US2005171136A1PendingUtilityA1
Modulators of the glucocorticoid receptor and method
Priority: Jul 18, 2002Filed: Mar 21, 2005Published: Aug 4, 2005
Est. expiryJul 18, 2022(expired)· nominal 20-yr term from priority
Inventors:Wayne VaccaroBingwei YangSoong-Hoon KimTram N. HuynhDavid R. TortolaniKenneth J. LeavittWenying LiArthur M. P. DoweykoXiao-Tao ChenLidia M. Doweyko
A61P 7/06A61P 5/00A61P 37/02A61P 37/06A61P 43/00A61P 37/08A61P 37/00A61P 3/10A61P 7/00A61P 9/10A61P 25/00A61P 27/14A61P 3/00A61P 3/04A61P 35/02A61P 27/02A61P 29/00A61P 31/04A61P 35/00A61P 19/06A61P 17/06C07D 217/22A61P 19/00C07D 233/88C07D 213/82C07D 239/42C07D 401/04C07D 213/75A61P 1/02A61P 11/00C07D 263/48A61P 17/02C07D 239/94C07D 235/30C07D 495/04A61K 31/403A61P 1/00A61P 1/04A61P 19/08A61P 11/02C07D 285/06C07D 417/12A61P 1/16A61P 19/02C07D 235/14A61P 1/18C07D 261/14C07D 215/38C07D 487/04A61K 45/06C07D 231/16C07D 317/58A61P 17/00A61P 11/16A61P 11/06C07D 333/20C07D 471/08C07D 277/64C07D 207/34C07D 213/40C07D 209/48C07D 471/04A61P 21/04A61P 13/12C07D 333/34C07D 277/46A61K 31/473C07D 405/04C07D 307/58C07D 417/04C07D 417/10C07D 241/20A61P 17/14C07D 261/12
49
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0
Cited by
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Claims
Abstract
Novel non-steroidal compounds are provided which are glucocorticoid receptor modulators which are useful in treating diseases requiring glucocorticoid receptor agonist or antagonist therapy such as obesity, diabetes, inflammatory and immune disorders, and have the structure where Z is CONR 1 R 2 or CH 2 NR 1 R 2 and where R, R a , R b , R c , R d , Z, A and B are defined herein.
Claims
exact text as granted — not AI-modified1 - 34 . (canceled)
35 . A method for preventing, inhibiting onset of or treating an inflammatory or immune associated disease or disorder which is an endocrine disorder, rheumatic disorder, collagen disease, dermatologic disease, allergic disease, ophthalmic disease, respiratory disease, hematologic disease, gastrointestinal disease, inflammatory disease, autoimmune disease, neoplastic disease and metabolic disease which is associated with the expression product of a gene whose transcription is stimulated or repressed by glucocorticoid receptors, or a method for preventing, inhibiting onset of or treating a disease associated with AP-1- and/or NF-κB-induced transcription, or a method for preventing, inhibiting onset of or treating a disease associated with AP-1 and/or NF-κB dependent gene expression, wherein the disease is associated with the expression of a gene under the regulatory control of AP-1 and/or NF-κB, the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound having below structure:
including all stereoisomers thereof, or a prodrug ester thereof, or a pharmaceutically acceptable salt thereof, wherein
R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, or hydroxyaryl;
R a is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarboyl, cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl, hydroxyaryl, aryloxyalkyl, nitro, amino, CHO, CO 2 alkyl, CONR e R f , CH 2 NR g R h , CO 2 H, CH 2 OH, CH 2 NHR g , NHCH 2 R g , NHCHR g R h , NHCOR e , NHCONR e R f or NHSO 2 R e ;
R b is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cyano, halogen, heteroarylaminocarbonyl, cycloheteroalkylcarbonyl, cyanoalkyl, alkylaminoalkyl, hydroxyalkyl, nitro, amino, CHO, CO 2 alkyl, hydroxyaryl, aryloxyalkyl, CONR i R j , CH 2 NR k R l , CO 2 H, CH 2 OH, CH 2 NHR k , NHCH 2 R k , NHCHR k R l , NHCOR i , NHCONR i R j or NHSO 2 R i ;
where R e and R f are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, and cycloalkylalkyl, and R e and R f can be taken together with the nitrogen to which they are attached to form a 5-, 6- or 7-membered heteroaryl or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, O or S;
R g and R h are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, and cycloalkylalkyl, and R g and R h can be taken together with the nitrogen to which they are attached to form a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, O or S;
R i and R j are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, and cycloalkylalkyl, and R i and R j can be taken together with the nitrogen to which they are attached to form a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, O or S;
