethylsilyl-7-triethylsilylpaclitaxel with Triton B in dichloromethane.  
     
     
         26 . A second paclitaxel analog compound consisting of a cyclic carbonate intermediate of the first paclitaxel analog compound of  claim 23 , wherein the second paclitaxel analog compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         27 . An intermediate of the second paclitaxel analog of  claim 26 , wherein R 1  and R 2  are phenyl, R 3  is acetoxy, R 4  is triethylsilyl, and R 7  is t-butyldimethylsilyl.  
     
     
         28 . A method of synthesizing the intermediate of  claim 27 , comprising reacting 2′-t-butyldimethylsilyl-2-debenzoyl-4-deacetyl-7-triethylsilylpaclitaxel with carbonyldiimidazole or triphosgene.  
     
     
         29 . A third paclitaxel analog compound consisting of the 4-acyl intermediate of the second paclitaxel analog compound of  claim 26 , wherein the third paclitaxel analog compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 5  is selected from the group consisting of alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls, alkynyls, aryls, and substituted aryls.  
     
     
         30 . An intermediate of the third paclitaxel analog compound of  claim 29  wherein R 1  and R 2  are phenyl, R 3  is acetoxy, R 4  is triethylsilyl, and R 7  is t-butyldimethylsilyl.  
     
     
         31 . A method of synthesizing the intermediate of a third paclitaxel analog compound:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently selected from the group consisting of aryl, substituted aryl or heteroaryl; R 3  is hydroxy or acyloxy; R 4  is trialkylsilyl; R 5  is selected from the group consisting of alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls, alkynyls, aryls, and substituted aryls; and R 7  is trialkylsilyl, comprising reacting the intermediate of  claim 27  with a carboxylic acid in the presence of DCC and DMAP.  
     
     
         32 . A fourth paclitaxel analog compound consisting of the 2-acyl intermediate of the first paclitaxel analog compound of  claim 23 , wherein the fourth paclitaxel analog compound has the following formula:  
       
         
           
           
               
               
           
         
       
       wherein R 6  is selected from the group consisting of alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls, alkynyls, aryls, and substituted aryls.  
     
     
         33 . An intermediate of the fourth paclitaxel analog compound of  claim 32 , wherein R 1  and R 2  are phenyl, R 3  is acetoxy, R 4  is triethylsilyl, and R 7  is t-butyldimethylsilyl.  
     
     
         34 . A method of synthesizing the intermediate of  claim 33 , comprising reacting 2′-t-butyldimethylsilyl-2-debenzoyl-4-deacetyl-7-triethylsilylpaclitaxel with a carboxylic acid (R 6 COOH) in the presence of DCC and DMAP.  
     
     
         35 . A fifth paclitaxel analog compound consisting of a diprotected paclitaxel analog with the composition:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are independently selected from the group consisting of aryl, substituted aryl or heteroaryl; R 3  is hydroxy or acyloxy; R 4  is trialkylsilyl; R 5  and R 6  are independently selected from the group consisting of alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls, alkynyls, aryls, and substituted aryls; and R 7  is trialkylsilyl.  
     
     
         36 . The intermediate of  claim 35  wherein R 1  and R 2  are phenyl, R 3  is acetoxy, R 4  is triethylsilyl, and R 7  is t-butyldimethylsilyl.  
     
     
         37 . A method of synthesizing the intermediate of  claim 36 , comprising reacting 2′-t-butyldimethylsilyl-4-deacetyl-7-triethylsilylpaclitaxel with a carboxylic acid under forcing conditions in the presence of DCC and DMAP.  
     
     
         38 . A second method of synthesizing a fifth paclitaxel analog compound consisting of a diprotected paclitaxel analog with the composition:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are phenyl, R 3  is acetoxy, R 4  is triethylsilyl, R 5  and R 6  are independently selected from the group consisting of alkyls, cycloalkyls, heterocycloalkyls, heterocycloaryls, alkenyls, alkynyls, aryls, and substituted aryls, and R 7  is t-butyldimethylsilyl, comprising reacting the intermediate of  claim 29  with lithium hydroxide followed by a carboxylic acid (R 6 COOH), DCC and DMAP.  
     
     
         39 . An antineoplastic pcalitaxel analog as shown in Table 1, or a pharmaceutically acceptable salt thereof.