WO2017202295A1 - Dérivé d'éther d'oxime de salinomycine, son procédé de préparation et son utilisation pour la préparation de médicaments antitumoraux - Google Patents

Dérivé d'éther d'oxime de salinomycine, son procédé de préparation et son utilisation pour la préparation de médicaments antitumoraux Download PDF

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WO2017202295A1
WO2017202295A1 PCT/CN2017/085516 CN2017085516W WO2017202295A1 WO 2017202295 A1 WO2017202295 A1 WO 2017202295A1 CN 2017085516 W CN2017085516 W CN 2017085516W WO 2017202295 A1 WO2017202295 A1 WO 2017202295A1
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group
substituted
unsubstituted
salinomycin
alkyl
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PCT/CN2017/085516
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English (en)
Chinese (zh)
Inventor
吴松
周琪
张文轩
吴骏
李波
连旭
王柳
郝捷
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中国医学科学院药物研究所
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Publication of WO2017202295A1 publication Critical patent/WO2017202295A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/20—Spiro-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a salinomycin oxime ether derivative, a preparation method and an anti-tumor use, in particular to the treatment of gastric cancer, breast cancer and colon cancer.
  • Cancer stem cells are a new potential therapeutic target for tumors in recent years. They are a small group of stem cell cells that exist in tumor tissues and have the ability to self-renew and form. Tumor cells of different degrees of differentiation. Existing methods for treating tumors such as chemotherapy and radiotherapy are mostly directed to general tumor cells, rather than tumor stem cells, which leads to incomplete treatment and still causes tumor resistance, recurrence and metastasis.
  • Salinomycin is a polyether-based ionophore-type antibiotic isolated from Streptomyces albus. It has been used as a growth promoter and anticoccidial agent for poultry. The 2009 study found that salinomycin can kill breast cancer stem cells in a highly selective manner in vitro, and can significantly inhibit the growth of breast cancer in mice, which is 100 times more potent than the clinically used antitumor drug paclitaxel (Gupta, PB; Onder, TT; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, RA; Lander, ESI identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009, 138, 645.).
  • Salinomycin also has good activity against stem cells in other tumor tissues, such as acute myeloid leukemia stem cells, lung cancer stem cells, gastric cancer stem cells, osteosarcoma stem cells, colorectal cancer stem cells, squamous cell carcinoma stem cells, pancreatic cancer stem cells, and prostate cancer. Stem cells, etc. (Mertins, SD Cancer stem cells: a systems biology view of their role in prognosis and therapy. Anti-Cancer Drugs: 2014, 25(4), 353-367.).
  • Salinomycin structural formula (salinomycin)
  • salinomycin has very good effects on differentiated tumor cells such as leukemia, breast cancer, gastric cancer, colon cancer, pancreatic cancer, esophageal cancer, glioma, liver cancer, bladder cancer, prostate cancer and lung cancer tumor cells. Good inhibitory effect, also has good inhibitory activity against multidrug resistance, radiotherapy tolerance and apoptosis-tolerant cancer cells, such as chronic lymphocytic leukemia and human metastatic breast cancer (Huczynski, A. Salinomycin–A New Cancer Drug Candidate. Chem. Biol. Drug Des., 2012, 79, 235.).
  • salinomycin inhibits P-glycoprotein gp170, interferes with the Wnt signaling cascade, increases DNA damage and decreases p21 protein levels, overcomes ABC transporter-mediated multidrug resistance and apoptosis tolerance, and increases oxidative stress. Improve the level of active oxygen and so on.
  • salinomycin induces apoptosis of tumor stem cells by inhibiting Wnt/ ⁇ -Catenin signaling pathway, which is considered to be one of the main mechanisms for exerting antitumor activity.
  • the Wnt/ ⁇ -Catenin pathway plays an important role in maintaining the characteristics of cancer stem cells.
  • Wnt/ ⁇ -Catenin activation can cause cancer stem cells to obtain radiotherapy and chemotherapy resistance.
  • Lu et al found that salinomycin can inhibit the Wnt/ ⁇ -Catenin signaling pathway in leukemia cells and elucidate the mechanism: salinomycin acts on Wnt/Fzd/LPR complex, and LPR (low-density lipoprotein receptor-related protein) complex activity is Inhibition, resulting in down-regulation of downstream Wnt target genes LEF1, Cyclin D1 and Fibronectin, the final result is cancer cell apoptosis (Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces Apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A.2011;108(32):13253-7.
  • Zhu et al found that salinomycin can induce Wnt receptor LRP protein levels in CNE-1, CNE-2 and CNE-2/DDP of nasopharyngeal carcinoma NPC cells and promote ⁇ -Catenin degradation.
  • Mao et al found that activation of wnt 1 signaling pathway can significantly accelerate the proliferation of gastric cancer stem cells, and salinomycin plays a key role in inhibiting wnt 1 signaling pathway, which in turn induces apoptosis of gastric cancer stem cells.
  • Lu et al recently found that salinomycin inhibits the expression of LRP6 in prostate cancer stem cells, inhibiting the related Wnt/ ⁇ -catenin signaling pathway and inhibiting the mTORC1 signaling pathway. The above results indicate that LRP protein and Wnt/ ⁇ -catenin pathway are potential important anti-tumor drug targets.
  • the technical problem to be solved by the present invention is to provide a class of salinomycin oxime ether organisms and pharmaceutically acceptable salts thereof, a process for the preparation thereof, a pharmaceutical composition and use thereof for the preparation of a medicament for preventing or/or treating tumors.
