Stilbenes and chalcones for the prevention and treatment of cardiovascular diseases

• US 7,846,915 B2
• Filed: 10/20/2005
• Issued: 12/07/2010
• Est. Priority Date: 10/20/2004
• Status: Active Grant

• Current Assignee: Resverlogix Corp.
• Original Assignee: Resverlogix Corp.
• Inventors: Chiacchia, Fabrizio S., McCaffrey, David, Hansen, Henrik C., Tucker, Joseph E. L., Wong, Norman C. W.
• Primary Examiner(s): Padmanabhan; Sreeni
• Assistant Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US11/254,420
• Publication Number:
  US 20060205792A1
• Time in Patent Office: 1,874 Days
• Field of Search: 514/183, 514/96, 514/456, 514/352
• US Class Current: 514/96
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/055 the aromatic ring being substituted by halogen
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/265 of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/382 having six-membered rings, e.g. thioxanthenes thiothixene A61K31/496
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/536 : ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 205/22 : having one nitro groups bound to the ring
• CPC Class Codes: C07C 311/29 : having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 327/28 : having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 37/003 : by hydrogenation of an unsaturated part
• CPC Class Codes: C07C 37/055 : the substituted group being bound to oxygen, e.g. ether group
• CPC Class Codes: C07C 37/18 : by condensation involving halogen atoms of halogenated compounds
• CPC Class Codes: C07C 39/14 : with at least one hydroxy group on a condensed ring system containing two rings
• CPC Class Codes: C07C 39/15 : with all hydroxy groups on non-condensed rings , e.g. phenylphenol
• CPC Class Codes: C07C 39/21 : with at least one hydroxy group on a non-condensed ring
• CPC Class Codes: C07C 43/23 : containing hydroxy or O-metal groups
• CPC Class Codes: C07C 46/00 : Preparation of quinones
• CPC Class Codes: C07C 49/83 : polycyclic
• CPC Class Codes: C07C 49/835 : having unsaturation outside an aromatic ring
• CPC Class Codes: C07C 50/32 : the quinoid structure being part of a condensed ring system having two rings
• CPC Class Codes: C07D 213/64 : attached in position 2 or 6
• CPC Class Codes: C07D 213/65 : attached in position 3 or 5
• CPC Class Codes: C07D 213/80 : in position 3
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/233 : only one oxygen atom which is attached in position 4
• CPC Class Codes: C07D 217/16 : substituted by oxygen atoms
• CPC Class Codes: C07D 217/22 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 217/24 : Oxygen atoms
• CPC Class Codes: C07D 265/22 : Oxygen atoms
• CPC Class Codes: C07D 311/30 : not hydrogenated in the hetero ring, e.g. flavones
• CPC Class Codes: C07D 311/32 : 2,3-Dihydro derivatives, e.g. flavanones
• CPC Class Codes: C07D 311/36 : not hydrogenated in the hetero ring, e.g. isoflavones
• CPC Class Codes: C07D 311/60 : with aryl radicals attached in position 2
• CPC Class Codes: C07D 319/20 : with substituents attached to the hetero ring
• CPC Class Codes: C07D 335/06 : Benzothiopyrans; Hydrogenated benzothiopyrans
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/052 : the oxygen-containing ring being six-membered

Abstract

The present disclosure provides non-naturally occurring polyphenol compounds that upregulate the expression of Apolipoprotein A-I (ApoA-I). The disclosed compositions and methods can be used for treatment and prevention of cardiovascular disease and related disease states, including cholesterol or lipid related disorders, such as, e.g., atherosclerosis.

Claims

1. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound of Formula I:

2. The method of claim 1, wherein the therapeutically effective amount of the compound of Formula I is sufficient to establish a concentration ranging from about 0.001 μ

M to about 100 μ

M in the mammal.

3. The method of claim 2, wherein the concentration ranges from about 1 μ

M to about 20 μ

M.

4. The method of claim 1, wherein the therapeutically effective amount of the compound of Formula I is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

5. The method of claim 1, further comprising treating or reducing the risk of developing a cardiovascular, cholesterol or lipid related disorder.

6. The method of claim 1, wherein the double bond is an E-double bond.

9. The method according to claim 5, wherein the cardiovascular, cholesterol or lipid related disorder is selected from acute coronary syndrome, angina pectoris, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, multi-infarct dementia, myocardial infarction, peripheral vascular disease, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorder, transitory ischemic attacks, and lipoprotein abnormalities associated with Alzheimer'"'"'s disease, obesity, diabetes mellitus, syndrome X and impotence.

10. The method according to claim 9, wherein the cardiovascular, cholesterol or lipid related disorder is selected from dyslipidemias, dyslipoproteinemias, hypertension, coronary artery disease, and atherosclerosis.

11. The method of claim 1, wherein R₁, R₅, R₆, and R₁₀ are each independently selected from alkoxy, aryloxy, alkyl, amide, amino, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, hydrogen, hydroxyl, nitro, phosphate, sulfonyl, sulfonic acid, and sulfonamide.

12. The method of claim 1, wherein R₂, R₄, R₇, and R₉, are each independently selected from amide, amino, carboxy, cyano, ester, ether, formyl, halogen, hydrogen, hydroxyl, phosphate, sulfide, sulfonic acid, and sulfonamide.

13. The method of claim 1, wherein only one W is N.

7. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound selected from:

4,4′

-dihydroxy-stilbene;

6-[(E)-2-(4-Hydroxy-phenyl)-vinyl]-pyridin-3-ol;

5-[(E)-2-(4-Hydroxy-phenyl)-vinyl]-pyrazin-2-ol;

5-{[1-(4-Hydroxy-phenyl)-meth-(E)-ylidene]-amino}-pyridin-2-ol;

5-(4-Hydroxy-phenylazo)-pyridin-2-ol;

3-Hydroxymethyl-4-[(E)-2-(4-hydroxy-phenyl)-vinyl]-phenol;

2-Hydroxy-5-[(E)-2-(4-hydroxyphenyl)vinyl]benzoic acid;

3-Nitro-4-[(E)-2-(4-hydroxyphenyl)-vinyl]phenol;

(E)-Ethyl 2-hydroxy-5-(4-hydroxystyryl) benzoate;

4-[(E)-2-(4-Hydroxyphenyl)vinyl]-3-methanesulfonylphenol;

3-Amino-4-[(E)-2-(4-hydroxy-phenyl)vinyl]phenol;

N-{5-Hydroxy-2-[(E)-2-(4-hydroxyphenyl)vinyl]phenyl}-acetamide;

5-Hydroxy-2-[2-(4-hydroxyphenyl)vinyl]-N,N-dimethylbenzamide;

4-[4-Hydroxy-phenethyl]-phenol;

4-Hydroxy-thiobenzoic acid S-(4-hydroxy-phenyl) ester;

4-Hydroxy-benzoic acid pyridin-2-yl ester;

4-(4-Hydroxy-phenyl)-azophenol,

and pharmaceutically acceptable salts thereof.

8. A method for increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of 5-[(E)-2-(4-Hydroxyphenyl)-vinyl]-pyridin-2-ol, or a pharmaceutically acceptable salt thereof.