Author: claimsbot

We claim:

1. A data storing method of a dynamic RAM, comprising:
a first operation of reading data, generating a check bit for error detection and correction, and storing the check bit when a dynamic RAM enters an operation mode of performing a data retaining operation;
a refresh operation performed on said data and, as necessary, on said check bit by an error correcting operation using said check bit in a predetermined cycle so that an error bit in said data can be corrected; and
a second operation of correcting an error bit in said data by using said check bit before the dynamic RAM returns from said data retaining operation to a normal operation,
said predetermined cycle being set on the basis of refresh cycle information which is stored in a non-volatile manner.
2. The data storing method of a dynamic RAM according to claim 1,
wherein said data and said check bit are stored in the dynamic RAM, and
wherein the error detecting and correcting operation using said check bit is performed by a built-in error detecting and correcting circuit.
3. A semiconductor integrated circuit device comprising:
a memory circuit including a dynamic memory cell which has a storage capacitor and an address selection MOSFET, and having an information retaining mode during which data is not read from or written to other circuits; and
a data retention control circuit, said data retention control circuit including an ECC circuit and a refresh cycle setting circuit,
wherein said ECC circuit is activated when said memory circuit enters an information retaining mode to perform a first operation of reading plural data stored in said memory circuit and generating and storing a check bit for error detection and correction, and is activated when said memory circuit returns from said information retaining mode to a normal operation mode in which data is read from or written to other circuit to perform a second operation of reading the plural data and the check bit stored in said memory circuit, correcting an error bit in the data, and writing corrected data into a corresponding memory cell,
wherein said refresh cycle setting circuit is controlled to perform a refresh operation in a predetermined cycle in which an error in the data can be corrected by using said check bit by said ECC circuit, and
wherein information indicative of said predetermined cycle is held in a non-volatile manner.
4. The semiconductor integrated circuit device according to claim 3, wherein said check bit is stored in a memory cell included in said memory circuit.
5. The semiconductor integrated circuit device according to claim 3 or 4, wherein said ECC circuit can correct two bits or more by using a cyclic code, allows data and a check bit to be stored in a memory cell read by an operation of selecting one of word lines in the memory circuit, and reads or writes data and the check bit corresponding to said one word line.
6. A semiconductor memory device having a plurality of memory cells to be refreshed for retaining data, comprising:
a first circuit for generating additional information on the basis of information of said plurality of memory cells when said semiconductor memory device changes from a normal operation mode in which data is written to or read from the outside of said semiconductor memory device to a refresh mode in which refresh is made in a refresh cycle, and for detecting and correcting an error in said plurality of memory cells on the basis of information of said plurality of memory cells and said additional information when said semiconductor memory device changes from said refresh mode to said normal operation mode;
a memory circuit for storing said additional information; and
a second circuit for storing information indicative of said refresh cycle in a non-volatile manner,
said refresh cycle in said refresh mode being determined on the basis of said information stored in said second circuit.
7. The semiconductor memory device according to claim 6, wherein said first circuit detects and corrects an error in said plurality of memory cells on the basis of the information of said plurality of memory cells and said additional information only when said semiconductor memory device changes from said refresh mode to said normal operation mode.
8. The semiconductor memory device according to claim 6, wherein said first circuit does not perform said detecting operation and said correcting operation during said refresh mode period except for the case where said semiconductor memory device changes from said refresh mode to said normal operation mode.
9. The semiconductor memory device according to claim 6, wherein said first circuit performs said detecting operation and said correcting operation a plurality of times during said refresh mode period.
10. The semiconductor memory device according to claim 6, wherein said first circuit periodically performs said detecting operation and said correcting operation during said refresh mode period.
11. A semiconductor memory device having a plurality of memory cells to be refreshed for retaining data, comprising:
a first circuit for generating first information on the basis of information held in said plurality of memory cells when said semiconductor memory device changes from a normal operation mode to a refresh mode and detecting and correcting an error in said plurality of memory cells on the basis of said first information when said semiconductor memory device changes from said refresh mode to said normal operation mode; and
a second circuit for storing information indicative of a refresh cycle in a non-volatile manner,
wherein said original refresh cycle at the time of the change from said normal operation mode to said refresh mode is determined on the basis of said information stored in said second circuit.
12. The semiconductor memory device according to claim 11, further comprising a refresh cycle adjusting circuit for adjusting said refresh cycle in said refresh mode in accordance with a temperature of said semiconductor memory device.
13. The semiconductor memory device according to claim 12, wherein said refresh cycle adjusting circuit includes a cell leak monitor.
14. A semiconductor memory device having a plurality of memory cells to be refreshed for retaining data, comprising:
a first circuit for generating first information on the basis of information held in said plurality of memory cells when said semiconductor memory device changes from a normal operation mode in which reading or writing is performed to a self refresh mode in which refresh is made in a refresh cycle and detecting and correcting an error in the information stored in said plurality of memory cells on the basis of the information stored in said plurality of memory cells and said first information when said semiconductor memory device changes from said refresh mode to said normal operation mode; and
a refresh cycle adjusting circuit for adjusting said refresh cycle in said self refresh mode in accordance with a temperature of said semiconductor memory device.
