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US 2007/0191336 A1Published application
Anti-inflammatory medicaments
OwnerDaniel Flynn, Peter Petilloinventors
Life of this patent
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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.
Claims83
A compound having the formula
- wherein:
- R1 is selected from the group consisting of aryls and heteroaryls;
- each X and Y is individually selected from the group consisting of —O—, —S—, —NR6—, —NR6SO2—, —NR6CO—, alkynyls, alkenyls, alkylenes, —O(CH2)h—, and —NR6(CH2)h—, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH2)h—, and —NP6(CH2)h—, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —O(CH2)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 R4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
- when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
- each R5 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 R6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
- each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
- each R9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
- and
- G is alkylene, N(R6), O;
- each Z is individually selected from the group consisting of —O— and —N(R4)—;
- each ring of formula (IA) optionally includes one or more of R7, where R7 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 (I) is not
- when Q is Q-7, q is 0, and R5 and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl;
- when Q is Q-7, R5 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, R5 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 (I) is not
- when Q is Q-8, then Y is not —CH2O—;
- when Q is Q-8, the compound of formula (I) is not
- when Q is Q-9, then the compound of formula (I) is not
- when Q is Q-10, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
- when Q is Q-10, then the compound of formula (I) is not
- when Q is Q-11, t is 0, and E is phenyl, then any R7 on E is not an o-alkoxy;
- when Q is Q-11, then the compound of formula (I) is not
- when Q is Q-15, then the compound of formula (I) is not
- when Q is Q-16 and Y is —NH—, then
- of formula (I) is not biphenyl;
- when Q is Q-16 and Y is —S—, then
- of formula (I) is not phenylsulfonylaminophenyl or phenylcarbonylaminophenyl;
- when Q is Q-16 and Y is —SO2NH—, then the compound of formula (I) is not
- when Q is Q-16 and Y is —CONH—, then
- of formula (I) is not imidazophenyl;
- when Q is Q-16 and Y is —CONH—, then the compound of formula (I) is not
- when Q is Q-16 and t is 0, then
- of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl;
- when Q is Q-17, then the compound of formula (I) is not
- when Q is Q-21, then the compound of formula (I) is not
- when Q is Q-22, then the compound of formula (I) is selected from the group consisting of
- when Q is Q-22 and q is 0, then the compound of formula (I) is selected from the group consisting of
- but excluding
- when Q is Q-23, then the compound of formula (I) is not
- when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (I) is selected from the group consisting of
- wherein each W is individually selected from the group consisting of —CH— and —N—;
- each G1 is individually selected from the group consisting of —O—, —S—, and —N(R4)—;
- 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(R4)—;
- when Q is Q-31, then the compound of formula (I) is not
- when Q is Q-28 or Q-29 and t is 0, then the compound of formula (I) is not
- when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula (I) is not
- when Q is Q-28 or Q-29 and Y is —CONH—, then the compound of formula (I) 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 (I) 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 (I) 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 (I) is not biphenyl or phenyloxazolyl;
- when Q is Q-32 and Y is —CH═CH—, then
- of formula (I) is not phenylaminophenyl;
- when Q is Q-32, then the compound of formula (I) is not
- when Q is Q-35 as shown
- wherein G is selected from the group consisting of —O—, —S—, —NR4—, and —CH2—,
- 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 (I) is not
80 more elements
A method of modulating the activation state of p38 α-kinase comprising the step of contacting said kinase with a molecule having the formula
- wherein:
- R1 is selected from the group consisting of aryls and heteroaryls;
- each X and Y is individually selected from the group consisting of —O—, —S—, —NR6—, —NR6SO2—, —NRrCO—, alkynyls, alkenyls, alkylenes, —O(CH2)h—, and —NR6(CH2)h—, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH2)h—, and —NR6(CH2)h—, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —O(CH2)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 R4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
- when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
- each R5 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 R6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
- each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
- each R9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
- G is alkylene, N(R6), O;
- each Z is individually selected from the group consisting of —O— and —N(R4)—;
- and
- each ring of formula (II) optionally includes one or more of R7, where R7 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,
- and thereby causing modulation of said activation state.
22 more elements
An adduct comprising a molecule binding with a kinase, said molecule having the formula
- wherein:
- R1 is selected from the group consisting of aryls and heteroaryls;
- each X and Y is individually selected from the group consisting of —O—, —S—, —NR6—, —NR6SO2—, —NR6CO—, alkynyls, alkenyls, alkylenes, —O(CH2)h—, and —NR6(CH2)h—, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH2)h—, and —NR6(CH2)h—, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —O(CH2)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 R4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
- when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
- each R5 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 R6 is individually selected from the group consisting of —H, alkyls, allyls, and β-trimethylsilylethyl;
- each R8 is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls;
- each R9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
- G is alkylene, N(R6), O;
- each Z is individually selected from the group consisting of —O— and —N(R4)—;
- and
- each ring of formula (III) optionally includes one or more of R7, where R7 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.
21 more elements
A compound 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—, —NR6—, —NR6SO2—, —NR6CO—, alkynyls, alkenyls, alkylenes, —O(CH2)h—, and —NR6(CH2)h—, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, —O(CH2)h—, and —NR6(CH2)h—, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where —O(CH2)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 NR6, O, alkylene, —O(CH2)h—, or —NR6(CH2)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,
- each R4 group is individually selected from the group consisting of —H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q;
- when two R4 groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring;
- each R6 is individually selected from the group consisting of —H, alkyls, allyls, and -trimethylsilylethyl;
- each R8 is individually selected from the group consisting of alkyls, phenyl, naphthyl, aralkyls, heterocyclyls, and heterocyclylalkyls;
- each R9 group is individually selected from the group consisting of —H, —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
- each R9′ group is individually selected from the group consisting of —F, and alkyls, wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring;
- each R10 is alkyl or perfluoroalkyl;
- G is alkylene, N(R6), O;
- each Z is individually selected from the group consisting of —O— and —N(R4)—;
- and each ring of formula (I) optionally includes one or more of R7, where R7′ 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, said Q36-Q59 groups being
37 more elements
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.
A method of altering the biological activity of a p38 kinase comprising the steps of:
- providing a p38-alpha kinase having a switch control pocket;
- contacting said kinase with a non-naturally occurring molecule modulator;
- and
- causing said modulator to bind with said kinase at the region of said pocket in order to at least partially regulate the biological activity of the kinase by inducing or restricting the conformation of the kinase.
1 more element
Dependencies are inferred from the claim text.