TW201020240A - Compositions comprising 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid and pharmaceutically acceptable salts thereof, and methods for preparing and using same - Google Patents

Compositions comprising 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid and pharmaceutically acceptable salts thereof, and methods for preparing and using same Download PDF

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TW201020240A
TW201020240A TW098136211A TW98136211A TW201020240A TW 201020240 A TW201020240 A TW 201020240A TW 098136211 A TW098136211 A TW 098136211A TW 98136211 A TW98136211 A TW 98136211A TW 201020240 A TW201020240 A TW 201020240A
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compound
pharmaceutical composition
weight
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TW098136211A
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Colin Edward Rowlings
Barry D Quart
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Ardea Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Abstract

The present invention relates to compositions comprising 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1, 2, 4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid or pharmaceutically acceptable salts thereof, and to the preparation and use of such compositions, in particular for the treatment of diseases.

Description

201020240 六、發明說明： 本申請案主張2008年1〇月24曰申請的美國臨時申請案第 61/108,412號之優先權，該案之全文以引用的方式併入本 文中。 【先前技術】 . 4-(2-(5-溴-4-(1-環丙基萘 _4_ 基）-4Η-1，2,4-***-3-基硫 基）乙醯胺基）-3 -氣苯甲酸、其前藥及/或醫藥上可接受之 鹽適用於治療及預防疾病。本文描述包含4-(2-(5-溴-4-(1-© 環丙基萘基）-4Η-1，2,4-三吐-3-基硫基）乙醯胺基）_3_氣苯 曱酸、其前藥及/或醫藥上可接受之鹽之組合物，及使用 該等組合物例如治療疾病之方法。201020240 VI. INSTRUCTIONS: This application claims priority to U.S. Provisional Application No. 61/108,412, filed on Jan. 24, 2008, the entire disclosure of which is hereby incorporated by reference. [Prior Art] . 4-(2-(5-Bromo-4-(1-cyclopropylnaphthalenyl-4-yl)-4Η-1,2,4-triazol-3-ylthio)acetamidoamine -3 - benzoic acid, its prodrugs and / or pharmaceutically acceptable salts are suitable for the treatment and prevention of diseases. Described herein includes 4-(2-(5-bromo-4-(1-)cyclopropylnaphthyl)-4Η-1,2,4-trioxa-3-ylthio)ethinyl)_3_ A composition of gas benzoic acid, a prodrug thereof, and/or a pharmaceutically acceptable salt, and a method of using the composition, for example, to treat a disease.

【發明内容】 在某些實施例中，本文揭示一種組合物，其包含大於約 ❿SUMMARY OF THE INVENTION In certain embodiments, disclosed herein is a composition comprising greater than about ❿

35重量°/〇之結構（I)化合物或結構⑴化合物之混合物： ①；其中Μ為氫、鈉、鉀、鈣或精胺酸。 在一些實施例中，該組合物包含大於約60重量％之結構⑴ 化合物或結構（I)化合物之混合物。在一些實施例中，該組 合物包含大於約70重量％之結構⑴化合物或結構（I)化合物 之混合物。在一些實施例中，該組合物包含大於約80重量 144188.doc 201020240 %之結構（i)化合物或結構（i)化合物之混合物。在一些實施 例中，該組合物包含至少100 mg結構（I)化合物或結構（I)化 合物之混合物。在一些實施例中，該組合物包含至少2 5 0 mg結構（I)化合物或結構（I)化合物之混合物。在一些實施 例中，該組合物包含至少500 mg結構（I)化合物或結構（I)化 合物之混合物。在一些實施例中，該組合物包含至少7 5 0 mg結構（I)化合物或結構（I)化合物之混合物。在一些實施 例中，該組合物包含至少800 mg結構（I)化合物或結構（I)化 合物之混合物。在一些實施例中，該組合物包含約100 mg、約 200 mg、約 300 mg、約 400 mg、約 500 mg、約 600 mg、約 700 mg、約 800 mg、約 900 mg或約 1000 mg結構（I) 化合物或結構（I)化合物之混合物。在一些實施例中，該組 合物包含約600 mg、約800 mg或約1000 mg結構（I)化合物 或結構（I)化合物之混合物。在一些實施例中，該組合物包 含約600 mg結構（I)化合物或結構（I)化合物之混合物。在一 些實施例中，該組合物包含約800 mg結構（I)化合物或結構 (I)化合物之混合物。在一些實施例中，該組合物包含約 1000 mg結構（I)化合物或結構（I)化合物之混合物。在一些 實施例中，該組合物進一步包含一或多種醫藥上可接受之 稀釋劑、黏合劑、潤滑劑、包衣劑（coating a_gent)、隔離 包衣（barrier coating)、增塑劑、分散劑或薄膜衣添加劑。 在一些實施例中，該組合物進一步包含一或多種醫藥上可 接受之稀釋劑。在一些實施例中，稀釋劑為微晶纖維素、 矽化微晶纖維素、纖維素、乳糖、可壓縮糖、甘露糖醇、 144188.doc 201020240 石夕_料_、磷酸鈉、碳義，或合。在一此實 施例中’稀釋劑呈粉末形式。在—些實施例中劑呈 顆粒形式。在一此眘说/丨丄 此實⑽… 釋劑為微晶纖維素。在- 合物進一步包含一或多種醫藥上可接受 σ 在些實施例中，黏合劑為羥丙甲纖维辛35 parts by weight / 〇 structure (I) compound or structure (1) a mixture of compounds: 1; wherein hydrazine is hydrogen, sodium, potassium, calcium or arginine. In some embodiments, the composition comprises greater than about 60% by weight of the structure (1) compound or a mixture of structures (I). In some embodiments, the composition comprises greater than about 70% by weight of the structure (1) compound or a mixture of structures (I). In some embodiments, the composition comprises greater than about 80 weights of 144188.doc 201020240% of the structure (i) compound or a mixture of structures (i). In some embodiments, the composition comprises at least 100 mg of a compound of structure (I) or a mixture of structures (I). In some embodiments, the composition comprises at least 250 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises at least 500 mg of a compound of structure (I) or a mixture of structures (I). In some embodiments, the composition comprises at least 750 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises at least 800 mg of a compound of structure (I) or a mixture of structures (I). In some embodiments, the composition comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg of structure (I) a compound or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 600 mg, about 800 mg, or about 1000 mg of a mixture of a structure (I) compound or a structure (I) compound. In some embodiments, the composition comprises about 600 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 800 mg of a compound of structure (I) or a mixture of structures (I). In some embodiments, the composition comprises about 1000 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition further comprises one or more pharmaceutically acceptable diluents, binders, lubricants, coating a_gent, barrier coating, plasticizers, dispersants Or film coating additives. In some embodiments, the composition further comprises one or more pharmaceutically acceptable diluents. In some embodiments, the diluent is microcrystalline cellulose, deuterated microcrystalline cellulose, cellulose, lactose, compressible sugar, mannitol, 144188.doc 201020240, ___, sodium phosphate, carbon, or Hehe. In one such embodiment the ' diluent is in powder form. In some embodiments the agent is in the form of particles. Be careful here / 丨丄 This is the real (10)... The release agent is microcrystalline cellulose. The composition further comprises one or more pharmaceutically acceptable σ. In some embodiments, the binder is hydroxyprocarbin

Venose)Venose)

基纖維素或㈣。在-些實施例中，黏合劑為㈣甲纖維 素。在-些實施例中，該組合物進一步包含—或多種醫藥 上可接受之潤滑齊卜在一些實施例中，潤滑劑為硬脂酸 鎂、硬脂酸或硬脂反丁烯二酸鈉。在一些實施例中，潤滑 劑為硬脂酸鎂。在一些實施例中’該組合物進一步包含一 或多種醫藥上可接受之隔離包衣。在—些實施例中，醫藥 上可接受之隔離包衣為醫藥上可接受之腸溶包衣。在一些 實施例中，隔離包衣為羥丙甲纖維素或聚乙烯醇。在一些 實施例中，隔離包衣為羥丙甲纖維素。在—些實施例中， 該組合物進一步包含一或多種醫藥上可接受之包衣劑。在 一些實施例中’包衣劑為基於甲基丙烯酸之共聚物、Cellulose or (iv). In some embodiments, the binder is (tetra)methylcellulose. In some embodiments, the composition further comprises - or a plurality of pharmaceutically acceptable lubricating agents. In some embodiments, the lubricant is magnesium stearate, stearic acid or sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the composition further comprises one or more pharmaceutically acceptable barrier coatings. In some embodiments, the pharmaceutically acceptable barrier coating is a pharmaceutically acceptable enteric coating. In some embodiments, the barrier coating is hypromellose or polyvinyl alcohol. In some embodiments, the barrier coating is hypromellose. In some embodiments, the composition further comprises one or more pharmaceutically acceptable coating agents. In some embodiments, the coating agent is a methacrylic acid based copolymer,

Eudragit L30D55、Acryl-Eze、乙酸丁二酸經丙基甲基纖 維素、聚乙酸乙烯酯鄰苯二曱酸酯、乙酸鄰笨二甲酸纖維 素或其組合。在一些實施例中，包衣劑為基於甲基丙烯酸 之共聚物、Eudragit L30D55或Acryl-Eze。在一些實施例 中，該組合物進一步包含一或多種醫藥上可接受之增塑 劑。在一些實施例中，增塑劑為檸檬酸三乙酯、三乙酸甘 油酯、鄰笨二甲酸二丁酯、鄰苯二甲酸二乙酯或甘油。在 144188.doc 201020240Eudragit L30D55, Acryl-Eze, succinic acid acetate by propylmethylcellulose, polyvinyl acetate phthalate, acetate o-dicarboxylate or a combination thereof. In some embodiments, the coating agent is a methacrylic acid based copolymer, Eudragit L30D55 or Acryl-Eze. In some embodiments, the composition further comprises one or more pharmaceutically acceptable plasticizers. In some embodiments, the plasticizer is triethyl citrate, glyceryl triacetate, dibutyl o-dicarboxylate, diethyl phthalate or glycerin. At 144188.doc 201020240

一些實施例中， 中，該組合物進-添加劑。在一些實施例中，薄膜衣添加劑為滑石粉、單硬 脂酸甘油醋或膠狀二氧化矽。在一些實施例中，薄膜衣添 加劑為滑石粉。在一些實施例中，該組合物進一步包含一 或多種醫藥活性化合物。在一些實施例中，該一或多種醫 藥活性化合物之至少一者具有抗病毒活性。在一些實施例 中，該組合物進一步包含兩種醫藥活性化合物。在一些實 施例中’該兩種醫藥活性化合物之至少一者具有抗病毒活 性。在一些實施例中，該組合物為單一劑型。在一些實施 例中，Μ為氫或鉀。在一些實施例中，μ為鉀。在一些實 施例中’該組合物適用於經口投與哺乳動物。在一些實施 例中，該組合物適用於經口投與人類。In some embodiments, the composition is an additive. In some embodiments, the film coating additive is talc, glycerol monostearate or colloidal cerium oxide. In some embodiments, the film coating additive is talc. In some embodiments, the composition further comprises one or more pharmaceutically active compounds. In some embodiments, at least one of the one or more pharmaceutically active compounds has antiviral activity. In some embodiments, the composition further comprises two pharmaceutically active compounds. In some embodiments, at least one of the two pharmaceutically active compounds has antiviral activity. In some embodiments, the composition is in a single dosage form. In some embodiments, the hydrazine is hydrogen or potassium. In some embodiments, μ is potassium. In some embodiments the composition is suitable for oral administration to a mammal. In some embodiments, the composition is suitable for oral administration to humans.

在某些實施例中，本文揭示一種組合物，其包含結構⑴ 化合物或結構（I)化合物之混合物： 其中Μ為氫、鈉、鉀、鈣或精胺酸；及一或多種稀釋劑； 一或多種黏合劑；一或多種包衣劑；一或多種分散劑；及 一或多種增塑劑。在一些實施例中，該組合物為單一劑 在一些實施例中’該組合物經囊封。在一些實施例中， 該組合物係囊封於硬明膠膠囊内。在一些實施例中，Μ為 氫或鉀。在一些實施例中，Μ為鉀。在一些實施例中，稀 144188.doc • 6 - 201020240 釋劑為微晶纖維素、矽化微晶纖維素、纖維素、乳糖、可 壓縮糖、甘露糖醇、呈粉末及顆粒形式之矽酸鈣及磷酸 鈣、磷酸鈉或碳酸鈉。在一些實施例中，稀釋劑為微晶纖 維素。在一些實施例中，黏合劑為羥丙甲纖維素、聚維 酮、羥丙基纖維素、羥乙基纖維素或澱粉。在一些實施例 中，黏合劑為羥丙甲纖維素。在一些實施例中，包衣劑為 基於甲基丙稀酸之共聚物、Eudragit L30D55、Acryl-Eze、乙酸丁二酸羥丙基甲基纖維素、聚乙酸乙烯酯鄰苯 二甲酸酯或乙酸鄰苯二甲酸纖維素。在一些實施例中，包 衣劑為基於甲基丙稀酸之共聚物。在一些實施例中，分散 劑為滑石粉、單硬脂酸甘油酯或膠狀二氧化矽。在一些實 施例中，分散劑為滑石粉。在一些實施例中，增塑劑為檸 檬酸三乙酯、三乙酸甘油酯、鄰苯二甲酸二丁酯、鄰苯二 甲酸二乙酯或甘油。在一些實施例中，增塑劑為檸檬酸三 乙酯。在一些實施例中，該組合物包含約1 mg至約1 000 mg結構（I)化合物或結構⑴化合物之混合物。在一些實施 例中，該組合物包含約10 mg至約1000 mg結構（I)化合物或 結構（I)化合物之混合物。在一些實施例中，該組合物包含 約50 mg至約1000 mg結構（I)化合物或結構（I)化合物之混合 物。在一些實施例中，該組合物包含約100 mg結構（I)化合 物或結構（I)化合物之混合物。在一些實施例中，該組合物 包含約200 mg結構（I)化合物或結構（I)化合物之混合物。在 一些實施例中，該組合物包含約300 mg結構（I)化合物或結 構（I)化合物之混合物。在一些實施例中，該組合物包含約 144188.doc 201020240 400 mg結構（I)化合物或結構（I)化合物之混合物。在一些實 施例中，該組合物包含約500 mg結構（I)化合物或結構（I)化 合物之混合物。在一些實施例中，該組合物包含約600 mg 結構（I)化合物或結構（I)化合物之混合物。在一些實施例 中，該組合物包含約700 mg結構（I)化合物或結構（I)化合物 之混合物。在一些實施例中，該組合物包含約800 mg結構 (I)化合物或結構（I)化合物之混合物。在一些實施例中，該 組合物包含約900 mg結構（I)化合物或結構（I)化合物之混合 物。在一些實施例中，該組合物包含約1〇〇〇 mg結構（I)化 合物或結構（I)化合物之混合物。在一些實施例中，該組合 物包含約10重量％至約90重量％之結構（I)化合物或結構（I) 化合物之混合物。在一些實施例中，該組合物包含約25重 量％至約90重量％之結構（I)化合物或結構（I)化合物之混合 物。在一些實施例中，該組合物包含約50重量％至約90重 量％之結構（I)化合物或結構（I)化合物之混合物。在一些實 施例中，該組合物包含約65重量％至約90重量％之結構（I) 化合物或結構（I)化合物之混合物。 在某些實施例中，本文揭示一種組合物，其包含：結構 (IB)化合物或結構（IB)化合物與其游離酸形式之混合物：In certain embodiments, disclosed herein is a composition comprising a compound of structure (1) or a mixture of compounds of structure (I): wherein hydrazine is hydrogen, sodium, potassium, calcium or arginine; and one or more diluents; Or a plurality of binders; one or more coating agents; one or more dispersing agents; and one or more plasticizers. In some embodiments, the composition is a single agent. In some embodiments, the composition is encapsulated. In some embodiments, the composition is encapsulated within a hard gelatin capsule. In some embodiments, the hydrazine is hydrogen or potassium. In some embodiments, the lanthanum is potassium. In some embodiments, the dilute 144188.doc • 6 - 201020240 release agent is microcrystalline cellulose, deuterated microcrystalline cellulose, cellulose, lactose, compressible sugar, mannitol, calcium citrate in powder and granule form And calcium phosphate, sodium phosphate or sodium carbonate. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the binder is hypromellose, povidone, hydroxypropylcellulose, hydroxyethylcellulose or starch. In some embodiments, the binder is hypromellose. In some embodiments, the coating agent is a copolymer based on methyl methic acid, Eudragit L30D55, Acryl-Eze, hydroxypropyl methyl sulphate succinate, polyvinyl acetate phthalate or Cellulose acetate phthalate. In some embodiments, the coating agent is a copolymer based on methyl acrylate. In some embodiments, the dispersing agent is talc, glyceryl monostearate or colloidal cerium oxide. In some embodiments, the dispersing agent is talc. In some embodiments, the plasticizer is triethyl citrate, triacetin, dibutyl phthalate, diethyl phthalate or glycerin. In some embodiments, the plasticizer is triethyl citrate. In some embodiments, the composition comprises from about 1 mg to about 1 000 mg of a mixture of a structure (I) compound or a structure (1) compound. In some embodiments, the composition comprises from about 10 mg to about 1000 mg of a mixture of a structure (I) compound or a structure (I) compound. In some embodiments, the composition comprises from about 50 mg to about 1000 mg of the compound of structure (I) or the compound of structure (I). In some embodiments, the composition comprises about 100 mg of a mixture of structure (I) compounds or structures (I). In some embodiments, the composition comprises about 200 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 300 mg of a compound of structure (I) or a mixture of structures (I). In some embodiments, the composition comprises about 144188.doc 201020240 400 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 500 mg of a compound of structure (I) or a mixture of structures (I). In some embodiments, the composition comprises about 600 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 700 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 800 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 900 mg of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises about 1 mg of a mixture of structure (I) compounds or structures (I). In some embodiments, the composition comprises from about 10% to about 90% by weight of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises from about 25 weight percent to about 90 weight percent of the compound of structure (I) or the compound of structure (I). In some embodiments, the composition comprises from about 50% to about 90% by weight of a compound of structure (I) or a mixture of compounds of structure (I). In some embodiments, the composition comprises from about 65% to about 90% by weight of a mixture of a structure (I) compound or a structure (I) compound. In certain embodiments, disclosed herein is a composition comprising: a structure (IB) compound or a mixture of a structure (IB) compound and its free acid form:

0®);微晶纖維素；羥丙曱纖維素；曱基 丙烯酸共聚物分散體；滑石粉；及檸檬酸三乙酯。 在一些實施例中，該組合物包含：約214 mg結構（IB)化 144188.doc 201020240 合物或結構（IB)化合物與其游離酸形式之混合物：0®); microcrystalline cellulose; hydroxypropyl hydrazine cellulose; fluorenyl acrylate copolymer dispersion; talc powder; and triethyl citrate. In some embodiments, the composition comprises: about 214 mg of structure (IB) 144188.doc 201020240 or a mixture of structure (IB) compounds and their free acid form:

(IB);約35 mg微晶纖維素；約29 mg經丙 甲纖維素；約30 mg曱基丙烯酸共聚物分散體；約6 mg滑 石粉；及約3 mg擰檬酸三乙酯。在一些實施例中，該組合 物為單一劑型。在一些實施例中，該組合物經囊封。在一 些實施例中，該組合物係囊封於硬明膠膠囊内。 φ 在某些實施例中，本文揭示一種組合物，其包含：約60 重量°/〇至約90重量％之結構（IB)化合物或結構（IB)化合物與 其游離酸形式之混合物：(IB); about 35 mg of microcrystalline cellulose; about 29 mg of propylcellulose; about 30 mg of methacrylic acid copolymer dispersion; about 6 mg of talc; and about 3 mg of triethyl citrate. In some embodiments, the composition is in a single dosage form. In some embodiments, the composition is encapsulated. In some embodiments, the composition is encapsulated within a hard gelatin capsule. φ In certain embodiments, disclosed herein is a composition comprising: from about 60 weight percent to about 90 weight percent of a structure (IB) compound or a mixture of a structure (IB) compound and a free acid form thereof:

(IB);約5重量％ 至約15重量％之微晶纖維素；約5重量％至約15重量％之羥 丙甲纖維素；約5重量％至約15重量％之曱基丙烯酸共聚物 分散體；約0.5重量％至約5重量％之滑石粉；及約0.1重量 Φ %至約3重量％之擰檬酸三乙酯。 在一些實施例中，該組合物包含約6 0重量％至約8 0重量 %之結構（IB)化合物或結構（IB)化合物與其游離酸形式之混 合物。在一些實施例中，該組合物包含約60重量％至約75 重量％之結構（IB)化合物或結構（IB)化合物與其游離酸形式 之混合物。在一些實施例中，該組合物包含約65重量％至 約70重量％之結構（IB)化合物或結構（IB)化合物與其游離酸 形式之混合物。在一些實施例中，該組合物包含約67重量 144188.doc 201020240 %之結構（IB)化合物或結構（IB)化合物與其游離酸形式之混 合物。在一些實施例中，該組合物包含約7重量％至約i 3 重量°/❶之微晶纖維素。在一些實施例中，該組合物包含約 11重量％之微晶纖維素。在一些實施例中，該組合物包含 約7重量％至約11重量％之羥丙甲纖維素。在一些實施例 中，該組合物包含約9重量％之羥丙曱纖維素。在一些實 施例中，該組合物包含約5重量％至約1 5重量％之甲基丙稀 酸共聚物分散體。在一些實施例中，該組合物包含約8重 量％至約12重量％之甲基丙烯酸共聚物分散體。在一些實 施例中，該組合物包含約10重量％之甲基丙烯酸共聚物分 散體。在一些實施例中，該組合物包含約1重量％至約4重 量％之滑石粉。在一些實施例中，該組合物包含約2重量％ 之滑石粉。在一些實施例中，該組合物包含約0.2重量％至 約2.5重量％之檸檬酸三乙酯。在一些實施例中，該組合物 包含約0·5重量％至約2重量％之檸檬酸三乙酯。在一些實 施例中，該組合物包含約1重量％之檸檬酸三乙酯。在一 些實施例中，該組合物包含：約67重量°/。之結構（IB)化合 物或結構（IB)化合物與其游離酸形式之混合物；約11重量 %之微晶纖維素；約9重量％之經丙甲纖雉素；約10重量％ 之甲基丙烯酸共聚物分散體；約2重量％之滑石粉；及約1 重量％之檸檬酸三乙酯。 在某些實施例中’本文揭示一種組合物’其包含：結構 (IB)化合物或結構（IB)化合物與其游離酸形式之混合物： 144188.doc •10- 201020240(IB); from about 5% by weight to about 15% by weight of microcrystalline cellulose; from about 5% by weight to about 15% by weight of hypromellose; from about 5% by weight to about 15% by weight of methacrylic acid copolymer Dispersion; from about 0.5% to about 5% by weight of talc; and from about 0.1% by weight to about 3% by weight of triethyl citrate. In some embodiments, the composition comprises from about 60% to about 80% by weight of the structure (IB) compound or a mixture of the structure (IB) compound and its free acid form. In some embodiments, the composition comprises from about 60% to about 75% by weight of the structure (IB) compound or a mixture of the structure (IB) compound and its free acid form. In some embodiments, the composition comprises from about 65% to about 70% by weight of the structure (IB) compound or a mixture of the structure (IB) compound and its free acid form. In some embodiments, the composition comprises about 67 weight 144188.doc 201020240% of the structure (IB) compound or a mixture of the structure (IB) compound and its free acid form. In some embodiments, the composition comprises from about 7% by weight to about i3 weight percent per gram of microcrystalline cellulose. In some embodiments, the composition comprises about 11% by weight microcrystalline cellulose. In some embodiments, the composition comprises from about 7% to about 11% by weight hypromellose. In some embodiments, the composition comprises about 9% by weight hydroxypropylcellulose. In some embodiments, the composition comprises from about 5% by weight to about 15% by weight of the methyl methacrylate copolymer dispersion. In some embodiments, the composition comprises from about 8% by weight to about 12% by weight of the methacrylic acid copolymer dispersion. In some embodiments, the composition comprises about 10% by weight of a methacrylic acid copolymer dispersion. In some embodiments, the composition comprises from about 1% to about 4% by weight talc. In some embodiments, the composition comprises about 2% by weight talc. In some embodiments, the composition comprises from about 0.2% to about 2.5% by weight of triethyl citrate. In some embodiments, the composition comprises from about 0.5% by weight to about 2% by weight of triethyl citrate. In some embodiments, the composition comprises about 1% by weight of triethyl citrate. In some embodiments, the composition comprises: about 67 weight percent /. a structure (IB) compound or a mixture of a structure (IB) compound and its free acid form; about 11% by weight of microcrystalline cellulose; about 9% by weight of propofol; about 10% by weight of methacrylic acid copolymerization Dispersion; about 2% by weight of talc; and about 1% by weight of triethyl citrate. In certain embodiments, a composition is disclosed herein which comprises: a structure (IB) compound or a mixture of a structure (IB) compound and its free acid form: 144188.doc •10- 201020240

COOK" (IB);微晶纖維素；及羥丙曱纖維素：其 中該組合物呈顆粒形式。在一些實施例中，該等顆粒不能 穿過40目篩網。在一些實施例中，該等顆粒係經羥丙甲纖 維素包覆。在一些實施例中，經包覆之顆粒進一步用包含 甲基丙烯酸共聚物分散體、滑石粉及檸檬酸三乙酯之組合 物包覆。 ® 在一些實施例中，該組合物為單一劑型。在一些實施例 中，該組合物經囊封。在一些實施例中，該組合物係囊封 於硬明膠膠囊内。 在某些實施例中，本文揭示一種組合物，其包含：約 214 mg結構（IB+p合物普結構（IB)化合物與其游離酸形式 、coaic 之混合物： (IB);約35 mg微晶纖維素COOK"(IB); microcrystalline cellulose; and hydroxypropylcellulose: wherein the composition is in the form of granules. In some embodiments, the particles cannot pass through a 40 mesh screen. In some embodiments, the particles are coated with hydroxypropylcellulose. In some embodiments, the coated particles are further coated with a composition comprising a dispersion of methacrylic acid copolymer, talc, and triethyl citrate. ® In some embodiments, the composition is in a single dosage form. In some embodiments, the composition is encapsulated. In some embodiments, the composition is encapsulated within a hard gelatin capsule. In certain embodiments, disclosed herein is a composition comprising: about 214 mg structure (a mixture of an IB+p complex (IB) compound and its free acid form, coaic: (IB); about 35 mg microcrystals Cellulose

約13.5 mg經丙甲纖維素；其中該組合物為不能穿過4〇目 篩網之顆粒形式；且其中該等顆粒係經約j 5 3 mg經丙甲 纖維素包覆；且其中經包覆之顆粒進一步用包含約3〇4 mg甲基丙烯酸共聚物分散體、約mg滑石粉及約3 〇 mg 檸檬酸三乙酯之組合物包覆。 在一些實施例中，該組合物經囊封。在—些實施例中， 該組合物係囊封於硬明膠膠囊内。在一些實施例中，不少 於約85%之結構（IB)化合物或結構（IB)化合物與其游離酸形 144188.doc 201020240 式之混合物在30分鐘内釋放；且不少於約9〇%之結構（IB) 化合物或結構（IB)化合物與其游離酸形式之混合物在45分 鐘内釋放；其係使用本文中某些具體實施例所揭示之美國 藥典<711>方法A設備2在37°C下於900 mL pH 6.8之溶解介 質中以50 rpm操作所量測。 在某些實施例中，本文揭示一種組合物，其包含：結構Approximately 13.5 mg of propylcellulose; wherein the composition is in the form of granules that are incapable of passing through a 4 mesh screen; and wherein the granules are coated with about 99 3 mg of propylmethylcellulose; The coated granules are further coated with a composition comprising about 3.4 mg of a methacrylic acid copolymer dispersion, about mg of talc, and about 3 mg of triethyl citrate. In some embodiments, the composition is encapsulated. In some embodiments, the composition is encapsulated in a hard gelatin capsule. In some embodiments, not less than about 85% of the structure (IB) compound or structure (IB) compound and its free acid form 144188.doc 201020240 are released within 30 minutes; and not less than about 9% The structure (IB) compound or a mixture of the structure (IB) compound and its free acid form is released within 45 minutes; it is disclosed using the US Pharmacopoeia <711> Method A Apparatus 2 disclosed at certain embodiments herein at 37 ° C The measurement was carried out in a 900 mL solution of pH 6.8 at 50 rpm. In certain embodiments, disclosed herein is a composition comprising: a structure

稀釋劑；及崩解劑 (〇’其中Μ為氫、納、卸、約或精胺酸； 在一些實施例中，稀釋劑為微晶纖維素。在一些實施例 中，微晶纖維素構成該組合物之約40重量％至約60重量 %。在一些實施例中，微晶纖維素構成該組合物之約50重 量°/〇。在一些實施例中，崩解劑為交聯羧甲基纖維素鈉。 在一些實施例中，交聯羧甲基纖維素鈉構成該組合物之約 〇. 1重量％至約2重量％。在一些實施例中，交聯羧曱基纖 維素納構成該組合物之約0.5重量％。在一些實施例中’該 組合物包含：約50重量％微晶纖維素；及約0.5重量％交聯 羧曱基纖維素鈉。 在一些實施例中，Μ為氫及/或鉀。在一些實施例中’ Μ 為if。在一些實施例中，該組合物包含至少5 0重量％之結 構（I)化合物或結構（I)化合物之混合物。在一些實施例中’ 該組合物包含至少60重量％之結構⑴化合物或結構⑴化合 144188.doc -12- 201020240 物之混合物。在一些實施例中，該組合物包含至少70重量 %之結構⑴化合物或結構⑴化合物之混合物。在一些實施 例中，該組合物包含至少80重量％之結構（I)化合物或結構 (I)化合物之混合物。在一些實施例中，該組合物包含：約 50重量％之結構⑴化合物或結構（I)化合物之混合物；約 49.4重量％之微晶纖維素；及約0.55重量％之交聯羧甲基纖 維素納。a diluent; and a disintegrant (wherein hydrazine is hydrogen, sodium, unloading, about or arginine; in some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is comprised) The composition is from about 40% to about 60% by weight. In some embodiments, the microcrystalline cellulose comprises about 50% by weight of the composition. In some embodiments, the disintegrant is a crosslinked carboxy group. Sodium cellulose sodium. In some embodiments, croscarmellose sodium constitutes from about 0.1% to about 2% by weight of the composition. In some embodiments, croscarmellose sodium It constitutes about 0.5% by weight of the composition. In some embodiments, the composition comprises: about 50% by weight of microcrystalline cellulose; and about 0.5% by weight of croscarmellose sodium. In some embodiments, The hydrazine is hydrogen and/or potassium. In some embodiments 'Μ is if. In some embodiments, the composition comprises at least 50% by weight of a compound of structure (I) or a mixture of compounds of structure (I). In the embodiment 'the composition comprises at least 60% by weight of the structure (1) compound or structure A mixture of 144188.doc -12- 201020240. In some embodiments, the composition comprises at least 70% by weight of a mixture of structure (1) compounds or structures (1). In some embodiments, the composition comprises at least 80 weights % of a structure (I) compound or a mixture of compounds of structure (I). In some embodiments, the composition comprises: about 50% by weight of a structure (1) compound or a mixture of compounds of structure (I); about 49.4% by weight Crystalline cellulose; and about 0.55% by weight of croscarmellose sodium.

在一些實施例中’該組合物為單一劑型》在一些實施例 中’該組合物係囊封於膠囊内。在一些實施例中，膠囊包 含硬明膠。在一些實施例中，硬明膠膠囊係經重覆囊封 (over-encapsulated)。在一些實施例中，硬明膠膠囊係重覆 囊封於羥丙甲纖維素膠囊内。 在某些揭"組合m含:約In some embodiments 'the composition is a single dosage form" in some embodiments' the composition is encapsulated within a capsule. In some embodiments, the capsules comprise hard gelatin. In some embodiments, the hard gelatin capsules are over-encapsulated. In some embodiments, the hard gelatin capsules are re-encapsulated in hypromellose capsules. In some uncovering "combination m contains: about

C00H H)0 mg結構^ 之化合物；約98.9 mg微晶纖 維素；及約1.1 mg交聯羧甲基纖維素鈉。在一些實施例 中，該組合物經囊封。 在某二實施例中，本文揭示—種組合物，其包含：約 106.8 mg，、.。構（IB)。合物，丨結構㈣化合物與其游離酸形 cocnc 式之混合物： ㈣；約92.1 mg微晶纖維 素；及約1‘1 mg交聯羧甲基纖維素鈉。 144188.doc •13· 201020240 在某些實施例中，本文揭示一種組合物，其包含：約 213 mg結構（IB)化合物或結構（IB)化合物與其游離酸形式C00H H) 0 mg of the compound of the compound; about 98.9 mg of microcrystalline cellulose; and about 1.1 mg of croscarmellose sodium. In some embodiments, the composition is encapsulated. In a second embodiment, disclosed herein is a composition comprising: about 106.8 mg, . Structure (IB). a mixture of a compound of the ruthenium structure (IV) and a free acid form of the cocnc formula: (d); about 92.1 mg of microcrystalline cellulose; and about 1 '1 mg of croscarmellose sodium. 144188.doc • 13· 201020240 In certain embodiments, disclosed herein is a composition comprising: about 213 mg of a structure (IB) compound or a structure (IB) compound and its free acid form

即）；微晶纖維素；及交聯羧 曱基纖維素鈉。 在某些實施例中，本文揭示一種組合物，其包含：約 430 mg結構（IB)化合物或結構（IB)化合物與其游離酸形式That is; microcrystalline cellulose; and croscarmellose sodium. In certain embodiments, disclosed herein is a composition comprising: about 430 mg of a structure (IB) compound or a structure (IB) compound and its free acid form

(ra);微晶纖維素；及交聯羧 曱基纖維素鈉。 在某些實施例中，本文揭示一種組合物，其包含：約 860 mg結構（IB)化合物或結構（IB)化合物與其游離酸形式(ra); microcrystalline cellulose; and croscarmellose sodium. In certain embodiments, disclosed herein is a composition comprising: about 860 mg of a structure (IB) compound or a structure (IB) compound and its free acid form

曱基纖維素鈉。 在某些實施例中，本文揭示一種組合物，其包含：約 1 000 mg結構（IB)化合物或結構（IB)化合物與其游離酸形式Sodium thioglycolate. In certain embodiments, disclosed herein is a composition comprising: about 1 000 mg of a structure (IB) compound or a structure (IB) compound and its free acid form

(IB);微晶纖維素；及交聯羧 甲基纖維素鈉。 在一些實施例中，該組合物經囊封。在一些實施例中， 144188.doc -14- 201020240 該組合物係囊封於硬明膠膠囊内。在一些實施例中，硬明 膠膠囊係經重覆囊封。在一些實施例中，硬明膠膠囊係重 覆囊封於羥丙甲纖維素膠囊内。在一些實施例中，不少於 約80%之結構（IB)化合物或結構（IB)化合物與其游離酸形式 之混合物在30分鐘内溶解，如使用美國藥典A設備1在37°C 下於900 mL水中以75 rpm操作所量測。在一些實施例中， 如使用美國藥典A設備1在37°C下於900 mL水中以75 rpm操 作所量測之活體外溶解速率為不少於約80%之結構（IB)化 合物在30分鐘内釋放。在一些實施例中，不少於約78%之 結構（IB)化合物或結構（IB)化合物與其游離酸形式之混合 物在30分鐘内溶解；且不少於約95%之結構（IB)化合物或 結構（IB)化合物與其游離酸形式之混合物在45分鐘内溶 解；其係使用本文中某些具體實施例所揭示之美國藥典之 設備1在37°C下於900 mL水中以75 rpm操作所量測。(IB); microcrystalline cellulose; and croscarmellose sodium. In some embodiments, the composition is encapsulated. In some embodiments, 144188.doc -14- 201020240 the composition is encapsulated within a hard gelatin capsule. In some embodiments, the hard gelatin capsules are repeatedly encapsulated. In some embodiments, the hard gelatin capsule is repeatedly encapsulated within a hypromellose capsule. In some embodiments, not less than about 80% of the structure (IB) compound or structure (IB) compound and its free acid form are dissolved within 30 minutes, such as using the United States Pharmacopoeia A Apparatus 1 at 37 ° C at 900 ° The mL water was measured at 75 rpm. In some embodiments, the compound (IB) compound having an in vitro dissolution rate of not less than about 80%, as measured using a U.S. Pharmacopoeia A apparatus 1 at 37 ° C in 75 mL of water at 75 rpm, is in 30 minutes. Released inside. In some embodiments, not less than about 78% of the structure (IB) compound or the mixture of the structure (IB) compound and its free acid form dissolves within 30 minutes; and not less than about 95% of the structure (IB) compound or The mixture of the structure (IB) compound and its free acid form is dissolved within 45 minutes; it is operated at 75 rpm in 900 mL water at 37 ° C using Apparatus 1 of the US Pharmacopoeia disclosed in certain embodiments herein. Measurement.

在某些實施例中，本文揭示一種組合物，其包含：結構 m化合物成結構（I)化合物之混合物： 0)，其中Μ為氫、鈉、鉀、鈣或精胺酸； 稀釋劑；黏合劑；潤滑劑；及包衣。在一些實施例中，該 組合物為單一劑型。在一些實施例中，該組合物為整塊固 體。 在某些實施例中，本文揭示一種組合物，其包含約200 144188.doc -15· 201020240In certain embodiments, disclosed herein is a composition comprising: a mixture of a compound of structure m and a compound of structure (I): 0) wherein hydrazine is hydrogen, sodium, potassium, calcium or arginine; a diluent; Agent; lubricant; and coating. In some embodiments, the composition is in a single dosage form. In some embodiments, the composition is a monolithic solid. In certain embodiments, disclosed herein is a composition comprising about 200 144188.doc -15· 201020240

之化合物。 mg結構 在某些實施例中，本文揭示一種組合物，其包含：約6〇 重量％至約90重量％之結構（IB)化合物或結構（IB)化合物與Compound. Mg Structures In certain embodiments, disclosed herein is a composition comprising: from about 6% by weight to about 90% by weight of a structure (IB) compound or structure (IB) compound and

至約15重量％之微晶纖維素；約2.5重量％至約10重量％之 白色Acryl-Eze ;約2.5重量％至約10重量％之羥丙曱纖維 素；約0.25重量％至約2重量％之硬脂酸鎂。 在某些實施例中，本文揭示一種組合物，其包含：約 213.6 mg結構（IB)化合物或結構（IB)化合物與其游離酸形Up to about 15% by weight of microcrystalline cellulose; from about 2.5% to about 10% by weight of white Acryl-Eze; from about 2.5% to about 10% by weight of hydroxypropylcellulose; from about 0.25% to about 2% by weight % magnesium stearate. In certain embodiments, disclosed herein is a composition comprising: about 213.6 mg of a structure (IB) compound or a structure (IB) compound and its free acid form

素·，約23.1 mg羥丙甲纖維素；約1.3 mg硬脂酸鎂；及約 27.1 mg 白色 Acryl-Eze。 在一些實施例中，該等顆粒與硬脂酸鎂摻合。在一些實 施例中，該組合物係經壓製成整塊固體。在一些實施例 中，該組合物係經羥丙甲纖維素包覆。在一些實施例中， 該組合物進一步經白色Acryl-Eze包覆。在一些實施例中， 如使用美國藥典A設備2在37°C下於700 mL pH 1.2之溶解 介質中以50 rpm操作2小時所量測之活體外溶解速率為約 0〇/〇至約5%之結構（IB)化合物於2小時内釋放；且2小時之 144188.doc • 16 - 201020240 後，如在37°C下於900 mL pH 6.8之緩衝液中所量測為約 15%至約45%之結構（IB)化合物或結構（IB)化合物與其游離 酸形式之混合物於30分鐘内釋放；為約50%至約85%之結 構（IB)化合物或結構（IB)化合物與其游離酸形式之混合物 於45分鐘内釋放；為不少於約80%之結構（IB)化合物或結 構（IB)化合物與其游離酸形式之混合物於60分鐘内釋放； 為不少於約90%之結構（IB)化合物或結構（IB)化合物與其游 離酸形式之混合物於90分鐘内釋放；且為不少於約95%之 結構（IB)化合物或結構（IB)化合物與其游離酸形式之混合 物於100分鐘内釋放。 在某些實施例中，本文揭示一種使需要降低之尿酸濃度 之個體之一或多種組織或器官中的尿酸濃度降低之方法， 其包含向個體投與降低尿酸濃度用量之本文揭示之組合 物。 在某些實施例中，本文揭示一種使個體尿酸生成減少、 尿酸***增加或使尿酸生成減少並使尿酸***增加之方 法，其包含向個體投與有效量之本文揭示之組合物。 在某些實施例中，本文揭示一種治療或預防個體高尿酸 血症之方法，其包含向個體投與有效量之本文揭示之組合 物。 在某些實施例中，本文揭示一種治療患有特徵在於組織 或器官尿酸濃度異常之病狀之個體的方法，其包含向個體 投與有效量之本文揭示之組合物。在一些實施例中，該病 狀係選自痛風、復發性痛風發作、痛風性關節炎、高尿酸 144188.doc -17- 201020240 血症、高血壓、心血管疾病、冠狀動脈心臟病、勒_奈二 氏症候群（Lesch-Nyhan syndrome)、飢利-西格米勒症候群 (Kelley-Seegmiller syndrome)、腎病、腎結石、腎衰竭、 關節發炎（joint inflammation)、關節炎（arthritis)、尿石 症、鉛中毒、副曱狀腺機能亢進、牛皮癖或類肉瘤病。 在某些實施例中’本文揭示一種預防個體之特徵在於組 織尿酸濃度異常之病狀的方法，其中該個體處於發展該病 狀之高風險中，該方法包含向個體投與有效量之本文揭示 之組合物。 在某些實施例中’本文揭示一種治療個體之痛風、復發 性痛風發作、痛風性關節炎、南尿酸血症、高金壓、心血 管疾病、冠狀動脈心臟病、勒-奈二氏症候群、凱利-西格 米勒症候群、腎病、腎結石、腎衰竭、關節發炎、關節 炎、尿石症、鉛中毒、副甲狀腺機能亢進、牛皮癖或類肉 瘤病的方法，其包含向個體投與有效量之本文揭示之組合 物0 在某些實施例中，本文揭示一種治療個體之痛風的方 法’其包含向個體投與有效量之本文揭示之組合物。 在某些實施例中’本文揭示一種預防個體體内形成痛風 石或減小痛風石大小的方法，其包含向個體投與有效量之 本文揭示之組合物。 在一些實施例中，本文揭示之組合物之AUCi：bg*h/mL) 係介於約0.6與約18之間。在一些實施例中，本文揭示之 組合物之AUCT：(Kg*h/mL)係介於約2.5與約11之間。在一些 144188.doc -18- 201020240 實施例中，本文揭示之組合物之AUCi：bg，h/mL)係介於約 4.8與約8之間。在一些實施例中，本文揭示之組合物之 (^1113\(^§/1111^)係介於約〇.15與約6之間。在一些實施例中， 本文揭示之組合物之Cmaxbg/mL)係介於約0.5與約5之 間。在一些實施例中，本文揭示之組合物之Cmax(pg/mL) 係介於約1與約4之間。 在一些實施例中，本文揭示之組合物提供代謝物M6(2-(5-溴-4-(4-環丙基萘-1-基）-4//-l，2,4-***-3-基硫基）乙 酸）。在一些實施例中，本文揭示之組合物提供代謝物M6 之介於約2.5與約30之間的AUCi:(pg-h/mL)。在一些實施例 中，本文揭示之組合物提供代謝物M6之介於約8與約25之 間的AUCi:(gg.h/mL)。在一些實施例中，本文揭示之組合 物提供代謝物M6之介於約12與約20之間的AUCt (pg，h/mL)。在一些實施例中，代謝物M6之Cmax(pg/mL) 係介於約0.25與約4之間。在一些實施例中，代謝物M6之 Cmax(pg/mL)係介於約1與約3之間。在一些實施例中，代 謝物M6之Cmax(pg/mL)係介於約2.4與約3之間。在一些實 施例中，代謝物M6之AUCT(pg，h/mL)與化合物I之AUCt (pg*h/mL)之莫耳比為約2至約11。在一些實施例中，代謝 物M6之AUCi:(Kg.h/mL)與化合物I之AUCT(pg.h/mL)之莫耳 比為約4至約8。在一些實施例中，代謝物M6之Cmax (pg/mL)與化合物I之Cmax(pg/mL)之莫耳比為約1至約7。 在一些實施例中，代謝物]V16之Cmax(pg/mL)與化合物I之 Cmax(pg/mL)之莫耳比為約2至約6。 144188.doc -19- 201020240 本說明♦中所提及之所有公開案及專利申請案均以引用 的方式併入本文中，其引用之程度就如同個別公開案或專 利申請案各自特定且個別經指示以引用的方式併入本文中 一般。 【實施方式】 隨附申請專利範圍中詳細地闡明本發明之新穎特徵。將 參考以下闡明利用本發明原理的說明性實施例之實施方式 及隨附圖式來更好地理解本發明之特徵及優點。 儘管本文中已展示且描述本發明之較佳實施例，但對於 熟習此項技術者而言，該等實施例顯然僅以實例方式提 供。在不脫離本發明之情況下’熟習此項技術者現將進行 多種變更、改變及取代。應瞭解，本文所描述之本發明實 施例之各種替代皆可用於實施本發明。以下申請專利範圍 意欲界定本發明之範疇且藉此涵蓋該等申請專利範圍的範 疇内之方法及結構及其相等物。本文使用之章節標題 (section heading)僅出於組織目的且不應理解為限制所述標 的物。 醫藥組合物 本文描述包含4-(2-(5 -漠-4-(1-環丙基萘-4-基）_4H-1，2,4-三0坐-3-基硫基）乙酿胺基）-3-氣苯甲酸、其前藥及/或醫藥 上可接受之鹽的醫藥組合物。在一些實施例中，該等醫藥 組合物包含有效量之4-(2-(5-溴-4-(1-環丙基萘_4_基）_4H-1，2,4-***-3-基硫基）乙醯胺基）-3-氣苯曱酸、其前藥及/或 醫藥上可接受之鹽。在一些實施例中，該等醫藥組合物包 144188.doc -20- 201020240 含有效量之4-(2-(5-溴-4-(1-環丙基萘_4_基）-411-1，2,4-***-3-基硫基）乙醯胺基）_3_氯苯甲酸、其前藥及/或醫藥上可接 丈之鹽及至少一種醫藥上可接受之載劑。在一些實施例 中，該等醫藥組合物係用於治療病症。在一些實施例中， 該等醫藥組合物係用於治療哺乳動物病症。在一些實施例 中，該等醫藥組合物係用於治療人類病症。 方法：異常尿酸濃度 ❿ 本發明亦提供一種適用於與異常尿酸濃度相關之疾病或 病症的方法。該方法包括向患有異常尿酸濃度之個體投與 有效量的如本文所述之組合物，如：恢復可接受之尿酸濃 度或非異常尿酸濃度。本發明亦提供一種適用於使需要降 低之尿酸濃度之個體之一或多種組織或器官中的尿酸濃度 降低之方法，其包含向個體投與降低尿酸濃度用量的如本 文所述之組合物。本發明亦提供一種適用於使個體尿酸生 成減少、尿酸***増加或使尿酸生成減少並使尿酸***增 ❹ 加之方法，其包含向個體投與有效量之如本文所述之組合 物。本發明亦提供一種適用於治療或預防個體高尿酸血症 之方法，其包含向個體投與有效量之如本文所述之組合 物。本發明亦提供一種適用於治療患有特徵在於組織或器 吕尿酸濃度異常之病狀之個體的方法，其包含向個體投與 有效量之如本文所述之組合物。本發明亦提供一種適用於 治療患有痛風、復發性痛風發作、痛風性關節炎、高尿酸 血症、高血壓、心血管疾病、冠狀動脈心臟病、勒-奈二 氏症候群、凱利-西格米勒症候群、腎病、腎結石、腎衰 144188.doc •21 - 201020240 竭、關節發炎、關節炎、尿石症、鉛中毒、副曱狀腺機能 宄進、牛皮癖或類肉瘤病之個體的方法，其包含向個體投 與有效量之如本文所述之組合物。本發明亦提供一種適用 於預防個趙之特徵在於組織尿酸濃度異常之病狀的方法’ 其中該個體處於發展該病狀之高風險中，該方法包含向個 體投與有效量之如本文所述之組合物。本發明亦提供一種 適用於治療個體之痛風、復發性痛風發作、痛風性關節 炎、高尿酸血症、高血壓、心血管疾病、冠狀動脈心臟 病、勒-奈一氏症候群、訊利-西格米勒症候群、腎病、腎 結石、腎衰竭、關節發炎、關節炎、尿石症、鉛中毒、副 甲狀腺機能亢進、牛皮癣或類肉瘤病的方法，其包含向個 體投與有效量之如本文所述之組合物。本發明亦提供一種 適用於治療個體之痛風的方法，其包含向個體投與有效量 之如本文所述之組合物。本發明亦提供一種適用於預防個 體中形成痛風石或減小痛風石大小的方法，其包含向個體 投與有效量之如本文所述之組合物。 術語 如本文中關於患有病症及其類似疾病之個體所使用之術 語「個體（subject)」、「患者」或「個體（individual)」涵蓋 哺乳動物及非哺乳動物。哺乳動物之實例包括（但不限於） 哺乳動物綱之任何成員：人類、非人類靈長類動物，諸如 黑猩猩及其他猿類及猴物種；農畜，諸如牛、馬、錦羊、 山羊、豬；家畜，諸如兔、犬及貓；實驗動物，包括齧齒 動物，諸如大鼠、小鼠及天竺鼠及其類似動物。非哺乳動 144188.doc -22. 201020240 ，之實例包括(但不限於)鳥、魚及其類似動物。在本文所 提供之方法及組合物之_實施例t，哺乳動物為人類。 —如本文所使用之術語「有效量」、「治療有效量」或「醫 藥有效量」係指所投與的至少-種藥劑或化合物之量足以 治療或預防特定疾病或病狀。結果可能為減少及/或減輕 疾病之徵兆、症狀或病因，或生物系統之任何其他所需變 化。舉例而言’用於治療用途之「有效量」為需要提供疾 病之臨床顯著減輕的組合物之量，該組合物包含如本文所 揭不之化合物。在任何個別情況下，適當「有效」量皆可 使用諸如劑量遞增研究之技術來確定。 如本文所使用之術語「醫藥上可接受」係指不會消除本 文所述化合物之生物活性或性質且相對無毒之物質（諸如 載劑或稀釋劑），亦即，可向個體投與該物質而不會導致 不良生物效應或與組合物中所含之任何組份以有害方式相 互作用。 如本文所使用之術語「組合物」及「醫藥組合物」係指 4-(2-(5-溴-4·(1-環丙基萘_4_基）-4丑-1，2,4-***-3-基硫基） 乙醯胺基）-3-氣苯甲酸、其前藥及/或醫藥上可接受之鹽視 情況與至少一種醫藥上可接受之化學組份混合，該化學組 份諸如（但不限於）載劑、穩定劑、稀釋劑、分散劑、懸浮 劑、增稠劑、賦形劑及其類似物。 如本文所使用之術語「醫藥上可接受之鹽」包括4-(2-(5-漠-4-(4-環丙基萘-1-基）-4Η-1，2,4-三。坐-3-基硫基）乙醢 胺基）-3·氯苯曱酸根與任何醫藥上可接受之陽離子形成之 144188.doc • 23- 201020240 鹽，其保持游離酸之生物有效性。舉例而言，4 (2气5•溴_ 4-(1-環丙基萘-4·基+***_3_基硫基）乙醯胺基）· 3-氣苯甲酸之游離酸基團可與以下各物反應：適合之鹼， 諸如醫藥上可接受之金屬陽離子之氫氧化物、碳酸鹽或碳 酸氫鹽，氨，或醫藥上可接受之有機一級胺、二級胺或三 級胺。代表性鹼金屬鹽或鹼土金屬鹽包括鋰、鈉、鉀、 鈣、鎂及鋁鹽及其類似鹽。鹼之說明性實例包括氫氧化 鈉、氫氧化鉀、氫氧化膽鹼、碳酸鈉、N+(Ci_4烷基沁及其 類似物。適用於形成驗加成鹽之代表性有機胺包括精胺 酸、離胺酸、乙胺、二乙胺、乙二胺、乙醇胺、二乙醇 胺、哌嗪及其類似物。該等鹽可在最終離析及純化過程中 於原位製備，或藉由分離反應及單離所形成之鹽而製得。 如本文所使用之術語「前藥」係指在投與個體且隨後吸 收之後經由一些過程（諸如藉由代謝路徑轉化）轉化成活性 物或活性更大之物質的藥物前驅體。因此，該術語涵蓋在 投與接受者後能夠直接或間接提供本發明化合物或其醫藥 活性代謝物或殘餘物的化合物之任何衍生物。一些前藥上 存在使該前藥活性較小及/或賦予藥物溶解性或一些其他 性質的化學基團。當該化學基團自前藥分解及/或改質 時，產生活性藥物。由於在一些狀況下，前藥可能比母體 藥物易於投藥，故前藥通常為適用的。例如，其可藉由經 口投藥而為生物可利用的，而母體藥物卻非如此。特別有 利之衍生物或前藥為向患者投與本發明化合物時增加該等 化合物之生物可用性（例如，使經口投與之化合物更易於 144188.doc -24· 201020240 吸收至血液中）或增強母體化合物至生物代謝區（例如腦或 淋巴系統）之傳遞的化合物。 渐量 4-(2-(5 -溴-4-(1-環丙基萘-4-基）-4Η-1，2,4-三嗅-3 -基硫 基）乙醢胺基）-3-氣苯曱酸、其前藥及/或醫藥上可接受之 鹽之總投與量將首先取決於所治療之哺乳動物。在投與人 類個體之情況下，該量將通常由處方醫師確定，其中劑量 一般根據個別患者之年齡、性別、飲食、體重、一般健康 ® 狀況及反應；患者症狀之嚴重程度；所治療之精確適應症 或病狀；所治療之適應症或病狀之嚴重程度；投藥時間； 投藥路徑；組合物之處置；***率；藥物組合；及處方醫 師的判斷而變化。該醫藥組合物可呈單位劑型。在該形式 中，為達成理想目的，將製劑再分成含有適當數量之活性 組份（例如有效量）的單位劑量。習此相關技藝之人士可針 對特定狀況決定適當劑量。為方便起見，必要時可將總曰 修 劑量分成數份，在一天内投與。投藥之量及頻率及適用之 其他治療劑及/或療法應根據主治臨床醫師（醫師）考慮如上 所述之該等因素作出之判斷進行調節。因此，醫藥組合物 之投藥量可廣泛變化。可以每日約〇〇〇1 mg/kg體重至約 100 mg/kg體重之間之量投藥（以單次劑量或分次劑量投 藥）’或可以每日至少約〇丨mg/kg體重之量投藥。特定治 療劑量包括例如約0.01 mg至約7〇〇〇 mg化合物，或例如約 0.05 mg至約2500 mg化合物。根據特定應用單位劑量中 4-(2-(5-漠-4-(1-環丙基萘_4•基）4Hi,2，4-***·3基硫基） 144188.doc •25· 201020240 乙醯胺基）-3-氣苯甲酸、其前藥及/或醫藥上可接受之鹽之 含量可為約1 mg至3000 mg之間、約2 mg至2000 mg之間或 10 mg至2000 mg之間。在一些實施例中，該量為約1〇〇 mg 至約1500 mg，約150 mg至約1200 mg，或約200 mg至約 1000 mg。在另外或其他實施例中，該量為至少1〇〇 mg、 至少200 mg、至少250 mg、至少300 mg、至少400 mg、至 少500 mg、至少600 mg、至少700 mg、至少750 mg、至少 800 mg、至少900 mg或至少1000 mg。在另外或其他實施 例中’該量為約100 mg、約200 mg、約250 mg、約300 mg、約 400 mg、約 500 mg、約 600 mg、約 700 mg、約 750 mg、約800 mg、約900 mg或約1000 mg。在一些實施例 中’該等組合物為每日投藥一次。在另外或其他實施例 中，該等組合物為每日投藥兩次。在另外或其他實施例 中，該等組合物為每日至少投藥兩次。在一些情況下，低 於上述範圍之下限的劑量濃度可能遠遠足夠，而在其他情 況下仍可能採用較大劑量而不導致任何有害副作用，例如 將該等較大劑量分成若干小劑量，以用於在一天内投藥。 在該化合物不為唯一療法之組合應用中，可能投與較少量 之化合物且仍具有治療或預防效應。 劑型 本文所述之醫藥組合物通常適用於作為固體劑型經口投 與，該等劑型諸如錠劑、膠囊、丸劑、散劑、顆粒劑及其 類似劑型。可投與該等組合物來實現4-(2-(5-溴-4-(1-環丙 基蔡-4 -基）-4Η-1，2,4 -三吐-3 -基硫基）乙酿胺基）-3 -氣苯甲 144188.doc -26 - 201020240 酸、其月·』藥及/或冑藥上可接受之鹽之A即釋放、延遲釋 放或持續釋放。 套組 本文所述之組合物及方法提供治療疾病及病症之套組。 此等套組包含谷器中本文所述之組合物及視情況選用之教 示套組之使用的說明書。該等套組亦可包括資訊，諸如科 學參考文獻、藥品說明書材料、臨床試驗結果及/或此等 資訊之概述及其類似資訊，其指出或確定組合物之活性及/ 或優點’及/或其描述適用於健康照護提供者之給藥、投 藥、副作用、藥物相互作用或其他資訊。此類資訊可基於 各種研究之結果，例如，使用涉及活體内模型之實驗動物 的研究及基於人類臨床試驗的研究。本文所述之套組可提 供、銷售及/或推廣至健康照護提供者，包括醫師、護 士、藥劑師、處方官員（formulary 〇fficial)及其類似提供 者。在一些實施例中，套組亦可直接銷售給消費者。 φ 本文所述之組合物亦適用於診斷劑及適用作研究試劑。 舉例而言，本文所述之化合物（單獨或與其他化合物組合） 可適用作差示分析及/或組合分析中之工具以闡明細胞及 組織内表現之基因的表現模式。作為一個非限制性實例， 比較經一或多種化合物處理之細胞或組織内之表現模式與 未經化合物處理之對照細胞或組織内之表現模式且分析所 產生之模式的差示基因表現量，因為該等模式係關於（例 如）所檢驗之基因的疾病相關（disease association)、信號傳 導路徑、細胞定位（cellular localization)、表現量、大小、 144188.doc -27- 201020240 結構或功能。可在影響表現模式之其他化合物存在或不存 在下對受激或未受激細胞進行此等分析。 除適用於人類治療之外，本文所述之組合物亦可能適用 於其他動物之獸醫學治療。 實例 下文提供之實例及製備進一步說明且例示本發明化合物 及製備該等化合物之方法。應瞭解，本發明之範疇不以任 何方式受限於以下實例及製備之範疇。 I.化學合成 實例 1 :合成 4-(2-(5 -溪-4-(1-環丙基秦-4 -基）-4Η-1，2,4 -二 唑-3-基硫基）乙醯胺基）-3-氣苯曱酸（化合物1)Approximately 23.1 mg of hypromellose; about 1.3 mg of magnesium stearate; and about 27.1 mg of white Acryl-Eze. In some embodiments, the particles are blended with magnesium stearate. In some embodiments, the composition is compressed into a monolithic solid. In some embodiments, the composition is coated with hypromellose. In some embodiments, the composition is further coated with a white Acryl-Eze. In some embodiments, the in vitro dissolution rate is about 0 〇 / 〇 to about 5 as measured using the United States Pharmacopoeia A Apparatus 2 at 37 ° C in a 700 mL pH 1.2 dissolution medium operating at 50 rpm for 2 hours. % of the structure (IB) compound is released within 2 hours; and after 2 hours of 144188.doc • 16 - 201020240, as measured at 900 ° C in 900 mL pH 6.8 buffer at about 37% to about 45% of the structure (IB) compound or a mixture of the structure (IB) compound and its free acid form is released within 30 minutes; from about 50% to about 85% of the structure (IB) compound or structure (IB) compound and its free acid form The mixture is released in 45 minutes; is not less than about 80% of the structure (IB) compound or the mixture of the structure (IB) compound and its free acid form is released within 60 minutes; is not less than about 90% of the structure (IB a compound or a mixture of the structure (IB) compound and its free acid form is released within 90 minutes; and is not less than about 95% of the structure (IB) compound or a mixture of the structure (IB) compound and its free acid form in 100 minutes. freed. In certain embodiments, disclosed herein is a method of reducing uric acid concentration in one or more tissues or organs of an individual in need of reduced uric acid concentration, comprising administering to the individual a composition disclosed herein that reduces the amount of uric acid concentration. In certain embodiments, disclosed herein is a method of reducing uric acid production, increasing uric acid excretion, or reducing uric acid production and increasing uric acid excretion, comprising administering to a subject an effective amount of a composition disclosed herein. In certain embodiments, disclosed herein is a method of treating or preventing hyperuricemia in an individual comprising administering to the individual an effective amount of a composition disclosed herein. In certain embodiments, disclosed herein is a method of treating an individual having a condition characterized by abnormal uric acid concentration in a tissue or organ comprising administering to the individual an effective amount of a composition disclosed herein. In some embodiments, the condition is selected from the group consisting of gout, recurrent gout attack, gouty arthritis, hyperuric acid 144188.doc -17-201020240, hypertension, cardiovascular disease, coronary heart disease, Le_ Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis Lead poisoning, parathyroid function hyperthyroidism, psoriasis or sarcoma-like disease. In certain embodiments, 'disclosed herein is a method of preventing a condition characterized by an abnormal uric acid concentration in a subject, wherein the individual is at a high risk of developing the condition, the method comprising administering to the individual an effective amount disclosed herein Composition. In certain embodiments, the invention discloses a method for treating gout, recurrent gout attack, gouty arthritis, southern uric acidemia, high gold pressure, cardiovascular disease, coronary heart disease, Le-Nei's syndrome, Kelly-Sigmüller syndrome, nephropathy, kidney stones, renal failure, joint inflammation, arthritis, urolithiasis, lead poisoning, parathyroid hyperactivity, psoriasis or sarcoma-like disease, including effective administration to individuals Compositions disclosed herein are disclosed herein. In certain embodiments, disclosed herein is a method of treating gout in an individual comprising administering to the subject an effective amount of a composition disclosed herein. In certain embodiments, a method of preventing the formation of tophi or reducing the size of a tophi in an individual comprises administering to the individual an effective amount of a composition disclosed herein. In some embodiments, the compositions disclosed herein have an AUCi:bg*h/mL) between about 0.6 and about 18. In some embodiments, the AUCT:(Kg*h/mL) of the compositions disclosed herein is between about 2.5 and about 11. In some 144188.doc -18-201020240 embodiments, the AUCi:bg,h/mL) of the compositions disclosed herein is between about 4.8 and about 8. In some embodiments, the compositions disclosed herein are between about 1515 and about 6. In some embodiments, the Cmaxbg/ of the compositions disclosed herein. The mL) is between about 0.5 and about 5. In some embodiments, the compositions disclosed herein have a Cmax (pg/mL) of between about 1 and about 4. In some embodiments, the compositions disclosed herein provide the metabolite M6 (2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4//-l,2,4-triazole) -3-ylthio)acetic acid). In some embodiments, the compositions disclosed herein provide an AUCi of between about 2.5 and about 30 of metabolite M6: (pg-h/mL). In some embodiments, the compositions disclosed herein provide an AUCi of between about 8 and about 25 of metabolite M6: (gg.h/mL). In some embodiments, the compositions disclosed herein provide an AUCt (pg, h/mL) of between about 12 and about 20 of metabolite M6. In some embodiments, the Cmax (pg/mL) of the metabolite M6 is between about 0.25 and about 4. In some embodiments, the Cmax (pg/mL) of metabolite M6 is between about 1 and about 3. In some embodiments, the Cmax (pg/mL) of the metabolite M6 is between about 2.4 and about 3. In some embodiments, the molar ratio of the UCT (pg, h/mL) of the metabolite M6 to the AUCt (pg*h/mL) of the compound I is from about 2 to about 11. In some embodiments, the molar ratio of AUCi:(Kg.h/mL) of metabolite M6 to AUCT (pg.h/mL) of Compound I is from about 4 to about 8. In some embodiments, the molar ratio of Cmax (pg/mL) of metabolite M6 to Cmax (pg/mL) of Compound I is from about 1 to about 7. In some embodiments, the molar ratio of the Cmax (pg/mL) of the metabolite V16 to the Cmax (pg/mL) of the compound I is from about 2 to about 6. 144188.doc -19- 201020240 All publications and patent applications referred to in this specification are incorporated herein by reference in their entirety as if individually and individually The instructions are incorporated herein by reference in their entirety. [Embodiment] The novel features of the present invention are set forth in detail in the appended claims. The features and advantages of the present invention will be better understood from the description of the embodiments of the invention. Although the preferred embodiment of the invention has been shown and described, it is apparent that the embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It will be appreciated that various alternatives to the embodiments of the invention described herein may be used in the practice of the invention. The scope of the invention is intended to be defined by the scope of the invention and the scope of the invention and the equivalents thereof. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter. Pharmaceutical Compositions Described herein include 4-(2-(5-indol-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-trioxa-3-ylthio)ethyl A pharmaceutical composition of an amino)-3- benzoic acid, a prodrug thereof and/or a pharmaceutically acceptable salt. In some embodiments, the pharmaceutical compositions comprise an effective amount of 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole- 3-ylthio)acetamido)-3- benzoquinone, a prodrug thereof and/or a pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition package 144188.doc -20- 201020240 contains an effective amount of 4-(2-(5-bromo-4-(1-cyclopropylnaphthalene)-4-yl)-411- 1,2,4-triazol-3-ylthio)ethinylamino)_3_chlorobenzoic acid, a prodrug thereof and/or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are for treating a condition. In some embodiments, the pharmaceutical compositions are for treating a condition in a mammal. In some embodiments, the pharmaceutical compositions are for use in treating a human condition. Method: Abnormal uric acid concentration ❿ The present invention also provides a method suitable for use in a disease or condition associated with abnormal uric acid concentrations. The method comprises administering to an individual having an abnormal uric acid concentration an effective amount of a composition as described herein, e.g., restoring an acceptable uric acid concentration or a non-abnormal uric acid concentration. The invention also provides a method of reducing the concentration of uric acid in one or more tissues or organs of an individual in need of reduced uric acid concentration, comprising administering to the individual a composition as described herein which reduces the amount of uric acid concentration. The invention also provides a method suitable for reducing uric acid production in a subject, uric acid excretion or reducing uric acid production, and uric acid excretion, comprising administering to the individual an effective amount of a composition as described herein. The invention also provides a method suitable for treating or preventing hyperuricemia in a subject comprising administering to the subject an effective amount of a composition as described herein. The invention also provides a method suitable for treating an individual having a condition characterized by abnormal tissue or a concentration of urinary acid comprising administering to the individual an effective amount of a composition as described herein. The invention also provides a method for treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Le-Nei's syndrome, Kelly-Siegel Miller syndrome, kidney disease, kidney stones, kidney failure 144188.doc •21 - 201020240 Exhaustion, joint inflammation, arthritis, urolithiasis, lead poisoning, parathyroid hyperfunction, psoriasis or sarcoma-like individuals A method comprising administering to an individual an effective amount of a composition as described herein. The present invention also provides a method suitable for preventing a condition characterized by abnormal tissue uric acid concentration, wherein the individual is at high risk of developing the condition, the method comprising administering to the individual an effective amount as described herein. Composition. The invention also provides a gout suitable for treating individuals, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Le-Nai syndrome, Xunli-West Gamille syndrome, nephropathy, kidney stones, renal failure, joint inflammation, arthritis, urolithiasis, lead poisoning, parathyroid hyperactivity, psoriasis or sarcoma-like disease, which involves administering an effective amount to an individual as herein Said composition. The invention also provides a method of treating gout in an individual comprising administering to the subject an effective amount of a composition as described herein. The invention also provides a method suitable for preventing the formation of tophi or reducing the size of the tophi in an individual comprising administering to the individual an effective amount of a composition as described herein. Terminology The term "subject", "patient" or "individual" as used herein with respect to an individual having a condition and the like encompasses both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates, such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, mutton, goats, pigs Livestock, such as rabbits, dogs and cats; experimental animals, including rodents such as rats, mice, and guinea pigs and the like. Non-mammal 144188.doc -22. 201020240 Examples include, but are not limited to, birds, fish and the like. In the methods and compositions provided herein - Example t, the mammal is a human. The term "effective amount", "therapeutically effective amount" or "medically effective amount" as used herein means that the amount of at least one agent or compound administered is sufficient to treat or prevent a particular disease or condition. The result may be to reduce and/or alleviate the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is an amount of a composition that is required to provide a clinically significant reduction in the disease, the composition comprising a compound as disclosed herein. In any individual case, an appropriate "effective" amount can be determined using techniques such as dose escalation studies. The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not abrogate the biological activity or properties of the compounds described herein and is relatively non-toxic, that is, the substance can be administered to an individual. It does not cause undesirable biological effects or interacts in a detrimental manner with any of the components contained in the composition. The terms "composition" and "pharmaceutical composition" as used herein mean 4-(2-(5-bromo-4.(1-cyclopropylnaphthalene-4-yl)-4 ugly-1,2, 4-Triazol-3-ylthio)acetamido)-3- benzoic acid, a prodrug thereof and/or a pharmaceutically acceptable salt, optionally mixed with at least one pharmaceutically acceptable chemical component, Such chemical components are, for example, but not limited to, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients, and the like. The term "pharmaceutically acceptable salt" as used herein includes 4-(2-(5-oxa-4-(4-cyclopropylnaphthalen-1-yl)-4?-1,2,4-tri). The -3- butyl thio) acetamino)-3 chlorobenzoate is formed with any pharmaceutically acceptable cation. 144188.doc • 23- 201020240 Salt, which maintains the biological effectiveness of the free acid. For example, 4 (2 gas 5 • bromo 4- 4-(1-cyclopropylnaphthalen-4-yl + triazole _3_ylthio) acetylamino)· 3- benzoic acid free acid group The group can be reacted with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+ (Ci_4 alkyl hydrazine, and the like. Representative organic amines suitable for use in the formation of test addition salts include arginine, Amine acid, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. These salts can be prepared in situ during the final isolation and purification, or by separation reaction and single The term "prodrug" as used herein refers to a substance that is converted to an active or more active substance by some process, such as by metabolic pathway transformation, after administration to an individual and subsequent absorption. A drug precursor. Thus, the term encompasses any derivative of a compound that is capable of providing, directly or indirectly, a compound of the invention or a pharmaceutically active metabolite or residue thereof upon administration to a recipient. The presence of the prodrug is present on some prodrugs. a chemical group that is small and/or imparts solubility to the drug or some other property. When the chemical group decomposes and/or modifies from the prodrug, it produces an active drug. Because in some cases, the prodrug may Prodrugs are generally easier to administer than parent drugs, for example, they can be bioavailable by oral administration, whereas parent drugs are not. A particularly advantageous derivative or prodrug is administered to a patient. The compounds of the invention increase the bioavailability of such compounds (e.g., making the orally administered compound easier to absorb into the blood) or enhancing the parent compound to the metabolic region (e.g., the brain or lymphatic system). Passive compound. Gradient 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4Η-1,2,4-tris-ol-3-ylthio)B The total amount of guanamine)-3- benzoquinone, its prodrug and/or pharmaceutically acceptable salt will depend first on the mammal being treated. In the case of administration to a human subject, the amount It will usually be determined by the prescribing physician, where the dose will generally be based on the age, sex, diet, weight, general health® status and response of the individual patient; the severity of the patient's symptoms; the precise indication or condition being treated; the indication being treated Or the severity of the condition; the time of administration; The composition; the composition of the composition; the excretion rate; the combination of drugs; and the judgment of the prescribing physician. The pharmaceutical composition may be in unit dosage form. In this form, the formulation is subdivided into the appropriate number of active groups for the desired purpose. A unit dose (e.g., an effective amount). Those skilled in the art can determine the appropriate dosage for a particular condition. For convenience, the total amount of the repair dose can be divided into several portions if necessary, and administered in one day. And the frequency and other therapeutic agents and/or therapies to be applied should be adjusted according to the judgment made by the attending clinician (physician) in consideration of such factors as described above. Therefore, the dosage of the pharmaceutical composition can be varied widely. Administration (in single or divided doses) from 1 mg/kg body weight to about 100 mg/kg body weight' may be administered in an amount of at least about 〇丨mg/kg body weight per day. Specific therapeutic doses include, for example, from about 0.01 mg to about 7 mg of the compound, or such as from about 0.05 mg to about 2500 mg of the compound. Depending on the specific application unit dose 4-(2-(5- Desert-4-(1-cyclopropylnaphthalene-4)) 4Hi, 2,4-triazole·3ylthio) 144188.doc •25· 201020240 Acetyla)-3- benzoic acid, a prodrug thereof and/or a pharmaceutically acceptable salt may be present in an amount between about 1 mg to 3000 mg, between about 2 mg to 2000 mg or 10 mg to Between 2000 mg. In some embodiments, the amount is from about 1 mg to about 1500 mg, from about 150 mg to about 1200 mg, or from about 200 mg to about 1000 mg. In further or additional embodiments, the amount is at least 1 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 900 mg or at least 1000 mg. In additional or additional embodiments, the amount is about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg. , about 900 mg or about 1000 mg. In some embodiments, the compositions are administered once daily. In further or additional embodiments, the compositions are administered twice daily. In further or additional embodiments, the compositions are administered at least twice daily. In some cases, a dose concentration below the lower limit of the above range may be far enough, while in other cases it may still be possible to use a larger dose without causing any harmful side effects, such as dividing the larger dose into several small doses, For administration within one day. In combination applications where the compound is not the sole therapy, it is possible to administer a smaller amount of the compound and still have a therapeutic or prophylactic effect. Dosage Forms The pharmaceutical compositions described herein are generally suitable for oral administration as a solid dosage form such as lozenges, capsules, pills, powders, granules and the like. These compositions can be administered to achieve 4-(2-(5-bromo-4-(1-cyclopropyl-cai-4-yl)-4Η-1,2,4-tris-3-ylthio) Ethylamino)-3 - gas benzophenone 144188.doc -26 - 201020240 A, ie, release, delayed release or sustained release of acid, its pharmaceutically acceptable salt and/or pharmaceutically acceptable salt. Kits The compositions and methods described herein provide kits for treating diseases and conditions. These kits contain instructions for the use of the compositions described herein and the teaching kits selected as appropriate. The kits may also include information such as scientific references, pharmaceutical instructional materials, clinical trial results, and/or an overview of such information and the like, indicating or determining the activity and/or advantages of the composition' and/or The description applies to the administration, administration, side effects, drug interactions or other information of a health care provider. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kits described herein can be provided, sold, and/or extended to health care providers, including physicians, nurses, pharmacists, prescription officers (formulary 〇fficial), and the like. In some embodiments, the kit can also be sold directly to the consumer. φ The compositions described herein are also suitable for use as diagnostic agents and as research reagents. For example, the compounds described herein (alone or in combination with other compounds) are useful as tools in differential analysis and/or combinatorial analysis to elucidate the pattern of expression of genes expressed in cells and tissues. As a non-limiting example, comparing the expression pattern in a cell or tissue treated with one or more compounds to the expression pattern in a control cell or tissue that has not been treated with the compound and analyzing the resulting differential gene expression, as Such patterns are related to, for example, disease association, signaling pathway, cellular localization, amount of expression, size, 144188.doc -27-201020240 structure or function of the gene being tested. Such analysis can be performed on stimulated or unstimulated cells in the presence or absence of other compounds that affect performance patterns. In addition to being suitable for human therapy, the compositions described herein may also be suitable for veterinary treatment of other animals. EXAMPLES The examples and preparations provided below further illustrate and exemplify the compounds of the invention and methods of preparing such compounds. It is to be understood that the scope of the invention is not limited by the following examples and preparations. I. Chemical Synthesis Example 1: Synthesis of 4-(2-(5-xi-4-(1-cyclopropylqin-4-yl)-4Η-1,2,4-oxadiazol-3-ylthio) Acetylamino)-3-phenylbenzoic acid (Compound 1)

4-(2-(5-溴-4-(1-環丙基萘-4-基）-4Η-1，2,4-***-3-基硫 基）乙醯胺基）-3-氣苯曱酸（化合物1)係如先前所述來製備 (參見美國公開專利申請案US 2006-0270725)且概述如下。4-(2-(5-Bromo-4-(1-cyclopropylnaphthalen-4-yl)-4Η-1,2,4-triazol-3-ylthio)acetamido)-3- Gas benzoic acid (Compound 1) was prepared as previously described (see U.S. Patent Application No. US 2006-0270725) and is summarized below.

4-環丙基萘-1-胺 ， 在氮氣氛圍下添加乙酸把（23 mg，0· 1 mmol)至4-澳萘-1-胺（500 mg，2.01 mmol)、環丙基晒酸（225 mg，2.62 mmol)、構酸鉀（1·49 g，7·04 mmol)及三環己基膦（56 mg， 144188.doc -28- 201020240 mL)中之溶液中。在 0.2 mmol)於甲苯（10 mL)及水（0.4 l〇〇°C下加熱該混合物3小時且隨後冷卻至室溫。添加水且 以乙酸乙酯萃取該混合物，經硫酸鈉乾燥並濃縮得到粗4_ 環丙基萘-1-胺（550 mg)，其不經進一步純化即用於下一步 驟中。4-cyclopropylnaphthalen-1-amine, acetic acid (23 mg, 0.1 mmol) to 4-ophthalen-1-amine (500 mg, 2.01 mmol), cyclopropyl tanning acid 225 mg, 2.62 mmol), potassium citrate (1·49 g, 7.04 mmol) and tricyclohexylphosphine (56 mg, 144188.doc -28- 201020240 mL). The mixture was heated at 0.2 mmol) in toluene (10 mL) and water (0.4 EtOAc) for 3h and then cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. Crude 4_cyclopropylnaphthalen-1-amine (550 mg) was used in the next step without further purification.

1-環丙基-4-異硫氰基萘 添加碳酸氫鈉（7 mL，飽和溶液）及硫光氣（〇 2 mL，2 6 ⑩ mmo1)至4-環丙基萘-1·胺（440 mg，2.6 mmol)於二氣甲烷 (14 mL)中之溶液中，並在室溫下攪拌該混合物1小時。分 離有機層，經硫酸鈉乾燥且濃縮得到粗丨_環丙基_4_異硫氰 基萘（877 mg，99%)，其不經進一步純化即用於下—步驟 中。1-cyclopropyl-4-isothiocyana naphthalene with sodium hydrogencarbonate (7 mL, saturated solution) and thiophosgene (〇 2 mL, 2 6 10 mmo1) to 4-cyclopropylnaphthalene-1. 440 mg, 2.6 mmol) in di-methane (14 mL) and the mixture was stirred at room temperature for one hour. The organic layer was separated, dried over sodium sulfate and evaporated tolululululululululululululululu

5-胺基-4-(1-環丙基萘-4-基）-4Η-1，2,4-三咕-3_硫酵 添加鹽酸胺基胍（3 55 mg，3.2 mmol)及二異丙基乙胺 Φ (0·56 mL，3.2 mmol)至 1-環丙基-4-異硫氰基萘（447 mg， 2.1 mmol)於二曱基曱醯胺（DMF，3 mL)中之溶液中，並在 5〇°C下攪拌該混合物18小時。隨後濃縮該混合物且添加氫 氧化納水溶液（2 Μ ’ 10 mL)。在50t下攪拌混合物18小 時’冷卻至室溫且以1 N HC1水溶液中和。單離所得沈 澱’得到5-胺基-4-(1-環丙基萘-4-基）-4Η-1,2,4-三唾-3-硫 醇（240 mg，44%)。 4-(2-(5-胺基-4-(1-環丙基萘_4_基）-4Η-1，2,4-***-3-基硫 144188.doc •29- 2010202405-Amino-4-(1-cyclopropylnaphthalen-4-yl)-4Η-1,2,4-triterpene-3_sulfurase added amine guanidine hydrochloride (3 55 mg, 3.2 mmol) and two Isopropylethylamine Φ (0·56 mL, 3.2 mmol) to 1-cyclopropyl-4-isothiocyana naphthalene (447 mg, 2.1 mmol) in dimercaptoamine (DMF, 3 mL) The solution was stirred at 5 ° C for 18 hours. The mixture was then concentrated and aqueous sodium hydroxide (2 Μ ' 10 mL) was added. The mixture was stirred at 50 t for 18 hours, cooled to room temperature and neutralized with a 1 N aqueous HCl solution. The resulting precipitate was isolated to give 5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4?-1,2,4-tris-trithiol (240 mg, 44%). 4-(2-(5-Amino-4-(1-cyclopropylnaphthalene-4-yl)-4Η-1,2,4-triazol-3-ylsulfide 144188.doc •29- 201020240

基）乙醢胺基）-3-氣苯甲酸 k 使5-胺基-4-(1-環丙基萘-4-基）-4札1，2,4-三。坐_3_硫醇 (789 mg’ 2.79 mmol)及3-氣-4-(2-氣乙醯胺基）笨甲酸（693 mg，2.79 mmol)溶解於DMF(6 mL)中且在5〇。〇下授掉該溶 液18小時。隨後添加水且以乙酸乙酯萃取該混合物。分離 有機層，經硫酸鈉乾燥且濃縮得到4-(2-(5-胺基環丙 基奈-4-基）-4Η-1,2,4-三11 坐-3-基硫基）乙酿胺基）_3 —氣苯甲酸 (1.04 g，75%)。Ethylamino)-3- benzoic acid k 5-Amino-4-(1-cyclopropylnaphthalen-4-yl)-4 za 1,2,4-tri. Separate _3_thiol (789 mg' 2.79 mmol) and 3-gas-4-(2-acetoamido) benzoic acid (693 mg, 2.79 mmol) in DMF (6 mL) at 5 〇 . The solution was given under the arm for 18 hours. Water was then added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 4-(2-(5-aminocyclopropylnaphthalen-4-yl)-4 Η-1,2,4-tri-l-yl-3-ylthio) Amino acid _3 - gas benzoic acid (1.04 g, 75%).

4-(2-(5-漠-4-(1-環丙基萘-4-基）-4Η-1，2·4-三攻 _3·基硫 基）乙醢胺基）-3-氯苯甲酸 添加二氣乙酸（0.35 mL，4.2 mmol)至所得4-(2-( 5-胺基-4-(1-環丙基萘-4-基）-4H-1，2,4-三°坐-3-基硫基）乙醯胺基）_ 3-氣苯甲酸（1.04 g’ 2.1 mmol)、溴化苄基三乙基鍵ρ 65 g，6.1 mmol)及亞石肖酸納（2.9 g，42.1 mmol)於二溴曱炫 (44 mL)中之混合物中。在室溫下’黑暗中攪拌該混合物 18小時，隨後濃縮且藉由管柱層析法（95%二氯甲炫/5%曱 醇）純化所得殘餘物，传到4-(2-(5 ->臭-4-(1-環丙基萘_4_基）_ 4H-1,2,4-***-3-基硫基）乙醯胺基）-3-氣苯甲酸（393 mg， 34%) ° U.組合物之製備及分析 實例2A:製備立即釋放膠囊，100 mg 4-(2-(5-溴-4-(1-環丙基萘-4-基）-4Η-1,2,4-***-3-基硫 144188.doc •30· 201020240 基）乙醯胺基）-3-氣苯曱酸（化合物1，如本文所述而製備）及 微晶纖維素經由40目篩網過篩。使用Turbular型T10B震盪 混合器將經過筛之混合物與交聯羧曱基纖維素鈉摻合在一 起歷時約15分鐘。將200 mg粉末摻合物囊封於2號尺寸之 深綠色不透明硬明膠Coni-Snap膠囊中。 根據此程序製備兩批膠囊；第一批量大小為3380粒膠囊 且第二批量大小為4400粒膠囊。分析該等膠囊之特性、強 度、純度、含量均一性及溶解概況，如下所述。 ® 單位組合物 成份 量(mg/膠囊） 化合物1 100.01 微晶纖維素，NF 98.9 交聯羧曱基纖維素鈉，NF 1.1 總填充重量 200.0 2號尺寸之深綠色不透明Coni-Snap膠囊 1 © 分批組成 成份 100 mg膠囊 mg/膠囊 g/3200粒膠囊 化合物1 100.01 320.01 微晶纖維素，NF 98.9 316.5 交聯羧曱基纖維素鈉，NF 1.1 3.5 144188.doc -31 - 1 作為游離酸，相當於106.8 mg鉀鹽。化合物1之用量係基 於實際效能進行調節且相應進行微晶纖維素調節。 201020240 實例2B :鑑別實例2A中製備之膠囊中之化合物1 使用等梯度逆相HPLC法（4.6x150 mm YMC ODS AQ ’ 3 μιη尺寸粒子管柱；移動相為45% 1〇 mM ΚΗ2Ρ04(ρΗ 3.0) 及55%乙腈）以220 nm之UV偵測來證實化合物1之特性。以 50/50(v/v)乙腈/水萃取膠囊。藉由比較樣本製劑與標準製 劑之峰值滯留時間來確定化合物1之特性，且展示相對於 參考標準之相對滯留值（Rr)為0.97-1.03 ’證實化合物1之存 在。 實例2C :測定實例2A中製備之膠囊中化合物1之量 使用等梯度逆相1^1^法（4.6><150|11〇1丫?4(：〇〇8八(），3 μιη尺寸粒子管柱；移動相為45% 10 mM KH2p〇4(pH 3.0) 及55%乙腈）以220 nm之UV偵測來測定化合物1之含量。以 50/50(v/v)乙腈/水萃取膠囊。藉由比較樣本峰值與伴隨獲 得之標準製劑之峰值來測定化合物1之含量。 實例2D :測定實例2 A中製備之膠囊中之雜質 使用梯度溶離逆相1^1^法（4.6><15〇111111丫]^€008入(5’ 3 尺寸粒子管柱；移動相A為10 mM KH2P〇4(pH 3.0)且 移動相B為乙腈）以220 nm之UV偵測來測定雜質含量。以 5〇/5t^v/v)乙腈/水萃取膠囊。藉由比較樣本製劑層析圖中 之雜質峰面積與伴隨獲得之標準製劑中化合物1之峰面積 來測定:雜質。已知雜質係藉由應用各別雜質之反應因子來 計算。該方法之報導極限為0·05%。分析結果展示於下表 中〇 -32- 144188.doc 201020240 雜質 極限 第1批 第2批 「漠代酸(bromo acid)」雜質 NMT 1.0% 未測出 0.06% 「脫漠化物(des-bromo)」雜質 NMT 1.0% 0.3% 0.41% 「甲酯」雜質 NMT 1.0% 0.4% 0.18% 「脫環丙基化物(des-cyclopropyl)」雜質 NMT 1.5% 未測出 未測出 非特定物質 各為NMT 0.5%，報導RRT RRT0.60: 0.1% RRT0.64: 0.1% RRT 0.98: 0.1% RRT 1.14: 0.2% RRT 0.62: 0.06% RRT 0.85:0.07% RRT 1.06: 0.07% RRT 1.14: 0.13% 總相關物質 NMT 4.0% 1.0% 0.99% NMT-不多於；RRT=相對滯留時間 實例2E :測定實例2A中製備之膠囊中之水含量 使用USP <921 >之卡耳-費雪法（Karl Fischer method)來測 定水含量。結果展示如下： 第1批 第2批 水含量 4.65% 5.71% 實例2F :實例2A中製備之膠囊中之化合物1的溶解概況 膠囊中之化合物1的溶解係使用以75 rpm操作之USP設備 1在37°C下於900 mL水中測定。在特定時間取得溶解介質 之過濾樣本，且藉由HPLC程序使用如上所述關於含量測 定之相同層析條件進行分析。藉由比較樣本層析圖之♦值 反應與伴隨獲得之標準層析圖之峰值反應來測定釋放，且 144188.doc -33- 201020240 結果展示如下。 極限 第1批 第2批 30分鐘内NLT 80%(Q=75%) 平均值：96.7% RSD ： 1.5% 最小值·· 94.4% 最大值：98.9% 平均值：107.4% RSD : 3.1% 最小值：103.4% 最大值：111.4% NLT=不少於；RRT=相對滯留時間 實例3A:製備重覆囊封之膠囊，100 mg 將1號尺寸之白色Vcaps膠囊外殼裝入profiii囊封機托盤 中’且使Vcaps之帽與膠囊主體分離。將2號尺寸之深綠色 不透明硬明膠Coni-Snap膠囊（如上文實例2A中所述而製備） 置於各Vcaps膠囊主體中。使用ProHll設備將膠囊帽放回膠 囊主體上並輕壓閉合以使帽固定於主體上。必要時使用額 外托盤重複此過程。 根據此程序製備兩批膠囊；第一批量大小為680粒膝囊 且第二批量大小為2200粒膠囊。分析該等膠囊之特性、強 度、純度、含量均一性及溶解概況，如下所述。 單位組合物 成份 量(mg/摩·囊） 化合物1 100.03 微晶纖維素，NF 98.9 交聯羧甲基纖維素鈉，NF 1.1 總填充重量 200.0 2號尺寸之深綠色不透明Coni-Snap膠囊(第一囊封） 1 1號尺寸之白色Vcaps®，HPMCConiSnap膠囊(重覆囊封） 1 a作為游離酸，相當於106.8 mg_鹽。化合物1之用量係基 於實際效能進行調節且相應進行微晶纖維素調節。 144188.doc -34- 201020240 實例3B :鑑別實例3 A中製備之膠囊中之化合物1 使用等梯度逆相1^1^法（4.6><150 111111丫]^(：〇〇8八(5’3 μιη尺寸粒子管柱；移動相為45% 10 mM KH2P〇4(pH 3.0) 及55%乙腈）以220 nm之UV偵測來證實化合物1之特性。以 50/50(ν/ν)乙腈/水萃取膠囊。藉由比較樣本製劑與標準製 劑之峰值滯留時間來確定化合物1之特性’且展示相對於 參考標準之相對滯留值（Rr)為0.97-1.03，證實化合物1之存 在。 實例3C :測定實例3 A中製備之膠囊中化合物1的量 使用等梯度逆相HPLC法（4.6x150 mm YMC ODS AQ ’ 3 μπι尺寸粒子管柱；移動相為45% 10 mM ΚΗ2Ρ04(ρΗ 3.0) 及55%乙腈）以220 nm之UV偵測來測定化合物1之含量。以 50/50(v/v)乙腈/水萃取膠囊。藉由比較樣本峰值與伴隨獲 得之標準製劑之峰值來測定化合物1之含量且展示如下。 第1批 第2批 含量 101.6% 103.5% 實例3D :測定實例3 A中製備之膠囊中之雜質 使用梯度溶離逆相1^1^法（4.6><150 111111丫]^(：〇〇8入(^， 3 μιη尺寸粒子管柱；移動相A為10 mM ΚΗ2Ρ04(ρΗ 3.0)且 移動相B為乙腈）以220 nm之UV偵測來測定雜質含量。以 50/50(v/v)乙腈/水萃取膠囊。藉由比較樣本製劑層析圖中 之雜質峰面積與伴隨獲得之標準製劑中化合物1之峰面積 來測定雜質。已知雜質係藉由應用各別雜質之反應因子來 144188.doc -35- 201020240 計算。該方法之報導極限為0.05%。分析結果展示於下表 中。 極限 第1批 第2批 「溴代酸」雜質 NMT1.0% 0.05% 0.06% 「脫溴化物」雜質 NMT 1.0% 0.33% 0.41% 「曱酯J雜質 NMT1.0% 0.36% 0.19% 「脫環丙基化物」 雜質 NMT 1.5% 0.08% 未測出 非特定物質 各為NMT 0.5%， 報導RRT RRT 0.07: 0.05% RRT 0.63: 0.06% RRT 0.89: 0.05% RRT 1.06: 0.05% RRT1.14: 0.05% RRT1.15: 0.14% RRT 0.62: 0.06% RRT 0.85: 0.08% RRT 1.06: 0.07% RRT 1.14: 0.15% 總相關物質 NMT 4.0% 1.21% 1.01% NMT-不多於；RRT=相對滯留時間 實例3E :測定實例3 A中製備之膠囊中之水含量 使用USP <921>之卡耳-費雪法來測定水含量。結果展示 如下： 批號 1 2 水含量 6.14% 6.40% 實例3F :實例3 A中製備之膠囊中之化合物1的溶解概況 膠囊中之化合物1的溶解係使用以75 rpm操作之USP設備 1在37°C下於900 mL水中測定。在特定時間（15、30、45及 60分鐘）取得溶解介質之過濾樣本，且藉由HPLC使用如上 144188.doc -36- 201020240 所述關於含量測定之相同層析條件進行分析。藉由比較樣 本層析圖之峰值反應與伴隨獲得之標準層析圖之峰值反應 來測定化合物釋放，且結果展示如下。 批號 1 2 溶解概況 平均值 RSD 最小值 最大值 平均值 RSD 最小值 最大值 15分錢= 7% 122% 0% 20% 15分鐘= 8% 163% 0% 34% 30分鐘= 92% 11% 77% 102% 30分鐘= 93% 4% 87% 97% 45分鐘= 101% 2% 98% 103% 45分鐘= 107% 3% 101% 109% 60分鐘= 101% 2% 98% 103% 60分鐘= 107% 3% 102% 109% NLT=不少於；RRT =相對滯留時間 β 實例4Α :製備包覆腸溶包衣之顆粒劑，200 mg 研磨4-(2-(5-溴-4-(1-環丙基萘-4-基）-4Η-1,2,4-***-3-基 硫基）乙酿胺基）-3-氯苯曱酸（化合物1，如本文所述而製 備），且接著於行星混合器中與微晶纖維素及羥丙曱纖維 素摻合。用純水使行星混合器中之摻合成份粒化，濕顆粒 經由8目篩網過篩且在烘箱中之托盤上於40°C下乾燥至水 分含量小於5%，如由乾燥失重法（LOD)所測定。乾燥顆粒 係經由40目篩網過篩；收集保留在該40目篩網上之顆粒， 且將剩餘細末轉移至回收廢料中。使用流體化床包覆單 元，將羥丙曱纖維素溶液（純水中7°/〇 w/w)塗覆於該等大於 40目之顆粒上，隨後塗覆滑石粉、檸檬酸三乙酯及甲基丙 烯酸分散體（預先經80目篩網過篩）。將約3 17 mg經包覆顆 粒人工填充至1700粒1號尺寸之瑞典橙色不透明硬明膠膠 囊之每一者中。 根據此程序製備一批1700粒膠囊。分析該等膠囊之特 性、強度、純度、含量均一性及溶解概況，如下所述。 144188.doc •37- 201020240 單位組合物 成份 量(mg/勝囊） 化合物1，經研磨 200.03 微晶纖維素，NF 34.9 羥丙曱纖維素2910，USP 13.5 未經包覆之顆粒之總重量 262.0 羥丙曱纖維素2910，USP(底包衣） 15.3 曱基丙烯酸共聚物分散體，NF(Eudmgit L30D-55)(腸溶包衣） 30.4 滑石粉，USP 6.1 檸檬酸三乙酯，NF 3.0 1號尺寸之瑞典撥色不透明之空的硬明膠膠囊(囊封） 各1 總膠囊填充重量 316.8 分批組成 成份 200 mg膠囊 mg/膠囊 g/1,700粒膠囊 活性成份 化合物1，經研磨 200.03 340.03 粒化介質 純水，USPb - 適量b 賦形劑 微晶纖維素，NF 34.9 59.3 羥丙曱纖維素2910，USP 13.5 23.0 未經包覆之顆粒之總重量 262.0 445.4 含水包衣 羥丙甲纖維素2910，USP 15.3 26.0 曱基丙烯酸共聚物分散體，NF(EudragitL30D-55)e 30.4 147.3C 滑石粉，USP 6.1 10.4 擰檬酸三乙酯，NF 3.0 5.1 1號尺寸之瑞典橙色不透明之空的硬明膠膠囊 各1 1700 總膠囊填充重量 316.8 538.6 a作為游離酸，相當於213.6 mg鉀鹽。化合物1之用量係基於實際 效能進行調節且相應進行微晶纖維素調節。 b足以促進顆粒形成之量，在乾燥過程中移除。 eEudragitL30D-55為含有30%固體之分散體。 144188.doc -38- 201020240 實例4B :鑑別實例4A中製備之膠囊中之化合物1 使用等梯度逆相1^1^法（4.6><15〇111111丫]^0：008八(），3 μηι尺寸粒子管柱；移動相為45% 10 mM ΚΗ2Ρ04(ρΗ 3.0) 及55%乙腈）以220 nm之UV偵測來證實化合物1之特性。該 等膠囊以20:80〇~)甲醇/磷酸鹽緩衝液（1)117.4)萃取且用甲 醇/水（20:80 v/v比率）按1:1〇稀釋。用於檢定之化合物1之 目標濃度為〇. 1 mg/mL。藉由比較樣本製劑與標準製劑之 峰值滯留時間來確定化合物1之特性，且展示相對於參考-標準之相對滯留值（Rr)為1.00士0.03，證實化合物1之存 在。 實例4C :測定實例4A中製備之膠囊中之化合物1的量 使用等梯度逆相HPLC法（4_6xl50 mm YMC ODS AQ，3 μηι尺寸粒子管柱；移動相為45% 10 mM ΚΗ2Ρ04(ρΗ 3.0) 及55%乙腈）以220 nm之UV偵測來測定化合物1之含量。該 等膠囊以20:80〇~)甲醇/磷酸鹽缓衝液（？^17.4)萃取且用甲 醇/水（20:80 v/v比率）按1:10稀釋。用於檢定之化合物1之 目標濃度為0.1 mg/mL。藉由比較樣本峰值與伴隨獲得之 標準製劑之峰值來測定化合物1之含量，且證實該量為 98.2%，在90.0-110.0%之極限集内。 實例4D :測定實例4A中製備之膠囊中的雜質 使用梯度溶離逆相HPLC法（4.6xl50mmYMC◦DSAQ， 3 μιη尺寸粒子管柱；移動相A為mM KH2P〇4(PH 3.〇)且 移動相B為乙腈）以220 nm之UV偵測來測定雜質含量。以 20/80〇/¥)曱醇/破酸鹽緩衝液（？117.4)萃取膠囊。藉由比較 144188.doc -39· 201020240 樣本製劑層析圖中之雜質峰面積與伴隨獲得之標準製劑中 化合物1之峰面積來測定雜質。已知雜質係藉由應用各別 雜質之反應因子來計算。該方法之報導極限為0.05%。分 析結果展示於下表中。 極限 結果 「溴代酸」雜質 NMT 1.0% 0.07%, 「脫溴化物」雜質 NMT 1.0% 0.39% 「曱酯」雜質 NMT 1.0% 0.20% 「脫環丙基化物」雜質 NMT 1.5% ND 非特定物質 各為 NMT0.5%， 報導RRT RRT 0.63=0.06% RRT 0.66=0.07% RRT 0.86=0.05% RRT 1.02=0.07% RRT 1.06=0.06% RRT 1.13 =0.07% RRT 1.22=0.06% 總相關物質 NMT 4.0% 1.10% 實例4E :測定實例4 A中製備之膠囊中的水含量 使用USP <921 >之卡耳-費雪法來測定水含量，且經量測 為 6·90/〇。 實例4F :實例4Α中製備之膠囊中之化合物1的溶解概況 膠囊中之化合物1的溶解係根據USP <711>方法Α對於延 遲釋放劑型之原理，使用設定為50 rpm之USP設備2在37°C 下測定。在700 mL pH 1.2之溶解介質中進行酸階段歷時2 小時，隨後在900 mL pH 6.8之溶解介質中進行緩衝階段。 144188.doc -40- 201020240 在特定時間（15、30、45及60分鐘）取得測試溶解介質之經 過濾等分試樣，且藉由HPLC使用如上所述關於含量測定 之相同層析條件進行分析。藉由比較樣本層析圖之峰值反 應與伴隨獲得之標準層析圖之峰值反應來測定化合物釋 放，且結果展示如下。 極限 結果 酸階段 1級：對於平均6個單位而言 為NMT10%，且無個體 溶解大於25% 平均值=0.0% RSD%=82.0 最小值=0.0% 最大值=0.0%，合格 緩衝階段 t=30、45、60、90 及100分鐘時之報導概況 30分鐘 平均值=93.0% RSD%=2.9% 最小值=88.5% 最大值=95.9% 45分鐘 平均值=95.9% RSD%=2.6% 最小值=91.3% 最大值=98.2% 60分鐘 平均值=96.8% RSD%=2.7% 最小值=91.8% 最大值=99.2% 90分鐘 平均值=97.6% RSD%=3.1% 最小值=92.0% 最大值=100.2% 100分鐘 平均值=98.4% RSD%=3.8% 最小值=91.9% 最大值=101.6% NMT=不多於；RRT=相對滯留時間 144188.doc -41 - 201020240 實例5A :製備包覆腸溶包衣之旋劑，2〇〇 mg 經由裝備0.033"圓孔篩之Fitzmill研磨4_(2_(5_溴_4_(丨_環 丙基萘-4-基）-4Η-1，2,4-***_3_基硫基）乙醯胺基）_3_氣苯甲 酸（化合物1，如本文所述而製備將經研磨之化合物1、 微晶纖維素及經丙曱纖維素用R〇b〇t C〇Upe RSI-3VG高剪 切旋轉粒化機摻合約5分鐘’且用純水使摻合成份粒化。 濕顆粒經由1 0目篩網過篩且在烘箱中之托盤上於4〇。〇下乾 操至水分含量為NMT 3% ’如由乾燥失重法（L〇D)所測 定。乾燥顆粒經由10目篩網過篩，且將約一半顆粒裝入 Bohle MC-5(5.0公升）箱中。硬脂酸鎂（NF)經由3〇目篩網過 篩並進入該MC-5箱内’將剩餘顆粒裝入該箱中。該混合 物用Bohle LM 40箱式摻合器（Bin blender)以25 RPM摻合3 分鐘’且使用旋轉製錠機壓製經摻合之顆粒至262 mg之目 標鍵劑重量。使用實驗室混合器製備純水中之7〇/〇 w/w羥丙 甲纖維素2910之包覆溶液’且使用vect〇r LCDS-3包覆系 統將其塗覆於壓製旋劑上以達成約3 %之重量增加（約8 mg/ 鍵劑）。使用實驗室混合器製備純水中之18% w/w白色 Acryl-Eze(曱基丙烯酸共聚物）之腸溶包衣懸浮液，且使用 Vector LCDS-3包覆系統將該懸浮液塗覆於先前經包覆之 錠劑上以達成約10°/。之重量增加（約27 mg/錠劑）。單獨之 錠劑為白色、囊片形狀之錠劑，大小為約〇.2" χ〇.43 ·'，每 錠重約298 mg且含有200 mg化合物1(以鉀鹽形式存在）。 根據此程序製備一批1700粒膠囊。分析該等膠囊之特 性、強度、純度、含量均一性及溶解概況，如下所述。 144188.doc -42- 201020240 單位組合物 成份 量(mg/錠劑） 化合物，經研磨 200.03 微晶纖維素，NF 34.0 羥丙曱纖維素2910，USP 13.1 硬脂酸鎂，NF 1.3 錠劑核心總重量 262.0 羥丙曱纖維素2910，USP(第一包衣） 10.0 白色Acryl-Eze(腸溶包衣） 27.1 包覆腸溶包衣之鍵:劑的總重量 299.1 分批組成 成份 200 mg疑劑 mg/疑劑 g/l，700粒錠劑 活性成份 200.0a 340.0a 化合物1，經研磨 粒化介質 純水，USPb 適量b 賦形劑 微晶纖維素，NF 34.0 57.8 羥丙甲纖維素2910，USP 13.1 22.3 硬脂酸鎂，USP 1.3 2.2 錠劑核心總重量 262.0 445.4 含水包衣 羥丙曱纖維素2910，USP 10.0 17.0 白色 Acryl-Eze 27.1 46.0 包衣錠劑總重量 299.1 508.5 a作為游離酸，相當於213.6 mg鉀鹽。化合物1之用量係基 於實際效能進行調節且相應進行微晶纖維素調節。 以促進顆粒形成之量，在乾燥過程中移除。 144188.doc •43· 201020240 實例5B :鑑別實例5 A中製備之膠囊中之化合物1 使用等梯度逆相1^1^法（4.以150 111111丫14(：〇〇8八(），3 μηι尺寸粒子管柱；移動相為45% 10 mM KH2P〇4(pH 3.0) 及55%乙腈）以220 nm之UV偵測來證實化合物1之特性。該 等膠囊以20:80(v/v)曱醇/磷酸鹽緩衝液（PH 7.4)萃取且用甲 醇/水（20:80 v/v比率）按1:1〇稀釋。用於檢定之化合物1之 目標濃度為〇. 1 mg/mL。藉由比較樣本製劑與標準製劑之 峰值滯留時間來確定化合物1之特性，且展示相對於參考 標準之相對滞留值（Rr)為1.00土〇.〇3 ’證實化合物1之存 在。 實例5C :測定實例5 A中製備之膠囊中之化合物1的量 使用等梯度逆相11?1^法（4.6><150 111111丫1^(：〇〇8入(）’3 μπι尺寸粒子管柱；移動相為45% 10 mM ΚΗ2Ρ04(ρΗ 3.0) 及55%乙腈）以220 nm之UV偵測來測定化合物1之含量。該 等膠囊以20:80(v/v)甲醇/磷酸鹽緩衝液（pH 7.4)萃取且用曱 醇/水（20:80 v/v比率）按1:10稀釋。用於檢定之化合物1之 目標濃度為〇. 1 mg/mL。藉由比較樣本峰值與伴隨獲得之 標準製劑之峰值來測定化合物1之含量，且證實該量為 102_8%，在90.0-110.0%之極限集内。 實例5D :測定實例5 A中製備之膠囊中的雜質 使用梯度溶離逆相11?1^法（4.6>^150 111111丫]^(：〇〇8入(）， 3 μιη尺寸粒子管柱；移動相A為10 mM KH2P〇4(pH 3.0)且 移動相B為乙腈）以220 nm之UV偵測來測定雜質含量。以 20/80(乂~)甲醇/磷酸鹽緩衝液（？117.4)萃取膠囊。用於雜質 144188.doc -44- 201020240 檢定之化合物1之目標濃度為1 mg/mL。藉由比較樣本製劑 層析圖中之雜質峰面積與伴隨獲得之標準製劑中化合物1 之峰面積來測定雜質。已知雜質係藉由應用各別雜質之反 應因子來計算。該方法之報導極限為0.05%。分析結果展 示於下表中。 極限 結果 「溴代酸」雜質 NMT1.0% 0.07% 「脫溴化物」雜質 NMT1.0% 0.41% 「甲酯」雜質 NMT1.0% 0.23% 「脫環丙基化物」雜質 NMT1.5% 0.05% 非特定物質 各為NMT0.5%，報導RRT RRT 0.63=0.06% RRT 0.66=0.07% RRT 0.86=0.06% RRT 1.02=0.07% RRT 1.06=0.06% RRT 1.13=0.09% RRT 1.22=0.05% 總相關物質 NMT4.0% 1.22% 〇 實例5E :測定實例5 A中製備之膠囊中的水含量 使用USP <92 1 >之卡耳-費雪法來測定水含量，且經量測 為 4.75%。 實例5F :實例5 A中製備之膠囊中之化合物1的溶解概況 膠囊中之化合物1的溶解係根據USP <711>方法A對於延 遲釋放劑型之原理，使用設定為50 rpm之USP設備2在3 7°C 下測定。在700 mL pH 1.2之溶解介質中進行酸階段歷時2 小時，隨後在900 mL pH 6.8之溶解介質中進行緩衝階段。 144188.doc •45- 201020240 在特定時卩&^ (3〇、45、60、90及100分鐘）取得測試溶解介質 之經過濾坌4-(2-(5-Dimethyl-4-(1-cyclopropylnaphthalen-4-yl)-4Η-1,2·4-tris- _3·ylthio)ethinyl)-3- Dichloroacetic acid (0.35 mL, 4.2 mmol) was added to the chlorobenzoic acid to the obtained 4-(2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4- Tris(3-ylthio)acetamido)_3-benzoic acid (1.04 g' 2.1 mmol), benzyltriethyl bromide ρ 65 g, 6.1 mmol) and succinate (2.9 g, 42.1 mmol) in a mixture of dibromide (44 mL). The mixture was stirred in the dark at room temperature for 18 hours, then concentrated and the residue obtained was purified by column chromatography (95% dichloromethane / 5% methanol) and passed to 4-(2-(5) ->Smelly 4-(1-cyclopropylnaphthalene-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3- benzoic acid (393 Mg, 34%) ° U. Composition Preparation and Analysis Example 2A: Preparation of immediate release capsules, 100 mg 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4Η) -1,2,4-triazol-3-ylsulfide 144188.doc •30·201020240 base) acetamino)-3- benzoquinone (compound 1, as described herein) and microcrystalline fibers The sifter was sieved through a 40 mesh screen. The sieved mixture was blended with croscarmellose sodium for about 15 minutes using a Turbular type T10B shake mixer. A 200 mg powder blend was encapsulated in size 2 dark green opaque hard gelatin Coni-Snap capsules. Two batches of capsules were prepared according to this procedure; the first batch size was 3,380 capsules and the second batch size was 4,400 capsules. The characteristics, strength, purity, content uniformity and dissolution profile of the capsules were analyzed as described below. ® Unit Composition Ingredients (mg/capsule) Compound 1 100.01 Microcrystalline Cellulose, NF 98.9 Cross-linked Carboxymethyl Cellulose Sodium, NF 1.1 Total Filling Weight 200.0 Dark Green Opaque Coni-Snap Capsule 2 Size 2 © Minutes Batch composition 100 mg capsule mg/capsule g/3200 capsule compound 1 100.01 320.01 microcrystalline cellulose, NF 98.9 316.5 croscarmellose sodium, NF 1.1 3.5 144188.doc -31 - 1 as free acid, equivalent At 106.8 mg potassium salt. The amount of Compound 1 is adjusted based on actual potency and the microcrystalline cellulose is adjusted accordingly. 201020240 Example 2B: Identification of Compound 1 in Capsules Prepared in Example 2A Using an Equal Gradient Reverse Phase HPLC Method (4.6 x 150 mm YMC ODS AQ '3 μιη Size Particle Column; Mobile Phase 45% 1 mM ΚΗ2Ρ04 (ρΗ 3.0) And 55% acetonitrile) was confirmed by UV detection at 220 nm. The capsules were extracted with 50/50 (v/v) acetonitrile/water. The identity of Compound 1 was determined by comparing the peak residence time of the sample formulation to the standard formulation, and the relative retention value (Rr) relative to the reference standard was shown to be 0.97-1.03' to confirm the presence of Compound 1. Example 2C: Determination of the amount of Compound 1 in the capsule prepared in Example 2A using an isocratic reverse phase 1^1^ method (4.6 >< 150|11〇1丫?4(:〇〇8八(), 3 μιη Size particle column; mobile phase 45% 10 mM KH2p〇4 (pH 3.0) and 55% acetonitrile) Determination of compound 1 by UV detection at 220 nm. 50/50 (v/v) acetonitrile/water The capsule was extracted. The content of Compound 1 was determined by comparing the peak value of the sample with the peak value of the standard preparation obtained. Example 2D: Determination of impurities in the capsule prepared in Example 2 A using gradient elution reverse phase 1^1^ method (4.6 >;<15〇111111丫]^€008 into (5' 3 size particle column; mobile phase A is 10 mM KH2P〇4 (pH 3.0) and mobile phase B is acetonitrile) measured by UV detection at 220 nm Impurity content. The capsule was extracted with 5 〇/5 t^v/v) acetonitrile/water. The impurity peak area in the chromatogram of the sample preparation was compared with the peak area of the compound 1 in the standard preparation obtained: impurity. The impurity is calculated by applying the reaction factors of the respective impurities. The reported limit of the method is 0. 05%. The analysis results are shown in the following table 〇-32- 144188.doc 201020 240 Impurity limit Batch 1 Batch 2 "bromo acid" impurity NMT 1.0% No 0.06% detected "des-bromo" impurity NMT 1.0% 0.3% 0.41% "Methyl ester" impurity NMT 1.0% 0.4% 0.18% "des-cyclopropyl" impurity NMT 1.5% Undetected non-specific substances were NMT 0.5%, reported RRT RRT0.60: 0.1% RRT0.64: 0.1% RRT 0.98: 0.1% RRT 1.14: 0.2% RRT 0.62: 0.06% RRT 0.85: 0.07% RRT 1.06: 0.07% RRT 1.14: 0.13% Total Related Substances NMT 4.0% 1.0% 0.99% NMT-No more; RRT= Relative residence time Example 2E: Determination of water content in capsules prepared in Example 2A The water content was determined using the Karl Fischer method of USP < 921 > The results are shown below: Batch water content 4.65% 5.71% Example 2F: Dissolution profile of Compound 1 in capsules prepared in Example 2A. Dissolution of Compound 1 in capsules was determined using USP Apparatus 1 operating at 75 rpm in 900 mL of water at 37 °C. . A filtered sample of the dissolution medium was taken at a specific time and analyzed by the HPLC procedure using the same chromatographic conditions as described above for the content determination. The release was determined by comparing the ♦ value of the sample chromatogram with the peak reaction of the accompanying standard chromatogram, and the results are shown below. 144188.doc -33- 201020240 The results are shown below. Limit 1st Batch 2nd Batch 30 minutes NLT 80% (Q=75%) Average: 96.7% RSD: 1.5% Minimum ·· 94.4% Maximum: 98.9% Average: 107.4% RSD : 3.1% Minimum : 103.4% Maximum: 111.4% NLT = not less than; RRT = relative residence time Example 3A: Preparation of re-encapsulated capsules, 100 mg The size 1 white Vcaps capsule shell was loaded into the profiii encapsulation tray' And the Vcaps cap is separated from the capsule body. A size 2 dark green opaque hard gelatin Coni-Snap capsule (prepared as described in Example 2A above) was placed in each Vcaps capsule body. The capsule cap was placed back onto the capsule body using a ProHll device and gently closed to secure the cap to the body. Repeat this process with an additional tray if necessary. Two batches of capsules were prepared according to this procedure; the first batch size was 680 capsules and the second batch size was 2200 capsules. The characteristics, strength, purity, content uniformity and dissolution profile of the capsules were analyzed as described below. Unit composition component amount (mg/mol·capsule) Compound 1 100.03 Microcrystalline cellulose, NF 98.9 Cross-linked carboxymethyl cellulose sodium, NF 1.1 Total filling weight 200.0 2 size dark green opaque Coni-Snap capsule (No. One encapsulated) 1 size white Vcaps®, HPMCConiSnap capsule (repeatedly encapsulated) 1 a as free acid, equivalent to 106.8 mg_salt. The amount of Compound 1 is adjusted based on actual potency and the microcrystalline cellulose is adjusted accordingly. 144188.doc -34- 201020240 Example 3B: Identification of Compound 1 in Capsules Prepared in Example 3 A Using an Equal Gradient Reverse Phase 1^1^ Method (4.6><150 111111丫]^(:〇〇8八( 5'3 μιη size particle column; mobile phase 45% 10 mM KH2P〇4 (pH 3.0) and 55% acetonitrile) was confirmed by UV detection at 220 nm. 50/50 (ν/ν) Acetonitrile/water extraction capsules. The presence of Compound 1 was confirmed by comparing the peak residence time of the sample preparation with the standard formulation to determine the identity of Compound 1 'and showing the relative retention value (Rr) relative to the reference standard of 0.97-1.03. Example 3C: Determination of the amount of Compound 1 in the capsule prepared in Example 3 A using an isocratic reverse phase HPLC method (4.6 x 150 mm YMC ODS AQ '3 μπι size particle column; mobile phase 45% 10 mM ΚΗ2Ρ04 (ρΗ 3.0) And 55% acetonitrile) The content of Compound 1 was determined by UV detection at 220 nm. The capsule was extracted with 50/50 (v/v) acetonitrile/water. The compound was determined by comparing the peak value of the sample with the peak value of the standard preparation obtained. The content of 1 is shown below. The first batch of the second batch content 101.6% 103.5% Example 3D: determination example 3 A The impurities in the prepared capsules were subjected to gradient elution reverse phase 1^1^ method (4.6 > 150 111111丫]^(: 〇〇8 into (^, 3 μιη size particle column; mobile phase A was 10 mM ΚΗ2Ρ04 (ρΗ 3.0) and mobile phase B is acetonitrile. The impurity content is determined by UV detection at 220 nm. The capsule is extracted with 50/50 (v/v) acetonitrile/water by comparing the impurity peaks in the chromatogram of the sample preparation. The area is determined by the peak area of Compound 1 in the standard preparation obtained. The impurity is known to be calculated by the reaction factor of 144188.doc -35- 201020240 using the respective impurities. The reported limit of the method is 0.05%. The results are shown in the table below. Limits Batch 1 Batch 2 "Bromoacids" Impurities NMT1.0% 0.05% 0.06% "Debromide" Impurities NMT 1.0% 0.33% 0.41% "Nonyl ester J impurity NMT 1.0% 0.36% 0.19% "Decyclopropylated" Impurity NMT 1.5% 0.08% NMT 0.5% not detected for each non-specific substance, reported RRT RRT 0.07: 0.05% RRT 0.63: 0.06% RRT 0.89: 0.05% RRT 1.06: 0.05 % RRT1.14: 0.05% RRT1.15: 0.14% RRT 0.62: 0.06% RRT 0.85: 0.08% RRT 1.06: 0.07% RRT 1.14: 0.15% Total correlation Substance NMT 4.0% 1.21% 1.01% NMT- no more; RRT = relative residence time Example 3E: Determination of water content in capsules prepared in Example 3 A Determination of water using the USP <921> content. The results are shown below: Batch No. 1 2 Water content 6.14% 6.40% Example 3F: Example 3 Dissolution profile of Compound 1 in capsules prepared in A The dissolution of Compound 1 in capsules was performed using a USP apparatus 1 operating at 75 rpm at 37°. Determined in 900 mL of water at C. Filter samples of the dissolution medium were taken at specific times (15, 30, 45 and 60 minutes) and analyzed by HPLC using the same chromatographic conditions as described above for 144188.doc-36-201020240. Compound release was determined by comparing the peak reaction of the sample chromatogram with the peak response of the accompanying standard chromatogram, and the results are shown below. Batch No. 1 2 Dissolution Profile Average RSD Min Max Average RSD Min Max 15 cents = 7% 122% 0% 20% 15 minutes = 8% 163% 0% 34% 30 minutes = 92% 11% 77 % 102% 30 minutes = 93% 4% 87% 97% 45 minutes = 101% 2% 98% 103% 45 minutes = 107% 3% 101% 109% 60 minutes = 101% 2% 98% 103% 60 minutes = 107% 3% 102% 109% NLT = not less than; RRT = relative residence time β Example 4: Preparation of coated enteric coated granules, 200 mg ground 4-(2-(5-bromo-4-() 1-cyclopropylnaphthalen-4-yl)-4Η-1,2,4-triazol-3-ylthio)ethinyl)-3-chlorobenzoic acid (Compound 1, as described herein Prepared) and then blended with microcrystalline cellulose and hydroxypropylcellulose in a planetary mixer. The blended components in the planetary mixer are granulated with pure water, the wet granules are sieved through an 8 mesh screen and dried on a tray in an oven at 40 ° C to a moisture content of less than 5%, as by the dry weight loss method ( Determined by LOD). The dried granules are sieved through a 40 mesh screen; the granules remaining on the 40 mesh screen are collected and the remaining fines are transferred to the recovered waste. Using a fluidized bed coating unit, a solution of hydroxypropionin (7°/〇w/w in pure water) is applied to the particles larger than 40 mesh, followed by coating of talc, triethyl citrate And a dispersion of methacrylic acid (pre-screened through an 80 mesh screen). Approximately 3 17 mg of coated granules were manually filled into each of 1700 sized Swedish orange opaque hard gelatin capsules of size 1. A batch of 1700 capsules was prepared according to this procedure. The characteristics, strength, purity, content uniformity and dissolution profile of the capsules were analyzed as described below. 144188.doc •37- 201020240 Unit composition component (mg/winner) Compound 1, ground 200.03 microcrystalline cellulose, NF 34.9 hydroxypropionin 2910, USP 13.5 total weight of uncoated granules 262.0 Hydroxypropylcellulose 2910, USP (bottom coating) 15.3 Mercaptoacrylic acid copolymer dispersion, NF (Eudmgit L30D-55) (enteric coating) 30.4 Talc, USP 6.1 Triethyl citrate, NF 3.0 1 Size of the Swedish color opaque empty hard gelatin capsules (encapsulated) 1 total capsule filling weight 316.8 batch composition 200 mg capsule mg / capsule g / 1,700 capsules of active ingredient compound 1, after grinding 200.03 340.03 granulation Medium pure water, USPb - q amount of excipient microcrystalline cellulose, NF 34.9 59.3 hydroxypropionin cellulose 2910, USP 13.5 23.0 total weight of uncoated granules 262.0 445.4 aqueous coated hypromellose 2910, USP 15.3 26.0 Mercapto-acrylic acid copolymer dispersion, NF (Eudragit L30D-55)e 30.4 147.3C talc, USP 6.1 10.4 Triethyl citrate, NF 3.0 5.1 Size 1 Swedish orange opaque empty hard Capsules 1 1700 Total capsule filling weight 316.8 538.6 a as free acid, equivalent to 213.6 mg potassium salt. The amount of Compound 1 is adjusted based on the actual potency and the microcrystalline cellulose is adjusted accordingly. b is sufficient to promote the amount of particle formation that is removed during the drying process. eEudragit L30D-55 is a dispersion containing 30% solids. 144188.doc -38- 201020240 Example 4B: Identification of Compound 1 in Capsules Prepared in Example 4A Using an Equal Gradient Reverse Phase 1^1^ Method (4.6><15〇111111丫]^0:0088(), 3 μηι size particle column; mobile phase 45% 10 mM ΚΗ2Ρ04 (ρΗ 3.0) and 55% acetonitrile) was confirmed by UV detection at 220 nm. The capsules were extracted with 20:80 Torr~) methanol/phosphate buffer (1) 117.4) and diluted 1:1 Torr with methanol/water (20:80 v/v ratio). The target concentration of Compound 1 used for assay is 〇. 1 mg/mL. The identity of Compound 1 was determined by comparing the peak residence time of the sample preparation with the standard formulation, and the relative retention value (Rr) relative to the reference-standard was shown to be 1.00 ± 0.03, confirming the presence of Compound 1. Example 4C: Determination of the amount of Compound 1 in the capsule prepared in Example 4A using an isocratic reverse phase HPLC method (4_6 x 150 mm YMC ODS AQ, 3 μηι size particle column; mobile phase 45% 10 mM ΚΗ2Ρ04 (ρΗ 3.0) and 55% acetonitrile) The content of Compound 1 was determined by UV detection at 220 nm. The capsules were extracted with 20:80 Torr~) methanol/phosphate buffer (?17.4) and diluted 1:10 with methanol/water (20:80 v/v ratio). The target concentration of Compound 1 used for assay is 0.1 mg/mL. The content of Compound 1 was determined by comparing the peak value of the sample with the peak value of the standard preparation obtained, and it was confirmed that the amount was 98.2% within the limit set of 90.0-110.0%. Example 4D: Determination of impurities in the capsule prepared in Example 4A using gradient elution reverse phase HPLC (4.6 x 150 mm YMC ◦ DSAQ, 3 μιη size particle column; mobile phase A was mM KH2P 〇 4 (PH 3. 〇) and mobile phase B is acetonitrile) The UV content of 220 nm is used to determine the impurity content. Capsules were extracted with 20/80 〇/¥) sterol/acid salt buffer (?117.4). The impurities were determined by comparing the peak area of the impurity in the chromatogram of the sample preparation with the peak area of the compound 1 in the standard preparation obtained. Impurities are known to be calculated by applying a reaction factor for each impurity. The reported limit of this method is 0.05%. The results of the analysis are shown in the table below. The ultimate result "brominated acid" impurity NMT 1.0% 0.07%, "debromide" impurity NMT 1.0% 0.39% "decyl ester" impurity NMT 1.0% 0.20% "de-cyclopropylated" impurity NMT 1.5% ND non-specific substance Each is NMT0.5%, reported RRT RRT 0.63=0.06% RRT 0.66=0.07% RRT 0.86=0.05% RRT 1.02=0.07% RRT 1.06=0.06% RRT 1.13 =0.07% RRT 1.22=0.06% Total Related Substances NMT 4.0% 1.10% Example 4E: Determination of water content in capsules prepared in Example 4 A The water content was determined using the Karl Fischer method of USP < 921 > and was measured to be 6.90 / Torr. Example 4F: Dissolution profile of Compound 1 in capsules prepared in Example 4 The dissolution of Compound 1 in capsules was according to USP <711> Method Α For the principle of delayed release dosage form, USP Apparatus 2 set at 50 rpm was used at 37 Measured at °C. The acid phase was carried out in 700 mL of a pH 1.2 dissolution medium for 2 hours, followed by a buffering stage in 900 mL of a pH 6.8 dissolution medium. 144188.doc -40- 201020240 A filtered aliquot of the test dissolution medium was taken at specific times (15, 30, 45 and 60 minutes) and analyzed by HPLC using the same chromatographic conditions as described above for the determination of the content. . Compound release was determined by comparing the peak response of the sample chromatogram with the peak response of the accompanying standard chromatogram, and the results are shown below. Limit Results Acid Stage 1: NMT 10% for an average of 6 units, and no individual dissolution greater than 25% Average = 0.0% RSD% = 82.0 Minimum = 0.0% Maximum = 0.0%, Qualified Buffer Phase t = Reports at 30, 45, 60, 90 and 100 minutes Overview of 30 minutes Average = 93.0% RSD% = 2.9% Minimum = 88.5% Maximum = 95.9% 45 minutes average = 95.9% RSD% = 2.6% Minimum =91.3% Maximum = 98.2% 60 minutes average = 96.8% RSD% = 2.7% Minimum = 91.8% Maximum = 99.2% 90 minutes average = 97.6% RSD% = 3.1% Minimum = 92.0% Maximum = 100.2% 100 minutes average = 98.4% RSD% = 3.8% minimum = 91.9% maximum = 101.6% NMT = no more; RRT = relative residence time 144188.doc -41 - 201020240 Example 5A: Preparation of coated enteric The coating agent, 2 〇〇mg was milled through a Fitzmill equipped with a 0.033"round sieve 4_(2_(5_bromo_4_(丨_cyclopropylnaphthalen-4-yl)-4Η-1,2,4 - Triazole _3_ylthio) acetamidine) _3_ benzoic acid (Compound 1, prepared as described herein to be ground, compound 1, microcrystalline cellulose and fluorene cellulose B〇t C〇Upe RSI-3VG high shear The granulator was blended for 5 minutes' and the blended granules were granulated with pure water. The wet granules were sieved through a 10 mesh screen and placed on a tray in an oven at 4 Torr. The underarms were dried to a moisture content of NMT. 3% 'as determined by the dry weight loss method (L〇D). The dried granules were sieved through a 10 mesh screen and about half of the granules were placed in a Bohle MC-5 (5.0 liter) tank. Magnesium stearate (NF) The sieve was passed through a 3 mesh screen and entered into the MC-5 tank. The remaining pellets were charged into the tank. The mixture was blended with a Bohle LM 40 Box Blender at 25 RPM for 3 minutes. And using a rotary tableting machine to press the blended granules to a target bond weight of 262 mg. A 7 〇/〇w/w hypromellose 2910 coating solution in pure water was prepared using a laboratory mixer' and It was applied to a compression spinner using a vect〇r LCDS-3 coating system to achieve a weight gain of approximately 3% (approximately 8 mg/key). 18% w/ of pure water was prepared using a laboratory mixer. An enteric coating suspension of w white Acryl-Eze (methacrylic acid copolymer), and the suspension was applied to the previously coated using a Vector LCDS-3 coating system The tablets to achieve of about 10 ° /. The weight is increased (about 27 mg / tablet). The lozenge alone is a white, caplet-shaped lozenge having a size of about 2.2" χ〇.43 ·', each weighing about 298 mg and containing 200 mg of Compound 1 (in the form of a potassium salt). A batch of 1700 capsules was prepared according to this procedure. The characteristics, strength, purity, content uniformity and dissolution profile of the capsules were analyzed as described below. 144188.doc -42- 201020240 Unit composition component (mg/tablet) compound, ground 200.03 microcrystalline cellulose, NF 34.0 hydroxypropionin 2910, USP 13.1 magnesium stearate, NF 1.3 lozenge core Weight 262.0 Hydroxypropylcellulose 2910, USP (first coating) 10.0 White Acryl-Eze (enteric coating) 27.1 Coated coating of the enteric coating: total weight of the agent 299.1 Batch composition 200 mg suspect Mg/suspect agent g/l, 700 granules active ingredient 200.0a 340.0a compound 1, ground granulated medium pure water, USPb appropriate amount b excipient microcrystalline cellulose, NF 34.0 57.8 hypromellose 2910, USP 13.1 22.3 Magnesium stearate, USP 1.3 2.2 Lozenges core total weight 262.0 445.4 Aqueous coated hydroxypropionin 2910, USP 10.0 17.0 White Acryl-Eze 27.1 46.0 Coated lozenges Total weight 299.1 508.5 a as free acid, Equivalent to 213.6 mg potassium salt. The amount of Compound 1 is adjusted based on actual potency and the microcrystalline cellulose is adjusted accordingly. In order to promote the amount of particle formation, it is removed during the drying process. 144188.doc •43· 201020240 Example 5B: Identification of Compound 1 in Capsules Prepared in Example 5 A Using an Equal Gradient Reverse Phase 1^1^ Method (4. to 150 111111丫14(:〇〇8八(), 3 Μηι size particle column; mobile phase 45% 10 mM KH2P〇4 (pH 3.0) and 55% acetonitrile) was confirmed by UV detection at 220 nm. The capsules were 20:80 (v/v). The sterol/phosphate buffer (pH 7.4) was extracted and diluted with methanol/water (20:80 v/v ratio) at 1:1 Torr. The target concentration of the compound 1 used for the assay was 〇. 1 mg/mL. The identity of Compound 1 was determined by comparing the peak residence time of the sample formulation to the standard formulation, and the relative retention value (Rr) relative to the reference standard was shown to be 1.00. The presence of Compound 1 was confirmed. Example 5C: The amount of Compound 1 in the capsule prepared in Example 5A was measured using an isocratic reverse phase 11?1^ method (4.6><150 111111丫1^(:〇〇8 into()'3 μπι size particle column The mobile phase was 45% 10 mM ΚΗ2Ρ04 (ρΗ 3.0) and 55% acetonitrile). The content of Compound 1 was determined by UV detection at 220 nm. The capsules were 20:80 (v/v) methanol/phosphate. Buffer (pH 7.4) was extracted and diluted 1:10 with methanol/water (20:80 v/v ratio). The target concentration of compound 1 used for assay was 〇. 1 mg/mL. By comparing sample peaks The content of Compound 1 was determined with the peak of the standard preparation obtained, and it was confirmed that the amount was 102-8% within the limit set of 90.0-110.0%. Example 5D: Determination of impurities in the capsule prepared in Example 5 A using gradient elution Reverse phase 11?1^ method (4.6>^150 111111丫]^(:〇〇8 into (), 3 μιη size particle column; mobile phase A is 10 mM KH2P〇4 (pH 3.0) and mobile phase B For acetonitrile), the impurity content was determined by UV detection at 220 nm. The capsule was extracted with 20/80 (乂~) methanol/phosphate buffer (?117.4). For the impurity 144188.doc -44- 201020240 The target concentration is 1 mg/mL. The impurity is determined by comparing the impurity peak area in the chromatogram of the sample preparation with the peak area of the compound 1 in the accompanying standard preparation. The impurity is known to be reacted by applying various impurities. The factor is calculated. The reported limit of this method is 0.05%. The results of the analysis are shown in the table below. Brominated acid" impurity NMT1.0% 0.07% "Debromide" impurity NMT1.0% 0.41% "Methyl ester" impurity NMT1.0% 0.23% "Decyclopropylated" impurity NMT1.5% 0.05% Non-specific The substance was 0.5% NMT, reported RRT RRT 0.63=0.06% RRT 0.66=0.07% RRT 0.86=0.06% RRT 1.02=0.07% RRT 1.06=0.06% RRT 1.13=0.09% RRT 1.22=0.05% Total related substance NMT4. 0% 1.22% 〇Example 5E: Determination of water content in capsules prepared in Example 5 A The water content was determined using the Karl Fischer method of USP <92 1 > and was measured to be 4.75%. Example 5F: Dissolution Profile of Compound 1 in Capsules Prepared in Example 5 A Dissolution of Compound 1 in Capsules was based on USP <711> Method A for the principle of a delayed release dosage form using USP Apparatus 2 set at 50 rpm. 3 Measured at 7 °C. The acid phase was carried out in 700 mL of a pH 1.2 dissolution medium for 2 hours, followed by a buffering stage in 900 mL of a pH 6.8 dissolution medium. 144188.doc •45- 201020240 At the specified time 卩&^ (3〇, 45, 60, 90 and 100 minutes) to obtain the filtered solution of the test medium

刀試樣’且使用同溶劑溶離及226 nm之UV偵 測藉由Ηΐ>ιΓη A L(如上所述關於含量測定之相同層析條件）進行 分析。藉山 田比較樣本層析圖之峰值反應與伴隨獲得之標準 層析圖之^The knife sample' was analyzed by the same solvent elution and UV detection at 226 nm by Ηΐ>ιΓη A L (the same chromatographic conditions as described above for the content determination). Compare the peak response of the sample chromatogram with the standard chromatogram obtained by Yamada

而言為 NMT 10/0 ’且無個體溶解大於 25% _ 卞值反應來測定化合物釋放，且結果展示如下。 結果 平均值=0.0% 最小值=0.0% 最大值=0.0% ;合格 30分鐘 平均值=33.9% RSD%=22.0°/〇 最小值=20.8% 最大值=43.1% 45分鐘 平均值=73.4% RSD%=12.5% 最小值=55.5% 最大值=80.9% 60分鐘 ----- 平均值=91.2% RSD%=4.1% 最小值=84.3% 最大值=95.2% 90分鐘 平均值=96.8¾ RSD%=2.0% 最小值=94.4% 最大值=99.4% 1〇〇分鐘 平均值=101.3% RSD%=2.8% 最小值=97.0% 最大值=105.1 % 緩衝階段_ t=30、45、60、90及 100分鐘時 之報導概況 ' NMT=不多於 144188.doc -46- 201020240 111.人類臨床研究 實例6 使用實例2A、3A、4A、5A中所述之組合物進行人類臨 床研究，如下所述：在48個未經治療之HIV-1感染個體中 進行多中心、雙盲、安慰劑對照研究，隨機3:1(治療：安慰 劑）。患者為患有慢性HIV感染、但無AIDS界定之疾病病 史的1 8至65歲男性。患者未接受抗反轉錄病毒治療或接受 小於14天之先前治療，且不具有預先存在之RTI或PI藥物 ® 抗性，且未合併感染急性HAV、慢性HB V、活動性HCV。 患者CD4+細胞計數對於2個群組而言為>50個細胞/mm3， 接著取決於部位為>200個細胞/mm3或23 50個細胞/mm3。 經7天治療時期投與該等組合物，外加在第8天出於藥物 動力學目的投與一劑早晨劑量。（應注意，在一些情況下 投與同一組合物之多次劑量，以便達成所需化合物1之總 劑量；亦即為達成400 mg化合物1之劑量，患者可服用四 次100 mg組合物或兩次200 mg組合物，取決於劑型。）四 個連續劑量群組如下投與： 膠囊 EC錠劑 400 mg BID，禁食 800 mg QD，進食 600 mg QD，禁食 1000 mgQD，禁食 進行如下評估： •給藥後第1天至第10天及2週後之藥物動力學及耐受性 •給藥後第1天、第4天、第9天及2週後之實驗室安全性 (Safety labs)、免疫學 144188.doc -47- 201020240In the case of NMT 10/0 ' and no individual dissolved greater than 25% _ 卞 value reaction to determine compound release, the results are shown below. Result average = 0.0% Minimum value = 0.0% Maximum value = 0.0%; Eligible 30 minutes average value = 33.9% RSD% = 22.0 ° / 〇 Minimum value = 20.8% Maximum value = 43.1% 45 minutes average value = 73.4% RSD %=12.5% Min.=55.5% Max=80.9% 60 min----- Mean=91.2% RSD%=4.1% Min.=84.3% Max=95.2% 90 min average=96.83⁄4 RSD% =2.0% min = 94.4% max = 99.4% 1 min average = 101.3% RSD% = 2.8% min = 97.0% max = 105.1 % Buffer phase _ t = 30, 45, 60, 90 and Reporting Profile at 100 minutes ' NMT = no more than 144188.doc -46- 201020240 111. Human Clinical Study Example 6 Human clinical studies were performed using the compositions described in Examples 2A, 3A, 4A, 5A, as follows: A multicenter, double-blind, placebo-controlled study was performed in 48 untreated HIV-1 infected individuals randomized to 3:1 (treatment: placebo). The patient is a 18 to 65 year old male with a history of disease with chronic HIV infection but no AIDS. The patient did not receive antiretroviral therapy or received prior treatment for less than 14 days and did not have pre-existing RTI or PI drug ® resistance and was not co-infected with acute HAV, chronic HB V, active HCV. The patient CD4+ cell count was > 50 cells/mm3 for 2 groups, then depending on the site > 200 cells/mm3 or 2350 cells/mm3. The compositions were administered over a 7 day treatment period, plus a morning dose was administered on day 8 for pharmacokinetic purposes. (It should be noted that in some cases multiple doses of the same composition are administered in order to achieve the total dose of Compound 1 required; that is, to achieve a dose of 400 mg of Compound 1, the patient may take four 100 mg of the composition or two 200 mg of the composition, depending on the dosage form.) Four consecutive dose groups were administered as follows: Capsule EC tablets 400 mg BID, fasting 800 mg QD, 600 mg QD, fasting 1000 mg QD, fasting as follows : • Pharmacokinetics and Tolerance on Days 1 to 10 and 2 weeks after administration • Laboratory safety on Days 1, 4, 9 and 2 after administration (Safety Labs), immunology 144188.doc -47- 201020240

•給藥後第1天、第3天、第4天、第7天、第9天及2週後 之ECG •給藥後第1天、第9天及2週後之基因型及表現型 安全性/耐受性觀察結果：在跟蹤過程中未發生嚴重不 良事件（3級/4級）或過早停藥。未觀測到CNS毒性之跡象、 藥物相關皮疹、臨床上顯著之實驗室異常、對脂質分布之 明顯影響、臨床有關ECG發現及基因型或表現型易感性之 特徵變化。不良事件通常為輕度的（1級），無需干預。患者 基線特徵如下所示進行測定： 化合物1 安慰劑 400 mg BID* 600 mg QD* 800 mg QD 1000 mg QD* N=9 N=9 N=9 N=9 N=12 年齡 平均年齡 35.3 39.9 31.2 33.0 36.3 種族 高加索人 7 9 7 7 8 黑人 2 - 1 2 1 亞洲人 - - - - - 其他 - - 1 - CD4細胞計數 平均細胞數/mL 288.1 319.9 303.6 407.2 325.9 病毒負荷 複本/mL 31,815 46,845 40,161 39,852 32,551 範圍 4880-113000 6060-879000 15900-244000 7520-469000 5730-233000 144188.doc -48- 201020240 測定各種劑型之穩態藥物動力學且展示如下： AUC〇-24h(pg.h/mL) Cmax(Kg/mL) Tmax(h) tl/2(h) 400 BID MR膠囊，禁食 15.4 4.33 2.11 12.1 600 QD MR膠囊，禁食+ 7.53 2.98 2.12 8.7 800 QD EC鍵劑，進食 9.76 2.76 5.67 10.8 1000 QD EC錠劑，禁食* 16.1 5.72 3.17 8.5 在研究之第9天記錄血清尿酸濃度，且展示於下表中， 並在圖5中圖示。 安慰劑 600 mg QD 800 mg QD 1000 mg QD 400 mg BID 平均血清尿酸減少量(％) -6 -21 -21 -28 -30 T-檢驗(與安慰劑比較） 0.0011 0.0010 <0.0001 <0.0001 實例7 進行其他人類臨床研究以進一步研究本文所述之組合物 〇 之藥物動力學性質。結果概述於下表中。 實例 劑量(mg) 1狀態 N AUCT(pg*h/mL) Cmax(M-§/mL) 化合物1 2M6 3比率 化合物1 2M6 3比率 2A 300 Fa 6 3.19 8.91 2.90 0.658 1.30 1.96 600 FeS 6 7.34 19.0 2.85 2.00 2.52 1.60 2A 300 Fa 8 3.96 17.6 5.36 1.44 2.64 2.93 FeH 8 3.43 17.9 5.88 0.467 1.60 3.76 2A 100 FeS 5 0.670 2.82 4.04 0.173 0.264 2.27 2A 300 FeS 6 3.16 12.4 5.83 0.667 1.76 4.39 500 FeS 6 3.77 24.8 10.1 0.746 3.17 6.98 144188.doc •49- 201020240• ECG on day 1, day 3, day 4, day 7, day 9 and week after dosing • genotype and phenotype on days 1, 9 and 2 after dosing Safety/tolerance observations: No serious adverse events (Grade 3/4) or premature withdrawal during the follow-up. No signs of CNS toxicity, drug-related rashes, clinically significant laboratory abnormalities, significant effects on lipid distribution, clinically relevant ECG findings, and changes in genotype or phenotypic susceptibility were observed. Adverse events are usually mild (level 1) without intervention. Baseline characteristics of the patients were determined as follows: Compound 1 Placebo 400 mg BID* 600 mg QD* 800 mg QD 1000 mg QD* N=9 N=9 N=9 N=9 N=12 Age average age 35.3 39.9 31.2 33.0 36.3 Ethnic Caucasian 7 9 7 7 8 Black 2 - 1 2 1 Asian - - - - - Other - - 1 - CD4 cell count mean cell number / mL 288.1 319.9 303.6 407.2 325.9 Virus load replica / mL 31,815 46,845 40,161 39,852 32,551 Range 4880-113000 6060-879000 15900-244000 7520-469000 5730-233000 144188.doc -48- 201020240 The steady-state pharmacokinetics of the various formulations were determined and shown below: AUC〇-24h (pg.h/mL) Cmax (Kg /mL) Tmax(h) tl/2(h) 400 BID MR capsules, fasted 15.4 4.33 2.11 12.1 600 QD MR capsules, fasted + 7.53 2.98 2.12 8.7 800 QD EC key, fed 9.76 2.76 5.67 10.8 1000 QD EC Lozenges, fasting * 16.1 5.72 3.17 8.5 Serum uric acid concentrations were recorded on the 9th day of the study and are shown in the table below and are illustrated in Figure 5. Placebo 600 mg QD 800 mg QD 1000 mg QD 400 mg BID Mean serum uric acid reduction (%) -6 -21 -21 -28 -30 T-test (compared to placebo) 0.0011 0.0010 <0.0001 <0.0001 Examples 7 Other human clinical studies were conducted to further investigate the pharmacokinetic properties of the compositions described herein. The results are summarized in the table below. Example dose (mg) 1 state N AUCT (pg*h/mL) Cmax (M-§/mL) Compound 1 2M6 3 ratio Compound 1 2M6 3 ratio 2A 300 Fa 6 3.19 8.91 2.90 0.658 1.30 1.96 600 FeS 6 7.34 19.0 2.85 2.00 2.52 1.60 2A 300 Fa 8 3.96 17.6 5.36 1.44 2.64 2.93 FeH 8 3.43 17.9 5.88 0.467 1.60 3.76 2A 100 FeS 5 0.670 2.82 4.04 0.173 0.264 2.27 2A 300 FeS 6 3.16 12.4 5.83 0.667 1.76 4.39 500 FeS 6 3.77 24.8 10.1 0.746 3.17 6.98 144188.doc •49- 201020240

1狀態：Fa =禁食；EF =晚間禁食；FeS =進食標準早餐；FeH 食FDA高脂肪早餐。 進 ❹ M6 為 2_(5'漠-4-(4-環丙基萘-1-基）-4//-1，2,4-三峻 酸’其為化合物1之主 基硫基）乙 要代謝物 !M6/化合物〗之莫耳比。 【圖式簡單說明】 圖1展示描繪製備實例2A中所述之組合物之步驟的流程 圖 圖2展示描繪製備實例3A中所述之組合物之步驟的流程 圖。 圖3展不描繪製備實例4 A中所述之組合物之步驟的流程 圖。 圖4展示描緣製備實例5A中所述之組合物之步驟的流程 圖。 144188.doc -50- 201020240 圖5展示投與包含化合物1之組合物之後的血清尿酸濃度 (在第9曰量測）。1 state: Fa = fasting; EF = fasting at night; FeS = standard breakfast; FeH FDA high fat breakfast. M6 is 2_(5'-di-4-(4-cyclopropylnaphthalen-1-yl)-4//-1,2,4-trisquaric acid' which is the main thio group of compound 1) To metabolite! M6 / compound〗 Moer than. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a flow chart depicting the steps of preparing the composition described in Example 2A. Fig. 2 is a flow chart showing the steps of preparing the composition described in Example 3A. Figure 3 is a flow chart showing the steps of preparing the composition described in Example 4A. Figure 4 shows a flow diagram of the steps of the preparation of the composition described in Example 5A. 144188.doc -50- 201020240 Figure 5 shows serum uric acid concentration (measured at ninth) after administration of a composition comprising Compound 1.

144188.doc -51 -144188.doc -51 -

Claims (1)

201020240 七、申請專利範圍： 1· 一種醫藥組合物’其包含：結構⑴化合物或結構⑴化合201020240 VII. Patent application scope: 1. A pharmaceutical composition comprising: structure (1) compound or structure (1) compound 斜、舞或精胺酸；及一或多種稀釋劑；一或多種黏合 劑’一或多種包衣劑；一或多種分散劑；及一或多種增 塑劑。 Ο 2.如請求項1之醫藥組合物，其中該稀釋劑為微晶纖維 素、石夕化微晶纖維素、纖維素、乳糖 '可壓縮糖、甘露 糖醇、呈粉末及顆粒形式之矽酸鈣及磷酸鈣、磷酸鈉或 碳酸鈉。 3. 如请求項1之醫藥組合物，其中該黏合劑為經丙甲纖維 素（hypromellose)、聚維 _ (povidone)、經丙基纖維素、 羥乙基纖維素或澱粉。 4. 如請求項1之醫藥組合物，其中該包衣劑為基於曱基丙 ❼ 烯酸之共聚物 、Eudragit L30D55、Acryl-Eze、乙酸丁二 酸羥丙基甲基纖維素、聚乙酸乙烯酯鄰苯二曱酸酯或乙 酸鄰笨二甲酸纖維素。 5·如請求項1之醫藥組合物，其中該分散劑為滑石粉、單 硬脂酸甘油酯或膠狀二氧化矽。 6_如請求項1之醫藥組合物’其中該增塑劑為檸檬酸三乙 酯、三乙酸甘油酯、鄰苯二曱酸二丁酯、鄰苯二曱酸二 乙酯或甘油。 144188.doc 201020240 7. 如請求項1之醫藥組合物，其包含約10 mg至約1000 mg 該結構（I)化合物或結構（I)化合物之混合物。 8. 如請求項1之醫藥組合物，其包含約100 mg、或約200 mg、或約300 mg、或約400 mg、或約500 mg、或約600 mg、或約 700 mg、或約 800 mg、或約 900 mg、或約 1000 mg該結構（I)化合物或結構（I)化合物之混合物。 9. 一種醫藥組合物，其包含：結構（IB)化合物或結構（IB) 化合物與其游離酸形式之混合物 ：Oblique, dance or arginine; and one or more diluents; one or more binders; one or more coating agents; one or more dispersing agents; and one or more plasticizers. 2. The pharmaceutical composition according to claim 1, wherein the diluent is microcrystalline cellulose, shihua microcrystalline cellulose, cellulose, lactose 'compressible sugar, mannitol, in the form of powder and granules. Calcium acid and calcium phosphate, sodium phosphate or sodium carbonate. 3. The pharmaceutical composition of claim 1, wherein the binder is hypromellose, povidone, propylcellulose, hydroxyethylcellulose or starch. 4. The pharmaceutical composition according to claim 1, wherein the coating agent is a copolymer based on mercaptopropionate, Eudragit L30D55, Acryl-Eze, hydroxypropylmethylcellulose succinate, polyvinyl acetate Ester phthalate or cellulose acetate o-dicarboxylate. 5. The pharmaceutical composition of claim 1, wherein the dispersing agent is talc, glyceryl monostearate or colloidal cerium oxide. 6_ The pharmaceutical composition of claim 1, wherein the plasticizer is triethyl citrate, triacetin, dibutyl phthalate, diethyl phthalate or glycerin. The pharmaceutical composition of claim 1, which comprises from about 10 mg to about 1000 mg of the compound of structure (I) or a mixture of compounds of structure (I). 8. The pharmaceutical composition of claim 1 which comprises about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 Mg, or about 900 mg, or about 1000 mg of the compound of structure (I) or a mixture of compounds of structure (I). 9. A pharmaceutical composition comprising: a structure (IB) compound or a mixture of a structure (IB) compound and its free acid form: (IB);微晶纖維素；羥丙曱纖維素；甲 基丙烯酸共聚物分散體；滑石粉；及檸檬酸三乙酯。 10. 如請求項9之組合物，其包含：約214 mg結構（IB)化合物 或結構（IB)化合物與其游離酸形式之混合物；約35 mg微 晶纖維素；約29 mg經丙曱纖維素；約30 mg曱基丙烯酸 共聚物分散體；約6 mg滑石粉；及約3 mg擰檬酸三乙 酉旨。 11. 一種醫藥組合物，其包含：約60重量％至約90重量％之 結構（IB)化合物或結構（IB)化合物與其游離酸形式之混(IB); microcrystalline cellulose; hydroxypropione cellulose; methacrylic acid copolymer dispersion; talc; and triethyl citrate. 10. The composition of claim 9, comprising: about 214 mg of a structure (IB) compound or a mixture of a structure (IB) compound and its free acid form; about 35 mg of microcrystalline cellulose; about 29 mg of acetonitrile About 30 mg of methacrylic acid copolymer dispersion; about 6 mg of talc; and about 3 mg of triethyl citrate. 11. A pharmaceutical composition comprising: from about 60% to about 90% by weight of a structure (IB) compound or a structure (IB) compound mixed with its free acid form 微晶纖維素；約5重量％至約15重量％之羥丙甲纖維素； 約5重量％至約15重量％之曱基丙烯酸共聚物分散體；約 144188.doc 201020240 0.5重量％至約5重量％之滑石粉；及約〇. 1重量β/❶至約3重 量％之檸檬酸三乙酯。 12. —種醫藥組合物，其包含：結構（ΙΒ)化合物或結構（ΙΒ) 化合物與其游離酸形式之混合物Microcrystalline cellulose; from about 5% by weight to about 15% by weight of hypromellose; from about 5% by weight to about 15% by weight of the methacrylic acid copolymer dispersion; about 144188.doc 201020240 0.5% by weight to about 5 % by weight of talc; and about 1% by weight of β/❶ to about 3% by weight of triethyl citrate. 12. A pharmaceutical composition comprising: a structure (ΙΒ) compound or a structure (ΙΒ) a mixture of a compound and its free acid form ㈣；微晶纖維素；及羥丙甲纖維素 其中該組合物呈顆粒形式。(d); microcrystalline cellulose; and hypromellose wherein the composition is in the form of granules. 13. —種醫藥組合物，其包含：約214 mg結構（ΙΒ)化合物或 結構（IB)化合物與其游離酸形式之混合物：13. A pharmaceutical composition comprising: about 214 mg of a structure (ΙΒ) compound or a mixture of a structure (IB) compound and its free acid form: 0®)，約3 5 mg微晶纖維素，約13.5 mg 經丙甲纖維素；其中該組合物呈不穿過4〇目篩網之顆粒 形式；且其中該等顆粒係經約丨5 3 mg羥丙甲纖維素包 覆；且其中該等經包覆之顆粒進一步用包含約30.4 mg曱 基丙烯酸共聚物分散體、約6丨mg滑石粉及約3 〇 11^檸 檬酸三乙酯之組合物包覆。 14.如任一岫述凊求項之組合物，其中如使用美國藥典設備 1 ’在37C下於900 mL水中，以75卬以操作所量測之活 體外溶解速率為不少於約8()%之該結構（IB)化合物在 分鐘内釋放。 15. 一種使需要降低之尿酸濃度 官中的尿酸濃度降低之方法 之個體之一或多種組織或器 ’其包括向該個體投與降低 I44I88.doc 201020240 尿酸濃度用量的如前述請求項中任一項之醫藥組人物。 16. —種使個體尿酸生成減少、尿酸***增加或使尿酸生成 減少並使尿酸***增加之方法，其包括向該個體投與有 效量的如前述請求項中任一項之醫藥組合物。 17. —種治療或預防個體高尿酸血症之方法，其包括向該個 體投與有效量的如前述請求項中任一項之醫藥組合物。 18· —種治療患有特徵在於組織或器官尿酸濃度異常之病狀 之個體的方法，其包括向該個體投與有效量的如前述請 求項中任一項之醫藥組合物。 19. 一種預防個體之特徵在於組織尿酸濃度異常之病狀的方 法，其中該個體處於發展出該病狀之高風險中，該方法 包括向該個體投與有效量的如前述請求項中任一項之醫 藥組合物。 20. —種治療個體之痛風、復發性痛風發作、痛風性關節 炎、高尿酸血症、高血壓、心血管疾病 '冠狀動脈心臟 病、勒-奈二氏症候群（Lesch-Nyhan syndrome)、凱利_西 格米勒症候群（Keiiey-Seegmiller syndr〇me)、腎病、腎 結石、腎衰竭、關節發炎G〇int inflammati〇n)、關節炎 (arthritis)、尿石症、錯中毒、副甲狀腺機能充進、牛皮 癖或類肉瘤病的方法，其包括向該個體投與有效量的如 前述請求項中任一項之醫藥組合物。 21. -種治療個體之錢的方法，#包括肖該個體投與有效 量的如前述請求項中任一項之醫藥組合物。 22. -種預防個體體内形成痛風石或減小痛風石大小的方 144188.doc 201020240 法’其包括向該個體投與有效量的如前述請求項中任一 項之醫藥組合物。0®), about 35 mg of microcrystalline cellulose, about 13.5 mg of propylmethylcellulose; wherein the composition is in the form of granules that do not pass through a 4 mesh screen; and wherein the granules are passed through about 5 3 Mold hypromellose; and wherein the coated particles further comprise about 30.4 mg of a methacrylic acid copolymer dispersion, about 6 mg of talc, and about 3 〇 11 ^ triethyl citrate The composition is coated. 14. A composition according to any of the above-mentioned claims, wherein the in vitro dissolution rate measured by operation at 75 Torr in 900 mL of water at 37 C is less than about 8 using the United States Pharmacopoeia Apparatus 1 ' % of this structure (IB) compound is released in minutes. 15. An individual or a plurality of tissues or devices of a method for reducing a concentration of uric acid in a uric acid concentration-reducing urinary acid comprising administering to the individual any one of the foregoing claims for reducing the amount of uric acid concentration used in the uric acid concentration The medical group of the item. 16. A method of reducing uric acid production, increasing uric acid excretion, or reducing uric acid production and increasing uric acid excretion, comprising administering to the individual an effective amount of a pharmaceutical composition according to any one of the preceding claims. 17. A method of treating or preventing hyperuricemia in a subject, comprising administering to the individual an effective amount of a pharmaceutical composition according to any one of the preceding claims. 18. A method of treating an individual having a condition characterized by abnormal uric acid concentration in a tissue or organ, comprising administering to the individual an effective amount of a pharmaceutical composition according to any one of the preceding claims. 19. A method of preventing an individual characterized by a condition characterized by abnormal tissue uric acid concentration, wherein the individual is at a high risk of developing the condition, the method comprising administering to the individual an effective amount of any of the foregoing claims Pharmaceutical composition of the item. 20. A treatment of gout, recurrent gout, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelly _Keiiey-Seegmiller syndr〇me, kidney disease, kidney stones, kidney failure, joint inflammation G〇int inflammati〇n), arthritis, urolithiasis, malocclusion, parathyroid function charge A method of, psoriasis or sarcoma-like disease comprising administering to the individual an effective amount of a pharmaceutical composition according to any one of the preceding claims. 21. A method of treating a person's money, comprising the administration of an effective amount of a pharmaceutical composition according to any one of the preceding claims. 22. A method of preventing the formation of a tophi or reducing the size of a tophi in an individual 144188.doc 201020240 The method comprising administering to the individual an effective amount of a pharmaceutical composition according to any of the preceding claims. 144188.doc144188.doc
TW098136211A 2008-10-24 2009-10-26 Compositions comprising 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid and pharmaceutically acceptable salts thereof, and methods for preparing and using same TW201020240A (en)

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