15. The semiconductor memory device according to claim 14, wherein said refresh cycle adjusting circuit includes a cell leak monitor.
16. The semiconductor memory device according to claim 14, further comprising a second circuit for retaining refresh cycle information,
wherein said original refresh cycle at the time of the change from said normal operation mode to said self refresh mode is determined on the basis of said refresh cycle information stored in the second circuit.
17. The semiconductor memory device according to claim 14, wherein said first circuit is a coder or decoder.
18. The semiconductor memory device according to claim 14, wherein said first circuit is an ECC circuit.
19. A semiconductor memory device having a plurality of memory cells to be refreshed, comprising:
a first circuit for generating first information on the basis of information held in said plurality of memory cells when said semiconductor memory device changes from a normal operation period in which reading or writing is performed to a refresh period in which refresh is made in a refresh cycle and detecting and correcting an error in the information on the basis of the information stored in said plurality of memory cells and said first information when said semiconductor memory device changes from said refresh period to said normal operation period; and
a voltage generating circuit,
wherein the operation of said voltage generating circuit is stopped in a part of said refresh period.
20. A semiconductor memory device having a plurality of memory cells to be refreshed for retaining data, comprising:
a circuit for generating additional information on the basis of information stored in said plurality of memory cells when said semiconductor memory device changes from a normal operation period in which reading or writing is performed to a refresh period in which refresh is made in a refresh cycle and detecting and correcting an error in the information stored in said plurality of memory cells on the basis of the information stored in said plurality of memory cells and said additional information when said semiconductor memory device changes from said refresh period to said normal operation period; and
a voltage generating circuit,
wherein the operation of the voltage generating circuit is stopped at least in a part of said refresh period and a period in which said plurality of memory cells are not accessed.
21. The semiconductor memory device according to claim 20, wherein the circuit for detecting and correcting an error in the information held in said plurality of memory cells is a coderdecoder.
22. The semiconductor memory device according to claim 20, wherein the circuit for detecting and correcting an error in the information stored in said plurality of memory cells is an ECC circuit.
23. The semiconductor memory device according to claim 20, wherein said voltage generating circuit is a booster.
24. The semiconductor memory device according to claim 20, wherein said voltage generating circuit is a voltage step-down circuit.
25. The semiconductor memory device according to claim 20, wherein said voltage generating circuit intermittently operates in said refresh cycle in said refresh period.
26. The semiconductor memory device according to claim 20, wherein said refresh period is a self refresh mode period.
27. The semiconductor memory device according to any one of claims 6, 11, 14, 19, and 20, wherein said plurality of memory cells are dynamic memory cells.
28. The semiconductor memory device according to any one of claims 6, 11, 14, 19, 20, and 27, wherein said semiconductor memory device is formed on a single semiconductor substrate.

The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.

What is claimed is:

1. A compound of compound of formula I:
51
wherein:
Z is a carbon or nitrogen atom;
52
is a 4 to 7-membered azaheterocyclyl or a 4 to 7-membered azaheterocyclenyl group;
53
is a single or double bond, provided that when Z is a nitrogen atom, then is a single bond;
54
is an aryl group, a monocyclic heteroaryl group, or a bicyclic azaheteroaryl group which includes a first proximal ring that is attached to the
55
moiety and a ring distal to said first ring, said distal ring including at least one nitrogen atom;
R1 is hydrogen, CH2OR12, CH2SR12, CO2R13, C(O)R13, or CONR13R13;
R2 is hydrogen, alkyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, Y1Y2N, Y1Y2N-alkyl-, Y1Y2NCO or Y1Y2NSO2;
R3 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl;
Xa, Xb, Xc are independently selected from hydrogen, R4R5N, (hydroxy)HN, (alkoxy)HN, R6O, R4R5NCO, R4R5NSO2, R6CO, halo, cyano, nitro R7(O)C(CH2)q and
56
and when
57
is a bicyclic heteroaryl group, then Xc is a substituent that is at the alpha position with respect to a nitrogen atom of said distal ring of
58
and Xc is selected from the group consisting of H, hydroxy and H2N, (optionally substituted lower alkyl)HN (hydroxy)HN, and (alkoxy)HN;
R4 and R5 are independently H or optionally substituted lower alkyl, or one of R4 and R5 is H and the other of R4 and R5 is R7(O)CCH2 or lower acyl;
R6 is H, optionally substituted lower alkyl, lower acyl or R7(O)CCH2;
R7 is H, optionally substituted lower alkyl, alkoxy or hydroxy;
R8 and R9 taken together are NR10;
R10 is hydrogen, R11O2C, R11O, HO, cyano, R11CO, HCO, lower alkyl, nitro, or YlaY2aN;
R11 is alkyl, aralkyl, or heteroaralkyl;
R12 is hydrogen, lower alkyl, aryl(lower alkyl), heteroaryl(lower alkyl), lower acyl, aroyl, or heteraroyl;
R13 is hydrogen, lower alkyl;
Y1 and Y2 are independently hydrogen, alkyl, aryl, and aralkyl, or where the substituent is
Y1Y2N or Y1Y2N-alkyl- then one of Y1 and Y2 is acyl or aroyl and the other of Y1 and Y2 is hydrogen, alkyl, aryl, or aralkyl;
Y1a and Y2a are independently hydrogen or alkyl;
