Fused imidazole derivatives as multidrug resistance modulators

Abstract

This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein the dotted line is an optional bond; n is 1 or 2; R 1 is hydrogen; halo; formyl; C 1-4 alkyl optionally substituted with hydroxy, C 1-4 alkyloxy, C 1-4 alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula —X—COOR 5 , —X—CONR 6 R 7 or —X—COR 10 wherein —X— is a direct bond, C 1-4 alkanediyl or C 2-6 alkenediyl; R 5 is hydrogen, C 1-12 alkyl, Ar, Het, C 1-6 alkyl substituted with C 1-4 alkyloxy, aryl or heteroaryl; R 6 and R 7 each independently are hydrogen or C 1-4 alkyl; R 2 is hydrogen, halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkyloxycarbonyl, carboxyl, formyl or phenyl; R 3 is hydrogen, C 1-4 alkyl or C 1-4 alkyloxy; R 4 is hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl; Z is —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CHOH—CH 2 —, —O—CH 2 —, —C(═O)—CH 2 — or —C(═NOH)—CH 2 —; —A—B— is a bivalent radical; A 1 is a direct bond, optionally substituted C 1-6 alkanediyl, C 1-6 alkanediyl-oxy-C 1-6 alkanediyl, carbonyl, C 1-6 alkanediylcarbonyl, optionally substituted C 1-6 alkanediyloxy; A 2 is a direct bond or C 1-6 alkanediyl; and Q is aryl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for inhibiting or reversing the effects of multidrug resistance.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein 
 the dotted line is an optional bond;  
 n is 1 or 2;  
 R 1  is hydrogen; halo; formyl; C 1-4 alkyl; C 1-4 alkyl substituted with 1 or 2 substituents each independently selected from hydroxy, C 1-4 alkyloxy, C 1-4 alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula  
                                             —X—CO—OR 5     (a-1);         —X—CO—NR 6 R 7     (a-2); or         —X—CO—R 10     (a-3);                                             
 wherein —X— is a direct bond, C 1-4 alkanediyl or C 2-6 alkenediyl;  
 R 5  is hydrogen; C 1-12 alkyl; Ar; Het; C 1-6 alkyl substituted with C 1-4 alkyloxy, C 1-4 alkyloxycarbonylC 1-4 alkyloxy, Ar or Het;  
 R 6  and R 7  each independently are hydrogen or C 1-4 alkyl;  
 R 10  is imidazolyl, thiazolyl or oxazolyl;  
 R 2  is hydrogen, halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkyloxycarbonyl, carboxyl, formyl or phenyl;  
 R 3  is hydrogen, C 1-4 alkyl or C 1-4 alkyloxy;  
 R 4  is hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl;  
 Z is Z 1  or Z 2 ;  
 wherein 
 Z 1  is a bivalent radical of formula —CH 2 —, —CH 2 —CH 2 — or —CH═CH—; provided that when the dotted line is a bond, then Z 1  is other than —CH 2 —;  
 Z 2  is a bivalent radical of formula —CHOH—CH 2 —, —O—CH 2 —, —C(═O)—CH 2 — or —C(═NOH)—CH 2 —;  
 —A—B— is a bivalent radical of formula  
                                             —Y—CR 8 ═CH—   (b-1);         —CH═CR 8 —Y—   (b-2);         —CH═CR 8 —CH═CH—   (b-3);         —CH═CH—CR 8 ═CH—   (b-4); or         —CH═CH—CH═CR 8 —   (b-5);                                               
 
 wherein 
 each R 8  independently is hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy, hydroxyC 1-4 alkyl, hydroxycarbonylC 1-4 alkyl, formyl, carboxyl, ethenyl substituted with carboxyl, or ethenyl substituted with C 1-4 alkyloxycarbonyl;  
 each Y independently is a bivalent radical of formula —O—, —S— or —NR 9 —; wherein R 9  is hydrogen, C 1-4 alkyl or C 1-4 alkylcarbonyl;  
 
