WO2020098658A1 - Dérivé de camptothécine substitué en position 20, procédé de préparation associé et utilisation correspondante - Google Patents

Dérivé de camptothécine substitué en position 20, procédé de préparation associé et utilisation correspondante Download PDF

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WO2020098658A1
WO2020098658A1 PCT/CN2019/117646 CN2019117646W WO2020098658A1 WO 2020098658 A1 WO2020098658 A1 WO 2020098658A1 CN 2019117646 W CN2019117646 W CN 2019117646W WO 2020098658 A1 WO2020098658 A1 WO 2020098658A1
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compound
substituted
group
preparation
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江涛
张海霖
吴贯召
张逸轩
李静
戚欣
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中国海洋大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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 invention belongs to the technical field of medicine, and specifically relates to a new type of camptothecin derivative and a preparation method and application thereof.
  • Camptothecin derivatives are known as one of the three major discoveries of anti-cancer drugs in the 1990s, showing broad-spectrum anti-tumor activity and great research and application value.
  • the early camptothecin compounds formed a ternary complex with Top I and DNA to block DNA replication and transcription, and had the disadvantages of low selectivity and toxic side effects.
  • molecular targeted anti-tumor drugs have become a research hotspot in recent years. Such drugs can selectively act on signal transduction pathways related to tumor cell differentiation and proliferation.
  • -Methylenedioxycamptothecin is the starting compound, which is structurally modified to develop more efficient and less toxic antitumor candidate compounds.
  • the present invention provides a camptothecin derivative and its preparation method and application in anti-tumor, which can solve the shortcomings of low selectivity and large toxic and side effects existing in the prior art, and can be used to prepare drugs for preventing or treating tumors.
  • the present invention provides a compound having the structure shown in formula (I), its isomer and a pharmaceutically acceptable salt:
  • Y is - (CH 2) n - or - (CH 2) n CONH-;
  • n and m are each independently 0 or a positive integer, preferably, n and m are each independently a positive integer, and more preferably, n and m are each independently 1, 2, 3, 4, 5, 6, 7 , 8, 9 or 10;
  • p is a positive integer, preferably, p is 1 or 2;
  • R is selected from any one of a hydrogen atom, a substituted or unsubstituted sulfonamide group, a substituted or unsubstituted base, a substituted or unsubstituted saturated nitrogen-containing heterocyclic ring, and a substituted or unsubstituted alkyl group; preferably Wherein R is any one of a substituted or unsubstituted sulfonamide group, a substituted or unsubstituted base group, a substituted or unsubstituted saturated nitrogen-containing heterocyclic ring, and a substituted or unsubstituted alkyl group.
  • the substituent is selected from hydrogen atom, halogen atom, hydroxyl group, nitro group, amino group, alkyl group, substituted alkyl group, alkoxy group, substituted alkoxy group, aromatic Any one of a group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group.
  • X in formula (I) is-(CH 2 ) n NH-, n is 1, R is hydrogen or alkyl, preferably, the compound of formula (I) is compound 2 or compound 3 .
  • X is-(CH 2 ) n NH-, n is 1, R is a substituted or unsubstituted sulfonamide group, and R has the structure shown in formula (II) :
  • R 1 is alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; preferably R 1 is C1-C4 alkyl, more preferably R 1 is methyl, ethyl, n-propyl Or n-butyl; likewise preferably R 1 can be phenyl, substituted phenyl, naphthyl, thiophene or pyridine, more preferably R 1 is para-fluorine substitution, chlorine substitution, nitro substitution, methyl substitution or methyl Oxygen substituted phenyl;
  • R 2 is phenyl or substituted phenyl, preferably para-fluorine substituted or methoxy substituted phenyl;
  • the compound of formula (I) is w-1, w-2, w-3, w-4, w-5, w-6, w-7, w-8, w-9, w-10, w-11, w-12, w-13, w-14, w-15, w-16, w-17, w-18, w-19, w-20, w-21, w-22, w- 23 or w-24.
