All The Claims

1. A method of removing contaminates from water in the form of raw water or wastewater, the method comprising:
exposing the water to an electric field between spaced electrodes of opposite polarity to establish a charge density wherein spaces between the electrodes are greater than about 0.25 inch(0.635 cm);
controlling the charge density by selecting a voltage and amperage from a dc power source connected to the electrodes, which voltage and amperage causes contaminates to separate from the water;
controlling the length of time the water is exposed to the electric field to minimize clogging of the electrodes; and
thereafter removing from the water contaminates separated from the water, but still present therein or in proximity therewith.
2. The method of claim 1 wherein the length of time is determined by retaining a defined quantity of the water in proximity with the electrodes for a selected time interval while the water is stationary or flowing.
3. The method of claim 2 wherein polarity of the electrodes is reversed at a rate sufficient to minimize clogging of space between the electrodes.
4. The method of claim 3 wherein the contaminates are removed from the water by gravitational or centrifugal action, by filtration andor by venting.
5. The method of claim 1 wherein the electrodes are separated by spaces in the range of about 0.25 inch (0.635 cm) to about 1.50 inches (3.810 cm), wherein the charge density is obtained by applying a dc voltage in the range of 5 volts to about 50 volts at an amperage of about 5 amps to about 35 amps and wherein the length of time the water is exposed to the electrodes is about 1 minute to about 5 minutes.
6. The method of claim 3 wherein the polarity of the electrodes is reversed in cycles of 1 second to about 15 minutes in order to minimize clogging.
7. The method of claim 1 wherein the electrodes are separated by spaces in the range of about 0.25 inch (0.635 cm) to about 1.00 inch (2.540 cm), wherein the charge density is obtained by applying a dc voltage in the range of about 10 volts to about 50 volts at an amperage of about 5 amps to about 35 amps, and wherein the length of time the water is exposed to the electrodes is about 1 minute to about 5 minutes.
8. The method of claim 7 wherein the contaminants removed comprise nitrogen, nitrogen compounds, phosphorous and phosphorous compounds.
9. The method of claim 8 wherein the contaminants removed further comprise effluent E coli, Raw TKN2, Filter EFF TOC and Filter EFF BOD.
10. The method of claim 1 wherein the electrodes are separated by spaces in the range of about 0.25 inch (0.635 cm) to about 0.85 inch (2.159 cm), wherein the charge density is obtained by applying a dc voltage in the range of about 10 volts to about 50 volts at an amperage of about 5 amps to about 35 amps, and wherein the length of time the water is exposed to the electrodes is about 1 minute to about 5 minutes.
11. The method of claim 10 wherein the contaminants removed comprise nitrogen, nitrogen compounds, phosphorous and phosphorous compounds.
12. The method of claim 11 wherein the contaminants removed further comprise effluent E coli, Raw TKN2, Filter EFF TOC and Filter EFF BOD.
13. The method of claim 11 wherein polarity of the electrodes is reversed at a rate sufficient to minimize clogging of space between the electrodes.
14. The method of claim 1 wherein the electrodes are rods that are substantially circular in cross-section.
15. The method of claim 14 wherein the electrodes have a diameter in a range of \u215b inch (0.317 cm) to \u215a inch (0.794 cm) and preferably \xbc inch (0.635 cm).
16. The method of claim 1 wherein exposing the water to the electric field, controlling the charge density and controlling the length of time the water is exposed to the electric field is performed during a continuous water flow process, an intermediate water flow process or a water batch process
17. A system for removing contaminates from raw water or waste water, the system including at least one electrochemical treatment module comprising:
a housing having an inlet for untreated water and an outlet for treated water that has been treated within the housing;
an array of electrodes within the housing, the electrodes having space therebetween of a selected distance, the space being greater than about 0.25 inch (0.635 cm); and
a source for applying direct current the electrodes to charge one portion of the array positively and another portion of the array negatively so as to create an electrical gradient between the portions of the array, the direct current being sufficient to ionize the contaminants but not large enough to clog the space between electrodes with precipitated contaminates.
18. The system of claim 17 further including a switch for reversing polarity at selected time intervals to minimize clogging tendencies in the space between electrodes.
19. The system of claim 18 further including a partial removal facility having an inlet connected to the outlet for gravitational or centrifugal removal andor filtering of contaminate particulates from the treated water to remove the contaminant particulates and a venting arrangement for venting gas contaminant from the treated water, the partial removal facility having an outlet.
20. The system of claim 17 wherein there are a plurality of modules arranged in parallel to form at least one group of modules to increase the capacity of the system.
21. The system of claim 20 wherein there are a plurality of groups of modules to further increase the capacity of the system.
22. The system of claim 17 wherein each positively charged electrode is adjacent at least one negatively charged electrode and wherein each negatively charged electrode is adjacent at least one positively charged electrode.
23. The system of claim 18 wherein the electrodes are circular in cross section.
24. The system of claim 23 wherein the electrodes have a diameter in the range of \u215b inch (0.317 cm) to 516 inch (0.794 cm) and preferably \xbc inch (0.635 cm).
25. The system of claim 17 wherein the array of electrodes is rectangular.
26. The system of claim 17 wherein the array of electrodes is polygonal.

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

1. A converter arrangement comprising:
a converter device with a clocked operating mode and a non-clocked operating mode, having a signal input, a control input, and a signal output;
a control device adapted to control the converter device in a clocked operating mode with a control signal of a constant frequency and a given, at least minimal pulse length, wherein an output of the control device is coupled to the control input of the converter device, and an input of the control device is coupled to the signal output of the converter device;
an input adapted for supplying a signal to be converted that is coupled to the signal input of the converter device; and
an output, adapted for providing a converted signal, that is coupled to the signal output of the converter device.
2. The converter arrangement according to claim 1, wherein, in the clocked operating mode, the control signal of the control device has a controlled pulse-duty ratio to at least minimal pulse length.
3. The converter arrangement according to claim 1, comprising:
an inductive element coupled to the input of the converter device;
a diode element coupled to the inductive element;
a circuit device coupled to the inductive element and having a switch input that is coupled to the control input of the converter device;
a current measurement device for detecting the current by the switching device, wherein the output of the current measurement device is coupled to an input of the control device; and
a current source coupled to the diode element, to the control device, and to the output of the converter arrangement.
4. The converter arrangement according to claim 3, comprising a capacitive element is coupled between the input of the current source and a reference potential terminal.
5. The converter arrangement according to claim 3, wherein the control device comprises:
a measurement device coupled on the input side to the current source and the current measurement device;
a pulse device coupled at one input to the measurement device;
a control terminal coupled to a control input of the pulse device; and
an overvoltage protection device coupled to the current source and to a second input of the pulse device.
6. The converter arrangement according to claim 5, wherein the measurement device comprises:
an amplifier coupled to the signal output and to the current source by a voltage source that generates a voltage corresponding to the voltage drop across the current source;
a filter device coupled on the input side to the output of the amplifier; and
an adder device coupled at one input to the output of the filter device and that is coupled at a second input to the current measurement device.
7. The converter arrangement according to claim 5, wherein the pulse device comprises:
a comparator having inputs coupled to the measurement device and to a sawtooth generator;
a clock generator device coupled to the input of the sawtooth generator and having an input coupled to the control terminal of the pulse device;
a flip-flop having a set input and a reset input, wherein the reset input is coupled to the control terminal of the pulse device, and the set input is coupled to the output of the comparator;
a pulse generator for preparing pulses with constant frequency and minimum pulse width having an input coupled to the clock generator device;
an AND-gate having inputs coupled to the flip-flop and the pulse generator;
an OR-gate having inputs coupled to the comparator and to the output of the AND-gate; and
a switching element coupled between the output of the OR-gate and the control input of the converter device, and to a control input coupled to the overvoltage protection device.
