[go: up one dir, main page]

WO2025140390A1 - Utilisation d'un inhibiteur de rasp dans la préparation d'un médicament pour le traitement ou la prévention de la toux chronique, de l'asthme et d'une hépatopathie alcoolique - Google Patents

Utilisation d'un inhibiteur de rasp dans la préparation d'un médicament pour le traitement ou la prévention de la toux chronique, de l'asthme et d'une hépatopathie alcoolique Download PDF

Info

Publication number
WO2025140390A1
WO2025140390A1 PCT/CN2024/142677 CN2024142677W WO2025140390A1 WO 2025140390 A1 WO2025140390 A1 WO 2025140390A1 CN 2024142677 W CN2024142677 W CN 2024142677W WO 2025140390 A1 WO2025140390 A1 WO 2025140390A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
mice
group
model
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/CN2024/142677
Other languages
English (en)
Chinese (zh)
Inventor
于婷婷
陕宁丽
张可瑜韵
覃媛媛
王铭溯
梁宇翠
穆利伟
王德刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhuhai United Laboratories Co Ltd
Original Assignee
Zhuhai United Laboratories Co Ltd
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 Zhuhai United Laboratories Co Ltd filed Critical Zhuhai United Laboratories Co Ltd
Publication of WO2025140390A1 publication Critical patent/WO2025140390A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to the pharmaceutical field, and in particular to the use of a RASP inhibitor in the preparation of a medicine for treating or preventing chronic cough, asthma and alcoholic liver disease.
  • Chronic cough is divided into unexplained chronic cough and refractory chronic cough.
  • Cough is usually the only or main symptom, with a course of >8 weeks and no obvious abnormalities on chest X-ray (children with chronic cough have a course of >4 weeks).
  • Cough variant asthma, upper airway cough syndrome, eosinophilic bronchitis, allergic cough and gastroesophageal reflux cough account for 70% to 95% of the causes of chronic cough.
  • An important pathophysiological feature of chronic cough is high cough sensitivity, which is related to the dysregulation of channels and receptors in peripheral nerves, central nerves and other neural regulation.
  • Various stimuli of the peripheral nerve potential activate cough receptor receptors and transmit signals on nerve fibers. Inflammatory mediators can sensitize cough receptors and increase their excitability, thereby lowering the cough threshold and increasing the peripheral impulse input to the cough center to induce cough.
  • the existing treatment methods for chronic cough are drug therapy and non-drug therapy.
  • Drug therapy includes central antitussive drugs, peripheral antitussive drugs and traditional Chinese medicine.
  • Non-drug treatment methods include speech pathology therapy and cough suppressant physiotherapy, which have shown certain effects in improving patients' cough-related quality of life and reducing cough sensitivity and cough frequency. Targeting different targets in the cough reflex process, some receptor antagonists have shown certain potential in clinical studies for the treatment of chronic cough.
  • drugs that can quickly relieve bronchospasm and thus relieve asthma symptoms including rapid-acting inhaled and short-acting oral beta2 receptor agonists, inhaled anticholinergics, short-acting theophylline and systemic hormones, etc.; there are additional therapeutic drugs for severe asthma: mainly biological targeted drugs, such as anti-IgE monoclonal antibodies, anti-IL-5 monoclonal antibodies, anti-IL-5 receptor monoclonal antibodies and anti-IL-4 receptor monoclonal antibodies, etc., and others include macrolide drugs, etc.
  • the above-mentioned inhaled and oral hormone drugs have many adverse reactions and are not suitable for long-term use.
  • Leukotriene modifiers can also cause adverse reactions such as psychiatric symptoms.
  • Theophylline drugs have large individual differences and are only additional maintenance treatment drugs.
  • Other drugs also have certain deficiencies in efficacy and safety. Therefore, there is a large unmet clinical need for asthma treatment drugs.
  • R 1 is selected from H, F, Cl, Br, I, OH or NH 2 ;
  • R 5, R 6 or R 7 are independently selected from H, F, Cl, Br or I;
  • n is selected from 1, 2 or 3;
  • R 2 is selected from H, CH 3 or CH 2 CH 3 , and other variables are as defined in the present invention.
  • L is selected from a single bond, -O-, -S-, -NH-, -(CH 2 ) 2 - or -CH 2 -, and other variables are as defined in the present invention.
  • the alcoholic liver disease includes alcoholic fatty liver, alcoholic hepatitis, alcoholic liver fibrosis or cirrhosis.
  • the application is the use of the compound of formula (II) or its pharmaceutically acceptable salt or crystal form in the preparation of a drug for treating alcoholic fatty liver.
  • the application is the use of the compound of formula (II) or its pharmaceutically acceptable salt or crystal form in the preparation of a drug for treating alcoholic liver fibrosis.
