WO2019238046A1 - 喜树碱衍生物及其制备方法和应用 - Google Patents

喜树碱衍生物及其制备方法和应用 Download PDF

Info

Publication number
WO2019238046A1
WO2019238046A1 PCT/CN2019/090731 CN2019090731W WO2019238046A1 WO 2019238046 A1 WO2019238046 A1 WO 2019238046A1 CN 2019090731 W CN2019090731 W CN 2019090731W WO 2019238046 A1 WO2019238046 A1 WO 2019238046A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
ring
cancer
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/CN2019/090731
Other languages
English (en)
French (fr)
Inventor
江涛
吴贯召
何�雄
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.)
Qingdao Marine Biomedical Research Institute Co Ltd
Original Assignee
Qingdao Marine Biomedical Research Institute 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 Qingdao Marine Biomedical Research Institute Co Ltd filed Critical Qingdao Marine Biomedical Research Institute Co Ltd
Priority to EP19818832.8A priority Critical patent/EP3808751B1/en
Priority to US17/251,583 priority patent/US20220177485A1/en
Priority to JP2021518840A priority patent/JP7485661B2/ja
Publication of WO2019238046A1 publication Critical patent/WO2019238046A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a new type of camptothecin derivative and a preparation method and application thereof.
  • Camptothecin derivatives are hailed as one of the three major discoveries of anticancer drugs in the 1990s, showing broad-spectrum antitumor activity and great research and application value.
  • the early camptothecin compounds acted as a ternary complex with Top I and DNA, blocking DNA replication and transcription, and had the disadvantages of low selectivity and large toxic and side effects.
  • molecularly 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.
  • the present invention uses camptothecin As a lead compound, it is structurally modified to develop more effective and low-toxicity antitumor candidate compounds.
  • camptothecin Based on the structure of camptothecin, we introduced methylenedioxy at positions 10 and 11 and introduced different substituent groups at position 7 to obtain compounds with better antitumor activity, less toxicity, and good solubility.
  • the invention provides a camptothecin derivative and a preparation method and application thereof, which can be used for preparing a medicine for preventing or treating tumors.
  • one aspect of the present invention provides a compound having a structure represented by formula (I), a stereoisomer thereof, and a pharmaceutically acceptable salt form:
  • X is selected from n is an integer of 0-2, and m is an integer of 0-2;
  • Z is a ring structure, and the Z ring is selected from a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole ring , Substituted or unsubstituted indole ring, substituted or unsubstituted benzopyrazole ring, substituted or unsubstituted piperidine ring, substituted or unsubstituted morpholine ring, substituted or unsubstituted thiomorpholine ring, Substituted or unsubstituted naphthalene ring and substituted or unsubstituted triazole ring;
  • the substituent is selected from a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted aryl group, a substituted or unsubstituted pyrrolidinyl group, a substituted Or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl and substituted or unsubstituted thiomorpholinyl;
  • substitution is mono- or poly-substituted
  • the Z ring is not an unsubstituted benzene ring.
  • the halogen atom is F.
  • the stereoisomers include: conformers, optical isomers (such as enantiomers and diastereomers), and geometric isomers (such as cis-trans isomers). These isomers or combinations thereof can exist as racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, cis or trans isomers.
  • the pharmaceutically acceptable salt refers to a salt formed by reacting the compound with an inorganic acid, an organic acid, an alkali metal, or an alkaline earth metal.
  • These salts include (but are not limited to): (1) salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; (2) salts with organic acids such as acetic acid , Lactic acid, citric acid, succinic acid, fumaric acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, tartaric acid, maleic acid, or arginine Acid (3)
  • Other salts including salts with alkali or alkaline earth metals (such as sodium, potassium, calcium or magnesium), ammonium or water-soluble amine salts
  • the present invention also provides a precursor of the above-mentioned compound, which means that when taken by an appropriate method, the precursor of the compound undergoes metabolism or chemical reaction in a patient to be converted into a compound included in the general formula of the present invention, A salt or solution of compounds.
  • Compound precursors include, but are not limited to, carboxylates, carbonates, phosphates, nitrates, sulfates, sulfones, sulfoxides, amino compounds, carbamates, azo compounds, phosphoramides of the compounds , Glucoside, ether, acetal and other forms.
  • X is m is 1 or 2; the Z ring is a substituted or unsubstituted benzene ring.
  • R in the formula (I) is any one of the following groups:
  • X is n is 2; the Z ring is a substituted or unsubstituted benzene ring.
  • R in the formula (I) is any one of the following groups:
  • X is Both n and m are 0.
  • R in the formula (I) is any one of the following groups:
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • X is n is an integer from 0 to 2; the Z ring is selected from a substituted or unsubstituted piperidine ring, a substituted or unsubstituted morpholine ring, and a substituted or unsubstituted thiomorpholine ring.
  • R in the formula (I) is any one of the following groups:
  • R in the formula (I) is a substituted or unsubstituted triazole ring, and the compound has a structure represented by the formula (II):
  • R 1 is selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted hydroxamic acid chain, and a substituted or unsubstituted aryl group.
  • Another aspect of the present invention provides the use of the above compounds in the manufacture of a medicament for the prevention and / or treatment of cancer.
  • the cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, leukemia and breast cancer.
  • Another aspect of the present invention provides the use of the aforementioned compound as an EGF or FGF inhibitor.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: 1) an effective amount of the above-mentioned compound, and 2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be made into liquid preparations such as tablets, capsules, powders, granules, lozenges, suppositories, oral solutions or sterile parenteral suspensions, and injections such as large or small volume injections, lyophilized powders, and the like.
  • the drugs in the above dosage forms can be prepared according to the conventional methods in the pharmaceutical field.
  • the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers.
  • the carriers include conventional diluents, fillers, binders, wetting agents, absorption enhancers, and surfactants. , Adsorption carrier, lubricant, etc.
  • Another aspect of the present invention also provides a method for preparing the above-mentioned compound, which is characterized by including the following steps:
  • R is a triazole ring containing different substituents and the structural formula is (II): the intermediate 20-O-acetyl-7-bromo-10,11-methylenedioxy Tree base (G) and trimethylsilane acetylene react with trimethylsilane acetylene under the catalysis of palladium acetate to obtain 20-O-acetyl-7-ethynyl-10,11-methylenedioxy by potassium fluoride Camptothecin (K), K undergoes a click chemical reaction with an azide compound containing different substituents to obtain a compound of formula (II).
  • G the intermediate 20-O-acetyl-7-bromo-10,11-methylenedioxy Tree base
  • trimethylsilane acetylene react with trimethylsilane acetylene under the catalysis of palladium acetate to obtain 20-O-acetyl-7-ethynyl-10,11-methylenedioxy by potassium fluoride Camp
  • the invention also provides a method for preparing the above-mentioned intermediate M:
  • intermediate M6 is reacted with diethyl carbonate under the action of potassium tert-butoxide to obtain intermediate M7; intermediate M7 and bromoethane are reacted to obtain intermediate M8; intermediate M8 is subjected to Raney nickel catalytic hydrogenation under high pressure to obtain intermediate M9; Intermediate M9 reacts with sodium nitrite to obtain intermediate M10; intermediate M10 is rearranged under reflux in carbon tetrachloride to obtain intermediate M11; intermediate M11 is oxidized by oxygen to obtain intermediate M12; intermediate M12 is a chiral compound. Chiral isocyanate derivatization method is used for chiral resolution.
  • Intermediate M12 is reacted with chiral isocyanate under the catalysis of cuprous chloride to obtain two non-corresponding isomers M13R and M13S, which are separated and purified by column chromatography; Intermediate M13S is hydrolyzed under alkaline conditions to obtain intermediate M14; intermediate M14 is deprotected under trifluoroacetic acid to obtain a stereospecific tricyclic intermediate M15 (ie, intermediate M).
  • the compounds of the present invention have higher selectivity for tumor tissues than traditional camptothecin compounds, and higher solubility than traditional camptothecin compounds.
  • the antitumor activity is significantly improved compared with the parent compound, while maintaining a small Toxicity, can be used in the preparation of drugs to prevent or treat cancer.
  • the camptothecin derivatives of the present invention have clear structural features, convenient synthesis, simple and fast purification methods, and good biological activity. Therefore, such compounds have broad application prospects in the prevention or treatment of cancer.
  • FIG. 1 Schematic diagram of the synthetic route of the compounds of the invention.
  • 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 lead to the formation of malignant tumors or cells that invade adjacent tissues and can also be transferred to the distal parts of the body through the lymphatic system or blood flow. Another equivalent description of “treating cancer” in the present invention is “treating tumor” or “anti-cancer” or “anti-tumor”.
  • Cancer is an uncontrolled condition that prevents the normal functioning of body organs and systems from growing cells.
  • a subject with cancer is a subject with objectively measurable cancer cells present in the subject's body.
  • Subjects at risk for developing cancer are subjects who are susceptible to developing cancer (e.g., based on family history, genetic predisposition), subjects exposed to radiation or other cancer-causing agents.
  • the compounds of the invention are useful for treating a variety of cancers or subjects at risk of developing cancer.
  • cancers include breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, skin cancer, melanoma, colon cancer, gastric 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) and so on.
  • cancers include, but are not limited to, basal cell cancer, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system (CNS) cancer, cervical cancer, chorionic cancer, 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's lymphoma and non-Hodgkin's lymphoma); melanoma Neuroblastoma; oral cancer (such as lips, tongue, mouth and pharynx); retinoblastoma; rhabdomyosarcoma; respiratory cancer; sarcoma; uterine cancer; urinary cancer; and other cancers and sarcomas.
  • CNS central nervous system
  • a “therapeutically effective dose” is any amount of the drug as described below.
  • the amount of the drug can promote the regression of the disease, which is manifested by a reduction in the severity of disease symptoms, without Increase the frequency and duration of symptomatic periods of the disease, or prevent disorders or disability caused by the disease.
  • a therapeutically effective amount or dose of a drug includes a "prophylactically effective amount” or “prophylactically effective dose”, and a “prophylactically effective amount” or “prophylactically effective dose” is any of the amounts of the drug as described below, when the amount of the drug is administered alone or When administered in combination with another therapeutic agent to a subject at risk of developing a disease or suffering from a relapse of the disease, the occurrence or recurrence of the disease can be suppressed.
  • a therapeutic agent to promote disease regression or inhibit disease progression or recurrence can be assessed by various methods known to the skilled person, for example in clinical trials in human subjects, in animal model systems that can predict efficacy in humans Or by measuring the activity of a reagent in an in vitro assay system.
  • anticancer agents promote tumor regression in a subject.
  • a therapeutically effective dose of the drug promotes the regression of cancer cells and even the elimination of cancer.
  • Promote cancer regression means that a therapeutically effective amount of the drug, administered alone or in combination with an anti-neoplastic agent, results in reduced tumor growth or size, tumor necrosis, reduced severity of at least one disease symptom, and no The frequency and duration of disease symptom periods increase, preventing disorders or disability caused by the disease, or otherwise improving the patient's disease symptoms.
  • the terms "effective” and “effective” with respect to treatment include both pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of a drug to promote cancer regression in a patient.
  • Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ and / or organism level due to drug administration.
  • a therapeutically effective amount or dose of a drug may preferably inhibit cell growth or tumor growth by at least about 20%, more preferably at least about 40%, and even more preferably at least at least compared to an untreated subject. About 60%, and still more preferably at least about 80%.
  • a therapeutically effective amount or dose of the drug can completely inhibit cell growth or tumor growth, ie, preferably inhibit cell growth or tumor growth by up to 100%.
  • the ability of compounds to inhibit tumor growth can be evaluated in animal model systems, and they can predict efficacy in human tumors. Alternatively, this property of the composition can be assessed by examining the compound's ability to inhibit cell growth, and such inhibition can be measured in vitro by assays known to the skilled person.
  • tumor regression is observed and lasts for a period of at least about 20 days, more preferably at least about 40 days, or even more preferably at least about 60 days.
  • Treatment of a subject refers to the treatment of a subject for the purpose of reversing, reducing, improving, inhibiting, slowing or preventing the appearance, progression, development, severity, or recurrence of disease-related symptoms, complications, illnesses, or biochemical indicators.
  • the participant performs any type of intervention or treatment.
  • the present invention synthesizes and tests a series of novel camptothecin derivatives that introduce methylenedioxy groups at the 10 and 11 positions of the parent ring and introduce different substituent groups at the 7-position. Some examples of such compounds are shown in the table below. Show:
  • the compounds synthesized by the compounds of the present invention generally have better water solubility.
  • FIG. 1 shows a simplified scheme for the synthesis of the above compounds. The following describes it with reference to specific embodiments:
  • step (1) the intermediate C obtained in step (1) of Example 1 is directly subjected to a condensation cyclization reaction according to the method of step (2) of Example 1, and then the hydroxyl group is protected with acetic anhydride in the presence of pyridine and DMAP.
  • Intermediate E was obtained.
  • the remaining required raw materials, reagents and preparation methods are the same as steps (1) and (2) of Example 1.
  • Step (2) Add 20 (S) -O-acetyl-10,11-methylenedioxycamptothecin (0.24g, 0.55mmol) and glacial acetic acid (20ml) to a 50ml eggplant-shaped bottle. 30% hydrogen peroxide solution (3.2ml, 28mmol) was added, and after reacting at 75 ° C for 3h, the reaction solution was concentrated and evaporated to dryness to obtain yellow powder intermediate F, 210mg, yield 85%;
  • Step (3) Add the solid intermediate F (0.21g, 0.47mmol) and DMF (20ml) obtained in the previous step to a 50ml eggplant-shaped bottle, cool the solution to 0 ° C, and add oxalyl bromide (0.1ml, 1.1mmol). After reacting at 15 ° C for 3 hours, the reaction solution was poured into ice water (50 ml), and extracted with dichloromethane three times. The organic phases were combined, and the organic phase was dried over anhydrous magnesium sulfate. The filtrate was concentrated, and a methanol solution of sodium methoxide (1.0 g / 100.0 mL, 2 ml) was added, and the reaction was carried out at room temperature for 2.0 hours.
  • Step (4) In a 25 mL two-neck flask, add 20 (S) -7-bromo-10,11-methylenedioxycamptothecin (G) (37.6mg, 0.08mmol), 4-pyridineboronic acid (20mg, 0.16mmol) and cesium fluoride (25mg, 0.16mmol). After filling with nitrogen for three times, tetrakistriphenylphosphine palladium (9.2mg, 8 ⁇ 10-3mmol) was added, followed by dioxane, ethanol and water. (9.2mL, 1.9mL, 3.2mL), filled with nitrogen 6 times, heated to 105 ° C, microwave reaction for 6h.
  • the intermediate C (7.6 g, 37.3 mmol) prepared in Example 1 was dissolved in an appropriate amount of N, N-dimethylformamide dimethyl acetal (DMF-DMA), and heated to reflux at 110 ° C for 2 hours, and then the reaction solution was cooled to At room temperature, n-hexane was added to precipitate a yellow solid, which was filtered by suction to obtain 9.4 g of a solid with a yield of 95%.
  • DMF-DMA N, N-dimethylformamide dimethyl acetal
  • Step (2) Add the compound 5 ′ (S) -1,5-dioxo- (5′-ethyl-5′-hydroxy-2′H, 5′H, 6′H- 6-oxopyran)-[3 ′, 4 ′, f] - ⁇ 6 (8) -tetrahydroindolizine M (200mg, 0.76mmol), dissolved in anhydrous toluene (70ml), and added to the above Prepared 6′-amino-3 ′, 4′-methylenedioxymorpholinyl benzophenone (0.38g, 1.37mmol), p-toluenesulfonic acid (26.2mg, 0.15mmol), 110 under nitrogen The reaction was carried out under reflux at 24 ° C for 24 hours. The temperature was lowered to room temperature, and the solvent was removed by rotary evaporation. mp> 250 °C.
  • Example 28 20 (S) -7-piperidineethane-10,11-methylenedioxycamptothecin (Compound 52), 20 (S) -7-((2-methyl) -piperidine ) -Ethyl-10,11-methylenedioxycamptothecin (Compound 53)
  • the intermediate G, 20 (S) -7-bromo-10,11-methylenedioxycamptothecin prepared in the steps (1), (2), and (3) of Example 17 was used as a raw material, and then acetic anhydride The hydroxyl group was protected by the reaction, and then protected by nitrogen in the presence of palladium acetate, rac-BINAP, and potassium carbonate.
  • Reagents and reaction conditions (g) CO (OEt) 2 , t-BuOK, THF; (h) C 2 H 5 Br, K 2 CO 3 , CH 3 CN; (i) H 2 , Raney Ni, HOAC, Ac 2 O; (j) NaNO 2 , 0 ° C; (k) CCl 4 , reflux; (l) 1) O 2 , Raney Ni, CuCl, 2) H 2 SO 4 ; (m) CuCl, CH 2 Cl 2 ; (n) KOH, CH 3 OH; (o) CF 3 COOH, rt
  • intermediate M6 reacts with diethyl carbonate under the action of potassium tert-butoxide to obtain intermediate M7; intermediate M7 and bromoethane react to obtain intermediate M8; intermediate M8 undergoes Raney nickel catalytic hydrogenation under high pressure
  • Intermediate M9 is obtained; intermediate M9 is reacted with sodium nitrite to obtain intermediate M10; intermediate M10 is rearranged under reflux in carbon tetrachloride to obtain intermediate M11; intermediate M11 is oxidized to obtain intermediate M12; intermediate M12 is Chiral compounds were resolved by chiral isocyanate derivatization.
  • Intermediate M12 was reacted with chiral isocyanate under the catalysis of cuprous chloride to obtain two non-corresponding isomers, 13R and 13S.
  • intermediate 13S is hydrolyzed under alkaline conditions to obtain intermediate M14; intermediate 14 is deprotected under trifluoroacetic acid to obtain a stereospecific tricyclic intermediate M (that is, the above-mentioned Intermediate M).
  • intermediate M that is, the above-mentioned Intermediate M.
  • Step (1) Preparation of 6-cyano-1,1-ethylenedioxy-7-ethoxycarbonylmethyl-5-oxo- ⁇ 6 (8) -tetrahydroindane (intermediate M7)
  • Step (2) 6-cyano-1,1-ethylenedioxy-7- (1′-ethoxycarbonyl) propyl-5-oxo- ⁇ 6 (intermediate 8) -tetrahydroindolizine (Intermediate M8) Preparation
  • Step (3) 6-acetoxymethyl-1,1-ethylenedioxy-7- (1′-ethoxycarbonyl) propyl-5-oxo- [3 ′, 4 ′, f]- Preparation of ⁇ 6 (8) -tetrahydroindolizine (intermediate M11)
  • the intermediate M8 (12.00 g, 36.1 mmol) was dissolved in a mixed solution of acetic anhydride (150 mL) and glacial acetic acid (50 mL), Raney nickel (6 g) was added, and hydrogen was charged to 4 ⁇ 105 Pa, and the reaction was stirred at 45 ° C. for 6 h.
  • the catalyst was removed by filtration, the filter residue was washed three times with glacial acetic acid, and the filtrate was concentrated to obtain a yellow oily liquid; acetic anhydride (150 mL) and glacial acetic acid (50 mL) were added, and sodium nitrite (13.0 g, 188 mmol) was added under an ice bath, and the reaction was stirred for 2 h.
  • the inorganic salt was removed by suction filtration, the filter residue was washed three times with glacial acetic acid, and the filtrate was concentrated by rotary evaporation to obtain a yellow oily liquid; 200 ml of carbon tetrachloride was added), and the reaction was refluxed for 12 hours.
  • Raney Ni (3.0 g, 51.1 mmol), cuprous chloride (0.2 g, 2 mmol) and anhydrous potassium carbonate (8.0 g, 57.9 mmol) were added to anhydrous methanol (300 ml), and nitrogen was bubbled through for 1 h at room temperature.
  • Add intermediate M11 (21.0g, 53mmol), bubbling with oxygen for 6h, filter to remove the catalyst, concentrate the organic phase to obtain a yellow oily liquid, add distilled water (200ml), and adjust the pH to 2 to 3 with 1N dilute sulfuric acid. Extracted three times with dichloromethane and combined the organic phases.
  • Step (6) (5 ′S) -1,1-ethylenedioxy-5-oxo- (5′-ethyl-5′-hydroxy-2′H, 5′H, 6′H- Preparation of 6-oxopyran)-[3 ′, 4′-f] - ⁇ 6 (8) -tetrahydroindane (intermediate M14)
  • Selected tumor cell lines include: A549 cells (human non-small cell lung cancer cell line), K562 cells (human chronic myeloid leukemia cells), NCI-H1975 cells (human non-small cell lung adenocarcinoma cells), MDA-MB- 231 cells (human breast cancer cells) and HCT-116 cells (human colon cancer cells).
  • the compounds 21-30 involved in the present invention are all superior to topotecan in three tumor cells (NCI-H1975 cells, MDA-MB-231 cells, and HCT-116 cells), of which 26 pairs NCI-H1975 and MDA-MB-231 cell lines had the strongest cytotoxic activity. 24 had the strongest cytotoxic activity on HCT-116 cell line. From the IC 50 value, we can also see that HCT-116 cell line is the most sensitive to compounds 21-29.
  • Example 32 The compound of the present invention demonstrates that the binding of the compound to EGF and FGF affects cell proliferation through macromolecular interaction experiments.
  • Topotecan 1 2 3 4 5 6 7 8 9 10 51 52 32 14 twenty one twenty three twenty four 25 Zh Zh
  • Flowing samples are: EGF (1 ⁇ M), FGF (1 ⁇ M), HSP90 (100nM), FKBP12 (100nM)
  • the positive controls were: RAPA and FKBP12
  • the tested transplant tumor models include A549 (lung cancer) transplant tumor models and RM-1 (prostate cancer).
  • the compound of the present invention is administered by intraperitoneal injection, and at a low concentration (9 mg / kg), it can effectively inhibit the growth of tumors (the tumor inhibition rate reaches more than 70%). At the same time, it has less toxicity to mice and has the potential to be a medicine.
  • the compounds 11, 15, 23, and 51 of the present invention have an antitumor activity superior to that of topotecan, and have potential for medicine.
  • Test methods include:
  • the human colon cancer cell line HCT-116 was resuscitated with liquid nitrogen and cultured with 5A medium containing 10% fetal bovine serum.
  • the cultured cells were expanded in a culture flask, and the cells were digested and collected. It was diluted with 5A medium containing 10% fetal bovine serum to 250 million / ml cell suspension, and after routine sterilization, it was inoculated subcutaneously in the right forearm armpit of BALB / c-nu mice at about 0.1 ml each.
  • the tumor mass with a short diameter of about 1 mm is cut, and it is implanted subcutaneously by a catheter method, and drug administration is started on the 6th day after transplantation.
  • Mice were randomly divided into 7 groups according to tumor volume, the solvent control group, the irinotecan group (6 mg / kg), the 5-fluorouracil group (20 mg / kg), the compound 23 low-dose group (2.5 mg / kg), and the high-dose Group (5mg / kg).
  • Compound 23 was administered to the low-dose group and high-dose group by intragastric administration, once a week.
  • Irinotecan group and 5-fluorouracil group were administered intravenously, once every three days, and mice were recorded three times a week. Changes in body weight and tumor volume.
  • mice After BALB / c-nu mice were inoculated subcutaneously with HCT-116 tumor mass, the tumor volume reached 1.01 ⁇ 0.65 mm 3 and was randomly divided into groups. On day 23, the tumor tissue of the solvent control group grew to 771.70 ⁇ 101.05 mm 3. All mice were sacrificed, and the tumor tissue was stripped and stored frozen at -80 ° C.
  • the tumor volume growth curve was plotted with the days of administration as the abscissa, as shown in FIG. 2. Compared with the solvent control group and the positive drug group, the low- and high-dose administration of Compound 23 significantly inhibited the growth of HCT-116 transplanted tumors in mice. The tumor inhibition rates were 95.45% and 87.04% after 23 days (Table). 4).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明涉及一种具有如式(I)所示结构的化合物、其立体异构体和药学上可接受的盐形式，也涉及所述化合物的制备方法、包含治疗有效剂量的所述化合物的药物组合物，以及其在用于制备预防和/或治疗癌症中的用途。本发明提供的化合物是一类结构新颖的在母环的10,11位引入亚甲二氧基、7-位引入不同取代基团的喜树碱衍生物，其制备方法原料易得，合成方法简单，纯化方式简便快捷，并且本发明所述化合物具有极好的体外细胞毒活性和优秀的体内抗肿瘤效果，因此此类化合物具有广泛的药用前景。

