1. An engine system comprising;
a source of liquid alcohol;
an internal combustion engine generating exhaust gas;
a structure for introducing a first portion of the liquid alcohol into the engine;
a series of heat exchangers forming a Rankine heat recovery cycle extracting heat from the exhaust gas and transferring the heat to a second portion of the liquid alcohol causing it to change phase to a gaseous alcohol;
a heat exchangercatalyst heated by the exhaust to reform the alcohol into a hydrogen-rich reformate;
a valve structure for introducing the reformate into the engine for combustion; and
a control system for controlling a ratio of the first and second portions of the liquid alcohol to maximize an amount of the second portion of the liquid alcohol while using a minimum amount of the first portion needed to prevent knock, further including an additional heat exchanger extracting heat from engine cooling water to preheat the liquid alcohol.
2. The engine system of claim 1 further including a turbine through which the reformate flows before introduction into the engine.
3. The engine system of claim 1 wherein the engine is operated with a lean fuel-to-air ratio.
4. The engine system of claim 1 wherein the engine is operated with EGR.
5. The engine system of claim 1 wherein the heat exchangercatalyst includes a metallic foam.
6. The engine system of claim 5 wherein the metallic foam is disposed on fins.
7. The engine system of claim 1 wherein the alcohol is methanol.
8. The engine system of claim 1 wherein the alcohol is ethanol.
9. The engine system of claim 1 wherein the engine is a spark ignition engine and the reformate is introduced into engine cylinders.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
We claim:
1. A compound having the formula:
15
or pharmaceutically acceptable salts thereof, wherein:
each of Q1 and Q2 are independently selected from 5-6 membered aromatic carbocyclic or heterocyclic ring systems, or 8-10 membered bicyclic ring systems consisting of aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring; wherein:
Q1 is substituted with 1 to 4 substituents, 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;
Q2 is optionally substituted with up to 4 substituents, 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 optionally substituted with NR2, OR, CO2R, S(O2)N(R)2, NCN(R)2, R3, or CONR2; NR2; OCF3; CF3; NO2; CO2R; CONR; R3; OR3; NR3; SR3; C(O)R3; C(O)N(R)R3; C(O)OR3; SR; S(O2)N(R)2; SCF3; NCN(R)2; or CN;
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;
R3 is selected from a 5-6 membered aromatic carbocyclic or heterocyclic ring system; and
R4 is (C1-C4)-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;
X, if present, is selected from S, O, S(O2), S(O), S(O2)N(R2), N(R2) S(O2), N(R2)C(O)O, OC(O)N(R2), C(O), C(O)O, OC(O), C(O)N(R2), N(R2)C(O), N(R2), C(R2)2, C(OR2)2;
each R is independently selected from hydrogen, R2, N(R2)2, OR2, SR2, C(O)N(R2)2, S(O2)N(R2)2, or C(O)OR2, 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, or R3;
Y is selected from N or C;
Z, if present, is selected from O, N or NH;
A, if present, is selected from N or CR;
n is 0 or 1; and
R1 is selected from hydrogen, (C1-C3)-alkyl, OH, or O(C1-C3)-alkyl.
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:
16
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 or pyridyl 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:
17
unsubstituted 2-pyridyl or unsubstituted phenyl.
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.
9. The compound according to claim 1, wherein X, if present, is selected from S, O, S(O2), S(O), NR, C(R2) or C(O).
10. The compound according to claim 8, wherein X is S.
11. The compound according to claim 1, wherein A, if present, is N, and n is 1.
12. The compound according to claim 1, wherein each Y is C.
13. The compound according to claim 12, wherein each R attached to Y is independently selected from hydrogen or methyl.
14. The compound according to claim 1, wherein said compound is
18
15. The compound according to claim 1, wherein said compound is selected from any one of
19
16. The compound according to claim 1, wherein said compound is
20
17. The compound according to claim 1, wherein said compound is
21
18. The compound according to claim 1, wherein said compound is selected from any one of
22
19. The compound according to claim 1, wherein said compound is selected from any one of
23
20. The compound according to claim 1, wherein said compound is
24
21. A pharmaceutical composition comprising an amount of a compound according to claim 1 effective to inhibit p38, and a pharmaceutically acceptable carrier.
22. 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 21.
23. The method according to claim 22, 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.
24. The method according to claim 22, 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.
25. The method according to claim 22, wherein said method is used to treat or prevent a destructive bone disorders selected from osteoarthritis, osteoporosis or multiple myeloma-related bone disorder.
26. The method according to claim 22, 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.
27. The method according to claim 22, wherein said method is used to treat or prevent an infectious disease selected from sepsis, septic shock, or Shigellosis.
28. The method according to claim 22, wherein said method is used to treat or prevent a viral disease selected from acute hepatitis infection, HIV infection or CMV retinitis.
29. The method according to claim 22, 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.
30. The method according to claim 22, 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.
31. The method according to claim 22, wherein said method is used to treat or prevent a condition associated with prostaglandin endoperoxide synthase-2 selected from edema, fever, analgesia or pain.
32. The method according to claim 31, wherein said pain is selected from neuromuscular pain, headache, cancer pain, dental pain or arthritis pain.
33. The method according to claim 22, wherein said method is used to treat or prevent an angiogenic disorder selected from solid tumors, ocular neovasculization, or infantile haemangiomas.