Anti-inflammatory agents
View Patent ↗Disclosed are methods of regulating interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1) and methods of treating and/or preventing 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) by administering a naturally occurring or synthetic quinazolone derivative. The invention provides novel synthetic quinazolone compounds, as well as pharmaceutical compositions comprising those compounds.
1. A method of treating or reducing the risk of acquiring asthma, chronic obstructive pulmonary disease (COPD), or a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of a composition consisting essentially of a compound of Formula II:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
P is selected from N and CRa 1 ;
V is selected from N and CRa 4 ;
W is selected from N and CH;
U is selected from C═O, C═S, SO 2 , S═O, and SR 1 ;
Ra 1 and Ra 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and halogen;
Ra 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and halogen, wherein the C 1 -C 6 alkoxy is optionally
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl;
Ra 2 is selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 1 -C 6 alkoxy, heterocycle, amino, amide, fluoro, and bromo;
Rb 2 and Rb 6 are independently selected from hydrogen, methyl, and fluoride;
Rb 3 and Rb 5 are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen, and amino;
Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a cycloalkyl, phenyl or heterocycle; and
XRd is selected from 2-hydroxyethoxy, 2,3-dihydroxypropoxy, aminocarbonylethoxy, methylaminocarbonylethoxy, (4-methoxyphenyl)aminocarbonylethoxy, benzylaminocarbonylethoxy, 4-hydroxybutoxy, methylcarbonylaminoethoxy, methylcarbonylaminomethyl, (2,2,2-trifluoro-ethylamino)ethoxy, methanesulfonylaminoethoxy, isobutyrylaminoethoxy, methylaminoethoxy, isopropylsulfonylaminoethoxy, methylcarbonylaminoethoxy, dimethylaminoethoxy, N-(2-hydroxyethyl)-N-methylacetamide, formamide-N-2-ethoxy, methylformamide-N-2-ethoxy, dimethylsulfonylaminoethoxy, cyanoaminoethoxy, 3-hydroxypropyl, and 2-hydroxyethyl,
provided that
at least one of Ra 1 , Ra 2 , Ra 1 , and Ra 4 is not hydrogen; and
if —XRd is —OCH 2 CH 2 OH, then Rb 3 is not pyrrolidine.
2. The method according to claim 1 , wherein:
U is C═O
P is CRa 1 ;
Ra 1 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogen;
Ra 2 is selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 1 -C 6 alkoxy, heterocycle, amide, and amino;
Ra 4 is selected from hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and halogen;
Ra 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogen, wherein the C 1 -C 6 alkoxy is optionally
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl; and
Rb 3 and Rb 5 are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen, and amino, wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
3. The method according to claim 2 , wherein Ra 1 is selected from hydrogen, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 alkoxy, and halogen.
4. The method according to claim 2 , wherein Ra 2 is selected from hydrogen, C 1 -C 6 alkyl substituted with heterocyclyl, unsubstituted C 1 -C 6 alkoxy, amino, and heterocycle.
5. The method according to claim 2 , wherein:
Ra 3 is selected from hydrogen, methoxy, unsubstituted C 1 -C 6 alkyl, halogen, and
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl.
6. The method according to claim 2 , wherein Ra 4 is selected from hydrogen, unsubstituted C 1 -C 6 alkoxy, and halogen.
7. The method according to claim 2 , wherein Rb 3 and Rb 5 are independently selected from hydrogen, methyl, C 1 -C 6 alkyl substituted with heterocyclyl, and unsubstituted C 1 -C 6 alkoxy wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
8. The method according to claim 7 , wherein Rb 3 and Rb 5 are independently selected from hydrogen, methyl, methoxy, and morpholinomethyl, and wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
9. A method of treating or reducing the risk of acquiring a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of a composition consisting essentially of a compound selected from:
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-morpholinoquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one;
5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one;
2-[4-(2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-naphthalen-1-yl]-5,7-dimethoxy-3H-quinazolin-4-one;
7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one;
7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one;
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetamide;
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-methyl-acetamide;
2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide;
N-benzyl-2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetamide;
2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;
7-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one;
5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one;
N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide;
N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylbenzyl)acetamide;
N-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-benzyl]-acetamide;
2-{3,5-Dimethyl-4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one;
N-{2-[4-(6, 8-Dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-formamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide;
2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide;
2-(4-(2-(isopropylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)acetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)isobutyramide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)methanesulfonamide;
2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)-N-methylacetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)formamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)-N-methylformamide;
N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)dimethylamino-N-sulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)cyanamide;
2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(3-hydroxy-propyl)-3-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[2-(2-hydroxyethyl)-1H-indol-6-yl]-5,7-dimethoxy-3H-quinazolin-4-one, and
tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates thereof.
