We claim:
1. A method for the treatment of an HCV infection in a host comprising administering an effective amount of a compound of the formula (I):
75
or a pharmaceutically acceptable salt thereof, wherein:
(j) each R4 and R4 is independently hydrogen, halogen (F, Br, Cl, I), pseudohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R4 and R4 is hydrogen;
(k) each R5 and R5 is independently hydrogen, halogen (F, Br, Cl, I), pseudohalogen, CN, NO2, lower alkyl of C1-C6, or halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R5 and R5 is hydrogen;
(l) each R6 and R7 is independently hydrogen, alkyl, halogenated alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl or acyl;
(m) R1 is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6;
(n) R2 is oxygen, sulfur, NR or CR2, wherein each R is independently hydrogen, lower alkyl, alkylene, alkenyl, aryl, or aralkyl of C1-C6;
(O) R3 is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6 (C1, C2, C3, C4, C5, C6);
(p) alternatively if R2 is NR, then R1 or R3 can come together with NR to form a substituted or unsubstituted 5-7 membered ring that can include one or more heteroatoms; or
(q) if R2 is CR2, then R or R3 can come together with CR2 to form a substituted or unsubstituted 5-7 membered ring that can include one or more heteroatoms; or
(r) if R2 is CR2, R1 and R3 can come together with CR2 to form a substituted or unsubstituted bicyclic ring that can include one or more heteroatoms;
optionally with a pharmaceutically acceptable carrier.
2. The method of claim 1, wherein R5 andor R5 is OH.
3. The method of claim 1, wherein R5 or R5 is a residue of an amino acid.
4. The method of claim 3, wherein the amino acid is valine.
5. The method of claim 3, wherein the amino acid is L-valine.
6. A method for the treatment of an HCV infection in a host comprising administering an effective amount of a compound of the general formula 1 (A-D), 2 (A-D), 3 (A-B), 4 (A-B), 5 (A-B), 6 (A-B), 7 (A-C) or 8 (A):
76
77
78
or a pharmaceutically acceptable salt thereof, wherein:
(a) each R4 and R4 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, 5 hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R4 and R4 is hydrogen;
(b) each R5 and R5 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R5 and R5 is hydrogen;
(c) each R6 and R7 is independently hydrogen, alkyl, halogenated alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl or acyl;
(d) R2 is oxygen, sulfur, NR or CR2, wherein each R is independently hydrogen, lower alkyl, alkylene, alkenyl, aryl, or aralkyl of C1-C6;
(e) each Z, Z and Z is independently CH, CX or N;
(f) each X, X and X is independently hydrogen, halogen (F, Cl, Br or I), NH2, NHRc, NRcRc, NHORc, NRcNRcRc, OH, ORc, SH or SRc;
(g) each Y and Y is O, S, NH, NRc, NORc or Se;
(h) each Ra is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6; and
(i) each Rc, Rc and Rc independently is hydrogen, lower alkyl, lower alkenyl, aryl, or arylalkyl such as unsubstituted or substituted phenyl or benzyl, cycloalkyl, cylcopropyl;
optionally with a pharmaceutically acceptable carrier.
7. A method for the treatment of an HCV infection in a host comprising administering an effective amount of a compound of the general formula:
79
or a pharmaceutically acceptable salt thereof, wherein:
(a) each R4 and R4 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R4 and R4 is hydrogen;
(b) each R5 and R5 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R5 and R5 is hydrogen;
(c) each R6 and R7 is independently hydrogen, alkyl, halogenated alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl or acyl;
(d) R2 is oxygen, sulfur, NR or CR2, wherein each R is independently hydrogen, lower alkyl, alkylene, alkenyl, aryl, or aralkyl of C1-C6;
(e) each Z, Z and Z is independently CH, CX or N;
(f) each X, X and X is independently hydrogen, halogen (F, Cl, Br or I), NH2, NHRc, NRcRc, NHORc, NRcNRcORc, OH, ORc, SH or SRc;
(g) each Y and Y is O, S, NH, NRc, NORc or Se;
(h) each Ra is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6;
(i) Rb is Rc, ORc, NH2,NHRc or NRCRC; and
(j) each Rc, Rc and Rc independently is hydrogen, lower alkyl, lower alkenyl, aryl, or arylalkyl such as unsubstituted or substituted phenyl or benzyl, cycloalkyl, cylcopropyl;
optionally with a pharmaceutically acceptable carrier.
8. A method for the treatment of an HCV infection in a host comprising administering an effective amount of a compound of the general formula:
80
or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier.
9. A method for the treatment of an HCV infection in a host comprising administering an effective amount of a compound of the general formula:
81
82
83
84
85
or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier.
10. The method of any one of claims 1, 6, 7, 8, or 9, further comprising administering to the host in combination andor alternation one or more effective anti-viral agents, optionally with a pharmaceutically acceptable carrier.
11. The method of claim 10, wherein the anti-viral agent is selected from the group consisting of ribavirin, interferon, PEGASYS (pegylated interferon alfa -2a), INFERGEN (interferon alfacon-1), OMNIFERON (natural interferon), ALBUFERON, REBIF (interferon beta-1a), Omega Interferon, Oral Interferon Alpha, Interferon gamma-1b, Interleukin-10, IP-501, Merimebodib VX-497, AMANTADINE (Symmetrel), HEPTAZYME, IDN-6556., XTL-002, HCVMF59, CIVACIR, LEVOVIRIN, VIRAMIDINE, ZADAXIN (thymosin alfa-1), CEPLENE (histamine dihydrochloride), VX 950LY 570310, ISIS 14803, IDN-6556 and JTK 003.
12. The method of any one of claims 1, 6, 7, 8, or 9, wherein the host is a human.
13. A compound of the formula (I):
86
or a pharmaceutically acceptable salt thereof, wherein:
(a) each R4 and R4 is independently hydrogen, halogen (F, Br, Cl, I), pseudohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R4 and R4 is hydrogen;
(b) each R5 and R5 is independently hydrogen, halogen (F, Br, Cl, I), pseudohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R5 and R5 is hydrogen;
(c) each R6 and R7 is independently hydrogen, alkyl, halogenated alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl or acyl;
(d) R1 is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6;
(e) R2 is oxygen, sulfur, NR or CR2, wherein each R is independently hydrogen, lower alkyl, alkylene, alkenyl, aryl, or aralkyl of C1-C6;
(f) R3 is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6;
(g) alternatively if R2 is NR, then R1 or R3 can come together with NR to form a substituted or unsubstituted 5-7 membered ring that can include one or more heteroatoms; or
(h) if R2 is CR2, then R1 or R3 can come together with CR2 to form a substituted or unsubstituted 5-7 membered ring that can include one or more heteroatoms; or
(i) if R2 is CR2, R1 and R3 can come together with CR2 to form a substituted or unsubstituted bicyclic ring that can include one or more heteroatoms.
14. The compound of claim 13, wherein R5 andor R5 is OH.
15. The compound of claim 13, wherein R5 or R5 is a residue of an amino acid.
16. The compound of claim 15, wherein the amino acid is valine.
17. The compound of claim 15, wherein the amino acid is L-valine.
18. A compound of the general formula 1 (A-D), 2 (A-D), 3 (A-B), 4 (A-B), 5 (A-B), 6 (A-B), 7 (A-C) or 8 (A):
87
88
89
or a pharmaceutically acceptable salt thereof, wherein:
(a) each R4 and R4 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R4 and R4 is hydrogen;
(b) each R5 and R5 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R5 and R5 is hydrogen;
(c) each R6 and R7 is independently hydrogen, alkyl, halogenated alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl or acyl;
(d) R2 is oxygen, sulfur, NR or CR2, wherein each R is independently hydrogen, lower alkyl, alkylene, alkenyl, aryl, or aralkyl of C1-C6;
(e) each Z, Z and Z is independently CH, CX or N;
(f) each X, X and X is independently hydrogen, halogen (F, Cl, Br or I), NH2, NHRc, NRcRc, NHORc, NRcNRcRc, OH, ORc, SH or SRc;
(g) each Y and Y is O, S, NH, NRc, NORc or Se;
(h) each R1 is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6; and
(i) each Rc, Rc and Rc independently is hydrogen, lower alkyl, lower alkenyl, aryl, or arylalkyl such as unsubstituted or substituted phenyl or benzyl, cycloalkyl, cylcopropyl.