8. The converter arrangement according to claim 5, wherein the overvoltage protection device includes a comparator having inputs coupled to the current source and to a reference voltage source.
9. The converter arrangement according to claim 5, further comprising another OR-gate coupled at two inputs to the control terminal and to the overvoltage protection device, and having an output coupled to the reset input of the flip-flop.
10. The converter arrangement according to claim 9,
wherein the pulse device includes a comparator to which, at a first input, a voltage is supplied that corresponds to the voltage drop across the load and to which, at a second input, a voltage is supplied that is coupled to the voltage drop across the supply potential source and that has an output coupled to another input of the other OR-gate.
11. A method for preparing a converted signal with a converter arrangement, comprising the steps of:
in a non-clocked operating mode of the converter arrangement, preparing a signal to be converted as a non-clocked, converted signal at an output of the converter arrangement; and
in a clocked operating mode of the converter arrangement, providing a control signal with a constant frequency and a given, at least minimal, pulse width to control the conversion of the signal to be converted into the converted signal.
12. The method according to claim 11, wherein the converter arrangement is operated according to a threshold value that is defined as a function of operating parameters of the converter arrangement in the non-clocked or in the clocked operating mode.
13. The method according to claim 12, wherein the converter arrangement is operated in the non-clocked operating mode when the signal to be converted is greater than the threshold value, and is operated in the clocked operating mode when the signal to be converted is less than the threshold value.
14. The method according to claim 11, comprising generating a control signal with a variable pulse-duty ratio by a pulse device in the clocked operating mode.
15. The method according to claim 12, wherein the operating parameters of the converter arrangement are defined from a set including the voltage of the signal to be converted, the voltage of the converted signal, a voltage output by a reference voltage source, a voltage drop across a capacitive element, and resistance losses of the converter arrangement.

1-5 (Cancelled)
6. A semiconductor memory device, comprising:
a memory cell array comprising memory cells which require refresh;
an access circuit which performs refresh of the memory cell array after performing reading of the memory cell array for an access address or writing of the memory cell array for the access address based on a write request and write data presented asynchronously for the access address;
an address transition detect circuit which detects whether a chip has transited from the non selected state to the selected state, or that the access address has changed; and
a control circuit which starts the reading or the writing after a skew period has elapsed which is set greater than or equal to the maximum value of a skew included in at least one of a chip select signal which controls the selected or non selected state, and the access address, and in which a completion timing has been set after it is determined whether the write request has been presented taking the time of detection as a reference.
7. A semiconductor memory device according to or claim 6,
wherein the control circuit sets the completion timing of the skew period after the time at which it is determined whether the write request is presented.
8. A semiconductor memory device, comprising:
a memory cell array comprising memory cells which require refresh;
an access circuit which performs refresh of the memory cell array after performing reading or writing of the memory cell array for the access address in the same memory cycle;
an address transition detect circuit which detects whether a chip has transited from the non selected state to the selected state, or that the access address has changed; and
a control circuit which sets a completion timing for a skew period having a length greater than or equal to the maximum value of a skew included in at least one of a chip select signal which controls the selected state or non selected state, and the access address, taking the time of detection as a reference, to a time after a write request and write data presented asynchronously for the access address are determined.
9. A semiconductor memory device according to any one of claims 6 and 8, wherein, if writing, reading, or refresh which was started in a memory cycle preceding to the current memory cycle in which a read request or a write request is supplied has not been completed by the completion timing of a skew period for the current memory cycle, the control circuit delays the start of writing or reading in the current memory cycle until the writing, reading, or refresh has been completed.
10. A semiconductor memory device according to claim 9, wherein the access circuit performs refresh after reading or writing only once in a plurality of memory cycles, and
the control circuit delays the start of writing or reading in a memory cycle which is subsequent to the memory cycle in which the refresh is performed.