  • the preparation method of such compounds includes the following steps:
  • 10,11-Methylenedioxycamptothecin undergoes an acylation reaction with Boc-protected glycine under the catalysis of a condensing agent, and the resulting product is deprotected by trifluoroacetic acid to obtain a 20-glycine modified 10,11-Methylenedioxycamptothecin;
  • the 20,10-glycine-modified 10,11-methylenedioxycamptothecin is catalyzed by cuprous iodide with one-pot reaction of benzenesulfonyl azide and alkynyl group containing different substituents to obtain the compound.
  • R 3 is H, F or Cl.
  • said R, X, Y, R 1 , R 2 and R 3 are corresponding groups in each specific compound in the examples.
  • the compound of formula (I) is w-25, w-26 or w-27.
  • the preparation method of such compounds includes the following steps:
  • 10,11-Methylenedioxycamptothecin undergoes an acylation reaction with Boc-protected glycine under the catalysis of a condensing agent, and the resulting product is deprotected by trifluoroacetic acid to obtain a 20-glycine modified 10,11-Methylenedioxycamptothecin;
  • R is a substituted or unsubstituted saturated nitrogen-containing Ring;
  • the compound of formula (I) is w-28, w-29, w-30, w-31, w-32 or w-33.
  • the preparation method of such compounds includes the following steps:
  • 10,11-Methylenedioxycamptothecin undergoes an acylation reaction with Boc-protected glycine under the catalysis of a condensing agent, and the resulting product is deprotected by trifluoroacetic acid to obtain a 20-glycine modified 10,11-Methylenedioxycamptothecin;
  • R is a substituted or unsubstituted alkyl group; preferably The compound of formula (I) is z-1-9 or z-2-5.
  • the preparation method of such compounds includes the following steps:
  • X is -O (CH 2 ) n SS (CH 2 ) m OCOY-
  • Y is-(CH 2 ) n -or-(CH 2 ) n CONH -
  • N and m are both 2
  • R is substituted or unsubstituted alkyl; preferably, the compound of formula (I) is z-3-3, z-4-2, z-5-1, z-6- 1. z-7-1 or z-8-1.
  • the preparation method of such compounds includes the following steps:
  • X is -CH 2 NH- or -OCH 2 CH 2 SSCH 2 CH 2 O-, and R is H.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the above compound, its isomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
  • the above compound, its isomer or pharmaceutically acceptable salt or the above pharmaceutical composition in the preparation of a medicament for preventing and / or treating cancer.
  • the cancer is lung cancer or colon cancer.
  • camptothecin derivatives of the present invention The selectivity of the camptothecin derivatives of the present invention to tumor tissue is higher than that of traditional camptothecin compounds, and the antitumor activity is significantly improved compared with the parent compound, while maintaining less toxicity, and can be used for preparation of prevention or Drugs used to treat tumors.
  • the camptothecin derivative of the present invention has clear structural characteristics, is convenient to synthesize, simple and quick to purify, and has good biological activity. Therefore, such compounds have broad prospects in preventing or treating tumors.
  • the mode of administration of the compound of the present invention, its isomer, its pharmaceutically acceptable salt, or the pharmaceutical composition containing the compound is not particularly limited.
  • Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the same or similar administration methods as dasatinib can be selected, including (but not limited to): oral, transdermal, intravenous, intramuscular, local administration, etc.
  • Figure 1 Effect of intragastric administration of compound w-31 on the growth of transplanted tumors in A549 mice.
  • Figure 3 Effect of intragastric administration of compound z-1-9 on the growth of transplanted tumors in A549 mice.
  • Figure 4 Effect of intragastric administration of compound z-1-9 on the body weight of A549 transplanted mice.
  • Figure 5 Effect of intragastric administration of compound z-3-3 on the growth of transplanted tumors in A549 mice.
  • isomers includes conformational isomers, optical isomers (such as enantiomers and diastereomers) and geometric isomers (such as cis-trans isomers). These isomers or combinations thereof can be used as racemic mixtures (racemates), individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans Isomers exist.
  • pharmaceutically acceptable salt refers to any pharmaceutically acceptable salt of the compound of formula (I), preferably to the acid addition salt of the compound.
