Nitrogen-containing heterocyclic compounds and medicinal use thereof

Abstract

The compound represented by formulae (I) and (II), the salt thereof, the N-oxide thereof or the solvate thereof, or the prodrug thereof and the pharmaceutical composition comprising thereof have a CXCR4-regulating effect, and they are effective in treatment and prevention of various inflammatory disease, various allergic disease, acquired immunodeficiency syndrome infection with human immunodeficiency virus, or agents for regeneration therapy. (wherein ring A represents a nitrogen-containing heterocyclic group which may have a substituent(s); ring B represents a homocyclic group which may have a substituent(s) or a heterocyclic group which may have a substituent(s); and Y represents a hydrocarbon group which may have a substituent(s), a heterocyclic group which may have a substituent(s), an amino group which may be protected, a hydroxyl group which may be protected or a mercapto group which may be protected; T represents ring A or an amino group which may be protected.)

1 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein ring A represents a nitrogen-containing heterocyclic group which may have a substituent(s); ring B represents a homocyclic group which may have a substituent(s) or a heterocyclic group which may have a substituent(s); and Y represents a hydrocarbon group which may have a substituent(s), a heterocyclic group which may have a substituent(s), an amino group which may be protected, a hydroxyl group which may be protected or a mercapto group which may be protected, 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein ring A is a 5- to 10-membered nitrogen-containing heterocyclic group which may have a substituent(s). 
     
     
         3 . The compound according to  claim 1 , wherein ring B is a nitrogen-containing heterocyclic group which may have a substituent(s). 
     
     
         4 . The compound according to  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
         wherein G represents a bond or a spacer containing 1 to 3 atoms as a main chain; ring J represents a 4- to 7-membered nitrogen-containing heterocyclic group which may have a substituent(s); and W represents hydrogen, a hydrocarbon group which may have a substituent(s) or a heterocyclic group which may have a substituent(s). 
       
     
     
         5 . The compound according to  claim 1 , which is represented by formula (I-1): 
       
         
           
           
               
               
           
         
         wherein ring A 1  represents a 5- to 10-membered nitrogen-containing saturated heterocyclic group which may have a substituent(s), or a 5- to 10-membered nitrogen-containing heterocyclic group which has one double bond and which may have a substituent(s); ring B 1  represents a 6- to 11-membered nitrogen-containing monocyclic or bicyclic heterocyclic group which may have a substituent(s); and other symbols have the same meanings as those described in  claim 4 . 
       
     
     
         6 . The compound according to  claim 1 , which is represented by formula (I-2): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as those described in  claim 1  or  4 . 
       
     
     
         7 . A compound represented by formula (I-A): 
       
         
           
           
               
               
           
         
         wherein ring A A  represents a 4- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which is saturated or has one double bond and which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; 
         ring B A  represents B A1  or B A2 ; 
         B A1  represents: 
       
       
         
           
           
               
               
           
         
         B A2  represents: 
       
       
         
           
           
               
               
           
         
