Canadian Patents Database

Claims page

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Patent Document Number: 2479249

(54) English Title: NEUROPROTECTIVE SPIROSTENOL PHARMACEUTICAL COMPOSITIONS

(54) French Title: COMPOSITIONS PHARMACEUTIQUES NEUROPROTECTRICES A BASE DE SPIROSTENOL

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Claims:

Note: Claims are shown in the official language in which they were submitted.




WHAT IS CLAIMED IS:
1. A method of treating a neurodegenerative disorder in a subject in need
thereof, comprising administering to the subject a compound of formula (I):
Image
wherein each of R1, R2, R4, R5, R6, R7, R11, R12, R15, and R16, independently,
is
hydrogen, alkyl, hydroxy, amino, carboxyl, oxo, sulfonic acid, or alkyl that
is optionally
inserted with -NH-, -N(alkyl)-, -O-, -S-, -SO-, -SO2-, -O-SO2-, -SO2-O-, -SO3-
O-,-CO-, -
CO-O-, -O-CO-, -CO-NR'-, or -NR'-CO-; R3 is a substituent as disclosed at R3
of the
compounds listed in Table 1 and Fig. 1; each of R8, R9, R10, R13, and R14,
independently, is
hydrogen, alkyl, hydroxyalkyl, alkoxy, or hydroxy; and R17 is a substituent as
disclosed at
R17 of the compounds listed in Table 1 and Fig. 1.
2. The method of claim 1 wherein the compound is selected from the group
consisting of the compounds listed in Table 1.
3. The method of claim 1 wherein the compound is in a dosage form
comprising a therapeutically effective amount of the compound.
4. The method of claim 3, wherein the dosage form is selected from the group
consisting of tablet, soft gelatin capsule, hard gelatin capsule, suspension
tablet,
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effervescent tablet, powder, effervescent powder, chewable tablet, solution,
suspension,
emulsion, cream, gel, patch, and suppository.

5. The method of claim 3, wherein the dosage form further comprises a
pharmaceutically acceptable excipient.

6. The method of claim 5, wherein the pharmaceutically acceptable excipient
comprises a binder, a disintegrant, a filler, a surfactant, a solubilizer, a
stabilizer, a
lubricant, a wetting agent, a diluent, an anti-adherent, a glidant, or a
pharmaceutically
compatible carrier.

7. The method of claim 1, further comprising administering at least one
acetylcholinesterase inhibitor.

8. The method of claim 1, wherein the neurodegenerative disorder is selected
from the group consisting of global and focal ischemic and hemorrhagic stroke,
head
trauma, spinal cord injury, hypoxia-induced nerve cell damage, nerve cell
damage caused
by cardiac arrest or neonatal distress, epilepsy, anxiety, diabetes mellitus,
multiple
sclerosis, phantom limb pain, causalgia, neuralgias, herpes zoster, spinal
cord lesions,
hyper algesia, allodynia, Alzheimer's Disease, Huntington's disease, and
Parkinson's
disease.

9. The method of claim 8, wherein the neurodegenerative disorder is
Alzheimer's disease.

10. A pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula (I):

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Image

wherein each of R1, R2, R4, R5, R6, R7, R11, R12, R15, and R16, independently,
is
hydrogen, alkyl, hydroxy, amino, carboxyl, oxo, sulfonic acid, or alkyl that
is optionally
inserted with -NH-, -N(alkyl)-, -O-, -S-, -SO-, -SO2-, -O-SO2-, -SO2-O-, -SO3-
O-,-CO-,
-CO-O-, -O-CO-, -CO-NR'-, or -NR'-CO-; R3 is a substituent as disclosed at R3
of the
compounds listed in Table 1 and Fig. 1; each of R8, R9, R10, R13, and R14,
independently, is
hydrogen, alkyl, hydroxyalkyl, alkoxy, or hydroxy; and R17 is a substituent as
disclosed at
R17 of the compounds listed in Table 1 and Fig. 1; and
a pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10, wherein the compound is
selected from the group consisting of the compounds listed in Table 1.

12. The pharmaceutical composition of claim 10, wherein the pharmaceutical
composition is in a dosage form selected from the group consisting of tablet,
soft gelatin
capsule, hard gelatin capsule, suspension tablet, effervescent tablet, powder,
effervescent
powder, chewable tablet, solution, suspension, emulsion, cream, gel, patch,
and
suppository.

