5-HT2B Antagonists

Abstract

The invention provides novel compounds and compositions comprising a 5-HT 2B antagonist of formula I: and related methods for treating a person having a disorder characterized by undesirable 5-HT 2B receptor signaling, such as migraine, irritable bowel syndrome (IBS), pulmonary arterial hypertension (PAH), fibrosis, hepatocellular cancer, a small intestinal neuroendocrine tumor, cardiovascular disorders, and gastrointestinal (GI) tract disorders.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a compound that is a 5-HT 2B  antagonist of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently H or Me; 
 R 3  and R 4  are independently a C1-C4 alkyl, or R 3  and R 4  are joined to form a C3-C8 cycloalkyl; and 
 R 5 -R 9  are independently H, halogen, hydroxyl, or an optionally substituted C1-C4 alykl, C1-C4 alkyoxy, carbonyl, carboxyl, or amine; 
 or salt thereof, wherein the salt is a pharmaceutically-acceptable salt, and a pharmaceutically-acceptable excipient, in unit dosage. 
 
     
     
         2 . The composition of  claim 1  wherein:
 R 1  and R 2  are independently H or methyl; 
 R 3  and R 4  are independently C1-C3 alkyl, or R 3  and R 4  are joined to form C4-C7 cycloalkyl; 
 R 5  and R 9  are independently H, halogen, methyl or methoxyl; and 
 R 6 -R 8  are independently H, halogen, methyl, —OR 10 , COR 10 , COOR 10 , or CONR 10 R 10 , wherein each R 10  is independently H or C1-C4 alkyl. 
 
     
     
         3 . The composition of  claim 1  wherein:
 R 1  and R 2  are independently H or methyl; 
 R 3  and R 4  are methyl or R 3  and R 4  form cyclopentyl or cyclohexyl; 
 R 5  is H, halogen, methyl or methoxyl; 
 R 6  is H, halogen (F, Cl, Br, I), methyl, methoxyl, or —OR 10 , COR 10 , COOR 10 , or CONR 10 R 10 , wherein each R 10  is independently H or C1-C4 alkyl. 
 R 7  is H, halogen, methyl, —OR 10  or COOR 10 , wherein each R 10  is independently H or C1-C3 alkyl; 
 R 8  is H, halogen, methyl or methoxyl; and 
 R 9  is H or methyl. 
 
     
     
         4 . The composition of  claim 1  wherein the antagonist is of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 1  wherein:
 R 1 ═H, R 2 ═H, R 6  is Cl, R 7 ═H, R 8 ═H; 
 R 1 ═H, R 2 ═H, R 6  is Br, R 7 ═H, R 8 ═H; 
 R 1 ═H, R 2 ═H, R 6  is I, R 7 ═H, R 8 ═H; 
 R 1 ═H, R 2 ═H, R 6  is CONHEt, R 7 ═H, R 8 ═H; 
 R 1 ═H, R 2 ═H, R 6  is COOPr, R 7 ═H, R 8 ═H; 
 R 1 ═H, R 2 ═H, R 6  is COOEt, R 7 ═Me, R 8 ═H; 
 R 1 ═H, R 2 ═H, R 6  is COOEt, R 7 ═Me, R 8 ═Br; 
 R 1 ═Me, R 2 ═H, R 6  is COOEt, R 7 ═H, R 8 ═H; 
 R 1 ═Me, R 2 ═Me, R 6  is COOEt, R 7 ═H, R 8 ═H; or 
 R 1 ═H, R 2 ═H, R 6  is COPr, R 7 ═H, R 8 ═H. 
 
     
     
         6 . The composition of  claim 1  wherein the antagonist is of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The composition of  claim 1  wherein the antagonist is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The composition of  claim 1  wherein the antagonist is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The composition of  claim 1  wherein the salt is an acid addition salt derived from an inorganic acid or nontoxic organic acid. 
     
     
         10 . The composition of  claim 1  wherein the salt is an acid addition salt derived from an inorganic acid selected from hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, and phosphorous acids. 
     
     
         11 . The composition of  claim 1  wherein the salt is an acid addition salt derived from a nontoxic organic acid selected from acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric methanesulfonic, or an amino acid. 
     
     
         12 . The composition of  claim 1  wherein the salt is an acid addition salt derived from an amino acid that is arginate or of a glucuronic or galactunoric acid. 
     
     
         13 . The composition of  claim 1  wherein the compound is in crystalline form. 
     
     
         14 . The composition of  claim 1  wherein the compound is in amorphous form 
     
     
         15 . The composition of  claim 1  wherein the unit dosage form is 1 to 1000 mg. 
     
     
         16 . A method for inhibiting 5-HT 2B  receptor signaling, comprising administering to a person in need thereof a composition of  claim 1 . 
     
     
         17 . A method for treating a disorder selected from migraine, pulmonary arterial hypertension (PAH), fibrosis, or a gastrointestinal (GI) tract disorder selected from the group consisting of hypertonic lower esophageal sphinter, irritable bowel syndrome (IBS), gastric motility disorder, dyspepsia, gastroesophageal reflux disease (GERD), and tachygastria, comprising administering to a person in need thereof a composition of  claim 1 .