US2002037872A1PendingUtilityA1
N6 heterocyclic 5' modified adenosine derivatives
Est. expiryDec 3, 2019(expired)· nominal 20-yr term from priority
A61P 9/00A61P 25/00C07H 19/16
46
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Claims
Abstract
N 6 heterocyclic 5′ modified adenosine derivatives that are adenosine A 1 receptor partial or full agonists, and as such, are useful for modifying cardiac activity, modifying adipocyte function, treating central nervous system disorders, and treating diabetic disorders and obesity in mammals, and especially in humans.
Claims
exact text as granted — not AI-modifiedWhat we claim is:
1 . A composition of matter having the formula:
wherein X 1 ═O, S, NR 6 ; Y═O, S, N—CN, N—OR 7 ; Z═O, S, NR 8 ;
R 1 is a monocyclic or polycyclic heterocyclic group containing from 3 to 15 carbon atoms wherein at least one carbon atom is substituted with an atom or molecule selected from the group consisting of N, O, P and S—(O) 0-2 and wherein R 1 does not contain an epoxide group;
R 2 is selected from the group consisting of hydrogen, halo, CF 3 , and cyano;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are independently selected from the group consisting of C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 and each optional heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , aLkyl, CF 3 , amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NR 22 COR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;
R 5 is selected from the group consisting of C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2 and each optional alkyl, heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NR 20 COR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R20) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;
R 6 is selected from the group consisting of H, C 1-6 alkyl and aryl optionally substituted with halo, CN, CF 3 , OR 20 and N(R 20 ) 2 ,;
R 7 and R 8 are independently selected from the group consisting of H, and C 1 -C 15 alkyl optionally substituted with one aryl substituent that is optionally substituted with halo or CF 3 ;
R 20 is selected from the group consisting of H, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C 1-6 alkyl, CF 3 , aryl, and heteroaryl; and
R 22 is selected from the group consisting of hydrogen, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C 1-6 alkyl, CF 3 , aryl, and heteroaryl wherein when Z═NR 8 then R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; wherein when X 1 ═NR 6 and when Z═NR 8 , then R 6 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; and wherein when X 1 ═N 6 and Y═O or S, then R 5 and R 6 may bond to form a 5 or a 6 membered saturated or unsaturated ring.
2 . The composition of claim 1 wherein Y═O, S;
R 2 is selected from hydrogen, and halo;
R 3 and R 4 are independently selected from the group consisting of hydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are independently selected from the group consisting of C 1-15 alkyl, heterocyclyl, aryl, and heteroaryl, which alkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 and each optional heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di- alkylamino, CN, or OR 20 ;
R 5 is selected from the group consisting of C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group of halo, alkyl, heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(R) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , and each optional alkyl, heteroaryl, and aryl substituent is optionally substituted with halo, alkyl CF 3 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;
R 20 is a member selected from the group consisting of H, C1-15 alkyl, aryl, and heteroaryl, which alkyl, aryl, and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from halo, alkyl, aryl, mono- or dialkylamino, CN, O—C 1-6 alkyl, CF 3 ; and
R 22 is a member selected from the group consisting of hydrogen, C 1-15 alkyl, aryl, and heteroaryl, which alkyl, aryl, and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from halo, aLkyl, mono- or dialkylarino, aLkyl or CN, O—C 1-6 alkyl, and CF 3 wherein when Z═NR 8 then R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; wherein when X 1 ═NR 6 and when Z═NR 8 , then R 6 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; and wherein when X 1 ═NR 6 and Y═O or S, then R 5 and R 6 may bond to form a 5 or a 6 membered saturated or unsaturated ring.
3 . The composition of claim 1 wherein Y═O, S;
R 2 is selected from the group consisting of hydrogen, and halo;
R 3 and R 4 are independently selected from the group consisting of hydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are each independently selected from the group consisting of C 1-10 alkyl, aryl, and heteroaryl, which alkyl, aryl, and heteroaryl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, NO 2 , aryl, heteroaryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , NR 20 COR 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , and each optional heteroaryl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 ;
R 5 is selected from the group consisting of C 1-15 alkyl, C 2-15 alkenyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , NR 20 COR 22 , NR 22 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 CO 2 R 20 , CON(R 20 ) 2 , and each optional alkyl, heteroaryl, and aryl substituent is optionally substituted with halo, alky, CF 3 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , S(O) 3 R20, P(O)(OR 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;
R 6 is selected from the group consisting of H, C 1-6 allyl optionally substituted with CF 3 , and OR 20 ;
R 8 is independently selected from the group consisting of H, and C 1 -C 8 alkyl optionally substituted with one aryl substituent that is optionally substituted with halo or CF 3 ;
R 20 is a member selected from the group consisting of H, C 1-6 alkyl, and aryl, which alkyl, and aryl, are optionally substituted with 1 substituent independently selected from halo, alkyl, aryl, mono- or dialkylamino, CN, O—C 1-6 alkyl, CF 3 ; and
R 22 is a member selected from the group consisting of hydrogen, C 1-6 alkyl and aryl, which alkyl and aryl are optionally substituted with 1 substituent independently selected from halo, alkyl, mono- or dialkylamino, alkyl or CN, O—C 1-6 alkyl, and CF 3 wherein when Z═NR 8 then R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; wherein when X 1 ═NR 6 and when Z═NR 8 , then R 6 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; and wherein when X 1 ═NR 6 and Y═O or S, then R 5 and R 6 may bond to form a 5 or a 6 membered saturated or unsaturated ring.
4 . The composition of claim 1 wherein Y═O, S;
R 2 is selected from the group consisting of hydrogen, and halo;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, and —(CO)—R′and —(CO)—R″ wherein R′, and R″ are independently selected from the group consisting of C 1-6 alkyl, and aryl, which alkyl and aryl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, NO 2 , aryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , NR 20 COR 22 , and each optional aryl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 ;
R 5 is selected from the group consisting of C 1-15 alkyl, C 2-15 alkenyl, aryl, and heteroaryl, which alkyl, alkenyl, aryl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional alkyl, heteroaryl, and aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , CON(R 20 ) 2 , S(O) 3 R 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;
R 6 is selected from the group consisting of H, C 1-4 alkyl;
R 8 is independently selected from the group consisting of H, and C 1 -C 8 alkyl;
R 20 is a member selected from the group consisting of H, C 1-6 alkyl, and aryl, which alkyl and aryl are optionally substituted with 1 substituent independently selected from halo, alkyl, aryl, mono- or dialkylamino, CN, O—C 1-6 alkyl, CF 3 ; and
R 22 is a member selected from the group consisting of hydrogen, C 1-6 alkyl and aryl, which alkyl and aryl are optionally substituted with 1 substituent independently selected from halo, alkyl or CN, O—C 1-6 alkyl, and CF 3 wherein when Z═NR 8 then R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; wherein when X 1 ═NR 6 and when Z═NR 8 , then R 6 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; and wherein when X 1 ═NR 6 and Y═O or S, then Rs and R 6 may bond to form a 5 or a 6 membered saturated or unsaturated ring.
5 . The composition of claim 1 wherein Y═O, S;
R 2 is selected from the group consisting of hydrogen, and halo;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are each independently selected from the group consisting of C 1-6 alkyl which alkyl is optionally substituted with 1 substituent selected from the group consisting of aryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , and wherein each optional aryl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 ;
R 5 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and aryl, which alkyl, alkenyl, and aryl, is optionally substituted with from 1 to 2 substituents independently selected from the group of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O)R 20 , NR 20 COR 22 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional alkyl and aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , S(O) 3 R 20 , CN, or OR 20 ;
R 6 is selected from the group consisting of H, C 1-3 alkyl;
R 8 is independently selected from the group consisting of H, and C 1 -C 3 alkyl;
R 20 is selected from the group consisting of H, C 1-6 alkyl, which alkyl is optionally substituted with aryl; and
R 22 is a member selected from the group consisting of hydrogen and C 1-6 wherein when Z═NR 8 then R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated or Air unsaturated ring; wherein when X 1 ═NR 6 and when Z═NR 8 , then R 6 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring; and wherein when X 1 ═NR 6 and Y═O or S, then R 5 and R 6 may bond to form a 5 or a 6 membered saturated or unsaturated ring.
6 . The composition of claims 1 or 2 or 3 or 4 wherein X 1 ═O; Y═O, S; Z═NR 8 ; and R 2 is selected from the group consisting of hydrogen, and halo.
7 . The composition of claims 1 or 2 or 3 or 4 wherein X 1 ═NR 6 ; Y═O, S; Z═O; and R 2 is selected from the group consisting of hydrogen, and halo.
8 . The composition of claims 1 or 2 or 3 or 4 wherein X 1 ═S; Y═O or S; Z═NR 8 ; and R 2 is selected from the group consisting of hydrogen, and halo.
