Method of preventing and treating airway remodeling and pulmonary inflammation using A2B adenosine receptor antagonists

Abstract

The present invention relates to methods of preventing airway remodeling using A 2B adenosine receptor antagonists. This invention finds utility in the treatment and prevention of asthma, COPD, pulmonary fibrosis, emphysema, and other pulmonary diseases. The invention also relates to pharmaceutical compositions for use in the method.

1 . A method for the treatment and prevention of airway remodeling and/or pulmonary inflammation by administration of a therapeutically effective amount of an A 2B  receptor antagonist to a mammal that is genetically and/or environmentally predisposed to airway remodeling and/or pulmonary inflammation.  
     
     
         2 . The method of  claim 1  wherein the method is for the treatment and prevention of airway remodeling.  
     
     
         3 . The method of  claim 1 , wherein the method is for the treatment and prevention of pulmonary inflammation.  
     
     
         4 . The method of  claim 1 , wherein the mammal is human.  
     
     
         5 . The method of  claim 1 , wherein the administration is systemic.  
     
     
         6 . The method of  claim 5 , wherein the administration is oral.  
     
     
         7 . The method of  claim 5 , wherein the administration is intravenous.  
     
     
         8 . The method of  claim 5 , wherein the administration is intramuscular.  
     
     
         9 . The method of  claim 5 , wherein the administration is intraperitoneal.  
     
     
         10 . The method of  claim 1 , wherein the A 2B  receptor agonist is administered by inhalation.  
     
     
         11 . The method of  claim 1 , wherein the mammal suffers from a disease state chosen from asthma, pulmonary fibrosis, and COPD.  
     
     
         12 . The method of  claim 11 , wherein the disease state is asthma.  
     
     
         13 . The method of  claim 11 , wherein the disease state is pulmonary fibrosis.  
     
     
         14 . The method of  claim 11 , wherein the disease state is COPD.  
     
     
         15 . The method of  claim 1 , wherein the A 2B  receptor antagonist has the structure of Formula I or Formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  and R 2  are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy;  
 R 3  is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;  
 X is optionally substituted arylene or heteroarylene;  
 Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino;  
 with the proviso that when the optional substitution is hydroxy or amino said substitution cannot be present on a carbon atom adjacent to a heteroatom; and  
 Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl;  
 with the proviso that 
 (a) Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene attached to the purine ring by a carbon atom; and,  
 (b) when X is optionally substituted arylene, Z is an optionally substituted monocyclic heteroaryl other than optionally substituted imidazole.  
 
 
     
     
         16 . The method of  claim 15 , wherein: 
 R 1  and R 2  are independently hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, and    R 3  is hydrogen.    
     
     
         17 . The method of  claim 16 , wherein: 
 X is optionally substituted phenylene; and    Y is a covalent bond or lower alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—.    
     
     
         18 . The method of  claim 17 , wherein R 1  and R 2  are independently lower alkyl optionally substituted by cycloalkyl.  
     
     
         19 . The method of  claim 18 , wherein R 1  and R 2  are n-propyl, Y is —OCH 2 —, and Z is optionally substituted oxadiazole.  
     
     
         20 . The method of  claim 19 , wherein Z is 5-(2-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;  
     
     
         21 . The method of  claim 19 , wherein Z is 5-(3-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.  
     
     
         22 . The method of  claim 19 , wherein Z is 5-(4-fluorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.  
     
     
         23 . The method of  claim 16 , wherein: 
 X is optionally substituted pyrazolene,    Y is a covalent bond, lower alkylene optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino; and    Z is hydrogen, optionally substituted phenyl, optionally substituted oxadiazolyl, optionally substituted isoxazolyl, or optionally substituted pyridyl.    
     
     
         24 . The method of  claim 23 , wherein X is optionally substituted 1,4-pyrazolene.  
     
     
         25 . The method of  claim 24 , wherein Z is optionally substituted phenyl.  
     
     
         26 . The method of  claim 25 , wherein R 1  is lower alkyl optionally substituted by cycloalkyl, R 2  is hydrogen, and Y is —CH 2 — or —CH(CH 3 ).  
     
     
         27 . The method of  claim 26 , wherein R 1  is n-propyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is 3-trifluoromethylphenyl, namely 1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]-methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.  
     
     
         28 . The method of  claim 26 , wherein R 1  is n-propyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is phenyl, namely 1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.  
     
     
         29 . The method of  claim 26 , wherein R 1  is n-butyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is 3-fluorophenyl, namely 1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.  
     
     
         30 . The method of  claim 26  wherein R 1  is n-propyl, X is 1,4-pyrazolene, Y is —CH(CH 3 )—, and Z is phenyl, namely 1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.  
     
     
         31 . The method of  claim 25 , wherein R 1  and R 2  are independently methyl, ethyl, n-propyl, or cyclopropylmethyl, and Y is methylene or ethylene which may be optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino.  
     
     
         32 . The method of  claim 31 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is 3-(1,2,3,4-tetrazol-5-yl)phenyl, namely 1,3-dipropyl-8-{1-[(3-(1H-1,2,3,4-tetraazol-5-yl)phenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.  
     
     
         33 . The method of  claim 31 , wherein R 1  is n-propyl, R 2  is ethyl, Y is —CH 2 —, and Z is 3-trifluoromethylphenyl, namely 3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.  
     
