Novel adenine compound and use thereof

Abstract

An antiallergic agent for topical administration containing an adenine compound of general formula (1): [wherein ring A represents a 6 to 10 membered, mono or bicyclic, aromatic hydrocarbon or a 5 to 10 membered, mono or bicyclic, aromatic heterocycle containing one to three heteroatoms selected among 0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom; n is an integer of 0 to 2; m is an integer of 0 to 2; R represents halogeno, (un)substituted alkyl, etc.; X 1 represents oxygen, sulfur, NR 1 (R 1 represents hydrogen or alkyl), or a single bond; Y 1 represents a single bond, alkylene, etc.; Y 2 represents a single bond, alkylene, etc.; Z represents alkylene; and at least one of Q 1 and Q 2 represents —COOR 10 (wherein R 10 represents (un)substituted alkyl, etc.), etc.] or a pharmaceutically acceptable salt of the compound.

1 . A topically administrable medicament containing an adenine compound represented by a general formula (1): 
       
         
           
           
               
               
           
         
         wherein 
         Ring A is a 6 to 10 membered mono or bicyclic aromatic hydrocarbon ring or a 5 to 10 membered mono or bicyclic heteroaromatic ring containing 1 to 3 hetero atoms selected from the group of 0 to 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, 
         n is an integer selected from 0 to 2, m is an integer selected from 0 to 2, 
         R is halogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkoxy group, or substituted or unsubstituted amino group, and when n is 2, R(s) may be the same or different, 
         X 1  is oxygen atom, sulfur atom, NR 1  (wherein R 1  is hydrogen atom or alkyl group) or a single bond, 
         Y 1  is a single bond, alkylene which may be substituted by oxo group, or divalent group of the formula below: 
       
       
         
           
           
               
               
           
         
         (wherein r 1  and r 2  are independently an integer selected from 1 to 3), 
         Y 2  is a single bond, alkylene optionally substituted by hydroxy group or oxo group, oxyalkylene, cycloalkylene, oxycycloalkylene, divalent group of a monocyclic hetero ring containing 1 or 2 hetero atoms selected from the group consisting of 1 or 2 nitrogen atoms wherein said nitrogen atom may be substituted, oxygen atoms and sulfur atoms wherein said sulfur atom(s) may be oxidized by 1 or 2 oxygen atoms, or divalent group of the formula below: 
       
       
         
           
           
               
               
           
         
         (wherein A′ is cycloalkylene, s 1  is an integer selected from 1 to 3), 
         Z is alkylene, 
         Q 1  is hydrogen atom, halogen atom, hydroxy group, alkoxy group, or a group selected from the group consisting of Substituents illustrated below, 
         Q 2  is a group selected from the group consisting of Substituents illustrated below, 
         R 10  or R 11  in Q 2  may be taken with R to form a 9 to 14 membered fused bi or tricyclic ring together with the adjacent Ring A, 
         when m is 0, Q 1  is a group selected from the group consisting of Substituents illustrated below, 
         Substituents: —COOR 10 ; —COSR 10 ; —OCOOR 10 ; —OCOR 10 ; —CONR 11 R 12 ; —OCONR 11 R 12    
         (wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, R 11  and R 12  are independently hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, or R 11  and R 12  may be taken together to form with the adjacent nitrogen atom a 5 to 7 membered heterocycle containing a nitrogen atom(s)); 
         and any group selected from the following formulas (3)˜(6): 
       
       
         
           
           
               
               
           
         
         (wherein M is a single bond, oxygen atom or sulfur atom, and q is an integer selected from 1 to 3), 
         and when m is 2, (Y 2 -Q 2 )(s) may be the same or different, 
         or a pharmaceutically acceptable salt thereof as an active ingredient. 
       
