US2003087957A1PendingUtilityA1
Alpha-aryl-N-alkylnitrones and pharmaceutical compositions containing the same
Priority: Oct 17, 1997Filed: Feb 11, 2002Published: May 8, 2003
Est. expiryOct 17, 2017(expired)· nominal 20-yr term from priority
A61P 37/06A61P 27/02A61P 29/00A61P 25/00C07C 2601/04A61P 19/02C07C 2601/14A61K 31/36C07C 291/04A61P 1/04A61P 11/00C07C 2603/74A61K 31/04C07C 2601/18A61P 21/00C07C 2601/08C07C 291/02
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Claims
Abstract
Disclosed are novel α-aryl-N-alkylnitrone compounds and pharmaceutical compositions containing such compounds. The disclosed compositions are useful as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals and as analytical reagents for detecting free radicals.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substituted alkyl having at least 3 carbon atoms and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R 5 is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 1 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
2 . The compound according to claim 1 wherein R 4 is hydrogen.
3 . The compound according to claim 2 wherein R 3 is selected from the group consisting of hydrogen and alkoxy.
4 . The compound according to claim 3 wherein R 2 is selected from the group consisting of hydrogen, alkoxy and fluoro.
5 . The compound according to claim 4 wherein R 1 is selected from the group consisting of alkoxy, alkaryloxy and cycloalkoxy.
6 . The compound according to claim 4 wherein R 1 and R 2 are joined together to form an alkylenedioxy group.
7 . The compound according to claim 5 or 6 wherein R 5 is selected from the group consisting of alkyl having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 10 carbon atoms.
8 . The compound according to claim 7 wherein R 5 is selected from the group consisting of n-propyl, isopropyl, 1-methoxy2-methylproo-2-yl, n-butyl, but-2-yl, tert-butyl, 2-methylbut-2-yl, 3-methylbut-1-yl, 3,3-dimethylbut-2-yl, 4-methylpent-2-yl, 2,4-dimethyl-2-pentyl, 2,2,4,4-tetramethylpent-3-yl, cyclopropyl, cyclobutyl, tert-octyl, cyclopentyl, cyclohexyl, cyclooctyl, 1-adamantyl, 2-adamantyl, 3,5-dimethyl-1-adamantyl and benzyl.
9 . A compound of formula II:
wherein
R 6 is selected from the group consisting of alkoxy having 1 to 8 carbon atoms, alkaryloxy having 7 to 10 carbon atoms and aryloxy having 6 to 10 carbon atoms;
R 7 is selected from the group consisting of alkoxy having 1 to 8 carbon atoms and fluoro, or when R 6 and R 7 are attached to adjacent carbon atoms, R 6 and R 7 may be joined together to form an alkylenedioxy group having 1 to about 6 carbon atoms;
R 8 is selected from the group consisting of hydrogen and alkoxy having 1 to 8 carbon atoms; and
R 9 is selected from the group consisting of alkyl having 3 to about 8 carbon atoms, substituted alkyl having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 10 carbon atoms;
provided that:
(i) when R 7 is methoxy and R 8 is hydrogen or methoxy, R 6 is not methoxy;
(ii) when R 6 and R 7 are joined together to form a 3,4-methylenedioxy group and R 8 is hydrogen, then R 9 is not isopropyl or tert-butyl; and
(iii) when R 6 is 4-methoxy, R 7 is 3-ethoxy and R 8 is hydrogen, then R 9 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl.
10 . The compound according to claim 9 wherein R 6 is alkoxy having 1 to 8 carbon atoms, R 7 is alkoxy having 2 to 8 carbon atoms and R 8 is hydrogen.
11 . The compound according to claim 10 wherein R 6 is methoxy, R 7 is ethoxy and R 8 is hydrogen.
12 . The compound according to claim 9 wherein R 6 is ethoxy; and R 7 and R 8 are hydrogen.
13 . The compound according to claim 9 wherein R 6 is benzyloxy, R 7 is alkoxy having 1 to 8 carbon atoms, and R 8 is hydrogen.
14 . The compound according to claim 9 wherein R 6 is benzyloxy; and R 7 and R 8 are hydrogen.
15 . The compound according to claim 9 wherein R 6 is alkoxy having 1 to 8 carbon atoms, R 7 is fluoro and R 8 is hydrogen.
16 . The compound according to claim 9 wherein R 6 and R 7 are joined together to form a methylenedioxy or ethylenedioxy group and R 8 is hydrogen.
17 . The compound according to claim 9 wherein R 6 , R 7 and R 8 are each independently alkoxy having 2 to 8 carbon atoms.
