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WO2010071865A1 - Compositions pharmaceutiques et procédés de traitement de l'hyperuricémie et des troubles associés - Google Patents

Compositions pharmaceutiques et procédés de traitement de l'hyperuricémie et des troubles associés Download PDF

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Publication number
WO2010071865A1
WO2010071865A1 PCT/US2009/068883 US2009068883W WO2010071865A1 WO 2010071865 A1 WO2010071865 A1 WO 2010071865A1 US 2009068883 W US2009068883 W US 2009068883W WO 2010071865 A1 WO2010071865 A1 WO 2010071865A1
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Prior art keywords
oxo
amino
propenyl
benzoic acid
methoxy
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PCT/US2009/068883
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English (en)
Inventor
Helen Jenkins
Michael Kitt
Rodney Pearlman
Tito Serafini
Eugene Thorsett
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NUON THERAPEUTICS Inc
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NUON THERAPEUTICS Inc
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Publication of WO2010071865A1 publication Critical patent/WO2010071865A1/fr
Priority to PCT/US2010/048823 priority Critical patent/WO2011032175A1/fr
Priority to US12/882,143 priority patent/US20110136835A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • Gout which is sometimes called podagre, affects 3 to 5 million individuals in the United
  • Gout includes a group of disorders including painful attacks of acute, monarticular, inflammatory arthritis due to uric acid crystals, deposition of urate crystals in joints, deposition of urate crystals in renal parenchyma, urolithiasis (formation of calculus in the urinary tract), and nephrolithiasis (formation of kidney stones).
  • Gouty arthritis is usually an extremely painful attack of gout with a rapid onset of joint inflammation. The joint inflammation is precipitated by deposits of uric-acid crystals in the joint fluid (synovial fluid) and joint lining (synovial lining).
  • Intense joint inflammation occurs as white blood cells engulf the uric-acid crystals and release chemicals of inflammation, causing pain, heat, and redness of the joint tissues.
  • Chronic gout can lead to deposits of hard lumps of uric acid in and around the joints, kidney stones, and blockage of the kidney-filtering tubules with uric-acid crystals, leading to kidney failure.
  • hyperuricemia has been associated with a serum uric acid (sUA) level of 6.8 mg/dL or greater, which is the upper limit of solubility of uric acid (also called urate) in extracellular fluids.
  • sUA serum uric acid
  • hyperuricemia also has been associated with other levels of serum uric acid depending on factors such as gender and age, for example. Hyperuricemia leads to gout when urate crystals are formed from supersaturated body fluids and deposited in joints, tophi, and parenchymal organs.
  • disorders related to elevated serum uric acid levels include gout- associated inflammation, renal disorders, cardiovascular disease, aberrant metabolic conditions, fatty liver disease, kidney stones, cognitive impairment and dementia. Elevated serum uric acid levels have been identified as an independent risk factor for chronic kidney disease, cardiovascular disease and hypertension. Edwards, N.L., Clev. Clin. J. Med., Vol. 75, Suppl. 5, July 2008, S13-16. With respect to cardiovascular disease, hyperuricemia has been identified as an independent risk factor for athersclerotic disease in general and for coronary artery disease in particular. Edwards, N.L., Curr. Opin. Rheum., 2009, 21 : 132-137.
  • Hyperuricemia independent of crystal deposition also may play a pathogenetic role in aberrant metabolic states, such as hypertriglyceridemia, obesity, insulin resistance, diabetes and metabolic syndrome. Beck, M.A., et. al, Rheum Dis. Clin. Am., 32 (2006), 275-293.
  • hyperuricemia has been linked to cerebral vascular disease. Edwards, N.L., Curr. Opin. Rheum., 2009, 21 :132-137.
  • Elevated serum uric acid also has been independently associated with non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • Hyperuricemia can result from increased production or decreased excretion of uric acid, or from a combination of the two processes. Urate is the end product of purine metabolism in humans, shown above in Scheme I.
  • Known methods for treating gout include the use of uric acid synthesis inhibitors to inhibit the accumulation of uric acid in the body. These compounds function by inhibiting an enzyme involved in uric acid synthesis. In fact, it may be possible to inhibit uric acid synthesis by inhibiting any one of several enzymes shown above to be involved in uric acid synthesis.
  • xanthine oxidase inhibitors such as febuxostat and allopurinol, reduce serum uric acid levels by inhibiting the enzyme xanthine oxidase.
  • Known methods also include introduction of a recombinant, non-human uricase enzyme into the body, such as rasburicase or pegloticase.
  • uric acid excretion promoters These compounds accelerate the rapid excretion of uric acid accumulated in the body.
  • Probenecid, sulfinpyrazone and benzbromarone are examples of uric acid excretion promoters. These compounds prevent the reuptake of urate back into the bloodstream in the kidney, leading to a net increase in excretion.
  • Interleukin-6 (IL-6) has been proposed for use in the treatment of gout as a serum uric acid decreasing agent (see U.S. Pat. No. 6,007,804).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • corticosteroids and colchicine have been used to treat some of the painful symptoms associated with gout.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II:
  • each of R 1 and R 2 is independently selected from a hydrogen atom or a C 1 -C 4 alkyl group
  • R 3 and R 4 are each hydrogen atoms or together form another chemical bond
  • each X is independently selected from a hydroxyl group, a halogen atom, a Ci-C 4 alkyl group or a C r C 4 alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring
  • n is an integer from 1 to 3
  • a second therapeutic agent wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent
  • a pharmaceutically acceptable diluent or carrier is an integer from 1 to 3
  • the present invention provides a method of treating a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II, or a pharmaceutically acceptable salt thereof; (b) a second therapeutic agent, wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent; and (c) a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a method of treating a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof of a pharmaceutically effective amount of compound of formula II, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a method of decreasing serum uric acid level in a subject having a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II, or a pharmaceutically acceptable salt thereof; (b) a second therapeutic agent, wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent; and (c) a pharmaceutically acceptable diluent or carrier.
  • Another aspect of the present invention provides a method of decreasing serum uric acid level in a subject having a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of decreasing serum uric acid level in a subject comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II, or a pharmaceutically acceptable salt thereof; (b) a second therapeutic agent, wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent; and (c) a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a method of decreasing serum uric acid level in a subject comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
  • FlG. 1 shows the effects of Tranilast on serum uric acid levels in hyperuricemic patients. All patients had uric acid baseline levels equal to or above 8 mg/dL. Tranilast was administered twice daily for one or three months at the indicated dosages.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II:
  • each of R 1 and R 2 is independently selected from a hydrogen atom or a Ci-C 4 alkyl group
  • R 3 and R 4 are each hydrogen atoms or together form another chemical bond
  • each X is independently selected from a hydroxyl group, a halogen atom, a Q-C 4 alkyl group or a C]-C 4 alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring
  • n is an integer from 1 to 3
  • a second therapeutic agent wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent
  • a pharmaceutically acceptable diluent or carrier is an integer from 1 to 3
  • the present invention provides a method of treating a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II, or a pharmaceutically acceptable salt thereof; (b) a second therapeutic agent, wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent; and (c) a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a method of treating a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof a pharmaceutically effective amount of compound of formula II, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of decreasing serum uric acid level in a subject having a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II, or a pharmaceutically acceptable salt thereof; (b) a second therapeutic agent, wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent; and (c) a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a method of decreasing serum uric acid level in a subject having a condition associated with an elevated serum uric acid level comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of decreasing serum uric acid level in a subject comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a first therapeutic agent, wherein said first therapeutic agent is a compound of formula II, or a pharmaceutically acceptable salt thereof; (b) a second therapeutic agent, wherein said second therapeutic agent is a uric acid synthesis inhibitor or a uricosuric agent; and (c) a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a method of decreasing serum uric acid level in a subject comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of decreasing serum uric acid level in a subject that has experienced insufficient lowering of serum uric acid following treatment with a uric acid synthesis inhibitor, a uricosuric agent and/or a recombinant uncase enzyme.
  • the compound of formula II is a compound selected from the group consisting of: 2-[[3-(2-methylphenyl)-l-oxo-2-propenyl]amino]benzoic acid; 2-[[3-(3- methylphenyl)-l -oxo-2 -propenyl]amino]benzoic acid; 2-[[3-(4-methylphenyl)-l -oxo-2 - propenyl]amino]benzoic acid; 2-[[3-(2-ethylphenyl)-l-oxo-2-propenyl]amino]benzoic acid; 2- [[3-(3-ethylphenyl)-l -oxo-2-propenyl]amino]benzoic acid; 2-[[3-(4-ethylphenyl)-l-oxo-2-propenyl]amino]benzoic acid; 2-[[3-(4-ethylpheny
  • the compound of formula II is 2-[[3-(3,4-dimethoxyphenyl)-l-oxo-2- propenyl]amino]benzoic acid (tranilast).
  • the second therapeutic agent is a uric acid synthesis inhibitor.
  • the uric acid synthesis inhibitor is a xanthine oxidase inhibitor.
  • the xanthine oxidase inhibitor is allopurinol, febuxostat, oxypurinol, tisopurine or an inositol.
  • the xanthine oxidase inhibitor is allopurinol or febuxostat.
  • the xanthine oxidase inhibitor is allopurinol.
  • the xanthine oxidase inhibitor is febuxostat.
  • the pharmaceutical composition comprises from about 100 mg to about 300 mg of tranilast and from about 100 mg to about 300 mg of allopurinol. In one such embodiment, the pharmaceutical composition comprises about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 300 mg of tranilast and about 100 mg, about 150 mg, about 200 mg, about 250 mg or about 300 mg of allopurinol. In one such embodiment the pharmaceutical composition comprises about 300 mg of tranilast and about 300 mg of allopurinol.
  • the second therapeutic agent is a uricosuric agent.
  • the uricosuric agent is probenecid, benzbromarone, sulfinpyrazone, guaifenesin, losartan, atorvastatin, amlodipine, adrenocorticotropic hormone or fenofibrate.
  • the uricosuric agent is probenecid.
  • the condition associated with an elevated serum uric acid level is hyperuricemia, gout, a renal disorder, cardiovascular disease, an aberrant metabolic condition, cognitive impairment, a fatty liver disease or kidney stones.
  • the subject has hyperuricemia, gout, gout-associated inflammation, a renal disorder, cardiovascular disease, an aberrant metabolic condition, cognitive impairment, fatty liver disease or kidney stones.
  • the subject has cognitive impairment.
  • Cognitive impairment may be associated with cerebral vascular conditions, Alzheimer's disease, Parkinson's disease or aging. Schretlen, D.J., et al., Neuropsychology, 2007, Vol. 21, No. 1, 136-140.
  • the condition associated with an elevated serum uric acid level is hyperuricemia.
  • the method comprises reducing inflammation associated with hyperuricemia.
  • the present invention provides methods for treating hyperuricemia in a subject with a condition selected from the group of gout, a renal disorder, cardiovascular disease, an aberrant metabolic condition, cognitive impairment, a fatty liver disease and kidney stones.
  • the subject has gout.
  • the condition associated with an elevated serum uric acid level is gout.
  • the method comprises treating gouty symptoms.
  • the method comprises treating gouty attacks.
  • the method comprises reducing the incidence and/or severity of gouty flares.
  • the method comprises preventing, reducing or reversing uric acid crystal formation.
  • the method comprises reducing uric acid burden.
  • the method comprises reducing the size and/or number of tophi. The size and/or number of tophi may be assessed by, for example, use of CT scans.
  • the condition associated with an elevated serum uric acid level is a renal disorder.
  • the renal disorder is chronic kidney disease.
  • condition associated with an elevated serum uric acid level is kidney stones.
  • the condition associated with an elevated serum uric acid level is cardiovascular disease.
  • the cardiovascular disease is coronary artery disease, stroke, peripheral artery disease, congestive heart failure or hypertension.
  • the cardiovascular disease is coronary heart disease.
  • the cardiovascular disease is stroke.
  • the cardiovascular disease is peripheral artery disease.
  • the cardiovascular disease is congestive heart failure.
  • the cardiovascular disease is hypertension.
  • the condition associated with an elevated serum uric acid level is an aberrant metabolic condition.
  • the aberrant metabolic condition is metabolic syndrome, obesity, hyperlipidemia, insulin resistance or diabetes.
  • the aberrant metabolic condition is metabolic syndrome.
  • the aberrant metabolic condition is obesity.
  • the aberrant metabolic condition is hyperlipidemia.
  • the aberrant metabolic condition is insulin resistance.
  • the aberrant metabolic condition is diabetes.
  • the condition associated with an elevated serum uric acid level is cognitive impairment.
  • the condition associated with an elevated serum uric acid level is a fatty liver disease.
  • the fatty liver disease is nonalcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH).
  • administration of a pharmaceutical composition of the present invention or administration of a compound of formula II or a pharmaceutically acceptable salt thereof to a subject in accordance with a method of the present invention decreases a serum uric acid level in the subject by at least about 5%, at least about 10%., at least about 20%, at least about 30%, at least about 40%, at least about 50%., at least about 60% , at least about 70%, at least about 80% or at least about 90%.
  • the serum uric acid level in the subject is decreased by at least about 33%.
  • the serum uric acid level in the subject is decreased by at least about 50%.
  • administration of a pharmaceutical composition of the present invention or administration of a compound of formula II or a pharmaceutically acceptable salt thereof to a subject in accordance with a method of the present invention decreases a serum uric acid level in the subject by from about 5% to about 90%, by from about 10% to about 50%, by from about 20% to about 40%, or by from about 25% to about 35%.
  • the methods of the present invention comprise administering a pharmaceutical composition of the present invention or a compound of formula II to a subject whose serum uric acid level is at least about 4.0 mg/dL, at least about 4.5 mg/dL, at least about 5.0 mg/dL, at least about 5.5 mg/dL, at least about 6.0 mg/dL, at least about 6.5 mg/dL, at least about 6.8 mg/dL, at least about 7.0 mg/dL, at least about 7.5 mg/dL, at least about 8.0 mg/dL, at least about 8.5 mg/dL, at least about 9.0 mg/dL, at least about 9.5 mg/dL, at least about 10.0 mg/dL, at least about 10.5 mg/dL or at least about 11.0 mg/dL.
