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US 2011/0257130 A1Published application
Compositions and Methods for Treatment of Renin-Angiotensin Aldosterone System (RAAS)- Related Disorders
OwnerDesikan Rajagopalinventor
Life of this patent
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Abstract
Compounds are provided which can be useful in reducing the activity of an angiotensin-converting enzyme and thus be used to treat or prevent a renin-angiotensin aldosterone system-related disorder. These compounds include lipoic acid derivatives such as prolyl lipoic acid and pipecolinyl lipoic acid, and other compounds, and these compounds are useful in treating hypertension, stroke, or other renin-angiotensin aldosterone system-related disorders in human or animal patients. Pharmaceutical compositions prepared using these compounds and methods of treatment using these compounds are also provided.
Claims40
A compound having the Formula (I):
- wherein:
- R1 is selected from the group consisting of
- R2 completes a 5- or 6-membered non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of CH3 and H;
- or a pharmaceutically acceptable salt or solvate thereof.
3 more elements
A compound having the Formula (X):
- wherein:
- R1 is selected from the group consisting of:
- R2 completes a five- or six-membered non-aromatic heterocyclic ring structure optionally containing a hydroxyl substituent, or an eight- or ten-membered bicyclic aromatic or non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of:
- or a pharmaceutically acceptable salt or solvate thereof.
3 more elements
A compound having the Formula (XI):
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- (CH2)2CH3, (CH2)3NH2, (CH2)3OH, (CH2)4COOH,
- and
- R3 is selected from the group consisting of:
- or a pharmaceutically acceptable salt or solvate thereof.
4 more elements
A compound having the Formula (XII):
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- and
- R3 is selected from the group consisting of:
- or a pharmaceutically acceptable salt of solvate thereof.
3 more elements
A compound having the Formula XIII:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- COOH,
- and CH2OCH3;
- and
- R3 is selected from the group consisting of:
- H, CH3, and COCH3;
- or a pharmaceutically acceptable salt or solvate thereof.
6 more elements
A compound having the Formula XIV:
- wherein R1 is selected from the group consisting of OH, NO2, NH2, and OCH3;
- or
- a pharmaceutically acceptable salt or solvate thereof.
A compound having the Formula XV:
- or a pharmaceutically acceptable salt or solvate thereof.
A compound having the Formula XVI:
- or a pharmaceutically acceptable salt or solvate thereof.
A compound having the Formula XVII:
- wherein R1 is selected from the group consisting of OH, NO2, OCH3, and NH2;
- or
- a pharmaceutically acceptable salt or solvate thereof.
A compound having the Formula (XVIII):
- wherein R1 is an optional ring that can be selected from the group consisting of a cyclopentyl ring, a cyclohexyl ring, a phenyl ring, and a substituted phenyl ring where the substituents on the phenyl ring are selected from the group consisting of OH, OCH3, NH2, NO2, COOH;
- wherein R2 is selected from the group consisting of a free carboxyl, methyl or ethyl ester, a primary alcohol, and a primary amine group;
- wherein n is an integer from 1 to 3, and the nitrogen-containing ring is a substituted or unsubstituted ring selected from the group consisting of a pyrrolidine ring, a piperidine ring, and a saturated azepine ring;
- wherein R3 is an alkyl group that includes from 1 to 3 carbon atoms, and which can include one or more conjugated or unconjugated double bonds;
- and
- wherein R4 is a substituted or unsubstituted 5- or 6-membered disulphide moiety or a 5- or 6-membered dithiol moiety selected from the group consisting of
3 more elements
A method of reducing angiotensin converting enzyme activity, comprising contacting an angiotensin converting enzyme with an effective amount of a compound selected from the group consisting of the following Formulas (I) and (X)-(XVIII), or pharmaceutically acceptable salts or solvates thereof:
- wherein:
- R1 is selected from the group consisting of