 —A 1 — is a direct bond; C 1-6 alkanediyl; C 1-6 alkanediyl-oxy-C 1-6 alkanediyl; C 1-6 alkanediyloxy; carbonyl; C 1-6 alkanediylcarbonyl; C 1-6 alkanediyloxy substituted with hydroxy; or C 1-6 alkanediyl substituted with hydroxy or ═NOH;  
 —A 2 — is a direct bond or C 1-6 alkanediyl;  
 Q is phenyl; phenyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl; naphthalenyl; naphthalenyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl; pyridinyl; pyridinyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl; quinolinyl; or quinolinyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl;  
 Ar is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, C 1-4 alkyl or C 1-4 alkyloxy;  
 Het is furanyl; furanyl substituted with C 1-4 alkyl, C 1-4 alkyloxy or hydroxyC 1-4 alkyl; oxazolyl; oxazolyl substituted with C 1-4 alkyl or C 1-4 alkyloxy; or quinolinyl.  
 
     
     
         2 . A compound according to  claim 1  wherein —A—B— is a bivalent radical of formula (b-2), (b-3) or (b-4); Z is Z 1  wherein Z 1  is a bivalent radical of formula —CH 2 —CH 2 — or —CH 2 —, or Z is Z 2  wherein Z 2  is a bivalent radical of formula —C(═O)—CH 2 —; —A 1 — is C 1-6 alkanediyl, C 1-6 alkanediyloxy, carbonyl, C 1-6 alkanediyloxy substituted with hydroxy, or C 1-6 alkanediyl substituted with hydroxy; —A 2 — is a direct bond or C 1-6 alkanediyl; Q is phenyl, naphthalenyl, pyridinyl, quinolinyl, phenyl substituted with halo or C 1-6 alkyloxy, naphthalenyl substituted with halo or C 1-6 alkyloxy, pyridinyl substituted with halo or C 1-6 alkyloxy or quinolinyl substituted with halo or C 1-6 alkyloxy; R 1  is hydrogen, halo, formyl, C 1-4 alkyl substituted with hydroxy, or a radical of formula (a-1) wherein X is a direct bond or C 1-4 alkanediyl and R 5  is hydrogen, C 1-12 alkyl, Ar or C 1-6 alkyl substituted with Het; R 2  is hydrogen, halo, C 1-4 alkyl, formyl, hydroxyC 1-4 alkyl or C 1-4 alkyloxycarbonyl; R 3  is hydrogen; R 4  is hydrogen, halo, C 1-6 alkyl or C 1-6 alkyloxy and the dotted line is a bond.  
     
     
         3 . A compound according to any of  claims 1  to  2  wherein Z is —CH 2 —CH 2 —; —A—B— is —CH═CH—CH═CH—; —A 1 — is —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 — or —O—CH 2 —CH 2 —; —A 2 — is —CH 2 —; R 1  is hydrogen, halo, formyl or a radical of formula (a-1) wherein X is a direct bond and R 5  is hydrogen, C 1-12 alkyl, Ar or C 1-6 alkyl substituted with Het; R 2  is hydrogen, C 1-4 alkyl, formyl or C 1-4 alkyloxycarbonyl; R 3  is hydrogen; R 4  is hydrogen or C 1-4 alkyloxy and the dotted line is a bond.  
     
     
         4 . A compound according to  claim 1  wherein the compound is 
 methyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; or  
 dimethyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-2,3-dicarboxylate; or  
 ethyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;  
 methyl 11-[1-[[3,5-dimethoxy-4-(2-quinolinylmethoxy)phenyl]methyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;  
 methyl 6,11-dihydro-11-[1-[3-[4-(2-quinolinylmethoxy)phenyl]propyl]-4-piperidinylidene]-5H-imidazo[2, 1-b][3]benzazepine-3-carboxylate;  
 methyl 6,11-dihydro-11-[1-[2-[4-(2-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;  
 methyl 6,11-dihydro-11-[1-[2-[4-(phenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; and  
 methyl 6,11-dihydro-11-[1-[2-[4-(1-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;  
 the stereoisomeric forms and the pharmaceutically acceptable addition salts thereof.  
 
     
     
         5 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as described in any one of  claims 1  to  4 .  
     
     
         6 . A process for preparing a pharmaceutical composition as claimed in  claim 5  characterized in that a therapeutically active amount of a compound as claimed in any one of  claims 1  to  4  is intimately mixed with a pharmaceutically acceptable carrier.  
     
     
         7 . A compound according to any one of  claims 1  to  4  for use as a medicine.  
     