18 . A compound selected from the group consisting of:
α-(4-heptyloxyphenyl)-N-tert-butylnitrone α-(4-hexyloxyphenyl)-N-n-propylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-tert-butylnitrone α-(4-ethoxyphenyl)-N-tert-butylnitrone α-(4-benzyloxy-3-methoxyphenyl)-N-tert-butylnitrone α-[3-(4-methoxyphenoxy)phenyl]-N-tert-butylnitrone α-(2-ethoxyphenyl)-N-tert-butylnitrone α-(3,4-ethylenedioxyphenyl)-N-tert-butylnitrone α-(3,4-methylenedioxyphenyl)-N-tert-butylnitrone α-(4-ethoxyphenyl)-N-cyclohexylnitrone α-(4-benzyloxy-3-methoxyphenyl)-N-cyclohexylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-cyclohexylnitrone α-(3,4-ethylenedioxyphenyl)-N-cyclohexylnitrone α-(4-ethoxy-3-methoxyphenyl)-N-cyclohexylnitrone α-(3,4-ethylenedioxyphenyl)-N-isopropylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-isopropylnitrone α-(2-ethoxyphenyl)-N-isopropylnitrone α-(2-ethoxyphenyl)-N-cyclohexylnitrone α-(4-benzyloxy-3-methoxyphenyl)-N-isopropylnitrone α-(4-ethoxy-3-methoxyphenyl)-N-isopropylnitrone α-(3-ethoxy-4-hexyloxyphenyl)-N-cyclohexylnitrone α-(4-benzyloxy-3-methoxyphenyl)-N-n-butylnitrone α-(4-ethoxy-3-methoxyphenyl)-N-n-butylnitrone α-(2-ethoxyphenyl)-N-n-butylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-n-butylnitrone α-(3-ethoxy-4-hexyloxyphenyl)-N-isopropylnitrone α-(3-ethoxy-4-hexyloxyphenyl)-N-tert-butylnitrone α-(2-fluoro-4-octyloxyphenyl)-N-tert-butylnitrone α-(2,4,6-triethoxyphenyl)-N-tert-butylnitrone α-(2,4,6-triethoxyphenyl)-N-cyclohexylnitrone α-(2-n-butoxyphenyl)-N-tert-butyylnitrone α-(3,4-diethoxyphenyl)-N-tert-butylnitrone α-(2-fluoro-4-heptyloxyphenyl)-N-tert-butylnitrone α-(2-fluoro-4-ethoxyphenyl)-N-tert-butylnitrone α-(2-fluoro-4-ethoxyphenyl)-N-cyclohexylnitrone α-(2-ethoxyphenyl)-N-adamantylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-adamantylnitrone α-(4-ethoxyphenyl)-N-cyclopentylnitrone α-(4-ethoxyphenyl)-N-tert-octylnitrone α-(4-benzyloxyphenyl)-N-tert-butylnitrone α-(4-benzyloxyphenyl)-N-cyclopentylnitrone α-(4-benzyloxyphenyl)-N-cyclohexylnitrone α-(2-ethoxyphenyl)-N-cyclopentylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-tert-octylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-(2,4-dimethyl-2-pentyl)nitrone α-(4-ethoxyphenyl)-N-n-butylnitrone α-(2-ethoxyphenyl)-N-benzylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-(2,2,4,4-tetramethylpent-3-yl)nitrone α-(3-ethoxy-4-methoxyphenyl)-N-(4-methylpent-2-yl)nitrone α-(3-ethoxy-4-methoxyphenyl)-N-2-methylbut-2-yl)nitrone α-(2-ethoxyphenyl)-N-but-2-ylnitrone α-[4-(4-fluorobenzyloxy)phenyl]-N-tert-butylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-cyclopentylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-n-propylnitrone α-(4-benzyloxyphenyl)-N-n-propylnitrone α-(4-benzyloxyphenyl)-N-isopropylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-(2-methylbut-2-yl)nitrone α-(2-ethoxyphenyl)-N-(2-methylbut-2-yl)nitrone α-(3-ethoxy-4-methoxyphenyl)-N-cyclooctylnitrone α-(2-ethoxyphenyl)-N-cyclobutylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-cyclobutylnitrone α-(4-benzyloxyphenyl)-N-cyclobutylnitrone α-(4-benzyloxyphenyl)-N-tert-octylnitrone α-[4-(4-fluorobenzyloxy)phenyl]-N-cyclohexylnitrone α-(2-ethoxyphenyl)-N-tert-octylnitrone α-[4-(4-fluorobenzyloxy)phenyl]-N-isopropylnitrone α-(2-ethoxyphenyl)-N-cycloctylnitrone α-(4-benzyloxyphenyl)-N-cyclopropylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-cyclopropylnitrone α-(4-benzyloxyphenyl)-N-cyclooctylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-(3,5-dimethyl-1-adamantyl)nitrone α-(4-benzyloxyphenyl)-N-1-adamantylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-(1-methoxy-2-methylprop-2-yl)nitrone α-(4-benzyloxyphenyl)-N-2-adamantylnitrone. α-(4-ethoxyphenyl)-N-cyclooctylnitrone α-(4-ethoxyphenyl)-N-1-adamantylnitrone α-[4-(4-methoxybenzyloxy)phenyl]-N-tert-butylnitrone α-(3-ethoxy-4-methoxyphenyl)-N-(3-methylbut-1-yl)nitrone α-(3-ethoxy-4-methoxyphenyl)-N-cyclooctylnitrone, and α-[4-(4-fluorobenzyloxy)phenyl]-N-cyclopentylnitrone.
