WO2016184122A1 - Composés pyrazoles - Google Patents

Composés pyrazoles Download PDF

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Publication number
WO2016184122A1
WO2016184122A1 PCT/CN2016/000143 CN2016000143W WO2016184122A1 WO 2016184122 A1 WO2016184122 A1 WO 2016184122A1 CN 2016000143 W CN2016000143 W CN 2016000143W WO 2016184122 A1 WO2016184122 A1 WO 2016184122A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
reaction
tumor
compounds
Prior art date
Application number
PCT/CN2016/000143
Other languages
English (en)
Chinese (zh)
Inventor
陈秀兰
Original Assignee
广州诺威生物技术有限公司
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 广州诺威生物技术有限公司 filed Critical 广州诺威生物技术有限公司
Publication of WO2016184122A1 publication Critical patent/WO2016184122A1/fr

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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
    • A61K31/33—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to an imidazole compound.
  • Non-steroidal anti-inflammatory drugs show their unique anti-inflammatory, antipyretic and analgesic effects by inhibiting the synthesis of prostaglandins.
  • NSAI non-steroidal anti-inflammatory drugs
  • the clinically widely used are aspirin, ibuprofen, ketoprofen, and flurbiol.
  • compound Z is a prodrug of celecoxib having the following structural formula:
  • Compound Z has better pharmacokinetic parameters than celecoxib in the published literature.
  • Tumors are serious diseases that endanger human health.
  • the prevention and treatment of cancer has always been the focus of medical research.
  • Radiotherapy and chemotherapy are the main means of treating tumors.
  • chemotherapy and radiotherapy inhibit the development of cancer cells while inhibiting the development of normal cells, reducing the body's immunity and leading to new complications.
  • the specific drugs for treating tumor diseases are not satisfactory.
  • the cytotoxic drugs used in clinical practice are not highly selective, resulting in malignant killing of normal cells, which limits their application. Therefore, the search for new, non-invasive, non-cytotoxic anti-tumor drugs has become an important direction in the international medical field.
  • the above compounds 1a, 1b, 1c, compound Z, and celecoxib were compared for the antitumor test, and it was found that the inhibitory effect on the melanoma B16, 1c (formula I), was significantly greater than that of the other compounds.
  • the above compounds 1a, 1b, 1c, compound Z, and celecoxib were tested for pharmacokinetics. It was found that the compounds of 1a, 1b, 1c, and Z were metabolized to different degrees in the blood after being administered by beagle dogs to celecoxib. Among them, 1c has the best pharmacokinetic characteristics, and the AUC value observed in the beagle dogs after gavage is significantly greater than other compounds.
  • B16 melanoma was subcultured in subcutaneously in C57BL/6 mice.
  • B16 melanoma-bearing mice preserved under the armpits with good tumor growth, no necrosis or liquefaction were selected, and the mice were sacrificed by cervical dislocation.
  • the tumor tissues were aseptically added and added 5 times volume (W/V).
  • the physiological saline for injection was ground into a homogenate by a tissue homogenizer, and the tumor cell suspension was filtered through a sterile 200-mesh stainless steel mesh.
  • the C57BL/6 mice were inoculated subcutaneously and routinely reared.
  • mice 70 tumor-bearing mice were randomly divided into 5 groups according to their body weight, 10 in each group, which were model group, cyclophosphamide group, 1a group, 1b group, 1c group, compound Z group, and Sailai.
  • the dose was 60 mg/kg, and the solution was prepared into a 3 mg/ml solution using physiological saline.
  • Each group of mice was administered at the dose and mode shown in Table 3.
  • the cyclophosphamide group was given intraperitoneal administration of cyclophosphamide only once on the second day of tumor-bearing, and each group in the experimental group was administered once per day for 10 consecutive times. day.
  • the administration volume was 20 ml/kg body weight. 24 hours after the last administration, the mice were sacrificed by cervical dislocation, the body weight was weighed, the tumor tissue was removed, and the tumor inhibition rate was calculated.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé (tel que représenté dans la formule I) et des sels de celui-ci, qui se sont avérés posséder de meilleures paramètres pharmacocinétiques et une activité anti-tumorale par des expériences, étant ainsi capable d'inhibition de la croissance de cellules tumorales. Par conséquent, le nouveau composé et les sels de celui-ci sont utilisés pour préparer des médicaments antinéoplasiques.
PCT/CN2016/000143 2015-05-19 2016-03-18 Composés pyrazoles WO2016184122A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510259338.3A CN104892514A (zh) 2015-05-19 2015-05-19 一种咪唑类新化合物
CN201510259338.3 2015-05-19