19. A compound of the general formula:
90
or a pharmaceutically acceptable salt thereof, wherein:
(a) each R4 and R4 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R4 and R4 is hydrogen;
(b) each R5 and R5 is independently hydrogen, halogen (F, Br, Cl, I), psuedohalogen, CN, NO2, lower alkyl of C1-C6, halogenated lower alkyl, hydroxyl, alkoxy, CH2OH, CH2OR6, NH2, NR6R7, or a residue of an amino acid; wherein at least one of R5 and R5 is hydrogen;
(c) each R6 and R7 is independently hydrogen, alkyl, halogenated alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl or acyl;
(d) R1 is oxygen, sulfur, NR or CR2, wherein each R is independently hydrogen, lower alkyl, alkylene, alkenyl, aryl, or aralkyl of C1-C6;
(e) each Z, Z and Z is independently CH, CX or N;
(f) each X, X and X is independently hydrogen, halogen (F, Cl, Br or I), NH2, NHRc, NRcRc, NHORc, NRcNRcRc, OH, ORc, SH or SRc;
(g) each Y and Y is O, S, NH, NRc, NORc or Se;
(h) each Ra is hydrogen, lower alkyl, alkylene, alkenyl, carbocycle, aryl, heterocycle, heteroaryl, aralkyl, aminoalkyl, aminoaryl or aminoacyl of C1-C6;
(i) Rb is Rc, ORc, NH2, NHRc or NRCRC; and
(j) each Rc, Rc and Rc independently is hydrogen, lower alkyl, lower alkenyl, aryl, or arylalkyl such as unsubstituted or substituted phenyl or benzyl, cycloalkyl, cylcopropyl.
20. A compound of the general formula:
91
or a pharmaceutically acceptable salt thereof.
21. A compound of the general formula:
92
93
94
95
96
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising an effective amount of any one of the compounds of claims 13, 18, 19, 20, or 21, together with a pharmaceutically acceptable carrier.
23. A pharmaceutical composition comprising an effective amount of any one of the compounds of claims 13, 18, 19, 20, or 21, together with one or more effective anti-viral agents, optionally with a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23, wherein the anti-viral agent is selected from the group consisting of ribavirin, interferon, PEGASYS (pegylated interferon alfa -2a), INFERGEN (interferon alfacon-1), OMNIFERON (natural interferon), ALBUFERON, REBIF (interferon beta-1a), Omega Interferon, Oral Interferon Alpha, Interferon gamma-1b, Interleukin-10, IP-501, Merimebodib VX-497, AMANTADINE (Symmetrel), HEPTAZYME , IDN-6556., XTL-002, HCVMF59, CIVACIR, LEVOVIRIN, VIRAMIDINE, ZADAXIN (thymosin alfa-1), CEPLENE (histamine dihydrochloride), VX 950LY 570310, ISIS 14803, IDN-6556 and JTK 003.
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 engine controller, comprising a combustion state detection or estimation means for detecting or estimating a combustion state in a combustion chamber and a combustion air-fuel ratio estimation means for estimating a combustion air-fuel ratio in the combustion chamber according to an exhaust air-fuel ratio and the detected or estimated combustion state.
2. The engine controller according to claim 1, further comprising a means for calculating an engine control parameter according to the estimated combustion exhaust air-fuel ratio.
3. The engine controller according to claim 1, wherein the combustion state detection or estimation means estimates the combustion state according to engine revolutions or an nth-order differential value (n: integer) of the engine revolutions.
4. The engine controller according to claim 1, wherein the combustion state detection or estimation means estimates the combustion state according to at least one of an intra-cylinder pressure, an intra-cylinder temperature, and a generated torque in the engine.
5. The engine controller according to claim 1, wherein an exhaust sensor for sensing the exhaust air-fuel ratio is provided in an exhaust path.
6. The engine controller according to claim 5, wherein the combustion state detection or estimation means calculates a basic combustion air-fuel ratio value from the combustion state and the combustion air-fuel ratio estimation means estimates the combustion air-fuel ratio according to the basic combustion air-fuel ratio value and the exhaust air-fuel ratio.
7. The engine controller according to claim 6, wherein the combustion air-fuel ratio estimation means compares the basic combustion air-fuel ratio value with the exhaust air-fuel ratio and estimates either the basic combustion air-fuel ratio value or the exhaust air-fuel ratio as the combustion air-fuel ratio according to a comparison result.