19 . α-(2-Ethoxyphenyl)-N-tert-butylnitrone.
20 . α-(2-Ethoxyphenyl)-N-cyclohexylnitrone.
21 . α-(4-Ethoxyphenyl)-N-cyclohexylnitrone.
22 . α-(4-Benzyloxyphenyl)-N-tert-butylnitrone.
23 . α-(4-Benzyloxyphenyl)-N-cyclopentylnitrone.
24 . α-(3-Ethoxy-4-methoxyphenyl)-N-adamantylnitrone.
25 . α-(3-Ethoxy-4-methoxyphenyl)-N-tert-octylnitrone.
26 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, alkcycloalkyl and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 1 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
27 . The pharmaceutical composition according to claim 26 wherein R 4 is hydrogen.
28 . The pharmaceutical composition according to claim 27 wherein R 3 is selected from the group consisting of hydrogen and alkoxy.
29 . The pharmaceutical composition according to claim 28 wherein R 2 is selected from the group consisting of hydrogen, alkoxy and fluoro.
30 . The pharmaceutical composition according to claim 29 wherein R 1 is selected from the group consisting of alkoxy, alkaryloxy and cycloalkoxy.
31 . The pharmaceutical composition according to claim 29 wherein R 1 and R 2 are joined together to form an alkylenedioxy group.
32 . The pharmaceutical composition according to claim 30 or 31 wherein R 5 is selected from the group consisting of alkyl having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 8 carbon atoms.
33 . The pharmaceutical composition according to claim 32 wherein R 5 is selected from the group consisting of n-propyl, isopropyl, 1-methoxy2-methylproo-2-yl, n-butyl, but-2-yl, tert-butyl, 2-methylbut-2-yl, 3-methylbut-1-yl, 3,3-dimethylbut-2-yl, 4-methylpent-2-yl, 2,4-dimethyl-2-pentyl, 2,2,4,4-tetramethylpent-3-yl, cyclopropyl, cyclobutyl, tert-octyl, cyclopentyl, cyclohexyl, cyclooctyl, 1-adamantyl, 2-adamantyl, 3,5-dimethyl-1-adamantyl and benzyl.
34 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of formula II:
wherein
R 6 is selected from the group consisting of alkoxy having 1 to 8 carbon atoms, alkaryloxy having 7 to 10 carbon atoms and aryloxy having 6 to 10 carbon atoms;
R 7 is selected from the group consisting of alkoxy having 1 to 8 carbon atoms and fluoro, or when R 6 and R 7 are attached to adjacent carbon atoms, R 6 and R 7 may be joined together to form an alkylenedioxy group having 1 to about 6 carbon atoms;
R 8 is selected from the group consisting of hydrogen and alkoxy having 1 to 8 carbon atoms; and
R 9 is selected from the group consisting of alkyl having 3 to about 8 carbon atoms, substituted alkyl having 3 to about 8 carbon atoms and cycloalkyl having 3 to about 10 carbon atoms;
provided that:
(i) when R 7 is methoxy and R 8 is hydrogen or methoxy, R 6 is not methoxy;
(ii) when R 6 and R 7 are joined together to form a 3,4-methylenedioxy group and R 8 is hydrogen, then R 9 is not isopropyl or tert-butyl; and
(iii) when R 6 is 4-methoxy, R 7 is 3-ethoxy and R 8 is hydrogen, then R 9 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl.
35 . The pharmaceutical composition according to claim 34 wherein R 6 is alkoxy having 1 to 8 carbon atoms, R 7 is alkoxy having 2 to 8 carbon atoms and R 8 is hydrogen.
36 . The pharmaceutical composition according to claim 35 wherein R 6 is methoxy, R 7 is ethoxy and R 8 is hydrogen.
37 . The pharmaceutical composition according to claim 34 wherein R 6 is benzyloxy, 4-fluorobenzyloxy or 4-methoxybenzyloxy and R 7 and R 8 are hydrogen.
38 . The pharmaceutical composition according to claim 34 wherein R 6 is ethoxy and R 7 and R 8 are hydrogen.
