WO2015158025A1 - 化合物及其制备方法和应用 - Google Patents

化合物及其制备方法和应用 Download PDF

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Publication number
WO2015158025A1
WO2015158025A1 PCT/CN2014/078068 CN2014078068W WO2015158025A1 WO 2015158025 A1 WO2015158025 A1 WO 2015158025A1 CN 2014078068 W CN2014078068 W CN 2014078068W WO 2015158025 A1 WO2015158025 A1 WO 2015158025A1
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cancer
compound
formula
unsubstituted
group
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PCT/CN2014/078068
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English (en)
French (fr)
Inventor
王学海
许勇
李莉娥
乐洋
黄璐
郭涤亮
张绪文
冯权武
肖强
杨仲文
田华
范昭泽
余艳平
廖娟娟
于静
杨菁
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人福医药集团股份公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/4353Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic 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
    • A61K31/5355Non-condensed oxazines and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic 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
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicine, and in particular, the present invention relates to a compound, a preparation method and application thereof, and more particularly, the present invention relates to a compound of the formula I and a derivative thereof, a process for the preparation thereof, a pharmaceutical composition, and a compound of the formula I Use in the preparation of drugs, drug combinations, and kits.
  • Background technique
  • Non-small-cell carcinoma is synonymous with "non-small cell carcinoma.”
  • Non-small cell lung cancer including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, has slower growth and cell division and longer metastatic spread than small cell carcinoma.
  • Non-small cell lung cancer accounts for about 80-85% of the total number of lung cancers. The data show that the incidence of lung cancer in China is increasing by 26.9% per year. From 2000 to 2005, the number of lung cancer cases in China is estimated to increase by 120,000. Among them, the number of male lung cancer patients increased from 260,000 in 2000 to 330,000 in 2005, and the number of female lung cancer patients increased from 120,000 to 170,000. In addition, lung cancer has become the "first cancer" in many parts of the country.
  • the treatment of advanced NSCLC has entered the era of individualized treatment.
  • the individualized targeted therapies for clinical application are mainly for EGFR mutant and ALK fusion genotypes (ie, positive lung cancer mediated by ALK). These two genetic variant lung cancers have clear molecular targets and target detection techniques. And the targeted drugs listed on the market, the clinical efficacy has been significantly improved.
  • the ALK mutation in lung cancer is mainly the rearrangement of ALK gene and fusion with other genes.
  • Echinoderms due to chromosomal rearrangement Microtubule-associated protein-like 4 (EML4)-ALK fusion has been reported in patients with non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • Amplification of the ALK gene, copy number gain, and site mutation have been reported in the neuroblastoma patient population.
  • crizotinib against the ALK target can specifically target the inhibition of ALK kinase and also inhibit Signal pathways such as c-MET and ROS1.
  • Clinical trials have shown that crizotinib is significantly better than conventional chemotherapy in patients with ALK-positive advanced NSCLC.
  • the median PFS for patients with second-line monotherapy is 7.7 months, with an effective rate of 65.3%.
  • crizotinib was approved by the US FDA for the treatment of patients with locally advanced or metastatic NSCLC who were positive for ALK fusion. In 2013, the drug was approved by CFDA.
  • crizotinib is more effective in treating patients with NSCLC (>80%)
  • patients who are effective for crizotinib usually develop resistance after 6 months to 1 year of treatment.
  • the most common adverse events observed in two crizotinib clinical studies were visual impairment, nausea, diarrhea, vomiting, edema, and constipation, with an incidence of adverse events ⁇ 25%.
  • NSKLC drugs that are positive for ALK fusion ie, drugs for ALK
  • drugs for ALK have a certain degree of defects, and the efficacy is good, the safety is high, the tolerance is good, and the drugs are convenient to take, it is developed safer.
  • Efficient treatment of NSCLC's new drugs has great social and economic benefits, and it is also a research hotspot of major pharmaceutical companies. Summary of the invention
  • the present invention is directed to solving at least some of the above technical problems or at least providing a useful commercial option. To this end, it is an object of the present invention to provide a compound which can be used for the preparation of a medicament for the treatment of cancer.
  • the invention proposes a compound.
  • the compound is an enantiomer, a diastereomer, a racemate, or a pharmaceutically acceptable compound of the compound of Formula I or the compound of Formula I.
  • X is any one selected from the group consisting of CH and N; and 1 and R 2 are each independently a C1-C12 linear or branched fluorenyl group, halogen, CF 3 , CN, N0 2 , H 2 , CH 2 any one of COOH, OCH 3 , OC 2 H 5 , OH, HS0 2 CH 3 , CH 2 CO H 2 and COCH 3 ; R 3 is selected from hydrogen or its isotope, halogen, unsubstituted or from 1 to 3 Halogen-substituted C1-C12 linear or branched fluorenyl, unsubstituted or substituted by 1 to 3 halogen or phenyl C1-C12 straight or branched decyloxy, unsubstituted or 1 to 3 Halogen-substituted C3-C12 cyclodecyl, C1-C6 straight or branched chain substituted by C1-C6 decyloxy Sulfhydr
  • R 5 and Re are each independently selected from hydrogen or an isotope thereof, halogen, a C1-C6 straight or branched fluorenyl group substituted or substituted with 1 to 3 halogens, Unsubstituted or substituted with 1 to 3 halogens any one embankment C3-C6 cycloalkyl group; the halogen is fluorine, chlorine, bromine or iodine.
  • the hetero atom is independently selected from 0, 8, and ⁇ .
  • the cyclic group is a monocyclic ring or a fused ring.
  • the ring of the cyclic group is composed of 3 to 12 ring atoms, and the hetero atom of the 3 to 12 ring atoms is selected as ⁇ , 0, and S(0) n Any one of them, wherein n is 0, 1 or 2, and the remaining ring atoms are C.
  • the ring may also have one or more double bonds.
  • the cyclic group is selected from one of the following:
  • X is any one selected from the group consisting of CH and N.
  • Ri is any one selected from the group consisting of hydrogen, halogen, CH 3 , C 2 H 5 , CF 3 , 0CH 3 , OC 2 H 5 , CH 2 C00H and COCH 3 .
  • R 2 is any one selected from the group consisting of hydrogen, halogen, CH 3 , C 2 H 5 , CF 3 , 0CH 3 , OC 2 H 5 , CH 2 C00H and COCH 3 .
  • R 3 is a C1-C6 straight or branched fluorenyl group selected from hydrogen, halogen, unsubstituted or substituted by 1 to 3 halogens, unsubstituted or substituted by 1 to 3 halogens C3-C12 cyclodecyl, unsubstituted or substituted by 1 to 3 halogen or phenyl C1-C6 straight or branched decyloxy, hydroxy, -NR 5 R 6 , -NCOR 5 R6, -S0 2 R 5 , -S0 2 R 5 R6 and -OCOR 5 .
  • R 4 is a C1-C6 straight or branched fluorenyl group selected from hydrogen, carboxy, unsubstituted or substituted by 1 to 3 halogens, unsubstituted or 1 to 3 halogen or a phenyl-substituted C1-C6 linear or branched fluorenyloxy group, a C3-C12 cyclodecyl group which is unsubstituted or substituted by 1 to 3 halogens, a C1 which is unsubstituted or substituted by 1 to 3 halogens or phenyl groups.
  • -C6 A linear or branched carboxy group, a substituted or unsubstituted C2-C12 cyclic group having 0 to 4 hetero atoms.
  • R 5 and Re are each independently any one selected from the group consisting of hydrogen, halogen, unsubstituted or C1-C4 straight or branched fluorenyl substituted by 1 to 3 halogens.
  • the halogen is fluorine, chlorine or bromine.
  • it is any one selected from the group consisting of hydrogen, halogen, CH 3 , CF 3 , and OCH 3 .
  • R 2 is any one selected from the group consisting of hydrogen, halogen, CH 3 , CF 3 , and OCH 3 .
  • R 3 is selected from hydrogen, or unsubstituted C1-C6 straight or branched fluorenyl, or unsubstituted C1-C6 straight or branched decyloxy, unsubstituted Any one of C3-C12 cyclodecyl, -S0 2 R 5 , -NCORsRe.
  • R 4 is a C1-C6 straight or branched fluorenyl group selected from hydrogen, carboxy, unsubstituted or substituted by 1 to 3 halogens, unsubstituted or 1 to 3 halogen or A phenyl-substituted C1-C6 linear or branched decyloxy group, unsubstituted or substituted by 1 to 3 halogens or phenyl groups, a C1-C6 straight or branched carboxy group, substituted or unsubstituted 1 ⁇ Any of four heterocyclic C2-C12 cyclic groups.
  • each of R 5 and Re is independently hydrogen, halogen, or a C1-C4 straight or branched fluorenyl group which is unsubstituted or substituted with 1 to 3 halogens.
  • the halogen is fluorine or chlorine.
  • the compound is a compound of formula I, or an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate or solvent thereof Compound.
  • the inventors of the present invention conducted experimental research Surprisingly, it has been found that the above compounds can be used for the treatment of cancer-related diseases, in particular for the treatment of lung cancer, non-small cell lung cancer, and particularly for the treatment of ALK fusion-positive non-small cell lung cancer.
  • the compound of the present invention (the compound represented by Formula I, also called
  • PG represents an amino protecting group.
  • the amino protecting group is a tert-butoxycarbonyl group.
  • the compound of formula I may be: a compound of formula I or an enantiomer thereof, a diastereomer, a racemate, a pharmaceutically acceptable salt, Crystalline hydrates or solvates.
  • the term "pharmaceutically acceptable salt” as used in the present invention is a conventional non-toxic salt formed by reacting a compound of the formula I with an inorganic or organic acid.
  • the conventional non-toxic salt can be obtained by reacting a compound of the formula I with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, and acrylic acid.
  • the invention provides a process for the preparation of a compound of formula I.
  • the method comprises the steps of:
  • the method of the present invention can rapidly and efficiently prepare the compound of the formula I, and has a short synthetic route, environmental friendliness, high yield and purity of the target product, easy availability of raw materials, easy handling and post-treatment, and suitability.
  • the compound of the formula 2a is contacted with the compound of the formula 3a to obtain a compound of the formula 4a; specifically, the compound represented by the formula 2a and the compound of the formula 3a are mixed and stirred uniformly to obtain a mixed solution.
  • THF, triphenylphosphine (PPh 3 ), diethyl azodicarboxylate (DEAD) were mixed and stirred to obtain a stock solution. Under nitrogen protection, slowly add the reserve solution to the mixture at -5 °C ⁇ 5 °C, and keep stirring for 3 ⁇ 6 hours. After completion of the reaction, the solvent is concentrated to give an oily product to give a crude product of the compound of formula 4a.
  • the crude product is purified by column chromatography eluting with petroleum ether/ethyl acetate. The organic phase is concentrated to give the compound of formula 4a. Pure.
  • the compound of the formula 4a is subjected to amino protection using an amino protecting agent to obtain a compound of the formula 5a; specifically, it can be at 25 to 75 ° C in dichloromethane and 4-dimethylaminopyridine (DMAP).
  • an amino protecting agent is at least one selected from the group consisting of di-tert-butyl dicarbonate (BOC anhydride), benzyl chloroformate, benzyl bromide and p-toluenesulfonyl chloride.
  • the amino protecting agent is selected from the group consisting of BOC anhydride and chlorine. At least one of benzyl formate, most preferably the amino protecting agent is a BOC anhydride.
  • the compound of the formula 5a is subjected to a bromination reaction to obtain a compound of the formula 6a;
  • the compound of the formula 5a is mixed with acetonitrile by an ice bath, stirred uniformly, and N-bromosuccinimide (BS) is slowly added at 0 ° C to 10 ° C, and the temperature is maintained at 0 ° C. After stirring at ⁇ 10 ° C for 10 to 90 minutes, the reaction is completed, and the solvent is concentrated under reduced pressure to give an oily compound.
  • BS N-bromosuccinimide
  • the compound of the formula 7a is contacted with the compound of the formula 8 to obtain a compound of the formula 9a; specifically, the compound of the formula 7a is dissolved in dimethyl sulfoxide (DMSO), and potassium acetate is added thereto.
  • DMSO dimethyl sulfoxide
  • the compound of formula 8 is protected by nitrogen, and then [ ⁇ , ⁇ -bis(diphenylphosphine;)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ) is added to the dichloromethane (CH 2 C1).
  • the compound of the formula 6a is contacted with the compound of the formula 9a to obtain a compound of the formula 10a; specifically, an acetonitrile, a compound of the formula 6a, a compound of the formula 9a is added to a three-necked flask, and the mixture is uniformly stirred.
  • ethyl acetate and the compound of the formula 10a are added to a three-necked flask, stirred, and a saturated hydrogen chloride-ethyl acetate solution is added dropwise thereto, and the reaction is stirred at 15 to 55 ° C for 1 to 6 hours.
  • acetic acid is added.
  • Ethyl ester the solid is removed by filtration, and the organic phase is separated. The organic phase is dried over anhydrous sodium sulfate.
  • the solvent is evaporated to give the crude compound of formula I, and the crude product is recrystallized with methanol/acetone mixed solvent and filtered to give white.
  • the solid or off-white solid is dried under reduced pressure to give the compound of formula I.
  • the compound of formula I may be: a compound of formula I or an enantiomer thereof, a diastereomer, a racemate, a pharmaceutically acceptable salt, Crystalline hydrates or solvates.
  • the compound of formula I is a compound of formula 11
  • the compound of formula I is a compound of formula 16
  • the synthetic route of the compound of formula 16 is:
  • the compound of formula I is a compound of formula 46, and the synthetic route of the compound of formula 46 is:
  • the compound of formula I is a compound of formula 52, and the synthetic route of the compound of formula 52 is:
  • the compound of formula I is a compound of formula 74, and the synthetic route of the compound of formula 74 is:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I of the invention, or an enantiomer or diastereomer of a compound of formula I, Or a racemate, or a pharmaceutically acceptable salt, or a crystalline hydrate, or a solvate.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may further comprise conventional additives such as odorants, flavoring agents and the like.
  • the pharmaceutical preparation can be used as a medicament for the treatment of tumors (or cancer) for the production of anti-tumor therapeutic drugs.
  • the pharmaceutical composition provided by the present invention preferably contains 0.1% to 99% by weight of the compound of the formula I as an active ingredient, and preferably, the compound of the formula I is used as an active ingredient in 5% by weight of the total weight of the pharmaceutical composition. 90%, the remainder being a pharmaceutically acceptable carrier and/or conventional additives.
  • the compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, hard capsules, soft capsules, injections, powders for injection, powders, syrups, solutions, suspensions, aerosols, etc., and may be present. Suitably in a suitable solid or liquid carrier or diluent and in a sterile device for injection or drip.
  • Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods of preparation in the pharmaceutical arts.
  • the unit dosage of the formulation contains 0.05 mg to 750 mg of the compound described above, and preferably, the unit dosage of the formulation contains 1 mg to 500 mg of the compound described above.
  • the compounds and pharmaceutical compositions of this invention may be administered to mammals clinically, including humans and animals, by routes such as the mouth, nose, skin, lungs or the gastrointestinal tract. Regardless of the method of administration, the optimal dosage for the individual should be based on the specific treatment regimen. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found. The most preferred route of administration is oral.
  • the invention provides a pharmaceutical composition.
  • the pharmaceutical composition of the present invention comprises the aforementioned compound, and a second therapeutic agent.
  • the pharmaceutical composition has a strong antitumor activity, and has a good effect on the treatment of cancer by the synergistic effect between the aforementioned compound and the second therapeutic agent.
  • the second therapeutic agent is one or more selected from the group consisting of a cytotoxic drug, an antitumor bioengineering drug, an anoxic selective drug, an anti-inflammatory drug, and a vasoactive drug.
  • the cytotoxic drug is N-methyl, phenylalanine mustard, chlorambucil, cyclophosphamide, ifosfamide, chlorophosphoramide, busulfan, simos Ting, ramustine, dacarbazine, cisplatin, carboplatin, dinaplatin, lobaplatin, nedaplatin, oxaliplatin, methotrexate, cytarabine, 5-fluorouracil, deoxyfluoride Uridine, capecitabine, gemcitabine, actinomycin D, mitomycin C, daunorubicin, doxorubicin, mitoxantrone, vincristine, vinorelbine, paclitaxel, docetaxel One or more of camptothecin, hydroxycamptothecin or irinotecan.
  • the anti-tumor bioengineering drug is one or more of an anti-CEA antibody, a recombinant modified tumor necrosis factor, and an anti-tumor monoclonal antibody-directed drug.
  • the hypoxic selective drug is tirapazamine, dinitrobenzene mustard, 2-nitroimidazole oxime agent CI-1010, hydroxycamptothecin, topotecan, sand One or more of erweixin or etoposide.
  • the anti-inflammatory drug is one or more of diclofenac sodium, ibuprofen, naproxen or ketoprofen.
  • the vasoactive drug is serotonin, scopolamine, dopamine, dobutamine, ephedrine, m-hydroxylamine, methoxyamine, epinephrine, isoproterenol, phenylephrine One or more of norepinephrine, aminoprolone, and L-nitroarginine.
  • the compound described above is administered at a synergistic ratio with one or more of the above-mentioned one selected from the group consisting of a cytotoxic drug, an antitumor bioengineering drug, an anoxic selective drug, an anti-inflammatory drug, and a vasoactive drug, and the antibiotic is enhanced.
  • Tumor activity plays a synergistic role in the treatment of cancer.
  • the term "potency ratio" means a compound of formula I or an enantiomer thereof, diastereomer, or exogenous a spinner, a pharmaceutically acceptable salt, a crystalline hydrate or a solvate, and one or more of a cytotoxic drug, an antitumor bioengineering drug, an anoxic selective drug, an anti-inflammatory drug, and a vasoactive drug Applying at such ratios; the combined antitumor activity is greater than the compound of formula I alone or an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate or a solvate, or an anti-tumor activity of a cytotoxic drug, an anti-tumor bioengineering drug, an anoxic selective drug, an anti-inflammatory drug, and a vasoactive drug, or a combination greater than the expected combination according to the activity of each component Active. Therefore, when the components are administered at a synergistic ratio, their compositions undergo a syner
  • the compounds and pharmaceutical compositions of the invention may also be formulated as a combination for oral administration. These oral preparations include tablets, capsules, granules, and dispersible tablets, but are not limited to the above dosage forms.
  • the present invention can also be formulated as an injection for administration by injection. These injections include intravenous fluids, intramuscular injections, but are not limited to the above dosage forms.
  • the invention provides the use of a compound as described above for the preparation of a medicament for the treatment of a cancer-related disease, which is a cancer mediated by anaplastic lymphoma kinase (ALK) .
  • ALK anaplastic lymphoma kinase
  • the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, head and neck cancer, epidermis or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer , breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, Penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal cell carcinoma, renal pelvic cancer, primary central nervous system lymphoma, spinal tumor, brain stem glioma, pituitary adenoma and combination.
  • the cancer is selected from the group consisting of: non-small cell lung cancer, squamous cell carcinoma, hormone refractory prostate cancer, papillary renal cell carcinoma, colorectal adenocarcinoma, neuroblastoma, anaplastic large cell lymphoma, and gastric cancer. .
  • the compounds described above of the present invention can be used to treat cancer patients carrying an ALK fusion gene due to chromosomal rearrangements, such as NSCLC patients carrying EML4-ALK, which carry amplified, increased copy number And point-mutated ALK genes, such as neuroblastoma patients or other tumor patients characterized by genetic abnormalities in the ALK gene or higher ALK expression than normal tissues.
  • the effects of the compounds described above on the growth of human lung cancer A549 cells in nude mice showed that compared with the model control group, the compound treatment group had significant inhibitory effects on the growth of human lung cancer A549 cells in nude mice.