  • the present invention provides the following technical solutions:
  • the first aspect of the present invention provides a compound represented by the formula I, and the specific structure of the compound represented by the formula I is as follows:
  • X is selected from H, Na, K, Ca, Mg;
  • R is selected from substituted or unsubstituted saturated or unsaturated C 1 -C 14 alkyl, substituted or unsubstituted with 1-2 heteroatoms or not saturated C 1 -C 14 alkyl group, a substituted or unsubstituted, saturated or unsaturated C 3 -C 8 cycloalkyl group, containing one to two hetero atoms substituted or unsubstituted, saturated or unsaturated C 3 -C 8 Cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 5 -C 12 heterocyclyl, substituted or unsubstituted C 6 -C 12 aryl C 1 -C 6 alkyl a substituted or unsubstituted C 5 -C 12 heterocyclyl C 1 -C 6 alkyl group, said substituent being independently selected from C 1 -C 3 al
  • R is selected from substituted or unsubstituted, saturated or unsaturated C 1 -C 8 alkyl group containing 1-2 heteroatoms substituted or unsubstituted, saturated or unsaturated C 1 -C 8 alkyl, a substituted or unsubstituted, saturated or unsaturated C 3 -C 6 cycloalkyl, containing 1-2 heteroatoms substituted or unsubstituted, saturated or unsaturated C 3 -C 6 cycloalkyl group, a substituted or unsubstituted C 6- C 12 aryl C 1 -C 3 alkyl, substituted or unsubstituted C 5 -C 12 heterocyclyl C 1 -C 3 alkyl, said substituent being independently selected from C 1 -C 3 alkyl, a halogen-substituted C 1 -C 3 alkyl group, a C 1 -C 4 alkoxy group, a carboxyl group, a cyano group,
  • R is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted saturated or unsaturated C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl C 1 - C 3 alkyl, the substituents are independently selected from C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl, C 1 -C 4 alkoxy, carboxy, cyano, halogen, hydroxy, nitro
  • the halogen is selected from the group consisting of F, Cl, Br, and I.
  • the most preferred compounds are:
  • a second aspect of the invention provides a process for the preparation of a compound of the first aspect of the invention, comprising the steps of:
  • Step 1 Compound a obtains compound b by oxidation reaction, wherein the oxidizing agent used is one of manganese dioxide, Dess-Martin reagent and 2-iodobenzoic acid, respectively, and the solvent used is dichloromethane, chloroform, tetrahydrofuran, Ethyl acetate, acetonitrile, and the like.
  • the reaction temperature is from 0 ° C to 100 ° C.
  • Step 2 Compound b is reacted with a corresponding hydroxylamine under the action of a base to obtain Compound I, wherein the base used is potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide or hydroxide. cesium,
  • a third aspect of the invention provides a pharmaceutical composition and dosage form comprising a therapeutically and/or prophylactically effective amount of a compound of the first aspect of the invention, and a pharmaceutically acceptable salt thereof, and optionally one or more A pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient of the compound of the present invention and a diluent can be dissolved.
  • the agents are mixed and the mixture is placed directly in a hard or soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrating agents, and solubilizing agents used in the preparation of the tablets of the present invention are also useful in the preparation of capsules of the compounds of the present invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizer, a solubilizer, a pH adjuster, an osmotic pressure adjusting agent which is commonly used in the art may be added.
  • the solubilizer or cosolvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.;
  • the pH adjuster may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.;
  • osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 5 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • a fourth aspect of the invention provides the use of the compound of the first aspect and the pharmaceutical composition or formulation of the third aspect for the preparation of an antitumor drug.
  • the tumors mentioned therein include, but are not limited to, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, kidney cancer, breast cancer, ovarian cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), prostate cancer, bladder cancer, epithelium.
  • the tumor is selected from the group consisting of gastric cancer, lung cancer, breast cancer, colon cancer or liver cancer.
  • the tumor is selected from the group consisting of liver cancer, gastric cancer or colon cancer.
  • the tumor is selected from the group consisting of liver cancer.
  • alkyl refers to a group of hydrocarbon atoms having the specified number of carbon atoms which may be a straight or branched alkyl group.
  • saturated means a group in which the number of carbon atoms and hydrogen atoms of the alkyl group satisfies the formula CnH2n+1, and the "unsaturated” alkyl group includes a structure in which one to several double bonds and triple bonds are contained.
  • substituted refers to the introduction of a substituent on a carbon atom in an alkyl group.
  • the "substituted or unsubstituted, saturated or unsaturated C 1 -C 14 alkyl", "containing 1-2 heteroatoms substituted or unsubstituted, saturated or unsaturated C 1 -C 14 alkyl” refers to a saturated or unsaturated alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 carbon atoms and a substituted alkyl group such as methyl , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, the above alkyl group contains an unsaturated double bond Or a group of a triple bond, a group in which the above saturated or unsaturated alkyl group is substituted.
  • C 1 -C 8 alkyl group means an alkyl group having 1, 2, 3, 4, 5, 6 , 7, 8 carbon atoms
  • C 1 -C 6 alkyl group means a carbon number. Is an alkyl group of 1, 2, 3, 4, 5, 6.
  • C 1 -C 3 alkyl group means an alkyl group having 1, 2 or 3 carbon atoms, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a propenyl group.
  • halogen-substituted C 1 -C 3 alkyl group means an alkyl group having 1, 2 or 3 carbon atoms substituted by a halogen such as F, Cl, Br, I, wherein the halogen may be 1-8 And may have different halogen substitutions on the same alkyl group, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-difluoro Alkenyl, 1,1,2,2-tetrafluoroethyl, 1,1-difluoro-2,2-dichloroethyl, etc., wherein the "fluoro” can be "chlorinated”"Bromo" and "iodide” are optionally substituted.
  • C 1 -C 4 alkoxy group means a group having 1, 2, 3 or 4 carbon atoms which are simultaneously substituted by an oxygen atom, such as a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group.
  • Base butyloxy, isobutyloxy, tert-butoxy, cyclopropoxy, cyclobutoxy.
  • the "substituted or unsubstituted, saturated or unsaturated C 3 -C 8 cycloalkyl", "substituted heteroaryl containing 1-2 atoms or unsubstituted, saturated or unsaturated C 3 -C 8 cycloalkyl” refers to a saturated or unsaturated cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms and a group in which the above cycloalkyl group is substituted, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, an alkyl group having an unsaturated double bond or a triple bond in the above cycloalkyl group, or a group obtained by substituting the above cycloalkyl group.
  • the "substituted or unsubstituted, saturated or unsaturated C 3 -C 6 cycloalkyl "substituted heteroaryl containing 1-2 atoms or unsubstituted, saturated or unsaturated C 3 -C 6 cycloalkyl
  • the C 3 -C 6 cycloalkyl group referred to in the "base” means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.
  • substituted or unsubstituted C 6 -C 12 aryl means a phenyl group, a naphthyl group, and a group substituted at any position of the above group, such as an alkyl-substituted phenyl group, an alkoxy-substituted phenyl group, Halogen substituted phenyl, nitro substituted phenyl, carboxy substituted phenyl, and corresponding naphthyl and the like.
  • heterocyclyl refers to a saturated or unsaturated cycloalkyl group in which a cycloalkyl group is substituted with a hetero atom such as N, O, S.
  • C 5 -C 12 heterocyclic group mentioned in the "substituted or unsubstituted C 5 -C 12 heterocyclic group” means 5, 6, 7, 8, 9, 10, 11, 12 a group comprising a carbon atom and a hetero atom, wherein the hetero atom has N, O, S, and the number of heteroatoms is 1, 2, 3, 4, 5, wherein the heterocyclic group includes a monocyclic ring structure and a cyclo-ring structure such as furan.
  • thiophene pyrrole, pyrazine, thiazole, imidazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, tetrahydrothiazole, pyridine, piperidine, morpholine, pyran, pyrimidine, indole, benzofuran, benzothiophene, Benzimidazole, hydrazine, and a group substituted with the above heterocyclic ring, such as furylmethyl, furanethyl and the like.
  • arylalkyl refers to an alkyl group substituted with an aryl group.
  • substituted or unsubstituted C 6 -C 12 aryl C 1 -C 6 alkyl group means a group substituted by an aryl group having 6, 7, 8, 9, 10, 11, 12 carbon atoms.
  • alkyl group 1, 2, 3, 4, 5, 6 carbon atoms of the alkyl group, such as benzyl, phenethyl, phenylpropyl, phenylisopropyl, phenylbutyl, phenylpentyl, phenylhexyl, Naphthylbenzyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthylhexyl and the above substituted arylalkyl groups.
  • substituted or unsubstituted C 6 -C 12 aryl C 1 -C 3 alkyl group means one or two carbon atoms substituted by an aryl group having 6, 12 carbon atoms. alkyl.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocyclic group.
  • the "substituted or unsubstituted C 5 -C 12 heterocyclyl C 1 -C 6 alkyl group” means that it is contained in 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms and An alkyl group having 1, 2, 3, 4, 5, 6 carbon atoms substituted by a heterocyclic group of an atom, such as furan, thiophene, pyrrole, thiazole, imidazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, tetrahydrogen Thiazole, pyridine, piperidine, morpholine, hydrazine, benzofuran, benzothiophene, benzopyrrole, benzimidazole, substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl
  • the "substituted or unsubstituted C 5 -C 12 heterocyclyl C 1 -C 3 alkyl” means having 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms And an alkyl group having 1, 2, and 3 carbon atoms which is substituted with a hetero atom of a hetero atom, and a group in which the above heterocyclic alkyl group is substituted.
  • This study provides a class of salinomycin derivatives with novel structure, strong pharmacological activity and low toxicity. It can be used for the prevention and treatment of cancer and its related diseases. Most of the salinomycin derivatives in the present invention have strong antitumor activity, are nearly 20-200 times higher than salinomycin, and are less toxic to nerve cells, and can be used for the prevention and treatment of cancer and related diseases. .
  • SH-SY5Y Numbering SH-SY5Y Numbering
  • SH-SY5Y 1 >1.0 12 >1.0 twenty three >1.0 2 >1.0 13 >1.0 3 >1.0 14 >1.0 4 >1.0 15 >1.0 5 >1.0 16 >1.0 6 >1.0 17 >1.0 7 >1.0 18 >1.0 8 >1.0 19 >1.0 9 >1.0 20 >1.0 10 >1.0 twenty one >1.0 11 >1.0 twenty two >1.0
  • the SH-SY5Y cell line is derived from a dopaminergic human neuroblastoma cell, which has a low degree of differentiation, rapid reproduction, and similar cell morphology, physiological and biochemical functions to human normal nerve cells.
  • the results showed that the salinomycin-20-oxime and oxime ether derivatives were less toxic to SH-SY5Y cells in vitro, indicating that they have better selectivity.

