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WO2017008757A1 - Composé 1-phényl-3-(4-phénylamino-6-quinazolinyl) urée, méthode de préparation et application de celui-ci - Google Patents

Composé 1-phényl-3-(4-phénylamino-6-quinazolinyl) urée, méthode de préparation et application de celui-ci Download PDF

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Publication number
WO2017008757A1
WO2017008757A1 PCT/CN2016/090098 CN2016090098W WO2017008757A1 WO 2017008757 A1 WO2017008757 A1 WO 2017008757A1 CN 2016090098 W CN2016090098 W CN 2016090098W WO 2017008757 A1 WO2017008757 A1 WO 2017008757A1
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WO
WIPO (PCT)
Prior art keywords
substituted
quinazolinyl
compound
urea
phenylamino
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Ceased
Application number
PCT/CN2016/090098
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English (en)
Chinese (zh)
Inventor
张三奇
曹永孝
左赛杰
张赛
吕社民
谢肖肖
辛敏行
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Xian Jiaotong University
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Xian Jiaotong University
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Publication date
Application filed by Xian Jiaotong University filed Critical Xian Jiaotong University
Publication of WO2017008757A1 publication Critical patent/WO2017008757A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the invention belongs to the technical field of antitumor drugs, and particularly relates to 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl) urea and a salt thereof, and a synthesis method and use thereof.
  • Cancer is one of the malignant diseases that pose a serious threat to human health. In the past 30 years, the incidence of cancer in China is rapidly rising. The incidence of cancer is about 200/100,000 people. The number of new cases is more than 3.2 million, the deaths are more than 2.7 million, and more than 7 million are treated.
  • the object of the present invention is to provide a 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl) urea and a salt thereof, and a synthesis method and use thereof, and the antitumor of the compound It is more active than gefitinib and can be applied to the preparation of anti-tumor pharmaceutical preparations, and its synthetic raw materials are easily available.
  • the synthesis method is simple and easy to implement.
  • the invention discloses a 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea compound, and the structural formula of the urea compound is as follows:
  • R 1 is a substituted secondary amino group
  • R 2 is a halogen, a substituted methyl group or an ethynyl group.
  • the secondary amino group is dimethylamino, diethylamino, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-pyrrolidinyl or 1-piperidinyl.
  • the R 2 is fluorine, chlorine, methoxy, trifluoromethyl, ethynyl or substituted benzyloxy.
  • the invention also discloses a method for synthesizing 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea compound, which comprises substituted benzoyl azide and substituted 6-amino-
  • the 4-arylamino quinazoline is refluxed in dry toluene to obtain a 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea compound.
  • R 1 is dimethylamino, diethylamino, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-pyrrolidinyl or 1-piperidinyl;
  • R 2 is fluorine, chlorine, methoxy, trifluoromethyl, ethynyl or substituted benzyloxy;
  • the synthetic route is as follows:
  • the molar ratio of substituted benzoyl azide to substituted 6-amino-4-arylaminoquinazoline is about 1:1; 5 to 10 L of toluene is added per 1 mole of raw material (per 1 mole of substituted benzoyl group) The amount of toluene added to the azide is 5 to 10 L).
  • the invention also discloses a salt compound of 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl) urea, which is 1-substituted phenyl-3-(4-substituted phenylamino) -6-quinazolinyl)urea compound and acid are prepared by refluxing in an alcohol at a molar ratio of 1:2 for 30 to 60 minutes;
  • the acid is hydrochloric acid or methanesulfonic acid
  • the alcohol is ethanol or isopropanol.
  • R 1 is a substituted secondary amino group
  • R 2 is a halogen, a substituted methyl group, an ethynyl group or the like
  • HX is hydrochloric acid or methanesulfonic acid.
  • the salt is a hydrochloride or a methanesulfonate or the like.
