TWI548630B - 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof - Google Patents

1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof Download PDF

Info

Publication number
TWI548630B
TWI548630B TW101111308A TW101111308A TWI548630B TW I548630 B TWI548630 B TW I548630B TW 101111308 A TW101111308 A TW 101111308A TW 101111308 A TW101111308 A TW 101111308A TW I548630 B TWI548630 B TW I548630B
Authority
TW
Taiwan
Prior art keywords
compound
crystalline form
formula
disease
solvent
Prior art date
Application number
TW101111308A
Other languages
Chinese (zh)
Other versions
TW201245182A (en
Inventor
尹精敏
朴基淑
尹胄鏞
李周泳
金根泰
鄭哲圭
Original Assignee
Lg生命科學有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lg生命科學有限公司 filed Critical Lg生命科學有限公司
Publication of TW201245182A publication Critical patent/TW201245182A/en
Application granted granted Critical
Publication of TWI548630B publication Critical patent/TWI548630B/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/4151,2-Diazoles
    • A61K31/41551,2-Diazoles non condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/06Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸結晶型及其製造方法 Crystal form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and preparation method thereof

本發明係有關一種如下式(1)代表之新穎化合物之結晶型(化學名稱:1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸),其適用為對抗黃嘌呤氧化酶之抑制劑,及其製備方法。 The present invention relates to a crystalline form of a novel compound represented by the following formula (1) (chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) It is suitable as an inhibitor against xanthine oxidase, and a preparation method thereof.

黃嘌呤氧化酶係一種轉化6-羥基嘌呤(hypozanthine)形成黃嘌呤,且再進一步將所形成之黃嘌呤轉化成尿酸之酵素。當身體出現太多尿酸時,即可能引起各種不同疾病,如:痛風。痛風係指尿酸結晶堆積在軟骨、韌帶與周圍組織,而誘發嚴重發炎與疼痛之疾病。過去40年來,痛風之發病率持續上升(N.L.Edwards,Arthritis & Rheumatism,2008,58,2587至2590)。此外,許多研究者已證實尿酸與心臟衰竭、高血壓、糖尿病、腎臟病及心血管疾病之間之緊密相關性,並已注意到控制尿酸之重要性(D.I.Feig et al.,N.Eng.J.Med,2008,23,1811至1821)。因此,抑制黃嘌呤氧化酶活性之物質即可有效用於治療與黃嘌呤氧化酶相關之疾病,如:高尿酸血症、痛風、心臟衰竭、心血管疾病、高血壓、糖尿病、腎臟病、發炎與關節 疾病、發炎性腸病,等等。 Xanthine oxidase is an enzyme that converts 6-hydroxypurine to form xanthine and further converts the formed xanthine into uric acid. When the body appears too much uric acid, it may cause a variety of different diseases, such as: gout. Gout is a disease in which uric acid crystals accumulate in cartilage, ligaments, and surrounding tissues, causing severe inflammation and pain. The incidence of gout has continued to rise over the past 40 years (N.L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587-2590). In addition, many researchers have confirmed the close relationship between uric acid and heart failure, hypertension, diabetes, kidney disease and cardiovascular disease, and have noticed the importance of controlling uric acid (DIFeig et al., N.Eng. J. Med, 2008, 23, 1811 to 1821). Therefore, substances that inhibit the activity of xanthine oxidase can be effectively used for the treatment of diseases associated with xanthine oxidase, such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation. With joints Disease, inflammatory bowel disease, etc.

另一方面,在要求高品質及長期保存之醫學領域中,使用具有物理及化學穩定性之醫藥作為活性成份相當重要。因此,這種活性成份之優異藥劑性質及其優越之藥理效力極有價值成為本發明之效應。 On the other hand, in the medical field where high quality and long-term preservation are required, it is important to use a medically and chemically stable drug as an active ingredient. Therefore, the excellent pharmaceutical properties of the active ingredient and its superior pharmacological potency are extremely valuable as the effects of the present invention.

本發明之目的在於提供一種新穎式(1)化合物之結晶型[下文稱為化合物(1)],藉以提供優異之藥劑性質(如:穩定性、不吸水性、容易操作,等等),及藉由選擇性與黃嘌呤氧化酶結合而達到之藥理活性。 It is an object of the present invention to provide a crystalline form of the novel compound of the formula (1) [hereinafter referred to as the compound (1)], thereby providing excellent pharmaceutical properties (e.g., stability, non-absorbability, ease of handling, etc.), and The pharmacological activity is achieved by selective binding to xanthine oxidase.

下文更詳細說明本發明。 The invention is described in more detail below.

本發明提供一種新穎化合物(1)之結晶型(化學名稱:1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸),其適用為對抗黃嘌呤氧化酶之抑制劑。 The present invention provides a crystalline form of the novel compound (1) (chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid), which is suitable for confrontation Inhibitor of xanthine oxidase.

化合物(1)結晶型(亦即1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸之結晶型)顯示對抗黃嘌呤氧化酶之抑制活性,且其製造方法將更詳細說明於下文之製法中。 The crystalline form of the compound (1) (i.e., the crystalline form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) exhibits inhibitory activity against xanthine oxidase And the method of its manufacture will be described in more detail in the following process.

黃嘌呤氧化酶為一種轉化6-羥基嘌呤形成黃嘌呤,且再進一步將所形成之黃嘌呤轉化成尿酸之酵素。當身體出現太多尿酸時,即可能引起各種不同疾病,如:痛風。化 合物(1)結晶型可選擇性抑制黃嘌呤氧化酶。 Xanthine oxidase is an enzyme that converts 6-hydroxyindole to form xanthine and further converts the formed xanthine into uric acid. When the body appears too much uric acid, it may cause a variety of different diseases, such as: gout. Chemical The crystalline form of the compound (1) selectively inhibits xanthine oxidase.

當採用X-射線粉末繞射法(XRD)分析時,化合物(1)結晶型顯示特徵峰值(2 θ)為12.1°、13.2°、15.7°、18.3°、24.8°、25.8°與26.6。更明確言之,當採用XRD分析時,化合物(1)結晶型顯示之特徵峰值(2 θ)為12.1°、13.2°、15.7°、16.6°、18.3°、19.6°、20.9°、23.1°、24.8°、25.8°與26.6°。 When analyzed by X-ray powder diffraction (XRD), the crystalline form of Compound (1) showed characteristic peaks (2 θ) of 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6. More specifically, when XRD analysis is used, the characteristic peak (2 θ) of the compound (1) crystal form is 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°, 20.9°, 23.1°, 24.8°, 25.8° and 26.6°.

此外,當採用示差掃描量熱法分析化合物(1)結晶型時,其出現自263至268℃之熔點所引起之初始吸熱峰,由此可見根據本發明新穎化合物(1)結晶型具有263至268℃之高熔點,極適合抗熱(第2圖)。此點可由在40±2℃,75±5% RH或60±2℃,5±5% RH之高溫條件下存放12周後之熱穩定性數據證實。甚至在化合物存放12週後,其原始之內容物完全沒有減少。在熱解重量分析法中,由示差掃描量熱法顯示之吸熱段(263至268℃)(第3圖),可證實沒有重量損失。 Further, when the compound (1) crystal form is analyzed by differential scanning calorimetry, it exhibits an initial endothermic peak caused by the melting point of 263 to 268 ° C, whereby it can be seen that the novel compound (1) crystal form according to the present invention has 263 to High melting point of 268 ° C, very suitable for heat resistance (Figure 2). This can be confirmed by thermal stability data after storage for 12 weeks at 40 ± 2 ° C, 75 ± 5% RH or 60 ± 2 ° C, 5 ± 5% RH. Even after 12 weeks of compound storage, the original contents did not decrease at all. In the thermogravimetric analysis, the endothermic section (263 to 268 ° C) (Fig. 3) shown by differential scanning calorimetry confirmed no loss of weight.