R k and R l are the same or different and are independently selected from hydrogen, aryl, alkyl, alkenyl, alkynyl, alkoxy, amino, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, and cycloalkylalkyl, and R k and R l can be taken together with the nitrogen to which they are attached to form a 5-, 6- or 7-membered heteroaryl ring or cycloheteroalkyl ring which contains 1, 2 or 3 hetero atoms which can be N, O or S;
R c and R d are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, hydroxy, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, hydroxyaryl, and aryloxyalkyl;
R c and R d may optionally be taken together with the carbon to which they are attached to form a 3- to 7-membered ring which may optionally include an O atom or an N atom;
Z is CONR 1 R 2 or CH 2 NR 1 R 2 wherein R 1 and R 2 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl and hydroxyalkyl;
the A ring represents a saturated, partially saturated or unsaturated 6-membered carbocyclic or heterocyclic ring; and
the B ring represents a saturated, partially saturated or unsaturated 6-membered carbocyclic or heterocyclic ring;
with the following provisos:
I. provided that where Z is CONR 1 R 2 and (a) R is CH 3 or H and R a , R b , R c and R d are each hydrogen, or (b) R a and R b are each hydrogen and one of R c and R d is alkyl, then
(1) at least one of R 1 and R 2 is heteroaryl, heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl, but where the heteroaryl is unsubstituted
or unsubstituted
or the heteroarylalkyl is unsubstituted
or unsubstituted
then the other of R 1 and R 2 is other than hydrogen, and/or the A ring includes a hetero atom and/or the B ring includes a hetero atom; or
(2) where one of R 1 and R 2 is phenyl which is substituted with alkyl, hydroxy, halo, C 1 -C 2 -alkoxycarbonyl or nitro, then (a) the phenyl must be substituted with at least one other group other than hydrogen, alkyl, hydroxy, halo, C 1 ,-C 2 -alkoxycarbonyl or nitro, except that the phenyl may be substituted with two or more halo atoms, and/or two or more hydroxy groups and/or (b) the other of R 1 and R 2 is other than hydrogen and/or (c) the A ring includes a hetero atom and/or the B ring includes a hetero atom;
(3) where one of R 1 and R 2 is phenyl substituted with C 1 -C 2 alkoxy, the phenyl cannot be substituted with a second C 1 -C 2 alkoxy or the other of R 1 and R 2 is other than hydrogen; or
(4) where at least one of R 1 and R 2 is hydrogen, unsubstituted alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkylphenyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl then (a) the other of R 1 and R 2 is other than hydrogen, unsubstituted alkyl, alkenyl, cycloaklyl, alkylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkylphenyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl or hydroxyalkyl and/or (b) at least one of R a , R b , R c and/or R d is other than hydrogen and/or (c) R is other than hydrogen or C 1 -C 2 alkyl and/or (d) the A ring includes a hetero atom and/or the B ring includes a hetero atom; and
II. provided that where Z is CH 2 NR 1 R 2 and/or where at least one of R 1 and R 2 is hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl, alkylphenyl, phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl, hydroxyalkyl, heteroaryl which is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or imidazolinyl, or cycloheteroalkyl which is 4,5-dihydro-imidazol-2-yl, piperidinyl or piperazinyl, then (a) the other of R 1 and R 2 is other than hydrogen, alkyl, alkenyl, cycloalkyl, alkylcycloalkyl, phenyl, alkylphenyl, phenylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryl, alkoxyalkyl, or hydroxyalkyl, and/or (b) at least one of R a , R b , R c and/or R d is other than hydrogen or C 1-2 alkyl, and/or (c) R is other than hydrogen or C 1 -C 2 alkyl and/or (d) the A ring includes a hetero atom and/or the B ring includes a hetero atom, and/or (e) one of R c and R d is other than hydroxyalkyl.
36 . The method as defined in claim 35 wherein the A ring of the compound has the structure
and the B ring has the structure
wherein X 1 , X 2 , X 3 and X 4 , are the same or different and are independently selected from CH, CH 2 , CHR 15 , CR 16 , CR 16 R 17 , N, NH, NR 18 , O and S, and X 5 , X 6 , X 7 and X 8 are the same or different and are independently selected from CH, CH 2 , CHR 19 , CR 20 , CR 20 R 21 , N, NH, NR 22 , O and S, wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are the same or different and are independently selected from hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, and cycloheteroalkyl, wherein each of said A ring and said B ring contains at most two nitrogen ring atoms, at most two oxygen ring atom and at most one sulfur ring atom.
