CN109908124A

CN109908124A - Utilize the method for hyperuricemia in Halofenate or HALOFENIC ACID and the second uric acid depressant treatment patient with gout

Info

Publication number: CN109908124A
Application number: CN201910004813.0A
Authority: CN
Inventors: 布赖恩·K·罗伯茨; 戈帕尔·钱德拉·萨哈; 布赖恩·爱德华·拉万; 查尔斯·A·麦克沃特
Original assignee: Dyer Tex Ltd By Share Ltd; Shellfish Pharmaceuticals Of Sigma
Current assignee: Dyer Tex Ltd By Share Ltd; Shellfish Pharmaceuticals Of Sigma
Priority date: 2011-11-04
Filing date: 2011-11-04
Publication date: 2019-06-21
Also published as: AU2011380507B2; EP2773336A4; MX2014005400A; JP6202633B2; CA2859686A1; IL232386A0; ZA201403575B; KR20140121383A; SG11201402032RA; CL2014001155A1; EP2773336A1; NZ624708A; AU2011380507A1; WO2013066349A1; CA2859686C; JP2014532758A; CN104066427A; MX357507B

Abstract

This application involves the methods using hyperuricemia in Halofenate or HALOFENIC ACID and the second uric acid depressant treatment patient with gout.Specifically, disclosed herein is for reducing subject serum uric acid level and for treat with pharmaceutical composition, method and the kit of raised serum uric acid level associated disease, including giving the composition comprising the first uric acid depressant and the second uric acid depressant.In some respects, the first uric acid depressant is (-)-Halofenate, (-)-HALOFENIC ACID or its pharmaceutical salts.In some respects, the second uric acid depressant is inhibitor, uricosuric agent, uricase or its pharmaceutical salts that uric acid generates.

Description

Utilize height in Halofenate or HALOFENIC ACID and the second uric acid depressant treatment patient with gout The method of uricacidemia

The application is " to be dropped using Halofenate or HALOFENIC ACID and the second uric acid for the entitled of on November 04th, 2011 applying date The divisional application of the Chinese Patent Application No. 201180076191.4 of the method for hyperuricemia in low dose for the treatment of patient with gout ".

Background technique

Illness (hyperuricemia) relevant to raised serum uric acid level include the illness of urate crystals deposition such as Gouty arthropathy and tophus, uriasis (lithangiuria), the sequelae of urate nephropathy and these diseases.High lithemia Mass formed by blood stasis to develop the increased risk of gouty arthropathy it is related, and the risk of gout with hyperuricemia degree and persistently Time and increase.In addition to gouty arthropathy, chronic hyperuricemia can cause uric acid crystal the urinary tract, kidney essence, It is deposited in soft tissue, to lead to uriasis, the urate nephropathy with chronic kidney disease and soft tissue tophus respectively.By In the limitation and disadvantage of current uric acid depressant, thus more effective way, composition and therapy are needed to reduce uric acid.

Summary of the invention

This application describes reduce hyperuricemia subject serum uric acid level method, this method include give by The first uric acid of examination person depressant (urate-lowering agent) and the second uric acid depressant, wherein the first uric acid depressant is The compound or pharmaceutically acceptable salt thereof of formula (I)

Wherein R is selected from the group being made of the following terms: hydroxyl, rudimentary aralkoxy, the rudimentary alcoxyl of two elementary alkyl amido- Base, lower al-kanoylamino-lower alkoxy, benzamido-lower alkoxy, urea groups-lower alkoxy, N '-low alkyl group- The substituted lower alkoxy of urea groups-lower alkoxy, carbamoyl-lower alkoxy, halogenated phenoxy-, carbamoyl- Substituted phenoxy group, carbonyl-loweralkyl amino, N, N- two elementary alkyl amido-low-grade alkyl amino, halogen replace rudimentary Low-grade alkyl amino that alkyl amino, hydroxyl replace, the substituted low-grade alkyl amino of lower alkyl alcohol radical oxygroup-, urea groups and rudimentary Alkoxycarbonyl amino；And each X is independently halogen.

The method of subject of the treatment with hyperuricemia associated disease is also disclosed, this method includes giving subject First uric acid depressant and the second uric acid depressant, wherein the first uric acid depressant is the compound of formula (I).Also disclose treatment The method of hyperuricemia in gout subject, including giving subject includes the first uric acid depressant and the second uric acid depressant Composition, wherein the first uric acid depressant is the compound of formula (I).

Composition and kit comprising the first uric acid depressant and the second uric acid depressant are also disclosed, wherein the first urine Sour depressant is the compound of formula (I).

In some respects, the compound of formula (I) is (-)-Halofenate (halophenol ester, halofenate), (-)-HALOFENIC ACID (halogen Phenolic acid, halofenic acid) or its pharmaceutical salts.In some respects, the second uric acid depressant is that xanthine oxidase inhibits Inhibitor, uricosuric agent or the uricase that agent, uric acid generate.In some respects, the second uric acid depressant be allopurinol or Febuxostat (febuxostat).Provided hereinafter other aspects.

Serum uric acid is reduced to desired by the other therapeutic agents being currently available that in uric acid depressant and exploitation at them There is limitation, and their application can be limited to various undesirable side effects or toxicity in terms of horizontal ability.For example, Certain medicaments (including allopurinol and Febuxostat), when being used to treat hyperuricemia with common prescribed dose, often not It is the common therapeutic purpose of 6mg/dL or lower that serum uric acid level, which can be reached,.Compared to be currently available that uric acid depressant (with Common prescribed dose) and using above-mentioned medicament treatment method, the advantages of compositions disclosed herein, method and kit, can To include improved treatment benefit；(that is, compared to the effect of single agenttherapy, there is addition effect to the synergistic effect for reducing uric acid Answer or surpass additive effect)；For the Beneficial Effect of hyperuricemia and the relevant other illnesss of urate crystals deposition；And draw Send out less or less strong side effect.In some respects, uric acid is currently available that relative to what is individually used with prescribed dose Depressant, synergistic effect acceptable dose is reduced or dosing interval extends.

Specific embodiment

Such as according to used in the present invention, unless otherwise specified, following term is interpreted as having following meanings:

Unless otherwise indicated, when limiting quantity, " about " refers to positive and negative 10 range of the value or quantity.Not In the case where the application for limiting the doctrine of equivalents about scope of the claims, each number should be taken into account that such factor is solved It releases, reports the number of effective digital and such as obtaining the mode of the number or method (such as detection instrument, sample preparation Deng).

" giving " or " administration " refers to the behavior that drug, prodrug or therapeutic agent are given to subject.It is discussed below exemplary Give approach.

" acute gout " refers to such gout, be present in have at least one gout symptom (for example, podagra or its His urarthritis, gout acute attack, gout breaking-out) subject in.

" fragrant Halofenate (arhalofenate) " refers to (-)-Halofenate, i.e. (-)-(R)-(the chloro- phenyl of 4-)-(3- trifluoro Methyl-phenoxv)-acetic acid 2- acetylaminohydroxyphenylarsonic acid ethyl ester.

" chronic gout " refers to such gout, is present in recurrent or the acute attack of persistence gout, gout In the subject of stone formation, chronic inflammatory arthritis or degenerative joint relevant to gout, and including extensive from acute gout Period after multiple and in the period of between gouty attack,acute (i.e. gout interictal).

" composition " or, interchangeably, " preparation " refers to preparation, it includes the mixing of various excipient and key component Object, provide compound or drug it is metastable, it is desirable that and useful form.

