Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them

Abstract

The invention relates to compounds of the formula I in which R1 to R9 are as defined herein. In one embodiment, these compounds may be used as antihypertensives, for reducing or preventing ischemia-induced damage, as medicaments for surgical intervention for the treatment of ischemias of the nervous system, of stroke and of cerebral edema, of shock, of impaired respiratory drive, for the treatment of snoring, as laxative, as agent against ectoparasites, to prevent the formation of gallstones, as antiatherosclerotics, agents against late complications of diabetes, cancers, fibrotic disorders, endothelial dysfunction, organ hypertrophies and hyperplasias. In one embodiment, the compounds may be inhibitors of the cellular sodium-proton antiporter and influence serum lipoproteins and thus be used for the prophylaxis and for the regression of atherosclerotic lesions.

1 . A process for preparing compounds of formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 R1, R2, R3 and R4 are independently of one another H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C a H 2a+1 , C qq H 2qq−1 , OC b H 2b+1 , COOR10, OCOR10, COR10 or O x —(CH 2 ) y -phenyl; wherein 
 a and b are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups C a H 2a+1  and OC b H 2b+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 qq is 3, 4, 5, 6, 7 or 8, wherein the group CqqH2qq−1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 R10 is H or C c H 2c+1 ; 
 c is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CcH2c+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 x is zero or 1;  
 y is zero, 1, 2, 3 or 4; where the phenyl ring in the group O x —(CH 2 ) y -phenyl is unsubstituted or substituted by 1-3 independently chosen from F, Cl, Br, CN, NO 2 , OH, NH 2  and C d H 2d+1 , 
 d is 1, 2, 3 or 4, wherein the group C d H 2d+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 or  
 R1, R2, R3 and R4 are independently of one another chosen from a heteroaryl with at least one heteroatom chosen from 1, 2, 3 or 4 N atoms, 1 oxygen atom and 1 S atom, present as ring atoms;  
 or  
 R1, R2, R3 and R4 are independently of one another CONR11R12 or NR11R12; wherein 
 R11 and R12 are independently of one another H, C e H 2e+1 , C rr H 2rr−1 ; 
 e is 1, 2, 3, 4, 5, 6, 7 or 8;  
 rr is 3, 4, 5, 6, 7, or 8, wherein the groups C e H 2e+1  and C rr H 2rr−1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by O or NR13; 
 R13 is H or C f H 2f+1 ;  
  f is 1, 2, 3 or 4, wherein the group C f H 2f+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;  
 or  
 R13 and a CH 2  group of R11 or R12 together with the N atom to which they are bonded form a 5- or 6-membered ring;  
 
 
 or  
 R11 and R12 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;  
 or  
 R11 and R12 are independently of one another COR14, CSR14 or SO 2 R14;  
 wherein 
 R14 is C g H 2g+1 ; 
 g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C g H 2g+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms, and/or one or more CH 2  groups are replaced by O or NR13;  
 
 
 
 or  
 R1, R2, R3 and R4 are independently of one another —O h —SO j —R15, with 
 h is zero or 1;  
 i is zero, 1 or 2;  
 R15 is C k H 2k+1 , OH, OC l H 2l+1  or NR17R18; 
 k is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C k H 2k+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;  
 l is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group OC l H 2l+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;  
 R17 and R18 are independently of one another H or C m H 2m+1 ; 
 m is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C m H 2m+1  is unsubstituted or substituted where one or more H atoms is replaced by F atoms and/or one or more CH 2  groups are replaced by O, CO, CS or NR19;  
  R19 is H or C n H 2n+1 ;  
  n is 1, 2, 3 or 4, wherein the group C n H 2n+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
  or  
  R19 and a CH 2  group of R17 or R18 together with the N atom to which they are bonded form a 5- or 6-membered ring;  
 
 or  
 R17 and R18 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;  
 
 
 but where R2 does not equal H in any of the foregoing definitions,  
 R5 is H, C p H 2p+1 , C ss H 2ss−1 , COR20 or SO 2 R20; wherein 
 p is 1, 2, 3, 4, 5, 6, 7 or 8,  
 ss is 3, 4, 5, 6, 7 or 8,  
 R20 is C q H 2q+1 ; 
 q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups C p H 2p+1 , C ss H 2ss−1  and C q H 2q+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by O or NR21;  
 R21 is H or C r H 2r+1 ; 
 r is 1, 2, 3 or 4; wherein the group C r H 2r+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 
 R6 is H;  
 R7, R8 and R9 are independently of one another —O v —SO w —R23; wherein 
 v is zero or 1;  
 w is zero, 1 or 2;  
 R23 is C nn H 2nn+1 , C mm H 2mm−1 , OH, OC pp H 2pp+1  or NR25R26; 
 nn and pp are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8,  
 mm is 3, 4, 5, 6, 7 or 8, wherein the groups C nn H 2nn+1 , C mm H 2mm−1  and OC pp H 2pp+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 R25 and R26 are independently of one another H, CN, C z H 2z+1 , or C zz H 2zz−1 ; 
 z is 1, 2, 3, 4, 5, 6, 7 or 8;  
 zz is 3, 4, 5, 6, 7 or 8, wherein the group C z H 2z+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms and, wherein the group C z H 2z+1 , is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by O, CO, CS or NR27;  
 R27 is H or C aa H 2aa+1 ;  
  aa is 1, 2, 3 or 4, wherein the group C aa H 2aa+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 or  
 R27 and a CH 2  group of R25 or R26 together with the N atom to which they are bonded form a 5- or 6-membered ring;  
 
 or  
 R25 and R26 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;  
 
 
 or  
 R7, R8 and R9 are independently of one another NR32COR30, NR32CSR30 or NR32SO bb R30; 
 R30 is H, C cc H 2cc+1 , C yy H 2yy−1 , pyrrolidinyl or piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstituted or substituted where a CH 2  group is replaced by O or NR33;  
 R32 and R33 are independently of one another H or C h H 2h+1 ;  
 bb is 2 or 3;  
 cc is 1, 2, 3, 4, 5, 6, 7 or 8;  
 yy is 3, 4, 5, 6, 7 or 8;  
 h is 1, 2, 3, 4, 5, 6, 7 or 8, 
 wherein the group C h H 2h+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms, and wherein the groups C cc H 2cc+1  and C yy H 2yy−1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by NR31 and/or one CH 2  group are replaced by O; 
 R31 is H, C kk H 2kk+1 , COR65 or SO 2  R65;  
  kk is 1, 2, 3, or 4; wherein the group C kk H 2kk+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms,  
  R65 is H, or C xx H 2xx+1 ;  
  xx is 1, 2, 3 or 4, wherein the group C xx H 2xx+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 or  
 R31 together with a CH 2  group of R30 forms a 5-, 6- or 7-membered ring;  
 or  
 R30 is a 5- or 6-membered heteroaryl with at least one hetero atom chosen from 1, 2, 3 or 4 N atoms, zero, 1 S atom and 1 O atom, which is unsubstituted or substituted by up to three substituents chosen from F, Cl, Br, I, C oo H 2oo+1 , and NR7OR71; 
 R70 and R71 are independently of one another H,  
 C uu H 2uu+1  or COR72; 
 R72 is H, or C vv H 2vv+1 ;  
 oo, uu and w are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups C oo H 2oo+1 , C uu H 2uu+1  and C vv H 2vv+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 
 or  
 R7, R8 and R9 are independently of one another H, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , C ee H 2ee+1 , C ww H 2ww−1 , OC ff H 2ff+1 , NR4OR41, CONR40R41, COOR42, COR42 or OCOR42, 
 ee and ff are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8;  
 ww is 3, 4, 5, 6, 7 or 8, wherein the groups C ee H 2ee+1 , C ww H 2ww−1  and OC ff H 2ff+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 R40 and R41 are independently of one another H, C tt H 2tt+1  or C(NH)NH 2 ; 
 tt is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C tt H 2tt+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or where one or more CH 2  groups are replaced by O or NR44;  
 R44 is H or C gg H 2gg+1 ; 
 gg is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C gg H 2gg+1  is unnsubstituted or substituted where one or more H atoms are replaced by F atoms  
 
 or  
 R44 forms a 5- or 6-membered ring together with a (CH 2 ) group of R40 or R41 and the N atom to which they are bound;  
 
 or  
 R40 and R41 with the N atom to which they are bonded form a 5- or 6-membered ring;  
 R42 is H or C hh H 2hh+1 ; 
 hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C hh H 2hh+1  is unnsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 with the proviso that two substituents chosen from the group R7, R8 and R9 can not simultaneously be OH and OCH 3 ,  
 and that at least one of the substituents R7, R8 and R9 is chosen from CONR40R41, —O v —SO w —R 23 , NR32COR30, NR32CSR30 and NR32SO bb R30;  
 or a pharmaceutically acceptable salt thereof, or a trifluoroacetate thereof in any stereoisomeric form, or a mixture of any such compounds in any ratio;  
 which process comprises  
 converting the alcohol of formula VII in the presence of an acid, to the compound of formula I  
                     
 where, in the compounds of the formulae VII  
 R1 to R5 and R7 to R9 are each as defined in formula I.  
 
