1,3-Dihydroimidazole-2-Thione Derivatives for Use in the Treatment of Pulmonary Arterial Hypertension and Lung Injury

Abstract

The present invention relates to compounds of formula I: for use in treating pulmonary arterial hypertension and associated conditions, where R 1 , R 2 and R 3 are the same or different and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4 signifies hydrogen, alkyl, -alkylaryl or -alkylheteroaryl; X signifies CH 2 , oxygen atom or sulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X is not CH 2 ; and the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts thereof.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a compound of formula I 
       
         
           
           
               
               
           
         
         wherein, R 1 , R 2  and R 3  are the same or different and signify hydrogen, halogen, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4  signifies hydrogen, alkyl, -alkylaryl or -alkylheteroaryl; X signifies CH 2 , oxygen atom or sulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X is not CH 2 ; and the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts thereof, in combination with at least one prostacyclin analogue. 
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula I has the formula IA 
       
         
           
           
               
               
           
         
         wherein, R 1 , R 2  and R 3  are the same or different and signify hydrogen, halogen, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4  signifies hydrogen, alkyl or -alkylaryl group; X signifies CH 2 , oxygen atom or sulphur atom; and n is 1, 2 or 3, with the proviso that when n is 1, X is not CH 2 . 
       
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula I has the formula IB 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4  signifies -alkyl-aryl or -alkyl-heteroaryl; X signifies CH 2 , oxygen atom or sulphur atom; and n is 2 or 3. 
       
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula I is selected from the group consisting of:
 (S)-5-(2-aminoethyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione;   (S)-5-(2-aminoethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-chroman-3-yl-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(8-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(8-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6-fluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(8-fluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6,7-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (S)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6,7,8-trifluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6-chloro-8-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6-methoxy-8-chlorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(8-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-[6-(acetylamino)chroman-3-yl]-1,3-dihydroimidazole-2-thione;   (R)-5-aminomethyl-1-chroman-3-yl-1,3-dihydroimidazole-2-thione;   (R)-5-aminomethyl-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-aminoethyl)-1-(6-hydroxy-7-benzylchroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-aminomethyl-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(3-aminopropyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (S)-5-(3-aminopropyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione;   (R,S)-5-(2-aminoethyl)-1-(6-hydroxythiochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R,S)-5-(2-aminoethyl)-1-(6-methoxythiochroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-5-(2-benzylaminoethyl)-1-(6-methoxychroman-3-yl)-1,3-dihydroimidazole7-2-thione;   (R)-5-(2-benzylaminoethyl)-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;   (R)-1-(6-hydroxychroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thione;   (R)-1-(6,8-difluorochroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thione;   (R)-1-chroman-3-yl-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thione; and   (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione.   
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula I is (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula I is (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione. 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the dose of (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione is from 10 mg/day to 50 mg/day. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the prostacyclin analogue is selected from the group consisting of epoprostenol, iloprost, treprostinil and beraprost. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the prostacyclin analogue is epoprostenol. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the prostacyclin analogue is iloprost. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the prostacyclin analogue is treprostinil. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the prostacyclin analogue is beraprost. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the composition is in the form of a single daily dosage. 
     
     
         14 . The pharmaceutical composition according to  claim 1 , further comprising one or more inert pharmaceutically acceptable carriers. 
     
     
         15 . The pharmaceutical composition according to  claim 1  in unit dosage form. 
     
     
         16 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula I is (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione and the prostacyclin analogue is selected from the group consisting of epoprostenol, iloprost, treprostinil and beraprost. 
     
     
         17 . A method of treating pulmonary arterial hypertension comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with at least one prostacyclin analogue, to a subject in need thereof. 
     
     
         18 . The method according to  claim 17 , wherein the compound of formula I is (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride. 
     
     
         19 . The method according to  claim 17 , wherein (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione. 
     
     
         20 . The method according to  claim 17 , wherein the prostacyclin analogue is selected from the group consisting of epoprostenol, iloprost, treprostinil and beraprost.