Prefix " d " and " l " or (+) and (-) are used to refer to the symbol of compound Plane of rotation polarised light, wherein (+) or d- Mean that compound is " dextrorotation " and (-) or l- mean that compound is " left-handed ".For given chemical structure, these Isomers or " optical isomer " they are identical, the difference is that, they are mirror image each other.In description optically-active compound When, prefix R and S are used to indicate absolute configuration of the molecule about its chiral centre.For absolute stereochemistry and for mapping Correlation (that is, R- isomers is also possible to l- isomers) is not present between the term of the rotation of body.Specific optical isomer The mixture for being referred to as " enantiomer " and above-mentioned isomers is frequently referred to as " enantiomer " or " racemic " mixture.Ginseng See, for example, A.Streitwiesser , &C.H.Heathcock, INTRODUCTION TO ORGANIC CHEMISTRY, 2^nd Edition,Chapter 7(MacMillan Publishing Co.,U.S.A.1981).(-)-Halofenate is measured in methyl alcohol Optical activity [α]_D。

" raised serum uric acid level " refers to the serum uric acid level greater than normal level, and, in patient with gout, Typically refer to the serum uric acid level greater than or equal to about 6mg/dL.In some cases, raised serum uric acid level is higher than Average level in given group, such as has those of particular sex or age.

" effective quantity " refers to amount required for the following terms: (i) at least partly obtains desired sound in subject It answers；(ii) postpone or prevent the breaking-out of particular condition to be treated in subject；Or (iii) inhibits or prevents in subject The progress of particular condition to be treated.Effective quantity for particular subject is variation, this depends on subject's to be treated Health and physical condition, the sorting group of individual to be treated, desired degree of protection, the formula of composition, medical conditions are commented Estimate and other correlative factors.Wish the amount fall in can by routine test determine relatively wide range in.

" the first uric acid depressant " refers to acceptable on the compound or its treatment of formula (I), (II), (III) or (IV) Salt or prodrug.

" gout " refer to most frequently with due to uric acid excessive production or kidney excretion uric acid ability reduce caused by uric acid Gather relevant one group of disease or symptom.The characteristics of gout often urate crystals (uric acid or its salt, such as monosodium urate) It is deposited on joint (gouty arthropathy) or soft tissue (tophus).As used in this article, " gout " includes acute pain Wind, chronic gout, moderate gout, intractable gout and severe gout.

" gout correlation inflammation " refers to due to caused by the immune response to urate crystals deposition locally or systemically Inflammation.

" Halofenate " refers to the compound of formula (III), i.e. (4- chlorphenyl)-(3- 4-trifluoromethylphenopendant)-acetic acid 2- second Acylamino- ethyl ester (the 2- acetylamino ethyl ester for being also known as 4- chlorphenyl-(3- 4-trifluoromethylphenopendant)-acetic acid).Unless otherwise Regulation, term Halofenate and corresponding chemical name include (+) and (-) enantiomer of formula (III) compound and mixing for theirs Close object.

" HALOFENIC ACID " and " CPTA " refers to the compound of formula (IV), i.e. 4- chlorphenyl-(3- 4-trifluoromethylphenopendant)-acetic acid [being also known as 2- (4- chlorphenyl) -2- (3- (trifluoromethyl) phenoxy group) acetic acid] and its pharmaceutical salts.Unless otherwise prescribed, art Language HALOFENIC ACID and corresponding chemical name include (+) and (-) enantiomer and their mixture of formula (II) compound.

" hyperuricemia " refers to raised serum uric acid level (seeing above).

When being used to describe the chemical substituents of formula (I) and the compound of (II), " rudimentary ", such as rudimentary aralkoxy, two Lower alkylamino-lower alkoxy, lower al-kanoylamino, lower alkoxy, benzamido-lower alkoxy, urea groups-are low Grade alkoxy, N '-low alkyl group-urea groups-lower alkoxy, carbamoyl-lower alkoxy, halogenated phenoxy replace low Grade alkoxy, carbonyl-loweralkyl amino, N, the low alkyl group that N- two elementary alkyl amido-low-grade alkyl amino, halogen replace Low-grade alkyl amino, the elementary alkoxy carbonyl ammonia of low-grade alkyl amino, the substitution of lower alkyl alcohol radical oxygroup that amino, hydroxyl replace Base, phenyl-lower alkyl group, lower al-kanoylamino-low alkyl group and benzamido-low alkyl group, refer to 1 to 6 carbon The group of atom.For example, " lower alkoxy " refers to C_1-6Alkoxy.

" moderate gout " refers to such gout, and being present in had the acute hair of gout at least twice in 12 middle of the month of past In the subject of work.

" pharmaceutically acceptable " referring to can be used for prepares those of pharmaceutical composition, be usually safe and nontoxic, simultaneously And neither biologically nor undesirable in other respects, and including animal doctor or human pharmaceutical use it is acceptable that A bit.

" pharmaceutical salts " include medicinal acid addition salt and medicinal basic formula addition salts and including solvation and non-solvated shape Formula.The representative non-limiting list of pharmaceutical salts may refer to S.M.Berge et al., J.Pharma Sci., 66 (1), 1-19 (1977) and Remington:The Science and Practice of Pharmacy, R.Hendrickson, ed.,21st edition,Lippincott,Williams&Wilkins,Philadelphia,PA,(2005),at p.732, Table 38-5, the two are incorporated into herein by reference.

" medicinal acid addition salt " refer to inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid), and and have Machine acid (such as acetic acid, trifluoroacetic acid, propionic acid, glycolic, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, winestone Acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc.) formed salt.

" medicinal basic formula addition salts " refer to the salt prepared and inorganic base or organic base are added to free acid.It is derived from The salt of inorganic base includes but is not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt Deng.Salt derived from organic base includes but is not limited to the salt of following substance: primary amine, secondary amine and tertiary amine, substituted amine, including day So existing amine replaced, cyclammonium and deacidite, as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA), Ethanol amine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, Procaine, Hai Baming, choline, glycine betaine, ethylenediamine, aminoglucose, methylglucosamine, theobromine, purines, piperazine, piperidines, N-ethylpiperidine, polyamines resin etc..

" intractable gout " refers to the gout of patient, wherein giving (1) one or more second uric acid depressants but not having There are the first uric acid depressant or (2) first uric acid depressants but that after the second uric acid depressant, which is not unresponsive Or reaction it is poor, undergone or in experience adverse events increase risk.In this context, term is " reactionless " and " reacting poor " include (1) serum uric acid without or indistinctively reduce, (2) fail to reach target serum uric acid water Flat (such as determined by doctor or other practitioners), and (3) one or more gouty illnesss or symptom are lasting Property, such as gout acute attack, tophus, urarthritis or other associated diseases, but regardless of any of serum uric acid level It reduces.

" the second uric acid depressant " refers to reduction serum uric acid level, and is not the therapeutic agent of the first uric acid depressant.The Two uric acid depressants include being currently available that the medicament for reducing serum uric acid (that is, ending to the submission date of the application, by FDA Or the medicament of other regulatory agencies appropriate approvals), and at present in exploitation or compound in the case where supervision examines.Hereafter mention For the example of the second uric acid depressant.

" subject " and " patient " refers to animal such as mammal, including the mankind, other primates, raising animal (such as Dog, cat), farm-animals (such as horse, ox, goat, sheep, pig), rat and mouse.

" severe gout " refers to the gout present in subject, which has pain in joint, skin or kidney Wind stone deposition, it is bad so as to cause chornic arthritis, destruction of joint, subcutaneous tophus or renal function, and, in some cases Under, there is subsequent deformation and/or deformity.

When for referring to (-)-Halofenate or (-)-HALOFENIC ACID (or its salt) is substantially free of corresponding (+) enantiomer When (that is, (+)-Halofenate, (+)-HALOFENIC ACID or its salt), " substantially free of " refers to such composition, right relative to (+) Body is reflected, it includes (-) enantiomers of a high proportion of compound.In one embodiment, which refers to, by weight, packet It is at least 85% (-) enantiomer and at most 15% (+) enantiomer containing compound in the composition.In one embodiment, The term refers to, by weight, is at least 90% (-) enantiomer comprising compound in the composition and at most 10% (+) is right Reflect body.In other embodiments, which refers to, is at least 91% (-) comprising compound in the composition by weight Enantiomer and at most 9% (+) enantiomer, at least 92% (-) enantiomer and at most 8% (+) enantiomer, the mapping of at least 93% (-) Body and at most 7% (+) enantiomer, at least 94% (-) enantiomer and at most 6% (+) enantiomer, at least 95% (-) enantiomer and At most 5% (+) enantiomer, at least 96% (-) enantiomer and at most 4% (+) enantiomer, at least 97% (-) enantiomer and at most 3% (+) enantiomer, at least 98% (-) enantiomer and at most 2% (+) enantiomer, or at least 99% (-) enantiomer are greater than 99% (-) enantiomer.(-) and (+) enantiomer of other percentages can also be provided.These percentages are based on relative in group Close the amount of the enantiomer of the total amount of two kinds of enantiomers of compound in object.

