Intravenous formulations of neurokinin-1 antagonists

Abstract

Pharmaceutical compositions for intravenous administration comprising the compound of Formula I or pharmaceutically acceptable salts, hydrates or prodrugs thereof are described herein. Methods of preparing the pharmaceutical compositions and methods for treating nausea and/or emesis with the pharmaceutical compositions are also described herein.

1 - 73 . (canceled) 
     
     
         74 . A compound of formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y and Z are each independently selected from the group consisting of H, —PO(OH)OM + , —PO(O − ) 2 .2M + , —PO(O − ) 2 .D 2+ , —[C(R 1 )(R 2 )] n —OPO(OH)O − M + , —[C(R 1 )(R 2 )] n —OPO(O − ) 2 .2M + , —[C(R 1 )(R 2 )] n —OPO(O − ) 2 D 2+ , —C(O)[C(R 1 )(R 2 )] m —OPO(O − ) 2 .2M + , —C(O)[C(R 1 )(R 2 )] o NR 1 R 2 , —C(O)[C(R 1 )(R 2 )] p CO 2 .M + , —SO 3 .M + , —[C(R 1 )(R 2 )] q OSO 3 .M +  and —[C(R 1 )(R 2 )] r OC(O)R 3 ; 
         wherein: 
         R 1  and R 2  are each independently H or C 1-6  alkyl; 
         R 3  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         M +  is a monovalent cation; 
         D 2+  is a divalent cation; 
         M −   is a monovalent anion; 
         n, q, and r are each an independently integer selected from 1, 2, 3, and 4; 
         m, o, and p are each independently an integer selected from 0, 1, 2, 3, and 4; and 
         R is C 1-6  alkyl; 
         provided that Y and Z are not simultaneously H. 
       
     
     
         75 . The compound according to  claim 74 , wherein Y and Z are each independently selected from the group consisting of H, —PO(OH)OM + , —PO(O − ) 2 .2M + , and —PO(O) 2 .D 2 . 
     
     
         76 . The compound according to  claim 74 , wherein Y and Z are each independently selected from the group consisting of H, —[C(R 1 )(R 2 )] n —OPO(OH)O − M + , —[C(R 1 )(R 2 )] n —OPO(O − ) 2 .2M + , and —[C(R 1 )(R 2 )] n —OPO(O − ) 2 D 2+ . 
     
     
         77 . The compound according to  claim 76 , wherein n is 1. 
     
     
         78 . The compound according to  claim 77 , wherein Y and Z are each independently selected from the group consisting of H, —CH 2 —OPO(OH)O − M + , —CH 2 —OPO(O − ) 2 .2M + , and —CH 2 —OPO(O − ) 2 D 2+ . 
     
     
         79 . The compound according to  claim 74 , wherein Y and Z are each independently selected from the group consisting of —C(O)[C(R 1 )(R 2 )] m —OPO(O − ) 2 .2M + . 
     
     
         80 . The compound according to  claim 79 , wherein m is 1. 
     
     
         81 . The compound according to  claim 80 , wherein Y and Z are each independently selected from the group consisting of —C(O)CH 2 —OPO(O − ) 2 .2M + . 
     
     
         82 . The compound according to  claim 74 , wherein Y and Z are each independently selected from the group consisting of —[C(R 1 )(R 2 )] r OC(O)R 3 . 
     
     
         83 . The compound according to  claim 82 , wherein r is 1. 
     
     
         84 . The compound according to  claim 83 , wherein Y and Z are each independently selected from the group consisting of —CH 2 —OC(O)R 3 . 
     
     
         85 . The compound according to  claim 74 , wherein M +  is selected from the group consisting of an alkali metal, an amino acid, an organic base, and ammonium. 
     
     
         86 . The compound according to  claim 85 , wherein M +  is an alkali metal. 
     
     
         87 . The compound according to  claim 86 , wherein the alkali metal is selected from the group consisting of sodium, lithium, and potassium. 
     
     
         88 . The compound according to  claim 85 , wherein M +  is an amino acid. 
     
     
         89 . The compound according to  claim 88 , wherein the amino acid is selected from the group consisting of arginine and lysine. 
     
     
         90 . The compound according to  claim 85 , wherein M +  is an organic base. 
     
     
         91 . The compound according to  claim 90 , wherein the organic base is selected from the group consisting of N-methyl-D-glucamine and dicyclohexylamine. 
     
     
         92 . The compound according to  claim 74 , wherein D 2+   is an alkaline earth metal. 
     
     
         93 . The compound according to  claim 92 , wherein the alkaline earth metal is selected from the group consisting of calcium and magnesium.