WO2023274310A1 - 嘌呤衍生物的晶型及其药物组合物 - Google Patents

嘌呤衍生物的晶型及其药物组合物 Download PDF

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WO2023274310A1
WO2023274310A1 PCT/CN2022/102452 CN2022102452W WO2023274310A1 WO 2023274310 A1 WO2023274310 A1 WO 2023274310A1 CN 2022102452 W CN2022102452 W CN 2022102452W WO 2023274310 A1 WO2023274310 A1 WO 2023274310A1
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dna
crystal form
compound
ray powder
crystal
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许学珍
雷飞全
朱丹
何吕学
魏用刚
孙毅
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成都百裕制药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to a purine derivative, or its hydrate, solvate crystal form, its preparation method, its pharmaceutical composition and its use in the field of preparing DNA-PK inhibitors.
  • DNA-dependent protein kinase is a DNA-PK enzyme complex composed of Ku70/Ku80 heterodimer and DNA-dependent protein kinase catalytic subunit (DNA-PKcs).
  • the enzyme complex needs to be activated with the participation of DNA to perform the corresponding functions (George et al., 2019).
  • DNA-PK belongs to the PIKK (phosphatidylinositol 3-kinase-related kinase) family member, which not only repairs intracellular DNA double-strand breaks (double-strand breaks; DSBs) and cellular DNA recombination It plays an important role in the process of antibody DNA rearrangement (V(D)J recombination), and also participates in physiological processes such as chromosome modification, transcription regulation, and telomere maintenance.
  • PIKK phosphatidylinositol 3-kinase-related kinase
  • DSBs In normal physiological process, a variety of factors may lead to the occurrence of DSBs in DNA: for example, DSBs often appear as intermediate products in the process of somatic DNA recombination, which is very important for the formation of the functional immune system of all vertebrates; When the replication fork encounters damaged bases, it may also cause single-strand or double-strand breaks; DNA may also generate DSBs due to the attack of reactive oxygen species (ROS) during normal metabolism (Cannan & Pederson, 2016).
  • ROS reactive oxygen species
  • exogenous factors such as ionizing radiation (Ionizing radiation, IR) and chemotherapeutic agents (such as topoisomerase II inhibitors), etc.
  • NHEJ non-homologous end-joining
  • the basic process is as follows: (1) Ku70/Ku80 heterodimers recognize and bind to the end of double-strand DNA breaks; (2) recruit DNA-PKcs, XRCC4-DNA ligase IV complex and other proteins to both sides of the DNA break double-strand; (3) DNA-PKcs autophosphorylation, activates its own kinase activity; (4) DNA-PKcs acts as an adhesive connection Breaks both ends of DNA to prevent DNA degradation by exonucleases; (5) DNA processing to remove non-ligatable ends or other forms of damage at the break; (6) XRCC4-DNA ligase IV complex repair DNA ends (in some cases, a DNA polymerase may also be required to synthesize new ends prior to ligation).
  • DNA-PKcs When DNA-PKcs is phosphorylated, it can induce a change in protein conformation and regulate the activity of various proteins (such as Artemis, Ku70, Ku80, DNA ligase) in the NHEJ process, which is crucial for the DNA repair process. Therefore, phosphorylated DNA-PKcs (pDNA-PKcs) is often used as a marker of cellular DSBs.
  • DNA-PK activity is related to the occurrence and development of various tumors: for example, DNA-PKcs in melanoma can promote angiogenesis and tumor metastasis; DNA-PKcs expression in multiple myeloma is significantly up-regulated; radiotherapy
  • the content of Ku protein is significantly increased in tolerant thyroid tumors (Ihara, Ashizawa, Shichijo, & Kudo, 2019). Therefore, it may be considered to combine DNA-PK inhibitors with anti-tumor therapies that cause DNA damage (such as IR, chemotherapy agents, etc.) to improve the effect.
  • the use of DNA-PK inhibitors will interfere with the DNA repair function of normal cells to a certain extent. However, there are multiple DNA repair pathways in normal cells as supplements, while tumor cells face strong DNA replication pressure and lack effective DNA repair methods. .
  • the killing effect of other antitumor drugs on tumor cells can be improved by inhibiting the activity of tumor cell DNA-PK.
