We claim:
1. A compound of the formula:
105
wherein each of Q1 and Q2 are independently selected from a phenyl or 5-6 membered aromatic heterocyclic ring system, or a 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring;
the rings that make up Q1 are substituted with 1 to 4 substituents, each of which is independently selected from halo; C1-C3 alkyl optionally substituted with NR2, OR, CO2R or CONR2; O(C1-C3)-alkyl optionally substituted with NR2, OR, CO2R or CONR2; NR2; OCF3; CF3; NO2; CO2R; CONR; SR; S(O2)N(R)2; SCF3; CN; N(R)C(O)R4; N(R)C(O)OR4; N(R)C(O)C(O)R4; N(R)S(O2)R4; N(R)R4; N(R4)2; OR4; OC(O)R4; OP(O)3H2; or NCN(R)2;
the rings that make UP Q2 are optionally substituted with up to 4 substituents, each of which is independently selected from halo; C1-C3 straight or branched alkyl optionally substituted with NR2, OR, CO2R, S(O2)N(R)2, NCN(R)2, R3, or CONR2; O(C1-C3)-alkyl; O(C1-C3)-alkyl optionally substituted with NR2, OR, CO2R, S(O2)N(R)2, NCN(R)2, R3, or CONR2; NR2; OCF3; CF3; NO2; CO2R; CONR; R3; OR; NR3; SR3; C(O)R C(O)N(R)R3; C(O)OR3; SR; S(O2)N(R)2; SCF3; NCN(R)2; or CN;
Q2 is selected from phenyl or a 5-6 member aromatic heterocyclic ring optionally substituted with 1-3 substituents, each of which is independently selected from halogen; C1-C3 alkyl optionally substituted with NR2, OR, CO2R, CONR2, or OP (O3) H2; O(C2-C3)-alkyl optionally substituted with NR2, OR, CO2R, CONR2, or OP(O3)H2; OCF3; CF3; OR4; OCO2R4; OP(O3)H2; CO2R; CONR; SR; S(O2) N(R)2; SCF3; CN; N(R)C(O) R4; N(R)C(O)OR4; N(R)C(O)C(O)R4; N(R)S(O2)R4; N(R)R4; N(R4)2; OR4; OC(O)R4; OP(O)3H2; or NCN(R)2; provided that Q2 is not phenyl optionally substituted 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
R is selected from hydrogen; (C1-C3)-alkyl; (C2-C3)-alkenyl or alkynyl; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
R3 is selected from 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with R, R4, C(O)R, C(O)R4, C(O)OR4 or J; or an 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring each optionally substituted with R, R4, C(O)R, C(O)R4, C(O) OR or J;
R4 is (C1-C4)-straight or branched alkyl optionally substituted with N(R)2, OR, CO2R, CON(R)2, or SO2N(R2)2; or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(R)2, OR, CO2R, CON(R)2, or SO2N(R2)2;
R5 is selected from hydrogen; (C1-C3)-alkyl optionally substituted with R3; (C2-C3)-alkenyl or alkynyl each optionally substituted with R3; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl;
W is selected from N(R2) SO2N(R2)2; N(R2) SO2N(R2)(R3); N(R2)C(O)OR; N(R2)C(O)N(R2)2; N(R2)C(O)N(R2)(R3); N(R2)C(O)R2; N(R2)2; C(O)R2; CH(OH)R2; C(O)N(R2)2; C(O)OR2; J; or (C1-C4) straight or branched alkyl optionally substituted with N(R)2, OR, CO2R, CON(R)2, R3, SO2N(R2)2, OC(O)R2, OC(O)R, OC(O)N(R2)2, N(R4)(R5), C(O)N(R5)(R2), C(O) R5, N(R2)C(O)N(R2)(R5), NC(O)R5, OC(O)N(R2)(R5), or J; a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(R)2, OR, CO2R, CON(R)2, or SO2N(R2)2; or a 8-10 membered carbocyclic or heterocyclic ring system optionally substituted with N(R)2, OR, CO2R, CON(R)2, or SO2N(R2)2; provided that W is not an R3 substituted C1 alkyl;
W is selected from N(R2)SO2Q2; N(R 2)CO2Q2; N(R2)C(O)Q2; N(R2)(Q2); C(O)Q2; CO2Q2; C(O)N(R2)(Q2); C(R2)2Q2;
each R is independently selected from hydrogen, R2, N(R2)2, OR2, SR2, C(O)N(R2)2, S(O2)N(R2)2, C(O)OR or C(O)R wherein two adjacent R are optionally bound to one another and, together with each Y to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring;
R2 is selected from hydrogen, (C1-C3)-alkyl, or (C1-C3)-alkenyl; each optionally substituted with N(R)2, OR, SR, C(O)N(R)2, S(O2)N(R)2, C(O)OR, NSO2R4, NSO2R3, C(O)N(R)(R3), NC(O)R4, N(R)(R3), N(R)(R4), C(O)R3, C(O)N(R)(R4), N(R4)2, C(O)NC(NH)2 or R3;
Y is N or C;
Z is CH, N, C(OCH3), C(CH3), C(NH2), C(OH) or C(F);
U is selected from R or W;
V is selected from C(O)NH2, P(O)(NH2)2, or SO2NH2;
A, B, and C are independently selected from O, CHR, CHR, NR, NR or S;
J is a (C1-C4) straight chain or branched alkyl derivative substituted with 1-3 substituents selected from D, TC(O)R, or OPO3H2;
D is selected from the group
106
T is either O or NH; and
G is either NH2 or OH.