     
         8 . A product containing 
 a) a composition comprising a pharmaceutically effective amount of a compound according to any of  claims 1  to  4  and a pharmaceutically acceptable carrier; and    b) a composition comprising a pharmaceutically effective amount of an anti-neoplastic agent and a pharmaceutically acceptable carrier, as a combined preparation for simultaneous, separate or sequential use in anti-neoplastic therapy.    
     
     
         9 . A product containing 
 a) a composition comprising a pharmaceutically effective amount of a compound according to any of  claims 1  to  4  and a pharmaceutically acceptable carrier;    b) and a composition comprising a pharmaceutically effective amount of a pharmaceutical agent useful to treat conditions caused by pathogens and a pharmaceutically acceptable carrier, as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions caused by pathogens.    
     
     
         10 . A compound of formula (II-b)  
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof wherein 
 n is 1 or 2;  
 R 4  is hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl;  
 Q 1  is phenyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C alkyloxy or haloC   1-4 alkyl; naphthalenyl; naphthalenyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl; pyridinyl; pyridinyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl; quinolinyl; or quinolinyl substituted with one or two substituents selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl;  
 —A 1′ — is C 1-6 alkanediyl, C 1-6 alkanediyloxy or C 1-6 alkanediyloxyC 1-6 alkanediyl;  
 —A 2 — is a direct bond or C 1-6 alkanediyl; and  
 W is halo, methanesulfonyloxy or benzenesulfonyloxy.  
 
     
     
         11 . A process for preparing a compound of formula (T) characterized by 
 a) reacting a reagent of formula (III), wherein T represents the fused imidazole moiety,                           with an intermediate of formula (II), wherein W represents an appropriate leaving group;                          b) O-alkylating an intermediate of formula (IV), wherein W represents an appropriate leaving group, with a reagent of formula (V);                          c) reductively N-alkylating in intermediate of formula (III) with an intermediate of formula (XIX), wherein A 1″  represents a direct bond, C 1-5  alkanediyl, C 1-5 alkanediyloxy or a C 1-6 alkanediyl-oxyC 1-5 alkanediyl moiety, thereby yielding compounds of formula (I-i) wherein —A 1′ — represents C 1-6 alkanediyl, C 1-6 alkanediyloxy or C 1-6 alkanediyloxyC 1-6 alkanediyl;                          d) converting a compound of formula (I-a), wherein M represents the substituted piperidine moiety,                           into a compound of formula (I-b), according to art-known esterification methods;                          e) reacting a compound of formula (I-a-1) with an oxidizing agent in a reaction-inert solvent;                          f) esterification of compound of formula (I-d) to a compound of formula (I-e);                          g) hydrolyzing a compound of formula (I-e) to a compound of formula (I-d) in the presence of an acid or a base;    h) reacting a compound of formula (I-c) with methyl methylthiomethyl sulfoxide in a suitable solvent, thus yielding a compound of formula (I-f);                          i) reacting a compound of formula (I-c) with an alcohol of formula R 5 OH in the presence of acetic acid, MnO 2  and NaCN, thus yielding a compound of formula (I-e-1);                          j) reacting a compound of formula (I-g) with a reducing agent in a reaction-inert solvent;                           wherein in the above reaction schemes the radicals R 1 , R 2 , R 3 , R 4 , Z, —A—B—, A 1 , A 2  and Q are as defined in  claim 1  and W is an appropriate leaving group;     or, converting compounds of formula (I) into each other following art-known transformation reactions; and further, if desired, converting the compounds of formula (I), into an acid addition salt by treatment with an acid, or into a base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing N-oxide and/or stereochemically isomeric forms thereof.    
     
     
         12 . A process for preparing a compound as claimed in  claim 10  wherein an intermediate of formula (VI) is O-alkylated with an intermediate of formula (IV), in a reaction-inert solvent and subsequently the hydroxy group of an intermediate of formula (VII) is converted into a leaving group W;  
       
         
           
           
               
               
           
         
       
       in the above reaction scheme n, R 4 , Q 1 , A 1′ , A 2  and W are as defined in  claim 10  and W 1  is an appropriate leaving group;  
       or an intermediate compound of formula (II-a) is converted into an acid addition salt, or conversely, an acid addition salt is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof.