| 摘要 |
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. |
| 主权项 |
1. A method of improving cardiac contractile performance or cardiac function in a mammal in need thereof, 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
Q1 is O or S;R1 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, or N(R6)2, wherein each R6 is independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;R2 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkynyl, N(R6)2, or halogen;R3 is hydrogen, optionally substituted alkyl, N(R6)2, or halogen;R4 is hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted —Oaryl, or N(R6)2;R5 is hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted —Oaryl; or
alternatively, R4 and R5 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; andY 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 R7 is optionally substituted alkyl or optionally substituted aryl, and wherein variables R1-R3 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 R1-R3 and Y are the same as above;or wherein R8 is optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl; and R9 is methoxy, and wherein variables R1-R3, R5 and Y are the same as above; or wherein G is O or S—S; and R10 is hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl, and wherein variables R1-R3 and Y are the same as above; or wherein R11 is hydrogen, optionally substituted alkyl, or optionally substituted aryl, and wherein variables R1-R3 and Y are the same as above; or wherein
Q1 is O or S;Q2 is O or S;Y1 is a linking group,variables R1-R5 are the same as abovewith the proviso that when Q1 and Q2 are both O, and Formula (VII) is not enriched with deuterium, then R4 and R5 are not both hydroxyl,a deuterium enriched isomer thereof, or a pharmaceutically acceptable salt thereof. |
