Indole derivatives

Abstract

The invention relates to new indole derivatives, processes for their preparation, and their use in medicaments.

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         15 . A method for the treatment and/or prophylaxis of arteriosclerosis and hypercholesterol aemia comprising administering to a subject in need thereof an effective amount of a compound of Formula I  
       
         
           
           
               
               
           
         
       
       in which 
 Z represents O, S, SO, SO 2 , CH 2 , CHF, CF 2  or represents NR 9 , in which R 9  denotes hydrogen or (C 1 l-C 4 )-alkyl,  
 R 1  and R  2  are identical or different and represent hydrogen, halogen, cyano, (C 1 -C 6 )-alkyl, CF 3 , CHF 2 , CH 2 F, vinyl or (C 3 -C 7 )-cycloalkyl, where at least one of the two substituents is unequal to hydrogen and in the ortho position to the bridge bond,  
 R 3  represents a group of the formula  
   -A m -D n -E o -G p -L-R 10 ,  
 in which  
 A represents O, S, NR 11  or represents the group —(CR 12 ≡CR 13 )—, in which R 11  denotes hydrogen or (C 1 -C 4 )-alkyl, and R 12  and R 13  are identical or different and denote hydrogen, cyano, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,  
 D represents a straight-chain (C 1 -C 3 )-alkylene group, which can be mono- or polysubstituted, identically or differently, by (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, halogen, amino, mono-(C 1 -C 4 )-alkylamino, mono-(C 1 -C 4 )-acylamino or (C 1 -C 4 )-alkoxycarbonylamino,  
 E and L independently of one another represent a C(O) or SO 2  group,  
 G represents NR 14 , in which R 14  denotes hydrogen or (C 1 -C 4 )-alkyl, or represents a straight-chain (C 1 -C 3 )-alkylene group, which can be mono- or polysubstituted, identically or differently, by (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino or mono-(C 1 -C 4 )-acylamino,  
 m, n, o and p independently of one another in each case represent the number 0 or 1, with the proviso that 
 in the case that L represents a C═O-group, the sum (m+n+o+p) is unequal to the number 0,  
 
 and 
 in the case that m and o in each case represent the number 1, A represents the radical NR 11  and E and L in each case represent a C═O-group, the sum (n+p) is unequal to the number 0,  
 
 and  
 R 10  represents OR 15 , NR 16 R 17 , (C 1 -C 10 )-alkyl, (C 3 -C 8 )-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 6 -C 10 )-aryl, (C 6 -C 10 -arylmethyl or represents a saturated, partly unsaturated or aromatic 5- to 10-membered heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, where the abovementioned radicals are optionally substituted by one, two or three identical or different substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, nitro, amino, NR 18 R 19 , trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy optionally substituted by R 20 , (C 3 -C 8 )-cycloalkyl, (C 6 -C 10 )-aryl, which for its part is optionally substituted by halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethyl, nitro or cyano, —O—C(O)—R 21 , —C(O)—OR 22 , —C(O)—NR 23 R 24 , —SO 2 —NR 25 R 26 , —NH—C(O)—R 27  and —NH—C(O)—OR 28 , where 
 R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27  and R 28  are identical or different and in each case represent hydrogen, phenyl, benzyl, (C 1 -C 6 )-alkyl or (C 3 -C 8 )-cycloalkyl, which for their part are optionally mono- or polysubstituted, identically or differently, by halogen, hydroxyl, amino, carboxyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkoxy-carbonylamino, (C 1 -C 5 )-alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxyl,  
 or the group  
 
 -L-R 10  represents a group of the formula  
                     
 in which 
 R 29  denotes hydrogen or (C 1 -C 4 -alkyl.  
 
