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WO2012138147A2 - Forme cristalline de l'acide 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylique et son procédé de préparation - Google Patents

Forme cristalline de l'acide 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylique et son procédé de préparation Download PDF

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Publication number
WO2012138147A2
WO2012138147A2 PCT/KR2012/002575 KR2012002575W WO2012138147A2 WO 2012138147 A2 WO2012138147 A2 WO 2012138147A2 KR 2012002575 W KR2012002575 W KR 2012002575W WO 2012138147 A2 WO2012138147 A2 WO 2012138147A2
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Prior art keywords
compound
crystalline form
formula
preparing
solvent
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Ceased
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WO2012138147A3 (fr
Inventor
Jung Min Yun
Ki Sook Park
Joo Yong Yoon
Ju Young Lee
Geun Tae Kim
Cheol Kyu Jung
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LG Chem Ltd
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LG Life Sciences Ltd
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Priority to CN201280016696.6A priority Critical patent/CN103459381B/zh
Priority to JP2014503602A priority patent/JP6008937B2/ja
Publication of WO2012138147A2 publication Critical patent/WO2012138147A2/fr
Publication of WO2012138147A3 publication Critical patent/WO2012138147A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic 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
    • C07D403/04—Heterocyclic 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
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a crystalline form of the novel compound represented by the following formula (1) (chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) which is useful as an inhibitor against xanthine oxidase, and a process for preparing the same.
  • formula (1) chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid
  • Xanthine oxidase is an enzyme which converts hypozanthine to xanthine and further converts thus-formed zanthine to uric acid.
  • various diseases such as gout
  • Gout indicates the condition in which uric acid crystals accumulated in cartilage, ligament and surrounding tissue induce severe inflammation and pain.
  • the incidence rate of gout has steadily increased over the past 40 years (N. L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587 ⁇ 2590).
  • substances inhibiting the activity of xanthine oxidase can be effectively used for the treatment of the diseases associated with xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and articular disease, inflammatory bowel disease, etc.
  • the object of the present invention is to provide a crystalline form of the novel compound of formula (1) [Compound (1), below], whereby superior pharmaceutical qualities such as stability, no moisture absorption, easy handling, etc. as well as pharmacological activity achieved by the selective binding to xanthine oxidase are provided.
  • the present invention provides a crystalline form of novel Compound (1) (chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) which is useful as an inhibitor against xanthine oxidase.
  • novel Compound (1) chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid
  • the crystalline form of Compound (1) i.e., the crystalline form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid ⁇ shows an inhibitory activity against xanthine oxidase, and the process for its preparation will be explained in detail in the Preparations hereinafter.
  • Xanthine oxidase is an enzyme which converts hypozanthine to xanthine and further converts thus-formed xanthine to uric acid. When too much uric acid is present in the body, sometimes causing various diseases such as gout.
  • the crystalline form of Compound (1) selectively inhibits xanthine oxidase.
  • the crystalline form of Compound (1) shows the characteristic peak values (2 ⁇ ) of 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6° when analyzed by X-ray powder diffraction (XRD). More specifically, the crystalline form of Compound (1) shows the characteristic peak values (2 ⁇ ) of 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°, 20.9°, 23.1°, 24.8°, 25.8° and 26.6° when analyzed by XRD.
  • the crystalline form of Compound (1) of the present invention is very stable against moisture. As is shown in Figure 4, it has been confirmed that the crystalline form of the present invention shows the weight change due to the moisture of only about 0.3% or less during the moisture adsorption isotherm. Thus, the crystalline form of the present invention was identified as very stable against moisture.
  • the crystalline form of Compound (1) according to the present invention shows little or no weight change due to the change of humidity under a wide range of relative humidity, shows no change of crystalline form due to the change of humidity and is very stable against heat.
  • it is particularly useful in the aspect of storage stability, process of milling, etc.
  • the present invention also provides a process for preparing the crystalline form of Compound (1) by crystallizing Compound (1) from a suitable solvent or solvent mixture.
  • the solvent or solvent mixture is preferably selected from the solvents used already in the process for the preparation of Compound (1).
  • the solvent or solvent mixture used is selected from the group consisting of anhydrous ethanol, 2-methoxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, t-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene and their mixtures. More preferably, the solvent is selected from the group
  • the crystallization of Compound (1) from a suitable solvent may be performed by methods such as cooling the solution, evaporating the solvent, adding the anti-solvent (a solvent in which Compound (1) is not dissolved well-for example, water) until super-saturation is achieved, converting to slurry state, etc.
  • the anti-solvent a solvent in which Compound (1) is not dissolved well-for example, water
