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US 2008/0318901 A1Published application
Novel Lysophosphatidic Acid Receptor Selective Antagonists
AssigneeUniversity of Virginia Patent Foundation
InventorsKevin R. Lynch, Timothy L. Macdonald, Brian H. Heasley
Life of this patent
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Abstract
The present invention is directed to compositions comprising lysophosphatidic acid analogs and methods of using such analogs as agonist or antagonists of LPA receptor activity. In addition the invention is directed to LPA receptor agonists that vary in the degree of selectivity at individual LPA receptors (i.e. LPA1, LPA2 and LPA3). More particularly the present invention is directed to LPA analogs wherein the glycerol is replaced with ethanolamine and a variety of substitutions have been linked at the second carbon atom.
Claims35
A compound represented by the formula:
- wherein R1 is selected from the group consisting of C8-C22 alkyl, C8-C22 alkenyl, C8-C22 alkanoyl, C8-C22 alkenoyl,
- wherein m is 0-20;
- Z is selected from the group consisting of C3-C10 cycloalkyl, C3-C15 bicycloalkyl, C5-C10 heterocyclic and aryl;
- R11 is selected from the group consisting of C1-C10 alkyl, C1-C20 alkoxyl, C1-C20 alkylthio, and C1-C20 alkylamino;
- R2 and R3 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)OH, —(C1-C4 alkyl)NH2, —COOR5, —(C1-C4 alkyl)COOR5, —(C1-C10 alkyl)aryl, C3-C8 cycloalkyl, C3-C8 heterocyclic, C7-C12 bicyclic, (C5-C8 alkyl)aryl, (C5-C8 alkenyl)aryl, (C5-C8 alkynyl)aryl, and
- wherein n is 0-10;
- R5 is selected from the group consisting of H and C1-C4 alkyl;
- R12 is selected from the group consisting of halo, C1-C10 alkyl, (C0-C12 alkyl)aryl, (C2-C12 alkenyl)aryl, (C2-C12 alkynyl)aryl, —(C1-C4 alkyl)OH, —(C2-C12 alkenyl)OH, SR6, SOR6, NHR6 and OR6;
- R13 is selected from the group consisting of H, halo, C1-C10 alkyl, (C0-C12 alkyl)aryl, (C2-C12 alkenyl)aryl, (C2-C12 alkynyl)aryl, —(C1-C4 alkyl)OH, —C2-C12 alkenyl)OH, SR6, SOR6, NHR6 and OR6;
- wherein R6 is selected from the group consisting of C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, —(C1-C4 alkyl)R7, —(C2-C4 alkenyl)R7, —(C1-C4 carboxy)R7 and —(C2-C4 alkynyl)R7;
- and
- R7 is selected from the group consisting of optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclic, optionally substituted C7-C12 bicyclic and optionally substituted C5-C8 cycloalkenyl and optionally substituted aryl;
- y is 0-4;
- and
- R4 is represented by the formula
- wherein R12 is selected from the group consisting of O, NH and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH CO2H, CHF, CF2, and
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- and pharmaceutically acceptable salts thereof.
17 more elements
A compound represented by the formula:
- wherein R1 is selected from the group consisting of C8-C22 alkyl, C8-C22 alkenyl;
- R2 is selected from the group consisting of C1-C3 alkyl —(C2-C4 alkyl)OH, —(C1-C4 alkyl)NH2, —(C1-C4 alkyl)COOR5, —(C1-C4 alkyl)aryl, and
- R4 is represented by the formula
- wherein R12 is selected from the group consisting of O, NH and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH, CO2H, CHF, CF2, and
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- R5 is selected from the group consisting of H and C1-C4 alkyl;
- and
- R6 is selected from the group consisting of C3-C16 alkyl, C3-C16 alkenyl, and —(C1-C4 alkyl)R7;
- R7 is selected from the group consisting of C3-C8 cycloalkyl, C3-C8 heterocyclic, C7-C12 bicyclic, C5-C8 cycloalkenyl and aryl;
- and
- y is 0-4 and pharmaceutically acceptable salts thereof.
10 more elements
An LPA receptor agonist represented by the formula:
- wherein R1 is selected from the group consisting of C8-C22 alkyl, C8-C22 alkenyl;
- R2 is selected from the group consisting of C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —(C2-C4 alkyl)OH, —(C1-C4 alkyl)NH2, —(C1-C4 alkyl)COOR5 and aryl;
- y is 0 or 1;
- R4 is represented by the formula
- wherein R12 is selected from the group consisting of O, NH and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH, CO2H, CHF, CF2, and
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- and R5 is selected from the group consisting of H and C1-C4 alkyl and pharmaceutically acceptable salts thereof.