  • the difference, especially compared with the model control group, the compound of the present invention has a significant difference in the inhibition of the growth of human lung cancer A549 cells in nude mice (P ⁇ 0.01), and the chemotherapy oxaliplatin group
  • the average tumor inhibition rate is improved, which indicates that the compound of the present invention has extremely remarkable curative effect in treating non-small cell lung cancer, and has remarkable toxic and side effects while obtaining remarkable pharmacological effects.
  • the compound of the present invention shows remarkable anti-tumor growth activity in crizotinib-resistant NCI-H2228, the compound of the present invention Decazol Tini 50 mg/kg has better activity and unexpected technical effects have been obtained. Therefore, the present invention has a good therapeutic effect for patients with non-small cell lung cancer who are resistant to crizotinib.
  • the compound of the invention has good anti-cancer application prospect, can be used for treating cancer-related diseases, can be used as a medicine for treating cancer, can be used for the production of cancer therapeutic drugs, and thus has good commercial value.
  • the inventors have found that the compounds of the present invention have more active anti-cancer properties and are useful as new ones compared to the marketed crizotinib-resistant mammals (including humans) that are resistant to crizotinib. A generation of anticancer drugs.
  • the compounds of the present invention are particularly useful for use in the treatment of ALK fusion-positive non-small cell lung cancer, and optionally against crizotinib-resistant ALK fusion-positive non-small cell lung cancer.
  • the invention provides a pharmaceutical combination.
  • the pharmaceutical combination comprises a compound as described above, and a second therapeutic agent.
  • the second therapeutic agent is one or more selected from the group consisting of a cytotoxic drug, an antitumor bioengineering drug, an anoxic selective drug, an anti-inflammatory drug, and a vasoactive drug.
  • the cytotoxic drug is N-methyl, phenylalanine mustard, chlorambucil, cyclophosphamide, ifosfamide, chlorophosphoramide, busulfan, semustine , ramustine, dacarbazine, cisplatin, carboplatin, dinaplatin, lobaplatin, nedaplatin, oxaliplatin, methotrexate, cytarabine, 5-fluorouracil, deoxyfluoride Glycosides, capecitabine, gemcitabine, actinomycin D, mitomycin C, daunorubicin, doxorubicin, mitoxantrone, vincristine, vinorelbine, paclitaxel, docetaxel, One or more of camptothecin, hydroxycamptothecin or irinotecan.
  • the anti-tumor bioengineered drug is one or more of an anti-CEA antibody, a recombinant modified tumor necrosis factor, and an anti-tumor monoclonal antibody-directed drug.
  • the hypoxic selective drug is tirapazamine, dinitrobenzene mustard, 2-nitroimidazole oxime agent CI-1010, hydroxycamptothecin, topotecan, shar One or more of wein or etoposide.
  • the anti-inflammatory drug is one or more of diclofenac sodium, ibuprofen, naproxen or ketoprofen.
  • the vasoactive drug is serotonin, scopolamine, dopamine, dobutamine, ephedrine, m-hydroxylamine, methoxyamine, epinephrine, isoproterenol, phenylephrine, One or more of norepinephrine, aminoprolone, and L-nitroarginine.
  • the invention provides a kit.
  • the kit includes: a first therapeutic agent, the first therapeutic agent being the compound described above; and a second therapeutic agent selected from the group consisting of cytotoxic drugs, One or more of an anti-tumor bioengineering drug, an anoxic selective drug, an anti-inflammatory drug, and a vasoactive drug, wherein the first therapeutic machine and the second therapeutic agent are disposed in different containers .
  • the cytotoxic drug is N-methyl, phenylalanine mustard, chlorambucil, cyclophosphamide, ifosfamide, chlorophosphoramide, busulfan, semustine , ramustine, dacarbazine, cisplatin, carboplatin, Desplatin, lobaplatin, nedaplatin, oxaliplatin, methotrexate, cytarabine, 5-fluorouracil, deoxyfluorouridine, capecitabine, gemcitabine, actinomycin D, silk a type of fibromycin C, daunorubicin, doxorubicin, mitoxantrone, vincristine, vinorelbine, paclitaxel, docetaxel, camptothecin, hydroxycamptothecin or irinotecan Or a variety.
  • the anti-tumor bioengineered drug is one or more of an anti-CEA antibody, a recombinant modified tumor necrosis factor, and an anti-tumor monoclonal antibody-directed drug.
  • the hypoxic selective drug is tirapazamine, dinitrobenzene mustard, 2-nitroimidazole oxime agent CI-1010, hydroxycamptothecin, topotecan, shar One or more of wein or etoposide.
  • the anti-inflammatory drug is one or more of diclofenac sodium, ibuprofen, naproxen or ketoprofen.
  • the vasoactive drug is serotonin, scopolamine, dopamine, dobutamine, ephedrine, m-hydroxylamine, methoxyamine, epinephrine, isoproterenol, phenylephrine, One or more of norepinephrine, aminoprolone, and L-nitroarginine.
  • the invention provides a method of treating cancer.
  • the method comprises: administering to a patient a compound as hereinbefore described or a pharmaceutical composition as hereinbefore described.
  • the cancer is a cancer mediated by anaplastic lymphoma kinase.
  • the cancer is at least one selected from the group consisting of: lung cancer, bone cancer, pancreatic cancer, head and neck cancer, epidermis or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal Area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, adrenal cancer , soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal cell carcinoma, renal pelvic cancer, primary central nervous system lymphoma, spinal tumor, brainstem glia Tumor and pituitary adenoma.
  • the cancer is at least one selected from the group consisting of: non-small cell lung cancer, squamous cell carcinoma, hormone refractory prostate cancer, papillary renal cell carcinoma, colorectal adenocarcinoma, neuroblast Tumor, anaplastic large cell lymphoma and gastric cancer.
  • the cancer is a non-small cell lung cancer disease mediated by anaplastic lymphoma kinase.
  • the cancer is an ALK fusion-positive non-small cell lung cancer that is resistant to crizotinib.
  • Figure 1 shows a compound of formula I in NCI-H2228 with crizotinib resistance, in accordance with an embodiment of the present invention. Anti-tumor growth activity in tumors. Detailed ways
  • Embodiments of the invention provide enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, crystalline hydrates or solvates of a compound of Formula I or a compound of Formula I.
  • Process for the preparation of an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate or solvate of a compound of formula I or a compound of formula I A pharmaceutical composition, and an enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate or solvate of a compound of formula I or a compound of formula I,
  • Uses in the preparation of the medicaments, the materials and reagents used in the description of the present invention are commercially available unless otherwise specified.
  • LiAH 4 (3.8 g, 0.1 mol) and P 50 ml of THF were added to a three-necked flask and protected with nitrogen.
  • the compound of formula la-1 (20.7 g, 0.1 mol) was dissolved in 200 ml of THF and was taken.
  • the THF solution of the compound of the formula la-1 was slowly dropped into a three-necked flask at 0 ° C, followed by heating under reflux for 2 hours.
  • the reaction was completed by thin layer chromatography (TLC) dot plate, then cooled with ice bath, 20 ml of water was added, and then 50 ml of 10% sodium hydroxide solution was slowly added dropwise, and the mixture was stirred for 10 minutes, filtered to remove solids, and then separated.
  • the organic layer was taken up, dried over anhydrous sodium sulfate, and evaporated, and evaporated to the solvent to give the compound of formula 2a-1 (19.3 g, yield 92.3%) as a pale yellow oil.
  • the analysis data is:
  • LiAH 4 (4.0 g, 0.1054 mol) and 50 ml of THF were added to a three-necked flask and protected with nitrogen.
  • the compound of formula la-1 (20.7 g, 0.1 mol) was dissolved in 200 ml of THF and was taken.
  • the THF solution of the compound of the formula la-1 was slowly dropped into a three-necked flask at -5 ° C, followed by heating under reflux for 3 hours. After completion of the reaction, the compound was treated in the same manner as in Example 1 to give the compound of formula 2a-1 (19.1 g, yield: 91.4%) as a pale yellow oil.
  • LiAH 4 (5 g, 0.13 mol) and 50 ml of THF were added to a three-necked flask and protected with nitrogen.
  • the compound of formula la-1 (20.7 g, 0.1 mol) was dissolved in 200 ml of THF and was taken.
  • the THF solution of the compound of the formula la-1 was slowly dropped into a three-necked flask at 5 ° C, and then heated under reflux for 1 hour. After completion of the reaction, the compound was treated in the same manner as in Example 1 to give the compound of formula 2a-1 (19.2 g, yield: 91.8%) as a pale yellow oil.
  • Example 4 Preparation of a compound of formula 2a-2 LiAH 4 (5 g, 0.13 mol) and 50 ml of THF were added to a three-necked flask and protected with nitrogen. The compound of formula la-2 (22.1 g, 0.1 mol) was dissolved in 200 ml of THF and was taken. The THF solution of the compound of the formula la-2 was slowly dropped into a three-necked flask at 5 ° C, and then heated under reflux for 1 hour. After completion of the reaction, the compound was treated in the same manner as in Example 1 to give the compound of the formula 2a-2 (20.4 g, yield: 91.5%) as a pale yellow oil.
  • the analysis data is:
  • LiAH 4 (5 g, 0.13 mol) and 50 ml of THF were added to a three-necked flask and protected with nitrogen.
  • the compound of formula la-2 (22.1 g, 0.1 mol) was dissolved in 200 ml of THF and was taken.
  • the THF solution of the compound of the formula la-2 was slowly dropped into a three-necked flask at 5 ° C, and then heated under reflux for 1 hour. After completion of the reaction, the compound was treated in the same manner as in Example 1 to give the compound of formula 2a-2 (19.8 g, yield: 88.8%) as a pale yellow oil.
  • LiAH 4 (5 g, 0.13 mol) and 50 ml of THF were added to a three-necked flask and protected with nitrogen.
  • the compound of formula la-2 (22.1 g, 0.1 mol) was dissolved in 200 ml of THF and was taken.
  • the THF solution of the compound of the formula la-2 was slowly dropped into a three-necked flask at 5 ° C, and then heated under reflux for 1 hour. After completion of the reaction, the compound was treated in the same manner as in Example 1 to give the compound of formula 2a-2 (20.1 g, yield 90.1%) as a pale yellow oil.
  • THF 200 ml
  • a compound of the formula 2a-1 (21.9 g, 0.105 mol)
  • a compound of the formula 3a (15.1 g, 0.1 mol)
  • THF 200 ml
  • triphenylphosphine 40 g, 0.153 mol
  • diethyl azodicarboxylate 35 g, 0.2 mol
  • the stock solution was slowly added dropwise to the mixture at 0 ° C, and the mixture was stirred for 5 hours.
  • the analysis data is:
  • THF 200 ml
  • a compound of the formula 2a-2 (22.3 g, 0.1 mol)
  • a compound of the formula 3a (15.1 g, 0.1 mol)
  • THF 200 ml
  • triphenylphosphine 40 g, 0.153 mol
  • diethyl azodicarboxylate 52.5 g, 0.3 mol
  • the stock solution was slowly added dropwise to the mixture at 0 ° C, and the mixture was stirred for 5 hours.
  • the analysis data is:
  • Example 12 Preparation of a compound of formula 4a-2 THF (200 ml), a compound of the formula 2a-2 (26.8 g, 0.12 mol), and a compound of the formula 3a (15.1 g, 0.1 mol) were mixed and stirred to obtain a mixed liquid.
  • THF (200 ml), triphenylphosphine (40 g, 0.153 mol), diethyl azodicarboxylate (35 g, 0.2 mol) were mixed and stirred to obtain a stock solution. Under nitrogen atmosphere, the stock solution was slowly added dropwise to the mixture at 5 ° C, and the mixture was stirred for 3 hours.
  • the compound of the formula 4a-1 (34.2 g, 0.1 mol) was dissolved in 500 ml of dichloromethane, and stirred with stirring, DMAP (0.5 g, 0.004 mol), di-tert-butyl dicarbonate (26.2 g, 0.12 mol) .
  • the reaction was stirred at 25 ° C for 16 hours. After completion of the reaction, the mixture was extracted with methylene chloride and washed with saturated aqueous sodium hydrogen carbonate and brine to give compound (50.5 g, yield: 91.5%).
  • the analysis data is:
  • the compound of the formula 4a-1 (34.2 g, 0.1 mol) was dissolved in 500 ml of dichloromethane, and stirred with stirring, DMAP (0.6 g, 0.005 mol), di-tert-butyl dicarbonate (32.8 g, 0.15 mol) .
  • the reaction was stirred at 75 ° C for 2 hours. After completion of the reaction, the mixture was extracted with methylene chloride and washed with saturated aqueous sodium hydrogen sulfate and brine to give compound (39.8 g, yield: 90.0%).
  • the compound of the formula 4a-1 (34.2 g, 0.1 mol) was dissolved in 500 ml of dichloromethane, and stirred with stirring, DMAP (0.25 g, 0.002 mol), di-tert-butyl dicarbonate (22.9 g, 0.105 mol) .
  • the reaction was stirred at 45 ° C for 8 hours. After completion of the reaction, the mixture was extracted with dichloromethane, and washed with saturated aqueous sodium hydrogen sulfate and brine to give compound (39.1 g, yield: 88.4%).
  • the compound of the formula 4a-2 (35.6 g, 0.1 mol) was dissolved in 500 ml of dichloromethane, and stirred with stirring, DMAP (0.25 g, 0.002 mol), di-tert-butyl dicarbonate (22.9 g, 0.105 mol) .
  • the reaction was stirred at 35 ° C for 10 hours. After completion of the reaction, the mixture was extracted with methylene chloride and washed with saturated aqueous sodium hydrogen carbonate and brine to give compound (yield: 40.6 g, yield: 89.0%).
  • the compound of the formula 4a-2 (35.6 g, 0.1 mol) was dissolved in 500 ml of dichloromethane, and stirred with stirring, DMAP (0.6 g, 0.005 mol), di-tert-butyl dicarbonate (32.8 g, 0.15 mol) .
  • the reaction was stirred at 55 ° C for 5 hours. After completion of the reaction, the mixture was extracted with methylene chloride and washed with saturated aqueous sodium hydrogen carbonate and brine to give compound (52.5 g, yield: 93.2%).
  • the compound of the formula 4a-2 (35.6 g, 0.1 mol) was dissolved in 500 ml of dichloromethane, and stirred with stirring, DMAP (0.5 g, 0.004 mol), di-tert-butyl dicarbonate (26.2 g, 0.12 mol) .
  • the reaction was stirred at 65 ° C for 3 hours. After completion of the reaction, the mixture was extracted with chloroformic acid and washed with saturated aqueous sodium hydrogen carbonate and saturated brine to give Compounds of formula 5a-2 (41.3 g, yield: 90.6%).
  • the compound of the formula 5a-l (44.2 g, 0.1 mol) was mixed with 500 ml of acetonitrile by an ice bath, stirred well, and N-bromosuccinimide (35.6 g) was slowly added at 0 ° C to 10 ° C. , 0.2 mol), and maintaining the temperature at 0 ° C ⁇ 10 ° C for 10 minutes, the reaction is completed, the solvent is concentrated under reduced pressure to give an oil, which is obtained as a compound of formula 6a-1 (36.6 g, yield 70.2% ).
  • the analysis data is:
  • the compound of the formula 5a-l (44.2 g, 0.1 mol) was mixed with 500 ml of acetonitrile by an ice bath, stirred uniformly, and N-bromosuccinimide (17.8 g) was slowly added at 0 ° C to 10 ° C. , 0.1 mol), and maintaining the temperature at 0 ° C ⁇ 10 ° C for 90 minutes, the reaction is completed, concentrated under reduced pressure to remove the solvent to give an oil, which is obtained as a compound of formula 6a-1 (27.5 g, yield 52.8%) ).
  • the compound of the formula 5a-1 (44.2 g, 0.1 mol) was mixed with 500 ml of acetonitrile by an ice bath, stirred uniformly, and N-bromosuccinimide (21.4 g) was slowly added at 0 ° C to 10 ° C. , 0.12 mol), and maintaining the temperature at 0 ° C ⁇ 10 ° C for 30 minutes, the reaction is completed, the solvent is concentrated under reduced pressure to give an oil, which is obtained as a compound of formula 6a-1 (33.3 g, yield 63.9%) ).
  • the compound of formula 5a-2 (45.6 g, 0.1 mol) was mixed with 500 ml of acetonitrile using an ice bath and stirred. Evenly, N-bromosuccinimide (35.6 g, 0.2 mol) was slowly added at 0 ° C ⁇ 10 ° C, and the temperature was kept at 0 ° C ⁇ 10 ° C for 60 minutes, the reaction was completed, concentrated under reduced pressure The solvent was removed to give an oily compound (35.0 g, yield: 65.4%).
  • the analysis data is:
  • the compound of the formula 5a-2 (45.6 g, 0.1 mol) was mixed with 500 ml of acetonitrile by an ice bath, and stirred uniformly. N-bromosuccinimide (17.8 g) was slowly added at 0 ° C to 10 ° C. , 0.1 mol), and maintaining the temperature at 0 ° C ⁇ 10 ° C for 15 minutes, the reaction is completed, the solvent is concentrated under reduced pressure to give an oil, which is obtained as a compound of formula 6a-2 (29.4 g, yield 55.0% ).
  • the compound of the formula 5a-2 (45.6 g, 0.1 mol) was mixed with 500 ml of acetonitrile by an ice bath, stirred uniformly, and N-bromosuccinimide (21.4 g) was slowly added at 0 ° C to 10 ° C. , 0.12 mol), and maintaining the temperature at 0 ° C ⁇ 10 ° C for 45 minutes, the reaction is completed, the solvent is concentrated under reduced pressure to give an oil, which is obtained as a compound of formula 6a-2 (36.9 g, yield 68.9%) ).
  • the compound of the formula 7a-1 (23.0 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (25.4 g, 0.1 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphine;)ferrocene]palladium dichloride ( 3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 50 ° After stirring at C ⁇ 60 ° C for 15 hours, the reaction was completed, the solid was removed by filtration, and then the liquid was separated. The organic phase was separated, and the solvent was concentrated to give a crude product.
  • the analysis data is:
  • the compound of the formula 7a-1 (23.0 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (30.5 g, 0.12 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene]palladium dichloride (3.67 g, 0.005 mol) in dichloromethane (CH2C12) at 70 ° C ⁇ 80 ° After stirring for 10 hours at C, the reaction was completed, and the workup was carried out in the same manner as in Example 25 to give the compound of formula 9a-1 (25.4 g, yield: 91.6%).
  • the compound of formula 7a-2 (24.4 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate was added.
  • the compound of the formula 7a-2 (24.4 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (30.5 g, 0.12 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphine;)ferrocene]palladium dichloride ( 3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 70 ° After stirring at C to 80 ° C for 8 hours, the reaction was carried out in the same manner as in Example 28 to obtain a compound of formula 9a-2 (26.5 g, yield: 91.0%).
  • the compound of the formula 7a-3 (22.8 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (25.4 g, 0.1 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphine;)ferrocene]palladium dichloride ( 3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 50 ° After stirring at C ⁇ 55 °C for 15 hours, the reaction was completed, the solid was removed by filtration, and then the organic phase was separated, and the solvent was concentrated to give a crude product.
  • the compound of the formula 7a-3 (22.8 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (50.8 g, 0.2 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene]palladium dichloride (3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 95 ° C After stirring at ⁇ 100 ° C for 6 hours, the reaction was carried out in the same manner as in Example 31 to give the compound of formula 9a-3 (23.4 g, yield: 85.0%).
  • the compound of the formula 7a-3 (22.8 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (30.5 g, 0.12 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphine;)ferrocene]palladium dichloride ( 3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 75 ° After stirring at C ⁇ 80 ° C for 9 hours, the reaction was completed, and the post-treatment method was the same as that in Example 31 to obtain the compound of formula 9a-3 (24.6 g, yield 89.4%).
  • the compound of the formula 7a -4 (25.4 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (50.8 g, 0.2 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene]palladium dichloride (3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 95 ° C After stirring at ⁇ 100 ° C for 6 hours, the reaction was carried out in the same manner as in Example 34 to give the compound of formula 9a-4 (24.7 g, yield: 82.0%).