8. The engine controller according to claim 6, wherein the combustion air-fuel ratio estimation means estimates the larger of the basic combustion air-fuel ratio value and the exhaust air-fuel ratio as the combustion air-fuel ratio.
9. The engine controller according to claim 5, wherein the combustion air-fuel ratio estimation means calculates the amount of exhaust air-fuel ratio correction according to the combustion state and estimates a value obtained by correcting the exhaust air-fuel ratio with the calculated amount of exhaust air-fuel ratio correction as a combustion air-fuel ratio.
10. The engine controller according to claim 2, wherein the control parameter calculation means calculates at least one of the amount of fuel to be injected, an ignition timing, and the amount of air to be inhaled as the control parameter.
11. The engine controller according to claim 2, further comprising a control parameter calculation permission means that permits or denies control parameter calculation, which is performed by the control parameter calculation means on the basis of the combustion air-fuel ratio, according to the running state of the engine.
12. The engine controller according to claim 11, wherein the control parameter calculation permission means permits or denies the control parameter calculation according to an engine cooling water temperature, an inhaled air temperature, a time elapsed from the time of start, the total number of cycles after the start, the total amount of air inhaled after the start, and other parameters that typify an engine temperature.
13. The engine controller according to claim 12, wherein the control parameter calculation permission means permits the engine control parameter calculation on the basis of the combustion air-fuel ratio when at least one of the following conditions is met: the engine cooling water temperature is equal to or lower than a prescribed value, the temperature of air to be inhaled into the engine is equal to or lower than a prescribed value, the time elapsed after the start of the engine is equal to or less than a prescribed value, the total number of cycles after the start of the engine is equal to or smaller than a prescribed value, and the total amount of air inhaled after the start of the engine is equal to or smaller than a prescribed value.
14. The engine controller according to claim 11, wherein the control parameter calculation permission means has the control parameter calculation means correct engine control parameters on the basis of the exhaust air-fuel ratio or deny the engine control parameter calculation, when a difference or a ratio between the combustion air-fuel ratio and the exhaust air-fuel ratio is equal to or greater than a prescribed value.
15. The engine controller according to claim 2, wherein the control parameter calculation means corrects a control parameter for controlling the amount of fuel according to a fed-back exhaust air-fuel ratio, or stops feedback control.
16. The engine controller according to claim 6, further comprising a means for learning the relation between the combustion state and the basic combustion air-fuel ratio value according to the exhaust air-fuel ratio.
17. The engine controller according to claim 16, wherein the learning means performs the learning according to the running state of the engine.
18. The engine controller according to claim 17, wherein the learning means performs the learning when at least one of the following conditions is met: an engine cooling water temperature is equal to or higher than a prescribed value, the temperature of air to be inhaled into the engine is equal to or higher than a prescribed value, a time elapsed after the start of the engine is equal to or more than a prescribed value, the total number of cycles after the start of the engine is equal to or more than a prescribed value, and the total amount of air inhaled after the start of the engine is equal to or more than a prescribed value.
19. The engine controller according to claim 1, further comprising a means for calculating a supply air-fuel ratio according to the amount of air to be inhaled into the engine and the amount of fuel to be injected.
20. The engine controller according to claim 19, wherein the supply air-fuel ratio, the combustion air-fuel ratio, and the exhaust air-fuel ratio are estimated or detected independently.
21. The engine controller according to claim 20, further comprising the control parameter calculation means for performing engine control parameter calculation according to the supply air-fuel ratio, the combustion air-fuel ratio, and the exhaust air-fuel ratio.
22. The engine controller according to claim 19, further comprising a means for estimating a fuel state according to at least one of the supply air-fuel ratio, the combustion air-fuel ratio, and the exhaust air-fuel ratio.
23. The engine controller according to claim 22, wherein the combustion air-fuel ratio estimation means, the control parameter calculation means, and the fuel state estimation means handle the air-fuel ratio in a dimension of an equivalence ratio.
24. The engine controller according to claim 1, wherein even when a detected value of the exhaust air-fuel ratio differs from the combustion exhaust air-fuel ratio during the execution of feedback control according to the exhaust air-fuel ratio, the combustion air-fuel ratio is controlled to a desired air-fuel ratio.