Description

喜树碱衍生物及其制备方法和应用 技术领域
本发明属于医药技术领域，具体涉及一类新型的喜树碱衍生物及其制备方法和应用。
背景技术
喜树碱衍生物被誉为20世纪90年代抗癌药物的三大发现之一，显示了广谱的抗肿瘤活性和巨大的研究与应用价值。早期的喜树碱类化合物其作用机制是与Top I和DNA形成三元复合物，阻断DNA的复制和转录，具有选择性低和毒副作用大等缺点。随着科技的发展，分子靶向性的抗肿瘤药物已经成为了近年来的研究热点，这类药物能够选择性的作用于与肿瘤细胞分化增殖相关的信号转导通路，本发明以喜树碱为先导化合物，对其进行结构改造来开发更加高效低毒的抗肿瘤候选化合物。
我们在喜树碱的结构基础上，在10,11位引入亚甲二氧基，在7位引入不同的取代基团，以获得抗肿瘤活性更好，毒性更小、溶解性好的化合物。
发明内容
本发明提供了一种喜树碱衍生物及其制备方法和应用，可用于制备预防或治疗肿瘤的药物。
为解决上述技术问题，本发明一方面提供一种具有式(I)所示结构的化合物、其立体异构体和药学上可接受的盐形式：
Figure PCTCN2019090731-appb-000001
式中R为
Figure PCTCN2019090731-appb-000002
其中：
X选自于
Figure PCTCN2019090731-appb-000003
n为0-2的整数，m为0-2的整数；
Z为环结构，Z环选自于取代或者非取代的苯环、取代或者非取代的吡啶环、取代或者非取代的呋喃环、取代或者非取代的噻吩环、取代或者非取代的吡唑环、取代或者非取代的吲哚环、取代或者非取代的苯并吡唑环、取代或者非取代的哌啶环、取代或者非取代的吗啉环、取代或者非取代的硫代吗啉环、取代或者非取代的萘环和取代或者非取代的三唑环；
当为取代结构时，所述取代基选自于卤素原子、取代或者非取代的烷基、取代或者非取代的酯基、取代或非取代的芳基、取代或者非取代的吡咯烷基、取代或非取代的哌啶基、取代或非取代的吗啉基和取代或非取代的硫代吗啉基；
所述取代为单取代或者多取代；
当n和m均为0时，所述Z环不为非取代的苯环。
优选地，所述卤素原子为F。
所述的立体异构体包括：构象异构体，光学异构体(如对映异构体和非对映异构体)，几何异构体(如顺反异构体)。这些异构体或其组合可以作为外消旋的混合物、单独的对映异构体、单独的非对映异构体、非对映异构体混合物、顺式或反式异构体存在。
所述的药学上可接受的盐，是指上述化合物与无机酸、有机酸、碱金属或碱土金属等反应生成的盐。这些盐包括(但不限于)：(1)与如下无机酸形成的盐：如盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸；(2)与如下有机酸形成的盐，如乙酸、乳酸、柠檬酸、琥珀酸、延胡索酸、葡萄糖酸、安息香酸、甲烷磺酸、乙烷磺酸、苯磺酸、对甲苯磺酸、草酸、丁二酸、酒石酸、马来酸、或精氨酸(3)其它的盐，包括与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐，铵盐或水溶性的胺盐(如N-甲基葡糖胺盐)、低级的烷醇铵盐以及其它药学上可接受的胺盐(比如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐)，或其它常规的“前体药物”的形式。
进一步的本发明还提供上述化合物的前体，所述前体指当用适当的方法服用后，该化合物的前体在病人体内进行代谢或化学反应而转变成本发明通式所包含的化合物，以及化合物所组成的盐或溶液。化合物的前体包括但不局限于所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
在一个优选的实施例中，所述X为
Figure PCTCN2019090731-appb-000004
m为1或2；Z环为取代或者非取代的苯环。特别优选地，式(I)中R为以下基团中的任意一种：
Figure PCTCN2019090731-appb-000005
在另一个优选的实施例中，所述X为
Figure PCTCN2019090731-appb-000006
n为2；Z环为取代或者非取代的苯环。特别优选地，式(I)中R为以下基团中的任意一种：
Figure PCTCN2019090731-appb-000007
在另一个优选的实施例中，X为
Figure PCTCN2019090731-appb-000008
所述n和m均为0。特别优选地，式(I)中R为以下基团中的任意一种：
Figure PCTCN2019090731-appb-000009
Figure PCTCN2019090731-appb-000010
更佳地，所述化合物为
Figure PCTCN2019090731-appb-000011
在另一个优选的实施例中，所述X为
Figure PCTCN2019090731-appb-000012
n为0-2的整数；Z环选自于取代或者非取代的哌啶环、取代或者非取代的吗啉环和取代或者非取代的硫代吗啉环。特别优选地，式(I)中R为以下基团中的任意一种：
Figure PCTCN2019090731-appb-000013
在另一个优选的实施例中，式(I)中R为取代或者非取代的三唑环，所述化合物具有式(II)所示结构：
Figure PCTCN2019090731-appb-000014
式中R 1选自于取代或者非取代的烷基、取代或者非取代的酯基、取代或非取代的异羟肟酸链和取代或者非取代的芳基。
本发明另一方面提供了上述化合物在用于制备预防和/或治疗癌症的药物中的用途。优选地，所述癌症选自于肺癌、结肠癌、前列腺癌、白血病和乳腺癌。
本发明另一方面提供了上述化合物作为EGF或FGF抑制剂的用途。
本发明另一方面还提供了一种药物组合物，包含：1)有效剂量的上述的化合物，以及2)药学上可接受的载体。
所述药物组合物可以制成片剂、胶囊、粉剂、颗粒、锭剂、栓剂、口服液或无菌胃肠外悬液等液体制剂形式，以及大或小容量注射剂、冻干粉剂等针剂形式。上述剂型的药物均可按照药学领域的常规方法制备。
如需要，本发明的药物组合物还可以加入一种或多种药学上可接受的载体，载体包括药学领域常规的稀释剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
本发明另一方面还提供了上述化合物的制备方法，其特征在于包括以下步骤：
(1)以3,4-亚甲二氧基苯乙酮(A)为起始原料，经过浓硝酸硝化、氢气钯碳还原两步反应得到了6-氨基-3,4-亚甲二氧基苯乙酮(C)。
Figure PCTCN2019090731-appb-000015
(2)当结构式为(I)，X为
Figure PCTCN2019090731-appb-000016
m为1或2；Z环为取代或者非取代的苯环，式(I)化合物的R基团为基团1-7时：将6-氨基-3,4-亚甲二氧基苯乙酮再和不同取代的苯甲醛或不同取代的肉桂醛通过克莱森施密特反应得到中间体D，再与5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ 6(8)-四氢中氮茚(M)缩合环化反应，获得化合物1-7。
Figure PCTCN2019090731-appb-000017
(3)当结构式为(I)，X为
Figure PCTCN2019090731-appb-000018
n为2；Z环为取代或者非取代的苯环，式(I)化合物的R基团为基团8-20时：将步骤(2)获得的7位苯乙烯基取代的喜树碱衍生物进行催化氢化，获得化合物8-20。
Figure PCTCN2019090731-appb-000019
(4)当结构式为(I)，n和m均为0，式(I)化合物的R基团为基团21-42时：将步骤(1)获得的6-氨基-3,4-亚甲二氧基苯乙酮(C)与5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ 6(8)-四氢中氮茚(M)在对甲苯磺酸的催化下，加热回流，发生缩合反应，再与乙酸酐酰化反应、过氧化氢氧化得到中间体F，F再与草酰溴溴代得到20-O-乙酰基-7-溴-10,11-亚甲二氧基喜树碱(G)，G与不同的芳杂环苯硼酸或芳环苯硼酸发生偶联反应，经甲醇钠脱去保护基乙酰基，得到7位为芳杂环或不同取代的苯基修饰的(上述结构式I所标示的21至42基团)化合物21-42。
Figure PCTCN2019090731-appb-000020
(5)当结构式为(I)，式(I)中R为基团43-46时：以步骤4获得的中间体20-O-乙酰基-7-溴-10,11-亚甲二氧基喜树碱(G)与不同的杂环发生取代反应得到7位为N-甲基 吗啉、N-甲基哌啶、N-甲基-2-甲基哌啶和N-甲基硫代吗啉修饰的化合物43-46。
(6)当结构式为(I)，式(I)中R为基团47-50时：以步骤4获得的中间体(F)与不同的含氮杂环发生取代反应得到7位为N-亚甲基吗啉、N-亚甲基哌啶、N-亚甲基-2-甲基哌啶和N-亚甲基硫代吗啉取代的(上述结构式I所标示的47至50基团)化合物47-50。
(7)当结构式为(I)，式(I)中R为基团51-54时：以步骤(1)制备的中间体C，经过与N,N-二甲基甲酰胺二甲基缩合、杂环取代基取代，得到含有不同杂环取代的中间体(J)，再与中氮茚M在对甲苯磺酸的催化下，加热回流，发生缩合反应获得7位含有N-乙基吗啉、N-乙基哌啶、N-乙基-2-甲基哌啶和N-乙基硫代吗啉修饰的化合物51-54。
(8)当R为含有不同取代基的三唑环，结构式为(II)时：以步骤4获得的中间体20-O-乙酰基-7-溴-10,11-亚甲二氧基喜树碱(G)与三甲基硅烷乙炔在醋酸钯催化下与三甲基硅烷乙炔，在氟化钾作用获得20-O-乙酰基-7-乙炔基-10,11-亚甲二氧基喜树碱(K)，K与含有不同取代基的叠氮化合物发生点击化学反应，得到式(II)化合物。
本发明还提供一种上述中间体M的制备方法：
Figure PCTCN2019090731-appb-000021
将M6在叔丁醇钾作用下和碳酸二乙酯反应得到中间体M7；中间体M7和溴乙烷反应得到中间体M8；中间体M8在高压下经过雷尼镍催化氢化得到中间体M9；中间体M9和亚硝酸钠反应得到中间体M10；中间体M10在四氯化碳中回流重排得到中间体M11；中间体M11经过氧气氧化得到中间体M12；中间体M12为手性化合物，采用手性异氰酸酯衍生化的方法进行手性拆分，中间体M12在氯化亚铜催化下和手性异氰酸酯反应得到两个非对应异构体M13R和M13S，用柱层析将二者分离纯化；中间体M13S在碱性条件下水解得到中间体M14；中间体M14在三氟乙酸条件下脱保护得到立体专一性的三环中间体M15(即中间体M)。
本发明的化合物对肿瘤组织的选择性要高于传统的喜树碱类化合物，溶解性高于传统的喜树碱类化合物，抗肿瘤活性与母体化合物相比显著提高，同时保持着较小的毒性，可用于制备预防或治疗癌症的药物。本发明的喜树碱衍生物结构特征清晰，合成方便，纯化方式简便快捷，具有良好的生物活性，因此此类化合物在预防或治疗癌症方面有着广泛的 应用前景。
附图说明
图1.本发明化合物的合成路线简图。
图2.化合物23对HCT-116移植瘤模型小鼠肿瘤体积变化的影响。
图3.化合物23对HCT-116移植瘤模型小鼠体重变化的影响。
具体实施方式
本发明的方法与技术通常依据本领域已知的传统方法进行，除非另有说明。与本文中描述的生物学、药理学、及医学与医药化学相关的命名法，及实验方法与技术是本领域已知且常用的。化学合成法、化学分析法、医药制法、调配法与传送法，及患者的治疗法均采用标准技术。
除非另有说明，否则本文中所使用的科学与技术术语应具有那些本领域普通技术人员通常理解的含义。但下列术语具有如下定义：
“癌症”是指一大类以异常细胞在体内不受控制地生长为特征的各种疾病。不受控制的细胞分裂和生长分裂和生长导致形成恶性肿瘤或细胞，它们侵入邻近组织，还可以通过淋巴系统或血流转移到身体的远端部分。在本发明中“治疗癌症”的另一种等同的描述是“治疗肿瘤”或者“抗癌”或者“抗肿瘤”。
癌症是不受控制的妨碍身体器官和系统的正常功能的细胞生长的病症。患有癌症的受试者是具有客观可测量的存在于受试者机体内的癌症细胞的受试者。处于发展癌症的危险中的受试者是易于发展癌症(例如基于家族史、遗传倾向)的受试者、接触放射或其他引起癌症的试剂的受试者。
本发明化合物可用于治疗多种癌症或处于发展癌症的危险中的受试者。这种癌症的例子包括乳腺癌、前列腺癌、肺癌、卵巢癌、宫颈癌、皮肤癌、黑素瘤、结肠癌、胃癌、肝癌、食道癌、肾癌、咽喉癌、甲状腺癌、胰腺癌、睾丸癌、脑癌、骨癌和血癌(如白血病、慢性淋巴细胞性白血病)等。其他的癌症包括但不限于基底细胞癌、胆道癌、膀胱癌、骨癌、脑和中枢神经系统(CNS)癌、宫颈癌、绒毛膜癌、结肠直肠癌、结缔组织癌、消化系统癌、子宫内膜癌、食道癌、眼癌、头颈癌、上皮内肿瘤、喉癌、肺癌(小细胞、大细胞)、淋巴瘤(包括霍奇金淋巴瘤和非霍奇金淋巴瘤)；黑素瘤；神经母细胞瘤；口腔癌(例如唇、舌头、口和咽)；视网膜母细胞瘤；横纹肌肉瘤；呼吸系统癌；肉瘤；子宫癌；泌尿系统癌；以及其他癌和肉瘤。
“治疗有效剂量”是药物的任何如下所述的量，当单独使用或与另一种治疗剂组合使用该量的药物时，可促进疾病消退，疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。药物的治疗有效量或剂量包括“预防有效量”或“预防有效剂量”，“预防有效量”或“预防有效剂量”是药物的任何如下所述的量，当将该量的药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时，可抑制疾病的发生或复发。治疗剂促进疾病消退或抑制疾病发展或复发的能力可以用技术人员已知的各种方法进行评估，例如在人类受试者的临床试 验中，在可预测在人类中的效力的动物模型系统中，或者通过在体外测定系统中测定试剂的活性。
作为举例，抗癌剂(治疗癌症的药物组合物)促进受试者体内的肿瘤消退。在优选的实施方案中，治疗有效剂量的药物促进癌细胞消退乃至消除癌症。“促进癌症消退”意思是单独施用或与抗肿瘤剂(anti-neoplastic agent)组合施用治疗有效量的药物导致肿瘤生长减少或大小减小、肿瘤坏死、至少一种疾病症状的严重程度降低，无疾病症状期的频率和持续时间增加，防止由患病导致的障碍或失能，或者以其他方式改善患者的疾病症状。此外，术语关于治疗的“有效”和“有效性”包括药理学有效性和生理学安全性二者。药理学有效性是指药物促进患者癌症消退的能力。生理学安全性是指由于药物施用导致的细胞、器官和/或生物体水平上的毒性或者其它不良生理效果(不良作用)的水平。
作为肿瘤治疗的例子，与未经治疗的受试者相比，治疗有效量或剂量的药物优选地可以抑制细胞生长或肿瘤生长达至少大约20％，更优选至少大约40％，甚至更优选至少大约60％，并且还更优选至少大约80％。在最优选的实施方案中，治疗有效量或剂量的药物可完全抑制细胞生长或肿瘤生长，即优选地抑制细胞生长或肿瘤生长达100％。化合物抑制肿瘤生长的能力可以在动物模型系统中进行评价，它们能够预测在人肿瘤中的效力。作为替代，组合物的这一性质可以通过检验化合物抑制细胞生长的能力进行评估，这样的抑制可以通过技术人员已知的测定法在体外加以测量。在本发明的其他优选实施方案中，肿瘤消退可以观察到，并持续至少约20天，更优选至少约40天，或甚至更优选至少约60天的时间。
对受试者的“治疗”是指以逆转、减轻、改善、抑制、减缓或防止与疾病有关的症状、并发症、病症或生化指标的出现、进展、发展、严重程度或复发为目的对受试者进行任何类型的干预或处理。
以下结合实施例对本发明作进一步的详细描述。
本发明合成并测试了一系列结构新颖的在母环的10,11位引入亚甲二氧基、7-位引入不同取代基团的喜树碱衍生物，一些该类化合物的实例如下表所示：
Figure PCTCN2019090731-appb-000022
Figure PCTCN2019090731-appb-000023
Figure PCTCN2019090731-appb-000024
Figure PCTCN2019090731-appb-000025
Figure PCTCN2019090731-appb-000026
Figure PCTCN2019090731-appb-000027
经测试，本发明化合物所合成的化合物一般都具有较佳的水溶性。
图1显示了上述化合物的合成路线简图。下面结合具体的实施例来说明：
化合物1-7的简要的合成路线如下：
Figure PCTCN2019090731-appb-000028
实施例1 20(S)-7-苯丁二烯基-10,11-亚甲二氧基喜树碱(化合物1)的制备
步骤(1)(2E,4E)-1-(5-氨基苯并[d][1,3]二氧代-6-基)-5-苯基戊-2,4-双烯-1-酮(D1)的制备
室温下，将浓硝酸(20.7ml)缓慢滴加入3,4-亚甲二氧基苯乙酮(8.1g,49.3mmol)的硝基甲烷(80ml)溶液中，搅拌反应2h，向反应液中缓慢滴加饱和碳酸氢钠溶液，调pH至中性后用二氯甲烷萃取三遍，合并有机相，饱和食盐水洗三次，无水硫酸镁干燥后浓缩得到黄色油状液体，硅胶柱层析(石油醚:乙酸乙酯＝8:1)进行分离，浓缩后得到浅黄色固体6-硝基-3,4-亚甲二氧基苯乙酮7.8g，收率76％；mp 110-112℃。
将6-硝基-3,4-亚甲二氧基苯乙酮(7.8g,37.3mmol)溶于乙酸乙酯(70ml)中，加入催化量钯碳，充氢气球，室温下搅拌反应12h，过滤除去催化剂，浓缩后得到浅黄色固体6-氨基-3,4-亚甲二氧基苯乙酮5.5g，收率83％。mp 123-124℃。
在100ml茄形瓶中加入6-氨基-3,4-亚甲二氧基苯乙酮(0.2g,1.1mmol)，用无水乙醇(10ml)溶解，依次加入氢氧化钠(0.4g,11mmol)和肉桂醛(0.14g,1.3mmol)，室温下搅拌反应12h，浓缩除去乙醇，硅胶柱层析(石油醚:乙酸乙酯＝4:1)进行纯化，浓缩后得到黄色固体D1(0.21g)，收率71％。mp 130-132℃。
1H NMR(500MHz,DMSO-d6)δ7.81(dd,J＝8.5,5.7Hz,2H),7.77(s,1H),7.35(d,J＝16.3Hz,1H),7.25(t,J＝7.4Hz,2H),7.23(s,1H),7.16(d,J＝16.3Hz,1H),6.31(s,2H).
13C NMR(126MHz,DMSO-d6)δ192.0,164.9,163.0,152.7,149.3,144.6,141.4,132.7,131.6,131.1,126.3,116.5,116.3,108.1,105.3,104.5.
步骤(2)在50ml茄形瓶中加入中间体(2E,4E)-1-(5-氨基苯并[d][1,3]二氧代-6-基)-5-苯基戊-2,4-双烯-1-酮(D1)(200mg,0.76mmol)，溶于无水甲苯(25ml)中，再加入(2E,4E)-1-(5-氨基苯并[d][1,3]二氧代-6-基)-5-苯基戊-2,4-双烯-1-酮(M)(0.41g,1.4mmol)，对甲苯磺酸(13.0mg,0.08mmol)，氮气保护下110℃回流反应24h后，降至室温，旋蒸浓缩除去溶剂，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分离，得到黄色片状固体化合物160mg，收率15％。mp 206–214℃；MS(ESI):m/z,521.4[M+H] +.
1H NMR(600MHz,CF 3COOD)δ8.23(s,1H),8.06–7.94(m,1H),7.92(s,1H),7.84(d,J＝16.4Hz,1H),7.79(s,1H),7.72(d,J＝7.4Hz,1H),7.67(d,J＝18.5Hz,1H),7.53(d,J＝8.1Hz,1H),7.48(d,J＝15.6Hz,1H),7.43(d,J＝9.7Hz,1H),7.36(s,2H),7.29–7.14(m,1H),6.57–6.43(m,2H),6.01(d,J＝26.7Hz,2H),5.70(d,J＝16.7Hz,1H),2.29(d,J＝27.2Hz,2H),1.35(dd,J＝117.8,12.9Hz,3H).
13C NMR(151MHz,CF 3COOD)δ176.5,161.1,157.5,157.6,149.3,147.4,146.5,145.5,134.3,131.7,130.3,129.5,128.7,128.5,128.0,127.9,127.4,126.9,121.0,117.9,115.7,113.8,111.2,105.5,97.4,74.0,66.5,65.5,31.7,11.8,5.4.
实施例2 20(S)-7-(4-氟苯乙烯基)-10,11-亚甲二氧基喜树碱(化合物3)的制备
将4-氟苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-氟苯乙烯基)-10,11-亚甲二氧基喜树碱黄色固体化合物3。mp>250℃；MS(ESI):m/z,513.5[M+H] +.
1H NMR(500MHz,CF 3COOD)δ8.23(s,1H),8.00(s,1H),7.95(dd,J＝7.8,5.4Hz,1H),7.87(d,J＝16.5Hz,1H),7.85–7.78(m,1H),7.73(s,1H),7.30(dd,J＝22.8,14.3Hz,2H), 7.10(dd,J＝36.5,25.0Hz,1H),6.52(s,2H),6.03(t,J＝11.9Hz,1H),6.01–5.83(m,2H),5.69(d,J＝17.0Hz,1H),2.24(dd,J＝17.8,11.0Hz,2H),1.33–1.16(m,3H).
13C NMR(125MHz,CF 3COOD)δ176.2,157.4,152.1,151.8,148.9,145.0,140.1,139.8,138.8,130.6,130.0,130.0,126.1,126.0,121.0,117.3,116.1,116.0,105.0,103.4,101.1,97.3,73.9,66.2,52.5,31.0,11.7,5.8.
实施例3 20(S)-7-(3-氟苯乙烯基)-10,11-亚甲二氧基喜树碱(化合物4)的制备
将3-氟苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-氟苯乙烯基)-10,11-亚甲二氧基喜树碱黄色固体化合物4。mp>250℃；MS(ESI):m/z,513.5[M+H] +.
1H NMR(500MHz,CF 3COOD)δ8.23(s,1H),8.00(s,1H),7.95(dd,J＝7.8,5.4Hz,1H),7.87(d,J＝16.5Hz,1H),7.85–7.78(m,1H),7.73(s,1H),7.30(dd,J＝22.8,14.3Hz,2H),7.14(dd,J＝36.5,25.0Hz,1H),6.56(s,2H),6.03(t,J＝11.9Hz,1H),6.21–5.84(m,2H),5.69(d,J＝17.0Hz,1H),2.24(dd,J＝17.8,11.0Hz,2H),1.33–1.16(m,3H).
13C NMR(126MHz,CF 3COOD)δ176.2,157.4,152.1,151.8,148.9,145.0,140.1,139.8,138.8,130.6,130.4,130.0,126.8,126.0,121.0,117.5,116.1,116.0,105.0,103.4,101.1,97.3,73.9,66.2,52.5,31.0,11.7,5.8.
实施例4 20(S)-7-(2-氟苯乙烯基)-10,11-亚甲二氧基喜树碱(化合物5)的制备
将2-氟苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-氟苯乙烯基)-10,11-亚甲二氧基喜树碱黄色固体化合物5。mp>250℃；MS(ESI):m/z,513.5[M+H] +.
1H NMR(500MHz,CF 3COOD)δ8.23(s,1H),8.00(s,1H),7.95(dd,J＝7.8,5.4Hz,1H),7.87(d,J＝16.5Hz,1H),7.81–7.78(m,1H),7.53(s,1H),7.30(dd,J＝22.8,14.3Hz,2H),7.28(dd,J＝36.5,25.0Hz,1H),6.56(s,2H),6.03(t,J＝11.9Hz,1H),6.21–5.84(m,2H),5.69(d,J＝17.0Hz,1H),2.24(dd,J＝17.8,11.0Hz,2H),1.33–1.16(m,3H).
13C NMR(126MHz,CF 3COOD)δ176.2,157.4,152.1,151.8,148.9,145.0,140.1,139.7,138.8,130.9,130.4,130.0,126.8,126.0,121.0,117.5,116.1,116.0,105.0,103.4,101.1,97.3,73.9,66.2,52.5,31.0,11.7,5.8.
化合物8-20的简要的合成路线如下：
Figure PCTCN2019090731-appb-000029
实施例5 20(S)-7-(4-(4-吗啉)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物8)的制备
将4-吗啉苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-(4-吗啉)-苯乙烯基)-10,11-亚甲 二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色固体20(S)-7-(4-(4-吗啉)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物8)；mp>250℃.
1H NMR(500MHz,DMSO)δ7.58(s,1H),7.46(s,1H),7.19(s,1H),6.95(d,J＝8.3Hz,2H),6.74(d,J＝8.1Hz,2H),6.25(s,2H),5.33(t,J＝11.8Hz,2H),4.75(q,J＝18.8Hz,2H),3.65(s,4H),3.26(s,2H),2.93(s,4H),2.83(s,2H),1.87–1.76(m,2H),0.83(t,J＝7.2Hz,3H).
13C NMR(125MHz,DMSO)δ172.94,157.14,151.29,150.49,150.10,149.44,149.38,147.54,146.67,142.38,131.83,129.60,128.32,124.68,118.31,115.57,105.88,103.01,99.94,96.45,72.74,66.40,65.63,49.85,49.22,34.39,32.34,30.62,8.17.
实施例6 20(S)-7-(4-(1-吡咯烷基)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物9)的制备
将4-(1-吡咯烷基)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-(1-吡咯烷基)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到黄色粉末20(S)-7-(4-(4--(1-吡咯烷基)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物9)。mp 205-207℃℃.
1H NMR(500MHz,DMSO)δ7.61(s,1H),7.47(s,1H),7.19(s,1H),6.89(d,J＝8.2Hz,2H),6.35(d,J＝8.1Hz,2H),6.26(s,2H),5.35(s,2H),4.77(q,J＝18.7Hz,2H),3.25(d,J＝7.4Hz,2H),3.06(s,4H),2.80(s,2H),1.91–1.76(m,6H),0.83(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ172.94,157.12,151.28,150.50,149.47,149.38,147.56,147.07,146.72,142.52,129.54,128.35,127.61,124.68,118.29,112.07,105.93,103.01,99.99,96.37,72.75,65.62,49.88,47.93,34.53,32.71,30.56,25.24,8.18.
实施例7 20(S)-7-(3-氟-4-(4-吗啉)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物10)的制备
将3-氟-4-(4-吗啉)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-(4-吗啉)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到黄色粉末20(S)-7-(3-氟-4-(4-吗啉)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物10)。mp>250℃.
1H NMR(500MHz,DMSO)δ7.56(s,1H),7.44(s,1H),7.20(s,1H),6.99(d,J＝13.3Hz,1H),6.91–6.82(m,2H),6.23(s,2H),5.35(q,J＝16.3Hz,2H),4.90(q,J＝18.7Hz,2H),3.66(s,4H),3.27(s,2H),2.84(s,6H),1.81(dt,J＝24.6,7.0Hz,2H),0.83(t,J＝7.2Hz,3H).
13C NMR(125MHz,DMSO)δ172.98,157.24,151.31,150.56,149.53,149.40,147.54,146.67,142.16,136.18,128.15,125.36,124.72,119.24,118.35,116.75,116.59,105.81,103.02,99.99,96.56,72.77,66.54,65.65,51.07,49.91,34.12,31.77,30.64,8.16.
实施例8 20(S)-7-(3-氟-4-(1-吡咯烷基)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物11)的制备
将3-氟-4-(1-吡咯烷基)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-(1-吡咯烷基)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到黄色粉末20(S)-7-(3-氟-4-(1-吡咯烷基)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物11)。mp>250℃。
1H NMR(600MHz,DMSO-D6)δ7.60(s,1H),7.47(s,1H),7.23(s,1H),6.89(dd,J＝14.9,1.9Hz,1H),6.75(d,J＝8.2Hz,1H),6.59–6.53(m,1H),6.26(d,J＝2.2Hz,2H),5.37(q,J＝16.0Hz,2H),4.86(q,J＝18.6Hz,2H),3.27(d,J＝6.1Hz,2H),3.15(d,J＝2.1Hz,4H),2.82(d,J＝5.0Hz,2H),1.87–1.78(m,6H),0.85(t,J＝7.3Hz,3H).
13C NMR(151MHz,DMSO-D6)δ173.14,157.34,151.44,150.71,149.53,149.51,147.62,146.78,142.40,136.22,130.86,128.28,125.27,124.79,118.43,116.50,115.97,105.91,103.16,100.04,96.70,72.90,65.74,50.12,49.97,34.11,32.25,30.73,25.07,8.26.
实施例9 20(S)-7-(3-氟-4-(哌啶-1-基)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物12)的制备
将3-氟-4-(哌啶-1-基)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-(哌啶-1-基)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到黄色粉末20(S)-7-(3-氟-4-(3-氟-4-(哌啶-1-基)苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物12)。mp>250℃。
1H NMR(500MHz,DMSO)δ7.61(s,1H),7.47(s,1H),7.20(s,1H),6.95(d,J＝13.4Hz,1H),6.86–6.80(m,2H),6.25(s,2H),5.34(t,J＝9.8Hz,2H),4.90(t,J＝13.9Hz,2H),3.30(s,2H),2.82(d,J＝25.5Hz,6H),1.82(td,J＝14.2,6.7Hz,2H),1.56(s,4H),1.45(s,2H),0.83(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ172.95,157.19,151.30,150.48,149.56,149.40,147.58,146.69,142.17,128.26,125.22,124.72,119.60,118.35,116.43,105.88,102.99,100.04,96.43,72.75,65.65,52.08,49.92,34.16,31.79,30.61,26.03,24.16,8.15.
实施例10 20(S)-7-(3-(4-吗啉)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物14)的制备
将3-(4-吗啉)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(3-(4-吗啉)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色粉末20(S)-7-(3-(4-吗啉)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物14)。mp 163-165℃。
