WO2013170757A1 - Composé acide 4-aminoquinazoline hydroxamique et application comme médicament anticancéreux - Google Patents

Composé acide 4-aminoquinazoline hydroxamique et application comme médicament anticancéreux Download PDF

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Publication number
WO2013170757A1
WO2013170757A1 PCT/CN2013/075687 CN2013075687W WO2013170757A1 WO 2013170757 A1 WO2013170757 A1 WO 2013170757A1 CN 2013075687 W CN2013075687 W CN 2013075687W WO 2013170757 A1 WO2013170757 A1 WO 2013170757A1
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WIPO (PCT)
Prior art keywords
group
amino
hydroxy
aminoquinazoline
heptanamide
Prior art date
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PCT/CN2013/075687
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English (en)
Chinese (zh)
Inventor
李建其
张庆伟
贾志丹
周斌
崔宁
梁晓东
Original Assignee
国药一心制药有限公司
上海医药工业研究院
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Publication of WO2013170757A1 publication Critical patent/WO2013170757A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to a class of 4-aminoquinazoline hydroxamic acid compounds, and the use of such compounds as antitumor drugs. Background technique
  • Tumors are major diseases that threaten human health, and the treatment of tumors has been closely watched by the whole world.
  • Traditional chemotherapeutic drugs non-specifically block cell division and cause cell death. While killing tumor cells, they also destroy normal human cells. And many cytotoxic drugs have a limited range of treatments, which can easily lead to treatment-related adverse reactions.
  • cytotoxic drugs have a limited range of treatments, which can easily lead to treatment-related adverse reactions.
  • tumor biotherapy has Great progress has entered the era of molecular targeted therapy.
  • Targeted anticancer drugs can target specific pathways, prevent tumor growth and reduce toxicity to normal cells.
  • the molecular basis is mainly related to two aspects: one is for methylation modification of DNA, and the other is Acetylation of chromatin histones.
  • Chromatin group Protein acetylation and deacetylation are one of the key links regulating gene expression, and two types of enzymes determine the degree of acetylation of histones, namely Histone acetyltransferases (HAT) and histones. Histone deacetylases (HDAC). Acetylation of histones activates the transcription of specific genes, while HDAC inhibits the transcriptional expression of genes.
  • Histone deacetylase inhibitors can be classified into four classes according to their structure: benzamides, hydroxamic acids, fatty acids and cyclic peptides.
  • SAHA also known as Vorinostat
  • HDAC histone deacetylase inhibitor
  • the 4-aminoquinazoline hydroxamic acid compound of the present invention has a compound as shown in (V)
  • R 2 , R 3 , R 4 or R 5 is hydrogen, halogen, amino, nitro, hydroxyamino, —C 4 decyloxycarbonyl, —aminodecyl, —indenyl, —C 4 Acylamino, decyloxy, decyl, ureido, trifluoromethyl, d-C 4 sulfonyl, arylsulfonyl, substituted phenyl, phenyl or heterocyclic;
  • n 0 ⁇ 5 integer
  • the heterocyclic ring refers to a saturated or unsaturated five-membered heterocyclic or six-membered heterocyclic ring containing one or more hetero atoms; the hetero atom is nitrogen, oxygen or sulfur;
  • the halogen is fluorine, chlorine, bromine or iodine
  • the fluorenyl group refers to a branched, unbranched, and cyclic saturated hydrocarbon chain containing a specified number of carbon atoms, and the fluorenyl group of -C 4 is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, or a ring.
  • the amino group means -NH 2 ;
  • the -C 4 aminoguanidino group is preferably an aminoethyl group, a 1-aminopropyl group or a 2-aminopropyl group; the -C 4 decylamino group is preferably N-methylamino, N-ethylamino or N-isopropyl an amino group;
  • amide group refers to a -C (O) NH -, " CC 4 amide group” as "C r C 4 alkyl with a” connected "amido", preferably acetylamino (C3 ⁇ 4C (O) NH -), propionylamino (CH 3 CH 2 C(O)NH -), butyrylamino or isobutyrylamino;
  • the salt is a hydrochloride, a hydrobromide, a sulfate, an acetate, a lactate, a tartrate, a citrate, a citrate, a trifluoroacetate, a malate, a maleic acid.
  • Salt succinate, p-toluenesulfonic acid or methanesulfonate;
  • the compound of the formula (V) may be salted with a mineral acid or an organic acid to obtain a salt form of a compound of the formula V, which is a hydrochloride, a hydrobromide, a sulfate, or an acetic acid. Salt, lactate, tartrate, citrate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.
  • the reaction was carried out for 3 h in an ice bath, and the reaction mixture was adjusted to pH 4-5 with hydrochloric acid.
  • the solid is recrystallized from acetonitrile or ethyl acetate/methanol (2: 1-5: 1) to give the title compound.
  • the above preparation method may further comprise reacting a compound of the formula V with a mineral acid (or an inorganic base), an organic acid (or an organic base), and cooling the salt of the compound of the structure of the formula V.
  • Ri, R 2 , R 3 , R 4 , R 5 , n in the above reaction method are the same as described above;
  • the raw materials involved, compounds a, b and hydroxylamine hydrochloride can be purchased through commercial channels;
  • MDA-MB-435 S human breast cancer cells
  • A549 human lung cancer cells
  • PANC-1 human pancreatic cancer cells
  • Hydroxamic acids have good inhibitory activity against a variety of tumor cells.
  • Pharmacological tests showed that the compound of the present invention has weak inhibitory activity against normal cells and has lower toxic side effects (Example 19), indicating that the 4-aminoquinazoline hydroxamic acid compound of the present invention and a positive control Compared with the drug SAHA, it has better selectivity for inhibiting proliferation of tumor cells and normal cells, indicating that it has lower toxic side effects when used as an antitumor drug.
  • Pharmacological tests show that the compounds of the present invention have low acute toxicity in mice (Examples)
  • HDACs histone deacetylase
  • the compound of the present invention has a weak inhibitory effect on normal cells while inhibiting tumor cells, exhibits good selective inhibitory activity, and has excellent antitumor activity. Prospects for clinical application.
  • the compounds of the present invention can be administered to mammals (including humans) in need of tumor treatment by oral, injection or the like in the form of a composition.
  • the composition comprises a therapeutically effective amount of a compound of the formula V or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the carrier refers to a carrier conventional in the pharmaceutical field, for example: a diluent, an excipient such as water, etc.; a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone or the like; a filler such as starch or the like; a cracking agent such as Calcium carbonate, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
  • the composition of the present invention can be prepared into a conventional solid preparation such as a tablet, a capsule or the like for oral administration; it can also be prepared into an injection preparation or the like for injection.
  • the various dosage forms of the compositions of the present invention can be prepared by conventional methods in the pharmaceutical arts.
  • the content of the compound having the active ingredient of the formula V is 0.1% by weight of the composition ⁇
  • the compounds of the formula V according to the present invention can be administered clinically to mammals (including humans) by oral or injection means, particularly preferably orally.
  • the dosage is 0.0001 mg/kg to 200 mg/kg body weight per day.
  • the optimal dose will depend on the individual, usually at the beginning of the dose, and then gradually increase the amount.
  • the present invention combines the structural characteristics of SAHA, adopts amide bond exchange, and skeleton migration to transform the mother nucleus, and introduces an antitumor drug-forming group 4-aminoquinazoline knot in the surface recognition region of the compound.
  • targeted drugs have certain specificities. They cannot directly obtain another series of compounds with corresponding activities or activities due to simple modification of a structure in a compound. It is necessary to consider the difference between the structure of the compound and the spatial conformation of the target protein and the key. Binding sites, design, synthesis and biological screening to obtain a series of active new derivatives.
  • the invention obtains a series of new compounds of 4-aminoquinazoline hydroxamic acid by a large number of experimental designs and active screening, and finds active compounds with better antitumor activity and low toxicity, and has intensive research. value.
  • the compound and its medicinal preparation have a good therapeutic effect for treating diseases caused by abnormal gene expression, such as tumors, endocrine disorders, immune system diseases, genetic diseases and nervous system diseases.
  • the tumor is a solid tumor and a hematoma, preferably liver cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, ovarian cancer, bladder cancer, rectal cancer, skin cancer, and lymphoma.
  • the compound of the present invention has less toxic side effects as an antitumor drug, and is more easily used as an antitumor drug, which is equivalent to the prior art, and the present invention has novel, creative and scientific advances. detailed description
  • Example 1 The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the invention are not limited thereto.
  • Example 1
  • the V-type compound was synthesized and synthesized by V-l, and the yield was 55.9%.
  • V-type compound synthesis synthesis V -4 yield 50%.
  • 6-Chloro-4-chloroquinazoline (0.197 g, 1 mmol)
  • 7-aminoheptanoic acid methyl ester hydrochloride (0.21 g, 1 mmol)
  • KOH 0.14 g, 2.5 mmol
  • hydroxylamine hydrochloride 0.7 g, 2.5 mmol
  • V compound was synthesized by the synthesis of V-7, and the yield was 44.9%.
  • 6-fluoro-4-chloroquinazoline (0.182 g, 1 mmol), 7-aminoheptanoic acid methyl ester hydrochloride (0.21 g, 1 mmol), KOH (0.14 g, 2.5 mmol), hydroxyamine hydrochloride (0.7 g, 2.5 mmol) was used as a raw material to synthesize V -8 according to the synthesis of compound V, with a yield of 63.0%.
  • V -10 (0.333 g, 1 mmol) was dissolved in methanol, 0.04 g of 5% palladium on carbon was added, hydrogen was introduced under normal temperature and normal pressure, and stirred for 3 hours. After completion of the reaction, the palladium on carbon was removed by filtration, and the filtrate was concentrated to obtain a product.
  • V-type compound was synthesized and synthesized by V-13, and the yield was 69.2%.
  • the inhibitory activity of the compound on HDACs was tested using the K340-100 kit from Biovision. The experimental procedure was carried out according to the kit instructions. First test ⁇ ⁇ and ⁇ . ⁇ ⁇ at two concentrations, the compound inhibits the percentage of the enzyme, the compound with better activity continues the inhibitory IC 5 () test. The experimental results are shown in Table 2. Table 2 Experimental results of in vitro inhibitory activity of compounds on HDACs
  • V-2 88.92 58.36 86.60
  • V-16 92.91 61.59 55.96 As can be seen from Table 2 above, the compounds of the present invention have strong inhibitory activity against HDACs, and some compounds such as V-3, V-6, V-7, V-9, V-10, V -13 HDACs inhibitory activity is superior to the positive control drug SAHA.
  • Example 18
  • V-16 0.07 0.10 6.70 0.09 50 0.82 2.53
  • some of the compounds of the present invention tested were inhibited against Jurkat E6-1 (human T cell lymphoma), Hut78 (T lymph) relative to the positive control drug SAHA.
  • Cell leukemia cells include Colo320 (human rectal cancer cell line), Caki-1 (human renal cell carcinoma cell line), MDA-MB-435S (human breast cancer cell), A549 (human lung cancer cell), PANC-1 (human) Pancreatic cancer cells) have better activity in tumor cell proliferation, indicating the 4-amino group of the present invention
  • the quinazoline hydroxamic acid compounds have good inhibitory activity against various tumor cells.
  • the activity of the compound of the present invention against MCF10A was measured, and the IC 5 o value was measured by the CCK-8 method (Cat# CK04-13, Dojindo).
  • the S AHA was selected as a control drug for the in vitro inhibitory activity test of normal cell lines.
  • the specific results are as follows (unit: ⁇ ): Table 4 In vitro inhibitory activity of the compound of the present invention and a control drug on normal cells
  • V-16 6.4 It can be seen from Table 4 that the compounds of the present invention V-1 to V-30 are relative to the control drug SAHA has weak inhibitory activity against normal cells and has lower toxic side effects, indicating that the 4-aminoquinazoline hydroxamic acid compounds of the present invention have better selectivity for inhibiting proliferation of tumor cells and normal cells. It indicates that it has lower toxic side effects when used as an anti-tumor drug, and is easy to use as a tumor drug.
  • Example 20 Example 20
  • Acute toxicity test The method reported by Zhang Juntian, "Modern Pharmacological Experimental Method” (Beijing Medical University, China Union Medical University, United Press, 1998), preliminary screening, using Bliss method statistics ("Practical pharmaceutical preparations” Technology, People's Health Publishing House, published in 1999), the LD 50 of single V4, V-7, V-9, V-16 mice was 1.6g/kg, l.lg/kg 1.9g/kg and 1.3g/kg.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un composé acide 4-aminoquinazoline hydroxamique tel que représenté par la formule (V) ou l'un de ses sels pharmaceutiquement acceptables. Le composé présente une grande activité inhibitrice d'histone désacétylase, de grandes activités contre différentes cellules tumorales du corps humain, une faible inhibition contre les cellules normales, et une toxicité réduite, et peut être appliqué au développement d'un médicament anticancéreux. En outre, le composé présente également une grande efficacité dans le traitement des maladies induites par une expression anormale d'un gène.
PCT/CN2013/075687 2012-05-18 2013-05-16 Composé acide 4-aminoquinazoline hydroxamique et application comme médicament anticancéreux WO2013170757A1 (fr)

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CN201210156309.0 2012-05-18
CN201210156309.0A CN103420923B (zh) 2012-05-18 2012-05-18 4-氨基喹唑啉异羟肟酸类化合物及作为抗肿瘤药物应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2802463C1 (ru) * 2022-08-12 2023-08-29 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр онкологии имени Н.Н. Блохина" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ онкологии им. Н.Н. Блохина" Минздрава России) Гидроксамовые кислоты, производные 4-аминохиназолина, обладающие противоопухолевой активностью

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WO2016146074A1 (fr) * 2015-03-18 2016-09-22 广东众生药业股份有限公司 Inhibiteur de l'histone désacétylase, son procédé de préparation et son utilisation
CN106045923A (zh) * 2016-03-17 2016-10-26 广东众生药业股份有限公司 一种组蛋白去乙酰化酶抑制剂及其制备方法和用途
WO2018005799A1 (fr) * 2016-06-29 2018-01-04 Georgia State University Research Foundation, Inc. Inhibiteurs d'histone désacétylase et d'histone méthyltransférase et leurs procédés de production et d'utilisation
KR102000035B1 (ko) * 2018-02-01 2019-07-15 충북대학교 산학협력단 Hdac 억제제로서 신규한 퀴나졸린 기반 하이드록사민산 또는 n-하이드록시벤즈아마이드 및 이를 유효성분으로 포함하는 항암제 조성물
CN111253325A (zh) * 2020-03-25 2020-06-09 广州大学 氨基喹唑啉芳基哌嗪类化合物及其药物组合物和应用
CN112480078B (zh) * 2020-11-10 2022-01-04 清华大学深圳国际研究生院 一种喹唑啉异羟肟酸衍生物及其制备方法与应用

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CN101906076A (zh) * 2009-06-04 2010-12-08 深圳微芯生物科技有限责任公司 作为蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘酰胺衍生物、其制备方法及应用

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CN1597671A (zh) * 2004-07-20 2005-03-23 贵州大学 喹唑啉衍生物及制备方法和生物活性
WO2009036057A1 (fr) * 2007-09-10 2009-03-19 Curis, Inc. Agents antiprolifératifs contenant une fraction de liaison au zinc
US20090111772A1 (en) * 2007-09-10 2009-04-30 Xiong Cai Formulation of quinazoline based egfr inhibitors containing a zinc binding moiety
CN101906076A (zh) * 2009-06-04 2010-12-08 深圳微芯生物科技有限责任公司 作为蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘酰胺衍生物、其制备方法及应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2802463C1 (ru) * 2022-08-12 2023-08-29 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр онкологии имени Н.Н. Блохина" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ онкологии им. Н.Н. Блохина" Минздрава России) Гидроксамовые кислоты, производные 4-аминохиназолина, обладающие противоопухолевой активностью

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