WO2020114290A1 - Dérivé de coumarine 3-carboxyle pouvant être utilisé en tant qu'agoniste de gpr35, procédé de préparation et utilisation - Google Patents

Dérivé de coumarine 3-carboxyle pouvant être utilisé en tant qu'agoniste de gpr35, procédé de préparation et utilisation Download PDF

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WO2020114290A1
WO2020114290A1 PCT/CN2019/121274 CN2019121274W WO2020114290A1 WO 2020114290 A1 WO2020114290 A1 WO 2020114290A1 CN 2019121274 W CN2019121274 W CN 2019121274W WO 2020114290 A1 WO2020114290 A1 WO 2020114290A1
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oxo
solution
chromene
carboxylic acid
add
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PCT/CN2019/121274
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English (en)
Chinese (zh)
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梁鑫淼
魏来
张秀莉
曲腊腊
赵耀鹏
王志伟
王纪霞
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泰州医药城国科化物生物医药科技有限公司
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Publication of WO2020114290A1 publication Critical patent/WO2020114290A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C409/00—Peroxy compounds
    • C07C409/02—Peroxy compounds the —O—O— group being bound between a carbon atom, not further substituted by oxygen atoms, and hydrogen, i.e. hydroperoxides
    • C07C409/04—Peroxy compounds the —O—O— group being bound between a carbon atom, not further substituted by oxygen atoms, and hydrogen, i.e. hydroperoxides the carbon atom being acyclic
    • C07C409/08—Compounds containing six-membered aromatic rings
    • C07C409/12—Compounds containing six-membered aromatic rings with two alpha,alpha-dialkylmethyl hydroperoxy groups bound to carbon atoms of the same six-membered aromatic ring
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Coumarins are a class of lactones that are widely present in natural inoculations, and are most common in rutaceae and umbelliferous plants. Among them, the anticoagulant drug dicoumarin has been shown to be a GPR35 receptor agonist. Agent.
  • the first object of the present invention is to provide a 3-carboxycoumarin derivative that can be used as a GPR35 agonist, including its pharmaceutically acceptable salts, solvates, hydrates or crystal forms, and its structure
  • the general formula is as follows:
  • R 1 and R 2 in the structure are each hydrogen or a halogen atom
  • R 3 is a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic aryl group.
  • R 3 is cyclohexyl
  • step b 6,7-dichlorobromo-8-hydroxy-2-oxo-2H-chromene-3-carboxylic acid is selected as the raw material in step b), and step 4 is selected from c) -Nitrobenzoyl chloride reaction, the product is a light yellow solid with a yield of 61%.
  • the inoculation volume of each well is 40 ⁇ L, and the number of cells in each well is 3.2 ⁇ 104.
  • the plate was placed in a cell culture incubator for 20-22h until the cell fusion reached 95%.
  • C1-10 alkyl means a linear or branched alkyl-C1-10 having 1 to 10 carbon atoms.
  • the compound 17 with the best activity was selected for pharmacological activity studies on a mouse model of inflammatory bowel disease.
  • the results are shown in FIG. 4.
  • the test results show that, after 7 consecutive days of administration, the dosage is 1 mg/Kg, compound 17 can increase the length of the colon, relieve spleen, and can increase body weight, which is basically equivalent to the positive control drug dexamethasone (DEX) .
  • DEX positive control drug dexamethasone

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal 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)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de coumarine 3-carboxyle pouvant être utilisé en tant qu'agoniste de GPR35, un procédé de préparation et une utilisation. Le composé selon la présente invention a généralement une activité agoniste vis-à-vis de GPR35 humain et est un agoniste spécifique d'un récepteur GPR35. Le composé selon la présente invention est un ligand actif du récepteur GPR35, et le composé et des sels pharmaceutiquement acceptables, un solvate, un hydrate ou une forme cristalline présentent généralement une activité agoniste élevée contre le récepteur GPR35 humain. Le composé selon la présente invention est un agoniste spécifique de GPR35, peut être utilisé pour traiter, prévenir et inhiber des maladies à médiation par le récepteur GPR35, et présente certaines perspectives dans le développement de médicament.
PCT/CN2019/121274 2018-12-06 2019-11-27 Dérivé de coumarine 3-carboxyle pouvant être utilisé en tant qu'agoniste de gpr35, procédé de préparation et utilisation WO2020114290A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811491406.9A CN111285790A (zh) 2018-12-06 2018-12-06 一种可作为gpr35激动剂的3-羧基香豆素衍生物、制备方法及应用
CN201811491406.9 2018-12-06

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WO2020114290A1 true WO2020114290A1 (fr) 2020-06-11

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PCT/CN2019/121274 WO2020114290A1 (fr) 2018-12-06 2019-11-27 Dérivé de coumarine 3-carboxyle pouvant être utilisé en tant qu'agoniste de gpr35, procédé de préparation et utilisation

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4303664A (en) * 1978-02-27 1981-12-01 Teijin Limited Novel penicillin derivatives containing a coumarin nucleus and medicines containing the same

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013022740A2 (fr) * 2011-08-05 2013-02-14 Corning Incorporated Ligands de gpr35 et leurs utilisations
US20130316985A1 (en) * 2012-05-25 2013-11-28 Corning Incorporated GPR35 Ligands And Uses Thereof
CN108069929B (zh) * 2016-11-18 2021-06-15 中国科学院大连化学物理研究所 3-取代香豆素类衍生物及应用和gpr35受体的激动剂

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4303664A (en) * 1978-02-27 1981-12-01 Teijin Limited Novel penicillin derivatives containing a coumarin nucleus and medicines containing the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 12 July 2016, Columbus, Ohio, US; abstract no. 892286-88-3, ANONYMOUS: "2H-1-Benzopyran-3-carboxylic acid, 2-oxo-8-(1-oxopropoxy)- (CA INDEX NAME)" XP055713351 *
JOEL ALVIM ET AL: "Preparation and Evaluation of a Coumarin Library towards the Inhibitory Activity of the Enzyme gGAPDH from Trypanosoma Cruzi", JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY, vol. 16, no. 4, 1 January 2005 (2005-01-01), pages 763 - 773, XP055713344, ISSN: 0103-5053, DOI: 10.1590/S0103-50532005000500014 *

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