IP Library › Granted Patent US 9,238,640

Granted Patent B2

US 9,238,640 · App. 13/257,082 · Granted Jan 19, 2016

Anti-inflammatory agents

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Quick Facts

Patent No.: US 9,238,640
App. No.: 13/257,082
Granted: Jan 19, 2016
Kind: B2

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Abstract

Disclosed are novel compounds that are useful in regulating the expression of interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1), and their use in the treatment and/or prevention of cardiovascular and inflammatory diseases and related disease states, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s). Also, disclosed are compositions comprising the novel compounds, as well as methods for their preparation.

Claims (173)

1. A method for treating non-cardiovascular inflammatory disorders mediated by VCAM-1 or IL-6, comprising administering a therapeutically effective amount of at least one compound of Formula III:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:

Q is CR 12 ;

V is nitrogen;

U is C═O;

X is selected from oxygen, sulfur, SR 1 , nitrogen, and CR 6 R 7 ;

Z is selected from unsubstituted C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with one or more groups selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, cyclopropyl, hydroxyl, amino, and halogen;

n is 0, 1, 2, 3, 4, or 5;

G is selected from heterocycle, cycloalkyl, and aryl;

R 1 is selected from hydrogen and C 1 -C 6 alkyl;

R 6 , R 7 , and R 12 are independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocycle, C 1 -C 6 alkoxy, and halogen;

Rc is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

Ra 1 , Ra 2 , and Ra 3 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, halogen, amino, amide, hydroxyl, and heterocycle, wherein Ra 1 and Ra 2 and/or Ra 2 and Ra 3 may be connected to form a cycloalkyl or a heterocycle;

Rb 2 and Rb 6 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkenyl, hydroxyl, and amino; and

Rb 3 and Rb 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, and amino, wherein

Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a cycloalkyl or a heterocycle;

provided that

if Ra 1 and Ra 3 are OMe, and Q=CH, then

is not

at least one of Ra 1 , Ra 2 , and Ra 3 is not hydrogen; and

if Ra 2 or Ra 3 is chloro, then Ra 1 is not hydrogen.

2. The method according to claim 1 , wherein

U is C═O;

Q is CR 12 ;

V is nitrogen;

Z is unsubstituted C 1 -C 6 alkyl;

R 12 is selected from C 1 -C 6 alkoxy and halogen;

Rc is selected from hydrogen and C 1 -C 6 alkyl;

Ra 2 is selected from hydrogen and C 1 -C 6 alkoxy;

Ra 1 and Ra 3 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, and heterocycle;

Rb 2 and Rb 6 are both hydrogen;

Rb 3 and Rb 5 are independently selected from hydrogen and C 1 -C 6 alkyl;

X is selected from oxygen and CH 2 ;

n is 0, 1, 2, 3, or 4; and

G is selected from heterocycle, cycloalkyl, and aryl.

3. The method according to claim 2 , wherein

U is C═O;

Q is CR 12 ;

R 12 is selected from methoxy and chlorine;

Rc is selected from hydrogen and (pyrrolidin-1-yl)propyl;

Ra 2 is selected from hydrogen and methoxy;

Ra 1 and Ra 3 are independently selected from hydrogen, methyl, chlorine, fluorine, methoxy, isopropoxy, and pyrrolidin-1-yl;

Rb 2 and Rb 6 are both hydrogen;

Rb 3 and Rb 5 are independently selected from hydrogen and methyl; and

is selected from (N,N-dimethylpiperidine-1-carboxamide)-4-oxy, 1-acetylpiperidin-4-yloxy, 2-(isoindolin-2-yl)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 4-(pyrrolidin-1-yl)butoxy, (4-acetylpiperazin-1-yl)ethoxy, (1H-imidazol-1-yl)ethoxy, (4-methylpiperazin-1-yl)ethoxy, (piperidin-1-yl)ethoxy, (1-isopropylimidazolidine-2,4-dione)-3-ethoxy, (5-phenylimidazolidine-2,4-dione)-3-ethoxy, (imidazolidine-2,4-dione)-3-methyl, (2-azepan-1-yl)ethoxy, (2-azetidin-1-yl)ethoxy, N-(azetidin-3-yl)acetamide-1-ethoxy, (isoindoline-1,3-dione)-2-ethoxy, (5-oxopyrrolidin-2-yl)methoxy, (4-isopropylpiperazin-1-yl)methyl, N-isopropyl-N-(piperidin-4-methyl)acetamide-1-methyl, (4-(isopropylamino)piperidin-1-yl)methyl, (pyrrolidine-2,5-dione)ethoxy, and (1H-tetrazol-5-yl)methyl.

