WO2021083315A1 - 口服给药的固体剂型药物 - Google Patents

口服给药的固体剂型药物 Download PDF

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WO2021083315A1
WO2021083315A1 PCT/CN2020/125168 CN2020125168W WO2021083315A1 WO 2021083315 A1 WO2021083315 A1 WO 2021083315A1 CN 2020125168 W CN2020125168 W CN 2020125168W WO 2021083315 A1 WO2021083315 A1 WO 2021083315A1
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dosage form
cancer
solid dosage
compound
ast
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PCT/CN2020/125168
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English (en)
French (fr)
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段建新
李安蓉
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深圳艾欣达伟医药科技有限公司
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Priority to EP20882841.8A priority Critical patent/EP4052699A4/en
Priority to US17/773,339 priority patent/US20220395464A1/en
Publication of WO2021083315A1 publication Critical patent/WO2021083315A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4833—Encapsulating processes; Filling of capsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/564—Three-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats

Definitions

  • the present invention relates to the research and development of solid preparations of compounds disclosed in patent application PCT/US2016/021581, publication number WO2016145092A1, corresponding to Chinese application number 2016800150788, publication number CN107530556A, and belongs to the field of preparation research and development of cancer therapeutic compounds.
  • the DNA alkylating cancer therapeutic drug AST-3424 developed by our company targeting overexpression of aldehyde ketone reductase 1C3 (AKR1C3) (see patent application: DNA alkylating agent, corresponding to PCT application number PCT/US2016/021581, publication number WO2016/145092, corresponding to Chinese application number 2016800150788, the compound TH2870 disclosed in publication number CN107530556A; (R)- and (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxy- 4-Nitrophenyl)-1-ethyl-N,N'-bis(ethylene)amino phosphate, composition and its use and preparation method, corresponding to PCT application number PCT/US2016/062114, publication number WO2017087428A1 , Corresponding to the Chinese application number 2016800446081, the S configuration compound number in the publication number CN108290911A is TH3424.
  • the RS configuration of the compound is determined to be the S configuration after our company's subsequent derivatization into a solid and single crystal analysis.
  • the corresponding TH3423 (AST-3423) configuration is R configuration
  • the Chinese name is (S)-1-(3-(3-N,N-dimethylaminocarbonyl)phenoxy-4-nitro (Phenyl)-1-ethyl-N,N'-bis(ethylene) phosphoramidate, also known as the S configuration compound of OBI-3424 and TH-2870)
  • the CAS number is 209713-69-2
  • Its structure is as follows:
  • a suitable dosage form for human administration usually oral or injection administration.
  • AST-3424 which is all H atoms.
  • the deuterated compound at a specific position can reduce the "first pass effect" of the liver, and is more suitable as an oral dosage form Administration.
  • Orally administered solid dosage form drugs for the treatment of cancer or tumors or cell proliferative disorders which contain a compound of the following structural formula I or II,
  • the solid dosage form medicine is a tablet.
  • the tablet here refers to an oral tablet: it includes ordinary tablets, sustained-release tablets, etc., but obviously does not include sublingual tablets (the active ingredients of which enter the human blood circulation through the sublingual capillaries).
  • the pH value of the aqueous solution or dispersion of the tablet is greater than 6.8, more preferably 6.8 to 10.0.
  • the tablet contains the compound of structural formula I or II and pharmaceutical excipients, and the compound I or II is uniformly dispersed in the tablet, instead of being wrapped or laminated in the tablet.
  • the tablet wherein the pharmaceutical excipients include NaCO 3 , NaHCO 3 , NaOH, KH 2 PO 4 ; and/or
  • compositions include ethanol or propylene glycol.
  • Na 2 CO 3 , NaHCO 3 , NaOH, KH 2 PO 4 and other compounds are alkaline in aqueous solution. The purpose is to ensure that AST-3424 is in an alkaline environment.
  • the compounds listed here are only preferred and more suitable for clinical use. Obviously other compounds such as KOH, K 2 CO 3 , KHCO 3 , NaH 2 PO 4 etc. are also equivalent.
  • ethanol and propylene glycol is to further dissolve and dilute AST-3424, which is convenient for the preparation of the API of the crude drug of thick oil.
  • the solid dosage form medicine is an enteric-coated tablet.
  • the purpose of the above-mentioned ordinary tablets by designing the entire medicine into an alkaline environment is to be able to stably exist in the gastric acid environment for a certain period of time after entering the stomach.
  • the enteric-coated tablet solution provided here is designed to not decompose and release the drug in the stomach, namely:
  • the enteric-coated tablet includes enteric-coated and encapsulated tablets, and the tablet contains a compound of structural formula I or II and pharmaceutical excipients.
  • Enteric-coated tablet refers to a special tablet that does not disintegrate in gastric juice, but can disintegrate and absorb in intestinal juice. It is usually coated with an enteric coating on the outside of ordinary tablets.
  • enteric coating materials include shellac, cellulose acetate phthalate, seaweed gum, polyvinyl acetate phthalate, acrylic resin, and hydroxypropyl methylcellulose phthalate.
  • MMA methyl methacrylate
  • MAA methacrylic acid
  • BA butyl acrylate
  • Opadry trademark product of Colorcon, UK
  • the enteric-coated tablet wherein the pharmaceutical excipients include Na 2 CO 3 or NaHCO 3 or NaOH or KH 2 PO 4 ; and/or
  • compositions include ethanol or propylene glycol.
  • Na 2 CO 3 , NaHCO 3 , NaOH, KH 2 PO 4 and other compounds are alkaline in aqueous solution. The purpose is to ensure that AST-3424 is in an alkaline environment.
  • the compounds listed here are only preferred and more suitable for clinical use. Obviously other compounds such as KOH, K 2 CO 3 , KHCO 3 , NaH 2 PO 4 etc. are also equivalent.
  • ethanol and propylene glycol is to further dissolve and dilute AST-3424, which is convenient for the preparation of API APIs of thick oily substances.
  • the enteric-coated tablet wherein the pH value of the aqueous solution or dispersion of the tablet is greater than 6.8, more preferably 6.8 to 10.0.
  • the solid dosage form medicine is an enteric-coated capsule.
  • enteric-coated tablets mentioned above are coated with an enteric coating on the outside of the ordinary tablets, and the enteric-coated capsules contain the particles containing the drug API in the enteric-coated capsules, namely:
  • the enteric-coated capsules include empty enteric-coated capsules and filled drug mixtures.
  • enteric-coated capsules in fact, only add a special medicinal polymer material into the capsule shell or undergo special treatment to make it insoluble in the gastric juice, but only disintegrate and melt in the intestinal juice.
  • the capsule will not be dissolved in the stomach, or in soaking water or even boiling water.
  • enteric-coated capsules are made of gelatin and suitable enteric-coated materials, and are divided into ordinary enteric-coated capsules and colon-coated enteric-coated capsules.
  • enteric-coated capsules uses some new coating materials, such as phthalic acid.
  • phthalic acid Cellulose acetate, polyvinyl acetate phthalate, polyvinylpyrrolidone, methyl propyl cellulose and acrylic resins, etc.
  • the enteric-coated capsule wherein the drug mixture is a granule, and the granule contains a compound of structural formula I or II and pharmaceutical excipients.
  • the enteric-coated capsule wherein the pharmaceutical excipients include Na 2 CO3 or NaHCO3 or NaOH or KH2PO4; or
  • compositions include ethanol or propylene glycol.
  • Na 2 CO 3 , NaHCO 3 , NaOH, KH 2 PO 4 and other compounds are alkaline in aqueous solution. The purpose is to ensure that AST-3424 is in an alkaline environment.
  • the compounds listed here are only preferred and more suitable for clinical use. Obviously other compounds such as KOH, K 2 CO 3 , KHCO 3 , NaH 2 PO 4 etc. are also equivalent.
  • ethanol and propylene glycol is to further dissolve and dilute AST-3424, which is convenient for the preparation of API APIs of thick oily substances.
  • the material of the enteric-coated capsule contains gelatin, it is necessary to pay attention to the proper hygroscopicity of the particles. Otherwise, the excessive hygroscopicity of the drug particles will cause the capsule to become dehydrated and brittle and break.
  • the pH value of the aqueous solution or dispersion of the drug mixture is greater than 6.8, and further preferably 6.8 to 10.0.
  • the enteric-coated capsules include empty soft enteric-coated capsules and filled drug solutions.
  • the soft enteric-coated capsule wherein the drug solution contains a compound of structural formula I or II and a solvent, and the solvent is a mixed solvent of ethanol and propylene glycol.
  • the volume ratio of ethanol in the mixed solvent is not less than 50%.
  • the mixed solvent is composed of 75% ethanol and 25% propylene glycol by volume.
  • water is not added to the drug solution, and the water content is controlled within 0.5% by mass.
  • the total tumors, cancers or proliferative disorders in this article include:
  • Lung cancer non-small cell lung cancer, liver cancer, pancreatic cancer, stomach cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma , Basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, osteocytic carcinoma, epithelial carcinoma, cholangiocarcinoma, choriocarcinoma Carcinoma, embryonic carcinoma, seminoma, Wilms carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hematoblastoma, Vocal cord neuroma, meningiom
  • the preparation method of solid dosage form medicine includes the following operations:
  • the auxiliary materials, the ethanol solution of the compound of structural formula I or II, and an appropriate amount of water are mixed uniformly, and then the granulation is carried out;
  • the granulated material is dried or pressed directly without drying to obtain tablets;
  • the granulated material is poured into the capsule to obtain the capsule.
  • the application here is mainly to prepare the aforementioned tablets, enteric-coated tablets, enteric-coated hard capsules, and enteric-coated soft capsules.
  • Each minimum administrable dosage unit of the solid dosage form medicine contains 0.2, 0.5, 1.0 mg of the compound of the above-mentioned structural formula I or II.
  • each tablet for ordinary tablets, enteric-coated tablets
  • it can also be other contents, but according to the dosage, these contents are more convenient to take.
  • the preparation method of the compound of structural formula I or II includes reacting compound III and IV with compound V with or without the participation of a base to produce compound I or II:
  • X is a halogen atom, preferably F
  • M is H or an alkali metal or alkaline earth metal.
  • the base here is in a broad sense, and it can be inorganic bases such as KOH, NaOH, CH 3 ONa, and NaH, or salts that exhibit basicity such as K 2 CO 3 and KHCO 3.
