WO2017152706A1 - 吡啶胺基嘧啶衍生物的盐及其制备方法和应用 - Google Patents

吡啶胺基嘧啶衍生物的盐及其制备方法和应用 Download PDF

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WO2017152706A1
WO2017152706A1 PCT/CN2017/000202 CN2017000202W WO2017152706A1 WO 2017152706 A1 WO2017152706 A1 WO 2017152706A1 CN 2017000202 W CN2017000202 W CN 2017000202W WO 2017152706 A1 WO2017152706 A1 WO 2017152706A1
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compound
formula
salt
preparation
mesylate salt
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罗会兵
周华勇
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Shanghai Allist Pharmaceuticals Inc
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Shanghai Allist Pharmaceuticals Inc
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Priority to KR1020187028797A priority Critical patent/KR102142796B1/ko
Priority to EP17762392.3A priority patent/EP3428158B1/en
Priority to ES17762392T priority patent/ES2818652T3/es
Priority to CA3016826A priority patent/CA3016826C/en
Priority to US16/083,209 priority patent/US10472349B2/en
Priority to JP2018547437A priority patent/JP6696670B2/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to a salt of a pyridylaminopyrimidine derivative, and in particular, the present invention relates to N- ⁇ 2- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ -6-(2, 2,2-Trifluoroethoxy)-5- ⁇ [4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide Methanesulfonate, a process for its preparation, a pharmaceutical composition comprising the same, and the use of the salt in the treatment of diseases, particularly cancer, mediated by EGFR-activated or drug-resistant mutants in mammals, particularly humans.
  • Epidermal growth factor receptor has been identified as a critical driver of cell growth and proliferation.
  • the epidermal growth factor receptor family consists of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4.
  • Epidermal growth factor receptors are involved in disease progression in most cancers, such as lung cancer, colon cancer, breast cancer, and the like. Overexpression and mutation of EGFR have been clearly identified as major risk factors for breast cancer with poor prognosis.
  • Patent application CN201410365911.4 discloses a structural compound of the formula (I) which is significantly more inhibitory against EGFR-activated mutations (such as exon 19 deletion activating mutation, or L858R activating mutation) and T790M resistance mutations than in wild
  • the inhibitory activity of EGFR (WT EGFR) is very selective, with low toxic side effects and good safety.
  • the technical problem to be solved by the present invention is to provide a methanesulfonate salt of a compound of the formula (I), a process for the preparation thereof, a pharmaceutical composition comprising the salt and the salt of the EGFR-activated or drug-resistant mutant in the treatment of a mammal, especially a human.
  • the present invention provides mesylate salts of the compounds of formula (I).
  • the present invention provides a process for the preparation of the mesylate salt of the compound of formula (I).
  • the invention further provides a process for the preparation of a mesylate salt of a compound of formula (I) which comprises reacting a compound of formula (I) directly with methanesulfonic acid in a solvent.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mesylate salt of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mesylate salt of a compound of formula (I), and a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention provides a mesylate salt of a compound of formula (I) for use as an antitumor drug.
  • the invention further provides the use of a mesylate salt of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, in particular a human.
  • the invention also provides the use of a mesylate salt of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • the invention further provides the use of a mesylate salt of a compound of formula (I) for the treatment of a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, especially a human.
  • the invention further provides the use of a pharmaceutical composition comprising a mesylate salt of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, in particular a human.
  • the invention also provides the use of a pharmaceutical composition comprising a mesylate salt of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • the invention also provides a method of treating a disease, particularly a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, particularly a human, comprising administering to the patient a mesylate salt of a compound of formula (I), Or a pharmaceutical composition comprising a therapeutically effective amount of a mesylate salt of a compound of formula (I) and a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention also provides a method of treating cancer, the method comprising administering to a patient a mesylate salt of a compound of formula (I), or a methanesulfonic acid comprising a therapeutically effective amount of a compound of formula (I)
  • a pharmaceutical composition of a salt and a pharmaceutically acceptable carrier, excipient or diluent comprising administering to a patient a mesylate salt of a compound of formula (I), or a methanesulfonic acid comprising a therapeutically effective amount of a compound of formula (I)
  • a pharmaceutical composition of a salt and a pharmaceutically acceptable carrier, excipient or diluent comprising administering to a patient a mesylate salt of a compound of formula (I), or a methanesulfonic acid comprising a therapeutically effective amount of a compound of formula (I)
  • a pharmaceutical composition of a salt and a pharmaceutically acceptable carrier, excipient or diluent comprising administering to
  • the cancers mentioned in the present invention include, but are not limited to, for example, lung cancer, ovarian cancer, cervical cancer, breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, Lymphoma, non-Hodgkin's lymphoma, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML) ), multiple myeloma, mesothelioma, especially for the tumor type of epidermal growth factor receptor 790 threonine mutation to methionine (EGFR T790M).