1H NMR(500MHz,DMSO)δ7.61(s,1H),7.47(s,1H),7.20(s,1H),7.07(t,J＝7.8Hz, 1H),6.70(d,J＝7.6Hz,1H),6.64(d,J＝7.5Hz,1H),6.57(s,1H),6.25(s,2H),5.36(s,2H),4.84(d,J＝18.7Hz,1H),4.73(d,J＝18.7Hz,1H),3.62(s,4H),3.37–3.26(m,2H),2.87(s,6H),1.86–1.76(m,2H),0.83(t,J＝7.2Hz,3H).
13C NMR(125MHz,DMSO)δ172.95,157.18,151.43,151.32,150.56,149.49,149.39,147.60,146.69,142.41,141.91,129.38,128.36,124.75,120.21,118.35,116.11,113.81,105.89,103.02,100.04,96.44,72.77,66.44,65.62,49.07,35.56,31.96,30.61,8.19.
实施例11 20(S)-7-(2-(4-吗啉)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物15)的制备
将2-(4-吗啉)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(2-(4吗啉)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色粉末20(S)-7-(2-(4-吗啉)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物15)。mp>250℃。
1H NMR(500MHz,DMSO)δ7.71(s,1H),7.47(s,1H),7.40(d,J＝7.1Hz,1H),7.19–7.14(m,2H),7.07(dd,J＝15.5,7.5Hz,2H),6.27(s,2H),5.36(s,2H),4.88(d,J＝18.7Hz,1H),4.76(d,J＝18.6Hz,1H),3.45(d,J＝9.8Hz,4H),3.31–3.20(m,2H),3.00(t,J＝7.4Hz,2H),2.55(dd,J＝34.3,13.2Hz,4H),1.81(td,J＝14.5,7.2Hz,2H),0.83(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ172.89,157.14,151.93,151.26,150.54,149.51,149.35,147.50,146.62,142.41,137.09,131.07,128.00,127.89,125.10,124.97,121.01,118.40,105.96,103.07,99.98,96.39,72.75,66.77,65.61,53.52,49.80,32.39,30.55,30.44,8.20.
实施例12 20(S)-7-(2-(1-吡咯烷基)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物16)的制备
将2-(1-吡咯烷基)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(2-(1-吡咯烷基)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色粉末20(S)-7-(2-(1-吡咯烷基)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物16)。mp 139-140℃。
1H NMR(500MHz,DMSO)δ7.66(s,1H),7.47(s,1H),7.18(d,J＝7.5Hz,2H),7.08(d,J＝7.4Hz,1H),6.99(d,J＝8.0Hz,1H),6.86(t,J＝7.2Hz,1H),6.26(s,2H),5.37(s,2H),4.95(d,J＝18.7Hz,1H),4.87(d,J＝18.7Hz,1H),3.26(d,J＝10.4Hz,2H),3.00(t,J＝7.4Hz,2H),2.96–2.87(m,4H),1.86–1.75(m,6H),0.83(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ172.88,157.19,151.20,150.44,149.58,149.28,147.56,147.46,146.72,142.52,134.59,131.16,128.35,127.61,125.03,122.68,118.97,112.07,105.90,103.01,99.99,96.35,72.75,65.59,52.49,34.53,32.71,30.56,25.24,8.18.
实施例13 20(S)-7-(4-(哌啶-1-基)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物17)的制备
将4-(哌啶-1-基)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、 制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-(哌啶-1-基)-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色粉末20(S)-7-(4-(哌啶-1-基)-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物17)。mp>250℃。
1H NMR(500MHz,DMSO)δ7.57(s,1H),7.45(s,1H),7.17(s,1H),6.84(s,2H),6.70(s,2H),6.24(s,2H),5.32(t,J＝10.8Hz,2H),4.64(q,J＝18.8Hz,2H),3.24(d,J＝7.2Hz,2H),2.97(s,4H),2.81(d,J＝4.8Hz,2H),1.80(dt,J＝23.4,7.0Hz,2H),1.45(s,6H),0.83(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ172.96,157.11,151.28,150.46,149.38,147.53,146.65,142.33,129.62,128.44,124.66,118.28,105.90,103.02,99.92,96.40,72.76,65.64,56.39,49.83,34.42,32.39,30.60,25.12,18.86,8.17.
实施例14 20(S)-7-(3,5-二氟-4-(4-吗啉))-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物18)的制备
将3,5-二氟-4-(4-吗啉))-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(3,5-二氟-4-(4-吗啉))-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色粉末20(S)-7-(3,5-二氟-4-(4-吗啉))-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物18)。mp 246-347℃。
1H NMR(500MHz,DMSO)δ7.62(s,1H),7.47(s,1H),7.21(s,1H),7.03–6.94(m,2H),6.24(s,2H),5.36(d,J＝16.8Hz,2H),5.10(t,J＝11.5Hz,2H),3.63(s,4H),3.31(s,2H),2.98(s,4H),2.85(s,2H),1.82(d,J＝10.8Hz,2H),0.83(t,J＝7.1Hz,3H).
13C NMR(125MHz,DMSO)δ172.98,157.24,154.12,151.31,150.56,149.53,149.40,147.54,146.67,142.16,138.44,136.18,128.15,125.36,124.72,119.24,118.35,116.75,116.59,105.81,103.02,99.99,96.56,72.77,66.54,65.65,51.07,49.91,34.12,31.77,30.64,8.16.
实施例15 20(S)-7-(3,5-二氟-4-(1-吡咯烷基))-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物19)的制备
将3,5-二氟-4-(1-吡咯烷基))-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(3,5-二氟-4-(1-吡咯烷基))-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色粉末20(S)-7-(3,5-二氟-4-(1-吡咯烷基))-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物19)。mp>250℃。
1H NMR(500MHz,DMSO)δ7.57(s,1H),7.44(s,1H),7.21(s,1H),6.90–6.84(m,2H),6.24(d,J＝1.6Hz,2H),5.37(t,J＝11.8Hz,2H),5.01(d,J＝1.9Hz,2H),3.27(d,J＝17.6Hz,6H),2.82–2.76(m,2H),1.89–1.77(m,6H),0.86(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ172.96,157.24,156.21,154.35,151.28,150.54,149.60, 149.38,147.53,146.68,141.96,133.30,128.01,124.67,124.47,118.38,113.03,112.84,105.79,103.02,99.99,96.49,72.76,65.67,51.29,49.92,33.83,31.45,30.66,25.45,8.17.
实施例16 20(S)-7-(4-(4-硫代吗啉))-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物20)的制备
将4-(4-硫代吗啉)-苯甲醛代替实施例1步骤(1)中的肉桂醛，其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)，可制备20(S)-7-(4-(4-硫代吗啉))-苯乙烯基)-10,11-亚甲二氧基喜树碱；然后将其在乙酸乙酯中加入催化量的钯碳，以氢气球通入氢气，室温下搅拌反应10h，过滤除去催化剂，滤液旋蒸浓缩，硅胶柱层析(二氯甲烷:丙酮＝10:1)进行分纯，得到白色粉末20(S)-7-(4--(4-硫代吗啉))-苯乙烷基)-10,11-亚甲二氧基喜树碱(化合物20)。mp 154-156℃。
1H NMR(600MHz,DMSO-D6)δ7.63(s,1H),7.49(s,1H),7.20(s,1H),6.81(d,J＝8.6Hz,2H),6.67(d,J＝8.6Hz,2H),6.28(d,J＝2.9Hz,2H),5.42–5.32(m,2H),4.58(q,J＝18.2Hz,2H),3.44(d,J＝4.9Hz,4H),3.30(d,J＝8.0Hz,2H),2.90–2.84(m,2H),2.46(d,J＝2.8Hz,4H),1.87–1.76(m,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ172.95,157.07,151.28,150.32,149.38,149.27,148.52,147.53,146.56,142.26,130.65,130.02,128.72,124.71,118.41,115.97,105.92,103.03,99.97,99.17,96.39,72.72,65.75,51.24,49.80,34.40,32.43,30.65,24.72,8.19.
化合物21-42的简要的合成路线如下：
Figure PCTCN2019090731-appb-000030
实施例17 20(S)-7-(吡啶-4-基)-10,11-亚甲二氧基喜树碱(化合物21)的制备
步骤(1)将实施例1步骤(1)中获得的中间体C，直接按照实施例1步骤(2)的方法发生缩合环化反应，然后再与乙酸酐在吡啶和DMAP存在下保护羟基，获得中间体E。其余所需原料、试剂、制备方法同实施例1的步骤(1)和(2)。
步骤(2)在50ml茄形瓶中分别加入20(S)-O-乙酰基-10,11-亚甲二氧基喜树碱(0.24g,0.55mmol)和冰乙酸(20ml)，搅拌下加入30％过氧化氢溶液(3.2ml,28mmol)，75℃反应3h后，将反应液浓缩蒸干，得到黄色粉末中间体F，210mg，产率85％；
步骤(3)在50ml茄形瓶中加入上步所得固体中间体F(0.21g,0.47mmol)和DMF(20ml)， 将溶液冷却至0℃，加入草酰溴(0.1ml,1.1mmol)，15℃反应3h后，将反应液倾入到冰水(50ml)中，二氯甲烷萃取三次，合并有机相，无水硫酸镁干燥有机相。将滤液浓缩，加入甲醇钠的甲醇溶液(1.0g/100.0mL，2ml)，室温反应2.0小时，TLC检测反应完全。加入1M的盐酸，调节pH至2，搅拌30分钟，减压蒸干有机溶剂，柱层析(二氯甲烷：甲醇＝10:1)，得0.16g黄色固体中间体G，0.16g，收率75％。mp>250℃.
1H NMR(500MHz,CF 3COOD)δ8.14(s,1H),7.89(s,1H),7.71(s,1H),6.47(s,2H),5.93(d,J＝17.2Hz,1H),5.72(s,2H),5.59(d,J＝17.1Hz,1H),2.16(q,J＝7.4Hz,2H),1.15(t,J＝7.4Hz,3H).
13C NMR(125MHz,CF 3COOD)δ176.01,158.41,153.96,151.23,139.54,139.37,138.51,138.21,131.56,128.70,125.52,122.45,109.98,105.38,102.83,97.44,73.68,66.17,53.26,31.09,5.76.
步骤(4)步骤(4)25mL两口瓶中，加入20(S)-7-溴-10,11-亚甲二氧基喜树碱(G)(37.6mg，0.08mmol)、4-吡啶硼酸(20mg，0.16mmol)和氟化铯(25mg，0.16mmol)，充放氮气三次后加入四三苯基膦钯(9.2mg，8×10-3mmol)，依次加入二氧六环、乙醇和水(9.2mL、1.9mL、3.2mL)，充放氮气6次，加热至105℃，微波反应6h。TLC检测反应完全后，旋蒸浓缩蒸除溶剂，柱层析(二氯甲烷：甲醇＝10:1)，得19mg棕色固体20(S)-7-(吡啶-4-基)-10,11-亚甲二氧基喜树碱(化合物21)，收率50.3％。mp>250℃。
1H NMR(500MHz,CF 3COOD)δ9.32(s,2H),8.48(dd,J＝13.7,5.3Hz,2H),8.22(s,1H),7.84(d,J＝11.1Hz,1H),7.13(d,J＝6.5Hz,1H),6.45(s,2H),5.87(d,J＝17.5Hz,1H),5.56(t,J＝14.9Hz,3H),2.19–2.10(m,2H),1.13(dd,J＝16.1,8.7Hz,3H).
13C NMR(125MHz,CF 3COOD)δ175.93,162.76,160.89,158.41,154.08,151.76,151.25,144.14,143.34,141.25,139.92,138.84,128.06,126.43,124.82,114.19,105.68,104.70,100.41,97.95,73.62,66.04,51.11,31.06,5.67.
实施例18 20(S)-7-(3-吡啶)-10,11-亚甲二氧基喜树碱(化合物22)的制备
制备和纯化方法同化合物21，用3-吡啶硼酸代替实施例17步骤(4)的4-吡啶硼酸，得到黄色粉末状固体23mg，收率62％。mp 245-246℃.
1H NMR(500MHz,CF 3COOD)δ9.39(d,J＝23.3Hz,1H),9.26(d,J＝5.8Hz,1H),8.98(dd,J＝14.9,8.0Hz,1H),8.51(t,J＝7.1Hz,1H),8.18(s,1H),7.80(d,J＝4.7Hz,1H),7.13(d,J＝2.4Hz,1H),6.42(d,J＝5.7Hz,2H),5.85(d,J＝17.3Hz,1H),5.58–5.49(m,3H),2.12(d,J＝7.6Hz,2H),1.12(t,J＝7.3Hz,3H).
