WO2023050975A1 - DÉRIVÉ DE α-FLUOROACYLE PIPÉRAZINE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION - Google Patents

DÉRIVÉ DE α-FLUOROACYLE PIPÉRAZINE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION Download PDF

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WO2023050975A1
WO2023050975A1 PCT/CN2022/105698 CN2022105698W WO2023050975A1 WO 2023050975 A1 WO2023050975 A1 WO 2023050975A1 CN 2022105698 W CN2022105698 W CN 2022105698W WO 2023050975 A1 WO2023050975 A1 WO 2023050975A1
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cancer
reaction
derivatives
preparation
derivative
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PCT/CN2022/105698
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English (en)
Chinese (zh)
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沈征武
邓斌
江亮
查雨峰
张梦麒
边泓竹
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云白药征武科技(上海)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to an ⁇ -fluoroacylpiperazine derivative and its preparation and application.
  • PI3K is closely related to intracellular signal transduction, and plays a regulatory role in many important cellular processes, such as cell growth, differentiation, proliferation, apoptosis, and intracellular transport.
  • the PI3K-Akt-mTOR signaling pathway plays an important role in cell growth, differentiation, and apoptosis.
  • Many member molecules of signal transduction are key drug targets in the processes of cancer, immunity, and thrombus control. . When this signaling pathway is abnormally activated in the human body, it often leads to the occurrence of cancer.
  • PI3K kinases are divided into three types: I, II, and III. Among them, type I PI3K is the most deeply studied, and type I PI3K is a heterodimer composed of a regulatory subunit and a catalytic subunit. There are four catalytic subunits, namely p110 ⁇ , ⁇ , ⁇ , ⁇ . Today, cancer and the target-pathological role of PI3K have been identified.
  • Each of the four catalytic subunits of class I PI3K kinases preferentially regulates specific signaling roles, depending on the type of malignancy and the genetic or epigenetic alterations that occur.
  • p110 ⁇ is critical for the growth of tumor cells driven by PIK3CA mutations or oncogene RAS and receptor tyrosine kinases; p110 ⁇ mediates PTEN-deficient tumorigenesis; and p110 ⁇ is highly expressed in leukocytes, thereby making It becomes an ideal target for the treatment of hematological malignancies.
  • p110 ⁇ may play an important role in the pathogenesis of IPF (idiopathic pulmonary fibrosis), and may be a specific pharmacological target of IPF.
  • PI3K inhibitors currently approved by the FDA include: Idelalisib, a PI3K ⁇ selective inhibitor, for the treatment of lymphoma; Copanlisib, a PI3K- ⁇ / ⁇ inhibitor, for the treatment of recurrent follicular lymphoma; Duvelisib, a PI3K ⁇ / ⁇ inhibitor, Treatment of lymphoma; Alpelisib, PI3K- ⁇ inhibitor, for the treatment of advanced metastatic breast cancer; Umbralisib, PI3K ⁇ and CK1 ⁇ inhibitor, for the treatment of lymphoma.
  • the PI3K inhibitor (Apitolisib, GDC-0980, RG7422, CAS: 1032754-93-0), developed by Genentech, is in the second phase of clinical trials. Kidney tumors;
  • the object of the present invention is to provide a kind of ⁇ -fluoroacylpiperazine derivative and its preparation and application, and the described ⁇ -fluoroacylpiperazine derivative and its preparation and application will solve the problems of drugs in the prior art for the treatment of Cancer's ineffective technical problems.
  • the present invention provides an ⁇ -fluoroacylpiperazine derivative, the ⁇ -fluoroacylpiperazine derivative having the general formula (I) or its isomer, or its pharmaceutically acceptable salt, or its prodrug molecule, which General formula (I) chemical structure is:
  • X O or S; wherein, the acyl ⁇ position of the acylpiperazine contains at least one fluorine atom;
  • R is H, halogen, cyano, alkyl, alkenyl, alkynyl or derivatives thereof of 1-15 carbons; monocyclic or condensed aromatic rings containing 5-22 carbon atoms Group or its derivatives; 5- to 8-membered heterocycle or heterocycle or its derivatives containing 1-4 heteroatoms; carboxyl or its derivatives; hydroxyl or its derivatives; amino or its derivatives; mercapto or derivatives thereof; sulfone or sulfoxide derivatives; sulfonates or sulfonates; phosphates or phosphates;
  • R2 is H, halogen, cyano, alkyl, alkenyl, alkynyl or derivatives thereof of 1-15 carbons; monocyclic or condensed aromatic rings containing 5-22 carbon atoms Group or its derivatives; 5- to 8-membered heterocycle or heterocycle or its derivatives containing 1-4 heteroatoms; carboxyl or its derivatives; hydroxyl or its derivatives; amino or its derivatives; mercapto or derivatives thereof; sulfone or sulfoxide derivatives; sulfonate or sulfonate; phosphate or phosphate.
