Pharmaceutical composition containing verbenone derivative for treating or preventing neurodegenerative disease

Patent metadata

Field	Value
Publication number	US-9603842-B2
Application number	US-201314405152-A
Country	US
Kind code	B2
Filing date	Jun 4, 2013
Priority date	Jun 5, 2012
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

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 method of treating stroke by administering a pharmaceutical composition comprising a verbenone derivative represented by a following Formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient:

wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently at least one selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br and I, 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, and a C 5 -C 8 heteroaromatic ring;
X, Y and Z are each independently a carbon atom or at least one heteroatom selected from the group consisting of N, O and S atoms; and

denotes a double bond or a single bond.

2. The method of claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently at least one selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br and I, 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, and a C 5 -C 6 heteroaromatic ring.

3. The method of claim 2 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently at least one selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br and I, a hydroxyl group, a methyl group, a methoxy group, a phenyl group, a pyrrole group, and a pyridine group.

4. The method of claim 1 , wherein the X, Y and Z are each independently at least one atom selected from the group consisting of a carbon atom and an N atom.

5. The method of claim 1 , wherein the composition comprises a compound selected from the group consisting of:
(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 (3e);
(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 (5 b); and
(1S,5R)-6,6-dimethyl-4-((E)-2-(pyridin-4-yl)-vinyl)-bicyclo[3.1.1]hept-3-en-2-one (5c).

6. A method of improving stroke by administering health functional food comprising a verbenone derivative represented by a following Formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient:

wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently at least one selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br and I, 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, and a C 5 -C 8 heteroaromatic ring;
X, Y and Z are each independently a carbon atom or at least one heteroatom selected from the group consisting of N, O and S atoms; and
denotes a double bond or a single bond.

7. The method of claim 6 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently at least one selected from the group consisting of a hydrogen atom, a halogen atom selected from F, Cl, Br and I, 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, and a C 5 -C 6 heteroaromatic ring.

8. The method of claim 7 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently at least one selected from the group consisting of a hydrogen, a halogen atom selected from F, Cl, Br and I, a hydroxyl group, a methyl group, a methoxy group, a phenyl group, a pyrrole group, and a pyridine group.

9. The method of claim 6 , wherein the X, Y and Z are each independently at least one atom selected from the group consisting of a carbon atom and an N atom.

10. The method of claim 6 , wherein the health functional food comprises a compound selected from the group consisting of:
(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-dimethyl bicyclo[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); and
(1S,5R)-6,6-dimethyl-4-((E)-2-(pyridin-4-yl)-vinyl)-bicyclo[3.1.1]hept-3-en-2-one (5c).

Assignees

• Univ Korea Res & Bus Found

Inventors

• Kim Won Ki
• Choi Yongseok
• Song Sumi

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title