n is 1,2,3, or 4; or
a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
2. A compound according to claim 1 wherein Z is a carbon atom.
3. A compound according to claim 1 wherein Z is a carbon atom;
59
is a 6-membered azaheterocyclyl or a 6-membered azaheterocyclenyl group; R1 is selected from the group consisting of hydrogen CH2OR12, CH2SR12, CO2R13, C(O)R13 and CONR13R13; R12 is hydrogen, lower alkyl, aryl(lower alkyl), or heteroaryl(lower alkyl); and R13 is hydrogen, or lower alkyl.
4. A compound according to claim 1 wherein Z is a carbon atom;
60
is a 6-membered azaheterocyclenyl group;
61
is a double bond; and R1 and R2 are hydrogen.
5. A compound according to claim 1 wherein Z is a carbon atom;
62
is a 6-membered azaheterocyclyl group; and R1 and R2 are hydrogen. A compound according to claim 1 wherein R3 is optionally substituted (phenyl substituted phenyl), optionally substituted (heteroaryl substituted phenyl), optionally substituted (phenyl substituted heteroaryl) or optionally substituted (heteroaryl substituted heteroaryl).
6. A compound according to claim 1 wherein
63
is aryl or a monocyclic heteroaryl group; and Xc is selected from the group consisting of, R4R5N, (hydroxy)HN, (alkoxy)HN, R6O, R4R5NCO, R4R5NSO1, R6CO, halo, cyano, nitro R7(O)C(CH2)q, and
64
7. A compound according to claim 1 wherein Xc is
65
is an aryl group, a monocyclic heteroaryl group.
8. A compound according to claim 1 wherein Xc is
66
and is in the meta position with respect to the to the position of attachment of the
67
moiety to the
68
moiety.
9. A compound according to claim 1 wherein
69
is a bicyclic azaheteroaryl group which includes a first proximal ring that is attached to the
70
moiety and a ring distal to said first ring; Xc is R4R5N, (hydroxy)HN, or (alkoxy)HN, and Xc is in the alpha position with respect to a nitrogen atom in said distal ring.
10. A compound according to claim 1, which is selected from the group consisting of
71
wherein R3 is selected from the group consisting of
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
11. A compound according to claim 1 selected from the group consisting of
3-1-4-(6-Oxo-1,6-dihydropyridine-3-yl)-benzoyl-1,2,3,6-tetrahydropyridin-4 ylbenzamidine;
3-1-4-(1-Oxypyridin-2-yl)-benzoyl-1,2,3,6-tetrahydropyridin-4 ylbenzamidine;
3-1-4-(1-Oxypyridin-4-yl)-benzoyl-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-4-(6-Oxo-1,6-dihydropyridine-3-yl)-benzoyl-piperidin-4-ylbenzamidine;
3-1-4-(1-Oxypyridin-4-yl)-benzoyl-piperidin-4-ylbenzamidine;
3-1-4-(1-Oxypyridin-2-yl)-benzoyl-piperidin-4-ylbenzamidine;
3-1-(4-Pyridine-2-yl-benzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-(4-Pyridin-3-yl-benzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-(4-Pyridin-4-yl-benzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-4-(5-Bromofuran-2-yl)-benzoyl-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-4-(5-Chlorothiophen-2-yl)-benzoyl-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-(4-Thiophen-2-yl-benzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-3-(5-Chlorothiophen-2-yl)-acryloyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-(4-2-(2-Dimethylaminoethyl)methylaminopyrimidin-4-ylbenzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-(1-4-2-(2-Dimethylaminoethyl)-6-oxo-1,6-dihydropyridin-3-ylbenzoyl-1,2,3,6-tetrahydropyridin-4-yl)benzamidine;
3-1-(4-Pyrimidin-2-ylbenzoyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(4-Pyrazin-2-ylbenzoyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(4-Sulfamoylbiphenyl-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(3-Sulfamoylbiphenyl-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-4-(6-Methoxypyridazin-3-yl)benzoyl-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-4-(6-Oxo-1,6 dihydropyridazin-3-yl)benzoyl-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-4-(2-Aminopyrimidin-5-yl)benzoyl-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-4-(6-Methoxypyridin-3-yl)benzoyl-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(4-(Pyrimidin-5-ylbenzoyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(4-Pyridin-2-ylbenzoyl)-piperidin-4-ylbenzamidine;