  • the crystalline form of Compound (1) used herein may be administered to a human patient as the compound per se or as a pharmaceutical composition comprising the compound with other active ingredients in combination therapy or with other suitable carriers or excipients.
  • the pharmaceutical composition of the present invention may be prepared by known methods, such as conventional mixing, dissolving, granulating, tabletting, powdering, emulsifying, capsulating, trapping or freeze-drying, etc.
  • the pharmaceutical composition of the present invention may be prepared by the conventional methods of using one or more pharmaceutically acceptable carriers.
  • the carriers include excipients or adjuvants by which the active compound can be easily converted to pharmaceutically acceptable formulations. Suitable formulations may depend on the selected administration route. Techniques, carriers and excipients, and means known in the art-for example, in “Remington’s Pharmaceutical Sciences”-may be appropriately selected.
  • the crystalline form of Compound (1) can be formulated as an injectable preparation, oral preparation, etc., depending on the present invention’s intended purpose.
  • the active compound of the present invention can be formulated as a liquid preparation by using pharmaceutically suitable buffers, preferably Hank solution, Ringer solution, physiological saline, etc.
  • pharmaceutically suitable buffers preferably Hank solution, Ringer solution, physiological saline, etc.
  • penetration promoters suitable for the barrier to be penetrated are used for the formulation. Such penetration promoters are conventionally known in the art.
  • the active compound of the present invention can be easily formulated as solid dosage forms for oral administration by combining the compound with pharmaceutically acceptable carriers known in the art. With the use of such carriers, the compound of the present invention can be formulated as tablets, powders, granules, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. Capsules, tablets, pills, powders and granules are advantageous, and capsules and tablets are particularly advantageous.
  • the dosage forms for oral administration can be obtained as follows.
  • the crystalline form of Compound (1) according to the present invention is mixed with one or more excipients, and the mixture is pulverized, if appropriate. Suitable adjuvants are added if necessary, and tablets or dragee cores can be obtained from the granule mixtures.
  • suitable excipients fillers such as lactose, sucrose, mannitol or sorbitol; cellulose substances such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone (PVP); etc. can be mentioned.
  • disintegrating agents such as cross-linked polyvinylpyrrolidone, agar-agar, alginic acid or its salts like sodium alginate, lubricating agents such as magnesium stearate and binding agents may be added as a carrier.
  • the oral preparations may include sealed soft capsules that are made from gelatin and plastic agents such as glycol or sorbitol, and hard gelatin capsules that are made from gelatin.
  • the hard gelatin capsules may contain the active compound as a mixture with fillers such as lactose, binding agents such as starch, and/or lubricating agents such as talc or magnesium stearate.
  • the active compound may be dissolved or dispersed in a suitable medium such as fatty acid, liquid paraffin or liquid polyethyleneglycol.
  • a stabilizing agent may be included. All formulations for oral administration may contain a suitable amount of the active compound.
  • the active compound-i.e., the crystalline form of Compound (1) ⁇ can also be formulated as an injection preparation, such as, for example, a large pill-type injection or continuous-type injection, for parenteral administration.
  • the injection preparation may be provided in the form of an ampoule having a preservative or a unit dosage form charged in a multi-dose container.
  • the compositions may take such forms as suspensions in oily or liquefied vehicles, solutions or emulsions and may contain such components for formulations as suspending agents, stabilizing agents and/or dispersing agents.
  • the active ingredient can be a form of powder which is intended to be reconstructed by dissolving in sterilized pyrogen-free water prior to use.
  • the active compound can also be formulated into a composition for rectal application such as suppository or retention enema comprising typical suppository bases ⁇ for example, cocoa butter or other glycerides.
  • compositions according to the present invention contain the crystalline form of Compound (1) in an amount effective to achieve its intended purpose.
  • the therapeutically effective amount means the amount of the active compound effective to prolong the survival of the patient to be treated, or to prevent, alleviate or ameliorate the symptoms of the disease.
  • a skilled artisan would be able to determine the therapeutically effective amount, particularly in light of the detailed description provided herein.
  • the crystal form of Compound (1) is preferably contained in an amount of about 0.1 to 1,000 mg per unit dosage based on Compound (1).
  • the dosage depends on the prescription of a physician, taking into account such factors as body weight or age of the patient, specific nature of the disease, severity of the disease, etc.
  • the dosage needed for the treatment of an adult is typically from about 1 to 1,000 mg per day, depending on the intensity and frequency of the administration.
  • a total dosage from about 1 to 500 mg per day will be sufficient when separately administered in a single dosage, although for some patients a higher daily dosage may be desirable.
  • the present invention further provides a method for the prevention or treatment of diseases associated with human xanthine oxidase, using a therapeutically effective amount of the crystalline form of Compound (1).