  • the invention also discloses 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea compounds or 1-substituted phenyl-3-(4-substituted phenylamino-6- Use of a salt compound of quinazolinyl urea in the preparation of an antitumor pharmaceutical preparation.
  • Each of the tablets, each or each preparation contains 50 to 500 mg of 1-substituted phenyl-3-(4-substituted phenyl) An amino-6-quinazolinyl)urea compound or a salt thereof.
  • the excipient includes one or more of a stabilizer, a solubilizer, a lubricant, and a disintegrant.
  • the present invention has the following beneficial technical effects:
  • the present invention combines a structural fragment of urea with the 6-position of a 4-arylaminoquinazoline skeleton structure to provide a 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea
  • the class and its salt compounds have not been reported in the literature.
  • the introduction of a tertiary amino group such as morpholinyl, 4-methyl-1-piperazinyl or pyrrolidinyl into a drug molecule improves the water solubility and pharmacokinetic properties of the drug.
  • the preparation of the 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea compound into a methanesulfonate or hydrochloride salt in the present invention is advantageous for improving the water solubility and stability of the compound.
  • the urea compound and the salt thereof provided by the invention have the activity of inhibiting the proliferation of human lung cancer cell A549, human epidermal cancer cell A431, human breast cancer cell MCF-7 and the like, and most of the compounds are more active than the positive drug Gefitse.
  • the compound 1-(4-(3-trifluoromethyl)phenyl)amino)-6-quinazolinyl)-3-(4-((1-pyrrolidinyl)methyl)phenyl)urea No. 11) of the IC A549, A431 and MCF-7 were 50 0.68 ⁇ mol ⁇ L -1, 1.36 ⁇ mol ⁇ L -1 and 0.92 ⁇ mol ⁇ L -1.
  • the positive drug gefitinib on IC A549, A431 and MCF-7 were 50 4.76 ⁇ mol ⁇ L -1, 3.74 ⁇ mol ⁇ L -1 and 4.97 ⁇ mol ⁇ L -1.
  • the 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea compound provided by the present invention and a salt compound thereof can be used for preparing an antitumor pharmaceutical preparation, wherein each tablet or granule Or the pharmaceutical preparation contains 10 to 500 mg.
  • the antitumor pharmaceutical preparation is prepared using the active compound given by the present invention, the medicament can be formulated into a tablet, a capsule or an injection.
  • These pharmaceutical preparations can be prepared according to a conventional preparation process of various preparations. For tablets or capsules, a preferred amount is from 50 to 300 mg.
  • oral preparations of the present invention may contain pharmaceutical excipients, including additives, stabilizers, solubilizers, lubricants, disintegrators, etc., such as starch, dextrin, glucose, lactose, cellulose, polyvinylpyrrolidone, cross-linking. Polyvinylpyrrolidone, pectin, cyclodextrin, soil temperature-80, polyvinyl alcohol, magnesium stearate, talc, and the like.
  • pharmaceutical excipients including additives, stabilizers, solubilizers, lubricants, disintegrators, etc., such as starch, dextrin, glucose, lactose, cellulose, polyvinylpyrrolidone, cross-linking. Polyvinylpyrrolidone, pectin, cyclodextrin, soil temperature-80, polyvinyl alcohol, magnesium stearate, talc, and the like.
  • Figure 1 is a schematic diagram of a synthetic process of the present invention
  • the structure of the compound was characterized by 1 H NMR.
  • the compound of No. 10 (0.26 g) was dissolved in isopropyl alcohol (10 mL), and concentrated hydrochloric acid (0.05 mL) was added, and the mixture was stirred at 50 ° C for 30 minutes, cooled, allowed to stand, suction filtered, and dried to give a solid. The yield was 85.7%.
  • the compound of No. 11 (0.26 g) was dissolved in anhydrous ethanol (10 mL), and methanesulfonic acid (0.05 g) was added, and the mixture was stirred at 50 ° C for 30 minutes, cooled, allowed to stand, filtered, and dried to give a solid. The yield was 80.0%.
  • gefitinib was used as a positive control drug.
  • the growth inhibition effect of compound 1-14 on human lung cancer cell A549, human epidermal carcinoma cell A431 and human breast cancer cell MCF-7 was determined by in vitro MTT assay.
  • Tumor cell A549 was cultured in RPMI1640 medium containing 10% calf serum, containing 100 U ⁇ mL -1 of penicillin and 100 ⁇ g ⁇ mL -1 of streptomycin at 37 ° C, 5% CO 2 incubator Intermediate generation and cultivation.