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Abstract

La présente invention relève du domaine de la chimie pharmaceutique et concerne un dérivé d'éther d'oxime de salinomycine, son procédé de préparation et son utilisation pour la préparation de médicaments antitumoraux, en particulier son utilisation pour le traitement du cancer de l'estomac, du cancer du sein et du cancer du côlon.
PCT/CN2017/085516 2016-05-24 2017-05-23 Dérivé d'éther d'oxime de salinomycine, son procédé de préparation et son utilisation pour la préparation de médicaments antitumoraux WO2017202295A1 (fr)

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CN201610347806.7A CN107417699B (zh) 2016-05-24 2016-05-24 盐霉素肟及肟醚衍生物、其制备方法和抗肿瘤用途

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Cited By (1)

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CN114380888A (zh) * 2020-10-22 2022-04-22 复旦大学 一种二氟取代的罗米地辛类似物、其制备方法和用途

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WO2016038223A1 (fr) * 2014-09-12 2016-03-17 Centre National De La Recherche Scientifique (Cnrs) Analogues contenant de l'azote de la salinomycine, synthèse et utilisation contre des cellules souches cancéreuses et le paludisme
CN105732655A (zh) * 2016-02-05 2016-07-06 武汉大学 一种结构新颖的盐霉素衍生物的制备与应用
CN106800561A (zh) * 2015-10-19 2017-06-06 中国医学科学院药物研究所 C20位差向异构化盐霉素及其衍生物、其制备方法和用途

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WO2013103993A1 (fr) * 2012-01-06 2013-07-11 Kevin Sprott Composés thérapeutiques et procédés d'utilisation associés
WO2016038223A1 (fr) * 2014-09-12 2016-03-17 Centre National De La Recherche Scientifique (Cnrs) Analogues contenant de l'azote de la salinomycine, synthèse et utilisation contre des cellules souches cancéreuses et le paludisme
CN106800561A (zh) * 2015-10-19 2017-06-06 中国医学科学院药物研究所 C20位差向异构化盐霉素及其衍生物、其制备方法和用途
CN105732655A (zh) * 2016-02-05 2016-07-06 武汉大学 一种结构新颖的盐霉素衍生物的制备与应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114380888A (zh) * 2020-10-22 2022-04-22 复旦大学 一种二氟取代的罗米地辛类似物、其制备方法和用途
CN114380888B (zh) * 2020-10-22 2024-02-27 复旦大学 一种二氟取代的罗米地辛类似物、其制备方法和用途

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