  • the mesylate salt of the compound of formula (I) of the invention can be used as a medicament for the treatment of non-small cell carcinoma (EGFR T790M).
  • the preparation method of the compound of the formula (I) provided by the present invention is as follows.
  • the method is the method of the embodiment 1 of the patent application CN201410365911.4, wherein the preparation of the intermediate 1c and the intermediate 2a is an example of directly referencing the patent application CN201410365911.4. .
  • the intermediate 1c is substituted or coupled with the intermediate 2a to give the compound (II), the nitro group of the compound (II) is reduced to obtain the compound (III), and the compound (III) is acylated with the acryloyl chloride to give the compound (I).
  • Substitution or coupling of intermediate 1c with intermediate 2a can also be carried out under the catalysis of a transition metal catalyst including, but not limited to, tris(dibenzylideneacetone)dipalladium/4,5-bisdiphenyl
  • a transition metal catalyst including, but not limited to, tris(dibenzylideneacetone)dipalladium/4,5-bisdiphenyl
  • the phosphinium-9,9-dimethylxanthene employs conventional reducing agents well known in the art including, but not limited to, iron powder, zinc powder, sodium sulfide, H 2 / platinum dioxide.
  • the preparation method of the methanesulfonate salt of the compound of the formula (I) provided by the invention is as follows:
  • the compound of formula (I) is directly reacted with methanesulfonic acid to form a methanesulfonate salt of the compound of formula (I) in a solvent, including but not limited to a mixed solvent of acetone and water.
  • the mesylate salt of the compound of the formula (I) of the present invention can be administered to mammals including humans, and can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powder, ointment or drops). ), or intratumoral administration.
  • the mesylate salt of the compound of the formula (I) of the present invention may be administered at a dose of about 0.05 to 50 mg/kg body weight/day, for example 0.1 to 45 mg/kg body weight/day, more preferably 0.5 to 35 mg/kg body weight/day.
  • the mesylate salt of the compound of the formula (I) of the present invention can be formulated into a solid dosage form for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules and the like.
  • the mesylate salt of the compound of the formula (I) of the present invention is mixed as an active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate, or with the following Ingredient mixing: (1) filler or compatibilizer, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid, etc.; (2) binders, such as hydroxymethylcellulose, alginate, gelatin, polyethylene Pyrrolidone, sucrose, gum arabic, etc.; (3) humectants, for example, glycerol, etc.; (4) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex
  • the solid dosage forms such as tablets, dragees, capsules, pills, and granules can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • the mesylate salt of the compound of formula (I) of the present invention may be formulated as a liquid dosage form for oral administration including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, and the like.
  • the liquid dosage form may comprise inert diluents conventionally employed in the art, such as water and other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, Ethyl carbonate, ethyl acetate, propylene glycol, 1,3- Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or a mixture of these substances.
  • the liquid dosage forms of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.
  • the suspending agent includes, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide, agar, and the like, or a mixture of these.
  • the mesylate salt of the compound of the formula (I) of the present invention may be formulated into a dosage form for parenteral injection, including, but not limited to, a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and A sterile powder that is reconstituted into a sterile injectable solution or dispersion.
  • Suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may also be formulated into a dosage form for topical administration, including, for example, ointments, powders, suppositories, drops, propellants, and inhalants.
  • a physiologically acceptable carrier and optionally a preservative, a buffer, or a propellant which may be required if necessary.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mesylate salt of a compound of formula (I) of the invention, together with a pharmaceutically acceptable carrier, excipient or diluent.
  • the mesylate salt of the compound of the formula (I) of the present invention is usually mixed with a pharmaceutically acceptable carrier, excipient or diluent.
  • composition of the present invention can be formulated into a conventional pharmaceutical preparation by a conventional preparation method.
  • a conventional preparation method for example, tablets, pills, capsules, powders, granules, emulsions, flocs, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, propellants, and the like.
  • the mesylate salt of the compound of formula (I) according to the invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, especially in combination with other anti-tumor drugs.
