Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases

• US 20060205767A1
• Filed: 10/20/2005
• Published: 09/14/2006
• Est. Priority Date: 10/20/2004
• Status: Active Grant

• Current Assignee: Resverlogix Corp.
• Original Assignee: Resverlogix Corp.
• Inventors: Tucker, Joseph E.L., Wong, Norman C.W., Chiacchia, Fabrizio S., McCaffrey, David, Hansen, Henrik C.
• Granted Patent: US 8,093,273 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• 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:

wherein;

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and NR₁₁, wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and NR₁₂, wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and a double bond;

wherein if Y is O, then X is not CO;

wherein if X is O, the Z₁ is a single bond;

wherein if X is O and Z₂ is a single bond, then R₁₀ is not hydroxyl or ester;

and pharmaceutically acceptable salts and hydrates thereof.

2. 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.

3. 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.

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

M to about 20 μ

M.

5. The method of claim 1, further comprising treating or preventing a cardiovascular, cholesterol or lipid related disorder.

6. The method of claim 1, wherein the compound of Formula I is selected from

5,7-Difluoro-2-(4-methoxy-phenyl)-chromen-4-one,

5,7-Difluoro-2-(4-hydroxy-phenyl)-chromen-4-one,

2-(3,5-Difluoro-4-hydroxyphenyl)chromen-4-one,

2-(4-Hydroxy-3,5-dimethylphenyl)chromen-4-one,

2-(5-Methoxy-pyridin-2-yl)-chromen-4-one,

2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one,

2-(6-Hydroxy-pyridin-3-yl)-chromen-4-one,

2-Pyridin-4-yl-chromen-4-one,

2-(4-Methoxy-phenyl)-thiochromen-4-one,

2-(4-Hydroxy-phenyl)-thiochromen-4-one,

2-(4-Hydroxyphenyl)-3-methyl-4H-chromen-4-one,

4-(6-Bromo-4-oxo-4H-chromen-2-yl )-2-fluorophenyl acetate,

1-(2-Nitro-4-methoxy-phenyl)-chromen-4-one,

2-(4-Hydroxy-2-nitrophenyl)chromen-4-one,

2-(2-Amino-4-methoxy-phenyl)-chromen-4-one,

2-(2-Amino-4-hydroxy-phenyl)-chromen-4-one,

N-[5-Hydroxy-2-(4-oxo-4H-chromen-2-yl )-phenyl]acetamide,

6-Hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one,

2-(2-Fluoro-4-hydroxyphenyl)chromen-4-one,

2-(4-Hydroxyphenyl)-8-nitro-4H-chromen-4-one,

2-(4-Hydroxyphenyl)-8-methoxy-4H-chromen-4-one,

2-(4-Hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-one,

2-(3-Bromo-4-hydroxyphenyl)-4H-chromen-4-one,

2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile,

2-(4-Methoxy-phenyl)-chromen-4-one,

2-(3-Fluoro-4-hydroxyphenyl)chromen-4-one,

2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid,

6-Hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one,

6-((Dimethylamino)methyl)-2-(4-hydrophenyl)-4H-chromen-4-one,

8-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,

2-(4-Hydroxy-phenyl)-chromen-4-one,

7-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,

5-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,

5,7-Djihydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,

5,7-Dihydroxy-2-phenyl-chromen-4-one,

5-Hydroxy-2-phenyl-chromen-4-one,

2-(4-Acetoxy-phenyl)-thiochromen-4-one,

2-(4-Acetoxy-phenyl)-1,1-dioxo-1H-1λ

⁶-thiochromen-4-one,

2-(4-Hydroxy-phenyl)-1,1-dioxo-1H-1λ

⁶-thiochromen-4-one,

5,7-Dimethoxy-2-(4′

-hydroxy-phenyl )-quinolin-4-one,

5,7-Dihydroxy-2-(4-hydroxy-phenyl)-quinolin-4-one,

2-(4-Hydroxy-phenyl)-1H-quinolin-4-one,

2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one,

2-(4-Methoxyphenyl )-4H-pyrano[2,3-b]pyridine-4-one,

2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one,

2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one,

2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one,

2-(4-Hydroxy-3-methyl phenyl)-4H-pyrano[2,3-b]pyridine-4-one,

4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile,

2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,

2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one,

2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,

2-(4-Hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one,

2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-c]pyridine 7-oxide,

2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-b]pyridine 8-oxide,

2-(4-hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one,

