Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D
View Patent ↗The compounds are of the class thienoisoxazolyl- and thienylpyrrazolyl-phenoxy substituted propyl derivatives, useful as D 4 antagonists. Said compounds are useful for the treatment of medical conditions mediated by inhibition of D 4 receptor. These conditions comprise, for example, Attention Deficit Hyperactivity Disorder, Obsessive-Compulsive Disorder, Psychoses, Substance Abuse, Substance Dependence, Parkinson's Disease, Parkinsonism, Tardive Diskinesia, Gilles de la Tourette Syndrome, Conduct Disorder, and Oppositional Defiant Disorder. A further aspect of the invention is to provide a pharmaceutical composition, intermediates, and a method of making said class of compounds.
1. A compound of Formula I:
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
X is N(CH 3 ) or O;
R 1 is OH or C 1-6 alkoxy;
R 2 is H or C 1-6 alkyl;
R 3 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl or furanyl and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O)H 2 NH 2 , trifluormethyl, or cyano, and
n is 1 or 2; and
R 4 is H or C 1-6 alkyl.
2. A compound according to claim 1 wherein
Q is thienyl.
3. The compound according to claim 2 which is (2R)-2-methyl-1-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[thienophen-2-ylmethyl)-amino-propan-2-ol.
4. The compound according to claim 2 which is (2S)-1-(2-thienylmethylamino)-2-methyl-3-[3-thieno[2,3-d]isoxazol-3-yl-phenoxy]propan-2-ol.
5. The compound according to claim 2 which is (2S)-1-(3-thienylmethylamino)-2-methyl-3-[3-thieno[2,3-d]isoxazol-3-yl-phenoxy]propan-2-ol.
6. A compound according to claim 2 wherein
R 1 is OH;
R 2 is H;
R 3 is (CH 2 ) n Q; and
n is 1.
7. A compound according to claim 6 wherein Q is thienyl.
8. The compound according to claim 7 which is (2R)-1-(4-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-3-ylmethyl)-amino]-propan-2-ol.
9. The compound of claim 7 which is (2R)-1-(4-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-2-ylmethyl)-amino]-propan-2-ol.
10. The compound of claim 7 which is (2R)-1-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-2-ylmethyl)amino]propan-2-ol.
11. The compound of claim 7 which is (2R)-1-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-3-[(thiophen-3-ylmethyl)amino]propan-2-ol.
12. A compound according to claim 1 wherein Q is furanyl.
13. The compound of claim 12 which is (2R)-1-[(furan-2-ylmethyl)-amino]-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propan-2-ol.
14. The compound of claim 12 which is (2R)-1-[(furan-2-ylmethyl)amino]-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propan-2-ol.
15. The compound of claim 12 which is (2R)-1-[(furan-2-ylmethyl)-amino]-3-(4-thieno[2,3-d]isoxazol-3-yl-phenoxy)propan-2-ol.
16. The compound of claim 12 which is (2S)-1-[(furan-2-ylmethyl)amino]-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)propan-2-ol.
17. A compound according to claim 1 wherein R 3 is indanyl.
18. The compound of claim 17 which is (2R)-1-(indan-1-ylamino)-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propan-2-ol.
19. The compound of claim 17 which is (2R)-1-(indan-2-ylamino)-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propan-2-ol.
20. A compound according to claim 1 , wherein R 3 is adamantyl.
21. The compound of claim 20 which is (2R)-1-(adamantan-1-ylamino)-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propan-2-ol.
22. A compound according to claim 1 , wherein R 3 is 1,2,3,4-tetrahydronaphthyl.
23. The compound of claim 22 which is (2R)-1-(1,2,3,4-tetrahydronaphthalen-1-ylamino)-3-[3-thieno[2,3-d]isoxazol-3-yl)phenoxy]propan-2-ol.
24. A composition comprising a compound according to claim 1 in admixture with an inert carrier.
25. The composition according to claim 24 wherein said inert carrier is a pharmaceutical carrier.
26. A method of making a compound of formula I
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
X is N(CH 3 ) or O;
R 1 is OH or C 1-6 alkoxy;
R 2 is H or C 1-6 alkyl;
R 3 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl or furanyl, and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2; and
R 4 is H or C 1-6 alkyl;
comprising the step of coupling a reagent of formula II
wherein X and R 2 are as defined in formula I;
with a reagent of formula III
wherein R 3 and R 4 are as defined in formula I;
to provide the compound of formula I.
27. A method of making a compound of formula I
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
X is N(CH 3 ) or O;
R 1 is OH or C 1-6 alkoxy;
R 2 is H or C 1-6 alkyl;
R 3 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl or furanyl, and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2; and
R 4 is H or C 1-6 alkyl;
comprising the step of coupling a compound of formula II
wherein X and R 2 are as defined in formula I; and
R 5 is CH 3 , CF 3 , F, p-bromobenzene, p-nitrobenzene, or p-methylbenzene;
with a reagent of formula m
wherein R 3 and R 4 are as defined in formula I;
to provide the compound of formula I.
28. A method of making a compound of formula I
a pharmaceutically acceptable salt or stereoisomer thereof,
wherein
X is N(CH 3 ) or O;
R 1 is OH or C 1-6 alkoxy;
R 2 is H or C 1-6 alkyl;
R 3 is (CH 2 ) n Q, CH 2 CH(OH)Q, CH(CH 3 )Q, 1,2,3,4-tetrahydronaphthyl, indanyl, or adamantyl, wherein
Q is thienyl or furanyl, and
Q is optionally substituted with one or two moieties independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, S(O) 2 NH 2 , trifluoromethyl, or cyano, and
n is 1 or 2; and
R 4 is H or C 1-6 alkyl;
comprising the step of coupling a reagent of formula II
wherein X is as defined in formula I;
with a reagent of formula III
wherein R 2 , R 3 , and R 4 are as defined in formula I;
to provide the compound of formula I.