 or  
 R 3  represents a group of the formula  
                     in which    Q represents a 5- to 6-membered saturated, partly unsaturated or aromatic heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, which for its part is optionally mono- to trisubstituted, identically or differently, by oxo (═O), thioxo (═S), hydroxyl, (C 1 -C 6 )-alkyl or phenyl,    r represents the number 0, 1 or 2,    and    
 the ring Het denotes a 5- to 6-membered saturated or partly unsaturated heterocycle having up to three identical or different heteroatoms from the group consisting of N, O and/or S, which is optionally mono- to trisubstituted, identically or differently, by oxo (═O), thioxo (═S), hydroxyl, (C 1 -C 6 )-alkyl or phenyl.  
 R 4  and R 5  are identical or different and in each case represent hydrogen, hydroxyl, halogen, cyano, nitro, (C 1 -C 4 )-alkyl or the radical of the formula NR 30 R 31 , where R 30  and R 31  have the meaning indicated for R 15  and independently of one another can be identical to or different from this substituent, 
 R 6  represents hydrogen, halogen or represents a group of the formula  
   -M a -R 32 ,  
 in which  
 M represents a carbonyl group, a sulphonyl group or a methylene group,  
 a represents the number 0 or 1,  
 and  
 R 32  has the meaning of R 10  indicated above and can be identical to or different from this substituent,  
 
 R 7  represents hydrogen or represents an acyl group which can be removed under physiological conditions with formation of an NH function, preferably represents hydrogen or acetyl,  
 and  
 R 8  has the meaning of R 6  indicated above and can be identical to or different from this substituent,  
 and their pharmaceutically tolerable salts, solvates, hydrates and hydrates of the salts.  
 
     
     
         16 . A method for the prophylaxis and/or treatment of disease forms which can be treated with natural thyroid hormone comprising administering to a subject in need thereof an effective amount of a compound of Formula I  
       
         
           
           
               
               
           
         
       
       in which 
 Z represents O, S, SO, SO 2 , CH 2 , CHF, CF 2  or represents NR 9 , in which R 9  denotes hydrogen or (C 1 -C 4 )-alkyl,  
 R 1  and R 2  are identical or different and represent hydrogen, halogen, cyano, (C 1 -C 6 )-alkyl, CF 3 , CHF 2 , CH 2 F, vinyl or (C 3 -C 7 )-cycloalkyl, where at least one of the two substituents is unequal to hydrogen and in the ortho position to the bridge bond,  
 R 3  represents a group of the formula  
   -A m -D n -E o -G p -L-R 10    
 in which  
 A represents O, S, NR 11  or represents the group —(CR 12 ═CR 13 )—, in which R 11  denotes hydrogen or (C 1 -C 4 )-alkyl, and R 12  and R 13  are identical or different and denote hydrogen, cyano, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,  
 D represents a straight-chain (C 1 -C 3 )-alkylene group, which can be mono- or polysubstituted, identically or differently, by (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, halogen, amino, mono-(C 1 -C 4 )-alkylamino, mono-(C 1 -C 4 )-acylamino or (C 1 -C 4 )-alkoxycarbonylamino,  
 E and L independently of one another represent a C(O) or SO 2  group,  
 G represents NR 14 , in which R 14  denotes hydrogen or (C 1 -C 4 -alkyl, or represents a straight chain (C 1 -C 3 -alkylene group, which can be mono- or polysubstituted, identically or differently, by (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino or mono-(C 1 -C 4 -acylamino,  
 m, n, o and p independently of one another in each case represent the number 0 or 1, with the proviso that 
 in the case that L represents a C═O-group, the sum (m+n+o+p) is unequal to the number 0,  
 
 and 
 in the case that m and o in each case represent the number 1, A represents the radical NR 11  and E and L in each case represent a C═O-group, the sum (n+p) is unequal to the number 0,  
 
 and  
 R 10  represents OR 15 , NR 16 R 17 , (C 1 -C 10 )-alkyl, (C 3 -C 8 )-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 6 -C 10 )-aryl, (C 6 -C 10 )-arylmethyl or represents a saturated, partly unsaturated or aromatic 5- to 10-membered heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, where the abovementioned radicals are optionally substituted by one, two or three identical or different substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, nitro, amino, NR 18 R 19 , trifluoromethyl. (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy optionally substituted by R 20 , (C 3 -C 8 )-cycloalkyl, (C 6 -C 10 )-aryl, which for its part is optionally substituted by halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethyl, nitro or cyano. —O—C(O)—R 21 , —C(O)—OR 22 , —C(O)—NR 23 R 24 , —SO—NR 25 R 26 , —NH—C(O)—R 27  and —NH—C(O)—OR 28 , where 
 R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27  and R 28  are identical or different and in each case represent hydrogen, phenyl, benzyl, (C 1 -C 6 )-alkyl or (C 3 -C 8 )-cycloalkyl, which for their part are optionally mono- or polysubstituted, identically or differently, by halogen, hydroxyl, amino, carboxyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkoxy-carbonylamino, (C 1 -C 5 -alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxyl,  
 or the group  
 