  • the compound of the formula 7a -4 (25.4 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (30.5 g, 0.12 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphine;)ferrocene]palladium dichloride ( 3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 75 ° After stirring at C ⁇ 80 ° C for 12 hours, the reaction was completed, and the same treatment method as in Example 34 gave the compound of formula 9a-4 (26.8 g, yield 88.9%).
  • Example 37 Preparation of a compound of formula 9a-5
  • the compound of the formula 7a-5 (20.3 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (25.4 g, 0.1 mol) were added.
  • the compound of the formula 7a-5 (20.3 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (50.8 g, 0.2 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene]palladium dichloride (3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 95 ° C After stirring at ⁇ 100 ° C for 6 hours, the reaction was carried out in the same manner as in Example 37 to give the compound of formula 9a-5 (19.6 g, yield 78.5%).
  • the compound of the formula 7a-5 (20.3 g, 0.1 mol) was dissolved in 300 ml of dimethyl sulfoxide, and potassium acetate (29.4 g, 0.3 mol) and a compound of formula 8 (30.5 g, 0.12 mol) were added. Protected with nitrogen, then [ ⁇ , ⁇ -bis(diphenylphosphine;)ferrocene]palladium dichloride ( 3.67 g, 0.005 mol) in dichloromethane (CH 2 C1 2 ) solution at 75 ° The mixture was stirred at C ⁇ 80 ° C for 6 hours, and the reaction was carried out in the same manner as in Example 37 to obtain the compound of the formula 9a-5 (20.1 g, yield: 80.4%).
  • Acetonitrile 550 ml
  • a compound of the formula 6a-3 52.1 g, 0.1 mol
  • a compound of the formula 9a-3 33.0 g, 0.12 mol
  • Example 51 Preparation of a compound of the formula 10A-4 In a three-necked flask, acetonitrile (550 ml), a compound of the formula 6a-4 (52.1 g, 0.1 mol), a compound of the formula 9a-4 (36.1 g, 0.12 mol) was added, and the mixture was stirred uniformly, and a 10% sodium carbonate solution was added thereto.
  • the compound of the formula lOa-1 (59.1 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 15 ° C for 6 hours. After completion of the reaction, ethyl acetate was added, and the solid was separated by filtration, and then the organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to give the crude salt of the compound of formula I, and the crude product was added to 300 ml of methanol/acetone.
  • the compound of the formula lOa-1 (59.1 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 55 ° C for 1 hour. After completion of the reaction, the same procedure as in Example 55 was carried out, and the hydrochloride salt of the compound of the formula I (the compound of the formula 11, 44.3 g, yield: 84.0%), purity 99.0% (high-performance liquid phase) was obtained.
  • the compound of the formula lOa-1 (59.1 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 25 ° C for 3 hours. After completion of the reaction, the same procedure as in Example 55 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 11, 48.8 g, yield: 92.5%) was obtained, and the purity was 99.2% (high-performance liquid phase).
  • the compound of the formula 10a-2 (62.0 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 15 ° C for 6 hours. After completion of the reaction, ethyl acetate was added, and the solid was separated by filtration, and then the organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to give the crude salt of the compound of formula I, and the crude product was added to 300 ml of methanol/acetone.
  • the compound of the formula 10a-2 (62.0 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 55 ° C for 1 hour. After completion of the reaction, the same procedure as in Example 58 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 16, 45.1 g, yield: 81.1%) was obtained, and the purity was 99.5 % (high-performance liquid phase).
  • the compound of the formula 10a-2 (62.0 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 25 ° C for 3 hours. After completion of the reaction, the same procedure as in Example 58 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 16, 49.8 g, yield: 89.6%) was obtained, and the purity was 99.4% (high-performance liquid phase).
  • the compound of the formula 10a-3 (58.9 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 15 ° C for 6 hours. Reaction, plus Ethyl acetate was added, and the solid was separated by filtration.
  • the compound of the formula 10a-3 (58.9 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 55 ° C for 1 hour. After completion of the reaction, the same procedure as in Example 61 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 46, 45.5 g, yield 86.6%) was obtained, and the purity was 99.5 % (high-performance liquid phase).
  • the compound of the formula 10a-3 (58.9 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 45 ° C for 2 hours. After completion of the reaction, the same procedure as in Example 61 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 46, 47.6 g, yield: 90.6%) was obtained, and the purity was 99.0% (high-performance liquid phase).
  • the compound of the formula 10a-4 (61.5 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 15 ° C for 6 hours. After completion of the reaction, ethyl acetate was added, and the solid was separated by filtration, and then the organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to give the crude salt of the compound of formula I, and the crude product was added to 300 ml of methanol/acetone.
  • the compound of the formula 10a-4 (61.5 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 55 ° C for 1 hour. After completion of the reaction, the same procedure as in Example 64 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 52, 48.7 g, yield: 88.3%) was obtained, and the purity was 99.1% (high-performance liquid phase).
  • the compound of the formula 10a-4 (61.5 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 45 ° C for 2.5 hours. After completion of the reaction, the same procedure as in Example 64 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 52, 50.2 g, yield: 91.0%) was obtained, and the purity was 99.5 % (high-performance liquid phase).
  • Example 67 Preparation of the hydrochloride salt of the compound of formula 74
  • the compound of the formula 10a-5 (56.4 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 15 ° C for 6 hours.
  • the compound of the formula 10a-5 (56.4 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 55 ° C for 1 hour. After completion of the reaction, the same procedure as in Example 67 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 74, 45.2 g, yield: 90.3%) was obtained, and the purity was 99.4% (high-performance liquid phase).
  • the compound of the formula 10a-4 (56.4 g, 0.1 mol) and 200 ml of ethyl acetate were added to a three-necked flask, stirred, and 300 ml of a saturated hydrogen chloride-ethyl acetate solution was added dropwise thereto, and the reaction was stirred at 45 ° C for 2.5 hours. After completion of the reaction, the same procedure as in Example 67 was carried out, and the hydrochloride salt of the compound of formula I (the compound of formula 74, 47.3 g, yield 94.5%), purity 99.1% (high-performance liquid phase) was obtained.
  • the compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, hard capsules, soft capsules, injections, powders for injection, powders, syrups, solutions, suspensions, aerosols, etc., and may be present. Suitably in a suitable solid or liquid carrier or diluent and in a sterile device for injection or drip.
  • a suitable solid or liquid carrier or diluent Suitably in a suitable solid or liquid carrier or diluent and in a sterile device for injection or drip.
  • Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional methods of preparation in the pharmaceutical arts.
  • the pharmaceutical excipients selected for use in the present invention include binders, disintegrants, fillers, glidants, and lubricants.
  • the binder selected is compressible starch
  • the disintegrant is hydroxypropylcellulose
  • the filler is ⁇ -anhydrous lactose and microcrystalline cellulose
  • the glidant is micronized silica gel
  • the lubricant is talc.
  • the pharmaceutical excipients are prepared by using a good disintegrating agent such as hydroxypropyl cellulose and other pharmaceutical excipients to prepare a compound preparation, so that not only the drug release is fast but also the physical properties are good, and the prepared tablet has the outstanding advantage that it can be quickly released. And scattered completely.
  • Example 70 Tablet of the compound of Formula 11 (Specification: lOOmg)
  • the compound shown in the main drug formula 11 was finely ground, passed through a 100 mesh sieve, and the auxiliary material was passed through an 80 mesh sieve. Weigh the prescribed amount of the compound of formula 11, compressible starch, ⁇ -anhydrous lactose, microcrystalline cellulose and 3% hydroxypropylcellulose, mix well, use soft material made of ethanol, pass 12 mesh nylon sieve, Dry at 60 ° C, sieve through 30 mesh, add micro-silica gel and talcum powder, and mix well. After the granules have passed the determination of the content, the granule powder is directly compressed by a 12 mm punch, which is obtained.
  • the compound shown in the main drug form 16 was finely ground, passed through a 100 mesh sieve, and the auxiliary material passed through an 80 mesh sieve. Weigh the prescribed amount of the compound of formula 16, ⁇ -anhydrous lactose, microcrystalline cellulose and sodium carboxymethylcellulose, mix well, soften with ethanol, pass through a 12 mesh nylon sieve, and dry at 60 ° C. 30 mesh sieves, add talcum powder, and mix well. After the granules have been tested for content, they are filled into capsules by a capsule machine.
  • Example 72 Tablet of the compound of Formula 46 (Specification: 150 mg)
  • Example 73 a capsule of the compound of formula 52
  • the compound shown in the main drug formula 52 was finely ground, passed through a 100 mesh sieve, and the auxiliary material passed through an 80 mesh sieve. Weigh the prescribed amount of the compound of formula 52, ⁇ -anhydrous lactose, microcrystalline cellulose and sodium carboxymethylcellulose, mix well, soften with ethanol, pass through a 12 mesh nylon sieve, and dry at 60 ° C. 30 mesh sieves, add talcum powder, and mix well. After the granules have been tested for content, they are filled into capsules by a capsule machine.
  • Example 74 Injection of a compound of the formula 74 (Specification: lOOmg)
  • Preparation of liquid medicine Weigh sodium chloride according to the prescription amount, add 5000ml of water for injection, stir until completely dissolved; weigh 0.3% solution of activated carbon, stir well, heat and boil for 15 minutes, after cooling, filter off activated carbon; Prescribe the compound of formula 74 accurately, add fluorouracil to the above sodium chloride solution, and add water for injection to the full amount; adjust the pH to 7.5 ⁇ 8.5 with 0.1% sodium hydroxide, add water for injection to the specified amount, and measure the middle.
  • the body content should be 93.0% ⁇ 107.0%. After passing the test, it is filtered with a 0.45 ⁇ microporous membrane. After checking the clarity, the filtrate is filled and filled.
  • the infusion bottle for filling is washed with injection water and dried. At the same time, the coated butyl rubber plug was rinsed with water for injection.
  • the prepared chemical solution is added to the injection liquid filling machine, filled in the infusion bottle, and after the cap is stoppered, the composite aluminum cover is pressed.
  • Sterilization The covered infusion bottle is placed in a sterilizing cabinet for sterilization. The sterilization temperature is 115 ° C, the sterilization time is 35 minutes, the light inspection is qualified, and the package is ready.
  • Example 75 Effect of the compound of the present invention on the growth of human lung cancer A549 cells transplanted in nude mice
  • A549 The logarithmic growth phase lung cancer cell line A549 was obtained.
  • the concentration of A549 cells was adjusted to 3 ⁇ 10 7 /mL with sterile PBS.
  • 0.1 ml of A549 cells were inoculated subcutaneously in the back of BALB/c-nu mice, and the volume of subcutaneous transplanted tumors was 75 mm 3 .
  • the left and right about 10 days; the model was manufactured successfully.
  • model control group the same amount of normal saline was administered once a day for 30 days;
  • oxaliplatin group intraperitoneal injection of 10 mg / kg oxaliplatin, administered once every other day, a total of 8 times;
  • crizotinib group intragastric administration of crizotinib capsule (produced by Pfizer, trade name: ⁇ ) powder, dosage 25mg / kg, 2 times / day, a total of 8 times;
  • Example 71 compound group of formula 11: The capsule powder prepared according to Example 71 was administered by gavage at a dose of 10 mg/kg once daily for 30 days;
  • E compound group of formula 16:
  • the capsule powder prepared according to Example 71 was administered by gavage at a dose of 10 mg/kg once daily for 30 days;
  • G a compound group of the formula 52:
  • the capsule powder prepared according to Example 71 was administered by gavage at a dose of 10 mg/kg.
  • Compound group represented by Formula 74 The capsule powder prepared according to Example 71 was administered by gavage at a dose of 10 mg/kg once daily for 30 days.
  • the compound of the formula I of the present invention (the compound of the formula 11, the compound of the formula 16, the compound of the formula 46, the compound of the formula 52, the compound of the formula 74) is grown on human lung cancer A549 cells transplanted in nude mice.
  • the experimental results of the effects are shown in Table 1.
  • test results in Table 1 show that: compared with the model control group, each treatment group has a significant difference in the inhibition of human lung cancer A549 cell xenograft growth in nude mice, especially compared with the model control group, the present invention
  • the compound of formula I has a significant difference in the inhibition of human lung cancer A549 cell xenograft growth in nude mice (P ⁇ 0.01), compared with the chemotherapy oxaliplatin group and the ALK inhibitor crizotinib group.
  • the average tumor inhibition rate is improved, which indicates that the compound of the present invention has an extremely remarkable therapeutic effect in the treatment of non-small cell lung cancer, and has an advantage of being low in toxic and side effects while obtaining remarkable pharmacological effects, and an unexpected technical effect is obtained.
  • Example 76 Antitumor activity of a compound of the invention in crizotinib resistant tumors
  • Xenograft tumors obtained from NCI-H2228 were first treated with crizotinib for 14 days at a dose of 50 mg/kg, and treatment with clizotinib was stopped for several days until the tumor re-grows.
  • the animal is treated with crizotinib 50 mg/kg until the tumor develops resistance to the treatment with crizotinib.
  • Tumors obtained from individual animals were collected when they became resistant to crizotinib.
  • Several drug-resistant tumors were randomly selected and used in the following studies.
  • Each of the drug-resistant tumors was cut into small pieces and implanted into 5 animals; when the tumor volume in 5 animals was large enough, the tumors were collected and then implanted into 25 animals for the compound test. A collection of tumors was also used for RNA extraction, followed by sequencing of the EML4-ALK transcription.
  • Blank control group oral starch at a dose of 50 mg/kg
  • the crizotinib group treated with crizotinib for 14 days at a dose of 50 mg/kg, then stopped for 2 days, and again dosed at 50 mg/kg from day 17 until the tumor was on the crizotinib
  • the treatment produced resistance (resistance to drug resistance on the 28th day after administration);
  • a compound group represented by Formula 1 a compound of the formula 11 is administered orally at a dose of 25 mg/kg, and administered to the 48th day;
  • the compound of the formula 11 of the present invention showed remarkable antitumor growth activity in crizotinib-resistant NCI-H2228, and the compound of the formula 11 showed better activity than crizotinib 50 mg/kg.
  • the toxicity of the compound of Formula 11 associated with 50 mg/kg in mice was lower than that of humans.
  • the inventors have verified the other compounds of the present invention by the same method, and have the same antitumor activity effects as the compounds of the formula 11 of the present invention.
  • the description of the terms “one embodiment”, “some embodiments”, “example”, “specific example” or “some examples” and the like means a specific feature described in connection with the embodiment or example, A structure, material or feature is included in at least one embodiment or example of the invention.
  • the schematic representation of the above terms does not necessarily mean the same embodiment or example.
  • the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.

