Adenosine A2a receptor antagonists
View Patent ↗Disclosed are compounds having the structural formula or pharmaceutically acceptable salts or solvates thereof, wherein R is optionally substituted heteroaryl, optionally substituted phenyl, cycloalkenyl, —C(═CH 2 )CH 3 , —C≡C—CH 3 , —CH═C(CH 3 ) 2 , or —CH═CH—CH 3 ; R 2 is —W—X, —NR 19 (CH 2 ) m —W—X, and —NR 19 CH(CH 3 )—W—X, or R 2 is alkyl, alkenyl and —NR 18 R 19 , each optionally substituted —W—X; R 3 is H, halo, alkyl, trifluoromethyl, alkoxy, alkoxyalkyl, hydroxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, aminoalkyl, aryl, heteroaryl, or CN; R 18 is a bond, —CH(OH)—, —CH(CH 3 )—, —C(CH 3 ) n —, —(CH 2 ) n —or —O(CH 2 ) n —; W is aryl or heteroaryl, each optionally substituted; X is H, NH 2 , or substituted amino, or X is —R 18 —Y-Z; and n, R 19 , Y and Z are as defined in the specification; pharmaceutical compositions thereof, and methods of treating stroke or central nervous system diseases by administering the compound of the present invention to a patient in need of such treatment.
1. A compound having the structural formula I
or a pharmaceutically acceptable salt thereof; wherein:
R is selected from the group consisting of R 4 -heteroaryl, R 5 -phenyl, (C 4 -C 6 )cycloalkenyl, —C(═CH 2 )CH 3 , —C≡C—CH 3 ,
—CH═C(CH 3 ) 2 ,
and —CH═CH—CH 3 ;
R 2 is selected from the group consisting of —W—X, —NR 19 (CH 2 ) m —W—X, and —NR 19 CH(CH 3 )—W—X;
R 3 is hydrogen;
R 4 is 1 to 3 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, —CF 3 , halogen, —NO 2 , —NR 15 R 16 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, —COOR 17 and —C(O)NR 6 R 7 ;
R 5 is 1 to 5 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, —CN, —NH 2 , (C 1 -C 6 )alkylamino, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3 , —S(O) 0-2 (C 1 -C 6 )alkyl and —CH 2 —SO 2 -phenyl;
R 6 and R 7 , which can be the same or different, are each independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl;
R 8 is 1 to 5 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, hydroxy, C 1 -C 6 alkoxy, —CN, amino, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3 , acetyl, —NO 2 , hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )-alkoxy)(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy-(C 1 -C 6 )-alkoxy, carboxy(C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkoxy, morpholinyl, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkyl-SO 2 —(C 1 -C 6 )alkoxy, tetrahydropyranyloxy, (C 1 -C 6 )alkylcarbonyl(C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )alkylcarbonyloxy(C 1 -C 6 )-alkoxy, —SO 2 NH 2 , phenoxy,
—O—CH 2 —P(O)(OR 6 ) 2 ,— and —P(O)(OR 6 ) 2 ; or adjacent R 8 substituents together are —O—CH 2 —O—, —O—CH 2 CH 2 —O—, —O—CF 2 —O— or —O—CF 2 CF 2 —O— and form a ring with the carbon atoms to which they are attached;
R 9 is selected from the group consisting of (C 1 -C 6 )alkyl, R 8 -aryl-, R 8 -aryl(C 1 -C 6 )alkyl-, thienyl, pyridyl, (C 3 -C 6 )-cycloalkyl, (C 1 -C 6 )alkyl-OC(O)—NH—(C 1 -C 6 )alkyl-, di-((C 1 -C 6 )alkyl)aminomethyl, cycloheteroalkyl(C 1 -C 6 )alkyl, aryloxy(C 1 -C 6 )alkyl, alkoxy(C 1 -C 6 )alkyl and
R 10 is 1-2 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, R 5 -aryl and R 4 -heteroaryl, or two R 10 substituents on the same carbon can form ═O;
R 11 is hydrogen or (C 1 -C 6 )alkyl; —C(O)alkyl, or R 17 and R 11 taken together are —(CH 2 ) p -A-(CH 2 ) q , wherein p and q are each independently 2 or 3 and A is selected from the group consisting of a bond, —CH 2 —, —S— and —O—, and form a ring with the nitrogen to which they are attached;