  • the therapeutic agent includes, but is not limited to, a drug antitumor drug acting on the chemical structure of DNA such as cisplatin, an antitumor drug affecting nucleotide synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc.
  • Anti-tumor drugs for nucleic acid transcription such as doxorubicin, epirubicin, aclarithromycin, phosfomycin, etc., antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as Aminoglutamine, lantron, letrozole, ruined, etc., cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitor Imatinib, Gefitinib, erlotinib (Erlotinib) and so on.
  • the components to be combined can be Simultaneous or sequential administration, in the form of a single preparation or in the form of no preparation.
  • the combination includes not only combinations of the compounds of the invention and one other active agent, but also combinations of the compounds of the invention and two or more other active agents.
  • the method for determining the absolute bioavailability of the mesylate salt of the compound of the formula (I) of the present invention is as follows:
  • Intravenous administration healthy SD rats, randomized.
  • the test compound was administered intravenously at a dose D, and blood was taken from the posterior venous plexus before and 5 minutes, 15 min, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 12 h, and 24 h after administration.
  • concentration of the drug in the plasma was determined by liquid chromatography/tandem mass spectrometry to obtain a drug concentration-time curve.
  • Oral administration healthy SD rats, randomized.
  • the test substance was administered by a certain dose of D, and venous blood was taken from the posterior venous plexus of the rat before and after administration at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 12 and 24 h after administration.
  • the concentration of the drug in the plasma was determined by liquid chromatography/tandem mass spectrometry to obtain a drug concentration-time curve.
  • the pharmacological effect of the mesylate salt of the compound of the formula (I) of the present invention for inhibiting the growth of an animal xenograft can be determined by a conventional method, and a preferred evaluation method is a growth inhibitory effect on the subcutaneous xenograft of human lung cancer H1975 nude mice.
  • Experimental method Human lung cancer H1975 cell line (5 ⁇ 10 6 cells/only) was inoculated subcutaneously in the right side of nude mice. When the tumors were grown to an average (100-150) mm 3 , they were randomly grouped according to tumor size and mouse body weight. The test compound was administered by a certain dose, and the solvent control group was intragastrically administered with an equal amount of solvent, once a day for 21 days. The body weight and tumor size of the mice were measured twice a week during the entire experiment to see if a toxic reaction occurred.
  • tumor volume (mm 3 ) 0.5 ⁇ (tumor long diameter ⁇ tumor short diameter 2 ).
  • the mesylate salt of the compound of formula (I) provided by the present invention has excellent bioavailability in animals.
  • the mesylate salt of the compound of formula (I) provided by the present invention can better inhibit the growth of transplanted tumors of animals and shows good safety.
  • Figure 2 is a preparation of the mesylate salt of the compound of the formula (I) and the substance of the control 2 (i.e., patent application CN201410365911.4 Example 16) in human lung cancer H1975 nude mice at a dose of 25 mg/kg. The weight change curve.
  • Test Example 1 Drug absorption test in SD rats (Sprague Dawley rats)
  • Intravenous administration healthy SD rats, 16 males and females, weighing 200-280 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. and randomly divided into four groups.
  • the materials of the above Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were intravenously administered at the doses listed below, respectively, before administration and 5 minutes, 15 minutes, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 minutes after administration.
  • 0.2 ml of venous blood was taken from the posterior venous plexus of rats, and plasma was separated and prepared. The concentration of the drug in the plasma was determined by liquid chromatography/tandem mass spectrometry to obtain the drug concentration-time curve.
  • Comparative Example 1 the material structure of Comparative Example 1 is as follows, and is prepared according to the method of Example 2 of Patent Application CN201410365911.4.
  • Comparative Example 2 was as follows, and was prepared according to the method of Example 16 of Patent Application CN201410365911.4.
  • T 1/2 elimination half-life
  • C max the highest concentration of drug in plasma
  • AUC 0-t area under the curve
  • Example 1 healthy SD rats, 16 males and females, weighing 200-280 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. and randomly divided into four groups.
  • the materials of the above Example 1, Example 2, Comparative Example 1 and Comparative Example 2 were intragastrically administered at the doses listed in the table below, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10 before and after the administration.
  • venous blood was taken from the posterior venous plexus of rats for 0.2 ml, and plasma was separated.
  • concentration of the drug in the plasma was determined by liquid chromatography/tandem mass spectrometry to obtain the drug concentration-time curve.
  • F see Table 2 above.