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Abstract

本发明提供了化合物及其制备方法和应用,该化合物为式I所示化合物或其对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物或溶剂合物。在式I所示化合物中,R 1、R 2、R 3、R 4如说明书所定义。

Description

化合物及其制备方法和应用
技术领域
本发明涉及医药领域, 具体的, 本发明涉及化合物及其制备方法和应用, 更具体的, 本发明涉及式 I所示化合物以及衍生物及其制备方法、药物组合物、式 I所示化合物在制备 药物中的用途、 药物联合以及药盒。 背景技术
在全球范围内, 每年肺癌造成的死亡要超过任何其他一种癌症。 在中国, 目前肺癌的 发病率和死亡人数已经位列恶性肿瘤第一位, 给患者的生命和财产造成巨大损失。 2013年 11月 16日, 在中国肺癌南北高峰论坛上, 专家表示, 肺癌从 30年前危害国人健康排名第 五位的恶性肿瘤, 目前已飞升至首位, 且发病率和死亡率仍在迅速上升。 预计到 2025年, 我国肺癌病人将达到 100万, 成为世界第一肺癌大国。
非小细胞肺癌 (Non-small-cell carcinoma, NSCLC) 与"非小细胞癌"同义。 非小细胞型 肺癌, 包括鳞癌、 腺癌、 大细胞癌, 与小细胞癌相比其癌细胞生长分裂较慢, 扩散转移相 对较晚。 非小细胞肺癌约占肺癌总数的 80-85%。 数据显示, 目前我国肺癌发病率每年增长 26.9%, 自 2000年至 2005年间, 中国肺癌的发病人数估计增加 12万人。 其中, 男性肺癌 病人从 2000年的 26万人增加到 2005年的 33万人, 同期女性肺癌患者从 12万人增加到 17万人。此外,肺癌也成为全国多地区的"众癌之首"。北京市肺癌发病率自 2001年至 2010 年增长 56%。 十年间, 北京新发癌症患者中五分之一为肺癌患者; 浙江省肿瘤医院发布的 2011年浙江省 "癌谱" 中, 肺癌依然是排名第一的癌症; 广州地区与 30年前相比, 肺癌 发病率增长了 7倍。
随着分子医学进展和靶向药物的不断涌现, 晚期 NSCLC 的治疗已进入到个体化治疗 的时代。 目前临床应用的个体化靶向治疗主要针对 EGFR突变型和 ALK融合基因型(即由 ALK介导的阳性肺癌) 肺癌, 这两种基因变异型肺癌均具有明确的分子靶点、 靶点检测技 术及上市的靶向药物, 临床疗效得到明显提高。 肺癌中 ALK变异主要为 ALK基因发生重 排与其他基因融合。
据报道 ALK基因位点上的基因异常与多种癌症有关。 由于染色体重排导致的棘皮动物 微管关联蛋白样 4(EML4)-ALK融合在非小细胞肺癌 (NSCLC)患者群中已有报道。 ALK基因 的扩增、 拷贝数增加 (copy number gain)和位点突变在成神经细胞瘤患者群中已有报道。
针对 ALK 靶点的小分子抑制剂克唑替尼, 可特异性靶向抑制 ALK激酶, 也可抑制 c-MET和 ROS1等信号通路。 临床试验显示对于 ALK阳性的晚期 NSCLC患者, 克唑替尼 的疗效显著优于传统化疗, 二线单药治疗患者的中位 PFS为 7.7个月, 有效率达到 65.3%。 2011年 8月, 克唑替尼获得美国 FDA批准用于治疗 ALK融合阳性的局部晚期或转移性 NSCLC患者, 2013年, 该药获得 CFDA批准。尽管克唑替尼治疗 NSCLC患者有效率比较 高(>80%), 但克唑替尼治疗有效的患者通常在用药 6个月至 1年后就会发生耐药。 而且, 两项克唑替尼临床研究观察到的最常见的不良反应为视力障碍、 恶心、 腹泻、 呕吐、 水肿 和便秘, 不良反应发生率≥25%。
由于目前针对治疗 ALK融合阳性的 NSCLC药物 (即针对 ALK的药物) 存在一定程 度的缺陷, 而疗效好、 安全性高、 耐受性好且服用方便的药物非常少, 因此, 开发出更安 全、 高效的治疗 NSCLC 的新型药物具有巨大的社会价值和经济效益, 也是目前各大药企 的研究热点。 发明内容
本发明旨在至少在一定程度上解决上述技术问题之一或至少提供一种有用的商业选 择。 为此, 本发明的一个目的在于提出一种能够用于制备治疗癌症的药物的化合物。
在本发明的第一方面, 本发明提出了一种化合物。 根据本发明的实施例, 所述化合物 为式 I所示化合物或式 I所示化合物的对映异构体、非对映异构体、外消旋体、药学上可接
Figure imgf000004_0001
其中,
X为选自 CH、 N中的任意一种; 1^和 R2各自独立的为选自 C1-C12直链或支链的垸 基、 卤素、 CF3、 CN、 N02、 H2、 CH2COOH、 OCH3、 OC2H5、 OH、 HS02CH3、 CH2CO H2 和 COCH3的任意一种; R3为选自氢或其同位素、卤素、未取代或由 1~3个卤素取代的 C1-C12 直链或支链的垸基、 未取代或者由 1~3个卤素或苯基取代的 C1-C12直链或支链的垸氧基、 未取代或由 1~3个卤素取代的 C3-C12环垸基、 由 C1-C6垸氧基取代的 C1-C6直链或支链 的垸基、 由 C3-C6环垸基取代的 C1-C6直链或支链的垸基、 羟基、 氰基、 硝基、 C1-C6直 链或支链的羟垸基、 羧基、 巯基、 -NR5R6、 -NCOR5R6、 -S02R5、 -S02 R5R6 以及 -OCOR5 的任意一种; R4为选自氢或其同位素、 卤素、 未取代或由 1~3个卤素取代的 C1-C12直链 或支链的垸基、未取代或由 1~3个卤素取代的 C3-C12环垸基、由 C1-C6垸氧基取代的 C1-C6 直链或支链的垸基、 由 C3-C6环垸基取代的 C1-C6直链或支链的垸基、 未取代或者由 1~3 个卤素或苯基取代的 C1-C6直链或支链的羧基、羟基、 C1-C6直链或支链的羟垸基、羧基、 巯基、 -NR5R6、 -NCOR5R6、 -S02R5、 -S02 R5R6 -OCOR5、 取代或未取代的苯环、 以及取 代或未取代的含有 0~4个杂原子的 C2-C12的环状基团的任意一种; R5和 Re分别独立地选 自氢或其同位素、 卤素、 未取代或由 1~3个卤素取代的 C1-C6直链或支链的垸基、 以及未 取代或由 1~3个卤素取代的 C3-C6环垸基的任意一种; 所述卤素为氟、 氯、 溴或碘。
根据本发明的实施例,在所述取代或未取代的含有 0~4个杂原子的 C2-C12的环状基团 中, 所述杂原子独立地选自 0、 8和 ^^。 根据本发明的实施例, 所述环状基团为单环或稠 环。 根据本发明的实施例, 所述环状基团的环由 3-12个环原子构成, 并且所述 3~12个环 原子中的杂原子为选 § Ν、 0、及 S(0)n的任意一种, 其中 n为 0、 1或 2, 其余环原子为 C。 根据本发明的实施例, 所述环也可具有一个或多个双键。
根据本发明的实施例, 所述环状基团为选自下列之一:
Figure imgf000006_0001
8908Z.0/l7l0ZN3/X3d 进一步的,
在本发明的实施例中, X为选自 CH、 N中的任意一种。
在本发明的实施例中, Ri为选自氢、卤素、 CH3、 C2H5、 CF3、 0CH3、 OC2H5、 CH2C00H 和 C0CH3的任意一种。
在本发明的实施例中, R2为选自氢、卤素、 CH3、 C2H5、 CF3、 0CH3、 OC2H5、 CH2C00H 和 C0CH3的任意一种。
在本发明的实施例中, R3为选自氢、 卤素、 未取代或由 1~3个卤素取代的 C1-C6直链 或支链的垸基、 未取代或由 1~3个卤素取代的 C3-C12环垸基、 未取代或者由 1~3个卤素 或苯基取代的 C1-C6直链或支链的垸氧基、羟基、 -NR5R6、 -NCOR5R6、 -S02R5、 -S02 R5R6 和 -OCOR5的任意一种。
在本发明的实施例中, R4为选自氢、 羧基、 未取代或由 1~3个卤素取代的 C1-C6直链 或支链的垸基、 未取代或者由 1~3个卤素或苯基取代的 C1-C6直链或支链的垸氧基、 未取 代或由 1~3个卤素取代的 C3-C12环垸基、 未取代或者由 1~3个卤素或苯基取代的 C1-C6 直链或支链的羧基、 取代或未取代的含有 0~4个杂原子的 C2-C12的环状基团。
在本发明的实施例中, R5和 Re各自独立地为选自氢、 卤素、未取代或由 1~3个卤素取 代的 C1-C4直链或支链的垸基的任意一种。
在本发明的实施例中, 所述的卤素为氟、 氯或溴。
进一步的,
在本发明的实施例中, 为?^。
在本发明的实施例中, 为选自氢、 卤素、 CH3、 CF3、 OCH3的任意一种。
在本发明的实施例中, R2为选自氢、 卤素、 CH3、 CF3、 OCH3的任意一种。
在本发明的实施例中, R3为选自氢、 或未取代的 C1-C6直链或支链的垸基、 或未取代 的 C1-C6直链或支链的垸氧基、未取代的 C3-C12环垸基、 -S02R5、 -NCORsRe的任意一种。
在本发明的实施例中, R4为选自氢、 羧基、 未取代或由 1~3个卤素取代的 C1-C6直链 或支链的垸基、 未取代或者由 1~3个卤素或苯基取代的 C1-C6直链或支链的垸氧基、 未取 代或者由 1~3个卤素或苯基取代的 C1-C6直链或支链的羧基、 取代或未取代的含有 1~4个 杂原子的 C2-C12的环状基团的任意一种。
在本发明的实施例中, R5和 Re各自独立地为氢、 卤素、或者未取代或由 1~3个卤素取 代的 C1-C4直链或支链的垸基的任意一种。
在本发明的实施例中, 所述的卤素为氟或氯。
在本发明的实施例中, 所述化合物为式 I所示化合物、 或其对映异构体、 非对映异构 体、 外消旋体、 药学上可接受的盐、 结晶水合物或溶剂合物。 本发明的发明人通过实验研 究, 惊奇地发现, 上述化合物可以用于治疗癌症相关疾病, 尤其可用于治疗肺癌、 非小细 胞肺癌, 特别适用于治疗 ALK融合阳性的非小细胞肺癌。
由此, 根据本发明的实施例, 优选地, 本发明所述的化合物 (通式 I所示化合物, 也称
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000013_0002
75 其中, PG表示氨基保护基团。根据本发明的实施例,所述氨基保护基团为叔丁氧羰基。 在本发明的实施例中, 所述式 I所示化合物可为: 式 I所示化合物或其对映异构体、非 对映异构体、 外消旋体、 药学上可接受的盐、 结晶水合物或溶剂合物。
在本发明中所使用的术语, "药学上可接受的盐"为通式 I化合物与无机酸或有机酸反应 形成的常规的无毒盐。 例如, 所述常规的无毒盐可通过通式 I化合物与无机酸或有机酸反 应制得, 所述无机酸包括盐酸、 氢溴酸、 硫酸、 硝酸、 胺基磺酸和磷酸等, 以及所述有机 酸包括柠檬酸、 酒石酸、 乳酸、 丙酮酸、 乙酸、 苯磺酸、 对甲苯磺酸、 甲磺酸、 萘磺酸、 乙磺酸、 萘二磺酸、 马来酸、 苹果酸、 丙二酸、 富马酸、 琥珀酸、 丙酸、 草酸、 三氟乙酸、 硬酯酸、 扑酸、 羟基马来酸、 苯乙酸、 苯甲酸、 水杨酸、 谷氨酸、 抗坏血酸、 对胺基苯磺 酸、 2-乙酰氧基苯甲酸和羟乙磺酸等; 或者通式 I化合物与丙酸、 草酸、 丙二酸、 琥珀酸、 富马酸、 马来酸、 乳酸、 苹果酸、 酒石酸、 柠檬酸、 天冬氨酸或谷氨酸形成酯后再与无机 碱形成的钠盐、 钾盐、 钙盐、 铝盐或铵盐; 或者通式 I化合物与有机碱形成的甲胺盐、 乙 胺盐或乙醇胺盐; 或者通式 I化合物与赖氨酸、 精氨酸、 鸟氨酸形成酯后再与盐酸、 氢溴 酸、 氢氟酸、 硫酸、 硝酸、 磷酸形成的对应的无机酸盐或与甲酸、 乙酸、 苦味酸、 甲磺酸 和乙磺酸形成的对应的有机酸盐。
在本发明的第二方面, 本发明提出了一种制备式 I所示化合物的方法。 根据本发明的 实施例, 该方法包括以下步骤:
(1) 使式 la所示化合物与四氢铝锂进行接触, 以便获得式 2a所示化合物;
(2) 使所述式 2a所示化合物与式 3a所示化合物进行接触, 以便获得式 4a所示化合 物;
(3)使所述式 4a所示化合物用氨基保护剂进行氨基保护, 以便获得式 5a所示化合物;
(4) 使所述式 5a所示化合物进行溴代反应, 以便获得式 6a所示化合物;
(5)使所述式 7a所示化合物与式 8所示化合物进行接触, 以便获得式 9a所示化合物;
(6) 使所述式 6a所示化合物与式 9a所示化合物进行接触, 以便获得式 10a所示化合 物;
Figure imgf000014_0001
10a 其中, X、 以及 R5、 Re为如前面中所定义的, PG为氨基保护基团。 根据本发明 的一个具体示例, 所述氨基保护基团为叔丁氧羰基。 发明人发现, 利用本发明的该方法能够快速有效地制备式 I所示化合物, 且合成路线 短、 环境友好、 目标产物的收率和纯度较高, 原料易得、 操作及后处理简单、 适合工业化 生产
Figure imgf000015_0001
下面对在本发明的实施例中所采用的制备式 I所示化合物的一般方法进行描述:
1 ) 式 2a所示化合物的制备
使式 la所示化合物与四氢铝锂 (LiAH4) 进行接触, 使发生还原反应, 以便获得式 2a 所示化合物;
具体地, 在三口瓶中加入 LiAH4和四氢呋喃 (THF), 通氮气保护。 将式 la所示化合 物用适量 THF溶解, 在 -5°C~5°C下, 将式 la所示化合物的 THF溶液缓慢滴入三口瓶中, 然后加热回流 1~3小时。 经薄层色谱 (TLC) 点板测试反应完全, 然后加冰浴冷却, 用水 和氢氧化钠淬灭, 过滤去除固体, 然后分液, 取上层有机相, 加入无水硫酸钠干燥, 浓缩 除去溶剂, 即得式 2a所示化合物。
2) 式 4a所示化合物的制备
使所述式 2a所示化合物与式 3a所示化合物进行接触, 以便获得式 4a所示化合物; 具体地, 将 THF、 式 2a所示化合物、 式 3a所示化合物混合, 搅拌均匀, 得混合液。 将 THF、 三苯基膦 (PPh3)、 偶氮二甲酸二乙酯 (DEAD) 混合, 搅拌均匀, 得备用液。 通 氮气保护, 在 -5 °C~5 °C下, 向混合液中缓慢滴加备用液, 保温搅拌 3~6小时。 反应毕, 浓 缩除去溶剂, 得油状物, 即得式 4a所示化合物的粗产品, 粗产品用石油醚 /乙酸乙酯的混 合溶剂柱层析纯化后, 浓缩有机相, 得到式 4a所示化合物纯品。
3 ) 式 5a所示化合物的制备
利用氨基保护剂, 使所述式 4a所示化合物进行氨基保护, 以便获得式 5a所示化合物; 具体地, 可以在 25~75摄氏度下, 在二氯甲垸及 4-二甲氨基吡啶 (DMAP) 存在下, 使式 4a所示化合物与氨基保护剂反应 2~16小时, 反应毕, 进行后处理, 得式 5a所示化合 物。 所述氨基保护剂为选自二碳酸二叔丁酯 (BOC 酸酐)、 氯甲酸苄酯、 溴苄和对甲苯磺 酰氯中的至少一种, 优选所述氨基保护试剂为选自 BOC酸酐和氯甲酸苄酯中的至少一种, 最优选所述氨基保护试剂为 BOC酸酐。
4) 式 6a所示化合物的制备
使所述式 5a所示化合物进行溴代反应, 以便获得式 6a所示化合物;
具体地, 利用冰浴, 将式 5a所示化合物与乙腈混合, 搅拌均匀, 在 0°C~10°C缓慢添 加 N-溴代丁二酰亚胺 ( BS), 并保持温度在 0°C~10°C搅拌 10~90分钟, 反应毕, 减压浓 缩除去溶剂, 得油状物, 即得式 6a所示化合物。
5 ) 式 9a所示化合物的制备
使所述式 7a所示化合物与式 8所示化合物进行接触, 以便获得式 9a所示化合物; 具体地, 将式 7a所示化合物溶于二甲基亚砜 (DMSO) 中, 加入醋酸钾与式 8所示化 合物, 通氮气保护, 然后加入 [Ι, Γ-双 (二苯基磷;)二茂铁]二氯化钯 (Pd(dppf)Cl2) 的二氯甲 垸 (CH2C12) 溶液, 在 50°C~100°C下搅拌 6~15小时, 反应毕, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 经过柱层析纯化后, 干燥即得式 9a所示 化合物。
6) 式 10a所示化合物的制备
使所述式 6a所示化合物与式 9a所示化合物进行接触, 以便获得式 10a所示化合物; 具体地, 在三口瓶中加入乙腈、 式 6a所示化合物、 式 9a所示化合物, 搅拌均匀, 加 入碳酸钠 (Na2C03 ) 溶液, 搅拌均匀后, 再加入双三苯基磷二氯化钯 (Pc PPh3)2Cl2), 升 温至 50°C~100°C, 搅拌反应 10~24小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分 液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 10a所示化合物。
7) 式 I所示化合物的制备
使所述式 10a所示化合物脱氨基保护, 以便获得式 I所示化合物;
具体地, 在三口瓶中加入乙酸乙酯和式 10a所示化合物, 搅拌, 滴加入饱和的氯化氢- 乙酸乙酯液, 在 15~55摄氏度下, 搅拌反应 1~6小时, 反应毕, 加入乙酸乙酯, 过滤去除 固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 I所示化合物的 粗品, 粗品用甲醇 /丙酮混合溶剂搅拌重结晶, 过滤, 得白色固体或类白色固体, 减压干燥, 即得式 I所示化合物。
在本发明的实施例中, 所述式 I所示化合物可为: 式 I所示化合物或其对映异构体、非 对映异构体、 外消旋体、 药学上可接受的盐、 结晶水合物或溶剂合物。
根据本发明的实施例, 优选式 I所示化合物为式 11所示化合物,
式 11所示化合物的合成路线为:
Figure imgf000018_0001
10a- 1 11 根据本发明的实施例, 优选式 I所示化合物为式 16所示化合物, 式 16所示化合物的合成路线为:
Figure imgf000019_0001
10a-2 16 根据本发明的实施例, 优选式 I所示化合物为式 46所示化合物, 式 46所示化合物的合成路线为:
Figure imgf000020_0001
10a-3 46 根据本发明的实施例, 优选式 I所示化合物为式 52所示化合物, 式 52所示化合物的合成路线为:
Figure imgf000021_0001