  • preferred pharmaceutically acceptable salts are acid addition salts of pharmaceutically acceptable inorganic or organic acids, such as hydrohalic acid, sulfuric acid, phosphoric acid, or aliphatic or aromatic carboxylic acids or sulfonic acids, such as acetic acid, succinic acid, Lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, niacin, methanesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid.
  • alkali metal salts sodium or potassium
  • alkaline earth metal salts calcium or magnesium
  • ammonia such as C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine Or tris (hydroxymethyl) aminomethane, a pharmaceutically acceptable organic amine-derived ammonium salt.
  • sulfonamide group refers to a collective name of compound groups having a structure of -SO 2 N-, and particularly preferably refers to a collective name of chemical groups having a structure of the following formula (II),
  • R1 is alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R2 is aryl or substituted aryl.
  • base includes substituted or unsubstituted natural bases and artificial bases; preferably, substituted or unsubstituted natural bases, including but not limited to substituted or unsubstituted adenine, substituted Or unsubstituted guanine, substituted or unsubstituted uracil, substituted or unsubstituted thymine and substituted or unsubstituted cytosine; more preferably substituted or unsubstituted uracil, such as 5- Fluorouracil.
  • saturated nitrogen-containing heterocyclic ring is preferably a 4-6 membered nitrogen-containing heterocyclic ring, including but not limited to substituted or unsubstituted tetrahydropyrrole, substituted or unsubstituted morpholine, substituted or unsubstituted piperidine, substituted Or unsubstituted piperazine and substituted or unsubstituted thiomorpholine and so on.
  • alkyl refers to any linear or branched, substituted or unsubstituted saturated hydrocarbon group, wherein the hydrocarbon group having 1 to 10 carbon atoms includes but is not limited to methyl, ethyl, n-propyl, isopropyl, cyclic Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2,4,4-trimethylpentyl, cyclopentyl , N-hexyl, isohexyl, cyclohexyl, n-heptyl, cycloheptyl, n-octyl, 2-ethylhexyl, cyclooctyl, n-nonyl, cyclononyl or n-decyl.
  • Other long-chain alkyl groups with
  • halogen atom refers to any radio-stable atom in column 7 of the periodic table, ie fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.
  • aryl refers to aromatic hydrocarbon rings, preferably having 5, 6 or 7 atoms, most preferably having 6 atoms Narration.
  • Heteroaryl and “substituted heteroaryl” refer to aromatic hydrocarbon rings having at least one heteroatom (eg, oxygen, sulfur, or nitrogen atom) and at least one carbon atom in the ring.
  • the "aryl” includes, but is not limited to, substituted or unsubstituted the following groups: phenyl, o-methylphenyl, m-tolyl, xylyl, naphthyl, or anthracenyl.
  • aryl refers to C6-20 aryl
  • heteroaryl refers to C2-18 heteroaryl, preferably C3-15 heteroaryl.
  • substituted refers to any group in which at least one hydrogen atom is replaced by a substituent selected from halogen atoms, alkyl groups, substituted alkyl groups, alkoxy groups, substituted alkoxy groups, cycloalkyl groups , Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, hydroxyl, carboxyl , Carboxyalkyl, keto, thioketo, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle Group, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO
  • the term "therapeutically effective dose” refers to any amount of the drug as described below. When used alone or in combination with another therapeutic agent, the amount of the drug can promote the regression of the disease, which manifests as a reduction in the severity of the symptoms of the disease 2. Increase the frequency and duration of the disease-free symptom period, or prevent the disorder or disability caused by the disease.
  • the "therapeutically effective dose” of the medicine of the present invention also includes the “prophylactically effective dose”.
  • the “prophylactically effective dose” is any amount of the drug as described below, when the amount of the drug is administered alone or in combination with another therapeutic agent When there is a risk of developing a disease or a subject suffering from a disease recurrence, the occurrence or recurrence of the disease can be suppressed.
  • the effective in vivo dosage and specific mode of administration will vary according to the type, weight and age of the mammal being treated, the specific compounds used and the specific purpose of using these compounds.