  • the acyl ⁇ position of the acylpiperazine is a single optical configuration or a racemate; R 1 and R 2 can be the same or different; in the general formula (I), R 1 and R2 can be connected to form a ring structure.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned ⁇ -fluoroacylpiperazine derivative or its isomer, or its pharmaceutically acceptable salt, or its prodrug molecule and one or more A pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention also provides a method for preparing the above-mentioned ⁇ -fluoroacylpiperazine derivative, the reaction equation of which is as follows:
  • P 1 is H or an amino protecting group
  • P 2 is H or an amino protecting group
  • P 1 and P 2 are not H at the same time
  • Amino protecting groups include formyl, acetyl, trifluoroacetyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthaloyl, cyclosuccinyl, 2- Biphenyl-2-propoxycarbonyl, p-toluenesulfonyl, trityl, etc.;
  • the reductive amination reaction solvent can be anhydrous or water-containing, including dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, 1,2-dichloroethane, ethylene glycol dimethyl ether, bis(ethylene glycol) Dimethyl ether, etc.;
  • the reducing reagents used in reductive amination include NaBH 4 , KBH 4 , LiBH 4 , Zn(BH 4 ) 2 , NaBH 3 CN, NaBH(OAc) 3 , borane complex, Bu 3 SnH, PhSiH 4 , etc.;
  • Catalysts used in reductive amination include protic acid and Lewis acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, BF 3 , SnCl 2 , SnCl 4 , Ti(O i Pr) 4 , SiO 2 , BuSnCl 2 etc. ;
  • Acids used for deprotection include protic acids and Lewis acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, BF 3 , SnCl 2 , SnCl 4 , Ti(O i Pr) 4 , SiO 2 , BuSnCl 2 , AlCl 3 etc.;
  • protic acids and Lewis acids such as hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, BF 3 , SnCl 2 , SnCl 4 , Ti(O i Pr) 4 , SiO 2 , BuSnCl 2 , AlCl 3 etc.;
  • the bases used for deprotection include inorganic bases and organic bases.
  • Inorganic bases include: sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydride, calcium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc.
  • Organic bases include: hydrazine hydrate, lithium diisopropylamide, butyllithium, lithium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, pyridine, pyrrole, piperidine, morpholine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, etc.;
  • the hydrogen source used in the catalytic reduction deprotection reaction includes hydrogen, formic acid, ammonium formate, etc.; the catalyst includes metal catalysts such as Pd, Pt, Ni, and Cu;
  • the solvent used in the deprotection reaction may be a protic solvent, an aprotic solvent or a mixed solvent.
  • a protic solvent Preferably dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, methanol, ethanol, water, ethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, etc.;
  • the thio reagents are P 2 S 5 , 2,4-bis(methylthio)-1,3,2,4-dithiadiphosphatidine-2,4-disulfide, 2,4 -Bis(phenylthio)-1,3-dithio-2,4-diphosphetane-2,4 disulfide, or 2,4-bis(4-phenoxyphenyl)- 1,3,2,4-dithiodiphosphetane-2,4-disulfide;
  • the solvent used in the reaction is either a protic solvent or an aprotic solvent or a mixture of both;
  • the fluorinated reagents used include HF and its salts, SF 4 , diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, 4-tert-butyl Base-2,6-dimethylphenylsulfur trifluoride, pyridine-2-sulfonyl fluoride, bis(2-methoxyethyl)aminosulfur trifluoride, diethylamino)difluorosulfonium tetrafluoro Borate, difluoro(4-morpholino)sulfonium tetrafluoroborate, 1,3-bis(2,6-diisopropylphenyl)-2,2-difluoroimidazoline, 4-chloro -N-[(4-methylphenyl)sulfonyl]-benzenesulfonyl fluoride; the solvent used in the reaction is an apro
  • the reaction temperature is -78 to 180 degrees Celsius
  • the crude product of the final product in the above-mentioned reaction can use solvent extraction method, precipitation method, crystallization method to further purify, also can use column chromatography to carry out purification, filler uses silica gel, gel, macroporous resin or aluminum oxide, and eluent can be Mix petroleum ether-acetone, petroleum ether-ethyl acetate, petroleum ether-dichloromethane, etc. in different proportions.
  • the present invention also provides an application of the above-mentioned ⁇ -fluoroacylpiperazine derivative or its isomer, or its pharmaceutically acceptable salt, or its prodrug molecule in the preparation of a drug for treating cancer.
  • the cancer is brain cancer, glioma, endometrial cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, lung cancer, prostate cancer, liver cancer, leukemia, lymphoma, skin cancer, basal cell tumor , hemangioma, uterine cancer, laryngeal cancer, stomach cancer, lip cancer, esophagus cancer, nasopharyngeal cancer, gallbladder cancer, pancreatic cancer, kidney cancer, tongue cancer, bladder cancer, melanoma, lipoma, thyroid cancer, thymus cancer or bone cancer.
  • the present invention also provides the above-mentioned ⁇ -fluoroacylpiperazine derivative or its isomer, or its pharmaceutically acceptable salt, or its prodrug molecule combined with at least one other anti-cancer agent in the preparation of the treatment of cancer application in medicines.
  • the other anticancer agents are doxorubicin, bleomycin, vinblastine, taxanes, etoposide, 5-fluorouracil, cyclophosphamide, methotrexate, cisplatin, Retinoic acid, temozolomide, actinomycin, imatinib, gefitinib, sorafenib, erlotinib, sunitinib, afatinib, cabozantinib, ostinib, Any one or both of rituximab, cetuximab, trastuzumab, nivolumab, panlizumab, atezolizumab, durvalumab, or avelumab combination of the above.
  • the ⁇ -fluorinated amide piperazine derivatives of the present invention introduce a fluorine atom with strong electron-withdrawing ability at the ortho-position of the amide group, which changes the electron cloud distribution of amide piperazine, not only enhances the PI3K kinase inhibitory activity of this type of molecule, but also On the one hand, the lipid-water distribution coefficient of the compound is also optimized, making it easier for this type of drug to permeate the cell membrane, so it has a strong anti-tumor activity and has a very broad application prospect.
  • Embodiment one the preparation of compound 1:
  • Embodiment two the preparation of compound 2:
  • starting material 13 (50 mg, 0.1 mmol) was dissolved in dichloromethane (1 mL), followed by dropwise addition of 4 drops of DAST. After the reaction solution was stirred at room temperature for 5 hours, the reaction solution was poured into 10 ml of saturated aqueous sodium bicarbonate solution and extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 31 mg of white solid.
  • Embodiment three the preparation of compound 3
  • Embodiment four the preparation of compound 4
  • Embodiment five the preparation of compound 5
  • Embodiment six the preparation of compound 6
  • Embodiment seven the preparation of compound 7
  • Embodiment eight the preparation of compound 8
  • Embodiment nine the preparation of compound 9
  • Embodiment 10 Preparation of compound 10
  • Embodiment 11 Preparation of compound 11
  • Embodiment 12 Preparation of compound 12
  • the clogP value refers to the logarithmic value of the ratio of the partition coefficient of a substance in n-octanol (oil) and water. It reflects the distribution of substances in the oil-water two-phase. The larger the clogP value, the more lipophilic the substance is, on the contrary, the smaller the value, the more hydrophilic, that is, the better the water solubility.
  • the dissolution, absorption, distribution, and transport of drugs in the body are related to the water solubility and fat solubility of the drug, that is, the oil-water partition coefficient clogP.
  • the data obtained from the calculation results show that the clogP corresponding to the compounds 1-12 is between 1-5, and has a good ester-water distribution coefficient.
  • the highest concentration of the compound is set to 10uM, diluted 4 times downward with DMSO, a total of 10 concentrations: 10uM, 2.5uM, 0.625uM, 0.156uM, 0.039uM, 0.0098uM, 0.0024uM, 0.0006uM, 0.00015uM, 0.000038 uM.
  • Example 15 Compounds inhibit the proliferation of tumor cells:
  • MCF-7 cells human breast cancer cells
  • NCI-H460 cells human large cell lung cancer cells
  • HCT116 cells human colon cancer cells
  • PC-3 cells human prostate cancer cells
  • HeLa cell human cervical cancer cell proliferation inhibitory toxicity
  • the initial concentration of the sample is 5 ⁇ M, and it is diluted 4 times downwards sequentially to obtain 10 concentrations: 5000nM, 1250nM, 312nM, 78nM, 19.5nM, 4.9nM, 1.2nM, 0.30nM, 0.076nM, 0.019nM.
  • 5000nM, 1250nM, 312nM, 78nM, 19.5nM, 4.9nM, 1.2nM, 0.30nM, 0.076nM, 0.019nM Take the cancer cells in the logarithmic growth phase, count them under a microscope, adjust the cell concentration to 7 ⁇ 104 /mL with the corresponding complete culture solution, plant them in a 96-well culture plate, 100 ⁇ L/well, and place at 37°C, 5% CO 2 incubator culture 24h.
  • the culture medium was sucked off with a syringe (suspended cells were centrifuged and the culture medium was sucked off, and the adherent cells were sucked directly), and then 200 ⁇ L of freshly prepared complete culture medium containing 10% MTT was added, and the culture was continued for 4 hours. Aspirate the upper layer culture solution, add 150 ⁇ L DMSO to each well, shake in the dark for 10 min, and measure the OD value of each well at a wavelength of 490 nm. IC50 values were calculated using SPSS17.0 software.