11. A semiconductor memory device according to claim 8, wherein the access circuit performs reading or late writing simultaneously for a plurality of addresses in the memory cell array, and
the control circuit performs the operation of sequentially outputting to the outside read data which have been obtained by the reading, or the operation of sequentially taking in write data which are input from the outside for the next late writing, in parallel with the refresh.
12. A semiconductor memory device according to claim 11, wherein the control circuit detects a change of predetermined upper bits in the access address, and, when performing the reading or the late writing, successively outputs the read data or successively takes in the write data for a plurality of addresses for which the predetermined upper bits in the access address are the same, while varying the lower address in the access address which is made up from the bits other than the predetermined upper bits.
13. A semiconductor memory device according to claim 12, wherein the control circuit successively outputs the read data or successively takes in the write data according to the lower address supplied from the outside.
14. A semiconductor memory device according to claim 12, wherein the control circuit successively outputs the read data or successively takes in the write data while varying the lower address according to a predetermined order based upon an initial value of the lower address supplied from the outside.
15. A semiconductor memory device according to claim 8, wherein the control circuit detects that a chip is in the non selected state or the deactivated state, and performs the refresh during the non selected state or the deactivated state.
16. A semiconductor memory device according to claim 8, further comprising:
a refresh control circuit comprising circuitry within the access circuit and the control circuit which performs control of the refresh, and a refresh address generation circuit which generates a refresh address showing memory cells to be refreshed, and which updates the refresh address each time the refresh is performed;
a voltage generation circuit which generates voltages supplied to parts within the device; and
a mode switching circuit which switches to one of a first mode in which power source is supplied both to the refresh control circuit and to the voltage generation circuit, a second mode in which supply of power source to the refresh control circuit is stopped while power source is supplied to the voltage generation circuit, and a third mode in which supply of power source both to the refresh control circuit and to the voltage generation circuit is stopped, and which controls whether supply of power source is performed to the refresh control circuit and the voltage generation circuit according to the switched mode.
17. A semiconductor memory device according to claim 16, wherein the mode switching circuit performs switching of mode by detecting that writing of predetermined data in each mode has been performed for a predetermined address.
18-20 (Cancelled)
21. A semiconductor memory device, comprising:
a memory cell array comprising memory cells which require refresh;
an access circuit which performs refresh of the memory cell array, after simultaneously performing reading for an access address or late writing for the access address based on a write request and writing data presented asynchronously for the access address, for a plurality of addresses in the memory cell array;
an address transition detect circuit which detects whether a chip has transited from the non selected state to the selected state, or that the access address has changed; and
a control circuit which starts the reading or the writing after a skew period has elapsed which is set greater than or equal to the maximum value of a skew included in at least one of a chip selection signal which controls the selected state or non selected state, and the access address, taking the time of detection as a reference, and performs the operation of sequentially outputting the outside read data which has been obtained by the reading, or the operation of sequentially taking in write data which are input from the outside for the next late writing, in parallel with the refresh.
22. A semiconductor memory device according to claim 21, wherein the control circuit detects a change of predetermined upper bits in the access address, and, when performing the reading or the late writing for the plurality of addresses for which the predetermined upper bits in the access address are the same, successively outputs the read data or successively takes in the write data, while varying the lower address in the access address which is made up from the bits other than the predetermined upper bits.
23. A semiconductor memory device according to claim 22, wherein the control circuit successively outputs the read data or successively takes in the write data according to the lower address supplied from the outside.
24. A semiconductor memory device according to claim 22, wherein the control circuit successively outputs the read data or successively takes in the write data while varying the lower address according to a predetermined order, based upon an initial value of the lower address supplied from the outside.