  • Those skilled in the art can determine the effective dose level (ie, the dose level necessary to achieve the desired effect) according to conventional pharmacological methods.
  • the human clinical application of the product starts at a lower dose level and then continuously increases the dose level until the desired effect is achieved.
  • acceptable in vitro studies can be used by existing pharmacological methods to establish useful doses and routes of administration of the compositions identified by this method.
  • the "pharmaceutical composition" of the present invention can be made into liquid preparation forms such as tablets, capsules, powders, granules, lozenges, suppositories, oral liquids or sterile parenteral suspensions, as well as large or small volume injections, lyophilized powders, etc. Injection form.
  • the drugs in the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.
  • the "pharmaceutically acceptable carrier” in the present invention includes conventional diluents, fillers, binders, wetting agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
  • cancer refers to a large class of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth Division and growth result in the formation of malignant tumors or cells that invade adjacent tissues and can also be transferred to the distal part of the body through the lymphatic system or blood flow.
  • treatment of cancer is "treatment of tumor” or “anti-cancer” or “anti-tumor”.
  • Cancer is an uncontrolled condition that prevents the growth of cells that interfere with the normal functioning of body organs and systems.
  • a subject with cancer is a subject with objectively measurable cancer cells present in the body of the subject.
  • Subjects at risk of developing cancer are subjects prone to developing cancer (eg based on family history, genetic predisposition), subjects exposed to radiation or other cancer-causing agents.
  • the compounds of the present invention and their pharmaceutical compositions can be used to prevent or treat various cancers.
  • cancers include breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, skin cancer, melanoma, colon cancer, stomach cancer, liver cancer, esophageal cancer, kidney cancer, throat cancer, thyroid cancer, pancreatic cancer, testis Cancer, brain cancer, bone cancer and blood cancer (such as leukemia, chronic lymphocytic leukemia), etc.
  • cancers include but are not limited to basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system (CNS) cancer, cervical cancer, choriocarcinoma, colorectal cancer, connective tissue cancer, digestive system cancer, uterus Endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, intraepithelial tumor, laryngeal cancer, lung cancer (small cell, large cell), lymphoma (including Hodgkin lymphoma and non-Hodgkin lymphoma), melanoma , Neuroblastoma, oral cancer (such as lips, tongue, mouth and pharynx), retinoblastoma, rhabdomyosarcoma, respiratory cancer, sarcoma, uterine cancer, urinary system cancer, and other cancers and sarcomas.
  • the compounds of the present invention and compositions thereof are preferably useful for colon cancer and / or lung cancer.
  • the present invention also provides a method for preventing and / or treating cancer, the method comprising administering to a patient a therapeutically effective dose of a compound having the structure represented by formula (I), an isomer thereof, or a pharmaceutical thereof as described above An acceptable salt, or a pharmaceutical composition containing the compound.
  • the cancer is lung cancer or colon cancer.
  • Some examples of the compounds of the present invention include the compounds shown in Table A (especially the compounds other than Nos. 2 and 3):
  • the compounds of the present invention can generally be obtained by multi-step reaction synthesis using 10,11-methylenedioxycamptothecin (FL118) unless otherwise specified.
  • the 10,11-methylenedioxycamptothecin can be purchased from the market, or can be prepared by the following method: using piperaldehyde as the starting material, after two steps of nitrification with concentrated nitric acid and hydrogen palladium-carbon reduction 6-Amino-3,4-methylenedioxybenzaldehyde was obtained, and then 5 ′ (S) -1,5-dioxo- (5′-ethyl-5′-hydroxy-2′H, 5′H, 6′H-6-oxopyran)-[3 ′, 4 ′, f] - ⁇ 6 (8) -tetrahydroindolizine under the catalysis of p-toluenesulfonic acid, Fried In the rand condensation reaction, the resulting reactant is purified by silica gel column chromatography to obtain 10,11-methylenedioxycamptothecin.
  • camptothecin derivative substituted with the 20-position sulfonamidino group of the present invention can be carried out by the following general formula.
  • Reaction conditions (a) DMAP, DIC, EDCI, DCM; (b) CF 3 COOD, CH 2 Cl 2 .; (C) R 1 SO 2 N 3 , alkyne, Et 3 N, CuI, DCM.
  • the preparation of the 20-position sulfonamidino substituted camptothecin derivative of the present invention includes the following steps:
  • 10,11-Methylenedioxycamptothecin (Compound 1, also known as FL118) undergoes an acylation reaction with Boc-protected glycine under the catalysis of a condensing agent, and the resulting product is deprotected under trifluoroacetic acid Group to obtain 10,11-methylenedioxycamptothecin modified with glycine at position 20;
  • the preparation and purification method is the same as compound w-1, using methylsulfonyl azide and p-fluorophenylacetylene instead of 4-methylbenzenesulfonyl azide and phenylacetylene to obtain 34 mg of yellow powdery solid, yield 73%, that is compound w -11. mp 174-175 ° C; HRMS (ESI): C 32 H 27 FN 4 O 9 S calculated value 663.6454, found value 663.1552.
  • the 10,11-methylenedioxycamptothecin derivative modified at the 20th position of the uracil group can be prepared by the following general formula.
  • Reaction conditions (a) DMAP, DIC, EDCI, DCM; (b) CF 3 COOD, CH 2 Cl 2 ; (c) 5'-substituted uracil 1 '(N) -acetic acid, DMAP, DIC, EDCI, DCM .
  • the preparation steps of the 10,11-methylenedioxycamptothecin derivative modified at the 20 position by uracil group include:
  • the 10,11-methylenedioxycamptothecin derivative modified by heterocyclic amide at position 20 of the present invention can be prepared by the following general formula.
  • Reaction conditions (a) DMAP, DIC, EDCI, DCM; (b) CF 3 COOH, CH 2 Cl 2 ; (c) CDI, suitable secondary amine (2 ° amine), Et 3 N, DCM, 0 ° C.
  • the preparation steps of the 10,11-methylenedioxycamptothecin derivative modified with heterocyclic amide at position 20 include:
  • 10,11-Methylenedioxycamptothecin undergoes an acylation reaction with Boc-protected glycine under the catalysis of a condensing agent, and the resulting product is deprotected by trifluoroacetic acid to obtain a 20-glycine modified 10,11-Methylenedioxycamptothecin;
  • Example 4 The 10,11-methylenedioxycamptothecin derivative modified with carboxylic acid at position 20
  • the compound z-1-9 of the present invention can be prepared by the following reaction.
  • the compound z-2-5 of the present invention can be prepared by the following reaction.
  • Reaction conditions (a) DMAP, DIC, EDCI, DCM.
  • the compound z-3-3 of the present invention can be prepared by the following reaction.
  • Reaction conditions (a) Triphosgene, CH 2 Cl 2 , DMAP, 2 , 2'-dithiobis-Ethanol; (b) DMAP, DIC, EDCI, DCM; (c) CF 3 COOH, CH 2 Cl 2 .
  • the compound z-4-2 of the present invention can be prepared by the following reaction.
  • Reaction conditions (a) Triphosgene, CH 2 Cl 2 , DMAP, 2,2'-dithiobis-Ethanol; (b) DMAP, DIC, EDCI, DCM.
  • the compound z-5-1 of the present invention can be prepared by the following reaction.
  • Reaction conditions (a) Triphosgene, CH 2 Cl 2 , DMAP, 2,2'-dithiobis-Ethanol; (b) DMAP, DIC, EDCI, DCM.
  • the compound z-7-1 of the present invention can be prepared by the following reaction.
  • Reaction conditions (a) Triphosgene, CH 2 Cl 2 , DMAP, 2,2'-dithiobis-Ethanol; (b) DMAP, DIC, EDCI, DCM.
  • the 20-position sulfonyl amidine-modified compound w-1-w-24 with glycine as the connecting arm, and the 20-position uracil-modified compound w- with glycine as the connecting arm have an inhibition rate of more than 50% on A549 cells, showing good cytotoxic activity and significant Better than irinotecan.
  • a table shows the inhibition rate of irinotecan at 10uM on the corresponding cell lines.