此外,本發明化合物(1)結晶型極適合對抗濕氣。如第4圖所示,已證實本發明結晶型在濕氣吸附等溫線中顯示其受濕氣影響造成之重量變化僅約0.3%或更低。因此認為本發明結晶型極適合對抗濕氣。 Further, the crystalline form of the compound (1) of the present invention is highly suitable for combating moisture. As shown in Fig. 4, it has been confirmed that the crystal form of the present invention exhibits a weight change by moisture influence of only about 0.3% or less in the moisture adsorption isotherm. It is therefore considered that the crystalline form of the present invention is highly suitable for combating moisture.

如上述,根據本發明化合物(1)結晶型在寬廣之相對濕度範圍內,其重量很少或不會隨濕度變化,此表示該結晶型不會隨濕度變化而改變,且極適合抗熱。因此,特別適用於穩定存放、研磨加工,等等。 As described above, the crystal form of the compound (1) according to the present invention has a little or no change in humidity in a wide range of relative humidity, which means that the crystal form does not change with changes in humidity, and is highly suitable for heat resistance. Therefore, it is particularly suitable for stable storage, grinding processing, and the like.

本發明亦提供一種製備化合物(1)結晶型之方法,其係使化合物(1)自合適溶劑或溶劑混合物中結晶。該溶劑或溶劑混合物較佳係選自已用於化合物(1)製法中之溶劑。所採用之該溶劑或溶劑混合物係選自下列各物所組成群中:無水乙醇、2-甲氧基乙醇、異丁醇、正丁醇、正辛醇、正丙醇、異丙醇、第三丁醇、乙酸、丙酮、乙酸丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸第三丁酯、乙酸異丁酯、甲基乙基酮、2-戊酮、四氫呋喃、乙腈、氯仿、甲苯與其混合物。更佳為該溶劑係選自下列各物所組成群中:無水乙醇、第三丁醇、丙酮、四氫呋喃、乙腈、氯仿與其混合物。 The present invention also provides a process for preparing a crystalline form of the compound (1) by crystallizing the compound (1) from a suitable solvent or solvent mixture. The solvent or solvent mixture is preferably selected from the solvents which have been used in the process for the preparation of the compound (1). The solvent or solvent mixture employed is selected from the group consisting of anhydrous ethanol, 2-methoxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, Tributyl alcohol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, Chloroform, toluene and its mixture. More preferably, the solvent is selected from the group consisting of anhydrous ethanol, tert-butanol, acetone, tetrahydrofuran, acetonitrile, chloroform and mixtures thereof.

使化合物(1)自合適溶劑中結晶之方法可為如:冷卻溶液、蒸發溶劑、添加反溶劑(不會溶解化合物(1)之溶劑,例如:水)至達到超飽和為止、轉換成漿液態,等等。 The method of crystallizing the compound (1) from a suitable solvent may be, for example, cooling the solution, evaporating the solvent, adding an anti-solvent (solvent which does not dissolve the compound (1), for example, water) until it is supersaturated, and is converted into a slurry liquid. ,and many more.

本文所採用化合物(1)結晶型可呈化合物本身或呈包含該化合物與其他用於組合療法之活性成份或與其他合適載劑或賦形劑之醫藥組合物投與人類患者。 The crystalline form of Compound (1) employed herein can be administered to a human patient either as the compound itself or as a pharmaceutical composition comprising the compound and other active ingredients for combination therapy or with other suitable carriers or excipients.

本發明醫藥組合物可依已知方法製備,如:習知之混合、溶解、製粒、壓錠、磨粉、乳化、囊封、包埋或冷凍乾燥,等等。 The pharmaceutical compositions of the present invention can be prepared by known methods such as conventional mixing, dissolving, granulating, tableting, milling, emulsifying, encapsulating, embedding or freeze drying, and the like.

因此本發明醫藥組合物可依傳統方法,使用一或多種醫藥上可接受之載劑製備。該等載劑包括容易將活性化合物轉換成醫藥上可接受之調配物之賦形劑或輔劑。合適調配物可隨所選用之投藥途徑變化。可在相關技藝上已知(例 如:"雷氏醫藥學(Remington’s Pharmaceutical Sciences)")之技術、載劑與賦形劑、及方法中適當選擇。 Thus, the pharmaceutical compositions of the present invention can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Such carriers include excipients or auxiliaries which facilitate the conversion of the active compound into a pharmaceutically acceptable formulation. Suitable formulations may vary depending on the route of administration chosen. Can be known in related art (example For example, "Remington's Pharmaceutical Sciences" technology, carriers and excipients, and methods are suitably selected.

例如:化合物(1)結晶型可調配成注射製劑、口服製劑,等等,端賴本發明之計畫目的而定。 For example, the crystalline form of the compound (1) can be formulated into an injection preparation, an oral preparation, and the like, depending on the purpose of the present invention.

製備注射製劑時,本發明活性化合物可使用醫藥上合適之緩衝液(較佳為漢克氏溶液(Hank solution)、林格氏溶液(Ringer solution)、生理食鹽水,等等)調配成液態製劑。為了通過黏膜投藥,可在調配物中使用適合滲透障壁之滲透加強劑。此等滲透加強劑係相關技藝上習知者。 In the preparation of the injectable preparation, the active compound of the present invention can be formulated into a liquid preparation using a pharmaceutically suitable buffer (preferably Hank's solution, Ringer's solution, physiological saline, etc.). . For administration through the mucosa, a penetration enhancer suitable for penetrating the barrier can be used in the formulation. Such penetration enhancers are known to those skilled in the art.

本發明活性化合物很容易藉由組合化合物與相關技藝上已知醫藥上可接受之載劑,而調配成口服投藥用之固體劑型。藉由使用此等載劑,本發明化合物可調配成錠劑、粉劑、粒劑、糖衣錠、膠囊、液體、凝膠、糖漿、漿液、懸浮液,等等。以膠囊、錠劑、丸劑、粉劑與粒劑較有利,且以膠囊與錠劑特別有利。例如:可依下列方法得到口服投藥用劑型。 The active compounds of the present invention are readily formulated into a solid dosage form for oral administration by combining the compound with a pharmaceutically acceptable carrier known in the art. By using such carriers, the compounds of the invention may be formulated into lozenges, powders, granules, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Capsules, troches, pills, powders and granules are advantageous, and capsules and troches are particularly advantageous. For example, an oral administration dosage form can be obtained by the following method.

由根據本發明化合物(1)結晶型與一或多種賦形劑混合,若適當時可研磨混合物。若必要時可添加合適輔劑,可由製粒混合物得到錠劑或糖衣錠核心。合適之賦形劑可述及填料,如:乳糖、蔗糖、甘露糖醇或山梨糖醇;纖維素物質,如:玉米澱粉、小麥澱粉、米澱粉、馬鈴薯澱粉、明膠、黃著膠、甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮(PVP);等等。若必要時,可添加崩解劑作為載劑,如:交聯聚乙烯吡咯啶酮、洋菜、 藻酸或其鹽(如:藻酸鈉)、潤滑劑(如:硬脂酸鎂)與結合劑。 The crystalline form of the compound (1) according to the invention is mixed with one or more excipients, and if appropriate, the mixture can be ground. A suitable locus can be added if necessary, and the lozenge or dragee core can be obtained from the granulation mixture. Suitable excipients may include fillers such as lactose, sucrose, mannitol or sorbitol; cellulosic materials such as corn starch, wheat starch, rice starch, potato starch, gelatin, yellow gum, methyl Cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP); and the like. If necessary, a disintegrant can be added as a carrier, such as: cross-linked polyvinylpyrrolidone, agar, Alginic acid or a salt thereof (such as sodium alginate), a lubricant (such as magnesium stearate) and a binder.

口服製劑可包括密封之軟膠囊(其係由明膠與增塑劑如:甘醇或山梨糖醇製成)及硬明膠囊(其係由明膠製成)。硬明膠囊可包含活性化合物與填料(如:乳糖)、結合劑(如:澱粉)及/或潤滑劑(如:滑石或硬脂酸鎂)之混合物。軟膠囊中,活性化合物可溶解或勻散於合適介質中,如:脂肪酸、液態石蠟或液態聚乙二醇。此外,可包括安定劑。所有口服投藥用調配物均可包含適量活性化合物。 Oral preparations may include sealed soft capsules (made of gelatin and a plasticizer such as glycol or sorbitol) and hard capsules (made of gelatin). The hard gelatin capsules may contain a mixture of the active compound with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate. In soft capsules, the active compound can be dissolved or dispersed in a suitable medium such as a fatty acid, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be included. All orally administered formulations may contain an appropriate amount of the active compound.