3-1-(4-Pyridin-3-ylbenzoyl)-piperidin-4-ylbenzamidine;
3-1-(4-Pyridin-4-ylbenzoyl)-piperidin-4-ylbenzamidine;
3-1-4-(6-Methoxypyridin-3-yl)benzoyl-piperidin-4-ylbenzamidine;
3-1-4-(6-Methoxypyridazin-3-yl)benzoyl-piperidin-4-ylbenzamidine;
3-1-4-(6-Oxo-1,6-dihydropyridazin-3-yl)benzoyl-piperidin-4-ylbenzamidine;
5-4-4-(1-Aminoisoquinolin-7-yl)piperidine-1-carbonylphenyl-1H-pyridin-2-one;
5-4-(1-Aminoisoquinolin-7-yl)piperidine-1-carbonyl-1H-2,3bipyridinyl-6-one;
4-(1-Aminoisoquinolin-7-yl)piperidin-1-yl2-fluoro-4-(6-methoxypyridin-3-yl)phenylmethanone;
4-(1-Aminoisoquinolin-7-yl)piperidin-1-yl(2-fluoro-4-pyridin-3-ylphenyl)methanone;
4-4-(1-Aminoisoquinolin-7-yl)piperidine-1-carbonylbiphenyl-3-carboxylic acid amide;
4-(1-Aminoisoquinolin-7-yl)piperidin-1-yl5-(6-methoxypyridin-3-yl)thiophen-2-ylmethanone;
5-4-4-(1-Aminoisoquinolin-7-yl)piperidine-1-carbonyl-3-fluorophenyl-1H-pyridin-2-one;
5-5-4-(1-Aminoisoquinolin-7-yl)piperidine-1-carbonylthiophen-2-yl-1H-pyridin-2-one;
5-4-4-(1-Aminoisoquinolin-7-yl)-3,6-dihydro-2H-pyridine-1-carbonylphenyl-1H-pyridin-2-one;
4-(1-Aminoisoquinolin-7-yl)-3,6-dihydro-2H-pyridin-1-yl(4-pyridin-4-ylphenyl)methanone;
4-(1-Aminoisoquinolin-7-yl)piperidin-1-yl4-(6-methoxypyridin-3-yl)phenylmethanone;
4-(1-Aminoisoquinolin-7-yl)piperidin-1-yl(4-pyridin-3-ylphenyl)methanone;
4-(1-Aminoisoquinolin-7-yl)piperidin-1-yl(6-methoxy-2,3bipyridin-5-yl)methanone;
5-4-4-(4-Amino-1H-pyrrolo3,2-cpyridin-2-yl)piperidine-1-carbonylphenyl-1H-pyridin-2-one;
5-4-(4-Amino-1H-pyrrolo3,2-cpyridin-2-yl)piperidine-1-carbonyl-1H-2,3bipyridinyl-6-one;
3-1-(5-Phenylethyl-pyridine-3-carbonyl)-piperidin-4-yl-benzamidine;
3-1-(5-Phenylethynyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(5-Phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl-benzamidine; and
3-4-(5-Phenylethyl-pyridine-3-carbonyl)-piperazin-1-yl-benzamidine.
12. A compound according to claim 1 wherein
Z is a nitrogen atom;
87
is a 6-membered azaheterocyclyl or a 6-membered azaheterocyclenyl group;
88
is a single bond; and R1 and R2 are hydrogen.
13. A compound according to claim 1 wherein
Z is a nitrogen atom;
89
is a 6-membered azaheterocyclyl or a 6-membered azaheterocyclenyl group;
90
is a single bond; and R1 is selected from the group consisting of hydrogen CH2OR12, CH2SR12, CO2R13, C(O)R13 and CONR13R13.
14. A compound according to claim 12 or 13 wherein
R3 is optionally substituted (phenyl substituted aralkyl), optionally substituted (heteroaryl substituted aralkyl), optionally substituted (phenyl substituted heteroaralkyl) or optionally substituted (heteroaryl substituted heteroaralkyl).
15. A compound according to claim 12 or 13 wherein R3 is optionally substituted (phenyl substituted aralkenyl), optionally substituted (heteroaryl substituted aralkenyl), optionally substituted (phenyl substituted heteroaralkenyl) or optionally substituted (heteroaryl substituted heteroaralkenyl).
16. A compound according to claim 12 or 13 wherein R3 is optionally substituted (phenyl substituted aralkynl), optionally substituted (heteroaryl substituted aralkynl), optionally substituted (phenyl substituted heteroaralkynl) or optionally substituted (heteroaryl substituted heteroaralkynl), (wherein the term optionally substituted before the term in the parenthesis, denote that the phenyl, heteroaryl, aralkynl, heteroaralkynl portions thereof could be further substituted as noted per their definitions).