     
     
         2 . A process for preparing compounds of formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 R1, R2, R3 and R4 are independently of one another H, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C a H 2a+1 , C qq H 2qq−1 , OC b H 2b+1 , COOR10, OCOR10, COR10 or O x —(CH 2 ) y -Phenyl; wherein 
 a and b are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups C a H 2a+1  and OC b H 2b+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 qq is 3, 4, 5, 6, 7 or 8, wherein the group CqqH2qq−1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 R10 is H or C c H 2c+1 ; 
 c is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group CcH2c+1 is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 x is zero or 1;  
 y is zero, 1, 2, 3 or 4; where the phenyl ring in the group O x —(CH 2 ) y -phenyl is unsubstituted or substituted by 1-3 independently chosen from F, Cl, Br, CN, NO 2 , OH, NH 2  and C d H 2d+1 , 
 d is 1, 2, 3 or 4, wherein the group C d H 2d+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 or  
 R1, R2, R3 and R4 are independently of one another chosen from a heteroaryl with at least one heteroatom chosen from 1, 2, 3 or 4 N atoms, 1 oxygen atom and 1 S atom, present as ring atoms;  
 or  
 R1, R2, R3 and R4 are independently of one another CONR11R12 or NR11R12; wherein 
 R11 and R12 are independently of one another H, C e H 2e+1 , C rr H 2rr−1 ; 
 e is 1, 2, 3, 4, 5, 6, 7 or 8;  
 rr is 3, 4, 5, 6, 7, or 8, wherein the groups C e H 2e+1  and C rr H 2rr−1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by O or NR13; 
 R13 is H or C f H 2f+1 ;  
  f is 1, 2, 3 or 4, wherein the group C f H 2f+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;  
 or  
 R13 and a CH 2  group of R11 or R12 together with the N atom to which they are bonded form a 5- or 6-membered ring;  
 
 
 or  
 R11 and R12 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;  
 or  
 R11 and R12 are independently of one another COR14, CSR14 or SO 2 R14;  
 wherein 
 R14 is C g H 2g+1 ; 
 g is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C g H 2g+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms, and/or one or more CH 2  groups are replaced by O or NR13;  
 
 
 
 or  
 R1, R2, R3 and R4 are independently of one another —O h —SO j —R15, with 
 h is zero or 1;  
 j is zero, 1 or 2;  
 R15 is C k H 2k+1 , OH, OC l H 2l+1  or NR17R18; 
 k is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C k H 2k+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;  
 l is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group OC l H 2l+1  is unsubsitituted or substituted where one or more H atoms are replaced by F atoms;  
 R17 and R18 are independently of one another H or C m H 2m+1 ; 
 m is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C m H 2m+1  is unsubstituted or substituted where one or more H atoms is replaced by F atoms and/or one or more CH 2  groups are replaced by O, CO, CS or NR19;  
  R19 is H or C n H 2n+1 ;  
  n is 1, 2, 3 or 4, wherein the group C n H 2n+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
  or  
  R19 and a CH 2  group of R17 or R18 together with the N atom to which they are bonded form a 5- or 6-membered ring;  
 
 or  
 R17 and R18 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;  
 
 
 but where R2 does not equal H in any of the foregoing definitions,  
 R5 is H, C p H 2p+1 , C ss H 2ss−1 , COR20 or SO 2 R20; wherein 
 p is 1, 2, 3, 4, 5, 6, 7 or 8,  
 ss is 3, 4, 5, 6, 7 or 8,  
 R20 is C q H 2q+1 ; 
 q is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups C p H 2p+1 , C ss H 2ss−1  and C q H 2q+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by O or NR21;  
 R21 is H or C r H 2r+1 ; 
 r is 1, 2, 3 or 4; wherein the group C r H 2r+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 
 R6 is C s H 2s+1 , 
 s is 1, 2, 3, 4, 5, 6, 7 or 8;  
 
 R7, R8 and R9 are independently of one another —O v —SO w —R23; wherein 
 v is zero or 1;  
 w is zero, 1 or 2;  
 R23 is C nn H 2nn+1 , C mm H 2mm−1 , OH, OC pp H 2pp+1  or NR25R26; 
 nn and pp are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8,  
 mm is 3, 4, 5, 6, 7 or 8, wherein the groups C nn H 2nn+1 , C mm H 2mm−1  and OC pp H 2pp+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 R25 and R26 are independently of one another H, CN, C z H 2z+1 , or C zz H 2zz−1 ; 
 z is 1, 2, 3, 4, 5, 6, 7 or 8;  
 zz is 3, 4, 5, 6, 7 or 8, wherein the group C z H 2z+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms and, wherein the group C z H 2z+1 , is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by O, CO, CS or NR27;  
 R27 is H or C aa H 2aa+1 ;  
  aa is 1, 2, 3 or 4, wherein the group C aa H 2aa+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 or  
 R27 and a CH 2  group of R25 or R26 together with the N atom to which they are bonded form a 5- or 6-membered ring;  
 
