Bicyclic compound, production and use thereof

Abstract

wherein, R1 is a 5- to 6-membered ring group which may be substituted; X1 is a bond or the like; ring A is a 5- to 6-membered ring group which may be substituted; ring B is a 8- to 10-membered ring group which may be substituted; X2 is a bivalent group of 1 to 4 atoms; Z1 is a bivalent cyclic ring group or the like; Z2 is a bond or the like; and R2 is an amino group, a nitrogen-containing heterocyclic group which may be substituted or the like, or a salt thereof.

1 .- 56 . (canceled) 
     
     
         57 . A method for inhibiting binding of a ligand to a CCR5 receptor comprising administering an effective amount of a compound of Formula I, 
       
         
           
           
               
               
           
         
       
       or a salt or hydrate thereof, 
       wherein,
 Z 1a  is a 5- or 6-membered aromatic ring group; 
 Z 2′  is a group of —Z 2a —W 2 —Z 2b — (wherein each of Z 2a  and Z 2b  is O, S(O)m (wherein m is 0, 1, or 2), an optionally substituted imino group, or a bond); 
 W 2  is an optionally substituted alkylene chain; 
 n is 1; 
 Y is NR 4 , wherein R 4  is hydrogen, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group); 
 R 2′  is (1) an optionally substituted amino group and whose nitrogen atom is optionally converted to quarternary ammonium or oxide; (2) a nitrogen-containing heterocyclic group which is optionally substituted and may contain a sulfur atom or an oxygen atom as a ring constituent atom, and whose nitrogen atom is optionally converted to quarternary ammonium or oxide; (3) an optionally substituted amidino group; or (4) an optionally substituted guanidino group; and 
 
       R 1  is an optionally substituted cyclic 5- to 6-membered ring. 
     
     
         58 . The method of  claim 57 , wherein the compound according to Formula (I) is administered as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. 
     
     
         59 . The method of  claim 57 , wherein the compound of Formula (I) is selected from the group consisting of
 (a) 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide;   (b) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide methanesulfonate;   (c) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamaide methanesulfonate;   (d) (S)-1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfiyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide;   (e) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-N-[4-[[(1-propyl-1H-imidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide; and   (f) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide.   
     
     
         60 . A method for inhibiting binding of a ligand to a CCR5 receptor comprising administering an effective amount of a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a salt or hydrate thereof, 
       wherein,
 R 1  is (C 1-6  alkoxy-C 1-6  alkoxy)phenyl, 
 R 2  is (1) N-C 1-6  alkyl-N-tetrahydropyranylamino, (2) imidazolyl which may be substituted with C 1-6  alkyl which may be substituted, or (3) triazolyl which may be substituted with C 1-6  alkyl which may be substituted, 
 
       R 3  is hydrogen, a lower alkyl group which is optionally substituted, or a lower alkoxy group which is optionally substituted,
 Y a  is NR 4 , wherein R 4  is selected from hydrogen, formyl, C 1-6  alkyl which is optionally substituted, C 2-6  alkenyl which is optionally substituted, aryl which is optionally substituted, a heterocyclic group which is optionally substituted, arylmethyl which is optionally substituted or a heterocyclic methyl which is optionally substituted, 
 n is 1, 
 na is 0 or 1, and 
 Z 2a  is a bond, S, SO or SO 2 . 
 
     
     
         61 . The method of  claim 60 , wherein Z 2a  is SO. 
     
     
         62 . The method of  claim 60 , wherein Z 2a  is SO whose configuration is (S). 
     
     
         63 . A method for inhibiting a biological function of CCR5, comprising contacting CCR5 with an effective amount of a compound according to Formula (I) or pharmaceutic ally acceptable salt thereof or a salt or hydrate thereof, wherein the compound is selected from the group consisting of:
 (a) 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide;   (b) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide methanesulfonate;   (c) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamaide methanesulfonate;   (d) (S)-1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfiyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide;   (e) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-N-[4-[[(1-propyl-1H-imidazol-5-yl]methyl] sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide; and   (f) (S)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide.   
     
     
         64 . The method of  claim 63 , wherein the biological function of CCR5 is selected from HIV infectivity, HIV replication, or AIDS progression. 
     
     
         65 . The method of  claim 63 , wherein the compound according to Formula (I) is administered as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. 
     
     
         66 . The method of  claim 63 , wherein the compound according to Formula (I) is administered as a pharmaceutical composition comprising the compound according to Formula (I), a pharmaceutically acceptable carrier, and a second compound selected from the group consisting of nucleic acid reverse transcriptase inhibitor, non-nucleic acid reverse transcriptase, inhibitor, protease inhibitor. 
     
     
         67 . The method of  claim 66 , wherein the second compound is a nucleic acid reverse transcriptase inhibitor selected from the group consisting of zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, adefovir, adefovir dipivoxil, and fozivudine tidoxil. 
     
     
         68 . The method of  claim 66 , wherein the second compound is a non-nucleic acid reverse transcriptase selected from the group consisting of nevirapine, delavirdine, efavirenz, loviride, immuncal, and oltipraz. 
     
     
         69 . The method of  claim 66 , wherein the second compound is a protease inhibitor selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, and lopinavir. 
     
     
         70 . The method  claim 63 , wherein the pharmaceutical composition is used in combination with blood for transfusion or blood derivatives.