Compositions and methods to treat cardiac diseases
Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba(bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogues of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogues for treatment of heart failure has been expanded.
1. A method of treating a mammalian subject in need of treatment for a cardiac or vascular disease or condition responsive to activation of the cardiac and/or vascular P2X receptor, comprising administering an effective amount of a phosphonate or phosphinate N-methanocarba derivative of AMP, wherein the phosphonate or phosphinate N-methanocarba derivative of AMP, is
wherein
Q 1 is O or S;
R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, or N(R 6 ) 2 , wherein each R 6 is independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
R 2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkynyl, N(R 6 ) 2 , or halogen;
R 3 is hydrogen, optionally substituted alkyl, N(R 6 ) 2 , or halogen;
R 4 is hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted —Oaryl, or N(R 6 ) 2 ;
R 5 is hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted —Oaryl; or
alternatively, R 4 and R 5 form a 5- or 6-membered cyclic structure with the phosphorus atom where the cyclic structure contains at least two oxygen atoms attached to the phosphorous atom and at least 2 carbon atoms, wherein the carbon atom or atoms closest to the phosphorous atom are optionally substituted with alkyl or aryl; and
Y is a linking group linked to the phosphorus atom by a carbon atom;
or
wherein X is O or S; n is 1, 2, or 3; and R 7 is optionally substituted alkyl or optionally substituted aryl, and wherein variables R 1 -R 3 and Y are the same as above;
or
wherein Z is a bond or —O—C(═O)— where the carbonyl carbon is bonded to the oxygen of the bicycle group and the oxygen is bonded to the phosphorus atom, and wherein variables R 1 -R 3 and Y are the same as above;
or
wherein R 8 is optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl; and R 9 is methoxy, and wherein variables R 1 -R 3 , R 5 and Y are the same as above;
or
wherein G is O or S—S; and R 10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl, and wherein variables R 1 -R 3 and Y are the same as above; or
wherein R 11 is hydrogen, optionally substituted alkyl, or optionally substituted aryl, and wherein variables R 1 -R 3 and Y are the same as above; or
wherein
Q 1 is O or S;
Q 2 is O or S;
Y 1 is a linking group,
variables R 1 -R 5 are the same as above
with the proviso that when Q 1 and Q 2 are both O, and Formula (VII) is not enriched with deuterium, then R 4 and R 5 are not both hydroxyl,
a deuterium enriched isomer thereof, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP of claim 1 is Formula (I) or (VII).
3. The method of claim 1 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (I) wherein Q 1 is O; R 1 is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y is a linking group linked to the phosphorus atom by a carbon atom.
4. The method of claim 1 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (I) wherein Q 1 is O; R 1 is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y is a C 1 -C 6 alkylene.
5. The method of claim 1 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (VII) wherein Q 1 is O; Q 2 is S; R 1 is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y 1 is a C 1 -C 6 alkylene.
6. The method of claim 1 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (VII) wherein Q 1 is S; Q 2 is O; R 1 is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y 1 is a C 1 -C 6 alkylene.
7. The method of claim 1 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is
8. The method of claim 1 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is
9. A method of treating a mammalian subject in need of treatment for a cardic hypertrophy, systolic heart failure, ischemic cardiomyopathy, non-ischemic cardiomyopathy , or adverse cardiac remodeling following injury to the heart as a result of ischemia/reperfusion or non-ischemic causes comprising administering an effective amount of phosphonate or phosphinate N-methanocarba derivative of AMP, wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is
wherein
Q 1 is O or S;
R 1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, or N(R 6 ) 2 , wherein each R 6 is independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
R 2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkynyl, N(R 6 ) 2 , or halogen;
R 3 is hydrogen, optionally substituted alkyl, N(R 6 ) 2 , or halogen;
R 4 is hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted —Oaryl, or N(R 6 ) 2 ;
R 5 is hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted —Oaryl; or
alternatively, R 4 and R 5 form a 5- or 6-membered cyclic structure with the phosphorus atom where the cyclic structure contains at least two oxygen atoms attached to the phosphorous atom and at least 2 carbon atoms, wherein the carbon atom or atoms closest to the phosphorous atom are optionally substituted with alkyl or aryl; and
Y is a linking group linked to the phosphorus atom by a carbon atom;
or
wherein X is O or S; n is 1, 2, or 3; and R 7 is optionally substituted alkyl or optionally substituted aryl, and wherein variables R 1 -R 3 and Y are the same as above;
or
wherein Z is a bond or —O—C(═O)— where the carbonyl carbon is bonded to the oxygen of the bicycle group and the oxygen is bonded to the phosphorus atom, and wherein variables R 1 -R 3 and Y are the same as above;
or
wherein R 8 is optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl; and R 9 is methoxy, and wherein variables R 1 -R 3 , R 5 and Y are the sames as above;
or
wherein G is O or S—S; and R 10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl, and wherein variables R 1 -R 3 and Y are the same as above; or
wherein R 11 is hydrogen, optionally substituted alkyl, or optionally substituted aryl, and wherein variables R 1 -R 3 and Y are the same as above; or
wherein
Q 1 is O or S;
Q 2 is O or S;
Y 1 is a linking group,
variables R 1 -R 5 are the same as above, with the proviso that when Q 1 and Q 2 are both O, and Formula (VII) is not enriched with deuterium, then R 4 and R 5 are not both hydroxyl,
a deuterium enriched isomer thereof, or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP of claim 1 is Formula (I) or (VII).
11. The method of claim 9 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (I) wherein Q 1 is O; R l is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y is a linking group linked to the phosphorus atom by a carbon atom.
12. The method of claim 9 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (I) wherein Q 1 is O; R l is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y is a C 1 -C 6 alkylene.
13. The method of claim 9 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (VII) wherein Q 1 is O; Q 2 is S; R l is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y 1 is a C 1 -C 6 alkylene.
14. The method of claim 9 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is Formula (VII) wherein Q 1 is S; Q 2 is O; R l is N(R 6 ) 2 wherein each R 6 is hydrogen; R 2 is halogen; R 3 is hydrogen; R 4 is hydroxyl or optionally substituted alkoxy; R 5 is hydroxyl or optionally substituted alkoxy; and Y 1 is a C 1 -C 6 alkylene.
15. The method of claim 9 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is
16. The method of claim 9 , wherein the phosphonate or phosphinate N-methanocarba derivative of AMP is