- R2 completes a 5- or 6-membered non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of CH3 and H;
- wherein:
- R1 is selected from the group consisting of:
- R2 completes a five- or six-membered non-aromatic heterocyclic ring structure optionally containing a hydroxyl substituent, or an eight- or ten-membered bicyclic aromatic or non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- and;
- R2 is selected from the group consisting of:
- (CH2)2CH3, (CH2)3NH2, (CH2)3OH, (CH2)4COOH,
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- COOH,
- and CH2OCH3;
- and
- R3 is selected from the group consisting of:
- H, CH3, and COCH3;
- wherein R1 is selected from the group consisting of OH, NO2, NH2, and OCH3;
- wherein R1 is selected from the group consisting of OH, NO2, OCH3, and NH2;
- and
- wherein R1 is an optional ring that can be selected from the group consisting of a cyclopentyl ring, a cyclohexyl ring, a phenyl ring, and a substituted phenyl ring where the substituents on the phenyl ring are selected from the group consisting of OH, OCH3, NH2, NO2, COOH;
- wherein R2 is selected from the group consisting of a free carboxyl, methyl or ethyl ester, a primary alcohol, and a primary amine group;
- wherein n is an integer from 1 to 3, and the nitrogen-containing ring is a substituted or unsubstituted ring selected from the group consisting of a pyrrolidine ring, a piperidine ring, and a saturated azepine ring;
- wherein R3 is an alkyl group that includes from 1 to 3 carbon atoms, and which can include one or more conjugated or unconjugated double bonds;
- and
- wherein R4 is a substituted or unsubstituted 5- or 6-membered disulphide moiety or a 5- or 6-membered dithiol moiety selected from the group consisting of
36 more elements
A method of treating a renin-angiotensin aldosterone system-related disorder, comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of the following Formulas (I) and (X)-(XVIII), or pharmaceutically acceptable salts or solvates thereof:
- wherein:
- R1 is selected from the group consisting of
- R2 completes a 5- or 6-membered non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of CH3 and H;
- wherein:
- R1 is selected from the group consisting of:
- R2 completes a five- or six-membered non-aromatic heterocyclic ring structure optionally containing a hydroxyl substituent, or an eight- or ten-membered bicyclic aromatic or non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of:
- COOH, CH2OH,
- wherein:
- R1 is selected from the group consisting of:
- and;
- R2 is selected from the group consisting of:
- (CH2)2CH3, (CH2)3NH2, (CH2)3OH, (CH2)4COOH,
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- COOH,
- and CH2OCH3;
- and
- R3 is selected from the group consisting of:
- H, CH3, and COCH3;
- wherein R1 is selected from the group consisting of OH, NO2, NH2, and OCH3;
- wherein R1 is selected from the group consisting of OH, NO2, OCH3, and NH2;
- and
- wherein R1 is an optional ring that can be selected from the group consisting of a cyclopentyl ring, a cyclohexyl ring, a phenyl ring, and a substituted phenyl ring where the substituents on the phenyl ring are selected from the group consisting of OH, OCH3, NH2, NO2, COOH;
- wherein R2 is selected from the group consisting of a free carboxyl, methyl or ethyl ester, a primary alcohol, and a primary amine group;
- wherein n is an integer from 1 to 3, and the nitrogen-containing ring is a substituted or unsubstituted ring selected from the group consisting of a pyrrolidine ring, a piperidine ring, and a saturated azepine ring;
- wherein R3 is an alkyl group that includes from 1 to 3 carbon atoms, and which can include one or more conjugated or unconjugated double bonds;
- and
- wherein R4 is a substituted or unsubstituted 5- or 6-membered disulphide moiety or a 5- or 6-membered dithiol moiety selected from the group consisting of
37 more elements
A method of reducing hypertension comprising contacting an angiotensin converting enzyme with an effective amount of a compound selected from the group consisting of the following Formulas (I) and (X)-(XVIII), or pharmaceutically acceptable salts or solvates thereof:
- wherein:
- R1 is selected from the group consisting of
- R2 completes a 5- or 6-membered non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of CH3 and H;
