Author: claimsbot

1. A frequency synthesizer to lock the voltage controlled oscillator (VCO) with a reference frequency, comprising:
a reference frequency;
a phase detector;
a low pass filter to filter out any ac component from said phase detector and to derive a dc control voltage; and
a voltage controlled oscillator, whose frequency is divided by a divider to compare with said reference frequency and is controlled by said dc control voltage, which is applied in two sequential modes: a calibration mode and an analog mode,
wherein said calibration mode locks coarsely said VCO into limited number of discrete frequency steps within a predetermined frequency tolerance of the reference frequency by resetting and holding a coarse calibrated dc control voltage in a coarse digital phase-locked loop, with a calibration clock frequency divided from said frequency of said VCO, and
wherein said analog mode starts with said coarse calibrated dc control voltage, reset and held during the calibration mode, for fine adjustment of said VCO frequency to lock with said reference frequency in a fine phase-locked loop.
2. The frequency synthesizer as described in claim 1, wherein the calibration clock frequency of the digital phase-locked loop is divided from the VCO frequency by a number no higher than the number of said discrete frequency steps.
3. The frequency synthesizer as described in claim 2, wherein the clock frequency of the digital phase-locked loop during the calibration mode divides the VCO frequency by a one half of the number of said discrete frequency steps.
4. The frequency synthesizer as described in claim 1, wherein:
said phase detector for the analog mode comprises a phase comparator and a charge pump, and
said phase detector for said calibration mode comprises a stepper to reset said coarse calibrated dc control voltage into a predetermined number of steps and is disabled to switched to said analog mode when the dc control voltage locks the VCO frequency within a preset tolerance of said reference frequency.
5. The frequency synthesizer as described in claim 4, wherein said stepper comprises a clock, a counter, and a decision-making block to incrementally step-change said coarse calibrated dc control voltage.
6. The frequency synthesizer as described in claim 5, wherein the number of steps is a binary-weighted number.
7. The frequency synthesizer as described in claim 6, wherein said decision-making block is a control unit that selects between enabling and disabling the counter, calculates the value of the VCO dc control voltage, and selects between breaking and reconnecting the PLL for the calibration mode.
8. The frequency synthesizer as described in claim 6, wherein said counter and said decision-making block are finite state machines.

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 search information providing apparatus comprising:
a receiving unit, implemented on a processor operatively coupled to a memory, which receives a search request including a search keyword from a user terminal;
a searching unit, implemented on the processor operatively coupled to the memory, which acquires information corresponding to the search keyword as a search result based on the search keyword included in the search request;
an advertisement information memory that stores advertisement information corresponding to a specific search keyword;
an acquiring unit, implemented on the processor operatively coupled to the memory, which acquires the advertisement information corresponding to the specific search keyword from the advertisement information memory when the search keyword included in the search request is the specific search keyword;
a generating unit, implemented on the processor operatively coupled to the memory, which generates a search result page for displaying the search result and a background image based on the advertisement information acquired by the acquiring unit; and
a transmitting unit, implemented on the processor operatively coupled to the memory, which transmits the search result page generated by the generating unit to the user terminal performing the search request including the specific search keyword, wherein
the receiving unit receives, from the user terminal, a registration request for registration of the background image that is displayed in the search result page and in response to receiving the registration request, information associated with the background image is stored,
and
the receiving unit further receives, from the user terminal, a cancellation request for cancellation of the background image registered by the user, and deletes the information associated with the background image that was stored to cancel the registration of the background image.
2. The search information providing apparatus according to claim 1, further comprising:
a user information memory, implemented on the processor operatively coupled to the memory, that stores information regarding a user of the user terminal,
wherein the acquiring unit selects advertisement information corresponding to the information stored in the user information memory among the advertisement information corresponding to the specific search keyword when the search keyword included in the search request is the specific search keyword.
3. The search information providing apparatus according to claim 1,
wherein the receiving unit determines a classification of the user terminal performing the search request,
wherein the advertisement information memory stores advertisement information corresponding to the classification of the user terminal as the advertisement information corresponding to the specific search keyword, and
wherein the acquiring unit selects the advertisement information corresponding to the classification of the user terminal performing the search request as the advertisement information corresponding to the specific search keyword when the search keyword included in the search request is the specific search keyword.
4. The search information providing apparatus according to claim 1,
wherein the acquiring unit acquires advertisement information corresponding to the background image of the registration request instead of the advertisement information corresponding to the specific search keyword included in the search request when the user terminal performing the registration request performs the search request including the specific search keyword.
5. The search information providing apparatus according to claim 1,
wherein the advertisement information memory stores an address of a predetermined page in correspondence with the advertisement information, and
wherein the generating unit adds, to the search result page, a button for accessing the predetermined page corresponding to the advertisement information acquired by the acquiring unit based on the address of the predetermined page stored in the advertisement information memory.
6. The search information providing apparatus according to claim 5, wherein the button has a color andor a shape according to an image based on the corresponding advertisement information.
7. The search information providing apparatus according to claim 1, further comprising:
a content memory, implemented on the processor operatively coupled to the memory, that stores a content to be provided to each user terminal;
a deciding unit, implemented on the processor operatively coupled to the memory, that decides a compensation for the provision of the content for each user terminal; and
a determining unit, implemented on the processor operatively coupled to the memory, that determines a use status of the advertisement information corresponding to the specific search keyword for each user terminal,
wherein the generating unit transmits a content page including the content stored in the content memory to the user terminal, and
wherein the deciding unit decides the compensation for the provision of the content based on the determination result of the determining unit.
8. The search information providing apparatus according to claim 1, wherein when information corresponding to the search keyword searched by the searching unit exceeds a predetermined number, the generating unit generates a plurality of search result pages of which each displays the background image and the search results less than or equal to a predetermined number, the background images being different.
9. The search information providing apparatus according to claim 8, wherein the generating unit sets images of which at least one of a color and a size is different as the different background images.
10. A search information providing method comprising:
(A) receiving, by a computer, a search request including a search keyword from a user terminal;
(B) acquiring, by the computer, information corresponding to the search keyword as a search result based on the search keyword included in the search request;
(C) acquiring, by the computer, advertisement information corresponding to a specific search keyword from an advertisement information memory that stores the advertisement information corresponding to the specific search keyword when the search keyword included in the search request is the specific search keyword;
(D) generating, by the computer, a search result page for displaying the search result and a background image based on the advertisement information acquired in the (C) acquiring; and
(E) transmitting, by the computer, the search result page generated in the (D) generating to the user terminal performing the search request including the specific search keyword, wherein
the receiving includes receiving, from the user terminal, a registration request for registration of the background image that is displayed in the search result page and in response to receiving the registration request, information associated with the background image is stored,
and
the receiving includes receiving, from the user terminal, a cancellation request for cancellation of the background image registered by the user, and deletes the information associated with the background image that was stored to cancel the registration of the background image.
11. A search information providing apparatus comprising:
a receiving unit, implemented on a processor operatively coupled to a memory, which receives a search request including a search keyword from a user terminal;
a searching unit, implemented on the processor operatively coupled to the memory, which acquires information corresponding to the search keyword as a search result based on the search keyword included in the search request;
an advertisement information memory that stores advertisement information corresponding to a specific search keyword;
an acquiring unit, implemented on the processor operatively coupled to the memory, which acquires the advertisement information corresponding to the specific search keyword from the advertisement information memory when the search keyword included in the search request is the specific search keyword;
a generating unit, implemented on the processor operatively coupled to the memory, which generates a search result page for displaying the search result and a background image based on the advertisement information acquired by the acquiring unit; and
a transmitting unit, implemented on the processor operatively coupled to the memory, which transmits the search result page generated by the generating unit to the user terminal performing the search request including the specific search keyword, wherein
the receiving unit receives, from the user terminal, a share registration request for registration of the background image of the search result page that is displayed on a terminal of another user and in response to receiving the share registration request, information associated with the background image is stored, and
wherein the receiving unit further receives, from the user terminal, a cancellation request for cancellation of the background image registered by the user, and deletes the information associated with the background image that was stored to cancel the registration of the background image.

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.