NOVEL ANTI-INFLAMMATORY AGENTS
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 - 46 . (canceled)
47 . A method of treating infectious disease or cancer mediated by IL-6 in a subject in need thereof comprising administering a therapeutically effective amount of at least one compound of Formula I:
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
Q is N or CRa 3 ;
V is N or CRa 4 ;
W is N or CH;
U is C═O, C═S, SO 2 , or S═O;
X is OH, SH, NH 2 , S(O)H, S(O) 2 H, S(O) 2 NH 2 , S(O)NH 2 , NHAc, or NHSO 2 Me;
Ra 1 , Ra 3 , and Ra 4 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, or halogen;
Ra 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, amino, amide, or halogen;
Rb 2 and Rb 6 are independently hydrogen, methyl or fluorine;
Rb 3 and Rb 5 are independently hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy; and
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 , Ra 3 , and Ra 4 is not hydrogen.
48 . The method according to claim 47 , wherein:
U is C═O;
Q is CRa 3 ;
X is OH, NH 2 , S(O) 2 NH 2 , NHAc, or NHSO 2 Me;
Ra 1 is hydrogen or C 1 -C 6 alkoxy;
Ra 2 is hydrogen, C 1 -C 6 alkoxy, amino, amide, or C 1 -C 6 alkyl;
Ra 3 and Ra 4 are independently hydrogen or C 1 -C 6 alkoxy;
Rb 2 and Rb 6 are both hydrogen; and
Rb 3 and Rb 5 are independently C 1 -C 6 alkyl or halogen.
49 . The method according to claim 48 , wherein:
Ra 3 is hydrogen, methoxy,
wherein
n is 1, 2, or 3;
R 1 , R 1 ′, R 2 , and R 2 ′ are independently hydrogen, C 1 -C 3 alkyl, cyclopropyl, or halogen wherein if n is 1, then R 2 and R 2 ′, R 1 and R 1 ′, R 1 and R 2 ′, or R 2 and R 1 ′ may form a double bond, wherein said double bond can be cis, trans, or a mixture thereof;
Rx is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl; and
Rn 1 and Rn 2 are independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl.
50 . The method according to claim 48 , wherein:
Ra 3 is hydrogen, methoxy,
wherein
n is 1, 2, or 3;
R 5 is C 1 -C 6 alkyl substituted with one or more groups which is methyl, phenyl, or pyridinyl; and
R 6 and R 7 are independently unsubstituted C 1 -C 6 alkyl.
51 . The method according to claim 50 , wherein Ra 3 is hydrogen, methoxy, 2-methoxy-ethoxy, 2-dimethylamino-ethoxy, 2-benzyloxy-ethoxy, or 2-(pyridin-3-ylmethoxy)ethoxy.
52 . The method according to claim 48 , wherein Ra 4 is hydrogen or unsubstituted C 1 -C 6 alkoxy.
53 . The method according to claim 52 , wherein Ra 4 is hydrogen or methoxy.
54 . The method according to claim 48 , wherein X is OH.
55 . The method according to claim 48 , wherein:
Ra 1 is hydrogen, methoxy,
wherein
n is 0, 1, or 3;
R 1 , R 1 ′, R 2 , and R 2 ′ are independently hydrogen, C 1 -C 3 alkyl, cyclopropyl, or halogen wherein if n is 1, then R 2 and R 2 ′, R 1 and R 1 ′, R 1 and R 2 ′, or R 2 and R 1 ′ may form a double bond, wherein said double bond can be cis, trans, or a mixture thereof;
Rx is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl; and
Rn 1 and Rn 2 are independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl.
56 . The method according to claim 48 , wherein:
Ra 1 is hydrogen, methoxy,
n is 1, 2, or 3; and
R 5 , R 6 and R 7 are independently unsubstituted C 1 -C 6 alkyl.
57 . The method according to claim 56 , wherein Ra 1 is hydrogen, methoxy, 2-methoxy-ethoxy, or 2-dimethylamino-ethoxy.
58 . The method according to claim 48 , wherein:
Ra 2 is hydrogen, unsubstituted C 1 -C 6 alkoxy, NHR 9 , or C 1 -C 6 alkyl substituted with heterocycle or amino; and
R 9 is acyl or heteroaryl.
59 . The method according to claim 58 , wherein Ra 2 is hydrogen, methoxy, acetamido, morpholin-4-ylmethyl, pyridin-2-ylamino, (4-methylpiperazin-1-yl)methyl, or methanesulfonamido.
60 . The method according to claim 48 , wherein Rb 3 and Rb 5 are independently unsubstituted C 1 -C 6 alkyl or halogen.
61 . The method according to claim 60 , wherein Rb 3 and Rb 5 are independently methyl, tert-butyl, fluorine, or chlorine.
62 . A method of treating infectious disease or cancer mediated by IL-6 in a subject in need thereof comprising administering a therapeutically effective amount of at least one compound of Formula I, wherein the compound of Formula I is:
3-(3-fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1 (2H)-one;
3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1 (2H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;
N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;
2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one;
5-(2-dimethylamino-ethoxy)-2(4-hydroxy-3,5-dimethylphenyl)-7-methoxy-3H-quinazolin-4-one;
2-(4-hydroxy-3,5-dimethyl-phenyl)-7-methoxy-5-(2-methoxy-ethoxy)-3H-quinazolin-4-one;
7-(2-amino-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one;
2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-7-(2-methoxy-ethoxy)-3H-quinazolin-4-one;
7-(2-benzyloxy-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one;
2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-7-[2-(pyridin-3-ylmethoxy)ethoxy]-3H-quinazolin-4-one;
7-(2-dimethylamino-ethoxy)-2-(4-hydroxy-3,5-dimethylphenyl)-3H-quinazolin-4-one;
2-(4-hydroxy-3,5-dimethyl-phenyl)-6-(pyridin-4-ylamino)-3H-quinazolin-4-one;
2-(4-hydroxy-3,5-dimethyl-phenyl)-6-(pyridin-2-ylamino)-3H-quinazolin-4-one;
2-(4-hydroxy-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one; or
N-((2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)methanesulfonamide, or a
tatutomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof.
63 . The method according to claim 47 , wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladder cancers, cardiac myxoma, tumor-induced cachexia, cerebral edema secondary to brain tumors, hormone-independent prostate cancer, B cell lymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma.
64 . The method according to claim 62 , wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladder cancers, cardiac myxoma, tumor-induced cachexia, cerebral edema secondary to brain tumors, hormone-independent prostate cancer, B cell lymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma.