Substituted 2-amidotetralins as melatonin agonists and antagonists
AssigneeNorthwestern University
InventorsAlan S. Horn, deceased, Margarita L. Dubocovich
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Abstract
The present invention relates generally to compounds having melatonin receptor activities and in particular to substituted 2-amidotetralin derivatives; to pharmaceutical preparations comprising such compounds; and to methods for using these compounds as therapeutic and diagnostic reagents.
Claims7
A method for treatment of disorders associated with abnormal melatonin activity in an organism, said method comprising the step of administering a therapeutically effective amount of a composition comprising a compound of the formula:
- ##STR10## wherein:
- R.sub.1 is hydrogen, halogen, amino, amino, a C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl;
- R.sub.2 is hydrogen, hydroxyl, halogen, amino, amido, C.sub.6 aryl, mono- or di- C.sub.1-4 alkylamino, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-6 alkoxyl;
- R.sub.3 is hydrogen, aryl, C.sub.1-4 alkyl-C.sub.6 -aryl or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or C.sub.1-4 alkynl;
- R.sub.4 is C.sub.6 aryl, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, halo-C .sub.1-4 -alkyl or C.sub.3-6 cycloalkyl;
- R.sub.5 is hydrogen, hydroxyl, halogen, oxo, C.sub.6 aryl, C.sub.1-4 alkylaryl, or C.sub.1-4 alkyl;
- wherein aryl substituents of R.sub.2, R.sub.3, R.sub.4, and R.sub.5 may optionally be halogen, hydroxyl, amino, mono- or di-C.sub.1-4 alkyl or alkoxyl substituted.
In a method inhibiting melatonin function by administering a melatonin antagonist, the improvement comprising the step of administering an effective amount of a compound of the formula:
- ##STR11## wherein:
- R.sub.1 is hydrogen, halogen, amino, amido, a C.sub.1-4 alkyl, C.sub.1-6 alkoxyl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl;
- R.sub.2 is hydrogen, hydroxyl, halogen, amino, amino C.sub.6 aryl, mono- or di- C.sub.1-4 alkylamino, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxyl;
- R.sub.3 is hydrogen, C.sub.6 aryl, C.sub.1-4 alkylaryl or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or C.sub.2-4 alkynyl;
- R.sub.4 is C.sub.6 aryl, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, halo-C.sub.6 -alkyl, or cycloalkyl:
- R.sub.5 is hydrogen, hydroxyl, halogen, oxo, C.sub.6 aryl, C.sub.1-4 alkylaryl, or C.sub.1-4 alkyl or alkoxyl substituted.
In a method for mimicking melatonin function by administering a melatonin agonist, the improvement comprising the step of administering an effective amount of a compound of the formula:
- ##STR12## wherein:
- R.sub.1 is hydrogen, halogen, amino, amido, a C.sub.1-4 alkyl, C.sub.1-6 alkoxyl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl;
- R.sub.2 is hydrogen, hydroxyl, halogen, amino, amido, C.sub.6 aryl, mono- or di- C.sub.1-4 alkylamino, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-6 alkoxyl;
- R.sub.3 is hydrogen, aryl, C.sub.1-4 alkyl-C.sub.6 -aryl or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or C.sub.2-4 alkynyl,
- R.sub.4 is C.sub.6 aryl, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, halo-C.sub.6 -alkyl, or C.sub.3-6 cycloalkyl;
- R.sub.5 is hydrogen, hydroxyl, halogen, oxo, C.sub.6 aryl, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkyl;
- wherein aryl substituents of R.sub.2, R.sub.3, R.sub.4, and R.sub.5 may optionally be halogen, hydroxyl, amino, mono- or di-C.sub.1-4 alkylamino, or C.sub.1-4 alkyl or alkoxyl substituted.
A method for localizing melatonin receptors in a sample, said method comprising the steps of:
- incubating said sample with a compound of the formula:
- ##STR13## wherein:
- R.sub.1 is hydrogen, halogen, amino, amido, a C.sub.1-4 alkyl, C.sub.1-4 alkoxyl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl;
- R.sub.2 is hydrogen, hydroxyl, halogen, amino, amido, C.sub.6 aryl, mono- or di- C.sub.1-4 alkylamino, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkoxyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-6 alkoxyl;
- R.sub.3 is hydrogen, aryl, C.sub.1-4 alkyl-C.sub.6 -aryl or C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or C.sub.2-4 alkynyl;
- R.sub.4 is C.sub.6 aryl, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkyl, halo-C.sub.6 -alkyl, or C.sub.3-6 cycloalkyl;
- R.sub.5 is hydrogen, hydroxyl, halogen, oxo, C.sub.6 aryl, C.sub.1-4 alkyl-C.sub.6 -aryl, or C.sub.1-4 alkyl;
- wherein aryl substituents of R.sub.2, R.sub.3, R.sub.4, and R.sub.5 may optionally be halogen, hydroxyl, amino, mono- or di-C.sub.1-4 alkylamino, or C.sub.1-4 alkyl or alkoxyl substituted, and wherein said compound is labelled with a marker;
- detecting said marker;
- and
- localizing said melatonin receptors in said sample.
A method for treatment of disorders associated with abnormal melatonin activity in an organism, said method comprising the step of administering a therapeutically effective amount of a composition comprising a compound selected from the group consisting of:
- 8-methoxy-2-propionamido-tetralin;
- 2-chloroacetamido-tetralin;
- 8-methoxy-2-n-butyramido-tetralin;
- 8-methoxy-2-cyclopropanecarbonylamido-tetralin;
- 8-methoxy-2-chloroacetamido-tetralin;
- 4-phenyl-2-acetamido-tetralin;
- 4-phenyl-2-propionamido-tetralin;
- 4-benzyl-2-acetamidotetralin;
- 4-phenyl-2-chloroacetamido-tetralin;
- and
- 4-benzyl-2-propionamido-tetralin.
In a method for inhibiting melatonin function by administering a melatonin antagonist, the improvement comprising the step of administering an effective amount of a compound selected from the group consisting of:
- 4-phenyl-2-acetamido-tetralin;
- 4-phenyl-2-propionamido-tetralin;
- and
- 4-phenyl-2-chloroacetamido-tetralin.
In a method for mimicking melatonin function by administering a melatonin agonist, the improvement comprising the step of administering an effective amount of a compound selected from the group consisting of:
- 8-methoxy-2-propionamido-tetralin;
- 2-chloroacetamido-tetralin;
- 8-methoxy-2-n-butyramido-tetralin;
- 8-methoxy-2-cyclopropanecarbonylamido-tetralin;
- 8-methoxy-2-chloroacetamido-tetralin;
- 4-benzyl-2-acetamido-tetralin;
- and
- 4-benzyl-2-propionamido-tetralin.
Dependencies are inferred from the claim text.