" treatment effective dose ", " therapeutically effective amount " or interchangeably, " pharmaceutically acceptable dosage " and " pharmaceutically Acceptable amount " refers to, the therapeutic agent, a variety of therapeutic agents or its metabolin of sufficient amount will be present, to realize desired knot Fruit, for example, uric acid level is reduced to target level or the various forms of gouts for the treatment of or the relevant disease for the treatment of hyperuricemia Disease.

" treatment " and " treatment " disease, disorder, illness or symptom refer to (1) prevention or reduce develop disease, disorder or The risk of illness, that is, can be exposed to or susceptible disease, disorder or illness but still without undergo or display disease, disorder or The clinical symptoms of disease, disorder or illness are made not develop and (prevent) in the subject of the symptom of illness；(2) inhibit disease, disorderly Unrest or illness, that is, prevent or reduce disease, disorder or the development of illness or its clinical symptoms；And (3) alleviate disease, disorder Or illness, that is, make disease, disorder or illness subside, reverse or improve, or reduce the number of its clinical symptoms, frequency, continue Time or severity.Term " processing " can synonymously be used.

" lithate " refers to uric acid (- 2,6,8 (3H)-triketone of 7,9- dihydro -1H- purine) and its ion and salt.

This application describes for treating hyperuricemia, that is, composition, kit for reducing serum uric acid level And method.One aspect of the present invention is related to the composition comprising the first uric acid depressant and the second uric acid depressant, wherein institute State the compound or pharmaceutically acceptable salt thereof that the first uric acid depressant is formula (I)

Wherein R is selected from the group being made of the following terms: hydroxyl, rudimentary aralkoxy, the rudimentary alcoxyl of two elementary alkyl amido- Base, lower al-kanoylamino-lower alkoxy, benzamido-lower alkoxy, urea groups-lower alkoxy, N '-low alkyl group- Lower alkoxy, the carbamoyl that urea groups-lower alkoxy, carbamoyl-lower alkoxy, halogenated phenoxy replace take Phenoxy group, the carbonyl-loweralkyl amino, N in generation, the lower alkyl that N- two elementary alkyl amido-low-grade alkyl amino, halogen replace Low-grade alkyl amino, urea groups and the lower alkyl of low-grade alkyl amino, the substitution of lower alkyl alcohol radical oxygroup that base amino, hydroxyl replace Epoxide carbonyl amino；And each X is independently halogen.

In some aspects, the first uric acid depressant is the compound or pharmaceutically acceptable salt thereof of formula (II)

Wherein R²Selected from the group being made of the following terms: phenyl-lower alkyl group, lower al-kanoylamino-low alkyl group and benzene Formamido group-low alkyl group；And each X is independently halogen.

In other respects, the first uric acid depressant is the compound of formula (III), is also known as Halofenate

Or its pharmaceutical salts.

In other respects, the first uric acid depressant is the compound of formula (IV), is also known as HALOFENIC ACID

Or its pharmaceutical salts.

It should also be noted that having any carbon atom for not meeting chemical valence hypothesis to make in formula and example herein Meet chemical valence with hydrogen atom.

In some embodiments, compound is such compound, and after giving, after chemical reaction is generated The compound or pharmaceutically acceptable salt thereof of formula (IV), as discussed in more detail below.

Another aspect provides for treat with the method for raised serum uric acid level associated disease, including give need Its subject's pharmaceutical composition is wanted, the composition includes the first uric acid depressant, wherein the first uric acid depressant is formula (I), the compound or pharmaceutically acceptable salt thereof of (II), (III) or (IV)；And the second uric acid depressant.Another aspect provides with In the method for reducing serum uric acid level in subject, its subject's pharmaceutical composition, the composition packet are needed including giving Containing the first uric acid depressant, wherein the first uric acid depressant is the compound or its medicine of formula (I), (II), (III) or (IV) Use salt；And the second uric acid depressant.

In some embodiments, the first uric acid depressant is (-)-Halofenate (i.e. (-)-(R)-(the chloro- phenyl of 4-)-(3- Tri fluoromethy I-phenoxy)-acetic acid 2- acetylaminohydroxyphenylarsonic acid ethyl ester, it is also known as fragrant Halofenate).In other embodiments, first Uric acid depressant is (-)-HALOFENIC ACID (i.e. (-) -4- chlorphenyl-(3- 4-trifluoromethylphenopendant) acetic acid) or its pharmaceutical salts.At certain In a little embodiments, (-)-Halofenate, (-)-HALOFENIC ACID or its pharmaceutical salts are substantially free of corresponding (+) enantiomer.

In the process, in the conceived case, by using the reactant or reagent or catalyst of single enantiomer form, Or by conventional method (including microbial resolution is used, split the diastereoisomeric salt formed with chiral acid or chiral base, Yi Jili With the chromatography of chiral support) by the mixture of fractionation stereoisomer, formula (I), (II), (III) or (IV) can be prepared and changed Close the enantiomer (stereoisomer) and its pharmaceutical salts of object.See also U.S. Patent number 7,199,259 (Daugs), United States Patent (USP) Number 6,646,004,6,624,194,6,613,802 and 6,262,118 (all authorizing Luskey et al.), U.S. Patent number 7, 714,131 (Zhu et al.), U.S. Patent number 7,432,394 (Cheng et al.) and US publication 2010/0093854 (Broggini et al.), respective full content are incorporated into herein by reference.

It can also method by being described in U.S. Patent number 3,517,050 (its instruct is incorporated by reference herein) Come carry out (3- trihalomethyl group phenoxy group) (4- halogenophenyl) acetogenin racemic mixture chemical synthesis.It utilizes Usual manner that is known to those skilled in the art and using can be obtained single by splitting the racemic mixture of enantiomer Enantiomer.See, e.g., Jaques, J., et al., in Enantiomers, Racemates, and Resolutions, John Wiley and Sons,New York(1981).Other marks of fractionation well known by persons skilled in the art can also be used Quasi- method, including but not limited to simple crystallization and chromatographic resolution are (see, e.g., Stereochemistry of Carbon Compounds(1962)E.L.Eliel,McGraw Hill；J.Lochmuller,Chromatography,113,283-302 (1975)).It is split in addition, being catalyzed by enzymatic living beings, Halofenate, HALOFENIC ACID or its pharmaceutical salts, that is, optically pure isomer, it can To be prepared by racemic mixture.Enzymatic living beings catalysis has previously been generally described to split (see, e.g., U.S. Patent number 5,057,427 and 5,077,217, the disclosure of which is incorporated into herein by reference).For obtain enantiomer other are general Method includes stereoselective syntheses (see, e.g., A.J.Li et al., Pharm.Sci.86,1073-77 (1997).

It is composition that a kind of embodiment, which provides the pharmaceutical salts comprising Halofenate or HALOFENIC ACID,.By make salt contact alkali or Acid simultaneously separates parent therapeutic agent (in a usual manner), can be with the neutral form of regenerative therapy agent.In terms of certain physical properties, such as The parent fo of dissolubility in polar solvent, therapeutic agent is different from various salt forms, but in other respects, salt is equivalent to mother Body form.

It (is not the reduction of the first uric acid that second uric acid depressant, which can be and reduce any other medicament of serum uric acid level, Agent, as defined herein).These the second uric acid depressants include inhibitor (such as the xanthine oxidase that uric acid generates Inhibitor and purine nucleoside phosphorylase inhibitor), uricosuric agent and uricase.

