Novel compounds with analgesic effect

Abstract

Compounds of the formula (I) as well as their pharmaceutically acceptable salts, and pharmaceutical compositions comprising the novel compounds. The novel compounds of the formula (I) are useful in the management of pain.

1 . A compound of the general formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 G is a carbon atom or a nitrogen atom;  
 A is selected from  
 (i) phenyl substituted by any of —COOH, —CONH 2 , COOCH 3 , —CN, NH 2  or —COCH 3 ;  
 (ii) naphtyl, benzofuranyl, and quinolinyl; and  
                     
  wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from hydrogen, CH 3 , (CH 2 ) o CF 3 , halogen, CONR 7 R 8 , CO 2 R 7 , COR 7 , (CH 2 ) o NR 7 R 8 , (CH 2 ) o CH 3 (CH 2 ) o SOR 7 , (CH 2 ) o SO 2 R 7  and (CH 2 ) o SO 2 NR 7 R 8  wherein o is 0, 1, or 2, and R 7  and R 8  are as defined below;  
 R 1  is selected from hydrogen; a branched or straight C 1 -C 6  alkyl, C 1 -C 6  alkenyl, —CO(C 1 -C 6  alkyl); (C 1 -C 6  alkyl)-B wherein B is as defined below; C 3 -C 8  cycloalkyl, C 4 -C 8  (alkyl-cycloalkyl) wherein alkyl is C 1 -C 2  alkyl and cycloalkyl is C 3 -C 6  cycloalkyl; C 6 -C 10  aryl; and heteroaryl having from 5-10 atoms selected from any of C, S, N and O; and whereby the C 6 -C 10  aryl and the heteroaryl may optionally be substituted by 1 or 2 substituents selected from hydrogen, CH 3 , (CH 2 ) o CF 3 , halogen, CONR 7 R 8 , CO 2 R 7 , COR 7 , (CH 2 ) o NR 7 R 8 , (CH 2 ) o CH 3 (CH 2 ) o SOR 7 , (CH 2 ) o SO 2 R 7  and (CH 2 ) o SO 2 NR 7 R 8  wherein o is 0, 1, or 2, and R 7  and R 8  are as defined below;  
 R 7  and R 8  is each and independently as defined for R 1  above;  
 R 2  is selected from hydrogen, CH 3 , OR 1 , CO 2 R 1 , and CH 2 CO 2 R 1  wherein  
 R 1  is as defined above;  
 R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 , is each and independently as defined for R1 above;  
 B is a substituted or unsubstituted aromatic; an optionally substituted C 5 -C 10  hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety, each having from 5 to 10 atoms selected from any of C, S, N and O, and each being optionally substituted by 1 or 2 substituents independently selected from hydrogen, CH 3 , CF 3 , halogen, (CH 2 ) p CONR 7 R 8 , (CH 2 ) p NR 7 R 8 , (CH 2 ) p COR 7 , (CH 2 ) p CO 2 R 7 , (CH 2 ) p SOR 7 , (CH 2 ) p SO 2 R 7 , and (CH 2 ) p SO 2 NR 7 R 8 ;  
 wherein p is 0, 1, 2 or 3 and wherein R 7  and R 8  are as defined above;  
 R 3 , R 4 , R 5  and R 6  is each and independently selected from  
 R 7 , (CH 2 ) p CONR 7 R 8 , (CH 2 ) p NR 7 R 8 , (CH 2 ) p CONR 7 R 8 , (CH 2 ) p CO 2 R 7 , (CH 2 ) p Ph, (CH 2 ) p (p-OH Ph), (CH 2 ) p -3-indolyl, (CH 2 ) p SR 7 , and (CH 2 ) p OR 7 ;  
 wherein p is 0, 1, 2, 3, or 4, and R 7  and R 8  are as defined above;  
 as well as pharmaceutically acceptable salts of the compounds of the formula (I), isomers, hydrates, isoforms and prodrugs thereof;  
 with the proviso that when A is a phenyl ring substituted by a —CN group or by a —NH 2  group, B may not be  
                     
  wherein  
 Z 1  is hydroxy, and esters thereof;  
 hydroxymethyl, and esters thereof; or  
 amino, and carboxamides and sulfonamides.  
 
