Preparation and utility of hmg-coa reductase inhibitors
AssigneeAuspex Pharmaceuticals, Inc.
InventorsThomas G. Gant, Sepehr Sarshar
Life of this patent
Estimating the term…
Abstract
Chemical syntheses and medical uses of novel modulators of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and diastereomeric mixtures of isomers, individual diastereomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, the chemical synthesis thereof, and the medical use of such compounds for the treatment and/or management of hypercholesterolemia, dyslipidemia, coronary artery disease, atherosclerosis, metabolic syndrome, a hyperproliferative disease such as colorectal cancer, prostate cancer, and melanoma, a neurodegenerative disease such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease are described.
Claims22
A compound of Formula 1
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R8, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2(−), and Y is selected from the group consisting of —OH, and —OD;
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and
- provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
A compound selected from the group consisting of:
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof.
A method of treating a mammal suffering from a disease or condition in which it is beneficial to inhibit HMG CoA reductase, comprising administering to said mammal a therapeutically effective amount of a compound of Formula 1 so as to affect decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;
- wherein said compound of Formula 1 has the structure
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R8, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2(−), and Y is selected from the group consisting of —OH, and —OD;
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and
- provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
A method of treating a mammal suffering from a disease or condition in which it is beneficial to inhibit HMG CoA reductase, comprising administering to said mammal a therapeutically effective amount of a compound of Formula 1 so as to affect increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;
- wherein said compound of Formula 1 has the structure
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R8, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2″, and Y is selected from the group consisting of —OH, and —OD;
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
A method of treating a mammal suffering from a disease or condition in which it is beneficial to inhibit HMG CoA reductase, comprising administering a therapeutically effective amount of a compound of Formula 1 so as to affect decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound, wherein said compound of Formula 1 has the structure
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R8, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2(−), and Y is selected from the group consisting of —OH, and —OD;
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and
- provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
A method of treating a mammal suffering from a disease or condition in which it is beneficial to inhibit HMG CoA reductase, comprising administering a therapeutically effective amount of a compound of Formula 1 so as to affect a decreased metabolism by at least one polymorphically-expressed cytochrome P450 isoform in mammalian subjects per dosage unit thereof as compared to the non-isotopically enriched compound,
- wherein said compound of Formula 1 has the structure
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R8, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X otherwise, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2(−), and Y is selected from the group consisting of —OH, and —OD;
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and
- provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
A method of treating a mammal suffering from a disease or condition in which it is beneficial to inhibit HMG CoA reductase, comprising administering a therapeutically effective amount of a compound of Formula 1 so as to affect a decreased inhibition of at least one cytochrome P450 isoform in mammalian subjects per dosage unit thereof as compared to the non-isotopically enriched compound,
- wherein said compound of Formula 1 has the structure
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R5, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2(−), and Y is selected from the group consisting of —OH, and —OD;
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and
- provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
A method of treating a mammal suffering from a disease or condition in which it is beneficial to inhibit HMG CoA reductase, comprising administering a therapeutically effective amount of a compound of Formula 1 so as to elicit an improved clinical effect during the treatment in said mammal per dosage unit thereof as compared to the non-isotopically enriched compound,
- wherein said compound of Formula 1 has the structure
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R8, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2(−), and Y is selected from the group consisting of —OH, and —OD;
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and
- provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
A method of treating a mammal suffering from a disease or condition in which it is beneficial to inhibit by HMG CoA reductase, comprising administering to said mammal a therapeutically effective amount of a compound of Formula 1 wherein said compound of Formula 1 has the structure
- or a diastereomeric mixture of isomers, an individual diastereomer, a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein:
- R1, R4, R9, and R15 are independently selected from the group consisting of —CH3, —CH2D, —CHD2, and —CD3;
- R2, R3, R6, R7, R8, R10, R11, R12, R13, R14, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 and R27 are independently selected from the group consisting of hydrogen, and deuterium;
- R5 is selected from the group consisting of hydrogen, deuterium, —CH3, —CH2D, —CHD2, and —CD3;
- the dashed line between X and Y is a single bond or absent;
- when the dashed line is a single bond, X is C═O and Y is oxygen;
- when the dashed line is absent, X is selected from the group consisting of —CO2H, and —CO2D, and —CO2″, and Y is selected from the group consisting of —OH, and —OD.
- provided that compounds of Formula 1 contain at least one deuterium atom;
- and
- provided that deuterium enrichment in compounds of Formula 1 is at least about 1%.
Dependencies are inferred from the claim text.