For example, in some embodiments, the second uric acid depressant is xanthine oxidase inhibitor.By reducing uric acid Synthesis, xanthine oxidase inhibitor reduce uric acid in blood salt amount.Xanthine oxidase is related to purine metabolism and inhibits Enzyme reduces uric acid level.Xanthine oxidase inhibitor includes but is not limited to: allopurinol, Febuxostat, oxipurinol, mercapto are different Purine, inositol and propolis.In some embodiments, xanthine oxidase inhibitor is that allopurinol, Febuxostat, former times difficult to understand are fast Alcohol, Tisopurine, bios Ⅰ, phytic acid, inositol, keampferol, myricetin 4 and Quercetin.Allopurinol (1,5- dihydro -4H- Pyrazolo [3,4-d] pyrimidin-4-one), a kind of xanthine oxidase inhibitor is the mesh for reducing the nursing of uric acid salt level Preceding first line standard.Another xanthine oxidase inhibitor, Febuxostat (2- (3- cyano-4-isobutoxy phenyl) -4- first Base -1,3-thiazoles -5- carboxylic acid), treatment gout is approved in February, 2009.In one embodiment, it is giving not Before purine alcohol, subsequently or simultaneously give Halofenate, HALOFENIC ACID or its pharmaceutical salts.In one embodiment, non-cloth is being given Before sotan, subsequently or simultaneously give Halofenate, HALOFENIC ACID or its pharmaceutical salts.

In other embodiments, the second uric acid depressant is purine nucleoside phosphorylase (PNP) inhibitor.Purine nucleosides Phosphorglase inhibitor is relatively new method, is used to reduce the blood in hyperuricemia, gout and associated disease patient Clear uric acid level.In some embodiments, PNP inhibitor is Forodesine (BCX-1777) (BioCryst Pharmaceuticals,Inc.).In other embodiments, PNP inhibitor is BCX-4208 (7- (((3R, 4R) -3- hydroxyl Base -4- (methylol) pyrrolidin-1-yl) methyl) -3H- pyrrolo- [3,2-d] pyrimidine -4 (5H) -one) (BioCryst Pharmaceuticals,Inc.).The BCX4208 monotherapy given with 40,80,120,160 and 240mg/ days has shown that Reduce the serum uric acid of patient with gout rapidly and significant out.

In some embodiments, the second uric acid depressant is uricosuric agent.Uricosuric agent can enhance the kidney of uric acid It drains and is usually played a role by reducing from Renal proximal tubular absorption uric acid back to blood, for example, by inhibiting urine Hydrochlorate transport protein, such as SLC22A12.Uricosuric agent includes but is not limited to probenecid, 2- ((5- bromo- 4- (4- cyclopropyl Naphthalene -1- base) -4H-1,2,4- triazole -3- bases) thio) acetic acid (RDEA594, lesinurad), 4- (2- ((5- bromo- 4- (4- ring Propyl naphthalene -1- base) -4H-1,2,4- triazole -3- base) it is thio) acetylamino) -3- chlorobenzoic acid potassium (RDEA806), RDEA684, Benzbromarone, Sulfinpyrazone, Amlodipine, Atorvastatin, fenofibrate, gualfenesin, Losartan, corticotrophins Element and cortisone.In the U.S., probenecid is most common uricosuric agent, and can be given in conjunction with allopurinol Patient with gout.Benzbromarone and Sulfinpyrazone also serve as a line uricosuric agent.Gualfenesin, Losartan, Atorvastatin, ammonia Also there is uricosuric to urinate effect for Flordipine, corticotropin (ACTH or corticotropin), fenofibrate and cortisone. In one embodiment, the first uric acid depressant (such as (-)-halogen is given before giving uricosuric agent, subsequently or simultaneously Fragrant ester, (-)-HALOFENIC ACID or its pharmaceutical salts).In one embodiment, give probenecid, Benzbromarone or Sulfinpyrazone it Before, subsequently or simultaneously give the first uric acid depressant (such as (-)-Halofenate, (-)-HALOFENIC ACID or its pharmaceutical salts).

In some embodiments, the second uric acid depressant is uricase or its segment or polyethylene glycol derivative.? Uricase or urate oxidase are found in many mammals but not in the mankind.They can be by being converted to allantois for uric acid Element, a kind of benign whole metabolite (it is easy to be discharged in urine) reduce uric acid level.Uricase includes but is not limited to granny rag Vertical enzyme or Pegylation uricase (PEG- uricase).In some embodiments, Pegylation uricase is(Pegloticase) (Savient Pharmaceuticals, Inc.), in beauty State is approved for the chronic gout in the refractory adult patients for the treatment of routine treatment.

The present invention also provides for treat it is relevant to raised serum uric acid level (i.e. hyperuricemia) one kind or The method of various diseases, this method include giving the subject's pharmaceutical composition for needing it, and the composition is dropped comprising the first uric acid Low dose, wherein the first uric acid depressant is the compound or pharmaceutically acceptable salt thereof of formula (I), (II), (III) or (IV)；And the Two uric acid depressants.Illness relevant to hyperuricemia includes but is not limited to gout；Acute gout；Chronic gout；Moderate pain Wind；Intractable gout；Severe gout；Deposition of the uric acid crystal in the urinary tract, kidney essence, soft tissue, joint, cartilage or bone； Uriasis；Urate nephropathy；Tophus；Podagra；Acute inflammatory urarthritis；Destruction of joint；Urethral infection；Kidney Damage；Chronic kidney disease；Nephrolith；Local inflammation；Systemic inflammatory；Immune correlated disease；Cardiovascular disease, including peripheral vascular disease Disease, Coronary Artery Disease and cranial vascular disease；Insulin resistance；Diabetes；Fatty liver；Dementia, including vascular dementia；Abnormal rouge Fat mass formed by blood stasis；Pre-eclampsia；Hypertension；Obesity；Muscle cramp；Local swelling；Pain, including arthralgia, muscular fatigue；And It stress feel.

Many factors will increase patient and will suffer from gout or will undergo the risk of its one or more symptom.Except antihyperuricemic Except disease, these factors include obesity, diabetes, chronic renal failure, hypertension, diuretics and certain other drugs (such as salicylic acid salt, pyrazinamide, ethambutol, niacin, cyclosporine, 2- ethylamino -1,3,4- thiadiazoles, fructose and Cytotoxic agent) use, hyperalimentation or fasting, high purine diet, high fructose diet, be exposed to lead, red meat and egg Consumption, Ethanol intake and the damage or operation in the recent period of white matter.Ketone during the operation that acute gout may arise from patient with operation Disease, reduced body temperature, for example, when he falls asleep, and due to dehydration, for example, due to diuretics is used.It has also been determined that The genetic risk factors of gout and hyperuricemia.

In various embodiments, method described herein can be used to treat any of above illness or disorder.That is, one In kind embodiment, illness relevant to raised serum uric acid level is gout.In some embodiments, subject suffers from Acute gout.In some embodiments, subject suffers from chronic gout.In some embodiments, subject suffers from moderate Gout.In some embodiments, subject suffers from intractable gout.In some embodiments, subject is with serious pain Wind.For example, a kind of method provides the hyperuricemia in processing gout subject.Certain methods provide treatment or processing pain Hyperuricemia in wind subject, including giving the pharmaceutical composition comprising the first uric acid depressant and the second uric acid depressant Object.In some embodiments, the first uric acid depressant is (-)-Halofenate, (-)-HALOFENIC ACID or its pharmaceutical salts.In certain realities Apply in mode, treatment can be about 4 weeks or longer time, about 1 month or longer time, about 12 weeks or for more time, about 3 months Or longer time, about 6 months or longer time, about 1 year or longer time, about 2 years or longer time, about 5 years or longer time, About 10 years or longer time.In some embodiments, treatment can be indefinite, for example, continuing the surplus of subject's service life Remaining part point.In some embodiments, the second uric acid depressant is selected from the group being made of the following terms: uric acid synthetic inhibitor, Uricase and uricosuric agent and their pharmaceutical salts.In some embodiments, second dose can be allopurinol or Febuxostat.

In various embodiments, these methods include treatment gout.In some embodiments, these methods include logical The acute attack of prevention gout is crossed to treat gout.In another embodiment, this method includes reducing one or more gouts Number, frequency, duration or the severity of acute attack.In another embodiment, this method includes prevention, reduces Or reverse uric acid Crystallization.In some embodiments of the method for treating uric acid Crystallization, uric acid Crystallization Be joint, it is subcutaneous and kidney it is one or more in.In some embodiments, it includes tophaceous deposition that these, which are formed,.? In some embodiments, subject suffers from uric acid Crystallization, this passes through suction tophus or the cunning by aspirating inflammation joint Liquid determines.In another embodiment, this method includes reducing uric acid load.In another embodiment, this method Size or quantity including reducing tophus.It can be by known method, for example, using CT scan, to assess the ruler of tophus Very little or quantity.

Present invention also provides being used to reduce serum uric acid level, treatment is suffered from and raised serum uric acid level related diseases The subject of disease, and treatment hyperuricemia is (in the subject with gout, in the subject for suffering from intractable gout In) method.In some embodiments, subject is with allopurinol, 2- ((the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- base) - 4H-1,2,4- triazole -3- base) thio) acetic acid (RDEA594, lesinurad), 2- (3- cyano-4-isobutoxy phenyl) -4- Methyl-1,3-thiazole-5-carboxylic acid (Febuxostat) or BCX4208 are refractory.In some embodiments, subject is with not Purine alcohol is refractory.For example, in one embodiment, subject is with (such as 100mg/ days 100mg/ days to 800mg/ days To 300mg/ days) allopurinol given, for about 1 month or the longer time, about 3 months or longer time, about 1 year or longer Time etc. is refractory.In some embodiments, subject is refractory with Febuxostat.For example, in one embodiment, Subject is the Febuxostat given with 40mg/ days to 120mg/ days, for about 1 month or for more time, about 3 months or longer Time, about 1 year or longer time etc. are refractory.In some embodiments, subject is with slight or moderate chronic kidney disease (CKD2-3).In other embodiments, subject suffers from severe chronic nephrosis (CKD4).In other embodiments, tested Person is just receiving aspirin or diuretic therapy.

It would be recognized by those skilled in the art that medicament can be given such as with gout or with the patient for developing gout risk Non-steroidal anti-inflammatory drugs (NSAID), colchicin, steroids or similar medicine are to treat or handle gout acute attack.Therefore, In the certain embodiments of method described herein, it is solid that subject can also be given medicament such as NSAID, colchicin or class Alcohol.

By giving compound, method described herein may be implemented, wherein the compound is after being given, passing through Reaction is learned, the compound or its salt of formula (IV) is generated.This kind of compound includes the prodrug of formula (IV) compound.By with such Mode carrys out the prodrug that functional group present in modified compound carrys out prepare compound, and allowing to vivo excision, these are modified to release Put parent compound or active metabolite.For example, prodrug includes such compound, wherein the hydroxyl in compound, amino, Or sulfydryl is bound to and can cut in vivo to regenerate any group of free hydroxyl, amino or sulfydryl respectively.When suchization It is certain when conjunction object is given subject (for example, by allowing the oral compound given to be more easily absorbed into blood) Prodrug can increase the bioavilability of embodiment compound, or, relative to parent material, enhancing parent compound delivering To a certain organ or tissue (for example, kidney, adipose tissue, liver, muscle or joint).The prodrug of the compound of formula (IV) includes Ester, amide and the carbamate (for example, N, N- Dimethylaminocarbonyl) of the hydroxy functional group of formula (IV) compound.Formula (I), the compound of (II) and (III) are the non-limiting examples of the prodrug of formula (IV) compound.The further example of prodrug It may refer to J.Rautio et al.Prodrugs:design and clinical applications, Nat.Rev.Drug Discov.,7,255-270(2008)；Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,(1987)；And T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series (1975) is respectively incorporated into herein by reference.

In various embodiments, compared to the serum uric acid water before giving method described herein in subject It is flat, the serum uric acid level of subject reduces about 5% by compositions described herein, method and kit, 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.In various embodiments, serum uric acid level reduces about 5% To about 50%, reduction about 25% to about 75% or reduction about 50% to about 99%.Method for determining serum uric acid level is A part that is well known in the art and being often measured the standard chemical plate for blood serum sample.

In some embodiments, compared to the blood before giving method described herein or composition in subject Serum uric acid level in subject is reduced to about 7mg/dL by clear uric acid level, composition of the invention, method and kit Below, to about 6.8mg/dL or less, to about 6mg/dL or less, to about 5mg/dL or less, to about 4mg/dL or less or to about 3mg/ DL or less.In some embodiments, compared to the blood before giving method described herein or composition in subject Clear uric acid level, method of the invention by subject serum uric acid level reduce 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 10.0mg/ DL or bigger.In further embodiment, serum uric acid level is reduced 0.1 to 10.0mg/ by method described herein DL, 0.5 to 6.0mg/dL, 1.0 to 4.0mg/dL or 1.5 to 2.5mg/dL.Serum uric acid level appropriate depends on subject It can will be different, and depend on the whole medical treatment situation of subject, over time may be used for given subject With variation.Similarly, the serum uric acid level appropriate of one group of subject with common medical conditions can be different from and have The serum uric acid level appropriate of the different group subjects of different medical situation.Accordingly, it is possible to it is appreciated that given group is tested The serum uric acid level of person is reduced to, for example, being below about 5mg/dL, and the serum uric acid level of different groups of subjects is reduced Extremely, for example, being below about 4mg/dL.In some embodiments, method of the invention reduces the serum uric acid level of subject Enough amounts with cause within the regular hour (for example, about 4 weeks or longer time, about 1 month or longer time, about 3 months or For more time, about 1 year or longer time, about 2 years or longer time etc.) relevant to raised serum uric acid one or more diseases Disease disappears, mitigates, improves, or prevents its breaking-out.For example, a kind of method can reduce the serum uric acid level of subject enough Amount with cause at about 4 weeks or longer time, about 1 month or longer time, about 3 months or longer time, about 1 year or longer when Between, the disappearance or reduction of tophus in the times such as about 2 years or longer time.

It in further embodiment, include the first uric acid depressant and the method for the present invention includes subject is given The pharmaceutical composition of two therapeutic agents (as described herein), wherein the serum uric acid level of the subject is at least about 4mg/ DL, at least about 5mg/dL, at least about 6mg/dL, at least about 6.8mg/dL, at least about 7mg/dL, at least about 8mg/dL, at least about 9mg/dL, at least about 10mg/dL or at least about 11mg/dL.Moreover, the reduction amount appropriate of serum uric acid level can basis Subject, it is different according to the whole medical treatment situation of subject.Similarly, for one group with common medical conditions by The reduction amount of serum uric acid level appropriate can be different from tested for the difference group with different medical situation for examination person The reduction amount of serum uric acid level appropriate for person.

When the amount can depend on specific condition is given, it may be considered that therapeutic agent disclosed herein and combinations thereof is presented Therapeutic activity.The variation of amount can depend on, for example, the subject treated and selected active component.Wider range Dosage can be applicable.Adjustable dosage is to provide optimal therapeutic response.For example, can daily, weekly, monthly Or multiple separate dosage is otherwise given at appropriate time intervals, or can proportionally reduce dosage (such as by feelings Indicated by the urgency of condition).Optionally change the dosage, this depends on a variety of variables, is not limited to used a kind of or more The disease or illness active, to be treated of kind of active component, administration mode, the requirement of individual subjects, the disease treated or The seriousness of illness and the judgement of doctor.

Such as through described herein, the present invention consider and meanwhile give the first and second uric acid depressants (wherein these First and second uric acid depressants are described above) conjoint therapy and method.It conjoint therapy and gives and refers to any simultaneously Mode (wherein showing the pharmacodynamics effects of two kinds of medicaments simultaneously in subject) gives two kinds of medicaments (that is, as described above the One and the second uric acid depressant).Therefore, this kind of to give the preparation, identical for not needing single drug composition, same type Dosage form or even identical administration route for giving the first and second uric acid depressants, or do not need to give two kinds simultaneously Medicament.It can be most conveniently by identical dosage form and identical administration route, in the substantially the same time, to realize in this way Give.For example, can in the form of single oral dosage composition by the first uric acid depressant, such as Halofenate, HALOFENIC ACID or Its pharmaceutical salts and the second uric acid depressant, such as xanthine oxidase inhibitor (for example, allopurinol or Febuxostat) is together Human experimenter is given, such as tablet or capsule, or every kind of medicament can be given in the form of individual oral dosage formulation.Individually One of preparation is the advantage is that give the increased flexibility of dosage, that is, can independently, rapidly and easily vary One and second uric acid depressant dosage.It, can be in the substantially the same time using individually dosed preparation (that is, contemporaneously or in parallel) or the first and second uric acid depressants are given in time (that is, sequentially) of individual interleaving.

Depending on the diagnosis of many factors such as particular subject, symptom and therapeutic purpose, it may be considered that the first and second examinations The dosage of the wider range of agent.In various embodiments, can give about 10mg to about 1000mg/ days the first uric acid reduces Agent and about 10mg to about 4000mg/ days the second uric acid depressants can be given.For example, can give Halofenate, HALOFENIC ACID, Or its pharmaceutical salts about 100mg/ days, about 200mg/ days, about 300mg/ days, about 400mg/ days, about 500mg/ days, about 600mg/ days, About 700mg/ days, about 800mg/ days, about 900mg/ days or about 1000mg/ days.

As described above, in some embodiments, second dose is allopurinol.Allopurinol it is presently recommended that daily agent Amount is 100mg/ days to 800mg/ days, and increment is 100mg/ days.It is given when as the second uric acid depressant as described herein When (that is, when also giving the first uric acid depressant), the dosage range of allopurinol can be it is presently recommended that daily dosage Within, higher or lower than it is presently recommended that daily dosage, as defined above and as fitted for the subject treated ?.By way of non-limiting example, in some embodiments, wherein the first uric acid depressant be fragrant Halofenate (i.e. (-)-Halofenate) and wherein the second uric acid depressant is allopurinol, can give following daily dose: fragrant Halofenate 100mg/ It, allopurinol 50mg/ days；Fragrant Halofenate 100mg/ days, allopurinol 100mg/ days；Fragrant Halofenate 100mg/ days, other purine Alcohol 200mg/ days；Fragrant Halofenate 100mg/ days, allopurinol 300mg/ days；Fragrant Halofenate 100mg/ days, allopurinol 400mg/ It；Fragrant Halofenate 100mg/ days, allopurinol 600mg/ days；Fragrant Halofenate 100mg/ days, allopurinol 800mg/ days；Fragrant halogen is fragrant Ester 200mg/ days, allopurinol 50mg/ days；Fragrant Halofenate 200mg/ days, allopurinol 100mg/ days；Fragrant Halofenate 200mg/ It, allopurinol 200mg/ days；Fragrant Halofenate 200mg/ days, allopurinol 300mg/ days；Fragrant Halofenate 200mg/ days, other purine Alcohol 400mg/ days；Fragrant Halofenate 200mg/ days, allopurinol 600mg/ days；Fragrant Halofenate 200mg/ days, allopurinol 800mg/ It；Fragrant Halofenate 300mg/ days, allopurinol 50mg/ days；Fragrant Halofenate 300mg/ days, allopurinol 100mg/ days；Fragrant halogen is fragrant Ester 300mg/ days, allopurinol 200mg/ days；Fragrant Halofenate 300mg/ days, allopurinol 300mg/ days；Fragrant Halofenate 300mg/ It, allopurinol 400mg/ days；Virtue

Halofenate 300mg/ days, allopurinol 600mg/ days；Fragrant Halofenate 300mg/ days, allopurinol 800mg/ days；Virtue Halofenate 400mg/ days, allopurinol 50mg/ days；Fragrant Halofenate 400mg/ days, allopurinol 100mg/ days；Fragrant Halofenate 400mg/ days, allopurinol 200mg/ days；Fragrant Halofenate 400mg/ days, allopurinol 300mg/ days；Fragrant Halofenate 400mg/ days, Allopurinol 400mg/ days；Fragrant Halofenate 400mg/ days, allopurinol 600mg/ days；Fragrant Halofenate 400mg/ days, allopurinol 800mg/ days；Fragrant Halofenate 600mg/ days, allopurinol 50mg/ days；Fragrant Halofenate 600mg/ days, allopurinol 100mg/ days； Fragrant Halofenate 600mg/ days, allopurinol 200mg/ days；Fragrant Halofenate 600mg/ days, allopurinol 300mg/ days；Fragrant Halofenate 600mg/ days, allopurinol 400mg/ days；Fragrant Halofenate 600mg/ days, allopurinol 600mg/ days；Fragrant Halofenate 600mg/ days, Allopurinol 800mg/ days.

As also described above, in some embodiments, second dose is Febuxostat.Febuxostat it is presently recommended that it is daily Dosage is 40mg/ days or 80mg/ days in the U.S., and in certain other countries is then 40mg/ days, 80mg/ days or 120mg/ days. When being given as described herein as the second uric acid depressant (i.e. when also giving the first uric acid depressant), Febuxostat Dosage range can be it is presently recommended that daily dosage within, higher or lower than it is presently recommended that daily dosage, such as above Defined and as being treated subject was applicable in.By way of non-limiting example, in certain embodiment party In formula, wherein the first uric acid depressant is fragrant Halofenate (i.e. (-)-Halofenate) and wherein the second uric acid depressant is non-cloth rope It is smooth, following daily dose can be given: fragrant Halofenate 100mg/ days, Febuxostat 20mg/ days；Fragrant Halofenate 100mg/ days, non-cloth Sotan 40mg/ days；Fragrant Halofenate 100mg/ days, Febuxostat 80mg/ days；Fragrant Halofenate 100mg/ days, Febuxostat 120mg/ It；Fragrant Halofenate 200mg/ days, Febuxostat 20mg/ days；Fragrant Halofenate 200mg/ days, Febuxostat 40mg/ days；Fragrant Halofenate 200mg/ days, Febuxostat 80mg/ days；Fragrant Halofenate 200mg/ days, Febuxostat 120mg/ days；Fragrant Halofenate 300mg/ days, Febuxostat 20mg/ days；Fragrant Halofenate 300mg/ days, Febuxostat 40mg/ days；Fragrant Halofenate 300mg/ days, Febuxostat 80mg/ days；Fragrant Halofenate 300mg/ days, Febuxostat 120mg/ days；Fragrant Halofenate 400mg/ days, Febuxostat 20mg/ days；Virtue Halofenate 400mg/ days, Febuxostat 40mg/ days；Fragrant Halofenate 400mg/ days, Febuxostat 80mg/ days；Fragrant Halofenate 400mg/ days, Febuxostat 120mg/ days；Fragrant Halofenate 600mg/ days, Febuxostat 20mg/ days；Fragrant Halofenate 600mg/ days, Febuxostat 40mg/ days；Fragrant Halofenate 600mg/ days, Febuxostat 80mg/ days；Fragrant Halofenate 600mg/ days, Febuxostat 120mg/ days；Fragrant Halofenate 800mg/ days, Febuxostat 20mg/ days；Fragrant Halofenate 800mg/ days, Febuxostat 40mg/ days；Virtue Halofenate 800mg/ days, Febuxostat 80mg/ days；Fragrant Halofenate 800mg/ days, Febuxostat 120mg/ days.