13. The pharmaceutical composition of claim 10, wherein the pharmaceutically
acceptable excipient comprises a binder, a disintegrant, a filler, a
surfactant, a solubilizer,

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a stabilizer, a lubricant, a wetting agent, a diluent, an anti-adherent, a
glidant, or a
pharmaceutically compatible carrier.
14. The pharmaceutical composition of claim 10, further comprising at least
one acetylcholinesterase inhibitor.
15. A method of identifying a compound having binding affinity to .beta.-
amyloid,
comprising:
screening a database of known chemical compounds for structural homology to
22R-hydroxycholesterol;
ranking the compounds in the database based on a degree of homology to 22R-
hydroxycholesterol;
extracting from the database compounds having a highest structural homology to
22R-hydroxycholesterol;
ranking the extracted compounds according to in vitro binding to .beta.-
amyloid; and
selecting the compound having the highest in vitro affinity.
16. A method of designing a compound having binding affinity to .beta.-
amyloid,
comprising:
mapping 22R-hydroxycholesterol into two or more separate building blocks;
designing a new compound by modifying one or more blocks of 22R-
hydroxycholesterol;
ranking the designed compound according to in vitro binding to .beta.-amyloid;
and
selecting the compound having the highest in vitro binding affinity.
17. A method of designing a compound having binding affinity to .beta.-amyloid
comprising:
mapping .beta.-amyloid;
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constructing on a computer screen a compound that complements the structure of
.beta.-amyloid or a fragment thereof;
ranking the constructed compound according to in vitro binding to .beta.-
amyloid; and
selecting the compound having the highest in vitro binding affinity.
18. The method of claim 17, wherein the fragment consists of amino acids 17
to 40 of .beta.-amyloid.
19. The method of claim 17, wherein the fragment consists of amino acids 15
to 40 of .beta.-amyloid.
20. The method of claim 17, wherein the fragment consists of amino acids 17
to 38 of .beta.-amyloid.
21. The method of claim 17, wherein the fragment consists of amino acids 16
to 39 of .beta.-amyloid.
22. A method of detection and quantification of A.beta. in biological fluid,
comprising:
obtaining a sample fluid;
incubating the fluid with a labeled compound of formula (I):
Image
wherein each of R1, R2, R4, R5, R6, R7, R11, R12, R15, and R16, independently,
is hydrogen,
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alkyl, hydroxy, amino, carboxyl, oxo, sulfonic acid, or alkyl that is
optionally inserted
with -NH-, -N(alkyl)-, -O-, -S-, -SO-, -SO2-, -O-SO2-, -SO2-O-, -SO3-O-,-CO-, -
CO-O-, -
O-CO-, -CO-NR'-, or -NR'-CO-; R3 is a substituent as disclosed at R3 of the
compounds
listed in Table 1 and Fig. 1; each of R8, R9, R10, R13, and R14,
independently, is hydrogen,
alkyl, hydroxyalkyl, alkoxy, or hydroxy; and R17 is a substituent as disclosed
at R17 of the
compounds listed in Table 1 and Fig. 1;
separating samples from the incubation fluid and transferring the samples to a
nitrocellulose membrane;
exposing the membrane to a tritium-sensitive screen; and
analyzing the contents of the membrane.

23. The method of claim 22, wherein incubating the fluid with the labeled
compound of formula (I) is in the presence of increasing concentrations of an
unlabeled
compound of formula (I).

24. The method of claim 22, wherein the step of analyzing the contents of the
membrane comprises analyzing the contents of the membrane by at least one of
phospho-
imaging to detect the presence of A.beta. and quantifying the amount of
A.beta. present in the
biological fluid.

25. A method of diagnosing Alzheimer's disease in a subject, comprising:
obtaining a sample fluid from the brain of the subject;
incubating the fluid with a labeled compound of formula (I):

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Image

wherein each of R1, R2, R4, R5, R6, R7, R11, R12, R15, and R16, independently,
is hydrogen,
alkyl, hydroxy, amino, carboxyl, oxo, sulfonic acid, or alkyl that is
optionally inserted
with -NH-, -N(alkyl)-, -O-, -S-, -SO-, -SO2-, -O-SO2-, -SO2-O-, -SO3-O-,-CO-, -
CO-O-, -
O-CO-, -CO-NR'-, or -NR'-CO-; R3 is a substituent as disclosed at R3 of the
compounds
listed in Table 1 and Fig. 1; each of R8, R9, R10, R13, and R14,
independently, is hydrogen,
alkyl, hydroxyalkyl, alkoxy, or hydroxy; and R17 is a substituent as disclosed
at R17 of the
compounds listed in Table 1 and Fig. 1;
separating samples from the incubation fluid and transferring the samples to a
nitrocellulose membrane;
exposing the membrane to a tritium-sensitive screen; and
analyzing the contents of the membrane.

26. The method of claim 25, wherein incubating the fluid with the labeled
compound of formula (I) is in the presence of increasing concentrations of
unlabeled
compound of formula (I).

27. The method of claim 25, wherein the step of analyzing the contents of the
membrane comprises analyzing the contents of the membrane by at least one of
phospho-

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imaging to detect the presence of A.beta. and quantifying the amount of
A.beta. present in the
biological fluid.

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