2. The compound according to claim 1, wherein Q1 is selected from phenyl or pyridyl containing 1 to 3 substituents independently selected from chloro, fluoro, bromo, CH3, OCH3, OH, CF3, OCF3, O(CH2)2CH3, NH2, 3,4-methylenedioxy, N(CH3)2, NHS(O)2-phenyl, NHC(O)OCH2-4-pyridine, NHC(O)CH2-morpholine, NHC(O)CH2N(CH3)2, NHC(O)CH2-piperazine, NHC(O)CH2-pyrrolidine, NHC(O)C(O)-morpholine, NHC(O)C(O)-piperazine, NHC(O)C(O)-pyrrolidine, OC(O)CH2N(CH3)2, or O(CH2)2N(CH3)2 and wherein at least one of said substituents is in the ortho position.
3. The compound according to claim 2, wherein Q1 contains at least two substituents, both of which are in the ortho position.
4. The compound according to claim 2, wherein Q1 is selected from:
107
5. The compound according to claim 4, wherein Q1 is selected from 2-fluoro-6-trifluoromethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-chloro-4-hydroxyphenyl, 2-chloro-4-aminophenyl, 2,6-dichloro-4-aminophenyl, 2,6-dichloro-3-aminophenyl, 2,6-dimethyl-4-hydroxyphenyl, 2-methoxy-3,5-dichloro-4-pyridyl, 2-chloro-4,5 methylenedioxy phenyl, or 2-chloro-4-(N-2-morpholino-acetamido)phenyl.
6. The compound according to claim 1, wherein Q2 is selected from phenyl, pyridyl or naphthyl and wherein Q2 optionally contains up to 3 substituents, each of which is independently selected from chloro, fluoro, bromo, methyl, ethyl, isopropyl, -OCH3, OH, NH2, CF3, OCF3, SCH3, OCH3, C(O)OH, C(O)OCH3, CH2NH2, N(CH3)2, CH2-pyrrolidine and CH2OH.
7. The compound according to claim 6, wherein Q2 is selected from:
108
8. The compound according to claim 7, wherein Q2 is selected from phenyl, 2-isopropylphenyl, 3,4-dimethylphenyl, 2-ethylphenyl, 3-fluorophenyl, 2-methylphenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 2-carbomethoxylphenyl, 2-carboxyphenyl, 2-methyl-4-chlorophenyl, 2-bromophenyl, 2-pyridyl, 2-methylenehydroxyphenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, 2-chloro-4-fluorphenyl, 2,4-difluorophenyl, 2-hydroxy-4-fluorphenyl or 2-methylenehydroxy-4-fluorophenyl, 1-naphthyl, 3-chloro-2-methylenehydroxy, 3-chloro-2-methyl, or 4-fluoro-2-methyl.
9. The compound according to claim 1, wherein each Y is C.
10. The compound according to claim 9, wherein each R and U attached to Y is independently selected from hydrogen or methyl.
11. The compound according to claim 1, wherein U, W or both U and W are a 0-4 atom chain terminating in an alcohol, amine, carboxylic acid, ester, amide or heterocycle.
12. The compound according to claim 11, wherein U, W or both U and W are selected from:
109
13. The compound according to claim 12, wherein U, W, or both U and W are selected from:
110
14. The compound according to claim 1, wherein the compound is selected from any one of the compounds depicted in Tables 1 to 6.
15. The compound according to claim 1, wherein the compound is
111
and X is selected from H,
112
16. The compound according to claim 1, wherein the compound is
113
and X is selected from NH2 or N(CH3)2;
17. The compound according to claim 1, wherein the compound is
114
and X is selected from OH, NH2, or N(CH3)2.
18. The compound according to claim 1, wherein the compound is
115
and X is selected from OH, NH2, or N(CH3)2.