37 . The method as defined in claim 35 wherein the compound has the structure
38 . The method as defined in claim 35 wherein the compound has the structure
where
R is H or alkyl;
R a is selected from H, CN, NO 2 , NH 2 , CHO, CO 2 alkyl, CONR e R f or CH 2 NR g R h ; and
R b is selected from H, CN, NO 2 , NH 2 , CHO, CO 2 alkyl, CONR i R j or CH 2 NR k R l .
39 . The method as defined in claim 35 wherein the compound has the structure
where R is H, CH 3 or C 2 H 5 and R c is H or OH,
and one of R 1 and R 2 is heteroaryl.
40 . The method as defined in claim 39 wherein one of R 1 and R 2 of the compound is
where R m is selected from H, alkyl, aryl, heteroaryl, halo, and alkoxy and R o is H or alkyl.
41 . A method for preventing, inhibiting onset of or treating an inflammatory or immune associated disease or disorder which is an endocrine disorder, rheumatic disorder, collagen disease, dermatologic disease, allergic disease, ophthalmic disease, respiratory disease, hematologic disease, gastrointestinal disease, inflammatory disease, autoimmune disease, neoplastic disease and metabolic disease which is associated with the expression product of a gene whose transcription is stimulated or repressed by glucocorticoid receptors, or a method for preventing inhibiting onset of or treating a disease associated with AP-1- and/or NF-κB-induced transcription, or a method for preventing, inhibiting onset of or treating a disease associated with AP-1 and/or NF-κB dependent gene expression, wherein the disease is associated with the expression of a gene under the regulatory control of AP-1 and/or NF-κB, the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound having below structure
where X is aryl or alkyl;
where X is aryl;
where X is aryl;
where X is aryl, alkyl, heteroaryl or halo and R is alkyl;
where X a is aryl, heteroaryl or heteroarylalkyl,
where
R a is alkoxycarbonyl (CO 2 alkyl), nitro, cyano, or hydrogen;
R b is hydrogen, CO 2 alkyl, nitro, cyano, formyl, cycloheteroalkylcarbonyl, alkylaminoalkyl or amino,
X is hydrogen, alkyl or halo;
42 . The method as defined in claim 41 wherein the compound has the structure
where X is 1-naphthyl, 1-(4-methyl)naphthyl, 1-(4-fluoro)naphthyl, 1-(6-methoxy)naphthyl, phenyl, or t-butyl,
where X is 1-naphthyl,
where X=1-naphthyl,
where R is CH 3 or C 2 H 5 and X is phenyl, t-butyl, 1-naphthyl, 1-(4-fluoro)naphthyl, benzthiophen-3-yl, 1-(4-methyl)naphthyl, 1-(2-methoxy)naphthyl, 1-(6-methoxy)naphthyl, 3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl, 2-chlorophenyl, 1-(4-methoxy)naphthyl, 1-(4-bromo)naphthyl, 1-(4-iodo)naphthyl, 5-anthracenyl, 1-anthracenyl, 4-quinolin-1-yl, 2-quinolin-1-yl, 1-(4-cyano)naphthyl, 5-iodo, 4-benzthiophenyl, 1-(2-hydroxy)naphthyl, 1-(6-hydroxy)naphthyl, or 1-(4-hydroxy)naphthyl,
where X a is phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-pyridyl, 2-(4-pridyl)ethyl, 2-(4-imidazolyl)ethyl, 3-chloro-4-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methyl-3-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 4-chlorophenyl, 2-naphthyl, 3-chlorophenyl, 3,4-dichlorophenyl, 4-azidophenyl, 2,4-dimethoxyphenyl, 3-ethoxyphenyl, 3-(methylthio)phenyl, 4-(methylthio)phenyl, 3-(acetylenyl)phenyl, 4-methoxy-3-pyridyl, 3-cyanophenyl, 2-methyl-4-methoxyphenyl, 3-azidophenyl, 3-methyl-isothiazolyl, 1-methyl-pyrazol-5-yl, or 5-trifluoromethyl-1,3,4-thiadiazol-2-yl,
R a
R b
X
CH 3 OOC—
H
H
Nitro
H
H
Cyano
H
H
CH 3 OOC—
H
Methyl
Nitro
H
Methyl
Cyano
H
Methyl
H
CH 3 OOC—
H
H
Nitro
H
H
Cyano
H
H
formyl
H
H
CO—(N-morpholine)
H
H
—CH2—NH-Ethyl
H
H
—CH2—(N-morpholine)
H
H
Nitro
Methyl
H
Cyano
Methyl
H
NH2
Methyl
H
Nitro
F
H
Cyano
F
H
Cl
H
H
Cl
F
H
Cl
Methyl
H
Br
F
H
Br
Methyl
H
CH3
H
H
CH3
F
H
CH3
Methyl
CH 3 OOC—
H
H
Nitro
H
H
Cyano
H
H
CH 3 OOC—
H
Methyl
Nitro
H
Methyl
Cyano
H
Methyl
H
CH 3 OOC—
H
H
Nitro
H
H
Cyano
H
H
formyl
H
H
CO—(N-morpholine)
H
H
—CH2—NH-Ethyl
H
H
—CH2—(N-morpholine)
H
H
Nitro
Methyl
H
Cyano
Methyl
H
NH2
Methyl
H
Nitro
F
H
Cyano
F
H
Cl
H
H
Cl
F
H
Cl
Methyl
H
Br
F
H
Br
Methyl
H
CH3
H
H
CH3
F
H
CH3
Methyl,
H
H
H
nitro
H
H
H
nitro
H
H
H
nitro
H
H
H
nitro
Q═N, Y═CH or Q═CH, and Y═N.
43 . A method for preventing, inhibiting onset of or treating an inflammatory or immune associated disease or disorder which is an endocrine disorder, rheumatic disorder, collagen disease, dermatologic disease, allergic disease, ophthalmic disease, respiratory disease, hematologic disease, gastrointestinal disease, inflammatory disease, autoimmune disease, neoplastic disease and metabolic disease which is associated with the expression product of a gene whose transcription is stimulated or repressed by glucocorticoid receptors, or a method for preventing inhibiting onset of or treating a disease associated with AP-1- and/or NF-κB-induced transcription, or a method for preventing, inhibiting onset of or treating a disease associated with AP-1 and/or NF-κB dependent gene expression, wherein the disease is associated with the expression of a gene under the regulatory control of AP-1 and/or NF-κB, the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound having below structure
where R is CH 3 , C 2 H 5 or 2-hydroxyethyl, and one of R 1 and R 2 is H and the other of R 1 and R 2 is benzothiazol-2-yl, alkylbenzothiazol-2-yl, alkoxybenzothiazol-2-yl, halobenzothiazol-2-yl, thiazol-2-yl, 4-(1-naphthyl)thiazol-2-yl, 2-quinolin-1-yl, or a thiazole which is optionally substituted with heteroarylthio, heteroaryl, dialkyl, alkyl, or aryl, where the aryl may be optionally substituted with halo, alkyl, nitro, hydroxy, alkoxy, dialkoxy, carboxy, alkylaminocarbonyl, arylaminocarbonyl, hydroxyalkylaminocarbonyl, cycloheteroalkylcarbonyl, alkoxyalkylaminocarbonyl or heteroarylaminocarbonyl; with the proviso that where one of R 1 and R 2 is thiazol-2-yl, then R is C 2 H 5 or 2-hydroxyethyl.
44 . The method as defined in claim 43 wherein the compound has the structure
where X is H, 6-CH 3 , 4-CH 3 O, 6-Cl or 6-F; or
where X is 4,5-dimethyl, 5-chloro, 4-methyl, 5-methyl, 4-phenyl, 4-(1-naphthyl), 4-(2-naphthyl), 4-(4-fluoronaphth-1-yl), 4-(4-methylnaphth-1-yl), 4-(3-nitrophenyl), 4-(6-hydroxynaphth-1-yl), 4-[(1,2,4-triazol-5-yl)thio]methyl, 4-benzoic acid, 4-(4-bromonaphth-1-yl), 4-(N-ethyl)benzamide, 4-(N-2-methoxyphenyl)benzamide, 4-(N-methyl-N-2-hydroxyethyl)benzamide, 4-(N-(pyrrolidinyl)benzamide, 4-(N-mopholinyl)benzamide, 4-(N-phenyl-N-methyl)benzamide, 3-(N-ethyl)benzamide, 3-(N-2-methoxyphenyl)benzamide, 3-(N-2-methoxyethyl)benzamide, 3-(N-methyl-N-2-hydroxyethyl)benzamide, 3-(N-methyl-N-phenyl)benzamide, 3-(N-4-acetylpiperaziny-1-yl)benzamide, 3-(N-3-methoxypropyl)benzamide, 2-(6-carboxy)pyridine, 3-(N-3-hydroxy-4-methoxyphenyl)benzamide, 3-(N-3-fluoro-4-methoxyphenyl)benzamide, 3-(N-2,3-dimethoxyphenyl)benzamide, 3-(N-3-dimethoxyphenyl)benzamide, 3-(N-5-trifluormethyl-1,3,4-thiadiazol-2-yl)benzamide, 3-(N-5-methyl-1,3,4-thiadiazol-2-yl)benzamide, 3-(N-5-chlorobenzoxazol-2-yl)benzamide, 3-(N-3-benzonitrile)benzamide, 3-(N-4-methoxypyrid-3-yl)benzamide, 5-(1,4-benzodioxane), or 4-(1,3-benzodioxole).
45 . The method as defined in claim 35 wherein the compound has the structure:
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (S)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
46 . The method as defined in claim 35 wherein the compound has the structure:
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
Chi- ral (R)
47 . A method for preventing, inhibiting onset of or treating an inflammatory or immune associated disease or disorder which is an endocrine disorder, rheumatic disorder, collagen disease, dermatologic disease, allergic disease, ophthalmic disease, respiratory disease, hematologic disease, gastrointestinal disease, inflammatory disease, autoimmune disease, neoplastic disease and metabolic disease which is associated with the expression product of a gene whose transcription is stimulated or repressed by glucocorticoid receptors, or a method for preventing inhibiting onset of or treating a disease associated with AP-1- and/or NF-B-induced transcription, or a method for preventing, inhibiting onset of or treating a disease associated with AP-1 and/or NF-κB dependent gene expression, wherein the disease is associated with the expression of a gene under the regulatory control of AP-1 and/or NF-κB, the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound having the structure:
or an alkyl ester thereof,
where R is CH 3 , C 2 H 5 ; R a is nitro, cyano, Cl, Br, CH 3 , —COOCH 3 , or formyl, and
R b is H, R b is nitro, cyano, Cl, Br, CH 3 , —COOCH 3 , or formyl, and R a is H;
or a compound having the structure:
where X 9 is S or NH; and X is:
48 . The method as defined in claim 35 wherein the compound has the structure
where
R is CH 3 , C 2 H 5 or 2-hydroxyethyl;
R b is H, CN, NO 2 , halogen, alkyl or amino; and
Xb is H, arylalkoxycarbonyl, arylalkylaminocarbonyl, alkoxyalkylaminocarbonyl, heteroarylcarbonyl, aryl, alkoxyalkylamidocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, arylaminocarbonylaryl or heteroaryl;
provided that where Xb is H, then R is C 2 H 5 or 2-hydroxymethyl or R b is CN or NO 2 .
49 . The compound as defined in claim 48 wherein the compound has the structure
50 . The method as defined in claim 35 wherein the compound has the structure
where R is CH 3 , C 2 H 5 or 2-hydroxyethyl; R b is H, CN, NO 2 , halogen, alkyl or amino; and Xc is aryl, quinolinyl or isoquinolinyl.
51 . The method as defined in claim 50 wherein the compound has the structure
52 . The method as defined in claim 35 wherein the inflammatory or immune associated disease or disorder is transplant rejection of kidney, liver, heart, lung, pancreas, bone marrow, cornea, small bowel, skin allografts, skin homografts, heart valve xenograft, serum sickness, and graft vs. host disease, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type I and Type II diabetes, juvenile diabetes, obesity, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pyoderma gangrenum, systemic lupus erythematosis, myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen's syndrome, pernicious or immunohaemolytic anaemia, atherosclerosis, Addison's disease, idiopathic adrenal insufficiency, autoimmune polyglandular disease, glomerulonephritis, scleroderma, morphea, lichen planus, viteligo, alopecia areata, autoimmune alopecia, autoimmune hypopituatarism, Guillain-Barre syndrome, and alveolitis; contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis, uticaria, skin allergies, respiratory allergies, hayfever, allergic rhinitis and gluten-sensitive enteropathy, osteoarthritis, acute pancreatis, chronic pancreatitis, acute respiratory distress syndrome, Sezary's syndrome, restenosis, stenosis and artherosclerosis, congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia associated with cancer, juvenile rheumatoid arthritis, Ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteroarthritis, synovitis of osteoarthritis, epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitis herpetitformis, severe erythema multiforme, exfoliative dermatitis, psoriasis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjuncivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemias and lymphomas in adults, acute leukemia of childhood, ulcerative colitis, regional enteritis, Crohn's disease, Sjogren's syndrome, autoimmune vasculitis, multiple sclerosis, myasthenia gravis, sepsis, and chronic obstructive pulmonary disease.
53 . The method as defined in claim 52 wherein inflammatory or immune associated disease or disorder is selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type I diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, psoriasis and chronic pulmonary disease.Cited by (0)
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