     
     
         2 . A compound of the formula I according to  claim 1 , wherein 
 G is a carbon atom or a nitrogen atom;    A is selected from    (i) phenyl substituted by any of —COOH, —CONH 2 , COOCH 3 , —CN, NH 2  or —COCH 3 ;    (ii) naphtyl, benzofuranyl, and quinolinyl; and    (iii)                           wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from hydrogen, CH 3 , (CH 2 ) o CF 3 , halogen CONR 7 R 8 , CO 2 R 7 , COR 7 , (CH 2 ) o NR 7 R 8 , (CH 2 ) o CH 3 (CH 2 ) o SOR 7 , (CH 2 ) o SO 2 R 7  and (CH 2 ) o SO 2 NR 7 R 8  wherein o is 0, 1, or 2, and R 7  and R 8  are as defined below;    R 1 , R 7  and R 8  is each and independently selected from hydrogen; a branched or straight C 1 -C 4  alkyl, allyl, —CO—(C 1 -C 6  alkyl); (C 1 -C 6  alkyl)-B wherein B is as defined below, C 3 -C 5  cycloalkyl, C 4 -C 8  (alkyl-cycloalkyl) wherein alkyl is C 1 -C 2  alkyl and cycloalkyl is C 3 -C 6  cycloalkyl; and phenyl;    R 2  is hydrogen, methyl, or OR 1  wherein R 1  is as defined above;    R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18  is each and independently as defined for R 1  above;    B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, indazolinyl, and                           each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH 3 , CF 3 , halogen, (CH 2 ) p CONR 7 R 8 , (CH 2 ) p NR 7 R 8 , (CH 2 ) p COR 7 , (CH 2 ) p (CO 2 R 7 , and OR 7 ,    wherein p is 0 or 1, and wherein R 7  and R 8  are as defined above; and    R 3 , R 4 , R 5  and R 6  is each and independently selected from hydrogen, CH 3 , CH(Me) 2 , CH 2 CH(Me) 2 , CH(Me)CH 2 CH 3 (CH 2 ) p CONR 7 R 8 , (CH 2 ) p NR 7 R 8 , (CH 2 ) p CONR 7 R 8 , (CH 2 ) p CO 2 R 7 , (CH 2 ) p Ph, (CH 2 ) p (p-OH Ph), (CH 2 ) p -3-indolyl, (CH 2 ) p SR 7 , and (CH 2 ) p OR 7 , wherein p is 0, 1, 2, or 3, and wherein R 7  and R 8  are as defined above;    with the proviso that when A is a phenyl ring substituted by a —CN group or by a —NH 2  group, B may not be                           wherein    Z 1  is hydroxy, and esters thereof;    hydroxymethyl, and esters thereof; or    amino, and carboxamides and sulfonamides.    
     
     
         3 . A compound of the formula I according to  claim 1 , wherein 
 G is a nitrogen atom;    A is selected from                           wherein    R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18  is each an ethyl group;    R 1  is selected from hydrogen, methyl, ethyl, allyl, or CH 2 -cyclopropyl;    R 2  is H, methyl, or OR 1 ;    B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and                           each B group being optionally substituted by 1-2 substituents-independently selected from hydrogen, methyl, CF 3 , halogen, (CH 2 )CONR 7 R 8 , (CH 2 ) p NR 7 R 8 , (CH 2 ) p COR 7 , (CH 2 ) p C 2 R 7 , and OR 7 ,    wherein p is 0, 1, or 2, and wherein R 7  and R 8  are as defined for R 1  above;    R 3 , R 4 , R 5  and R 6  is each and independently selected from H, CH 3 , CH(Me) 2 , CH 2 CH(Me) 2 , CH(Me)CH 2 CH 3 (CH 2 ) p CONR 7 R 8 , (CH 2 ) p NR 7 R 8 , (CH 2 ) p CONR 7 R 8 , (CH 2 ) p CO 2 R 7 , (CH 2 ) p Ph, (CH 2 ) p (p-OH Ph), (CH 2 ) p SR 7 , and (CH 2 ) p OR 7      wherein p is 0, 1 or 2, and wherein R 7  and R 8  are as defined above.    
     
