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WO2010060277A1 - Dérivés d'hydrazide de type acétyle substitué, leur synthèse et leurs applications - Google Patents

Dérivés d'hydrazide de type acétyle substitué, leur synthèse et leurs applications Download PDF

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Publication number
WO2010060277A1
WO2010060277A1 PCT/CN2009/001311 CN2009001311W WO2010060277A1 WO 2010060277 A1 WO2010060277 A1 WO 2010060277A1 CN 2009001311 W CN2009001311 W CN 2009001311W WO 2010060277 A1 WO2010060277 A1 WO 2010060277A1
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WIPO (PCT)
Prior art keywords
compound
formula
hydroxybenzylidene
tert
ethyl
Prior art date
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Ceased
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PCT/CN2009/001311
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English (en)
Chinese (zh)
Inventor
李松
杨春玲
肖军海
王莉莉
钟武
郑志兵
谢云德
李行舟
赵国明
王晓奎
周辛波
刘洪英
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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Publication of WO2010060277A1 publication Critical patent/WO2010060277A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
    • 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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel substituted acetyl sulfonium derivatives capable of activating procaspase-3, a process for preparing the compounds, a pharmaceutical composition comprising the above compounds, and a compound for use in the preparation of a medicament for treating cancer use.
  • Apoptosis also known as programmed cell death (PCD)
  • PCD programmed cell death
  • Kerr three scientists, such as Kerr, first proposed the concept of apoptosis: Apoptosis is a cell-removing mechanism involved in many processes of organisms, and active suicides by cells programmed by gene programming.
  • a common feature of cancer is its resistance to natural apoptotic signals, which are involved in the up-regulation or down-regulation of several key protein factors in the process of apoptosis, with caspase-3 being the executive protein of apoptosis.
  • caspase-3 The most important substrate for caspase-3 is poly(ADP-ribose) polymerase PARP, which is involved in DNA repair and gene integrity monitoring and is the promoter of apoptosis programs.
  • Caspase-3 is synthesized as an inactive zymogen and maintained in this dormant state by a safe brake pad, 3-aspartate.
  • the safety brake pad is located in a flexible collar at the junction of the large and small subunits. By multi-ion interaction, a salt bridge is formed to protect the hydrolysis site IETD175.
  • caspase-3 in normal cells can be activated by caspase-3 depending on the intracellular pH [ ⁇ , after the cell receives the apoptotic signal, the intracellular pH will decrease from 7.4 to 6.8. , destroying the formation of the salt bridge, thereby exposing the hydrolysis site for automatic activation. Therefore, in most tumor cells, the level of caspase-3 is high, the cells cannot activate the auto-apoptotic system, and the diseased cells eventually accumulate into tumors. If the external force can help the conversion of procaspase-3 to the active apoptotic enzyme caspase-3, which induces apoptosis, the purpose of cancer treatment can be achieved. Therefore, the development of caspase-3 activator has a good application prospect. Summary of the invention
  • the object of the present invention is to find and develop a small molecule compound which can directly act and activate procaspase-3 to induce tumor cell apoptosis and to treat cancer.
  • the present inventors have found that the compound of the structural formula a-c has an effect of inhibiting tumor cells, and the inventors have also found that the compound of the formula I has an action of inhibiting tumor cells, and the present invention has been completed based on the above findings.
  • a first aspect of the invention provides a compound of formula I,
  • n 1 or 2;
  • Ar 1 is an aromatic carbocyclic ring or an aromatic heterocyclic ring which is optionally mono- or poly-substituted with a substituent selected from the group consisting of halogen, nitrile group, trifluoromethyl group, trifluoromethoxy group, hydroxyl group, nitro group, carboxy group.
  • Ar 2 is an aromatic carbocyclic ring or an aromatic heterocyclic ring substituted at the ortho position of its point of attachment by an OR 2 group, wherein the aromatic carbocyclic or aromatic heterocyclic ring is optionally mono- or more selected from the substituents below -Substitution: halogen, nitrile, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, carboxyalkyl, oxime oxycarbonyl, alkoxycarbonylalkyl, carboxamide, carboxamidoalkyl, alkyl , cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, decyl, cyano, amino, acylamino, alkylamino, dialkylamino, decylaminoalkyl, allyl Alkynyl group; A is O or S;
  • the compound according to the first aspect of the invention wherein the aromatic carbocyclic ring is selected from the group consisting of benzene, naphthalene, anthracene, phenanthrene, anthracene, anthracene, anthracene.
