Anti-inflammatory medicaments
Novel compounds and methods of using those compounds for the treatment of inflammatory conditions are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein comprises the step of contacting the kinase protein with the novel compounds.
1 - 31 . (canceled)
32 . A compound having the formula
wherein:
R 1 is selected from the group consisting of
each R 2 is individually selected from the group consisting of —H, alkyls, aminos, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, halogens, alkoxys, and hydroxys;
each R 3 is individually selected from the group consisting of —H, alkyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, alkoxys, hydroxys, cyanos, halogens, perfluoroalkyls, alkylsulfinyls, alkylsulfonyls, R 4 NHSO 2 —, and —NHSO 2 R 4 ;
each R 5 is individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; and each W is individually selected from the group consisting of CH and N;
each X is individually selected from the group consisting of —O—, —S—, —NR 6 —, —NR 6 SO 2 —, —NR 6 CO—, alkynyls, alkenyls, alkylenes, —O(CH 2 ) h —, and —NR 6 (CH 2 ) h —, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH 2 ) h —, and —NR 6 (CH 2 ) h —, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —O(CH 2 ) h — the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and
where each W 1 is individually selected from the group consisting of —CH— and —N—;
D is selected from the group consisting of furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
G is —CH 2 —;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
Q is
each R 4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R 4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R 4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R 6 is individually selected from the group consisting of —H and alkyls;
each Z is individually selected from the group consisting of —O— and —N(R 4 )—;
R 7 ′ is selected from the group consisting of alkyls, aryls, heterocyclyls, and perfluoroalkyls;
and wherein A or Q is optionally substituted with one or more R 7 substituents selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
33 . The compound of claim 32 , wherein A is phenyl substituted by one or more R 7 substituents, said R 7 substituents being halogens.
34 . The compound of claim 32 , wherein A is an R 7 -substituted naphthyl.
35 . The compound of claim 32 , wherein m is 1; R 1 is taken from the group consisting of
36 . The compound of claim 35 , wherein A is taken from phenyl or naphthyl.
37 . The compound of claim 32 , where R 7 ′ is selected from the group consisting of aryls and heterocyclyls.
38 . A method of modulating the activation state of a p38-alpha kinase comprising the step of contacting said kinase with a molecule having the formula
wherein:
R 1 is selected from the group consisting of
each R 2 is individually selected from the group consisting of —H, alkyls, aminos, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, halogens, alkoxys, and hydroxys;
each R 3 is individually selected from the group consisting of —H, alkyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, alkoxys, hydroxys, cyanos, halogens, perfluoroalkyls, alkylsulfinyls, alkylsulfonyls, R 4 NHSO 2 —, and —NHSO 2 R 4 ;
each R 5 is individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; and each W is individually selected from the group consisting of CH and N;
each X is individually selected from the group consisting of —O—, —S—, —NR 6 —, —NR 6 SO 2 —, —NR 6 CO—, alkynyls, alkenyls, alkylenes, —O(CH 2 ) h —, and —NR 6 (CH 2 ) h —, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH 2 ) h —, and —NR 6 (CH 2 ) h —, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —O(CH 2 ) h — the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and
where each W 1 is individually selected from the group consisting of —CH— and —N—;
D is selected from the group consisting of furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
G is —CH 2 —;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
Q is
each R 4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R 4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R 4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R 6 is individually selected from the group consisting of —H and alkyls;
each Z is individually selected from the group consisting of —O— and —N(R 4 )—;
R 7 ′ is selected from the group consisting of alkyls, aryls, heterocyclyls, and perfluoroalkyls;
and wherein A or Q is optionally substituted with one or more R 7 substituents selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
39 . The method of claim 38 , wherein A is phenyl substituted by one or more R 7 substituents, said R 7 substituents being halogens.
40 . The method of claim 38 , wherein A is an R 7 -substituted naphthyl.
41 . The method of claim 38 , wherein m is 1; R 1 is taken from the group consisting of
42 . The method of claim 41 , wherein A is taken from phenyl or naphthyl.
43 . The method of claim 38 , where R 7 ′ is selected from the group consisting of aryls and heterocyclyls.
44 . An adduct comprising a molecule bound with a kinase, said molecule having the formula
wherein:
R 1 is selected from the group consisting of
each R 2 is individually selected from the group consisting of —H, alkyls, aminos, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, halogens, alkoxys, and hydroxys;
each R 3 is individually selected from the group consisting of —H, alkyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, alkoxys, hydroxys, cyanos, halogens, perfluoroalkyls, alkylsulfinyls, alkylsulfonyls, R 4 NHSO 2 —, and —NHSO 2 R 4 ;
each R 5 is individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; and each W is individually selected from the group consisting of CH and N;
each X is individually selected from the group consisting of —O—, —S—, —NR 6 —, —NR 6 SO 2 —, —NR 6 CO—, alkynyls, alkenyls, alkylenes, —O(CH 2 ) h —, and —NR 6 (CH 2 ) h —, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH 2 ) h —, and —NR 6 (CH 2 ) h —, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —O(CH 2 ) h — the introduction of the side-chain oxo group does not form an ester moiety;
A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and
where each W 1 is individually selected from the group consisting of —CH— and —N—;
D is selected from the group consisting of furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
G is —CH 2 —;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
Q is
each R 4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R 4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
when two R 4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
each R 6 is individually selected from the group consisting of —H and alkyls;
each Z is individually selected from the group consisting of —O— and —N(R 4 )—;
R 7 ′ is selected from the group consisting of alkyls, aryls, heterocyclyls, and perfluoroalkyls;
and wherein A or Q is optionally substituted with one or more R 7 substituents selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
45 . The adduct of claim 44 , wherein A is phenyl substituted by one or more R 7 substituents, said R 7 substituents being halogens.
46 . The adduct of claim 44 , wherein A is an R 7 -substituted naphthyl.
47 . The adduct of claim 44 , wherein m is 1; R 1 is taken from the group consisting of
48 . The adduct of claim 47 , wherein A is taken from phenyl or naphthyl.
49 . The adduct of claim 44 , where R 7 ′ is selected from the group consisting of aryls and heterocyclyls.
50 . A method of treating an individual suffering from a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, osteo-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof, said method comprising the step of administering to said individual a compound of the formula of claim 32 .