9 . The composition of claims 1 or 2 or 3 or 4 wherein X 1 ═NR 6 ; Y═O or S; Z═NR 8 ; and R 2 is selected from the group consisting of hydrogen, and halo.
10 . The composition of claim 5 wherein X 1 ═O; Y═O or S; and Z═N 8 .
11 . The composition of claim 10 wherein R 3 and R 4 are each independently selected
from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are each independently selected from the group consisting of C 1-6 alkyl;
R 5 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and aryl, which alkyl, alkenyl, and aryl, are each optionally substituted with from 1 to 2 substituents independently selected from the group of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , NR 20 COR 22 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and each optional alkyl, and aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , S(O) 3 R 20 , CN, or OR 20 ; and
R 8 is independently selected from the group consisting of H., and C 1 -C 3 alkyl and wherein R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated ring.
12 . The composition of claim 11 wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′, and R″ are each independently selected from the group consisting of methyl, isopropyl, or cyclopentyl;
R 5 is selected from the group consisting of C 1-8 alkyl, and C 2-8 alkenyl, which alkyl and alkenyl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, aLkyl, ayl, CF 3 , CN, OR 20 , S(O) 3 R 20 , CO 2 R 20 , and wherein each optional alkyl, and aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , S(O) 3 R 20 , CN, or OR 20 ; and
R 8 is selected from the group consisting of H, and C 1 -C 3 alkyl and wherein R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated ring.
13 . The composition of claim 11 wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′, and R″ are each methyl;
R 5 is selected from the group consisting of C 1-8 alkyl, and C 2-8 alkenyl, which alkyl, and alkenyl are optionally substituted with from 1 to 2 substituents independently selected from the group of alkyl, aryl, OR 20 , CO 2 R 20 , and wherein each optional alkyl and aryl substituent are optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , or OR 20 ;
R 8 is selected from the group consisting of H, and C 1 -C 3 alkyl; and
R 20 is a selected from the group consisting of H, C 1-6 alkyl, which alkyl is optionally substituted with aryl, wherein RW and R 8 may bond to form a 4 or 5 or 6 membered saturated ring.
14 . The composition of claim 11 wherein R 3 and R 4 are each hydrogen;
R 5 is selected from the group consisting of C 1-8 alkyl, and C 2-8 alkenyl, which alkyl and alkenyl are optionally substituted with from 1 to 2 substituents independently selected from the group of alkyl, aryl, OR 20 , CO 2 R 20 , and wherein each optional alkyl and aryl substituent is optionally substituted with halo, or CO 2 R 20 ;
R 8 is selected from the group consisting of H, and C 1 -C 3 alkyl; and
R 20 is a member selected from the group consisting of H, and C 1-3 alkyl, which alkyl is optionally substituted with aryl wherein R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated ring.
15 . The composition of claim 11 wherein R 3 and R 4 are each hydrogen;
R 5 is selected from the group consisting of C 1-8 alkyl, and C 2-8 alkenyl, which alkyl, and alkenyl, are optionally substituted with from 1 to 2 substituents independently selected from the group of aryl, OR 20 , C 2 R 20 , and wherein each optional aryl substituent is optionally substituted with halo;
R 8 is independently selected from the group consisting of H, and C 1 -C 3 alkyl; and
R 20 is selected from the group consisting of H, and methyl wherein R 5 and R 8 may bond to form a 4 or 5 or 6 membered saturated ring.
16 . The composition of claims 6 or 10 or 11 or 12 or 13 or 14 wherein R 2 ═H.
17 . The composition of claim 15 wherein R 2 ═H.
18 . The composition of claim 17 wherein Y═O; R 8 is H; and R 5 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopentyl, benzyl, (4 fluorophenylmethyl), isopropyl, cyclopropyl, cyclohexyl, allyl, 2-carboethoxyethyl, carbomethoxymethyl, 2-phenylcyclopropyl, cyclobutyl, 2-benzyloxycyclopentyl, 2-hydroxycyclopentyl, 2-carbomethoxycyclopentyl, 2-(3-carboethoxy-norborn-5-enyl), 2-(3-carboxy-norborn-5-enyl), 2-(3-carboethoxy-norbornyl), and 2-carboxycyclopentyl.
19 . The composition of claim 17 wherein Y═S; R 5 is methyl, and R 8 is methyl.