4. The method according to claim 1 , comprising administering a therapeutically effective amount of at least one compound selected from:

2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;

2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)-N,N-dimethylpiperidine-1-carboxamide;

2-(4-(1-acetylpiperidin-4-yloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-(isoindolin-2-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methoxyquinazolin-4(3H)-one;

5,7-dichloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxy-3-(3-(pyrrolidin-1-yl)propyl)quinazolin-4(3H)-one;

2-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-(1H-imidazol-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-methoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-dimethoxy-2-(3-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;

3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1-isopropylimidazolidine-2,4-dione;

2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(4-(pyrrolidin-1-yl)butoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-methoxyquinazolin-4(3H)-one;

3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-5-phenylimidazolidine-2,4-dione;

3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)imidazolidine-2,4-dione;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-methoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-fluoro-5-(pyrrolidin-1-yl)quinazolin-4(3H)-one;

5-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;

2-(4-(2-(azepan-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-4(3H)-one;

2-(4-(2-(azetidin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

N-(1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)azetidin-3-yl)acetamide;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxyquinazolin-4(3H)-one;

8-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethylquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxypyrido[2,3-d]pyrimidin-4(3H)-one;

2-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isoindoline-1,3-dione;

(S)-2-(3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)piperidin-4-yl)-N-isopropylacetamide;

2-(4-((4-(isopropylamino)piperidin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; and

2-(4-((1H-tetrazol-5-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one, or a pharmaceutically acceptable salt or hydrate thereof.

5. The method according to claim 1 , wherein the therapeutically effective amount of the compound is administered with at least one pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

6. A compound of Formula III:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:

Q is CR 12 ;

V is nitrogen;

U is C═O;

Is selected from (N,N-dimethylpiperidine-1-carboxamide)-4-oxy, 1-acetylpiperidin-4-yloxy, 2-(isoindolin-2-yl)ethoxy, (4-acetylpiperazin-1-yl)ethoxy, (1H-imidazol-1-yl)ethoxy, (piperidin-1-yl)ethoxy, (1-isopropylimidazolidine-2,4-dione)-3-ethoxy, (5-phenylimidazolidine-2,4-dione)-3-ethoxy, (imidazolidine-2,4-dione)-3-methyl, (2-azepan-1-yl)ethoxy, (2-azetidin-1-yl)ethoxy, N-(azetidin-3-yl)acetamide-1-ethoxy, (5-oxopyrrolidin-2-yl)methoxy, (4-isopropylpiperazin-1-yl)methyl, N-isopropyl-N-(piperidin-4-methyl)acetamide-1-methyl, (4-(isopropylamino)piperidin-1-yl)methyl, (pyrrolidine-2,5-dione)ethoxy, and (1H-tetrazol-5-yl)methyl;

R 12 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and halogen;

Rc is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

Rb 2 and Rb 6 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkenyl, hydroxyl, and amino; and

Rb 3 and Rb 5 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, hydroxyl, and amino, wherein

Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a cycloalkyl or a heterocycle;

provided that

at least one of Ra 1 , Ra 2 , and Ra 3 is not hydrogen; and

if Ra 2 or Ra 3 is chloro, then Ra 1 is not hydrogen.

7. The compound according to claim 6 , wherein:

Q is CR 12 ;

V is nitrogen;

R 12 is selected from C 1 -C 6 alkoxy and halogen;

Rc is selected from hydrogen and C 1 -C 6 alkyl;

Ra 2 is selected from hydrogen and C 1 -C 6 alkoxy;

Ra 1 and Ra 3 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, and heterocycle;

Rb 2 and Rb 6 are both hydrogen;

Rb 3 and Rb 5 are independently selected from hydrogen and C 1 -C 6 alkyl.

8. The compound according to claim 7 , wherein:

Q is CR 12 ;

V is nitrogen;

R 12 is selected from methoxy and chlorine;

Rc is selected from hydrogen and (pyrrolidin-1-yl)propyl;

Ra 2 is selected from hydrogen and methoxy;

Ra 1 and Ra 3 are independently selected from hydrogen, methyl, chlorine, fluorine, methoxy, isopropoxy, and pyrrolidin-1-yl;

Rb 2 and Rb 6 are both hydrogen; and

Rb 3 and Rb 5 are independently selected from hydrogen and methyl.

9. A compound selected from: