US2010249239A1PendingUtilityA1

Bis(thio-hydrazide amide) formulation

53
Assignee: SYNTA PHARMACEUTICALS CORPPriority: Aug 16, 2005Filed: Feb 1, 2010Published: Sep 30, 2010
Est. expiryAug 16, 2025(expired)· nominal 20-yr term from priority
A61K 31/4025A61K 31/444A61P 35/00A61K 31/165A61K 31/16A61P 35/04A61K 31/277
53
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Claims

Abstract

Disclosed herein are compositions comprising a compound represented by structural formula (I): 2 g of which is reconstitutable in 10 mL of a water in less than 10 minutes, and methods for preparing these compositions. Also disclosed are compositions comprising a compound represented by structural formula (I) and a pharmaceutically acceptable excipient, wherein the molar ratio of said compound to said excipient is from 1:20 to 1:1, and methods for preparing these compositions.

Claims

exact text as granted — not AI-modified
1 . A composition comprising a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group; 
 R 1 -R 4  are independently —H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or R 1  and R 3  taken together with the carbon and nitrogen atoms to which they are bonded, and/or R 2  and R 4  taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring; 
 Z is —O or —S; and 
 M +  is a pharmaceutically acceptable monovalent cation and M 2+  is a pharmaceutically acceptable divalent cation; and 
 wherein 2 g of said composition is reconstitutable in 10 mL of a water in less than 10 minutes. 
 
     
     
         2 . The composition of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable excipient, and wherein the molar ratio of said compound to said excipient is from 1:20 to 1:1. 
     
     
         3 . The composition of  claim 2 , wherein the pharmaceutically acceptable excipient is a crystalline bulking excipient. 
     
     
         4 . The composition of  claim 3 , wherein the pharmaceutically acceptable cation is Na +  or K + . 
     
     
         5 . The composition of  claim 4 , wherein Z is O; R 1  and R 2  are the same; and R 3  and R 4  are the same. 
     
     
         6 . The composition of  claim 5 , wherein:
 Y is a covalent bond, —C(R 5 R 6 )—, —(CH 2 CH 2 )—, trans-(CH═CH)—, cis-(CH═CH)— or —(CC)— group; and   R 5  and R 6  are each independently —H, an aliphatic or substituted aliphatic group, or R 5  is —H and R 6  is a substituted or unsubstituted aryl group, or R 5  and R 6 , taken together, are a C2-C6 substituted or unsubstituted alkylene group.   
     
     
         7 . The composition of  claim 6 , wherein:
 Y is —C(R 5 R 6 )—;   R 1  and R 2  are each a substituted or unsubstituted aryl group; and   R 3  and R 4  are each a substituted or unsubstituted aliphatic group.   
     
     
         8 . The composition of  claim 7 , wherein: R 3  and R 4  are each an alkyl group; R 5  is —H; and R 6  is —H or methyl. 
     
     
         9 . The composition of  claim 8 , wherein R 1  and R 2  are each a substituted or unsubstituted phenyl group and R 3  and R 4  are each methyl or ethyl. 
     
     
         10 . The composition of  claim 6 , wherein
 Y is —CR 5 R 6 —;   R 1  and R 2  are both a substituted or unsubstituted aliphatic group;   R 5  is —H; and   R 6  is —H or an optionally substituted aliphatic group.   
     
     
         11 . The composition of  claim 10 , wherein R 1  and R 2  are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group; R 3  and R 4  are both an alkyl group; and R 6  is —H or methyl. 
     
     
         12 . The composition of  claim 11 , wherein R 1  and R 2  are both cyclopropyl or 1-methylcyclopropyl. 
     
     
         13 . The composition of  claim 3 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both phenyl; R 3  and R 4  are both ethyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 4-cyanophenyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both 4-methoxyphenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both phenyl; R 3  and R 4  are both ethyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both 4-cyanophenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both 3-cyanophenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 3-fluorophenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 4-chlorophenyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both 2-dimethoxyphenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 3-methoxyphenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2,3-dimethoxyphenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2,3-dimethoxyphenyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both 2,5-difluorophenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2,5-difluorophenyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both 2,5-dichlorophenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2,5-dimethylphenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both phenyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; R 1  and R 2  are both 2,5-dimethoxyphenyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1 , and R 2  are both cyclopropyl; R 3  and R 4  are both ethyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both cyclopropyl; R 3  and R 4  are both methyl; R 5  is methyl; R 6  is —H; 
 R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 5  is methyl and R 6  is —H; 
 R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 5  is ethyl and R 6  is —H; 
 R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 5  is n-propyl and R 6  is —H; 
 R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both methyl; R 5  and R 6  are both methyl; 
 R 1  and R 2  are both 1-methylcyclopropyl; R 3  and R 4  are both ethyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 1-methylcyclopropyl; R 3  is methyl, and R 4  is ethyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2-methylcyclopropyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 2-phenylcyclopropyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both 1-phenylcyclopropyl; R 3  and R 4  are both methyl; R 5  and are both —H; 
 R 1  and R 2  are both cyclobutyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2 , are both cyclopentyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both cyclohexyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both cyclohexyl; R 3  and R 4  are both phenyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both methyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both methyl; R 3  and R 4  are both t-butyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both methyl; R 3  and R 4  are both phenyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are both t-butyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; 
 R 1  and R 2  are ethyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H; or 
 R 1  and R 2  are both n-propyl; R 3  and R 4  are both methyl; R 5  and R 6  are both —H. 
 
     
     
         14 . The composition of  claim 9 , wherein said composition is reconstitutable in a water in less than 2 minutes. 
     
     
         15 . The composition of  claim 9 , wherein said composition is reconstitutable in a water in less than 1 minute. 
     
     
         16 . The composition of  claim 14 , wherein the composition is a lyophilizate. 
     
     
         17 . The composition of  claim 16 , wherein the crystalline bulking excipient, is selected from the group consisting of glycine, mannitol, dextran, dextrose, lactose, sucrose, polyvinylpyrrolidone, trehalose, glucose and combinations thereof. 
     
     
         18 . The composition of  claim 17 , wherein the molar ratio of said compound to said excipient is from 1:10 to 1:1. 
     
     
         19 . The composition of  claim 18 , wherein the molar ratio of said compound to said excipient is from 1:5.5 to 1:2. 
     
     
         20 . The composition of  claim 19 , wherein the crystalline bulking excipient is glycine or mannitol. 
     
     
         21 . The composition of  claim 20 , wherein the crystalline bulking excipient is mannitol. 
     
     
         22 . The composition of  claim 21 , wherein the composition is an annealed composition. 
     
     
         23 . The composition of  claim 22 , wherein said composition is reconstitutable in a water in less than 30 seconds. 
     
     
         24 . A composition comprising a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group; 
 R 1 -R 4  are independently —H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or R 1  and R 3  taken together with the carbon and nitrogen atoms to which they are bonded, and/or R 2  and R 4  taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring; 
 Z is —O or —S; and 
 M +  is a pharmaceutically acceptable monovalent cation and M 2+  is a pharmaceutically acceptable divalent cation; and 
 a pharmaceutically acceptable excipient, wherein the molar ratio of said compound to said excipient is from 1:20 to 1:1. 
 
     
     
         25 - 103 . (canceled)

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