20 . The composition of claim 17 wherein Z═NR 8 and R 5 and R 8 bond to form a 5 or 6 membered saturated rings.
21 . The composition of claim 17 wherein Y═S; R 8 is H; and R 5 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopentyl, benzyl, isopropyl, cyclopropyl, cyclohexyl, allyl, cyclobutyl, 2-benzyloxycyclopentyl, 2-hydroxycyclopentyl.
22 . The composition of claim 5 wherein X 1 ═NR 6 ; Y═O or S; Z═O; and R 2 is H.
23 . The composition of claim 22 wherein R 3 and R 4 are independently selected from the group consisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′, and R″ are each methyl;
R 5 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and aryl, which alkyl, alkenyl, and aryl, are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , NR 20 COR 22 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional allyl, and aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , S(O) 3 R 20 , CN, or OR 20 ; and
R 6 is selected from the group consisting of H, and C 1 -C 3 alkyl wherein when X 1 ═NR 6 then R 5 and R 6 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring.
24 . The composition of claim 22 wherein R 3 and R 4 are hydrogen;
R 5 is C 1-8 alkyl, which alkyl is optionally substituted with 1 substituent independently selected from the group consisting of aryl, OR 20 ,CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 ; and
R 6 is independently selected from the group consisting of H, and C 1 -C 3 alkyl wherein when X 1 ═NR 6 then R 5 and R 6 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring.
25 . The composition of claim 22 wherein R 3 and R 4 are each hydrogen; R 5 is a C 1-8 alkyl; and
R 6 is selected from the group consisting of H, and C 1 -C 3 alkyl wherein when=NR 6 then R 5 and R 6 may form a 4 or 5 or 6 membered saturated or unsaturated ring.
26 . The composition of claim 25 wherein R 5 is methyl or cyclopentyl and R 6 ═H.
26 . The composition of claim 25 wherein X 1 ═NR 6 , Y═O, and R 5 and R 6 bond to form a S membered unsaturated ring wherein R 5 and R 6 together form CH═CH.
28 . The composition of claim 5 wherein X 1 ═S; Y═O or S; Z═NR 8 ; and R 2 is H.
29 . The composition of claim 28 wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″, wherein R′ and R″ are each methyl;
R 5 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and aryl, which alkyl, alkenyl and aryl, are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , NR 20 COR 22 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional alkyl and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , S(O) 3 R 20 , CN, or OR 20 ; and
R 8 is selected from the group consisting of H, and C 1 -C 3 alkyl.
30 . The composition of claim 28 wherein R 3 and R 4 are each hydrogen;
R 5 is C 1-8 alkyl that is optionally substituted with 1 substituent selected from the group consisting of aryl, OR 20 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 ; and
R 8 is H.
31 . The composition of claim 28 wherein R 3 and R 4 are each hydrogen; R 5 is C 1-8 alkyl; and R 8 is H.
32 . The composition of claim 31 wherein R 5 is methyl or cyclopentyl.
33 . The composition of claim 5 wherein X 1 ═NR 6 ; Y═O or S; Z═NR 8 ; and R 2 is H.
34 . The composition of claim 33 wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are each methyl;
R 5 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and aryl, which alkyl, alkenyl, and aryl, are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , S(O) 3 R 20 , NR 20 COR 22 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional alkyl, and aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , S(O) 3 R 20 , CN, or OR 20 ;
R 6 is selected from the group consisting of H, and C 1 -C 3 alkyl; and
R 8 is selected from the group consisting of H, and C 1 -C 3 alkyl, wherein R 6 and R 8 may bond to form a 4 or 5 or 6 membered saturated or unsaturated ring.
35 . The composition of claim 33 wherein R 3 and R 4 are hydrogen;
R 5 is selected from the group consisting of C 1-8 alkyl, which alkyl is optionally substituted with 1 substituent independently selected from the group consisting of aryl, OR 20 , CO 2 R 20 , CON(R 20 ) 2 , and each optional aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 ; and
R 8 is H.
36 . The composition of claim 33 wherein R 3 and R 4 are each hydrogen; R 5 is C 1-8 alkyl; R 6 ═H; and R 8 is H.
37 . The composition of claim 36 wherein R 5 is methyl or cyclopentyl.
38 . The composition of claim 1 wherein R 1 is mono or polysubstituted with one or more compounds selected from the group consisting of halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof.