Abstract

La présente invention concerne un dérivé de α-fluoroacyle pipérazine, comprenant un dérivé de α-fluoroacyle pipérazine de formule générale (I) ou un isomère ou un sel pharmaceutiquement acceptable ou une molécule de promédicament de celui-ci, et ayant une structure chimique telle que représentée dans la formule générale (I). La présente invention concerne également un procédé de préparation du dérivé de α-fluoroacyle pipérazine. La présente invention concerne en outre une utilisation du dérivé de α-fluoroacyle pipérazine ou de son isomère, sel pharmaceutiquement acceptable ou molécule de promédicament dans la préparation d'un médicament pour le traitement du cancer. Le dérivé de α-fluoroacyle pipérazine selon la présente invention a un atome de fluor ayant une forte capacité de retrait d'électrons introduit dans une position ortho d'un groupe acyle, de façon à modifier la distribution du nuage d'électrons de la pipérazine acyle. Par conséquent, le dérivé de α-fluoroacyle pipérazine a une activité inhibitrice extrêmement forte de la PI3K-kinase et une activité antitumorale extrêmement forte, et a de vastes perspectives d'application.
PCT/CN2022/105698 2021-09-28 2022-07-14 DÉRIVÉ DE α-FLUOROACYLE PIPÉRAZINE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION WO2023050975A1 (fr)

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CN202111140554.8 2021-09-28

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CN113754680B (zh) * 2021-09-28 2022-07-22 云白药征武科技(上海)有限公司 一种α氟代酰基哌嗪衍生物及其制备和应用
CN114853754B (zh) * 2022-05-23 2023-04-18 云白药征武科技(上海)有限公司 一种硫代酰胺衍生物及其制备方法和应用

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WO2010080996A1 (fr) * 2009-01-08 2010-07-15 Curis, Inc. Inhibiteurs de phosphoinositide 3-kinase avec une fraction de liaison au zinc
CN113754680A (zh) * 2021-09-28 2021-12-07 云白药征武科技(上海)有限公司 一种α氟代酰基哌嗪衍生物及其制备和应用

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CN101600720A (zh) * 2006-12-07 2009-12-09 霍夫曼-拉罗奇有限公司 磷酸肌醇3-激酶抑制剂化合物及使用方法
SG179085A1 (en) * 2009-09-09 2012-04-27 Avila Therapeutics Inc Pi3 kinase inhibitors and uses thereof
CN113045582B (zh) * 2021-02-05 2022-12-23 中国药科大学 Parp-1/pi3k双靶点抑制剂或其药学上可接受的盐及其制备方法与用途

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Publication number Priority date Publication date Assignee Title
WO2010080996A1 (fr) * 2009-01-08 2010-07-15 Curis, Inc. Inhibiteurs de phosphoinositide 3-kinase avec une fraction de liaison au zinc
CN113754680A (zh) * 2021-09-28 2021-12-07 云白药征武科技(上海)有限公司 一种α氟代酰基哌嗪衍生物及其制备和应用

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