US2009186857A1PendingUtilityA1

Combretastatin A-4 Phosphate Prodrug Mono- and Di- Organic Amine Salts, Mono- and Di- Amino Acid Salts, and Mono- and Di- Amino Acid Ester Salts

60
Individually held — no corporate assignee on recordPriority: Sep 14, 2000Filed: Nov 5, 2008Published: Jul 23, 2009
Est. expirySep 14, 2020(expired)· nominal 20-yr term from priority
Inventors:John J. VenitMandar V. DaliManisha M. DaliYande HuangCharles E. DahlheimRavindra W. Tejwani
C07F 9/12A61K 9/0053A61K 31/66A61K 9/28
60
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

Provided herein are novel and useful combretastatin A-4 prodrug salts that increase the solubility of combretastatin A-4, readily regenerate combretastatin A-4 in vivo under normal physiological conditions, and which produce physiologically tolerable products as a result of the regeneration of combretastatin A-4.

Claims

exact text as granted — not AI-modified
1 . A compound having the structure of formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 one of —OR 1  or —OR 2  is —O − QH + , and the other is hydroxyl or —O − QH + ; and 
 Q is
 (A) an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + ; 
 (B) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + ; or 
 (C) an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters. 
 
 
   
   
       2 . The compound of  claim 1 , wherein Q is an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + . 
   
   
       3 . The compound of  claim 2 , wherein the nitrogen of Q forming the quaternary ammonium cation QH +  in the formula I is a primary amine bonded to an optionally substituted aliphatic group or a secondary amine bonded to two optionally substituted aliphatic groups, wherein the optional substituents are one or more hydroxyl or amino groups. 
   
   
       4 . The compound of  claim 2 , wherein Q is an optionally substituted aliphatic organic amine selected from the group consisting of ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)ethyl amine, choline, and hydrabamine and stereoisomers thereof. 
   
   
       5 . The compound of  claim 1 , wherein Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + . 
   
   
       6 . The compound of  claim 5 , wherein said amino acid is selected from the group consisting of lysine, tryptophan, arginine, ornithine, proline, glutamine, asparagine, hydroxyproline and stereoisomers thereof. 
   
   
       7 . The compound of  claim 1 , wherein Q is an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters. 
   
   
       8 . The compound of  claim 7 , wherein Q is a glycine C 1-6  alkyl ester. 
   
   
       9 . A pharmaceutical composition comprising:
 (a) a compound having the structure of formula I:   
     
       
         
         
             
             
         
       
     
     wherein:
 one of —OR 1  or —OR 2  is —O − QH + , and the other is hydroxyl or —O − QH + ; and 
 Q is
 (A) an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + ; 
 (B) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + ; or 
 (C) an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters; and 
 
 (b) a pharmaceutically acceptable carrier thereof. 
 
   
   
       10 . The pharmaceutical composition of  claim 9 , wherein Q is an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + . 
   
   
       11 . The pharmaceutical composition of  claim 9 , wherein said optionally substituted aliphatic organic amine is selected from the group consisting of ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)ethyl amine, choline, hydrabamine and stereoisomers thereof. 
   
   
       12 . The pharmaceutical composition of  claim 11 , wherein the pH is adjusted by an agent other than sodium hydroxide. 
   
   
       13 . The pharmaceutical composition of  claim 9 , wherein Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + . 
   
   
       14 . The pharmaceutical composition of  claim 9 , wherein said amino acid is selected from the group consisting of lysine, tryptophan, arginine, ornithine, proline, glutamine, asparagine, hydroxyproline and stereoisomers thereof. 
   
   
       15 . The pharmaceutical composition of  claim 9 , wherein Q is an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters. 
   
   
       16 . The pharmaceutical composition of  claim 9 , wherein Q is a glycine C 1-6  alkyl ester. 
   
   
       17 . A method of modulating tumor growth or metastasis in an animal comprising the administration of an amount effective therefor of a compound having the structure of formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 one of —OR 1  or —OR 2  is —O − QH + , and the other is hydroxyl or —O − QH + ; and Q is
 (A) an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + ; 
 (B) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + ; or 
 (C) an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters. 
 
 
   
   
       18 . The method of  claim 17 , wherein Q is an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + . 
   
   
       19 . The method of  claim 18 , wherein the nitrogen of QH +  forming the quaternary ammonium cation QH +  in the formula I is a primary amine bonded to an optionally substituted aliphatic group or a secondary amine bonded to two optionally substituted aliphatic groups, wherein the optional substituents are one or more hydroxyl or amino groups. 
   
   
       20 . The method of  claim 18  wherein said optionally substituted aliphatic organic amine is selected from the group consisting of ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)ethyl amine, choline, hydrabamine and stereoisomers thereof. 
   
   
       21 . The method of  claim 18 , wherein Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + . 
   
   
       22 . The method of  claim 18 , wherein said amino acid is selected from the group consisting of lysine, tryptophan, arginine, ornithine, proline, glutamine, asparagine, hydroxyproline, and stereoisomers thereof. 
   
   
       23 . The method of  claim 18 , wherein Q is an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters. 
   
   
       24 . The method of  claim 18 , wherein Q is a glycine C 1-6  alkyl ester. 
   
   
       25 . A composition formed by mixing compounds comprising:
 (a) a CA4P free acid having the structure:   
     
       
         
         
             
             
         
       
       (b) compound Q, wherein Q is
 (A) an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + ; 
 (B) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + ; or 
 (C) an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters. 
 
     
   
   
       26 . The composition of  claim 25  further comprising a pharmaceutically acceptable carrier. 
   
   
       27 . A process for preparing a compound of  claim 1 , comprising the step of contacting, in a solvent, CA4P free acid having the structure: 
     
       
         
         
             
             
         
       
     
     with compound Q, wherein Q is
 (A) an optionally substituted aliphatic organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation QH + ; 
 (B) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + ; or 
 (C) an amino acid containing one or more nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and where, further, all carboxylic acid groups of the amino acid are in the form of esters. 
 
   
   
       28 . The process of  claim 27 , wherein said compound of  claim 1  is precipitated in crystalline form from said solvent.

Join the waitlist — get patent alerts

Track US2009186857A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.