10a-4 52 根据本发明的实施例, 优选式 I所示化合物为式 74所示化合物, 式 74所示化合物的合成路线为:
Figure imgf000022_0001
Figure imgf000022_0002
10a-5 74
在本发明的第三方面, 本发明提出了一种药物组合物, 其包含本发明的式 I所示化合 物, 或式 I所示化合物的对映异构体、 或非对映异构体、 或外消旋体、 或药学上可接受的 盐、 或结晶水合物、 或溶剂合物。 根据本发明的实施例, 所述药物组合物可以进一步包括 药学上可接受的赋形剂。 该药用组合物还可以进一步包含气味剂、 香味剂等常规添加剂。
该药物制剂可用作肿瘤 (或癌症) 治疗的药物, 用于抗肿瘤治疗药物的生产。
本发明所提供的药物组合物优选含有重量比为 0.1%~99%的式 I所示化合物作为活性成 份, 优选的是, 式 I所示化合物作为活性成分占药物组合物总重量的 5%〜90%, 其余部分 为药学可接受的载体和 /或常规添加剂。
本发明所提供的化合物和药物组合物可以是多种形式, 如片剂、 硬胶囊、 软胶囊、 注 射剂、 注射用粉针、 粉剂、 糖浆、 溶液状、 悬浮液和气雾剂等, 并可以存在于适宜的固体 或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。 本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。 其制剂配方的 单位计量中包含 0.05 mg~750 mg的前面所述的化合物, 优选地, 制剂配方的单位计量中包 含 1 mg~500 mg的前面所述的化合物。 本发明的化合物和药物组合物可对哺乳动物临床使 用, 包括人和动物, 可以通过口、 鼻、 皮肤、 肺或者胃肠道等的途径给药。 不管采用何种 服用方法, 个人的最佳剂量应依据具体的治疗方案而定。 通常情况下是从小剂量开始, 逐 渐增加剂量一直到找到最适合的剂量。 最优选的给药途径为口服。
在本发明的第四方面, 本发明提供了一种药物组合物。 根据本发明的实施例, 本发明 所述的药物组合物, 包括前面所述的化合物, 以及第二治疗剂。 利用该药物组合物, 具有 较强的抗肿瘤活性, 通过前面所述的化合物和所述第二治疗剂之间的协同作用, 对治疗癌 症具有很好的效果。
根据本发明的实施例, 所述第二治疗剂为选自细胞毒性药物、 抗肿瘤生物工程药物、 缺氧选择性药物、 抗炎药物、 以及血管活性药物中的一种或多种药物。
根据本发明的实施例, 所述的细胞毒性药物为氮甲、 苯丙氨酸氮芥、 苯丁酸氮芥、 环 磷酰胺、 异环磷酰胺、 氯磷酰胺、 白消安、 司莫司汀、 雷莫司汀、 达卡巴嗪、 顺铂、 卡铂、 得那铂、 洛铂、 奈达铂、 奥沙利铂、 甲氨喋吟、 阿糖胞苷、 5-氟尿嘧啶、 去氧氟尿苷、 卡 培他滨、 吉西他滨、 放线菌素 D、 丝裂霉素 C、 柔红霉素、 多柔比星、 米托蒽醌、 长春新 碱、 长春瑞宾, 紫杉醇、 多西紫杉醇、 喜树碱、 羟基喜树碱或伊立替康中的一种或多种。
根据本发明的实施例, 所述的抗肿瘤生物工程药物为抗 CEA抗体、重组改构肿瘤坏死 因子、 抗肿瘤单克隆抗体导向药物中的一种或多种。
根据本发明的实施例, 所述的缺氧选择性药物为替拉扎明、 二硝基苯芥、 2-硝基咪唑 垸化剂 CI-1010、 羟基喜树碱、 托泊替康、 沙尔威辛或依托泊苷中的一种或多种。
根据本发明的实施例, 所述的抗炎药物为双氯芬酸钠、 布洛芬、 萘普生或酮洛芬中的 一种或多种。
根据本发明的实施例, 所述的血管活性药物为 5-羟色胺、 东莨菪碱、 多巴胺、 多巴酚 丁胺、 麻黄素、 间羟胺、 甲氧胺、 肾上腺素、 异丙肾上腺素、 去氧肾上腺素、 去甲肾上腺 素、 氨利酮、 左旋硝基精氨酸中的一种或多种。
以上各种药物的有效剂量在中国药典和国内外公开的临床资料中均可以查到, 因此不 列举。
前面所述的化合物与上述选自细胞毒性药物、抗肿瘤生物工程药物、缺氧选择性药物、 抗炎药物、 以及血管活性药物中的一种或多种药物以增效比率施用, 增强了抗肿瘤活性, 起到协同治疗癌症的作用。
本文中, "增效比率"用语表示式 I所示化合物或其对映异构体、 非对映异构体、 外消 旋体、 药学上可接受的盐、 结晶水合物或溶剂合物, 与细胞毒性药物、 抗肿瘤生物工程药 物、 缺氧选择性药物、 抗炎药物、 以及血管活性药物中的一种或多种以这样的比率施用; 组合的抗肿瘤活性大于单独的式 I所示化合物或其对映异构体、 非对映异构体、 外消旋体、 药学上可接受的盐、 结晶水合物或溶剂合物, 或单独的细胞毒性药物、 抗肿瘤生物工程药 物、 缺氧选择性药物、 抗炎药物、 以及血管活性药物的抗肿瘤活性, 或者大于根据各组分 的活性而预期的组合的加合活性。 因此, 各组分以增效比率施用, 则它们的组合物发生协 同治疗作用, 达到很好的疗效。
本发明的化合物及药物组合物也可以制成复方制剂, 适用于口服给药。 这些口服制剂 包括片剂、 胶囊、 颗粒剂、 分散片, 但不仅限于上述剂型。 本发明还可以制成注射液, 适 用于注射给药。 这些注射液包括静脉注射液、 肌肉注射液, 但不仅限于上述剂型。
在本发明的第五方面, 本发明提出了前面所述的化合物在制备药物中的用途, 所述药 物用于治疗癌症相关疾病, 该癌症是由间变性淋巴瘤激酶 (ALK)介导的癌症。 根据本发明 的实施例, 所述癌症选自肺癌、 骨癌、 胰腺癌、 头和颈部癌、 表皮或眼内黑色素瘤、 子宫 癌、 卵巢癌、 直肠癌、 肛区癌、 胃癌、 结肠癌、 乳腺癌、 输卵管癌、 子宫内膜癌、 宫颈癌、 阴道癌、 外阴癌、 何杰金氏病、 食道癌、 小肠癌、 甲状腺癌、 甲状旁腺癌、 肾上腺癌、 软 组织肉瘤、 尿道癌、 阴茎癌、 前列腺癌、 慢性或急性白血病、 淋巴细胞性淋巴瘤、 膀胱癌、 肾细胞癌、 肾盂癌、 原发性中枢神经系统淋巴瘤、 脊柱肿瘤、 脑干胶质瘤、 垂体腺瘤及其 组合。 进一步的, 所述癌症选自: 非小细胞肺癌、 鳞状细胞癌、 激素难治性前列腺癌、 乳 头状肾细胞癌、 结肠直肠腺癌、 神经母细胞瘤、 间变性大细胞淋巴瘤及胃癌。
特别的,本发明前面所述的化合物可以用于治疗由于染色体重排导致的携有 ALK融合 基因的癌症患者, 例如携有 EML4-ALK的 NSCLC患者, 其携有扩增的、 拷贝数增加的和 点突变的 ALK基因, 例如成神经细胞瘤患者或其它特征在于 ALK基因中有基因异常或较 正常组织有较高的 ALK表达的肿瘤患者。
本发明前面所述的化合物对人肺癌 A549细胞裸鼠移植瘤生长影响的试验结果表明:与 模型对照组相比, 化合物治疗组对人肺癌 A549 细胞裸鼠移植瘤生长的抑制作用均具有显 著性差异, 尤其是与模型对照组相比, 本发明所述的化合物在对人肺癌 A549 细胞裸鼠移 植瘤生长的抑制作用方面具有极显著性差异(P<0.01 ) , 与化疗奥沙利铂组、 ALK抑制剂 克唑替尼组相比, 平均抑瘤率有所提高, 这说明本发明的化合物在治疗非小细胞肺癌方面 具有极其显著的疗效, 在获得显著药效的同时具有毒副作用低的优势, 获得了预料不到的 技术效果。
本发明的化合物在克唑替尼耐药性肿瘤中的抗肿瘤活性实验中, 本发明的化合物在克 唑替尼耐药性 NCI-H2228中显示了显著的抗肿瘤生长活性, 本发明的化合物显示了较克唑 替尼 50mg/kg具有更好的活性, 又获得了预料不到的技术效果。 因此, 本发明对于对克唑 替尼有耐药性的非小细胞肺癌患者, 有很好的治疗效果。
本发明所述的化合物, 具有很好的抗癌应用前景, 可用于治疗癌症相关疾病, 可用作 治疗癌症的药物, 可用于癌症治疗药物的生产, 因而具有良好的商业价值。 发明人发现本 发明的化合物相比于已上市的克唑替尼,其对克唑替尼产生有耐药性的哺乳动物(包括人), 有更活跃的抗癌特性, 可作为良好的新一代抗癌药物。
本发明的化合物, 尤其适用于为用于治疗 ALK融合阳性的非小细胞肺癌, 并任选对克 唑替尼有耐药性的 ALK融合阳性的非小细胞肺癌。
在本发明的第六方面, 本发明提供了一种药物联合。 根据本发明的实施例, 所述药物 联合包括前面所述的化合物, 以及第二治疗剂。 根据本发明的实施例, 所述第二治疗剂为 选自细胞毒性药物、 抗肿瘤生物工程药物、 缺氧选择性药物、 抗炎药物、 以及血管活性药 物中的一种或多种药物。
根据本发明的实施例, 所述细胞毒性药物为氮甲、 苯丙氨酸氮芥、 苯丁酸氮芥、 环磷 酰胺、 异环磷酰胺、 氯磷酰胺、 白消安、 司莫司汀、 雷莫司汀、 达卡巴嗪、 顺铂、 卡铂、 得那铂、 洛铂、 奈达铂、 奥沙利铂、 甲氨喋吟、 阿糖胞苷、 5-氟尿嘧啶、 去氧氟尿苷、 卡 培他滨、 吉西他滨、 放线菌素 D、 丝裂霉素 C、 柔红霉素、 多柔比星、 米托蒽醌、 长春新 碱、 长春瑞宾, 紫杉醇、 多西紫杉醇、 喜树碱、 羟基喜树碱或伊立替康中的一种或多种。
根据本发明的实施例, 所述抗肿瘤生物工程药物为抗 CEA抗体、重组改构肿瘤坏死因 子、 抗肿瘤单克隆抗体导向药物中的一种或多种。
根据本发明的实施例, 所述缺氧选择性药物为替拉扎明、 二硝基苯芥、 2-硝基咪唑垸 化剂 CI-1010、 羟基喜树碱、 托泊替康、 沙尔威辛或依托泊苷中的一种或多种。
根据本发明的实施例, 所述抗炎药物为双氯芬酸钠、 布洛芬、 萘普生或酮洛芬中的一 种或多种。
根据本发明的实施例, 所述血管活性药物为 5-羟色胺、 东莨菪碱、 多巴胺、 多巴酚丁 胺、 麻黄素、 间羟胺、 甲氧胺、 肾上腺素、 异丙肾上腺素、 去氧肾上腺素、 去甲肾上腺素、 氨利酮、 左旋硝基精氨酸中的一种或多种。
在本发明的第七方面, 本发明提供了一种药盒。 根据本发明的实施例, 所述药盒包括: 第一治疗剂, 所述第一治疗剂为前面所述的化合物; 以及第二治疗剂, 所述第二治疗剂为 选自细胞毒性药物、 抗肿瘤生物工程药物、 缺氧选择性药物、 抗炎药物、 以及血管活性药 物中的一种或多种药物, 其中, 所述第一治疗机与所述第二治疗剂设置在不同的容器中。
根据本发明的实施例, 所述细胞毒性药物为氮甲、 苯丙氨酸氮芥、 苯丁酸氮芥、 环磷 酰胺、 异环磷酰胺、 氯磷酰胺、 白消安、 司莫司汀、 雷莫司汀、 达卡巴嗪、 顺铂、 卡铂、 得那铂、 洛铂、 奈达铂、 奥沙利铂、 甲氨喋吟、 阿糖胞苷、 5-氟尿嘧啶、 去氧氟尿苷、 卡 培他滨、 吉西他滨、 放线菌素 D、 丝裂霉素 C、 柔红霉素、 多柔比星、 米托蒽醌、 长春新 碱、 长春瑞宾, 紫杉醇、 多西紫杉醇、 喜树碱、 羟基喜树碱或伊立替康中的一种或多种。
根据本发明的实施例, 所述抗肿瘤生物工程药物为抗 CEA抗体、重组改构肿瘤坏死因 子、 抗肿瘤单克隆抗体导向药物中的一种或多种。
根据本发明的实施例, 所述缺氧选择性药物为替拉扎明、 二硝基苯芥、 2-硝基咪唑垸 化剂 CI-1010、 羟基喜树碱、 托泊替康、 沙尔威辛或依托泊苷中的一种或多种。
根据本发明的实施例, 所述抗炎药物为双氯芬酸钠、 布洛芬、 萘普生或酮洛芬中的一 种或多种。
根据本发明的实施例, 所述血管活性药物为 5-羟色胺、 东莨菪碱、 多巴胺、 多巴酚丁 胺、 麻黄素、 间羟胺、 甲氧胺、 肾上腺素、 异丙肾上腺素、 去氧肾上腺素、 去甲肾上腺素、 氨利酮、 左旋硝基精氨酸中的一种或多种。
在本发明的第八方面, 本发明提供了一种治疗癌症的方法。 根据本发明的实施例, 该 方法包括: 对患者给药前面所述的化合物或前面所述的药物组合物。
根据本发明的实施例, 所述癌症为由间变性淋巴瘤激酶介导的癌症。
根据本发明的实施例, 所述癌症为选自下列的至少之一: 肺癌、 骨癌、 胰腺癌、 头和 颈部癌、 表皮或眼内黑色素瘤、 子宫癌、 卵巢癌、 直肠癌、 肛区癌、 胃癌、 结肠癌、 乳腺 癌、 输卵管癌、 子宫内膜癌、 宫颈癌、 阴道癌、 外阴癌、 何杰金氏病、 食道癌、 小肠癌、 甲状腺癌、 甲状旁腺癌、 肾上腺癌、 软组织肉瘤、 尿道癌、 阴茎癌、 前列腺癌、 慢性或急 性白血病、 淋巴细胞性淋巴瘤、 膀胱癌、 肾细胞癌、 肾盂癌、 原发性中枢神经系统淋巴瘤、 脊柱肿瘤、 脑干胶质瘤以及垂体腺瘤。
根据本发明的实施例, 所述癌症为选自下列的至少之一: 非小细胞肺癌、 鳞状细胞癌、 激素难治性前列腺癌、 乳头状肾细胞癌、 结肠直肠腺癌、 神经母细胞瘤、 间变性大细胞淋 巴瘤及胃癌。
根据本发明的实施例, 所述癌症为由间变性淋巴瘤激酶介导的非小细胞肺癌疾病。 根据本发明的实施例,所述癌症为对克唑替尼有耐药性的 ALK融合阳性的非小细胞肺 癌。
本发明的附加方面和优点将在下面的描述中部分给出, 部分将从下面的描述中变得明 显, 或通过本发明的实践了解到。 附图说明
图 1 显示了根据本发明的实施例, 式 I所示化合物在具有克唑替尼耐药性的 NCI-H2228 肿瘤中的抗肿瘤生长活性。 具体实施方式
在以下的实施例中将进一步举例说明本发明。 这些实施例仅用于说明本发明, 但不以 任何方式限制本发明。
本发明的实施例提供了式 I所示化合物或式 I所示化合物的对映异构体、非对映异构体、 外消旋体、药学上可接受的盐、结晶水合物或溶剂合物、式 I所示化合物或式 I所示化合物 的对映异构体、 非对映异构体、 外消旋体、 药学上可接受的盐、 结晶水合物或溶剂合物的 制备方法、药物组合物、 以及式 I所示化合物或式 I所示化合物的对映异构体、非对映异构 体、 外消旋体、 药学上可接受的盐、 结晶水合物或溶剂合物在制备药物中的用途, 本发明 说明书中所用原料及试剂如无特殊说明, 均为商业购买。
实施例 1 : 式 2a-l所示化合物的制备
在三口瓶中加入 LiAH4 ( 3.8克, 0.1摩尔) 禾 P 50毫升 THF, 通氮气保护。 将式 la-1 所示化合物 (20.7克, 0.1摩尔) 用 200毫升 THF溶解, 备用。 在 0°C下, 将式 la-1所示 化合物的 THF溶液缓慢滴入三口瓶中, 然后加热回流 2小时。 经薄层色谱 (TLC) 点板测 试反应完全, 然后加冰浴冷却, 加入水 20毫升、 再缓慢滴加 10%氢氧化钠溶液 50毫升, 滴毕, 搅拌 10分钟, 过滤去除固体, 然后分液, 取上层有机相, 加入无水硫酸钠干燥, 浓 缩除去溶剂, 即得式 2a-l所示化合物 (19.3克, 收率 92.3%), 为淡黄色油状液。
分析数据为:
1H MR (400 MHz, CDC13) δ 7.26 (dd, 1H), 7.02 (dd, 1H), 5.57 (q, 1H), 2.86 (s, 1H), 1.64
(d, 3H)。
实施例 2: 式 2a-l所示化合物的制备
在三口瓶中加入 LiAH4 (4.0克, 0.1054摩尔)和 50毫升 THF, 通氮气保护。将式 la-1 所示化合物 (20.7克, 0.1摩尔) 用 200毫升 THF溶解, 备用。 在 -5 °C下, 将式 la-1所示 化合物的 THF溶液缓慢滴入三口瓶中, 然后加热回流 3小时。 反应毕, 后处理方式同实施 例 1, 得式 2a-l所示化合物 (19.1克, 收率 91.4%), 为淡黄色油状液。
实施例 3 : 式 2a-l所示化合物的制备
在三口瓶中加入 LiAH4 ( 5克, 0.13摩尔)和 50毫升 THF, 通氮气保护。 将式 la-1所 示化合物 (20.7克, 0.1摩尔) 用 200毫升 THF溶解, 备用。 在 5 °C下, 将式 la-1所示化 合物的 THF溶液缓慢滴入三口瓶中, 然后加热回流 1小时。 反应毕, 后处理方式同实施例 1, 得式 2a-l所示化合物 (19.2克, 收率 91.8%), 为淡黄色油状液。
实施例 4: 式 2a-2所示化合物的制备 在三口瓶中加入 LiAH4 ( 5克, 0.13摩尔)和 50毫升 THF, 通氮气保护。 将式 la-2所 示化合物 (22.1克, 0.1摩尔) 用 200毫升 THF溶解, 备用。 在 5°C下, 将式 la-2所示化 合物的 THF溶液缓慢滴入三口瓶中, 然后加热回流 1小时。 反应毕, 后处理方式同实施例 1, 得式 2a-2所示化合物 (20.4克, 收率 91.5%), 为淡黄色油状液。
分析数据为:
1H MR (400 MHz, CDC13) δ 7.26 (dd, 1H), 7.02 (dd, 1H), 5.56 (t,lH), 2.80 (s, 1H), 1.7(m, 2H) , 0.92 (t, 3H)。
实施例 5: 式 2a-2所示化合物的制备
在三口瓶中加入 LiAH4 ( 5克, 0.13摩尔)和 50毫升 THF, 通氮气保护。 将式 la-2所 示化合物 (22.1克, 0.1摩尔) 用 200毫升 THF溶解, 备用。 在 5°C下, 将式 la-2所示化 合物的 THF溶液缓慢滴入三口瓶中, 然后加热回流 1小时。 反应毕, 后处理方式同实施例 1, 得式 2a-2所示化合物 (19.8克, 收率 88.8%), 为淡黄色油状液。
实施例 6: 式 2a-2所示化合物的制备
在三口瓶中加入 LiAH4 ( 5克, 0.13摩尔)和 50毫升 THF, 通氮气保护。 将式 la-2所 示化合物 (22.1克, 0.1摩尔) 用 200毫升 THF溶解, 备用。 在 5°C下, 将式 la-2所示化 合物的 THF溶液缓慢滴入三口瓶中, 然后加热回流 1小时。 反应毕, 后处理方式同实施例 1, 得式 2a-2所示化合物 (20.1克, 收率 90.1%), 为淡黄色油状液。
实施例 7: 式 4a-l所示化合物的制备
将 THF (200毫升)、式 2a- 1所示化合物(21.9克, 0.105摩尔)、式 3a所示化合物(15.1 克, 0.1摩尔) 混合, 搅拌均匀, 得混合液。 将 THF (200毫升)、 三苯基膦 (40克, 0.153 摩尔)、 偶氮二甲酸二乙酯 (35克, 0.2摩尔) 混合, 搅拌均匀, 得备用液。 通氮气保护, 在 0°C下, 向混合液中缓慢滴加备用液, 保温搅拌 5 小时。 反应毕, 浓缩除去溶剂, 得油 状物, 为式 4a-l所示化合物的粗产品, 粗产品用石油醚 /乙酸乙酯的混合溶剂 (V: V=l : 5) 进行柱层析纯化后,浓缩有机相除去溶剂,得到式 4a-l所示化合物(24.8克,收率 72.5%), 为类白色固体。
分析数据为:
1H MR (400 MHz, CDCI3) δ 8.32(dd,lH), 7.81(dd,lH), 7.26 (dd, 1H), 7.23(dd, 1H), 7.02 (dd, 1H), 5.57 (q, 1H), 1.68 (d, 3H).
