Amine compound and use thereof

Abstract

It is intended to provide novel amine compounds which are efficacious against diseases such as infection with HIV virus, rheumatism and cancer metastasis. Namely, amine compounds represented by the following general formula (1): In a typical case, A1 and A2 represent each an optionally substituted monocyclic or polycyclic aromatic heterocycle; W represents cyclic C3-10 alkylene, an optionally substituted monocyclic or polycyclic aromatic heterocycle, a monocyclic or polycyclic aromatic ring or a partly saturated polycyclic aromatic ring; X represents O, CH2, C(═O) or NR11; and D is a group represented by the following general formula (4) or (6). In the formula (6), Q represents a single bond, S, O or NR12; and Y is a group represented by the following general formula (7). —(CR 18 R 19 )m 3 — Or —(CR 20 R 21 )m 4 -z-(CR 22 R 23 )m 5   (7) z represents an optionally substituted monocyclic or polycyclic aromatic ring. In the formula (6), B represents NR25R26. In the above formulae, R1 to R26 each represents hydrogen, alkyl, alkenyl or alkynyl.

1 .- 17 . (canceled) 
     
     
         18 . A compound represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 each of n 1 , n 2 , and n 3  is an integer of 1; 
 each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  is independently a hydrogen atom; 
 A 1  is an imidazole ring or an imidazole ring substituted with an alkyl group; 
 A 2  is a monocyclic or polycyclic heteroaromatic ring which may be substituted with an alkyl group, a hydroxyalkyl group, an alkoxy group, a hydroxy group or a halogen atom; 
 W is a phenylene group or a naphthylene group; 
 X is —(C═O)—; 
 D is a group represented by the following formula (6):
   -Q-Y—B  (6)
 
 
 
       wherein
 Q is NR 12  and R 12  is a hydrogen atom, or an alkyl group having 1 to 15 carbon atoms;
   Y is —(CH 2 ) m4 -z-(CH 2 ) m5 —;
 
 
 
       wherein
 each of m 4  and m 5  is an integer of 0 to 2; 
 z is a phenylene group; and 
 B is —NR 25 R 26    
 
       wherein
 each of R 25  and R 26  is, independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or cyclic alkyl group having 3 to 6 carbon atoms, 
 wherein one or two or more asymmetric carbon atoms may exist in the compound represented by the general formula (1), where when one asymmetric carbon atom exists, the compound may be in the form of any one of a pure optically active substance represented by the absolute configuration R or S, a mixture thereof in a predetermined ratio, and a racemic mixture thereof or when two or more asymmetric carbon atoms exist, the compound may be in the form of any one of an optically pure diastereomer, a racemic mixture thereof, and a combination thereof in a predetermined ratio. 
 
     
     
         19 . A compound, a pharmacologically acceptable salt thereof or a prodrug thereof according to  claim 18  wherein A 1  is an imidazole ring or an imidazole ring substituted with a methyl group. 
     
     
         20 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 18  wherein A 1  is an imidazole ring. 
     
     
         21 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 18  wherein A 2  is a monocyclic or polycyclic heteroaromatic ring which may be substituted with an alkyl group, a hydroxyalkyl group, an alkoxy group, a hydroxy group, or a bromine atom. 
     
     
         22 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 18  wherein A 2  is a heteroaromatic ring selected from the group consisting of an imidazole ring, a pyridine ring, an isoquinoline ring, a quinoline ring, a pyrazine ring, a thiazole ring, a thiaziazole ring, an isoxazole ring, a benzimidazole ring, and a triazole ring, where the heteroaromatic ring may be substituted with an alkyl group, a hydroxyalkyl group, an alkoxy group, a hydroxy group, or a bromine atom. 
     
     
         23 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 22  wherein said heteroaromatic ring may be substituted with a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, a hydroxy group, a hydroxyethyl group, or a bromine atom. 
     
     
         24 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 23  wherein A 1  is an imidazole ring. 
     
     
         25 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 21  wherein W is a phenylene group. 
     
     
         26 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 21  wherein m 4  is 0, and m 5  is 1. 
     
     
         27 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 21  wherein each of R 25  and R 26  is a propyl group. 
     
     
         28 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 23  wherein A 1  is an imidazole ring, W is a phenylene group, m 4  is 0, m 5  is 1, and each of R 25  and R 26  is a propyl group. 
     