  • the adherent tumor cells were digested with 0.3% trypsin, and the cell suspension was prepared in a RPMI1640 medium containing 10% calf serum at a concentration of 6 ⁇ 10 3 cells/ml.
  • 200 ⁇ L (containing about 1000 tumor cells) per well was seeded in a 96-well culture plate, and cultured at 37 ° C for 24 hours.
  • the drug-administered group was added with different concentrations of drugs, and each drug was set to have a concentration gradient of 100, 10, 5, 1, and 0.1 ⁇ mol ⁇ L -1 , and each group was provided with 3 parallel holes.
  • the control group was added with an equal volume of solvent, placed in a 37 ° C, 5% CO 2 incubator for 72 h, and then the culture solution was discarded. 20 ⁇ L of 5 mg ⁇ mL -1 MTT solution was added to each well, and after incubating for 4 h, discarded. The supernatant was added with 150 ⁇ L of DMSO per well, and after light shaking, the optical density value (OD) was measured at 570 nm with a microplate reader.
  • the tumor cells treated with the solvent control were used as the control group, and the inhibition rate of the drug on the tumor cells was determined according to the following formula:
  • the half-inhibitory concentration (IC 50 ) was further determined by linear regression.
  • Verification method Kunming mice, male, weighing 18-21g.
  • the ascites on the 8th day after S180 was inoculated into the peritoneal cavity of the mice, and diluted with physiological saline at a ratio of 1:1 to prepare a S180 cell suspension.
  • 0.1 mL was inoculated subcutaneously in the right axilla of each mouse with a syringe.
  • the mice were randomly divided into 3 groups of 8 animals each, which were:
  • Compound 11 was dissolved in NMP/PEG400/H 2 O (volume ratio 1:6:3).
  • the administration was intragastrically administered according to the above-mentioned administration schedule, once a day for 8 days.
  • the administration date was d1
  • the administration volume was 10 mL ⁇ kg -1 body weight.
  • Mouse body weights were recorded before daily dosing. The mice were sacrificed on the next day of drug withdrawal (d9), and the tumor pieces were peeled off, and other tissues were removed and weighed.
  • RESULTS The growth inhibition rate of S180 xenografts in mice at doses of 20 mg ⁇ kg -1 and 50 mg ⁇ kg -1 was 37.6% and 56.8%, respectively.
  • nude mice were subcutaneously inoculated with human breast cancer MCF-7 cell line. When the tumor grew to about 100 mm 3 , the nude mice were randomly divided into 5 groups, 6 in each group, respectively:
  • Compound 11 was dissolved in NMP/PEG400/H 2 O (volume ratio 1:6:3) and administered intragastrically once a day.
  • the tumor volume of each administration group during administration was smaller than that of the control group.
  • the animals were sacrificed and the tumor was excised and weighed.
  • the growth inhibition rate of compound 11 on MCF-7 xenografts in nude mice was 52.0%, 64.3% and 80.0% at doses of 1, 5, 25 mg/kg, respectively; the growth inhibition rate of capecitabine group was 86.6%.
  • the tumor weight of the administration group was significantly lower than that of the control group. During the administration period, the animal's body weight did not change much, or increased slightly.
  • the compound 11 provided by the present invention has significant in vivo antitumor activity.
  • the present invention relates to a composition of a 1-substituted phenyl-3-(4-substituted phenylamino-6-quinazolinyl)urea compound and a salt thereof for use in the preparation of an antitumor drug, and these applications may be Capsules, oral liquids or granules or injections.
  • These preparations can be prepared according to a conventional preparation process of various preparations, wherein the active ingredient is contained in an amount of from 1 to 500 mg, preferably from 50 to 300 mg.
  • the oral preparations of the present invention may contain pharmaceutical excipients, including additives, stabilizers, solubilizers, lubricants, etc., such as glucose, lactose, cellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, starch, pectin, and rings. Dextrin, soil temperature -80, polyvinyl alcohol, magnesium stearate, talcum powder, etc.
  • test methods not described in detail in the present invention are test methods or existing methods which are commonly used in the art, and will not be described herein.

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  • 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

La présente invention appartient au domaine technique des médicaments antitumoraux, et fournit un composé 1-phényl-3-(4-phénylamino-6-quinazolinyl) urée et un sel de celui-ci, et une méthode de synthèse et une application de celui-ci. La méthode de synthèse consiste à chauffer à reflux dans du toluène anhydre du benzoylazide substitué et de la 6-amino-4-arylaminoquinazoline substituée pour obtenir un composé 1-phényl-3-(4-phénylamino-6-quinazolinyl) urée. Le composé comporte une structure nouvelle et un procédé de synthèse facilement mis en œuvre. Les expériences in vitro et in vivo portant sur l'activité antitumorale indiquent que l'activité antitumorale du composé est supérieure à celle d'un traitement utilisé en clinique, tel que le géfitinib et la capécitabine. Le composé a une application dans la préparation d'une préparation pharmaceutique antitumorale.
PCT/CN2016/090098 2015-07-16 2016-07-15 Composé 1-phényl-3-(4-phénylamino-6-quinazolinyl) urée, méthode de préparation et application de celui-ci Ceased WO2017008757A1 (fr)

Applications Claiming Priority (2)

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CN201510419210.9A CN105001167B (zh) 2015-07-16 2015-07-16 1‑取代苯基‑3‑（4‑取代苯基氨基‑6‑喹唑啉基）脲类化合物及制备方法和用途
CN201510419210.9 2015-07-16

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105001167B (zh) * 2015-07-16 2018-01-05 西安交通大学 1‑取代苯基‑3‑（4‑取代苯基氨基‑6‑喹唑啉基）脲类化合物及制备方法和用途
CN105753793B (zh) * 2016-01-19 2018-09-04 河北医科大学 芳甲酰脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457105A (en) * 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
WO2008033747A2 (fr) * 2006-09-11 2008-03-20 Curis, Inc. Petites molécules multifonctionnelles servant d'agents anti-prolifératifs
CN101535279A (zh) * 2006-09-11 2009-09-16 柯瑞斯公司 含锌结合基的喹唑啉基egfr抑制剂
CN103382182A (zh) * 2013-05-17 2013-11-06 河北医科大学 苯基脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途
CN105001167A (zh) * 2015-07-16 2015-10-28 西安交通大学 1-取代苯基-3-（4-取代苯基氨基-6-喹唑啉基）脲类化合物及制备方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090092317A (ko) * 2006-12-11 2009-08-31 아이알엠 엘엘씨 키나제 억제제로서의 화합물 및 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457105A (en) * 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
WO2008033747A2 (fr) * 2006-09-11 2008-03-20 Curis, Inc. Petites molécules multifonctionnelles servant d'agents anti-prolifératifs
CN101535279A (zh) * 2006-09-11 2009-09-16 柯瑞斯公司 含锌结合基的喹唑啉基egfr抑制剂
CN103382182A (zh) * 2013-05-17 2013-11-06 河北医科大学 苯基脲偶联喹唑啉类化合物及其制备方法、药物组合物及药物用途
CN105001167A (zh) * 2015-07-16 2015-10-28 西安交通大学 1-取代苯基-3-（4-取代苯基氨基-6-喹唑啉基）脲类化合物及制备方法和用途

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Title
MARVANIA, B. ET AL.: "Design, Synthesis and Antitumor Evaluation of Phenyl N-mustard-quinazoline Conjugates", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 19, 2 February 2011 (2011-02-02), pages 1987 - 1998, XP028176802 *

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CN105001167A (zh) 2015-10-28

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