 -L-R 10  represents a group of the formula  
                     
 in which  
 R 29  denotes hydrogen or (C 1 -C 4 -alkyl,  
 or  
 R 3  represents a group of the formula  
                     in which    represents a 5- to 6-membered saturated, partly unsaturated or aromatic heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, which for its part is optionally mono- to trisubstituted, identically or differently, by oxo (═O), thioxo (═S), hydroxyl. (C 1 -C 6 )-alkyl or phenyl,    r represents the number 0, 1 or 2, and    
 the ring Het denotes a 5- to 6-membered saturated or partly unsaturated heterocycle having up to three identical or different heteroatoms from the group consisting of N, O and/or S, which is optionally mono- to trisubstituted, identically or differently, by oxo (═O), thioxo (═S), hydroxyl, (C 1 -C 6 )-alkyl or phenyl,  
 R 4  and R 5  are identical or different and in each case represent hydrogen, hydroxyl, halogen, cyano, nitro, (C 1 -C 4 )-alkyl or the radical of the formula NR 30 R 31 , where R 30  and R 31  have the meaning indicated for R 15  and independently of one another can be identical to or different from this substituent, 
 R 6  represents hydrogen, halogen or represents a group of the formula  
   -M a -R 32 ,  
 in which  
 M represents a carbonyl soup, a sulphonyl group or a methylene group,  
 a represents the number 0 or 1,  
 and  
 R 32  has the meaning of R 10  indicated above and can be identical to or different from this substituent,  
 
 R 7  represents hydrogen or represents an acyl group which can be removed under physiological conditions with formation of an Nil function, preferably represents hydrogen or acetyl,  
 and  
 R 8  has the meaning of R 6  indicated above and can be identical to or different from this substituent,  
 and their pharmaceutically tolerable salts, solvates, hydrates and hydrates of the salts,  
 
     
     
         17 . The method of  claim 15  or  16 , wherein the compound of Formula I is administered in combination with other medicaments.  
     
     
         18 . (Cancelled).  
     
     
         19 . A process for the preparation of compounds of the Formula (I),  
       
         
           
           
               
               
           
         
       
       in which 
 Z represents O, S, SO, SO 2 , CH 2 , CHF, CF 2  or represents NR 9 , in which R 9  denotes hydrogen or (C 1 -C 4 -alkyl.  
 R 1  and R 2  are identical or different and represent hydrogen, halogen, cyano. (C 1 -C 6 )-alkyl, CF 3 , CHF 2 CH 2 F, vinyl or (C 3 -C 7 )-cycloalkyl, where at least one of the two substituents is unequal to hydrogen and in the ortho position to the bridge bond,  
 R 3  represents a group of the formula  
   -A m -D n -E o -G p -L-R 10 ,  
 in which  
 A represents O, S, NR 11  or represents the group —(CR 12 ═CR 13 )—, in which R 11  denotes hydrogen or (C 1 -C 4 )-alkyl, and R 12  and R 13  are identical or different and denote hydrogen, cyano, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,  
 D represents a straight-chain (C 1 -C 3 )-alkylene group, which can be mono- or polysubstituted, identically or differently, by (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, halogen, amino, mono-(C 1 -C 4 )-alkylamino, mono-(C 1 -C 4 )-acylamino or (C 1 -C 4 )-alkoxycarbonylamino,  
 E and L independently of one another represent a C(O) or SO 2  group,  
 G represents NR 14 , in which R 14  denotes hydrogen or (C 1 -C 4 )-alkyl, or represents a straight-chain (C 1 -C 3 )-alkylene group, which can be mono- or polysubstituted, identically or differently, by (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, halogen, amino, mono- or di-(C 1 -C 4 )-alkylamino or mono-(C 1 -C 4 )-acylamino.  
 m, n, o and p independently of one another in each case represent the number 0 or 1, with the proviso that 
 in the case that L represents a C═O-group, the sum (m+n+o+p) is unequal to the number 0,  
 
