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 PDFInfo
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- 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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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
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- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic 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
- C07D471/02—Heterocyclic 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
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the 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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