  • Test Example 2 Growth inhibition of human lung cancer H1975 nude mice subcutaneously transplanted tumor
  • the mesylate salt of the compound of the formula (I) prepared in Example 2 of the present invention and the material of the control example 2 were observed.
  • the structure of the control example 2 is as follows, and the preparation method refers to the patent application. CN201410365911.4 Example 16) Inhibition of subcutaneous xenografts in human lung cancer H1975 nude mice.
  • H1975 culture was cultured in RPMI-1640 medium supplemented with 10% FBS, and cultured in a constant temperature incubator containing 5% CO 2 at 37 °C. Cells in the exponential growth phase are collected and counted for inoculation.
  • mice BALB/c nude nude mice, 15 males, 6 weeks, 18-20 g, 5 rats in each group, purchased from Shanghai Animal Experimental Center.
  • Three experimental groups were set up: 0.5% carboxymethylcellulose sodium solvent control group, Example 2 (25 mg/kg) group and Control 2 (25 mg/kg) group.
  • the tumor growth growth curves of the three experimental groups are shown in Fig. 1, and the body weight curves are shown in Fig. 2.
  • the mesylate salt of the compound of formula (I) of Example 2 of the present invention has a good inhibitory effect on the growth of human lung cancer H1975 nude mice subcutaneously transplanted tumor, and the inhibition effect is obviously superior to that of the control example 2; and shows good safety. Sex.

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Abstract

式(I)化合物的甲磺酸盐、其制备方法，包含该盐的药物组合物及该盐在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症中的应用。式(I)化合物的甲磺酸盐在动物体内的生物利用度高，能更好的抑制动物移植瘤的生长，并显示良好的安全性。

Description

吡啶胺基嘧啶衍生物的盐及其制备方法和应用 技术领域
本发明涉及吡啶胺基嘧啶衍生物的盐，具体的说，本发明涉及N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐、其制备方法、包含该盐的药物组合物及该盐在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症中的应用。
背景技术
表皮生长因子受体(EGFR)被确认为是在细胞生长和增值过程中至关重要的驱动因素。表皮生长因子受体家族由EGFR(Erb-B1)、Erb-B2(HER-2/neu)、Erb-B3和Erb-B4组成。表皮生长因子受体与大部分癌症的疾病进程有关，如肺癌、结肠癌、乳腺癌等。EGFR的过度表达和突变已被明确证实是预后不好的乳腺癌的主要危险因素。
目前，研究前沿的已经是不可逆的第三代EGFR抑制剂。专利申请CN201410365911.4公开如下式(I)结构化合物，该化合物对EGFR激活型突变(如19号外显子缺失激活突变、或L858R激活突变)和T790M耐药型突变的抑制活性显著高于对野生型EGFR(WT EGFR)的抑制活性，有很好的选择性，并且毒副作用较低，安全性好。
Figure PCTCN2017000202-appb-000001
发明内容
本发明所要解决的技术问题是提供式(I)化合物的甲磺酸盐、其制备方法，包含该盐的药物组合物及该盐在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症中的应用。
本发明提供了式(I)化合物的甲磺酸盐。