  • the methods of the present invention decrease a serum uric acid level in the subject below about 7.0 mg/dL, 6.5 mg/dL, below about 6.0 mg/dL, below about 5.5 mg/dL, below about 5.0 mg/dL, below about 4.5 mg/dL, below about 4.0 mg/dL, below about 3.5 mg/dL, below about 3.0 mg/dL, below about 2.5 mg/dL, below about 2.0 mg/dL or below about 1.5 mg/dL.
  • the appropriate serum uric acid level may vary depending on the subject, and may vary for a given subject over time, depending upon the subject's overall medical condition.
  • the appropriate serum uric acid level for one group of subjects sharing a common medical condition may be different from that which is appropriate for a different group of subjects sharing a different medical condition.
  • the methods of the present invention decrease a serum uric acid level in the subject by an amount sufficient to cause the disappearance of tophi over a timeframe of weeks or months.
  • a serum uric acid level in the subject is decreased by between about
  • a serum uric acid level in the subject is decreased by between about 0.5 to about 8.0 mg/dL, by between about 1.0 to about 6.0 mg/dL, or by between about 2.0 to about 5.0 mg/dL. In certain other embodiment the serum uric acid level in the subject is decreased by between about 1.0 to about 4.0 mg/dL, or by between about 1.0 to about 2.0 mg/dL.
  • the amount of decrease of serum uric acid level that is appropriate may vary depending on the subject, depending upon the subject's overall medical condition. Similarly, the amount of decrease of serum uric acid level that is appropriate for one group of subjects sharing a common medical condition may be different from that which is appropriate for a different group of subjects sharing a different medical condition.
  • the methods of the present invention comprise administering a pharmaceutical composition of the present invention or a compound of formula II to a subject whose serum uric acid level is within the normal range.
  • the subject has gout.
  • the subject has severe gout.
  • the subject has chronic gout.
  • the subject has acute gout.
  • the subject has refractory gout.
  • the subject has had at least one gouty attack.
  • the subject has uric acid crystal formation determined by aspiration of tophi or by aspiration of synovial fluid of an inflamed joint.
  • the subject has a known risk of gouty attack.
  • the risk of gouty attack is determined by a combination of hyperuricemia and one or more of a history of gouty attack, obesity, diabetes, chronic kidney failure, hypertension, use of diuretic drugs, high purine diet, high fructose diet, exposure to lead, high consumption of red meat and protein, and high alcohol intake.
  • the gouty symptoms comprise one or more of pain, inflammation, swelling, muscle fatigue, stress feelings, kidney stones, tophi, podagra or myocardial infarction. In one such embodiment the gouty symptoms are tophi.
  • the uric acid crystal formation is in one or more of the joints, under skin, and kidney. In some embodiments, the formations include tophaceous deposits. [0055] In some embodiments of the methods for treating kidney stones, the kidney stones comprise one or more of uric acid, calcium oxalate and calcium phosphate. In some embodiments, the kidney stones are caused by increased uric acid levels and formation of uric acid crystals.
  • the renal disorder is urinary lithiasis, hyperuricemic nephropathy, acute uric acid nephropathy, microalbuminuria, renal dysfunction, impaired glomerular filtration rate, or nephrolithiasis.
  • the renal disorder is renal insufficiency or chronic kidney disease. In one such embodiment the renal disorder is renal insufficiency. In another such embodiment the renal disorder is chronic kidney disease.
  • the cardiovascular disease is hypertension, myocardial infarction, coronary artery disease, cerebrovascular disease, vascular dementia, preeclampsia, heart disease, congestive heart failure, stroke, atherogenesis, thrombogenesis, atherosclerosis, inflammatory disease or peripheral, carotid, or coronary vascular disease.
  • the cardiovascular disease is hypertension.
  • the cardiovascular disease is coronary artery disease.
  • the cardiovascular disease is congestive heart failure.
  • the cardiovascular disease is stroke.
  • the cardiovascular disease is atherosclerosis.
  • the cardiovascular disease is peripheral vascular disease.
  • the aberrant metabolic condition is metabolic syndrome, obesity, hyperlipidemia, insulin resistance or diabetes.
  • the aberrant metabolic condition is metabolic syndrome.
  • the aberrant metabolic condition is obesity.
  • the aberrant metabolic condition is hyperlipidemia.
  • the aberrant metabolic condition is insulin resistance.
  • the aberrant metabolic condition is diabetes.
  • the cognitive impairment is dementia or Alzheimer's disease.
  • the fatty liver disease is non-alcoholic fatty liver disease (NAFLD).
  • the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH).
  • the uric acid synthesis inhibitor is a xanthine oxidase inhibitor.
  • the xanthine oxidase inhibitor is allopurinol.
  • the xanthine oxidase inhibitor is febuxostat.
  • the uricosuric agent is probenecid.
  • the uricosuric agent is a uricase.
  • the methods can further comprise measuring serum uric acid levels in the subject before and after administration of a compound of the invention, wherein a decrease in serum uric acid levels after the administration indicates an effective treatment.
  • the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent can be administered at between about 10 mg per day and about 2000 mg per day.
  • t the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent can be administered at between about 50 mg per day and about 600 mg per day.
  • the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent is ,administered at about 50 mg per day.
  • the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent is administered at about 100 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 150 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 200 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 250 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 300 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 350 mg per day.
  • the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent is administered at about 400 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 450 mg per day. In some embodiments, t the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 500 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 550 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 600 mg per day.
  • the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent is administered at about 650 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 700 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 750 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 800 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 850 mg per day.
  • the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent is administered at about 900 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 950 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 1000 mg per day. In some embodiments, the compound of formula II or pharmaceutically acceptable salt thereof, or the second therapeutic agent, is administered at about 2000 mg per day.
  • the present invention provides a method of treating hyperuricemia in a subject with gout comprising administering Tranilast to the subject.
  • the Tranilast is administered at between about 50 mg and about 900 mg per day. In some such embodiments, Tranilast is administered at between about 100 mg and about 300 mg per day.
  • the subject is administered, in addition to a compound of formula II, or a pharmaceutically acceptable salt thereof (e.g., Tranilast), a second therapeutic agent sequentially or simultaneously.
  • a compound of formula II, or a pharmaceutically acceptable salt thereof and second therapeutic agent may be administered in a single pharmaceutical composition, as described above.
  • the second agent is a xanthine oxidase inhibitor.
  • the xanthine oxidase inhibitor is allopurinol, febuxostat, oxypurinol, tisopurine, or an inositol.
  • the second agent is a uricosuric agent.
  • the uricosuric agent is probenecid, benzbromarone, sulfinpyrazone, guaifenesin, losartan, atorvastatin, amlodipine, adrenocorticotropic hormone (ACTH or corticotropin), or fenofibrate.
  • the second agent is a uricase enzyme, or a fragment or pegylated derivative thereof.
  • the uricase enzyme is rasburicase or pegloticase.
  • the second agent is cortisone.
  • the second agent is an anti-inflammatory agent.
  • the anti- inflammatory agent is a nonsteroidal anti-inflammatory drug (NSAID).
  • the NSAED is diclofenac, indomethacin, naproxen, sulindac, lumiracoxib or a Cox-2 selective inhibitor.
  • the Cox-2 selective inhibitor is etoricoxib, celecoxib (SC-58635), 5-bromo-2-(4-fluorophenyl)-3-(4-(methylsufonyl)phenyl)-thiophene (DUP-697), flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), MK-966 (Vioxx), nabumetone (6-MNA prodrug), nimesulide, N-[2-(cyclohexyloxy)-4- nitrophenyl]-methanesulfonamide (NS-398), SC-5766, SC-58215, or 3-Formylamino-7- methylsulfonylamino-6-phenoxy-4H-l-benzopyran-l-one (T-614).
  • the anti-inflammatory agent is a corticosteroid.
  • the corticosteroid is methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro- 17- [(2-furanylcarbonyl)oxy] - 11 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-androsta- 1 ,4-diene- 17 ⁇ - carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-l 1 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo- 17.alpha.-propionyloxy-androsta-l ,4-diene- 17 ⁇ -carbothioic acid S-(2-oxo-tetrahydro-furan- 3S-yl) ester, beclomethasone esters, the 17-propionate ester or the 17,21-dipropionate ester,
  • the second agent is Colchicine or a prodrug thereof.
  • the second agent is an opioid agent.
  • the opioid agent is morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine.
  • the second agent is an IL-I antagonist.
  • the IL-I antagonist is Canakinumab (ACZ885) or Rilonacept (Arcalyst).
  • the second agent comprises IL-6 or a fragment thereof.
  • the second agent is insulin.
  • the second agent is selected from Table 2. [0067]
  • the second therapeutic agent comprises a treatment for a cardiovascular disorder, diabetes, or obesity, or complications thereof.
  • the second therapeutic agent is glitazone, troglitazone, rosiglitazone (Avandia), pioglitazone, a sulphonylurea, gliquidone, tolbutamide, glimepride, chlorpropamide, glipizide, glyburide, acetohexamide, meglitinide, repaglinide, nateglinide, metformin, an endothelin receptor antagonist, bosentan, darusentan, enrasentan, tezosentan, atrasentan, ambrisentan sitaxsentan, a smooth muscle relaxant, a PDE5 inhibitor, minoxidil, an angiotensin converting enzyme (ACE) inhibitor, captopril, enalapril, lisinopril, fosinopril, perindopril, quinapril, trandolapril, benazepril, ramipril
  • ACE an
  • the second therapeutic agent comprises a treatment for a renal disorder.
  • the second therapeutic agent is a NO donor, a calcium channel blocker, a cholinergic modulator, an alpha-adrenergic receptor antagonist, a beta- adrenergic receptor agonist, a phosphodiesterase inhibitor, a cAMP-dependent protein kinase activator, a cAMP mimetic, a superoxide scavenger, a potassium channel activator, an estrogen-like compound, a testosterone-like compound, a benzodiazepine, an adrenergic nerve inhibitor, an antidiarrheal agent, a HMG-CoA reductase inhibitor, a smooth muscle relaxant, a adenosine receptor modulator, an adenylyl cyclase activator, an endothelin receptor antagonist, a bisphosphonate, a cGMP-dependent protein kinase activator
  • the present invention provides a method of treating hyperuricemia in a subject with gout, cardiovascular disease, renal disease, a fatty liver disease, kidney stones or an aberrant metabolic condition comprising administering Tranilast to the subject in combination with a second therapeutic agent.
  • the method comprises treating hyperuricemia in a subject with gout.
  • the method comprises treating hyperuricemia in a subject with refractory gout.
  • the method comprises treating hyperuricemia in a subject with cardiovascular disease.
  • the method comprises treating hyperuricemia in a subject with renal disease.
  • the method comprises treating hyperuricemia in a subject with a fatty liver disease.
  • the method comprises treating hyperuricemia in a subject with kidney stones. In another such embodiment the method comprises treating hyperuricemia in a subject with an aberrant metabolic condition.
  • the second therapeutic agent is a xanthine oxidase inhibitor or a uricosuric agent.
  • the effect of administering Tranilast to the subject in combination with one or more xanthine oxidase inhibitors or uricosuric agents may be additive or, in certain instances, more than additive.
  • the Tranilast is administered in combination with allopurinol.
  • the daily dose of allopurinol may range from 50 mg to 900 mg, from 100 mg to 600 mg or from 100 mg to 300 mg.
  • the allopurinol is administered in 100 mg, 200 mg or 300 mg doses.
  • the Tranilast is administered in combination with febuxostat.
  • the daily dose of febuxostat may range from 10 mg to 200 mg, from 20 mg to 120 mg or from 40 mg to 80 mg.
  • the febuxostat is administered in 40 mg or 80 mg doses.
  • 300 mg of Tranilast is administered with 100 mg of allopurinol.
  • 300 mg of Tranilast is administered with 200 mg of allopurinol.
  • 300 mg of Tranilast is administered with 300 mg of allopurinol.
  • 300 mg of Tranilast is administered with 20 mg of febuxostat. In certain embodiment, 300 mg of Tranilast is administered with 40 mg of febuxostat. In certain embodiment, 300 mg of Tranilast is administered with 80 mg of febuxostat.
  • the dose of the first and second therapeutic agents may be titrated.
  • the amount of each therapeutic agent, as well as the weight ratio of the first therapeutic agent to second therapeutic agent may vary as appropriate given the subject's condition and response to treatment.
  • the combination therapies disclosed herein can provide a beneficial therapeutic effect, particularly an additive or over-additive effect.
  • the combination therapies disclosed herein can provide an overall reduction of side effects, e.g., adverse effects.
  • the additive or over-additive beneficial therapeutic effect of the combination therapies disclosed herein provides for dose reduction and/or interval extension when compared to the isolated use of the individual therapeutic agents.
  • the effect of Tranilast on reducing the pain associated with inflammation may be of additional benefit during the arthritic flares associated with gout attacks, thus presenting a unique and differentiating therapy for the disease.
  • the present invention provides compositions and methods for treating hyperuricemia and related disorders.
  • Hyperuricemia may be defined as a serum urate concentration greater than or equal to 6.8 mg/dL.
  • uric acid crystals can precipitate out of solution and deposit in joints and other body tissues where they can produce an inflammatory response, neutrophil recruitment, and the production of proinflammatory cytokines as well as other inflammatory mediators.
  • uric acid crystals may precipitate at lower concentrations, such as 6.0 mg/dL or lower. Hyperuricemia may be due to overproduction of uric acid.
  • hyperuricemia may be result of underexcretion of uric acid, such as conditions due to alterations in renal function. Hyperuricemia can lead to hyperuricosuria, which refers to excessive amounts of uric acid in the urine.
