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Publication Number
US-9101613-B2
Publication Date
2015-08-11
Expiration Date
Abstract
Neurological disorders and diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Down's syndrome, can be ameliorated or beneficially treated by administration of a formulation comprising an effective amount of a pyrone-indole derivative of formula (I) Ar—B—Ar′ (I) wherein AR represents an indole nucleus ring system: Ar′ represents an alpha-, beta- or gamma-pyrone nucleus ring system: and each of B, R1, R2, R3, R4, R1′ and R2′ are as defined herein.
Core Innovation
The invention relates to pyrone-indole derivative compounds having a formula (I) in which an Ar group represents an indole nucleus ring system and an Ar group represents an alpha-, beta- or gamma-pyrone nucleus ring system. The compounds further comprise a linker B defined as X-Y-Z, where X is (CH2)n (n is 0-6), Y is oxygen, sulphur, >NH or is absent, and Z is >C(O), >O or >COO or is absent, with at least one of X, Y and Z present.
The disclosed compounds are used in methods that include promoting neurite outgrowth and inhibiting neuronal loss. The methods also include increasing sleep efficiency, enhancing learning and memory, or augmenting sleep maintenance in an animal or human, by administering a formulation comprising an effective amount of the compound of formula (I) or a salt or stereoisomer thereof.
The invention also covers methods for activating or inhibiting 5HT receptors in an animal or human and methods of activating MT-1 and/or MT-2 receptors in an animal or human. In addition, methods of modulating MT-1 and/or MT-2 receptors are disclosed, with treatment areas including neurodegenerative diseases and other CNS/metabolic disorders, and preferred neurodegenerative indications including Alzheimers disease, ALS, Huntingtons disease, Parkinsons disease, and Downs syndrome.
Claims Coverage
The provided claim set includes four independent claims. Across these claims, the coverage centers on administering a formulation containing an effective amount of a compound of formula (I) having defined Ar-B-Ar structure constraints, with optional salts or stereoisomers.
Method for promoting neurite outgrowth, inhibiting neuronal loss, sleep efficiency, learning and memory, or sleep maintenance
A method comprising administering to an animal or human in need thereof a formulation comprising an effective amount of a compound having the formula Ar-B-Ar (I), wherein B represents X-Y-Z with X=(CH2)n (n is 0-6), Y represents oxygen, sulphur, >NH or is absent, Z represents >C(O), >O or >COO or is absent, and at least one of X, Y and Z must be present; wherein Ar represents an indole nucleus ring system; wherein Ar represents an alpha-, beta- or gamma-pyrone nucleus ring system; and wherein ring substitutions R1-R4 and R1-R2 are defined, including bond locations between Ar and B and between Ar and B, with administration of a salt or stereoisomer thereof.
Method for activating MT-1 and/or MT-2 receptors
A method comprising administering a formulation comprising an effective amount of a compound having the formula Ar-B-Ar (I) to activate MT-1 and/or MT-2 receptors in an animal or human, where B represents X-Y-Z with X=(CH2)n (n is 0-6), Y represents oxygen, sulphur or >NH, Z represents >C(O), >O or >COO or is absent, and at least one of X, Y and Z must be present; Ar is an indole nucleus ring system; Ar is an alpha-, beta- or gamma-pyrone nucleus ring system; ring substituents R1-R4 and R1-R2 are defined; and Ar and Ar are permitted to bond to B at specified positions, including salts or stereoisomers.
Method for activating or inhibiting 5HT receptors
A method comprising administering a formulation comprising an effective amount of a compound having the formula Ar-B-Ar (I) to activate or inhibit 5HT receptors in an animal or human, where B represents X-Y-Z with X=(CH2)n (n is 0-6), Y represents oxygen, sulphur or >NH, Z represents >C(O), >O or >COO or is absent, and at least one of X, Y and Z must be present; Ar is an indole nucleus ring system; Ar is an alpha-, beta- or gamma-pyrone nucleus ring system; and R1-R4 and R1-R2 substituent definitions and bond positions between Ar and B and between Ar and B are included, with administration of a salt or stereoisomer thereof.
Method for modulating MT-1 and/or MT-2 receptors
A method comprising administering a formulation comprising an effective amount of a compound having the formula Ar-B-Ar (I) to modulate MT-1 and/or MT-2 receptors in an animal or human, where B represents X-Y-Z with X=(CH2)n (n is 0-6), Y represents oxygen, sulphur or >NH, Z represents >C(O), >O or >COO or is absent, and at least one of X, Y and Z must be present; Ar is an indole nucleus ring system; Ar is an alpha-, beta- or gamma-pyrone nucleus ring system; and ring substituent definitions and permitted bond positions between Ar and B and between Ar and B are specified, including salts or stereoisomers.
Across the independent claims, the inventive scope is the use of an Ar-B-Ar pyrone-indole derivative of formula (I) with defined linker composition (X-Y-Z) and defined indole (Ar) and alpha/beta/gamma-pyrone (Ar) ring systems, including specified substitution and bonding constraints, in methods addressing neurite outgrowth/neuronal loss, sleep outcomes, learning and memory, and receptor modulation involving MT-1/MT-2 receptors and 5HT receptors.
Stated Advantages
Avoiding benzodiazepine-like tolerance/dependence.
Improving sleep quality with daytime vigilance.
Treating neurodegenerative diseases and other CNS/metabolic disorders.
Documented Applications
Treatment of neurodegenerative diseases, with preferred neurodegenerative indications including Alzheimers disease, ALS, Huntingtons disease, and Parkinsons disease.
Treatment of Downs syndrome.
Methods for promoting neurite outgrowth and inhibiting neuronal loss in an animal or human.
Methods for increasing sleep efficiency, enhancing learning and memory, or augmenting sleep maintenance in an animal or human.
Activation or inhibition of 5HT receptors in an animal or human.
Activation and modulation of MT-1 and/or MT-2 receptors in an animal or human.
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