活性化合物(亦即化合物(1)結晶型)亦可調配成注射製劑,如,例如:大丸型注射劑或連續型注射劑,供非經腸式投藥。該注射製劑可呈包含防腐劑之安瓿型式或填裝在多劑量容器中之單位劑型。該組合物可呈含於油或液態媒劑中之懸浮液、溶液或乳液,且可包含調配用組份,如:懸浮劑、安定劑及/或崩解劑。活性成份可呈粉末型式,其計畫在臨用前才溶解於無菌無熱原水中重新組成。該活性化合物亦可調配成供直腸投藥用組合物,如:包含習知栓劑基質(例如:可可脂或其他甘油酯)之栓劑或灌腸劑。 The active compound (i.e., the crystalline form of the compound (1)) can also be formulated into an injection preparation such as, for example, a bolus injection or a continuous injection for parenteral administration. The injectable preparation may be in the form of a ampule containing a preservative or in a unit dosage form filled in a multi-dose container. The composition may be in the form of a suspension, solution or emulsion contained in an oil or liquid vehicle, and may contain formulation ingredients such as suspending, stabilizing and/or disintegrating agents. The active ingredient can be in the form of a powder which is reconstituted by dissolving in sterile pyrogen-free water just prior to use. The active compound can also be formulated for rectal pharmaceutical compositions such as suppositories or enemas containing conventional suppository bases such as cocoa butter or other glycerides.

根據本發明醫藥組合物中之化合物(1)結晶型包含可有效達到其計畫目的之用量。明確言之,該醫療有效量意指活性化合物之用量可有效延長所治療患者之存活,或可預防、減輕或緩解疾病之症狀。熟悉此相關技術者特別依據本文所提供之詳細說明,應可以決定醫療有效量。 The crystalline form of the compound (1) in the pharmaceutical composition according to the present invention contains an amount effective for the purpose of the plan. In particular, the medically effective amount means that the amount of active compound is effective to prolong the survival of the patient being treated, or to prevent, alleviate or ameliorate the symptoms of the disease. Those skilled in the art will be able to determine the medically effective amount, particularly in light of the detailed description provided herein.

當化合物調配成單位劑型時,每單位劑量中基於化合 物(1)計,化合物(1)之結晶型較佳含量為約0.1至1,000 mg。該劑量依醫師之處方,考量諸如患者體重或年齡、疾病之明確性質、疾病之嚴重性,等等而定。然而,治療成人所需之劑量通常為每天約1至1,000 mg,依投藥強度與頻率而定。當經由肌內或靜脈內途徑投與成人時,以單一劑量分開投與時,每天總劑量約1至500 mg應已足夠,但有些患者可能需要更高日劑量。 When a compound is formulated into a unit dosage form, it is based on a compound per unit dose. The compound (1) preferably has a crystalline form of the compound (1) in an amount of from about 0.1 to 1,000 mg. The dosage depends on the physician's location, such as the patient's weight or age, the nature of the disease, the severity of the disease, and the like. However, the dosage required to treat an adult is usually from about 1 to 1,000 mg per day, depending on the strength and frequency of administration. When administered to an adult via the intramuscular or intravenous route, a total daily dose of about 1 to 500 mg should be sufficient when administered separately in a single dose, although some patients may require a higher daily dose.

本發明進一步提供一種使用醫療有效量化合物(1)結晶型來預防或治療與人類黃嘌呤氧化酶有關之疾病之方法。"與人類黃嘌呤氧化酶有關之疾病"一詞係指該疾病可藉由抑制人類黃嘌呤氧化酶來預防或治療,其包括(但不限於):高尿酸血症、痛風、心臟衰竭、心血管疾病、高血壓、糖尿病、糖尿病併發症、腎臟病、發炎與關節疾病、發炎性腸病,等等。該糖尿病併發症之某些實例為高血脂症、動脈粥樣硬化、肥胖、高血壓、視網膜變性、腎衰竭,等等(Circulation Research,2006,98,169至171;Hypertension 2003,41,1183至1190)。此外,如動物毒性試驗數據所證實,本發明化合物(1)結晶型沒有遺傳毒性、重覆毒性,等等,且極為安全。 The present invention further provides a method of preventing or treating a disease associated with human xanthine oxidase using a medically effective amount of the compound (1) crystalline form. The term "disease associated with human xanthine oxidase" means that the disease can be prevented or treated by inhibiting human xanthine oxidase, including but not limited to: hyperuricemia, gout, heart failure, heart Vascular disease, hypertension, diabetes, diabetic complications, kidney disease, inflammation and joint disease, inflammatory bowel disease, etc. Some examples of such diabetic complications are hyperlipidemia, atherosclerosis, obesity, hypertension, retinal degeneration, renal failure, and the like (Circulation Research, 2006, 98, 169 to 171; Hypertension 2003, 41, 1183 to 1190) . Further, as confirmed by the animal toxicity test data, the crystalline form of the compound (1) of the present invention has no genotoxicity, repeated toxicity, and the like, and is extremely safe.

如本文所採用"治療"一詞係指當施用於開始出現疾病症狀之個體時,可干擾或延緩疾病進展,且"預防"一詞意指當施用於尚未出現疾病症狀但處於疾病症狀發作風險之個體時,可干擾或延緩疾病癥狀發作。 As used herein, the term "therapeutic" means that when administered to an individual who is beginning to develop symptoms of the disease, it may interfere with or delay the progression of the disease, and the term "prevention" means when administered to a patient who has not yet developed symptoms of the disease but is at risk of developing the symptoms of the disease. Individuals can interfere with or delay the onset of disease symptoms.

本發明將利用下列實例與試驗實例更詳細說明。然 而,其僅供協助了解本發明,但無意以任何方式藉由此等實例與試驗實例來限制本發明之範圍。 The invention will be illustrated in more detail using the following examples and experimental examples. Of course Rather, it is intended to be illustrative only, and is not intended to limit the scope of the invention.

本發明新提供之化合物(1)之結晶型係藉由選擇性抑制黃嘌呤氧化酶而具有藥理活性,同時具有優異之醫藥穩定性,如:熱穩定性、儲存穩定性,等等。作為新穎物質之化合物(1)結晶型適用之原因在於其在寬廣之相對濕度範圍下,其重量很少或不會隨濕度變化,且其結晶型不會隨濕度變化而改變。此外,根據本發明所提供之各種不同方法,可能控制此結晶型之製法。 The crystalline form of the compound (1) newly provided by the present invention has pharmacological activity by selectively inhibiting xanthine oxidase, and has excellent medical stability such as thermal stability, storage stability, and the like. The reason why the crystalline form of the compound (1) as a novel substance is suitable is that it has little or no change in humidity over a wide range of relative humidity, and its crystal form does not change with changes in humidity. Furthermore, it is possible to control the preparation of this crystalline form in accordance with the various methods provided by the present invention.