13C NMR(125MHz,CF 3COOD)δ175.96,158.35,157.70,154.05,151.22,147.63,143.39,142.60,141.88,141.12,139.87,138.95,133.06,128.98,127.58,122.52,109.99,105.65,104.68,100.55,97.86,73.66,66.09,31.07,18.44,5.67.
实施例19 20(S)-7-(3-呋喃)-10,11-亚甲二氧基喜树碱(化合物23)的制备
制备和纯化方法同化合物21，用3-呋喃硼酸代替实施例17步骤(4)的4-吡啶硼酸，得到黄色粉末状固体化合物23 22mg，收率62％。mp 246-247℃.
1H NMR(500MHz,CF 3COOD)δ8.14(s,1H),8.07(s,1H),7.85(s,1H),7.77(s,1H),7.69(d,J＝12.2Hz,1H),6.88(s,1H),6.42(d,J＝24.8Hz,2H),5.89(d,J＝16.6Hz,1H),5.61 (dd,J＝50.1,25.2Hz,3H),2.13(s,2H),1.13(s,3H).
13C NMR(125MHz,CF 3COOD)δ176.07,157.97,157.61,152.85,151.26,145.88,144.05,140.68,140.07,139.79,139.13,128.06,127.08,109.47,105.36,104.93,103.85,102.25,97.47,97.24,73.74,66.15,52.07,31.01,5.71.
实施例20 20(S)-7-(3-噻吩)-10,11-亚甲二氧基喜树碱(化合物24)的制备
制备和纯化方法同化合物21，用3-噻吩硼酸代替实施例17步骤(4)的4-吡啶硼酸，其他所用原料、试剂相同。mp 237-238℃。
1H NMR(500MHz,CF 3COOD)δ8.15(s,1H),7.91(s,1H),7.84(s,1H),7.69(s,1H),7.63(s,1H),7.45(d,J＝4.6Hz,1H),6.40(s,2H),5.90(d,J＝17.1Hz,1H),5.56(d,J＝15.6Hz,2H),2.15(q,J＝7.2Hz,2H),1.14(t,J＝7.3Hz,3H).
13C NMR(125MHz,CF 3COOD)δ176.08,157.58,152.77,151.24,149.15,140.04,139.83,139.33,131.51,128.93,128.64,128.31,127.41,126.44,121.64,109.99,104.88,103.77,102.55,97.08,73.74,66.14,51.89,30.98,5.68.
实施例21 20(S)-7-(4-(1-甲基吡唑))-10,11-亚甲二氧基喜树碱(化合物25)的制备
制备和纯化方法同化合物21，用4-(1-甲基吡唑)-硼酸代替实施例17步骤(4)的4-吡啶硼酸，其他所用原料、试剂相同。mp 237-238℃。
1H NMR(500MHz,CF 3COOD)δ8.76(s,1H),8.70(s,1H),8.17(s,1H),7.75(s,1H),7.59(s,1H),6.45(s,2H),5.91(d,J＝17.2Hz,1H),5.72(d,J＝3.1Hz,2H),5.57(d,J＝17.1Hz,1H),4.50(s,3H),2.16(q,J＝7.3Hz,2H),1.15(t,J＝7.3Hz,3H).
13C NMR(125MHz,CF 3COOD)δ176.02,158.09,157.73,153.71,151.21,140.58,139.68,139.52,139.23,136.11,135.92,129.22,127.27,122.20,109.99,105.41,104.17,101.01,97.61,73.68,66.09,51.85,38.46,31.03,5.67.
实施例22 20(S)-7-(2-噻吩)-10,11-亚甲二氧基喜树碱(化合物26)的制备
制备和纯化方法同化合物21，用2-噻吩-硼酸代替实施例17步骤(4)的4-吡啶硼酸，其他所用原料、试剂相同。mp 240-241℃。
1H NMR(500MHz,CF 3COOD)δ8.15(s,1H),7.99(d,J＝5.0Hz,1H),7.87(s,1H),7.69(d,J＝4.2Hz,2H),7.51(t,J＝4.1Hz,1H),6.42(s,2H),5.91(d,J＝17.0Hz,1H),5.68(s,2H),5.57(d,J＝17.0Hz,1H),2.16(q,J＝7.3Hz,2H),1.15(t,J＝7.3Hz,3H).
13C NMR(125MHz,CF 3COOD)δ176.08,157.57,153.02,151.24,146.96,140.00,139.77,139.42,132.81,132.01,131.02,128.78,128.19,127.21,121.69,109.99,104.97,103.75,102.77,97.17,73.75,66.15,52.35,30.99,5.68.
实施例23 20(S)-7-(2-呋喃)-10,11-亚甲二氧基喜树碱(化合物27)的制备
制备和纯化方法同化合物21，用2-呋喃-硼酸代替实施例17步骤(4)的4-吡啶硼酸，其他所用原料、试剂相同。mp>250℃。
1H NMR(500MHz,CF 3COOD)δ8.19(s,1H),8.12(d,J＝15.7Hz,2H),7.71–7.67(m,1H),7.64(s,1H),7.00(s,1H),6.44(d,J＝16.8Hz,2H),5.93(d,J＝23.4Hz,3H),5.59(d,J＝16.9Hz,1H),2.16(d,J＝7.2Hz,2H),1.15(t,J＝7.1Hz,3H).
13C NMR(125MHz,CF 3COOD)δ176.08,157.58,152.77,151.24,149.15,140.04,139.83,139.33,131.51,128.93,128.64,128.31,127.41,126.44,121.64,110.80,104.88,103.77,102.55, 97.08,73.74,66.14,51.89,30.98,5.68.
化合物43-46的简要的合成路线如下：
Figure PCTCN2019090731-appb-000031
实施例24 20(S)-7-吗啉基-10,11-亚甲二氧基喜树碱(化合物43)的制备
25mL两口瓶中，加入实施例17步骤(1)、(2)、(3)制备的中间体G 20(S)-7-溴-10,11-亚甲二氧基喜树碱(37.6mg，0.08mmol)、吗啉(1mL)和碳酸铯(52mg，0.16mmol)，加入1,4-二氧六环(15mL)，氮气气氛下，加热至85℃，搅拌反应过夜。TLC检测反应完全后，旋蒸浓缩蒸除溶剂，柱层析(二氯甲烷：甲醇＝10:1)，得19mg棕色固体化合物43，收率50.3％。mp>250℃。
1H NMR(500MHz,CF 3COOD)δ8.14(s,1H),7.89(s,1H),7.71(s,1H),6.47(s,2H),5.93(d,J＝17.2Hz,1H),5.72(s,2H),5.59(d,J＝17.1Hz,1H),3.37–3.26(m,2H),2.87(s,6H)，2.16(q,J＝7.4Hz,2H),1.15(t,J＝7.4Hz,3H).
13C NMR(125MHz,CF 3COOD)δ176.01,158.41,153.96,151.23,139.54,139.37,138.51,138.21,131.56,128.70,125.52,122.45,109.98,105.38,102.83,97.44,73.68,66.17,53.26,35.56,31.96,31.09,30.61,5.76.
化合物47-50的简要的合成路线如下：
Figure PCTCN2019090731-appb-000032
实施例25 20(S)-7-吗啉甲基-10,11-亚甲二氧基喜树碱(化合物47)的制备
步骤(1)中间体20(S)-7-氯甲基-10,11-亚甲二氧基喜树碱(H)的制备
25mL两口瓶中，25mL两口瓶中，加入实施例17步骤(1)、(2)制备的中间体F(37.6mg，0.06mmol)，冰浴下加入冰乙酸(1mL)，充分搅拌溶解后，加入2-氯乙醛(0.5mL)，室温搅拌反应过夜。TLC检测反应完全后，旋蒸浓缩蒸除溶剂，柱层析(二氯甲烷：甲醇＝10:1)，得21mg黄色固体中间体H，收率60.3％。mp>250℃。
1H NMR(500MHz,DMSO)δ8.45(s,1H),7.49(s,2H),7.24(s,1H),6.47(s,1H),6.27(s,2H),5.39(d,J＝16.5Hz,2H),5.20(s,2H),4.52(s,2H),1.90–1.79(m,2H),0.91–0.81(m,3H).
13C NMR(125MHz,DMSO)δ172.98,157.28,151.78,150.50,150.41,149.09,147.03,146.37,130.60,128.88,126.06,118.54,105.29,103.56,103.03,96.34,72.85,65.69,62.21,50.63,30.68,8.23.
步骤(2)25mL两口瓶中，加入上述步骤(1)制备的中间体H(26.4mg，0.08mmol)，室温下依次加入吗啉(3mL)和DMF(10mL)，室温搅拌反应过夜。TLC检测反应完全后，旋蒸浓缩蒸除溶剂，柱层析(二氯甲烷：甲醇＝10:1)，得13mg黄色固体化合物47，收率33.3％。mp>250℃。
1H NMR(500MHz,DMSO)δ8.45(s,1H),7.49(s,2H),7.24(s,1H),6.47(s,1H),6.27(s,2H),5.39(d,J＝16.5Hz,2H),5.20(s,2H),4.52(s,2H),3.37–3.26(m,2H),2.87(s,6H)，1.90–1.79(m,2H),0.91–0.81(m,3H).
13C NMR(125MHz,DMSO)δ172.98,157.28,151.78,150.50,150.41,149.09,147.03,146.37,130.60,128.88,126.06,118.54,105.29,103.56,103.03,96.34,72.85,65.69,62.21,50.63,35.56,31.96,31.09,30.68,30.61,8.23.
化合物51-54的简要的合成路线如下：
Figure PCTCN2019090731-appb-000033
实施例26 20(S)-7-吗啉乙烷基-10,11-亚甲二氧基喜树碱(化合物51)的制备
步骤(1)中间体6′-氨基-3′,4′-亚甲二氧基吗啉乙烷基苯甲酮的制备
将实施例1制备的中间体C(7.6g,37.3mmol)溶于适量N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)，110℃加热回流2h后，反应液冷却至室温，加入正己烷，析出黄色固体，抽滤，得到固体9.4g，收率95％；将上述得到的固体(9.4g,35.6mmol)溶于二氧六环(60ml)，加入吗啉(3.6ml,36mmol)，加热回流6h后，将反应液减压浓缩得到黄色油状液体，硅胶柱层析(石油醚:乙酸乙酯＝1:2)进行分离，浓缩后得到浅黄色固体8.7g，收率80％；将上述所得固体(8.0g,26.1mmol)溶于冰乙酸(20ml)，将反应液冷却至0℃，加入硼氢化钠(493.1mg,13.1mmol)搅拌3h，再将反应液减压浓缩，硅胶柱层析(石油醚:乙酸乙酯＝1:2)进行分纯，浓缩后得到浅黄色固体中间体6′-氨基-3′,4′-亚甲二氧基吗啉乙烷基苯甲酮5.6g，收率70％；
1H NMR(500MHz,DMSO)δ7.34(s,2H),7.24(s,1H),6.29(s,1H),5.92(s,2H),3.57–3.50(m,2H),2.94(t,J＝7.4Hz,2H),2.57(t,J＝7.3Hz,2H),2.37(s,4H).
步骤(2)在250ml茄形瓶中加入化合物5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ 6(8)-四氢中氮茚M(200mg,0.76mmol)，溶于无水甲苯(70ml)中，再加入上述制备的6′-氨基-3′,4′-亚甲二氧基吗啉乙烷基苯甲酮(0.38g,1.37mmol)，对甲苯 磺酸(26.2mg,0.15mmol)，氮气保护下110℃回流反应24h，降至室温，旋蒸浓缩除去溶剂，硅胶柱层析(二氯甲烷:甲醇＝97:3)进行分纯，得到淡黄色粉末状固体化合物51 0.15g，收率40％。mp>250℃.
1H NMR(CF 3COOD,600MHz)δ:7.26(s,1H),6.98(s,1H),6.74(s,1H),5.9(s,2H),4.76(d,1H),4.74(d,1H),4.22(s,2H),3.67(m,4H),2.69(d,2H),2.65(d,2H),2.37(d,4H),1.87(m,2H),0.96(t,3H).
13C NMR(CF 3COOD,150MHz)δ:178.6,159.4,157.7,156.9,151.7,149.4,145.8,141.4,139.2,126.2,123.5,120.9,108.3,102.2,101.5,101.4,73.0,66.8,58.1,55.5,53.7,45.6,30.2,28.5,28.4,26.2,5.6.
实施例27 20(S)-7-硫代吗啉乙烷基-10,11-亚甲二氧基喜树碱(化合物54)的制备
制备和纯化方法同化合物51，用硫代吗啉代替实施例24步骤(1)的吗啉，其他所用原料、试剂相同，制备得到6′-氨基-3′,4′-亚甲二氧基硫代吗啉乙烷基苯甲酮。在按照实施例24步骤(2)相同的方法制备20(S)-7-硫代吗啉乙烷基-10,11-亚甲二氧基喜树碱(化合物54)。mp>250℃.
1H NMR(CF 3COOD,600MHz)δ:7.26(s,1H),6.98(s,1H),6.74(s,1H),5.9(s,2H),4.76(d,1H),4.74(d,1H),4.22(s,2H),2.73(m,4H),2.69(d,2H),2.65(d,2H),2.54(d,4H),1.87(m,2H),0.96(t,3H).
13C NMR(CF 3COOD,150MHz)δ:172.6,159.4,157.7,156.9,151.7,149.4,145.8,141.4,139.2,126.2,123.5,120.9,108.3,102.2,101.5,101.4,73.0,65.1,58.3,58.1,55.5,45.6,30.2,28.5,28.4,26.2,5.6.
实施例28 20(S)-7-哌啶乙烷基-10,11-亚甲二氧基喜树碱(化合物52)、20(S)-7-((2-甲基)-哌啶)-乙烷基-10,11-亚甲二氧基喜树碱(化合物53)的制备
制备和纯化方法同化合物51，用哌啶代替实施例24步骤(1)的吗啉，其他所用原料、试剂相同，制备得到6′-氨基-3′,4′-亚甲二氧基哌啶乙烷基苯甲酮。在按照实施例24步骤(2)相同的方法制备20(S)-7-哌啶乙烷基-10,11-亚甲二氧基喜树碱(化合物52)。
制备和纯化方法同化合物51，用2-甲基哌啶代替实施例24步骤(1)的吗啉，其他所用原料、试剂相同，制备得到6′-氨基-3′,4′-亚甲二氧基-((2-甲基)-哌啶)-乙烷基苯甲酮。在按照实施例24步骤(2)相同的方法制备20(S)-7-((2-甲基)哌啶)-乙烷基-10,11-亚甲二氧基喜树碱(化合物53)。
7位引入不同三唑取代基的10,11-亚甲二氧基喜树碱衍生物的简要的合成路线如下：
Figure PCTCN2019090731-appb-000034
实施例29 20(S)-7-(1-丁基-1H-1,2,3-三唑-4-基)-10,11-亚甲二氧基喜树碱(化合物55)的制备
步骤(1)中间体20(S)-O-乙酰基-7-乙炔基-10,11-亚甲二氧基喜树碱(K)的制备
以实施例17步骤(1)、(2)、(3)制备的中间体G，20(S)-7-溴-10,11-亚甲二氧基喜树碱为原料，先与醋酐反应保护羟基，再在醋酸钯、rac-BINAP和碳酸钾存在下，氮气保护，加入溶于脱气的三甲基硅烷乙炔的甲苯溶液，反应混合液升温至100℃，反应9h。反应毕，将反应液浓缩蒸干，硅胶柱层析(二氯甲烷:丙酮＝30:1)进行纯化，浓缩后得到固体20(S)-O-乙酰基-7-(2-三甲基硅烷乙炔基)-10,11-亚甲二氧基喜树碱，收率65％；该在三颈烧瓶中加入上述合成的固体20(S)-O-乙酰基-7-(2-三甲基硅烷乙炔基)-10,11-亚甲二氧基喜树碱(0.35g,0.66mmol)、氟化钾(77mg,1.32mmol)和无水甲醇(25ml)，室温搅拌反应12h。反应毕，将反应液减压浓缩后加入适量的水，用氯仿萃取三次，合并有机相，无水硫酸镁干燥有机相。将有机相减压浓缩，硅胶柱层析(二氯甲烷:丙酮＝30:1)进行纯化，浓缩后得到黄色固体中间体K，0.24g，收率80％。 1H NMR(CF 3COOD,600MHz)δ:7.29(s,1H),6.88(s,1H),6.74(s,1H),5.90(s,2H),4.76(d,1H),4.74(d,1H),4.22(s,2H),3.06(s,1H),2.04(d,1H),1.96(m,2H),0.96(t,3H).
