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WO2013064029A1 - Dérivé de benzoylurée ayant une activité anticancéreuse et son procédé de préparation et son utilisation - Google Patents

Dérivé de benzoylurée ayant une activité anticancéreuse et son procédé de préparation et son utilisation Download PDF

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Publication number
WO2013064029A1
WO2013064029A1 PCT/CN2012/083431 CN2012083431W WO2013064029A1 WO 2013064029 A1 WO2013064029 A1 WO 2013064029A1 CN 2012083431 W CN2012083431 W CN 2012083431W WO 2013064029 A1 WO2013064029 A1 WO 2013064029A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitrobenzoyl
substituted
unsubstituted
ethynyl
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2012/083431
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English (en)
Chinese (zh)
Inventor
白骅
赵旭阳
龚永祥
钟金清
朱齐凤
刘晓宇
刘礼飞
林海鸣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Hisun Pharmaceutical Co Ltd
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
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.)
Filing date
Publication date
Application filed by Zhejiang Hisun Pharmaceutical Co Ltd filed Critical Zhejiang Hisun Pharmaceutical Co Ltd
Publication of WO2013064029A1 publication Critical patent/WO2013064029A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/48—Y being a hydrogen or a carbon atom
    • C07C275/54—Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid

Definitions

  • the present invention relates to a benzoylurea derivative having an anticancer activity and a metabolite thereof.
  • the invention also relates to the synthesis of such anticancer drugs and methods of using such compounds to treat cancer. Background technique
  • R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted (C r C 5 )alkyl, substituted or unsubstituted (c 3 -c 5 )alkenyl, substituted or unsubstituted Substituted (c 3 -c 5 )alkynyl, substituted or unsubstituted (C 3 -C 5 )cycloalkyl; R 1 and R 2 may also be cyclized to form a substituted or unsubstituted five, six or seven member Rings; R 2 and R 3 may also be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring; wherein the above substituted or unsubstituted (C 3 -C 5 )alkenyl group, substituted or unsubstituted Preferably, the (C 3 -C 5 ) alkynyl group is a double bond of an
  • RR 2 and R 3 are independently selected from hydrogen, substituted or unsubstituted (dC 5 )alkyl.
  • the second aspect of the invention also discloses the use of a compound of the formula (I) and a pharmaceutical composition thereof for the preparation of a medicament for the treatment of cancer.
  • the cancer includes colon cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, acute leukemia, chronic leukemia, prostate cancer, human uterine cancer, pancreatic cancer, liver cancer, brain cancer, CNS tumor, bladder cancer, kidney cancer, skin cancer, Cervical cancer, muscle tumors, lymphoma, bone cancer, and other types of cancer.
  • the compound represented by the general formula (I) and a pharmaceutical composition for the preparation of a medicament for treating a disorder, associated or concomitant disorder caused by cell proliferation and/or angiogenesis are also disclosed.
  • a further aspect of the invention resides in the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease associated with a poly(ADP-ribose) polymerase (PARP) inhibitor.
  • Diseases associated with poly(ADP-ribose) polymerase (PARP) inhibitors include cancer, Stroke, Myocardial infarction, and Neuodegenerative diseases.
  • a further aspect of the present invention provides the use of an effective amount of the compound represented by the formula (I) or a pharmaceutical composition comprising the compound represented by the formula (I), alone or in combination with other drugs, for treatment by cell proliferation and/or A method of causing, associated or concomitant disorders of angiogenesis.
  • Pharmaceutically acceptable carriers compatible with the compounds of formula (I) may also be included in the pharmaceutical compositions of the invention.
  • the compound of the formula (I) can be administered in a usual dosage form, such as an injection form and an oral form, including a capsule, a tablet, a powder, a sputum, a suspension or a solution, preferably administered by injection.
  • the dosage form and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives, as well as conventional techniques.
  • the pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, moisturizers A slipper, a flavoring agent, a thickener, a colorant, an emulsifier, and the like.
  • Another aspect of the present invention is to disclose a process for producing the benzoylurea derivative.
  • Another object of the present invention is to provide a process for producing a compound of the formula (I) using the compound III as a raw material (shown as the following Reaction Scheme 2).
  • This method is applicable to the compound of formula (I) wherein R 2 , R 3 are hydrogen, substituted or unsubstituted (dC 5 )alkyl, substituted or unsubstituted (C 3 -C 5 )alkenyl, substituted or unsubstituted (C 3 -C 5 ) alkynyl, substituted or unsubstituted (C 3 -C 5 )cycloalkyl; R 2 and R 3 may also be cyclized to form a substituted or unsubstituted four, five, six or seven member Ring, R 1 is a substituted or unsubstituted (C r C 5 ) alkyl group, a substituted or unsubstituted (C 3 -C 5 ) alkenyl group, a substituted or unsubstit
  • a further object of the present invention is to provide a process for preparing a compound of the formula (I) (shown as the following Reaction Scheme 3).
  • This method is applicable to the compound of formula (I) wherein R 2 , R 3 are hydrogen, substituted or unsubstituted (C r C 5 )alkyl, substituted or unsubstituted (C 3 -C 5 )alkenyl, substituted or not Substituted (C 3 -C 5 ) alkynyl, substituted or unsubstituted (C 3 -C 5 )cycloalkyl; R 2 and R 3 may also be cyclized to form a substituted or unsubstituted four, five, six or a seven-membered ring, wherein R 1 is hydrogen, R 4 is a nitro group, and R 5 is an ethynyl group, as used in the preparation of compound 1-27, compound 1-28, compound 1-29, compound 1-30, compound 1 -31, Compound
  • a further object of the present invention is to provide a process for the preparation of a compound of formula (I) (shown below in Scheme 4).