  • Human lung cancer A549 cells were subcutaneously inoculated into the right armpit of mice, and when they grew to about 100mm 3 , they were divided into groups.
  • the w-31 high, medium and low dose groups were given 20mg / kg, 10mg / kg and 5mg / kg compound w-31, twice a week, the solvent control group was gavaged with an equal volume of solvent.
  • the body weight of mice was measured three times a week. 19 days after the administration, the control mice were sacrificed. The mice in the remaining groups stopped the administration and continued to measure until 28 days, and the mice were sacrificed.
  • the present inventors tested the in vivo antitumor activity of the compound z-1-9 of the present invention through a mouse xenograft model.
  • Test methods include:
  • Human lung cancer A549 cells were cultured to the required number in vitro, collected cells were centrifuged, the supernatant was washed, washed once with PBS, resuspended the cells with PBS, and subcutaneously inoculated into the armpit of the right forelimb of BALB / c-nu mice, each 8 ⁇ 10 6 cells.
  • the mice were randomly divided into 3 groups according to the tumor volume, the solvent control group, the z-1-9 high-dose group and the low-dose group.
  • the z-1-9 high-dose group and the low-dose group were given intragastrically 24 mg / kg and 12 mg / kg z-1-9, once every 2 days.
  • the changes in body weight and tumor volume were recorded three times a week.
  • mice After BALB / c-nu mice were subcutaneously inoculated with A549 cells, the tumor volume reached 100 mm 3 in about 10 days, and were randomly administered in groups. On the 19th day, the tumor tissue of the solvent control group grew to 1157.21 ⁇ 370.81 mm 3 , the mice were sacrificed, the tumor tissue was stripped, and frozen at -80 ° C. The rest of the groups stopped the drug administration, continued observation, and recorded the tumor volume. All mice were sacrificed on the 28th day after the drug administration, the tumor tissue was stripped, and frozen at -80 ° C.
  • the high-dose and low-dose administration of z-1-9 compound can significantly inhibit the growth of A549 transplanted tumors in mice, and it has a certain dose dependence.
  • the tumor inhibition rates after administration for 19 days were 73.79, respectively. % And 54.66%.
  • the mouse body weight change curve is drawn. The results are shown in Figure 4.
  • the body weight of the mice in the solvent control group gradually increased. After z-1-9 administration, the body weight of mice in the high and low dose groups decreased significantly. It gradually recovered after 5 days, but was still lower than the body weight of the control mice, especially in the high-dose group, which indicated that it had certain toxic and side effects. Slight toxic and side effects are common problems of camptothecin compounds.
  • Human lung cancer A549 cells were subcutaneously inoculated into the right armpit of mice, and when they grew to about 100mm 3 , they were administered in groups.
  • the two dose groups of z-3-3 high and low were given 5mg / kg and 2.5mg / kg in the tail vein.
  • Compound z-3-3 was administered three times a week for a total of six times for two weeks.
  • the solvent control group was gavaged with an equal volume of solvent.
  • the positive control was irinotecan (3 mg / kg).
  • the body weight of mice was measured three times a week. 28 days after the administration, the mice were sacrificed.

Abstract

La présente invention concerne un composé ayant une structure représentée par la formule (I), un isomère de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation associé, et une composition pharmaceutique comprenant ledit composé. L'invention concerne également une utilisation du composé et de la composition pharmaceutique associée dans la préparation d'un médicament destiné à prévenir et/ou à traiter un cancer. Le composé selon l'invention présente une bonne activité cytotoxique ex vivo et un bon effet antitumoral in vivo. Le procédé de préparation du composé est facile et les matières premières sont disponibles. Par conséquent, le composé selon l'invention présente de grandes perspectives sur le plan médical. (I)
PCT/CN2019/117646 2018-11-12 2019-11-12 Dérivé de camptothécine substitué en position 20, procédé de préparation associé et utilisation correspondante WO2020098658A1 (fr)

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US7064202B1 (en) * 2003-05-12 2006-06-20 University Of Kentucky Research Foundation Camptothecin intermediates and prodrugs and methods of preparation thereof
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