Substituted 8-heteroaryl xanthines

Abstract

The present invention provides compounds and pharmaceutical compositions that are selective antagonists of A 2B adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R is hydrogen, (C 1 -C 5 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 5 )alkenyl, or (C 3 -C 5 )alkynyl; 
         R 1  is (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-; 
         R 2  is hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heterocycle, (C 4 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, or (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-; 
         X is 3-pyridyl substituted in the 6 position with Z; 
         Z is —NR 4 R 5  or (C 4 -C 10 )heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 1 -C 8 )alkyl, (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; 
         each Z 1  is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —OR 6 , —SR 6 , halo, R 6 O(C 1 -C 8 )alkyl, R 7 R 8 N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR 7 R 8 , R 7 R 8 N(C 1 -C 8 )alkyl, —C(O)R 6 , —COOR 6 , and —C(O)NR 7 R 8 ; 
         R 3  is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —C(O)R 6 , or —C(O)NR 7 R 8 ; 
         R 4  is selected from hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 6 -C 18 )polycycloalkyl, (C 6 -C 18 )polycycloalkyl(C 1 -C 8 )alkyl-, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, —NR 7 R 8 , (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —((CH 2 ) 2-4 —Y) q —(CH 2 ) 2-4 —X 1 , —C(O)R 6 , —CO 2 R 6 , —C(O)NR 7 R 8 , or —S(O) 2 —NR 7 R 8 ; 
         R 5  is selected from —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 ; 
         or R 4  and R 5  together with the atoms to which they are attached form a saturated or partially unsaturated, mono or bicyclic-ring having 3, 4, 5, 6, 7, or 8, ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )— in the ring, and wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; 
         X 1  is —OR 6 , —C(O)R 6 , —CO 2 R 6 , or —NR 7 R 8 ; and Y is oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )—; 
         wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocycle or heteroaryl groups of R 1 , R 2 , R 3 , R 4  and R 5  groups are optionally substituted with one or more substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; 
         wherein R 6  is hydrogen, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl, (C 4 -C 10 )heteroaryl(C 1 -C 8 )alkyl-; wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; 
         wherein R 7 , R 8  and R 9  are independently hydrogen, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl; —COOR a , —C(O)R a , or —C(O)NR b R c  wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; 
         or R 7  and R 8  together with the atoms to which they are attached form a saturated or partially unsaturated, mono- or bicyclic-ring having 3, 4, 5, 6, 7, or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine —N(R b )— in the ring; 
         R a  is hydrogen, or (C 1 -C 6 )alkyl; 
         R b  and R c  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkylthio, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl-; 
         or R b  and R c  together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring; and 
         where n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
         m is 1, or 2; and 
         q is 1, 2, 3, or 4; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R is hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl or halo(C 1 -C 4 )alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R is hydrogen. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is cyclopropyl or cyclopropylmethyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, phenyl, phenyl(C 1 -C 4 )alkyl, or (methoxyphenyl)ethyl. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is cyclopropyl or cyclopropylmethyl. 
     
     
         8 . The compound of  claim 1 , wherein R 4  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, (C 5 -C 6 )heteroaryl(C 1 -C 4 )alkyl-, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 . 
     
     
         9 . The compound of  claim 1 , wherein R 4  is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 . 
     
     
         10 . The compound of  claim 1 , wherein R 4  is methyl, ethyl, cyclopropyl, cyclopropylmethyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 . 
     
     
         11 . The compound of  claim 1 , wherein R 4  and R 5  together with the nitrogen to which they are attached, form a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring, wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c . 
     
     
         12 . The compound of  claim 1 , wherein R 4  is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 . 
     
     
         13 . The compound of  claim 1 , wherein R 6  is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, or (C 5 -C 6 )heteroaryl(C 1 -C 4 )-alkyl-, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, nitro, (C 1 -C 8 )alkyl, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c . 
     
     
         14 . The compound of  claim 1 , wherein R 6  is (C 6 -C 10 )aryl, (C 5 -C 6 )heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, nitro, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —COOR a , and —C(O)NR b R c . 
     
     
         15 . The compound of  claim 1 , wherein R 6  is pyridyl, optionally substituted with F, Cl, Br, I, CF 3 , cyano, nitro, —COOR a , or —CONHR a . 
     
     
         16 . The compound of  claim 1 , wherein:
 R is hydrogen, methyl, or ethyl;   R 1  is cyclopropyl or cyclopropylmethyl;   R 2  is methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, or n-butyl; and   R 4  is methyl, ethyl, cyclopropyl, cyclopropylmethyl   R 5  is —C(O)R 6 ,   R 6  is heteroaryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, nitro, halo(C 1 -C 8 )alkyl, —C(O)R a , —COOR a , and —C(O)NR b R c , and wherein R a , R b  and R c  are independently hydrogen, methyl, ethyl, propyl, isopropyl, or cyclopropyl.   
     
     
         17 . The compound of  claim 1 , wherein:
 R is hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl or halo(C 1 -C 4 )alkyl;   R 1  is cyclopropyl or cyclopropylmethyl; and,   R 2  is hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, phenyl, phenethyl, or benzyl.   
     
     
         18 . The compound of  claim 1 , wherein:
 R 6  is methyl, methoxy, or pyridyl; and   R 7  is phenyl, fluorophenyl, or methoxyphenyl.   
     
     
         19 . The compound of  claim 1 , wherein:
 R is hydrogen, methyl, or ethyl;   R 1  is cyclopropyl or cyclopropylmethyl;   R 2  is methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl; and   Z is (C 4 -C 10 )heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .   
     
     
         20 . The compound of  claim 1 , wherein:
 R 2  is n-propyl;   R is hydrogen; and   n is zero.   
     
     
         21 . The compound of  claim 1 , wherein Z is —NR 4 R 5 . 
     
     
         22 . The compound of  claim 1 , wherein Z is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1 , wherein —X(Z 1 ) n —Z is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1 , wherein —X(Z 1 ) n —Z is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . A compound of  claim 1  selected from the group consisting of:
 1-Cyclopropyl-3-propyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;   1,3-Dicylopropylmethyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;   1,3-Dicylopropylmethyl-8-[6-[N-nicotinoylethylamino]-3-pyridyl)xanthine;   1,3-Dicyclopropylmethyl-8-(6-methylaminopyridin-3-yl)xanthine;   1,3-Dicyclopropylmethyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;   1,3-Dicyclopropylmethyl-8-[6-[N-nicotinoylethylamino]-3-pyridyl)xanthine;   1-Cyclopropylmethyl-3-ethyl-8-(6-methylaminopyridin-3-yl)xanthine;   1-Cyclopropyl-3-ethyl-8-(6-methylamino-3-pyridyl)xanthine;   1-Cyclopropyl-3-propyl-8-(6-methylamino-3-pyridyl)xanthine;   1-Cyclopropyl-3-propyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;   1-Cyclopropyl-3-propyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;   1-Cyclopropyl-3-propyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl)xanthine; and,   1-Cyclopropylmethyl-3-ethyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl)xanthine;   or a pharmaceutical acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.   
     
     
         26 . A pharmaceutical composition comprising:
 (a) a therapeutically effective amount of a compound of  claim 1 ; and   (b) a pharmaceutically acceptable excipient.   
     
     
         27 . A method for treating asthma, comprising administering an effective amount of a compound of  claim 1  to a mammal in need of such treatment. 
     
     
         28 . A method for treating improving insulin sensitivity, comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.