39 . The composition of claim 1 wherein R 1 is a monocyclic, bicyclic, or tricyclic cycloalkyl group containing from 3 to 15 carbon atoms wherein at least one carbon atom is substituted with an atom or molecule selected from the group consisting of O or S—(O) 0-2 .
40 . The composition of claim 39 wherein R 1 is mono or polysubstituted with one or more compounds selected from the group consisting of halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof.
41 . The composition of claim 1 wherein R 1 is:
wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are each individually selected from the group halogen, hydroxyl, lower alkyl, substituted lower allyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, and cyano, and X is O, or S(—O) 0-2 .
42 . The composition of claim 41 wherein R 1 ′″ and R 1 ″″ is a single oxygen atom.
43 . The composition of claim 42 wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are each individually selected from the group H, lower alkyl, substituted lower alkyl, alkoxy, aryl, and substituted aryl.
44 . The composition of claim 42 wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are each individually selected from the group hydrogen, lower alkyl, and substituted lower alkyl.
45 . The composition of claim 1 wherein R 1 is selected from the group consisting of:
wherein each R is individually selected from the group consisting of H, lower alkyl, and substituted lower alkyl and wherein X is O, or S(—O) 0-2 .
46 . The composition of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 wherein R 1 is selected from the group consisting of 3-tetrahydrofuranyl, 3-tetrahydrothiofiuranyl, 4-pyranyl, and 4 thiopyranyl.
47 . The composition of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 wherein R 1 is 3-tetrahydrofuranyl.
48 . The composition of claim 1 wherein the compound is selected from (5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-methylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-ethylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-propylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-butylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-benzylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(4-fluorophenyl)methyl]carboxamide; {(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclohexylcarboxamide; {(5-{6-[((3R)oxolan-3-yl)anmino]purin-9-yl}(3S,2R,4R,5R)-3,4-2“z 0 dihydroxyoxolan-2-yl)methoxy]-N-(methylethyl)carboxamide; {(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2-yl)methoxy]-N-cyclopropylcarboxamide; Methyl 2-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylate; Ethyl 3-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicylo[2.2.1]hept-5-ene-2-carboxylate; Ethyl 3-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicylo[2.2.1]heptane-2-carboxylate; {(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4 dihydroxyoxolan-2-yl)methoxy]-N-[(lR,2R)-2-(phenylmethoxy)cyclopentyl]carboxamide; {(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(1 S,2S)-2-(phenylmethoxy)cyclopentyl]carboxamide; (5-{6-[((3R)oxolan-3-yl)amino}purin-9-yl }(3 S ,2R,4R,5R)-3 , 4 -dihydroxyoxolan-2-yl)methoxy]-N-cyclobutylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino}purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-(2-phenylcyclopropyl)carboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S, 2R, 4R, 5R)- 3 , 4 -dihydroxyoxolan-2-yl)methoxy]-N-prop-2-enylcarboxamide; Ethyl 3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S, 2R,4R,5R)-3,4-dihydroxyoxolane-2-yl)methoxy}carbonylamino}propanoate; Methyl 2-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S, 2R,4R,5R)-3,4-dihydroxyoxolane-2-yl)methoxy}carbonylamino}acetate; {(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N,N-dimethylcarboxamide; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(methylamino)thioxomethoxy]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(ethylamino)thioxomethoxy]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,SR)-5-({[(methylethyl)amiiio]thioxomethoxy}methyl)oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(butylamino)thioxomethoxy]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amiino]purin-9-yl}(4S,2R,3R,5R)-5-{[(propylamino)thioxomethoxy]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}( 4 S, 2 R, 3 R,5R)-5-[(piperidylthioxomethoxy)methyl]oxolane-3,4-diol; 2-:2io {6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(cyclopentylamino)thioxomethoxy]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}( 4 S, 2 R, 3 R,SR)-5-[(pyrrolidinylthioxomethoxy)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(dimethylamino)thioxomethoxy]methyl}oxolane-3,4&iol; 2-{6-[((3R)oxolan-3-yl)amino]puin-9-yl}(4S,2R,3R,5R)-5-({[benzylamino]thioxomethoxy}methyl)oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R5-({[cyclohexylamino]thioxomethoxy}methyl)oxolane-3,4diol; 2-{6-[((3R)oxolan-3-yl)amfio]purin-9-yl}(4S,2R,3R,5R)-5-[({[(1 S,2S)-2-(phenylmethoxy)cyclopentyl]amino}thioxomethoxy)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-[({[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}thioxomethoxy)methyl]oxolane-3,4-diol; 2-{6-[((3)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(cyclobutylamino)thioxomethoxy]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,SR)-5-{[(cyclopropylamino)thioxomethoxy]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(prop-2-enylamino)thioxomethoxy]methyl}oxolane-3,4-diol; {(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3 ,4-dihydroxyoxolan-2-yl)methoxy]-N-((1 S,2S)-2-hydroxycyclopentyl)carboxamide; {(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3 ,4-dihydroxyoxolan-2-yl)methoxy]-N-((1 R,2R)-2-hydroxycyclopentyl)carboxamide; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[((1R,2R)-2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[((1S,2S)-2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane-3,4-diol; 2-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylic acid; 3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicyclo[2.2. 