25. A semiconductor memory device, comprising:
a memory cell array comprising memory cells which require refresh;
an access circuit which performs refresh of the memory cell array after performing reading of the memory cell array for an access address or writing of the memory cell array for the access address based on a write request and write data presented asynchronously for the access address;
an address transition detect circuit which detects whether a chip has transited from the non selected state to the selected state, or that the access address has changed; and
a control circuit which starts the reading or the writing after a skew period has elapsed which is set greater than or equal to the maximum value of a skew included in at least one of a chip select signal which controls the selected state or non selected state, and the access address, taking the time of detection as a reference, and detects that a chip is in the non selected state or the deactivated state, and performs the refresh during the non selected state or the deactivated state.
26. A semiconductor memory device, comprising:
a memory cell array comprising memory cells which require refresh;
an access circuit which performs refresh of the memory cell array after performing reading of the memory cell array for an access address or writing of the memory cell array for the access address based on a write request and write data presented asynchronously for the access address;
an address transition detect circuit which detects whether a chip has transited from the non selected state to the selected state, or that the access address has changed;
a control circuit which starts the reading or the writing after a skew period has elapsed which is set greater than or equal to the maximum value of a skew included in at least one of a chip select signal which controls the selected or non selected state, and the access address, taking the time of detection as a reference;
a refresh control circuit comprising circuitry within the access circuit and the control circuit which performs control of the refresh, and a refresh address generation circuit which generates a refresh address showing the memory cell to be refreshed, and which updates the refresh address each time the refresh is performed;
a voltage generation circuit which generates voltages supplied to parts within the device; and
a mode switching circuit which switches to one of a first mode in which power source is supplied both to the refresh control circuit and to the voltage generation circuit, a second mode in which supply of power source to the refresh control circuit is stopped while power source is supplied to the voltage generation circuit, and a third mode in which supply of power source both to the refresh control circuit and to the voltage generation circuit is stopped, and which controls whether supply of power source is performed o the refresh control circuit and the voltage generation circuit according to the switched mode.
27. A semiconductor memory device according to claim 26, wherein the mode switching circuit performs switching of mode by detecting that writing of predetermined data in each mode has been performed for a predetermined address.

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

1. A method of preventing the progression of joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound is a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
2. The method of claim 1, wherein the xanthine oxidoreductase inhibitor is selected from the group consisting of: 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid, 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylic acid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid, pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1), 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole and a pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
4. The method of claim 2, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
5. The method of claim 2, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
6. The method of claim 1, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
7. The method of claim 1, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
8. The method of claim 1, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
9. The method of claim 8, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
10. A method of preventing joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound is a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
11. The method of claim 10, wherein the xanthine oxidoreductase inhibitor is selected from the group consisting of: 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid, 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylic acid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid, pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1), 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole and a pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
13. The method of claim 11, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
14. The method of claim 11, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
15. The method of claim 10, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
16. The method of claim 10, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
17. The method of claim 10, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
18. The method of claim 17, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
19. A method of preventing the progression of joint damage in a subject the method comprising the steps of:
selecting a patient having at least hyperuricemia and gout; and administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R1 and R2 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, a phenylsulfinyl group or a cyano (\u2014CN) group;
wherein R3 and R4 are each independently a hydrogen or A, B, C or D as shown below:
wherein T connects A, B, C or D to the aromatic ring shown above at R1, R2, R3 or R4,
wherein R5 and R6 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R7 and R8 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R9 is an unsubstituted pyridyl group or a substituted pyridyl group; and
wherein R10 is a hydrogen or a lower alkyl group, a lower alkyl group substituted with a pivaloyloxy group and in each case, R10 bonds to one of the nitrogen atoms in the 1,2,4-triazole ring shown above, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
20. The method of claim 19, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
21. The method of claim 19, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
22. The method of claim 19, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
23. The method of claim 19, wherein the compound is 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
24. The method of claim 19, wherein the compound is 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
25. The method of claim 19, wherein the compound is 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
26. The method of claim 19, wherein the compound is pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1).
27. The method of claim 19, wherein the compound is 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole or a pharmaceutically acceptable salt thereof.