  • the compound according to the first aspect of the invention wherein the aromatic heterocyclic ring is selected from the group consisting of: pyridine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, oxazole, isoxazole, hydrazine, benzofuran, benzo imidazole, carbazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, purine, phenothiazine-11 Qin, phenoxazine.
  • a compound according to the first aspect of the invention which is selected from the group consisting of
  • a second aspect of the invention provides a compound of formula 3, b, or C,
  • a third aspect of the invention provides a process for the preparation of a compound of the first aspect of the invention, the method comprising the steps of:
  • the compound of formula 2 is preferably, for example, a compound represented by formula 2: 2']
  • a fourth aspect of the present invention provides a process for the preparation of the compounds of the formulae b and C according to the second aspect of the invention, the process comprising the steps of:
  • a fifth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any one of the first aspect and the second aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable Carrier, diluent or excipient.
  • a sixth aspect of the invention provides the use of a compound according to any of the first and second aspects of the invention for the manufacture of a medicament as a tumor cell inhibitor.
  • a seventh aspect of the invention provides a method of treating or preventing a disease or condition associated with a tumor, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of any of the first and second aspects of the invention.
  • aromatic carbocyclic ring has its ordinary meaning as is well known in the art, which forms a moiety in the compound of formula I, and which generally includes, but is not limited to, benzene, naphthalene, anthracene, phenanthrene, anthracene , ⁇ , ⁇ , which may optionally be replaced by a single substitution or multiple substitutions.
  • aromatic heterocycle has its ordinary meaning as is well known in the art, which forms a moiety in a compound of formula I, and which typically includes, but is not limited to, pyridine, pyrrole, furan, thiophene, pyridyl Azole, imidazole, thiazole, oxazole, isoxazole, hydrazine, benzofuran, benzophenanthrene, oxazole, noisy, pyrimidine, pyrazine, quinoline, isoquinoline, hydrazine, phenothiazine, phenanthrene A azine, which may optionally be substituted a single time or multiple times.
  • alkyl has its general meaning as is known in the art. And usually includes straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like.
  • aryl nitrile, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, carboxyalkyl, alkoxy, Alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyaryl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl , fluorenyl, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, propyl, alkynyl.
  • the above compound of the formula I or a pharmaceutically acceptable salt or solvate thereof can be prepared by the following exemplary method, wherein the intermediate used is merely exemplary, and other examples not enumerated in the present invention are applicable in the middle of the reaction.
  • the body is of course also suitable, and the exemplary method comprises the following steps:
  • each group is as defined for Formula I. 3) using ethanol as a solvent, adding hydrazine hydrate or the corresponding substituted hydrazine, refluxing, and dropping the compound of the formula 2 obtained in the second step, and generating a hydrazino reaction to form a compound of the formula 3: 3 , preferably for example a compound:
  • the above structural formulas b and C or a pharmaceutically acceptable salt or solvate thereof can be produced by the following exemplary method, which comprises the following steps:
  • Physiologically acceptable salts of the compound of formula I and the compound of formula ac include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts.
  • Suitable acid salts include 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 of benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, steroic, citric acid or the like.
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts.
  • suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and Pu Rucaine salt.
  • the present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs.
  • prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compounds of formula I and compounds of formula a-c.
  • conventional methods for the selection and preparation of suitable prodrug derivatives are described in "Design Of Prodrugs", H Bund Saard, Elsevier, ed., 1985.
  • the invention also includes active metabolites of the compounds of the invention.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • the compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.
  • compositions of the present invention comprise an effective amount of a compound of formula I of the present invention and a compound of formula a-c, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants.
