JP6192142B2 - How to treat gout redness - Google Patents

Description

  This application relates to the treatment (including prevention) of gout redness.

（Ｉ）
［式中、Ｒは、ヒドロキシ、低級アラルコキシ、ジ−低級アルキルアミノ−低級アルコキシ、低級アルカンアミド−低級アルコキシ、ベンズアミド−低級アルコキシ、ウレイド−低級アルコキシ、Ｎ’−低級アルキル−ウレイド−低級アルコキシ、カルバモイル−低級アルコキシ、ハロフェノキシ置換低級アルコキシ、カルバモイル置換フェノキシ、カルボニル−低級アルキルアミノ、Ｎ，Ｎ−ジ−低級アルキルアミノ−低級アルキルアミノ、ハロ置換低級アルキルアミノ、ヒドロキシ置換低級アルキルアミノ、低級アルカノイルオキシ置換低級アルキルアミノ、ウレイドおよび低級アルコキシカルボニルアミノからなる群から選択され；ならびに各Ｘは、独立して、ハロゲンである］
の化合物またはその医薬的に許容される塩を対象に投与することを特徴とする、対象によって経験される痛風発赤の治療方法を記載する。 The present application provides a compound of formula (I)

(I)
[Wherein, R is hydroxy, lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamide-lower alkoxy, benzamide-lower alkoxy, ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl -Lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N, N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanoyloxy substituted Selected from the group consisting of lower alkylamino, ureido and lower alkoxycarbonylamino; and each X is independently halogen]
A method of treating gout redness experienced by a subject is described, comprising administering to the subject a compound of the above or a pharmaceutically acceptable salt thereof.

  Another aspect reduces the number, duration, frequency or intensity of gout redness experienced by a subject, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof. Provide a method. Another aspect is the treatment of hyperuricemia in a subject suffering from gout, characterized in that the compound of formula (I) is administered to a subject in need thereof, the dosage, frequency and duration of administration Provides a treatment that is effective to reduce the number, duration, frequency or intensity of gout redness experienced by the subject during said period. Yet another aspect provides a method of providing (-)-halofenic acid to a subject in a ratio between day-to-day maximum and minimum of about 2.0 or less. Further embodiments are provided below.

  Uric acid-lowering drugs, such as allopurinol or febuxostat, generally increase the number, duration, frequency, or intensity of gout redness at the start of treatment, and this hatred continues for weeks to months after the start of such treatment Yes. Uric acid-lowering drugs often require a dose-setting strategy that gradually increases to the therapeutic dose in order to minimize the number, duration, frequency, or intensity of redness. Treatment or prevention of redness with additional therapeutic agents such as non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine is often recommended during this time. During long-term maintenance use of uric acid lowering therapeutic agents, redness can also accumulate due to fluctuations in uric acid levels caused by failure to prescribe. Benefits of current methods include a reduction in the number, duration, frequency or intensity of redness experienced by the patient (eg, initiation or maintenance period of hypouric acid therapy), reduced need for dose setting, and further A reduction in the amount or duration of anti-redox drugs.

FIG. 1 shows the mean trough plasma concentration of (−)-halofenic acid during and after the 30-day dosing schedule of 400 mg alhalofenate once daily oral. FIG. 2 shows the mean and standard deviation (SD) of (−)-halofenic acid plasma concentrations on days 15 and 30 after oral administration of 400 mg alhalofenate once daily in 20 human subjects. FIG. FIG. 3 is a diagram showing a decrease in serum uric acid in a subject over time after dosing once a day with alhalofenate. FIG. 4 shows the effect of (−)-halofenic acid in reducing messenger RNA encoding the pro-inflammatory cytokine IL-1β in primary mouse macrophages stimulated with lipopolysaccharide (LPS). FIG. 5 is a diagram showing the effect of (−)-halofenic acid that decreases the secretion of pro-inflammatory cytokine IL-1β in primary mouse macrophages stimulated with lipopolysaccharide. FIG. 6 shows the mean reduction in highly sensitive C-reactive protein (hs-CRP) levels in human subjects after treatment with (−)-halofenate 600 mg. FIG. 7 shows the mean percent reduction in highly sensitive C-reactive protein (hs-CRP) levels in human subjects after treatment with 600 mg of (−)-halofenate.

  As utilized in this disclosure, the following terms shall be understood to have the following meanings unless otherwise indicated.

  “About” when specifying a number means an upper or lower range of 10% of that value or number, unless otherwise indicated. For the claims, without limitation to the application of the doctrine of equivalents, each number is a description of the number of significant digits and the technique or method used to obtain the number (eg, spirit, sample preparation, etc.) Should be interpreted in consideration of factors such as

  “Administer” or “administration” means the act of imparting a drug, prodrug or therapeutic agent to a subject. A typical route of administration is described below.

  “Acute gout” means gout that appears in a subject suffering from at least one gout symptom (eg foot gout or other gout arthritis, gout redness, gout attack).

  `` Chronic gout '' means gout appearing in subjects suffering from recurrent or long-term gout redness, gout nodule formation, chronic inflammatory arthritis or gout-related joint deterioration, after recovery from acute gout and acute The period between gout attacks (ie, the intermittent period of gout) is included.

  “Composition” or “formulation” that is interchangeable means a preparation containing a mixture of various excipients and active ingredients that provide a relatively stable and desired useful form of a compound or drug. .

The prefixes “d” and “l” or (+) and (−) are used to indicate an indication of rotation of the plane of plane polarization by the compound, and (+) or d− indicates that the compound is “dextrorotatory” (−) Or 1− means that the compound is “left-handed”. For a given chemical structure, these isomers or “optical isomers” are identical except that they are mirror images of one another. In describing an optically active compound, the prefixes R and S are used to indicate the absolute configuration of the compound with respect to its chiral center. There is no correlation for nomenclature between absolute stereochemistry and enantiomeric rotation (ie, the R-isomer may also be the l-isomer). Certain optical isomers are also referred to as “enantiomers” and mixtures of such isomers are sometimes referred to as “enantiomers” or “racemic” mixtures (eg, A. Streitwiesser, & CH Heathcock, INTRODUCTION TO ^{ORGANIC CHEMISTRY, 2 nd Edition, Chapter} 7 (MacMillan Publishing Co., USA 1981)). The optical rotation [α] _D of (−)-halofenate was measured in methyl alcohol.

  “Elevated serum uric acid level” means a serum uric acid level that is higher than normal and generally means a serum uric acid level that is higher than or equal to about 6 mg / dL in a patient suffering from gout. In certain instances, the increase in serum uric acid levels is higher than the average level in a given population, such as a particular generation or age population.

  An “effective amount” is (i) at least partially to achieve a desired response in the subject; (ii) to delay or prevent the onset of a particular condition being treated in the subject; or (Iii) means the amount required to inhibit or prevent the progression of a particular condition being treated in a subject. Effective amounts for a particular subject include the health and physical condition of the subject to be treated, the taxon of the individual to be treated, the degree of protection desired, the formulation of the composition, the assessment of the medical situation and Varies depending on other relevant factors. The amount is expected to be determined over a relatively wide range that can be determined by a given test.

  “First uric acid lowering agent” means a compound of any of formulas (I), (II), (III) or (IV), or a pharmaceutically acceptable salt or prodrug thereof. For clarity, this term means, for example, that there is no time phase and no relevance for the second uric acid lowering drug.