  • hereditary fructose intolerance glycogen storage disease
  • myeloproliferative disease lymphoproliferative disease
  • hemolytic anemia psoriasis
  • obesity renal insufficiency
  • lead intoxication chronic beryllium disease
  • sarcoidosis and various drugs, e.g., low-dose salicylates, diuretics, pyrazinamide, ethambutol, nicotinamide and ethanol.
  • Table 1 list various causes in terms of their pathophysiology.
  • hyperuricemia Certain events can cause hyperuricemia. Rapid purine degradation can cause hyperuricemia, e.g., in conditions of rapid cell proliferation or death, e.g., leukimic blast crises, cytotoxic cancer treatment, hemolysis or rhabdomylosis. Hyperuricemia can also result from excessive degradation of ATP from muscles, e.g., after exercise or due to glycogen storage diseases III, V and VII. Relatedly, hyperuricemia can be caused by myocardial infarction, smoke inhalation, and acute respiratory failure.
  • compositions of the present invention can be used to treat hyperuricemia related to most, if not all, of the above causes, e.g., by reducing serum uric acid levels.
  • disorders associated with high levels of serum uric acid levels include, but are not limited to hyperuricemia, gout, urinary lithiasis, hyperuricemic nephropathy, acute uric acid nephropathy, cardiovascular disorders, renal disorders, metabolic disorders, fatty liver diseases, kidney stones and the like.
  • Complications resulting from high levels of uric acid and uric acid crystal formation include, but are not limited to, muscle spasm, localized swelling, inflammation, joint pains, muscle fatigue, stress feelings, and myocardial infarction.
  • the present invention provides compositions and methods for treating hyperuricemia and such related disorders.
  • Gout is a group of metabolic rheumatic disorders caused by aberrant purine metabolism and hyperuricemia and is the most common cause of an inflammatory arthropathy in middle-aged men. Gout is essentially a disorder of urate metabolism. Deposition of urate crystals in hyperuricemic individuals results in acute gout, characterized by agonizing pain and inflammation of rapid onset, most frequently affecting the first metatarsophalangeal joint. It can take decades for uric acid levels to rise to levels where uric acid crystals precipitate. Such precipitation can activate the NLRP3 (NALP3) inflammasome and result in a gouty attack.
  • NALP3 NLRP3
  • Hyperuricemia is associated with an increased risk of developing gout, and the risk of gout increases with the degree and duration of the hyperuricemia. Hyperuricemia in gout is typically accompanied by renal complications and suboptimal excretion of uric acid. Gouty attacks are typically severely painful and disabling.
  • a variety of risk factors have been identified for gout.
  • these include obesity, diabetes, chronic kidney failure, hypertension, use of diuretic drugs, high purine diet, high fructose diet, exposure to lead, consumption of red meat and protein, and alcohol intake. See also Table 1.
  • Gouty attack can be precipitated by perioperative ketosis in surgical patients, reduced body temperature, e.g., while sleeping, and by dehydration, e.g., by use of diuretic drugs.
  • Genetic risk factors for gout and hyperuricemia have also been identified.
  • LNS Lesch-Nyhan syndrome
  • HGPRT hypoxanthine-guanine phosphoribosyltransferase
  • urate transporters include SLC22A12 (URATl), solute carrier family 2 (facilitative glucose transporter), member 9 gene (SLC2A9; Glut9), ABCG2 and SLC17A3.
  • SLC22A12 URATl
  • solute carrier family 2 facilitative glucose transporter
  • member 9 gene SLC2A9; Glut9
  • Cameron JS and Simmonds HA Hereditary hyperuricemia and renal disease. Semin Nephrol. 2005 25:9-18; Bleyer AJ and Hart TC, Genetic factors associated with gout and hyperuricemia. Adv Chronic Kidney Dis. 2006 13:124-30; Enomoto A., et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002 417:447-52; Vitart V., et al.
  • SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008 40:437-42; Dehghan A., et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 2008 372:1953-61.
  • Gout can be either acute or chronic. Triggers for acute gouty attacks include infection, intravenous contrast media, acidosis, and rapid fluctuations in serum uric acid concentrations such as with trauma, surgery, psoriasis flare-ups, initiation of chemotherapy, diuretic therapy, and stopping or starting allopurinol. Acute attacks usually begin in the joints of lower extremities. The attacks are characterized by joint pain and swelling. The first attack often comprises podagra, a sudden, unexplained swelling and pain of the big toe joint on just one foot. During an attack, which can last several days, pain can be so severe that patients are often unable to wear clothing or even touch bedsheets. Recurrent acute attacks can lead to chronic tophaceous deposits. Tophi are crystallized uric acid deposits that form firm swellings in joints, cartilage and bone. Tophi deposits sometimes disrupt the skin, exposing large chalky nodules. Extensive tophi can erode bone or other tissues and may require surgical removal.
  • Patients having "severe gout” include those with serum uric acid levels that are greater than or equal to 8.0 mg/dL and have at least one gout tophus or gouty arthritis or have had at least three gouty flares in the past 18 months.
  • Refractory gout comprises patients with severe gout wherein, in addition, conventional therapies are contraindicated or have been or become ineffective.
  • the patient may have a history of hypersensitivity or of failure to normalize serum uric acid (sUA) with at least 3 months of treatment with allopurinol at the maximum labeled dose (800 mg/dL in the U.S.), or at a medically appropriate lower dose based on dose-limiting toxicity or dose-limiting co-morbidity.
  • sUA serum uric acid
  • Such hypertension may further be related to chronic kidney disease and other renal diseases, e.g., microalbuminuria and renal dysfunction in subjects with normal renal function and impaired glomerular filtration rate in type 1 diabetics without proteinuria.
  • Other renal problems associated with hyperuricemia include nephrolithiasis, urate nephropathy, and uric acid nephropathy.
  • Nephrolithiasis, or kidney stones are found most often in gout patients comprising uric acid stones, although hyperuricemia is also associated with other types of stones, e.g., calcium oxalate or calcium phosphate stones in non-gouty patients.
  • uric acid may act to seed calcium deposits.
  • Urate nephropathy manifests from severe gout and is characterized by urate crystals in the renal interstitium.
  • Uric acid nephropathy can cause renal failure from deposition of large amounts of crystals in the renal collecting ducts, pelvis and ureters.
  • Other cardiovascular diseases associated with hyperuricemia include peripheral, carotid, and coronary vascular disease, stroke, preeclampsia, and vascular dementia.
  • drugs used to treat hyperuricemia e.g., allopurinol, may be effective in treating diabetes, hypertension, and other uric acid related disorders. See, e.g., Feng et al, Uric Acid and Cardiovascular Risk, N Engl J Med 2008 359:1811-21.
  • Gout patients have higher death rates from all causes, although gout associated mortality is largely related to cardiovascular complications.
  • cardiovascular complications relate to high serum uric acid levels, as described above.
  • hypertension is often observed in subjects with hyperuricemia.
  • Higher serum uric acid levels are also associated with ongoing inflammatory response.
  • hyperuricemic patients often display higher levels of serum markers of inflammation, e.g., C reactive protein, fibrinogen, interleukin-6 (IL-6), and increased neutrophil count.
  • the serum of gout patients contains high levels of inflammatory markers even in the absence of an ongoing gouty attack.
  • crystal formation activates monocytes and stimulates the release of inflammatory markers including tumor necrosis factor- ⁇ , EL-I, IL-6, IL-8, and cyclooxygenase-2.
  • inflammatory markers including tumor necrosis factor- ⁇ , EL-I, IL-6, IL-8, and cyclooxygenase-2.
  • Ongoing low-grade inflammation among patients with gout may promote atherogenesis and thrombogenesis.
  • Similar complications are also observed in other inflammatory rheumatic disorders associated with higher risk of cardiovascular disease, e.g., rheumatoid arthritis or systemic lupus erythematosus.
  • the present invention provides compositions and methods for treating hyperuricemia and such related disorders as described herein, including, but not limited to, gout, severe gout, refractory gout, chronic gout, cardiovascular disorders and related disorders, renal disorders and related disorders, fatty liver disease, kidney stones and aberrant metabolic conditions.
  • One standard for diagnosis of gout comprises aspiration of tophi or synovial fluid from an inflamed joint.
  • Tophi are crystallized uric acid deposits that form firm swellings in joints, cartilage and bone.
  • Synovial fluid is a thick fluid which lubricates and cushions synovial joints, e.g., the wrist, elbow, knee, shoulder and hip joints. Needlelike monosodium urate crystals observed in the synovial fluid when viewed under a microscope are highly indicative of gout.
  • aspiration techniques are not performed routinely in the clinical setting for various reasons, e.g., lack of availability of synovial fluid, time of the procedure and lack of physician experience.
  • gout can indicate hyperuricemia and gout.
  • serum urate levels are measured during and following a gouty attack.
  • elevated levels are only observed post-attack, e.g., two weeks later.
  • uric acid levels below 4.0 mg/dL e.g., uric acid levels below 4.0 mg/dL
  • Radiology can also assist in diagnosis of gout, e.g., to ascertain joint damage and urate deposits.
  • Radiological techniques include x-ray film, computed tomography (CT) scans, magnetic resonance imaging (MRI), Dual Energy Computed Tomography (DECT), and ultrasound. See, e.g., Schlesinger, Diagnosis of Gout: Clinical, Laboratory, and Radiologic Findings, Am J Manag Care. 2005 11 :S443-S450; Dore, The Gout Diagnosis, Cleve Clin J Med. 2008 75:S17-S21. The aforementioned diagnostic techniques also may be used to monitor the efficacy of treatment.
  • Diagnosis of other conditions associated with an elevated serum uric acid level for example, hyperuricemia, gout-associated inflammation, renal disorders, cardiovascular disease, aberrant metabolic conditions, fatty liver disease or kidney stones, may be performed according to current medical standards.
  • a pharmaceutical composition for treating a condition associated with an elevated serum uric acid level. Accordingly, in one embodiment a pharmaceutical composition comprises a compound of formula (I):
  • E is selected from N and CR N ; represents a single or double bond;
  • R A is selected from H, d_ 4 alkyl, OH, C,. 4 alkoxy, halo, CO 2 H and CO 2 C M alkyl
  • R B is selected from H, Ci_ 4 alkyl, OH, C]. 4 alkoxy, halo, or R A and R B together form an optionally substituted fused phenyl or heterocyclic ring
  • R c is selected from H, C]_ 4 alkyl, OH, C ⁇ alkoxy and halo;
  • R D is selected from H, C M alkyl, C 2 - 4 alkenyl, OH, C M alkoxy, CO 2 H, CO 2 C M alkyl and
  • R E is selected from Ci. 4 alkyl, OH, C,. 4 alkoxy, halo, CO 2 H, CO 2 C 1-4 alkyl, NH 2 and NHR K ;
  • R N is selected from H, C]. 4 alkyl, OH and C ]-4 alkoxy;
  • R F , R G , R H and R 1 are each independently H and C M alkyl or R F and R G together form an oxo group or
  • R F and R H form a bond
  • R J is selected from CH(CO 2 H)NH 2 , CH(CO 2 C , ⁇ alkyl)NH 2 , C(O)CO 2 H, C(O)CO 2 C 1 . 4 alkyl, C(O)H,
  • R ⁇ is selected from H, C ⁇ alkyl and C(O)H;
  • R L is selected from H, C]. 4 alkyl and optionally substituted phenyl or heterocyclic ring, wherein optionally substituted phenyl or heterocyclic ring is optionally substituted with one or more, Ci_ 4 alkyl, halo, NH 2 , NHC M alkyl, N(C 1 . 4 alkyl) 2 ,
  • a pharmaceutical composition for use in methods of the invention comprises a compound of formula (II):
  • each of R 1 and R 2 is independently selected from a hydrogen atom or a Ci -C 4 alkyl group
  • R 3 and R 4 are each hydrogen atoms or together form another chemical bond
  • each X is independently selected from a hydroxyl group, a halogen atom, a C r C 4 alkyl group or a C r C 4 alkoxy group, or when two X groups are alkyl or alkoxy groups, they may be connected together to form a ring
  • n is an integer from 1 to 3.
  • the carboxyl group may be in the 2-, 3- or 4-position of the aromatic ring. In one embodiment the carboxyl group is in the 2-position. [0090] In one embodiment at least one of R 1 and R 2 is a hydrogen atom. In one such embodiment, both of R 1 and R 2 are hydrogen atoms. [0091] In one embodiment R 3 and R 4 taken together form a chemical bond. Such compounds having an unsaturated bond may be in the form of E or Z geometric isomers.
  • n is 1 or 2 and each X, which may be the same or different, is selected from halogen, Ci-C 4 alkyl or C 1 -C 4 alkoxy. In one such embodiment X is selected from halogen and C]-C 4 alkoxy. In one embodiment, n is 2 and both X are selected from Ci -C 4 alkoxy. In one such embodiment both X are methoxy.
  • compounds useful in the present invention are those of formula (III):
  • Examples of compounds of formula (III) include: 2-[[3-(2-methylphenyl)-l -oxo-2-propenyl]amino]benzoic acid; 2-[[3-(3-methylphenyl)-l -oxo-2-propenyl]amino]benzoic acid; 2-[[3-(4-methylphenyl)-l -oxo-2-propenyl]amino]benzoic acid; 2-[[3-(2-ethylphenyl)-l -oxo-2-propenyl]amino]benzoic acid; 2-[[3-(3-ethylphenyl)-l -oxo-2-propenyl]amino]benzoic acid; 2-[[3-(4-ethylphenyl)-l -oxo-2-propenyl]amino]benzoic acid; -[[3-(2-propylphenyl)-l -l
  • the compound of formula (III) is Tranilast (TNL), which is 2-[[3-(3,4- dimethoxyphenyl)-l -oxo-2 -propenyl]amino]benzoic acid.