         R 4  represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with 1 to 5 of R 10 , (iii) a C3-8 carbocyclic group which may be substituted with 1 to 5 of R 3 , (iv) a 5- to 15-membered heterocyclic group which contains 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom and which may be substituted with 1 to 5 of R 3 , (v) COR 5  wherein R 5  represents C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl or phenyl, or (vi) COOR 6  wherein R 6  represents C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl or phenyl; the upward arrow represents a binding position to ring A A ; and the right-downward arrow represents a binding position to the nitrogen atom bound to L; 
         L represents (1) a bond, (2) C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, wherein the alkylene, alkenylene and alkynylene each may be substituted with 1 to 5 of R 10 , or (3) a C3-8 carbocyclic group which may be substituted with R 3 ; 
         Q represents (1) NR 1 R 2  wherein R 1  and R 2  each independently represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with 1 to 5 of R 10 , (iii) a C3-8 carbocyclic group which may be substituted with 1 to 5 of R 3 , or (iv) a 5- to 15-membered heterocyclic group which contains 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom and which may be substituted 1 to 5 of R 3 , or (2) ring C; 
         ring C represents a 4- to 15-membered heterocyclic group which contains at least one nitrogen atom and may further contain 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom and which may be substituted with 1 to 5 of R 3 ; 
         plural R 3 's each independently represents (1) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted with 1 to 5 of R 10 , (2) oxo, or (3)R 10 ; 
         plural R 10 's each independently represents (1) OR 11 , (2) OCOR 12 , (3) OCOOR 13 , (4) NR 14 R 15 , (5) NR 16 COR 12 , (6) NR 16 CONR 14 R 15 , (7) NR 16 COOR 13 , (8) COOR 13 , (9) COR 12 , (10) CONR 14 R 15 , (11) SO 2 R 12 , (12) SOR 22 , (13) SO 2 NR 24 R 25 , (14) NR 16 SO 2 R 12 , (15) B(OH) 2 , (16) SR 11 , (17) halogen, (18) nitro, (19) cyano, or (20) ring D; 
         R 11  represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted with 1 to 5 of halogen, NR 14 R 15 , OR 21 , SR 21 , COOR 13 , or ring D, or (iii) ring D; 
         R 12 , R 13 , R 14 , R 15  and R 16  each independently represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with ring D, or (iii) ring D; 
         ring D represents a C3-15 monocyclic, bicyclic or tricyclic carbocyclic group, or a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; and 
         ring D may be substituted with 1 to 5 of the groups selected from the following (1) to (22): 
         (1) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, wherein the alkyl, alkenyl or alkynyl may be substituted with 1 to 5 of OR 21 , OCOR 22 , OCOOR 23 , NR 24 R 25 , NR 26 COR 22 , NR 26 CONR 24 R 25 , NR 26 COOR 23 , COOR 23 , COR 22 , CONR 24 R 25 , SO 2 R 22 , SOR 22 , SO 2 NR 24 R 25 , NR 26 SO 2 R 22 , B(OH) 2 , SR 21 , halogen, nitro or cyano, (2) oxo, (3) OR 21 , (4) OCOR 22 , (5) OCOOR 23 , (6) NR 24 R 25 , (7) NR 26 COR 22 , (8) NR 26 CONR 24 R 25 , (9) NR 26 COOR 23 , (10) COOR 23 , (11) COR 22 , (12) CONR 24 R 25 , (13) SO 2 R 22 , (14) SOR 22 , (15) SO 2 NR 24 R 25 , (16) NR 26 SO 2 R 22 , (17) B(OH) 2 , (18) SR 21 , (19) halogen, (20) nitro, (21) cyano or (22) ring E; 
         R 21  represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with COR 22 , NR 24 R 25  or ring E, or (iii) ring E; 
         R 22 , R 23 , R 24 , R 25  and R 26  each independently represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with ring E, or (iii) ring E; 
         ring E represents a C3-15 monocyclic, bicyclic or tricyclic carbocyclic group, or a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom, and 
         ring E may be substituted with 1 to 5 of (i) C1-15 alkyl which may be substituted with phenyl, (ii) halogen, (iii) phenyl, (iv) C1-15 alkoxy, (v) hydroxyl, (vi) amino, (vii) mono(C1-8 alkyl)amino, or (viii) di(C1-8 alkyl)amino; 
         ring A A  may be substituted with 1-5 of R a ; 
         ring B A  may be substituted with 1-5 of R b ; 
         R a  and R b  each independently represents a group which has the same meaning as the group represented by R 3 ; and 
         wherein the following compounds (1) to (6) are excluded: 
         (1) N-[4-(4-morpholinyl)-2-quinazolinyl]-1,2-ethanediamine dihydrochloride, 
         (2) N,N-dimethyl-N′42-(4-phenyl-1-piperidinyl)-4-pyrimidinyl]-1,2-ethylenediamine, 
         (3) N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N′-[2-(1-piperidinyl)-4-pyrimidinyl]-1,3-propanediamine, 
         (4) N-[(3,4-dihydro-2H-1-benzopyrane-2-yl)methyl]-N′-[2-(1-piperidinyl)-4-pyrimidinyl]-1,3-propanediamine oxalate, 
         (5) N,N-diethyl-N′-[2-(1-pyrrolidinyl)-4-quinazolinyl-1,2-ethanediamine, and 
         (6) N,N-diethyl-N′-[2-(1-pyrrolidinyl)-4-quinazolinyl-1,2-ethanediamine dihydrochloride, 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. 
       