  “Redness” or “gout redness” refers to symptoms of gout associated with the sudden onset of pain and inflammation, particularly in peripheral joints such as toes and fingers.

  “Gout” means a group of disorders or symptoms that are most often associated with uric acid accumulation due to overproduction of uric acid or decreased ability of the kidney to excrete uric acid. Gout is often characterized by the accumulation of uric acid crystals (uric acid or its salts, such as monosodium urate) in joints (gouty arthropathy) or soft tissues (gouty nodules). “Gout” as used herein includes acute gout, chronic gout, moderate gout, refractory gout and severe gout.

  “Gout associated inflammation” means local or systemic inflammation resulting from an immune response to the accumulation of uricemia.

  “Halophenate” is a compound of the following formula (III): (4-chlorophenyl)-(3-trifluoromethylphenoxy) -acetic acid 2-acetylaminoethyl ester (4-chlorophenyl- (3-trifluoromethylphenoxy) ) -Acetic acid 2-acetamidoethyl ester). The term halofenate and the corresponding chemical name include both the (+) and (−) enantiomers of compounds of formula (III), and mixtures thereof, unless otherwise specified.

  “Halofenic acid” and “CPTA” are compounds of formula (IV), ie 4-chlorophenyl- (3-trifluoromethylphenoxy) -acetic acid [2- (4-chlorophenyl) -2- (3 -(Trifluoromethyl) phenoxy) acetic acid] as well as pharmaceutically acceptable salts thereof. The term halofenic acid and the corresponding chemical name include both the (+) and (−) enantiomers of compounds of formula (IV), and mixtures thereof, unless otherwise specified.

  “Hyperuricemia” means an increase in serum uric acid levels (see above).

  “Renal dysfunction” means a medical condition in which the kidney cannot properly filter blood toxins and waste products. Renal dysfunction can manifest in the form of acute kidney injury or chronic kidney disease (ie, CKD1-5).

  “Moderate gout” means gout present in a subject suffering from gout redness at least twice in the last 12 months.

  “Pharmaceutically acceptable” means something useful in preparing a pharmaceutical composition that is generally safe, non-toxic, biologically unsuitable, veterinary or Those that are acceptable for human pharmaceutical use are included.

  “Pharmaceutically acceptable salts” include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, and include both solvated and unsolvated forms. Representative non-limiting descriptions of pharmaceutically acceptable salts include SM 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), page 382, Table 38-5, both of which are incorporated herein by reference. Is taken in.

  "Pharmaceutically acceptable acid addition salts" include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, as well as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, Salts formed with organic acids such as maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid Means.

  “Pharmaceutically acceptable base addition salt” means a salt prepared by adding an inorganic or organic base to a free acid. Examples of the salt derived from an inorganic base include, but are not limited to, sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, and aluminum salt. It is done. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins, For example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine , Salts of glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin and the like.

  “Refractory gout” refers to (1) one or more second uric acid lowering drugs that are not the first uric acid lowering drug, or (2) the first uric acid lowering drug rather than the second uric acid lowering drug. Refers to gout in patients who are either unresponsive or poorly responsive after being administered either, or who experience or are at high risk of experiencing adverse events. As used herein, the terms “not responding” and “poor responsiveness” include: (1) serum uric acid does not decrease or hardly decreases, and (2) (eg, by a doctor or other health professional Failure to achieve target serum uric acid levels (as determined), and (3) one or more gout conditions or symptoms such as gout redness, gout nodules, gout arthritis or low serum uric acid levels It includes the persistence of other states that do not take place.

  “Second uric acid lowering drug” means a therapeutic agent that lowers serum uric acid levels rather than the first uric acid lowering drug. Secondary uric acid lowering drugs include currently available drugs that lower serum uric acid (ie, drugs that are approved by the FDA or other appropriate authority as of the filing date of this application) and are currently under development or review by the authorities The compound in is included. Examples of second uric acid lowering drugs are provided below. For clarity, this means that there is no time phase and no relevance for the first uric acid lowering drug.

  “Subject” and “patient” include, for example, mammals (including humans), other primates, companion animals (eg, dogs, cats), livestock animals (eg, horses, cows, sheep, pigs), rats and mice. Means.

  “Severe gout” means gout present in a subject with nodular deposition in the joint, skin or kidney, which causes chronic arthritis, joint destruction, subcutaneous gout nodule or renal failure, in some cases later Causes deformation and / or disability.

  “Substantially free” is (−)-halofenate substantially free of the corresponding (+) enantiomer (ie (+)-halofenate, (+)-halofenic acid or salt thereof) or (−) — When used with halofenic acid (or a salt thereof), it means a composition containing a (−) enantiomer of a compound in a high proportion relative to the (+) enantiomer. In one embodiment, the term means that the compounds included in the composition are, by weight, at least 85% (−) enantiomer and 15% or less (+) enantiomer. In one embodiment, the terms mean that the compounds included in the composition are, by weight, at least 90% (−) enantiomer and 10% or less (+) enantiomer. In another embodiment, the term indicates that the compound contained in the composition comprises, by weight, at least 91% (−) enantiomer and 9% or less (+) enantiomer, at least 92% (−) enantiomer and 8% or less (+) enantiomer, at least 93% (−) enantiomer and 7% or less (+) enantiomer, at least 94% (−) enantiomer and 6% or less (+) enantiomer, at least 95% ( -) Enantiomers and 5% or less (+) enantiomer, at least 96% (-) enantiomer and 4% or less (+) enantiomer, at least 97% (-) enantiomer and 3% or less (+) enantiomer, at least 98% of the (−) enantiomer and 2% or less of the (+) enantiomer Nchioma, or at least 99% (-) enantiomer or 99% (-) means that enantiomer. Other proportions of (−) and (+) enantiomers can also be provided. These proportions are based on the amount of enantiomer compared to the total amount of both enantiomers of the compound in the composition.

  A “therapeutically effective dose”, “therapeutically effective amount” or “a pharmaceutically acceptable dose” and a “pharmacologically acceptable amount” which are interchangeable refers to a sufficient amount of a therapeutic agent or The metabolite, for example, reduces uric acid levels to a target value, or treats its various types of gout, or treats disorders associated with hyperuricemia to achieve the desired result Means to exist.

  “Treatment” and “treating” of a disease, disorder, condition or symptom (1) prevent or reduce the risk of developing the disease, disorder or condition, ie, clinical symptoms of the disease, disorder or condition, (2) Diseases that are exposed to or susceptible to a disease, disorder, or illness but that have not yet experienced or exhibited symptoms of the disease, disorder, or illness (ie, prevention); Suppress the disorder or illness, ie stop or reduce the onset of the disease, disorder or illness or its clinical symptoms; and (3) alleviate the disease, disorder or illness, ie regress the disease, disorder or illness Means to reverse, ameliorate, or reduce the number, frequency, duration or severity of its clinical symptoms. The term “management” may be used as a synonym.

  “Urate” means uric acid (7,9-dihydro-1H-purine-2,6,8 (3H) -trione) and its ions and salts.