  • TNL Tranilast
  • the compound is 3-hydroxykynurenic acid (3-HKA), 3-hydroxyanthranilic acid (3-HAA), picolinic acid (PA), or quinolinic acid (QA).
  • treating includes treating, preventing and/or ameliorating the condition or disease to which it refers.
  • the term "elevated serum uric acid level” means serum uric acid level greater than normal.
  • elevated serum uric acid levels are above the mean level in a given population, such as gender and/or age.
  • hyperuricemia means serum uric acid level greater than the normal level for the population. In some instances, hyperuricemia includes serum uric acid levels greater than or equal to 6.0 mg/dL, 6.8 mg/dL, 7 mg/dL or 8 mg/dL.
  • severe gout includes gout present in a subject having serum uric acid levels that are greater than or equal to 8.0 mg/dL and have at least one gout tophus or gouty arthritis or have had at least three gouty flares in the past 18 months.
  • chronic gout includes gout present in a subject having recurrent or prolonged gout flares, tophus formation, chronic inflammatory arthritis and/or joint destruction associated with gout.
  • acute gout includes gout present in a subject that has had or is having at least one gouty symptom, such as a gout flare or gouty attack.
  • gout-associated inflammation refers to local or systemic inflammation due to immune response to urate crystals.
  • Ci-C 4 alkyl refers to linear or branched hydrocarbon chains having
  • C 2 -C 4 alkenyl refers to linear or branched hydrocarbon chains having 2 to 4 carbon atoms and one or two double bonds. Examples of such groups include vinyl, propenyl, butenyl and butadienyl.
  • C]-C 4 alkoxy refers to hydroxy groups substituted with linear or branched alkyl groups having 1 to 4 carbon atoms.
  • C r C 4 alkyl refers to linear, branched, or cyclized hydrocarbon chains having 1 to 6 carbon atoms.
  • Ci-C 4 alkoxy refers to hydroxy groups substituted with linear or branched alkyl groups having 1 to
  • cyclized groups include cyclopropyl, cyclopropyl methyl, cyclobutyl, cyclopentyl, or cyclohexyl and related alkoxy groups.
  • halogen or halo refers to fluoro, chloro or bromo atoms.
  • heterocyclic ring refers to optionally substituted unsaturated, five- to six-membered cyclic structure in which one or more skeletal atoms is oxygen, nitrogen, sulfur, or combinations thereof.
  • Heterocyclic ring includes, but is not limited to furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, triazolyl, thiazolyl, thiophenyl, tetrazolyl, thiadiazolyl, and thienyl.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, ni
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centers, e.g., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds represented by the present structures but with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Scheme 1 describes but one method to prepare such a deuterated analog; other methods are well-known to those of skill in the art.
  • the starting material deuterated anthranilic acid, A-I (CAS 60124-83-6)
  • A-I deuterated anthranilic acid
  • B-I cinnamic acid analog
  • a deuterated cinnamic acid analog, B-2 can be prepared from a deuterated dimethoxybenzaldehyde derivative, such as:
  • a deuterated dimethoxybenzaldehyde derivative can be converted to a deuterated cinnamic acid analog according to Scheme 2, where each of R a and R b is independently -CH 3 or -CD 3 .
  • Deuterated cinnamic acid analog (B-2) is prepared by the Doebner modification of the
  • the compounds of formula (I) can be orally active anti-hyperuricemic compounds, and can have a direct or indirect affect on uric acid transporters in the brush border membrane.
  • a particularly preferred compound of the invention is known either of the chemical names N-[3,4- dimethoxycinnamoyl]-anthranilic acid or 2-[[3-(3,4-dimethoxyphenyl)-l-oxo-2- propenyljaminojbenzoic acid and may also be referred to as Tranilast.
  • Tranilast The structure is depicted below:
  • Anthranilic acids such as N-[3,4-dimethoxycinnamoyl]-anthranilic acid (also known by benzoic acid names such as 2-[[3-(3,4-dimethoxyphenyl)-l-oxo-2-propenyl]amino]benzoic acid are useful for the methods of the present invention.
  • esters and amides of anthranilic acids are used in the methods of the present invention.
  • bioisosteric replacements known in the art for carboxylic acids, esters and amides are used.
  • the compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof or their antagonists may be linked, bound or otherwise associated with any proteinaceous or non- proteinaceous molecules.
  • said compounds of formula (I) or pharmaceutically acceptable salts thereof may be associated with a molecule which permits targeting to a localized region.
  • Tranilast and a second drug or agent can allow the use of a lower dose of Tranilast or the second drug or agent than would ordinarily be used.
  • the compounds of the present invention may be modified in order to reduce side effects, improve pharmacokinetic and/or pharmacodynamic profiles.
  • Incorporation of a heavy atom particularly substitution of deuterium for hydrogen can give rise to an isotope effect that can alter the pharmacokinetics of the drug.
  • the safety profile of a composition may be improved through incorporation of a heavy atom (e.g., deuterium).
  • a heavy atom e.g., deuterium
  • compositions with substituted deuterium may be delivered in smaller doses with equivalent efficacy. By reducing the dosage, corresponding side effects may be diminished as well.
  • substitution of hydrogens with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • the compounds of the present invention are used in combination with other therapeutic agents to bring about a desired effect. Selection of additional agents depends, in large part, on the desired target therapy. It is known that modulation of serum uric acid levels can be further improved by the addition of a second agent to the therapeutic regimen. See, e.g., Chung et al., Optimizing therapy with allopurinol: factors limiting hypouricemic efficacy. Am J Med Sci. 2008 Mar;335(3):219-26. Combination therapy includes administration of a single pharmaceutical dosage formulation that contains a compound of the present invention, e.g., Tranilast, as well as administration of a compound of the present invention and each additional active agent in its own separate pharmaceutical dosage formulation.
  • a compound of the present invention e.g., Tranilast
  • a compound of formula (II) e.g., Tranilast
  • a pharmaceutically acceptable salt thereof e.g., a xanthane oxidase inhibitor
  • each agent can be administered in separate oral dosage formulations.
  • the compositions of the present invention and one or more additional active agents can be administered at essentially the same time (i.e., simultaneously or concurrently), or at separately staggered times (i.e., sequentially).
  • Combinations can include two or more active agents in addition to one or more compounds of the present invention. Combination therapy is understood to include all these regimens.
  • Hyperuricemia and chronic gout are treated with agents that lower urate levels, e.g., xanthine oxidase inhibitors and uricosuric agents, thereby reducing uric acid levels and potential crystal formation.
  • Xanthine oxidase is involved in purine metabolism and inhibiting the enzyme reduces uric acid levels. Allopurinol, a xanthine oxidase inhibitor, is the current first line standard of care for lowering urate levels.
  • Another xanthine oxidase inhibitor, Febuxostat was approved for treatment of gout in February 2009.
  • xanthine oxidase inhibitors include oxypurinol, tisopurine, inositols (e.g., phytic acid and myo-inositol) and potentially propolis.
  • Uricosuric agents enhance excretion of uric acid and generally act by lowering the absorption of uric acid from the kidneys back to the blood, e.g., by inhibiting urate transporters, e.g, SLC22A12.
  • Probenecid is the most commonly used uricosuric agent in the U.S. and may be given in combination with allopurinol to refractory gout patients.
  • Benzbromarone and sulfinpyrazone are also used as first line uricosuric agents.
  • Guaifenesin, Io sartan, atorvastatin, amlodipine, adrenocorticotropic hormone (ACTH or corticotropin), fenofibrate and cortisone also have uricosuric effects. Additionally, other uricosuric agents are being developed or are in clinical trials, such uricase enzymes including rasburicase or the pegylated uricase enzyme PURICASE® (Pegloticase), which has completed Phase III trials. Uricase or urate oxidase enzymes can lower uric acid levels by converting uric acid into allantoin, a benign end metabolite which is easily excreted in the urine.
  • IL-6 has also been shown to reduce serum uric acid levels and proposed as a treatment for hyperuricemia and gout. See U.S. Patent No. 6,007,804, issued December 28, 1999 and entitled "IL-6 as serum uric acid decreasing compound.”
  • Interleukin 1 (IL-I) antagonists are being developed for chronic gout.
  • Canakinumab ACZ885
  • ACZ885 is a human monoclonal antibody targeted at IL-I beta, being developed by Novartis for the treatment of rheumatoid arthritis and gout.
  • Rilonacept marketed under the trade name Arcalyst by Regeneron Pharmaceuticals, is under going trials is a dimeric fusion protein and IL-I blocker, also undergoing trials as a treatment for gout. See also U.S. Patent Publication No. 2008/0300185, filed October 19, 2007 and entitled "Use of IL-I antagonists to treat gout and pseudogout.” Diet and lifestyle can be modified to reduce urate levels, e.g., lowering red meat or alcohol consumption, or substituting alternate treatments for diuretic drugs.
  • Acute gout typically presents with inflammation, pain and swelling.
  • Urate-lowering therapies described above for hyperuricemia and chronic gout, are usually not used until the acute phase of gout has resolved because fluctuations in serum uric acid can exacerbate the inflammatory process.
  • Therapy is generally directed at reducing the inflammation, pain and swelling, e.g., anti-inflammatory agents and pain killers.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids are typically given for acute gouty attacks, depending on co-morbidities.
  • NSAIDS include, but are not limited to, indomethacin, naproxen and sulindac.
  • Corticosteroids include, but are not limited to, prednisone or methylprednisone.
  • Colchicine is given as a second line therapy, but has toxicities at higher levels. For example, Colchicine can lead to bone marrow suppression and neuromyopathy in patients with severe renal or hepatic impairment. More common adverse effects include nausea, vomiting, and diarrhea. In some cases, opioid agents are given to acute gout sufferers.
  • compositions of the invention can be used in combination with one or more agents described herein for reducing uric acid or otherwise treating gout.
  • the composition of the invention and the one or more gout treatments can be administered or applied sequentially or simultaneously.
  • the composition of the invention may further comprise one or more uricosuric agents in a single dosage form.
  • the composition of the invention and the one or more uricosuric agents are formulated as separate dosage forms and administrated or applied simultaneously or sequentially to a subject.
  • methods and compositions of the invention are administered before, concurrent to or after treatment of a subject in need thereof with one or more standards of care used to treat gout.
  • Standards of Care for gout include but are not limited to administration of one or more therapeutic agents to treat pain and reduce urate in blood.
  • drugs used to lower the amount of urate or analgesic drugs may be administered before, concurrent to or after treatment of a subject in need thereof with compounds and methods of the present invention.
  • pharmacologically active compounds e.g., for the treatment of inflammation, pain, or hyperuricemia, are administered before, concurrent to or after treatment of a subject in need thereof with compounds and methods of the present invention.
  • pharmacologically active compounds include, without limitation, the following:
  • Tranilast is administered before, concurrently or subsequent to administration of a xanthane oxidase inhibitor.
  • Xanthane oxidase inhibitors lower the amount of urate in blood.
  • Xanthane oxidase inhibitors include, but are not limited to, allopurinol, febuxostat, oxypurinol, tisopurine, or an inositol.
  • a compound of the invention is administered before, concurrently or subsequent to administration of allopurinol.
  • a compound of the invention is administered before, concurrently or subsequent to administration of Febuxostat.
  • Uricosuric agents In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of a uricosuric agent. Uricosuric agents enhance the excretion of uric acid. Uricosuric agents include, but are not limited to, probenecid, benzbromarone, sulfinpyrazone, guaifenesin, losartan, atorvastatin, amlodipine, adrenocorticotropic hormone (ACTH or corticotropin), or fenofibrate. In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of probenecid, benzbromarone, or sulfinpyrazone.
  • RDEA806 Another uricosuric agent is Ardea Biosciences' RDEA594, a metabolite of their antiviral RDEA806.
  • RDEA594 is believed to be responsible for essentially all of the uric acid lowering effects seen with RDEA806.
  • the chemical structure of RDEA806 may be represented as follows:
  • RDEA594 The chemical structure of RDEA594 is believed to be as follows:
  • Still another Ardea Biosciences uricosuric agent is RDEA684, which is currently in preclinical development.
  • Uricase enzymes In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of a uricase enzyme.
  • Uricase or urate oxidase enzymes are found in many mammals but not humans. They can lower uric acid levels by converting uric acid into allantoin, a benign end metabolite which is easily excreted in the urine.
  • Uricase enzymes include, but are not limited to, rasburicase or a pegylated uricase enzyme (PEG-uricase). In some embodiments, the pegylated uricase enzyme is PURICASE® (Pegloticase).
  • Non-steroidal anti-inflammatory drugs NSAIDs
  • a compound of the invention is administered before, concurrently or subsequent to administration of one or more non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • administration of an NSAID can reduce the pain and inflammation experienced with gout.
  • a non-limiting list of NSAIDs includes diclofenac, indomethacin, naproxen, sulindac and lumiracoxib.
  • Further NSAIDs capable of use with methods and compositions of the invention are disclosed in U.S. Patents Nos.: 7,423,042; 7,341,737; 7,303,761; and 6,787,155, all of which are hereby incorporated by reference in their entirety.
  • Cox-2 selective inhibitors In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of one or more Cox-2 inhibitors.
  • Cox-2 inhibitors are a newer type of NSAID which are designed to be less harmful to the stomach.
  • Etoricoxib is the Cox-2 selective inhibitor normally prescribed to treat gout.
  • COX-2 inhibitors have been reported in the art and many chemical structures are known to produce inhibition of cyclooxygenase-2. COX-2 inhibitors are described, for example, in U.S. Pat. Nos.
  • COX-2 inhibitors include celecoxib (SC-58635), 5-bromo-2-(4-fluorophenyl)-3 -(4-(methylsufonyl)phenyl)-thiophene (DUP-697), flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA), nimesulide, N-[2- (cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), SC-5766, SC-58215, or 3- Formylamino-7-methylsulfonylamino-6-phenoxy-4H- 1 -benzopyran- 1 -one (T-614) ; or combinations thereof.
  • Corticosteroids In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of one or more corticosteroids. Corticosteroids are a type of steroid, and they sometimes are used in severe cases of gout. In some cases, a corticosteroid can be injected directly into the affected joint. The type of corticosteroid received will depend on the size of the affected joint.
  • Suitable corticosteroids which may be used in combination with the compounds of the invention include, but are not limited to, methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro- 17-[(2-furanylcarbonyl)oxy]-l 1 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-androsta- 1 ,4-diene- 17 ⁇ - carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo- 17.alpha.-propionyloxy-androsta-l,4-diene-17 ⁇ -carbothioic acid S-(2-oxo-tetrahydro-furan- 3S-yl) ester, beclomethasone esters (e.g., the 17-propionate ester or the 17,21-dipropionate ester), bude
  • Preferred corticosteroids include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-l 1 ⁇ -hydroxy- 16 ⁇ - methyl-17 ⁇ -[(- 4-methyl- 1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta- 1 ,4-diene- 17 ⁇ - carbothioic acid S-fluoromethyl ester and 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-l l ⁇ - hydroxy-16 ⁇ -methyl-3-oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, more preferably 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-l 1 ⁇ -hydroxy- 16 ⁇ -methyl-3- oxo-androsta-l ⁇ -diene- ⁇ -carbothioic acid S-fluoromethyl ester; and those disclosed in
  • Colchicine In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of colchicine. Colchicine inhibits uric acid crystal deposition, possibly by inhibiting oxidation of glucose and subsequent lactic acid production in leukocytes. Colchicine is available in tablet form and is usually taken every two to six hours. Colchicine can be administered in prodrug form.
  • Opioid agents In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of an opioid analgesic. Opioids act as agonists, interacting, with stereo specific and saturable binding sites in the brain and other tissues. Endogenous opioid-like peptides are present particularly in areas of the central nervous system that are presumed to be related to the perception of pain; to movement, mood and behavior, and to the regulation of neuroendocrinological functions.
  • Opioid analgesics include, for example, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine.
  • Cytokines In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of a modulator of one or more cytokines. Cytokines can be involved in an inflammatory response. Cytokines include, without limitation, BDNF, CREB pS133, CREB Total, DR-5, EGF,ENA-78, Eotaxin, Fatty Acid Binding Protein, FGF-basic, granulocyte colony-stimulating factor (G-CSF), GCP-2, Granulocyte-macrophage Colony-stimulating Factor GM-CSF (GM-CSF), growth-related oncogene - keratinocytes (GRO-KC), HGF, ICAM-I, IFN-alpha, IFN-gamma, the interleukins IL-IO, IL-I l, IL-12, IL-12 p40, IL-12 p40/p70, IL-12 P 70, BL-13, IL
  • the cytokine is IL-12p70, IL-10, IL-I alpha, IL-3, IL-12 p40, IL-lra, IL-12, IL-6, EL-4, IL-18, IL-10, IL-5, eotaxin, EL-16, MIG, IL-8, IL-17, IL-7, IL-15, IL-13, IL-2R (soluble), BL-2, LIF/HDLDA, IL-I beta, Fas/CD95/Apo-1, or MCP-I.
  • Modulation can comprise up or downregulating the biological action of the one or more cytokines. For example, gout can be treated by inhibiting IL-I.
  • Inhibitors can comprise small molecules, peptides, proteins or the like. Alternately, serum uric acid levels can be decreased by administration of IL-6, or fragments, conjugates or mimetics thereof. In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of a modulator of one or more IL-I antagonists. In one embodiment, a compound of the invention is administered before, concurrently or subsequent to administration of a modulator of IL-6, or a fragment, conjugate or mimetic thereof.
  • Table 2 lists therapeutic agents for treatment of hyperuricemia, gout and related disorders.
  • a compound of the invention is administered before, concurrently or subsequent to administration of one or more of the compounds listed in Table 2.
  • a combination therapy comprising a pharmaceutical agent of the present invention, e.g., Tranilast
  • a pharmaceutical agent of the present invention can further comprise a plurality of other pharmaceutically active agents as described herein.
  • a patient with chronic gout may be administered a xanthane oxidase inhibitor, e.g., allopurinol, and a uricosuric agent, e.g., probenecid.
  • the patient can be treated with a pharmaceutical agent of the present invention, e.g., Tranilast, as well. Any such combinations are within the scope of the present invention.
  • hyperuricemia is associated with any number of cardiovascular disorders, including without limitation cardiovascular disease and other conditions, including hypertension, metabolic syndrome, hyperlipidemia, insulin resistance, coronary artery disease, peripheral artery disease cerebrovascular disease, vascular dementia, preeclampsia, heart disease, congestive heart failure, atherosclerosis and kidney disease. Furthermore, high levels of uric acid can predict the onset of hypertension, obesity, diabetes and kidney disease.
  • a compound of the present invention may be administered in combination with any other therapeutic agent and/or intervention that is commonly used for the treatment of cardiovascular or related disorders.
  • agents include but are not limited to agents used to treat diabetes, including but not limited to agents that improve insulin sensitivity such as PPAR gamma ligands (thiazolidinedones, glitazones, troglitazones, rosiglitazone (Avandia), pioglitazone, stimulators of insulin secretion such as sulphonylureas (gliquidone, tolbutamide, glimepride, chlorpropamide, glipizide, glyburide, acetohexamide) and meglitinides (meglitinide, repaglinide, nateglinide) and agents that reduce liver production of glucose such as metformin.
  • PPAR gamma ligands thiazolidinedones, glitazones, troglitazones, rosigli
  • agents used to treat vascular disease including but not limited to endothelin receptor antagonists commonly used for the treatment of hypertension and other endothelial dysfunction-related disorders, such as bosentan, darusentan, enrasentan, tezosentan, atrasentan, ambrisentan sitaxsentan; smooth muscle relaxants such as PDE5 inhibitors (indirect-acting) and minoxidil (direct-acting); angiotensin converting enzyme (ACE) inhibitors such as captopril, enalapril, lisinopril, fosinopril, perindopril, quinapril, trandolapril, benazepril, ramipril; angiotensin II receptor blockers such as irbesartan, losartan, valsartan, eprosartan, olmesartan, candesartan, telmisartan; beta blockers such as ateno
  • agents used to treat hyperlipidemia include but are not limited to agents used to treat hyperlipidemia, including but not limited to agents that lower LDL such as statins (atovastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin calcium, simvastatin) and nicotinic acid, agents that stimulate PPAR alpha such as fibrates, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, agents that bind and prevent readsorption of bile acids and reduce cholesterol levels such as bile acid sequestrants, cholestyramine and colestipol, and cholesterol absorption inhibitors.
  • statins atovastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin calcium, simvastatin
  • agents that stimulate PPAR alpha such as fibrates, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate
  • Such agents include those that reduce risk of heart attack, including COX-I inhibitors including aspirin and NSAIDs, as described herein, or COX-2 inhibitors, also described herein.
  • a compound of the present invention e.g., Tranilast, or a pharmaceutically acceptable salt thereof, may be administered in combination with any other therapeutic agent and/or intervention that is commonly used for the treatment of diabetes or related disorders.
  • combination therapy can be used for modulating (preventing the onset of the symptoms or complications associated with) diabetes (or treating, preventing or reducing the risk of developing, diabetes and its related symptoms, complications, and disorders), wherein the compounds of the present invention, e.g., Tranilast, can be effectively used in combination with, for example, biguanides (such as metformin); thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone); dipeptidyl-peptidase-4 (“DPP-IV”) inhibitors (such as vildagliptin and sitagliptin); glucagonlike peptide- 1 ("GLP-I”) receptor agonists (such as exanatide) (or GLP- 1 mimetics); PPAR gamma agonists or partial agonists; dual PPAR alpha, PPAR gamma agonists or partial agonists; dual PPAR delta,
  • a compound of the present invention may be administered in combination with any other therapeutic agent and/or intervention that is commonly used for the treatment of obesity or obesity-related disorders.
  • the compounds of the present invention can be used in combination with, for example, phenylpropanolamine, phenteramine; diethylpropion; mazindol; fenfluramine; dexfenfluramine; phentiramine, beta-3 adrenoceptor agonist agents; sibutramine; gastrointestinal lipase inhibitors (such as orlistat); and leptins.
  • CBD-I cannabinoid-1
  • PPAR delta agonists or partial agonists such as rimonabant
  • dual PPAR delta, PPAR gamma agonists or partial agonists pan PPAR agonists or partial agonists
  • neuropeptide Y enterostatin; cholecytokinin; bombesin; amylin; histamine H3 receptors; dopamine D2 receptors; melanocyte stimulating hormone; corticotrophin releasing factor; galanin; and gamma amino butyric acid (GABA).
  • CB-I cannabinoid-1
  • GABA gamma amino butyric acid
  • a compound of the present invention may be administered in combination with any other therapeutic agent and/or intervention that is commonly used for the treatment of hyperlipidemia and related complications, wherein the compounds of the present invention are used in combination with, for example, statins (such as atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin), CETP inhibitors (such as torcetrapib); a cholesterol absorption inhibitor (such as ezetimibe); PPAR alpha agonists or partial agonists; PPAR delta agonists or partial agonists; dual PPAR alpha, PPAR delta agonists or partial agonists; dual PPAR alpha, PPAR gamma agonists or partial agonists; dual PPAR delta, PPAR gamma agonists or partial agonists; pan PPAR agonists or partial agonists; fen
  • a compound of the present invention may be administered in combination with any other therapeutic agent and/or intervention that is commonly used for the treatment of atherosclerosis, wherein a compound of the present invention, e.g., Tranilast, is administered in combination with one or more of the following active agents: an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent, such as a cholesterol biosynthesis inhibitor, e.g., an hydroxymethylglutaryl (HMG) CoA reductase inhibitor (also referred to as statins, such as lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin); an HMG-CoA synthase inhibitor; a squalene epoxidase inhibitor; or a squalene synthetase inhibitor (also known as squalene synth
  • the compounds of the present invention can be administered in combination with more than one additional active agent, for example, a combination of Tranilast with an HMG-CoA reductase inhibitor (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) and aspirin, or a combination of Tranilast with an HMG-CoA reductase inhibitor and a blocker.
  • HMG-CoA reductase inhibitor e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin
  • a compound of the present invention e.g., Tranilast, or a pharmaceutically acceptable salt thereof, are administered in combination with any other therapeutic agent and/or intervention used for the treatment of metabolic syndrome (or treating metabolic syndrome and its related symptoms, complications and disorders), wherein the compounds of the present invention can be effectively used in combination with, for example, the active agents discussed above for modulating or treating diabetes, obesity, hyperlipidemia, atherosclerosis, and/or their respective related symptoms, complications and disorders.
  • a compound of the present invention can be administered in combination with halofenic acid, an ester of halofenic acid, or another prodrug of halofenic acid, preferably with (-)-(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid 2- acetylaminoethyl ester (metaglidasen).
  • a compound of the present invention may be administered in combination with any other therapeutic agent and/or intervention that is used for the treatment of renal or urological or related disorders, e.g., NO donors, calcium channel blockers, cholinergic modulators, alpha- adrenergic receptor antagonists, beta-adrenergic receptor agonists, phosphodiesterase inhibitors, cAMP-dependent protein kinase activators (e.g., cAMP mimetics), superoxide scavengers, potassium channel activators, estrogen-like compounds, testosterone-like compounds, benzodiazepines, adrenergic nerve inhibitors, antidiarrheal agents, HMG-CoA reductase inhibitors, smooth muscle relaxants, adenosine receptor modulators, adenylyl cyclase activators, endothelin receptor antagonists, bisphosphonates, c
  • the treatments for renal disorders comprise treatments for kidney stones.
  • the compound of the present invention can be given with muscle relaxants that assist in stone passage, including alpha adrenergic blocking agents such as Flomax, Uroxatral, terazosin or doxazosin. Pain of stones can be treated with nonsteroidal antiinflammatories (NSAIDs) or opioids such as codeine or hydrocodone. NSAIDs and additional opioids are described herein.
  • NSAIDs nonsteroidal antiinflammatories
  • opioids such as codeine or hydrocodone. NSAIDs and additional opioids are described herein.
  • thiazides, potassium citrate, magnesium citrate and allopurinol are prescribed depending on the type of stone. For high urinary calcium, thiazides may be prescribed. For uric acid stones, allopurinol or other treatments for hyperuricemia can be used. Calgranulin may help prevent calcium oxalate kidney stone formation.
  • compositions and compounds of the invention may be administered by the usual routes and the dosage level depends upon the age, weight, conditions of the patient and the administration route.
  • the compositions and compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • agents described herein, where combinational therapy is employed do not have to be administered in the same pharmaceutical composition, and, because of different physical and chemical characteristics, are optionally administered by different routes.
  • the initial administration is generally made according to established protocols, and then, based upon the observed effects, the dosage, modes of administration and times of administration subsequently modified.
  • the active ingredients described above can be administered simultaneously or sequentially with a uric acid-binding polymer.
  • the ingredients can optionally be bound to the polymer, for example, by covalent bonding or a hydrolyzable bonding, or by physically encapsulating the ingredient, on the exterior or interior of the polymeric particle.
  • Covalent bonding can be accomplished by reacting the polymer and ingredient(s) with suitable cross-linking agents.
  • Therapeutically effective dosages vary when the drugs are used in treatment combinations.
  • Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • multiple therapeutic agents can be administered in any order, or even simultaneously. If simultaneously, the multiple therapeutic agents are optionally provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). In some embodiments, one of the therapeutic agents is given in multiple doses, or both are given as multiple doses.
  • the timing between the multiple doses optionally varies from more than zero weeks to less than four weeks.
  • the combination methods, compositions and formulations are not to be limited to the use of only two agents; the use of multiple therapeutic combinations are also envisioned (e.g., 2, 3, 4 or more combinations).