It can be easy to imagine for every kind of first uric acid depressant and the second uric acid depressant range described above Other interior dosage ranges.It would be recognized by those skilled in the art that when therapeutic agent is applied in combination, adjustable dosage and dosage Scheme.When using this kind of combination, the dosage of one or more medicaments can be reduced to such level, and being lower than individually to make With when one or more medicaments to reach level required for desired effect.Similarly, dosage, example can be improved Such as, to synchronize giving for one or more therapeutic agents, to facilitate the ease for use and biddability of improvement patient.Alternatively, The dosage of one or more therapeutic agents can be sequence, for example, to reduce the combined load in given time medicament.Example Such as, in some embodiments, when giving the first uric acid depressant and the second uric acid depressant, the second uric acid can be reduced The dosage of agent (such as allopurinol, Febuxostat or other the second uric acid depressants described herein) is adjusted to lower than current The level of recommendation.

Dosage adjustment or dosage escalation regimens may be used to determine the dosage appropriate or optimal for giving subject.Example Such as, dosage adjustment or incremental research can choose the dosage for improving curative effect or tolerance.Dosage adjustment is incremented by the progressive tune of permission Dosage to be administered is saved until reaching desired effect.Dosage adjustment gradually decreases the dosage given, and dosage escalation then by It is cumulative to add to the dosage given.Dosage adjustment and incremental method are well known in the art.As non-limiting examples, may be used Subject 200mg/ days Halofenates, HALOFENIC ACID or its pharmaceutical salts are given once daily, and serum uric acid level is measured daily.It can With, such as weekly, increase or decrease dosage.Subject can be monitored, for example, 2 to 12 weeks are to find desired dosage.

According to compositions described herein, method and kit, can give in any way the first uric acid depressant and Second uric acid depressant, wherein the pharmacodynamics effect of the two may be apparent in subject in the about the same time.It is this kind of to give Single drug composition, the preparation of same type, identical dosage form or even identical administration route is not needed to be used to give First and second uric acid depressants, or do not need to give two kinds of medicaments simultaneously.That is, in various embodiments, it is described herein First uric acid depressant and the second uric acid depressant can reside in one-pack type (such as monolithic agent or capsule, for take orally to Give) in, and in other embodiments, the first uric acid depressant can reside in the first dosage form (such as first tablet or glue Wafer) and the second uric acid depressant can reside in the second dosage form (such as the second tablet or capsule).Dosage form may include According to the first and second uric acid depressants of the dosage of examples provided above.One-pack type (such as monolithic agent or capsule) can be with Including the first and second uric acid depressants of single daily supply, or part thereof, for example, the half of daily supply amount, daily to supply The one third of amount, a quarter etc. of daily supply amount.For example, pharmaceutical composition described herein can reside in monolithic Agent, it includes 200mg virtue Halofenates and 150mg allopurinol.By further example way, pharmaceutical composition described herein Object can reside in monolithic agent, and it includes 200mg virtue Halofenates and 40mg Febuxostat.It can be easy to imagine in model of the invention Enclose other interior dosage forms.

In unit dosage forms, preparation can be divided into unit dose, it includes suitable one or more active components.? In some embodiments, unit dose has wrapped form, and it includes the preparations of discrete magnitude.Non-limiting example includes packaging Tablet or capsule, and the powder in bottle or ampoule.In some embodiments, by aqueous suspension composition packet In single dose not reclosable container.Alternatively, in this case, typical using multi-dose reclosable container , in the composition include preservative.Only by way of example, with unit dosage forms (it includes but is not limited to ampulla) or The preparation for parenteral administration is provided with the multi-dose container preservative of addition (its have).Tablet, pastille, pill, Capsule etc. can also include ingredient as listed below: adhesive such as natural gum, Arabic gum, cornstarch or gelatin；Figuration Agent such as Dicalcium Phosphate；Disintegrating agent such as cornstarch, potato starch, alginic acid etc.；Lubricant such as magnesium stearate；And sweetener As sucrose, lactose or saccharin can add；Or flavouring agent such as lavender, wintergreen or cherry flavor enhancement.Work as dosage unit form When being capsule, in addition to the material of the above-mentioned type, it can also include liquid-carrier.Various other materials can be used as coating In the presence of or otherwise change the physical form of dosage unit.For example, tablet, pill or capsule can be coated with purple Glue, sugar or both.Syrup or elixir may include one or more active components, as the sucrose of sweetener, as anti-corrosion The methylparaben and propylben of agent, dyestuff and flavouring agent such as cherry or orange flavor.In some embodiments, it adds Other ingredient, for example, non-steroidal anti-inflammatory drugs or colchicin, for treating the ingredient or inert material of other related idicatios Matter such as artificial tanning agent.Certainly, any material for being used to prepare any dosage unit form should be medicinal pure and used It is substantially nontoxic in the case where amount.Furthermore it is possible to which sustained release preparation and preparation is added (such as in one or more active components It is described herein).

It can (QD), twice daily (BID), three times a day (TID) or four times a day (QID) gives the present invention once a day Pharmaceutical composition.In one embodiment, (QD) gives pharmaceutical composition of the invention once a day.Implement in another kind In mode, twice daily (BID) gives pharmaceutical composition of the invention.

Invention further describes products such as comprising the kit of composition, and wherein the composition includes the first and second uric acid Depressant (wherein, described above is these the first and second uric acid depressants).In some embodiments, in kit First uric acid depressant is (-)-Halofenate (i.e. fragrant Halofenate).In some embodiments, the second uric acid in kit Depressant is allopurinol.In other embodiments, the second uric acid depressant in kit is Febuxostat.Kit It may include packaging for the composition of distribution and have enough amounts to carry out method described herein.Kit can also wrap Specification (such as package insert, packaging label etc.) is included, for using kit in one or more methods described herein Ingredient.For example, kit may include the dosage form of the first uric acid depressant described herein and the second uric acid depressant, and say Bright book, for prescribing, giving or otherwise reduce serum uric acid level using dosage form.In some embodiments, Kit is for the subject with hyperuricemia or hyperuricemia associated disease (for example, gout) for pharmaceutical composition Self give, wherein kit includes container, is accommodated a variety of comprising the first and second uric acid depressant described herein Dosage form, and the specification given for carrying out drug whereby.In one embodiment, kit includes the first dosage form, Include Halofenate, HALOFENIC ACID or its pharmaceutical salts (there are one or more forms identified above), and second dose of at least one Type presents in an amount at least sufficient to it includes one or more forms identified above and carries out method of the invention.Second dosage form and any another Outer dosage form (for example, the dosage form of third, the 4th or the 5th) may include disclosed herein for treating antihyperuricemic disease (example Such as, gout) any active component.All dosage forms may include every kind of compound of therapeutically effective amount together, for treating height The relevant illness of uricacidemia (for example, gout).In some embodiments, kit is for relevant with hyperuricemia The subject of illness (for example, gout) self gives at least one oral agents, and wherein kit includes container, accommodates A variety of oral agents, and the specification given for carrying out drug whereby.Presently filed embodiment is characterized in that The corresponding pharmaceutical composition of the feature and these compounds of bright book and the claims hereof submitted, method and Using the characteristics of.

Embodiment

Embodiment 1: clinical test

This is random, double blind, placebo-controlled study, for assessing 400 to 600mg virtue Halofenate (i.e. (-)-Halofenate) Safety and curative effect of every daily oral dose in conjunction with the allopurinol of 300mg oral dose, can be to independent other purine It is carried out in about 90 patient with gout that there is alcohol unsuitable Hypouricemia (uric acid reduction) to react.This 90 patients' is big About 45 will participate in allopurinol/oxipurinol Series P K sample collection research.

It will be randomized 90 patients in total；3 study groups are each about 30 ((1:1:1) in the following manner) own:

1) fragrant Halofenate 400mg (adding allopurinol 300mg)

2) fragrant Halofenate 600mg (adding allopurinol 300mg)

3) placebo (adding allopurinol 300mg)

Dosage/approach/scheme

Patient in all treatment groups is by oral colchicin 0.6mg, once a day, starts from for the -3rd week until last Research follow-up, as the background therapy for preventing gout acute attack.Patient in all treatment groups will also be oral other Purine alcohol 300mg started from for the -3rd week, during operation, and lasts up to the 4th week once a day.Individually not with allopurinol The patient that the reduction of target serum uric acid can be reached will be randomized into research.