     
         29 . A compound, a pharmacologically acceptable salt thereof, or a prodrug thereof as claimed in  claim 18  selected from the group consisting of:
 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminophenyl)-benzamide, 
 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide, 
 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(3-dipropylaminomethylphenyl)-benzamide, 
 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-naphthalene-1-carboxylic acid (4-dipropylaminomethylphenyl)-amide, 
 4-{[bis(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethylphenyl)-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-3-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-methylpyridin-2-ylmethyl)-amino}-methyl]-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(6-bromopyridin-2-ylmethyl)-amino}-methyl]-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-4-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(quinolin-2-ylmethyl)-amino}-methyl]-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-3-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyridin-4-ylmethyl)-amino]-methyl}-benzami de, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(3-ethoxypyridin-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(2-methylthiazol-4-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(isoquinolin-1-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-{[(1H-imidazol-2-ylmethyl)-(quinolin-3-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(8-hydroxyquinolin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylpyrazine-2-ylmethyl}-amino]-methyl)-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1-methyl-1H-imidazol-2-ylmethyl)-(5-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[N-(1H-imidazol-2-ylmethyl)-(4-methylpyridin-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-([1,2,3]-thiadiazol e-4-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(pyrazine-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(5-methylisoxazol-3-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-cyclohexylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide, 
 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-cyclohexylaminomethylphenyl)-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1-ethyl-1H-imidazol-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-propyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[1-(2-hydroxyethyl)-1H-imidazol-2-ylmethyl]-(1H-imidazol-2-ylmethyl)-amino}-methyl)-benzamide, 
 4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-(4-dipropylaminomethyl-phenyl)-benzamide, 
 N-(4-dipropylaminomethyl-phenyl)-4-{[(5-ethyl-pyridin-2-ylmethyl)-(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide, 
 N-(4-di-n-propylaminomethyl-phenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide, and 
 N-(4-di-n-propylaminomethyl-phenyl)-4-{[(1-methyl-imidazol-2-ylmethyl)-(1H-[1,2,4]-triazol-3-ylmethyl)-amino]-methyl}-benzamide. 
 
     
     
         30 . A pharmaceutical composition comprising a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 18  as an active ingredient. 
     
     
         31 . A pharmaceutical composition comprising a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 21  as an active ingredient. 
     
     
         32 . A pharmaceutical composition comprising a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 29  as an active ingredient. 
     
     
         33 . A method for treating a CXCR4 associated disease comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 18 . 
     
     
         34 . A method for treating a CXCR4 associated disease comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 21 . 
     
     
         35 . A method for treating a CXCR4 associated disease comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound, a pharmacologically acceptable salt thereof, or a prodrug thereof according to  claim 29 . 
     
     
         36 . A method for treating a CXCR4 associated disease as claimed in  claim 33  wherein the CXCR4 associated disease is a viral disease, rheumatic disease, or cancer metastasis. 
     
     
         37 . A method for treating a CXCR4 associated disease as claimed in  claim 33  wherein the CXCR4 associated disease is caused by HIV. 
     
     
         38 . A method for treating a CXCR4 associated disease as claimed in  claim 34  wherein the CXCR4 associated disease is a viral disease, rheumatic disease, or cancer metastasis. 
     
     
         39 . A method for treating a CXCR4 associated disease as claimed in  claim 34  wherein the CXCR4 associated disease is caused by HIV. 
     
     
         40 . A method for treating a CXCR4 associated disease as claimed in  claim 35  wherein the CXCR4 associated disease is a viral disease, rheumatic disease, or cancer metastasis. 
     
     
         41 . A method for treating a CXCR4 associated disease as claimed in  claim 35  wherein the CXCR4 associated disease is caused by HIV. 
     
     
         42 . A method for treating a CXCR4 associated disease as claimed in  claim 33  wherein said compound is selected from the group consisting of:
 4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}dipropylaminomethylphenyl)-benzamide, 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzamide, and 
 N-(4-dipropylaminomethylphenyl)-4-{[(1H-imidazol-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-amino]-methyl}-benzamide. 
 
     
     
         43 . A method for treating a CXCR4 associated disease comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 each of n 1 , n 2 , and n 3  is an integer of 1; 
 each of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  is independently a hydrogen atom; 
 A 1  is imidazole; 
 A 2  is imidazole or imidazole substituted with an alkyl group; 
 W is a phenylene group or naphthylene group; 
 X is CH 2 : 
 D is a group represented by -Q-Y—B, 
 wherein: 
 Q is NR 12  and R 12  is a hydrogen atom or an alkyl group; 
 Y is (CH 2 )m 3  and m 3  is an integer of 2 to 4; and 
 B is N(R 25 R 26 ), wherein each of R 25  and R 26  are independently a hydrogen atom, a C 1 -C 6  alkyl group or a C 3 -C 6  cycloalkyl group. 
 
     
     
         44 . A method for treating a CXCR 4  associated disease as claimed in  claim 43  wherein W is a phenylene group, R 12  is a methyl group, and R 25  and R 26  are a C 1 -C 6  alkyl group. 
     
     
         45 . A method for treating a CXCR4 associated disease as claimed in  claim 43  wherein said compound is selected from the group consisting of:
 N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine, 
 N-(4-{[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine, 
 N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′,N′-dipropylbutane-1,4-diamine, 
 N-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N-methyl-N′,N′-dipropylbutane-1,4-diamine, and 
 N-cyclohexyl-N′-(4-{[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-benzyl)-N′-methyl-butane-1,4-diamine. 
 
     
     
         46 . A method for treating a CXCR4 associated disease as claimed in  claim 43  wherein the CXCR4 associated disease is a viral disease, rheumatic disease, or cancer metastasis. 
     
     
         47 . A method for treating a CXCR4 associated disease as claimed in  claim 43  wherein the CXCR4 associated disease is caused by HIV. 
     
     
         48 . A method for treating a CXCR4 associated disease as claimed in  claim 45  wherein the CXCR4 associated disease is caused by HIV.