2-(4-Hydroxyphenyl )-4-oxo-4H-pyrano[3,2-c]pyridine-6-oxide,

3-((Dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one,

2-(2-(4-Hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile,

3-(Hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one,

2-(4-Hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one,

3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one,

7-(3-Fluoro-4-hydroxyphenyl)-6-methyl-1,6-naphthyridin-5(6H)-one,

3-(3-Fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1(2H)-one,

2-Fluoro-4-(5-methoxy-1-(methylamino)-isoquinolin-3-yl)phenol,

4-Naphthalen-2-yl-phenol,

6-Naphthalen-2-yl-pyridin-3-ol,

3-(4-Hydroxyphenyl)-naphthalene-1-ol,

4-Isoquinolin-3-yl-phenol,

4-(1,6-Naphthyridin-7-yl)phenol,

2-(4-Hydroxy-phenyl)-[1,4]naphthoquinone,

4-(Benzo[b][1,4]dioxin-2-yl)phenyl acetate,

4-(Benzo[b][1,4]dioxin-2-yl)phenol,

4-(4H-Chromen-2-yl)-phenol,

2-(4-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one,

6-Naphthalen-2-yl-pyridin-3-ol,

2-(4-Ethoxycarbonyloxy-phenyl )-4-oxo-4H-quinoline-1-carboxylic acid ethyl ester,

Nicotinic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester,

Acetic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester,

4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate,

2-Amino-5-guanidino-pentanoic acid 4-(4-oxo-4H-chromen-2-yl)phenyl ester,

4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate,

4-(1 -Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate,

2-(4-(Nicotinoyloxy)phenyl)-4-oxochroman-5,7-diyl dinicotinate, and

2-(4-(Nicotinoyloxy)phenyl)-4-oxo-4H-chromene-5,7-diyl dinicotinate.

7. The method of claim 1, wherein the compound of Formula I is 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one.

8. The method of claim 1, wherein the compound of Formula I is 3-(4-hydroxyphenyl)-2H-isoquinolin-1-one.

9. The method of claim 1, wherein the compound of Formula I is 4-isoquinolin-3-yl-phenol.

10. A compound of Formula l:

wherein

X is selected from CR₁₁, CR₁₁R₁₃, CO, O, N and NR₁₁,wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, O, N and NR₁₂, wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;

at least one W is N;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and a double bond;

wherein if X is O and Z₂ is a single bond, then R₁₀ is not hydroxyl or ester;

wherein if

a W in the C ring is selected from N and NR₁₀,

Z₁ is a double bond, and

R₅, R₆, R₈, and R₉ are each hydrogen,

then R₇ is not hydroxyl or alkoxy;

and pharmaceutically acceptable salts or hydrates thereof.

11. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.

12. A method of increasing expression of ApoA-I in a mammal comprising administering a therapeutically effective amount of a compound of claim 10.

13. A method of treating or preventing cardiovascular, cholesterol or lipid related disorders comprising administering a therapeutically effective amount of a compound of claim 10.

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

wherein;

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and NR₁₁, wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and NR₁₂, wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇ and R₁₈ are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₈ are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and a double bond;

wherein if Y is O, then X is not CO;

wherein if X is O, Y is CO and Z₂ is a double bond, then at least one of R₅, R₆, R₈ and R₉ is not hydrogen;

and pharmaceutically acceptable salts and hydrates thereof.

15. The method of claim 14, wherein the therapeutically effective amount of the compound of Formula I is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

16. The method of claim 14, wherein the therapeutically effective amount of the compound of Formula IV is sufficient to establish a concentration ranging from about 0.001 μ

M to about 100 μ

M in the mammal.

17. The method of claim 16, wherein the concentration ranges from about 1 μ

M to about 20 μ

M.

18. The method of claim 14, further comprising treating or preventing a cardiovascular, cholesterol or lipid related disorder.

19. The method of claim 14, wherein the compound of Formula IV is 3-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one.