28. The method of claim 19, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
29. The method of claim 19, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
30. The method of claim 19, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
31. The method of claim 30, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
32. A method of preventing the progression of joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R11 and R12 are each independently a hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl, or R11 and R12 may together form a four- to eight-membered carbon ring together with the carbon atom to which they are attached;
wherein R13 is a hydrogen or a substituted or unsubstituted lower alkyl group;
wherein R14 is one or two radicals selected from a group consisting of a hydrogen, a halogen, a nitro group, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted phenyl, \u2014OR16 and \u2014SO2NR17R17\u2032, wherein R16 is a hydrogen, a substituted or unsubstituted lower alkyl, a phenyl-substituted lower alkyl, a carboxymethyl or ester thereof, a hydroxyethyl or ether thereof, or an allyl; R17 and R17\u2032 are each independently a hydrogen or a substituted or unsubstituted lower alkyl;
wherein R15 is a hydrogen or a pharmaceutically active ester-forming group;
wherein A is a straight or branched hydrocarbon radical having one to five carbon atoms;
wherein B is a halogen, an oxygen, or an ethylenedithio;
wherein Y is an oxygen, a sulfur, a nitrogen or a substituted nitrogen;
wherein Z is an oxygen, a nitrogen or a substituted nitrogen; and
the dotted line refers to either a single bond, a double bond, or two single bonds, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
33. A method of preventing joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R1 and R2 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, a phenylsulfinyl group or a cyano (\u2014CN) group;
wherein R3 and R4 are each independently a hydrogen or A, B, C or D as shown below:
wherein T connects A, B, C or D to the aromatic ring shown above at R1, R2, R3 or R4,
wherein R5 and R6 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R7 and R8 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R9 is an unsubstituted pyridyl group or a substituted pyridyl group; and
wherein R10 is a hydrogen or a lower alkyl group, a lower alkyl group substituted with a pivaloyloxy group and in each case, R10 bonds to one of the nitrogen atoms in the 1,2,4-triazole ring shown above, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
34. The method of claim 33, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
35. The method of claim 33, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
36. The method of claim 33, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
37. The method of claim 33, wherein the compound is 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
38. The method of claim 33, wherein the compound is 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
39. The method of claim 33, wherein the compound is 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
40. The method of claim 33, wherein the compound is pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1).
41. The method of claim 33, wherein the compound is 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole or a pharmaceutically acceptable salt thereof.
42. The method of claim 33, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
43. The method of claim 33, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
44. The method of claim 33, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
45. The method of claim 44, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
46. A method of preventing joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R11 and R12 are each independently a hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl, or R11 and R12 may together form a four- to eight-membered carbon ring together with the carbon atom to which they are attached;
wherein R13 is a hydrogen or a substituted or unsubstituted lower alkyl group;
wherein R14 is one or two radicals selected from a group consisting of a hydrogen, a halogen, a nitro group, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted phenyl, \u2014OR16 and \u2014SO2NR17R17\u2032, wherein R16 is a hydrogen, a substituted or unsubstituted lower alkyl, a phenyl-substituted lower alkyl, a carboxymethyl or ester thereof, a hydroxyethyl or ether thereof, or an allyl; R17 and R17\u2032 are each independently a hydrogen or a substituted or unsubstituted lower alkyl;
wherein R15 is a hydrogen or a pharmaceutically active ester-forming group;
wherein A is a straight or branched hydrocarbon radical having one to five carbon atoms;
wherein B is a halogen, an oxygen, or an ethylenedithio;
wherein Y is an oxygen, a sulfur, a nitrogen or a substituted nitrogen;
wherein Z is an oxygen, a nitrogen or a substituted nitrogen; and
the dotted line refers to either a single bond, a double bond, or two single bonds, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
47. A method of identifying a patient suitable for treatment with at least one xanthine oxidoreductase inhibitor in order to prevent joint damage or the progression of joint damage in a subject, the method comprising the step of:
obtaining a test sample from a subject;
determining whether said subject is hyperuricemic and has gout; wherein if said subject is hyperurecimeic and has gout identifying said patient as eligible for treatment with at least one xanthine oxidoreductase inhibitor in order to prevent joint damage or the progression of joint damage in said subject.