Figure PCTCN2017000202-appb-000002
本发明提供了式(I)化合物的甲磺酸盐的制备方法。
本发明进一步提供了式(I)化合物的甲磺酸盐的制备方法，包括在溶剂当中将式(I)化合物直接与甲磺酸反应得到。
本发明提供了药物组合物，包括式(I)化合物的甲磺酸盐及药学上可接受的载体。
本发明进一步提供药物组合物，包括式(I)化合物的甲磺酸盐，以及药学上可接受的载体、赋形剂或稀释剂。
本发明提供了用作抗肿瘤药物的式(I)化合物的甲磺酸盐。
本发明还提供式(I)化合物的甲磺酸盐在制备治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的药物中的用途。
本发明还提供式(I)化合物的甲磺酸盐在制备治疗癌症的药物中的用途。
本发明还提供式(I)化合物的甲磺酸盐在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症方面中的用途。
本发明还提供含有式(I)化合物的甲磺酸盐的药物组合物在制备治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的药物中的用途。
本发明还提供含有式(I)化合物的甲磺酸盐的药物组合物在制备治疗癌症的药物中的用途。
本发明还提供一种治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的方法，所述方法包括对患者施用式(I)化合物的甲磺酸盐、或包括治疗有效量的式(I)化合物的甲磺酸盐和药物可接受载体、赋形剂或稀释剂的药物组合物。
本发明还提供一种治疗癌症的方法，所述方法包括对患者施用式(I)化合物的甲磺酸盐、或包括治疗有效量的式(I)化合物的甲磺酸 盐和药物可接受载体、赋形剂或稀释剂的药物组合物。
本发明所提及癌症包括但不限于，例如肺癌、卵巢癌、宫颈癌、乳腺癌、胃癌、结肠直肠癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、肝细胞癌、胃肠道基质瘤(GIST)、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病(AML)、多发性骨髓瘤、间皮瘤，尤其对于表皮生长因子受体790位苏氨酸突变为蛋氨酸(EGFR T790M)的肿瘤类型有更好的应用。举例来说，本发明式(I)化合物的甲磺酸盐可作为和用于治疗非小细胞癌(EGFR T790M)的药物。
本发明提供的式(I)化合物的制备方法如下，该方法是参考专利申请CN201410365911.4实施例1的方法，其中中间体1c与中间体2a的制备是直接引用专利申请CN201410365911.4的实施例。
Figure PCTCN2017000202-appb-000003
中间体1c与中间体2a经取代或偶联反应得到化合物(II)，化合物(II)硝基被还原得到化合物(III)，化合物(III)与丙烯酰氯经酰化得到化合物(I)。中间体1c与中间体2a取代或偶联反应包括也可以在过渡金属催化剂催化下进行，所述过渡金属催化剂包括但不限于三(二亚苄基丙酮)二钯/4，5-双二苯基膦-9，9-二甲基氧杂蒽；还原硝基的方法采用本领域中公知的常规还原剂，包括但不限于铁粉、锌粉、硫化钠、H2/二氧化铂。
本发明提供的式(I)化合物的甲磺酸盐的制备方法如下：
Figure PCTCN2017000202-appb-000004
在溶剂中式(I)化合物直接与甲磺酸反应成盐得到式(I)化合物的甲磺酸盐，所述溶剂包括但不限于丙酮与水的混合溶剂。
本发明的式(I)化合物的甲磺酸盐可给药于哺乳动物包括人，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂或滴剂)、或瘤内给药。
本发明式(I)化合物的甲磺酸盐的给药剂量可以大约为0.05～50mg/kg体重/天，例如0.1～45mg/kg体重/天，更例如0.5～35mg/kg体重/天。
本发明式(I)化合物的甲磺酸盐可以配制为用于口服给药的固体剂型，包括，但不限于胶囊剂、片剂、丸剂、散剂和颗粒剂等。在这些固体剂型中，本发明式(I)化合物的甲磺酸盐作为活性成分与至少一种常规惰性赋形剂(或载体)混合，例如与柠檬酸钠或磷酸二钙，或与下述成分混合：(1)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等；(2)粘合剂，例如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶等；(3)保湿剂，例如，甘油等；(4)崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠等；(5)缓溶剂，例如石蜡等；(6)吸收加速剂，例如，季铵化合物等；(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯等；(8)吸附剂，例如，高岭土等；和(9)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠等，或其混合物。胶囊剂、片剂和丸剂中也可包含缓冲剂。
所述固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料例如肠溶衣和其他本领域公知的材料进行包衣或微囊化。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
