US2008187978A1PendingUtilityA1
Anti-inflammatory medicaments
Est. expiryDec 31, 2022(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/08A61P 7/00A61P 37/02A61P 7/06A61P 9/10A61P 25/00A61P 29/00C07D 417/12C07D 413/14A61P 19/06C07D 401/04A61P 1/00A61P 11/06A61P 17/06C07D 417/14A61P 19/02C07D 239/42A61P 11/16A61P 19/00A61P 11/00C07D 403/12C07D 295/10C07D 413/12
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . An adduct comprising a molecule binding with a kinase, said molecule having the formula
wherein:
R 1 is selected from the group consisting of aryls and heteroaryls;
each X and Y 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 aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of —C(O)— and —S(O) 2 —;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of
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 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;
each R 6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
each R 8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R 9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R 9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
G is alkylene, N(R 6 ), O;
each Z is individually selected from the group consisting of —O— and —N(R 4 )—; and
each ring of formula (III) optionally includes one or more of R 7 , where R 7 is a noninterfering substituent individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.
2 . The adduct of claim 1 , said molecule binding at the region of a switch control pocket of said kinase.
3 . The adduct of claim 2 , said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (III) molecule.
4 . The adduct of claim 2 , said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
5 . The adduct of claim 4 , said region being selected from the group consisting of the α-C helix, the α-D helix, the catalytic loop, the switch control ligand sequence, the C-terminal residues, the glycine rich loop residues, and combinations thereof.
6 . The adduct of claim 5 , said α-C helix including SEQ ID NO. 2.
7 . The adduct of claim 5 , said catalytic loop including SEQ ID NO. 3.
8 . The adduct of claim 5 , said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
9 . The adduct of claim 5 , said C-lobe residues selected from SEQ ID NO. 6.
10 . The adduct of claim 5 , said glycine rich loop residues taken from SEQ ID NO. 7.
11 . The adduct of claim 1 , said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.
12 . The adduct of claim 1 , said molecule having the formula
wherein:
R 1 is selected from the group consisting of aryls and heteroaryls;
each X and Y 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 aromatic, monocycloheterocyclic, and bicycloheterocyclic rings;
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of —C(O)— and —S(O) 2 —;
j is 0 or 1;
m is 0 or 1;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
Q is selected from the group consisting of
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 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;
each R 6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
each R 8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R 9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R 9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; and
G is alkylene, N(R 6 ), O;
each Z is individually selected from the group consisting of —O— and —N(R 4 )—;
each ring of formula (IA) optionally includes one or more of R 7 , where R 7 is a noninterfering substituent individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls;
except that:
when Q is Q-3 or Q-4, then the compound of formula (IA) is not
when Q is Q-7, q is 0, and R 5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl;
when Q is Q-7, R 5 is —OH, Y is —O—, —S—, or —CO—, m is 0, n is 0, p is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, R 5 is —OH, m is 0, n is 0, p is 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl;
when Q is Q-7, then the compound of formula (IA) is not
when Q is Q-8, then Y is not —CH 2 O—;
when Q is Q-8, the compound of formula (IA) is not
when Q is Q-9, then the compound of formula (IA) is not
when Q is Q-10, t is 0, and E is phenyl, then any R 7 on E is not an o-alkoxy;
when Q is Q-10, then the compound of formula (IA) is not
when Q is Q-11, t is 0, and E is phenyl, then any R 7 on E is not an o-alkoxy;
when Q is Q-11, then the compound of formula (IA) is not
when Q is Q-15, then the compound of formula (IA) is not
when Q is Q-16 and Y is —NH—, then
of formula (IA) is not biphenyl;
when Q is Q-16 and Y is —S—, then
of formula (IA) is not phenylsulfonylaminophenyl or phenylcarbonylaminophenyl;
when Q is Q-16 and Y is —SO 2 NH—, then the compound of formula (IA) is not
when Q is Q-16 and Y is —CONH—, then
of formula (IA) is not imidazophenyl;
when Q is Q-16 and Y is —CONH—, then the compound of formula (IA) is not
when Q is Q-16 and t is 0, then
of formula (IA) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl;
when Q is Q-17, then the compound of formula (IA) is not
when Q is Q-21, then the compound of formula (IA) is not
when Q is Q-22, then the compound of formula (IA) is selected from the group consisting of
when Q is Q-22 and q is 0, then the compound of formula (IA) is selected from the group consisting of
when Q is Q-23, then the compound of formula (IA) is not
when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (IA) is selected from the group consisting of
wherein each W is individually selected from the group consisting of —CH— and —N—;
each G 1 is individually selected from the group consisting of —O—, —S—, and —N(R 4 )—; and
* denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows:
wherein each Z is individually selected from the group consisting of —O— and —N(R 4 )—;
when Q is Q-31, then the compound of formula (IA) is not
when Q is Q-28 or Q-29 and t is 0, then the compound of formula (IA) is not
when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula (IA) is not
when Q is Q-28 or Q-29 and Y is —CONH—, then the compound of formula (IA) is not
when Q is Q-32, then
is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl;
when Q is Q-32, Y is —CONH—, q is 0, m is 0, and
of formula (IA) is —CONH—, then A is not phenyl;
when Q is Q-32, q is 0, m is 0, and
is —CONH—, then the compound of formula (IA) is not
when Q is Q-32, D is thiazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone;
when Q is Q-32, D is oxazolyl or isoxazolyl, q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
when Q is Q-32, D is pyrimidyl q is 0, t is 0, p is 0, n is 0, and m is 0, then A is not phenyl;
when Q is Q-32 and Y is an ether linkage, then
of formula (IA) is not biphenyl or phenyloxazolyl;
when Q is Q-32 and Y is —CH═CH—, then
of formula (IA) is not phenylaminophenyl;
when Q is Q-32, then the compound of formula (IA) is not
when Q is Q-35 as shown
wherein G is selected from the group consisting of —O—, —S—, —NR 4 —, and —CH 2 —, k is 0 or 1, and u is 1, 2, 3, or 4, then
is selected from the group consisting of
except that the compound of formula (IA) is not
13 . An adduct comprising a molecule binding with a p 38-alpha kinase, said molecule having the formula
A-T-(L) n -(NH) p -D-(E) q -(Y) t -Q (IB)
wherein:
Y is 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 aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; and most preferably phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxaxolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, purinyl, and
where each W1 is individually selected form the group consisting of —CH— and —N—.
D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, thienyl, pyridyl, and pyrimidyl;
E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl;
L is selected from the group consisting of —C(O)— and —S(O) 2 —;
T is N 6 , O, alkylene, —O(CH 2 ) h —, or —NR 6 (CH 2 ) h —, where each h is individually selected from the group consisting of 1, 2, 3, or 4, or T is absent wherein A is directly bonded to -(L) n (NH) p -D-(E) q -(Y) t -Q;
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
t is 0 or 1;
v is 1, 2, or 3;
x is 1 or 2;
Q is selected from the group consisting of formulae Q36-Q59, inclusive, said Q36-Q59 groups being selected from the group consisting of
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, alkyls, allyls, and B-trimethylsilylethyl;
each R 8 is individually selected from the group consisting of alkyls, phenyl, naphthyl, aralkyls, heterocyclyls, and heterocyclylalkyls;
each R 9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R 9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R 9 , group is individually selected from the group consisting of —F, and alkyls, wherein when two R 9 , groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
each R 10 is alkyl or perfluoroalkyl;
G is alkylene, N(R 6 ), O; and
each Z is individually selected from the group consisting of —O— and —N(R 4 )—; and each ring of formula (IB) optionally includes one or more of R 7′ , where R 7′ is a substituent individually selected from the group consisting of —H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, perfluoroalkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, perfluoroalkyls; aminooxaloylamino; alkylaminooxaloylamino; dialkylaminooxaloylamino; morpholinooxaloylamino; piperazinooxaloylamino; alkoxycarbonylamino; heterocyclyloxycarbonylamino; heterocyclylalkyloxycarbonylamino; heterocyclylcarbonylamino; heterocyclylalkylcarbonylamino; aminoalkyloxycarbonylamino; alkylaminoalkyloxycarbonylamino; or dialkylaminoalkyloxycarbonylamino,
14 . The adduct of claim 13 , said molecule binding at the region of a switch control pocket of said kinase.
15 . The adduct of claim 14 , said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said molecule.
16 . The adduct of claim 14 , said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.
17 . The adduct of claim 14 , said region being selected from the group consisting of the α-C helix, the α-D helix, the catalytic loop, the switch control ligand sequence, the C-terminal residues, the glycine rich loop residues, and combinations thereof.
18 . The adduct of claim 17 , said α-C helix including SEQ ID NO. 2.
19 . The adduct of claim 17 , said catalytic loop including SEQ ID NO. 3.
20 . The adduct of claim 17 , said switch control sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
21 . The adduct of claim 17 , said C-lobe residues selected from the group consisting of SEQ ID NO. 6.
22 . The adduct of claim 17 , said glycine rich loop residues including SEQ ID NO. 7.
23 . The adduct of claim 13 , said kinase selected from the group consisting of the consensus wild type P 38-alpha kinase sequence and disease polymorphs thereof.
24 . A kinase-modulator adduct comprising a p38-alpha kinase having a switch control pocket with a non-naturally occurring molecule bound to the kinase at the region of said switch control pocket, said molecule serving to at least partially regulate the biological activity of said protein by inducing or restricting the conformation of the protein.
25 . The adduct of claim 24 , said molecule serving to induce a conformation change in said kinase.
26 . The adduct of claim 24 , said molecule serving to restrict a conformation change in said kinase.
27 . The adduct of claim 24 , said region of the switch control pocket being selected from the group consisting of the α-C helix, the α-D helix, the catalytic loop, the switch control ligand sequence, the C-terminal residues, the glycine rich loop residues, and combinations thereof.
28 . The adduct of claim 27 , said α-C helix including SEQ ID NO. 2.
29 . The adduct of claim 27 , said catalytic loop including SEQ ID NO. 3.
30 . The adduct of claim 27 , said switch control sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.
31 . The adduct of claim 27 , said C-lobe residues selected from the group consisting of SEQ ID NO. 6.
32 . The adduct of claim 27 , said glycine rich loop residues including SEQ ID NO. 7.
33 . The adduct of claim 24 , said kinase also having a switch control ligand, said ligand interacting in vivo with said pocket to regulate the conformation and biological activity of said kinase such that the kinase will assume a first conformation and a first biological activity upon said ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence of said ligand-pocket interaction.
34 . The adduct of claim 24 , said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an agonist.
35 . The adduct of claim 24 , said pocket being an on-pocket, said molecule binding with said kinase at the region of said on-pocket as an antagonist.
36 . The adduct of claim 24 , said pocket being an off-pocket, said molecule binding with said kinase at the region of said off-pocket as an agonist.Cited by (0)
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