  • This method is applicable to the compound of formula (I) wherein RR 2 , R 3 is hydrogen, substituted or unsubstituted (C r C 5 )alkyl, substituted or unsubstituted (C 3 -C 5 )alkenyl, substituted or not Substituted (C 3 -C 5 )alkynyl, substituted or unsubstituted (C 3 -C 5 )cycloalkyl; R 1 and R 2 may also be cyclized to form a substituted or unsubstituted five, six or seven member Rings; R 2 and R 3 may also be cyclized to form a substituted or unsubstituted tetra, five, six or seven membered ring, R 4 is a nitro group, and R 5 is an ethynyl group, as used in the preparation of compound
  • Halogen means fluorine, chlorine, bromine and iodine.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group.
  • the alkyl group of CC 5 is preferred.
  • Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like.
  • alkenyl as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight-chain or branched. Preferred is an alkenyl group of c 3 -c 5 . Examples of alkenyl groups include, but are not limited to, allyl, 2-butenyl and the like.
  • Alkynyl as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight-chain or branched. Preference is given to C 3 -C 5 alkynyl groups. Examples of alkynyl groups include, but are not limited to, propargyl, 2-butynyl, and the like.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt, an amine salt formed with a suitable acid; the metal salt is preferably an alkali metal or an alkaline earth metal salt, and suitable acids include inorganic acids and organic acids, for example Acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, mala Acid, mandelic acid, methanesulfonic acid, nitric acid, brick acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like, particularly preferred are hydrochloric acid, hydrobromic acid
  • Cycloalkyl means a saturated or partially saturated carbocyclic ring. A ring composed of 3-5 carbon atoms is preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • Alkoxy means a group of (alkyl-0-). Among them, the alkyl group is defined in the relevant definition herein. The alkoxy group of dC 5 is preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • the compounds of the invention are highly active tumor growth inhibitors.
  • the glassware i is dried in an oven and/or dried by heating.
  • the reaction was followed by glass silica gel - 60 F254 plate (0.25 mm) (TLC).
  • Analytical thin layer chromatography was carried out and developed in a suitable solvent ratio (v/v). The end point of the reaction was taken as the starting material was depleted on the TLC.
  • the succinct is measured by LC/MS, and the ionization method can be ESI or APCI.
  • Il 1-18 Add 10 g (0.0275 mol) of 1-(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea (compound 1-1) and 100 to a 250-liter single-mouth bottle. Soaring N, N-dimethylformamide, stirring and stirring, then adding 12.7 g (0.092 mol) of anhydrous carbonic acid clock and 16.7 liters (0.268 mol) of methyl iodide, reacting at room temperature for 1 hour, TLC detection reaction is completed, add 100 Soaring water, Ethyl acetate (200 liters x 3) was extracted, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / n-hexane as eluent).
  • Example 34 Preparation of 1-(4-ethynyl-3-nitrobenzoyl)-3,3-dimethylurea (1-34): Step 1: Add 5 g (13.77 mmol) of 1-(4-iodo-3-nitrobenzoyl)-3,3-dimethylurea (compound 1-1) to a single-mouth vial, 4.3 liters of three Ethylamine and 75 liters of tetrahydrofuran, nitrogen protection, magnetic stirring, then add 0.5 g (0.712 ⁇ mol) of bis(triphenyl brick) palladium dichloride, 0.3 g (1.57 mol) of cuprous iodide, 7.4 liters (52 ⁇ mol) trimethylsilylacetylene, reacted at room temperature for 15 minutes, the reaction was completed by TLC, the solvent was evaporated under reduced pressure, and extracted with 100 liters of ethyl acetate.
  • Step 2 Add 2.5 g (7.5 mmol) of 1-[4-(2-trimethylsilyl)ethynyl-3-nitrobenzoyl]-3,3-dimethylurea to the reaction flask.
  • reaction solution is poured into a 1N aqueous hydrochloric acid solution to precipitate a solid, which is filtered, washed with water to neutrality, dried, decolorized by activated carbon, and recrystallized from ethyl acetate to give 1-(4-ethynyl-3-nitrate Benzoyl)-3,3-dimethylurea
  • the pharmacodynamic screening of the compounds of the invention is carried out as follows: Cell culture Human colon cancer cell lines (COLO205 and HCT-116), human breast cancer cell lines (MCF-7 and MDA-MB435), human lung cancer cell lines (A549 and NCI460), human leukemia (HL-60), human prostate cancer ( BXPC-3) and human uterine cancer (HELA) were obtained from ATCC. COLO205, HL-60 cells were cultured in RPMI 1640 containing 2 mM/L-glutamine, 10% FBS, 1.0 mM sodium pyruvate.
  • HCT-116, MCF-7, A549, NCI460, BXPC-3, HELA cells were cultured in DMEM containing 2 mM/L-glutamine and 10% FBS.
  • MDA-MB435 cells were cultured in L-15 containing 2 mM/L-glutamine, 10% FBS.
  • COLO205 and HL-60 cells were seeded in 96-well plates, 150 ⁇ ! 7 wells, 8000 cells per well, and 96-well plates were pre-incubated for 24 hours at 37 ° C, 5% C0 2 , 100% relative humidity incubator.
  • HCT-116, MCF-7 > NCI460, HELA and MDA-MB435 cells were seeded in 96-well plates at 5000 cells per well; A549 and BXPC-3 cells were seeded in 96-well plates at 10,000 cells per well.
  • the 96-well plates were pre-incubated for 24 hours at 37 ° C, 5% C0 2 , 100% relative humidity incubator to allow the cells to adhere.
  • TCA fixed cells 50 pre-cooled 50% (mass/volume) TCA fixed cells were added to the culture fluid level. Then, it was allowed to stand at 4 ° C for 1 h, the supernatant was discarded, and each well was washed 5 times with deionized water to remove TCA and serum proteins. After drying in air, add a sufficient amount of 0.4% SRB (prepared with 1% acetic acid) to each well for about 100 L, and leave it at room temperature for 20-30 min. The liquid in each well was discarded and quickly washed 5 times with 1% acetic acid to remove unbound dye until the unbound dye was rinsed clean.
  • SRB prepared with 1% acetic acid
  • BSI-201 (Iniparib) was used as a positive drug, and the results showed that compounds 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-8, 1 -9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21 , 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1 -34, 1-35, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-46 , 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53 inhibit tumor cell proliferation; Compound 1-7 also has certain tumor suppressor activity, but its GI 5 .

