Novel substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments

Abstract

The invention relates to substituted tetrahydronaphthalenes and derivatives thereof, and also to the physiologically compatible salts and physiologically functional derivatives thereof, to preparation thereof, to medicaments comprising at least one inventive substituted tetrahydronaphthalene or derivative thereof, and to the use of the inventive substituted tetrahydronaphthalenes and derivatives thereof as medicaments.

We claim: 
     
         1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein: 
         R1 and R2 
         are each independently H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO(R9), (C(R10)(R11)) q -R12, CO(C(R13)(R14)) r -R15, CO—O(C 1 -C 8 )-alkyl, and CO(C(R13)(R14)) r —N(R16)(R17); 
         R10 and R11 are each independently H, (C 1 -C 6 )-alkyl, hydroxy-(C 1 -C 2 )-alkyl, F, and OH; 
         R9, R13, R14, R16, and R17 are each independently H or (C 1 -C 6 )-alkyl; 
         or 
         R16 and R17, each independently taken together with the nitrogen atom to which they are attached form a 5-6-membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatom from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur; 
         q and r are each independently 0, 1, 2, 3, 4, 5, 6; 
         R12 and R15 are each independently H, OH, F, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, O-phenyl, CN, COO(R25), N(R26)CO(C 1 -C 6 )-alkyl, N(R27)(R28), CON(R29)(R30), SO 2 (C 1 -C 6 )-alkyl, or 3-12-membered mono-, bi- or spirocyclic ring, which may contain one to four heteroatoms from the group of N, O and S, and the 3-12-membered ring is optionally substituted by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, N(R31)(R32), COO(R33), SO 2 (C 1 -C 6 )-alkyl and COOH; 
         R25, R26, R27, R28, R29, R30, R31, R32 and R33 are each independently H or (C 1 -C 8 )-alkyl; 
         or 
         R27 and R28, R29 and R30, and R31 and R32 each independently taken together with the nitrogen atom to which they are attached form a 5-6-membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatom from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur; 
         L1 is C(R34)(R35), C(R36)(R37)C(R38)(R39), or (C 3 -C 6 )-cycloalkyl; 
         optionally, R1 may be joined to one of R34, R35, R36, R37, R38 or R39 radicals, so as to form a 5-6-membered ring; 
         R34, R35, R36, R37, R38 and R39 are each independently H or (C 1 -C 8 )-alkyl; 
         R3, R4, and R5 are independently H, F, Cl, Br, I, OH, CF 3 , NO2, CN, OCF 3 , O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, CON(R40)(R41), or CO(R42); 
         R40, R41 and R42 are each independently H or (C 1 -C 8 )-alkyl; 
         or 
         R40 and R41 taken together with the nitrogen atom to which they are attached form a 5-6-membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatom from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen, and sulfur; 
         X is O or C(R43)(R43′); 
         R6, R6′, R7, R7′, R43 and R43′ are each independently H, F, (C 1 -C 8 )-alkyl, OH, or O—(C 1 -C 6 )-alkyl; 
         or 
         R6 and R6′, or R43 and R43′ together are oxo; 
         R8 is H or (C 1 -C 8 )-alkyl; 
         L2 is a bond or C(R44)(R45); 
         R44 and R45 are each independently H or (C 1 -C 8 )-alkyl; 
         A is a 5-6-membered aromatic ring that may include up to 2 heteroatoms selected from the group of nitrogen, oxygen and sulfur, and is optionally substituted by one or more of the substituents selected from H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R54)(R55), SO 2 —CH 3 , CON(R56)(R57), N(R58)CO(R59), and CO(R60); 
         provided that when L2 is a bond, then C(O)NR8 may be joined to an ortho substituent of A via a bridge containing one or two elements from the group of carbon and nitrogen, so as to form a 9- to 10-membered bicyclic ring overall; 
         R54, R55, R56, R57, R58, R59, and R60 are each independently H or (C 1 -C 8 )-alkyl; 
         or 
         R54 and R55, and R56 and R57 each independently taken together with the nitrogen atom to which they are attached form a 5-6-membered ring which, apart from the nitrogen atom, may also include 0-1 further heteroatom from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur; 
         L3 is a bond or a linker having from 1 to 4 members, where the members are selected from the group consisting of O, S, SO 2 , N(R61), CO, C(R62)(R63), and C≡C, to give rise to a chemically viable radical, and the linker does not have any O—CO or COO groups; 
         B is (C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 6 )-alkyl, or a 3 to 10-membered mono-, bi- or spirocyclic nonaromatic ring, which may include from 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system is optionally substituted by one or more substituents selected from F, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R64), and hydroxyl; and 
         R61, R62, R63, and R64 are each independently H or (C 1 -C 8 )-alkyl; 
         provided that when X is C(R43)(R43′), then 
         L3 is C(R62)(R63)O, and 
         B is a 4- to 10-membered mono-, bi- or spirocyclic nonaromatic ring which includes from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring is optionally by one or more substituents selected from F, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R64), and hydroxyl; 
         or a physiologically compatible salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein:
 L2 is a bond;   or a physiologically compatible salt thereof.   
     