  • the dosage regimen to treat the condition(s) for which relief is sought is optionally modified in accordance with a variety of factors. These factors include the condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed varies widely, in some embodiments, and therefore deviates from the dosage regimens set forth herein.
  • the pharmaceutical agents which make up the combination therapy disclosed herein are optionally a combined dosage form (e.g., combined in the same formulation) or in separate dosage forms (e.g., two or more different formulations) intended for substantially simultaneous administration. Simultaneous administration can be by the same route or by different routes.
  • the pharmaceutical agents that make up the combination therapy can optionally be administered sequentially, with either therapeutic agent being administered by a regimen calling for multi-step administration.
  • the multi-step administration regimen optionally calls for sequential administration of the active agents or spaced-apart administration of the separate active agents.
  • sequential administration is meant a time difference of from seconds, minutes, hours or days between the two or more administration steps of the two or more active ingredients.
  • the two or more agents may be administered in any order.
  • the time period between the multiple administration steps may depend upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation of the target molecule concentrations are optionally used to determine the optimal dose interval.
  • a modulatory agent e.g., Tranilast
  • a modulatory agent is optionally used in combination with procedures that provide additional or synergistic benefit to the patient.
  • patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical compositions of a modulatory agent with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is correlated with a certain disease or condition.
  • compositions comprising two or more active ingredients (e.g., Tranilast and at least one other active ingredient) can be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition varies in some embodiments.
  • a composition comprising Tranilast and at least one other active ingredient can be used as a prophylactic and can be administered continuously to subjects at risk of developing a condition or disease (e.g., inflammatory bowel disease, myocardial infarction or an autoimmune disorder) in order to prevent the occurrence of the disease or condition.
  • a condition or disease e.g., inflammatory bowel disease, myocardial infarction or an autoimmune disorder
  • Said subjects may be asymptomatic.
  • compositions comprising two or more active ingredients can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • compositions comprising two or more active ingredients can be administered within the first 48 hours of the onset of the symptoms, hi some embodiments the compositions can be administered within the first 6 hours of the onset of the symptoms or within 3 hours after the onset of the symptoms.
  • the initial administration can be via any suitable route.
  • Compositions comprising two or more active ingredients as disclosed herein can be administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for any length of time necessary for the treatment of the disease.
  • Tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint, oil of wintergreen, or
  • a syrup or elixir may contain one or more active ingredients, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor, hi some embodiments, additional ingredients, for example, nonsteroidal anti-inflammatory drugs or colchicine, ingredients for treating other related indications, or inert substances such as artificial coloring agents are added.
  • active ingredients sucrose as a sweetening agent
  • methyl and propylparabens as preservatives
  • additional ingredients for example, nonsteroidal anti-inflammatory drugs or colchicine, ingredients for treating other related indications, or inert substances such as artificial coloring agents are added.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed, hi addition, the one or more active ingredients may be incorporated into sustained-release preparations and formulations as described herein.
  • compositions or modalities that can be combined with one or more compositions or methods of the invention are disclosed relevant portions of the following U.S. Patents or Patent Application Publications: Publication Nos. 2008/0221060; 2008/0249091; 2008/0233113; 2008/0200494; 2008/0114058; 2008/0076776; 2008/0038242; 2008/0188426; Patent Nos: 7,452,867; 7,361,671; 7,232,812; 7,186,695; 7,030,119; 6,500,459; and 6,815,464.
  • Additional active agents that can be selected for combination therapy according to the present invention include structurally or functionally related therapeutic agents to those disclosed herein, e.g., without limitation, prodrugs, analogs, homologs, derivatives, isomers, mimetics, metabolic derivatives, secondary metabolites, esters, or salt forms.
  • Analogs include compounds with substituted atoms or functional groups, transition state analogs or similar structure.
  • Isomers include, without limitation, stereoisomers, enantiomers, geometrical isomers, cis-trans isomers, conformers, rotamers, tautomers, topoisomers or constitutional (structural) isomers.
  • a structurally related compound could be a drug modified to improve pharmacological properties or processability.
  • a biological therapeutic agent for a biological therapeutic agent, this could comprise a related peptide or immunotoxin.
  • a monoclonal antibody might be used in a combination therapy of the present invention.
  • combination therapy according to the present invention further comprises the monoclonal antibody conjugated to one or more toxic agents.
  • antibody drug conjugates are well known in the art. See, e.g., U.S. Patent Publication No. 2008/0025989, filed April 13, 2007 and entitled "Anti-Cd70 Antibody-Drug Conjugates and Their Use for the Treatment of Cancer and Immune Disorders.” Further, the present invention envisions the use of a peptide mimetic.
  • compositions of the present invention may be administered once daily (QD), twice daily (BID), three times daily (TID) or four times per day (QID).
  • the pharmaceutical composition of the present invention, or the compound of formula II, or pharmaceutically acceptable salt thereof is administered once daily (QD).
  • pharmaceutical composition of the present invention, or the compound of formula II, or pharmaceutically acceptable salt thereof is administered twice daily (BID).
  • a common target of treatment of gout aims to relieve pain and inflammation of the acute attack, and reduce the incidence of recurrent attacks.
  • Dietary and pharmacological urate- lowering therapies principally aim to prevent or reverse uric acid crystal formation and clinical joint damage.
  • Common approaches to the treatment of acute gout include corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and colchicine. The side effects of these drugs, particularly in the frail, elderly population who experience the highest incidence of acute gout, can be serious.
  • An approach to the prevention of recurrent gout is the use of a xanthine oxidase inhibitor, allopurinol. However, allopurinol can have serious side effects such as allopurinol hypersensitivity syndrome. See, e.g., Arellano et al. (1993) Ann Pharmacother 27:337-343.
  • the compounds of the invention when used as a medicament, are useful in reducing uric acid in a subject, such as a mammal.
  • a mammal can include humans, primates, livestock animals (e.g., sheep, pigs, cattle, horses, donkeys), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), companion animals (e.g., dogs, cats) and captive wild animals (e.g., foxes, kangaroos, deer).
  • the mammal can be a human or a laboratory test animal. In some embodiments, the mammal is a human. Even in embodiments exemplified with respect to laboratory test animals, this should not be understood in any way as limiting the application of the present invention to humans.
  • the term "subject" as used herein can be a mammal.
  • the term “subject” refers to a human.
  • the human is a patient.
  • the subject is known to suffer from a hyperuricemic disorder.
  • the subject has uric acid crystal formation determined by aspiration of tophi or by aspiration of synovial fluid of an inflamed joint.
  • gouty conditions are determined by clinical criteria, e.g., podagra, tophi, or other joint pain and swellings, or an elevated serum uric acid level.
  • Radiography techniques may also help determine whether a patient suffers from hyperuricemia, e.g., by showing evidence of joint damage or uric acid crystal formation.
  • Such techniques include x-ray film, computed tomography (CT) scans, magnetic resonance imaging (MRI), DECT and ultrasound.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • DECT ultrasound.
  • the subject is known to suffer from gout, e.g., by one or more prior occurrences of gouty attack.
  • the subject has severe gout.
  • the subject has refractory gout wherein prior art treatments have proven insufficient to control disease.
  • the subject has chronic gout.
  • the methods of the present invention are used to treat a patient with acute gout, e.g., presenting with a first attack comprising podagra.
  • compositions of the invention are useful in controlling the level of uric acid and uric acid crystal formation in a subject suffering from gout and ameliorating symptoms related to a high level of uric acid and uric acid crystal formation such as muscle spasm, localized swelling, inflammation, joint pains, muscle fatigue, stress feelings, and myocardial infraction.
  • Crystal formation can be in one or more of the joints, under the skin, or in the kidneys. Some deposits may be so severe as to cause tophi.
  • Diseases associated with high levels of serum uric acid levels include, but are not limited to, gout, hyperuricemia, urinary lithiasis, hyperuricemic nephropathy, acute uric acid nephropathy and the like, especially gout and hyperuricemia.
  • an "effective amount” means an amount necessary at least partly to attain the desired response, or to delay the onset or inhibit progression or halt altogether, the onset or progression of a particular condition being treated.
  • the amount varies depending upon the health and physical condition of the subject to be treated, the taxonomic group of individual to be treated, the degree of protection desired, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
  • the effective amount may be adjusted when therapeutic agents are used in combination.
  • a compound provided by the present invention e.g., Tranilast, or a pharmaceutically acceptable salt thereof, may be used in combination with a xanthane oxidase inhibitor, e.g., allopurinol or febuxostat.
  • a xanthane oxidase inhibitor e.g., allopurinol or febuxostat.
  • the dose of one or more of the agents may be reduced to a level below the level required for a desired efficacy when the one or more agents are used alone.
  • treatment and prophylaxis are to be considered in its broadest context.
  • the term “treatment” does not necessarily imply that a subject is treated until total recovery.
  • “prophylaxis” does not necessarily mean that the subject will not eventually contract a disease condition.
  • treatment and prophylaxis can include amelioration of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.
  • the term “prophylaxis” may be considered as reducing the severity or onset of a particular condition.
  • Treatment may also reduce the severity of an existing condition.
  • treatment includes prophylaxis.
  • the methods of the present invention lower serum uric acid levels in a subject by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or more, as compared to serum uric acid levels in the subject prior to administering the methods of the present invention.
  • serum uric acid levels are decreased by at least between 5% to 50%, decreased by at least 25% to 75%, or decreased by at least 50% to 99%.
  • the methods of the present invention lower serum uric acid levels by 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0 mg/dL, or greater, as compared to serum uric acid levels in the subject prior to administering the methods of the present invention.
  • the methods of the present invention lower serum uric acid levels by between 0.1-10.0 mg/dL, 0.5-6.0 mg/dL, 1.0-4.0 mg/dL or 1.5-2.5 mg/dL.
  • the methods of the present invention are used to treat a patient diagnosed with hyperuricemia, ameliorate symptoms associated with hyperuricemia, or prevent the onset of hyperuricemia by lowering or maintaining serum uric acid levels in a subject below 7.0 or 6.5 or 6.0 mg/dL,or lower.
  • the methods are used to treat or prevent gout in a subject in need thereof.
  • the methods are used to reduce the severity or number of gouty attacks in a subject in need thereof.
  • the methods are used to reduce uric acid crystal formation in a subject in need thereof.
  • the methods may ameliorate gout by reducing serum uric acid levels to an acceptable level wherein gouty attacks are less frequent or do not occur.
  • the methods may ameliorate gouty symptoms by reducing serum uric acid levels to a level wherein adverse affects are no longer observed.
  • one or more other therapeutic agents are administered in combination with one or more pharmaceutical compositions of the invention or pharmaceutically acceptable salts thereof to treat hyperuricemia or the effects thereof, e.g., gout.
  • the one or more other therapeutic agents comprise a xanthine oxidase inhibitor.
  • the xanthine oxidase inhibitor is allopurinol, febuxostat, oxypurinol, tisopurine, or an inositol.
  • the one or more other therapeutic agents comprise a uricosuric agent.
  • the uricosuric agent is probenecid, benzbromarone, sulfinpyrazone, guaifenesin, losartan, atorvastatin, amlodipine, adrenocorticotropic hormone (ACTH or corticotropin), or fenofibrate.
  • the one or more other therapeutic agents comprise a uricase enzyme, or a fragment or pegylated derivative thereof.
  • the uricase enzyme is rasburicase or pegloticase.
  • the one or more other therapeutic agents comprise cortisone.
  • the one or more other therapeutic agents comprise an anti- inflammatory agent.
  • the anti-inflammatory agent is a nonsteroidal antiinflammatory drug (NSAID).
  • NSAID nonsteroidal antiinflammatory drug
  • the NSAID is diclofenac, indomethacin, naproxen, sulindac, lumiracoxib or a Cox-2 selective inhibitor.
  • the Cox-2 selective inhibitor is etoricoxib, celecoxib (SC-58635), 5-bromo-2-(4-fluorophenyi)-3- (4-(methylsufonyl)phenyl)-thiophene (DUP-697), flosulide (CGP-28238), meloxicam, 6- methoxy-2 naphthylacetic acid (6-MNA), MK-966 (Vioxx), nabumetone (6-MNA prodrug), nimesulide, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), SC-5766, SC-58215 , or 3 -Formylamino-7-methylsulfonylamino-6-phenoxy-4H- 1 -benzopyran- 1 -one (T-614).
  • the anti-inflammatory agent is a corticosteroid.
  • corticosteroid is methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-17-[(2-furanylcarbonyl)oxy]-l 1 ⁇ -hydroxy- 16 ⁇ - methyl-3-oxo-androsta-l,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro- l l ⁇ -hydroxy-l ⁇ -methyl-S-oxo- ⁇ .alpha.-propionyloxy-androsta-l ⁇ -diene- ⁇ -carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters, the 17-propionate ester or the 17,21-dipropionate ester, budesonide,
  • the one or more other therapeutic agents comprise Colchicine or a prodrug thereof.
  • the one or more other therapeutic agents comprise an opioid agent.
  • the opioid agent is morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine.
  • the one or more other therapeutic agents comprise an EL-I antagonist.
  • the IL-I antagonist is Canakinumab (ACZ885) or Rilonacept (Arcalyst).
  • the one or more other therapeutic agents comprise EL-6 or a fragment thereof.
  • the one or more other therapeutic agents comprise a therapeutic agent selected from Table 2.
  • the invention provides a method of treating hyperuricemia in a subject with gout comprising administering Tranilast to the subject in combination with one or more xanthine oxidase inhibitors or uricosuric agents.
  • the gout is refractory gout.
  • the Tranilast is administered in combination with allopurinol.
  • the allopurinol can be administered in, for example, 100 mg or 300 mg doses, or in an optimized dose for combination with the composition of the present invention.
  • a lower dose of allopurinol may be effective when combined with Tranilast.
  • the Tranilast is administered in combination with febuxostat.