  • a partial glyceride mixture of fatty acids, water, salt or electrolyte such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, Cellulose material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Internal, intraventricular, intrasternal and intracranial injection or input, or with an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier generally comprises lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the gel attack formulation generally comprises lactose and dried corn starch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs.
  • the form is as follows:
  • the compound of the present invention When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution in a form of isotonic, sterile saline at a pH which may or may not be added with a preservative such as benzyl chloride. Alkoxide.
  • the compound can also be formulated into a cream form such as a vaseline cream.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers for ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used, including but not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension barrier, such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention depends 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 Subjective judgment of the doctor.
  • a preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is from 5 mg/kg to 10 mg/kg body weight per day.
  • the melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected.
  • the 1 H-NMR spectrum was measured by a Bruker ARX 400 type nuclear magnetic apparatus.
  • FAB mass spectra were determined by a Zabspect high resolution magnetic mass spectrometer.
  • the intermediate 5 was used as the starting material and the intermediate 3 was operated. Light yellow liquid product
  • the intermediate 11 was used as the starting material, and the intermediate 2 was operated. A light yellow liquid product is obtained.
  • the intermediate 12 was used as the starting material, and the intermediate 3 was operated. Get a yellow liquid product.
  • the intermediate 15 was used as the starting material, and the intermediate 3 was operated. Get a yellow liquid product.
  • the intermediate 17 was used as the starting material, and the intermediate 2 was operated. A light yellow liquid product is obtained.
  • the intermediate 18 was used as the starting material and the intermediate 3 was operated. A light yellow liquid product is obtained.
  • the intermediate 20 was used as the starting material, and the intermediate 2 was operated. A light yellow liquid product is obtained.
  • the intermediate 21 was used as the starting material, and the intermediate 3 was operated. A light yellow liquid product is obtained.
  • Example 8 (E)-N,-(4-N,N,-Diethylamino-2-hydroxybenzylidene)-2-(N-(2-(N-(4-tert-butyl)) Benzyl)-N-mercaptoamino)ethyl)N-decylamino)acetyl hydrazine;
  • Example 12 (E)-N,-(3,5-di-tert-butyl-2-hydroxybenzylidene)-2-(N-(2-(N-(4-benzyloxybenzyl)) Methylamino)ethyl)N-methylamino)acetyl hydrazine;
  • Example 13 (E)-N,-( 3 _allyl- 2 -hydroxybenzylidene) _ 2 -(N-( 2 _(N-( 4 -benzyloxybenzyl) -N- Methylamino)ethyl)N-decylamino)acetyl hydrazine;
  • Example 14 (E)-N,-(2-hydroxy-1-naphthalenylene)-2-(N-(2-(N-(4-benzyloxybenzyl)methylamino)ethyl N-methyl thiol) acetohydrazide;
  • Example 15 N,N,-bis(4-(benzyloxy)benzyl)-N,N,-didecylethylenediamine;
  • THF 100 mL, N,N,-dimethylethylenediamine 2.4 mL (0.02 mol)
  • 10 g of Intermediate 10 (0.04 mol) was initially added dropwise to control the drop rate, and a white precipitate formed gradually, and the reaction was monitored by TLC.
  • Example 16 (E)-N,-(3,5-di-tert-butyl- 2-hydroxybenzylidene)-3-(N-(2-(N-benzylbenzylamino)propyl) N-methylamino)acetylhydrazine;
  • Example 17 (E)-N,-(4-N,N,-DiethylJ ⁇ -2-hydroxybenzimidyl)-3-(N-(2-(N-benzylmercaptoamino) )propyl) N-methylamino)acetyl hydrazine;
  • Example 19 (E)-N ,-(2-hydroxy-1-naphthalenylene)-3-(N-(2-(N-benzyl-N-decylamino)propyl) N-decylamino)ethyl ugly;
  • Example 20 (E)-N,-(3,5-di-tert-butyl-2-hydroxybenzylidene)-3-(N-(2-(N-) (4-tert-butylbenzyl)-N-decylamino)propyl) N-methylamino)acetyl hydrazine;
  • Example 21 (E)-N,-(3-allyl-2-hydroxybenzylidene)-3-(N-(2-(N-(4-tert-butylbenzyl))-N- Methylamino)propyl) N-methylamino)acetyl hydrazine;
  • Example 22 (E)-N,-(2-hydroxy-1-naphthylmethyl)-3-(N-(2-(N-(4-tert-butylbenzyl)methylamino)propyl) N-decylamino)acetyl hydrazine;
  • Example 23 (E)-N,-(4-N,N,-Diethylamino-2-hydroxybenzylidene)-3-(N-(2-(N-(4-tert-butyl)) Benzyl)nonylamino)propyl)N-fluorenyl ⁇ )acetyl hydrazine;
  • Example 26 (E)-N,-(3,5-di-tert-butyl-2-hydroxybenzylidene)-3-(N-(2-(N-(4-decyloxybenzyl)) Methylamino)propyl) N-methylamino)acetyl hydrazine;
  • Example 27 (E)-N,-(3-allyl-2-hydroxybenzylidene)-3-(N-(2-(N-(4-decyloxybenzyl))-N- Mercaptoamino)propyl) N-methylamino)acetyl hydrazine;
  • the activity of the antitumor cells of the present invention relating to the compound can be detected by the MTT method, and is as follows.
  • Example 31 Evaluation of the activity of the compound of the present invention against tumor cells