 or  
 R25 and R26 together with the N atom to which they are bonded form a 5-, 6- or 7-membered ring;  
 
 
 or  
 R7, R8 and R9 are independently of one another NR32COR30, NR32CSR30 or NR32SO bb R30; 
 R30 is H, C cc H 2cc+1 , C yy H 2yy−1 , pyrrolidinyl or piperidinyl, wherein the pyrrolidinyl or piperidinyl is unsubstituted or substituted where a CH 2  group is replaced by O or NR33;  
 R32 and R33 are independently of one another H or C h H 2h+1 ;  
 bb is 2 or 3;  
 cc is 1, 2, 3, 4, 5, 6, 7 or 8;  
 yy is3,4,5,6,7or8;  
 h is 1, 2, 3, 4, 5, 6, 7 or 8, 
 wherein the group C h H 2h+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms, and  
 wherein the groups C cc H 2cc+1  and C yy H 2yy−1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or one or more CH 2  groups are replaced by NR31 and/or one CH 2  group are replaced by O; 
 R31 is H, C kk H 2kk+1 , COR65 or SO 2  R65;  
  kk is 1, 2, 3, or 4; wherein the group C kk H 2kk+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms,  
  R65 is H, or C xx H 2xx+1 ;  
  xx is 1, 2, 3 or 4, wherein the group C xx H 2xx+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 or  
 R31 together with a CH 2  group of R30 forms a 5-, 6- or 7-membered ring;  
 
 or 
 R30 is a 5- or 6-membered heteroaryl with at least one hetero atom chosen from 1, 2, 3 or 4 N atoms, zero, 1 S atom and 1 O atom, which is unsubstituted or substituted by up to three substituents chosen from F, Cl, Br, I, C oo H 2oo+1 , and NR70R71; 
 R70 and R71 are independently of one another H, C uu H 2uu+1  or COR72; 
 R72 is H, or C vv H 2vv+1 ;  
 oo, uu and w are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8, wherein the groups C oo H 2oo+1 , C uu H 2uu+1  and C vv H 2vv+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 
 or  
 R7, R8 and R9 are independently of one another H, F, Cl, Br, I, NO 2 , CN, OH, NH 2 , C ee H 2ee+1 , C ww H 2ww−1 , OC ff H 2ff+1 , NR4OR41, CONR4OR41, COOR42, COR42 or OCOR42, 
 ee and ff are independently of one another 1, 2, 3, 4, 5, 6, 7 or 8;  
 ww is 3, 4, 5, 6, 7 or 8, wherein the groups C ee H 2ee+1 , C ww H 2ww−1  and OC ff H 2ff+1  independently of one another are unsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 R40 and R41 are independently of one another H, C tt H 2tt+1  or C(NH)NH 2 ; 
 it is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C tt H 2tt+1  is unsubstituted or substituted where one or more H atoms are replaced by F atoms and/or where one or more CH 2  groups are replaced by O or NR44;  
 R44 is H or C gg H 2gg+1 ; 
 gg is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C gg H 2gg+1  is unnsubstituted or substituted where one or more H atoms are replaced by F atoms  
 
 or  
 R44 forms a 5- or 6-membered ring together with a (CH 2 ) group of R40 or R41 and the N atom to which they are bound;  
 
 or  
 R40 and R41 with the N atom to which they are bonded form a 5- or 6-membered ring;  
 R42 is H or C hh H 2hh+1 ; 
 hh is 1, 2, 3, 4, 5, 6, 7 or 8, wherein the group C hh H 2hh+1  is unnsubstituted or substituted where one or more H atoms are replaced by F atoms;  
 
 
 with the proviso that two substituents chosen from the group R7, R8 and R9 can not simultaneously be OH and OCH 3 ,  
 and that at least one of the substituents R7, R8 and R9 is chosen from CONR40R41, —O v —SO w —R23, NR32COR30, NR32CSR30 and NR32SO bb R30;  
 or a pharmaceutically acceptable salt thereof, or a trifluoroacetate thereof in any stereoisomeric form, or a mixture of any such compounds in any ratio;  
 which process comprises  
 converting the amide of formula XII to the compound of formula I  
                     
 where, in the compounds of the formulae XII  
 R1 to R9 are each as defined in formula I.