实施例 8: 式 4a-l所示化合物的制备
将 THF (200毫升)、式 2a-l所示化合物(25.1克, 0.12摩尔)、式 3a所示化合物( 15.1 克, 0.1摩尔) 混合, 搅拌均匀, 得混合液。 将甲苯 (200毫升)、 三苯基膦 (40克, 0.153 摩尔)、 偶氮二甲酸二乙酯 (35克, 0.2摩尔) 混合, 搅拌均匀, 得备用液。 通氮气保护, 在 -5°C下, 向混合液中缓慢滴加备用液, 保温搅拌 6小时。 反应毕, 浓缩除去溶剂, 得油 状物, 为式 4a-l所示化合物的粗产品, 粗产品用石油醚 /乙酸乙酯的混合溶剂 (V: V=2: 1) 进行柱层析纯化后,浓缩有机相除去溶剂,得到式 4a-l所示化合物(25.6克,收率 74.8%), 为类白色固体。
实施例 9: 式 4a-l所示化合物的制备
将 THF (200毫升)、 式 2a-l所示化合物 (21克, 0.1摩尔) 、 式 3a所示化合物 (16 克, 0.106摩尔)混合, 搅拌均匀, 得混合液。将甲苯(200毫升)、三苯基膦(40克, 0.153 摩尔) 、 偶氮二甲酸二乙酯 (35克, 0.2摩尔) 混合, 搅拌均匀, 得备用液。 通氮气保护, 在 5°C下, 向混合液中缓慢滴加备用液, 保温搅拌 3 小时。 反应毕, 浓缩除去溶剂, 得油 状物, 为式 4a-l所示化合物的粗产品, 粗产品用石油醚 /乙酸乙酯的混合溶剂 (V: V=2: 1) 进行柱层析纯化后,浓缩有机相除去溶剂,得到式 4a-l所示化合物(24.2克,收率 70.7%), 为类白色固体。
实施例 10: 式 4a-2所示化合物的制备
将 THF (200毫升)、 式 2a-2所示化合物(22.3克, 0.1摩尔)、 式 3a所示化合物(15.1 克, 0.1摩尔) 混合, 搅拌均匀, 得混合液。 将 THF (200毫升)、 三苯基膦 (40克, 0.153 摩尔)、 偶氮二甲酸二乙酯 (52.5克, 0.3摩尔) 混合, 搅拌均匀, 得备用液。 通氮气保护, 在 0°C下, 向混合液中缓慢滴加备用液, 保温搅拌 5 小时。 反应毕, 浓缩除去溶剂, 得油 状物, 为式 4a-2所示化合物的粗产品, 粗产品用石油醚 /乙酸乙酯的混合溶剂 (V: V=l : 5) 进行柱层析纯化后,浓缩有机相除去溶剂,得到式 4a-2所示化合物(26.8克, 收率 75.2%), 为类白色固体。
分析数据为:
1H MR (400 MHz, CDC13) δ 8.30(dd,lH), 7.80(dd,lH), 7.25 (dd, 1H), 7.30(dd, 1H), 7.01 (dd, 1H), 5.55 (q, 1H), 1.8(m, 2H) , 0.95 (t, 3H)。
实施例 11 : 式 4a-2所示化合物的制备
将 THF (200毫升)、式 2a-2所示化合物(23.4克, 0.105摩尔)、式 3a所示化合物( 15.1 克, 0.1摩尔) 混合, 搅拌均匀, 得混合液。 将甲苯 (200毫升)、 三苯基膦 (40克, 0.153 摩尔)、 偶氮二甲酸二乙酯 (35克, 0.2摩尔) 混合, 搅拌均匀, 得备用液。 通氮气保护, 在 -5°C下, 向混合液中缓慢滴加备用液, 保温搅拌 6小时。 反应毕, 浓缩除去溶剂, 得油 状物, 为式 4a-2所示化合物的粗产品, 粗产品用石油醚 /乙酸乙酯的混合溶剂 (V: V=2: 1) 进行柱层析纯化后,浓缩有机相除去溶剂,得到式 4a-2所示化合物(26.0克,收率 73.0%), 为类白色固体。
实施例 12: 式 4a-2所示化合物的制备 将 THF (200毫升)、式 2a-2所示化合物(26.8克, 0.12摩尔)、式 3a所示化合物(15.1 克, 0.1摩尔) 混合, 搅拌均匀, 得混合液。 将 THF (200毫升)、 三苯基膦 (40克, 0.153 摩尔)、 偶氮二甲酸二乙酯 (35克, 0.2摩尔) 混合, 搅拌均匀, 得备用液。 通氮气保护, 在 5°C下, 向混合液中缓慢滴加备用液, 保温搅拌 3 小时。 反应毕, 浓缩除去溶剂, 得油 状物, 为式 4a-2所示化合物的粗产品, 粗产品用石油醚 /乙酸乙酯的混合溶剂 (V: V=2: 1) 进行柱层析纯化后,浓缩有机相除去溶剂,得到式 4a-2所示化合物(24.4克,收率 68.5%), 为类白色固体。
实施例 13 : 式 5a-l所示化合物的制备
将式 4a-l所示化合物 (34.2克, 0.1摩尔) 溶于二氯甲垸 500毫升, 机械搅拌, 加入 DMAP (0.5克, 0.004摩尔), 二碳酸二叔丁酯 (26.2克, 0.12摩尔)。 在 25摄氏度下搅拌 反应 16小时。 反应毕, 二氯甲垸萃取, 用饱和碳酸氢钠水溶液和饱和食盐水洗涤, 得到式 5a-l所示化合物 (40.5克, 收率 91.5% )。
分析数据为:
1H MR (400 MHz, CDC13) δ 8.30(dd,lH), 7.80(dd,lH), 7.25 (dd, 1H), 7.22(dd, 1H), 7.01 (dd, 1H), 5.56 (q, 1H), 1.67 (d, 3H).1.45(s, 9H)
实施例 14: 式 5a-l所示化合物的制备
将式 4a-l所示化合物 (34.2克, 0.1摩尔) 溶于二氯甲垸 500毫升, 机械搅拌, 加入 DMAP (0.6克, 0.005摩尔), 二碳酸二叔丁酯 (32.8克, 0.15摩尔)。 在 75摄氏度下搅拌 反应 2小时。 反应毕, 二氯甲垸萃取, 用饱和碳酸氢钠水溶液和饱和食盐水洗涤, 得到式 5a-l所示化合物 (39.8克, 收率 90.0% )。
实施例 15: 式 5a-l所示化合物的制备
将式 4a-l所示化合物 (34.2克, 0.1摩尔) 溶于二氯甲垸 500毫升, 机械搅拌, 加入 DMAP (0.25克, 0.002摩尔), 二碳酸二叔丁酯 (22.9克, 0.105摩尔)。 在 45摄氏度下搅 拌反应 8小时。 反应毕, 二氯甲垸萃取, 用饱和碳酸氢钠水溶液和饱和食盐水洗涤, 得到 式 5a-l所示化合物 (39.1克, 收率 88.4% )。
实施例 16: 式 5a-2所示化合物的制备
将式 4a-2所示化合物 (35.6克, 0.1摩尔) 溶于二氯甲垸 500毫升, 机械搅拌, 加入 DMAP (0.25克, 0.002摩尔), 二碳酸二叔丁酯 (22.9克, 0.105摩尔)。 在 35摄氏度下搅 拌反应 10小时。 反应毕, 二氯甲垸萃取, 用饱和碳酸氢钠水溶液和饱和食盐水洗涤, 得到 式 5a-2所示化合物 (40.6克, 收率 89.0% )。
分析数据为: Ή MR (400 MHz, CDC13) δ 8.34(dd, lH), 7.83(dd,lH), 7.23 (dd, IH), 7.35(dd, IH), 7.09 (dd, IH), 5.53 (q, IH), 1.6(m, 2H) , 1.44(s,9H) 0.96 (t, 3H)。
实施例 17: 式 5a-2所示化合物的制备
将式 4a-2所示化合物 (35.6克, 0.1摩尔) 溶于二氯甲垸 500毫升, 机械搅拌, 加入 DMAP ( 0.6克, 0.005摩尔), 二碳酸二叔丁酯 (32.8克, 0.15摩尔)。 在 55摄氏度下搅拌 反应 5小时。 反应毕, 二氯甲垸萃取, 用饱和碳酸氢钠水溶液和饱和食盐水洗涤, 得到式 5a-2所示化合物 (42.5克, 收率 93.2% )。
实施例 18: 式 5a-2所示化合物的制备
将式 4a-2所示化合物 (35.6克, 0.1摩尔) 溶于二氯甲垸 500毫升, 机械搅拌, 加入 DMAP ( 0.5克, 0.004摩尔), 二碳酸二叔丁酯 (26.2克, 0.12摩尔)。 在 65摄氏度下搅拌 反应 3小时。 反应毕, 二氯甲垸萃取, 用饱和碳酸氢钠水溶液和饱和食盐水洗涤, 得到式 5a-2所示化合物 (41.3克, 收率 90.6% )。
实施例 19: 式 6a-l所示化合物的制备
利用冰浴, 将式 5a-l所示化合物 (44.2克, 0.1摩尔) 与乙腈 500毫升混合, 搅拌均 匀, 在 0°C~10°C缓慢添加 N-溴代丁二酰亚胺(35.6克, 0.2摩尔), 并保持温度在 0°C~10°C 搅拌 10分钟, 反应毕, 减压浓缩除去溶剂, 得油状物, 即得式 6a-l所示化合物 (36.6克, 收率 70.2% )。
分析数据为:
1H MR (400 MHz, CDC13) δ 8.25(s,lH), 7.20 (s, IH), 7.22(dd, IH), 7.01 (dd, IH), 5.58 (q: IH), 1.65 (d, 3H).1.44(s, 9H).
实施例 20: 式 6a-l所示化合物的制备
利用冰浴, 将式 5a-l所示化合物 (44.2克, 0.1摩尔) 与乙腈 500毫升混合, 搅拌均 匀, 在 0°C~10°C缓慢添加 N-溴代丁二酰亚胺(17.8克, 0.1摩尔), 并保持温度在 0°C~10°C 搅拌 90分钟, 反应毕, 减压浓缩除去溶剂, 得油状物, 即得式 6a-l所示化合物 (27.5克, 收率 52.8% )。
实施例 21 : 式 6a-l所示化合物的制备
利用冰浴, 将式 5a-l所示化合物 (44.2克, 0.1摩尔) 与乙腈 500毫升混合, 搅拌均 匀,在 0°C~10°C缓慢添加 N-溴代丁二酰亚胺(21.4克, 0.12摩尔),并保持温度在 0°C~10°C 搅拌 30分钟, 反应毕, 减压浓缩除去溶剂, 得油状物, 即得式 6a-l所示化合物 (33.3克, 收率 63.9% )。
实施例 22: 式 6a-2所示化合物的制备
利用冰浴, 将式 5a-2所示化合物 (45.6克, 0.1摩尔) 与乙腈 500毫升混合, 搅拌均 匀, 在 0°C~10°C缓慢添加 N-溴代丁二酰亚胺(35.6克, 0.2摩尔), 并保持温度在 0°C~10°C 搅拌 60分钟, 反应毕, 减压浓缩除去溶剂, 得油状物, 即得式 6a-2所示化合物 (35.0克, 收率 65.4% )。
分析数据为:
1H MR (400 MHz, CDC13) δ 8.34(s,lH), 7.23 (dd, 1H), 7.35(s, 1H), 7.07 (dd, 1H), 5.54 (q,
1H), 1.59(m, 2H) , 1.46(s,9H) 0.97 (t, 3H)
实施例 23 : 式 6a-2所示化合物的制备
利用冰浴, 将式 5a-2所示化合物 (45.6克, 0.1摩尔) 与乙腈 500毫升混合, 搅拌均 匀, 在 0°C~10°C缓慢添加 N-溴代丁二酰亚胺(17.8克, 0.1摩尔), 并保持温度在 0°C~10°C 搅拌 15分钟, 反应毕, 减压浓缩除去溶剂, 得油状物, 即得式 6a-2所示化合物 (29.4克, 收率 55.0% )。
实施例 24: 式 6a-2所示化合物的制备
利用冰浴, 将式 5a-2所示化合物 (45.6克, 0.1摩尔) 与乙腈 500毫升混合, 搅拌均 匀,在 0°C~10°C缓慢添加 N-溴代丁二酰亚胺(21.4克, 0.12摩尔),并保持温度在 0°C~10°C 搅拌 45分钟, 反应毕, 减压浓缩除去溶剂, 得油状物, 即得式 6a-2所示化合物 (36.9克, 收率 68.9% )。
实施例 25 : 式 9a-l所示化合物的制备
将式 7a-l所示化合物 (23.0克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(25.4克, 0.1摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 50°C~60°C 下搅拌 15小时, 反应毕, 过滤去除固体, 然后分液, 取有机相, 浓缩除去溶剂得粗产品, 粗产品经石油醚 /乙酸乙酯的混合溶剂 (V: V=l : 2)进行柱层析纯化后, 浓缩有机相除去溶 剂, 即得式 9a-l所示化合物 (23.1克, 收率 83.5%)。
分析数据为:
1H MR (400 MHz, CDCI3): δ = 1.33 (s, 12H), 2.49 (br s, 4H), 3.18 (br s, 2H), 3.59-3.70 (m:
2H), 4.71 (br s, 1 H), 7.87 (s, 2H), 9.84 (br s, 2H).
实施例 26: 式 9a-l所示化合物的制备
将式 7a-l所示化合物 (23.0克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(50.8克, 0.2摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷)二茂铁]二氯化钯 (3.67 克, 0.005 摩尔) 的二氯甲垸 (CH2C12 ) 溶液, 在 90°C~100°C下搅拌 6小时, 反应毕, 后处理方法同实施例 25, 得式 9a- 1所示化合物 (23.8 克, 收率 85.8% )。 实施例 27: 式 9a-l所示化合物的制备
将式 7a-l所示化合物 (23.0克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(30.5克, 0.12摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷)二茂铁]二氯化钯 (3.67 克, 0.005 摩尔) 的二氯甲垸 (CH2C12 ) 溶液, 在 70°C~80°C下搅拌 10小时, 反应毕, 后处理方法同实施例 25, 得式 9a- 1所示化合物 (25.4 克, 收率 91.6% )。
实施例 28: 式 9a-2所示化合物的制备
将式 7a-2所示化合物 (24.4克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(25.4克, 0.1摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 50°C~55 °C 下搅拌 15小时, 反应毕, 过滤去除固体, 然后分液, 取有机相, 浓缩除去溶剂得粗产品, 粗产品经石油醚 /乙酸乙酯的混合溶剂 (V: V=l : 1)进行柱层析纯化后, 浓缩有机相除去溶 剂, 即得式 9a-2所示化合物 (24.5克, 收率 84.1%)。
实施例 29: 式 9a-2所示化合物的制备
将式 7a-2所示化合物 (24.4克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾
(29.4克, 0.3摩尔)与式 8所示化合物(50.8克, 0.2摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷)二茂铁]二氯化钯 (3.67 克, 0.005 摩尔) 的二氯甲垸 (CH2C12 ) 溶液, 在 90°C~100°C下搅拌 6小时, 反应毕, 后处理方法同实施例 28, 得式 9a-2所示化合物 (25.4 克, 收率 87.2% )。
实施例 30: 式 9a-2所示化合物的制备
将式 7a-2所示化合物 (24.4克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(30.5克, 0.12摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 70°C~80°C 下搅拌 8小时, 反应毕, 后处理方法同实施例 28, 得式 9a-2所示化合物 (26.5克, 收率 91.0% )。
实施例 31 : 式 9a-3所示化合物的制备
将式 7a-3所示化合物 (22.8克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(25.4克, 0.1摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 50°C~55 °C 下搅拌 15小时, 反应毕, 过滤去除固体, 然后分液, 取有机相, 浓缩除去溶剂得粗产品, 粗产品经石油醚 /乙酸乙酯的混合溶剂 (V: V=l : 1)进行柱层析纯化后, 浓缩有机相除去溶 剂, 即得式 9a-3所示化合物 (24.2克, 收率 88.0%)。 实施例 32: 式 9a-3所示化合物的制备
将式 7a-3所示化合物 (22.8克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(50.8克, 0.2摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷)二茂铁]二氯化钯 (3.67 克, 0.005 摩尔) 的二氯甲垸 (CH2C12 ) 溶液, 在 95 °C~100°C下搅拌 6小时, 反应毕, 后处理方法同实施例 31, 得式 9a-3所示化合物 (23.4 克, 收率 85.0% )。
实施例 33 : 式 9a-3所示化合物的制备
将式 7a-3所示化合物 (22.8克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(30.5克, 0.12摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 75 °C~80°C 下搅拌 9小时, 反应毕, 后处理方法同实施例 31, 得式 9a-3所示化合物 (24.6克, 收率 89.4%
实施例 34: 式 9a-4所示化合物的制备
将式 7a-4所示化合物 (25.4克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(25.4克, 0.1摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 50°C~55 °C 下搅拌 15小时, 反应毕, 过滤去除固体, 然后分液, 取有机相, 浓缩除去溶剂得粗产品, 粗产品经石油醚 /乙酸乙酯的混合溶剂 (V: V=l : 1)进行柱层析纯化后, 浓缩有机相除去溶 剂, 即得式 9a-4所示化合物 (26.2克, 收率 87.1%)。
实施例 35 : 式 9a-4所示化合物的制备
将式 7a-4所示化合物 (25.4克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(50.8克, 0.2摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷)二茂铁]二氯化钯 (3.67 克, 0.005 摩尔) 的二氯甲垸 (CH2C12 ) 溶液, 在 95 °C~100°C下搅拌 6小时, 反应毕, 后处理方法同实施例 34, 得式 9a-4所示化合物 (24.7 克, 收率 82.0% )。
实施例 36: 式 9a-4所示化合物的制备
将式 7a-4所示化合物 (25.4克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(30.5克, 0.12摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 75 °C~80°C 下搅拌 12小时, 反应毕, 后处理方法同实施例 34, 得式 9a-4所示化合物 (26.8克, 收率 88.9%
实施例 37: 式 9a-5所示化合物的制备 将式 7a-5所示化合物 (20.3克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(25.4克, 0.1摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 50°C~55 °C 下搅拌 15小时, 反应毕, 过滤去除固体, 然后分液, 取有机相, 浓缩除去溶剂得粗产品, 粗产品经石油醚 /乙酸乙酯的混合溶剂 (V: V=l : 1)进行柱层析纯化后, 浓缩有机相除去溶 剂, 即得式 9a-5所示化合物 (20.3克, 收率 81.2%)。
实施例 38: 式 9a-5所示化合物的制备
将式 7a-5所示化合物 (20.3克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(50.8克, 0.2摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷)二茂铁]二氯化钯 (3.67 克, 0.005 摩尔) 的二氯甲垸 (CH2C12 ) 溶液, 在 95 °C~100°C下搅拌 6小时, 反应毕, 后处理方法同实施例 37, 得式 9a-5所示化合物 (19.6 克, 收率 78.5% )。
实施例 39: 式 9a-5所示化合物的制备
将式 7a-5所示化合物 (20.3克, 0.1摩尔) 溶于二甲基亚砜 300毫升中, 加入醋酸钾 (29.4克, 0.3摩尔)与式 8所示化合物(30.5克, 0.12摩尔), 通氮气保护, 然后加入 [Ι,Γ- 双 (二苯基磷;)二茂铁]二氯化钯 ( 3.67克, 0.005摩尔)的二氯甲垸 ( CH2C12)溶液,在 75 °C~80°C 下搅拌 6小时, 反应毕, 后处理方法同实施例 37, 得式 9a-5所示化合物 (20.1克, 收率 80.4% ) o
实施例 40: 式 lOa-1所示化合物的制备
在三口瓶中加入乙腈 (500毫升)、 式 6a-l所示化合物 (52.1 克, 0.1摩尔)、 式 9a-l 所示化合物(27.7克, 0.1摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) ( 3.5克, 0.005摩尔), 升温至 50°C, 保温搅拌反应 24小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-1所示化合物 (42.2克, 收率 71.4% )。
实施例 41 : 式 lOa-1所示化合物的制备
