Cyclopentathiophene Carboxamide Derivatives as Platelet Activating Factor Receptor Antagonists

Abstract

The invention relates to cyclopentathiophene carboxamides of formula (I.0) wherein R 1 , R 2 , R 3 , R 4 , and n are as defined herein, and pharmaceutically acceptable salts thereof. The invention also relates to the use of the cyclopentathiophene carboxamides of formula (I.0) for the treatment of diseases which can be influenced by antagonizing the activity mediated by the platelet activating factor receptor.

1 . A compound of formula (I.1) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of C 1-4 -alkyl optionally substituted with 1 to 3 F and of C 3-4 -cycloalkyl; 
         R 2  is selected from the group consisting of F, Cl, Br, I, C 1-4 -alkyl, C 3-4 -cycloalkyl, —CN, —CONH 2 , —CONH(C 1-4 -alkyl), —CON(C 1-4 -alkyl) 2 , —COOH, —COO—C 1-4 -alkyl, OH, —O—C 1-4 -alkyl, and —S(O) r —C 1-4 -alkyl with r=0, 1, or 2, wherein
 the C 1-4 -alkyl R 2  group may be optionally substituted with 1 to 3 F or optionally substituted with 1 CN, with 1 OH, or with 1 —O—C 1-4 -alkyl, and 
 the —O—C 1-4 -alkyl R 2  group may be optionally substituted with 1 to 3 F; 
 
         n is selected from the group consisting of 0, 1, 2, and 3; 
         R 3  is selected from the group consisting of H and C 1-4 -alkyl optionally substituted with 1 to 5 F; and 
         R 4  is selected from the group consisting of C 1-6 -alkyl
 optionally substituted with 1 to 3 F and 
 optionally substituted with 1 to 2 substituents independently selected from —CN, —CONH 2 , —CONH(C 1-4 -alkyl), —CON(C 1-4 -alkyl) 2 , —COOH, —COO—C 1-4 -alkyl, C 1-3 -alkyl-CO—NH—, C 1-3 -alkyl-S(═O) 2 —NH—, OH, and —O—C 1-3 -alkyl 
 
         optionally substituted with 1 to 3 F; 
         or 
         R 4  is selected from the group consisting of —C 0-3 -alkylene-C 3-10 -cycloalkyl and —C 0-3 -alkylene-C 3-10 -heterocyclyl,
 wherein said alkylene is optionally substituted with 1 to 2 substituents selected from F and CH 3 , 
 wherein the 2 H atoms of 1>CH 2  group of said alkylene are optionally replaced by an ethylene (—CH 2 —CH 2 —) bridge to form a cyclopropylene moiety >C(—CH 2 —CH 2 —), 
 wherein said cycloalkyl and heterocyclyl are saturated mono- or bicyclic ring systems, 
 wherein said heterocyclyl contains 1 to 2 ring members independently selected from N, NH, >N(C 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(═O) 2 (C 1-4 -alkyl), and O, and optionally 1 ring member selected from >C═O and >S(═O) r , with r=0, 1, or 2, 
 provided that said heterocyclyl does not contain any heteroatom-heteroatom bonds other than N—N, N—O, and N—S(═O) r=1,2  between ring members, and 
 wherein said cycloalkyl and heterocyclyl are optionally substituted with 1 to 2 F and optionally substituted with 1 to 2 substituents independently selected from Cl, —CN, —CONH 2 , —CONH(C 1-4 -alkyl), —CON(C 1-4 -alkyl) 2 , —COOH, —COO—C 1-4 -alkyl, OH, —O—C 1-3 -alkyl optionally substituted with 1 to 3 F, and from C 1-4 -alkyl optionally substituted with 1 to 3 F or with 1 substituent selected from —CN, OH, —O—C 1-4 -alkyl; 
 
         or 
         R 4  is selected from the group consisting of —C 0-3 -alkylene-phenyl and —C 0-3 -alkylene-heteroaryl,
 wherein said alkylene is optionally substituted with 1 to 2 substituents selected from F and CH 3 , 
 wherein the 2 H atoms of 1>CH 2  group of said alkylene are optionally replaced by an ethylene (—CH 2 —CH 2 —) bridge to form a cyclopropylene moiety >C(—CH 2 —CH 2 —), 
 wherein said heteroaryl is a 5-membered monocycle containing 1 ring member selected from N, NH, O, and S and optionally further containing 1 to 2 ring members N, or a 6-membered monocycle containing 1 to 2 ring members N, and 
 wherein said phenyl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from F, Cl, Br, C 3-4 -cycloalkyl, —CN, —CONH 2 , —CONH(C 1-4 -alkyl), —CON(C 1-4 -alkyl) 2 , —COOH, —COO—C 1-4 -alkyl, —NHCO—C 1-4 -alkyl, —NHS(═O) 2 —C 1-4 -alkyl, —S(═O) r C 1-4 -alkyl with r=0, 1, or 2, from —O—C 1-4 -alkyl optionally substituted with 1 to 3 F, and from C 1-4 -alkyl optionally substituted with 1 to 3 F or with 1 substituent selected from —CN, OH, and —O—C 1-4 -alkyl; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 R 1  is selected from the group consisting of CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CHF 2 , CF 3 , and cyclopropyl or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The compound according to  claim 1 , wherein
 R 1  is CH 3 ;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 1 , wherein
 R 2  is selected from the group consisting of F, Cl, Br, CH 3 , CH 2 CH 3 , cyclopropyl, CF 3 , CH 2 OH, OH, OCH 3 , and S—CH 3 ; and   n is selected from the group consisting of 0, 1, and 2;   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The compound according to  claim 1 , wherein
 R 2  is selected from the group consisting of F, Cl, and Br; and   n is 1;   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The compound according to  claim 1 , wherein
 R 2  is Cl; and   n is 1;   or a pharmaceutically acceptable salt thereof.   
     