     
     
         2 . A topically administrable medicament containing an adenine compound represented by a general formula (1): 
       
         
           
           
               
               
           
         
         wherein 
         Ring A is a 6 to 10 membered mono or bicyclic aromatic hydrocarbon ring or a 5 to 10 membered mono or bicyclic heteroaromatic ring containing 1 to 3 hetero atoms selected from the group of 0 to 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, 
         n is an integer selected from 0 to 2, m is an integer selected from 0 to 2, 
         R is halogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkoxy group, or substituted or unsubstituted amino group, and when n is 2, R(s) may be the same or different, 
         X 1  is oxygen atom, sulfur atom, NR 1  (wherein R 1  is hydrogen atom or alkyl group) or a single bond, 
         Y 1  is a single bond, alkylene which may be substituted by oxo group, or divalent group of the formula below: 
       
       
         
           
           
               
               
           
         
         (wherein r 1  and r 2  are independently an integer selected from 1 to 3), 
         Y 2  is a single bond, alkylene optionally substituted by hydroxy group or oxo group, oxyalkylene, cycloalkylene, oxycycloalkylene, divalent group of a monocyclic hetero ring containing 1 or 2 hetero atoms selected from the group consisting of 1 or 2 nitrogen atoms wherein said nitrogen atom may be substituted, oxygen atoms and sulfur atoms wherein said sulfur atom(s) may be oxidized by 1 or 2 oxygen atoms, or divalent group of the formula below: 
       
       
         
           
           
               
               
           
         
         (wherein A′ is cycloalkylene, s 1  is an integer selected from 1 to 3), 
         Z is alkylene, 
         Q 1  is hydrogen atom, halogen atom, hydroxy group, alkoxy group, or a group selected from the group consisting of Substituents illustrated below, 
         Q 2  is a group selected from the group consisting of Substituents illustrated below, 
         R 10  or R 11  in Q 2  may be taken with R to form a 9 to 14 membered fused bi or tricyclic ring together with the adjacent Ring A, 
         when m is 0, Q 1  is a group selected from the group consisting of Substituents illustrated below, 
         Substituents: —COOR 10 ; —COSR 10 ; —OCOOR 10 ; —OCOR 10 ; and —CONR 11 R 12 ; 
         wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, R 11  and R 12  are independently hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, or R 11  and R 12  may be taken together to form with the adjacent nitrogen atom a 5 to 7 membered heterocycle containing a nitrogen atom(s); 
         and when m is 2, (Y 2 -Q 2 )(s) may be the same or different, 
         or a pharmaceutically acceptable salt thereof as an active ingredient. 
       
     
     
         3 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), the substituent(s), by which alkyl group, alkenyl group or alkynyl group in R 10 , R 11  and R 12  is substituted, are the same or different and at least one substituent selected from the group consisting of halogen atom, hydroxy group, substituted or unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted aryl group, and substituted or unsubstituted heterocyclic group. 
     
     
         4 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), Z is methylene and Ring A is benzene. 
     
     
         5 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), Y 1  is C 1-5  alkylene, Q 1  is hydrogen atom, hydroxy group or alkoxy group, Y 2  is a single bond, and Q 2  is —COOR 10 . 
     
     
         6 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), Z is methylene, Ring A is benzene, R 10  is alkyl group substituted by hydroxy group, amino group, alkylamino group or dialkylamino group, and m is 1. 
     
     
         7 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), Y 1  is C 1-5  alkylene, Q 1  is hydrogen atom, hydroxy group or alkoxy group, Y 2  is C 1-3  alkylene, Q 2  is —COOR 10 , and m is 1. 
     
     
         8 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), m is 0, Y 1  is C 1-6  alkylene which may be substituted with oxo group, and Q 1  is —COOR 10 , —COSR 10 , —OCOR 10 , —OCOOR 10 , —CONR 11 R 12  or —OCONR 11 R 12 . 
     
     
         9 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1) X 1  is oxygen atom, sulfur atom or NR 1  (wherein R 1  is hydrogen atom or alkyl group). 
     
     
         10 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), m is 0, X 1  is a single bond, Y 1  is C 1-4  alkylene which may be substituted by oxo group, and Q 1  is —COOR 10 . 
     
     
         11 . The topically administrable medicament according to  claim 2 , wherein in the general formula (1), the limitation is either 1) or 2) below:
 1) n is 0;   2) n is 1 or 2, and R is alkyl group, alkoxy group or halogen atom.   
     