製法:化合物(1)製法Method: Compound (1) 製法1-1:1-(3-氰基-1H-吲哚-5-基)吡唑-4-羧酸乙酯Process 1-1: ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate

標題化合物係依據下列製程(1)、(2)與(3)製得。(1)1-(3-甲醯基-1H-吲哚-5-基)吡唑-4-羧酸乙酯製法 The title compound was prepared according to the following processes (1), (2) and (3). (1) Method for preparing ethyl 1-(3-methylindolyl-1H-indol-5-yl)pyrazole-4-carboxylate

於0℃下,在無水二氯甲烷(50 mL)中依序添加草醯氯(0.56 mL,6.6 mmol)與N,N-二甲基甲醯胺(0.51 mL,6.6 mmol)。混合物於0℃下攪拌30分鐘。在此反應溶液中添加含1-(1H-吲哚-5-基)吡唑-4-羧酸乙酯(1.40 g,5.47 mmol)與二氯甲烷(50 mL)之混合物,然後於室溫回流下攪拌1小時。排除溶劑。添加四氫呋喃(100 mL)與20%乙酸 銨水溶液(100 mL)至殘質中,加熱30分鐘,並於回流下攪拌。反應完成後,冷卻反應溶液,添加乙酸乙酯。混合物經碳酸氫鈉水溶液洗滌,有機層經無水硫酸鎂脫水,及減壓濃縮,產生標題化合物。 Toluene chloride (0.56 mL, 6.6 mmol) and N,N-dimethylformamide (0.51 mL, 6.6 mmol) were added sequentially in anhydrous dichloromethane (50 mL). The mixture was stirred at 0 ° C for 30 minutes. A mixture of ethyl 1-(1H-indol-5-yl)pyrazole-4-carboxylate (1.40 g, 5.47 mmol) and dichloromethane (50 mL) was added to the reaction mixture, then at room temperature Stir under reflux for 1 hour. Exclude solvent. Add tetrahydrofuran (100 mL) with 20% acetic acid Aqueous ammonium solution (100 mL) was added to the residue, heated for 30 min and stirred under reflux. After the reaction was completed, the reaction solution was cooled, and ethyl acetate was added. The mixture was washed with aq.

質量(EI)284(M++1) Quality (EI) 284 (M + +1)

(2)1-[3-[(E,Z)-羥基亞胺基甲基]-1H-吲哚-5-基]吡唑-4-羧酸乙酯製法 (2) Method for preparing 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylic acid ethyl ester

將得自上述步驟(1)之1-(3-甲醯基-1H-吲哚-5-基)吡唑-4-羧酸乙酯溶於吡啶(150 mL),添加羥基氯化銨(499 mg,7.18 mmol)。加熱混合物,於回流下攪拌5小時。反應完成後,減壓濃縮溶劑。殘質通過矽膠,使用丙酮作為溶劑進行過濾,產生標題化合物。 Ethyl 1-(3-methylindol-1H-indol-5-yl)pyrazole-4-carboxylate obtained from the above step (1) was dissolved in pyridine (150 mL), and hydroxy ammonium chloride was added ( 499 mg, 7.18 mmol). The mixture was heated and stirred under reflux for 5 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was filtered through silica gel using acetone as solvent to give the title compound.

質量(EI)299(M++1) Quality (EI) 299 (M + +1)

(3)1-(3-氰基-1H-吲哚-5-基)吡唑-4-羧酸乙酯製法 (3) Method for preparing ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate

將得自上述步驟(2)之1-[3-[(E,Z)-羥基亞胺基甲基]-1H-吲哚-5-基]比唑-4-羧酸乙酯溶於無水四氫呋喃(94 mL)。於其中加入二(咪唑-1-基)甲硫酮(90%,2.79 g,14.1 mmol),於室溫下攪拌混合物2小時。反應完成後,反應溶 液減壓濃縮。所得固體化合物採用管柱層析法分離,產生標題化合物(1.32 g,4.71 mmol,產率86%)。 Ethyl 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylic acid ethyl ester obtained from the above step (2) is dissolved in anhydrous Tetrahydrofuran (94 mL). Di(imidazol-1-yl)methylthione (90%, 2.79 g, 14.1 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. After the reaction is completed, the reaction dissolves. The liquid was concentrated under reduced pressure. The obtained solid was isolated by column chromatography toiel

NMR:1H-NMR(DMSO-d6)δ 12.40(1H,br),9.20(1H,s),8.37(1H,s),8.21(1H,d),8.14(1H,s),7.89(1H,dd),7.68(1H,d),4.29(2H,q),1.32(3H,t) NMR: 1 H-NMR (DMSO-d 6 ) δ 12.40 (1H, br), 9.20 (1H, s), 8.37 (1H, s), 8.21 (1H, d), 8.14 (1H, s), 7. 1H, dd), 7.68 (1H, d), 4.29 (2H, q), 1.32 (3H, t)

質量EI)281(M++1) Quality EI) 281 (M + +1)

製法1-2:1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸乙酯Process 1-2: ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate

將得自製法1-1之1-(3-氰基-1H-吲哚-5-基)吡唑-4-羧酸乙酯(13.84 g,49.38 mmol)溶於乙腈(200 mL)。添加碳酸銫(32.17 g,98.74 mmol)與2-碘丙烷(19.7 mL,198 mmol),加熱混合物後,於回流下攪拌5小時。反應完成後,反應溶液減壓濃縮。所得固體化合物採用管柱層析法分離,產生標題化合物(13.87 g,43.03 mmol,產率87%)。 Ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate (13.84 g, 49.38 mmol) from m.p. Cesium carbonate (32.17 g, 98.74 mmol) and 2-iodopropane (19.7 mL, 198 mmol) were added, and the mixture was stirred and stirred under reflux for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained solid compound was purified by column chromatography toield

NMR:1M-NMR(CDCl3)δ 8.48(1H,s),8.16(1H,s),8.06(1H,d),7.82(1H,s),7.78(1H,dd),7.57(1H,d),4.80-4,73(1H,m),4.38(2H,q),1.64(6H,d),1.42(3H,t) NMR: 1 M-NMR (CDCl 3 ) δ 8.48 (1H, s), 8.16 (1H, s), 8.06 (1H, d), 7.82 (1H, s), 7.78 (1H, dd), 7.57 (1H, d), 4.80-4, 73 (1H, m), 4.38 (2H, q), 1.64 (6H, d), 1.42 (3H, t)

質量(EI)323(M++1) Quality (EI) 323 (M + +1)

製法1-3:1-(3-氰基-1-異丙基-吲哚-5-基)比唑-4-羧酸(化合物(1))Process 1-3: 1-(3-Cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (compound (1))

將得自製法1-2之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸乙酯(13.87 g,43.03 mmol)加至含四氫呋喃(140 mL)、甲醇(140 mL)與6N氫氧化鈉(70 mL)之溶液中,然後於室溫下反應1小時。反應後,減壓排除有機溶劑,殘留之水溶液層經乙酸乙酯洗滌。添加濃鹽酸酸化水溶液至pH 1。濾出沉澱之固體化合物,以蒸餾水洗滌,及乾燥,產生標題化合物(12.09 g,41.08 mmol,產率95%)。 Ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate (13.87 g, 43.03 mmol) from 1-2 (m. 140 mL), a solution of methanol (140 mL) and 6N sodium hydroxide (70 mL), then react at room temperature for 1 hour. After the reaction, the organic solvent was removed under reduced pressure and the residual aqueous layer was washed with ethyl acetate. A concentrated hydrochloric acid aqueous solution was added to pH 1. The precipitated solid was filtered, washed with EtOAc EtOAcjjjjj

NMR:1H-NMR(DMSP-d6)δ 12.55(1H,br),9.10(1H,s),8.53(1H,s),8.16(1H,d),8.06(1H,s),7.90(1H,dd),7.86(1H,d),4.92-4.86(1H,m),1.48(6H,d) NMR: 1 H-NMR (DMSP-d 6 ) δ 12.55 (1H, br), 9.10 (1H, s), 8.53 (1H, s), 8.16 (1H, d), 8.06 (1H, s), 7.90 ( 1H, dd), 7.86 (1H, d), 4.92-4.86 (1H, m), 1.48 (6H, d)

質量(EI)295(M++1) Quality (EI) 295 (M + +1)

實施例1:化合物(1)結晶型製法Example 1: Compound (1) Crystal Forming Method

將所製得之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸(3.82 kg)溶於丙酮(382 L),然後在攪拌下慢慢滴加至90℃溫度之水(40 L)中。滴加完畢後,再攪拌混合物約12小時,冷卻與過濾,產生本發明化合物(1)結晶型(3.40 kg)。所得化合物(1)結晶型以1H-NMR與IR分析特徵。結果示於下列。 The 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (3.82 kg) obtained was dissolved in acetone (382 L) and then slowly stirred. Slowly add to the water (40 L) at a temperature of 90 °C. After completion of the dropwise addition, the mixture was further stirred for about 12 hours, cooled and filtered to give a crystalline form (3.40 kg) of the compound (1) of the present invention. The obtained compound (1) crystal form was characterized by 1 H-NMR and IR analysis. The results are shown below.

1H-NMR(DMSO-D6,ppm)1.5(6H,d),4.9(1H,q),8.6(1H,s),8.2(1H,d),7.9(1H,dd),7.9(1H,d),8.1(1H,s),9.1(1H,s),12.6(1H,br) 1 H-NMR (DMSO-D 6 , ppm) 1.5 (6H, d), 4.9 (1H, q), 8.6 (1H, s), 8.2 (1H, d), 7.9 (1H, dd), 7.9 (1H , d), 8.1 (1H, s), 9.1 (1H, s), 12.6 (1H, br)

IR(cm-1)2500至3150,2215,1669,1558,1502,1263 IR (cm -1 ) 2500 to 3150, 2215, 1669, 1558, 1502, 1263

此外,如得自XRD之第1圖光譜所示,化合物(1)結晶型顯示特徵峰值(2 θ)為12.1°、13.2°、15.7°、18.3°、24.8°、25.8°與26.6°。XRD之明確數值示於下表1。 Further, as shown in the spectrum of the first graph obtained from XRD, the crystal form of the compound (1) showed characteristic peaks (2 θ) of 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6°. The clear values for XRD are shown in Table 1 below.

實施例2Example 2

將所製得之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸(40 mg)溶於四氫呋喃(10 ml),於室溫下慢慢蒸發溶劑,產生化合物(1)結晶型(35 g)。 The obtained 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (40 mg) was dissolved in tetrahydrofuran (10 ml), slow at room temperature The solvent was slowly evaporated to give the compound (1) crystal form (35 g).

XRD之明確數值示於下表2。 The clear values for XRD are shown in Table 2 below.

實施例3Example 3

將所製得之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸(200 mg)加至第三丁醇(120 ml)中,於室溫下蒸發溶劑,產生化合物(1)結晶型(190 g)。 The obtained 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) was added to a tributanol (120 ml). The solvent was evaporated at room temperature to give the compound (1) crystal form (190 g).

XRD之明確數值示於下表3。 The clear values for XRD are shown in Table 3 below.

實施例4Example 4

將所製得之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸(200 mg)加至乙醇(60 ml)中,然後於呈漿狀物狀態下攪拌24小時,並過濾,產生化合物(1)結晶型(184 g)。 The 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) obtained was added to ethanol (60 ml) and then slurried. The mixture was stirred for 24 hours, and filtered to give Compound (1) crystal form (184 g).

XRD之明確數值示於下表4。 The clear values for XRD are shown in Table 4 below.

實施例5Example 5

將所製得之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸(200 mg)加至乙腈(70 ml)中,然後於呈漿狀物狀態下攪拌24小時,並過濾,產生化合物(1)結晶型(179 g)。 The 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) obtained was added to acetonitrile (70 ml) and then slurried. The mixture was stirred for 24 hours, and filtered to give Compound (1) crystal form (179 g).

XRD之明確數值示於下表5。 The clear values for XRD are shown in Table 5 below.

實施例6Example 6

將所製得之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸(200 mg)加至氯仿(120 ml)中,然後於呈漿狀物狀態下攪拌24小時,並過濾,產生化合物(1)結晶型(196 g)。 The obtained 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) was added to chloroform (120 ml) and then slurried. The mixture was stirred for 24 hours, and filtered to give Compound (1) crystal form (196 g).

XRD之明確數值示於下表6。 The clear values for XRD are shown in Table 6 below.

實施例7Example 7

將所製得之1-(3-氰基-1-異丙基-吲哚-5-基)吡唑-4-羧酸鈉鹽(7.3 kg)溶於10N NaOH溶液(11.6 L)。於攪拌下,在此溶液中慢慢滴加鹽酸(12.1 kg)。化合物(1)結晶型開始沉澱。當pH達到約1至2時,停止滴加鹽酸。攪拌混合物直到呈均勻為止,然後過濾,產生化合物(1)結晶型(15.96 kg)。 The obtained sodium 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate (7.3 kg) was dissolved in a 10N NaOH solution (11.6 L). Hydrochloric acid (12.1 kg) was slowly added dropwise to the solution with stirring. The crystalline form of the compound (1) starts to precipitate. When the pH reached about 1 to 2, the dropwise addition of hydrochloric acid was stopped. The mixture was stirred until it became homogeneous, and then filtered to give a compound (1) crystal form (15.96 kg).

試驗例1Test example 1 粉末X-射線繞射分析法 Powder X-ray diffraction analysis

將得自實例1之約40 mg化合物(1)結晶型加至樣本固定器中,架在X’Pert PRO(來自Panalytical)上,測定4至40°/2 θ範圍內之繞射圖型。其結果示於第1圖。分析法之明確條件如下。 About 40 mg of Compound (1) crystal form from Example 1 was added to a sample holder and mounted on an X'Pert PRO (from Panalytical) to determine a diffraction pattern in the range of 4 to 40 °/2 θ. The result is shown in Fig. 1. The clear conditions of the analytical method are as follows.

積分時間(Time per step):99.45 s Time per step: 99.45 s

解析度:0.0394° Resolution: 0.0394°

掃瞄模式:連續 Scan mode: continuous

電壓/電流:45 kV/40 mA Voltage / current: 45 kV / 40 mA

Cu-鈀(Ni-濾器) Cu-palladium (Ni-filter)

固定發散狹縫 Fixed divergence slit

平行板狹縫:平行板0.04 rad Parallel plate slit: parallel plate 0.04 rad

檢測器狹縫0.04 rad平行板狹縫,反散射狹縫P7.5 Detector slit 0.04 rad parallel plate slit, backscatter slit P7.5

由第1圖可證實,所分析之本發明化合物(1)結晶型在CuK α,45Kv,40m Å下測定XRD光譜所出現之特徵峰值(2 θ)為12.1°、13.2°、15.7°、18.3°、24.8°、25.8°與26.6°。 It can be confirmed from Fig. 1 that the characteristic peaks (2 θ) of the XRD spectrum measured by the crystal form of the compound (1) of the present invention analyzed at CuK α, 45 Kv, 40 m Å are 12.1°, 13.2°, 15.7°, 18.3. °, 24.8 °, 25.8 ° and 26.6 °.

試驗例2Test example 2 差示性掃瞄熱量儀(DSC) Differential Scanning Calorimeter (DSC)

DSC係採用Mettler Toledo公司之DSC821e進行。取3 mg得自實施例1之化合物(1)結晶型置於鋁盤,精確記錄其重量。在鋁盤上加蓋。在蓋上打孔並成型。鋁盤架在儀器上。在氮氣吹掃下,依10℃/分鐘之速率自25℃加熱至300℃。使用銦金屬作為校正標準物。所得結果示於第2圖。如第2圖所證實,本發明化合物(1)結晶型因為其熔點從263至268℃而出現初始吸熱峰,由此可見本發明結晶型具有高熔點,而且可以穩定抗熱。 The DSC was carried out using the DSC821 e from Mettler Toledo. 3 mg of the crystalline form of the compound (1) from Example 1 was placed in an aluminum pan, and the weight was accurately recorded. Cover the aluminum plate. Punch and shape the cover. The aluminum frame is on the instrument. Heated from 25 ° C to 300 ° C at a rate of 10 ° C / min under a nitrogen purge. Indium metal was used as a calibration standard. The results obtained are shown in Fig. 2. As confirmed from Fig. 2, the crystalline form of the compound (1) of the present invention exhibits an initial endothermic peak because its melting point is from 263 to 268 ° C, whereby it can be seen that the crystalline form of the present invention has a high melting point and is stable against heat.

試驗例3Test Example 3 熱重量分析法(TGA) Thermogravimetric analysis (TGA)

TGA係於Mettler Toledo公司之TGA850進行。將得自實施例1之化合物(1)結晶型5 mg置於鋁盤。鋁盤架在儀器上,然後在氮氣吹掃下,依10℃/分鐘之速率,自25℃加熱至300℃。使用鎳與鋁(Nickel and AluminumTM)作為校正標準物。所得結果示於第3圖。由第3圖所證實,本發明化合物(1)結晶型在DSC之吸熱階段並未顯示重量損失,由此可見本發明結晶型可以穩定抗熱。 The TGA was carried out at the TGA850 of Mettler Toledo. The crystalline form 5 mg of the compound (1) from Example 1 was placed in an aluminum pan. The aluminum pan was placed on the instrument and then heated from 25 ° C to 300 ° C at a rate of 10 ° C / min under a nitrogen purge. Use of nickel and aluminum (Nickel and Aluminum TM) as a calibration standard. The results obtained are shown in Figure 3. As confirmed from Fig. 3, the crystalline form of the compound (1) of the present invention showed no weight loss in the endothermic phase of DSC, and thus it was found that the crystalline form of the present invention can be stably resistant to heat.

試驗例4Test Example 4 等溫濕氣吸附/解吸分析法 Isothermal moisture adsorption/desorption analysis

將得自實施例1之化合物(1)結晶型,於VTI-SA蒸汽吸收分析儀(Vapor Sorption Analyzer)上收集濕氣吸附/解吸數據。樣本未在分析前先乾燥。在維持25℃溫度下,在相對濕度(RH)為5至95%之範圍內,依5% RH之間隔分析濕氣之吸附與解吸。其結果示於第4圖。由第4圖可見,根據5至95% RH範圍內之外部濕度變化,本發明化合物(1)結晶型所出現之重量變化僅0.3%或更小。亦即,本發明結晶型可極穩定對抗相對濕度之任何變化,且隨著濕度變化,該結晶型仍無變化。 The compound (1) crystal form from Example 1 was collected, and moisture adsorption/desorption data was collected on a VTI-SA vapor absorption analyzer (Vapor Sorption Analyzer). The sample was not dried prior to analysis. The adsorption and desorption of moisture was analyzed at intervals of 5% RH while maintaining a temperature of 25 ° C in the range of 5 to 95% relative humidity (RH). The result is shown in Fig. 4. As seen from Fig. 4, the change in weight of the crystalline form of the compound (1) of the present invention is only 0.3% or less based on the change in external humidity in the range of 5 to 95% RH. That is, the crystalline form of the present invention is extremely stable against any change in relative humidity, and the crystal form remains unchanged as humidity changes.

試驗例5Test Example 5 熱穩定性 Thermal stability

將得自實施例1之本發明結晶型約50 mg置入Duma瓶中,然後保存在40±2℃,75±5% RH或60±2℃,5±5% RH下。經過2週、8週與12週後,自Duma瓶中取出各樣本。樣本溶於乙腈/水/0.1N氫氧化鈉溶液=30/60/10(v/v/v%)溶劑混合物中,然後進行HPLC分析。HPLC分析之條件如下:HPLC分析之條件 Approximately 50 mg of the crystalline form of the invention from Example 1 was placed in a Duma bottle and then stored at 40 ± 2 ° C, 75 ± 5% RH or 60 ± 2 ° C, 5 ± 5% RH. After 2 weeks, 8 weeks, and 12 weeks, each sample was taken from the Duma bottle. The sample was dissolved in an acetonitrile/water/0.1 N sodium hydroxide solution = 30/60/10 (v/v/v%) solvent mixture, followed by HPLC analysis. The conditions for HPLC analysis are as follows: Conditions for HPLC analysis

管柱:dC18(4.6 mm I.Dx450 mm L,粒度5.0μm,Agilent) Column: dC18 (4.6 mm I.Dx450 mm L, particle size 5.0 μm, Agilent)

管柱溫度:20℃ Column temperature: 20 ° C

移動相:MeCN/H2O/TFA=35/65/0.1 Mobile phase: MeCN/H 2 O/TFA=35/65/0.1

流速:1.0 mL/min. Flow rate: 1.0 mL/min.

偵測:250 nm,UV Detection: 250 nm, UV

注射體積:10μl Injection volume: 10μl

總分析時間:40 min. Total analysis time: 40 min.

結晶型之熱穩定性結果示於下表8中。 The thermal stability results of the crystalline form are shown in Table 8 below.

表8中數據顯示,本發明化合物(1)結晶型在40±2℃,75±5%RH或60±2℃,5±5% RH之條件下12週後,仍具有優異之穩定性。 The data in Table 8 shows that the crystalline form of the compound (1) of the present invention has excellent stability after 12 weeks at 40 ± 2 ° C, 75 ± 5% RH or 60 ± 2 ° C, 5 ± 5% RH.

試驗例6Test Example 6 對黃嘌呤氧化酶選擇性之估測法 Estimation of the selectivity of xanthine oxidase

將本發明化合物(1)結晶型投與雄性小鼠(BALB/c),劑量為100或300 mg/kg。24小時後,收集血液,分離血漿。採用LC-MS/MS定量分析血漿中乳清酸(OA)與乳清苷(OD)濃度。結果示於下表9。本試驗試圖證實化合物(1)結晶型對嘧啶代謝作用中之主要酵素(亦即乳清酸磷酸核糖基轉移酶(OPRT)與乳清苷單磷酸脫羧基酶(OMPDC))是否具有選擇性。本活體試驗中,血中OA與OD並未增加(見下表9)。由此結果可預測,化合物(1)結晶型可與黃嘌呤氧化酶 選擇性結合。 The compound of the present invention (1) was administered to a male mouse (BALB/c) at a dose of 100 or 300 mg/kg. After 24 hours, blood was collected and plasma was separated. The concentration of orotate (OA) and orotidine (OD) in plasma was quantitatively analyzed by LC-MS/MS. The results are shown in Table 9 below. This test attempts to confirm whether the compound (1) crystal form is selective for the main enzyme in pyrimidine metabolism (i.e., orotic acid phosphoribosyltransferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC)). In this in vivo test, OA and OD in blood did not increase (see Table 9 below). The result is predictable, the compound (1) crystal form and xanthine oxidase Selective combination.

試驗例7Test Example 7 評估對動物之生體可用率 Assessing the availability of animals to animals

為了評估本發明化合物(1)結晶型之生體可用率,對大鼠、猴子與狗經靜脈內及經口投與單劑量之化合物(1)結晶型。收集血液,採用LC-MS/MS定量分析血漿中化合物(1)結晶型濃度。取得各投藥途徑之藥物動力學參數 (Cmax、AUCinf、CL、Vdss、t1.2),由經口投藥之AUC相對於靜脈內投藥之AUC之百分比計算生體可用率。分析大鼠、猴子與狗之生體可用率分別為37至61%、23至39%與75%。 In order to evaluate the bioavailability of the crystalline form of the compound (1) of the present invention, a single dose of the compound (1) is administered intravenously and orally to rats, monkeys and dogs. Blood was collected and the concentration of the compound (1) in plasma was quantitatively analyzed by LC-MS/MS. The pharmacokinetic parameters (C max , AUC inf , CL, Vd ss , t 1.2 ) of each route of administration were obtained, and the bioavailability was calculated from the percentage of AUC of the orally administered drug relative to the AUC of the intravenous administration. The bioavailability of rats, monkeys and dogs was analyzed to be 37 to 61%, 23 to 39% and 75%, respectively.

第1圖代表化合物(1)結晶型之X-射線粉末繞射法(XRD)圖型。 Fig. 1 represents an X-ray powder diffraction method (XRD) pattern of the compound (1) crystal form.

第2圖代表化合物(1)結晶型之示差掃描量熱法(DSC)結果。 Fig. 2 shows the results of differential scanning calorimetry (DSC) of the crystal form of the compound (1).

第3圖代表化合物(1)結晶型之熱解重量分析法(TGA)結果。 Fig. 3 represents the results of thermogravimetric analysis (TGA) of the crystalline form of the compound (1).

第4圖代表化合物(1)結晶型之濕氣吸附/解吸等溫線。 Figure 4 represents the moisture adsorption/desorption isotherm of the crystalline form of Compound (1).

Claims (10)

一種如下式(1)代表之化合物之結晶型: 其中所述之結晶型,其在X-射線繞射圖型光譜中出現之特徵峰值(2 θ)為12.1°、13.2°、15.7°、18.3°、24.8°、25.8°與26.6°;12.1°、13.2°、15.6°、18.2°、24.7°、25.6°與26.6°;12.2°、13.3°、15.9°、18.4°、24.7°、25.9°與26.7°;12.1°、13.2°、15.7°、18.3°、24.9°、25.8°與26.6°;12.1°、13.2°、15.8°、18.3°、24.9°、25.8°與26.6°;或12.1°、13.3°、15.8°、18.3°、24.9°、25.8°與26.7°。 A crystal form of a compound represented by the following formula (1): Among the crystal forms, the characteristic peaks (2 θ) appearing in the X-ray diffraction pattern spectrum are 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6°; 12.1°. 13.2°, 15.6°, 18.2°, 24.7°, 25.6° and 26.6°; 12.2°, 13.3°, 15.9°, 18.4°, 24.7°, 25.9° and 26.7°; 12.1°, 13.2°, 15.7°, 18.3 °, 24.9°, 25.8° and 26.6°; 12.1°, 13.2°, 15.8°, 18.3°, 24.9°, 25.8° and 26.6°; or 12.1°, 13.3°, 15.8°, 18.3°, 24.9°, 25.8° With 26.7°. 如申請專利範圍第1項所述之結晶型,其在X-射線繞射圖型光譜中出現之特徵峰值(2 θ)為12.1°、13.2°、15.7°、16.6°、18.3°、19.6°、20.9°、23.1°、24.8°、25.8°與26.6°;12.1°、13.2°、15.6°、16.6°、18.2°、19.6°、20.9°、24.7°、25.6°與26.6°;12.2°、13.3°、15.9°、16.7°、18.4°、19.7°、21.1°、24.7°、25.9°與26.7°;12.1°、13.2°、15.7°、16.6°、18.3°、19.6°、20.9°、 24.9°、25.8°與26.6°;12.1°、13.2°、15.7°、16.6°、18.3°、19.6°、21.0°、23.3°、24.9°、25.8°與26.6°;12.1°、13.2°、15.8°、16.7°、18.3°、19.6°、21.0°、23.1°、24.9°、25.8°與26.6°;或12.1°、13.3°、15.8°、16.7°、18.3°、19.6°、21.0°、23.2°、24.9°、25.8°與26.7°。 As shown in the crystalline form of claim 1, the characteristic peaks (2 θ) appearing in the X-ray diffraction pattern spectrum are 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°. 20.9°, 23.1°, 24.8°, 25.8° and 26.6°; 12.1°, 13.2°, 15.6°, 16.6°, 18.2°, 19.6°, 20.9°, 24.7°, 25.6° and 26.6°; 12.2°, 13.3 °, 15.9°, 16.7°, 18.4°, 19.7°, 21.1°, 24.7°, 25.9° and 26.7°; 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°, 20.9°, 24.9°, 25.8° and 26.6°; 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°, 21.0°, 23.3°, 24.9°, 25.8° and 26.6°; 12.1°, 13.2°, 15.8° , 16.7°, 18.3°, 19.6°, 21.0°, 23.1°, 24.9°, 25.8° and 26.6°; or 12.1°, 13.3°, 15.8°, 16.7°, 18.3°, 19.6°, 21.0°, 23.2°, 24.9°, 25.8° and 26.7°. 如申請專利範圍第1項所述之結晶型,其由DSC之起始溫度顯示示差掃描熱量分析曲線之熔點為263至268℃。 The crystalline form according to claim 1, wherein the melting temperature of the differential scanning calorimetry curve is 263 to 268 ° C from the initial temperature of the DSC. 一種製備式(1)化合物結晶型之方法,其係使如申請專利範圍第1項所定義之式(1)化合物溶於選自下列各物所組成群之溶劑中:無水乙醇、2-甲氧基乙醇、異丁醇、正丁醇、正辛醇、正丙醇、異丙醇、第三丁醇、乙酸、丙酮、乙酸丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸第三丁酯、乙酸異丁酯、甲基乙基酮、2-戊酮、四氫呋喃、乙腈、氯仿、甲苯與該等之混合物,並自其中結晶,其中所述之結晶型,其在X-射線繞射圖型光譜中出現之特徵峰值(2 θ)為下列:12.1°、13.2°、15.7°、18.3°、24.8°、25.8°與26.6°;12.1°、13.2°、15.6°、18.2°、24.7°、25.6°與26.6°;12.2°、13.3°、15.9°、18.4°、24.7°、25.9°與26.7°;12.1°、13.2°、15.7°、18.3°、24.9°、25.8°與26.6°;12.1°、13.2°、15.8°、18.3°、24.9°、25.8°與26.6°;或 12.1°、13.3°、15.8°、18.3°、24.9°、25.8°與26.7°。 A process for preparing a crystalline form of a compound of the formula (1), which is obtained by dissolving a compound of the formula (1) as defined in the first aspect of the patent application in a solvent selected from the group consisting of: anhydrous ethanol, 2-methyl Oxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, tert-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate, propyl acetate, acetic acid And a mixture of the third butyl ester, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene, and the like, wherein the crystalline form is X- The characteristic peaks (2 θ) appearing in the ray diffraction pattern spectrum are as follows: 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6°; 12.1°, 13.2°, 15.6°, 18.2° 24.7°, 25.6° and 26.6°; 12.2°, 13.3°, 15.9°, 18.4°, 24.7°, 25.9° and 26.7°; 12.1°, 13.2°, 15.7°, 18.3°, 24.9°, 25.8° and 26.6 °; 12.1 °, 13.2 °, 15.8 °, 18.3 °, 24.9 °, 25.8 ° and 26.6 °; or 12.1°, 13.3°, 15.8°, 18.3°, 24.9°, 25.8° and 26.7°. 如申請專利範圍第4項所述之製備式(1)化合物結晶型之方法,其中,該結晶化係藉由選自下列之方法而進行:冷卻溶液、蒸發溶劑、添加反溶劑直到達到超飽和、及轉化成漿液態。 The method for preparing a crystalline form of the compound of the formula (1) as described in claim 4, wherein the crystallization is carried out by a method selected from the group consisting of cooling a solution, evaporating a solvent, and adding an anti-solvent until supersaturation is achieved. And converted into a liquid state. 如申請專利範圍第4項所述之製備式(1)化合物結晶型之方法,其中,使如申請專利範圍第1項所定義之式(1)化合物溶於丙酮中,然後蒸發。 A method for producing a crystalline form of the compound of the formula (1) as described in claim 4, wherein the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in acetone and then evaporated. 如申請專利範圍第4項所述之製備式(1)化合物結晶型之方法,其中,使如申請專利範圍第1項所定義之式(1)化合物溶於無水乙醇、乙腈或氯仿,形成漿液,然後攪拌與過濾。 A method for producing a crystalline form of the compound of the formula (1) as described in claim 4, wherein the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in anhydrous ethanol, acetonitrile or chloroform to form a slurry. Then stir and filter. 如申請專利範圍第4項所述之製備式(1)化合物結晶型之方法,其中,使如申請專利範圍第1項所定義之式(1)化合物溶於四氫呋喃或第三丁醇,並於室溫下蒸發溶劑。 A method for producing a crystalline form of the compound of the formula (1), as described in claim 4, wherein the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in tetrahydrofuran or tert-butanol, and The solvent was evaporated at room temperature. 一種製備如申請專利範圍第1項所述之式(1)化合物結晶型之方法,其中,使如申請專利範圍第1項所定義之式(1)化合物之鈉鹽溶於氫氧化鈉溶液中,滴加鹽酸以產生結晶,並攪拌混合物,直到轉呈均勻為止。 A process for preparing a crystalline form of a compound of the formula (1) according to the first aspect of the invention, wherein the sodium salt of the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in a sodium hydroxide solution. Hydrochloric acid was added dropwise to cause crystallization, and the mixture was stirred until the conversion was uniform. 一種組合物,其包含如申請專利範圍第1項所定義之式(1)化合物之結晶型,係供治療或預防與黃嘌呤氧化酶相關疾病,該相關疾病係選自由高尿酸血症、痛風、心臟衰竭、心血管疾病、高血壓、糖尿病、腎臟病、發炎與關節疾病、及發炎性腸道疾病所組成群者。 A composition comprising a crystalline form of a compound of formula (1) as defined in claim 1 for the treatment or prevention of a disease associated with xanthine oxidase, the related disease being selected from the group consisting of hyperuricemia, gout , a group of heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and joint disease, and inflammatory bowel disease.
TW101111308A 2011-04-06 2012-03-30 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof TWI548630B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR20110031490 2011-04-06

Publications (2)

Publication Number Publication Date
TW201245182A TW201245182A (en) 2012-11-16
TWI548630B true TWI548630B (en) 2016-09-11

Family

ID=46969691

Family Applications (1)

Application Number Title Priority Date Filing Date
TW101111308A TWI548630B (en) 2011-04-06 2012-03-30 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof

Country Status (5)

Country Link
JP (1) JP6008937B2 (en)
KR (1) KR101424013B1 (en)
CN (1) CN103459381B (en)
TW (1) TWI548630B (en)
WO (1) WO2012138147A2 (en)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008488B (en) * 2016-05-20 2018-10-30 广东东阳光药业有限公司 Cyanoindole analog derivative and its preparation method and application
CN106045898B (en) * 2016-06-28 2019-05-24 广东东阳光药业有限公司 A kind of Benzazole compounds and its preparation method and application
US20190374515A1 (en) * 2016-11-28 2019-12-12 Teijin Pharma Limited Therapeutic drug or prophylactic drug for diabetic nephropathy
EP4218755A4 (en) * 2020-11-04 2024-03-27 Lg Chem, Ltd. Method for preparing crystalline particles of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid, and pharmaceutical composition comprising same
JP2023551524A (en) 2020-12-01 2023-12-08 エルジー・ケム・リミテッド Oral preparation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and method for producing the same
JP2023551712A (en) 2020-12-01 2023-12-12 エルジー・ケム・リミテッド Stable oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid
US20240216331A1 (en) * 2021-04-16 2024-07-04 Lg Chem, Ltd. Oral formulation containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid
CN117255785A (en) * 2021-04-27 2023-12-19 株式会社Lg化学 Process for the preparation of intermediates useful in the synthesis of xanthine oxidase inhibitors
CA3218011A1 (en) * 2021-04-29 2022-11-10 Jiangsu Atom Bioscience And Pharmaceutical Co., Ltd. A xanthine oxidase inhibitor
CN117425477A (en) * 2021-06-15 2024-01-19 株式会社Lg化学 Pharmaceutical composition comprising 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid
AR126164A1 (en) 2021-06-17 2023-09-27 Lg Chemical Ltd COMPOUND FORMULATION FOR ORAL DOSAGE COMPRISING 1-(3-CYANO-1-ISOPROPYL-INDOL-5-IL)PYRAZOLE-4-CARBOXYLIC ACID
TWI822151B (en) * 2021-07-02 2023-11-11 南韓商Lg化學股份有限公司 Method for preparing xanthine oxidase inhibitor
WO2023208108A1 (en) * 2022-04-27 2023-11-02 江苏新元素医药科技有限公司 Compound for reducing uric acid
TW202342455A (en) * 2022-04-27 2023-11-01 大陸商江蘇新元素醫藥科技有限公司 Compounds for gout

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027186A1 (en) * 1996-01-25 1997-07-31 MERCK Patent Gesellschaft mit beschränkter Haftung 1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine used as medicine acting on the central nervous system
WO2007113647A1 (en) * 2006-04-04 2007-10-11 Pfizer Products Inc. Polymorphic forms of (2r,z)-2-amino-2-cyclohexyl-n-(5-(1-methyl-1h-pyrazol-4υl)-1-oxo-2,6-dihydro-1h-[1,2]diazepino[4,5,6-cd]indol-8-yl)acetamide
WO2011043568A2 (en) * 2009-10-07 2011-04-14 Lg Life Sciences Ltd. Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2431815T3 (en) * 2007-04-11 2013-11-28 Kissei Pharmaceutical Co., Ltd. Derived from (aza) indole and use thereof for medical purposes
WO2008126901A1 (en) * 2007-04-11 2008-10-23 Kissei Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic compound and pharmaceutical composition containing the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027186A1 (en) * 1996-01-25 1997-07-31 MERCK Patent Gesellschaft mit beschränkter Haftung 1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine used as medicine acting on the central nervous system
WO2007113647A1 (en) * 2006-04-04 2007-10-11 Pfizer Products Inc. Polymorphic forms of (2r,z)-2-amino-2-cyclohexyl-n-(5-(1-methyl-1h-pyrazol-4υl)-1-oxo-2,6-dihydro-1h-[1,2]diazepino[4,5,6-cd]indol-8-yl)acetamide
WO2011043568A2 (en) * 2009-10-07 2011-04-14 Lg Life Sciences Ltd. Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same

Also Published As

Publication number Publication date
WO2012138147A3 (en) 2012-11-29
KR101424013B1 (en) 2014-08-18
KR20120114174A (en) 2012-10-16
CN103459381B (en) 2015-12-09
JP2014510133A (en) 2014-04-24
CN103459381A (en) 2013-12-18
JP6008937B2 (en) 2016-10-19
TW201245182A (en) 2012-11-16
WO2012138147A2 (en) 2012-10-11

Similar Documents

Publication Publication Date Title
TWI548630B (en) 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof
KR101829595B1 (en) Novel polymorphic forms of 3-(1-{3-[5-(1-methyl-piperidin-4ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof
AU2014351486C1 (en) Crystalline forms of lesinurad and its sodium salt
RU2577334C2 (en) CRYSTALLINE FORM OF (R)-7-CHLORO-N-(QUINUCLIDIN-3-YL)BENZO[b]THIOPHENE-2-CARBOXAMIDE HYDROCHLORIDE MONOHYDRATE
JP2008519049A (en) Combination medicine of SRC kinase inhibitor and BCR-ABL inhibitor for the treatment of proliferative disease
WO2017152707A1 (en) Crystalline forms of mesylate salt of pyridinyl amino pyrimidine derivative, preparation methods therefor, and applications thereof
WO2016000568A1 (en) Compound for treating gout
JP2023071922A (en) 7h-pyrrolo[2,3-d]pyrimidine jak inhibitor
TW202308991A (en) Solid forms of a terphenyl compound
CN102574838B (en) Pyrrole and [2,3-C] pyridine derivative using as P38 kinase inhibiting agents
WO2016188444A1 (en) Sodium salt of uric acid transporter inhibitor and crystalline form thereof
JP5860125B2 (en) A novel polymorphic form of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl] -benzyl } -2H-pyridazine-3-one dihydrogen phosphate and process for producing the same
CN104768944B (en) 2 pyridinone compounds
TWI752980B (en) Crystalline forms of 4-cyano-n-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2h-pyran-4-yl)pyridin-3-yl)-1h-imidazole-2-carboxamide
US8471032B2 (en) Benzimidazole compound in crystal form and salt thereof
CN102666528B (en) Crystalline CDC7 inhibitor salts
JP6767382B2 (en) New crystal form of topiroxostat and its manufacturing method
WO2017076358A1 (en) New crystal form of imidazolyl biphenyl compound salt and preparation method thereof
WO2020156150A1 (en) Polymorph of pomalidomide prodrug salt
KR20210155806A (en) Polymorphism of PI3K inhibitor and method for preparing same
US20060270685A1 (en) Anhydrous ziprasidone mesylate and a process for its preparation