Piperidinylamino-thieno[2,3-D] Pyrimidine Compounds

Abstract

The invention relates to 5-HT receptor modulators, particularly 5-HT 2B antagonists. Novel piperidinylamino-thieno[2,3-d]pyrimidine compounds represented by Formula I, II and III, and uses thereof for treating conditions including pulmonary arterial hypertension, congestive heart failure, and hypertension.

1 . A compound having the formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of halo, lower alkyl, cyano, and trihalomethyl; 
 each R 2  is independently hydrogen, halo, cyano, trihalomethyl, lower alkoxy, carboxylate, an amide, or a sulfonyl group; and 
 n is 1 or 2, provided that when n is 1, R 2  is not hydrogen, and when n is 2, both R 2  groups are not hydrogen; 
 
       or a pharmaceutically acceptable salt and/or ester thereof. 
     
     
         2 . A compound having the formula 
       
         
           
           
               
               
           
         
       
       wherein
 X is halo; 
 R 3  is hydrogen, halo, cyano, or trihalomethyl; and 
 n is 1 or 2, provided that when n is 1, R 3  is not hydrogen, and when n is 2, both R 3  groups are not hydrogen; 
 
       or a pharmaceutically acceptable salt and/or ester thereof. 
     
     
         3 . A pharmaceutically acceptable salt of the compound of  claim 1  which is a maleate, hydrochloride or fumarate salt. 
     
     
         4 . A method of treating pulmonary hypertension, comprising administering to a patient in need thereof the compound of  claim 1 . 
     
     
         5 . A method of treating erectile dysfunction, comprising administering to a patient in need thereof the compound of  claim 1 . 
     
     
         6 . A method of treating systemic hypertension, comprising administering to a patient in need thereof the compound of  claim 1 . 
     
     
         7 . A method of treating a disease state that is alleviated by treatment with a 5-HT 2B  antagonist, comprising administering to a patient in need thereof a composition comprising a compound of formula II or III or its salt in an amount effective to treat the disease state, wherein formula II is represented by 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of halo, lower alkyl, cyano, and trihalomethyl; 
 each R 2  is independently hydrogen, halo, cyano, trihalomethyl, lower alkoxy, carboxylate, an amide, or a sulfonyl group; and 
 n is 1 or 2, provided that when n is 1, R 2  is not hydrogen, and when n is 2, both R 2  groups are not hydrogen; 
 
       or a pharmaceutically acceptable salt and/or ester thereof; and 
       wherein formula III is represented by 
       
         
           
           
               
               
           
         
       
       wherein
 X is halo; 
 R 3  is hydrogen, halo, cyano, or trihalomethyl; and 
 n is 1 or 2, provided that when n is 1, R 3  is not hydrogen, and when n is 2, both R 3  groups are not hydrogen; 
 
       or a pharmaceutically acceptable salt and/or ester thereof. 
     
     
         8 . The method of  claim 7 , wherein the disease state is selected from the diseases pulmonary arterial hypertension, CHF, migraine, hypertension, disorders of the gastrointestinal tract, restenosis, asthma, obstructive airway disease, prostatic hyperplasia, erectile dysfunction and priapism. 
     
     
         9 . The method of  claim 7 , wherein the disease state comprises inflammatory pain, neuropathic pain, cancer pain, acute pain or chronic pain. 
     
     
         10 . The method of  claim 7 , wherein the disease state comprises allergic asthma, irritable bowel syndrome, hypertonic lower esophageal sphincter, motility disorders or benign prostatic hyperplasia. 
     
     
         11 . The method of  claim 7 , wherein the disease state comprises depression, anxiety, attention deficit hyperactivity disorder, obesity, sleeping disorder, Alzheimer's disease, or Parkinson disease. 
     
     
         12 . The method of  claim 7 , wherein the disease state comprises carcinoid tumors or teratocarcinoma. 
     
     
         13 . The method of  claim 7 , wherein the disease state comprises hyperprolactinemia or acromegaly. 
     
     
         14 . A pharmaceutically acceptable salt of the compound of  claim 2  which is a maleate, hydrochloride or fumarate salt. 
     
     
         15 . A method of treating pulmonary hypertension, comprising administering to a patient in need thereof the compound of  claim 2 . 
     
     
         16 . A method of treating erectile dysfunction, comprising administering to a patient in need thereof the compound of  claim 2 . 
     
     
         17 . A method of treating systemic hypertension, comprising administering to a patient in need thereof the compound of  claim 2 .