Polysubstituted indan-1-ol compounds, and methods for their preparation and use

Abstract

Polysubstituted indan-1-ol compounds, methods for their preparation; and methods for their use are disclosed herein. In particular, the invention relates to polysubstituted indan-1-ol compounds of the formula I and their physiologically acceptable salts. The compounds are useful, for example, as anorectics.

What is claimed is:  
     
         1 . A compound of the formula I,  
       
         
           
           
               
               
           
         
       
       in which 
 R1, R2, R3, R4 independently of one another are H; F, Cl, Br, I, ON, N 3 , NO 2 , OH, O(C 1 -C 8 )-alkyl, O(C 3 -C 8 )-cycloalkyl, O—CH 2 -phenyl, O-phenyl, O—CO-(C 1 -C 8 )-alkyl, O—CO-(C 3 -C 8 )-cycloalkyl, where in the alkyl radicals up to seven hydrogen atoms may be replaced by fluorine; 
 S(O) 0-2 (C 1 -C 8 )-alkyl, S(O) 0-2 (C 3 -C 8 )-cycloalkyl, where in the alkyl radicals up to seven hydrogen atoms may be replaced by fluorine; NH 2 , NH-(C 1 -C 8 )-alkyl, NH-(C 3 -C 8 )-cycloalkyl, N[(C 1 -C 8 )-alkyl] 2 , N[(C 3 -C 8 )-cycloalkyl] 2 , NH—CO-(C 1 -C 8 )-alkyl, NH—CO-(C 3 -C 8 )-cycloalkyl;  
 SO 3 H, SO 2 —NH 2 , SO 2 —NH-(C 1 -C 8 )-alkyl, SO 2 —NH-(C 3 -C 8 )-cycloalkyl;  
 SO 2 -(C 1 -C 6 )-alkyl;  
 NH—SO 2 —NH 2 ; NH—SO 2 -(C 1 -C 8 )-alkyl, NH—SO 2 -(C 3 -C 8 )-cycloalkyl;  
 O—CH 2 —COOH, O—CH 2 —CO—O(C 1 -C 8 )-alkyl, COOH, COO(C 1 -C 8 )-alkyl, CO—O-(C 3 -C 8 )-cycloalkyl, CO—NH 2 , CO—NH(C 1 -C 8 )-alkyl, CO—N[(C 1 -C 8 )-alkyl] 2    
 (C 1 -C 8 )-alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, wherein the alkyl, alkenyl, and alkynyl groups one to seven hydrogen atoms may be replaced by fluorine;  
 or one hydrogen may be replaced by OH, OC(O)CH 3 , O—CH 2 -Ph, NH 2 , NH—CO—CH 3  or N(COOCH 2 Ph) 2    
 phenyl, 1- or 2-naphthyl,  
 5-tetrazolyl, 1-[(C 1 -C 6 )-alkyl]-5-tetrazolyl, 2-[(C 1 -C 6 )-alkyl]-5-tetrazolyl,  
 1-imidazolyl,  
 1- or 4-[1,2,4]-triazolyl,  
 2- or 3-thienyl,  
 2- or 3-furyl,  
 2-, 3- or 4-pyridyl,  
 2-, 4- or 5-oxazolyl,  
 3-, 4- or 5-isoxazolyl,  
 2-, 4- or 5-thiazolyl,  
 3-, 4- or 5-isothiazolyl,  
 where the aryl radical or heterocycle may be substituted up to two times by 
 F, Cl, Br, CN,  
 OH, (C 1 -C 4 )-alkyl, CF 3 , O-(C 1 -C 4 )-alkyl,  
 S(O) 0-2 (C 1 -C 6 )-alkyl, NH 2 , NH—SO 2 -(C 1 -C 4 )-alkyl;  
 COOH, CO—O-(C 1 -C 4 )-alkyl, CO—NH 2  and where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; or  
 
 
 R2 and R3 together form the radical —O—CH 2 —O—; 
 X is S, SO, SO 2 ;  
 Y is (CH 2 ) p , where p may be 0, 1, 2 or 3;  
 
