WO2018202039A1 - Composé hétérocyclique et son procédé de préparation - Google Patents

Composé hétérocyclique et son procédé de préparation Download PDF

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Publication number
WO2018202039A1
WO2018202039A1 PCT/CN2018/085330 CN2018085330W WO2018202039A1 WO 2018202039 A1 WO2018202039 A1 WO 2018202039A1 CN 2018085330 W CN2018085330 W CN 2018085330W WO 2018202039 A1 WO2018202039 A1 WO 2018202039A1
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WO
WIPO (PCT)
Prior art keywords
group
product
hydrogen
alkyl
pharmaceutically acceptable
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Application number
PCT/CN2018/085330
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English (en)
Chinese (zh)
Inventor
樊磊
杜武
胥珂馨
陈锞
王飞
吴孝全
罗童川
张少华
李兴海
陈元伟
Original Assignee
成都海创药业有限公司
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Publication of WO2018202039A1 publication Critical patent/WO2018202039A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the urate transporter 1 (URAT1) is located on the brush border of the epithelial cells of the proximal convoluted tubules of the kidney. It is an important uric acid transporter found in the kidney in recent years and is responsible for the reabsorption of uric acid in the kidney. It has been proven that inhibition of URAT1 inhibits the reabsorption of uric acid in the kidney and increases the excretion of uric acid in the urine, thereby achieving the goal of lowering blood uric acid and controlling the onset of gout.
  • R 1 is selected from the group consisting of alkyl, halogen, and hydrogen
  • the R 3 and R 4 are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group, or a combination of R 3 and R 4 is a cyclobutyl group.
  • the compound is any one of the following compounds 50-54:
  • the present invention also provides a process for the preparation of the aforementioned compound, characterized in that it comprises the steps carried out according to the following route:
  • the starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int5, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromobutyrate, and the same preparation method as the product 1 was used.
  • the product 80 (2-(2,3-dibromo-thiophene[3,2-b]pyridin-7-mercapto)-butyric acid) was obtained: mass spectrum: 410.0, 412.0, 414.0 (M+H + ).
  • R 2 is selected from the group consisting of a hydrogen atom, a bromine atom, a methyl group, a pyridine, a 3-chloropyridine, and a p-cyanophenyl group.
  • R 4 and R 5 are combined in a cyclobutyl or cyclopentyl group.

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)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne un composé tel que représenté par la formule (A), ou un stéréoisomère de celui-ci, ou son sel pharmaceutiquement acceptable, ou un solvate dudit composé. Le nouveau composé représenté par la formule (A) de la présente invention a de bonnes activités inhibitrices de l'URAT1, fournissant ainsi une nouvelle possibilité médicinale pour le traitement clinique de maladies associées à des activités anormales d'URAT1.
PCT/CN2018/085330 2017-05-03 2018-05-02 Composé hétérocyclique et son procédé de préparation WO2018202039A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710305385 2017-05-03
CN201710305385.6 2017-05-03

Publications (1)

Publication Number Publication Date
WO2018202039A1 true WO2018202039A1 (fr) 2018-11-08

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Application Number Title Priority Date Filing Date
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Country Status (2)

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CN (1) CN108659000B (fr)
WO (1) WO2018202039A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109608432B (zh) * 2018-12-17 2022-10-11 江苏艾立康医药科技有限公司 作为urat1抑制剂的噻吩类衍生物
CN111943957B (zh) * 2019-05-17 2023-01-06 中国医学科学院药物研究所 喹啉甲酰胺类化合物及其制备方法和用途
CN111303161B (zh) * 2020-04-14 2021-01-05 遵义医科大学珠海校区 嘧啶并氮杂环类化合物及其用途
CN114315715B (zh) * 2020-09-29 2024-02-20 杭州中美华东制药有限公司 一类urat1抑制剂及其制备方法与应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1047292A (zh) * 1989-05-16 1990-11-28 默里尔多药物公司 兴奋性氨基酸拮抗剂
WO2004074284A1 (fr) * 2003-02-21 2004-09-02 Pfizer Inc. Derives d'oxazole utilises en tant qu'agonistes de ppar
CN103068801A (zh) * 2010-06-16 2013-04-24 亚德生化公司 硫代乙酸盐化合物、组合物及其使用方法
WO2017121308A1 (fr) * 2016-01-11 2017-07-20 Chongqing Fochon Pharmaceutical Co., Ltd. Composés de pyrimidine fusionnés, compositions et procédés d'utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1047292A (zh) * 1989-05-16 1990-11-28 默里尔多药物公司 兴奋性氨基酸拮抗剂
WO2004074284A1 (fr) * 2003-02-21 2004-09-02 Pfizer Inc. Derives d'oxazole utilises en tant qu'agonistes de ppar
CN103068801A (zh) * 2010-06-16 2013-04-24 亚德生化公司 硫代乙酸盐化合物、组合物及其使用方法
WO2017121308A1 (fr) * 2016-01-11 2017-07-20 Chongqing Fochon Pharmaceutical Co., Ltd. Composés de pyrimidine fusionnés, compositions et procédés d'utilisation

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CN108659000A (zh) 2018-10-16
CN108659000B (zh) 2020-03-31

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