Substituted cyclohexane derivatives

Abstract

The present invention provides compounds of formula (I) wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , A 10 , U, V, W, m, n and p-are as indicated in the specification, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with 2,3-oxidosqualene-lanosterol cyclase such as hypercholesterolemia and hyperlipemia.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 U is O or a lone pair,  
 V is O, S, —CH═CH—, —CH═CH—CH 2 -O—, or —C≡C—,  
 W is CO, COO, CONR 1 , CSO, CSNR 1 , or SO 2 NR 1 ,  
 m and n independently from each other are from 0 to 7 and m+n is from 0 to 7, with the proviso that m is not 0 if V is O or S,  
 A 1  is hydrogen, lower-alkyl, hydroxy-lower-alkyl, or lower-alkenyl,  
 A 2  is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkynyl, heteroaryl, substituted heteroaryl, or lower-alkyl optionally substituted by R 2 , or  
 A 1  and A 2  are bonded to each other to form a ring with the N atom to which they are attached, and -A 1 -A- is lower-alkylene or lower-alkenylene, optionally substituted by R 2 , in which one —CH 2 — group of  
 -A 1 -A 2 - can optionally be replaced by NR 3 , S, or O, or -A 1 -A 2 - is  
 —CH=N—CH═CH— which can optionally be substituted by lower-alkyl,  
 A 3  and A 4  independently from each other are hydrogen or lower-alkyl, or  
 A 3  and A 4  are bonded to each other to form a ring together with the carbon atom to which they are attached and -A 3 -A 4 - is —(CH 2 ) 2-5 —,  
 A 5 , A 6 , A 7  and A 8  independently from each other are hydrogen or lower-alkyl,  
 A 9  is hydrogen, lower-alkyl, lower-alkenyl, or aryl-lower-alkyl,  
 A 10  is lower-alkyl, cycloalkyl, aryl-lower-alkyl, substituted aryl-lower alkyl, heteroaryl, substituted heteroaryl, heteroaryl-lower-alkyl, or substituted heteroaryl-lower alkyl,  
 p is 0 or 1,  
 R 2  is hydroxy, hydroxy-lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl, N(R 4 ,R 5 ), thio-lower-alkoxy or halogen,  
 R 1 , R 3 , R 4  and R 5  independently from each other are hydrogen or lower-alkyl, substituted aryl and substituted heteroaryl are aryl and heteroaryl, respectively, substituted by 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF 3 , NH 2 , N(H, lower-alkyl), N(lower-alkyl) 2 , aminocarbonyl, carboxy, NO 2 , lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, phenyl, and phenyloxy, and pharmaceutically acceptable salts thereof,  
 with the proviso that the compound of formula (I) is not trans-naphthalene-1-sulfonic acid methyl-(4-methylaminomethyl-cyclohexylmethyl)-amide.  
 
     
     
         2 . The compound according to  claim 1 , wherein U is a lone pair.  
     
     
         3 . The compound according to  claim 1 , wherein V is O, CH═CH—, —CH═CH—CH 2 —O—, or —C≡C—.  
     
     
         4 . (canceled)  
     
     
         5 . (canceled)  
     
     
         6 . The compound according to  claim 3 , wherein V is —CH═CH—.  
     
     
         7 . The compound according to  claim 3 , wherein V is —C≡C—.  
     
     
         8 . The compound according to  claim 1 , wherein W is COO.  
     
     
         9 . (canceled)  
     
     
         10 . The compound according to  claim 1 , wherein m is from 0 to 4 and n is from 0 to 1.  
     
     
         11 . The compound according to  claim 10 , wherein m is 0.  
     
     
         12 . The compound according to  claim 10 , wherein n is 0.  
     
     
         13 . The compound according to  claim 1 , wherein A 1  is hydrogen, lower-alkyl or hydroxy-lower-alkyl.  
     
     
         14 . The compound according to  claim 13 , wherein A 1  is methyl, ethyl, or 2-hydroxy-ethyl.  
     