本发明式(I)化合物的甲磺酸盐可以配制为用于口服给药的液体剂型，包括，但不限于药学上可接受的乳液、溶液、悬浮液、糖浆和酊剂等。除了作为活性成分的式(I)化合物的甲磺酸盐外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水和其他溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3- 丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外，本发明液体剂型也可包含常规助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
所述悬浮剂包括，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇只、微晶纤维素、甲醇铝和琼脂等或这些物质的混合物。
本发明式(I)化合物的甲磺酸盐可以配制为用于肠胃外注射的剂型，包括，但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物或其药学上可接受的盐也可以配制为用于局部给药的剂型，包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明式(I)化合物的甲磺酸盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明还提供药物组合物，它含有本发明式(I)化合物的甲磺酸盐，以及药学上可接受载体、赋形剂或稀释剂。在制备药物组合物时，通常是将本发明式(I)化合物的甲磺酸盐与药学上可接受载体、赋形剂或稀释剂混合。
可以按常规制备方法将所述本发明组合物配制为常规药物制剂。例如片剂、丸剂、胶囊剂、散剂、颗粒剂、乳液剂、混浮剂、分散液、溶液剂、糖浆剂、酏剂、软膏剂、滴剂、栓剂、吸入剂、喷射剂等。
本发明所述的式(I)化合物的甲磺酸盐可以单独给药，或者与其他药学上可接受的治疗剂联合给药，特别是与其他抗肿瘤药物组合。所述治疗剂包括但不限于：作用于DNA化学结构的药物抗肿瘤药如顺铂，影响核苷酸合成的抗肿瘤药物如甲氨蝶呤(MTX)、5-氟尿嘧啶(5FU)等，影响核酸转录的抗肿瘤药物如阿霉素、表阿霉素、阿克拉霉素、光辉霉素等，作用于微管蛋白合成的抗肿瘤药物如紫杉醇、长春瑞滨等，芳香化酶抑制剂如氨鲁米特、兰特隆、来曲唑、瑞宁德等，细胞信号通路抑制剂如表皮生长因子受体抑制剂伊马替尼(Imatinib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)等。待组合的各成分可 同时或顺序的给予，以单一制剂形式或以不用制剂的形式给予。所述组合不仅包括本发明化合物和一种其他活性剂的组合，而且也包括本发明化合物和两种或更多种其他活性剂的组合。
本发明式(I)化合物的甲磺酸盐灌胃给药的绝对生物利用度的测定方法如下：
静脉给药：健康SD大鼠，随机分组。测试化合物按一定剂量D静脉给药，于给药前及给药后5min、15min、0.5h、1.0h、2.0h、4.0h、8.0h、12h和24h经眼球后静脉丛取血，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
灌胃给药：健康SD大鼠，随机分组。测试物质按一定剂量D灌胃给药，于给药前和给药后0.5、1.0、2.0、4.0、6.0、8.0、10、12和24h经大鼠眼球后静脉丛取静脉血，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
经剂量校正，按药时曲线下面积(AUC0-t)计算，得到绝对生物利用度F，计算公式F＝(AUC灌胃×D静脉)/(AUC静脉×D灌胃)×100％。
本发明式(I)化合物的甲磺酸盐抑制动物移植瘤生长的药效可用常规方法测定，一种优选的评价方法为对人肺癌H1975裸小鼠皮下移植瘤的生长抑制作用。实验方法：人肺癌H1975细胞株(5×106个/只)接种于裸小鼠右侧背部皮下。待肿瘤生长至平均(100～150)mm3时根据肿瘤大小和小鼠体重随机分组。测试化合物按一定剂量灌胃给药，溶剂对照组灌胃给予等量溶剂，每天给药一次，连续给药21天。整个实验过程中，每周测量两次小鼠的体重和肿瘤的大小，观察是否出现毒性反应。
肿瘤体积的计算公式为：肿瘤体积(mm3)＝0.5×(肿瘤长径×肿瘤短径2)。
本发明的有益效果为：
本发明提供的式(I)化合物的甲磺酸盐在动物体内具有优异的生物利用度。
本发明提供的式(I)化合物的甲磺酸盐能更好的抑制动物移植瘤的生长，并显示良好的安全性。
附图说明
附图1是实施例2制备得到式(I)化合物的甲磺酸盐和对照例2物质(即专利申请CN201410365911.4实施例16)在25mg/kg给药剂量下的人肺癌H1975裸小鼠皮下移植瘤的肿瘤体积变化曲线。
附图2是实施例2制备得到式(I)化合物的甲磺酸盐和对照例2物质(即专利申请CN201410365911.4实施例16)在25mg/kg给药剂量下的人肺癌H1975裸小鼠的体重变化曲线。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于举例说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比分别为重量份和重量百分比。
具体实施方式
I.制备实施例
实施例1：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺
中间体1c：N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-3-硝基吡啶-2，5-二胺，制备方法引用专利申请CN201410365911.4实施例
Figure PCTCN2017000202-appb-000005
中间体2a：3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚，制备方法引用专利申请CN201410365911.4实施例
Figure PCTCN2017000202-appb-000006
化合物(II)：N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]-3-硝基吡啶-2，5-二胺 的合成
Figure PCTCN2017000202-appb-000007
在圆底烧瓶中加入3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(73mg，0.3mmol)、N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-3-硝基吡啶-2，5-二胺(100mg，0.3mmol)、三(二亚苄基丙酮)二钯(14mg，0.015mmol)，4，5-双二苯基膦-9，9-二甲基氧杂蒽(14mg，0.03mmol)，磷酸钾(127mg，0.6mmol)和8ml二氧六环，氩气保护下，95℃反应5h。过滤，滤液减压蒸干，硅胶柱层析(二氯甲烷∶甲醇＝20∶1)，得到140mg产物。收率为86％。MS m/z：545[M+1]。
化合物(III)：N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]吡啶-2，3，5-三胺的合成
Figure PCTCN2017000202-appb-000008
在圆底烧瓶中加入N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]-3-硝基吡啶-2，5-二胺(150mg，0.27mmol)、二氧化铂(60mg)和10ml甲醇，通入氢气，室温反应1h。过滤，制备板分离(二氯甲烷∶甲醇＝10∶1)，得到80mg目标化合物。收率为56％。MS m/z：515[M+1]。
化合物(I)：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的合成
Figure PCTCN2017000202-appb-000009
向圆底烧瓶中加入N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]吡啶-2，3，5-三胺(80mg，0.16mmol)和5ml二氯甲烷，冰水浴冷却，加入0.5N丙烯酰氯的二氯甲烷溶液(0.5ml，0.25mmol)。冰水浴下反应1.5小时，反应液用50ml乙酸乙酯稀释，饱和碳酸氢钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，制备板分离纯化(二氯甲烷∶甲醇＝10∶1)，得到20mg目标产物。收率为23％。MS m/z：569[M+1]。
1H NMR(400MHz，DMSO-d6)δ10.41(s，1H)，10.27(s，1H)，8.68(s，1H)，8.44(s，1H)，8.28(t，J＝8.5Hz，2H)，8.18(s，1H)，7.52(d，J＝8.0Hz，1H)，7.29-7.14(m，3H)，6.98(s，1H)，6.28(d，J＝17.1Hz，1H)，5.76(d，J＝10.4Hz，1H)，5.00(q，J＝9.0Hz，2H)，3.89(s，3H)，3.61(s，2H)，3.28(s，2H)，2.80(s，3H)，2.73(s，6H)。
其中化合物(II)、(III)、(I)的制备方法参考专利申请CN201410365911.4实施例1。
实施例2：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺甲磺酸盐的合成
Figure PCTCN2017000202-appb-000010
在三口瓶中加入N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺1g(1.76mmol)，35ml丙酮，7ml水，169mg甲烷磺酸，50℃加热至全溶。减压蒸干，加入乙腈，再减压蒸干。向残留物中加入丙酮，超声，过滤，滤饼烘干得到685mg目标产物。收率为59％。
1H NMR(400MHz，DMSO-d6)δ9.80(s，1H)，9.23(s，1H)，8.53(s， 1H)，8.42(s，1H)，8.30(d，J＝5.4Hz，2H)，8.23(s，1H)，7.52(d，J＝8.2Hz，1H)，7.25(t，J＝7.2Hz，1H)，7.22(d，J＝8.0Hz，1H)，7.15(t，J＝7.4Hz，1H)，6.70(dd，J＝17.0，10.2Hz，1H)，6.34(dd，J＝17.0，1.7Hz，1H)，5.83(dd，J＝10.3，1.6Hz，1H)，5.02(q，J＝9.1Hz，2H)，3.88(s，3H)，3.65(t，J＝6.0Hz，2H)，3.33(t，J＝6.0Hz，2H)，2.86(s，6H)，2.81(s，3H)，2.44(s，3H)。
II.活性测试实施例
测试实施例1：SD大鼠(Sprague Dawley大鼠)药物吸收实验
静脉给药：健康SD大鼠，雌雄各半共16只，体重200～280g，由上海西普尔-必凯实验动物有限公司提供，随机分成四组。分别按下表所列剂量静脉给予上述实施例1、实施例2、对照例1和对照例2的物质，于给药前及给药后5min、15min、0.5h、1.0h、2.0h、4.0h、8.0h、12h和24h经大鼠眼球后静脉丛取静脉血0.2ml，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
其主要的药物动力学参数如下表1所示：
参数 实施例1 实施例2 对照例1 对照例2
剂量D(mg/kg) 2.5 4.0 3.0 4.0
Cmax(ng/mL) 81.3 429.7 327.5 630.2
AUC0-t(ng·h/mL) 307.3 405.9 437.8 810.7
T1/2(h) 3.96 3.13 2.72 1.71
表1
表1中，对照例1物质结构如下，按专利申请CN201410365911.4实施例2方法制备得到，
Figure PCTCN2017000202-appb-000011
对照例2物质结构如下，按专利申请CN201410365911.4实施例16方法制备得到，
Figure PCTCN2017000202-appb-000012
T1/2：消除半衰期；Cmax：血浆中药物的最高浓度；AUC0-t：药时曲线下面积
灌胃给药：健康SD大鼠，雌雄各半共16只，体重200～280g，由上海西普尔-必凯实验动物有限公司提供，随机分成四组。分别按下表所列剂量灌胃给予上述实施例1、实施例2、对照例1和对照例2的物质，于给药前和给药后0.5、1.0、2.0、4.0、6.0、8.0、10、12和24h经大鼠眼球后静脉丛取静脉血0.2m1，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
其主要的药物动力学参数如下表2所示：
参数 实施例1 实施例2 对照例1 对照例2
剂量D(mg/kg) 10 10 6 10
Cmax(ng/mL) 17.6 44.54 12.63 28.3
AUC0-t(ng·h/mL) 231.7 287 77.66 172.2
T1/2(h) 4.14 8.33 8.60 5.76
F(％) 18.85 28.28 8.9 8.5
表2，其中对照例1、2的结构与制备方法同表1
经剂量校正后，按AUC0-t计算，得到绝对生物利用度F，计算公式F＝(AUC灌胃×D静脉)/(AUC静脉×D灌胃)×100％，得到的绝对生物利用度F见上表2。
结论：实施例2的式(I)化合物的甲磺酸盐灌胃给药的绝对生物利用度最高达到28.28％，明显优于实施例1式(I)化合物、对照例1和对照例2灌胃给药的绝对生物利用度。
测试实施例2：对人肺癌H1975裸小鼠皮下移植瘤的生长抑制作用
观察本发明实施例2制备得到的式(I)化合物的甲磺酸盐和对照例2物质(对照例2的结构如下，制备方法参考专利申请 CN201410365911.4实施例16)对人肺癌H1975裸小鼠皮下移植瘤的抑制作用。
Figure PCTCN2017000202-appb-000013
细胞培养：H1975培养在加有10％FBS的RPMI-1640培养基中培养，放在37℃含有5％CO2的恒温培养箱中培养。收取指数生长期的细胞并计数，以供接种。
实验动物：BALB/c nude裸鼠，15只，雄性，6周，18-20g，每组5只，购自上海动物实验中心。
设3个实验组，分别为：0.5％羧甲基纤维素钠溶剂对照组，实施例2(25mg/kg)组与对照例2(25mg/kg)组。
实验方法：人肺癌H1975细胞株(5×106个/只)接种于实验小鼠于右侧背部皮下，定期观察肿瘤生长情况，用游标卡尺测量移植瘤直径，待肿瘤生长至平均(100～150)mm3时根据肿瘤大小和小鼠体重随机分组。实施例2与对照例2的物质各自按25mg/kg灌胃给药，溶剂对照组灌胃给予等量溶剂，每天给药一次，连续21天。整个实验过程中，每周测量两次小鼠的体重和肿瘤的大小，观察是否出现毒性反应。
肿瘤体积计算公式：肿瘤体积(mm3)＝0.5×(肿瘤长径×肿瘤短径2)。
三个实验组肿瘤增长生长曲线见附图1，体重曲线见附图2。
结论：本发明实施例2的式(I)化合物的甲磺酸盐对人肺癌H1975裸小鼠皮下移植瘤的生长具有良好的抑制作用，抑制效果明显优于对照例2；并且显示良好的安全性。
在本文中提及的所有文献均通过引用被并入本申请中。此外还应指明的是，在阅读了本申请的上述公开内容之后，本领域技术人员可以无需背离本发明的精神和范围，对本发明作出各种修饰、改动或修改，但这些变化形式同样都应落于本申请所附权利要求书所记载的范围。

Claims (6)

  1. 式(I)化合物的甲磺酸盐，
    Figure PCTCN2017000202-appb-100001
  2. 权利要求1所述式(I)化合物甲磺酸盐的制备方法，其特征在于在溶剂当中将式(I)化合物直接与甲磺酸反应得到。
  3. 如权利要求2所述的制备方法，其特征在于所述溶剂是丙酮与水的混合溶剂。
  4. 药物组合物，其特征在于含有权利要求1所述的式(I)化合物的甲磺酸盐以及药学上可接受的载体。
  5. 权利要求1所述的式(I)化合物的甲磺酸盐在制备治疗癌症的药物中的用途。
  6. 权利要求3所述的药物组合物在制备治疗癌症的药物中的用途。
PCT/CN2017/000202 2016-03-07 2017-03-01 吡啶胺基嘧啶衍生物的盐及其制备方法和应用 Ceased WO2017152706A1 (zh)

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