Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease

Patent metadata

Field	Value
Publication number	US-10710951-B2
Application number	US-201715432522-A
Country	US
Kind code	B2
Filing date	Feb 14, 2017
Priority date	Jun 5, 2012
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

The present invention relates to a pharmaceutical composition or a functional health food comprising a verbenone derivative and pharmaceutically acceptable salts thereof as active ingredients for treating or preventing a neurodegenerative disease. More specifically, the verbenone derivative according to the present invention reduces neuronal cell death and oxidative stress, and is highly effective in preventing ischemic brain damage and inflammatory cell migration in rats, thereby providing the pharmaceutical composition or the functional health food which is useful in treating neurodegenerative diseases.

First claim

What is claimed is:

1. A verbenone derivative represented by a following Formula 1 or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, an amino group, a C 1 -C 3 alkylamine group, a C 1 -C 3 alkyldiamine group, a C 5 -C 8 aromatic ring, a C 5 -C 8 cyclic ring, or a C 5 -C 8 heteroaromatic ring;
X, Y and Z are each independently a carbon atom, N atom, O atom or S atom; and
denotes a double bond or a single bond.

2. The verbenone derivative of claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, an ethyl group, a methoxy group, an ethoxy group, an amino group, a C 5 -C 6 aromatic ring, a C 5 -C 6 cyclic ring, or a C 5 -C 6 heteroaromatic ring.

3. The verbenone derivative of claim 2 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a methoxy group, a phenyl group, a pyrrole group, or a pyridine group.

4. The verbenone derivative of claim 1 , wherein the X, Y and Z are each independently a carbon atom or N atom, O atom or S atom.

5. The verbenone derivative of claim 4 , wherein the X, Y and Z are each independently a carbon atom or an N atom.

6. The verbenone derivative of claim 1 , which is:
(1S,5R)-4-(4-hydroxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3a);
(1S,5R)-4-(4-hydroxy-2-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3b);
(1S,5R)-4-(3,4-dihydroxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3c);
(1S,5R)-4-(3-bromo-4-hydroxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3d);
(1S,5R)-4-(4-hydroxy-2,6-dimethoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3e);
(1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3f);
(1S,5R)-4-(3-hydroxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3g);
(1S,5R)-4-(2-hydroxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3h);
(1S,5R)-4-(2-hydroxy-4-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3i);
(1S,5R)-6,6-dimethyl-4-styryl-bicyclo[3.1.1]hept-3-en-2-one (4a);
(1S,5R)-4-(4-fluorostyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4b);
(1S,5R)-4-(4-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4c);
(1S,5R)-4-(2-(biphenyl-4-yl)vinyl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4d);
(1S,5R)-4-(4-(1H-pyrrol-1-yl)styryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4e);
(1S,5R)-4-(3,4-dimethoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4f);
(1S,5R)-4-(3,5-dimethoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4g);
(1S,5R)-4-(2,5-dimethoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4h);
(1S,5R)-4-(5-bromo-2-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (4i);
(1S,5R)-6,6-dimethyl-4-((E)-2-(pyridin-2-yl)vinyl)-bicyclo[3.1.1]hept-3-en-2-one (5a);
(1S,5R)-6,6-dimethyl-4-((E)-2-(pyridin-3-yl)vinyl)-bicyclo[3.1.1]hept-3-en-2-one (5b); or
(1S,5R)-6,6-dimethyl-4-((E)-2-(pyridin-4-yl)-vinyl)-bicyclo[3.1.1]hept-3-en-2-one (5c).

7. The verbenone derivative of claim 1 , which is:
(1S,5R)-4-(4-hydroxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3a);
(1S,5R)-4-(3,4-dihydroxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3c);
(1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3f);
(1S,5R)-4-(2-hydroxy-4-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3i);
(1S,5R)-6,6-dimethyl-4-((E)-2-(pyridin-2-yl)vinyl)-bicyclo[3.1.1]hept-3-en-2-one (5a);
or a pharmaceutically acceptable salt thereof.

8. The verbenone derivative of claim 1 , which is (1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3f).

Assignees

• Univ Korea Res & Bus Found
• Shin Poong Pharmaceutical Co Ltd

Inventors

• Kim Won Ki
• Choi Yongseok
• Song Sumi

Classifications

• A23L29/055 Primary

  containing sulfur as heteroatom · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/435 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K31/045 Primary

  Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title