     
         34 . The method of  claim 31 , wherein R 1  and R 2  are n-propyl, Y is —CH(CH 3 )—, and Z is 3-trifluoromethylphenyl, namely 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.  
     
     
         35 . The method of  claim 31 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is 4-carboxyphenyl, namely 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.  
     
     
         36 . The method of  claim 31 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is 3-carboxyphenyl, namely 3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}benzoic acid.  
     
     
         37 . The method of  claim 31 , wherein R 1  and R 2  are n-propyl, Y is —CH(CO 2 H)—, and Z is phenyl, namely 2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic acid.  
     
     
         38 . The method of  claim 24 , wherein Z is optionally substituted oxadiazole.  
     
     
         39 . The method of  claim 38 , wherein R 1  is lower alkyl optionally substituted by cycloalkyl, R 2  is H, and Y is —CH 2 — or —CH(CH 3 )—.  
     
     
         40 . The method of  claim 31 , wherein R 1  is n-propyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione.  
     
     
         41 . The method of  claim 31 , wherein R 1  is n-butyl, X is 1,4-pyrazolene, Y is —CH 2 —, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione.  
     
     
         42 . The compound of  claim 38 , wherein R 1  and R 2  are independently lower alkyl optionally substituted by cycloalkyl and Y is —CH 2 — or —CH(CH 3 )—.  
     
     
         43 . The method of  claim 42 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is 3-(4-chlorophenyl) [1,2,4]oxadiazol-5-yl, namely 8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.  
     
     
         44 . The method of  claim 42 , wherein R 1  is n-propyl, R 2  is ethyl, Y is —CH 2 —, and Z is 3-(4-chlorophenyl)-[1,2,4]-oxadiazol-5-yl, namely 8-(1-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-3-ethyl-1-propyl-1,3,7-trihydropurine-2,6-dione.  
     
     
         45 . The method of  claim 24 , wherein Z is hydrogen.  
     
     
         46 . The method of  claim 44 , wherein R 1  and R 2  are independently lower alkyl optionally substituted by cycloalkyl, and Y is —CH 2 —, —CH(CH 3 )— or a covalent bond-.  
     
     
         47 . The method of  claim 46 , wherein R 1  and R 2  are n-propyl, Y is a covalent bond, and Z is hydrogen, namely 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.  
     
     
         48 . The method of  claim 46 , wherein R 1  is sec-butyl, R 2  is methyl, Y is a covalent bond, and Z is hydrogen, namely 1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.  
     
     
         49 . The method of  claim 24 , wherein Z is optionally substituted isoxazolyl.  
     
     
         50 . The method of  claim 49 , wherein R 1  and R 2  are independently lower alkyl optionally substituted by cycloalkyl, and Y is —CH 2 —, —CH(CH 3 )—, or a covalent bond-.  
     
     
         51 . The method of  claim 50 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is 5-(4-trifluoromethylphenyl)isoxazol-3-yl, namely 1,3-dipropyl-8-[1-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.  
     
     
         52 . The method of  claim 50 , wherein R 1  is n-propyl, R 2  is ethyl, Y is —CH 2 —, and Z is 5-(4-chlorophenyl)-isoxazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)isoxazol-3-yl]methyl}pyrazol-4-yl)-3-ethyl-1-propyl-1,3,7-trihydropurine-2,6-dione.  
     
     
         53 . The method of  claim 24 , wherein Z is optionally substituted pyridyl.  
     
     
         54 . The method of  claim 52 , wherein R 1  and R 2  are independently lower alkyl optionally substituted by cycloalkyl, and Y is —CH 2 —, —CH(CH 3 )—, or a covalent bond-.  
     
     
         55 . The method of  claim 54 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is pyrid-2-yl, namely 1,3-dipropyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.  
     
     
         56 . The method of  claim 54 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is 2-trifluoromethylpyrid-3-yl, namely 1,3-dipropyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.  
     
     
         57 . The method of  claim 54 , wherein R 1  and R 2  are n-propyl, Y is —CH 2 —, and Z is 6-carboxy-pyrid-2-yl, namely 6-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)pyrazolyl]methyl}pyridine-2-carboxylic acid.  
     
     
         58 . The method of  claim 54 , wherein R 1  is n-propyl, R 2  is ethyl, Y is —CH 2 —, and Z is 2-pyridyl, namely 3-ethyl-1-propyl-8-[1-(2-pyridylmethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.  
     
     
         59 . 2 The method of  claim 54 , wherein R 1  is n-propyl, R 2  is ethyl, Y is —CH 2 —, and Z is 6-(trifluoromethyl)-pyrid-3-yl, namely 3-ethyl-1-propyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.  
     
     
         60 . The method of  claim 54 , wherein R 1  is cyclopropylmethyl, R 2  is ethyl, Y is —CH 2 —, and Z is 6-(trifluoromethyl)-pyrid-3-yl, namely 1-(cyclopropylmethyl)-3-ethyl-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.  
     
     
         61 . The method of  claim 54 , wherein R 1  is 2-methylpropyl, R 2  is ethyl, Y is —CH 2 —, and Z is 6-(trifluoromethyl)-pyrid-3-yl, namely 3-ethyl-1-(2-methylpropyl)-8-(1-{[6-(trifluoromethyl)(3-pyridyl)]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.