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WO2017008757A1 - 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 - Google Patents

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 Download PDF

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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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substituted
quinazolinyl
compound
urea
phenylamino
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French (fr)
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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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    • 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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Abstract

公开了1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲及其盐类化合物以及其合成方法和用途，属于抗肿瘤药物技术领域。合成方法是将取代的苯甲酰基叠氮与取代的6-氨基-4-芳胺基喹唑啉在干燥的甲苯中回流，制得1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物。该类化合物结构新颖、合成方法容易实现。体外、体内抗肿瘤活性实验表明，该类化合物的抗肿瘤活性强于临床用药吉非替尼和卡培他滨。该类化合物具有制备抗肿瘤药物制剂的用途。

Description

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 技术领域
本发明属于抗肿瘤药物技术领域，具体涉及1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲及其盐类化合物以及其合成方法和用途。
背景技术
癌症是严重威胁人类健康的恶性疾病之一。近30年来，我国癌症发生率正处于快速上升期，癌症发病率约为200/10万人，每年新发病例达320万例以上，死亡约270多万，在治患者700万人以上。
目前癌症的主要治疗手段仍然是手术治疗、放射治疗及药物治疗，但在很大程度上仍是以药物治疗为主。因此，研究开发新的抗肿瘤药物具有重要意义。
近年来，随着肿瘤分子生物学研究的进展，对肿瘤发病机理有了更多的认识，找到了许多抗肿瘤药物作用的新靶点，使抗肿瘤药物的发展取得许多新的成就，如拓扑异构酶抑制剂、蛋白激酶抑制剂、PI3K抑制剂，mTOR抑制剂等。
在多数肿瘤细胞中，一些激酶呈现高表达或过度激活。针对这一特点，已经开发了吉非替尼、伊马替尼、埃罗替尼、埃克替尼、索拉非尼、舒尼替尼和拉帕替尼等靶向激酶的抗肿瘤药物。但是，吉非替尼等药物应用于临床后发现其有效率并不高，还容易产生耐药性。因此，研发新的高效低毒的抗肿瘤药物具有重要意义。
发明内容
本发明的目的在于提供一种1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲及其盐类化合物以及其合成方法和用途，该类化合物的抗肿瘤活性强于吉非替尼，可应用于抗肿瘤药物制剂的制备，而且其合成原料易得，合成方法操作简单，容易实现。
本发明是通过以下技术方案来实现：
本发明公开了一种1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物，该脲类化合物的结构式如下：
Figure PCTCN2016090098-appb-000001
其中，R1为取代仲氨基；R2为卤素、取代甲基或乙炔基。
所述的仲氨基为二甲氨基、二乙氨基、4-吗啉基、4-甲基-1-哌嗪基、1-吡咯烷基或1-哌啶基。
所述的R2为氟、氯、甲氧基、三氟甲基、乙炔基、或取代的苄氧基。
本发明还公开了1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物的合成方法，将取代的苯甲酰基叠氮与取代的6-氨基-4-芳胺基喹唑啉在干燥的甲苯中回流，制得1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物，
其中，取代的苯甲酰基叠氮的结构式如下：
Figure PCTCN2016090098-appb-000002
其中，R1为二甲氨基、二乙氨基、4-吗啉基、4-甲基-1-哌嗪基、1-吡咯烷基或1-哌啶基；
取代的6-氨基-4-芳胺基喹唑啉的结构式如下：
Figure PCTCN2016090098-appb-000003
其中，R2为氟、氯、甲氧基、三氟甲基、乙炔基、或取代的苄氧基；
合成路线如下：
Figure PCTCN2016090098-appb-000004
取代的苯甲酰基叠氮与取代的6-氨基-4-芳胺基喹唑啉的摩尔比约为1:1；每1摩尔原料需要加甲苯5～10L(每1摩尔取代的苯甲酰基叠氮加入的甲苯量为5～10L)。
本发明还公开了1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲的盐类化合物，是1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物与酸按照1:2的摩尔比在醇中回流30～60分钟后制得；
所述的酸为盐酸或甲磺酸，醇为乙醇或异丙醇。
该盐类化合物的结构式如下：
Figure PCTCN2016090098-appb-000005
式中，R1为取代仲氨基；R2为卤素、取代甲基、乙炔基等；HX为盐酸或甲磺酸等。所述的盐类为盐酸盐或甲磺酸盐等。
本发明还公开了1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物或1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲的盐类化合物在制备抗肿瘤药物制剂中的应用。
在1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物或1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲的盐类化合物中添加辅料制成片剂、胶囊剂或注射剂；
其中每片、每粒或每支制剂中含50～500mg的1-取代苯基-3-(4-取代苯基 氨基-6-喹唑啉基)脲类化合物或其盐类化合物。
所述的辅料包括稳定剂、增溶剂、润滑剂、崩解剂中的一种或几种。
与现有技术相比，本发明具有以下有益的技术效果：
本发明将脲的结构片段与4-芳基氨基喹唑啉骨架结构的6-位相结合，提供的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类及其盐类化合物未见文献报道。将吗啉基、4-甲基-1-哌嗪基、吡咯烷基等叔胺基引入药物分子中，可改善药物的水溶性和药代动力学性质。
本发明将1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物制备成甲磺酸盐或盐酸盐有利于提高化合物的水溶性和稳定性。
本发明提供的脲类化合物及其盐具有抑制人肺癌细胞A549，人表皮癌细胞A431、人乳腺癌细胞MCF-7等肿瘤细胞增殖的活性，其中大部分化合物的活性强于阳性药吉非替尼。比如化合物1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-((1-吡咯烷基)甲基)苯基)脲(编号11)对A549、A431和MCF-7的IC50分别为0.68μmol·L-1、1.36μmol·L-1和0.92μmol·L-1。而在同样条件下，阳性药吉非替尼对A549、A431和MCF-7的IC50分别为4.76μmol·L-1、3.74μmol·L-1和4.97μmol·L-1。
本发明提供的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物及其盐类化合物，能够用于制备抗肿瘤药物制剂，其中每片或粒或支该药物制剂中含有10～500mg。在利用本发明给出的活性化合物制备抗肿瘤药物制剂时，可以将该药物制成片剂、胶囊剂或注射剂。这些药物制剂可按照各种制剂的常规制备工艺制成。对于片剂或胶囊剂，优选的含量为50～300mg。并且本发明涉及的口服制剂中可含有药用辅料，包括添加剂、稳定剂、增溶剂、润滑剂、崩解剂等，如淀粉、糊精、葡萄糖、乳糖、纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、果胶、环糊精、土温-80、聚乙烯醇、硬脂酸镁、滑石粉等。
附图说明
图1为本发明的合成工艺路线图；
图2为本发明的盐类化合物的合成工艺路线图；
图3为化合物11对MCF-7移植瘤生长的抑制效应结果图，其中，(a)为对肿瘤生长体积的影响；(b)为对肿瘤重量的影响(mean±SE.n＝6,*p<0.05,**p<0.01vs.control)。
具体实施方式
下面结合具体的实施例对本发明做进一步的详细说明，所述是对本发明的解释而不是限定。
本发明的代表性化合物的结构式、编号如下：
Figure PCTCN2016090098-appb-000006
Figure PCTCN2016090098-appb-000007
1、下面给出上述化合物的合成实施例
化合物的结构经1H NMR表征。
实施例1
1-(4-((3-乙炔基苯基)氨基)-6-喹唑啉基)-3-(4-((4-甲基-1-哌嗪基)甲基)苯基)脲(结构式1)的合成：
于100mL圆底烧瓶内加入4-((4-甲基-1-哌嗪基)甲基)苯甲酰叠氮0.20g，4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉0.20g和无水甲苯5mL，混合物在氮气保护下搅拌回流2.5h，减压蒸出溶剂，残余物用硅胶柱色谱分离(氯仿：甲醇＝10:1)得粗产物，用氯仿重结晶得到浅黄色固体0.22g，产率58.4％。1H-NMR(DMSO-d6):δ9.86(s,1H),9.32(s,1H),9.28(s,1H),8.54(s,1H),8.51(s,1H),8.04(s,1H),7.90(d,2H,J＝8.4Hz),7.76(d,1H,J＝8.0Hz),7.61(d,2H,J＝8.4Hz),7.40(t,1H,J＝8.0Hz),7.22(m,3H,Ar-H),4.23(s,1H),3.46(s,2H),3.04(m,4H),2.65(s,3H),2.37(s,4H)。
实施例2
1-(4-((3-氯-4-氟苯基)氨基)-6-喹唑啉基)-3-(4-((4-甲基-1-哌嗪基)甲基)苯基)脲(结构式2)的合成：
同实施例1编号1化合物的合成，用4-((3-氯-4-氟苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉，产率57.5％。1H-NMR(DMSO-d6):δ9.90(s,1H),9.02(s,1H),8.92(s,1H),8.54(s,1H),8.50(s,1H),8.17(m,1H),7.88(dd,1H),7.83(m,1H,Ar-H),7.77(d,1H,Ar-H),7.47(s,1H),7.44(d,2H,Ar-H),7.21(d,2H,Ar-H),3.46(s,2H),2.34(b,8H),2.17(s,3H)。
实施例3
1-(4-((3-三氟甲基苯基)氨基)-6-喹唑啉基)-3-(4-((4-甲基-1-哌嗪基)甲基)苯基)脲(结构式3)的合成：
同实施例1编号1化合物的合成，用4-((3-三氟甲基苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉，产率37.7％。1H-NMR(DMSO-d6):δ10.02(s,1H),9.04(s,1H),8.93(s,1H,8.57(s,1H),8.55(d,1H),8.31(s,1H),8.23(d,1H),7.89(dd,1H),7.79(d,1H),7.63(t,1H),7.46(m,3H),7.22(d,2H,Ar-H),3.39(s,2H),2.35(b,8H),2.17(s,3H)。
实施例4
1-(4-((3-氯-4-(3-氟苯甲氧基)苯基)氨基)-6-喹唑啉基)-3-(4-((4-甲基-1-哌嗪基)甲基)苯基)脲(结构式4)的合成：
同实施例1编号1化合物的合成，用4-((3-氯-4-(3-氟苯甲氧基)苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉，产率56.7％。1H-NMR(DMSO-d6):δ9.76(s,1H),8.97(s,1H),8.90(s,1H),8.49(s,1H),8.46(d,1H,Ar-H),8.01(d,1H,Ar-H),7.87(dd,1H),7.75(d,1H),7.71(d,1H),7.48(m,3H),7.33(m,2H),7.26(d,1H,Ar-H),7.21(d,2H),7.18(m,1H),5.26(s,2H),3.39(s,2H),2.33(b,8H),2.15(s,3H)。
实施例5
1-(4-((3-氯-4-甲氧基苯基)氨基)-6-喹唑啉基)-3-(4-((4-甲基-1-哌嗪基)甲基)苯基)脲(结构式4)的合成：
同实施例1编号1化合物的合成，用4-((3-氯-4-甲氧基苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉，产率31.7％。1H-NMR(DMSO-d6):δ9.74(s,1H),8.98(s,1H),8.91(s,1H),8.49(s,1H),8.46(d,1H),7.98(d,1H),7.87(dd,1H),7.73(m,2H),7.46(d,2H),7.20(m,3H),3.88(s,3H),3.39(s,2H),2.35(b,8H),2.17(s,3H)。
实施例6
1-(4-((3-氯-4-(3-氟苯甲氧基)苯基)氨基)-7-甲氧基-6-喹唑啉基)-3-(4-((4-甲基-1-哌嗪基)甲基)苯基)脲(结构式6)的合成：
同实施例1化合物1的合成，用4-((3-氯-4-(3-氟苯甲氧基)苯基)氨基)-7-甲氧基-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉，产率37.6％。1H-NMR(DMSO-d6):δ9.67(s,1H),9.45(s,1H),8.93(s,1H),8.57(s,1H),8.46(s,1H),7.96(s,1H),7.71(d,1H,Ar-H),7.48(m,3H),7.34(m,2H),7.27(s,1H),7.23(m,4H),5.25(s,2H),4.07(s,3H),3.38(s,2H),2.35(b,8H),2.17(s,3H)。
实施例7
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-(二甲氨基甲基)苯基)脲(结构式7)的合成：
同实施例1化合物1的合成，用4-((3-三氟甲基苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉；用4-(二甲氨基甲基)苯甲酰叠氮代替4-((4-甲基-1-哌嗪基)甲基)苯甲酰叠氮，产率31.4％。1H-NMR(DMSO-d6):δ10.06(s,1H),9.46(s,1H),9.43(s,1H),8.57(s,1H),8.56(s,1H),8.31(s,1H),8.23(d,1H),7.91(d,1H),7.80(d,1H),7.63(t,1H),7.56(d,2H),7.45(d,1H),7.36(d,2H),3.86(s,2H),2.48(s,6H)。
实施例8
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-(二乙基氨基甲基)苯基)脲(结构式8)的合成：
同实施例1化合物1的合成，用4-((3-三氟甲基苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉；用4-(二乙基氨基甲基)苯甲酰叠氮代替4-((4-甲基-1-哌嗪基)甲基)苯甲酰叠氮，产率29.8％。1H-NMR(DMSO-d6):δ10.03(s,1H),9.17(m,2H,8.58(s,1H),8.55(d,1H),8.30(s,1H),8.23(d,1H),7.90(dd,1H,Ar-H),7.80(d,1H),7.63(t,1H),7.48(m,3H),7.33(m,2H),3.53(s,2H),2.56(m,4H),1.11(m,6H)。
实施例9
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-((4-吗啉基)甲基)苯基)脲(结构式9)的合成：
同实施例1化合物1的合成，用4-((3-三氟甲基苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉；用4-((4-吗啉基)甲基)苯甲酰叠氮代替4-((4-甲基-1-哌嗪基)甲基)苯甲酰叠氮，产率32.1％。1H-NMR(DMSO-d6):δ10.02(s,1H),9.00(s,1H),8.90(s,1H),8.57(s,1H),8.55(d,1H),8.30(s,1H),8.23(d,1H),7.89(dd,1H),7.79(d,1H),7.63(t,1H),7.46(m,3H),7.24(d,2H,Ar-H),3.57(t,4H),3.41(s,2H),2.42(m,4H)。
实施例10
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-((1-哌啶基)甲基)苯基)脲(结构式10)的合成：
同实施例1编号1化合物的合成，用4-((3-三氟甲基苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉；用4-((1-哌啶基)甲基)苯甲酰叠氮代替4-((4-甲基-1-哌嗪基)甲基)苯甲酰叠氮，产率34.6％。1H-NMR(DMSO-d6):δ10.02(s,1H),9.06(s,1H),8.97(s,1H),8.58(s,1H),8.55 (d,1H,Ar-H),8.30(s,1H),8.23(d,1H,Ar-H),7.90(dd,1H),7.80(d,1H),7.63(t,1H,Ar-H),7.49(d,2H),7.46(d,1H,Ar-H),7.26(d,2H),3.56(s,2H),2.45(m,4H),1.54(m,4H),1.42(m,2H)。
实施例11
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-((1-吡咯烷基)甲基)苯基)脲(结构式11)的合成：
同实施例1编号1化合物的合成，用4-((3-三氟甲基苯基)氨基)-6-氨基喹唑啉代替4-((3-乙炔基苯基)氨基)-6-氨基喹唑啉；用4-((1-吡咯烷基)甲基)苯甲酰叠氮代替4-((4-甲基-1-哌嗪基)甲基)苯甲酰叠氮，产率31.2％。1H-NMR(DMSO-d6):δ10.02(s,1H),9.03(s,1H),8.91(s,1H),8.57(s,1H),8.56(d,1H,Ar-H),8.31(s,1H),8.23(d,1H),7.89(dd,1H),7.79(d,1H),7.63(t,1H),7.46(m,3H),7.24(d,2H),3.53(s,2H),2.44(s,4H),1.70(s,4H)。
实施例12
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-(4-甲基-1-哌嗪基)苯基)脲(结构式12)的合成：
于100mL圆底烧瓶中，加入4-((3-三氟甲基苯基)氨基)-6-氨基喹唑啉0.10g，羰基二咪唑0.16g和乙腈5mL，混合物在氮气保护下室温搅拌10h，随后加入4-(4-甲基-1-哌嗪基)苯胺，混合物继续室温搅拌8h，减压蒸出溶剂，残余物用硅胶柱色谱分离(氯仿：甲醇＝10:1)得粗产物，用氯仿重结晶得白色固体0.08g，产率47.1％。1H-NMR(DMSO-d6):δ10.00(s,1H),8.91(s,1H),8.65(s,1H),8.56(s,1H),8.53(d,1H,Ar-H),8.30(s,1H),8.22(d,1H),7.88(dd,1H),7.78(d,1H),7.63(t,1H),7.45(d,1H),7.36(d,2H),6.91(d,2H),3.07(t,4H),2.46(t,4H),2.23(s,3H)。
实施例13
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-((1-哌啶基)甲基) 苯基)脲盐酸盐(结构13)的合成：
编号10的化合物(0.26g)溶解于异丙醇(10mL)中，加入浓盐酸(0.05mL)，混合物于50℃搅拌30分钟，冷却，静置，抽滤，晾干，得固体0.24g。收率85.7％。
实施例14
1-(4-(3-三氟甲基)苯基)氨基)-6-喹唑啉基)-3-(4-((1-吡咯烷基)甲基)苯基)脲甲磺酸盐(结构式见表1编号14)的合成：
编号11化合物(0.26g)溶解于无水乙醇(10mL)中，加入甲磺酸(0.05g)，混合物于50℃搅拌30分钟，冷却，静置，抽滤，晾干，得固体0.24g。收率80.0％。
2、体外抗肿瘤活性的验证
为了验证本发明合成的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲及其盐类化合物的抗肿瘤活性，以吉非替尼为阳性对照药物，采用体外MTT法测定了化合物1-14对人肺癌细胞A549、人表皮癌细胞A431和人乳腺癌细胞MCF-7的生长抑制作用。
验证方法：将肿瘤细胞A549培养在含10％小牛血清的RPMI1640培养基中，内含青霉素有100U·mL-1，链霉素100μg·mL-1，于37℃、5％CO2培养箱中传代培养。取0.3％胰酶消化贴壁的肿瘤细胞，含10％小牛血清的RPMI1640培养液配制细胞悬液，浓度为6×103个细胞/毫升。于96孔培养板内每孔接种200μL(约含1000个肿瘤细胞)，37℃培养24h。给药组加入不同浓度药物，每药设定100、10、5、1和0.1μmol·L-1 5个浓度梯度，每组设3个平行孔。对照组加入与药等体积的溶剂，置于37℃、5％CO2培养箱中培养72h后弃去培养液，每孔加入20μL 5mg·mL-1的MTT溶液，孵育4h后，弃去上清液，每孔加入DMSO 150μL，轻度振荡后用酶标仪在570nm下测定光密度值(OD)。
结果计算：
以溶剂对照处理的肿瘤细胞为对照组，按照下式求药物对肿瘤细胞的抑制率：
Figure PCTCN2016090098-appb-000008
并进一步采用线性回归法求出半数抑制浓度(IC50)。
测定结果显示，化合物1-12对A549的IC50为0.68-5.17μmol·L-1；对A431的IC50为0.64-5.63μmol·L-1；对MCF-7的IC50值为0.92-8.39μmol·L-1。而在同样条件下，阳性药吉非替尼抑制A549、A431和MCF-7增殖的IC50分别为5.76μmol·L-1、3.74μmol·L-1和4.97μmol·L-1。
3、体内抗肿瘤活性的验证
①为了验证本发明提供化合物的体内抗肿瘤活性，我们采用小鼠S180移植瘤模型，灌胃给药，考察了化合物11的体内抗肿瘤活性。
验证方法：昆明种小鼠，雄性，体重18-21g。取出小鼠腹腔接种S180后第8天的腹水，用生理盐水以1:1比例稀释，制成S180细胞混悬液。用注射器在每只小鼠右腋窝皮下接种0.1mL。接种次日，将小鼠随机分为3组，每组8只，分别为：
1)空白对照组(NMP/PEG400/H2O)
2)化合物11低剂量组(20mg·kg-1)
3)化合物11高剂量组(50mg·kg-1)
将化合物11用NMP/PEG400/H2O(体积比为1:6:3)溶解。接种后第二天开始按上述给药方案灌胃给药，一日一次，连续给药8天。给药当日记为d1，给药体积为10mL·kg-1体重。每日给药前记录小鼠体重。停药次日(d9)将小鼠处死，剥离出瘤块，剔除其他组织后称重。
Figure PCTCN2016090098-appb-000009
结果：化合物11在剂量为20mg·kg-1和50mg·kg-1时，对小鼠体内S180移植瘤的生长抑制率分别为37.6％和56.8％。
②为了验证本发明提供化合物的体内抗肿瘤活性，我们采用裸鼠异种移植瘤模型，灌胃给药，考察了化合物11的体内抗肿瘤活性。
验证方法：裸鼠皮下接种人乳腺癌MCF-7细胞株，肿瘤生长到约100mm3时，将裸鼠随机分为5组，每组6只，分别为：
1)空白对照组(NMP/PEG400/H2O)
2)化合物11低剂量组(1mg/kg)
3)化合物11中剂量组(5mg/kg)
4)化合物11高剂量组(25mg/kg)
5)卡培他滨(capecitabine)组(200mg/kg)
将化合物11用NMP/PEG400/H2O(体积比为1：6：3)溶解，灌胃给药，一日1次。给药期间各给药组的肿瘤体积均小于对照组。给药24天后，处死动物，剥离肿瘤，称瘤重。
结果：化合物11对MCF-7移植瘤生长的抑制效应见图3，其中，(a)为对肿瘤生长体积的影响；(b)为对肿瘤重量的影响(mean±SE.n＝6,*p<0.05,**p<0.01vs.control)。
化合物11在剂量为1,5,25mg/kg时，对裸鼠MCF-7移植瘤的生长抑制率分别为52.0％、64.3％和80.0％；卡培他滨组的生长抑制率为86.6％。给药组瘤重均明显低于对照组。给药期间，动物体重变化不大，或略有增加。
结论：本发明提供的化合物11具有明显的体内抗肿瘤活性。
4、急性毒性试验
化合物11用NMP、PEG400和水溶解，以不同的剂量，给昆明种小鼠一次性灌胃给药，观察7天。结果表明：本发明中编号11的化合物给药剂量为400mg·kg-1时，小鼠活动正常。试验结果表明本发明提供的化合物毒性很小。
本发明涉及的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物及其盐类的组合物在制备抗肿瘤药物中的应用，这些应用可以是胶囊剂、口服液或颗粒剂或注射剂。这些制剂可按照各种制剂的常规制备工艺制成，其中有效成分的含量为1-500mg，优选的含量为50-300mg。
本发明涉及的口服制剂中可含有药用辅料，包括添加剂、稳定剂、增溶剂、润滑剂等，如葡萄糖、乳糖、纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、淀粉、果胶、环糊精、土温-80、聚乙烯醇、硬脂酸镁、滑石粉等。
本发明没有详细叙述的测试方法为本领域内常用的测试方法或现有方法，在此不一一叙述。
以上列举仅仅是对本发明的举例说明，并不构成对本发明的保护范围的限制，尽管用较佳的实施例对本发明进行了详细的说明，但本领域的普通技术人员应当理解，在不脱离本发明的范围下可以对本发明进行修改、变形或等同替换，均属于本发明的保护范围。

Claims (10)

1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物，其特征在于，该脲类化合物的结构式如下：
Figure PCTCN2016090098-appb-100001
其中，R1为取代仲氨基；R2为卤素、取代甲基或乙炔基。
如权利要求1所述的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物，其特征在于，所述的仲氨基为二甲氨基、二乙氨基、4-吗啉基、4-甲基-1-哌嗪基、1-吡咯烷基或1-哌啶基。
如权利要求1所述的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物，其特征在于，R2为氟、氯、甲氧基、三氟甲基、乙炔基、或取代的苄氧基。
1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物的合成方法，其特征在于，将取代的苯甲酰基叠氮与取代的6-氨基-4-芳胺基喹唑啉在干燥的甲苯中回流，制得1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物；
其中，取代的苯甲酰基叠氮的结构式如下：
Figure PCTCN2016090098-appb-100002
其中，R1为二甲氨基、二乙氨基、4-吗啉基、4-甲基-1-哌嗪基、1-吡咯烷基或1-哌啶基；
取代的6-氨基-4-芳胺基喹唑啉的结构式如下：
Figure PCTCN2016090098-appb-100003
其中，R2为氟、氯、甲氧基、三氟甲基、乙炔基、或取代的苄氧基。
如权利要求4所述的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物的合成方法，其特征在于，取代的苯甲酰基叠氮与取代的6-氨基-4-芳胺基喹唑啉的摩尔比为1:1；每1摩尔取代的苯甲酰基叠氮加入的甲苯量为5～10L。
1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲的盐类化合物，其特征在于，该盐类化合物是将权利要求1所述的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物与酸按1:2的摩尔比在醇中回流30～60分钟后制得。
根据权利要求6所述的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲的盐类化合物，所述的酸为盐酸或甲磺酸，醇为乙醇或异丙醇。
权利要求1所述的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物或权利要求6所述的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲的盐类化合物在制备抗肿瘤药物制剂中的应用。
如权利要求8所述的应用，其特征在于，在1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物或1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲的盐类化合物中添加辅料制成片剂、胶囊剂或注射剂；
其中每片、每粒或每支制剂中含50～500mg的1-取代苯基-3-(4-取代苯基氨基-6-喹唑啉基)脲类化合物或其盐类化合物。
如权利要求9所述的应用，其特征在于，所述的辅料为稳定剂、增溶剂、润滑剂、崩解剂中的一种或几种。
PCT/CN2016/090098 2015-07-16 2016-07-15 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 Ceased WO2017008757A1 (zh)

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