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Abstract

La présente invention concerne un dérivé de benzoylurée de formule (I) ayant une activité anticancéreuse ou le sel ou promédicament pharmaceutiquement acceptable de celui-ci, et la préparation d'un tel dérivé et l'utilisation de celui-ci dans la préparation de médicament pour le traitement de maladies associées à un inhibiteur de poly(ADP-ribose)polymérase (PARP), tel qu'un médicament pour le traitement d'un cancer.
PCT/CN2012/083431 2011-11-04 2012-10-24 Dérivé de benzoylurée ayant une activité anticancéreuse et son procédé de préparation et son utilisation Ceased WO2013064029A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110344421.2A CN103086925B (zh) 2011-11-04 2011-11-04 具有抗癌活性的苯甲酰脲衍生物及其制备方法和用途
CN201110344421.2 2011-11-04

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WO2013064029A1 true WO2013064029A1 (fr) 2013-05-10

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* Cited by examiner, † Cited by third party
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TWI703130B (zh) * 2014-03-07 2020-09-01 瑞士商赫爾辛保健股份有限公司 對位取代的不對稱脲及其醫療用途
CN105326821A (zh) * 2015-09-23 2016-02-17 华东理工大学 取代脲类小分子亲环素a抑制剂新型抗癌用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1049497A (zh) * 1989-07-28 1991-02-27 石原产业株式会社 取代的苯甲酰脲化合物或它们的盐、它们的制备方法及含有该类物质的抗肿瘤组合物
CN1850794A (zh) * 2006-05-30 2006-10-25 中国医学科学院医药生物技术研究所 3－酰胺基取代苯甲酰脲类化合物及其抗肿瘤作用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1049497A (zh) * 1989-07-28 1991-02-27 石原产业株式会社 取代的苯甲酰脲化合物或它们的盐、它们的制备方法及含有该类物质的抗肿瘤组合物
CN1850794A (zh) * 2006-05-30 2006-10-25 中国医学科学院医药生物技术研究所 3－酰胺基取代苯甲酰脲类化合物及其抗肿瘤作用

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