  • the present invention provides 3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8 oxo Forms I and II of -8,9-dihydro-7hydro-purin-9-yl)adamantane-1-carbonitrile (Compound A), which has the following chemical structure:
  • the crystal form of the present invention exhibits at least one of the following advantages: good solubility, high stability, easy handling, processing, and purification, improved oral bioavailability of drugs, extended drug shelf life, and easy manufacture of various dosage forms.
  • the crystalline form of the present invention exhibits pharmaceutical advantages over the amorphous form of Compound A.
  • the crystal form enhances the chemical and physical stability, which is more conducive to the preparation of solid pharmaceutical dosage forms containing pharmacologically active ingredients.
  • the crystalline form of the invention is present from about 5% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 10% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present at about 15% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 20% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 25% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 30% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 35% to about 100% by weight of the drug substance.
  • the crystalline form of the invention is present in about 40% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 45% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 50% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 55% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 60% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 65% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 70% to about 100% by weight of the drug substance.
  • the crystalline form of the invention is present in about 75% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 80% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 85% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 90% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 95% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present in about 98% to about 100% by weight of the drug substance.
  • the crystalline form of the invention is present in about 99% to about 100% by weight of the drug substance. In certain embodiments, substantially all of the drug substance is a crystalline form of the invention, ie, the drug substance is substantially phase-pure crystals.
  • Compound A of the present invention is an amorphous form of compound A unless otherwise specified.
  • crystal form I is anhydrous compound A (crystal form I), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 9.4472° ⁇ 0.3°, 18.836 ° ⁇ 0.3°, 23.79° ⁇ 0.3°.
  • the 2 ⁇ diffraction angles are still 7.414° ⁇ 0.2°, 13.514° ⁇ 0.2°, 15.119° ⁇ 0.2°, 15.43° ⁇ 0.2°, 16.601° ⁇ 0.2°, 23.496 There are characteristic diffraction peaks at ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form I also has characteristic diffraction peaks at the following 2 ⁇ positions: 13.077° ⁇ 0.2°, 17.027° ⁇ 0.2°, 17.527° ⁇ 0.2°, 24.55° ⁇ 0.2°, 27.407° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I also has characteristic diffraction peaks at the following 2 ⁇ positions: 4.7909° ⁇ 0.2°, 10.404° ⁇ 0.2°, 13.790° ⁇ 0.2°, 18.01° ⁇ 0.2°, 21.389° ⁇ 0.2° 0.2°, 22.064° ⁇ 0.2°, 25.154° ⁇ 0.2°, 25.912° ⁇ 0.2°.
  • X-ray powder diffraction pattern (XRD) of the crystal form I is basically shown in Figure 1.
  • crystal form II is anhydrous compound A (crystal form II), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 7.8763° ⁇ 0.3°, 16.633 ° ⁇ 0.3°, 18.059° ⁇ 0.3°, 27.085° ⁇ 0.3°.
  • the 2 ⁇ diffraction angles also have characteristic diffraction peaks at 11.619° ⁇ 0.2°, 17.075° ⁇ 0.2°, 22.088° ⁇ 0.2°, and 27.915° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form II also has characteristic diffraction peaks at the following 2 ⁇ positions: 9.243° ⁇ 0.2°, 10.912° ⁇ 0.2°, 13.019° ⁇ 0.2°, 14.591° ⁇ 0.2°, 22.504° ⁇ 0.2°, 23.475° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II also has characteristic diffraction peaks at the following 2 ⁇ positions: 9.624° ⁇ 0.2°, 10.156° ⁇ 0.2°, 19.26° ⁇ 0.2°, 23.807° ⁇ 0.2°, 25.080° ⁇ 0.2° 0.2°.
  • X-ray powder diffraction pattern (XRD) of the crystal form II is basically shown in Figure 2.
  • the present invention also relates to a pharmaceutical composition, comprising a therapeutically effective amount of the crystalline compound described in the present invention, and one or more pharmaceutically acceptable carriers or excipients.
  • the crystal form described in the present invention can be used as an active pharmaceutical ingredient, or a pharmaceutical composition as an active ingredient, to prepare a DNA-PK inhibitor drug.
  • the DNA-PK inhibitor is used to prepare medicines for treating and preventing cancer.
  • the X-ray powder diffraction patterns disclosed by the present invention which are substantially the same as those disclosed by the present invention, also belong to the scope of the present invention.
  • Effective dose means the amount of a compound that causes a physiological or medical translation of a tissue, system, or subject that is sought, including one or more doses sufficient to prevent the disease or condition being treated when administered in a subject. The amount of compound that causes or alleviates a symptom to some extent.
