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WO2021036495A1 - Nouveau dérivé d'acide phénylacétique, son procédé de préparation et son utilisation comme médicament - Google Patents

Nouveau dérivé d'acide phénylacétique, son procédé de préparation et son utilisation comme médicament Download PDF

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Publication number
WO2021036495A1
WO2021036495A1 PCT/CN2020/099650 CN2020099650W WO2021036495A1 WO 2021036495 A1 WO2021036495 A1 WO 2021036495A1 CN 2020099650 W CN2020099650 W CN 2020099650W WO 2021036495 A1 WO2021036495 A1 WO 2021036495A1
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Prior art keywords
fibrosis
compound
organs
pharmaceutically acceptable
acceptable salt
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PCT/CN2020/099650
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English (en)
Chinese (zh)
Inventor
李政
张陆勇
刘冰
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Guangdong Pharmaceutical University
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Guangdong Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • 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
    • 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
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to a deuterated 3-pentylphenylacetic acid derivative, a preparation method and application thereof, and belongs to the technical field of medicine.
  • the structure of the deuterated derivative involved in the present invention is unique and novel in this field.
  • Organ fibrosis refers to the accumulation of infection, inflammation, fat and other substances in the living body caused by various reasons such as microorganisms, chemical substances, immune responses, eating habits, environment, genetic background and other reasons (including unknown causes). After the degeneration of tissues or cells causes organ damage, necrosis, etc., it cannot fully regenerate, and connective tissue proliferation and fibrosis occur. It is known to occur in various organs such as the liver, lungs, heart, kidney, cranial nervous system, and many organs and tissues such as muscles, bones, and skin. Liver cirrhosis is a typical pathological state of fibrosis in the liver.
  • liver function is significantly reduced.
  • liver cirrhosis in addition to fibrosis caused by lung injury accompanied by pneumonia such as interstitial pneumonia, there is also idiopathic pulmonary fibrosis of unknown cause.
  • Myocardial fibrosis is a disease in which the tissues of the myocardium and heart valves become fibrotic.
  • the primary disease is cardiomyopathy and valvular disease caused by coronary circulatory failure, infection or immune response, etc., and can progress to a state of heart failure.
  • fibrosis is caused in the kidney tissue along with the development of chronic kidney disease, it will cause the kidney function to deteriorate rapidly and reach an irreversible state.
  • organ fibrosis is a serious disease that causes irreversible deterioration of the function of the organ and tissue and has a very poor prognosis.
  • liver transplantation is the only effective treatment method for liver cirrhosis, but liver transplantation has many problems such as insufficient organ donors, high medical costs, and health risks to the donor in the case of living donor liver transplantation. Therefore, the development of drugs for organ fibrosis has become a research hotspot in this field, in order to bring more economical, safe and effective new drugs to patients with organ fibrosis.
  • Pirfenidone has anti-inflammatory, anti-fibrotic and antioxidant properties, and can significantly delay the rate of forced expiratory vital capacity (FVC) decline. It was approved for the treatment of idiopathic pulmonary fibrosis (IPF) in 2008 and is recommended for light It is not clear whether IPF patients with moderate pulmonary dysfunction and severe pulmonary dysfunction can benefit. Nintanib is a VEGFR/FGFR/PDGFR inhibitor, which can significantly reduce the absolute value of FVC decline in patients with IPF and relieve the disease process to a certain extent. It was approved for IPF in the United States and the European Union in 2014 and 2015, respectively. Like pirfenidone, this product is recommended for patients with mild and moderate pulmonary dysfunction. Whether severe patients can benefit or not requires further research.
  • FVC forced expiratory vital capacity
  • the present invention uses a deuteration strategy to block the potential metabolic sites of PBI-4050, which has better drug metabolism properties and anti-organ fibrosis effects in vivo. Therefore, the deuterated PBI-4050 and its pharmaceutically acceptable salts can be potentially used to treat or prevent organ fibrosis-related diseases, and have broad development prospects.
  • the purpose of the present invention is to provide deuterated PBI-4050 derivatives and their medical applications, and provide a solution for the prevention or/and treatment of organ fibrosis-related diseases. Class of new potential drugs.
  • the deuterated PBI-4050 derivative of the present invention contains an effective amount of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 and R 3 are each independently selected from hydrogen and deuterium, and at least one of the R 1 , R 2 and R 3 groups is a deuterium atom;
  • More preferred compounds of the invention include, but are not limited to:
  • the pharmaceutically acceptable salt involved in the present invention is a sodium salt, a potassium salt or a lithium salt.
  • Another aspect of the present invention relates to a pharmaceutical composition, which contains a therapeutically effective dose of the compound or a pharmaceutically acceptable salt thereof and a suitable carrier, diluent or excipient.
  • the present invention also relates to the use of the compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a medicament for the prevention or/and treatment of organ fibrotic diseases, wherein the organ fibrosis occurs in the digestive organs, respiratory organs, Fibrosis of circulatory organs, genitourinary organs, motor organs, cranial nervous system, endocrine organs, or skin; including prevention or/and treatment of fatty liver, liver fibrosis, pulmonary fibrosis, kidney fibrosis, heart fibrosis, Syndrome and other organ fibrosis-related diseases in medicine for at least one disease.
  • the present invention can be measured by using the test system described below.
  • test examples of the present invention are usually in accordance with the conventional conditions or in accordance with the conditions recommended by the commercial manufacturer.
  • the reagents without specific sources are commonly used reagents purchased on the market.
  • Test Example 2 The in vivo anti-hepatic fibrosis effect of the compound of the present invention can be measured by using the following measurement system:
  • mice were sacrificed on the 61st day, serum was collected, and serum AST and ALT levels were determined by an automatic biochemical analyzer; the liver was removed, and the content of hydroxyproline in the liver was determined by alkaline hydrolysis, and the liver fibrosis of mice was observed by Masson staining status.
  • AST, ALT and hydroxyproline levels are shown in Table 2. See Figure 1 for the results of Masson staining.
  • Test Example 3 The in vivo anti-kidney fibrosis effect of the compound of the present invention can be measured by using the measurement system described below:
  • **P ⁇ 0.01 is the result of Student’s t test relative to the blank control group.
  • test compound can significantly improve the renal function indicators of the renal fibrosis model.
  • Masson staining (figure 2) shows that the model control group has dilated renal tubules, thickened glomerular basement membrane, and increased fibrous proliferation. Renal fibrosis of the group was significantly improved, and the compound of the present invention showed a better anti-renal fibrosis effect.
  • Figure 1 Masson staining results of liver fibrosis model induced by CCl 4
  • Figure 2 Masson staining results of adenine-induced renal fibrosis model kidney
  • Step 1 In the sealed tube, add Pd(PPh 3 ) 2 Cl 2 (0.6g, 0.78mmol), 1-pentyne (5.4g, 78.6mmol), and (3-bromophenyl) methyl acetate (6g , 26.2mmol) and tetrabutylammonium fluoride hydrate (20.6g, 78.6mmol), mixed well and heated at 80°C for 3h. The mixture was added with 50 mL of water, and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was evaporated under reduced pressure.
  • Step 2 Mix 10% Pd/C (0.36g) with D 2 O (30 mL), after replacing hydrogen, react at room temperature for 24 hours, add (3-(pentyn-1-yl)phenyl)acetate to the reaction flask Ester (3.6g) in methanol dilution, continue to react at room temperature for 6h, the reaction solution was filtered with diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was collected, 20mL of water was added, ethyl acetate extracted, and the organic phases were combined with anhydrous sodium sulfate Dry, filter, and evaporate the organic solvent under reduced pressure.
  • Step 3 Dissolve methyl 2-(3-(pentyl-1,1,2,2-D 4 )phenyl)acetate (3.2g, 14.3mmol) in a mixture of THF/CH 3 OH/H 2 O LiOH (1.7g, 71.4mmol) was added to the solvent. After the addition, the reaction was carried out at room temperature for 5h. The solvent was evaporated under reduced pressure, acidified with 1N HCl, and extracted with ethyl acetate. The combined organic phases were dried with anhydrous sodium sulfate, filtered, and reduced under reduced pressure. The organic solvent is evaporated.
  • the active ingredients, pregelatinized starch and microcrystalline cellulose are sieved, mixed thoroughly, added to the polyvinylpyrrolidone solution, mixed, soft materials are made, sieved, wet granules are made, dried at 50-60°C, and the carboxymethyl starch
  • the sodium salt, magnesium stearate and talc are sieved and added to the above granules to form a tablet.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un nouveau dérivé d'acide 3-pentylphénylacétique deutéré représenté par la formule générale (I), un procédé de préparation de celui-ci, et une utilisation d'une composition pharmaceutique contenant le dérivé dans la préparation d'un médicament pour prévenir et/ou traiter des maladies associées à une fibrose d'organe. Le composé selon la présente invention a d'excellentes propriétés de métabolisme médicamenteux et un effet anti-fibrose d'organe in vivo, et peut être utilisé dans la préparation de médicaments pour la prévention et/ou le traitement de la stéatose hépatique, la fibrose hépatique, la fibrose rénale, la fibrose cardiaque, le syndrome d'Alström et d'autres maladies associées à la fibrose d'organe, et a une large perspective d'application.
PCT/CN2020/099650 2019-08-29 2020-07-01 Nouveau dérivé d'acide phénylacétique, son procédé de préparation et son utilisation comme médicament Ceased WO2021036495A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910811324.6 2019-08-29
CN201910811324.6A CN112441916A (zh) 2019-08-29 2019-08-29 新型苯乙酸衍生物、其制备方法及其作为药物的用途

