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US 2009/0156668 A1Published application
Ginkgolide Compounds, Compositions, And Extracts, And Uses Thereof
AssigneeThe Trustees of Columbia University in the City of New York
InventorsOttavio V. Vitolo, Koji Nakanishi, Michael L. Shelanski, Sonja Krane, Ottavio Arancio, Stanislav Jaracz, Nina D. Berova
Life of this patent
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Abstract
The present invention relates to Ginkgolide derivatives, compositions and extracts comprising one or more Ginkgolides and/or derivatives thereof and methods of use of the compositions to treat neurological disorders and as imaging agents.
Claims40
A compound having the formula:
- or a pharmaceutically acceptable salt thereof,
- wherein:
- each occurrence of Y is independently —CH2— or —C(O)—;
- R1 and R3 are each independently —H or —C1-C6 alkyl;
- R2 is —H, —OH, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- R4 is —C1-C5 alkyl, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and
- R5 is —H or —OH.
5 more elements
A composition consisting essentially of two or more structurally distinct compounds, each having the formula:
- wherein:
- each occurrence of Y is independently —CH2— or —C(O)—;
- R1 and R3 and are each independently —H or —C1-C6 alkyl;
- R1 and R3 are each independently —H or —C1-C6 alkyl;
- R2 is —H, —OH, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- R4 is —C1-C5 alkyl, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and
- R5 is —H or —OH.
5 more elements
A composition consisting essentially of a first compound having the formula:
- wherein R2 is —H, —C1-C5 alkyl, —OH, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and one or more structurally distinct compounds, each having the formula:
- wherein each occurrence of Y is independently —CH2— or —C(O)—;
- R1 and R3 and are each independently —H or —C1-C6 alkyl;
- R1 and R3 are each independently —H or —C1-C6 alkyl;
- R2 is —H, —OH, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- R4 is —C1-C5 alkyl, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and
- R5 is —H or —OH.
6 more elements
(canceled)
16-17. (canceled)
A composition consisting essentially of Ginkgolide A and Ginkgolide J.
A composition consisting essentially of (i) an antioxidant, a pharmaceutical carrier, or a combination thereof and (ii) two or more structurally distinct compounds, each having the formula:
- wherein:
- each occurrence of Y is independently —CH2— or —C(O)—;
- R1 and R3 and are each independently —H or —C1-C6 alkyl;
- R1 and R3 are each independently —H or —C1-C6 alkyl;
- R2 is —H, —OH, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- R4 is —C1-C5 alkyl, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and
- R5 is —H or —OH.
5 more elements
26-28. (canceled)
An extract comprising more than 10% terpene trilactones, wherein the proportion of terpene trilactones, by weight of the total amount of terpene trilactiones, is
- from about 20% to about 30% or about 52% to about 62% bilobalide,
- from about 10% to about 20% or about 37% to about 47% ginkgolide A,
- from about 5% to about 20% ginkgolide B,
- from about 5% to about 20% ginkgolide C, and
- from about 1% to about 8% ginkgolide J, and
- wherein the percentages of bilobalide, ginkgolide A, ginkgolide B, ginkgolide C and ginkgolide J add up to 100%.
3 more elements
(canceled)
A method of treating a disease or disorder comprising administering to a subject an effective amount of
- (i) an enriched Ginkgo biloba extract comprising at least about 60% terpene trilactones;
- or
- (ii) a compound having the formula:
- or a pharmaceutically acceptable salt thereof;
- or
- (iii) a composition consisting essentially of two or more structurally distinct compounds, each having the formula:
- (iv) a composition consisting essentially of a first compound having the formula:
- wherein R2 is —H, —C1-C5 alkyl, —OH, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and one or more structurally distinct compounds, each having the formula:
- (v) a composition consisting essentially of Ginkgolide A, Ginkgolide J, or combinations thereof;
- or
- (vi) a composition consisting essentially of (a) an antioxidant, a pharmaceutical carrier, or a combination thereof and (b) two or more structurally distinct compounds, each having the formula:
- wherein in formula (II):
- each occurrence of Y is independently —CH2— or —C(O)—;
- R1 and R3 and are each independently —H or —C1-C6 alkyl;
- R1 and R3 are each independently —H or —C1-C6 alkyl;
- R2 is —H, —OH, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- R4 is —C1-C5 alkyl, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl or —O—SO2-aryl;
- and
- R5 is —H or —OH.
17 more elements
36-39. (canceled)
A method for protecting a neuron against neuronal cell death or long term potentiation impairment by beta amyloid protein comprising contacting the neuron with
- (i) an enriched Ginkgo biloba extract comprising at least about 60% terpene trilactones;
- or
- (ii) a compound having the formula:
- or a pharmaceutically acceptable salt thereof;
- or
- (iii) a composition consisting essentially of two or more structurally distinct compounds, each having the formula:
- (iv) a composition consisting essentially of a first compound having the formula:
- wherein R2 is —H, —C1-C5 alkyl, —OH, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and one or more structurally distinct compounds, each having the formula:
- (v) a composition consisting essentially of Ginkgolide A, Ginkgolide J, or combinations thereof;
- or
- (vi) a composition consisting essentially of (a) an antioxidant, a pharmaceutical carrier, or a combination thereof and (b) two or more structurally distinct compounds, each having the formula:
- wherein in formula (II):
- each occurrence of Y is independently —CH2— or —C(O)—;
- R1 and R3 and are each independently —H or —C1-C6 alkyl;
- R1 and R3 are each independently —H or —C1-C6 alkyl;
- R2 is —H, —OH, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- R4 is —C1-C5 alkyl, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and
- R5 is —H or —OH.
17 more elements
A method for stimulating axonal out growth of a neuron comprising contacting the neuron with
- (i) an enriched Ginkgo biloba extract comprising at least about 60% terpene trilactones;
- or
- (ii) a compound having the formula:
- or a pharmaceutically acceptable salt thereof;
- or
- (iii) a composition consisting essentially of two or more structurally distinct compounds, each having the formula:
- (iv) a composition consisting essentially of a first compound having the formula:
- wherein R2 is —H, —C1-C5 alkyl, —OH, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and one or more structurally distinct compounds, each having the formula:
- (v) a composition consisting essentially of Ginkgolide A, Ginkgolide J, or combinations thereof;
- or
- (vi) a composition consisting essentially of (a) an antioxidant, a pharmaceutical carrier, or a combination thereof and (b) two or more structurally distinct compounds, each having the formula:
- wherein in formula (II):
- each occurrence of Y is independently —CH2— or —C(O)—;
- R1 and R3 and are each independently —H or —C1-C6 alkyl;
- R1 and R3 are each independently —H or —C1-C6 alkyl;
- R2 is —H, —OH, —O—C1-C5 alkyl, —O—C2-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- R4 is —C1-C5 alkyl, —NH2, -halo, —C2-C5 alkenyl, —C2-C5 alkynyl, —O—C1-C5 alkyl, O—C1-C5 alkenyl, —O—C2-C5 alkynyl, —O—C(O)—C1-C5 alkyl, —O—C(O)-aryl, —O—CO—NH—C1-C5 alkyl, —O—SO2—C1-C5 alkyl, or —O—SO2-aryl;
- and
- R5 is —H or —OH.
17 more elements
42-43. (canceled)
A method of identifying a receptor that binds a compound that protects against neuronal cell death or long term potentiation impairment by beta amyloid protein comprising administering the phosphodiesterase inhibitor to a subject a compound having the formula:
- wherein R2 is a detectable moiety.
(canceled)
47-57. (canceled)
Dependencies are inferred from the claim text.