  • the application is the use of the compound of formula (II) or its pharmaceutically acceptable salt or crystal form in the preparation of a drug for treating liver cirrhosis.
  • the compound or its pharmaceutically acceptable salt or crystal form is selected from
  • T 3 and T 4 are independently selected from N or CR 1 ;
  • R1 and L are as defined herein.
  • the compound or its pharmaceutically acceptable salt or crystal form is selected from
  • R1 and L are as defined herein.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt or crystal form thereof, which is selected from:
  • the RASP inhibitor-related drug is a drug for chronic cough, asthma and alcoholic liver disease.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.
  • substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it.
  • pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • connection direction is arbitrary.
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.
  • the compound of the present invention has excellent aldehyde complexing ability, good water solubility, good permeability and excellent pharmacokinetic properties; through the efficacy test of the compound in citric acid-induced chronic cough of guinea pigs, the efficacy test in Gao-binge diet-induced mouse alcoholic hepatitis model and the efficacy test study on OVA-induced mouse asthma model, the effect of treating chronic cough, asthma and alcoholic liver disease is demonstrated.
  • Figure 3 The number of coughs in guinea pigs on day 12, * p ⁇ 0.05 vs Model, ** p ⁇ 0.01 vs Model, *** p ⁇ 0.001 vs Model;
  • Figure 4 The number of coughs in guinea pigs on day 15, * p ⁇ 0.05 vs Model, ** p ⁇ 0.01 vs Model, *** p ⁇ 0.001 vs Model;
  • Fig. 7 Serum alanine aminotransferase (ALT) levels in mice. * p ⁇ 0.05 vs Model, ## p ⁇ 0.01 vs Control;
  • Fig. 15 shows the number of basophils in BALF of mice on day 28, ** p ⁇ 0.01 vs Model.
  • Substrate 1-2 (200 mg, 605 ⁇ mol, 1 eq) was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (3 M, 4.04 mL, 20 eq) was slowly added dropwise at 0°C. The reaction was stirred at 0°C for 2 hours. Water (20 mL) was added to quench the reaction, and ethyl acetate (50 mL*3) was added for extraction. The organic phase was concentrated. The mixture was dissolved in dimethylformamide (DMF) and purified by HPLC (neutral). Compound 1 was obtained.
  • DMF dimethylformamide
  • the number of coughs in the model group guinea pigs was significantly increased ( *** p ⁇ 0.001; Figure 4; Table 10).
  • the number of coughs in the positive drug group guinea pigs was significantly reduced ( *** p ⁇ 0.001; Figure 4; Table 10).
  • the number of coughs in guinea pigs was significantly reduced when the compound of formula (III) to be tested was administered orally at a dose of 25 mg/kg, twice a day ( *** p ⁇ 0.001; Figure 4; Table 10).
  • the number of coughs in guinea pigs was significantly reduced when the compound of formula (III) to be tested was administered orally at a dose of 50 mg/kg, twice a day ( ** p ⁇ 0.01; Figure 4; Table 10).
  • the number of coughs was significantly reduced on the 12th and 15th days of the study when benproperine was administered orally at a dose of 10 mg/kg once a day, indicating that the positive drug benproperine can significantly inhibit cough.
  • the compound of formula (III) at a dose of 25 mg/kg, administered orally twice a day, significantly reduced the number of coughs of the model animals on the 12th day and at the end of the study.
  • the compound of formula (III) at a dose of 50 mg/kg, intragastrically administered twice a day showed a decreasing trend in the number of coughs in the model animals on the 12th day after modeling (the 4th day of administration), but there was no statistical difference.
  • the number of coughs in the model animals at the end of the study was significantly reduced.
  • the cough and wheeze indicators of behavioral detection include the cough and wheeze latency and the number of cough and wheeze; the morphological score includes the number of nose scratching and the degree of wheezing.
  • the BALF bronchoalveolar lavage fluid cell analysis includes the analysis of total cells, eosinophils, and basophils.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un inhibiteur de RASP dans le traitement de la toux chronique, de l'asthme et d'une hépatopathie alcoolique. L'inhibiteur de RASP contient un composé représenté par la formule (II) ou un sel ou une forme cristalline pharmaceutiquement acceptable de celui-ci. L'inhibiteur de RASP présente une bonne efficacité dans des tests de modèle animal de la toux chronique, de l'asthme, de l'hépatopathie alcoolique et d'autres maladies.
PCT/CN2024/142677 2023-12-28 2024-12-26 Utilisation d'un inhibiteur de rasp dans la préparation d'un médicament pour le traitement ou la prévention de la toux chronique, de l'asthme et d'une hépatopathie alcoolique Pending WO2025140390A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202311839375 2023-12-28
CN202311839375.2 2023-12-28

Publications (1)

Publication Number Publication Date
WO2025140390A1 true WO2025140390A1 (fr) 2025-07-03

