1. A method comprising:
providing, from a tracking unit of a navigation device to a measurement unit of the navigation device, a first indication that a predetermined number of navigation satellites have been acquired and that navigation signals transmitted by the acquired navigation satellites have been locked;
providing, from a positioning unit of the navigation device to the measurement unit of the navigation device, a second indication that the positioning unit of the navigation device has been initialized to compute navigation parameters of the navigation device for positioning and routing the navigation device;
in response to the measurement unit of the navigation device receiving the first indication and the second indication, determining pseudo-range measurements at the measurement unit based, at least in part, on the navigation signals transmitted by the acquired navigation satellites; and
computing, at the positioning unit, the navigation parameters of the navigation device based, at least in part, on the pseudo-range measurements.
2. The method of claim 1, further comprising:
determining, at the tracking unit of the navigation device, that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked;
waiting, at the tracking unit, for a predetermined locking delay interval in response to said determining that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked, wherein the predetermined locking delay interval enables the tracking unit to refine a lock established on the navigation signals transmitted by the acquired navigation satellites; and
transmitting, from the tracking unit, the first indication to the measurement unit after the predetermined locking delay interval expires.
3. The method of claim 1, wherein the navigation parameters comprise at least one of a position of the navigation device, a velocity of the navigation device, and timing information associated with the navigation device.
4. The method of claim 1, wherein said computing the navigation parameters of the navigation device comprises computing a position of the navigation device based on previously stored navigation data associated with the predetermined number of navigation satellites, wherein the previously stored navigation data comprises at least an almanac and ephemeris associated with the predetermined number of navigation satellites.
5. The method of claim 1, wherein
said providing the first indication comprises providing a first control signal indicating that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked; and
said providing the second indication comprises providing a second control signal indicating that the positioning unit of the navigation device has been initialized to compute the navigation parameters of the navigation device.
6. The method of claim 5, wherein each of said providing the first control signal and said providing the second control signal comprises one of transmitting a message, transmitting a voltage level on a physical wire, and setting a bit in a configuration register.
7. The method of claim 1, wherein the predetermined number of navigation satellites comprises four or more navigation satellites.
8. The method of claim 1, further comprising at least one of:
providing the navigation parameters of the navigation device for presentation by the navigation device, and
determining a route to a destination based, at least in part, on the navigation parameters of the navigation device.
9. The method of claim 1, wherein:
said providing, from the tracking unit to the measurement unit, providing the first indication that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked is prior to said providing, from the positioning unit to the measurement unit, the second indication that the positioning unit of the navigation device has been initialized to compute the navigation parameters of the navigation device; or
said providing, from the positioning unit to the measurement unit, the second indication that the positioning unit of the navigation device has been initialized to compute the navigation parameters of the navigation device is prior to said providing, from the tracking unit to the measurement unit, providing the first indication that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked.
10. A navigation device comprising:
a tracking unit operable to provide, to a measurement unit of the navigation device, a first indication that a predetermined number of navigation satellites have been acquired and that navigation signals transmitted by the acquired navigation satellites have been locked;
a positioning unit operable to provide, to the measurement unit, a second indication that the positioning unit has been initialized to compute navigation parameters of the navigation device for positioning and routing the navigation device;
the measurement unit operable to determine pseudo-range measurements based, at least in part, on the navigation signals transmitted by the acquired navigation satellites in response to receiving the first indication from the tracking unit and the second indication from the positioning unit; and
the positioning unit operable to compute the navigation parameters of the navigation device based, at least in part, on the pseudo-range measurements received from the measurement unit.
11. The navigation device of claim 10, wherein the tracking unit is further operable to:
determine that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked;
wait for a predetermined locking delay interval in response to the tracking unit determining that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked, wherein the predetermined locking delay interval enables the tracking unit to refine a lock established on the navigation signals transmitted by the acquired navigation satellites; and
transmit the first indication to the measurement unit after the predetermined locking delay interval expires.
12. The navigation device of claim 10, wherein the positioning unit operable to compute the navigation parameters of the navigation device comprises the positioning unit operable to compute a position of the navigation device based on previously stored navigation data associated with the predetermined number of navigation satellites, wherein the previously stored navigation data comprises at least an almanac and ephemeris associated with the predetermined number of navigation satellites.
13. The navigation device of claim 10, wherein
the tracking unit operable to provide the first indication to the measurement unit comprises the tracking unit operable to provide a first control signal indicating that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked; and
the positioning unit operable to provide the second indication to the measurement unit comprises the positioning unit operable to provide a second control signal indicating that the positioning unit has been initialized to compute the navigation parameters of the navigation device.
14. The navigation device of claim 10, wherein the positioning unit further operable to:
provide the navigation parameters of the navigation device for presentation by the navigation device, and
determine a route to a destination based, at least in part, on the navigation parameters of the navigation device.
15. The navigation device of claim 10, wherein the navigation parameters comprise at least one of a position of the navigation device, a velocity of the navigation device, and timing information associated with the navigation device.
16. One or more non-transitory machine-readable storage media, having instructions stored therein, which, when executed by one or more processors causes the one or more processors to perform operations that comprise:
acquiring a predetermined number of navigation satellites at a navigation device;
locking onto navigation signals transmitted by the acquired predetermined number of navigation satellites;
initializing a positioning unit of the navigation device to compute navigation parameters of the navigation device for positioning and routing the navigation device;
generating a first indication that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked;
generating a second indication that the positioning unit of the navigation device has been initialized to compute the navigation parameters of the navigation device;
in response to detecting the first indication and the second indication, determining pseudo-range measurements based, at least in part, on the navigation signals transmitted by the acquired navigation satellites; and
computing the navigation parameters of the navigation device based, at least in part, on the pseudo-range measurements.
17. The machine-readable storage media of claim 16, wherein the operations further comprise:
determining that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked;
waiting for a predetermined locking delay interval in response to said operation of determining that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked, wherein the predetermined locking delay interval enables a lock established on the navigation signals transmitted by the acquired navigation satellites to be refined; and
transmitting the first indication after the predetermined locking delay interval expires.
18. The machine-readable storage media of claim 16, wherein
said operation of generating the first indication comprises generating a first control signal indicating that the predetermined number of navigation satellites have been acquired and that the navigation signals transmitted by the acquired navigation satellites have been locked; and
said operation of generating the second indication comprises generating a second control signal indicating that the positioning unit of the navigation device has been initialized to compute the navigation parameters of the navigation device.
19. The machine-readable storage media of claim 18, wherein each of said operation of generating the first control signal and said operation of generating the second control signal comprises one of generating a message, generating a voltage level on a physical wire, and setting a bit in a configuration register.
20. The machine-readable storage media of claim 16, wherein the operations further comprise at least one of:
presenting the navigation parameters at the navigation device, and
determining a route to a destination based, at least in part, on the navigation parameters of the navigation device.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
We claim:
1. A compound of formula (I):
3
wherein R1 is hydrogen, carboxy or a metabolically labile ester derivative thereof, cyano, halo, nitro, amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl, carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio, phenylsulfinyl or phenylsulfonyl said phenyl being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkoxycarbonyl, (1-4C)alkylamino-(2-4C)alkoxycarbonyl, di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycarbonyl or N-amino-(2-8C)alkylcarbamoyl;
R2 is hydrogen, hydroxy, amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl, N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-amino-(2-8C)alkyl)carbamoyl, N-(1-4C)alkylamino-(1-8C)alkylcarbamoyl, N-di-(1-4C)alkylamino-(1-8C)alkyl)carbamoyl, N-cyclohexylcarbamoyl, N-cyclopentylcarbamoyl, N-(1-4C)alkylcyclohexylcarbamoyl or N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl, N-phenyl-(1-4C)alkylcarbamoyl, N-(1-4C)alkyl-N-phenyl-(1-4C)alkylcarbamoyl, or N,N-di-phenyl-(1-4C)alkylcarbamoyl said phenyl or phenyl groups being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; N-(2-4C)alkanoylcarbamoyl, N-(1-4C)alkoxycarbonylcarbamoyl, N-fluoro-(2-6C)alkylcarbamoyl, N-fluoro-(2-6C)alkyl-N-(1-4C)alkylcarbamoyl or N,N-di-fluoro-(2-6C)alkylcarbamoyl; pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; 1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl, N,N-di-(1-4C)alkylthiocarbamoyl, N-(2-4C)alkanoylamino or N-(1-4)alkoxycarbonylamino;
R3 and R4, which may be the same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo, nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl;
or R4 is methoxy; or R3 is methoxy; and
R5 is hydrogen, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo, (1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl, piperidino, piperazin-1-yl or morpholino wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; or
a pharmaceutically-acceptable salt thereof; provided that:
R1, R2, R3 , R4 and R5 are not together H;
where R1 is carboxy and R3 and R4 are hydroxy; R2 and R5 are not together H;
where R1 is carboxy, R2 is H or OH, R3 is H and R5 is H; R4is not H, OH alkoxy, alkyl or halo;
where R1 is carboxy, R2 is H or OH, R4 is H and R5 is H; R3 is not H, OH alkoxy, alkyl or halo;
where R1 is ethoxycarbonyl; R2, R3, R4 and R5 are not together H;
where R1 is ethoxycarbonyl and R4 is F; R2, R3 and R5 are not together H
where R1 is carboxy and R3 is H or alkyl; R2, R4 and R5 are not together H;
where R3 is OH; R1 , R2, R4 and R5 are not together H;
where R5 is OH, R3 is H or alkyl, and R4 is H; R1 and R2 are not together ethoxycarbonyl, carboxy, methoxycarbonyl or H; and
where R5 is N(CH3)2; R1, R2, R3 and R4 are not together H.
2. A compound of claim 1:
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazin-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-trifluoromethylsulphonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-(2-morpholinoethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline; or
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or
a pharmaceutically-acceptable salt thereof, or a metabolically labile ester derivative of those compounds bearing a carboxy group.
3. A pharmaceutical composition comprising one or more compounds of formula (I):
4
wherein R1 is hydrogen, carboxy or a metabolically labile ester derivative thereof, cyano, halo, nitro, amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl, carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio, phenylsulfinyl or phenylsulfonyl said phenyl being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkoxycarbonyl, (1-4C)alkylamino-(2-4C)alkoxycarbonyl, di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycarbonyl or N-amino-(2-8C)alkylcarbamoyl;
R2 is hydrogen, hydroxy, amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl, N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-amino-(2-8C)alkyl)carbamoyl, N-(1-4C)alkylamino-(1-8C)alkylcarbamoyl, N-di-(1-4C)alkylamino-(1-8C)alkyl)carbamoyl, N-cyclohexylcarbamoyl, N-cyclopentylcarbamoyl, N-(1-4C)alkylcyclohexylcarbamoyl or N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl, N-phenyl-(1-4C)alkylcarbamoyl, N-(1-4C)alkyl-N-phenyl-(1-4C)alkylcarbamoyl or N,N-di-phenyl-(1-4C)alkylcarbamoyl said phenyl or phenyl groups being optionally substituted with 1 to 4 substituents selected from halo, (1-4C) alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; N-(2-4C)alkanoylcarbamoyl, N-(1-4C)alkoxycarbonylcarbamoyl, N-fluoro-(2-6C)alkylcarbamoyl, N-fluoro-(2-6C)alkyl-N-(1-4C)alkylcarbamoyl or N,N-di-fluoro-(2-6C)alkylcarbamoyl; pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; 1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl, N,N-di-(1-4C)alkylthiocarbamoyl, N-(2-4C)alkanoylamino or N-(1-4)alkoxycarbonylamino;
R3 and R4, which may be the same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo, nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl;
or R4 is methoxy; or R3 is methoxy; and
R5 is hydrogen, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo, (1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl, piperidino, piperazin-1-yl or morpholino wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; or
a pharmaceutically-acceptable salt thereof; and
a pharmaceutically-acceptable diluent or carrier.
4. The composition of claim 3, comprising a compound selected from:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-2,4-difluorobenzylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro 1,10-phenanthroline;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro 1,10-phenanthroline;
3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-2-(2-methoxyethoxy)ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-(2-morpholinoethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.
5. A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of a composition of claim 3.
6. The method of claim 5 wherein said composition comprises:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-2,4-difluorobenzylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-2-(2-methoxyethoxy)ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-(2-morpholinoethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.
7. A method of treating the symptoms of a fibroproliferative disease or disorder in a host in need of such treatment comprising administering an effective amount of a composition of claim 3.