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés d'hydrazide de type acétyle substitué de formule I et des composés de formule a-c ayant pour effet d'inhiber les cellules tumorales, leurs sels ou solvates de qualité pharmaceutique, leur synthèse, les compositions pharmaceutiques incluant les composés des revendications 1-5 et l’application des principes actifs ci-avant à la synthèse d'agents antitumoraux.
PCT/CN2009/001311 2008-11-28 2009-11-24 Dérivés d'hydrazide de type acétyle substitué, leur synthèse et leurs applications Ceased WO2010060277A1 (fr)

Applications Claiming Priority (2)

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CN2008101804866A CN101402587B (zh) 2008-11-28 2008-11-28 取代乙酰肼类衍生物及其制备方法和用途
CN200810180486.6 2008-11-28

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WO2010060277A1 true WO2010060277A1 (fr) 2010-06-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017517522A (ja) * 2014-05-30 2017-06-29 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 置換アセチドラジド誘導体、その調製方法及び使用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101402587B (zh) * 2008-11-28 2012-04-11 中国人民解放军军事医学科学院毒物药物研究所 取代乙酰肼类衍生物及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4239526A (en) * 1979-09-04 1980-12-16 W. R. Grace & Co. Substituted ureas as sugarcane ripeners
CN1145075A (zh) * 1994-03-28 1997-03-12 贾帕特有限公司 内皮素受体拮抗剂
CN101402587A (zh) * 2008-11-28 2009-04-08 中国人民解放军军事医学科学院毒物药物研究所 取代乙酰肼类衍生物及其制备方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10346913A1 (de) * 2003-10-09 2005-05-04 Merck Patent Gmbh Acylhydrazonderivate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4239526A (en) * 1979-09-04 1980-12-16 W. R. Grace & Co. Substituted ureas as sugarcane ripeners
CN1145075A (zh) * 1994-03-28 1997-03-12 贾帕特有限公司 内皮素受体拮抗剂
CN101402587A (zh) * 2008-11-28 2009-04-08 中国人民解放军军事医学科学院毒物药物研究所 取代乙酰肼类衍生物及其制备方法和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUSUF M. ET AL.: "Steps Towards a Practical Synthesis of Macrocyclic isbenzylisoquinolines.", J. HETEROCYCLIC CHEM., vol. 42, 2005, pages 647 - 659 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017517522A (ja) * 2014-05-30 2017-06-29 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 置換アセチドラジド誘導体、その調製方法及び使用
EP3150576A4 (fr) * 2014-05-30 2017-12-06 Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. China Dérivés d'acétohydrazide substitué, procédé de préparation associé et utilisation correspondante
US10196346B2 (en) 2014-05-30 2019-02-05 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Substituted acethydrazide derivative, preparation method and use thereof

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CN101402587A (zh) 2009-04-08
CN101402587B (zh) 2012-04-11

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