  • diseases associated with human xanthine oxidase refers to diseases that can be treated or prevented by inhibiting human xanthine oxidase, and they include but are not limited to hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, complications of diabetes, kidney disease, inflammation and articular disease, inflammatory bowel disease, etc. Some examples of said complications of diabetes are hyperlipidemia, atherosclerosis, obesity, hypertension, retinosis, renal failure, etc.
  • the crystal form of Compound (1) of the present invention has no genetic toxicity, repeated toxicity, etc. and is very safe as has been confirmed by the toxicity test data with animals.
  • treatment means the interruption or delay of the progress of a disease when applied to a subject showing the onset of disease symptoms
  • prevention means the interruption or delay of the sign of the onset of the disease when applied to a subject who does not show, but is at risk of, the onset of disease symptoms.
  • the crystalline form of Compound (1) newly provided by the present invention has a pharmacological activity that can be achieved by selectively inhibiting xanthine oxidase and at the same time has superior pharmaceutical effect of stability such as thermal stability, storage stability, etc.
  • the crystalline form of Compound (1) as a new substance is useful because it shows little or no weight change due to the change of humidity under a wide range of relative humidity and shows no change of crystalline form due to the change of humidity.
  • Figure 1 represents the X-ray powder diffraction (XRD) pattern of the crystalline form of Compound (1).
  • Figure 2 represents the result of differential scanning calorimetry (DSC) of the crystalline form of Compound (1).
  • Figure 3 represents the result of thermogravimetric analysis (TGA) of the crystalline form of Compound (1).
  • Figure 4 represents the moisture adsorption/desorption isotherm of the crystalline form of Compound (1).
  • Tetrahydrofuran (100 mL) and 20% aqueous ammonium acetate solution (100 mL) were added to the residue, heated for 30 min and stirred under reflux. After completion of the reaction, the reaction solution was cooled, and ethyl acetate was added thereto. The mixture was washed with aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound.
  • Example 2 DSC was conducted using Mettler Toledo’s DSC821 e .
  • 3 mg of the crystalline form of Compound (1) obtained in Example 1 was charged into the aluminum pan, and the weight thereof was accurately recorded.
  • the pan was covered with a lid through which a hole was punched and made into the shape.
  • the pan was mounted on the equipment and heated from 25 to 300°C at the rate of 10°C/min under nitrogen purge. Indium metal was used as the standard for calibration.
  • Figure 2 the crystalline form of Compound (1) of the present invention represents the endothermic peak due to the melting point of 263 ⁇ 268°C as the onset value, from which it can be seen that the crystalline form of the present invention has a high melting point and is stable against heat.
  • TGA was conducted using Mettler Toledo’s TGA850. 5 mg of the crystalline form of Compound (1) obtained in Example 1 was charged into the aluminum pan. The pan was mounted on the equipment and then heated from 25 to 300°C at the rate of 10°C/min under nitrogen purge. Nickel and AluminumTM were used as the standard for calibration. The result thus obtained is represented in Figure 3. As is confirmed from Figure 3, the crystalline form of Compound (1) of the present invention shows no weight loss in the endothermic section of the DSC, from which it can be seen that the crystalline form of the present invention is stable against heat.
  • the moisture adsorption/desorption data were collected for the crystalline form of Compound (1) obtained in Example 1 on VTI-SA Vapor Sorption Analyzer. The sample was not dried prior to the analysis. While maintaining a temperature of 25°C, the moisture adsorption and desorption were performed at intervals of 5% RH in the range of relative humidity (RH) 5 ⁇ 95%.
  • RH relative humidity
  • the result is represented in Figure 4.
  • the crystalline form of Compound (1) of the present invention shows a weight change of only 0.3% or less according to the change of external humidity in the range of 5 ⁇ 95% RH. That is, the crystalline form of the present invention is very stable against any change of relative humidity, and there is no change in the crystalline form according to the change of humidity.
  • the conditions for HPLC analysis are as follows:
  • the crystalline form of Compound (1) of the present invention was administered to a male mouse (BALB/c) in a dose of 100 or 300 mg/kg. After 24 h, the blood was collected and plasma was separated. The concentrations of orotic acid (OA) and orotidine (OD) in the plasma were analyzed quantitatively using LC-MS/MS. The results are represented in the following Table 9.
  • the present test seeks to confirm whether the crystalline form of Compound (1) has the selectivity for the main enzymes in the pyrimidine metabolism-i.e., orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC). In the present in vivo test, the OA and OD in blood did not increase (see Table 9 below). From this result, it was estimated that the crystalline form of Compound (1) selectively combines with xanthine oxidase.
  • OPRT orotate phosphoribosyl transferase
  • OPDC oro
  • the crystalline form of Compound (1) was intravenously and orally administered in a single dose to rats, monkeys and dogs.
  • the blood was collected, and the concentration of the crystalline form of Compound (1) in the plasma was quantitatively analyzed by LC-MS/MS.
  • the pharmacokinetic parameters (C max , AUC inf , CL, Vd ss , t 1.2 ) in each administration route were obtained, from which the bioavailability as the percentage of AUC in the oral administration to AUC in the intravenous administration was calculated.
  • the bioavailabilities in rats, monkeys and dogs were evaluated to 37 ⁇ 61%, 23 ⁇ 39% and 75%, respectively.