1 ]hept-5-ene-2-carboxylic acid; 3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3 ,4-dihydroxyoxolan-2-yl)methoxy]carbonylarnino}propanoic acid; 2-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}acetic acid, 5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2R,3R,4R,5R)-4-acetyloxy-2-[(N-methylcarbamoyloxy)methyl]oxolan-3-yl acetate; [(5-{6-[((3R)oxolan-3-yl)anmino]-2-chloropurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-methylcarboxamide, [(5-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide; N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl]methoxycarboxamide; N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methy]cyclopentyloxycarboxamide; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[methoxythioxomethyl)amino]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[cyclopentyloxythioxomethyl)amino]methyl}oxolane-3,4-diol; [(5-{6-[((3R)oxolan-3-yl)arnino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methythio]-N-methylcarboxamide; [(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methythio]-N-cyclopentylcarboxamide; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-{[(methylamino)thioxomethylthio]methyl}oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-{[(cyclopentylamino)thioxomethylthio]methyl}oxolane-3,4-diol; N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3 ,4-dihydroxyoxolan-2-yl)methyl](methylamino)carboxamide; N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](cyclopentylamino)carboxamide; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(methylamino)thioxomethyl]amino}methyl)oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(cyclopentylamino)thioxomethyl]amino}methyl)oxolane-3,4-diol; N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](ethylamino)carboxamide; and 3-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R)-3,4-dihydroxyoxolan-2-yl)methyl]-1 ,3-oxazolin-2-one.
49 . A method for modifying cardiac activity in a mammal experiencing a heart electrical disorder that can be treated by stimulating an A 1 adenosine receptor comprising the administration of a therapeutically effective amount of the composition of claim 1 to the mammal.
50 . A method for modifyg mammalian adipocyte function by stimulating an A 1 adenosine receptor comprising administering a therapeutically effective amount of the composition of claim 1 to the mammal.
51 . A method to restore sensitivity and efficacy of insulin in a mammal by stimulating an A 1 adenosine receptor comprising the administration of a therapeutically effective amount of a composition of claim 1 to the mammal.
52 . A method for providing a mammal with central nervous system neuroprotection by stimulating an A 1 adenosine receptor comprising administering a therapeutically effective amount of the composition of claim 1 to the mammal.
53 . A method for providing a mammal with cardiomyocyte protection from ischemia by stimulating an A 1 adenosine receptor comprising administering a therapeutically effective amount of the composition of claim 1 to the mammal.
54 . The method of claim 49 or 50 or 51 or 52 or 53 wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.
55 . The method of claim 49 wherein the composition is administered to the mammal experiencing a heart electrical disorder selected from the group consisting of supraventricular tachycardias, atrial fibrillation, atrial flutter, and AV nodal re-entrant tachycardia.
56 . The method of claim 50 or 51 wherein the composition is administered to a mammal experiencing a disorder selected from the group consisting of diabetes and obesity.
57 . The method of claim 52 wherein the composition is administered to a mammal experiencing an central nervous system disorder selected from the group consisting of epilepsy, and stroke.
58 . The method of claim 53 wherein the composition is administered to a mammal experiencing an ischemic event in the heart selected from the group consisting of stable angina, unstable angina, cardiac transplant, and myocardial infarction.
59 . The method of claim 49 or 50 or 51 or 52 or 53 wherein the mammal is a human.
60 . A pharmaceutical composition of matter comprising the composition of claim 1 and one or more pharmaceutical excipients.
61 . The pharmaceutical composition of matter of claim 60 wherein the pharmaceutical composition is in the form of a solution.
62 . The pharmaceutical composition of matter of claim 60 wherein the pharmaceutical composition is in the form of a tablet.Join the waitlist — get patent alerts
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