Oxadiazolo[3,2-a]pyrimidines and thiadiazolo[3,2-a]pyrimidines
The present invention relates to compounds of formula P-1 and related compounds and compositions useful for inhibiting and/or reducing platelet deposition, adhesion and/or aggregation. The definitions of A, Y, R 1 , R 2 , R a , R a′ , R b , R b′ , R c , R c′ , R d , R d′ , R e , and R e′ are provided herein. The present invention further relates to methods for the treatment or prophylaxis of thrombotic disorders, including stroke, myocardial infarction, unstable angina, peripheral vascular disease, abrupt closure following angioplasty or stent placement and thrombosis as a result of vascular surgery.
1. A compound of Formula P-I:
wherein:
i) A is S, N(H), CH 2 , or O;
ii) R 1 is:
phenyl optionally substituted with one or more nitro, —C(O)N(R 5 )(R 6 ) and/or —N(R 5 )(R 6 ) and Y is a —C 1 -C 4 alkylene (e.g., methylene) or arylene;
phenyl substituted with one or more nitro and/or —N(R 5 )(R 6 ) and Y is a single bond;
phenyl substituted with —C(O)OR 3 and Y is a —C 1 -C 4 alkylene or arylene;
heteroaryl wherein said heteroaryl group is optionally substituted with one or more —C 1 -C 4 alkyl and Y is a single bond, or —C 1 -C 4 alkylene;
heteroaryl wherein said heteroaryl group is substituted with halo, C(O)OH, —CH 2 C(O)OH, or —NH 2 , and Y is arylene;
pyrazolyl, isoxazolyl, furyl or thienyl and Y is arylene wherein said pyrazolyl, isoxazolyl, furyl or thienyl is optionally substituted with one or more —C 1 -C 4 alkyl, C 0-4 alkyl-C(O)OH, —N(R 13 )(R 14 ), or halo; or
—C(O)N(R 4 )(CH 2 ) 1-4 —C(O)OR 3 and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—C(O)N(R 4 )(CH 2 ) 1-4 —N(R 13 )(R 14 ) and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 4 )—C(O)-heteroaryl wherein said heteroaryl is optionally substituted with halo and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 4 )—C 1-4 alkylene-heteroaryl and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 10 )—C(O)—[C(R 11 )(R 12 )] 1-4 —N(R 13 )(R 14 ), and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 4 )(CH 2 ) 1-4 —C(O)OR 4 and Y is arylene;
—N(R 4 )C(O)C(H)(NH 2 )CH 2 CH 2 —C(O)OR 3 and Y is arylene;
—N(R 4 )C(O)C(H)(NH 2 )CH 2 -heteroaryl) and Y is arylene;
—N(R 4 )C(O)C(H)(CH 3 )—NH 2 and Y is arylene;
—N(R 4 )C(O)CH 2 CH 2 C(H)(NH 2 )—COOH and Y is arylene;
—N(R 4 )C(O)—C(H)(NH 2 )CH 2 CH 2 —COOH and Y is arylene; or
—N(R 4 )C(O)-heteroaryl (—N(H)C(O)isoxazolyl) and Y is arylene;
iii) R 2 is H, halo or C 1 -C 4 alkyl;
iv) R a , R a ′, R b , R b ′, R c , R d , R d ′, R e , and R e ′ are independently H or C 1 -C 4 alkyl;
V) R 3 , R 4 , R 5 and R 6 are independently H or C 1 -C 4 alkyl;
vi) R 10 , R 11 , R 12 R 13 and R 14 are independently H or C 1-4 alkyl, in free or salt form.
2. The compound according to claim 1 , wherein said compound is a compound of Formula Q-I:
wherein:
i) A is S, N(H), CH 2 , or O;
ii) R 1 is
phenyl optionally substituted with one or more nitro and/or —N(R 5 )(R 6 ) and Y is a —C 1 -C 4 alkylene or arylene;
phenyl substituted with one or more nitro and/or —N(R 5 )(R 6 ) and Y is a single bond;
phenyl substituted with —C(O)OR 3 and Y is a —C 1 -C 4 alkylene or arylene;
heteroaryl wherein said heteroaryl group is optionally substituted with one or more —C 1 -C 4 alkyl and Y is a single bond, —C 1 -C 4 alkylene;
pyrazolyl, isoxazolyl, furyl or thienyl and Y is arylene wherein said pyrazolyl, isoxazolyl, furyl or thienyl is optionally substituted with one or more —C 1 -C 4 alkyl, C 0-4 alkyl-C(O)OH, —N(R 13 )(R 14 ), or halo; or
—C(O)N(R 4 )(CH 2 ) 1-4 —C(O)OR 3 and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—C(O)N(R 4 )(CH 2 ) 1-4 —N(R 13 )(R 14 ) and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 4 )—C(O)-heteroaryl wherein said heteroaryl is optionally substituted with halo and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 4 )—C 1-4 alkylene-heteroaryl and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 10 )—C(O)—C(R 11 )(R 12 )—N(R 13 )(R 14 ) and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 10 )—C(O)—C 3-10 heterocycloalkyl and Y is a single bond, —C 1 -C 4 alkylene or arylene;
—N(R 4 )(CH 2 ) 1-4 —C(O)OR 4 and Y is arylene;
—N(R 4 )C(O)C(H)(NH 2 )CH 2 CH 2 —C(O)OR 3 and Y is arylene;
—N(R 4 )C(O)C(H)(NH 2 )CH 2 -heteroaryl and Y is arylene;
—N(R 4 )C(O)C(H)(CH 3 )—NH 2 and Y is arylene;
—N(R 4 )C(O)CH 2 CH 2 C(H)(NH 2 )—COOH and Y is arylene;
—N(R 4 )C(O)—C(H)(NH 2 )CH 2 CH 2 —COOH and Y is arylene;
—N(R 4 )C(O)-heteroaryl (—N(H)C(O)isoxazolyl) and Y is arylene;
iii) R 2 is H, halo or C 1 -C 4 alkyl;
iv) R a , R b , R b ′, R c , R d , R d ′, R e , and R e ′ are independently H or C 1 -C 4 alkyl;
v) R 3 , R 4 , R 5 and R 6 are independently H or C 1 -C 4 alkyl;
vi) R 10 , R 11 , R 12 R 13 and R 14 are independently H or C 1-4 alkyl,
in free or salt form.
3. The compound according to claim 1 , wherein said compound is:
wherein
R 1 is —N(R 10 )—C(O)—C(R 11 )(R 12 )—N(R 13 )(R 14 );
R 2 is H or halo;
R a , R a ′, R b , R b ′, R c , R d , R d ′, R e , and R e ′ are independently H or C 1 -C 4 alkyl;
R 10 , R 11 , R 12 R 13 and R 14 are independently H or C 1-4 alkyl;
in free or salt form.
4. The compound according to claim 1 , wherein the compound is a compound selected from any of the following:
in free or salt form.
5. The compound according to claim 1 , wherein said compound is:
in free or salt form.
6. A pharmaceutical composition comprising a compound according to claim 1 , in combination or association with a pharmaceutically acceptable diluent or carrier.