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102421742A (zh) * 2009-05-04 2012-04-18 普罗米蒂克生物科学公司 3-戊基苯乙酸的盐及其药物用途
WO2012097428A1 (fr) * 2010-10-27 2012-07-26 Prometic Biosciences Inc. Composés et compositions pharmaceutiques pour utilisation dans le diabète
CN105143170A (zh) * 2013-03-15 2015-12-09 普罗米蒂克生物科学公司 用于治疗肺纤维化、肝纤维化、皮肤纤维化和心脏纤维化的经取代的芳族化合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4385571A3 (fr) * 2016-09-07 2024-08-28 Pharmakea, Inc. Utilisations d'un inhibiteur de lysyl oxydase de type 2
CN110177549A (zh) * 2016-11-23 2019-08-27 坎莫森特里克斯公司 治疗局灶性节段性肾小球硬化的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102421742A (zh) * 2009-05-04 2012-04-18 普罗米蒂克生物科学公司 3-戊基苯乙酸的盐及其药物用途
WO2012097428A1 (fr) * 2010-10-27 2012-07-26 Prometic Biosciences Inc. Composés et compositions pharmaceutiques pour utilisation dans le diabète
CN105143170A (zh) * 2013-03-15 2015-12-09 普罗米蒂克生物科学公司 用于治疗肺纤维化、肝纤维化、皮肤纤维化和心脏纤维化的经取代的芳族化合物

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