（Ｉ）
［式中、Ｒは、ヒドロキシ、低級アラルコキシ、ジ−低級アルキルアミノ−低級アルコキシ、低級アルカンアミド−低級アルコキシ、ベンズアミド−低級アルコキシ、ウレイド−低級アルコキシ、Ｎ’−低級アルキル−ウレイド−低級アルコキシ、カルバモイル−低級アルコキシ、ハロフェノキシ置換低級アルコキシ、カルバモイル置換フェノキシ、カルボニル−低級アルキルアミノ、Ｎ，Ｎ−ジ−低級アルキルアミノ−低級アルキルアミノ、ハロ置換低級アルキルアミノ、ヒドロキシ置換低級アルキルアミノ、低級アルカノイルオキシ置換低級アルキルアミノ、ウレイドおよび低級アルコキシカルボニルアミノからなる群から選択され；ならびに各Ｘは、独立して、ハロゲンである］
の化合物またはその医薬的に許容される塩を対象に投与することを特徴とする、痛風発赤の治療方法を記載する。 The present application relates to formula (I)

(I)
[Wherein, R is hydroxy, lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamide-lower alkoxy, benzamide-lower alkoxy, ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl -Lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N, N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanoyloxy substituted Selected from the group consisting of lower alkylamino, ureido and lower alkoxycarbonylamino; and each X is independently halogen]
A method for treating gout redness, characterized in that a compound of the above or a pharmaceutically acceptable salt thereof is administered to a subject.

（ＩＩ）
［式中、Ｒ^２は、フェニル−低級アルキル、低級アルカンアミド−低級アルキルおよびベンズアミド−低級アルキルからなる群から選択され；ならびに各Ｘは、独立して、ハロゲンである］
の化合物またはその医薬的に許容される塩である。 In certain embodiments, the compound has the formula (II)

(II)
Wherein R ² is selected from the group consisting of phenyl-lower alkyl, lower alkanamide-lower alkyl and benzamide-lower alkyl; and each X is independently halogen.
Or a pharmaceutically acceptable salt thereof.

（ＩＩＩ）
の化合物（ハロフェナートとも称される）またはその医薬的に許容される塩である。 In another embodiment, the compound has the formula (III)

(III)
(Also referred to as halofenate) or a pharmaceutically acceptable salt thereof.

（ＩＶ）
の化合物（ハロフェン酸とも称される）またはその医薬的に許容される塩である。 In another embodiment, the compound has the formula (IV)

(IV)
(Also referred to as halofenic acid) or a pharmaceutically acceptable salt thereof.

  It should be noted that any carbon atom that does not meet the valence in the formulas and examples herein will have a hydrogen atom so that it satisfies the valence.

  In certain embodiments, the compound is a compound that, after administration, yields a compound of formula (IV) or a pharmaceutically acceptable salt thereof after administration, as described in more detail below.

  In certain embodiments, the compound is the (−) enantiomer of a compound of formula (I), (II), (III) or (IV). In certain embodiments, the compound comprises (-)-halofenate (ie, (-)-(R)-(4-chloro-phenyl)-(3-trifluoromethyl-phenoxy) -acetic acid 2-acetylamino-ethyl. Also referred to as ester or alhalofenate). In another embodiment, the compound is (−)-halofenic acid (ie, (−)-4-chlorophenyl- (3-trifluoromethylphenoxy) acetic acid) or a pharmaceutically acceptable salt thereof. In certain embodiments, the (-)-halofenate, (-)-halofenic acid or a pharmaceutically acceptable salt thereof is substantially free of the corresponding (+) enantiomer.

  Enantiomers (stereoisomers) of the compounds of formula (I), (II), (III) or (IV) and their pharmaceutically acceptable salts are reacted in their single enantiomeric form in the process whenever possible By using an agent or reagent or catalyst, or by resolving a mixture of stereoisomers by conventional methods, including microbial resolution to resolve diastereomeric salts formed with chiral acids or chiral bases and the use of chiral carriers Can be manufactured. US Pat. No. 7,199,259 (Daugs), US Pat. No. 6,646,004; US Pat. No. 6,624,194; US Pat. No. 6,613,802, which is hereby incorporated by reference in its entirety. And US Pat. No. 6,262,118 (Luskey et al.), US Pat. No. 7,714,131 (Zhu et al.), US Pat. No. 7,432,394 (Cheng et al.) And US 2010/0093854. See also Broggini et al.

  Chemical synthesis of racemic mixtures of (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives is also performed by the method described in US Pat. No. 3,517,050, the teachings of which are incorporated herein by reference. can do. Each enantiomer is known to those skilled in the art and can be obtained by resolution of a racemic mixture of enantiomers using conventional techniques used. See, for example, Jaques, J., et al., In Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York (1981). Other standard methods of resolution known to those skilled in the art, including but not limited to simple crystallization and chromatographic resolution, can also be used (eg, Stereochemistry of Carbon Compounds (1962) ELEliel, McGraw Hill; J. Lochmuller, Chromatography, 113, 283-302 (1975)). Alternatively, halofenate, halofenic acid or pharmaceutically acceptable salts thereof, ie optically pure isomers, can be prepared from racemic mixtures by enzymatic biocatalytic resolution. Enzymatic biocatalytic resolution has generally been published previously (see, eg, US Pat. Nos. 5,057,427 and 5,077,217, incorporated herein by reference). . Other common methods for obtaining enantiomers include stereospecific synthetic methods (see, for example, A.J.Li et al., Pharm. Sci. 86, 1073-77 (1997)).

  Without being bound by any theory, some properties of the compounds described herein may e.g. treat gout redness (numbers) during the onset and maintenance use of these compounds for uric acid reduction. It is thought to be a factor in their successful use in terms of duration, frequency or strength): (1) their pharmacokinetic profiles and (2) their anti-inflammatory properties (interleukin-1 beta (IL Including inhibition of -1β) and reduced effects of highly sensitive C-reactive protein), and (3) their ability to inhibit entry of uric acid into cells.

  Figures 1-2 show the pharmacokinetic profiles of (-)-halofenic acid. FIG. 1 shows mean trough plasma concentration values of (−)-halofenic acid during and after a 30-day dosing schedule of 400 mg alhalofenate once daily oral. FIG. 2 shows the mean and standard deviation (SD) plasma concentration values of (−)-halofenic acid on days 15 and 30 after oral administration of 400 mg of alhalofenate once daily. These figures show a long half-life where sustained drug levels exist for several days after the last dose, as well as a relatively constant daytime plasma concentration. It is expected that the plasma concentration of (−)-halofenic acid is correlated with the plasma concentration of uric acid. Thus, the ratio between a long half-life and a low day-to-day maximum is one that predicts a gradual change in serum uric acid during the onset and maintenance use of treatment accordingly. FIG. 3 shows a decrease in serum uric acid over time with several doses of alhalofenate, which supports this idea. Large or rapid changes in serum uric acid (eg, resulting in certain secondary uric acid lowering drugs such as allopurinol, febuxostat, etc.) can occur during weeks and months after the start of such drugs, for example Alternatively, the failure to use such drugs once a day may induce gout redness, or it may cause longer, more frequent, or stronger redness. Thus, the pharmacokinetic profile of this (−)-halofenic acid is compared to other uric acid lowering therapies (eg, for a period of time such as the first weeks to months after the start of administration) in preventing gout redness. It contributes to the successful utilization of the compounds of formula (I), (II), (III) and (IV) and their pharmaceutically acceptable salts.

  The compounds of formula (I), (II), (III) and (IV) and their pharmaceutically acceptable salts also have an inhibitory effect and inhibit important pathways of inflammation. The inflammasome is a molecular basis activated by cellular infection or stress that induces maturation of inflammatory cytokines such as interleukin-1 beta (IL-1β) to provide innate immune defense. Therefore, inhibitors of IL-1β have a role in the treatment of gout. See, for example, A. So. and N. Busso, Ann. Rheum. Dis., 68 (10) (2009) and references cited therein. FIG. 4 shows the effect of (−)-halofenic acid in reducing messenger RNA encoding the inflammatory cytokine IL-1β in primary mouse macrophages stimulated with lipopolysaccharide (LPS). (−)-Halofenic acid binds to the transcription factor PPAR-γ and directly exerts its anti-inflammatory effect in this ligand type that interacts and stabilizes with the transcription mechanism located in the promoter of IL-1β. Assumed. In this way, activation of the IL-1β promoter in response to LPS treatment is inhibited by (−)-halofenic acid. FIG. 5 shows the effect of (−)-halofenic acid on decreasing secretion of pro-inflammatory cytokine IL-1β from primary mouse macrophages stimulated with lipopolysaccharide.

  Hypersensitive C-reactive protein (hs-CRP) is another inflammatory marker. FIGS. 6-7 show that administration of (−)-halofenate in human subjects reduced hs-CRP, indicating that formulas (I), (II), (III) for treating gout redness ) Or (IV) or a pharmaceutically acceptable salt or prodrug thereof.

  An additional mechanism that contributes to the successful treatment of gout redness is to inhibit the entry of uric acid into the cells. Uric acid transport into cells is mediated by a number of uric acid transporters, including URAT1, GLUT9 (SLC2A9), OAT4 and OAT10. For example, in adipocytes, uric acid increases the expression of pro-inflammatory cytokines such as MCP-1 (Baldwin et al., Diabetes 60 1258-1269 (2011)). (−)-Halofenic acid is a URAT1 inhibitor, and as such, administration of compounds of formula (I), (II), (III) and (IV) and pharmaceutically acceptable salts thereof is: It would be expected to reduce uric acid-induced inflammatory responses in cells, including adipocytes, macrophages and endothelial cells.

  The methods described herein include reducing the number, duration, frequency or intensity of one or more gout rashes, said method comprising the steps of formulas (I), (II), (III ) Or (IV), or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof. In certain embodiments, the compound is (-)-halofenate, (-)-halofenic acid or a pharmaceutically acceptable salt thereof. In certain embodiments, the number, duration, frequency or intensity of gout redness experienced by the subject is reduced compared to that experienced by the subject before such administration is initiated. In other embodiments, the number, duration, frequency, or intensity of gout redness experienced by the subject is experienced by the subject when the subject has previously received uric acid lowering treatment with a second uric acid lowering drug. Reduced compared to the number, duration, frequency or intensity of gout redness. In some methods of reducing the number, duration, frequency or intensity of gout redness experienced by the subject, any of the additional therapeutic agents (eg, non-steroidal anti-inflammatory drugs (NSAIDs) or redness prevention agents such as colchicine) Dosage or duration is reduced, and in other such methods, no such additional therapeutic agent (eg, NSAID or colchicine) is administered.

  Said second uric acid lowering drug is not a first uric acid lowering drug (ie any compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof) It may be an agent that lowers serum uric acid levels. These second uric acid lowering agents include uric acid production inhibitors (eg, xanthine oxidase inhibitors and purine nucleoside phosphorylase inhibitors), uric acid excretion drugs and uricase. Xanthine oxidase inhibitors include, but are not limited to: allopurinol, febuxostat, oxypurinol, tisoprin, inositol and propolis. In one embodiment, the xanthine oxidase inhibitor is allopurinol, febuxostat, oxypurinol, tisoprine, inositol, phytic acid, myo-inositol, kaempferol, myricetin and quercetin. Allopurinol (1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one), a xanthine oxidase inhibitor, is the primary standard of treatment for lowering uric acid levels. Another xanthine oxidase inhibitor, febuxostat (2- (3-cyano-4-isobutoxyphenyl) -4-methyl-1,3-thiazole-5-carboxylic acid) was reported in February 2009 for gout. Approved for treatment. Purine nucleoside phosphorylase (PNP) inhibitors represent a relatively new approach to lowering serum uric acid levels in patients suffering from hyperuricemia, gout and related diseases. In one embodiment, the PNP inhibitor is forodesine (BCX-1777) (BioCryst Pharmaceuticals, Inc.). In another embodiment, the PNP inhibitor is BCX-4208 (7-(((3R, 4R) -3-hydroxy-4- (hydroxymethyl) pyrrolidin-1-yl) methyl) -3H-pyrrolo [3, 2-d] pyrimidin-4 (5H) -one) (BioCryst Pharmaceuticals, Inc.). BCX4208 monotherapy administered at 40, 80, 120, 160 and 240 mg / day showed a rapid and significant reduction in serum uric acid in gout patients. Uric acid excretion drugs increase renal excretion of uric acid and generally act by reducing absorption of uric acid back to the blood from the renal proximal tubule, for example, by inhibiting uric acid transporters such as SLC22A12. Uric acid excretion drugs include, but are not limited to, probenecid, 2-((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) Thio) acetic acid (RDEA594, lesinurad), potassium 4- (2-((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) thio ) Acetamido) -3-chlorobenzoate (RDEA806), RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin, fenofibrate, guaifenesin, losartan, corticotropin and cortisone. Probenecid is the most commonly used uric acid excretion drug in the United States and can be given to gout patients in combination with allopurinol. Benzbromarone and sulfinpyrazone are also used as first-line uric acid excretion drugs. Guaifenesin, losartan, atorvastatin, amlodipine, adrenocorticotropic hormone (ACTH or corticotropin), fenofibrate and cortisone also have uric acid excretory effects. The uricase or urate oxidase enzyme is found in many mammals other than humans. They can lower uric acid levels by converting uric acid to allantoin, a benign end metabolite that is easily excreted in the urine. Uricase enzymes include, but are not limited to, rasburicase or PEGylated uricase enzyme (PEG-uricase). In one embodiment, the PEGylated uricase enzyme is Krystexa® (PURICASE®; pegloticase) (Savient) approved in the United States for the treatment of chronic gout in adult patients who are ineffective with conventional therapy. Pharmaceuticals, Inc.).

  In certain embodiments, the number of gout redness experienced by a subject is determined by a subject with a second uric acid lowering drug (the second uric acid lowering drug is allopurinol, febuxostat, lesinura or BCX4208). Reduced compared to the number, duration, frequency, or intensity of gout redness experienced by the subject if it was received in the past.

  One method provides for the treatment or management of hyperuricemia in a subject suffering from gout and having reduced the number, duration, frequency or intensity of gout redness experienced by the subject. These methods are characterized by administering a compound of any of formulas (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof to a subject in need of treatment or management. And In certain embodiments, the compound is (-)-halofenate, (-)-halofenic acid or a pharmaceutically acceptable salt thereof.

  In various embodiments, the methods described herein are about 5%, about 10%, about 15%, about 15% compared to serum uric acid levels in a subject prior to administration of the methods described herein. 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% Reducing serum uric acid levels in the subject to about 85%, about 90% or more. In various embodiments, serum uric acid levels are reduced from about 5% to about 50%, from about 25% to about 75%, or from about 50% to about 99%. Methods for determining serum uric acid levels are well known in the art and may be measured as part of a standard chemical panel of blood serum samples.

  In certain embodiments, the methods of the present disclosure can be about 7 mg / dL or less at about 6.5 mg / dL compared to serum uric acid levels in a subject prior to administration of the methods or compositions described herein. Reduce serum uric acid levels in a subject to dL or less, about 6 mg / dL or less, about 5 mg / dL or less, about 4 mg / dL or less, or about 3 mg / dL or less . In certain embodiments, the methods of the present disclosure may be 0.1, 0.2, 0.3, 0.00 compared to serum uric acid levels in a subject prior to administration with the methods or compositions described herein. 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, Reduce serum uric acid levels in subjects to 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0 mg / dL, or higher. In further embodiments, the methods described herein may be 0.1-10.0 mg / dL, 0.5-6.0 mg / dL, 1.0-4.0 mg / dL, or 1.5-2. Reduce serum uric acid levels to 5 mg / dL. Appropriate serum uric acid levels vary from subject to subject, and can vary from subject to subject over time depending on the subject's overall condition. Similarly, the appropriate serum uric acid levels of a group of subjects exhibiting a common medical condition may be different from different groups of subjects exhibiting a different medical condition. Thus, it may be desirable to reduce the serum uric acid level of a given group of subjects to, for example, about 5 mg / dL or less and reduce the serum uric acid level of another group of subjects, for example, to about 4 mg / dL or less. . In certain embodiments, the methods of the present disclosure can measure serum uric acid levels in a subject over a period of time, eg, about 1 week, about 1 month, about 6 months, about 1 year, about 2 years or more. Reducing to an amount sufficient to result in the disappearance, mitigation, remission or prevention of one or more disorders associated with elevated serum uric acid. For example, the method can include serum uric acid in an amount sufficient to eliminate or reduce gout nodules over a period of about 1 week, about 1 month, about 6 months, about 1 year, about 2 years or more. The level can be lowered.

  In a further embodiment, the method of the present disclosure comprises a pharmaceutical composition comprising a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein the serum uric acid level is At least about 4 mg / dL, at least about 5 mg / dL, at least about 6 mg / dL, at least about 6.8 mg / dL, at least about 7 mg / dL, at least about 8 mg / dL, at least about 9 mg / dL, at least about 10 mg / dL, or Administered to a patient that is at least about 11 mg / dL. Again, the appropriate amount of reduction in serum uric acid levels can vary depending on the patient and the overall condition of the patient. Similarly, an appropriate amount of reduction in serum uric acid levels in a group of subjects exhibiting a common medical condition may be different from another group of subjects exhibiting a different medical condition.

  The methods described herein can be performed by administration of a compound that results in a chemical reaction after administration, resulting in a compound of formula (IV) or a salt thereof. Such compounds include prodrugs of compounds of formula (IV). Prodrugs of compounds are prepared by modifying functional groups present in the compound so that it can be cleaved in vivo to release the parent compound or active metabolite. For example, prodrugs include compounds in which a hydroxy, amino or sulfhydryl group in a compound is cleaved in vivo to attach a free hydroxyl, amino or sulfhydryl group to a group that can be regenerated, respectively. Certain prodrugs increase the bioavailability of such compounds when the compound of an embodiment is administered to a subject (eg, by making the orally administered compound more readily absorbed into the blood) or the parental Compared to a species, delivery of the parent compound to certain organs or tissues (eg, kidney, adipose tissue, liver, muscle or joint) may be enhanced. More specifically, prodrugs of compounds of formula (IV) include esters, amides and carbamates (eg, N, N-dimethylaminocarbonyl) of hydroxy functional groups of compounds of formula (IV). Compounds of formula (I), (II) and (III) are non-limiting examples of prodrugs of formula (IV). Additional examples of prodrugs can be found in 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 ACS Symposium Series (1975), each of which can be found in Which is incorporated herein by reference.

  Compounds of formula (I), (II), (III) and (IV) and their pharmaceutically acceptable salts exhibit therapeutic activity when administered in amounts that may depend on the specific case. it is conceivable that. The variation in amount can depend, for example, on the subject being treated and the active ingredient chosen. A wide range of doses may be applicable. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses can be administered once a day, once a week, once a month, or at other suitable time intervals, or as indicated by the urgency of the situation Can be reduced proportionally. Such dosage is a number of variables, including but not limited to, one or more active ingredients used, the disease or disorder to be treated, the mode of administration, the condition of each subject, the condition being treated It may vary as appropriate depending on the severity of the disease or disorder and the judgment of the doctor.

  A wide range of doses of a compound of formula (I), (II), (III) or (IV) may be considered, depending on factors such as diagnosis, symptoms and therapeutic purpose of a subject. In various embodiments, the compound may be administered at about 10 mg to about 1000 mg per day. For example, halofenate, halofenic acid or a pharmaceutically acceptable salt thereof is about 50 mg / day, about 100 mg / day, about 200 mg / day, about 300 mg / day, about 400 mg / day, about 500 mg / day, about 600 mg / day. It may be administered at about 700 mg / day, about 800 mg / day, about 900 mg / day, or about 1000 mg / day.

  Dose escalation or escalation protocols may be used to determine the appropriate or optimal dose for administration to a subject. For example, dose escalation or escalation experiments can be selected for doses that improve efficacy and tolerability. Dose escalation or increase makes it possible to gradually adjust the dose administered until the desired effect is achieved. Dose escalation gradually decreases the dose administered, while dose increase gradually increases the dose administered. Methods of dose escalation or increase are well known in the art. As a non-limiting example, a subject can be administered halofenate, halofenic acid or a pharmaceutically acceptable salt thereof at 200 mg / day once daily and measured daily for serum uric acid levels. The dose may be increased or decreased, for example, on a weekly basis. The subject can be monitored, for example, for 2-12 weeks to find the desired dose.

  The compounds of formula (I), (II), (III) or (IV) can be incorporated into various formulations and medicaments for therapeutic administration. More specifically, these compounds can be formulated into a pharmaceutical composition or formulation in combination with a suitable pharmaceutically acceptable carrier or diluent, such as tablets, capsules, pills, powders , Granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants and aerosols, and can be formulated into preparations in solid, semi-solid, liquid or gaseous form. As such, administration of the compound can be accomplished in a variety of ways, including buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal or intratracheal administration. Furthermore, the compounds can be administered locally rather than systemically in a depot or sustained release formulation. Alternatively, the compound can be administered in liposomes.

  A compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof may also be formulated with common excipients, diluents or carriers and compressed into tablets. Or formulated as an elixir or vehicle for convenience of oral administration, or administered by intramuscular or intravenous routes. The compound can be administered transdermally and can be formulated as a sustained release preparation. In one embodiment, the method may further comprise administration of a second uric acid lowering drug selected from the group consisting of a xanthine oxidase inhibitor, a uric acid production inhibitor, a uric acid excretion drug and a uricase. In one embodiment, the method has a serum uric acid level of at least about 4 mg / dL, at least about 5 mg / dL, at least about 6 mg / dL, at least about 6.8 mg / dL, as described herein. A first uric acid lowering agent and a second therapeutic agent in a subject that is at least about 7 mg / dL, at least about 8 mg / dL, at least about 9 mg / dL, at least about 10 mg / dL, or at least about 11 mg / dL It is characterized by administering a composition. The appropriate amount of reduction in serum uric acid levels can vary depending on the subject and on the overall condition of the subject. Similarly, the appropriate amount of reduction in serum uric acid levels for a group of subjects sharing a common medical condition may differ from that appropriate for different groups of subjects sharing a different medical condition. In certain embodiments, the application provides a method of combination therapy and co-administration of first and second uric acid lowering drugs (these first and second uric acid lowering drugs are described herein). provide. Combination therapy and co-administration mean administration of the two agents (ie, a first agent and a second uric acid lowering agent as described herein) in a manner where a pharmacological effect appears simultaneously in the subject. Thus, such administration should be used to administer both the first and second uric acid lowering drugs, even in a single pharmaceutical composition, the same type of formulation, the same dosage form or even the same route of administration. Neither does it require, nor does it require that the two drugs be administered kinetically. Such administration can be most conveniently accomplished by the same formulation and route of administration at substantially the same time. For example, a first uric acid lowering drug, such as halofenate, halofenic acid or a pharmaceutically acceptable salt thereof, and a second uric acid lowering drug, such as a xanthine oxidase inhibitor (eg, allopurinol or febuxostat) A single oral dosage composition (eg, tablet or capsule) can be administered together to a human subject, or each agent can be administered in a separate oral dosage formulation. One advantage of the separate formulation is that it adds a degree of freedom during dosing, that is, the dosing of the first and second urate-lowering drugs can be changed independently, rapidly and conveniently. it can. When separate dosage formulations are used, the first and second uric acid lowering agents can be administered as essential (i.e., simultaneously or together), or separately in time lag (i.e., sequentially). In another embodiment, the second uric acid lowering drug is a xanthine oxidase inhibitor, preferably allopurinol, febuxostat, oxypurinol, tisoprine, inositol, phytic acid, myo-inositol, kaempferol, myricetin and quercetin Selected from the group consisting of, in particular, allopurinol or febuxostat. In yet another embodiment, the second uric acid lowering agent is allopurinol and is administered at about 50 mg to about 800 mg per day. In another embodiment, the first uric acid lowering drug is (−)-halofenate and is administered at about 100 mg to about 600 mg per day, and the second uric acid lowering drug is febuxostat, Administered at about 40 mg to about 120 mg per day. In another embodiment, the second uric acid lowering drug is a uric acid excretion drug, preferably probenecid, 2-((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1 , 2,4-Triazol-3-yl) thio) acetic acid, potassium 4- (2-((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole) Selected from the group consisting of -3-yl) thio) acetamido) -3-chlorobenzoate, RDEA684, benzbromarone, sulfinpyrazone, amlodipine, atorvastatin, fenofibrate, guaifenesin, losartan, corticotropin and cortisone, in particular , Probenecid.

  In various embodiments, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof can be administered at a high frequency. For example, in various embodiments, the compound can be administered once daily (QD), twice daily (BID), three times daily (TID), or four times daily (QID). In one embodiment, the compound is administered once daily (QD). In another embodiment, the compound is administered twice daily (BID). In other embodiments, administration of the compound can be omitted without adverse effects, i.e., the compound exceeds the “drug period” (drug period is the omitted period of dosing). (Ie, before and after). For example, in a daily dosing schedule, the compound can be administered over a one-day washout period without the subject experiencing substantial or material adverse effects due to omission of administration (ie, Can be administered on days N and N + 2 instead of days N + 1 (where N is any day)). In certain embodiments, the drug holiday may be 2 days. In other embodiments, the drug holiday can be 2 days or more.

  In various embodiments, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof can be administered over a wide range of periods. For example, in various embodiments, the compound is about 4 weeks or longer, about 1 month or longer, about 3 months or longer, about 6 months or longer, about 1 year or longer, It can be administered for about 2 years or longer, about 5 years or longer, or about 10 years or longer. In certain embodiments, the administration can be non-limiting, for example, during the lifetime of the subject.

  The pharmacokinetic profile of (−)-halofenic acid can be adjusted by the dose, frequency and duration of administration of the compound or prodrug thereof. One indicator of the pharmacokinetic profile is the highest-lowest plasma concentration defined as the highest blood plasma concentration divided by the lowest blood plasma concentration of the compound or drug within a time interval (eg, within the corresponding interval of dosing frequency). Is the ratio. For example, one method comprises administering to a subject about 100 to about 1000 mg per day of a compound of formula (I), (II), (III) and (IV) or a pharmaceutically acceptable salt thereof. It includes providing the subject with a ratio between the highest and lowest daily (−)-halofenic acid characteristics of about 2.0 or less. In various embodiments, the ratio between the day's highest and lowest is about 1.7 or less, about 1.5 or less, about 1.4 or less, or about 1.3 or less. In embodiments, the ratio between the day's highest and lowest is provided after daily administration of the compound for at least about 10 days, such as at least about 12 days. The pharmacokinetic profile will also depend on the route of administration and may depend on the compound and formulation administered to the subject. For example, some methods include oral alhalofenates (ie, (ie, (as described above, tablets, capsules, pills, etc.) at doses of 100-1000 mg per day. Including providing the subject with a ratio between the day's highest and lowest (−)-halofenic acid of about 2.0 or less, characterized in that-)-halofenate) is administered to the subject.

  Certain methods described herein may comprise a compound of formula (I), (II), (III) and (IV) or pharmaceutical thereof at a fixed dosage, frequency and duration as provided herein. Can be performed by administering a pharmaceutically acceptable salt. For example, one method is the treatment of hyperuricemia in a subject suffering from gout, wherein the subject is in need of a compound of formula (I), (II), (III) and (IV) or Administering a pharmaceutically acceptable salt, wherein the dosage, frequency and duration of said administration are to reduce the number, duration, frequency or intensity of gout redness experienced by the subject during said period. Provide a treatment that is effective. In certain embodiments, the compound is an alhalofenate. In certain embodiments, the dose is about 100 mg to about 1000 mg. In one embodiment, the frequency is daily. In certain embodiments, the period is about 4 weeks or longer. In another embodiment, the period is about 1 month or longer, about 3 months or longer, about 6 months or longer, about 1 year or longer, about 2 years or longer, about 5 months Annual or longer, or about 10 years or longer. In certain embodiments, the administration can be non-limiting, for example, during the lifetime of the subject. In certain embodiments, the administration spans a daily and daily drug holiday. In certain embodiments, the method is further characterized by administering alhalofenate to the subject orally in an oral formulation. Specific embodiments covering the compositions, formulations and methods of their use are described in the title of the invention filed on the same date as this application “high in patients suffering from gout with halofenate or halofenic acid and a second uric acid lowering drug”. PCT patent application "Method for treating uricemia", which is incorporated herein in its entirety. Embodiments of the present application are characterized by the specification and by the features of the claims of the present application as filed and the corresponding pharmaceutical compositions, methods and uses of these compounds.

Method The method used with respect to FIGS. 1-2 showing the pharmacokinetic profile of (−)-halofenic acid was as follows:

  Plasma proteins in human plasma samples containing (-)-halofenic acid, internal standard (IS) and heparin as anticoagulant were precipitated with acetonitrile. The sample was vortexed, centrifuged, and aliquots were analyzed by reverse phase high performance liquid chromatography using a Phenomenex Polar RP column while maintaining 45 ° C. The mobile phase was nebulized with heated nitrogen in a Z-spray source / interface and the ionized compounds were detected using a tandem quadrupole mass spectrometer.

  The plasma concentration was rounded to the nearest 0.1 μg / mL before calculation. A plasma sample containing a concentration below the limit of quantification (BQL) of 1.0 μg / mL was taken as a value of zero.

  The method used with respect to FIG. 3 showing the decrease in serum uric acid in the subject over time after administration once a day with alhalofenate was as follows.

Single-center, phase I, placebo- and positive control, double-blind, randomized dose escalation study (MAD study, MBX102-2DM01011b) is a protocol for healthy adult subjects--oral daily at a specific dose for 10 days This was done to evaluate the multi-dose pharmacokinetics (PK) of (−)-halofenate administered as a dose. A total of 119 subjects completed the study treatment according to the protocol: 6 subjects who took MBX-102 100 mg / day for 10 days; 6 subjects who took MBXZ-102 200 mg / day for 10 days; MBX-102 400 mg 9 subjects who took 10 days / day; 20 subjects who took MBX-102 600 mg / day for 10 days; 10 people who took 600 mg / day MBX-102 (EX) with enteric coating 9 subjects who received MBX-102 800 mg EC / day for 10 days; 10 subjects who received MBX-102 1000 mg EC / day for 10 days; 24 subjects who took placebo treatment every day for 10 days; Naproxen 500 mg b. i. d 25 subjects who took 7 days of monotherapy. In this experiment, serum uric acid was measured at screening and on days 1, 3, 5, 7, 9, 14, and 21.
Table 1

  As shown in FIG. 3 and Table 1, the data from the MBX102-2DM01011b experiment show that treatment with (−)-halofenate resulted in a gradual increase in serum uric acid over time at all dose levels tested in a dose-dependent manner. Indicates to decrease.

  The method used with respect to FIGS. 4-5 showing the effect of (−)-halofenic acid IL-1β was as follows:

  Eight week old male C57BL / 6J mice were injected intraperitoneally with 2.5 mL of 3% thioglycolate. On day 3 after injection, the mice were sacrificed by cervical dislocation. Macrophages were quickly collected by injecting 5 mL of PBS into the abdominal cavity, surgically exposing the abdominal cavity, and aspirating the peritoneal fluid with a 1 mL syringe. Macrophages from multiple animals were stored and centrifuged at 1500 rpm for 10 minutes at 4 ° C. Contaminated red blood cells were removed from the precipitate by lysis with 10 mL RBC lysis buffer for 5 minutes at room temperature followed by centrifugation at 1500 rpm for 10 minutes at 4 ° C. The fat was washed once, resuspended in RPMI 1640, 10% FBS / 0.1% Pen / Strep and plated into multiwell plates (for 24 well plates, 1,000,000 cells / 100,000 cells / well for wells and 96-well plates). The cells were cultured for 30 hours, re-fed with fresh RPMI 1640, 0.5% FBS and incubated overnight. The cells were treated with DMSO, (−)-halofenic acid (75 and 150 μM) for 1 hour, followed by stimulation with 100 ng / mL LPS for an additional 8 hours. Subsequently, cell supernatants stimulated with LPS were harvested and stored at −20 ° C., after which secreted cytokine levels were analyzed using the Procarta® Cytokine Profiling Kit (Panomics Inc., Fremont, Calif.).

The cells were harvested with Qiazol lysis solution for gene expression analysis. RNA is isolated (using MagAttract RNA Universal Tissue M48 Kit according to manufacturer's instructions), cDNA is prepared by reverse transcription (using High Capacity cDNA reverse transcription kit according to manufacturer's instructions), then RT-PCR ( Taqman) was performed in 96 well PCR plates using a gene expression assay mix for IL-1β (ABI catalog number: Mm00434228_m1) and Taqman fast universal PCR master mix. IL-1β Ct values were determined using ABI sequence detection software. Gene expression “fold change compared to LPS” was calculated using the comparative Ct method for relative quantification as recommended by ABI (Foster City, Calif.). This method is related to comparing the Ct value of sample + LPS pre-treated with the compound with sample + LPS treated with vehicle. Ct values for both compound and vehicle treated samples were normalized with the endogenous housekeeping gene (GAPDH). This method is also known as the 2 ^-[delta] [delta] Ct method, where [delta] [delta] Ct = [delta] Ct (sample)-[delta] Ct (control)). Where [delta] Ct (sample) is the Ct value for the sample treated with the compound normalized to the endogenous housekeeping gene, and [delta] Ct (control) is the vehicle normalized to the endogenous housekeeping gene. It is a Ct value about the sample processed by. Next, the change in magnification is calculated using Expression 2 ^-[delta] [delta] Ct. Each experimental condition was performed in 4 wells. “Fold change compared to LPS” data from replicate experiments were pooled and significant differences were tested using one-way analysis of variance with Tukey post hoc test ( ^* = p <0.05, ^** = p <0 .01 and ^*** = p <0.001).

The data shown in FIGS. 6 and 7 is the first of a single institution to evaluate the effect of (−)-halofenate given to type 2 diabetic patients who received a stable dose of Glynase® (micronized glyburide). Created based on a phased, randomized, single-blind repeated dose study (M102-0507). Eligible patients are initially administered Glynase® at 3 mg / day for 3 days, and if safety and tolerability is approved by the investigator, the dose is up to Glynase® 6 mg / day Increased for 4 days, then up to day 21 administered Glynase® 6 mg and either (−)-halofenate 400 mg or 600 mg for 14 days and the patient was discharged on day 22. This schedule is summarized in Table 2.
Table 2

In this experiment, the change in hypersensitive C-reactive protein (hs-CRP) from baseline was one of the endpoints. It was observed that hs-CRP increased from day 1 to day 8 (20.8% in group 1 and 15.6% in group 2) and then decreased between days 8 and 22. . On day 22, the mean percent change in C-reactive protein compared to day 1 was -21.1 in group 1 ((-)-halofenate 400 mg) and group 2 ((-)-halofenate 600 mg), respectively. % And -32.9%.
Table 3
Treatment with (-)-halofenate 600 mg (days 8-22)

  As shown in FIGS. 6-7 and Table 3, data from the M102-10507 study indicated that treatment with (−)-halofenate at a daily dose of 600 mg was achieved on day 1 (baseline) and day 8 (glyburide only The period) shows a significant decrease in hs-CRP. The mean hs-CRP changes were -32.9% (p = 0.0001) and -33.3% (p = 0.0214), respectively.

Example 1: Suppression of uric acid-induced inflammation in vitro Differentiated mouse 3T3-L1 adipocytes are cultured in vitro in 24-well plates. To the medium, (−)-halofenic acid was added at a final concentration of 50 to 150 μM, uric acid was added at 5 mg / dL or 15 mg / dL, and the culture was continued for 3 or 7 days. Parallel culture of the cells is performed in the presence of a vehicle such as dimethyl sulfoxide (DMSO). At the end of the culture period, the medium was removed, the cells were isolated, and messenger RNA was prepared. Pro-inflammatory cytokine populations (including but not limited to monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor α (TNF-α), interleukin-1β, (IL-1β), interleukin Levels of secreted cytokines (including -6 (IL-6) and interleukin-12 (Il-12)) are examined in media isolated from cells using commercially available cytokine assay kits. Pro-inflammatory cytokine populations (including but not limited to monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor α (TNF-α), interleukin-1β, (IL-1β), interleukin The level of gene expression of mRNA for -6 (including IL-6) and interleukin-12 (Il-12) is examined using real-time PCR. The addition of (−)-halofenate inhibits the uptake of uric acid into 3T3-L1 adipocytes, thereby suppressing the uric acid-induced inflammatory response, resulting in the expression level of this pro-inflammatory cytokine population, Subsequently secretion is reduced. Similar tests are also performed on primary mouse macrophages and human umbilical vein endothelial cells.

Example 2: Animal Gout Redness Model R. Torres et al., Ann. Rheum. Dis. 68, 1602-08 (2009) (http://ard.bmj.com), which is incorporated herein by reference in its entirety. Use the model described in /content/68/10/1602.long). Briefly, 20 C57BL6 mice are obtained from Jackson Laboratories (Bar Harbor, Maine, USA) and 12-16 weeks old are used. The mice are kept alone for at least one week prior to testing and are always free to take food and water. Alhalofenate is administered to half (10 mice) of mice (test mice) at a dose of 125 mg / kg daily during periods including, for example, 1 day, 5 days and 2 weeks prior to induction of inflammation by uric acid. Oral administration. The remaining 10 mice (control mice) receive a vehicle consisting of 1% carboxymethylcellulose // 2% Tween-80. In another method of treatment, alhalofenate is co-administered during uric acid treatment.

  Crystals of monosodium urate (MSU) are prepared as described in R. Liu-Bryan et al., Arthritis Rheum. 52, 2936-46 (2005). In one model, MSU crystals (0.5 mg) are suspended in 20 microliters of endotoxin-free PBS and injected intramuscularly into tibia tarsal joints (ankles) of mice anesthetized with 2.5% isoflurane. Thermal hyperalgesia, load capacity, angular joint diameter and histological analysis are performed according to Torres et al. Above. Pro-inflammatory cytokine populations (including but not limited to monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor α (TNF-α), interleukin-1β, (IL-1β), interleukin Secretion levels of -6 (including IL-6) and interleukin-12 (Il-12) are measured in fluid isolated from the injected joint. The joints were dissected and homogenized to prepare mRNA and the gene expression level of the same population of pro-inflammatory cytokines was determined. In another model, mice are injected intraperitoneally with 1 mg MSU suspended in 0.5 mL of endotoxin-free PBS. After 6 hours, the mice were sacrificed, their peritoneal cavity was washed, and stained with a rat anti-mouse Ly-6G monoclonal antibody conjugated with the neutrophil specific antibody R-phycoerythrin for measurement of neutrophil influx. Collect in In another model, an air sac is introduced subcutaneously and 1 mg of MSU is injected into the air sac. Six hours after crystal injection, cells resident in the air sac are collected by perfusion with 5 mL of buffer. Neutrophil infiltration is measured by staining as described above. Monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor α (TNF-α), interleukin-1β, (IL-1β), interleukin-6 (IL-6) and interleukin-12 ( The level of Il-12) is also measured in the perfused fluid isolated from the air sac infused with uric acid.

Example 3: Clinical trial comparing the efficacy of alhalofenate in reducing gout redness between initiation and maintenance of treatment for uric acid reduction This is a double-blind, parallel group, multicenter, randomized trial It is.

Primary endpoint Percentage of patients experiencing acute gout redness in each time frame of treatment weeks 0-2, treatment weeks 3-12, and treatment weeks 11-12.

Secondary endpoint:
a. Total number of gout redness b. Gout redness period c. Patient discontinuation due to gout redness d. The severity of gout redness

Treatment plan:
Individuals are randomized into three groups: a control group (n = 100) and two experimental groups (each n = 100). Allopurinol (300 mg) is administered once daily to subjects in the control group. Subjects in the experimental group are administered alhalofenate (400 mg or 600 mg) in tablets once a day. All patients receive redness prevention for the first 2 weeks of treatment. The duration of treatment with the blinded study drug is 3 months.

Study patient criteria:
Male or female, 18 years old or older.
Women with the possibility of pregnancy must be negative in the pregnancy test. Women who are likely to become pregnant should be infertile or contraceptive.
Serum uric acid> 6.0 mg / dL and <12 mg / dL
Gout is diagnosed according to the 1980 ARA classification criteria for primary arthritis of primary gout.

analysis:
The main analysis is based on a comparison of the control and alhalofenate groups with the proportion of subjects experiencing redness, with the purpose for the therapeutic approach. Pairwise comparisons between groups are performed using Fisher's exact test.

  While the above description describes specific embodiments, those skilled in the art will recognize that various modifications and alternatives may be developed. Accordingly, the specific embodiments and examples described above are illustrative only and are not intended to limit the scope of the invention, which is encompassed by the full scope of the claims and any one thereof. It should be given to all equivalents.

Claims (16)

  Gout redness experienced by a subject comprising a compound (-)-halofenate or (-)-halofenic acid substantially free of their (+)-enantiomer or a pharmaceutically acceptable salt thereof. An oral drug to treat or to reduce the number, duration, frequency, or intensity of gout redness.   The oral medicament according to claim 1 for treating gout redness.   The oral medicament according to claim 1 for reducing the number, duration, frequency or intensity of gout redness.   The oral drug according to any one of claims 1 to 3, wherein the compound is (-)-halofenate and is substantially free of the (+)-enantiomer.   The compound according to any one of claims 1 to 3, wherein the compound is (-)-halofenic acid which is substantially free of the (+)-enantiomer or a pharmaceutically acceptable salt thereof. The oral drug described.   The oral drug according to any one of claims 1 to 5, wherein the compound is administered at 100 mg to 1000 mg per day.   The oral drug according to claim 6, wherein the compound is administered at 400 mg, 600 mg, 800 mg, or 1000 mg per day.   The oral drug according to any one of claims 1 to 7, wherein the amount of the compound is effective for once-daily dosing.   The oral drug according to any one of claims 1 to 8, wherein the compound is administered for 4 weeks or longer.   The oral medicine according to any one of claims 1 to 9, wherein the subject is also administered with a redness preventing agent.   The oral medicine according to claim 10, wherein the redness preventing agent is NSAID or colchicine.   The oral medicine according to claim 11, wherein the redness preventing agent is colchicine.   The oral medicine according to any one of claims 1 to 12, wherein the subject is further administered with a uric acid lowering drug which is a xanthine oxidase inhibitor, a uric acid production inhibitor, a uric acid excretion drug or a uricase.   The oral drug according to claim 13, wherein the uric acid lowering drug is allopurinol or febuxostat.   The oral drug according to claim 14, wherein the uric acid lowering drug is febuxostat.   14. The agent according to claim 13, wherein the uric acid lowering drug is probenecid, benzbromarone, or sulfinpyrazone.

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