  • the present invention is a re-development of the dosage form of AST-3424 drug, the present invention applies the following patent applications for AST-3424 API
  • DNA alkylating agent corresponding to PCT application number PCT/US2016/021581, publication number WO2016/145092, corresponding to Chinese application number 2016800150788, publication number CN107530556A disclosed compound TH2870;
  • the prepared medicine may also contain pharmaceutically acceptable excipients or excipients.
  • the pharmaceutically acceptable excipients or excipients in the medicine may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, correctives Flavoring agents, sweeteners, antioxidants, surfactants, preservatives, wrapping agents and colorings, etc.
  • Figure 1 is a graph showing the proliferation curve of deuterated and non-deuterated AST-3424 with and without AKR1C3 inhibitor;
  • Figure 2 is a graph showing the time-concentration curve of liver microsome metabolism of AST-3424-D6 and AST-3424;
  • Figure 3 is a graph of plasma drug concentration-time curve after administration of AST-3424-D6 and AST-3424 to cynomolgus monkeys.
  • Patient and “individual” are used interchangeably and refer to mammals in need of cancer treatment. Usually, the patient is a human. Generally, the patient is a human being diagnosed with cancer. In certain embodiments, “patient” or “individual” may refer to non-human mammals used for screening, characterizing, and evaluating drugs and therapies, such as non-human primates, dogs, cats, rabbits, pigs, mice Or rat.
  • Prodrug refers to a compound that is metabolized or otherwise converted into a compound (or drug) with at least one property of biological activity or higher activity after administration or administration.
  • prodrugs are chemically modified in such a way that they are less or inactive relative to the drug, but chemical modification allows the corresponding drug to be produced through metabolism or other biological processes after the prodrug is administered.
  • Prodrugs can have altered metabolic stability or delivery characteristics, fewer side effects or lower toxicity, or improved flavors relative to the active drug (see (for example) Reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388 to 392, which are incorporated herein by reference).
  • Prodrugs can be synthesized using reactants other than the corresponding drugs.
  • Solid tumor refers to a solid tumor including (but not limited to) metastatic tumors in bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin, and soft tissue (sarcoma).
  • the "therapeutically effective amount" of a drug refers to a drug that, when administered or administered to a patient suffering from cancer, will have the expected therapeutic effect (for example, alleviation, improvement, alleviation or elimination of the clinical manifestations of one or more cancers in the patient) ⁇ The amount.
  • the therapeutic effect does not have to occur through administration or administration of one dose, and may only occur after administration or administration of a series of doses. Therefore, the therapeutically effective amount can be administered or administered one or more times.
  • Treatment of a condition or patient refers to taking steps to obtain beneficial or desired results (including clinical results).
  • beneficial or desired clinical results include (but are not limited to) alleviation or improvement of one or more cancer symptoms; reduction of disease degree; delay or reduction of disease progression; improvement, alleviation or stabilization of disease state; Or other beneficial results.
  • treatment of cancer can result in a partial response or stabilize the disease.
  • Tumor cells refer to tumor cells of any appropriate species (e.g., mammals, such as murine, dog, cat, horse, or human).
  • Sodium hydroxide solution 0.2mol/L: Take 8.00g of sodium hydroxide [NaOH], add water to dissolve, add water to dilute to 1000ml.
  • Potassium dihydrogen phosphate 0.2mol/L: Take 27.22g of potassium dihydrogen phosphate [KH 2 PO 4 ], dissolve in water, and dilute to 1000ml with water.
  • Acetic acid, 2mol/L Measure 114.4ml of acetic acid, dilute to 1000ml with water, and mix well.
  • Boric acid and potassium chloride 0.2mol/L: Take 12.37g of boric acid [H 3 BO 3 ] and 14.91g of potassium chloride (KCl), dissolve in water, and dilute to 1000ml with water.
  • pH4.5 acetate buffer Take 2.99g of sodium acetate NaC 2 H 3 O 2 ⁇ 3H 2 O, put it in a 1000ml measuring flask, add 14.0ml of acetic acid solution, then add water to the mark and mix.
  • pH6.8 phosphate buffer Put 50ml of potassium dihydrogen phosphate solution in a 200ml measuring flask, add 22.4ml of sodium hydroxide solution, and then add water to the mark.
  • pH7.4 phosphate buffer Take 50ml of potassium dihydrogen phosphate solution, put it in a 200ml measuring flask, add 39.1ml of sodium hydroxide solution, and then add water to the mark.
  • pH10.0 alkaline borate buffer Take 50ml of boric acid and potassium chloride solution, put it in a 200ml measuring flask, add 43.7ml of sodium hydroxide solution, and then add water to the mark.
  • API AST-3424
  • AST-3424 (50% v/v, ethanol), put it in a 50ml volumetric flask, and add solvents (organic solvent, buffer solution or purified water) to the mark. At each predetermined time point, a 1 ml sample was measured for HPLC analysis. If the API is stable in different pH solutions, extend the sampling time point, for example, 5 days or more.
  • solvents organic solvent, buffer solution or purified water
  • HPLC method was used to determine content: AST-3424 was used as an external standard for quantification.
  • Table 3 summarizes the solution stability data of AST-3424.
  • API is unstable in pH4.5 solution and water, especially in pH4.5 acetate buffer.
  • AST-3424 is very unstable in pH 4.5 acetate buffer. Therefore, choose pH6.8 phosphate buffer, pH7.4 phosphate buffer, pH10.0 alkaline borate buffer and purified water for solubility test. Weigh an appropriate amount of AST-3424 to 40mL of medium (8mL for ethanol/propylene glycol, 50:50V/V) until there is excess flocculation in the solution. If the solubility of API in aqueous solution is> 2% (20 mg/ml), there is no need to add more API.
  • the solubility of AST-3424 in ethanol/propylene glycol (50:50, v/v) solution is greater than 270mg/mL.
  • the solubility of API in pH6.8, pH7.4 and pH10.0 is about 23mg/mL, and the solubility in water is about 20mg/mL. Since API is unstable in pH 6.8 and water, the solubility gradually decreases with time. At different times, the pH of the API solution in the medium of pH 6.8, pH 7.4, and pH 10.0 remained unchanged. In the aqueous solution containing API, the pH value gradually increased from pH 5.004 to pH 6.512 within 48 hours.
  • AST-3424 Solubility. Table 5 summarizes the solubility of AST-3424 in different solvents at 25°C. AST-3424 is easily soluble in alcoholic solvents such as ethanol/propylene glycol. Special researchers also preliminarily investigate other monohydric alcohols such as methanol, propanol, butanol and ethylene glycol, propylene glycol, glycerol, 1,3-butanedi Alcohol, 1,2-butanediol, etc., these solvents all have good solubility for APIs.
  • alcoholic solvents such as ethanol/propylene glycol.
  • Special researchers also preliminarily investigate other monohydric alcohols such as methanol, propanol, butanol and ethylene glycol, propylene glycol, glycerol, 1,3-butanedi Alcohol, 1,2-butanediol, etc., these solvents all have good solubility for APIs.
  • AST-3424 is slightly soluble in water, pH6.8 phosphate buffer, pH7.4 phosphate buffer and pH10.0 alkaline borate buffer.
  • AST-3424 is stable in pH 7.4 phosphate buffer, but has poor stability in water and pH 6.8 phosphate buffer. Therefore, the water content should be minimized in the production and storage of injections (the inventors speculate that It is that the N-containing three-membered ring structure in AST-3424 is prone to ring-opening and hydrolysis in the presence of water).
  • AST-3424 pharmaceutical preparation prescription investigation includes choosing various solvents and preparing different prescriptions.
  • the inventor team chose a prescription solvent composed of ethanol, propylene glycol, and triethanolamine (organic amine, used to condition the pH to make it alkaline). Prepare different prescriptions.
  • the dosages of 10 and 200 mg/mL were selected to prepare different prescriptions for research.
  • the HPLC method is used to monitor the chemical properties of the product, including content, related substances and ee value (enantiomeric excess) to determine the optimal formulation of AST-3424.
  • AST-3424 (dissolved in ethanol), put it in a suitable measuring flask, and add different solvents to make the final API concentration of 10mg/mL or 200mg/mL.
  • the different formulations are listed in Table 3 and Table 4. Measure one milliliter of the bulk solution and pour it into a 6ml brown vial. After being sealed with a rubber stopper and an aluminum cap, the pharmaceutical preparations are stored at -20 ⁇ 2°C, 5 ⁇ 2°C or 25 ⁇ 2°C, dark brown vials, and humidity 60 ⁇ 5%RH for different periods of time. At a predetermined time, samples are taken out and tested. The test method is the same as the solubility and solution stability of the first section above.
  • Table 8 Summary of the stability data of different formulations at 25°C (25 ⁇ 2°C)
  • F9 is the most stable prescription among other prescriptions.
  • the stability of the sample is significantly increased. Compared with the prescription stored at 2-8°C, the sample stored at -20°C is more stable.
  • Check stable prescriptions i.e. F1 (10mg/ml), F7 (10mg/ml), F9 (10mg/ml), F1-1 (10mg/ml), F1 (200mg/ml), F3 (200mg/ml) and F2 -1 (200mg/ml)
  • EE value of the relatively stable prescription is shown in Table 11. The EE values of all prescriptions remained unchanged for 6 months under different storage conditions, indicating that the active ingredients in these prescriptions did not undergo isomer conversion.
  • prescription F9 75.0% ethanol and 25.0% propylene glycol was selected as the final candidate prescription for the solution in the AST-3424 soft capsule.
  • the pH value of the aqueous solution or dispersion of the tablet is greater than 6.8, more preferably 6.8 to 10.0.
  • the pharmaceutical excipients are Na 2 CO 3 , NaHCO 3 , NaOH, KH 2 PO 4 ; ethanol or propylene glycol is more suitable.
  • the content of compound I or II in the drug solution is 1-270 mg/ml.
  • the medicinal solution in the soft capsule contains a compound of structural formula I or II and a solvent.
  • the solvent is a mixed solvent of ethanol and propylene glycol.
  • the mixed solvent is composed of 75% ethanol and 25% propylene glycol in a volume ratio that is relatively stable, facilitating stable storage of the soft capsule.
  • the manufacturing method can be divided into two types: compression method (molding method) and dripping method.
  • the first step is to prepare the capsule material glue. According to the capsule material formula, soak the gelatin in distilled water to make it swell. After the gelatin is melted, add other materials together, stir and mix evenly.