     
         4 . A compound of the formula (I) of  claim 1  above, being anyone of 
 (±)-trans-1-(3-methoxy-α-(naphthyl)benzyl)-2,5-dimethylpiperazine (compound 3);  
 (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-1-naphthyl)anisole (compound 4 and 5);  
 (±)-trans-1-(3-methoxy-α-(2-naphthyl)benzyl)-2,5-dimethylpiperazine (compound 8);  
 (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-2-naphthyl)anisole (compound 9 and 10);  
 (±)-trans-1-(3-methoxy-α-(2′-benzofuranyl)benzyl)-2,5-dimethylpiperazine (compound 13);  
 (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-2-benzofuranyl)anisole (compound 14 and 15);  
 (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Cyclopropylmethyl-2,5-dimethyl-1-piperazinyl)-2-benzofuranyl)anisole (compound 16 and 17);  
 (±)-trans-1-(3-methoxy-α-(6′-quinolinyl)benzyl)-2,5-dimethylpiperazine (compound 20 and 21);  
 (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-6-quinolinyl)anisole (compound 22);  
 (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-6-quinolinyl)anisole (compound 23);  
 (±)-3-((αR*/S*)-α-((2S*,5R*)-4-Cyclopropylmethyl-2,5-dimethyl-1-piperazinyl)-6-quinolinyl)anisole (compound 24 and 25);  
 (±)-trans-1-(3-methoxy-α-(4-quinolinyl)benzyl)-2,5-dimethyl-piperazine (compound 28);  
 (±)-3-((αR*/S*)-α-((2S*,5R*) Allyl-2, ethyl-1-piperazinyl)-4-quinolinyl)anisole (compound 29 and 30);  
 (±)4-((α-(1-Piperazinyl))-4-chlorobenzyl)-N,N-diethylbenzamide (compound 33);  
 (±)4-((α-((4-Allyl)-1-piperazinyl))-4-chlorobenzyl)-N,N-diethylbenzamide.2hcl (compound 34);  
 (±)4-((α-(1-Piperazinyl))-2-naphtylmethyl)-N,N-diethylbenzamide (compound 37);  
 (±)4-((α-((4-Allyl)-1-piperazinyl)-2-naphtylmethyl)-N,N-diethylbenzamide (compound 38);  
 (±)4-((α-(1-Piperazinyl))-4-xylyl)-N,N-diethylbenzamide, (compound 41);  
 (±)4-((α-((4-Allyl)-1-piperazinyl))-4-xylyl)-N,N-diethylbenzamide.2HCl (compound 42);  
 (±)4-((α-(1-Piperazinyl))-3-xylyl)-N,N-diethylbenzamide.2HCl (compound 45);  
 (±)4-((α-(1-Piperazinyl))-cyclohexylmethyl)-N,N-diethylbenzamide (compound 48);  
 (±)4-((α-(1-Piperazinyl))-3,4-dimethylbenzyl)-N,N-diethylbenzamide (compound 51);  
 (±)4-((α-(1-Piperazinyl))-1-naphtylmethyl)-N,N-diethylbenzamide (compound 54);  
 4-(4-(2-Dimethyl-5-methyl-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 57);  
 4-(4-(1-Allyl-2-dimethyl-5-methyl-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 58);  
 4-(1-(4-Allyl-2-dimethyl-5-methyl-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 60);  
 4-(1-(2-dimethyl-5-methyl-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 61);  
 4-((1-piperazinyl)-benzyl) N,N-diethylbenzamide dihydrochloride (compound 64);  
 4-((4-Allyl-1-piperazinyl)-benzyl)-N,N-diethylbenzamide dihydrochloride (compound 65);  
 4-((4-Acetyl-1-piperazinyl)-benzyl)-N,N-diethylbenzamide hydrochloride (compound 77);  
 4-(4-(2-Hydroxymethyl-5-methyl)piperazinyl-benzyl)-N,N-diethyl-benzamide dihydrochloride (compound 69);  
 4-((4-(2-Hydroxymethyl-5-methyl)piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 70);  
 4-((4-(1-Allyl-2-hydroxymethyl-5-methyl)piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide dihydrochloride (compound 71);  
 Methyl 3-((2-naphtyl)(3-methyl-piperazinyl)methyl)phenyl ether dihydrochloride (compound 75);  
 Methyl 3-((2-naphtyl)(4-Allyl-2-methyl-piperazinyl)methyl)phenyl ether dihydrochloride (compound 76);  
 4-((1-piperazinyl)benzyl)benzoic acid dihydrochloride (compound 79);  
 4-((1-piperazinyl)benzyl-N,N-diethylbenzamide hydrochloride (compound 83);  
 Methyl 4-((4-t-butoxycarbonyl-piperazinyl)-benzyl)benzoate (compound 80);  
 Methyl 4-((1-piperazinyl)benzyl)benzoate dihydrochloride (compound 81);  
 4-(1-piperazinyl-benzyl)benzonitrile dihydrochloride (compound 84);  
 4-(1-piperazinyl-benzyl)-acetophenone dihydrochloride (compound 85);  
 4-((α-piperidinyl)-benzyl)-N,N-diethylbenzmide (compound 88);  
 N,N-Diethyl-4-(3-methoxybenzyl-1-piperazinyl)-benzamide (Example 50);  
 N,N-Diethyl-4-[(4-allyl-1-piperazinyl)-3-methoxybenzyl]-benzamide (Example 51);  
 4-[(N-benzyl-1-piperazinyl)-benzyl]-aniline (compound 91);  
 4-[(N-benzyl-1-piperazinyl)-benzyl]-acetanilide (compound 92);  
 4-[(N-benzyl-1-piperazinyl)-benzyl]-methanesulfonamide (Example 54);  
 Methyl-N-4-[(N-benzyl-1-piperazinyl)-benzyl]-2-methylacetate Example 55); and  
 4-[(N-benzyl-1-piperazinyl)-3-fluorobenzyl]-acetanilide (compound 95).  
 