10. 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.
11. The method according to claim 1 , wherein the disease is selected from cystic fibrosis, post transplantation late and chronic solid organ rejection, systemic lupus erythematosus, ocular inflammation, uveitis, rhinitis, glomerulonephritis, Grave's disease, gastrointestinal allergies, and conjunctivitis.
12. A method for treating a cancer associated with elevated levels of IL-6, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula II:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
P is selected from N and CRa 1 ;
V is selected from N and CRa 4 ;
W is selected from N and CH;
U is selected from C═O, C═S, SO 2 , S═O, and SR 1 ;
Ra 1 and Ra 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and halogen;
Ra 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloakyl, and halogen, wherein the C 1 -C 6 alkoxy is optionally
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl;
Ra 2 is selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 1 -C 6 alkoxy, heterocycle, amino, amide, fluoro, and bromo;
Rb 2 and Rb 6 are independently selected from hydrogen, methyl, and fluoride;
Rb 3 and Rb 5 are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen, and amino;
Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a cycloalkyl, phenyl or heterocycle; and
XRd is selected from 2-hydroxyethoxy, 2,3-dihydroxypropoxy, aminocarbonylethoxy, methylaminocarbonylethoxy, (4-methoxyphenyl)aminocarbonylethoxy, benzylaminocarbonylethoxy, 4-hydroxybutoxy, methylcarbonylaminoethoxy, methylcarbonylaminomethyl, (2,2,2-trifluoro-ethylamino)ethoxy, methanesulfonylaminoethoxy, isobutyrylaminoethoxy, methylaminoethoxy, isopropylsulfonylaminoethoxy, methylcarbonylaminoethoxy, dimethylaminoethoxy, N-(2-hydroxyethyl)-N-methylacetamide, formamide-N-2-ethoxy, methylformamide-N-2-ethoxy, dimethylsulfonylaminoethoxy, cyanoaminoethoxy, 3-hydroxypropyl, and 2-hydroxyethyl,
provided that
at least one of Ra 1 , Ra 2 , Ra 3 , and Ra 4 is not hydrogen; and
if —XRd is —OCH 2 CH 2 OH, then Rb 3 is not pyrrolidine.
13. The method according to claim 12 , wherein:
U is C═O
P is CRa 1 ;
Ra 1 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogen;
Ra 2 is selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 1 -C 6 alkoxy, heterocycle, amide, and amino;
Ra 4 is selected from hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and halogen;
Ra 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogen, wherein the C 1 -C 6 alkoxy is optionally
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl; and
Rb 3 and Rb 5 are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen, and amino, wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
14. The method according to claim 13 , wherein Ra 1 is selected from hydrogen, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 alkoxy, and halogen.
15. The method according to claim 13 , wherein Ra 2 is selected from hydrogen, C 1 -C 6 alkyl substituted with heterocyclyl, unsubstituted C 1 -C 6 alkoxy, amino, and heterocycle.
16. The method according to claim 13 , wherein:
Ra 3 is selected from selected from hydrogen, methoxy, unsubstituted C 1 -C 6 alkyl, halogen, and
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl.
17. The method according to claim 13 , wherein Ra 4 is selected from hydrogen, unsubstituted C 1 -C 6 alkoxy, and halogen.