  • the second step is to make film. Take out the prepared capsule material glue solution, apply it on a flat board surface to make the thickness uniform, and then heat it at a temperature of about 90°C to evaporate the surface water and become a flexible film with a certain degree of toughness and elasticity.
  • the third step is to compress the soft capsule. In small batch production, it is manually pressed with a press pill mold; in large batch production, an automatic rotary capsule mill is often used for production.
  • the film here is modified gelatin, or other medical polymer materials are directly used to ensure that it will not disintegrate or release in the stomach, but will disintegrate and release in the intestinal tract.
  • the dripping method is completed by a dripping pill machine with a double dripper.
  • Gelatin-based soft capsule material generally referred to as glue
  • liquid medicine flow out at different speeds from the outer layer and inner layer of the double-layer dripper, respectively, so that the quantitative glue liquid wraps the quantitative liquid medicine.
  • the dripping method refers to the method of preparing soft capsules through a dripping machine. Pay attention to the formula and viscosity of the glue liquid, as well as the density and temperature of all added liquids.
  • the auxiliary materials include fillers (starch, dextrin, microcrystalline cellulose, etc.), lubricants, binders, disintegrants, etc.
  • the auxiliary materials added in this granulation operation are only part of the prescription. Add another part.
  • the amount of water added is as small as possible on the basis of granulation. If possible, it is best to use ethanol, propylene glycol, etc. without adding water.
  • the water content after adding water should be controlled within 0.5% by mass.
  • the auxiliary materials here include alkaline substances for adjusting pH, such as Na2CO3, NaHCO3, NaOH, KH2PO4 and so on.
  • Tablet After the granulated material is dried or not dried, add an appropriate amount of auxiliary materials (fillers, lubricants, binders, disintegrants, etc.), mix them evenly, and then press them directly to obtain tablets.
  • auxiliary materials fillers, lubricants, binders, disintegrants, etc.
  • enteric-coated tablets to obtain enteric-coated tablets.
  • enteric coating materials are cellulose acetate phthalate (CAP), polyacrylol phthalate (PVAP), methacrylic acid copolymer, cellulose acetate trimellit (CAT), hypromellose Phthalate (HPMCP), acrylic resin (Eudragit L100, Eu-dragit S100), etc.
  • the granulated materials are poured into enteric-coated capsules to obtain hard enteric-coated capsules.
  • IC50 values are reported in nanomoles and are obtained from exposure of the compound at each concentration for 2 hours, followed by a washing step and addition of fresh medium, then growth and cell viability staining and comparison with the medium-only control.
  • exponentially growing cells were seeded in a 96-well plate at a density of 4 ⁇ 10 3 cells/well and incubated at 37° C. in 5% CO 2 , 95% air and 100% relative humidity for 24 hours, and then Add test compound.
  • the compound was dissolved in 100% DMSO at 200 times the expected final test concentration.
  • complete medium is used to further dilute the compound to 4-fold the desired final concentration.
  • An aliquot of 50 ⁇ l of the compound at a specific concentration was added to a microwell that already contained 150 ⁇ l of medium to obtain the reported final drug concentration.
  • the plate was incubated at 37°C, 5% CO2, 95% air, and 100% relative humidity for another 2 hours, then the drug was washed off and fresh medium was added and the plate was heated at 37°C, 5% CO2, Incubate for another 70 hours under 95% air and 100% relative humidity.
  • AlamarBlue analysis was used to quantify live cells.
  • Computer software was used to calculate the drug concentration (IC50) that caused 50% growth inhibition, and the results are listed in the table below.
  • the cancer cell proliferation activity of the compound when the AKR1C3 enzyme is inhibited is measured by adding and not adding TH3021, an inhibitor of AKR1C3 (sufficient concentration).
  • Table 12 Cancer cell proliferation activity of deuterated and non-deuterated AST-3424 with and without AKR1C3 inhibitor
  • DNA alkylating agent corresponding to PCT application number PCT/US2016/021581, publication number WO2016/145092, corresponding to Chinese application number 2016800150788, publication number CN107530556A disclosed compound TH2870;
  • liver microsomes final concentration of 0.5mg/mL, human, male, mixed type purchase
  • reduced coenzyme NADPH final concentration of 2mM
  • buffer 100mM KH2PO4-K2HPO4
  • the compound concentration in each sample is expressed by the peak area ratio (the ratio of the peak area of the compound to the peak area of the internal standard), and then the compound concentration at 0 minutes is used as a reference to calculate the remaining percentage of the compound at each incubation time point (% Remaining ), linearly fit the logarithm of the remaining percentage of ln to the incubation time, and calculate the half-life and intrinsic clearance according to the following formula:
  • Remaining percentage% Remaining the ratio of the area under the peak at a certain time PAR appointedtime / the ratio of the area under the peak at 0 minutes PAR 0-min x 100 (PAR: area under the peak ratio peak area ratio)
  • Table 13 Stability test data of AST-3424 and AST-3424-D6 in human liver microsomes
  • liver microsomal metabolism curves of deuterated compound AST-3424-D6 and non-deuterated AST-3424 are similar, but it is obvious that AST-3424-D6 is more stable than non-deuterated AST-3424. In the same time, the remaining percentage is higher than 10%, showing that AST-3424-D6 has higher liver metabolic stability than AST-3424, and is more suitable for development as an oral dosage form.
  • AST-3424 and AST-3424-D6 were administered to cynomolgus monkeys by intravenous drip, and blood samples were collected at different time points.
  • LC-MS/MS determines the concentration of the test substance in the plasma of the cynomolgus monkey after the administration of the test substance and calculates the relevant pharmacokinetic parameters.
  • Preparation method Pipette 0.447mL of AST-3424 (0.2mg/ml) and 0.481mL of AST-3424-D6 (0.2mg/ml) into 104.272mL of the above solvent and stir for 5min to obtain a colorless pH of about 7 Clear solution.
  • the blood samples were collected on ice and centrifuged to separate the plasma (centrifugation conditions: 3500 rpm, 10 minutes, 4°C).
  • the collected plasma was stored at -80°C before analysis.
  • the plasma samples were analyzed by the analysis department of the laboratory using LC-MS/MS, and the LLOQ detected by AST-3424 and AST-3424-D6 was 1ng/mL.
  • the accuracy of the analysis results of the accompanying standard curve and quality control samples in the sample detection process meets the relevant requirements of biological analysis (more than 66.7% of the quality control samples have an accuracy of 85-115%).
  • the pharmacokinetic calculation software non-compartment model was used to calculate the pharmacokinetic parameters AUC 0-t , AUC 0- ⁇ , MRT 0- ⁇ of the test product. , C max , T max , t 1/2 and other parameters.
  • the samples sampled before reaching C max should be calculated as zero.
  • the sample at the sampling point should be regarded as unquantifiable (marked as "BLQ ”) Calculation.
  • Table 14 Plasma concentrations of AST-3424 and AST-3424-D6 in the plasma of cynomolgus monkeys after a single intravenous infusion
  • Table 15 The main pharmacokinetic parameters of AST-3424 and AST-3424-D6 in the plasma of cynomolgus monkeys after a single intravenous infusion
  • AUC(0-t) the area under the plasma concentration-time curve from time 0 to time t;
  • AUC(0- ⁇ ) the area under the plasma concentration-time curve when the time goes from 0 o'clock to infinity
  • Tmax the time of highest concentration
  • MRT(0-t) The average residence time during the time period from 0:00 to t;
  • MRT(0- ⁇ ) The average residence time from 0:00 to infinity
  • Vss steady state distribution volume
  • Vz Statistical moment parameter distribution volume
  • 101/102/103 is the number of the three animals.
  • Both AST-3424 and AST-3424-D6 were administered at a dose of 1 mg/kg, with a concentration of 0.2 mg/mL. By analyzing the dosing solution, the actual concentration of AST-3424 was 0.117 mg/mL. The actual concentration of AST-3424-D6 is 0.085mg/mL, and the actual dosage is 0.58mg/kg and 0.42mg/kg, respectively.
  • the integrated area under the AUC line of the drug-time curve of the new generation AST-3424 is smaller, that is, the exposure of AST-3424-D6 in the blood circulatory system is smaller than that of AST-3424, and the correspondingly less harmful to the blood circulatory system, that is, AST-3424 Compared with AST-3424-D6, AST-3424-D6 is more suitable for development as an injection, and AST-3424-D6 is more suitable for the development of solid tumors than AST-3424 (solid tumors are tumors that exclude blood tumors, blood tumors such as various leukemias) Oral drugs.
  • AST-3423-D6 R configuration, structural formula II
  • TH3423-D6 deuterated compound AST-3423-D6
  • TH3423 non-deuterated AST-3423
  • the curve should be similar, but it is obvious that AST-3423-D6 has a smaller integrated area under the AUC line of the drug-time curve of non-deuterated AST-3423, that is, the exposure of AST-3423-D6 in the blood circulatory system is smaller than that of AST-3423.
  • AST-3423 is more suitable for development as an injection than AST-3423-D6, and AST-3423-D6 is more suitable for development as a treatment for solid tumors than AST-3423 (solid tumors are excluded Oral drugs for tumors other than hematological tumors, hematological tumors such as various leukemias.
  • AST-3424-D6-A (30g, 0.217mol) was dissolved in anhydrous methanol (300mL), the temperature was raised to reflux, and thionyl chloride (51.7g, 0.335mol) was slowly added dropwise. After the ratio, reflux and stir, the reaction is completed in 6 hours. The thionyl chloride was concentrated, the residue was dissolved in ethyl acetate (200 mL), washed with water, brine, dried and concentrated, and MTBE methyl tert-butyl ether was beaten to obtain a pure product (30.4 g, 92.1%) as a white solid.
  • AST-3424-D6-B (15g, 98.6mmol) was dissolved in DMF (200mL), the temperature was reduced to 0°C, NaH (7.9g, 197.2, 60%) was added in batches, and the temperature was kept at 0°C for one hour.
  • Benzyl bromide (25.1 g, 147.9 mmol) was added dropwise, and after the dropping, the reaction was completed by stirring at room temperature for one hour.
  • AST-3424-D6-D (7.1g, 31.1mmol) and deuterated dimethylamine hydrochloride (3g, 34.3mmol, purchased) were added to ultra-dry dichloromethane (70mL), and propyl group was added Phosphoric anhydride (39.6g, 62.2mmol, 50% inEA), the temperature was lowered to 0°C, N,N-diisopropylethylamine (16g, 124.4mmol) was added dropwise, after the addition, the mixture was stirred at room temperature and the reaction was completed in four hours.
  • phosphorus oxychloride (1.2mL, 12.98mmol) was added to anhydrous dichloromethane (10mL), the temperature was reduced to -40°C, and AST-3424-D6-H (1.2g, 6.49mmol, Commercially available dichloromethane solution (10 mL), and then triethylamine (1.7 g, 16.87 mmol) in dichloromethane solution (10 mL) was added dropwise, and the temperature was kept at -40° C. for 6 hours. The conversion of the raw materials was completed.

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Abstract

治疗癌症或肿瘤或细胞增生性病症的口服给药的固体剂型药物，其含有如下结构式I或II的化合物。

Description

口服给药的固体剂型药物 技术领域
本发明涉及对专利申请PCT/US2016/021581，公开号WO2016145092A1，对应中国申请号2016800150788，公开号CN107530556A所公开的化合物的固体制剂研发，属于癌症治疗化合物的制剂研发领域。
背景技术
我公司开发的以过表达醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化癌症治疗药物AST-3424(参见专利申请：DNA烷化剂，对应PCT申请号PCT/US2016/021581,公开号WO2016/145092，对应中国申请号2016800150788，公开号CN107530556A中公开化合物TH2870；(R)-及(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法，对应PCT申请号PCT/US2016/062114,公开号WO2017087428A1，对应中国申请号2016800446081，公开号CN108290911A中的S构型化合物编号TH3424，其RS构型经我公司后续衍生为固体并进行单晶解析后确定TH3424(AST-3424)的构型为S构型，对应的TH3423(AST-3423)的构型为R构型)，中文名为(S)-1-(3-(3-N,N-二甲氨基羰基)苯氧基-4-硝基苯基)-1-乙基-N,N'-双(亚乙基)氨基磷酸酯，也称为OBI-3424、TH-2870的S构型化合物)，CAS号为2097713-69-2，其结构如下：
Figure PCTCN2020125168-appb-000001
已有行业权威文献(KathrynEvans,JianXinDuan,TaraPritchard,etal.OBI-3424,anovelAKR1C3-activatedprodrug,exhibitspotentefficacyagainstpreclinicalmodelsofT-ALL[J]，ClinicalCancerResearch,2019,DOI:10.1158/1078-0432.CCR-19-0551；RichardB.Lock,KathrynEvans,RaymondYung,TaraPritchard,BeverlyA.Teicher,JianXinDuan,YuelongGuo,StephenW.EricksonandMalcolmA.Smith，AbstractLB-B16:TheAKR1C3-ActivatedProdrugOBI-3424ExertsProfoundInVivoEfficacyAgainstPreclinicalModelsofT-CellAcuteLymphoblasticLeukemia(T-ALL)；aPediatricPreclinicalTestingConsortiumStudy[C]，AACR-NCI-EORTCInternationalConference:MolecularTargetsandCancerTherapeutics；October26-30,2017；Philadelphia,PA，DOI:10.1158/1535-7163.)证实该化合物为一种广谱的小分子抗癌前药,对多种实体肿瘤和血液肿瘤具有疗效。
为了进行后续的临床试验，需要制备合适的剂型进行人体给药：通常是口服或是注射给药。
由于该化合物不是固体，为油状物，虽然我公司已经在临床试验阶段开发出了注射剂，但在某些国家，比如美国、欧洲地区，当地的患者并不太愿意使用注射的给药方式，而且当地的医生和药师更乐意给患者开具口服的固体制剂：口服对于患者而言便于自我给药而不需要到医疗机构花费高昂的费用请医护人员提供注射或是静脉滴注给药，同时口服的风险较小，对于医生和药师而言，风险比较小。
因此有必要开发固体制剂。
发明内容
为了解决上述技术问题，公司研发人员通过实验意外发现AST-3424特定位置的H被D取代后的氘代化合物，具有更好的肝代谢稳定性，而其他药效学、药代特性与普通H原子的AST-3424化合物相当，即下列结构的化合物：
Figure PCTCN2020125168-appb-000002
在经过肝脏代谢过程中，具有更好的稳定性，而其他特性与全部为H原子的AST-3424相当，特定位置氘代后的化合物能够减弱肝脏的“首过效应”，更适合作为口服剂型给药。
为此提出以下的技术方案。
技术方案一
治疗癌症或肿瘤或细胞增生性病症的口服给药的固体剂型药物，其含有如下结构式I或II的化合物，
Figure PCTCN2020125168-appb-000003
进一步，所述的固体剂型药物，其为片剂。显然，这里的片剂是指口服的片剂：包含普通的片剂，缓释片剂等，但显然不包括舌下含片(其有效成分通过舌下毛细血管进入人体血液循环中)。
进一步，药片的水溶液或水分散液的pH值大于6.8，进一步优选为6.8至10.0。
之所以会出现如此的pH值，是因为经过实验发现AST-3424化合物的溶液在pH＝6.8或以上时比较稳定，为此经过处方调整在片剂中添加各种辅料、原料后会使得药片在溶解后自动呈现出该pH值。
显然，药片中含有结构式I或II的化合物以及药用辅料，化合物I或II是均匀分散在药片中的，而不是被包裹或层压在药片中。
所述的药片，其中药用辅料包括NaCO 3、NaHCO 3、NaOH、KH 2PO 4；和/或
药用辅料包括乙醇或丙二醇。
显然，Na 2CO 3、NaHCO 3、NaOH、KH 2PO 4这些化合物都是水溶液碱性的，目的是保证AST-3424处于碱性环境，这里列举的化合物只是优选的比较适合于临床使用的，显然其他的化合物比如KOH、K 2CO 3、KHCO 3、NaH 2PO 4等也是等同的。
而使用乙醇、丙二醇则是为了进一步的溶解、稀释AST-3424，便于对浓稠油状物的原 料药API进行制剂操作。
进一步，作为一种优选，所述的固体剂型药物，其为肠溶片。
显然上述的普通片剂通过将整个药品设计为碱性环境目的就是为了在进入胃中能够在胃酸环境中稳定存在一定时间。而这里提供的肠溶片方案则设计为不在胃中分解释放药物，即：
所述肠溶片包括肠溶包衣和被包裹在内的药片，该药片含有结构式I或II的化合物以及药用辅料。
肠溶片是指在胃液中不崩解、而在肠液中能够崩解吸收的一种特殊的片剂。它通常是在普通片剂外面包裹一层肠溶包衣。
肠溶包衣材料常见的有：虫胶、苯二甲酸醋酸纤维素、海藻胶、聚乙烯醇醋酸苯二甲酸酯、丙烯酸树脂、羟丙基甲基纤维素酞酸酯等。其中，甲基丙烯酸甲酯(MMA)、甲基丙烯酸(MAA)和丙烯酸丁酯(BA)的三元共聚物及新型包衣材料欧巴代(英国卡乐康Colorcon公司商标产品
Figure PCTCN2020125168-appb-000004
)在肠溶药物制剂中展示了广阔的前景。
所述的肠溶片，其中药用辅料包括Na 2CO 3或NaHCO 3或NaOH或KH 2PO 4；和/或
药用辅料包括乙醇或丙二醇。
显然，Na 2CO 3、NaHCO 3、NaOH、KH 2PO 4这些化合物都是水溶液碱性的，目的是保证AST-3424处于碱性环境，这里列举的化合物只是优选的比较适合于临床使用的，显然其他的化合物比如KOH、K 2CO 3、KHCO 3、NaH 2PO 4等也是等同的。
而使用乙醇、丙二醇则是为了进一步的溶解、稀释AST-3424，便于对浓稠油状物的原料药API进行制剂操作。
所述的肠溶片，其中，所述药片的水溶液或水分散液的pH值大于6.8，进一步优选为6.8至10.0。
作为一种优选，所述的固体剂型药物，其为肠溶胶囊。
显然上述的肠溶片通过在普通片剂外包覆肠溶包衣，肠溶胶囊将含有药物API的颗粒盛装在肠溶胶囊中，即：
所述肠溶胶囊包括空的肠溶胶囊和填充在内的药物混合物。
所谓的肠溶胶囊，其实只是在囊壳中加入了特殊的药用高分子材料或经特殊处理，使其在胃液中不溶解，仅在肠液中崩解溶化。该胶囊在胃内，或者说泡水里甚至沸水里，都不会被溶解。
通常的，肠溶胶囊用明胶和适宜的肠溶材料制成，分为普通肠溶胶囊和结肠溶肠溶胶囊，现在肠溶胶囊的工业化生产使用一些新的包衣材料，如邻苯二甲酸醋酸纤维素、邻苯二甲酸聚乙酸乙烯酯、聚乙烯毗咯烷酮、经甲基丙基纤维素及丙烯酸树脂类等。
所述的肠溶胶囊，其中，所述药物混合物为颗粒，该颗粒含有结构式I或II的化合物、药用辅料。
所述的肠溶胶囊，其中药用辅料包括Na 2CO3或NaHCO3或NaOH或KH2PO4；或
药用辅料包括乙醇或丙二醇。
显然，Na 2CO 3、NaHCO 3、NaOH、KH 2PO 4这些化合物都是水溶液碱性的，目的是保证AST-3424处于碱性环境，这里列举的化合物只是优选的比较适合于临床使用的，显然其他的化合物比如KOH、K 2CO 3、KHCO 3、NaH 2PO 4等也是等同的。
而使用乙醇、丙二醇则是为了进一步的溶解、稀释AST-3424，便于对浓稠油状物的原料药API进行制剂操作。
如果肠溶胶囊的材料含有明胶，那么需要注意颗粒的吸湿性合适，否则药物颗粒具有过强的吸湿性会导致胶囊脱水脆化而破裂。
所述的肠溶胶囊，其中，所述药物混合物的水溶液或水分散液的pH值大于6.8，进一 步优选为6.8至10.0。
作为一种选择，所述的肠溶胶囊包括空的软肠溶胶囊和填充在内的药物溶液。
所述的软肠溶胶囊，其中，所述药物溶液含有结构式I或II的化合物和溶剂，溶剂为乙醇和丙二醇的混合溶剂。
所述的软肠溶胶囊，其中，所述混合溶剂中乙醇的体积比不小于50％。
所述的软肠溶胶囊，其中，所述混合溶剂由体积比75％的乙醇和25％的丙二醇组成。
所述的软肠溶胶囊，其中，所述药物溶液不添加水，水含量控制在质量比0.5％内。
显然，在本文总肿瘤、癌症或增生性病症包括：
肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、子宫内膜癌、胶质瘤、结直肠癌、甲状腺癌、尿路上皮癌或多发性骨髓瘤。
技术方案二
固体剂型药物制备方法，包括以下操作：
混合造粒，将辅料、结构式I或II的化合物的乙醇溶液、适量水混合均匀后，进行造粒；
压片，将造粒后的物料干燥或未经干燥直接压片，即得片剂；
将药片进行包衣，即得肠溶片；
造粒后的物料灌入到胶囊中即得胶囊。
技术方案三
结构式I或II的化合物，
Figure PCTCN2020125168-appb-000005
Figure PCTCN2020125168-appb-000006
技术方案四
结构式I或II的化合物在制备治疗癌症或肿瘤或细胞增生性病症的口服给药的固体剂型药物中的用途，
Figure PCTCN2020125168-appb-000007
显然这里的用途主要是制备上述的片剂、肠溶片、肠溶硬胶囊、肠溶软胶囊的用途。
所述固体剂型药物的每个最小可服用剂量单位中，含有上述结构式I或II的化合物的含量0.2、0.5、1.0mg。
具体到每一个剂型而言，就是每片(对于普通药片、肠溶片)、每颗(对于肠溶硬胶囊、肠溶软胶囊)含有化合物I或II的质量为0.2、0.5、1.0mg。当然，也可以为其他的含量，只是根据剂量而言，这几个含量比较方便服用。
结构式I或II的化合物的制备方法，其包括将化合物III和IV与化合物V在碱参与或不参与的情况下反应来生成化合物I或II：
Figure PCTCN2020125168-appb-000008
其中，X为卤素原子，优选为F，M为H或碱金属、碱土金属。
这里的碱是广义的，可以为KOH、NaOH、CH 3ONa、NaH等无机碱，也可以是K 2CO 3、KHC0 3等呈现碱性的盐。
当M为H时，一般需要使用碱作为缚酸剂来促进反应的进行。当然即使不加碱反应也可进行，但反应可能较慢。
由于本发明是对AST-3424药物的剂型进行再研发，因此本发明将下列关于AST-3424原料药API的专利申请
DNA烷化剂，对应PCT申请号PCT/US2016/021581,公开号WO2016/145092，对应中国 申请号2016800150788，公开号CN107530556A中公开化合物TH2870；
(R)-及(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法，对应PCT申请号PCT/US2016/062114,公开号WO2017087428A1，对应中国申请号2016800446081，公开号CN108290911，公开的内容引入本文。
本文中对于定义概念有与上述申请不同或差别的，以本文为准；本文中出现的概念或是定义未有明确定义或是限制的，均遵照上述申请进行定义；其余本文及上述申请未定义的以有机化学、药物化学、药剂学的教科书、手册等为准。
关于本文所述用途，所制得的药物还可包含药学上可接受的辅料或赋形剂。所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂和色素等。
附图说明
附图1为添加和不添加AKR1C3的抑制剂条件下，氘代和非氘代的AST-3424的癌细胞增殖曲线图；
附图2为AST-3424-D6和AST-3424的肝微粒体代谢时间-浓度曲线图；以及
附图3为食蟹猴给予AST-3424-D6和AST-3424后血浆药物浓度-时间曲线图。
具体实施方式
以下参照具体的实验数据来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
“患者”及“个体”可互换使用，是指需要癌症治疗的哺乳动物。通常，患者是人类。通常，患者是诊断患有癌症的人类。在某些实施例中，“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物，例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物，前药以使其相对于药物活性较低或无活性的方式化学修饰，但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味(参见(例如)参考文献Nogrady，1985，Medicinal Chemistry A Biochemical Approach，0xford University Press，New York，第388页至392页，其以引用式并入本文中)。前药可使用除相应药物以外的反应物来合成。
“实体肿瘤”是指包括(但不限于)骨、脑、肝、肺、淋巴结、胰脏、前列腺、皮肤及软组织(肉瘤)中的转移肿瘤的实体肿瘤。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用时，将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现，且可仅在投与或施用一系列剂量后出现。因此，治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的，有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善；疾病程度的减弱；疾病进展的延迟或减缓；疾病状态的改善、缓解或稳定；或其他有益结果。在一些情形下，癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如，哺乳动物，例如鼠类、犬、猫、马或人类)的肿瘤细胞。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
一、AST-3424(全部为H原子)溶解性、溶液稳定性研究
1.1缓冲液/溶液制备
只要目标浓度不变，可使用与规定不同的贮备溶液和缓冲液的体积。
氢氧化钠溶液，0.2mol/L:取氢氧化钠[NaOH]8.00g，加水溶解，加水稀释至1000ml。
磷酸二氢钾，0.2mol/L:取磷酸二氢钾[KH 2PO 4]27.22g，加水溶解，加水稀释至1000ml。
醋酸，2mol/L:量取醋酸114.4ml，加水稀释至1000ml，混合均匀。
硼酸和氯化钾，0.2mol/L:取硼酸[H 3BO 3]12.37g和氯化钾(KCl)14.91g，加水溶解，加水稀释至1000ml。
pH4.5醋酸盐缓冲液。取醋酸钠NaC 2H 3O 2·3H 2O2.99g，置1000ml量瓶中，加醋酸溶液14.0ml，然后加水至刻度，混合。
pH6.8磷酸盐缓冲液。磷酸二氢钾溶液50ml，置200ml量瓶中，加氢氧化钠溶液22.4ml，然后加水至刻度。
pH7.4磷酸盐缓冲液。取磷酸二氢钾溶液50ml，置200ml量瓶中，加氢氧化钠溶液39.1ml，然后加水至刻度。
pH10.0碱性硼酸盐缓冲液。取硼酸和氯化钾溶液50ml，置200ml量瓶中，加氢氧化钠溶液43.7ml，然后加水至刻度。
1.2溶解度检验
取AST-3424(以下称为原料药或API)适量，置装有上述的40ml溶液(对于有机溶剂为20ml)的适宜容器中，直至溶液中存在过量的AST-3424油滴。
将样品放入恒温振摇培养箱中，维持温度为25℃，按适宜速度(100rpm)振摇。依照表1中的规定，在每个预定时间点处取样，检查pH，然后离心分离(10000rpm，10分钟)，加相应的溶液或有机溶剂(溶解API供溶解度研究)稀释至HPLC分析的适宜浓度(注：精确记录试验后的稀释比例)，以得到溶解度数据。
如果观察到明显下降的溶解度，则不需要检验48h和72h的溶解度。
表1：取样时间和溶解度检验项目
溶液/缓冲液 1h 4h 8h 24h 48h 72h
乙醇 A A A A A A
丙二醇 A A A A A A
pH4.5醋酸钠缓冲液 A，P A，P A，P A，P A，P A，P
pH6.8磷酸盐缓冲液 A，P A，P A，P A，P A，P A，P
pH7.4磷酸盐缓冲液 A，P A，P A，P A，P A，P A，P
pH10.0碱性硼酸盐缓冲液 A，P A，P A，P A，P A，P A，P
纯化水 A，P A，P A，P A，P A，P A，P
备注：A＝含量测定，测定溶液中AST-3424的含量；P＝pH
1.3溶液稳定性研究
取AST-3424(50％v/v，乙醇)约107.32mg，置50ml容量瓶中，分别加溶剂(有机溶剂、缓冲溶液或纯化水)至刻度。在每个预定时间点处，量取1ml样品供HPLC分析。如果API在不同pH溶液中稳定，延长取样时间点，例如5天或更久。具体取样时间以及检测项目见下表2。
表2：溶液稳定性研究的样品分析时间
溶液/缓冲液 0h 1h 4h 8h 24h 48h 72h
乙醇 A A A A A A A
丙二醇 A A A A A A A
pH4.5醋酸钠缓冲液 A，P A A A A A A，P
pH6.8磷酸盐缓冲液 A，P A A A A A A，P
pH7.4磷酸盐缓冲液 A，P A A A A A A，P
pH10.0碱性硼酸盐缓冲液 A，P A A A A A A，P
纯化水 A，P A A A A A A，P
备注：A＝含量测定，测定溶液中AST-3424的含量以及HPLC峰纯度和总杂质；P＝pH
1.4测试方法
对于溶解度研究的含量测定样品，量取培养基约1ml，然后按10000rpm离心分离10分钟，收集下层澄明溶液供HPLC分析。对于溶液稳定性研究，可将样品直接进样至HPLC供分析。
使用HPLC法测定含量：以AST-3424作为外标进行定量。
UVDAD检测器波长230nm，C18柱，柱温25℃。
流动相：
A：乙酸铵溶于95％水和5％乙腈体积比的混合溶剂的10mmol/L乙酸铵溶液；
B：乙酸铵溶于95％乙腈和5％水体积比的混合溶剂的8mmol/L乙酸铵溶液；
进行梯度洗脱。
1.5测试结果
表3中总结了AST-3424的溶液稳定性的数据。AST-3424的溶液稳定性结果表明，室温条件下，API在乙醇、乙醇/丙二醇＝1/1、pH7.4和pH10.0缓冲溶液中至少72h稳定，在pH6.8溶液中至少24h稳定。API在pH4.5溶液和水中不稳定，特别是在pH4.5乙酸盐缓冲液中。
表3：AST-3424在不同溶液中的溶液稳定性研究结果
Figure PCTCN2020125168-appb-000009
根据溶液稳定性结果，AST-3424在pH4.5乙酸盐缓冲液中的非常不稳定。因此，选择pH6.8磷酸盐缓冲液、pH7.4磷酸盐缓冲液、pH10.0碱性硼酸盐缓冲液和纯化水进行溶解度测试。称取适量AST-3424至40mL介质中(乙醇/丙二醇用8mL，50:50V/V)，直到溶液中存在过量絮状物。如果API在水溶液中的溶解度＞2％(20毫克/毫升)，则不需要添加更多的API。
表4：AST-3424的溶解性研究结果
Figure PCTCN2020125168-appb-000010
AST-3424在乙醇/丙二醇(50:50,v/v)溶液中的溶解度大于270mg/mL。API在pH6.8，pH7.4和pH10.0中的溶解度均约为23mg/mL，在水中的溶解度约为20mg/mL。由于API在pH6.8和水中不稳定，溶解度随时间增加而逐渐降低。不同时间下，API在pH6.8、pH7.4、pH10.0介质中的溶液pH保持不变。含有API的水溶液中，其pH值在48h内从pH5.004逐渐增加至pH6.512。
1.6与溶液相关的理化性质总结
溶解度。表5概括了25℃下AST-3424在不同溶剂中的溶解度。AST-3424易溶于乙醇/丙二醇等醇类溶剂，特别的研究人员还初步考察其他的如甲醇、丙醇、丁醇等一元醇和乙二醇、丙二醇、丙三醇、1,3-丁二醇、1,2-丁二醇等，这些溶剂对原料药均具有较好的溶解性。
AST-3424略溶于水，pH6.8磷酸盐缓冲液，pH7.4磷酸盐缓冲液和pH10.0碱性硼酸盐缓冲液。
此外，AST-3424在pH7.4磷酸盐缓冲液中稳定，但在水和pH6.8磷酸盐缓冲液中稳定性较差，因此注射剂的生产和存储中应尽量减少水含量(发明人推测可能是AST-3424中的含N三元环结构在水存在下容易开环水解变质)。
表5：AST-3424溶解度
Figure PCTCN2020125168-appb-000011
以上实验证明了AST-3424化合物溶解度以及pH稳定性，为固体制剂辅料的选择提供了依据。
二、AST-3424溶液处方设计及稳定性研究
通过以上的溶解性以及溶液稳定性研究揭示的有关AST-3424在碱性条件下稳定的性质，进行了溶液处方设计、配制及稳定性研究。
2.1处方设计及配制
AST-3424药物制剂处方考察包括选择各种溶剂，制备不同的处方。
从物质的毒性以及注射剂的溶剂安全性、易得等角度进行考虑后，发明人团队选择乙醇、丙二醇及三乙醇胺(有机胺，用于条件pH值使其为碱性)等组成的处方溶剂，制备不同的处方。
然后根据溶解度，选择10、200mg/mL的剂量以制备不同的处方，进行研究。
随后在-20℃、2-8℃和25℃下进行这些不同处方的稳定性研究。
使用HPLC方法来监测产品的化学性质，包括含量、有关物质和ee值(对映体过量)以确定AST-3424的最优处方。
下表6列出了10mg/mLAST-3424溶液的不同处方组成
表6：AST-3424溶液的不同处方组成(10mg/mL)
Figure PCTCN2020125168-appb-000012
下表7列出了200mg/mLAST-3424溶液的不同处方组成
表7：AST-3424溶液的不同处方组成(200mg/mL)
Figure PCTCN2020125168-appb-000013
准确称量AST-3424(溶解于乙醇)，置适用的量瓶中，然后加不同溶剂，制成10mg/mL或200mg/mL的API最终浓度。不同处方组成列在表3和表4中。量取一毫升散装溶液，灌注至6ml棕色西林瓶中。用橡皮塞和铝盖密封后，将药物制剂在-20±2℃、5±2℃或25±2℃，避光棕色西林瓶、湿度60±5％RH下贮藏不同时长。在预定时间处，取出样品并检验。检验方法和上述第一节的溶解性、溶液稳定性一样。
2.2稳定性试验结果
在每个预定时间处，取出样品，对溶液中的原料药含量、有关物质(就是杂质)进行HPLC检测，得到表8-10的取样时间表分析含量和有关物质的稳定性试验数据。
表8：不同处方在25℃下稳定性的数据总结(25±2℃)
Figure PCTCN2020125168-appb-000014
表9：不同处方在5℃下稳定性的数据总结(2-8℃)
Figure PCTCN2020125168-appb-000015
表10：不同处方在-20℃下稳定性的数据总结(-22--18℃)
Figure PCTCN2020125168-appb-000016
将比较稳定的7个处方的EE值测定并记录如下表11：
表11：相对稳定处方的EE％值
Figure PCTCN2020125168-appb-000017
备注：/表示没有测试；TBD表示未检测，*表示该数据为坏值；ND表示低于仪器检测限而未检测到；N/A表示未添加，不含有。
2.3结果和讨论
AST-3424溶液的不同处方的稳定性结果，见表8-11。对于25℃下贮藏的不同处方的稳定性结果，发现处方的稳定性随处方中乙醇的比例升高而增大。对于含三乙醇胺的处方，这些处方的稳定性低于不含三乙醇胺的处方。
在10mg/ml的剂量规格下，F9是其他处方中最稳定的处方。
对于2-8℃和-20℃下贮藏的处方，样品的稳定性显著升高。与2-8℃下贮藏的处方相比，-20℃下贮藏的样品更稳定。检验稳定处方(即F1(10mg/ml)、F7(10mg/ml)、F9(10mg/ml)、F1-1(10mg/ml)、F1(200mg/ml)、F3(200mg/ml)和F2-1(200mg/ml))的对映体过量(EE)，相对稳定处方的EE值见表11。所有处方的EE值，在不同贮藏条件下6个月未改变，表明这些处方中的活性成分未发生异构体转化。
通过比较不同处方的稳定性试验结果，可知：
(1)根据上表处方筛选研究结果，随着处方中乙醇的比例增加，药物制剂的稳定性随之提高。另一方面，如果在制剂中加入三乙醇胺，则药物制剂就变得不稳定。
(2)稳定性研究结果表明，药物制剂在-20℃下的贮藏温度比在2-8℃或25℃下贮藏更稳定。贮藏温度对药物制剂稳定性有显著影响。
(3)通过AST-3424药物制剂浓度筛选，确定了代码为F9的候选处方是候选处方中最稳定的。六个月稳定性结果显示相关物质和ee值检测项目没有显著变化。
(4)根据处方考察结果，选取处方F9(75.0％乙醇和25.0％丙二醇)作为AST-3424软胶囊中溶液的最终候选处方。
以上第一、第二实验部分，证明：
药片的水溶液或水分散液的pH值大于6.8，进一步优选为6.8至10.0。
药用辅料选用Na 2CO 3、NaHCO 3、NaOH、KH 2PO 4；乙醇或丙二醇是比较合适的。
药物溶液中化合物I或II的含量为1-270mg/ml。
软胶囊中药物溶液含有结构式I或II的化合物和溶剂，溶剂为乙醇和丙二醇的混合溶剂，混合溶剂由体积比75％的乙醇和25％的丙二醇组成比较稳定，便于软胶囊稳定的存储。
对于软胶囊而言，制作方法可分为压制法(模压法)和滴制法两种。
压制法。
第一步，要配制囊材胶液。根据囊材配方，将明胶放入蒸馏水中浸泡使其膨胀，待明胶溶化后把其他物料一并加入，搅拌混合均匀。第二步，制胶片。取出配制好的囊材胶液，涂在平坦的板表面上，使厚薄均匀，然后用90℃左右的温度加热，使表面水分蒸发，成为有一定韧性、有一定弹性的软胶片。第三步，压制软胶囊。小批量生产时，用压丸模手工压制；大批量生产时，常采用自动旋转轧囊机进行生产。这里的胶片是经过改性的明胶，或直接使用其他医用高分子材料，保证在胃中不崩解不释放，而是在肠道中崩解释放。
滴制法
滴制法由具双层滴头的滴丸机完成。以明胶为主的软质囊材(一般称为胶液)与药液，分别在双层滴头的外层与内层以不同速度流出，使定量的胶液将定量的药液包裹后，滴入与胶液不相混溶的冷却液中，由于表面张力作用使之形成球形，并逐渐冷却、凝固成软胶囊，如常见的鱼肝油胶丸等。
滴制法是指通过滴制机制备软胶囊的方法。制作时需注意胶液的配方、粘度，以及所有添加液的密度与温度。
对于药片而言，主要包括以下操作：
混合造粒。将辅料、结构式I或II的化合物的乙醇溶液(根据情况添加乙二醇)、适量水混合均匀后，进行造粒。
显然，辅料包括填充剂(淀粉、糊精、微晶纤维素等)、润滑剂、粘合剂、崩解剂等，本次造粒操作添加的辅料只是处方的一部分，后续在压片中会添加另一部分。
特别的，根据情况在混合均匀后添加乙醇、水来进行润湿，一般的添加的水量在能够进行造粒的基础上越少越好，如果可以最好不添加水而使用乙醇、丙二醇等达到润湿的效果，添加水后水含量应控制在质量比0.5％内。
这里的辅料包含调节pH碱性物质，如Na2CO3、NaHCO3、NaOH、KH2PO4等。
压片。将造粒后的物料干燥或未经干燥后，添加适量辅料(填充剂、润滑剂、粘合剂、崩解剂等)混合均匀后直接压片，即得片剂。
将药片进行肠溶包衣，即得肠溶片。肠溶型包衣材料常用的有醋酸纤维素酞酸酯(CAP)、聚丙烯醇酞酸酯(PVAP)、甲基丙烯酸共聚物、醋酸纤维素苯三酸酯(CAT)、羟丙甲纤维素酞酸酯(HPMCP)、丙烯酸树脂(Eudragit L100、Eu-dragit S100)等。
造粒后的物料灌入到肠溶胶囊中即得硬肠溶胶囊。
三、AST-3424与AST-3424-D6(即结构式I的化合物)的体外癌细胞抑制比较
通过体外活性癌细胞增殖抑制试验来评价化合物的活性
Figure PCTCN2020125168-appb-000018
H460非小细胞肺癌人类肿瘤细胞系的活体外增殖数据报告于下文化合物表中。
IC50值是以纳摩尔报告且自以下得到：将化合物以各浓度暴露达2小时，随后洗涤步骤并添加新鲜培养基，然后生长及细胞存活率染色并与仅经培养基处理的对照比较。
特定而言，以4×10 3个细胞/孔密度将指数生长的细胞接种于96孔板中且在37℃下在5％CO 2、95％空气及100％相对湿度中培育24小时，然后添加测试化合物。将化合物以200倍的期望最终测试浓度溶解于100％DMSO中。在添加药物时，使用完全培养基将化合物进一步稀释至4倍的期望终浓度。将50μl特定浓度的化合物的等份试样添加至已含有150μl培养基的微量孔中，得到所报告的最终药物浓度。在药物添加之后，将板在37℃、5％CO2、95％空气及100％相对湿度下再培育2小时，然后将药物洗掉且添加新鲜培养基且将板在37℃、5％CO2、95％空气及100％相对湿度下再培育70小时。在此培育结束时，使用AlamarBlue分析来量化活细胞。使用计算机软件计算导致50％生长抑制的药物浓度(IC50)，且结果列示于下表中。
通过添加和不添加AKR1C3的抑制剂TH3021(足够抑制的浓度)来测量化合物在AKR1C3酶是否被抑制时的癌细胞增殖活性。
结果如下表12所示，将原始数据作图得图1。
表12：添加和不添加AKR1C3的抑制剂条件下，氘代和非氘代的AST-3424的癌细胞增殖活性
化合物 IC50(nmol)
AST-3424-D6(图1中1) <4.57
AST-3424-D6+TH3021(图1中2) 109.2
AST-3424-D6(图1中3) <4.57
AST-3424-D6+TH3021(图1中4) 164.7
AST-3424文献(图1中5) <4.57
AST-3424+TH3021文献(图1中6) 140.6
文献表示在下述申请
DNA烷化剂，对应PCT申请号PCT/US2016/021581,公开号WO2016/145092，对应中国申请号2016800150788，公开号CN107530556A中公开化合物TH2870；
(R)-及(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法，对应PCT申请号PCT/US2016/062114,公开号WO2017087428A1，对应中国申请号2016800446081，公开号CN108290911A中的S构型化合物
中测试的活性。
比较图1和表12可知，氘代化合物AST-3424-D6和非氘代的AST-3424的体外活性是类似的，没有本质区别。
四、AST-3424与AST-3424-D6(即结构式I的化合物)的肝微粒体稳定性比较
将化合物与肝微粒体(终浓度为0.5mg/mL，人，雄性，混合型购买)以及还原辅酶NADPH(终浓度为2mM)混合，在37℃条件下于缓冲液(100mM KH2PO4-K2HPO4)中分别孵育0,5,15,30,45和60分钟。到指定的孵育时间点时，加入内标溶液终止反应。最后，离心处理样品，取上清用LC-MS/MS检测。
通过质谱分析，各样品中的化合物浓度用峰面积比(化合物的峰面积与内标峰面积比值)来表示，然后以0分钟的化合物浓度为参照计算各孵育时间点的化合物剩余百分比(％Remaining)，将剩余百分比的ln对数值与孵育时间线性拟合，并根据以下公式计算半衰期(Half-life)和清除率(Intrinsic clearance)：
剩余百分比％Remaining＝某个时间的峰下面积比PAR appointedtime/0分钟时的峰下面积比PAR 0-min x 100(PAR:峰下面积比peak area ratio)
消除速率常数The elimination rate constant(k)＝斜率的负数(-gradient)
半衰期Halflife(t 1/2)(minutes)＝0.693/k
体外固有清除率In vitro clearance(CLint,in vitro)(ml/min/mg)＝k/c,
c:肝微粒体在系统中的浓度concentration of microsome in the incubation system
表13：AST-3424和AST-3424-D6在人肝微粒体中的稳定性测试数据
Figure PCTCN2020125168-appb-000019
将上表13数据作图得图2。
比较图2和表13可知，氘代化合物AST-3424-D6和非氘代的AST-3424的肝微粒体代谢曲线类似，但明显AST-3424-D6比非氘代的AST-3424更稳定，在相同时间内剩余百分比高10％以上，显示了AST-3424-D6相对于AST-3424具有更高的肝代谢稳定性，更适合于开发为口服给药剂型。
五、AST-3424与AST-3424-D6(即结构式I的化合物)的活体动物静脉注射稳定性研究
通过静脉滴注给予AST-3424和AST-3424-D6到食蟹猴体内，于不同时间点采集血样。LC-MS/MS测定给予受试物后食蟹猴血浆中受试物的浓度并计算相关药代动力学参数。
5.1实验过程
供试品溶液制备
供试品给药溶液的配制：
溶媒：pH为7.4的5％质量分数的葡萄糖溶液
配制方法：吸取0.447mL的AST-3424(0.2mg/ml)和0.481mL的AST-3424-D6(0.2mg/ml)加入104.272mL的上述溶媒中，搅拌5min，得到pH约为7的无色澄清溶液。
动物接收与适应
从广西雄森灵长类开发实验有限公司购入4只雄性食蟹猴，所有动物均为体检合格、无异常的健康食蟹猴。其中3只用于实验，其余的动物用于制备空白血浆。
动物给药
3只食蟹猴，按下表进行实验。
Figure PCTCN2020125168-appb-000020
样品采集与处理
经股静脉采血约0.8mL，肝素钠抗凝，采血时间点如下：
给药前、给药开始后0.17、0.25、0.5、0.75、1、2、4小时。
血液样本采集后置于冰上，离心分离血浆(离心条件：3500转/分钟，10分钟，4℃)。收集的血浆分析前存放于-80℃。血浆样品由实验机构分析部门采用LC-MS/MS进行分析，AST-3424和AST-3424-D6检测的LLOQ为1ng/mL。样品检测过程中随行标准曲线及质控样品的分析结果准确度均符合生物分析的相关要求(超过66.7％的质控样品的准确度在85-115％之间)。
试验结束后，给药动物返还到储备动物库。
5.2实验数据处理及结果
药物代谢动力学分析
根据药物各组各时间点的平均血药浓度数据，使用药代动力学计算软件非房室模型分别计算供试品的药代动力学参数AUC 0-t、AUC 0-∞、MRT 0-∞、C max、T max、t 1/2等参数。对于浓度低于定量下限的样品，在进行药代动力学参数计算时，在达到C max以前取样的样品应以零值计算，在达到C max以后取样点样品应以无法定量(标注为“BLQ”)计算。
血浆药物浓度
单次静脉滴注给予食蟹猴受试物AST-3424和AST-3424-D6后，在拟定时间点采集对应动物的全血样品，经样品处理、生物分析得到不同时间血浆中供试品原药浓度。测定结果列于下表14中，相应的平均血浆药物浓度-时间曲线见图3。
表14：食蟹猴单次静脉滴注给药后的血浆中AST-3424和AST-3424-D6血浆浓度
Figure PCTCN2020125168-appb-000021
Figure PCTCN2020125168-appb-000022
主要药代动力学参数
根据药物各组的血药浓度数据，使用药代动力学计算软件非房室模型分别计算化合物各组的药代动力学参数，见表15。
表15：食蟹猴单次静脉滴注给药后的血浆中AST-3424和AST-3424-D6的主要药代动力学参数
AST-3424-0.58mg/kg
Figure PCTCN2020125168-appb-000023
AST-3424-D6-0.42mg/kg
Figure PCTCN2020125168-appb-000024
备注：
1)计算软件Phoenix Winnolin7.0非房室模型
2)PK参数说明
AUC(0-t)：时间从0时到t时血药浓度-时间曲线下面积；
AUC(0-∞)：时间从0时到无穷大时血药浓度-时间曲线下面积；
Cmax：血浆最高浓度
Tmax：最高浓度的时间；
T1/2：半衰期；
MRT(0-t)：时间从0时到t时时段内的平均滞留时间；
MRT(0-∞)：时间从0时到无穷大时段内的平均滞留时间；
CL：清除率；
Vss:稳态分配体积；
Vz：统计矩参数分配体积；
NO Peak：没有色谱峰即未检测到，视为零；
NA：不适用。
101/102/103是三只动物的编号。
结果
AST-3424和AST-3424-D6均以1mg/kg的给药剂量给药，给药浓度为0.2mg/mL，通过对给药溶液进行分析，AST-3424的实际浓度为0.117mg/mL，AST-3424-D6的实际浓度为0.085mg/mL，折算实际的给药剂量分别为0.58mg/kg和0.42mg/kg。
食蟹猴给予0.58mg/kg的AST-3424后，平均0.31h至峰浓度(Cmax为724.60±66.62ng/mL)，消除半衰期(t 1/2)均值为0.16h，AUC(0-t)为436.41±35.60h*ng/mL，AUC(0-∞)为438.39±33.49h*ng/mL，MRT(0-t)为0.17±0.03h，MRT(0-∞)为0.17±0.03h。
食蟹猴给予0.42mg/kg的AST-3424-D6后，平均0.31h至峰浓度(Cmax为522.46±45.99ng/mL)，消除半衰期(t 1/2)均值为0.12h，AUC(0-t)为301.56±22.57h*ng/mL，AUC(0-∞)为314.90±27.19h*ng/mL，MRT(0-t)为0.14±0.01h，MRT(0-∞)为0.15。
通过比较相关药物代谢动力学参数可以明显的看到，两者的达峰时间(都为0.31小时)相等、消除半衰期(一个为0.16小时，一个为0.12小时)接近、平均滞留时间(一个为0.17±0.03h，一个为0.14±0.01h)也接近。
进一步，我们通过对照图3可知，氘代化合物AST-3424-D6(TH3424-D6)和非氘代的AST-3424(TH3424)的血液中代谢曲线类似，但明显AST-3424-D6比非氘代的AST-3424的药时曲线AUC线下积分面积更小，即AST-3424-D6在血液循环系统中暴露量较AST-3424小，相应的对血液循环系统的毒害小，即AST-3424相较于AST-3424-D6更适合开发为注射剂，AST-3424-D6较AST-3424更适合开发为治疗实体瘤(实体瘤即为排除血液肿瘤外的肿瘤，血液肿瘤例如各种白血病)的口服药物。
基于以上实验并结合本领域技术人员的知识可知，与
Figure PCTCN2020125168-appb-000025
(AST-3424-D6，S构型，结构式I)相类似，R构型的化合物
Figure PCTCN2020125168-appb-000026
(AST-3423-D6，R构型，结构式II)也具有类似的性质和结论：氘代化合物AST-3423-D6(TH3423-D6)和非氘代的AST-3423(TH3423)的血液中代谢曲线应该类似，但明显AST-3423-D6比非氘代的AST-3423的药时曲线AUC线下积分面积更小，即AST-3423-D6在血液循环系统中暴露量较AST-3423小，相应的对血液循环系统的毒害小，即AST-3423相较于AST-3423-D6更适合开发为注射剂，AST-3423-D6较AST-3423更适合开发为治疗实体瘤(实体瘤即为排除血液肿瘤外的肿瘤，血液肿瘤例如各种白血病)的口服药物。
六、AST-3424-D6(即结构式I的化合物)的合成
6.1合成路线
Figure PCTCN2020125168-appb-000027
6.2合成步骤
AST-3424-D6-B的合成
AST-3424-D6-A(30g，0.217mol)溶于无水甲醇中(300mL)，升温至回流，缓慢滴加入氯化亚砜(51.7g，0.335mol)。投比之后，回流搅拌，6h反应完毕。浓缩掉氯化亚砜，剩余物溶于乙酸乙酯中(200mL)，水洗，盐水洗，干燥浓缩，MTBE甲基叔丁基醚打浆得纯品(30.4g,92.1％),为白色固体。 1H-NMR(400MHz,CDCl 3):δ7.59-7.61(m,2H),7.29-7.33(m,1H),7.07(d,J＝7.6Hz,1H),5.04(brs,1H),3.92(s,3H).MS:153.0[(M+1) +].
AST-3424-D6-C的合成
氮气保护下，AST-3424-D6-B(15g，98.6mmol)溶于DMF中(200mL)，降温至0℃，分批加入NaH(7.9g，197.2，60％)，保温0℃一小时，滴加入溴化苄(25.1g，147.9mmol)，滴毕之后常温搅拌一小时反应完毕。降温至0℃，滴加入饱和氯化铵水溶液(50mL)，乙酸乙酯萃取(100mL*3)，水洗(20mL*5)，盐水洗，干燥浓缩得粗品(26.0g,定量)，为白色固体，直接投于下一步。
AST-3424-D6-D的合成
将上述所得的AST-3424-D6-C粗品(26g)加入到水和乙醇的混合溶液中(100mL:100mL)，分批加入氢氧化钠固体(11.8g)，投毕之后，50℃搅拌过夜。反应完毕之后，降温至0-5℃，滴加入6N的盐酸溶液调节pH至酸性，有大量白色固体析出，抽滤，水洗，烘干之后得纯品(20.8g，收率为92.4％)，为白色粉末。 1H-NMR(400MHz,DMSO-d 6):δ13.03(brs,1H),7.25-7.54(m,9H),5.16(s,2H)。MS:226.9[(M-H) -],
AST-3424-D6-E的合成
氮气保护下，AST-3424-D6-D(7.1g，31.1mmol)和氘代二甲胺盐酸盐(3g，34.3mmol，购买)加入到超干二氯甲烷中(70mL)，加入丙基磷酸酐(39.6g，62.2mmol，50％inEA)，降温至0℃，滴加入N，N-二异丙基乙胺(16g，124.4mmol)，投毕之后，常温搅拌，四小时反应完毕。降温至0℃，滴加入1M的磷酸二氢钠水溶液200mL，二氯甲烷萃取(100mL*3)，干燥浓缩，柱分离。Flash柱，200-300目硅胶，石油醚：乙酸乙酯(18％-40％EA得产品)，m＝6.0g，黄褐色固体，收率＝94.2％。 1H-NMR(400MHz,CDCl 3):δ7.28-7.48(m,6H),7.68-7.02(m,3H),5.08(s,2H).MS:262.2[(M+1) +],
AST-3424-D6-F的合成
氮气保护下，AST-3424-D6-E(5g，19.2mool)溶于无水乙醇中(50mL)，加入钯碳催化剂(2.5g)，室温搅拌过夜。反应完毕之后，氮气置换，抽滤，无水乙醇洗涤钯碳，浓缩之后得纯品。m＝3.1g，白色固体，收率＝93.9％。 1H-NMR(400MHz,CDCl 3):δ8.05(brs,1H),7.16-7.20(m,1H),6.97-6.98(m,1H),6.83-6.84(m,1H),6.81-6.82(m,1H).MS:172.2[(M+1) +].
AST-3424-D6-I的合成
氮气保护下，三氯氧磷(1.2mL，12.98mmol)加入到无水二氯甲烷中(10mL)，降温至-40℃，缓慢滴加入AST-3424-D6-H(1.2g，6.49mmol，市售)的二氯甲烷溶液(10mL)，然后滴加入三乙胺(1.7g，16.87mmol)的二氯甲烷溶液(10mL)，保温-40℃6小时，原料转化完毕。-40℃，加入2-溴乙胺氢溴酸盐(10.7g，52mmol)，然后滴加入三乙胺(5.3g，52mmol)的二氯甲烷溶液(20mL)，保温-40℃30min，自然升至常温搅拌过夜。反应完毕之后，降温至0℃，滴加入10％的碳酸钾水溶液(10mL)，搅拌5min，二氯甲烷萃取(15mL*3)，干燥浓缩柱分离得到(200-300目硅胶，EA冲洗得产品1.3g，42.0％)，为黄色油状液体。 1H-NMR(400MHz,CDCl 3):δ8.05-8.09(m,1H),7.28-7.33(m,2H),5.53-5.57(m,1H),3.49-3.52(m,2H),3.31-3.42(m,4H),3.18-3.24(m,4H),1.61(d,J＝6.4Hz,3H)MS:477.9[(M+1) +].
AST-3424-D6-J的合成
氮气保护下，讲AST-3424-D6-I(1.0g,2.1)溶于THF(20mL),加入氧化银(5.8g，25.2mmol)，DIEA(1.4g,10.5g)完毕后，加热至回流反应2h，抽滤，THF洗涤(10mL)，除去溶剂，柱分离(200-300目，乙酸乙酯的庚烷溶液80％到100％)，得到AST-3424-D6-J(370mg,55.9％),为黄色液体。 1H-NMR(400MHz,CDCl 3):δ7.98-8.02(m,1H),7.20-7.30(m,2H),5.58-5.65(m,1H),2.00-2.17(m,8H),1.56(d,J＝6.8Hz,3H).MS:316.1[(M+1) +].
AST-3424-D6的合成
氮气保护下，将AST-3424-D6-J(100mg,0.32mmol)、AST-3424-D6-F(81mg,0.48mmol)溶于干燥DMF(5mL)中，加入碳酸钾(87mg，0.63mmol)，室温搅拌过夜，完毕后，加入乙酸乙酯(60mL)稀释，水洗(3x5mL),盐水(3x5mL)洗,无水硫酸钠干燥，除去溶剂，柱分离(200-300目,DCM:MeOH＝50:1)，得到AST-3424-D6(93mg,63％),为黄色油状液体。 1H-NMR(400MHz,CDCl 3):δ7.98-8.02(m,1H),7.20-7.30(m,2H),5.58-5.65(m,1H),2.00-2.17(m,8H),1.56(d,J＝6.8Hz,3H).MS:467.1[(M+1) +].
同样类似的路线，更换起始化合物为AST-3423-D6-H后可以合成R构型的化合物II。

Claims (23)

  1. 治疗癌症或肿瘤或细胞增生性病症的口服给药的固体剂型药物，其含有如下结构式I或II的化合物，
    Figure PCTCN2020125168-appb-100001
  2. 根据权利要求1所述的固体剂型药物，其为片剂。
  3. 根据权利要求2所述的固体剂型药物，药片的水溶液或水分散液的pH值大于6.8，进一步优选为6.8至10.0。
  4. 根据权利要求2所述的固体剂型药物，药片中含有结构式I或II的化合物以及药用辅料。
  5. 根据权利要求1所述的固体剂型药物，其为肠溶片。
  6. 根据权利要求5所述的固体剂型药物，所述肠溶片包括肠溶包衣和被包裹在内的药片，该药片含有结构式I或II的化合物以及药用辅料。
  7. 根据权利要求6所述的固体剂型药物，其中，所述药片的水溶液或水分散液的pH值大于6.8，进一步优选为6.8至10.0。
  8. 根据权利要求1所述的固体剂型药物，其为肠溶胶囊。
  9. 根据权利要求8所述的固体剂型药物，所述肠溶胶囊包括空的肠溶胶囊和填充在内的药物混合物。
  10. 根据权利要求9所述的固体剂型药物，其中，所述药物混合物为颗粒，该颗粒含有结构式I或II的化合物、药用辅料。
  11. 根据权利要求11所述的固体剂型药物，其中，所述药物混合物的水溶液或水分散液的pH值大于6.8，进一步优选为6.8至10.0。
  12. 根据权利要求10所述的固体剂型药物，所述肠溶胶囊包括空的软肠溶胶囊和填充在内的药物溶液，药物溶液中化合物I或II的含量为 1-270mg/ml。
  13. 根据权利要求12所述的固体剂型药物，其中，所述药物溶液含有结构式I或II的化合物和溶剂，溶剂为乙醇和丙二醇的混合溶剂。
  14. 根据权利要求12所述的固体剂型药物，其中，所述混合溶剂中乙醇的体积比不小于50％。
  15. 根据权利要求14所述的固体剂型药物，其中，所述混合溶剂由体积比75％的乙醇和25％的丙二醇组成。
  16. 根据权利要求12所述的固体剂型药物，其中，所述药物溶液不添加水，水含量控制在质量比0.5％内。
  17. 根据权利要求1所述的固体剂型药物，其中肿瘤、癌症或增生性病症包括：
    肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成 内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、子宫内膜癌、胶质瘤、结直肠癌、甲状腺癌、尿路上皮癌或多发性骨髓瘤，优选为实体肿瘤。
  18. 根据权利要求4或6或10所述的固体剂型药物，其中药用辅料包括Na 2CO 3或NaHCO 3或NaOH或KH 2PO 4；和/或
    药用辅料包括乙醇或丙二醇。
  19. 固体剂型药物制备方法，包括以下操作：
    混合造粒，将辅料、结构式I或II的化合物的乙醇溶液、适量水混合均匀后，进行造粒；
    压片，将造粒后的物料干燥或未经干燥直接压片，即得片剂；
    将药片进行包衣，即得肠溶片；
    造粒后的物料灌入到胶囊中即得胶囊。
  20. 结构式I或II的化合物，
    Figure PCTCN2020125168-appb-100002
  21. 结构式I或II的化合物在制备治疗癌症或肿瘤或细胞增生性病症的口服给药的固体剂型药物中的用途，
    Figure PCTCN2020125168-appb-100003
    Figure PCTCN2020125168-appb-100004
  22. 根据权利要求21所述的用途，所述固体剂型药物的每个最小可服用剂量单位中，含有上述结构式I或II的化合物的含量0.2、0.5、1.0mg。
  23. 结构式I或II的化合物的制备方法，其包括将化合物III和IV与化合物V在碱参与或不参与的情况下反应来生成化合物I或II：
    Figure PCTCN2020125168-appb-100005
    其中，X为卤素原子，优选为F，M为H或碱金属、碱土金属。
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