8. The method of claim 7 wherein said composition comprises:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-2,4-difluorobenzylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-2-(2-methoxyethoxy)ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-(2-morpholinoethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.
9. The method of claim 7 wherein the disease is rheumatoid arthritis, chronic arthritis or osteoarthritis.
10. The method of claim 7 wherein the disease is hepatic cirrhosis.
11. The method of claim 7 wherein the disease is pulmonary fibrosis, renal fibrosis, cardiac fibrosis, arteriosclerosis or tumor associated fibrosis.
12. A method of treating scar tissue formation following injury or surgery in a host in need of such treatment comprising administering an effective amount of a composition of claim 3.
13. The method of claim 12 wherein said composition comprises:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-2,4-difluorobenzylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-2-(2-methoxyethoxy)ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-(2-morpholino ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof.
14. The use of one or more phenanthroline derivatives of formula (I):
5
wherein R1 is hydrogen, carboxy or a metabolically labile ester derivative thereof, cyano, halo, nitro, amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl, carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio, phenylsulfinyl or phenylsulfonyl said phenyl being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkoxycarbonyl, (1-4C)alkylamino-(2-4C)alkoxycarbonyl, di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycarbonyl or N-amino-(2-8C)alkylcarbamoyl;
R2 is hydrogen, hydroxy, amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy, carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl, N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-amino-(2-8C)alkyl)carbamoyl, N-(1-4C)alkylamino-(1-8C)alkylcarbamoyl, N-di-(1-4C)alkylamino-(1-8C)alkyl)carbamoyl, N-cyclohexylcarbamoyl, N-cyclopentylcarbamoyl, N-(1-4C)alkylcyclohexylcarbamoyl or N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl, N-phenyl-(1-4C)alkylcarbamoyl, N-(1-4C)alkyl-N-phenyl-(1-4C)alkylcarbamoyl or N,N-di-phenyl-(1-4C)alkylcarbamoyl said phenyl or phenyl groups being optionally substituted with 1 to 4 substituents selected from halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl; N-(2-4C)alkanoylcarbamoyl, N-(1-4C)alkoxycarbonylcarbamoyl, N-fluoro-(2-6C)alkylcarbamoyl, N-fluoro-(2-6C)alkyl-N-(1-4C)alkylcarbamoyl or N,N-di-fluoro-(2-6C)alkylcarbamoyl; pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl; 1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl, N,N-di-(1-4C)alkylthiocarbamoyl, N-(2-4C)alkanoylamino or N-(1-4)alkoxycarbonylamino;
R3 and R4, which may be the same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo, nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl;
or R4 is methoxy; or R3 is methoxy; and
R5 is hydrogen, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo, (1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl, piperidino, piperazin-1-yl or morpholino wherein the heterocyclic group is optionally substituted with 1 to 4 substituents selected from (1-4C)alkyl and benzyl in the manufacture of a medicament for use in the production of an anti-fibroproliferative effect.
15. The use of 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-2,4-difluorobenzylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-2-(2-methoxyethoxy)ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-(2-morpholinoethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline; or
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile ester derivative thereof, according to claim 14.
16. The use of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline according to claim 14.
17. A pharmaceutical composition comprising 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a pharmaceutically-acceptable salt, or a metabolically labile ester derivative thereof; and a pharmaceutically-acceptable diluent or carrier.
18. A pharmaceutical composition comprising 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline and a pharmaceutically-acceptable diluent or carrier.
19. A pharmaceutical composition comprising a pharmaceutically-acceptable salt of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline and a pharmaceutically-acceptable diluent or carrier.
20. A pharmaceutical composition comprising a metabolically labile ester derivative of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline and a pharmaceutically-acceptable diluent or carrier.
21. A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a pharmaceutically-acceptable salt, or a metabolically labile ester derivative thereof; or an effective amount of a composition comprising 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a pharmaceutically-acceptable salt, or a metabolically labile ester derivative thereof; and a pharmaceutically-acceptable diluent or carrier.
22. A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline.
23. A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of a pharmaceutically-acceptable salt of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline.
24. A method for producing an anti-fibroproliferative effect in a host in need of such treatment, comprising administering an effective amount of a metabolically labile ester derivative of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline.