WO2009049492A1 - Composés de diaryléthers multi-substitués et d'aniline d'hydrocarbures aromatiques n-substitués - Google Patents

Composés de diaryléthers multi-substitués et d'aniline d'hydrocarbures aromatiques n-substitués Download PDF

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Publication number
WO2009049492A1
WO2009049492A1 PCT/CN2008/001700 CN2008001700W WO2009049492A1 WO 2009049492 A1 WO2009049492 A1 WO 2009049492A1 CN 2008001700 W CN2008001700 W CN 2008001700W WO 2009049492 A1 WO2009049492 A1 WO 2009049492A1
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WO
WIPO (PCT)
Prior art keywords
chloro
compound
substituted
aniline
nitropyridine
Prior art date
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PCT/CN2008/001700
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English (en)
Chinese (zh)
Inventor
Lan Xie
Bingjie Qin
Xingtao Tian
Kou-Hsiung Lee
Original Assignee
Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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.)
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Application filed by Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China filed Critical Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
Publication of WO2009049492A1 publication Critical patent/WO2009049492A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
    • C07C211/56—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an N-substituted arene aniline/polysubstituted diaryl ether compound having various anticancer activities, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition containing the same, and an antitumor drug thereof Application in . Background technique:
  • Inhibitors targeting cell signaling molecules or targets of neovascularization, anti-metastatic or anti-drug resistant drugs, differentiation inducers, targeted therapy, improving or regulating immune function, and gene therapy have become The focus of research and development of new anticancer drugs.
  • Gefet inib a protein tyrosine kinase inhibitor targeting cell signaling molecules, has been successful and has become the first non-small cell lung cancer drug on the market.
  • the present inventors discovered a series of N-substituted aromatic anilines and polysubstituted diaryl ether compounds by investigating the anticancer activity of small molecule synthetic compounds in vitro in the research process of searching for new anticancer drugs.
  • the cancer cells have strong inhibitory activities and exhibit a certain structure-activity relationship, and accordingly, the inventors conducted intensive studies on the compounds. The anticancer activity of this class of compounds has not been reported.
  • a first aspect of the invention relates to N-substituted arene anilines and polysubstituted diaryl ether compounds having the structure of the following general formula (I): or a pharmaceutically acceptable salt thereof:
  • Z is CH or N
  • X is a hormone or hydrogen
  • Y is -0- or - NR,-;
  • R, R 2 , R 3 are each independently H, halogen, -N0 2 , -CN, -NH 2 , d- 6 alkyl, C! -6 alkoxy, 0H, -0CH 2 0-, - CF 3 ,, -C00H, -S0 3 H, -C0NH 2 , -C0NHR' or - C00R,;
  • R 2 or R 2 and R 3 may together form -CHCH 2 0-;
  • R an H, d- 4 hydrocarbyl-substituted aromatic ring, a five- or six-membered heteroaryl ring, optionally a d-aliphatic hydrocarbon group containing a double or triple bond, or optionally a double or triple bond Fatty acyl group;
  • R" is a d- 4 hydrocarbon group optionally containing a double bond or a triple bond
  • a second aspect of the invention relates to a process for the preparation of a compound of formula I above.
  • a third aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I above and one or more pharmaceutically acceptable carriers or excipients.
  • a fourth aspect of the invention relates to the use of a compound of formula I for the preparation of an anti-tumor drug.
  • hydrocarbyl as used in the present invention includes alkyl, alkenyl and alkynyl groups.
  • Cy.aromatic ring as used in the present invention means a single or fused aromatic ring system having 6 to 10 carbon atoms, including but not limited to phenyl, naphthyl.