     
         12 . The adenine compound or its pharmaceutically acceptable salt of  claim 1 , wherein in the general formula (1), Z is methylene, Ring A is a 5 to 10 membered mono or bicyclic hetero ring containing 1 to 3 heteroatoms selected from the group consisting of 0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom. 
     
     
         13 . The adenine compound or its pharmaceutically acceptable salt of  claim 1 , wherein in the general formula (1), the heteroaromatic ring in Ring A is furan, thiophene, or pyridine. 
     
     
         14 . The adenine compound or its pharmaceutically acceptable salt according to  claim 12 , wherein in the general formula (1), Q 1  is hydrogen atom, hydroxy group or alkoxy group, Y 1  is C 1-5  alkylene, Q 2  is —COOR 10  (wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group), and m is 1. 
     
     
         15 . The adenine compound or its pharmaceutically acceptable salt according to  claim 12 , wherein in the general formula (1), Y 2  is a single bond. 
     
     
         16 . The adenine compound, its tautomer or its pharmaceutically acceptable salt according to  claim 12 , wherein in the general formula (1), m is 0, Y 1  is C 1-6  alkylene which may be substituted by oxo group, and Q 1  is —COOR 10 , —COSR 10 , —OCOR 10 , —OCOOR 10 , —CONR 11 R 12  or —OCONR 11 R 12  (wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, R 11  and R 12  are independently hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, or R 11  and R 12  may be taken together to form with the adjacent nitrogen atom a 5 to 7 membered heterocycle containing a nitrogen atom(s));
 and any group selected from the following formulas (3)˜(6): 
 
       
         
           
           
               
               
           
         
         (wherein M is a single bond, oxygen atom or sulfur atom, and q is an integer selected from 1 to 3). 
       
     
     
         17 . The adenine compound or its pharmaceutically acceptable salt according to  claim 12 , wherein in the general formula (1), the substituent(s) by which alkyl group, alkenyl group or alkynyl group in R 10 , R 11 , R 12 , R 20 , R 21  and R 22  is substituted, are at least one substituent selected from the group consisting of halogen atom, hydroxy group, substituted or unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted aryl group, and substituted or unsubstituted heterocyclic group. 
     
     
         18 . The adenine compound or its pharmaceutically acceptable salt according to  claim 12 , wherein R is hydrogen atom, alkyl group, alkoxy group, or halogen atom. 
     
     
         19 . The adenine compound or its pharmaceutically acceptable salt according to  claim 1 , wherein in the general formula (1), Z is methylene, Ring A is benzene, Q 1  is hydrogen atom, hydroxy group or alkoxy group, Y 1  is C 1-5  alkylene, Y 2  is a single bond, Q 2  is —COOR 23  (wherein R 23  is alkyl group substituted by amino group, alkylamino group or dialkylamino group), and m is 1. 
     
     
         20 . The adenine compound or its pharmaceutically acceptable salt according to  claim 12  or  19 , wherein in the general formula (1), X 1  is oxygen atom, sulfur atom or NR 1  (wherein R 1  is hydrogen atom or alkyl group). 
     
     
         21 . The topically administrable preparation according to  claim 2 , wherein the preparation is a prophylactic or therapeutic agent for viral diseases, dermal diseases or allergic diseases. 
     
     
         22 . The topically administrable preparation according to  claim 2  wherein the allergic disease is asthma. 
     
     
         23 . The topically administrable preparation according to  claim 2  wherein the allergic disease is atopic dermatosis. 
     
     
         24 . The topically administrable preparation according to  claim 2 , wherein the half-life in serum on the compound of the general formula (1) is less than 1 hour. 
     
     
         25 . The topically administrable preparation according to  claim 2 , wherein the half-life in liver S9 of the compound of the general formula (1) is less than 1 hour. 
     
     
         26 . The topically administrable preparation according to  claim 2 , wherein the interferon concentration in serum is less than 10 IU/ml after said compound is topically administered. 
     
     
         27 . The topically administrable preparation according to  claim 2 , wherein the preparation is an inhalation formulation. 
     
     
         28 . A method for regulating immune response, comprising topically administering to a patient in need an effective amount of an adenine compound of  claim 1 . 
     
