Adenosine A2a receptor antagonists
View Patent ↗Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, cycloalkenyl, or heteroaryl; X is alkylene or —C(O)CH 2 —; Y is —N(R 2 )CH 2 CH 2 N(R 3 )—, —OCH 2 CH 2 N(R 2 )—, —O—, —S—, —CH 2 S—, —(CH 2 ) 2 —NH—, or optionally substituted m and n are 2–3, and Q is nitrogen or optionally substituted carbon; and Z is optionally substituted phenyl, phenylalkyl or heteroaryl, diphenylmethyl, R 6 —C(O)—, R 6 —SO 2 —, R 6 —OC(O)—, R 7 —N(R 8 )—C(O)—, R 7 —N(R 8 )—C(S)—, phenyl-CH(OH)—, or phenyl-C(═NOR 2 )—; or when Q is CH, phenylamino or pyridylamino; or Z and Y together are substituted piperidinyl or substituted phenyl; and R 2 , R 3 , R 6 , R 7 , and R 8 are as defined in the specification are disclosed, their use in the treatment of Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them; also disclosed are a processes for preparing intermediates useful for preparing compounds of formula I.
1. A process of preparing a compound of formula II
wherein R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or C 4 –C 6 cycloalkenyl;
R 1 is 1 to 3 substituents independently selected from hydrogen, C 1 –C 6 -alkyl, —CF 3 , halogen, —NO 2 , NR 12 R 13 , C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, C 1 –C 6 alkylsulfinyl, and C 1 –C 6 alkylsulfonyl;
R 10 is 1 to 5 substituents 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 and —S(O) 0-2 (C 1 –C 6 )alkyl;
R 12 is H or C 1 –C 6 alkyl; and
R 13 is (C 1 –C 6 )alkyl-C(O)— or (C 1 –C 6 )alkyl-SO 2 —; comprising
(1) treating 2-amino-4,6-dihydroxypyrimidine
with POCl 3 in dimethylformamide to obtain 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde
(2) treating carboxaldehyde VII with a hydrazide of the formula H 2 N—NH—C(O)—R, wherein R is as defined above, to obtain
(3) treating the intermediate of formula VIII with hydrazine hydrate to form a pyrazolo ring, thus obtaining the intermediate of formula IX
(4) forming the desired compound of formula II by dehydrative rearrangement.
2. A process for preparing a compound of the formula II
wherein R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or C 4 –C 6 cycloalkenyl;
R 1 is 1 to 3 substituents independently selected from hydrogen, C 1 –C 6 -alkyl, —CF 3 , halogen, —NO 2 , —NR 12 R 13 , C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, C 1 –C 6 alkylsulfinyl, and C 1 –C 6 alkylsulfonyl;
R 10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 –C 6 alkyl, hydroxy, C 1 –C 6 alkoxy, —ON, —N H 2 , C 1 –C 6 alkylamino, di-((C 1 –C 6 )alkyl)amino, —CF 3 , —OCF 3 and —S(O) 0-2 (C 1 –C 6 )alkyl;
R 12 is H or C 1 –C 6 alkyl; and
R 13 is (C 1 –C 6 )alkyl-C(O)— or (C 1 –C 6 )alkyl-S 2 —; comprising converting a compound of formula IX
into the desired compound of formula II by dehydrative rearrangement.
3. A process for preparing a compound of formula IIIa
wherein R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or C 4 –C 6 cycloalkenyl;
R 1 is 1 to 3 substituents independently selected from hydrogen, C 1 –C 6 -alkyl, —CF 3 , halogen, —NO 2 , —NR 12 R 13 , C 1 –C 6 alkoxy, C 1 –C 6 alkylthio, C 1 –C 6 alkylsulfinyl, and C 1 –C 6 alkylsulfonyl;
R 10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 –C 6 alkyl, hydroxy, C 1 –C 6 alkoxy, —ON, —NH 2 , C 1 –C 6 alkylamino, di-((C 1 –C 6 )alkyl)amino, —CF 3 , —OCF 3 and —S(O) 0-2 (C 1 –C 6 )alkyl;
R 12 is H or C 1 –C 6 alkyl; and
R 13 is (C 1 –C 6 )alkyl-C(O)— or (C 1 –C 6 )alkyl-SO 2 —; comprising
(1) treating a chloride of formula VIII
with a hydroxyalkyl hydrazine of the formula HO—(CH 2 ) r —NHNH 2 , wherein r is 2–6, to obtain
(2) cyclizing the intermediate of formula X by dehydrative rearrangement to obtain the tricyclic intermediate of formula XI
(3) converting the hydroxy compound of formula XI to the bromide of formula IIIa.