Randomization therapeutic scheme will be following (the 1st day to the 4th week):

Treatment group #1: fragrant Halofenate 400mg (adding allopurinol)

Treatment group #2: fragrant Halofenate 600mg (adding allopurinol)

Treatment group #3: placebo (adds allopurinol)

Analysis

The patient that all participations will be analyzed in PK analysis, receives treatment and its original PK in any dosage group Data are considered enough and interpretable.For including the patient in Series P K subset, there is and be not present fragrant halogen Under conditions of fragrant ester (under two kinds of dosage), allopurinol and oxipurinol pharmacokinetics will by repeated doses (the 3rd week, the 5th Secondary follow-up) plasma concentration, including following PK parameter (depending on the circumstances) determination:

Exposed or area under the concentration-time curve (AUC0-24, AUC0- are finally, AUC0-inf)

Maximum concentration (Cmax)

Reach the time (Tmax) of maximum concentration

Terminal eliminates half-life period (t¹/₂)

Safety

By the estimation based on the security parameters assessed in entire research, including clinical labororatory's test, 12 leads ECG, vital sign, physical examination, concomitant medication examines and AE (does not include such medical events, is to give on day 1 Captured " AE " in the past), to illustrate safety and tolerance.The report of safety data is descriptive, and will include receiving All patients of at least one dosage of fragrant Halofenate or allopurinol.Descriptive analysis by include treatment group AE incidence And type, including seriousness list and laboratory, vital sign and 12 lead ECG measurement results are (to all before giving Give rear time point) real data and variation.

Pharmacokinetics

3 respective effects for the treatment of group will be assessed as selected giving the rear time from baseline to each for following terminal The absolute sum percentage variation of point:

SUA when treating the 4th week

Reach the ratio of the patient of sUA < 6mg/dL

Reach the ratio of the patient of sUA < 5mg/dL

Reach the ratio of the patient of sUA < 4mg/dL

Embodiment 2: clinical test

This research assessment in about 10 to 15 patient with gout the fragrant Halofenate of 400 to 600mg single oral dose with The Febuxostat of 80mg oral dose combines the safety and curative effect for treating the hyperuricemia of patient with gout.

In addition to the daily 0.6mg colchicin prevented for acute attack, during treatment stage, all patients will be with Following order receives Febuxostat and fragrant Halofenate:

1st day to the 7th day: oral Febuxostat 80mg, once a day (only Febuxostat period)

8th day to the 21st day: oral Febuxostat 80mg added fragrant Halofenate 400mg, and (Febuxostat adds once a day Upper virtue Halofenate 400mg period)

22nd day to the 35th day: oral Febuxostat 80mg added fragrant Halofenate 600mg, once a day (Febuxostat In addition fragrant Halofenate 600mg period)

It will be horizontal in (the 7th day, the 21st day and the 35th day) last day of each treatment phase assessment sUA；In these days, SUA samples will be collected four different time points: (empty stomach) before giving, give after 2 hours, give 6 hours and after giving afterwards 10 hours (before dinner).

Dosage/approach/scheme

Colchicin: 0.6mg/ is oral/day, from the -16th day to the 49th day

Febuxostat: 80mg/ is oral/day, from the 1st day to the 35th day

Fragrant Halofenate: 400mg/ is oral/day, from the 8th day to the 21st day；600mg/ takes orally/day, from the 22nd day to the 35th It

Duration for the treatment of

Stage 1: screening stage: 1 to 4 week

Stage 2: operation/stabilization sub stage: >=2 weeks

Stage 3: treatment stage: 5 weeks

Stage 4: follow-up phase: 2 weeks

Analysis

Safety

By the estimation based on the security parameters assessed in entire research, including clinical labororatory's test, 12 leads ECG, vital sign, physical examination, concomitant medication examines and AE, to illustrate safety and tolerance.The report of safety data It is descriptive, and will includes all patients for receiving the fragrant Halofenate of at least one dosage.Descriptive analysis will include AE Incidence and type comprising the reality in seriousness list and laboratory, vital sign and 12 lead ECG measurement results Data and variation.The list of clinically significant abnormal laboratory data will be provided.Using classified statistic method, to summarize Case report no The ECG of form (CRF)-capture and physical examination.

Pharmacokinetics

The effect that each Febuxostat adds the fragrant Halofenate combination therapy phase will be assessed as following terminal from baseline The variation that (the 1st day) to treatment phase terminates:

Reach the ratio of the patient of sUA < 6mg/dL

Reach the ratio of the patient of sUA < 5mg/dL

Reach the ratio of the patient of sUA < 4mg/dL

Reach the ratio of the patient of sUA < 3mg/dL

The absolute sum percentage of sUA changes

Although the description of front illustrates specific embodiment, it will be recognized to those skilled in the art that can carry out each Kind modification and replacement.Therefore, above-described specific embodiment and embodiment are merely illustrative, rather than are used to limit this The range of invention, the scope of the present invention are provided by the full scope of appended claims and its any and all equivalents.

Claims

1. a kind of method of the serum uric acid level for reducing hyperuricemia subject, the method includes give it is described by Examination person's the first uric acid depressant and the second uric acid depressant, wherein the first uric acid depressant be formula (I) compound or its Pharmaceutical salts

Wherein R is selected from the group that is made of the following terms: hydroxyl, rudimentary aralkoxy, two elementary alkyl amido-lower alkoxy, Lower al-kanoylamino-lower alkoxy, benzamido-lower alkoxy, urea groups-lower alkoxy, N '-low alkyl group-urea The substituted lower alkoxy of base-lower alkoxy, carbamoyl-lower alkoxy, halogenated phenoxy-, carbamoyl-take Phenoxy group, the carbonyl-loweralkyl amino, N in generation, substituted rudimentary of N- two elementary alkyl amido-low-grade alkyl amino, halogen- The substituted low-grade alkyl amino of the substituted low-grade alkyl amino of alkyl amino, hydroxyl-, lower alkyl alcohol radical oxygroup-, urea groups and low Grade alkoxycarbonyl amino；And each X is independently halogen.

2. a kind of for treating the method for suffering from the subject of hyperuricemia associated disease, the method includes give it is described by Examination person's the first uric acid depressant and the second uric acid depressant, wherein the first uric acid depressant be formula (I) compound or its Pharmaceutical salts

3. according to the method described in claim 2, wherein, the relevant illness of the hyperuricemia is gout.

4. according to the method described in claim 3, wherein, the illness is acute gout, chronic gout, moderate gout, refractory Property gout or severe gout.

5. a kind of method for treating hyperuricemia in gout subject, including will include the first uric acid depressant and the The composition of two uric acid depressants gives the subject, wherein the first uric acid depressant be formula (I) compound or its Pharmaceutical salts

6. the method according to any one of claims 1 to 5, wherein the first uric acid depressant is the change of formula (II) Close object or its pharmaceutical salts

Wherein R²Selected from the group being made of the following terms: phenyl-lower alkyl group, lower al-kanoylamino-low alkyl group and benzene carbon amide Base-low alkyl group and each X are independently halogens.

7. method according to any one of claim 1 to 6, wherein the first uric acid depressant is Halofenate or halogen Fragrant acid or its pharmaceutical salts, preferably (-)-Halofenate or (-)-HALOFENIC ACID or its pharmaceutical salts.

8. method according to any one of claim 1 to 7, wherein the first uric acid depressant is (-)-Halofenate.

9. method according to any one of claim 1 to 8, wherein the second uric acid depressant is selected from by following The group of item composition: inhibitor, uricosuric agent and the uricase that xanthine oxidase inhibitor, uric acid generate.

10. according to the method described in claim 9, wherein, the second uric acid depressant is xanthine oxidase inhibitor, excellent Choosing is selected from the group being made of the following terms: allopurinol, Febuxostat, oxipurinol, Tisopurine, bios Ⅰ, phytic acid, flesh Alcohol, keampferol, myricetin and Quercetin, especially allopurinol or Febuxostat.