  • the febuxostat can be administered in, for example, 40 mg or 80 mg or 120 mg doses, or in an optimized dose for combination with the composition of the present invention.
  • a lower dose of febuxostat may be effective when combined with Tranilast.
  • the compositions of the present invention can be used in combination with any of the therapeutic agents listed in Table 2 in a similar manner.
  • a combination comprises Tranilast, a xanthane oxidase inhibitor, e.g., allopurinol or febuxostat, and a compound useful for the treatment of cardiovascular disorders, e.g., a statin.
  • Tranilast a xanthane oxidase inhibitor
  • a compound useful for the treatment of cardiovascular disorders e.g., a statin.
  • the methods of the present invention are used to treat effects associated with hyperuricemia and gout.
  • the methods of the present invention are used to treat pain associated with inflammation attributable to flares associate with gout attacks.
  • a method is provided for treating inflammatory pain associated with gout, comprising administering Tranilast or a pharmaceutically acceptable salt thereof.
  • one or more other therapeutic agents are administered in combination with Tranilast or a pharmaceutically acceptable salt thereof.
  • a method is provided for treating inflammatory pain associated with gout, comprising administering one or more pharmaceutical compositions of the invention or pharmaceutically acceptable salts thereof.
  • Pain may be assessed using a measurement index.
  • Indices that are useful in the methods of the present invention for the measurement of pain associated with hyperuricemia and gout include a visual analog scale (VAS), a Likert scale, categorical pain scales, descriptors, and the AUSCAN index, each of which is well known in the art.
  • VAS visual analog scale
  • Likert scale categorical pain scales
  • descriptors categorical pain scales
  • AUSCAN index each of which is well known in the art.
  • a visual analog scale provides a measure of a one-dimensional quantity.
  • a VAS generally utilizes a representation of distance, such as a picture of a line with hash marks drawn at regular distance intervals, e.g., ten 1-cm intervals. For example, a patient can be asked to rank a sensation of pain by choosing the spot on the line that best corresponds to the sensation of pain, where one end of the line corresponds to "no pain" (score of 0 cm) and the other end of the line corresponds to "unbearable pain” (score of 10 cm). This procedure provides a simple and rapid approach to obtaining quantitative information about how the patient is experiencing pain.
  • VAS scales and their use are described, e.g., in U.S. Pat. Nos. 6,709,406 and 6,432,937.
  • a Likert scale similarly provides a measure of a one-dimensional quantity.
  • a Likert scale has discrete integer values ranging from a low value (e.g., 0, meaning no pain) to a high value (e.g., 7, meaning extreme pain).
  • a patient experiencing pain is asked to choose a number between the low value and the high value to represent the degree of pain experienced.
  • Likert scales and their use are described, e.g., in U.S. Pat. Nos. 6,623,040 and 6,766,319.
  • the AUSCAN (Australian-Canadian hand arthritis) index employs a valid, reliable, and responsive patient self-reported questionnaire. In one instance, this questionnaire contains 15 questions within three dimensions (Pain, 5 questions; Stiffness, 1 question; and Physical function, 9 questions).
  • An AUSCAN index may utilize, e.g., a Likert or a VAS scale.
  • Indices that are useful in the methods, compositions, and kits of the invention for the measurement of pain include the Pain Descriptor Scale (PDS), the Visual Analog Scale (VAS), the Verbal Descriptor Scales (VDS), the Numeric Pain Intensity Scale (NPIS), the Neuropathic Pain Scale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), the Present Pain Inventory (PPI), the Geriatric Pain Measure (GPM), the McGiIl Pain Questionnaire (MPQ), mean pain intensity (Descriptor Differential Scale), numeric pain scale (NPS) global evaluation score (GES) the Short-Form McGiIl Pain Questionnaire, the Minnesota Multiphasic Personality Inventory, the Pain Profile and Multidimensional Pain Inventory, the Child Heath Questionnaire, and the Child Assessment Questionnaire.
  • PDS Pain Descriptor Scale
  • VAS Visual Analog Scale
  • VDS Verbal Descriptor Scales
  • NPIS Numeric Pain Intensity Scale
  • NPS Neuropathic Pain Scale
  • the methods of the present invention are further useful for the treatment of inflammation and immune-related disorders.
  • the administration of conventional urate lowering therapies leads to uric acid crystal remodeling that may result in inflammatory attacks and increase in painful flares, e.g., gout flares, during treatment.
  • patients suffering from gout suffer from chronic low level inflammation and the presence of inflammatory immune markers even in the absence of gouty attacks, as described herein.
  • the compositions and methods of the present invention provide anti-inflammatory and immune modulatory capabilities and are useful for reducing serum uric acid levels and concomitantly treating one or more of inflammation, inflammatory immune response, and pain associated therewith.
  • a number of conditions are associated with hyperuricemia in addition to gout. These include a number of cardiovascular and renal complications.
  • the methods of the present invention are used to treat a renal disorder in a subject in need thereof. Renal disorders that can be treated with the methods of the invention include, but are not limited to, urinary lithiasis, hyperuricemic nephropathy, acute uric acid nephropathy, microalbuminuria, renal dysfunction, impaired glomerular filtration rate, and nephrolithiasis.
  • the methods of the present invention are used to treat kidney stones.
  • kidney stones may result directly from the deposition of uric acid, but may also result from the deposition of other materials, e.g., calcium oxalate or calcium phosphate, as sometimes observed in patients with hyperuricemia.
  • the methods of the present invention facilitate serum uric acid reduction in subjects suffering from renal insufficiency or chronic kidney disease.
  • treatments comprise administering a combination of a compound of the invention or pharmaceutically acceptable salt thereof and one or more therapeutic agents known to treat renal or urological disorders, including, but not limited to, a NO donor, a calcium channel blocker, a cholinergic modulator, an alpha-adrenergic receptor antagonist, a beta-adrenergic receptor agonist, a phosphodiesterase inhibitor, a cAMP-dependent protein kinase activator, a cAMP mimetic, a superoxide scavenger, a potassium channel activator, an estrogen-like compound, a testosterone-like compound, a benzodiazepine, an adrenergic nerve inhibitor, an antidiarrheal agent, a HMG-CoA reductase inhibitor, a smooth muscle relaxant, a adenosine receptor modulator, an adenylyl cyclase activator, an endothelin receptor antagonist, a bisphosphonate, a NO donor, a
  • the methods of the invention are used to treat a cardiovascular disorder in a subject.
  • Cardiovascular disorders that can be treated with the methods of the invention include, but are not limited to, hypertension, myocardial infraction, metabolic syndrome, ischemic cardiac disease, coronary artery disease, cerebrovascular disease, vascular dementia, preeclampsia, heart disease, stroke, atherogenesis, thrombogenesis, atheroscleorsis, inflammatory disease or peripheral, carotid, or coronary vascular disease.
  • the methods are useful for treating or preventing any disorder associated with hyperuricemia, e.g., metabolic syndrome, hyperlipidemia, insulin resistance, diabetes, and adverse effects of obesity.
  • treatments comprise administering a combination of a compound of the invention or pharmaceutically acceptable salt thereof and one or more therapeutic agents known to treat a cardiovascular disorder, diabetes, or obesity, or complications thereof, including, but not limited to, glitazone, troglitazone, rosiglitazone (Avandia), pioglitazone, a sulphonylurea, gliquidone, tolbutamide, glimepride, chlorpropamide, glipizide, glyburide, acetohexamide, meglitinide, repaglinide, nateglinide, metformin, an endothelin receptor antagonist, bosentan, darusentan, enrasentan, tezosentan, atrasentan, ambrisentan sitaxsentan, a smooth muscle relaxant, a PDE5 inhibitor, minoxidil, an angiotensin converting enzyme (ACE) inhibitor, captopril, enalapril, lis
  • ACE
  • the methods can further comprise measuring serum uric acid levels in the subject before and after the administering, wherein a decrease in serum uric acid levels after the administering indicates an effective treatment. For example, a decrease below about 6 mg/dL indicates lack of hyperuricemia. But any decrease might be beneficial to the patient, e.g., by lowering serum uric acid level below a level where uric acid crystals form. Other diagnostic approaches can be used with the present invention to indicate a beneficial treatment.
  • uric acid crystals as determined by aspiration, visible reduction of tophi, reduced or eliminated symptoms of gout, e.g., reduced inflammation or pain, as decreased uric acid in urine, as well as imaging of uric acid crystal burden.
  • One or more active ingredients are optionally used in the preparation of medicaments for the prophylactic and/or therapeutic treatment of hyperuricemic conditions (e.g., gout) or conditions that would benefit, at least in part, from amelioration.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing one or more active ingredients as described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • the administration of one or more active ingredients are optionally administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the administration of one or more active ingredients are optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the pharmaceutical composition described herein is in unit dosage forms suitable for single administration of precise dosages, e.g., about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1500 mg, or up to 2000 mg.
  • the formulation is divided into unit doses containing appropriate quantities of the one or more active ingredients.
  • the unit dosage is in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules, hi some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection are presented in unit dosage form, which include, but are not limited to ampoules, or in multi dose containers, with an added preservative.
  • the active ingredients and combinations thereof disclosed herein are contemplated to exhibit therapeutic activity when administered in an amount which can depend on the particular case.
  • the variation in amount can depend, for example, on the human or animal and the active ingredients chosen.
  • a broad range of doses can be applicable. Considering a subject, for example, from about 0.01 mg to about 2000 mg of a modulatory agent or active ingredient may be administered per day.
  • compounds of formula (I), formula (II), Tranilast or pharmaceutically acceptable salts thereof can be administered from about 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg to about 2000 mg of Tranilast per day.
  • the daily dosages appropriate for one or more active ingredients can be from about 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1500 mg, or up to 2000 mg per day.
  • the term "about" in the context of a particular measurement means 20% upward or downward of a number.
  • An indicated daily dosage in a larger mammal can be in the range from about 0.5 mg to about 5000 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other at suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation. Suitable unit dosage forms for oral administration can include from about 1 to 5000 mg active ingredient. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon.
  • Such dosages are optionally altered depending on a number of variables, not limited to the activity of the one or more active ingredients used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • the dose and dosing regimen may be adjusted when therapeutic agents are used in combination.
  • a composition provided by the present invention e.g., Tranilast or a pharmaceutically acceptable salt thereof, may be used in combination with a xanthane oxidase inhibitor, e.g., allopurinol or febuxostat.
  • a xanthane oxidase inhibitor e.g., allopurinol or febuxostat.
  • the dose of one or more of the agents may be reduced to a level below the level required for a desired efficacy when the one or more agents are used alone.
  • the dosing regimen may be modified, e.g., to synchronize the dosing of the one or more therapeutic agents to facilitate improved patient ease of use and compliance.
  • the dosing regimen of the one or more therapeutic agents can be sequential, e.g., to reduce the combined load of the agents at a given time.
  • Dose titration or dose escalation protocols may be employed to determine the proper or optimal dose to administer to a subject. For example, dose titration or escalation studies may select for doses that improve efficacy or tolerability. Dose titration or escalation allows for the gradual adjusting of the dose administered until the desired effect is achieved. Dose titration gradually decreased the dosage administered while dose escalation gradually increases the dose administered. Methods of dose titration and escalation are well known in the art. As a non-limiting example, a mammal may be administered 10 mg/day Tranilast every day and measured for serum uric acid levels on a daily basis. The dosage may be increased in increments of 5 mg/day on a weekly basis. The mammal may be monitored for a period of 12 weeks to find the desired dose.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures, experimental animals, or human studies, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50.
  • Active ingredients exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such active ingredients lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • Kits are contemplated for use herein.
  • a kit comprises a first dosage form comprising a pharmaceutical composition of the present invention, e.g., containing Tranilast, in quantities sufficient to carry out the methods of the present invention, e.g., decreasing serum uric acid level, treating or preventing hyperuricemia, reducing pain or inflammation associated with hyperuricemia, treating or preventing gout, treating gouty symptoms, reducing the severity or number of gouty attacks, preventing, reducing or reversing uric acid crystal formation, treating a renal disorder, treating kidney stones, or treating a cardiovascular disorder.
  • a pharmaceutical composition of the present invention e.g., containing Tranilast
  • kits are for a subject with a hyperuricemic disorder (e.g., gout) to use in the self-administration of the pharmaceutical composition, wherein the kit comprises a container housing a plurality of dosage forms and instructions for carrying out drug administration therewith.
  • a kit comprises a first dosage form comprising Tranilast in one or more of the forms identified above (e.g., a tablet, capsule, pill, delayed release formulation) and at least a second dosage form comprising one or more of the forms identified above, in quantities sufficient to carry out the methods of the present invention.
  • the second dosage form, and any additional dosage forms can comprise any active ingredient disclosed herein for the treatment of a hyperuricemic disorder (e.g., gout). All dosage forms together can comprise a therapeutically effective amount of each compound for the treatment of a hyperuricemic disorder (e.g., gout).
  • a kit is for a subject with a hyperuricemic disorder (e.g., gout) to use in the self-administration of at least one oral agent, wherein the kit comprises a container housing a plurality of said oral agents and instructions for carrying out drug administration therewith.
  • At least one oral agent can comprise a combination of a therapeutically effective dose of Tranilast and a therapeutically effective dose of one or more of the following agents selected from the list consisting of Benzbromarone (URINORM), Probenecid, Allopurinol, Febuxostat (Uloric®), Bucolome, Cinchophan and Colchicine, hi some embodiments a kit for use by a subject with a hyperuricemic disorder (e.g., gout) comprises at least one oral agent, a container housing a plurality of said oral agents and instructions for carrying out drug administration therewith, wherein said at least one oral agent comprises a combination of a therapeutically effective daily dose of Tranilast, or a pharmaceutically acceptable salt thereof and a daily dose of one or more of the following agents selected from the list consisting of Benzbromarone (URINORM), Probenecid, Allopurinol, Bucolome, Cinchophan and Colchicine.