- wherein:
- R1 is selected from the group consisting of:
- R2 completes a five- or six-membered non-aromatic heterocyclic ring structure optionally containing a hydroxyl substituent, or an eight- or ten-membered bicyclic aromatic or non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of:
- COOH, CH2OH,
- wherein:
- R1 is selected from the group consisting of:
- and;
- R2 is selected from the group consisting of:
- (CH2)2CH3, (CH2)3NH2, (CH2)3OH, (CH2)4COOH,
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- H,
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- COOH,
- and CH2OCH3;
- and
- R3 is selected from the group consisting of:
- H, CH3, and COCH3;
- wherein R1 is selected from the group consisting of OH, NO2, NH2, and OCH3;
- wherein R1 is selected from the group consisting of OH, NO2, OCH3, and NH2;
- and
- wherein R1 is an optional ring that can be selected from the group consisting of a cyclopentyl ring, a cyclohexyl ring, a phenyl ring, and a substituted phenyl ring where the substituents on the phenyl ring are selected from the group consisting of OH, OCH3, NH2, NO2, COOH;
- wherein R2 is selected from the group consisting of a free carboxyl, methyl or ethyl ester, a primary alcohol, and a primary amine group;
- wherein n is an integer from 1 to 3, and the nitrogen-containing ring is a substituted or unsubstituted ring selected from the group consisting of a pyrrolidine ring, a piperidine ring, and a saturated azepine ring;
- wherein R3 is an alkyl group that includes from 1 to 3 carbon atoms, and which can include one or more conjugated or unconjugated double bonds;
- and
- wherein R4 is a substituted or unsubstituted 5- or 6-membered disulphide moiety or a 5- or 6-membered dithiol moiety selected from the group consisting of
38 more elements
A method of treating stroke comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of the following Formulas (I) and (X)-(XVIII), or pharmaceutically acceptable salts or solvates thereof:
- wherein:
- R1 is selected from the group consisting of
- R2 completes a 5- or 6-membered non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of CH3 and H;
- wherein:
- R1 is selected from the group consisting of:
- R2 completes a five- or six-membered non-aromatic heterocyclic ring structure optionally containing a hydroxyl substituent, or an eight- or ten-membered bicyclic aromatic or non-aromatic heterocyclic ring structure;
- and
- R3 is selected from the group consisting of:
- COOH, CH2OH,
- or a pharmaceutically acceptable salt or solvate thereof;
- wherein:
- R1 is selected from the group consisting of:
- and;
- R2 is selected from the group consisting of:
- (CH2)2CH3, (CH2)3NH2, (CH2)3OH, (CH2)4COOH,
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- and
- R3 is selected from the group consisting of:
- wherein:
- R1 is selected from the group consisting of:
- R2 is selected from the group consisting of:
- COOH,
- and CH2OCH3;
- and
- R3 is selected from the group consisting of:
- H, CH3, and COCH3;
- wherein R1 is selected from the group consisting of OH, NO2, NH2, and OCH3;
- wherein R1 is selected from the group consisting of OH, NO2, OCH3, and NH2;
- and
- wherein R1 is an optional ring that can be selected from the group consisting of a cyclopentyl ring, a cyclohexyl ring, a phenyl ring, and a substituted phenyl ring where the substituents on the phenyl ring are selected from the group consisting of OH, OCH3, NH2, NO2, COOH, and CONHR, where R is methyl or ethyl;
- wherein R2 is selected from the group consisting of a free carboxyl, methyl or ethyl ester, a primary alcohol, and a primary amine group;
- wherein n is an integer from 1 to 3, and the nitrogen-containing ring is a substituted or unsubstituted ring selected from the group consisting of a pyrrolidine ring, a piperidine ring, and a saturated azepine ring;
- wherein R3 is an alkyl group that includes from 1 to 3 carbon atoms, and which can include one or more conjugated or unconjugated double bonds;
- and
- wherein R4 is a substituted or unsubstituted 5- or 6-membered disulphide moiety or a 5- or 6-membered dithiol moiety selected from the group consisting of
38 more elements
Dependencies are inferred from the claim text.