     
         15 . The compound according to  claim 1 , wherein A 2  is lower-alkenyl, 2-methyl-pyrimidinyl, or lower-alkyl optionally substituted by R 2 , wherein R 2  is hydroxy.  
     
     
         16 . The compound according to  claim 15 , wherein A 2  is methyl or 2-hydroxy-ethyl.  
     
     
         17 . The compound according to  claim 1 , wherein A 1  and A 2  are bonded to each other to form a ring with the N atom to which they are attached, and -A 1 -A 2 - is lower-alkylene optionally substituted by R 2 , in which one —CH 2 — group of -A 1 -A 2 - can optionally be replaced by NR 3  or O, or -A 1 -A 2 - is —CH=N—CH═CH—, wherein R 2  is hydroxy or hydroxy-lower-alkyl, and R 3  is hydrogen or lower-alkyl.  
     
     
         18 . The compound according to  claim 17 , wherein -A 1 -A 2 - is —(CH 2 ) 4 — or —(CH 2 ) 5 —.  
     
     
         19 . The compound according to  claim 1 , wherein A 3  and A 4  are hydrogen.  
     
     
         20 . The compound according to  claim 1 , wherein A 5  and A 6  are hydrogen.  
     
     
         21 . The compound according to  claim 1 , wherein A 7  and A 8  are hydrogen.  
     
     
         22 . The compound according to  claim 1 , wherein A 9  is lower-alkyl.  
     
     
         23 . The compound according to  claim 22 , wherein A 9  is methyl.  
     
     
         24 . (canceled)  
     
     
         25 . The compound according to  claim 1 , wherein A 10  is phenyl optionally substituted with halogen or CF 3 .  
     
     
         26 . The compound according to  claim 25 , wherein A 10  is 4-chloro-phenyl or 4-trifluoromethyl-phenyl.  
     
     
         27 . The compound according to  claim 1 , selected from the group consisting of trans-Methyl-[4-(2-piperidin-1-yl-ethyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester, trans-N-Methyl-N-[4-(2-piperidin-1-yl-ethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide, trans-N-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, trans-[2-(4-Dimethylaminomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, trans-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexyl)-ethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, trans-Methyl-[2-(4-piperidin-1-ylmethyl-cyclohexyl)-ethyl] -carbamic acid 4-trifluoromethyl-phenyl ester, trans-Methyl-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester, trans-Methyl-{2-[4-(3-pyrrolidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester, trans-(4-{5-[Bis-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexylmethyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-prop-1-ynyl}-cyclohexylmethyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, and trans-N-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-propyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, and pharmaceutically acceptable salts thereof.  
     
     
         28 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         29 . A method of treatment of hypercholesterolemia or hyperlipemia, comprising administering from 1 to 1000 mg per day of a compound or a salt thereof according to  claim 1 , to a patient in need of treatment.  
     
     
         30 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 U is a lone pair,  
 V is —CH═CH—, or —C≡C—,  
 W is COO,  
 m and n independently from each other are from 0 to 3 and m+n is from 0 to 3,  
 A 1  is hydroxy lower-alkyl, or lower-alkyl,  
 A 2  is hydroxy lower-alkyl or lower-alkyl, or  
 A 1  and A 2  are bonded to each other to form a ring with the N atom to which they are attached, and -A 1 -A 2 - is lower-alkylene,  
 A 3  and A 4  are each hydrogen,  
 A 5 , A 6 , A 7  and A 8  are each hydrogen,  
 A 9  is lower-alkyl,  
 A 10  is phenyl substituted with chlorine or —CF 3 ,  
 p is 0 or 1,  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         31 . The compound according to  claim 30 , wherein hydroxy lower-alkyl for each of A 1  and A 2  is —CH 2 CH 2 OH.  
     
     
         32 . The compound according to  claim 30 , wherein lower alkyl for each of A 1  and A 2  is independently selected from the group consisting of —CH 3  and —CH 2 CH 3 .  
     
     
         33 . The compound according to  claim 30 , wherein A 9  is —CH 3 .