     
     
         8 . A Compound represented by formula (I-B): 
       
         
           
           
               
               
           
         
         wherein ring A B  represents a 7- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which is saturated or contains one double bond and which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; 
         ring B B  represents: 
       
       
         
           
           
               
               
           
         
         wherein ring Z represents a C5-10 monocyclic or bicyclic carbocyclic group, or a 5- to 10-membered monocyclic or bicyclic heterocyclic group which may contain 1 or 2 nitrogen atoms, one oxygen atom and/or one sulfur atom; the upward arrow represents a binding position to ring A B ; and the right-downward arrow represents a binding position to the nitrogen atom bound to L; 
         ring A B  may be substituted with 1 to 5 of R a ; ring B B  may be substituted with 1 to 5 of R b ; and R a , R b  and other symbols have the same meanings as those described in  claim 7 , and 
         wherein the following compounds (1) to (7) are excluded: 
         (1) N-[4-(hexahydro-1H-azepin-1-yl)thieno[3,2-d.]pyrimidin-2-yl]-1,4-butandiamine dihydrochloride, 
         (2) 7-[4-[4,6-bis(hexahydro-1H-azepin-1-yl)-1,3,5-triazin-2-yl]amino-2H-1,2,3-triazol-2-yl]-3-phenyl-2H-1-benzopyran-2-one, 
         (3) 4-ethoxy-6-(hexahydro-1H-azepin-1-yl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine, 
         (4) 4-(hexahydro-1H-azepin-1-yl)-6-methyl-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine, 
         (5) 4-chloro-6-(hexahydro-1H)-azepin-1-yl)-N-[2-(4-morpholinyl)ethyl]-1,3,5-triazin-2-amine, 
         (6) 4-(hexahydro-1H-azepin-1-yl)-6-methoxy-N-[3-(4-morpholinyl)propyl-1,3,5-triazin-2-amine, and 
         (7) N-[4-(hexahydro-1H-azepin-1-yl)thieno[3,2-d]pyrimidin-2-yl-1,4-butanediamine, or 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. 
       
     
     
         9 . The compound according to any one of  claims 1 ,  7  and  8 , which is
 (1) N-(4-azepan-1-ylpyrimidin-2-yl)ethane-1,2-diamine, 
 (2) N 1 -(4-azepan-1-ylpyrimidin-2-yl)-N 2 ,N 2 -dimethylethane-1,2-diamine, 
 (3) 4-azepan-1-yl-N-((3S)-1-cyclohexylpyrrolidin-3-yl)pyrimidin-2-amine, 
 (4) 4-azepan-1-yl-N-((3S)-1-benzylpyrrolidin-3-yl)pyrimidin-2-amine, 
 (5) 4-azepan-1-yl-N-((3S)-1-(2-ethylbutyl)piperidin-3-yl)pyrimidin-2-amine, 
 (6) 4-azepan-1-yl-N-[(3S)-1-cyclohexylpiperidin-3-yl]pyrimidin-2-amine, 
 (7) 4-azepan-1-yl-N-[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]pyrimidin-2-amine, 
 (8) 4-(3S)-3-[(4-azepan-1-ylpyrimidin-2-yk)amino]piperidin-1-ylcyclohexanol, or 
 (9) (3S)-N-(4-azepan-1-ylpyrimidin-2-yl)-1′-(cyclohexylcarbonyl)-1,4′-bipiperidin-3-amine. 
 
     
     
         10 . A pharmaceutical composition, which comprises a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as those described in  claim 1 , 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier. 
       
     
     
         11 . The pharmaceutical composition according to  claim 10 , which is a CXCR4 regulating agent. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the CXCR4 regulating agent is a CXCR4 antagonist. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , which is a preventive and/or therapeutic agent for human immunodeficiency virus infection. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , which is a preventive and/or therapeutic agent for acquired immunodeficiency syndrome. 
     
