IP Library › Patent Application 13587275

Patent Application

App. No. 13/587,275

SELECTIVE ANTAGONISTS OF A2A ADENOSINE RECEPTORS

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Patent No.: US None
App. No.: 13/587,275

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Abstract

The present invention provides compounds of formulae Ia and Ib: wherein R 1-5 , Q, X, Y, Z, p, q, and r are as defined herein. The compounds are potent and selective antagonists of A 2A adenosine receptors (ARs). The invention further includes pharmaceutical compositions containing these compounds and methods of using the same.

Claims (98)

1 - 17 . (canceled)

18 . A therapeutic method for preventing or treating a pathological condition or symptom in a mammal, wherein the activity of adenosine A2A receptors is implicated and antagonisim of its action is desired comprising administering to the mammal an effective amount of a compound of formula Ia or Ib or stereoisomer or a pharmaceutically acceptable salt thereof:

wherein:

the (CH 2 ) portions of (CH 2 ) n and (CH 2 ) q are independently substituted with 0-2 groups selected from OH, ═O, C 1-4 alkyl, C 3-6 cycloalkyl, and benzyl;

Q is O or S;

X is CH or N;

Y is selected from the group consisting of O, NY 1 , OCH 2 CH 2 OCH 2 , OCH 2 CH 2 OCH 2 CH 2 OCH 2 , OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 , NY 1 CH 2 CH 2 OCH 2 , NY 1 CH 2 CH 2 OCH 2 CH 2 OCH 2 , and NY 1 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 ;

alternatively, Y is a bond;

Y 1 is selected from the group consisting of H, C 1-4 alkyl, benzyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-4 alkylene;

Z is selected from the group consisting of aryl and heteroaryl, wherein Z is attached via a carbon atom and is substituted with 1-4 Z 1 groups;

Z 1 is independently selected from the group consisting of F, Cl, Br, I, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , and OCF 3 ;

R a is independently selected from the group consisting of H, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 8 cycloalkyl, (C 3 - 8 cycloalkyl)C 1 - 8 alkylene, aryl, (aryl)C 1 - 8 alkylene, heteroaryl, and (heteroaryl)C 1 - 8 alkylene, wherein the alkyl and cycloalkyl optionally are interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NR c —;

R 1 is independently selected from the group consisting of II, C 1 - 8 alkyl, C 3 - 8 cycloalkyl, (C 3 - 8 cycloalkyl)C 1 - 8 alkylene, aryl, (aryl)C 1 - 8 alkylene, heteroaryl, (heteroaryl)C 1 - 8 alkylene, (aryl)(aryl)-C 1 - 8 alkylene, (heteroaryl)(heteroaryl)-C 1 - 8 alkylene, and (aryl)(heteroaryl)C 1-8 alkylene, wherein the alkyl and cycloalkyl optionally may be interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NR c —, and the groups of R 1 are substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , and OCF 3 ;

R 2 is selected from the group consisting of H, C 1-6 alkyl, OR a , N(R a ) 2 , C 3-8 cycloalkyl, aryl, heterocycle, and heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl optionally are substituted with 1-2 groups independently selected from the group consisting of F, Cl, I, Br, CH 3 , CF 3 , and CH 3 O;

R 3 is a bond or is C 1-8 alkylene, wherein the alkylene group optionally is interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NH—;

R 3 is unsubstituted or is substituted with 1-2 groups selected from the group consisting of F, Cl, Br, I, —OR d , —SR d , —N(R d ) 2 , C 3-6 cycloalkyl, (C 3-6 cycloalkyl)C 1-4 alkylene, aryl, (aryl)C 1 - 4 alkylene, heteroaryl, and (heteroaryl)C 1 - 4 alkylene, wherein the alkyl and cycloalkyl optionally are interrupted by 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 —; and —NR c —;

R 4 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 - 12 cycloalkyl, (C 3-12 cycloalkyl)C 1 - 8 alkylene, aryl, (aryl)C 1 - 8 alkylene, heteroaryl, (heteroaryl)C 1 - 8 alkylene, CF 3 , —CO 2 R b , R b C(O)—, (R b ) 2 NC(O)—, R b OC(S)—, R b C(S)—, and R b S(═O)—, wherein the alkyl and cycloalkyl optionally are interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NH—, and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl are unsubstituted or are substituted with 1-4 groups independently selected from the group consisting of F, Cl, Br, I, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , OCF 3 , and —OS(O 2 )R a ;

alternatively, when R 3 is present, R 4 is additionally selected from the group consisting of H, F, Cl, Br, I, N(R b ) 2 , OR b , SR b , —CN, NO 2 , CF 3 O, R b C(O)O—, —OCO 2 R b , (R b ) 2 NC(O)O—, R b OC(O)NR b —, R b C(O)NR b —, (R b ) 2 NC(O)NR b —, and (R b ) 2 NC(S)NR b —;

provided that when R 2 is H and R 3 is a bond, then R 4 is other than

wherein:

(a) “*” is the point of attachment;

(b) R z is —CH 2 OR, —CO 2 R, —OC(O)R, —CH 2 OC(O)R, —CH 2 SR, —C(S)OR, —CH 2 OC(S)R, —CH 2 NRR, —C(S)NRR, and, —C(O)NRR; and,

R b is independently selected from the group consisting of H, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 8 cycloalkyl, (C 3 - 8 cycloalkyl)C 1 - 8 alkylene, aryl, (aryl)C 1 - 8 alkylene, heteroaryl, and (heteroaryl)C 1 - 8 alkylene, wherein the alkyl and cycloalkyl optionally are interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NH— and wherein the alkyl, cycloalkyl, aryl, and heteroaryl are substituted with 0-4 substituents selected from the group consisting of F, Cl, Br, I, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , and OCF 3 ;

R c is independently selected from the group consisting of H, C 1 - 6 alkyl, and benzyl;

R d is independently selected from the group consisting of H, C 1 - 6 alkyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)C 1-4 alkylene, phenyl, and benzyl;

R 5 is independently selected from the group consisting of H, F, Cl, Br, I, —OR c , —N(R c ) 2 , C 1 - 6 alkyl, C 3-6 cycloalkyl, aryl, and (aryl)C 1 - 4 alkylene, wherein the alkyl and cycloalkyl optionally are interrupted by 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 —, and —NR—;

R 6 is selected from the group consisting of CH 2 CH 2 , CH═CH, and C≡C;

a is independently selected from the group consisting of 0, 1, and 2;

n is independently selected from the group consisting of 0, 1, and 2;

p is independently selected from the group consisting of 0, 1, and 2;

q is independently selected from the group consisting of 0, 1, and 2; and,

r is independently selected from the group consisting of 0, 1, and 2.

19 . A method for treating a movement disorder comprising administering to a subject suffering from a movement disorder with unwanted or excessive activity of the adenosine A2A receptor, a therapeutically effective amount of a compound of formula Ia or Ib or stereoisomer or a pharmaceutically acceptable salt thereof:

wherein:

the (CH 2 ) portions of (CH 2 ) n and (CH 2 ) q are independently substituted with 0-2 groups selected from OH, ═O, C 1-4 alkyl, C 3-6 cycloalkyl, and benzyl;

Q is O or S;

X is CH or N;

Y is selected from the group consisting of O, NY 1 , OCH 2 CH 2 OCH 2 , OCH 2 CH 2 OCH 2 CH 2 OCH 2 , OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 , NY I CH 2 CH 2 OCH 2 , NY 1 CH 2 CH 2 OCH 2 CH 2 OCH 2 , and NY 1 CH 2 C H 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 ;

alternatively, Y is a bond;

Y 1 is selected from the group consisting of H, C 1-4 alkyl, benzyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-4 alkylene;

Z is selected from the group consisting of aryl and heteroaryl, wherein Z is attached via a carbon atom and is substituted with 1-4 Z 1 groups;

R 1 is independently selected from the group consisting of H, C 1 - 8 alkyl, C 3 - 8 cycloalkyl, (C 3 - 8 cycloalkyl)C 1 - 8 alkylene, aryl, (aryl)C 1 - 8 alkylene, heteroaryl, (heteroaryl)C 1 - 8 alkylene, (aryl)(aryl)-C 1 - 8 alkylene, (heteroaryl)(heteroaryl)-C 1 - 8 alkylene, and (aryl)(heteroaryl)C 1-8 alkylene, wherein the alkyl and cycloalkyl optionally may be interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NR c —, and the groups of R 1 are substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , and OCF 3 ;

R 3 is a bond or is C 1-8 alkylene, wherein the alkylene group optionally is interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NH—;

R 4 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 - 12 cycloalkyl, (C 3-12 cycloalkyl)C 1 - 8 alkylene, aryl, (aryl)C 1 - 8 alkylene, heteroaryl, (heteroaryl)C 1 - 8 alkylene, CF 3 , —CO 2 R b , R b C(O)—, (R b ) 2 NC(O)—, R b OC(S)—, R b C(S)—, and R b S(═O)—, wherein the alkyl and cycloalkyl optionally are interrupted with 1-2 heteroatoms selected from the group consisting of —O—, —S(O) 0-2 — and —NH—, and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl are usubstituted or are substituted with 1-4 groups independently selected from the group consisting of F, Cl, Br, I, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) a OR a , —(CH 2 ) a NR a R a , —(CH 2 ) a NHOH, —(CH 2 ) a NR a NR a R a , —(CH 2 ) a NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R a , —(CH 2 ) a C(O)R a , —(CH 2 ) a OC(O)R a , —(CH 2 ) a CONR a R a , CF 3 , OCF 3 , and —OS(O 2 )R a ;