R 12 is 1-2 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, halogen, and —CF 3 ;
R 13 is selected from the group consisting of H, (C 1 -C 6 )alkyl, phenyl, benzyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, di-((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkyl, pyrrolidinyl(C 1 -C 6 )alkyl and piperidino(C 1 -C 6 )alkyl;
R 14 is selected from the group consisting of H, halogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;
R 15 is selected from the group consisting of H and (C 1 -C 6 )alkyl;
R 16 is selected from the group consisting of H, (C 1 -C 6 )alkyl-C(O)— and (C 1 -C 6 )alkyl-SO 2 —;
R 17 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )hydroxyalkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, allyl, propargyl, R 8 -heteroaryl-, R 8 -aryl- and R 8 -aryl(C 1 -C 6 )alkyl-;
R 18 is selected from the group consisting of a bond, —CH 2 —, —CH(OH)—, —CH(CH 3 )—, —C(CH 3 ) n —, —(CH 2 ) n —, and —O(CH 2 ) n —,
R 19 is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 1 -C 6 )cycloalkyl, (C 1 -C 6 )cycloalkyl(C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
Q and Q 1 can be the same or different and are each independently selected from the group consisting of
m and n are each independently 1-3;
p and q are each independently 0-2;
s is 0-4;
W is aryl pyridyl or thienyl, and wherein said aryl, pyridyl or thienyl is optionally substituted with 1-3 substituents, which can be the same or different, and are independently selected from the group consisting of alkyl,aryl, alkylcycloalkyl, halo, hydroxy, hydroxyalkyl, alkoxy, alkylalkoxy, alkoxyalkoxy, —NR 6 R 7 , (C 2 -C 6 )alkenyl, and —CN;
X is selected from the group consisting of H, NH 2 , —N(R 6 )(CH 2 ) s -aryl, —N(R 6 )(CH 2 ) s -heteroaryl, —N(R 6 )(CH 2 ) m+1 —OH, and —N(CH 3 ) 2 , or
X is —R 18 —Y-Z;
Y is selected from the group consisting of —N(R 5 )CH 2 CH 2 N(R 7 )—, —N(R 6 )(CH 2 ) n aryl, —OCH 2 CH 2 N(R 6 )—, —O—, —S—, —CH 2 S—, —(CH 2 ) 2-3 —N(R 6 )—, R 8 -divalent heteroaryl,
Z is selected from the group consisting of H, alkyl, alkoxyalkyl, R 8 -aryl-, R 8 -aryl(C 1 -C 6 )alkyl-, R 8 -heteroaryl-, R 8 -bicyclicalkyl-, aminoalkyl, alkylamino, NH 2 , —N—(R 6 )(CH 2 ) s -aryl, —N(R 6 )(CH 2 ) s -heteroaryl, —N(R 6 )C(O)OR 17 , alkylcycloheteroalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkoxycycloheteroalkyl, heteroaryl; R 8 -benzofused heteroaryl-, diphenylmethyl and R 9 —C(O)—; or
when Y is
Z can also be —OH, R 9 —SO 2 —, R 17 —N(R 11 )(CH 2 ) s —C(O)—, R 17 —OC(O)—, R 17 —O(CH 2 ) n C(O)—, benzofused heteroaryl(CH 2 ) n C(O)—, benzofused heteroaryl(CH 2 ) n — or R 17 —N(R 11 )—C(S)—; or
when Q is
Z can also be R 17 R 11 N—, phenylamino or pyridylamino; or Z and Y taken together are selected from the group consisting of
2. The compound according to claim 1 wherein R is
3. The compound according to claim 1 wherein R 3 is H.
4. The compound according to claim 1 wherein R is
and R 3 is H.
5. A compound selected from the group consisting of
6. The compound according to claim 5 selected from the group consisting of:
7. A pharmaceutical composition comprising one or more compounds of claim 1 and one or more pharmaceutically acceptable carriers.
8. A method of treating psychoses, comprising administering one or more compounds of claim 1 to a patient in need of such treatment.