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US 6,277,838 B1Granted
Methods for allosteric modulation of the GABA receptor by members of the androstane and pregnane series
AssigneeCoCensys, Inc.
InventorsRavindra B. Upasani, Haiji Xia, Derk Hogenkamp
Life of this patent
Estimating the term…
Abstract
Methods, compositions, and compounds for modulating the GABAA receptor-chloride ionophore complex to alleviate stress, anxiety, seizures, mood disorders, PMS and PND and to induce anesthesia.
Claims22
A method of treating or preventing stress or anxiety, treating or preventing mood disorders, alleviating or preventing seizure activity, insomnia, premenstrual syndrome or postnatal depression, or inducing anesthesia, comprising administering to said animal subject in need of such treatment an effective amount of a compound of Formula I:
- wherein:
- R is hydrogen, halogen, lower alkoxy, alkyl, optionally substituted 1-alkynyl or substituted alkyl;
- R1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, alkynyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, a substituted aralkynyl, arylalkyl, arylalkenyl, aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, optionally substituted heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl;
- R2 is hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a keto group or amino group;
- R3 is an optionally substituted heteroarylacetyl group;
- R4 is hydrogen or methyl,
- R5 is hydrogen;
- R6 is hydrogen, alkanoyl, aminocarbonyl or alkoxycarbonyl;
- R7 is hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a methylene group (together with R3), or an alkoxymethylene group (together with R3);
- R8 is hydrogen or halogen;
- R9 is hydrogen, halogen, alkyl, alkoxy, arylalkoxy or amino;
- and
- R10 is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, cyano, thiocyano or mercapto;
- or a physiologically acceptable 3-ester, 20-ester, 21-ester, 3,20-diester, or 3,21-diester thereof.
11 more elements
A method of inducing anesthesia in an animal subject in need of said inducing, comprising administering to said animal subject an effective amount of a compound of Formula I:
- wherein:
- R is hydrogen, halogen, lower alkoxy, alkyl, optionally substituted 1-alkynyl or substituted alkyl;
- R1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, alkynyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, a substituted aralkynyl, arylalkyl, arylalkenyl, aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroarylalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, optionally substituted heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl;
- R2 is hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a keto group or amino group;
- R3 is an optionally substituted heteroarylacetyl group;
- R4 is hydrogen or methyl,
- R5 is hydrogen;
- R6 is hydrogen, alkanoyl, aminocarbonyl or alkoxycarbonyl;
- R7 is hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a methylene group (together with R3), or an alkoxymethylene group (together with R3);
- R8 is hydrogen or halogen;
- R9 is hydrogen, halogen, alkyl, alkoxy, arylalkoxy or amino;
- and
- R10 is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, cyano, thiocyano or mercapto;
- or a physiologically acceptable 3-ester, 20-ester, 21-ester, 3,20-diester, or 3,21-diester thereof.
11 more elements
A method of modulating the GABA receptor-chloride ionophore complex in an animal subject in need of said modulating through binding to the neurosteroid site on said complex, comprising administering to said animal subject an amount, effective to modulate said complex, of a compound of Formula I:
- wherein:
- R is hydrogen, halogen, lower alkoxy, alkyl, optionally substituted 1-alkynyl or substituted alkyl;
- R1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, alkynyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, a substituted aralkynyl, arylalkyl, arylalkenyl, aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, optionally substituted heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl;
- R2 is hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a keto group or amino group;
- R3 is an optionally substituted heteroarylacetyl group;
- R4 is hydrogen or methyl,
- R5 is hydrogen;
- R6 is hydrogen, alkanoyl, aminocarbonyl or alkoxycarbonyl;
- R7 is hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a methylene group (together with R3), or an alkoxymethylene group (together with R3);
- R8 is hydrogen or halogen;
- R9 is hydrogen, halogen, alkyl, alkoxy, arylalkoxy or amino;
- and
- R10 is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, cyano, thiocyano or mercapto;
- or a physiologically acceptable 3-ester, 20-ester, 21-ester, 3,20-diester, or 3,21-diester thereof.
11 more elements
A method of treating anxiety and stress in an animal subject, comprising administering to said animal subject in need of such treatment an effective amount of a compound of Formula I:
- wherein:
- R is hydrogen, halogen, lower alkoxy, alkyl, optionally substituted 1-alkynyl or substituted alkyl;
- R1 is hydrogen, alkyl, alkenyl, aryl, aralkyl, alkynyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, a substituted aralkynyl, arylalkyl, arylalkenyl, aryl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, optionally substituted heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkynyloxyalkynyl;
- R2 is hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a keto group or amino group;
- R3 is an optionally substituted heteroarylacetyl group;
- R4 is hydrogen or methyl,
- R5 is hydrogen;
- R6 is hydrogen, alkanoyl, aminocarbonyl or alkoxycarbonyl;
- R7 is hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a methylene group (together with R3), or an alkoxymethylene group (together with R3);
- R8 is hydrogen or halogen;
- R9 is hydrogen, halogen, alkyl, alkoxy, arylalkoxy or amino;
- and
- R10 is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, cyano, thiocyano or mercapto;
- or a physiologically acceptable 3-ester, 20-ester, 21-ester, 3,20-diester, or 3,21-diester thereof.
11 more elements
Dependencies are inferred from the claim text.