     
         7 . The compound according to  claim 1 , wherein
 R 1  is CH 3 ;   R 2 , n, and the phenyl substitution pattern are selected such that the resulting substituted phenyl ring shown in formula (I.0) is   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound according to  claim 1 , wherein
 R 3  is selected from the group consisting of H, CH 3 , and CH 2 CH 2 CH 3 ;   or a pharmaceutically acceptable salt thereof.   
     
     
         9 . The compound according to  claim 1 , wherein
 R 4  is selected from the group consisting of C 1-4 -alkyl
 optionally substituted with 1 to 3 F and 
 optionally substituted with 1 substituent selected from —CN, —CONH 2 , —COOH, OH, and —O—C 1-2 -alkyl optionally substituted with 1 to 3 F; 
   or a pharmaceutically acceptable salt thereof.   
     
     
         10 . The compound according to  claim 1 , wherein
 R 4  is selected from the group consisting of C 1-4 -alkyl   optionally substituted with 1 substituent selected from F, OH, and OCF 3 ;   or a pharmaceutically acceptable salt thereof.   
     
     
         11 . The compound according to  claim 1 , wherein
 R 4  is selected from the group consisting of   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound according to  claim 1 , wherein
 R 4  is selected from the group consisting of —C 0-1 -alkylene-C 3-6 -cycloalkyl,
 wherein said cycloalkyl is a saturated mono- or bicyclic ring system, and 
 wherein said cycloalkyl is optionally substituted with 1 to 2 F and optionally substituted with 1 CH 3  or CH 2 CH 3 ; 
   or a pharmaceutically acceptable salt thereof.   
     
     
         13 . The compound according to  claim 1 , wherein
 R 4  is selected from the group consisting of   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The compound according to  claim 1 , wherein
 R 4  is selected from the group consisting of —C 0-2 -alkylene-phenyl and —C 0-2 -alkylene-heteroaryl,
 wherein said alkylene is optionally substituted with 1 to 2 CH 3 , 
 wherein the 2 H atoms of 1>CH 2  group of said alkylene are optionally replaced by an ethylene (—CH 2 —CH 2 —) bridge to form a cyclopropylene moiety >C(—CH 2 —CH 2 —), 
 wherein said heteroaryl is a 5-membered monocycle containing 1 ring member selected from N, NH, O, and S and optionally further containing 1 ring member N, or a 6-membered monocycle containing 1 to 2 ring members N, and 
 wherein said phenyl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from F, Cl, Br, —CN, —O—C 1-3 -alkyl optionally substituted with 1 to 3 F, and from C 1-3 -alkyl optionally substituted with 1 to 3 F or with 1 substituent selected from —CN and —O—C 1-2 -alkyl; 
   or a pharmaceutically acceptable salt thereof.   
     
     
         15 . The compound according to  claim 1 , wherein
 R 4  is selected from the group consisting of   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The compound according to  claim 1 , wherein
 the stereochemistry of the compound is according to formula (I.1)   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . A pharmaceutically acceptable salt of the compound according to  claim 1 . 
     
     
         18 . A pharmaceutical composition comprising one or more compounds according to  claim 1 , or pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents. 
     
     
         19 . A pharmaceutical composition comprising one or more compounds according to  claim 1 , or pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the one or more additional therapeutic agents are selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity, agents for the treatment of high blood pressure, heart failure and/or atherosclerosis, agents for the treatment of ocular diseases, and agents for the treatment of allergies and inflammation-related conditions and diseases. 
     
     
         21 . A method for treating an ocular disease in a patient in need thereof, the method comprising administering to the patient a pharmaceutically effective amount of one or more compounds according to  claim 1 , or pharmaceutically acceptable salt thereof. 
     
     
         22 . The method according to  claim 21 , wherein the ocular disease is selected from the group consisting of diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy and non-exudative choroidal neovascularization. 
     
     
         23 . A method for treating allergies and inflammation-related conditions and diseases, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of one or more compounds according to  claim 1 , or pharmaceutically acceptable salt thereof. 
     
     
         24 . A method for treating urticaria or non alcoholic steatohepatitis (NASH), the method comprising administering to a patient in need thereof a pharmaceutically effective amount of one or more compounds according to  claim 1 , or pharmaceutically acceptable salts thereof. 
     
     
         25 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.