     
         29 . A method for regulating immune response, comprising: topically administering to a patient in need an effective amount of the medicament comprising an adenine compound represented by the formula (1) of  claim 2 . 
     
     
         30 . A method for regulating immune response, comprising topically administering to a patient in need an effective amount of an adenine compound in  claim 12  or  19 . 
     
     
         31 . A method for treatment or prophylaxis of viral diseases, dermal diseases or allergic diseases, comprising topically administering to a patient in need an effective amount of an adenine compound of  claim 1 . 
     
     
         32 . The method according to  claim 31  wherein the allergic disease is asthma or atopic dermatosis. 
     
     
         33 . A method for treatment or prophylaxis of viral diseases, dermal diseases or allergic diseases, comprising topically administering to a patient in need an effective amount of the medicament of  claim 2 . 
     
     
         34 . A method for treatment or prophylaxis of viral diseases, dermal diseases or allergic diseases, comprising topically administering to a patient in need an effective amount of an adenine compound in  claim 12  or  19 . 
     
     
         35 . The method according to  claim 31  wherein the half-life in serum on the compound of the formula (1) is less than 1 hour after said compound is locally administered. 
     
     
         36 . The method according to  claim 31  wherein the half-life in liver S9 on the compound of the formula (1) is less than 1 hour after said compound is locally administered. 
     
     
         37 . The method according to  claim 31  wherein the interferon concentration in serum is less than 10 IU/ml after said compound is topically administered. 
     
     
         38 . The method according to  claim 31 , wherein the compound is administered by inhalation formulation. 
     
     
         39 . The adenine compound or its pharmaceutically acceptable salt according to  claim 17 , in which, in formula (1), at least one of Q 1  and Q 2  is —COSR 10 , —OCOOR 10 , —OCOR 10  or —OCONR 11 R 12  (wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, R 11  and R 12  are independently hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, or R 11  and R 12  may be taken together to form with the adjacent nitrogen atom a 5 to 7 membered heterocycle containing a nitrogen atom(s));
 and any group selected from the following formulas (3)˜(6): 
 
       
         
           
           
               
               
           
         
         (wherein M is a single bond, oxygen atom or sulfur atom, and q is an integer selected from 1 to 3). 
       
     
     
         40 . The adenine compound or its pharmaceutically acceptable salt according to  claim 20 , in which, in formula (1), at least one of Q 1  and Q 2  is —COSR 10 , —OCOOR 10 , —OCOR 10  or —OCONR 11 R 12  (wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, R 11  and R 12  are independently hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, or R 11  and R 12  may be taken together to form with the adjacent nitrogen atom a 5 to 7 membered heterocycle containing a nitrogen atom(s));
 and any group selected from the following formulas (3)˜(6): 
 
       
         
           
           
               
               
           
         
         (wherein M is a single bond, oxygen atom or sulfur atom, and q is an integer selected from 1 to 3). 
       
     
     
         41 . The method of  claim 30 , in which in the compound of the formula (1), at least one of Q 1  and Q 2  is —COSR 10 , —OCOOR 10 , —OCOR 10  or —OCONR 11 R 12  (wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, R 11  and R 12  are independently hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, or R 11  and R 12  may be taken together to form with the adjacent nitrogen atom a 5 to 7 membered heterocycle containing a nitrogen atom(s));
 and any group selected from the following formulas (3)˜(6): 
 
       
         
           
           
               
               
           
         
         (wherein M is a single bond, oxygen atom or sulfur atom, and q is an integer selected from 1 to 3). 
       
     
     
         42 . The method of  claim 34 , in which in the compound of the formula (1), at least one of Q 1  and Q 2  is —COSR 10 , —OCOOR 10 , —OCOR 10  or —OCONR 11 R 12  (wherein R 10  is substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, R 11  and R 12  are independently hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted alkynyl group, or R 11  and R 12  may be taken together to form with the adjacent nitrogen atom a 5 to 7 membered heterocycle containing a nitrogen atom(s));
 and any group selected from the following formulas (3)˜(6): 
 
       
         
           
           
               
               
           
         
         (wherein M is a single bond, oxygen atom or sulfur atom, and q is an integer selected from 1 to 3).