  • five- or six-membered heteroaryl ring as used in the present invention means a five- or six-membered aromatic ring system containing at least one hetero atom selected from 0, S or N in the ring system, including but not limited to Pyrrole, pyrazole, furan, thiophene, pyridine, and the like.
  • the present invention relates to N-substituted arene anilines and polysubstituted diaryl ether compounds having the following general formula (I):
  • Z is CH or N; X is! 3 ⁇ 4 prime or hydrogen;
  • Y is -0- or -NR,-;
  • R 2 and R 3 are each independently H, halogen, -N0 2 , -CN, -NH 2 , alkyl, C 16 alkoxy, OH, - 0CH 2 0-, -CF 3 , -C00H, -S0 3 H, - C0NH 2 , -C0NHR' or -C00R,;
  • R 2 or R 2 and R 3 may together form - 0CH 2 0-;
  • ⁇ is single-(neighbor, meta, para) or multiple substitution
  • R is an H, d- 4 hydrocarbyl-substituted (.. aromatic ring, five- or six-membered heteroaryl ring, optionally containing a double or triple bond CH. an aliphatic hydrocarbon group, or optionally containing a double or triple bond D—monthly fat ugly base;
  • R" is a hydrocarbon group optionally containing a double bond or a triple bond
  • R 4 is a para substitution.
  • Y is -NH-.
  • RR 3 is each independently halogen, -N0 2 , -CN, -NH 2 , -CH 3 , -0CH 3 , 0H, -0CH 2 0-, -CF 3 , -C00H, -S0 3 H, -C0NH 2 ;
  • R 2 is H.
  • ⁇ is halogen, -N0 2 , -CN, -NH 2 , -CH 3 , -0CH 3 , 0H, -0CH 2 0-, -CF 3 , - C00H, -S0 3 H, -C0NH 2 ;
  • R 2 and R 3 are H. According to another preferred embodiment of the present invention, wherein
  • R 2 is halogen, -N0 2 , —CN, —NH 2 , —CH 3 , —0CH 3 , 0H, —0CH 2 0-, —CF 3 , —C00H, —S0 3 H, —CONH 2 ;
  • RR 3 is H.
  • ⁇ and R 3 are each independently halogen, -N0 2 , -CN, -NH 2 , -CH 3 , - 0CH 3 ,
  • R 2 is H.
  • R 3 is independently halogen, -N0 2 , -CN, -NH 2 , -CH 3 , - 0CH 3 , 0H, - 0CH 2 0-, -CF 3 , - C00H, -S0 3 H, -C0NH 2 ;
  • R 2 , R 3 and R 4 are as defined above for formula I.
  • halogenated benzene or halopyridine substituted by the formula II is reacted with a substituted aniline or a substituted phenolic compound of the formula III under the action of a base to form a compound of the formula I.
  • the coupling reaction can also be carried out under microwave conditions, and the ratio of the base to the reactants is the same as described above, and the reaction is carried out at 150 to 180 ° C for 10 to 30 minutes using DMF or DMS0 as a solvent.
  • the compounds of the invention exhibit potent inhibitory activity in a variety of cancer cell tests. As described below, the compounds showed positive inhibition with the positive control drug [Homoharr ingtonine] in lung cancer cells (A549), breast cancer cells (MCF-7) and nasopharyngeal carcinoma cells (KB). Etopos ide (VP-16) is equivalent or better inhibitory activity. Of particular note is that some of these compounds also show potent inhibitory activity against resistant KB-VIN cells. Therefore, intensive research on the compounds of the present invention is expected to develop new anticancer drugs.
  • the positive control drug Homoharr ingtonine
  • MCF-7 breast cancer cells
  • KB nasopharyngeal carcinoma cells
  • Etopos ide (VP-16) is equivalent or better inhibitory activity.
  • some of these compounds also show potent inhibitory activity against resistant KB-VIN cells. Therefore, intensive research on the compounds of the present invention is expected to develop new anticancer drugs.
  • the compound of the present invention can be used either in its own form or in the form of a pharmaceutically acceptable salt or solvate thereof.
  • Pharmaceutically acceptable salts of the compounds of formula I include the conventional salts formed with pharmaceutically acceptable inorganic or organic acids, or inorganic or organic bases.
  • suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid a salt formed of benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like.
  • Suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. a salt formed by a diamine, N-methylglucamine, and procaine.
  • the compounds of formula I of the present invention may be combined with conventional pharmaceutical carriers or excipients to form a pharmaceutical composition.
  • the pharmaceutical composition can be administered orally or parenterally.
  • the pharmaceutical compositions of the present invention can be prepared into a variety of dosage forms according to conventional methods in the art, including However, it is not limited to tablets, gelatine, solutions, suspensions, granules or injections, and the like, and is administered orally or parenterally.
  • the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician.
  • the preferred dosage is between 0.01 and 100 mg/kg body weight per day.
  • Example 1 hydroxyphenyl)-5-chloro-2,4-dinitroaniline (A1) 1,5-dichloro-2,4-dinitrobenzene (237 mg 1.0 mmol) and m-aminophenol (230 mg, 2.11 awake) Dissolved in DMF (0.5 mL), placed directly in an oil bath of 1201:, stirred for 2 minutes, the reaction solution turned red, then cooled to room temperature, water was added, and the pH was adjusted to 3 with dilute HC1.
  • Example 3 5-Chloro-2,4-dinitro-N-(4,-methoxyphenyl)-aniline (A3) 2,4-Dichloro-1,5-dinitrobenzene ( 0.5 g, 2.11 mmol ) and p-nonylaniline (0.26 g, 2.11 mmol) dissolved in DMSO (5 mL), K 2 C0 3 (0.58 g, 4.22 mmol) and a catalytic amount of metal Cu, under nitrogen , 115 X: Stir for 2 hours.
  • A3 2,4-Dichloro-1,5-dinitrobenzene ( 0.5 g, 2.11 mmol ) and p-nonylaniline (0.26 g, 2.11 mmol) dissolved in DMSO (5 mL), K 2 C0 3 (0.58 g, 4.22 mmol) and a catalytic amount of metal Cu, under nitrogen , 115 X: Stir for 2 hours.
  • Example 4 5-Chloro-2,4-dinitro-indole 4,-nonylphenyl)-aniline (A4) 1, 5-dichloro-2,4-dinitrobenzene (370 ⁇ , 1 Methyl aniline (128 mg, 1.2 mmol) and potassium t-butoxide (224 mg, 2 mmol) were stirred in DMF (3 mL) 40 min. The mixture was poured into water, EtOAc (EtOAc m. .
  • Example 6 5-Chloro-N-(4,-nitrophenyl)-2,4-dinitroaniline (A6) 1, 5-dichloro- 2,4-dinitrobenzene (237 mg, l mmol), p-Nitroaniline (166 mg, 1.2 mmol) and potassium t-butoxide (236 mg, 2.1 mmol) in DMF (3 mL). Work-up with A5 gave the title compound 280 mg, m.
  • Example 19 2-(4,-Methylanilino)-3-nitropyridine (B5)2-bromo-3-nitropyridine (101.5 mg, 0.5 mmol), p-methylaniline (53.5 mg, 0.5 Methyl) and K 2 C0 3 (69 mg, 0.5 mmol) in DMSO (1.5 mL) with N2 protection and external bath. The reaction was carried out for 4 h under C conditions. The reaction was monitored by TLC (ethyl acetate / petroleum ether). The reaction solution was poured into distilled water, and the precipitate was filtered.
  • TLC ethyl acetate / petroleum ether
  • Example 20 2- ( 4 , -cyanoanilino)-3-nitropyridine (B6)2-bromo-3-nitropyridine (203 mg, 1 mmol), 4-cyanoaniline (354 mg, 3 mmol) and potassium tert-butoxide (112 mg, 1 mmol) in t-BuOH (4 ml), reacted for 10 min at 110 ° C under microwave conditions. The reaction was monitored by TLC (ethyl acetate / petroleum ether). dilute HC1 pH was adjusted to acidic, and the precipitated solid was chromatographed crude product was purified by column to give a yellow solid 18 mg, yield:. 7.5%:.
  • the human cancer cells (A549, MCF-7, KB, KB-VIN, etc.) used were placed in a single medium PMI-16 40 containing 10% (v/v) calf serum), and the cells were cultured in a microscope. The morphological characteristics and growth conditions in the liquid were examined. The cells were placed in a 2.5 cm 2 Petri dish, 37. C, cultured in 5% CO 2 humidified air. Cell line sticker Wall growth. The process of sample preparation and dilution and inoculation into the cell fluid should be aseptic. Test samples are usually dissolved in DMS0 and stored at -70 °C. In a 96-well culture plate, each well was placed at different concentrations of the test sample and approximately 5,000-20,000 cells were placed for 72 hours. ED 5 that inhibits cancer cell growth. The value is determined by the SRB (sulforhodamine B) method. The anticancer drugs homoharringtonine and VP16 served as positive controls.
  • A549 lung cancer cells; MCF-7: breast cancer cells; KB: nasopharyngeal carcinoma cells; KB-VIN: drug-resistant nasopharyngeal carcinoma cells.
  • ED 5 The value is an effective dose that inhibits the growth of half of cancer cells, indicating anticancer activity.
  • the test results of partial anticancer activity of the compounds of the present invention are shown in Table 1. Compounds of formula I and their anticancer activity data
  • NA no inhibitory activity

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

Abstract

L'invention concerne des composés de diaryléthers multi-substitués et d'aniline d'hydrocarbures aromatiques n-substitués de formule (I) ou leurs sels pharmaceutiquement acceptables, X, Y, Z et R1 à R4 étant tels que définis dans les revendications. L'invention concerne également la préparation de ces composés, la composition pharmaceutique contenant lesdits composés et l'utilisation de ces composés dans la préparation de médicaments contre les tumeurs.
PCT/CN2008/001700 2007-10-12 2008-10-07 Composés de diaryléthers multi-substitués et d'aniline d'hydrocarbures aromatiques n-substitués WO2009049492A1 (fr)

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CN200710163960.X 2007-10-12
CNA200710163960XA CN101407467A (zh) 2007-10-12 2007-10-12 N-取代芳烃苯胺/多取代二芳基醚类化合物,其制备方法及抗肿瘤应用

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WO2009049492A1 true WO2009049492A1 (fr) 2009-04-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2826474A1 (fr) * 2012-03-14 2015-01-21 Sinochem Corporation Utilisation de composés de diphénylamine dans la préparation des médicaments anti-tumeurs

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827072B (zh) * 2011-06-17 2014-08-06 中国中化股份有限公司 一种取代硝基苯胺类化合物及其应用
CN103301096B (zh) * 2012-03-14 2015-05-06 中国中化股份有限公司 取代二苯胺类化合物作为制备抗肿瘤药物的应用
CN103301103B (zh) * 2012-03-14 2015-07-15 中国中化股份有限公司 含氰基二苯胺类化合物作为制备抗肿瘤药物的应用
EP3043784B9 (fr) * 2013-09-09 2019-11-20 Peloton Therapeutics, Inc. Aryléthers et utilisations de ceux-ci
CN105287460B (zh) * 2014-07-21 2019-03-22 沈阳化工研究院有限公司 取代二苯胺类化合物作为制备抗肿瘤药物的应用
CN105267214B (zh) * 2014-07-21 2019-04-30 沈阳化工研究院有限公司 N-杂芳基苯胺类化合物作为制备抗肿瘤药物的应用

Citations (2)

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WO2006038738A1 (fr) * 2004-10-08 2006-04-13 Takeda Pharmaceutical Company Limited Agent de régulation du fonctionnement d'un récepteur
CN1878769A (zh) * 2003-09-11 2006-12-13 凯米亚公司 细胞因子抑制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1878769A (zh) * 2003-09-11 2006-12-13 凯米亚公司 细胞因子抑制剂
WO2006038738A1 (fr) * 2004-10-08 2006-04-13 Takeda Pharmaceutical Company Limited Agent de régulation du fonctionnement d'un récepteur

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* Cited by examiner, † Cited by third party
Title
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BENZIMIDAZOLE SERIES, vol. ., no. . *
CHEMICAL ABSTRACTS, 1927, Columbus, Ohio, US; abstract no. 21:21900, MODROW E ET AL: "Benzimidazole series" *
CHEMICAL ABSTRACTS, 1975, Columbus, Ohio, US; abstract no. 83:108362, WINKELMANN E ET AL: "Chemotherapeutically active nitro compounds. 1. Nitroanilines" *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2826474A1 (fr) * 2012-03-14 2015-01-21 Sinochem Corporation Utilisation de composés de diphénylamine dans la préparation des médicaments anti-tumeurs
EP2826474A4 (fr) * 2012-03-14 2015-04-08 Sinochem Corp Utilisation de composés de diphénylamine dans la préparation des médicaments anti-tumeurs

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