13C NMR(CF 3COOD,150MHz)δ:172.5,170.3,159.7,157.3,157.0,150.7,149.9,145.5,141.0,130.6,129.1,126.8,120.0,108.1,106.3,101.6,101.2,76.0,73.5,69.7,65.5,43.8,27.0,21.1,5.8。
步骤(2)20(S)-7-(1-丁基-1H-1,2,3-三唑-4-基)-10,11-亚甲二氧基喜树碱的制备
50ml茄形瓶中加入20(S)-O-乙酰基-7-乙炔基-10,11-亚甲二氧基喜树碱(0.24g,0.52mmol)、叔丁醇(10ml)和水(10ml),搅拌下依次加入1-丁基叠氮(0.10g,1.04mmol)、硫酸铜溶液(10mmol/L,0.005mmol)和抗坏血酸钠(0.02g,0.1mmol)。将反应液缓慢加热到60℃，反应6h。反应毕，将反应液倾入到冰水中，用氯仿萃取。合并有机相，有机相用无水硫酸镁干燥。将干燥后的有机相减压浓缩，硅胶柱层析(二氯甲烷:丙酮＝30:1)进行纯化，浓缩后得到黄色固体0.23g，收率80％。在50ml茄形瓶中依次加入20(S)-O-乙酰基-7-(1-丁基-1H-1,2,3-三唑-4-基)-10,11-亚甲二氧基喜树碱(0.23g,0.41mmol)和甲醇 (20ml)，搅拌下加入甲醇钠(0.05g，0.84mmol),室温搅拌反应3h。反应毕，将反应液调至pH＝7.0，将反应液减压浓缩。硅胶柱层析(二氯甲烷:丙酮＝30:1)进行纯化，浓缩后得到黄色固体20(S)-7-(1-丁基-1H-1,2,3-三唑-4-基)-10,11-亚甲二氧基喜树碱0.18g，收率85％。.
1H NMR(CF 3COOD,600MHz)δ:7.6(s,1H),7.29(s,1H),6.88(s,1H),6.74(s,1H),5.90(s,2H),4.76(d,1H),4.74(d,1H),4.22(s,2H),3.73(t,2H),1.87(m,2H),1.77(m,2H),1.33(m,2H),0.98(t,2H),0.96(t,3H).
13C NMR(CF 3COOD,150MHz)δ:172.5,159.7,157.3,157.0,151.6,149.9,146.3,145.5,141.9,141.0,130.4,124.0,120.0,119.1,108.1,106.3,101.6,101.2,73.5,65.8,52.2,44.6,30.6,30.3,30.3,20.3,13.8,5.8.
实施例30 本发明涉及的重要中间体M的合成
中间体M的简要的合成路线如下：
Figure PCTCN2019090731-appb-000035
试剂和反应条件:(g)CO(OEt) 2,t-BuOK,THF；(h)C 2H 5Br,K 2CO 3,CH 3CN；(i)H 2,Raney Ni,HOAC,Ac 2O；(j)NaNO 2,0℃；(k)CCl 4,reflux；(l)1)O 2,Raney Ni,CuCl,2)H 2SO 4；(m)CuCl,CH 2Cl 2；(n)KOH,CH 3OH；(o)CF 3COOH,r.t.
概括地讲，中间体M6在叔丁醇钾作用下和碳酸二乙酯反应得到中间体M7；中间体M7和溴乙烷反应得到中间体M8；中间体M8在高压下经过雷尼镍催化氢化得到中间体M9；中间体M9和亚硝酸钠反应得到中间体M10；中间体M10在四氯化碳中回流重排得到中间体M11；中间体M11经过氧气氧化得到中间体M12；中间体M12为手性化合物，采用手性异氰酸酯衍生化的方法进行手性拆分，中间体M12在氯化亚铜催化下和手性异氰酸酯反应得到两个非对应异构体13R和13S，用柱层析将二者分离纯化；中间体13S在碱性条件下水解得到中间体M14；中间体14在三氟乙酸条件下脱保护得到立体专一性的三环中间体M(即本发明上文所述的中间体M)。具体的合成步骤如下：
步骤(1)：6-氰基-1,1-亚乙二氧基-7-乙氧羰基甲基-5-氧代-Δ6(8)-四氢中氮茚(中间体M7) 的制备
将M6(20g,86mmol)溶于无水四氢呋喃(120ml)中，室温下加入叔丁醇钾(43.43g,387mmol)，搅拌下，缓慢滴加碳酸二乙酯(40.6g,344mmol)，加热回流反应5h，降至室温，加入冰乙酸(5ml)淬灭反应，浓缩得黑褐色固体，硅胶柱层析分纯(二氯甲烷:乙酸乙酯＝6:1)，得到白色固体23.65g，产率90％，mp 172-173℃。
步骤(2)：6-氰基-1,1-亚乙二氧基-7-(1′-乙氧羰基)丙基-5-氧代-Δ6(中间体8)-四氢中氮茚(中间体M8)的制备
Figure PCTCN2019090731-appb-000036
将上述合成的M7(20.00g,65.64mmol)溶于乙腈(300ml)中，依次加入碳酸钾(24.00g,172mmol)和溴乙烷(17.58g,162mmol)，85℃回流反应3h，降至室温，过滤除去无机盐，滤渣用乙腈洗涤三次，滤液旋蒸浓缩得到土黄色固体21.82g，产率95％。
步骤(3)：6-乙酰氧甲基-1,1-亚乙二氧基-7-(1′-乙氧羰基)丙基-5-氧代-[3′,4′,f]-Δ6(8)-四氢中氮茚(中间体M11)的制备
Figure PCTCN2019090731-appb-000037
将中间体M8(12.00g,36.1mmol)溶于乙酸酐(150mL)和冰乙酸(50mL)的混合溶液中，加入雷尼镍(6g)，充氢气至4×105Pa，45℃搅拌反应6h，过滤除去催化剂，滤渣用冰乙酸洗涤三次，滤液浓缩得到黄色油状液体；再加入乙酸酐(150mL)和冰乙酸(50mL)，冰浴下加入亚硝酸钠(13.0g,188mmol)，搅拌反应2h，抽滤除去无机盐，滤渣用冰乙酸洗涤三次，滤液旋蒸浓缩得到黄色油状液体；加入四氯化碳200ml)，回流反应12h，降至室温，依次用蒸馏水，饱和食盐水洗三遍，合并有机相，有机相用无水硫酸镁干燥，过滤浓缩得到黄色油状液体16.2g，产率80％。
步骤(4)：1,1-亚乙二氧基-5-氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚(中间体M12)的制备
Figure PCTCN2019090731-appb-000038
在无水甲醇(300ml)中加入Raney Ni(3.0g,51.1mmol)，氯化亚铜(0.2g,2mmol)和无水碳酸钾(8.0g,57.9mmol)，室温下通入氮气鼓泡1h，加入中间体M11(21.0g,53mmol)，通入氧气鼓泡反应6h，过滤除去催化剂，浓缩有机相得到黄色油状液体，加入蒸馏水(200ml)，用1N的稀硫酸调PH至2～3，二氯甲烷萃取三次，合并有机相，有机相用无水硫酸镁干燥， 过滤浓缩，硅胶柱层析(二氯甲烷:乙酸乙酯＝8:1)进行纯化，浓缩后得到白色固体8g，收率49％，mp 177-179℃。
1H NMR(CDCl3,600MHz)δ:6.57(s,1H,Ar-H),5.16-5.63(m,2H,ArCH2O),4.16(m,6H,OCH2CH2O,NCH2),3.69(s,1H,OH),2.42(t,2H,NCH2CH2),1.81(m,2H,CH2CH3),0.98(t,3H,CH3).
步骤(5)：(4′S)-4′-乙基-3′,10′-二氧代-3′,4′,7′,8′-四氢螺[1,3-亚乙二氧基-2,6′-1′H,6′H-吡喃[3,4,f]吲哚哩啶]-4′-基N-(1-苯基乙基)氨基甲酸酯(中间体M13S)的制备
Figure PCTCN2019090731-appb-000039
将中间体M12(5.5g,17.90mmol)溶于无水二氯甲烷(200ml)中，依次加入(R)-α-苯乙异氰酸酯(5.26g,35.80mmol)和氯化亚铜(3.54g,35.80mmol)，室温下搅拌反应8h，过滤除去催化剂，滤渣用二氯甲烷洗涤三次，滤液依次用蒸馏水、饱和食盐水洗，合并有机相，有机相用无水硫酸镁干燥过夜，过滤，滤液浓缩后得到黄色油状液体，硅胶柱层析(二氯甲烷:乙酸乙酯＝4:1)分离，得到两个非对映异构体M13R和M13S。
得到化合物M13R 3.92g，收率50％。[α]20D-9.36°(c 0.5，CHCl3)；MS(ESI):m/z,455.3[M+H]+.
1H NMR(CDCl3,600MHz)δ:7.30(m,5H,Ar-H),6.10(s,1H,Ar-H),5.23、5.55(s,2H,ArCH2O),4.78(m,1H,ArCH),4.0-4.2(m,6H,OCH2CH2O,NCH2),2.38(t,2H,NCH2CH2),1.95、2.13(s,2H,CH2CH3),1.52(d,3H,CHCH3),0.95(t,3H,CH3).
得到化合物M13S 2.86g，收率45％。[α]20D+139°(c 0.5，CHCl3)；MS(ESI):m/z,455.1[M+H]+.
1H NMR(CDCl3,600MHz)δ:7.31(m,5H,Ar-H),6.12(s,1H,Ar-H),5.20、5.55(s,2H,ArCH2O),4.71(m,1H,ArCH),3.9-4.1(m,6H,OCH2CH2O,NCH2),2.38(t,2H,NCH2CH2),1.98、2.17(s,2H,CH2CH3),1.55(d,3H,CHCH3),0.95(t,3H,CH3).
步骤(6)：(5′S)-1,1-亚乙二氧基-5-氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′-f]-Δ6(8)-四氢中氮茚(中间体M14)的制备
Figure PCTCN2019090731-appb-000040
将氢氧化钾(0.56g,9.9mmol)加入到化合物M13S(1.1g,2.4mmol)的甲醇(25ml)溶液中，升温至67℃搅拌反应5h，反应液用1M的稀盐酸调pH至3-4，浓缩，加入二氯甲烷(25ml)，依次用蒸馏水，饱和食盐水洗三次，合并有机相，有机相用无水硫酸镁干燥，过滤，浓缩。硅胶柱层析(二氯甲烷:乙酸乙酯＝4:1)进行纯化，得到白色固体0.58g，收率80％。mp163-164℃；MS(ESI):m/z,308.4[M+H]+.
步骤(7)：(5′S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚(中间体M)的制备
Figure PCTCN2019090731-appb-000041
将中间体M14(1.0g,3.26mmol)溶于三氟乙酸(30ml)中，室温下搅拌反应6h，旋蒸浓缩得到黑褐色油状液体，硅胶柱层析(二氯甲烷:乙酸乙酯＝4:1)进行纯化，得到浅黄色固体0.88g，收率93％。mp 183-185℃；[α]20D+101°(c 0.5,CHCl3)；MS(ESI):m/z,264.3[M+H]+.
1H NMR(CDCl3,600MHz)δ:6.85(s,1H,Ar-H),5.34-5.42(ABq,2H,ArCH2O),4.13(m,2H,NCH2),2.89(t,2H,NCH2CH2),1.78(m,2H,CH2CH3),0.80(t,3H,CH3).
实施例31 本发明化合物体外抗肿瘤活性测试
运用本领域技术人员公知的方法，我们测试了本发明化合物对各种肿瘤细胞系的生长抑制情况，以显示其抗肿瘤活性。所选用的肿瘤细胞系包括：A549细胞(人非小细胞肺癌细胞系)、K562细胞(人慢性髓系白血病细胞)、NCI-H1975细胞(人非小细胞肺腺癌细胞)、MDA-MB-231细胞(人乳腺癌细胞)和HCT-116细胞(人结肠癌细胞)。
表1 化合物对A549细胞和K562细胞株的IC 50
Figure PCTCN2019090731-appb-000042
如表1所示，本发明所涉及的化合物与已上市药物喜树碱衍生物拓扑替康相比，大部分化合物表现出较好的细胞抑制活性。化合物3、11、16、20、42、43和51对A549细胞的抑制IC 50在1-10nM，化合物12、14、18、32、41和43对A549细胞的抑制IC 50在10-50nM；与K562人红白血病细胞株相比，所测目标化合物对A549人肺腺癌细胞普遍具有较 好的抑制活性，表明本发明化合物的抗肿瘤活性具有选择性。
表2 化合物对NCI-H1975细胞、MDA-MB-231细胞和HCT-116细胞株的IC 50
Figure PCTCN2019090731-appb-000043
如表2所示，本发明所涉及的化合物21-30对三种肿瘤细胞(NCI-H1975细胞、MDA-MB-231细胞和HCT-116细胞)的活性全部优于拓扑替康，其中26对NCI-H1975和MDA-MB-231细胞株的细胞毒活性最强。24对HCT-116细胞株的细胞毒活性最强。从IC 50值，我们也可以看出，HCT-116细胞株对化合物21-29化合物最敏感。
以上体外试验表明，本发明化合物具有显著的抗肿瘤活性，可以用于制备预防或治疗癌症的药物。
实施例32 本发明的化合物通过大分子相互作用实验说明化合物与EGF、FGF结合影响细胞增殖。
实验方案：
1、将小分子固定于芯片上，化合物为
拓扑替康 1 2 3 4 5 6
7 8 9 10 51 52 32
14 21 23 24 25    
流动样品为：EGF(1μM)、FGF(1μM)、HSP90(100nM)、FKBP12(100nM)
阳性对照为：RAPA和FKBP12
2、检测指标
检测所提供的小分子化合物与热休克蛋白HSP90，表皮生长因子EGF和成纤维细胞成长因子FGF是否有结合；并提供结合动力学相关数据。
3、检测结果
表3 化合物和不同蛋白分子的亲和力(KD)
Figure PCTCN2019090731-appb-000044
Figure PCTCN2019090731-appb-000045
如表3所示，通过大分子相互作用仪的检测，所测样品与热休克蛋白Hsp90均无结合。化合物3、7、51、21与EGF结合，化合物6、7、51、52和21与FGF结合，这些化合物能与细胞增殖相关蛋白结合，说明化合物通过成纤维细胞生长因子(FGFs)、表皮生长因子(EGF)的结合抑制，影响肿瘤细胞的增殖，靶向这两种蛋白。因而，本发明化合物可望用作FGF或EGF抑制剂。
实施例33 体内抗肿瘤活性测试
运用本领域公知的技术，本发明人通过昆明小鼠移植瘤模型对本发明化合物的体内抗肿瘤活性进行了测试，测试的移植瘤模型包括A549(肺癌)移植瘤模型以及RM-1(前列腺癌)移植瘤模型。本发明化合物经腹腔注射给药，在低浓度下(9mg/kg)即能够有效的抑制肿瘤的生长(抑瘤率达到70％以上)，同时对小鼠的毒性较小，具有成药的潜质。
本发明的化合物11、15、23和51具有优于拓扑替康的抗肿瘤活性，具有成药的潜质。
实施例34 化合物23体内抗肿瘤活性测试
运用本领域公知的技术，本发明人通过小鼠移植瘤模型对本发明化合物23的体内抗肿瘤活性进行了测试。
测试方法包括：
液氮复苏小鼠结肠癌细胞株HCT‐116，用含10％胎牛血清的5A培养基培养,培养瓶中扩大培养细胞，达到所需细胞量后，消化收集细胞。用含10％胎牛血清的5A培养基稀释 成25000万/ml细胞悬液，常规消毒后按每只0.1ml左右接种于BALB/c‐nu小鼠右前肢腋窝部皮下。待肿瘤生长至1g左右的组织块时，切割成长短径均为1mm左右的瘤块，采用导管法植入皮下，移植后第6天开始给药。将小鼠按瘤体积随机分为7组，溶剂对照组、伊立替康组(6mg/kg)、5‐氟尿嘧啶组(20mg/kg)、化合物23低剂量组(2.5mg/kg)和高剂量组(5mg/kg)。化合物23低剂量组和高剂量组分别灌胃给药，每周给药1次，伊立替康组、5‐氟尿嘧啶组分别静脉给药，每三天给药1次，每周三次记录小鼠体重变化情况以及瘤体积大小。
结果观察：
BALB/c‐nu小鼠皮下接种HCT‐116瘤块后，肿瘤体积达到1.01±0.65mm 3，随机分组给药。第23天，溶剂对照组肿瘤组织生长至771.70±101.05mm 3，处死全部小鼠，剥取肿瘤组织，冻存于‐80℃。
以给药天数为横坐标，绘制肿瘤体积生长曲线，如附图2所示。与溶剂对照组和阳性药组相比，化合物23低剂量和高剂量给药均能明显抑制小鼠HCT‐116移植瘤的生长，给药23天后抑瘤率分别为95.45％和87.04％(表4)。
表4 化合物对小鼠HCT‐116瘤生长的影响
Figure PCTCN2019090731-appb-000046
Figure PCTCN2019090731-appb-000047
注： *p<0.01vs溶剂对照组； a根据给药23天后数据计算。
以给药天数为横坐标，绘制小鼠体重变化曲线，结果见附图3。溶剂对照组小鼠体重呈逐渐增高趋势。化合物23给药后，高、低剂量组小鼠体重均有所下降。10天后逐渐恢复，但是仍低于对照组小鼠体重，提示其具有一定的毒副作用，轻微的毒副作用是喜树碱类化合物普遍存在的问题。
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其它形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。