Publications (1)

Publication Number Publication Date
WO2016184122A1 true WO2016184122A1 (fr) 2016-11-24

Family

ID=54025531

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/000143 WO2016184122A1 (fr) 2015-05-19 2016-03-18 Composés pyrazoles

Country Status (2)

Country Link
CN (2) CN104892514A (fr)
WO (1) WO2016184122A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892514A (zh) * 2015-05-19 2015-09-09 广州诺威生物技术有限公司 一种咪唑类新化合物
CN106279353A (zh) * 2016-03-18 2017-01-04 广州诺威生物技术有限公司 一种用于抗炎的化合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064669A1 (fr) * 2000-03-03 2001-09-07 Pfizer Products Inc. Derives d'ether de pyrazole utilises comme agents anti-inflammatoires/analgesiques
WO2004037798A1 (fr) * 2002-10-22 2004-05-06 Merck Frosst Canada & Co. Inhibiteurs selectifs de la cyclo-oxygenase-2 liberant de l'oxyde nitrique
CN1516581A (zh) * 2001-04-17 2004-07-28 含具有氨基磺酰基的活性化合物(cox-2抑制剂)、聚乙二醇和清除游离基的抗氧化物的口服传递的药用组合物
CN104892514A (zh) * 2015-05-19 2015-09-09 广州诺威生物技术有限公司 一种咪唑类新化合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040092566A1 (en) * 2002-11-12 2004-05-13 Graneto Matthew J. Celecoxib prodrug
AU2011270701B2 (en) * 2010-06-24 2015-05-14 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064669A1 (fr) * 2000-03-03 2001-09-07 Pfizer Products Inc. Derives d'ether de pyrazole utilises comme agents anti-inflammatoires/analgesiques
CN1516581A (zh) * 2001-04-17 2004-07-28 含具有氨基磺酰基的活性化合物(cox-2抑制剂)、聚乙二醇和清除游离基的抗氧化物的口服传递的药用组合物
WO2004037798A1 (fr) * 2002-10-22 2004-05-06 Merck Frosst Canada & Co. Inhibiteurs selectifs de la cyclo-oxygenase-2 liberant de l'oxyde nitrique
CN104892514A (zh) * 2015-05-19 2015-09-09 广州诺威生物技术有限公司 一种咪唑类新化合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MAMIDI, R.N.V.S. ET AL.: "Pharmacological and Pharmacokinetic Evaluation of Celecoxib Prodrugs in Rats", BIOPHARMACEUTICS & DRUG DISPOSITION, vol. 23, no. 7, 31 October 2002 (2002-10-31), pages 273 - 282, XP008028873, ISSN: 1099-081X *
QANDIL, A.M. ET AL.: "Chemical and in Vitro Enzymatic Stability of Newly Synthesized Celecoxib Lipophilic and Hydrophilic Amides", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 416, no. 1, 15 June 2011 (2011-06-15), pages 85 - 96, XP028264514, ISSN: 0378-5173 *

Also Published As

Publication number Publication date
CN104892514A (zh) 2015-09-09
CN105646354A (zh) 2016-06-08
CN105646354B (zh) 2018-04-10

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