18. The method according to claim 13 , wherein Rb 3 and Rb 5 are independently selected from hydrogen, methyl, C 1 -C 6 alkyl substituted with heterocyclyl, and unsubstituted C 1 -C 6 alkoxy wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
19. The method according to claim 18 , wherein Rb 3 and Rb 5 are independently selected from hydrogen, methyl, methoxy, and morpholinomethyl, and wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
20. A method for treating a cancer associated with elevated levels of IL-6, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound selected from:
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-morpholinoquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one;
5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one;
2-[4-(2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-naphthalen-1-yl]-5,7-dimethoxy-3H-quinazolin-4-one;
7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one;
7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one;
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetamide;
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-methyl-acetamide;
2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide;
N-benzyl-2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetamide;
2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;
7-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one;
5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one;
N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide;
N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylbenzyl)acetamide;
N-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-benzyl]-acetamide;
2-{3,5-Dimethyl-4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one;
N-{2-[4-(6, 8-Dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-formamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide;
2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide;
2-(4-(2-(isopropylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)acetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)isobutyramide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)methanesulfonamide;
2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylacetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)formamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)-N-methylformamide;
N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)dimethylamino-N-sulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2, 6-dimethylphenoxy)ethyl)cyanamide;
2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(3-hydroxy-propyl)-3-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; and
2-[2-(2-hydroxyethyl)-1H-indol-6-yl]-5,7-dimethoxy-3H-quinazolin-4-one, and
tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof.
21. The method according to claim 12 , wherein the therapeutically effective amount of the compound is administered with at least one pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.
22. The method according to claim 12 , wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladder cancers, cardiac myxoma, tumor-induced cachexia, cancer-associated depression, cerebral edema secondary to brain tumors, hormone-independent prostate cancer, B cell lymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma.
23. A method of treating or reducing the risk of acquiring asthma chronic obstructive pulmonary disease (COPD), or a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula II:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
P is selected from N and CRa 1 ;
V is selected from N and CRa 4 ;
W is selected from N and CH;
U is selected from C═O, C═S, SO 2 , S═O, and SR 1 ;
Ra 1 and Ra 4 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and halogen;
Ra 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloakyl, and halogen, wherein the C 1 -C 6 alkoxy is optionally
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl;
Ra 2 is selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 1 -C 6 alkoxy, heterocycle, amino, amide, fluoro, and bromo;
Rb 2 and Rb 6 are independently selected from hydrogen, methyl, and fluoride;
Rb 3 and Rb 5 are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen, and amino;
Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a cycloalkyl, phenyl or heterocycle; and
XRd is selected from 2-hydroxyethoxy, 2,3-dihydroxypropoxy, aminocarbonylethoxy, methylaminocarbonylethoxy, (4-methoxyphenyl)aminocarbonylethoxy, benzylaminocarbonylethoxy, 4-hydroxybutoxy, methylcarbonylaminoethoxy, methylcarbonylaminomethyl, (2,2,2-trifluoro-ethylamino)ethoxy, methanesulfonylaminoethoxy, isobutyrylaminoethoxy, methylaminoethoxy, isopropylsulfonylaminoethoxy, methylcarbonylaminoethoxy, dimethylaminoethoxy, N-(2-hydroxyethyl)-N-methylacetamide, formamide-N-2-ethoxy, methylformamide-N-2-ethoxy, dimethylsulfonylaminoethoxy, cyanoaminoethoxy, 3-hydroxypropyl, and 2-hydroxyethyl,
provided that
at least one of Ra 1 , Ra 2 , Ra 3 , and Ra 4 is not hydrogen;
if —XRd is —OCH 2 CH 2 OH, then Rb 3 is not pyrrolidine;
and
wherein the compound is not 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one.
24. The method according to claim 23 , wherein:
U is C═O
P is CRa 1 ;
Ra 1 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogen;
Ra 2 is selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 1 -C 6 alkoxy, heterocycle, amide, and amino;
Ra 4 is selected from hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and halogen;
Ra 3 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogen, wherein the C 1 -C 6 alkoxy is optionally
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl; and
Rb 3 and Rb 5 are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with heterocyclyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen, and amino, wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
25. The method according to claim 24 , wherein Ra 1 is selected from hydrogen, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 alkoxy, and halogen.