6 more elements
An LPA receptor antagonist represented by the formula:
- wherein R1 is selected from the group consisting of C8-C22 alkyl and C8-C22 alkenyl;
- R2 is selected from the group consisting of H, C1-C4 alkyl;
- y is 0 or 1;
- R4 is represented by the formula
- wherein R12 is selected from the group consisting of O, NH and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH, CO2H, CHF, CF2, and
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- and
- R7 is selected from the group consisting of C3-C8 cycloalkyl, C3-C8 heterocyclic, C7-C12 bicyclic, C5-C8 cycloalkenyl and aryl and pharmaceutically acceptable salts thereof.
7 more elements
A lyso-lipid phosphate phosphatase resistant LPA analog, said agonist represented by the formula
- wherein R1 is selected from the group consisting of C8-C22 alkyl, C8-C22 alkenyl, C8-C22 alkanoyl, C8-C22 alkenoyl,
- wherein m is 0-20;
- Z is selected from the group consisting of C3-C10 cycloalkyl, C3-C15 bicycloalkyl, C5-C10 heterocyclic and aryl;
- R11 is selected from the group consisting of C1-C10 alkyl, C1-C20 alkoxyl, C1-C20 alkylthio, and C1-C20 alkylamino;
- R2 and R3 are independently selected from the group consisting of H, hydroxy, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)OH, —(C1-C4 alkyl)NH2, —COOR5, —(C1-C4 alkyl)COOR5, —(C1-C4 alkyl)aryl, C3-C8 cycloalkyl, C3-C8 heterocyclic, C7-C12 bicyclic, (C5-C10 alkyl)aryl, (C5-C8 alkenyl)aryl, (C5-C8 alkynyl)aryl, and
- wherein n is 0-10;
- R5 is selected from the group consisting of H and C1-C4 alkyl;
- R12 is selected from the group consisting of halo, C1-C10 alkyl, (C0-C12 alkyl)aryl, (C2-C12 alkenyl)aryl, (C2-C12 alkynyl)aryl, —(C1-C4 alkyl)OH, —(C2-C12 alkenyl)OH, SR6, SOR6, NHR6 and OR6;
- R13 is selected from the group consisting of H, halo, C1-C10 alkyl, (C0-C12 alkyl)aryl, (C2-C12 alkenyl)aryl, (C2-C12 alkynyl)aryl, —(C1-C4 alkyl)OH, —(C2-C12 alkenyl)OH, SR6, SOR6, NHR6 and OR6;
- wherein R6 is selected from the group consisting of C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, —(C1-C4 alkyl)R7, —(C2-C4 alkenyl)R7, —(C1-C4 carboxy)R7 and —(C2-C4 alkynyl)R7;
- and
- R7 is selected from the group consisting of optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclic, optionally substituted C7-C12 bicyclic, optionally substituted C5-C8 cycloalkenyl and optionally substituted aryl;
- q is 0-4;
- R8 and R9 are independently selected from H, hydroxyl, amino, COOH, halo, —PO3;
- or R8 and R9 taken together form a keto group or a methylene group;
- R10 is selected from the group consisting of O, S and NH;
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- and pharmaceutically acceptable salts thereof.
16 more elements
A lyso-lipid phosphate phosphatase resistant LPA analog, said agonist represented by the formula
- wherein R1 is selected from the group consisting of C8-C22 alkyl and C8-C22 alkenyl;
- R2 and R3 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)OH, —(C1-C4 alkyl)NH2, —COOR5, —(C1-C4 alkyl)COOR5, and
- R5 is selected from the group consisting of H and C1-C4 alkyl;
- and
- R6 is selected from the group consisting of C3-C16 alkyl, C3-C16 alkenyl, —(C1-C4 alkyl)R7;
- R7 is selected from the group consisting of C3-C8 cycloalkyl, C3-C8 heterocyclic, C7-C12 bicyclic and C5-C8 aryl;
- R8 and R9 are independently selected from the group consisting of H, C1-C4 alkyl, and —PO3, or R8 and R9 are combined to form a keto group;
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- and pharmaceutically acceptable salts thereof.
7 more elements
A lyso-lipid phosphate phosphatase resistant LPA receptor agonist represented by the formula:
- wherein R1 is selected from the group consisting of C8-C22 alkyl and C8-C22 alkenyl;
- R2 is selected from the group consisting of H, hydroxyl, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)OH, —(C1-C4 alkyl)NH2, —COOR5, —(C1-C4 alkyl)COOR5, and benzyl;
- and
- R9 is selected from the group consisting of H, C1-C4 alkyl, halo and —PO3;
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- and pharmaceutically acceptable salts thereof.
4 more elements
A method of enhancing wound repair, said method comprising the steps of
- contacting the wound with a composition comprising a compound represented by the formula:
- wherein R1 is selected from the group consisting of C8-C22 alkyl and C8-C22 alkenyl;
- R2 is selected from the group consisting of C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —(C2-C4 alkyl)OH, —C1-C4 alkyl)NH2, —(C1-C4 alkyl)COOR5 and benzyl;
- y is 0 or 1;
- R4 is represented by the formula
- wherein R12 is selected from the group consisting of O, NH and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH, CO2H, CHF, CF2, and
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- and R5 is selected from the group consisting of H and C1-C4 alkyl.
7 more elements
A method of treating a disease characterized by cell hyper proliferation, said method comprising the step of administering to a patient a composition comprising a compound represented by the formula
- wherein R1 is selected from the group consisting of C8-C22 alkyl and C8-C22 alkenyl;
- y is 0 or 1;
- R4 is represented by the formula
- wherein R12 is selected from the group consisting of O and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH, CO2H, CHF, CF2, and
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- R6 is selected from the group consisting of C3-C16 alkyl, C3-C16 alkenyl, —(C1-C4 alkyl)R7;
- and
- R7 is selected from the group consisting of C3-C8 cycloalkyl, C3-C8 heterocyclic, C7-C12 bicyclic, C5-C8 cycloalkenyl and aryl, with the proviso that R2 and R3 are not both H.
7 more elements
A method of treating reperfusion type injury, said method comprising the step of administering to a patient a composition comprising a compound represented by the formula
- wherein R1 is selected from the group consisting of C8-C22 alkyl and C8-C22 alkenyl;
- y is 0 or 1;
- R4 is represented by the formula
- wherein R12 is selected from the group consisting of O, NH and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH, CO2H, CHF, CF2, and
- and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
- R6 is selected from the group consisting of C3-C16 alkyl, C3-C16 alkenyl, —(C1-C4 alkyl)R7;
- and
- R7 is selected from the group consisting of C3-C8 cycloalkyl, C3-C8 heterocyclic, C7-C12 bicyclic, C5-C8 cycloalkenyl and aryl, with the proviso that R2 and R3 are not both H.
7 more elements
A method of inhibiting LPP activity, said method comprising the step of administering a compound represented by the formula
- wherein R1 is selected from the group consisting of C8-C22 alkyl and C8-C22 alkenyl;
- R2 and R3 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, —(C1-C4 alkyl)OH, —(C1-C4 alkyl)NH2, —COOR5, and —(C1-C4 alkyl)COOR5;
- R5 is selected from the group consisting of H and C1-C4 allyl;
- and
- R8 and R9 are independently selected from the group consisting of H, halo, C1-C4 alkyl, and —PO3, or R8 and R9 are combined to form a keto group and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy,
3 more elements
A compound of the general structure
- wherein R1 is selected from the group consisting of C8-C22 alkyl, C8-C22 alkenyl, and —(CH2)m-Z-R11;
- wherein m is 0-20;
- Z is selected from the group consisting of C4-C8 cycloalkyl, C5-C8 heterocyclic and C5-C8 aryl;
- R11 is selected from the group consisting of C1-C10 alkyl, C1-C20 alkoxyl, C1-C20 alkylthio, and C1-C20 alkylamino;
- R4 is selected from the group consisting of hydroxy, and
- wherein R32 is selected from the group consisting of O, NH and S;
- X is selected from the group consisting of O, NH, S, CH2, CHOH, CHF, CF2, and
- R30 and R31 are independently selected from the group consisting of C1-C2 alkoxy, hydroxy,
- is a heterocyclic substituent selected from the group consisting of
- wherein L, M, and Q are selected from the group consisting of N, NR15, O, S, CHR15 and CR15R16;
- R13, R14, R15 and R16 are independently selected from the group consisting of H, halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 alkoxy;
- and
- pharmaceutically acceptable salts thereof.
10 more elements
Dependencies are inferred from the claim text.