     
     
         5 . A compound according to any of claims  1 - 4 , in form of its hydrochloride salt.  
     
     
         6 . A compound according to any of claims  1 - 5 , for use in therapy.  
     
     
         7 . A compound according to  claim 6 , wherein the therapy is pain management.  
     
     
         8 . A compound according to  claim 6 , wherein the therapy is directed towards gastrointestinal disorders.  
     
     
         9 . A compound according to  claim 6 , wherein the therapy is directed towards spinal injuries.  
     
     
         10 . A compound according to  claim 6 , wherein the therapy is directed to disorders of the sympathetic nervous system.  
     
     
         11 . Use of a compound according to any of claims  1 - 5  for the manufacture of a medicament for use in the treatment of pain.  
     
     
         12 . Use of a compound according to any of claims  1 - 5  for the manufacture of a medicament for use in the treatment of gastrointestinal disorders.  
     
     
         13 . Use of a compound according to any of claims  1 - 5  for the manufacture of a medicament for use in the treatment of spinal injuries.  
     
     
         14 . A compound according to any of claims  1 - 5 , further characterized in that it is isotopically labelled.  
     
     
         15 . Use of a compound according to  claim 14  as a diagnostic agent.  
     
     
         16 . A pharmaceutical composition comprising a compound according to any of claims  1 - 5  as an active ingredient, together with a pharmaceutically acceptable carrier.  
     
     
         17 . A process for the preparation of a compound according to any of claims  1 - 5 , whereby 
 A) (i) An aldehyde or ketone is treated with a nucleophile, giving the corresponding alcohol;     (ii) the alcohol is converted into a suitable leaving group, which in turn is displaced with a nucleophile; and     (iii) a N-(4)-unsubstituted piperazine derivative is substituted via its organo halide or equivalent species, or acylated; or    B) (i) A N-protected amino acid ester is reacted with a second amino acid ester, and thereafter treated with an acid, giving a piparazinedione;     (ii) the dione is reduced to the corresponding pip raze; and     (iii) the piperazine is alkylated or acylated on one or more of the nitrogens.    
     
     
         18 . A method for the treatment of pain, whereby an effective amount of a compound according to any of claims  1 - 5  is administered to a subject in need of pain management.