 and 
 in the case that m and o in each case represent the number 1, A represents the radical NR 11  and E and L in each case represent a C═O-group, the sum (n+p) is unequal to the number 0,  
 
 and  
 R 10  represents OR 15 , NR 16 R 17 , (C 1 -C 10 )-alkyl, (C 3 -C 8 )-cycloalkyl, (C 2 -C 6 )-alkenyl, (C 6 -C 10 )-aryl, (C 6 -C 10 )-arylmethyl or represents a saturated, partly unsaturated or aromatic 5- to 10-membered heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, where the abovementioned radicals are optionally substituted by one, two or three identical or different substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, nitro, amino. NR 18 R 19 , trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy optionally substituted by R 20 , (C 3 -C 8 )-cycloalkyl, (C 6 -C 10 -aryl, which for its part is optionally substituted by halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethyl, nitro or cyano, —O—C(O)—R 21 , —C(O)—OR 22 , —C(O)—NR 23 R 24 , —SO 2 —NR 25 R 26 , —NH—C(O)—R 27  and —NH—C(O)—OR 28 , where 
 R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27  and R 28  are identical or different and in each case represent hydrogen, phenyl, benzyl. (C 1 -C 6 )-alkyl or (C 3 -C 8 )-cycloalkyl, which for their part are optionally mono- or polysubstituted, identically or differently, by halogen, hydroxyl, amino, carboxyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, (C 1 -C 4 )-alkoxy-carbonylamino. (C 1 -C 5 )-alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxyl,  
 or the group  
 
 -L-R 10  represents a group of the formula  
                     
 in which  
 R 29  denotes hydrogen or (C 1 -C 4 -alkyl,  
 or  
 R 3  represents a group of the formula  
                     in which    Q represents a 5- to 6-membered saturated partly unsaturated or aromatic heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, which for its part is optionally mono- to trisubstituted, identically or differently, by oxo (═O) thioxo (═O), hydroxyl, (C 1 -C 6 )-alkyl or phenyl,    r represents the number 0, 1 or 2,    and    
 the ring Het denotes a 5- to 6-membered saturated or partly unsaturated heterocycle having up to three identical or different heteroatoms from the group consisting of N, O and/or S, which is optionally mono- to trisubstituted, identically or differently, by oxo (═O), thioxo (═S), hydroxyl, (C 1 -C 6 -alkyl or phenyl,  
 R 4  and R 5  are identical or different and in each case represent hydrogen, hydroxyl, halogen, cyano, nitro. (C 1 -C 4 )-alkyl or the radical of the formula NR 30 R 31 , where R 30  and R 31  have the meaning indicated for R 15  and independently of one another can be identical to or different from this substituent, 
 R 6  represents hydrogen, halogen or represents a group of the formula  
   -M a -R 12 ,  
 in which  
 M represents a carbonyl group, a sulphonyl group or a methylene group,  
 a represents the number 0 or 1,  
 and  
 R 32  has the meaning of R 10  indicated above and can be identical to or different from this substituent,  
 
 R 7  represents hydrogen or represents an acyl group which can be removed under physiological conditions with formation of an NH function, preferably represents hydrogen or acetyl,  
 and  
 R 8  has the meaning of R 6  indicated above and can be identical to or different from this substituent,  
 characterized in that reactive indole derivatives of the general formula (II) are reacted with reactive phenyl derivatives of the general formula (III)  
                     where the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  have the meanings as defined above, and    
 R 3 ′ has the meaning indicated for R 3  or represents NO 2 , NH 2 , NH—PG, OH, O—PG, SH, S—PG, or represents an aldehyde, cyano, carboxyl or (C 1 -C 4 )-alkoxy-carbonyl group,  
 where PG represents a protective group,  
 X and Y in each case represent groups of opposite reactivity,  
 Z′ has the meaning indicated for Z or represents  
                     
 optionally in the presence of inert solvents and catalysts and optionally with isolation of the intermediates of the general formula (IV) or directly to give compounds of the formula (I).  
 
     
     
         20 . (Cancelled).