  • Benzbromarone URINORM
  • Probenecid Probenecid
  • the one or more agents can be in distinct individual dosage forms or combined in a single dosage form or a combination of dosage forms thereof.
  • Tranilast, or a pharmaceutically acceptable salt thereof is in a distinct individual dosage form or combined in a single dosage form with one or more agents or a combination of dosage forms thereof.
  • the PRESTO (Prevention of Restenosis with Tranilast and its Outcomes) study was a multicenter study of ⁇ 11,500 patients undergoing percutaneous transluminal coronary revascularization (PTCR) with or without stenting for single or multiple vessels over a 9- month period.
  • the study compared the composite clinical event rate of death, myocardial infarction, or need for ischemia-driven target vessel revascularization in patients treated with Tranilast (300 and 450 mg twice daily) for 1 or 3 months versus placebo.
  • Gout was a contraindication for patient enrollment in the PRESTO trial. Nevertheless, 1100 patients enrolled in the trial were identified with baseline hyperuricemia defined as initial serum uric acid (sUA) levels greater than or equal to 7 mg/dL. Of these, approximately 300 participants had baseline serum uric acid levels greater than or equal to 8 mg/dL. In a prospective analysis of PRESTO data, serum uric acid levels were markedly decreased in patients treated with Tranilast.
  • FlG. 1 shows the effects of Tranilast on uric acid levels in the hyperuricemic patients having uric acid baseline levels greater than or equal to 8 mg/dL. Data for FlG. 1 are shown in Table 3. Table 4 shows the demographic characteristics of patient population for FlG. 1 and Table 4. As indicated in FlG. 1 and Table 4, some patients were treated with placebo, some patients were treated with Tranilast for 4 weeks followed by placebo, and some patients were treated with Tranilast for 12 weeks.
  • Study A3006GT was a phase 2, randomized, double-blind, 3-period, 3-treatment crossover trial. The primary objective was to compare the effects of three treatments on serum uric acid (sUA) levels in healthy subjects with a screening sUA level of at least 7.1 mg/dL. The three treatments were: 300 mg QD tranilast and 40 mg QD febuxostat (C); 300 mg QD tranilast alone (T); 40 mg QD febuxostat alone (F).
  • sUA serum uric acid
  • Table 9 displays the baseline sUA level for each subject, as well as the change and percent change from baseline at the end of the 1-week treatment period.
  • Table 9 displays the baseline sUA level for each subject, as well as the change and percent change from baseline at the end of the 1-week treatment period.
  • Subject 1001 completed only the first two periods of the study (C and F).
  • subject 1024 completed all three periods, this subject did not receive the assigned treatment in period 3 (F). Therefore, the period 3 data for subject 1024 are excluded from the analyses presented here.
  • Table 5 provides basic summary statistics (mean, standard deviation [SD], median, minimum, maximum) for the change from baseline and the percent change from baseline for each of the three treatments. For both the change from baseline and the percent change from baseline, the mean and median change in the combination group (C) is larger than the change in either group F or group T.
  • SD standard deviation
  • each of these three subsets was analyzed using all available data (regardless as to whether a subject provided data for all three periods of the study) and additionally using only those subjects who provided complete data for all three periods. Assessment of Subject-Specific Differences
  • x denote the 3x1 column vector of the estimated mean changes, ordered as (C F T), and let V denote the estimated variance-covariance matrix of x.
  • the variance of y is estimated by aVa', where a' denotes the transpose of a.
  • the p-value from the two-sided test that the mean difference is equal to zero and the two-sided 95% confidence interval for this difference was then computed using the appropriate t distribution. If the upper limit of this confidence interval is less than zero, then the mean change for C is assessed as being greater than the sum of the mean changes for F and T.
  • each of these three subsets was analyzed using all available data (regardless as to whether a subject provided data for all three periods of the study) and also using only those subjects who provided complete data for all three periods.
  • Table 6 displays the results for the comparisons between C and F, and between C and T. Comparisons between C and F, and between C and T
  • Table 7 displays the resulting p-values from the sign test and signed rank test for the change and percent change from baseline. In all analyses, the null hypothesis of equality of C and F+T is rejected.
  • Table 8 displays results based on the ANOVA models for both endpoints (change, percent change) using all available data and using only the data from subjects with complete data for all three periods of the study. For each analysis, the number of subjects and the total number of data values (number of observations) are first displayed. The estimated mean difference between C and F+T and the SD of this difference are also provided, as well as the p-value from the test of the null hypothesis that the mean difference between C and F+T is equal to zero. Finally, the 95% confidence interval (CI) for the difference is reported.
  • CI 95% confidence interval
  • the point estimates of the mean difference between C and F+T are negative, indicating that the mean change (or percent change) due to C is larger than the sum of the mean changes for F+T.
  • the 95% confidence interval for the estimated mean difference between C and F+T does not include zero, indicating that this difference is statistically significantly different from zero.
  • the study utilizes 3 dosing periods with each subject receiving all 3 treatments orally: 300 mg QD tranilast alone (T), 300 mg QD allopurinol alone (A), and the combination of 300 mg QD tranilast and 300 mg QD allopurinol (C).
  • Subjects are randomized in a 1:1:1 :1: 1:1 ratio to receive each of the 3 treatments in one of 6 possible sequences: TAC, TCA, ATC, ACT, CTA, or CAT. Each period is 14 days in duration with 7 consecutive days of active treatment (Days 1-7), followed by a 7-day drug-free washout interval (Days 8-14).
  • Subjects are screened for eligibility within 28 days before the start of dosing in Period 1. During each of the 3 periods, subjects check-in to the Clinical Study Unit (CSU) on the morning of Day -2 and will be domiciled until all study procedures are completed the morning of Day 8 (i.e., in the CSU for 9 full days and nights in each period, for a total of 27 full days and nights in the CSU to complete the study).
  • CSU Clinical Study Unit
  • baseline PD testing sUA and urinary uric acid [uUA]
  • Active treatment will occur on Days 1 - 7 of each period.
  • Blood samples for the determination of sUA are collected on each day of dosing.
  • Urine is collected over 24 hours, at timed intervals, to evaluate uric acid excretion and creatinine clearance at baseline of each period (Day -1), on the first day of dosing in each period (Day 1), and the last day of dosing in each period (Day 7). Blood samples for the determination of trough plasma levels of tranilast and/or allopurinol and its metabolite oxipurinol are obtained on Days 6, 7, and 8 of each dosing period.
  • Complete plasma concentration versus time profiles for the key PK measurements are evaluated over the 24-hour interval after the last dose(s) of tranilast and/or allopurinol/oxipurinol in each period, with samples collected at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, and 24 hours after the last dose of study drug on Day 7 of each period.
  • Safety laboratory testing including liver and renal function assessments
  • CRP C-reactive protein
  • a marker of inflammation are collected at screening, at baseline of each period (Day -1), the day after completion of dosing in each period (Day 8), and on Day 14 ( ⁇ 1 day) of Period 3.
  • a biochemistry panel is tested on Days 3 and 5 to monitor the liver and renal function.
  • the objective of this study was to evaluate the anti- inflammatory affects of tranilast versus a clinically active treatment for gout, colchicine, as well as a clinically active non-steroidal antiinflammatory drug, indomethacin.
  • This evaluation was carried out in male Sprague- Dawley rats in a rodent model of gout. The animals were injected subcutaneously with 20 ml of sterile air, followed three days later by a supplemental injection with 20 ml of sterile air.
  • the rats were injected intravenously with Evan's Blue and pretreated for thirty minutes with either a subcutaneous injection of colchicine (1 mg/kg) or indomethacin (5 mg/kg) or oral administration with either 200 mg/kg or 400 mg/kg of tranilast.
  • the rats were injected with 150 mg of monosodium urate (MSU) crystals (10 mg.ml) into the air pouch.
  • MSU monosodium urate
  • the air pouch was injected with 5 ml heparinized saline and the entire contents of the air pouch removed, recording the total volume. The air pouch contents were evaluated for plasma extravasation and total white blood cell (WBC) count.
  • WBC white blood cell
  • rats were weighed (Mettler, Model PE3000, SN: F69474) and sorted into six treatment groups often animals each, based upon average weight.
  • the animals were either dosed subcutaneously with 1 ml/kg colchicine or indomethacin, or orally with either 4 ml/kg or 8 ml/kg tranilast, or 8 ml/kg vehicle.
  • the rats were intravenously injected with 2 ml/kg Evans Blue.
  • the exudate collected from the MSU treated animals had an average OD 62 0 nm of 1.612 relative to 0.004 OD in the saline treated rats, indicative of plasma extravasation associated with the inflammatory cell infiltration of the air pouch in response to MSU challenge.
  • MSU challenge resulted in an 88% reduction in inflammatory cell infiltration associated with a 52% inhibition of plasma extravasation.
  • pretreatment with orally administered tranilast regardless of dose, was as effective as colchicine in reducing the plasma extravasation and as effective as indomethacin in preventing inflammatory cell infiltration of the air pouch in response to MSU challenge.
  • the objective of this study was to evaluate the anti-inflammatory potency of Tranilast. This evaluation was carried out in male Sprague-Dawley rats in a rodent model of gout. The animals were injected subcutaneously with 20 ml of sterile air, followed three days later by a supplemental injection with 20 ml of sterile air. Six days after the initial sterile air injection, the rats were injected intravenously with Evan's Blue and pretreated for thirty minutes with oral administration of 25 mg/kg, 50 mg/kg, 100 mg/kg or 200 mg/kg tranilast. After the pretreatment period, the rats were injected with 150 mg of monosodium urate (MSU) crystals (10 mg/ml) into the air pouch. Four hours later, the air pouch was injected with 5 ml heparinized saline and the entire contents of the air pouch removed, recording the total volume. The air pouch contents were evaluated for plasma extravasation and total white blood cell (WBC) count.
  • WBC white blood cell
  • the exudate collected from the MSU treated animals had an average OD 62 0 nm of 1.420 relative to -0.002 OD in the saline treated rats, indicative of plasma extravasation associated with the inflammatory cell infiltration of the air pouch in response to MSU challenge.
  • the objective of this study was to evaluate the anti-inflammatory potency of Tranilast. This evaluation was carried out in male Sprague-Dawley rats in a rodent model of gout. The animals were injected subcutaneously with 20 ml of sterile air, followed three days later by a supplemental injection with 20 ml of sterile air. Six days after the initial sterile air injection, the rats were injected intravenously with Evan's Blue and pretreated for thirty minutes with oral administration of 25 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, or 300 mg/kg tranilast.
  • the rats were injected with 150 mg of monosodium urate (MSU) crystals (10 mg/ml) into the air pouch.
  • MSU monosodium urate
  • the air pouch was injected with 5 ml heparinized saline and the entire contents of the air pouch removed, recording the total volume.
  • the air pouch contents were evaluated for plasma extravasation and total white blood cell (WBC) count.
  • WBC white blood cell
  • the exudate collected from the MSU treated animals had an average OD 620nm of 1.753 relative to 0.008 OD in the saline treated rats, indicative of plasma extravasation associated with the inflammatory cell infiltration of the air pouch in response to MSU challenge.
  • the objective of this study was to evaluate the anti-inflammatory potency of Tranilast. This evaluation was carried out in male Sprague-Dawley rats in a rodent model of gout. The animals were injected subcutaneously with 20 ml of sterile air, followed three days later by a supplemental injection with 20 ml of sterile air. Six days after the initial sterile air injection, the rats were injected intravenously with Evan's Blue and pretreated for thirty minutes with oral administration of 3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg, or 300 mg/kg tranilast.
  • the rats were injected with 150 mg of monosodium urate (MSU) crystals (10 mg/ml) into the air pouch.
  • MSU monosodium urate
  • the air pouch was injected with 5 ml heparinized saline and the entire contents of the air pouch removed, recording the total volume.
  • the air pouch contents were evaluated for plasma extravasation and total white blood cell (WBC) count.
  • WBC white blood cell

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Abstract

L'invention concerne une composition pharmaceutique qui comporte (a) un premier agent thérapeutique qui est un composé de la formule II ou un sel de qualité pharmaceutique de celui-ci, R1, R2, R3, R4, X et n étant tels que définis dans la description; (b) un second agent thérapeutique qui est un inhibiteur de la synthèse d'acide urique ou un agent uricosurique, et (c) un diluant ou un vecteur de qualité pharmaceutique.
PCT/US2009/068883 2008-12-19 2009-12-19 Compositions pharmaceutiques et procédés de traitement de l'hyperuricémie et des troubles associés Ceased WO2010071865A1 (fr)

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US12/882,143 US20110136835A1 (en) 2009-09-14 2010-09-14 Combination formulations of tranilast and allopurinol and methods related thereto

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US16511409P 2009-03-31 2009-03-31
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WO2017156270A1 (fr) * 2016-03-11 2017-09-14 Ardea Biosciences, Inc. Inhibiteurs du cxcr-2 permettant de traiter des troubles associés à une arthropathie cristalline
CN107206002A (zh) * 2015-01-30 2017-09-26 上海珊顿医药科技有限公司 尿酸性或痛风性疾病的预防或治疗
WO2018089808A1 (fr) 2016-11-11 2018-05-17 Horizon Pharma Rheumatology Llc Polythérapies de molécules de prednisone et d'uricase et leurs utilisations
US10183012B2 (en) 2007-11-27 2019-01-22 Ardea Biosciences, Inc. Compounds and compositions and methods of use
EP3417858A4 (fr) * 2016-02-19 2019-03-27 National University Corporation Tottori University Médicament thérapeutique ou prophylactique pour la démence
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US11598767B2 (en) 2009-06-25 2023-03-07 Horizon Therapeutics Usa, Inc. Methods and kits for predicting infusion reaction risk and antibody-mediated loss of response by monitoring serum uric acid during pegylated uricase therapy
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CN118512454A (zh) * 2024-06-06 2024-08-20 中国药科大学 纳曲酮在制备治疗高尿酸血症药物中的应用
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