17. A compound according to claim 1 selected from the group consisting of
3-1-(5-Phenylethyl-pyridine-3-carbonyl)-piperidin-4-yl-benzamidine;
3-1-(5-Phenylethynyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(5-Phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl-benzamidine;
3-1-4-(6-Methoxypyridin-3-yl)benzoyl-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-(4-(Pyrimidin-5-ylbenzoyl)-1,2,3,6-tetrahydropyridin-4-yl-benzamidine;
3-1-4-(6-Methoxypyridazin-3-yl)benzoyl-piperidin-4-ylbenzamidine;
3-1-4-(1-Oxypyridin-2-yl)-benzoyl-piperidin-4-ylbenzamidine;
3-1-(4-Pyridine-2-yl-benzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-(4-Pyridin-4-yl-benzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-(4-2-(2-Dimethylaminoethyl)methylaminopyrimidin-4-ylbenzoyl)-1,2,3,6-tetrahydropyridin-4-ylbenzamidine; and
3-4-(5-Phenylethyl-pyridine-3-carbonyl)-piperazin-1-yl-benzamidine.
18. A compound according to claim 1 selected from the group consisting of
3-1-4-(1-Oxypyridin-4-yl)-benzoyl-1,2,3,6-tetrahydropyridin-4-ylbenzamidine;
3-1-4-(6-Oxo-1,6-dihydropyridine-3-yl)-benzoyl-piperidin-4-ylbenzamidine;
3-1-4-(1-Oxypyridin-4-yl)-benzoyl-piperidin-4-ylbenzamidine;
3-1-4-(6-Oxo-1,6-dihydropyridine-3-yl)-benzoyl-1,2,3,6-tetrahydropyridin-4ylbenzamidine;
3-1-4-(6-Oxo-1,6 dihydropyridazin-3-yl)benzoyl-1,2,3,6-tetrahydropyridin-4ylbenzamidine; and
3-1-4-(6-Oxo-1,6-dihydropyridazin-3-yl)benzoyl-piperidin-4-ylbenzamidine.
19. A method for treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 or claim 17.
20. A method for preventing and treating an inflammatory diseases associated with tryptase activity comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 or claim 17.
21. A method for preventing and treating late phase bronchoconstriction associated with chronic asthma comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1 or claim 17.
22. A method according to claim 19 wherein said disease state is selected from the group consisting of immunomediated inflammatory disorders associated with tryptase activity, such as rheumatoid arthritis, osteoarthritis, gouty arthritis, rheumatoid spondylitis, diseases of joint cartilage destruction, ocular conjunctivitis, vernal conjunctivis, inflammatory bowel disease, asthma, allergic rhinitis, and interstitial lung diseases.
23. A method according to claim 19 wherein said disease state is selected from the group consisting of fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hypertrophic scars, and various dermatological conditions, for example, atopic dermatitis and psoriasis.
24. A method according to claim 19 wherein said disease state is selected from the group consisting of myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture; as well as periodontal disease, diabetic retinopathy, tumor growth, anaphylaxis, multiple sclerosis, peptic ulcers, and syncytial viral infections.
25. A method of inhibiting tryptase activity comprising contacting a tryptase inhibitory amount of a compound of according to claim 1 or claim 17 with a composition containing tryptase.
26. A method of treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising administering to a patient, in need thereof, a compound according to claim 1 or claim 17 or a pharmaceutically acceptable salt thereof, and optionally at least one compound selected from the group consisting of a -adrenergic agonist compound, an anti-inflammatory corticosteroid compound, an anticholinergics compound, and an anti-inflammatory compound, or a pharmaceutically acceptable salt thereof, wherein said -adrenergic agonist compound is selected from the group consisting of albuterol, terbutaline, formoterol, fenoterol, and prenaline; said anti-inflammatory corticosteroid compound is selected from the group consisting of beclomethasone, triamcinolone, flurisolide, and dexamethasone; said anticholinergics compound is ipratropium bromide; and said anti-inflammatory compound is selected from the group consiting of sodium cromoglycate and nedocromil sodium.
27. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
28. A method for treating a patient suffering from a physiological condition capable of being modulated by inhibiting activity of Factor Xa comprising administering to said patient a pharmaceutically effective amount of the compound according to claim 2 or 18.
29. The method according to claim 28 wherein the physiological condition is venous vasculature, arterial vasculature, abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, intermittent claudication or bypass grafting of the coronary or peripheral arteries, vessel luminal narrowing, restenosis post coronary or venous angioplasty, maintenance of vascular access patency in long-term hemodialysis patients, pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery, a risk of pulmonary thromboembolism, or disseminated systemic intravascular coagulopathy occurring in vascular systems during septic shock, certain viral infections or cancer.
30. The method according to claim 28 wherein the physiological condition is abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, transient ischemic attacks, intermittent claudication or bypass grafting of the coronary or peripheral arteries, restenosis post coronary or venous angioplasty, pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery or a risk of pulmonary thromboembolism.
31. The method according to claim 28 wherein the physiological condition is stroke, vessel luminal narrowing, maintenance of vascular access patency in long-term hemodialysis patients, or disseminated systemic intravascular coagulopathy occurring in vascular systems during septic shock, certain viral infections or cancer.
32. A method of inhibiting Factor Xa comprising contacting a Factor Xa inhibitory amount of a compound according to claim 2 or claim 18 with a composition containing Factor Xa.
33. A method of inhibiting the formation of thrombin comprising contacting Factor Xa inhibitory amount of a compound according to claim 2 or claim 18 with a composition containing Factor Xa.
34. A method for treating a patient suffering from a physiological condition capable of being modulated by directly inhibiting activity of both Factor Xa and Factor IIa (thrombin) comprising administering to said patient a pharmaceutically effective amount of the compound according to claim 2 or claim 18.
35. A method of treating a patient suffering from a disease state capable of being modulated by inhibiting Factor Xa activity comprising administering to a patient, in need thereof, a compound according to claim 2 or claim 18 or a pharmaceutically acceptable salt thereof, and optionally at least one compound selected from the group consisting of a cardioprotective agent, a direct thrombin inhibitor, an anticoagulant, an antiplatelet agent or fibrinolytic agent.

1. A method for selecting a panel of biomarkers useful for determining the stage of sepsis in an animal species comprising:
(a) providing a plurality of biological samples taken at a selected timepoint from at least two groups of animals, wherein the first group of animals comprises survived immunocompromised individuals infected by a sepsis-causing pathogen and the second group of animals comprises doomed immunocompromised individuals infected by a sepsis-causing pathogen;
(b) measuring the amount of each of a plurality of analytes in the biological samples from each group and generating a dataset for each group; and
(c) performing a statistical analysis on the data comprising:
(i) conducting a univariate statistical test on the dataset for each analyte, to compare the dataset for biological samples from the first group to the dataset for biological samples from the second group of animals; and
(ii) selecting as biomarkers analytes according to their significance level as determined by the univariate statistical test.
2. The method of claim 1 wherein the univariate statistical test is a T-test.
3. The method of claim 1 further comprising transforming the data for each group to log scale.
4. The method of claim 1, wherein the p value of each of the selected analytes is less than a significance level of 0.05.
5. The method of claim 1 further comprising:
deriving a discrimination function for the selected biomarkers, wherein said deriving comprises performing a principle component analysis and a linear discriminant analysis; and
using the discrimination function to generate a score for each animal.
6. The method of claim 5, wherein the analytes comprise MCP-1JE, IL-6, MCP-3, IL-3, MIP-1\u03b2, and KC-GRO.
7. The method of claim 6 wherein the discrimination function is 19(MCP-1-JE)+27(IL-6)+18(MCP-3)+21(IL-3)+18(MIP-1\u03b2)+25(KC-GRO).
8. The method of claim 1, wherein the analytes comprise Apolipoprotein A1, \u03b22 Microglobulin, C Reactive Protein, D-dimer, EGF, Endothelin-1, Eotaxin, Factor VII, FGF-9, FGF-Basic, Fibrinogen, GCP-2, LIX, GM-CSF, Growth Hormone, GST, Haptoglobin, IFN-\u03b1, IgA, IL-10, IL-11, IL-12p70, IL-17, IL-18, IL-1\u03b1, IL-1\u03b2, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, Insulin, IP-10, KC-GRO, Leptin, LIF, Lymphotactin, MCP-1-JE, MCP-3, MCP-5, M-CSF, MDC, MIP-1\u03b1, MIP-1\u03b2, MIP-1\u03b1, MIP-2, MIP-3\u03b2, Myoglobin, OSM, RANTES, SCF, SGOT, TIMP-1, Tissue Factor, TNF-\u03b1, TPO, VCAM-1, VEGF, and VWF.
9. The method of claim 1, wherein the animals are mice.
10. The method of claim 8, wherein the timepoint is selected from the group consisting of 4 hours post infection, 10 hours post infection, 22 hours post infection, 24 hours post infection, 48 hours post infection, 72 hours post infection, and 96 hours post infection.
11. The method of claim 1, wherein the species is human.
12. The method of claim 1, wherein the biomarker panel consists of fifteen or fewer biomarkers.
13. The method of claim 1, wherein the biomarker panel consists of ten or fewer biomarkers.
14. The method of claim 1, wherein the biomarker panel consists of five or fewer biomarkers.
15. The method of claim 1, further comprising using data-visualization software to evaluate the ability of the panel biomarkers to predict disease outcome for a subject diagnosed with sepsis.
16. The method of claim 1, wherein the biological samples are serum samples.
17. A method for providing a survival prognosis for an animal diagnosed with sepsis, comprising:
(a) providing a biological sample from an animal suspected of being infected by a sepsis-causing pathogen;
(b) providing a panel of biomarkers useful for determining the stage of sepsis syndrome in the animal species, said panel selected according to the method defined in claim 5;
(c) measuring in the biological sample the amount of each of the biomarkers;
(d) generating a score for the biological sample using the discrimination function; and
(e) comparing the score with at least one score determined using a biological sample from a survived immunocompromised animal and at least one score determined using a biological sample from a doomed immunocompromised animal.
18. The method of claim 17, further comprising confirming that the animal is infected by a sepsis-causing pathogen.
19. The method of claim 17 wherein the animal species is a mammal.
20. The method of claim 17 where the animal is a mouse.
21. The method of claim 17 where the animal is a human.
22. A method for determining the stage of sepsis in an animal comprising:
(a) providing a biological sample from an animal suspected of being infected by a sepsis-causing pathogen;
(b) providing a panel of biomarkers useful for determining the stage of sepsis syndrome in the animal species, said panel selected according to the method defined in claim 5;
(c) measuring in the biological sample the amount of each of the biomarkers;
(d) generating a score for the biological sample using a discrimination function determined for the stage of sepsis syndrome; and
(e) comparing the score for the biological sample with at least one reference score determined using a biological sample from at least one animal in said stage of sepsis syndrome.
23. The method of claim 22 further comprising confirming that the animal is infected by a sepsis-causing pathogen.
24. The method of claim 22 where the animal is a mammal.
25. The method of claim 22 where the animal is a mouse.
26. The method of claim 22 where the animal is a human.
27. A method of evaluating a test compound for treating sepsis syndrome, comprising:
(a) developing experimental animals modeling sepsis syndrome, comprising infecting experimental immunocompromised animals and control immunocompromised animals of the same species with a pathogen species a pathogen species capable of causing sepsis in the animal species, wherein the survival rate of immunocompromised infected animals in the model system is 10-90%;
(b) administering a test compound to the experimental animals;
(c) obtaining biological samples from the experimental and control animals at a selected timepoint following infection;
(d) measuring the amounts of a plurality of analytes in the biological samples; and
(e) determining the scores for the experimental and control animals using a discrimination function for the animal species;
whereby if the test compound is determined to be effective in causing a statistically significant change in the score for the biological sample compared to the score for the control animals, the test compound is a candidate drug for treating sepsis syndrome.
28. The method of claim 27 wherein said test compound is a modulator of vascular endothelial growth factor, monocyte chemoattractant protein 1, or peroxisome proliferator-activated receptor gamma.
29. The method of claim 27, wherein said survival rate of immunocompromised infected animals in the model system is 30-70%.
30. The method of claim 27 wherein the test compound is a toll-like receptor (TLR) inhibitor.
31. The method of claim 27, further comprising administering an antibiotic to the animals.
32. A method of determining a reference score for a group of immunocompromised infected animals in a model system comprising:
(a) providing a model system of sepsis syndrome, said model system comprising immunocompromised survived animals and immunocompromised doomed animals from an animal species and a sepsis-causing pathogen species;
(b) infecting the animals in the model system;
(c) obtaining biological samples from the animals at a selected time after infecting;
(d) measuring the level of a panel of biomarkers selected using the method of claim 5 in each biological sample; and
(e) determining a first reference score for immunocompromised survived animals using a discrimination function, and determining a second reference score for immunocompromised doomed animals using a discrimination function.
33. A method of determining a reference score for a group of sepsis patients comprising:
(a) providing a group of patients having sepsis;
(b) obtaining biological samples from said patients;
(c) measuring the level of a panel of biomarkers selected using the method of claims 5 in each biological sample; and
(d) determining a first reference score for actual doomed patients with sepsis using a discrimination function, and determining a second reference score for actual survived patients using a discrimination function.
34. A method as defined in claim 33, wherein the biomarker panel comprises an MCP-1 analyte.
35. A method as defined in claim 34, wherein the biomarker panel further comprises a VEGF analyte.
36. A model system for septic syndrome comprising:
(a) at least one immunocompromised animal infected with a sepsis-causing pathogen; and
(b) at least one immunocompromised animal not infected with a sepsis-causing pathogen.
37. A method of using the model system of claim 36 to test the effectiveness of a compound active against a sepsis target, comprising:
(a) providing a test compound to said at least one infected animal and to said at least one not infected animal;
(b) determining the survival rate for each said treated animal; and
(c) determining the level of at least one serum analyte in each said treated animal, whereby change in the survival rates and the at least one analyte level reflects the effectiveness of the compound as a treatment for septic syndrome.
38. The method of claim 37, wherein said animals are each a mouse.
39. The method of claim 37, wherein the test compound is an anti-vascular endothelial growth factor (VEGF) antibody or an anti-MCP-1 antibody.