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Abstract

La présente invention concerne une forme cristalline du composé de formule (1) et son procédé de préparation.
PCT/KR2012/002575 2011-04-06 2012-04-05 Forme cristalline de l'acide 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylique et son procédé de préparation Ceased WO2012138147A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201280016696.6A CN103459381B (zh) 2011-04-06 2012-04-05 1-(3-氰基-1-异丙基-吲哚-5-基)吡唑-4-甲酸晶型及其生产方法
JP2014503602A JP6008937B2 (ja) 2011-04-06 2012-04-05 １−（３−シアノ−１−イソプロピル−インドール−５−イル）ピラゾール−４−カルボン酸の結晶形とその製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20110031490 2011-04-06
KR10-2011-0031490 2011-04-06

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WO2012138147A2 true WO2012138147A2 (fr) 2012-10-11
WO2012138147A3 WO2012138147A3 (fr) 2012-11-29

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US20240000750A1 (en) * 2020-11-04 2024-01-04 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
EP4257123A4 (fr) * 2020-12-01 2024-05-08 Lg Chem, Ltd. Formulation orale stable contenant de l'acide 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylique
EP4257124A4 (fr) * 2020-12-01 2024-05-29 Lg Chem, Ltd. Formulation orale comprenant de l'acide 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylique et son procédé de préparation
EP4324459A4 (fr) * 2021-04-16 2024-08-07 Lg Chem, Ltd. Formulation orale contenant de l'acide 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylique
EP4342894A4 (fr) * 2021-07-02 2024-08-21 Lg Chem, Ltd. Procédé de préparation d'un inhibiteur de xanthine oxydase
EP4342458A4 (fr) * 2021-06-17 2025-06-04 Lg Chem, Ltd. Formulation orale contenant de l'acide 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylique

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CN106008488B (zh) * 2016-05-20 2018-10-30 广东东阳光药业有限公司 氰基吲哚类衍生物及其制备方法和用途
CN106045898B (zh) * 2016-06-28 2019-05-24 广东东阳光药业有限公司 一种吲哚类化合物及其制备方法和用途
BR112019008388A2 (pt) * 2016-11-28 2019-07-09 Teijin Pharma Ltd fármaco terapêutico ou fármaco profilático para nefropatia diabética.
WO2022231263A1 (fr) * 2021-04-27 2022-11-03 주식회사 엘지화학 Procédé de préparation d'un intermédiaire pour la synthèse d'un inhibiteur de la xanthine oxydase
KR20220147531A (ko) * 2021-04-27 2022-11-03 주식회사 엘지화학 잔틴 옥시다아제 저해제의 제조 방법
WO2022233264A1 (fr) * 2021-05-07 2022-11-10 江苏新元素医药科技有限公司 Classe d'inhibiteurs de xanthine oxydase
BR112023026415A2 (pt) 2021-06-15 2024-03-05 Lg Chemical Ltd Composição farmacêutica que compreende ácido 1-(3-ciano-1-isopropil-indol-5-il)pirazol-4-carboxílico
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TW201245182A (en) 2012-11-16
JP2014510133A (ja) 2014-04-24
CN103459381B (zh) 2015-12-09
KR101424013B1 (ko) 2014-08-18
JP6008937B2 (ja) 2016-10-19
KR20120114174A (ko) 2012-10-16

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