48. The method of claim 47, wherein the method further comprising determining if the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
49. A method of preventing the progression of joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and early gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound is a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
50. The method of claim 49, wherein the xanthine oxidoreductase inhibitor is selected from the group consisting of: 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid, 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylic acid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid, pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1), 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole and a pharmaceutically acceptable salt thereof.
51. The method of claim 50, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
52. The method of claim 50, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
53. The method of claim 50, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
54. The method of claim 49, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
55. The method of claim 49, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
56. The method of claim 49, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
57. The method of claim 56, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
58. A method of preventing joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and early gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound is a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
59. The method of claim 58, wherein the xanthine oxidoreductase inhibitor is selected from the group consisting of: 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid, 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylic acid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid, pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1), 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole and a pharmaceutically acceptable salt thereof.
60. The method of claim 59, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
61. The method of claim 59, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
62. The method of claim 59, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
63. The method of claim 58, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
64. The method of claim 58, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
65. The method of claim 58, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
66. The method of claim 65, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
67. A method of preventing the progression of joint damage in a subject the method comprising the steps of:
selecting a patient having at least hyperuricemia and early gout; and administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R1 and R2 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, a phenylsulfinyl group or a cyano (\u2014CN) group;
wherein R3 and R4 are each independently a hydrogen or A, B, C or D as shown below:
wherein T connects A, B, C or D to the aromatic ring shown above at R1, R2, R3 or R4,
wherein R5 and R6 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R7 and R8 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R9 is an unsubstituted pyridyl group or a substituted pyridyl group; and
wherein R10 is a hydrogen or a lower alkyl group, a lower alkyl group substituted with a pivaloyloxy group and in each case, R10 bonds to one of the nitrogen atoms in the 1,2,4-triazole ring shown above, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
68. The method of claim 67, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
69. The method of claim 67, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
70. The method of claim 67, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
71. The method of claim 67, wherein the compound is 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
72. The method of claim 67, wherein the compound is 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
73. The method of claim 67, wherein the compound is 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
74. The method of claim 67, wherein the compound is pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1).
75. The method of claim 67, wherein the compound is 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole or a pharmaceutically acceptable salt thereof.
76. The method of claim 67, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
77. The method of claim 67, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
78. The method of claim 67, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
79. The method of claim 78, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
80. A method of preventing the progression of joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and early gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R11 and R12 are each independently a hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl, or R11 and R12 may together form a four- to eight-membered carbon ring together with the carbon atom to which they are attached;
wherein R13 is a hydrogen or a substituted or unsubstituted lower alkyl group;
wherein R14 is one or two radicals selected from a group consisting of a hydrogen, a halogen, a nitro group, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted phenyl, \u2014OR16 and SO2NR17R17\u2032, wherein R16 is a hydrogen, a substituted or unsubstituted lower alkyl, a phenyl-substituted lower alkyl, a carboxymethyl or ester thereof, a hydroxyethyl or ether thereof, or an allyl; R17 and R17\u2032 are each independently a hydrogen or a substituted or unsubstituted lower alkyl;
wherein R15 is a hydrogen or a pharmaceutically active ester-forming group;
wherein A is a straight or branched hydrocarbon radical having one to five carbon atoms;
wherein B is a halogen, an oxygen, or an ethylenedithio;
wherein Y is an oxygen, a sulfur, a nitrogen or a substituted nitrogen;
wherein Z is an oxygen, a nitrogen or a substituted nitrogen; and
the dotted line refers to either a single bond, a double bond, or two single bonds, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
81. A method of preventing joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and early gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R1 and R2 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, a phenylsulfinyl group or a cyano (\u2014CN) group;
wherein R3 and R4 are each independently a hydrogen or A, B, C or D as shown below:
wherein T connects A, B, C or D to the aromatic ring shown above at R1, R2, R3 or R4,
wherein R5 and R6 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R7 and R8 are each independently a hydrogen, a hydroxyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
wherein R9 is an unsubstituted pyridyl group or a substituted pyridyl group; and
wherein R10 is a hydrogen or a lower alkyl group, a lower alkyl group substituted with a pivaloyloxy group and in each case, R10 bonds to one of the nitrogen atoms in the 1,2,4-triazole ring shown above, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.