40. The method of claim 37, further comprising administering an antibiotic to the animals.
41. A method for identifying biomarkers involved in the systemic inflammatory response to infection comprising:
(a) providing a plurality of biological samples taken at a selected timepoint from at least two groups of animals wherein the first group comprises survived immunocompromised individuals infected by a sepsis-causing pathogen and the second group comprises doomed immunocompromised individuals infected by a sepsis-causing pathogen;
(b) measuring the amount of each of a plurality of analytes in the biological samples from each group and generating a dataset for each group; and
(c) performing a statistical analysis on the data comprising:
(i) conducting a univariate statistical test on the dataset, for each analyte, to compare the dataset for biological samples from the first group to the dataset for biological samples from the second group of animals; and
(ii) selecting analytes according to their significance level as determined by the univariate statistical test.
42. A method for selecting a panel of biomarkers useful for determining the stage of sepsis in an animal species comprising:
(a) providing a plurality of biological samples taken at a selected timepoint from at least two groups of animals wherein the first group comprises survived immunocompromised individuals infected by a sepsis-causing pathogen and the second group comprises doomed immunocompromised individuals infected by a sepsis-causing pathogen;
(b) measuring the amount of each of a plurality of analytes in the biological samples from each group and generating a dataset for each group; and
(c) selecting analytes according to their ability to discriminate between the groups.
43. A method of treating sepsis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound modulating MCP-1 activity.
44. A method as defined in claim 43, wherein said compound is an anti-MCP-1 antibody.

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. An improved applepotato peeler, comprising:
a base;
a main frame mounted to a slightly L-shaped structure on said base;
a rotatable and axially movable screw horizontally supported on a screw support member on a vertical frame member disposed at the rear of said main frame;
a 3-prong fork fixed to the end of said screw;
a guide piece pivotally front mounted on said vertical frame member and being releasably engageable relative to a screw channel of said screw;
a resiliently movable peeling arm fore-and-aft swingeably pivoted to the front part of the horizontal frame member of said main frame;
a U-shaped peeling blade fixed to the upper end of said movable peeling arm by means of a blade positioning device;
a coringslicing blade fixed to the front end of said horizontal frame member for cutting flesh of a vegetable or fruit held by the 3-prong fork of said screw into continuous spiral slices and coring said vegetable or fruit;
an annular blade for coring at the upper end of said coringslicing blade is inlaid within a centering cylinder having at the center thereof located with a small-caliber center through hole aiming exactly at the center of the 3-prong fork and through the center through hole of said centering cylinder is passed a center pin with one end inserting into a central indent of said 3-prong fork and the other end penetrating through said center through hole of said centering cylinder; and
a tail end centering device comprising said centering cylinder and said center pin and coupled with said 3-prong fork of said screw, and said peeler is capable of holding an applepotato by the head and tail ends thereof in a supporting manner and maintain accurate centering and steady rotation thereof.
2. The applepotato peeler of claim 1, wherein the downward edge of a U-shaped peeling blade is formed into an edge with finely arranged continuous dentate or wavy shape.
3. The applepotato peeler of claim 1, wherein a blade positioning device fixed to said U-shaped peeling blade at the top of said movable peeling arm comprises: a blade housing with the upper part thereof having a blade holder and the lower part thereof having a skirt portion fore-and-aft slidably engaged to the flat top portion at the upper end of said movable peeling arm and with a section being of a slight T-shape, a thumb screw for penetrating through an elongate hole at the top surface of said blade housing to fix said blade housing onto said flat top portion, and an adjusting screw screwed into a screw hole on the rear vertical lug of said blade housing and having front end thereof pressing against the rear wall of said flat top portion.
4. The applepotato peeler of claim 1, wherein said blade positioning device of said U-shaped peeling blade comprises: said blade housing with the upper part thereof having a blade holder and the lower part thereof having a skirt portion fore-and-aft slidably engaged to the flat top portion at the upper end of said movable peeling arm and with a section being of a T-shape, a thumb screw for penetrating through an elongate hole at the top surface of said blade housing, to fix said blade housing onto said flat top portion, and an adjusting screw screwed into a screw hole on the rear vertical lug of said blade housing and having front end thereof pressing against the rear wall of said flat top portion; wherein an inwardly protruding transverse rib is formed on each of the two side walls at the intersection of said skirt portion and said blade holder having the same width, whereas said blade housing is engaged in said flat top portion by means of said skirt portion and locked on said flat top portion of movable peeling arm by means of said ribs.
5. The applepotato peeler of claim 1, wherein said blade positioning device of said U-shaped peeling blade comprises a trough-shaped base member having an opening in the front thereof and a screw hole on the rear wall thereof a blade housing fore-and aft slidably engaged in said base member and having an elongate hole on the top surface thereof, a thumb screw for penetrating through said elongate hole of said blade housing and said bottom hole of said base member to be screwed into said screw hole of said flat top portion to fix said blade housing and said base member onto said flat top portion, and an adjusting screw screwed into a screw hole provided on the rear wall of said base member and the front end thereof pressing against the rear wall of said blade housing.