26. The method according to claim 24 , wherein Ra 2 is selected from hydrogen, C 1 -C 6 alkyl substituted with heterocyclyl, unsubstituted C 1 -C 6 alkoxy, amino, and heterocycle.
27. The method according to claim 24 , wherein:
Ra 3 is selected from selected from hydrogen, methoxy, unsubstituted C 1 -C 6 alkyl, halogen, and
n is 1, 2, or 3; and
R 5 is C 1 -C 6 alkyl substituted with phenyl or heteroaryl.
28. The method according to claim 24 , wherein Ra 4 is selected from hydrogen, unsubstituted C 1 -C 6 alkoxy, and halogen.
29. The method according to claim 24 , wherein Rb 3 and Rb 5 are independently selected from hydrogen, methyl, C 1 -C 6 alkyl substituted with heterocyclyl, and unsubstituted C 1 -C 6 alkoxy wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
30. The method according to claim 29 , wherein Rb 3 and Rb 5 are independently selected from hydrogen, methyl, methoxy, and morpholinomethyl, and wherein Rb 2 and Rb 3 and/or Rb 5 and Rb 6 may be connected to form a phenyl ring.
31. A method of treating or reducing the risk of acquiring a non-cardiovascular inflammatory disease mediated by IL-6 in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound selected from:
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-morpholinoquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-4(3H)-one;
5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl]-6-morpholin-4-ylmethyl-3H-quinazolin-4-one;
2-[4-(2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-6-morpholin-4-ylmethyl-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(2-hydroxy-ethoxy)-naphthalen-1-yl]-5,7-dimethoxy-3H-quinazolin-4-one;
7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one;
7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one;
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetamide;
2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-methyl-acetamide;
2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide;
N-benzyl-2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]acetamide;
2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;
7-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
8-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-8-methoxyquinazolin-4(3H)-one;
5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one;
N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide;
N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylbenzyl)acetamide;
N-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-benzyl]-acetamide;
2-{3,5-Dimethyl-4-[2-(2,2,2-trifluoro-ethylamino)-ethoxy]-phenyl}-5,7-dimethoxy-3H-quinazolin-4-one;
N-{2-[4-(6, 8-Dimethoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-2,6-dimethyl-phenoxy]-ethyl}-formamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)acetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isobutyramide;
2-(3,5-dimethyl-4-(2-(methylamino)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide;
2-(4-(2-(isopropylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)acetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)isobutyramide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylphenoxy)ethyl)methanesulfonamide;
2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylacetamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)formamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N-methylformamide;
N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)dimethylamino-N-sulfonamide;
N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)cyanamide;
2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7-dimethoxy-3H-quinazolin-4-one;
2-[4-(3-hydroxy-propyl)-3-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one; and
2-[2-(2-hydroxyethyl)-1H-indol-6-yl]-5,7-dimethoxy-3H-quinazolin-4-one, and
tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates thereof.
32. The method according to claim 23 , wherein the therapeutically effective amount of the compound is administered with at least one pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.
33. The method according to claim 23 , wherein the disease is selected from cystic fibrosis, post transplantation late and chronic solid organ rejection, systemic lupus erythematosus, ocular inflammation, uveitis, rhinitis, glomerulonephritis, Grave's disease, gastrointestinal allergies, and conjunctivitis.
34. The method according to claim 1 or 23 , wherein the disease is asthma.
35. The method of claim 11 or claim 33 , wherein the disease is selected from liver transplant rejection, heart transplant rejection, kidney transplant rejection, proliferative glomerulonephritis, and membranous glomerulonephritis.
36. The method according to claim 12 , wherein the cancer is selected from uterine cancer, multiple myeloma, histiocytomas, plasmacytoma, hormone-independent prostate cancer, cancer induced cachexia, B cell lymphoma, and metastatic renal cell carcinoma.