Family

ID=96218318

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/142677 Pending WO2025140390A1 (fr) 2023-12-28 2024-12-26 Utilisation d'un inhibiteur de rasp dans la préparation d'un médicament pour le traitement ou la prévention de la toux chronique, de l'asthme et d'une hépatopathie alcoolique

Country Status (1)

Country Link
WO (1) WO2025140390A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109640983A (zh) * 2016-08-22 2019-04-16 奥尔德拉医疗公司 醛捕获化合物和其用途
WO2020125659A1 (fr) * 2018-12-18 2020-06-25 南京明德新药研发有限公司 Composé destiné à être utilisé dans des maladies rétiniennes
WO2021254456A1 (fr) * 2020-06-17 2021-12-23 南京明德新药研发有限公司 Forme cristalline de 2-méthyl-2-propanol et composé aryle amino-substitué
WO2022063325A1 (fr) * 2020-09-28 2022-03-31 南京明德新药研发有限公司 Forme cristalline de composé pyridinylphényle et son procédé de préparation
CN115551507A (zh) * 2020-04-13 2022-12-30 奥尔德拉医疗公司 用于治疗肺、肝脏和肾脏疾病、病症或病况的喹啉化合物
CN115697336A (zh) * 2020-05-13 2023-02-03 奥尔德拉医疗公司 药物制剂及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109640983A (zh) * 2016-08-22 2019-04-16 奥尔德拉医疗公司 醛捕获化合物和其用途
WO2020125659A1 (fr) * 2018-12-18 2020-06-25 南京明德新药研发有限公司 Composé destiné à être utilisé dans des maladies rétiniennes
CN115551507A (zh) * 2020-04-13 2022-12-30 奥尔德拉医疗公司 用于治疗肺、肝脏和肾脏疾病、病症或病况的喹啉化合物
CN115697336A (zh) * 2020-05-13 2023-02-03 奥尔德拉医疗公司 药物制剂及其用途
WO2021254456A1 (fr) * 2020-06-17 2021-12-23 南京明德新药研发有限公司 Forme cristalline de 2-méthyl-2-propanol et composé aryle amino-substitué
WO2022063325A1 (fr) * 2020-09-28 2022-03-31 南京明德新药研发有限公司 Forme cristalline de composé pyridinylphényle et son procédé de préparation

Similar Documents

Publication Publication Date Title
CN113227051B (zh) 用于视网膜疾病的化合物
CN115244056B (zh) 稠合咪唑类衍生物、其制备方法及其在医药上的应用
CN110944997B (zh) Fxr受体激动剂
TWI486343B (zh) Quaternary ammonium compounds
WO2021027911A1 (fr) Nouvel inhibiteur de k-ras g12c spirocyclique
CN114426568A (zh) 2-氧代-3-吡咯烷基丙腈类化合物及其药物组合物和用途
EP2257171B1 (fr) Pyridones fusionnés à tétrahydro-1h-pyrrolo
RU2617401C2 (ru) Производные 1-фенил 2-пиридинилалкиловых спиртов в качестве ингибиторов фосфодиэстеразы
WO2022121805A1 (fr) Composé à cycles fusionnés en tant qu'inhibiteur de nav1.8 et son utilisation
JPH09500904A (ja) ジアザビシクロニューロキニンアンタゴニスト
WO2020011254A1 (fr) Composé tri-cyclique condensé en tant que double inhibiteur de pde3/pde4
CN113880767B (zh) 一种免疫调节剂
JP6107650B2 (ja) テトラヒドロカルボリン誘導体
JP2005520797A (ja) プロスタグランジン受容体リガンドとしてのキノリノン
TW202024093A (zh) 作為抗病毒劑之官能化雜環
JP2011513222A (ja) テトラヒドロチエノピリジン
WO2004048326A1 (fr) Agent therapeutique pour maladies respiratoires contenant un derive de 4-hydroxypiperidine en tant qu'ingredient actif
WO2021244634A1 (fr) Composé imidazopyridine et son utilisation
JP3204456B2 (ja) ２，７―置換オクタヒドロ―ピロロ［１，２―ａ］ピラジン誘導体
CN107849009B (zh) 一种八氢环戊二烯并[c]吡咯衍生物及其制备方法和在医药上的用途
JP2011519934A (ja) スピロアザインドール
WO2025140390A1 (fr) Utilisation d'un inhibiteur de rasp dans la préparation d'un médicament pour le traitement ou la prévention de la toux chronique, de l'asthme et d'une hépatopathie alcoolique
WO2021238834A1 (fr) Composé arylformamide et son procédé de préparation et son utilisation médicale
TW200813040A (en) Xinafoate salt of a substituted 5-oxazol-2-yl-quinoline compound
JP2003146972A (ja) カルボスチリル誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24911312

Country of ref document: EP

Kind code of ref document: A1