在三口瓶中加入乙腈 (600毫升)、 式 6a-l所示化合物 (52.1 克, 0.1摩尔)、 式 9a-l 所示化合物(55.4克, 0.2摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) ( 3.5克, 0.005摩尔), 升温至 100°C, 保温搅拌反应 10小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-1所示化合物 (44.7克, 收率 75.6% )。 实施例 42: 式 lOa-1所示化合物的制备
在三口瓶中加入乙腈 (550毫升)、 式 6a-l所示化合物 (52.1 克, 0.1摩尔)、 式 9a-l 所示化合物 (33.2克, 0.12摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克 (含碳酸钠 30 克, 水 270克), 搅拌均匀后, 再加入双三苯基磷二氯化钯 (Pc PPh3;)2Cl2) (3.5克, 0.005 摩尔), 升温至 70°C, 保温搅拌反应 15小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然 后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-1 所示化合物 (51.1 克, 收率 86.4% )。
实施例 43 : 式 lOa-2所示化合物的制备
在三口瓶中加入乙腈 (500毫升)、 式 6a-2所示化合物 (53.5克, 0.1摩尔)、 式 9a-2 所示化合物(29.1克, 0.1摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) (3.5克, 0.005摩尔), 升温至 50°C, 保温搅拌反应 24小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-2所示化合物 (34.4克, 收率 55.6
实施例 44: 式 10a-2所示化合物的制备
在三口瓶中加入乙腈 (600毫升)、 式 6a-2所示化合物 (53.5克, 0.1摩尔)、 式 9a-2 所示化合物(58.2克, 0.2摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) (3.5克, 0.005摩尔), 升温至 100°C, 保温搅拌反应 10小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-2所示化合物 (39.5克, 收率 63.7% )。
实施例 45: 式 lOa-2所示化合物的制备
在三口瓶中加入乙腈 (550毫升)、 式 6a-2所示化合物 (53.5克, 0.1摩尔)、 式 9a-2 所示化合物 (34.9克, 0.12摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克 (含碳酸钠 30 克, 水 270克), 搅拌均匀后, 再加入双三苯基磷二氯化钯 (Pd(PPh3;)2Cl2) (3.5克, 0.005 摩尔), 升温至 80°C, 保温搅拌反应 12小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然 后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-2 所示化合物 (47.6 克, 收率 76.9% )。
实施例 46: 式 lOa-3所示化合物的制备
在三口瓶中加入乙腈 (500毫升)、 式 6a-3所示化合物 (52.1 克, 0.1摩尔)、 式 9a-3 所示化合物(27.5克, 0.1摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) (3.5克, 0.005摩尔), 升温至 50°C, 保温搅拌反应 24小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-3所示化合物 (37.1 克, 收率 63.0
实施例 47: 式 lOa-3所示化合物的制备
在三口瓶中加入乙腈 (600毫升)、 式 6a-3所示化合物 (52.1 克, 0.1摩尔)、 式 9a-3 所示化合物(55.0克, 0.2摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) (3.5克, 0.005摩尔), 升温至 100°C, 保温搅拌反应 10小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-3所示化合物 (40.1 克, 收率 68.1% )。
实施例 48: 式 lOa-3所示化合物的制备
在三口瓶中加入乙腈 (550毫升)、 式 6a-3所示化合物 (52.1 克, 0.1摩尔)、 式 9a-3 所示化合物 (33.0克, 0.12摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克 (含碳酸钠 30 克, 水 270克), 搅拌均匀后, 再加入双三苯基磷二氯化钯 (Pc PPh3;)2Cl2) (3.5克, 0.005 摩尔), 升温至 60°C, 保温搅拌反应 16小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然 后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-3 所示化合物 (47.5 克, 收率 80.6% )。
实施例 49: 式 10a-4所示化合物的制备
在三口瓶中加入乙腈 (500毫升)、 式 6a-4所示化合物 (52.1 克, 0.1摩尔)、 式 9a-4 所示化合物(30.1克, 0.1摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) (3.5克, 0.005摩尔), 升温至 50°C, 保温搅拌反应 24小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-4所示化合物 (47.9克, 收率 77.8% )。
实施例 50: 式 10a-4所示化合物的制备
在三口瓶中加入乙腈 (600毫升)、 式 6a-4所示化合物 (52.1 克, 0.1摩尔)、 式 9a-4 所示化合物(60.2克, 0.2摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) (3.5克, 0.005摩尔), 升温至 100°C, 保温搅拌反应 10小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-4所示化合物 (46.2克, 收率 75.0% )。
实施例 51 : 式 lOa-4所示化合物的制备 在三口瓶中加入乙腈 (550毫升)、 式 6a-4所示化合物 (52.1 克, 0.1摩尔)、 式 9a-4 所示化合物 (36.1克, 0.12摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克 (含碳酸钠 30 克, 水 270克), 搅拌均匀后, 再加入双三苯基磷二氯化钯 (Pc PPh3;)2Cl2) (3.5克, 0.005 摩尔), 升温至 55°C, 保温搅拌反应 18小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然 后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-4 所示化合物 (50.8 克, 收率 82.6% )。
实施例 52: 式 lOa-5所示化合物的制备
在三口瓶中加入乙腈 (500毫升)、 式 6a-5所示化合物 (52.1 克, 0.1摩尔)、 式 9a-5 所示化合物(25.0克, 0.1摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh C ) (3.5克, 0.005摩尔), 升温至 50°C, 保温搅拌反应 24小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-5所示化合物 (37.6克, 收率 66.6%
实施例 53 : 式 lOa-5所示化合物的制备
在三口瓶中加入乙腈 (600毫升)、 式 6a-5所示化合物 (52.1 克, 0.1摩尔)、 式 9a-5 所示化合物(50.0克, 0.2摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克(含碳酸钠 30克, 水 270克),搅拌均匀后,再加入双三苯基磷二氯化钯(PdCPPh3)2Cl2) (3.5克, 0.005摩尔), 升温至 100°C, 保温搅拌反应 10小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-5所示化合物 (41.2克, 收率 73.0% )。
实施例 54: 式 lOa-5所示化合物的制备
在三口瓶中加入乙腈 (550毫升)、 式 6a-5所示化合物 (52.1 克, 0.1摩尔)、 式 9a-5 所示化合物 (30.0克, 0.12摩尔), 搅拌均匀, 加入 10%碳酸钠溶液 300克 (含碳酸钠 30 克, 水 270克), 搅拌均匀后, 再加入双三苯基磷二氯化钯 (Pc PPh3;)2Cl2) (3.5克, 0.005 摩尔), 升温至 65°C, 保温搅拌反应 15小时, 反应毕, 加入乙酸乙酯, 过滤去除固体, 然 后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 lOa-5 所示化合物 (45.0 克, 收率 79.7% )。
实施例 55: 式 11所示化合物盐酸盐的制备
在三口瓶中加入式 lOa-1所示化合物(59.1克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 15摄氏度下, 搅拌反应 6小时, 反应毕, 加 入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 I所示化合物盐酸盐的粗品, 粗品加入 300毫升甲醇 /丙酮混合溶剂 (V:V=3 : 1 )搅拌 重结晶, 过滤, 得白色固体或类白色固体, 减压干燥, 即得式 I所示化合物的盐酸盐 (式 11所示化合物, 46.5克, 收率 88.1%), 纯度 99.8 % (高效液相) 。
实施例 56: 式 11所示化合物盐酸盐的制备
在三口瓶中加入式 lOa-1所示化合物(59.1克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 55摄氏度下, 搅拌反应 1小时, 反应毕, 后 处理同实施例 55,最后得式 I所示化合物的盐酸盐 (式 11所示化合物, 44.3克,收率 84.0%), 纯度 99.0% (高效液相) 。
实施例 57: 式 11所示化合物盐酸盐的制备
在三口瓶中加入式 lOa-1所示化合物(59.1克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 25摄氏度下, 搅拌反应 3小时, 反应毕, 后 处理同实施例 55,最后得式 I所示化合物的盐酸盐 (式 11所示化合物, 48.8克,收率 92.5%), 纯度 99.2% (高效液相) 。
实施例 58: 式 16所示化合物盐酸盐的制备
在三口瓶中加入式 10a-2所示化合物(62.0克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 15摄氏度下, 搅拌反应 6小时, 反应毕, 加 入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 I所示化合物盐酸盐的粗品, 粗品加入 300毫升甲醇 /丙酮混合溶剂 (V:V=2: 1 )搅拌 重结晶, 过滤, 得白色固体或类白色固体, 减压干燥, 即得式 I所示化合物的盐酸盐 (式 16所示化合物, 47.5克, 收率 85.4%), 纯度 99.2% (高效液相) 。
实施例 59: 式 16所示化合物盐酸盐的制备
在三口瓶中加入式 10a-2所示化合物(62.0克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 55摄氏度下, 搅拌反应 1小时, 反应毕, 后 处理同实施例 58,最后得式 I所示化合物的盐酸盐 (式 16所示化合物, 45.1克,收率 81.1%), 纯度 99.5 % (高效液相) 。
实施例 60: 式 16所示化合物盐酸盐的制备
在三口瓶中加入式 10a-2所示化合物(62.0克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 25摄氏度下, 搅拌反应 3小时, 反应毕, 后 处理同实施例 58,最后得式 I所示化合物的盐酸盐(式 16所示化合物, 49.8克,收率 89.6%), 纯度 99.4% (高效液相) 。
实施例 61 : 式 46所示化合物盐酸盐的制备
在三口瓶中加入式 10a-3所示化合物(58.9克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 15摄氏度下, 搅拌反应 6小时, 反应毕, 加 入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 I所示化合物盐酸盐的粗品, 粗品加入 300毫升甲醇 /丙酮混合溶剂 (V:V=1 : 1 )搅拌 重结晶, 过滤, 得白色固体或类白色固体, 减压干燥, 即得式 I所示化合物的盐酸盐 (式 46所示化合物, 46.4克, 收率 88.2%), 纯度 99.3 % (高效液相) 。
实施例 62: 式 46所示化合物盐酸盐的制备
在三口瓶中加入式 10a-3所示化合物(58.9克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 55摄氏度下, 搅拌反应 1小时, 反应毕, 后 处理同实施例 61,最后得式 I所示化合物的盐酸盐 (式 46所示化合物, 45.5克,收率 86.6%), 纯度 99.5 % (高效液相) 。
实施例 63 : 式 46所示化合物盐酸盐的制备
在三口瓶中加入式 10a-3所示化合物(58.9克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 45摄氏度下, 搅拌反应 2小时, 反应毕, 后 处理同实施例 61,最后得式 I所示化合物的盐酸盐(式 46所示化合物, 47.6克,收率 90.6%), 纯度 99.0% (高效液相) 。
实施例 64: 式 52所示化合物盐酸盐的制备
在三口瓶中加入式 10a-4所示化合物(61.5克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 15摄氏度下, 搅拌反应 6小时, 反应毕, 加 入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 I所示化合物盐酸盐的粗品, 粗品加入 300毫升甲醇 /丙酮混合溶剂 (V:V=1 : 1 )搅拌 重结晶, 过滤, 得白色固体或类白色固体, 减压干燥, 即得式 I所示化合物的盐酸盐 (式 52所示化合物, 48.1克, 收率 87.2%), 纯度 99.3 % (高效液相) 。
实施例 65: 式 52所示化合物盐酸盐的制备
在三口瓶中加入式 10a-4所示化合物(61.5克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 55摄氏度下, 搅拌反应 1小时, 反应毕, 后 处理同实施例 64,最后得式 I所示化合物的盐酸盐(式 52所示化合物, 48.7克,收率 88.3%), 纯度 99.1 % (高效液相) 。
实施例 66: 式 52所示化合物盐酸盐的制备
在三口瓶中加入式 10a-4所示化合物(61.5克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 45摄氏度下, 搅拌反应 2.5小时, 反应毕, 后 处理同实施例 64,最后得式 I所示化合物的盐酸盐(式 52所示化合物, 50.2克,收率 91.0%), 纯度 99.5 % (高效液相) 。
实施例 67: 式 74所示化合物盐酸盐的制备 在三口瓶中加入式 10a-5所示化合物(56.4克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 15摄氏度下, 搅拌反应 6小时, 反应毕, 加 入乙酸乙酯, 过滤去除固体, 然后分液, 取有机相, 加入无水硫酸钠干燥, 浓缩除去溶剂, 得式 I所示化合物盐酸盐的粗品, 粗品加入 300毫升甲醇 /丙酮混合溶剂 (V:V=1 : 1 )搅拌 重结晶, 过滤, 得白色固体或类白色固体, 减压干燥, 即得式 I所示化合物的盐酸盐 (式 74所示化合物, 45.7克, 收率 91.2%), 纯度 99.6% (高效液相) 。
实施例 68: 式 74所示化合物盐酸盐的制备
在三口瓶中加入式 10a-5所示化合物(56.4克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 55摄氏度下, 搅拌反应 1小时, 反应毕, 后 处理同实施例 67,最后得式 I所示化合物的盐酸盐(式 74所示化合物, 45.2克,收率 90.3%), 纯度 99.4% (高效液相) 。
实施例 69: 式 74所示化合物盐酸盐的制备
在三口瓶中加入式 10a-4所示化合物(56.4克, 0.1摩尔)和乙酸乙酯 200毫升, 搅拌, 滴加入 300ml饱和的氯化氢-乙酸乙酯液, 在 45摄氏度下, 搅拌反应 2.5小时, 反应毕, 后 处理同实施例 67,最后得式 I所示化合物的盐酸盐(式 74所示化合物, 47.3克,收率 94.5%), 纯度 99.1 % (高效液相) 。
药物制剂:
本发明所提供的化合物和药物组合物可以是多种形式, 如片剂、 硬胶囊、 软胶囊、 注 射剂、 注射用粉针、 粉剂、 糖浆、 溶液状、 悬浮液和气雾剂等, 并可以存在于适宜的固体 或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。 本发明的药物组合物的 各种剂型可按照药学领域的常规制备方法制备。 根据本发明的具体实施例, 本发明选用的 药用辅料包括粘合剂、 崩解剂、 填充剂、 助流剂和润滑剂。 选用的粘合剂为可压性淀粉、 崩解剂为羟丙纤维素, 填充剂为 β-无水乳糖和微晶纤维素, 助流剂为微粉硅胶, 润滑剂为 滑石粉。 药用辅料选用羟丙纤维素等性能良好的崩解剂辅以其他药用辅料制得复方制剂, 使其不仅释药快速而且物理性能良好, 制备得到的片剂突出的优点是能快速释放, 且分散 完全。
实施例 70: 式 11所示化合物的片剂 (规格: lOOmg)
1 ) 处方:
式 11所示化合物 100g
羟丙纤维素 10g
微晶纤维素 50g
可压性淀粉 40g 微粉硅胶 0.8g
β-无水乳糖 67.5g
滑石粉 1.5g
共计 1000片
2) 工艺
主药式 11所示化合物研细, 过 100目筛, 辅料过 80目筛。 称取处方量的式 11所示化 合物、可压性淀粉、 β-无水乳糖、微晶纤维素和 3%羟丙纤维素, 充分混匀, 用乙醇制软材, 过 12 目尼龙筛, 60°C干燥, 30 目筛整粒, 加入微粉硅胶及滑石粉, 充分混匀。 颗粒经含 量测定合格后, 将颗粒粉末用 12mm冲直接压片, 即得。
实施例 71 : 式 16所示化合物的胶囊剂
1 ) 处方:
式 16所示化合物 100g
微晶纤维素 50g
羧甲基纤维素钠 20g
β-无水乳糖 60g
滑石粉 1.5g
共计 1000粒
2) 工艺
主药式 16所示化合物研细, 过 100目筛, 辅料过 80目筛。 称取处方量的式 16所示化 合物、 β-无水乳糖、 微晶纤维素和羧甲基纤维素钠, 充分混匀, 用乙醇制软材, 过 12目尼 龙筛, 60°C干燥, 30目筛整粒, 加入滑石粉, 充分混匀。 颗粒经含量测定合格后, 用胶囊 机灌装成胶囊, 即得。
实施例 72: 式 46所示化合物的片剂 (规格: 150mg)
1 ) 处方:
式 46所示化合物 150g
羟丙纤维素 10g
微晶纤维素 40g
可压性淀粉 20g
微粉硅胶 2g
β-无水乳糖 50g
共计 1000片
2) 工艺 主药式 46所示化合物研细, 过 100目筛, 辅料过 80目筛。 称取处方量的式 46所示化 合物、可压性淀粉、 β-无水乳糖、微晶纤维素和 3%羟丙纤维素, 充分混匀, 用乙醇制软材, 过 12 目尼龙筛, 60°C干燥, 30 目筛整粒, 加入微粉硅胶, 充分混匀。 颗粒经含量测定合 格后, 将颗粒粉末用 12mm冲直接压片, 即得。
实施例 73 : 式 52所示化合物的胶囊剂
1 ) 处方:
式 52所示化合物 100g
微晶纤维素 50g
羧甲基纤维素钠 20g
β-无水乳糖 60g
滑石粉 1.5g
共计 1000粒
2) 工艺
主药式 52所示化合物研细, 过 100目筛, 辅料过 80目筛。 称取处方量的式 52所示化 合物、 β-无水乳糖、 微晶纤维素和羧甲基纤维素钠, 充分混匀, 用乙醇制软材, 过 12目尼 龙筛, 60°C干燥, 30目筛整粒, 加入滑石粉, 充分混匀。 颗粒经含量测定合格后, 用胶囊 机灌装成胶囊, 即得。
实施例 74: 式 74所示化合物的注射液 (规格: lOOmg)
1 ) 处方:
式 74所示化合物 100g
氟尿嘧啶 250g
氯化钠 900g
注射用水至 100000ml
共制成注射液 1000瓶
2) 制备工艺:
药液的配制: 按处方量称取氯化钠, 加入注射用水 5000ml中, 搅拌至完全溶解; 称取 0.3 %溶液量的活性炭, 搅匀, 加热煮沸 15 分钟, 冷却后, 滤除活性炭; 按处方量准确称 取式 74所示化合物, 氟尿嘧啶加入上述氯化钠溶液中, 并加注射用水至近全量; 用 0.1 % 的氢氧化钠调节 pH 至 7.5〜8.5, 加注射用水到规定量, 测定中间体含量应为 93.0 %〜 107.0 % , 合格后, 用 0.45μιη微孔滤膜过滤, 检查澄明度合格后, 滤液交灌装组。
灌装: 灌装用的输液瓶用注射水洗净, 烘干。 同时镀膜丁基胶塞用注射水漂洗干净。 将上述配制好的药液加入注射液灌装机, 灌装于输液瓶中, 盖塞后, 压制复合铝盖。 灭菌: 将盖好的输液瓶放入灭菌柜中进行灭菌, 灭菌温度为 115°C, 灭菌时间 35分钟, 灯检合格, 包装, 即可。
实施例 75: 本发明的化合物对人肺癌 A549细胞裸鼠移植瘤生长的影响
( 1 ) 人肺癌裸鼠移植瘤模型的制备
SPF级 BALB/c-nu小鼠 36只, 6周龄, 重量 16g-18g。 取对数生长期肺癌细胞株 A549 细胞,用无菌 PBS调整 A549细胞浓度为 3x l07/mL,在 BALB/c-nu小鼠背部皮下接种 A549 细胞 0.1ml, 待皮下移植瘤体积达 75 mm3 左右时 (约 10天;), 模型制造成功。
(2) 分组与给药
按瘤体积和荷瘤鼠体重均衡原则分为如下 8组, 每组 12只:
A、 模型对照组: 灌胃等量的生理盐水 1次 /日, 共给药 30日;
B、 奥沙利铂组: 腹腔注射 10mg/kg奥沙利铂, 隔日给药 1次, 共计 8次;
C、 克唑替尼组: 灌胃给予克唑替尼胶囊 (辉瑞公司生产, 商品名: 赛可瑞)粉末, 剂 量为 25mg/kg, 2次 /日, 给药共计 8次;
D、 式 11所示化合物组: 灌胃给予按照实施例 71制备的胶囊粉末, 剂量为 10mg/kg, 1次 /日, 共给药 30日;
E、 式 16所示化合物组: 灌胃给予按照实施例 71制备的胶囊粉末, 剂量为 10mg/kg, 1次 /日, 共给药 30日;
F、 式 46所示化合物组: 灌胃给予按照实施例 71制备的胶囊粉末, 剂量为 10mg/kg, 1次 /日, 共给药 30日;
G、 式 52所示化合物组: 灌胃给予按照实施例 71制备的胶囊粉末, 剂量为 10mg/kg,
1次 /日, 共给药 30日;
H、 式 74所示化合物组: 灌胃给予按照实施例 71制备的胶囊粉末, 剂量为 10mg/kg, 1次 /日, 共给药 30日。
给药期间每 4日用游标卡尺测量移植瘤最长径 (L)和最短径 (w)。 末次给药 48小时后脱 白处死小鼠, 切除移植瘤, 称取瘤重。 瘤重抑制率 (%)IR = (1-实验组瘤重均值 /模型对照组 瘤重均值; )x l00%。通过瘤重的比较来体现药物对人肺癌 A549细胞裸鼠抑制瘤生长的影响。 数据以均数 ±标准差 (x±s)表示, 采用 SPSS15.0软件进行方差分析。
(3 ) 结果与分析
本发明式 I所示化合物 (取式 11所示化合物、式 16所示化合物、式 46所示化合物、式 52所示化合物、 式 74所示化合物)对人肺癌 A549细胞裸鼠移植瘤生长的影响的实验结果 见表 1。
瘤重 (mg) 平均抑瘤率(%) 模型对照组 384.80±59.7
奥沙利铂组 209.83±82.0* 45.71
克唑替尼组 198.36±78.1 * 48.02
式 11所示化合物组 179.80±58.56** 52.77
式 16所示化合物组 194.05±75.0* 48.86
式 46所示化合物组 191.22±72.9* 49.28
式 52所示化合物组 185.46±66.67** 51.65
式 74所示化合物组 181.87±60.26** 52.07
注: 与模型对照组比较, *P<0.05, **P<0.01。
表 1 的试验结果表明: 与模型对照组相比, 各治疗组对人肺癌 A549细胞裸鼠移植瘤 生长的抑制作用均具有显著性差异, 尤其是与模型对照组相比, 本发明所述的式 I所示化 合物在对人肺癌 A549细胞裸鼠移植瘤生长的抑制作用方面具有极显著性差异(P<0.01 ), 与化疗奥沙利铂组、 ALK抑制剂克唑替尼组相比, 平均抑瘤率有所提高, 这说明本发明的 化合物在治疗非小细胞肺癌方面具有极其显著的疗效, 在获得显著药效的同时具有毒副作 用低的优势, 获得了预料不到的技术效果。
实施例 76: 本发明的化合物在克唑替尼耐药性肿瘤中的抗肿瘤活性
获自 NCI-H2228的异种移植肿瘤先以 50mg/kg的剂量用克唑替尼治疗 14天, 采用克 唑替尼的治疗停止数天直到肿瘤再次生长。当肿瘤再次生长时,动物采用克唑替尼 50mg/kg 治疗直到肿瘤对克唑替尼的治疗产生耐药性。 当它们对克唑替尼变得有耐药性时, 收集获 自各个动物的肿瘤。 随机选择数个耐药性肿瘤, 用于如下研究。 将每一个耐药性肿瘤切成 小碎块并植入 5个动物中; 当 5个动物中的肿瘤体积足够大时, 收集肿瘤, 然后植入用于 化合物试验的 25个动物中。一块收集的肿瘤也用于 RNA提取, 随后定序 EML4-ALK的转 录。
具体如图 1所示,
其中:
空白对照组: 为以 50mg/kg的剂量口服淀粉;
克唑替尼组: 为以 50mg/kg的剂量用克唑替尼治疗 14天, 然后停止给药 2天, 自第 17天再次以 50mg/kg的剂量给药, 直到肿瘤对克唑替尼的治疗产生耐药性 (给药后第 28 天再次产生耐药性) ;
式 1 1所示化合物组: 为以 25mg/kg的剂量口服式 1 1所示化合物, 给药至第 48天; 本发明式 11所示化合物在克唑替尼耐药性 NCI-H2228中显示了显著的抗肿瘤生长活 性, 而且式 11所示化合物显示了较克唑替尼 50mg/kg具有更好的活性。 根据 4周的 GLP 毒理学研究, 在小鼠中与 50mg/kg相关的式 11所示化合物的致毒量低于人类的致毒量。
同样, 发明人用相同的方法验证了本发明其它所示化合物, 具有本发明式 11所示化合 物相同的抗肿瘤活性效果。 在本说明书的描述中, 参考术语"一个实施例"、 "一些实施例"、 "示例"、 "具体示例" 或"一些示例"等的描述意指结合该实施例或示例描述的具体特征、 结构、 材料或者特点包 含于本发明的至少一个实施例或示例中。 在本说明书中, 对上述术语的示意性表述不一定 指的是相同的实施例或示例。 而且, 描述的具体特征、 结构、 材料或者特点可以在任何的 一个或多个实施例或示例中以合适的方式结合。
尽管上面已经示出和描述了本发明的实施例, 可以理解的是, 上述实施例是示例性的, 不能理解为对本发明的限制, 本领域的普通技术人员在不脱离本发明的原理和宗旨的情况 下在本发明的范围内可以对上述实施例进行变化、 修改、 替换和变型。

Claims

权利要求书
1、 一种化合物, 其特征在于, 所述化合物为式 I所示化合物或式 I所示化合物的对映 异构体、 非对映异构体、 外消 合物或溶剂合物,
Figure imgf000047_0001
I
其中,
X为选自 CH、 N中的任意一种;
和 各自独立的为选自 C1-C12直链或支链的垸基、 卤素、 CF3、 CN、 N02、 H2、 CH2COOH、 OCH3、 OC2H5、 OH、 HS02CH3、 CH2CO H2和 COCH3的任意一种;
R3为选自氢或其同位素、 卤素、 未取代或由 1~3个卤素取代的 C1-C12直链或支链的 垸基、 未取代或者由 1~3个卤素或苯基取代的 C 1-C 12直链或支链的垸氧基、 未取代或由 1~3个卤素取代的 C3-C12环垸基、 由 C 1-C6垸氧基取代的 C 1-C6直链或支链的垸基、 由 C3-C6环垸基取代的 C1-C6直链或支链的垸基、 羟基、 氰基、 硝基、 C1-C6直链或支链的 羟垸基、 羧基、 巯基、 -NR5R6、 -NCOR5R6、 -S02R5、 -S02 R5R6 以及 -OCOR5的任意一 种;
为选自氢或其同位素、 卤素、 未取代或由 1~3个卤素取代的 C1-C12直链或支链的 垸基、 未取代或由 1~3个卤素取代的 C3-C12环垸基、 由 C1-C6垸氧基取代的 C1-C6直链 或支链的垸基、 由 C3-C6环垸基取代的 C1-C6直链或支链的垸基、 未取代或者由 1~3个卤 素或苯基取代的 C1-C6直链或支链的羧基、 羟基、 C1-C6直链或支链的羟垸基、 羧基、 巯 基、 -NR5R6、 -NCOR5R6、 -S02R5、 -S02 R5R6 -OCOR5、 取代或未取代的苯环、 以及取代 或未取代的含有 0~4个杂原子的 C2-C12的环状基团的任意一种;
R5和 Re分别独立地为选自氢或其同位素、 卤素、 未取代或由 1~3个卤素取代的 C1-C6 直链或支链的垸基、 以及未取代或由 1~3个卤素取代的 C3-C6环垸基的任意一种;
所述卤素为氟、 氯、 溴或碘。
2、 根据权利要求 1所述的化合物, 其特征在于, 在所述取代或未取代的含有 0~4个杂 原子的 C2-C12的环状基团中, 所述杂原子独立地为选自 0、 S和 N的任意一种。
3、 根据权利要求 2所述的化合物, 其特征在于, 所述环状基团为单环或稠环。
4、 根据权利要求 3所述的化合物, 其特征在于, 所述环状基团的环由 3-12个环原子 构成, 并且所述 3~12个环原子中的杂原子为选自 N、 0、 及 S(0)n的任意一种, 其中, n 为 0、 1或 2, 其余环原子为 C。
5、 根据权利要求 4所述的化合物, 其特征在于, 所述环也可具有一个或多个双键。
6、 根据权利要求 5所述的化合物, 其特征在于, 所述环状基团为选自下列之一:
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000049_0003
7、 根据权利要求 1所述的化合物, 其特征在于,
X为选自 CH、 N中的任意一种;
Ri为选自氢、 卤素、 CH3、 C2H5、 CF3、 OCH3、 OC2H5、 CH2COOH和 COCH3的任意 种; R2为选自氢、 卤素、 CH3、 C2H5、 CF3、 OCH3、 OC2H5、 CH2COOH和 COCH3的任意 一种;
R3为选自氢、 卤素、 未取代或由 1~3个卤素取代的 C1-C6直链或支链的垸基、 未取代 或由 1~3个卤素取代的 C3-C12环垸基、 未取代或者由 1~3个卤素或苯基取代的 C1-C6直 链或支链的垸氧基、 羟基、 -NR5R6、 -NCOR5R6、 -S02R5、 -S02 R5R6禾 B-OCOR5的任意一 种;
R4为选自氢、 羧基、 未取代或由 1~3个卤素取代的 C1-C6直链或支链的垸基、 未取代 或者由 1~3个卤素或苯基取代的 C1-C6直链或支链的垸氧基、 未取代或由 1~3个卤素取代 的 C3-C12环垸基、 未取代或者由 1~3个卤素或苯基取代的 C1-C6直链或支链的羧基、 取 代或未取代的含有 0~4个杂原子的 C2-C12的环状基团;
R5和 R6各自独立地为选自氢、 卤素、 未取代或由 1~3个卤素取代的 C1-C4直链或支 链的垸基的任意一种;
所述卤素为氟、 氯或溴。
8、 根据权利要求 7所述的化合物, 其特征在于,
X为 N;
Ri为选自氢、 卤素、 CH3、 CF3和 OCH3的任意一种;
R2为选自氢、 卤素、 CH3、 CF3和 OCH3的任意一种;
R3为选自氢、未取代的 C1-C6直链或支链的垸基、未取代的 C1-C6直链或支链的垸氧 基、 未取代的 C3-C12环垸基、 -S02R5和- NCOR5R6的任意一种;
R4为选自氢、 羧基、 未取代或由 1~3个卤素取代的 C1-C6直链或支链的垸基、 未取代 或者由 1~3个卤素或苯基取代的 C1-C6直链或支链的垸氧基、 未取代或者由 1~3个卤素或 苯基取代的 C1-C6直链或支链的羧基、 取代或未取代的含有 0~4个杂原子的 C2-C12的环 状基团的任意一种;
和1 6各自独立地为选自氢、 卤素、 或者未取代或由 1~3个卤素取代的 C1-C4直链 或支链的垸基的任意一种;
所述卤素为氟或氯。
9、 根据权利要求 1所述的化合物, 其特征在于, 所述化合物为选自下列的一种或其对 映异构体、 非对映异构体、 外消旋体、 药学上可接受的盐、 结晶水合物或溶剂合物:
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
75 其中, PG表示氨基保护基团。
10、 根据权利要求 9所述的化合物, 其特征在于, 所述氨基保护基团为叔丁氧羰基。
11、 一种制备权利要求 1~10任一项所述化合物的方法, 其特征在于, 包括以下步骤: 使式 la所示化合物与四氢铝锂进行接触, 以便获得式 2a所示化合物;
使所述式 2a所示化合物与式 3a所示化合物进行接触, 以便获得式 4a所示化合物; 使所述式 4a所示化合物用氨基保护剂进行氨基保护, 以便获得式 5a所示化合物; 使所述式 5a所示化合物进行溴代反应, 以便获得式 6a所示化合物;
使所述式 7a所示化合物与式 8所示化合物进行接触, 以便获得式 9a所示化合物; 使所述式 6a所示化合物与式 9a所示化合物进行接触, 以便获得式 10a所示化合物; 使所述式 10a所示化合物脱氨基保护, 以便获得式 I所示化合物,
Figure imgf000057_0001
Figure imgf000057_0002
其中, X、 为如权利要求 1~10任一项中所定义的, PG表示氨基保护基团。
12、 根据权利要求 11所述的方法, 其特征在于, 所述氨基保护基团为叔丁氧羰基。
13、 一种药物组合物, 其特征在于, 包括:
权利要求 1~10任一项所述的化合物。
14、 根据权利要求 13所述的药物组合物, 其特征在于, 进一步包括: 药学上可以接受 的赋形剂。
15、 一种药物组合物, 其特征在于, 包括:
权利要求 1~10任一项所述的化合物; 以及
第二治疗剂。
16、 根据权利要求 15所述的药物组合物, 其特征在于, 所述第二治疗剂为选自细胞毒 性药物、 抗肿瘤生物工程药物、 缺氧选择性药物、 抗炎药物、 以及血管活性药物中的一种 或多种。
17、 根据权利要求 16所述的药物组合物, 其特征在于, 所述细胞毒性药物为氮甲、 苯 丙氨酸氮芥、 苯丁酸氮芥、 环磷酰胺、 异环磷酰胺、 氯磷酰胺、 白消安、 司莫司汀、 雷莫 司汀、 达卡巴嗪、 顺铂、 卡铂、 得那铂、 洛铂、 奈达铂、 奥沙利铂、 甲氨喋吟、 阿糖胞苷、 5-氟尿嘧啶、 去氧氟尿苷、 卡培他滨、 吉西他滨、 放线菌素 D、 丝裂霉素 C、 柔红霉素、 多柔比星、 米托蒽醌、 长春新碱、 长春瑞宾, 紫杉醇、 多西紫杉醇、 喜树碱、 羟基喜树碱 或伊立替康中的一种或多种。
18、 根据权利要求 16所述的药物组合物, 其特征在于, 所述的抗肿瘤生物工程药物为 抗 CEA抗体、 重组改构肿瘤坏死因子、 抗肿瘤单克隆抗体导向药物中的一种或多种。
19、 根据权利要求 16所述的药物组合物, 其特征在于, 所述缺氧选择性药物为替拉扎 明、 二硝基苯芥、 2-硝基咪唑垸化剂 CI-1010、 羟基喜树碱、 托泊替康、 沙尔威辛或依托泊 苷中的一种或多种。
20、 根据权利要求 16所述的药物组合物, 其特征在于, 所述抗炎药物为双氯芬酸钠、 布洛芬、 萘普生或酮洛芬中的一种或多种。
21、根据权利要求 16所述的药物组合物,其特征在于,所述血管活性药物为 5-羟色胺、 东莨菪碱、 多巴胺、 多巴酚丁胺、 麻黄素、 间羟胺、 甲氧胺、 肾上腺素、 异丙肾上腺素、 去氧肾上腺素、 去甲肾上腺素、 氨利酮、 左旋硝基精氨酸中的一种或多种。
22、权利要求 1~10任一项所述的化合物在制备药物中的用途,所述药物用于治疗癌症。
23、 根据权利要求 22所述的用途, 其特征在于, 所述癌症为由间变性淋巴瘤激酶介导 的癌症。
24、 根据权利要求 23所述的用途, 其特征在于, 所述癌症为选自下列的至少之一: 肺 癌、 骨癌、 胰腺癌、 头和颈部癌、 表皮或眼内黑色素瘤、 子宫癌、 卵巢癌、 直肠癌、 肛区 癌、 胃癌、 结肠癌、 乳腺癌、 输卵管癌、 子宫内膜癌、 宫颈癌、 阴道癌、 外阴癌、 何杰金 氏病、 食道癌、 小肠癌、 甲状腺癌、 甲状旁腺癌、 肾上腺癌、 软组织肉瘤、 尿道癌、 阴茎 癌、 前列腺癌、 慢性或急性白血病、 淋巴细胞性淋巴瘤、 膀胱癌、 肾细胞癌、 肾盂癌、 原 发性中枢神经系统淋巴瘤、 脊柱肿瘤、 脑干胶质瘤以及垂体腺瘤。
25、 根据权利要求 24所述的用途, 其特征在于, 所述癌症为选自下列的至少之一: 非 小细胞肺癌、 鳞状细胞癌、 激素难治性前列腺癌、 乳头状肾细胞癌、 结肠直肠腺癌、 神经 母细胞瘤、 间变性大细胞淋巴瘤及胃癌。
26、 根据权利要求 25所述的用途, 其特征在于, 所述癌症为由间变性淋巴瘤激酶介导 的非小细胞肺癌疾病。
27、 根据权利要求 26 所述的用途, 其特征在于, 所述癌症为对克唑替尼有耐药性的 ALK融合阳性的非小细胞肺癌。
28、 一种药物联合, 其特征在于, 包括:
权利要求 1~10任一项所述的化合物; 以及
第二治疗剂。
29、 根据权利要求 28所述的药物联合, 其特征在于, 所述第二治疗剂为选自细胞毒性 药物、 抗肿瘤生物工程药物、 缺氧选择性药物、 抗炎药物、 以及血管活性药物中的一种或 多种药物。
30、 根据权利要求 29所述的药物联合, 其特征在于, 所述细胞毒性药物为氮甲、 苯丙 氨酸氮芥、 苯丁酸氮芥、 环磷酰胺、 异环磷酰胺、 氯磷酰胺、 白消安、 司莫司汀、 雷莫司 汀、 达卡巴嗪、 顺铂、 卡铂、 得那铂、 洛铂、 奈达铂、 奥沙利铂、 甲氨喋吟、 阿糖胞苷、 5-氟尿嘧啶、 去氧氟尿苷、 卡培他滨、 吉西他滨、 放线菌素 D、 丝裂霉素 C、 柔红霉素、 多柔比星、 米托蒽醌、 长春新碱、 长春瑞宾, 紫杉醇、 多西紫杉醇、 喜树碱、 羟基喜树碱 或伊立替康中的一种或多种。
31、 根据权利要求 29 所述的药物联合, 其特征在于, 所述抗肿瘤生物工程药物为抗 CEA抗体、 重组改构肿瘤坏死因子、 抗肿瘤单克隆抗体导向药物中的一种或多种。
32、根据权利要求 29所述的药物联合,其特征在于,所述缺氧选择性药物为替拉扎明、 二硝基苯芥、 2-硝基咪唑垸化剂 CI-1010、 羟基喜树碱、 托泊替康、 沙尔威辛或依托泊苷中 的一种或多种。
33、 根据权利要求 29所述的药物联合, 其特征在于, 所述抗炎药物为双氯芬酸钠、 布 洛芬、 萘普生或酮洛芬中的一种或多种。
34、 根据权利要求 29所述的药物联合, 其特征在于, 所述血管活性药物为 5-羟色胺、 东莨菪碱、 多巴胺、 多巴酚丁胺、 麻黄素、 间羟胺、 甲氧胺、 肾上腺素、 异丙肾上腺素、 去氧肾上腺素、 去甲肾上腺素、 氨利酮、 左旋硝基精氨酸中的一种或多种。
35、 一种药盒, 其特征在于, 包括:
第一治疗剂, 所述第一治疗剂为权利要求 1~10任一项所述的化合物; 以及
第二治疗剂, 所述第二治疗剂为选自细胞毒性药物、 抗肿瘤生物工程药物、 缺氧选择 性药物、 抗炎药物、 以及血管活性药物中的一种或多种药物,
其中, 所述第一治疗剂与所述第二治疗剂设置在不同的容器中。
36、 根据权利要求 35所述的药盒, 其特征在于, 所述细胞毒性药物为氮甲、 苯丙氨酸 氮芥、 苯丁酸氮芥、 环磷酰胺、 异环磷酰胺、 氯磷酰胺、 白消安、 司莫司汀、 雷莫司汀、 达卡巴嗪、 顺铂、 卡铂、 得那铂、 洛铂、 奈达铂、 奥沙利铂、 甲氨喋吟、 阿糖胞苷、 5-氟 尿嘧啶、 去氧氟尿苷、 卡培他滨、 吉西他滨、 放线菌素 D、 丝裂霉素 C、 柔红霉素、 多柔 比星、 米托蒽醌、 长春新碱、 长春瑞宾, 紫杉醇、 多西紫杉醇、 喜树碱、 羟基喜树碱或伊 立替康中的一种或多种。
37、 根据权利要求 35所述的药盒, 其特征在于, 所述抗肿瘤生物工程药物为抗 CEA 抗体、 重组改构肿瘤坏死因子、 抗肿瘤单克隆抗体导向药物中的一种或多种。
38、 根据权利要求 35所述的药盒, 其特征在于, 所述缺氧选择性药物为替拉扎明、 二 硝基苯芥、 2-硝基咪唑垸化剂 CI-1010、 羟基喜树碱、 托泊替康、 沙尔威辛或依托泊苷中的 一种或多种。
39、根据权利要求 35所述的药盒, 其特征在于, 所述抗炎药物为双氯芬酸钠、布洛芬、 萘普生或酮洛芬中的一种或多种。
40、 根据权利要求 35所述的药盒, 其特征在于, 所述血管活性药物为 5-羟色胺、 东莨 菪碱、 多巴胺、 多巴酚丁胺、 麻黄素、 间羟胺、 甲氧胺、 肾上腺素、 异丙肾上腺素、 去氧 肾上腺素、 去甲肾上腺素、 氨利酮、 左旋硝基精氨酸中的一种或多种。
41、 一种治疗癌症的方法, 其特征在于, 对患者给药权利要求 1~10任一项所述的化合 物或权利要求 13 21任一项所述的药物组合物。
42、 根据权利要求 41所述的方法, 其特征在于, 所述癌症为由间变性淋巴瘤激酶介导 的癌症。
43、 根据权利要求 42所述的方法, 其特征在于, 所述癌症为选自下列的至少之一: 肺 癌、 骨癌、 胰腺癌、 头和颈部癌、 表皮或眼内黑色素瘤、 子宫癌、 卵巢癌、 直肠癌、 肛区 癌、 胃癌、 结肠癌、 乳腺癌、 输卵管癌、 子宫内膜癌、 宫颈癌、 阴道癌、 外阴癌、 何杰金 氏病、 食道癌、 小肠癌、 甲状腺癌、 甲状旁腺癌、 肾上腺癌、 软组织肉瘤、 尿道癌、 阴茎 癌、 前列腺癌、 慢性或急性白血病、 淋巴细胞性淋巴瘤、 膀胱癌、 肾细胞癌、 肾盂癌、 原 发性中枢神经系统淋巴瘤、 脊柱肿瘤、 脑干胶质瘤以及垂体腺瘤。
44、 根据权利要求 43所述的方法, 其特征在于, 所述癌症为选自下列的至少之一: 非 小细胞肺癌、 鳞状细胞癌、 激素难治性前列腺癌、 乳头状肾细胞癌、 结肠直肠腺癌、 神经 母细胞瘤、 间变性大细胞淋巴瘤及胃癌。
45、 根据权利要求 44所述的方法, 其特征在于, 所述癌症为由间变性淋巴瘤激酶介导 的非小细胞肺癌疾病。
46、 根据权利要求 45 所述的方法, 其特征在于, 所述癌症为对克唑替尼有耐药性的 ALK融合阳性的非小细胞肺癌。
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