Claims (15)

  1. 一种具有式(I)所示结构的化合物、其立体异构体和药学上可接受的盐形式：
    Figure PCTCN2019090731-appb-100001
    式中R为
    Figure PCTCN2019090731-appb-100002
    其中：
    X为
    Figure PCTCN2019090731-appb-100003
    n为0-2的整数，m为0-2的整数；
    Z为环结构，Z环选自于取代或者非取代的苯环、取代或者非取代的吡啶环、取代或者非取代的呋喃环、取代或者非取代的噻吩环、取代或者非取代的吡唑环、取代或者非取代的吲哚环、取代或者非取代的苯并吡唑环、取代或者非取代的哌啶环、取代或者非取代的吗啉环、取代或者非取代的硫代吗啉环、取代或者非取代的萘环和取代或者非取代的三唑环；
    当为取代结构时，所述取代基选自于卤素原子、取代或者非取代的烷基、取代或者非取代的酯基、取代或非取代的芳基、取代或者非取代的吡咯烷基、取代或非取代的哌啶基、取代或非取代的吗啉基和取代或非取代的硫代吗啉基；
    所述取代为单取代或者多取代；
    当n和m均为0时，所述Z环不为非取代的苯环。
  2. 如权利要求1所述的化合物，其特征在于，所述X为
    Figure PCTCN2019090731-appb-100004
    m为1或2；Z环为取代或者非取代的苯环。
  3. 如权利要求1所述的化合物，其特征在于，式(I)中R为以下基团中的任意一种：
    Figure PCTCN2019090731-appb-100005
  4. 如权利要求1所述的化合物，其特征在于，所述X为
    Figure PCTCN2019090731-appb-100006
    n为2；Z环为取代或者非取代的苯环。
  5. 如权利要求1所述的化合物，其特征在于，式(I)中R为以下基团中的任意一种：
    Figure PCTCN2019090731-appb-100007
  6. 如权利要求1所述的化合物，其特征在于，X为
    Figure PCTCN2019090731-appb-100008
    所述n和m均为0。
  7. 如权利要求1所述的化合物，其特征在于，式(I)中R为以下基团中的任意一种：
    Figure PCTCN2019090731-appb-100009
    Figure PCTCN2019090731-appb-100010
  8. 如权利要求1所述的化合物，其特征在于，所述化合物为
    Figure PCTCN2019090731-appb-100011
  9. 如权利要求1所述的化合物，其特征在于，所述X为
    Figure PCTCN2019090731-appb-100012
    n为0-2的整数；Z环选自于取代或者非取代的哌啶环、取代或者非取代的吗啉环和取代或者非取代的硫代吗啉环。
  10. 如权利要求1所述的化合物，其特征在于，式(I)中R为以下基团中的任意一种：
    Figure PCTCN2019090731-appb-100013
  11. 如权利要求1所述的化合物，其特征在于，R为取代或者非取代的三唑环，所述化合物具有式(II)所示结构：
    Figure PCTCN2019090731-appb-100014
    式中R 1选自于取代或者非取代的烷基、取代或者非取代的酯基、取代或非取代的异羟肟酸链和取代或者非取代的芳基。
  12. 如权利要求1-11任一所述的化合物在用于制备预防和/或治疗癌症的药物中的用途。
  13. 如权利要求12所述的用途，其特征在于所述癌症选自于肺癌、结肠癌、前列腺癌、白血病和乳腺癌。
  14. 如权利要求1-11任一所述的化合物作为EGF或FGF抑制剂的用途。
  15. 一种药物组合物，包含：
    1)治疗有效剂量的权利要求1-11任一所述的化合物，以及
    2)药学上可接受的载体。
PCT/CN2019/090731 2018-06-12 2019-06-11 喜树碱衍生物及其制备方法和应用 Ceased WO2019238046A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP19818832.8A EP3808751B1 (en) 2018-06-12 2019-06-11 Camptothecin derivative, preparation method therefor and application thereof
US17/251,583 US20220177485A1 (en) 2018-06-12 2019-06-11 Camptothecin derivative, preparation method therefor and application thereof
JP2021518840A JP7485661B2 (ja) 2018-06-12 2019-06-11 カンプトテシン誘導体およびその調製方法並びに用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810600770.8 2018-06-12
CN201810600770.8A CN110590796B (zh) 2018-06-12 2018-06-12 喜树碱衍生物及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2019238046A1 true WO2019238046A1 (zh) 2019-12-19

Family

ID=68842730

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/090731 Ceased WO2019238046A1 (zh) 2018-06-12 2019-06-11 喜树碱衍生物及其制备方法和应用

Country Status (5)

Country Link
US (1) US20220177485A1 (zh)
EP (1) EP3808751B1 (zh)
JP (1) JP7485661B2 (zh)
CN (1) CN110590796B (zh)
WO (1) WO2019238046A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3852760A4 (en) * 2018-09-17 2022-05-18 Canget Biotekpharma, LLC MATERIAL OF COMPOSITION, SYNTHESIS, FORMULATION AND APPLICATION OF ANALOGS DERIVED AT POSITIONS 9 AND 7 ON THE FL118 PLATFORM FOR THE TREATMENT OF A HUMAN DISEASE
WO2024109840A1 (zh) 2022-11-22 2024-05-30 康诺亚生物医药科技（成都）有限公司 稠环类化合物及其偶联物和用途
WO2025016467A1 (zh) * 2023-07-20 2025-01-23 上海医药集团股份有限公司 一种喜树碱类化合物、抗体药物偶联物及其制备方法和应用
WO2025040012A1 (zh) 2023-08-18 2025-02-27 康诺亚生物医药科技（成都）有限公司 五环类活性化合物及其偶联物和用途
US12291537B2 (en) 2022-10-09 2025-05-06 LaNova Medicines Limited Compounds, compositions and methods

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111171041B (zh) * 2018-11-12 2021-07-27 中国海洋大学 20位取代的喜树碱衍生物及其制备方法和应用
CN113956267B (zh) * 2021-11-03 2022-06-21 上海禧耀医药科技有限公司 一种抗肿瘤药物依喜替康甲磺酸盐的制备方法
CN117164599A (zh) * 2021-12-30 2023-12-05 南京格亚医药科技有限公司 一种伊沙替康关键中间体的制备方法
CN121064210A (zh) * 2022-09-09 2025-12-05 杭州爱科瑞思生物医药有限公司 喜树碱-7-乙基胺衍生物及其制备方法和应用
CN117304198B (zh) * 2023-09-27 2026-03-31 中国海洋大学 7-位及20-位取代的喜树碱衍生物及其用途
CN117777153A (zh) * 2023-12-19 2024-03-29 浙江工业大学 20(s)-10,11-二氟亚甲二氧基喜树碱衍生物及其制备方法和应用
WO2025242090A1 (zh) * 2024-05-21 2025-11-27 康诺亚生物医药科技（成都）有限公司 喜树碱衍生物及其中间体的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1074908A (zh) * 1992-01-28 1993-08-04 格拉克索有限公司 水溶性喜树碱衍生物
US5342947A (en) * 1992-10-09 1994-08-30 Glaxo Inc. Preparation of water soluble camptothecin derivatives
CN1091742A (zh) * 1992-11-12 1994-09-07 格拉克索有限公司 水溶性喜树碱衍生物
WO2005009347A2 (en) * 2003-06-27 2005-02-03 Research Triangle Institute 7-substituted camptothecin and camptothecin analogs and methods for preparing same

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559235A (en) * 1991-10-29 1996-09-24 Glaxo Wellcome Inc. Water soluble camptothecin derivatives
EP0540099B1 (en) * 1991-10-29 1996-04-17 Glaxo Wellcome Inc. Water soluble camptothecin derivatives
KR100516593B1 (ko) 1996-08-19 2005-09-22 바이오누머릭 파마슈티칼스, 인코포레이티드 고 친유성 캠프토테신 유도체
US6350756B1 (en) * 2001-01-18 2002-02-26 California Pacific Medical Center Camptothecin derivatives
CN100408582C (zh) * 2004-02-12 2008-08-06 中国人民解放军第二军医大学 高喜树碱类化合物及其制备方法和用途
CN102574866B (zh) 2009-06-17 2015-02-18 四川恒康发展有限责任公司 喜树碱衍生物
BR112020020466A2 (pt) * 2018-04-06 2021-01-12 Seattle Genetics, Inc. Conjugados de peptídeo de camptotecina
JP2022501432A (ja) * 2018-09-17 2022-01-06 キャンゲット バイオテクファーマ， エルエルシー ヒト疾患の治療のためのｆｌ１１８プラットフォーム位置７および９由来の類似体の組成、合成、処方および適用の問題

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1074908A (zh) * 1992-01-28 1993-08-04 格拉克索有限公司 水溶性喜树碱衍生物
US5342947A (en) * 1992-10-09 1994-08-30 Glaxo Inc. Preparation of water soluble camptothecin derivatives
CN1091742A (zh) * 1992-11-12 1994-09-07 格拉克索有限公司 水溶性喜树碱衍生物
WO2005009347A2 (en) * 2003-06-27 2005-02-03 Research Triangle Institute 7-substituted camptothecin and camptothecin analogs and methods for preparing same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BACILIERI, MAGDALENA: "A Novel Generalized 3D-QSAR Model of Camptothecin Analogs", MOL. INF., vol. 30, no. 11-12, 1 December 2011 (2011-12-01), pages 930, XP055668537, ISSN: 1868-1751, DOI: 10.1002/minf.201100060 *
HANSCH, CORWIN: "20-(S)-Camptothecin Analogues as DNA Topoisomerase I Inhibitors: A QSAR Study", CHEMMEDCHEM, vol. 2, no. 12, 20 September 2007 (2007-09-20), pages 1810, XP055668530, ISSN: 1860-7187, DOI: 10.1002/cmdc.200700138 *
MANIKUMAR, GOVINDARAJAN: "Camptothecin Analogs with Bulky, Hydrophobic Substituents at the 7-position via a Grignard Reaction", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 21, 3 September 2004 (2004-09-03), pages 5378 - 5379, XP004580533, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2004.08.010 *
See also references of EP3808751A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3852760A4 (en) * 2018-09-17 2022-05-18 Canget Biotekpharma, LLC MATERIAL OF COMPOSITION, SYNTHESIS, FORMULATION AND APPLICATION OF ANALOGS DERIVED AT POSITIONS 9 AND 7 ON THE FL118 PLATFORM FOR THE TREATMENT OF A HUMAN DISEASE
US12187735B2 (en) 2018-09-17 2025-01-07 Canget Biotekpharma Llc Matter of composition, synthesis, formulation and application of FL118 platform positions 7 and 9-derived analogues for treatment of human disease
US12291537B2 (en) 2022-10-09 2025-05-06 LaNova Medicines Limited Compounds, compositions and methods
WO2024109840A1 (zh) 2022-11-22 2024-05-30 康诺亚生物医药科技（成都）有限公司 稠环类化合物及其偶联物和用途
EP4623936A1 (en) 2022-11-22 2025-10-01 Keymed Biosciences (Chengdu) Co., Ltd. Fused ring compound, conjugate thereof and use thereof
WO2025016467A1 (zh) * 2023-07-20 2025-01-23 上海医药集团股份有限公司 一种喜树碱类化合物、抗体药物偶联物及其制备方法和应用
WO2025040012A1 (zh) 2023-08-18 2025-02-27 康诺亚生物医药科技（成都）有限公司 五环类活性化合物及其偶联物和用途

Also Published As

Publication number Publication date
EP3808751B1 (en) 2025-02-26
JP2021526560A (ja) 2021-10-07
EP3808751A4 (en) 2022-03-23
JP7485661B2 (ja) 2024-05-16
US20220177485A1 (en) 2022-06-09
CN110590796A (zh) 2019-12-20
EP3808751A1 (en) 2021-04-21
CN110590796B (zh) 2022-07-15

Similar Documents

Publication Publication Date Title
WO2019238046A1 (zh) 喜树碱衍生物及其制备方法和应用
WO2021129824A1 (zh) 新型K-Ras G12C抑制剂
WO2021190467A1 (zh) 含螺环的喹唑啉化合物
KR100628013B1 (ko) 트리시클릭 락탐 및 술탐 유도체, 및 히스톤 디아세틸라제억제제로서 이들의 용도
WO2023280182A1 (zh) 作为kat6抑制剂的化合物
WO2019057123A1 (zh) 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物
WO2013107428A1 (zh) 7-位取代的汉防己乙素衍生物、及其制备方法和应用
CN110627801A (zh) 一类hdac抑制剂及其用途
CN113929729B (zh) 一种藜芦胺类化合物、其制备方法及其应用
JP7054528B2 (ja) プロテインキナーゼ活性を抑制する化合物の結晶形態、及びその適用
WO2020173417A1 (zh) 含丙烯酰基的核转运调节剂及其用途
WO2023142518A1 (zh) 羟基萘酮-苯硼酸类化合物、制备方法和用途
CN103373986B (zh) 克里唑替尼前药及其制备方法与用途
CN107216283B (zh) 一种含有二氢吡啶结构的β-榄香烯衍生物及其制备方法和用途
CN114736202A (zh) 具有ido1/tdo抑制活性的小檗碱衍生物的制备及用途
WO2013185613A1 (zh) 重楼皂苷i的酰化衍生物、及其制备方法和应用
CN115677714B (zh) (+)-水鬼蕉碱制备中的中间体及其应用
CN103626761B (zh) 苯并吡啶氮杂卓类化合物及其作为抗肿瘤药物的应用
CN110054627A (zh) 一类新型的ido抑制剂、制备方法、药物组合物及其用途
CN111171041B (zh) 20位取代的喜树碱衍生物及其制备方法和应用
CN116143661B (zh) β-榄香烯不对称取代衍生物及其制备和用途
CN107365322B (zh) 一类新型的吴茱萸碱类衍生物、其制备方法及用途
CN115340526B (zh) 邻二甲酰亚胺类化合物及其药物组合物、制备方法和用途
WO2020098516A1 (zh) 4-(苯并噻唑-2-基)芳胺类化合物治疗胃癌的用途
CN113912604B (zh) 具有ido抑制活性的化合物、其制备方法、组合物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19818832

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021518840

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019818832

Country of ref document: EP

Effective date: 20210112