39 . The pharmaceutical composition according to claim 34 wherein R 6 is alkoxy having 1 to 8 carbon atoms, R 7 is fluoro and R 8 is hydrogen.
40 . The pharmaceutical composition according to claim 34 wherein R 6 and R 7 are joined together to form a methylenedioxy or ethylenedioxy group and R 8 is hydrogen.
41 . The pharmaceutical composition according to claim 34 wherein R 6 , R 7 and R 8 are each independently alkoxy having 2 to 8 carbon atoms.
42 . The pharmaceutical composition according to claim 26 or 34 wherein the carrier is an oral carrier.
43 . The pharmaceutical composition according to claim 26 or 34 wherein the carrier is an injectable carrier.
44 . A method for treating a patient with a neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-treating amount of a compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substitututed alkyl having at least 3 carbon atoms and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R 5 is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 1 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
45 . A method for preventing the onset of a neurodegenerative disease in a patient at risk for developing the neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-preventing amount of a compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substitututed alkyl having at least 3 carbon atoms and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R 5 is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 1 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 5 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
46 . The method according to claim 44 or 45 wherein the neurodegenerative disease is Alzheimer's disease.
47 . The method according to claim 44 or 45 wherein the neurodegenerative disease is Parkinson's disease.
48 . The method according to claim 44 or 45 wherein the neurodegenerative disease is HIV dementia.
49 . A method for treating a patient with an autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-treating amount of a compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substitututed alkyl having at least 3 carbon atoms and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R 5 is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 1 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
50 . A method for preventing the onset of an autoimmune disease in a patient at risk for developing the autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-preventing amount of a compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substitututed alkyl having at least 3 carbon atoms and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R 5 is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 1 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
51 . The method according to claim 49 or 50 wherein the autoimmune disease is systemic lupus.
52 . The method according to claim 49 or 50 wherein the autoimmune disease is multiple sclerosis.
53 . A method for treating a patient with an inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-treating amount of a compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting of alkyl having at least 3 carbon atoms, substitututed alkyl having at least 3 carbon atoms and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or-tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R 5 is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 3 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
54 . A method for preventing the onset of an inflammatory disease in a patient at risk for developing the inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-preventing amount of a compound of formula I:
wherein
R 1 is selected from the group consisting of alkoxy, alkaryloxy, alkcycloalkoxy, aryloxy, and cycloalkoxy;
R 2 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen, or when R 1 and R 2 are attached to adjacent carbon atoms, R 1 and R 2 may be joined together to form an alkylenedioxy group;
R 3 is selected from the group consisting of hydrogen, alkoxy, alkcycloalkoxy, cycloalkoxy and halogen;
R 4 is selected from the group consisting of hydrogen and alkyl;
R 5 is selected from the group consisting-of alkyl having at least 3 carbon atoms, substitututed alkyl having at least 3 carbon atoms and cycloalkyl;
provided that:
(i) when R 2 and R 3 are independently hydrogen or methoxy, R 1 is not methoxy;
(ii) when R 2 , R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-n-butoxy, 4-n-pentyloxy or 4-n-hexyloxy;
(iii) when R 2 , R 3 and R 4 are hydrogen and R 5 is isopropyl, then R 1 is not 4-ethoxy;
(iv) when R 1 and R 2 are joined together to form a 3,4-methylenedioxy group and R 3 and R 4 are hydrogen, then R 5 is not isopropyl or tert-butyl;
(v) when R 2 , R 3 and R 4 are hydrogen and R 5 is 1-hydroxy-2-methylprop-2-yl, then R 1 is not 2-ethoxy;
(vi) when R 1 is 4-methoxy, R 2 is 3-ethoxy, and R 3 and R 4 are hydrogen, then R 5 is not 2,2-dimethylbut-3-yl or 1-hydroxy-2-methylprop-2-yl; and
(vii) when R 3 and R 4 are hydrogen and R 5 is tert-butyl, then R 1 is not 4-methoxy when R 2 is 2-fluoro, and R 1 is not 2-methoxy when R 2 is 4-fluoro.
55 . The method according to claim 53 or 54 wherein the inflammatory disease is rheumatoid arthritis.
56 . The method according to claim 53 or 54 wherein the inflammatory disease is septic shock.
57 . The method according to claim 53 or 54 wherein the inflammatory disease is erythema nodosum leprosy.
58 . The method according to claim 53 or 54 wherein the inflammatory disease is septicemia.
59 . The method according to claim 53 or 54 wherein the inflammatory disease is uveitis.
60 . The method according to claim 53 or 54 wherein the inflammatory disease is adult respiratory distress syndrome.
61 . The method according to claim 53 or 54 wherein the inflammatory disease is inflammatory bowel disease.Join the waitlist — get patent alerts
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