 R5 is (C 1 -C 18 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 6 -C 8 )-cycloalkyl, where in the alkyl groups up to seven hydrogen atoms may be replaced by fluorine; 
 (CH 2 ) 1-6 -COOH, (CH 2 ) 1-6 -COO-(C 1 -C 6 )-alkyl, (CH 2 ) 1-6 -CONH 2  CH 2 —CH(NHR10)-COR11, where R10 may be H or C(O)-(C 1 -C 6 )-alkyl and R11 may be OH, O-(C 1 -C 6 )-alkyl or NH 2 ;  
 phenyl, 1- or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings or ring systems are in each case substituted up to three times by 
 F, Cl, Br, I, CN, OH, O(C 1 -C 8 )-alkyl, O(C 3 -C 8 )-cycloalkyl, O—CO-(C 1 -C 8 )-alkyl, O—CO-(C 3 -C 8 )-cycloalkyl, S(O) 0-2 (C 1 -C 8 )-alkyl, S(O) 0-2 (C 3 -C 8 )-cycloalkyl, NH 2 , NH-(C 1 -C 8 )-alkyl, NH-(C 3 -C 8 )-cycloalkyl, N[(C 1 -C 8 )-alkyl] 2 , N[(C 3 -C 8 )-cycloalkyl] 2 , NH—CO-(C 1 -C 8 )-alkyl, NH—CO-(C 3 -C 8 )-cycloalkyl, SO 3 H; SO 2 —NH 2 , SO 2 —NH-(C 1 -C 8 )-alkyl, SO 2 —NH-(C 3 -C 8 )-cycloalkyl, NH—SO 2 —NH 2 ; NH—SO 2 -(C 1 -C 8 )-alkyl, NH—SO 2 -(C 3 -C 8 )-cycloalkyl; O—CH 2 —COOH, O—CH 2 —CO—O(C 1 -C 8 )-alkyl, COOH, CO—O(C 1 -C 8 )-alkyl, CO—O-(C 3 -C 8 )-cycloalkyl, CO—NH 2 , CO—NH(C 1 -C 8 )-alkyl, CO—N[(C 1 -C 8 )-alkyl] 2 ;  
 (C 1 -C 8 )-alkyl, (C 3 -C 8 )-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;  
 
 
 R6 is (CH 2 ) 0-6 -R9, (CH 2 ) 0-6 -COOH, (CH 2 ) 0-6 -COO-(C 1 -C 6 )-alkyl, (CH 2 ) 0-6 -CONH 2 , (CH 2 ) 0-6 -CH(NHR15)-COR16, F, Cl, Br, CN, (C 1 -C 18 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 6 -C 8 )-cycloalkyl, where in the alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may be replaced by fluorine;  
 R15 is H, C(O)-(C 1 -C 6 )-alkyl;  
 R16 is OH, O-(C 1 -C 6 )-alkyl, NH 2    
 R7 is (CH 2 ) 0-4 -R12, H, (C 1 -C 12 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 6 -C 8 )-cycloalkyl, COO(C 1 -C 6 )-alkyl, COO(C 3 -C 8 )-cycloalkyl, where in the alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may be replaced by fluorine;  
 R8 is (CH 2 ) 0-4 -R14, (C 1 -C 12 )-alkyl, (C 3 -C 4 -cycloalkyl, (C 6 -C 8 )-cycloalkyl, where in the alkyl or cycloalkyl radicals up to seven hydrogen atoms may be replaced by fluorine atoms;  
 R9, R12, R14 independently of one another are 
 phenyl, 1- or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings or ring systems are in each case substituted up to three times by 
 F, Cl, Br, I, CN, OH, O(C 1 -C 8 )-alkyl, O(C 3 -C 8 )-cycloalkyl, O—CO-(C 1 -C 8 )-alkyl, O—CO-(C 3 -C 8 )-cycloalkyl, S(O) 0-2 (C 1 -C 8 )-alkyl, S(O) 0-2 (C 3 -C 8 )-cycloalkyl, NH 2 , NH-(C 1 -C 8 )-alkyl, NH-(C 3 -C 8 )-cycloalkyl, N[(C 1 -C 8 )-alkyl] 2 , N[(C 3 -C 8 )-cycloalkyl] 2 , NH—CO-(C 1 -C 8 )-alkyl, NH—CO-(C 3 -C 8 )-cycloalkyl, SO 3 H; SO 2 —NH 2 , SO 2 —NH-(C 1 -C 8 )-alkyl, SO 2 —NH-(C 3 -C 8 )-cycloalkyl, NH—SO 2 —NH 2 ; NH—SO 2 -(C 1 -C 8 )-alkyl, NH—SO 2 -(C 3 -C 8 )-cycloalkyl; O—CH 2 —COOH, O—CH 2 —CO—O(C 1 -C 8 )-alkyl, COOH, CO—O(C 1 -C 8 )-alkyl, CO—O-(C 3 -C 8 )-cycloalkyl, CO—NH 2 , CO—NH(C 1 -C 8 )-alkyl, CO—N[(C 1 -C 8 )-alkyl] 2 ;  
 (C 1 -C 8 )-alkyl, (C 3 -C 8 )-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;  
 and its physiologically acceptable salts.  
 
 
 
     
     
         2 . A compound of the formula I as claimed in  claim 1  in which 
 R1, R2, R3, R4 independently of one another are H, F, Cl, Br, N 3 , O(C 1 -C 8 )-alkyl, or (C 1 -C 8 )-alkyl and where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;  
 where in each case at least one of the radicals R1, R2, R3 and R4 is different from hydrogen;  
 X is S, SO, or SO 2 ;  
 Y is (CH 2 ) p , where p may be 0, 1, 2, or 3;  
 R5 is (C 1 -C 18 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 6 -C 8 )-cycloalkyl, where in the alkyl groups up to seven hydrogen atoms may be replaced by fluorine; 
 (CH 2 ) 1-6 -COOH, (CH 2 ) 1-6 -COO-(C 1 -C 6 )-alkyl, (CH 2 ) 1-6 -CONH 2  CH 2 —CH(NHR10)-COR11, where R10 may be H or C(O)-(C 1 -C 6 )-alkyl and R11 may be OH, O-(C 1 -C 6 )-alkyl or NH 2 ;  
 Phenyl, 1- or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings or ring systems are in each case substituted up to three times by 
 F, Cl, Br, I, CN, OH, O(C 1 -C 8 )-alkyl, O(C 3 -C 8 )-cycloalkyl, O—CO-(C 1 -C 8 )-alkyl, O—CO-(C 3 -C 8 )-cycloalkyl, S(O) 0-2 (C 1 -C 8 )-alkyl, S(O) 0-2 (C 3 -C 8 )-cycloalkyl, NH 2 , NH-(C 1 -C 8 )-alkyl, NH-(C 3 -C 8 )-cycloalkyl, N[(C 1 -C 8 )-alkyl] 2 , N[(C 3 -C 8 )-cycloalkyl] 2 , NH—CO-(C 1 -C 8 )-alkyl, NH—CO-(C 3 -C 8 )-cycloalkyl, SO 3 H; SO 2 —NH 2 , SO 2 —NH-(C 1 -C 8 )-alkyl, SO 2 —NH-(C 3 -C 8 )-cycloalkyl, NH—SO 2 —NH 2 ; NH—SO 2 -(C 1 -C 8 )-alkyl, NH—SO 2 -(C 3 -C 8 )-cycloalkyl; O—CH 2 —COOH, O—CH 2 —CO—O(C 1 -C 8 )-alkyl, COOH, CO—O(C 1 -C 8 )-alkyl, CO—O-(C 3 -C 8 )-cycloalkyl, CO—NH 2 , CO—NH(C 1 -C 8 )-alkyl, CO—N[(C 1 -C 8 )-alkyl] 2 ;  
 (C 1 -C 8 )-alkyl, (C 3 -C 8 )-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;  
 