     
         15 . The pharmaceutical composition according to  claim 10 , which is an agent for regeneration medicine. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the agent for regeneration medicine is an agent for transplantation medicine. 
     
     
         17 . A CXCR4 regulating agent, which comprises a compound represented by formula (II): 
       
         
           
           
               
               
           
         
         wherein T represents 
       
       
         
           
           
               
               
           
         
         wherein R 101  and R 102  each independently represents hydrogen or a hydrocarbon group which may have a substituent(s); ring A has the same meaning as that described in  claim 1 ; and other symbols have the same meanings as those described in  claim 1 , 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier. 
       
     
     
         18 . The agent according to  claim 17 , wherein the CXCR4 regulating agent is a CXCR4 antagonist. 
     
     
         19 . A CXCR4 regulating agent, which comprises a compound represented by formula (I-3) 
       
         
           
           
               
               
           
         
         wherein ring A 2  represents a 4- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; ring B 2  represents a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; ring A 2  may be substituted with 1 to 5 of R a ; ring B 2  may be substituted with 1 to 5 of R b ; and R a , R b  and other symbols have the same meanings as those described in  claim 7 , 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier. 
       
     
     
         20 . The CXCR4 regulating agent according to  claim 19 , which is a CXCR4 antagonist. 
     
     
         21 . A CXCR4 regulating agent, which comprises the compound represented by formula (I-A) according to  claim 7 , a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier. 
     
     
         22 . The CXCR4 regulating agent according to  claim 21 , which is a CXCR4 antagonist. 
     
     
         23 . A CXCR4 regulating agent, which comprises the compound represented by formula (I-B) according to  claim 8 , a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient. 
     
     
         24 . The CXCR4 regulating agent according to  claim 23 , which is a CXCR4 antagonist. 
     
     
         25 . The CXCR4 regulating agent according to  claim 17  or  19 , which is a preventive and/or therapeutic agent for inflammatory/immune diseases, allergic diseases, infectious diseases, HIV infection or diseases accompanied therewith, psychoneurotic diseases, cerebral diseases, cardiovascular diseases, metabolic diseases and cancerous diseases. 
     
     
         26 . The CXCR4 regulating agent according to  claim 25 , which is a preventive and/or therapeutic agent for HIV infection or diseases accompanied therewith. 
     
     
         27 . The CXCR4 regulating agent according to  claim 17  or  19 , which is useful for regeneration medicine. 
     
     
         28 . A medicament which comprises the compound according to any one of  claims 1 ,  7 ,  8  and  17 , a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, in combination with one or at least two of a reverse transferase inhibitor, a protease inhibitor, a CCR2 antagonist, a CCR3 antagonist, a CCR4 antagonist, a CCR5 antagonist, a fusion inhibitor, an antibody against a surface antigen of HIV-1, and a vaccine of HIV-1. 
     
     
         29 . The medicament according to  claim 28 , wherein the reverse transferase inhibitor is one or at least two selected from zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir, dipivoxil, emtricitabine, tenofovir, nevirapine, nevirapine, efavirenz and capravirine. 
     
     
         30 . The medicament according to  claim 28 , wherein the protease inhibitor is one or at least two selected from indinavir, ritonavir, nelfinavir, saquinavir, amprenavir, lopinavir and lopinavir. 
     
     
         31 . A method for antagonizing CXCR4 in a mammal, which comprises administering to a mammal an effective amount of a compound represented by formula (II): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as those described in  claim 1  or  17 , 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, 
       
     
     
         32 . A method for preventing and/or treating human immunodeficiency virus infection, which comprises administering to a subject in need thereof an effective amount of a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as those described in  claim 1 , 
         a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. 
       
     
     
         33 . A method for preventing and/or treating inflammatory/immune diseases, allergic diseases, infectious diseases, HIV infection or diseases accompanied therewith, psychoneurotic diseases, cerebral diseases, cardiovascular diseases, metabolic diseases and cancerous diseases, which comprises administering to a subject in need thereof an effective amount of the CXCR4 regulating agent according to  claim 17  or  19 .