82. The method of claim 81, wherein the compound is 2-3-cyano-4-(2-methylpropoxy)phenyl-4-methylthiazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
83. The method of claim 81, wherein the compound is 2-3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
84. The method of claim 81, wherein the compound is 2-3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
85. The method of claim 81, wherein the compound is 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
86. The method of claim 81, wherein the compound is 2-4-(2-carboxypropoxy)-3-cyanophenyl-4-methyl-5-thiazolecarboxylic acid or a pharmaceutically acceptable salt thereof.
87. The method of claim 81, wherein the compound is 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl-1H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
88. The method of claim 81, wherein the compound is pyrazolo1,5-a-1,3,5-triazin-4-(1H)-one, 8-3-methoxy-4-(phenylsulfinyl)phenyl-sodium salt (\xb1).
89. The method of claim 81, wherein the compound is 3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole or a pharmaceutically acceptable salt thereof.
90. The method of claim 81, wherein the subject has acute gouty arthritis, chronic gouty joint disease, tophaceous gout, or uric acid urolithiasis.
91. The method of claim 81, wherein the subject further exhibits at least one of: inflammation developed within one (1) day, monoarticular arthritis, redness observed over one or more joints, a first metatarsophalangeal joint painful or swollen, an unilateral first metatarsophalangeal joint attack, unilateral tarsal joint attack, tophus (proven or suspected), asymmetric swelling within a joint on X-ray, sub-cortical cysts without erosions, joint fluid culture negative for organisms during attacks, a tophus proven to contain urate crystals, characteristic urate crystals in the joint fluid or combinations thereof.
92. The method of claim 81, further comprising the step of assessing the subject’s response to administration of the compound through radiographic imaging.
93. The method of claim 92, wherein the radiographic imaging is Magnetic Resonance Imaging (MRI), X-ray, or Dual Energy Computed Tomography (DECT).
94. A method of preventing joint damage in a subject, the method comprising the steps of:
selecting a patient having at least hyperuricemia and early gout; and
administering to the subject a therapeutically effective amount of at least one compound, wherein said at least one compound comprises the formula:
wherein R11 and R12 are each independently a hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl, or R11 and R12 may together form a four- to eight-membered carbon ring together with the carbon atom to which they are attached;
wherein R13 is a hydrogen or a substituted or unsubstituted lower alkyl group;
wherein R14 is one or two radicals selected from a group consisting of a hydrogen, a halogen, a nitro group, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted phenyl, \u2014OR16 and \u2014SO2NR17R17\u2032, wherein R16 is a hydrogen, a substituted or unsubstituted lower alkyl, a phenyl-substituted lower alkyl, a carboxymethyl or ester thereof, a hydroxyethyl or ether thereof, or an allyl; R17 and R17\u2032 are each independently a hydrogen or a substituted or unsubstituted lower alkyl;
wherein R15 is a hydrogen or a pharmaceutically active ester-forming group;
wherein A is a straight or branched hydrocarbon radical having one to five carbon atoms;
wherein B is a halogen, an oxygen, or an ethylenedithio;
wherein Y is an oxygen, a sulfur, a nitrogen or a substituted nitrogen;
wherein Z is an oxygen, a nitrogen or a substituted nitrogen; and
the dotted line refers to either a single bond, a double bond, or two single bonds, wherein the administration of said at least one compound to the subject prevents the progression of joint damage in said subject.