19. The compound according to claim 1, wherein the compound is
116
and X is selected from OH, NH2, N(CH3)2,
117
20. The compound according to claim 1, wherein the compound is
118
21. The compound according to claim 1, wherein the compound is
119
22. The compound according to claim 1, wherein the compound is
120
23. The compound according to claim 1, wherein the compound is
121
24. The compound according to claim 1, wherein said compound is selected from any one of
122
25. A pharmaceutical composition comprising an amount of a compound according to any one of claims 1 to 24 effective to inhibit p38, and a pharmaceutically acceptable carrier.
26. A method of treating or preventing inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusionischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation or conditions associated with prostaglandin endoperoxidase synthase-2 in a patient, said method comprising administering to said patient a composition according to claim 25.
27. The method according to claim 26, wherein said method is used to treat or prevent an inflammatory disease selected from acute pancreatitis, chronic pancreatitis, asthma, allergies, or adult respiratory distress syndrome.
28. The method according to claim 26, wherein said method is used to treat or prevent an autoimmune disease selected from glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, or graft vs. host disease.
29. The method according to claim 26, wherein said method is used to treat or prevent a destructive bone disorders selected from osteoarthritis, osteoporosis or multiple myeloma-related bone disorder.
30. The method according to claim 26, wherein said method is used to treat or prevent a proliferative disease selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, or multiple myeloma.
31. The method according to claim 26, wherein said method is used to treat or prevent an infectious disease selected from sepsis, septic shock, or Shigellosis.
32. The method according to claim 26, wherein said method is used to treat or prevent a viral disease selected from acute hepatitis infection, HIV infection or CMV retinitis.
33. The method according to claim 26, wherein said method is used to treat or prevent a neurodegenerative disease selected from Alzheimer’s disease, Parkinson’s disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury.
34. The method according to claim 26, wherein said method is used to treat or prevent ischemiareperfusion in stroke or myocardial ischemia, renal ischemia, heart attacks, organ hypoxia or thrombin-induced platelet aggregation.
35. The method according to claim 26, wherein said method is used to treat or prevent a condition associated with prostaglandin endoperoxide synthase-2 selected from edema, fever, analgesia or pain.
36. The method according to claim 35, wherein said pain is selected from neuromuscular pain, headache, cancer pain, dental pain or arthritis pain.
37. The method according to claim 26, wherein said method is used to treat or prevent an angiogenic disorder selected from solid tumors, ocular neovasculization, or infantile haemangiomas.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A laboratory method for screening, diagnosing, monitoring andor staging early onset Alzheimer’s disease which consists of mild cognitive impairment comprises conducting a blood test after an oxidative exposure of serum to assay for the presence of an elevated level of redox-reactive autoantibodies.
2. The method of claim 1, wherein the antiphospholipid autoantibody is anticardiolipin, antiphosphatidylcholine, antiphosphatidylethanolamine or antiphosphatidylserine.
3. The method of claim 1 wherein the subject is selected as exhibiting physical or cognitive symptoms of an early onset Alzheimer’s disease.
4. The method of claim 1, wherein the subject has a family history of Alzheimer’s disease.
5. The method of claim 1, wherein the subject has a family history of Alzheimer’s disease and wherein the subject is at or beyond an average age of onset of family members having said Alzheimer’s disease.
6. The method of claim 1, wherein an elevated level of at least one antiphospholipid autoantibody is determined relative to a baseline value.
7. The method of claim 1, wherein an elevated level of redox-reactive autoantibodies is determined relative to a baseline value or wherein the baseline value is an average or mean value of a level found in a population of control individuals.
8. A method of monitoring the development or progress of early onset Alzheimer’s disease over a period of time, wherein the method comprises carrying out the method of claim 1 at the beginning of a period of time and then carrying out repetitions of the method at subsequent times.
9. A method of detecting or diagnosing early onset Alzheimer’s disease in a subject, the method comprising the steps of assaying an oxidized first blood sample from the subject to determine a baseline level of oxidized autoantibodies having a selected specificities, treating a second longitudinal blood sample with an oxidizing agent and assaying the oxidized second sample to determine the level of autoantibodies having the selected specificities, and comparing the level of the autoantibodies in the first sample with the level of autoantibodies in the oxidized second sample, wherein an increase in the level of autoantibodies in the oxidized second sample as compared to the level of the oxidized first sample correlates with early onset Alzheimer’s disease defined as mild cognitive impairment in said subject.
10. The method of claim 9, wherein the autoantibodies having selected specificities are anticardiolipin, antiphosphatidylcholine, antiphosphatidylethanolamine or antiphosphatidylserine.
11. A blood serum biomarker for diagnosing, monitoring andor staging early onset Alzheimer’s disease defined as mild cognitively impairment comprising redox-reactive autoantibodies.
12. A kit for diagnosing, monitoring andor staging early onset Alzheimer’s disease defined as mildly cognitively impaired individuals which comprises a laboratory assay which can detect redox reactive autoantibodies before and after exposure to an oxidative agent.