     
         3 . The compound according to  claim 1 , wherein:
 A is selected from the group of   
       
         
           
           
               
               
           
         
         which is optionally by one or more of the substituents selected from H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R54)(R55), SO 2 —CH 3 , CON(R56)(R57), N(R58)CO(R59), and CO(R60); 
         or a physiologically compatible salt thereof. 
       
     
     
         4 . The compound according to  claim 1 , wherein:
 L3 is a bond, O, or C(R62)(R63)O;   or a physiologically compatible salt thereof.   
     
     
         5 . The compound according to  claim 1 , wherein:
 B is a 4- to 6-membered nonaromatic ring which includes from 1 to 2 oxygen atoms, where the ring system is optionally substituted by one or more substituents selected from (C 1 -C 6 )-alkyl and hydroxyl;   or a physiologically compatible salt thereof.   
     
     
         6 . The compound according to  claim 1 , wherein:
 B-L3 is   
       
         
           
           
               
               
           
         
         or a physiologically compatible salt thereof. 
       
     
     
         7 . The compound according to  claim 1 , which is a compound of formula II 
       
         
           
           
               
               
           
         
         wherein: 
         L1, R3, R4 and R8 are each as defined in  claim 1 ; 
         R, R′, R″ and R′″ are each independently H, F, Cl, Br, I, OH, CF 3 , NO2, CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, N(R54)(R55), SO 2 —CH 3 , CON(R56)(R57), N(R58)CO(R59), and CO(R60); 
         L3 is CH 2 O; and 
         B is a 4- to 6-membered nonaromatic ring which includes from 1 to 2 oxygen atoms, wherein the ring is optionally substituted by one or more substituents selected from F, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, oxo, hydroxyl, preferably (C 1 -C 6 )-alkyl and hydroxyl; 
         or a physiologically compatible salt thereof. 
       
     
     
         8 . The compound according to  claim 7 , wherein:
 B-L3 is   
       
         
           
           
               
               
           
         
         or a physiologically compatible salt thereof. 
       
     
     
         9 . The compound according to  claim 1 , which is a compound of formula III 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4, R8, A, L1, L3 and B are each as defined in  claim 1 ; 
         or a physiologically compatible salt thereof. 
       
     
     
         10 . The compound according to  claim 1 , which is a compound of formula IV 
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4, X, L1, L3 and B are each as defined in  claim 1 , and the broken line indicates an optional double bond; 
         or a physiologically compatible salt thereof. 
       
     
     
         11 . A pharmaceutical composition comprising the compound according to  claim 1  or a physiologically compatible salt thereof, in combination with a pharmacologically acceptable carrier or excipient. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , further comprising one or more active ingredients which are effective in treating a metabolic disorder or a disease associated therewith. 
     
     
         13 . The pharmaceutical composition according to  claim 11 , further comprising one or more antidiabetics. 
     
     
         14 . The pharmaceutical composition according to  claim 11 , further comprising one or more lipid modulators. 
     
     
         15 . The pharmaceutical composition according to  claim 11 , further comprising one or more antiobesity agents. 
     
     
         16 . A pharmaceutical composition comprising the compound according to  claim 7  or a physiologically compatible salt thereof, in combination with a pharmacologically acceptable carrier or excipient. 
     
     
         17 . A pharmaceutical composition comprising the compound according to  claim 8  or a physiologically compatible salt thereof, in combination with a pharmacologically acceptable carrier or excipient. 
     
     
         18 . A pharmaceutical composition comprising the compound according to  claim 9  or a physiologically compatible salt thereof, in combination with a pharmacologically acceptable carrier or excipient. 
     
     
         19 . A pharmaceutical composition comprising the compound according to  claim 10  or a physiologically compatible salt thereof, in combination with a pharmacologically acceptable carrier or excipient. 
     
     
         20 . A method for treating a disorder of fatty acid metabolism, glucose utilization disorder, a disorder in which insulin resistance plays a role, diabetes mellitus or a sequel associated therewith, dyslipidemia or a consequence thereof, nonalcoholic fatty liver or a variant thereof, a state associated with metabolic syndrome, or obesity or a sequel associated therewith, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 1  or a physiologically compatible salt thereof. 
     
     
         21 . A process for preparing a pharmaceutical composition comprising the compound according to  claim 1  or a physiologically compatible salt thereof, in combination with a pharmacologically acceptable carrier or excipient, comprising mixing the compound according to  claim 1  or the physiologically compatible salt thereof with the pharmacologically acceptable carrier or excipient, and converting the mixture into to a form suitable for administration.