 
 R6 (CH 2 ) 0-6 -R9, (CH 2 ) 0-6 -COOH, (CH 2 ) 0-6 -COO-(C 1 -C 6 )-alkyl, (CH 2 ) 0-6 -CONH 2 , (CH 2 ) 0-6 -CH(NHR15)-COR16, F, Cl, Br, CN, (C 1 -C 18 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 6 -C 8 )-cycloalkyl, where in the alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may be replaced by fluorine;  
 R15 is H, C(O)-(C 1 -C 6 )-alkyl;  
 R16 is OH, O-(C 1 -C 6 )-alkyl, NH 2 ;  
 R7 is (CH 2 ) 0-4 -R12, H, (C 1 -C 12 )-alkyl, (C 3 -C 4 )-cycloalkyl, (C 6 -C 8 )-cycloalkyl, COO(C 1 -C 6 )-alkyl, COO(C 3 -C 8 )-cycloalkyl, where in the alkyl radicals or cycloalkyl radicals up to seven hydrogen atoms may be replaced by fluorine;  
 R8 is (CH 2 ) 0-4 -R14, (C 1 -C 12 )-alkyl, (C 3 -C 4 -cycloalkyl, (C 6 -C 8 )-cycloalkyl, where in the alkyl or cycloalkyl radicals up to seven hydrogen atoms may be replaced by fluorine atoms;  
 R9, R12, R14 independently of one another are 
 phenyl, 1- or 2-naphthyl, biphenyl, or a heterocyclic radical, where the rings or ring systems are in each case substituted up to three times by 
 F, Cl, Br, I, CN, OH, O(C 1 -C 8 )-alkyl, O(C 3 -C 8 )-cycloalkyl, O—CO-(C 1 -C 8 )-alkyl, O—CO-(C 3 -C 8 )-cycloalkyl, S(O) 0-2 (C 1 -C 8 )-alkyl, S(O) 0-2 (C 3 -C 8 )-cycloalkyl, NH 2 , NH-(C 1 -C 8 )-alkyl, NH-(C 3 -C 8 )-cycloalkyl, N[(C 1 -C 8 )-alkyl] 2 , N[(C 3 -C 8 )-cycloalkyl] 2 , NH—CO-(C 1 -C 8 )-alkyl, NH—CO-(C 3 -C 8 )-cycloalkyl, SO 3 H; SO 2 —NH 2 , SO 2 —NH-(C 1 -C 8 )-alkyl, SO 2 —NH-(C 3 -C 8 )-cycloalkyl, NH—SO 2 —NH 2 ; NH—SO 2 -(C 1 -C 8 )-alkyl, NH—SO 2 -(C 3 -C 8 )-cycloalkyl; O—CH 2 —COOH, O—CH 2 —CO—O(C 1 -C 8 )-alkyl, COOH, CO—O(C 1 -C 8 )-alkyl, CO—O-(C 3 -C 8 )-cycloalkyl, CO—NH 2 , CO—NH(C 1 -C 8 )-alkyl, CO—N[(C 1 -C 8 )-alkyl] 2 ;  
 (C 1 -C 8 )-alkyl, (C 3 -C 8 )-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;  
 and its physiologically acceptable salts.  
 
 
 
     
     
         3 . A compound of the formula I as claimed in  claim 1  in which 
 R1, R2, R3, R4 independently of one another are H, F, Cl, Br, N 3 , O(C 1 -C 8 )-alkyl, or (C 1 -C 8 )-alkyl and where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine;  
 where in each case at least one of the radicals R1, R2, R3 and R4 is different from hydrogen;  
 X is SO 2 ;  
 Y is (CH 2 ) p , where p may be 0, 1 or 2;  
 R5 is (C 1 -C 8 )-alkyl, where in the alkyl group up to seven hydrogen atoms may be replaced by fluorine;  
 R6 is F, Cl, Br, CN, or (C 1 -C 8 )-alkyl, where in the alkyl group up to seven hydrogen atoms may be replaced by fluorine;  
 R7 is H, or (C 1 -C 12 )-alkyl, where in the alkyl group up to seven hydrogen atoms may be replaced by fluorine;  
 R8 is (C 1 -C 12 )-alkyl, where in the alkyl group up to seven hydrogen atoms may be replaced by fluorine;  
 and its physiologically acceptable salts.  
 
     
     
         4 . A pharmaceutical composition comprising one or more compounds as claimed in  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         5 . The pharmaceutical composition according to  claim 4 , further comprising one or more active compounds for reducing weight in mammals.  
     
     
         6 . A method for reducing weight in mammals, comprising administering to said mammal a compound of formula I as claimed in  claim 1 .  
     
     
         7 . A method of treating obesity, comprising administering to a subject in need thereof, an effective amount of a compound of formula I as claimed in  claim 1 .  
     
     
         8 . The method of  claim 7 , further comprising administering one or more active compounds for reducing weight in mammals.  
     
     
         9 . A method of treating type II diabetes, comprising administering to a subject in need thereof, an effective amount of a compound of formula I as claimed in  claim 1 .  
     
     
         10 . The method of  claim 9 , further comprising administering one or more active compounds for reducing weight in mammals.  
     
     
         11 . A method of maintaining weight loss, comprising administering to a subject in need thereof, an effective amount of a compound of formula I as claimed in  claim 1 .  
     
     
         12 . The method of  claim 11 , further comprising administering one or more active compounds for reducing weight in mammals.