  • IC 50 refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • the structure of the crystalline forms of the present invention can be analyzed using various analytical techniques known to those of ordinary skill in the art, including but not limited to X-ray powder diffraction (XRD).
  • XRD X-ray powder diffraction
  • crystal form of the present invention is not limited to the characteristic spectra that are completely the same as those described in the drawings disclosed in the present invention, such as XRD, have substantially the same or essentially the same characteristics as those described in the drawings. Any crystal form with a characteristic spectrum falls within the scope of the present invention.
  • Figure 1 is the X-ray powder diffraction pattern of compound A crystal form I using Cu-K ⁇ radiation.
  • Fig. 2 is an X-ray powder diffraction pattern of compound A crystal form II using Cu-K ⁇ radiation.
  • the solution refers to an aqueous solution.
  • the experimental conditions for crystallization are generally room temperature (20-30° C., 30-70% RH), and the solvent ratio refers to the volume ratio.
  • Embodiment 2 Preparation of Compound A Crystalline Form I
  • Compound A was recrystallized in a dichloromethane/methanol (volume ratio 9/1) mixed solution to obtain a crystalline form II sample of compound A.
  • Olex2 the structure was analyzed by SHELXT structure analysis program, and the packet was subjected to minimum variance refinement using the SHELXL-97 direct method.
  • DNA-PK kinase assay kit (DNA-PK kinase assay kit) (purchased from Promega Company, article number: V4107, batch number: 0000366495). The results were quantified by chemiluminescence, and the specific experimental scheme is as follows:
  • ii Prepare 5 ⁇ L reaction system in a 384-well white plate, add 1 ⁇ L of compound A (set concentration gradient 1 ⁇ M, 200nM, 40nM, 8nM, 1.6nM, 0.32nM, 0.064nM, 0.013nM respectively) and 20units DNA to each well -PK kinase, 0.2 ⁇ g/ ⁇ L substrate, 10 ⁇ g/ ⁇ L DNA, 50 ⁇ M ATP, 1% DMSO;
  • control example is compound 3 of J.Med.Chem(2020), 63(7), 3461-3471, which was prepared according to its preparation method.

Abstract

涉及取代的嘌呤衍生物的晶型及其药物组合物，制备方法和用于制备DNA-PK抑制剂的用途。具体涉及式(A)所示化合物的晶型及其药物组合物，制备方法和用于制备DNA-PK抑制剂的用途。

Description

嘌呤衍生物的晶型及其药物组合物 技术领域
本发明涉及一种嘌呤衍生物，或其水合物、溶剂化物的晶型，以及其制备方法或其药物组合物和其在制备DNA-PK抑制剂领域的用途。
背景技术
DNA依赖的蛋白激酶(DNA-dependent protein kinase，DNA-PK)是由Ku70/Ku80异二聚体和DNA依赖的蛋白激酶催化亚基(DNA-PKcs)构成的DNA-PK酶复合物。该酶复合物需要在DNA参与下才能被激活发挥出相应的功能(George et al.,2019)。作为一种丝氨酸/苏氨酸蛋白激酶，DNA-PK属于PIKK(phosphatidylinositol 3-kinase-related kinase)家族成员，它不仅在修复细胞内DNA双链断裂(double-strand breaks；DSBs)和细胞DNA重组或抗体DNA重排(V(D)J重组)过程中具有重要作用，还参与染色体修饰、转录调节、端粒维持等生理过程。
在正常生理过程中，多种因素可能导致DNA发生DSBs：如体细胞DNA重组过程中DSBs常常作为中间产物出现，这一生理过程对所有脊椎动物的功能性免疫系统的形成十分重要；DNA复制中复制叉遇到受损的碱基，也可能造成单链或双链断裂；DNA也可能因为正常代谢过程中活性氧(reactive oxygen species；ROS)的攻击而产生DSBs(Cannan&Pederson,2016)。此外，还有多种外源性因素也可能导致DSBs，如电离辐射(Ionizing radiation，IR)和化疗试剂(如拓扑异构酶II抑制剂)等(George et al.,2019)。如果DSBs未被修复或者错误地修复，将会产生突变和/或染色体畸变，最终导致细胞死亡。为了应对DSBs带来的危害，真核细胞已进化出多种机制来修复受损的DNA以维持细胞的活力和基因组的稳定性。在真核细胞中，最主要的DNA修复方式是非同源末端连接(non-homologous end-joining，NHEJ)。这种直接将断裂DNA连接起来的方式并不需要有同源DNA片段参与，可以发生在细胞周期的任何阶段。NHEJ是由DNA-PK介导的需要多种蛋白与信号通路共同参与的动态过程，基本过程如下：(1)Ku70/Ku80异二聚体识别并结合至双链DNA断裂末端；(2)募集DNA-PKcs、XRCC4-DNA连接酶IV复合体等蛋白至DNA断裂双链的两侧；(3)DNA-PKcs自身 磷酸化，激活自身的激酶活性；(4)DNA-PKcs作为粘合剂连接断裂DNA的两端，防止核酸外切酶对DNA的降解作用；(5)对DNA进行加工以移除断裂处的不可连接末端或其他损伤形式；(6)XRCC4-DNA连接酶IV复合体修复DNA末端(某些情况下，在连接之前可能还需要DNA聚合酶来合成新的末端)。当DNA-PKcs发生磷酸化后，可诱导蛋白构象发生改变，调节NHEJ过程中多种蛋白的活性(如Artemis、Ku70、Ku80、DNA ligase)，这对DNA修复过程至关重要。因此，磷酸化的DNA-PKcs(pDNA-PKcs)常常作为细胞DSBs的标志物。
已有研究表明，DNA-PK活性与多种肿瘤的发生发展有关：如黑色素瘤中的DNA-PKcs可以促进血管再生和肿瘤的转移；多发性骨髓瘤中的DNA-PKcs表达量显著上调；放疗耐受的甲状腺肿瘤中的Ku蛋白的含量明显增加(Ihara,Ashizawa,Shichijo,&Kudo,2019)。因此，可以考虑将DNA-PK抑制剂与引起DNA损伤的抗肿瘤疗法(如IR、化疗试剂等)联用来提高效果。DNA-PK抑制剂的使用在一定程度上会干扰正常细胞的DNA修复功能，然而正常细胞体内还存在多种DNA修复途径作为补充，而肿瘤细胞面临强大的DNA复制压力且缺乏有效的DNA修复方式。通过抑制肿瘤细胞DNA-PK的活性能够提高其他抗肿瘤药物对肿瘤细胞的杀伤效果。
发明内容
本发明提供了3-(7-甲基-2-[(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基]-8氧代-8,9-二氢-7氢-嘌呤-9-基)金刚烷-1-甲腈(化合物A)的晶型I和II，化合物A具有以下化学结构：
Figure PCTCN2022102452-appb-000001
本发明的晶型表现出了以下至少一方面优势：溶解度好，稳定性高，易于处理、加工、提纯，改善药物口服生物利用度，延长药物储存期限，易于各种剂型制造。
本发明的晶型表现出优于化合物A的无定形态的制药学优势。尤其是，晶型增强了化学和物理的稳定性，更有利于在制备包含药理学活性成分的固体药物剂型。
本发明的晶形以原料药的约5重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约10重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约15重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约20重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约25重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约30重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约35重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约40重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约45重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约50重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约55重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约60重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约65重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约70重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约75重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约80重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约85重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约90重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约95重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约98重量％至约100重量％存在。在某些实施方案中，本发明的晶形以原料药的约99重量％至约100重量％存在。在某些实施方案中，基本上所有的原料药都是本发明的晶形，即原料药基本上是相纯晶体。
本发明化合物A无特殊说明，则为化合物A的无定形态。
本发明所述晶型的一个实施方案为无水化合物A(晶型I)，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：9.4472°±0.3°，18.836°±0.3°，23.79°±0.3°。
其中，该晶型I的X-射线粉末衍射中，2θ衍射角度还在7.414°±0.2°，13.514°±0.2°，15.119°±0.2°，15.43°±0.2°，16.601°±0.2°，23.496°±0.2°处具有特征衍射峰。
进一步的，该晶型I的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：13.077°±0.2°，17.027°±0.2°，17.527°±0.2°，24.55°±0.2°，27.407°±0.2°。
再进一步，晶型I的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：4.7909°±0.2°，10.404°±0.2°，13.790°±0.2°，18.01°±0.2°，21.389°±0.2°，22.064°±0.2°，25.154°±0.2°，25.912°±0.2°。
更进一步，该晶型I的X-射线粉末衍射图谱(XRD)基本如附图1所示。
本发明所述晶型的一个实施方案为无水化合物A(晶型II)，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：7.8763°±0.3°，16.633°±0.3°，18.059°±0.3°，27.085°±0.3°。
其中，该晶型II的X-射线粉末衍射中，2θ衍射角度还在11.619°±0.2°，17.075°±0.2°，22.088°±0.2°，27.915°±0.2°处具有特征衍射峰。
进一步的，该晶型II的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：9.243°±0.2°，10.912°±0.2°，13.019°±0.2°，14.591°±0.2°，22.504°±0.2°，23.475°±0.2°。
再进一步，晶型II的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：9.624°±0.2°，10.156°±0.2°，19.26°±0.2°，23.807°±0.2°，25.080°±0.2°。
更进一步，该晶型II的X-射线粉末衍射图谱(XRD)基本如附图2所示。
本发明还涉及一种药物组合物，包含治疗有效量的本发明中所述的晶型化合物，以及一种或多种药学上可接受的载体或赋形剂。
本发明所述的晶型作为活性药物成分，或其作为活性成分的药物组合物可以用于制备DNA-PK抑制剂药物。
其中，DNA-PK抑制剂用于制备治疗与预防癌症的药物。
本发明公开的X-射线粉末衍射图，与其实质上相同的也属于本发明的范围。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
本发明晶型结构可以使用本领域普通技术人员已知的各种分析技术分析，包括但 不限于X-射线粉末衍射(XRD)。
可以理解的是，本发明描述的和保护的数值为近似值。数值内的变化可能归因于设备的校准、设备误差、晶体的纯度、晶体大小、样本大小以及其他因素。
可以理解的是，本发明的晶型不限于与本发明公开的附图中描述的特征图谱完全相同的特征图谱，比如XRD，具有与附图中描述的哪些图谱基本上相同或本质上相同的特征图谱的任何晶型均落入本发明的范围内。
在不背离本发明的范围和主旨下，通过考虑本发明的说明书和实施例操作内容后，对本发明进行各种不同的改进和改变对本领域技术人员将是显而易见的。
附图说明
图1是化合物A晶型I使用Cu-Kα辐射的X-射线粉末衍射图谱。
图2是化合物A晶型II使用Cu-Kα辐射的X-射线粉末衍射图谱。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
实施例中无特殊说明，溶液是指水溶液。
除非特殊说明，结晶的实验条件一般为室温(20-30℃，30-70％RH)，溶剂比例是指体积比。
实施例1化合物A的制备
3-(7-甲基-2-[(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基]-8氧代-8,9-二氢-7氢-嘌呤-9-基)金刚烷-1-甲腈(化合物A)
3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carbonitrile
Figure PCTCN2022102452-appb-000002
Figure PCTCN2022102452-appb-000003
第一步：
3-氨基金刚烷-1-羧酸叔丁酯(1b)
tert-butyl 3-aminoadamantane-1-carboxylate
将化合物1a(10g,51.21mmol)溶于氯化亚砜(70mL)，90℃回流1h。将反应液直接浓缩，并用甲苯(50mL)复溶后浓缩除去多余的氯化亚砜，冰浴加入叔丁醇(60mL)，随后室温反应1h，TLC监测至反应完全，直接将反应液浓缩，收集固体得到目标化合物1b(白色固体，12g,产率93.22％)。
LC-MS m/z(ESI)＝252.20[M+1]。
第二步：
4-((3-(叔丁氧基羰基)金刚烷-1-基)氨基)-2-氯嘧啶-5-羧酸乙酯(1c)
ethyl4-(((1s,3r,5R,7S)-3-(tert-butoxycarbonyl)adamantan-1-yl)amino)-2-chloropyrimidine-5-carboxylate
将化合物2,4-二氯嘧啶-5-羧酸乙酯(12g,54.29mmol)，化合物1b(13.65g,54.29mmol)，碳酸钾(15.01g,108.58mmol)溶于乙腈(150mL)，反应液在室温反应16h。TLC监测反应结束，过滤，并用少量乙腈清洗固体，将滤液合并后浓缩，粗品经柱层析分离(石油醚/乙酸乙酯(v/v)＝1/1)后得到目标化合物1c(白色固体,15g,产率63.38％)。
1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.36(s,1H),4.30(q,2H),2.00–2.18(m,8H),1.61-1.73(m,6H),1.38(s,9H),1.31(t,3H)。
第三步：
4-((3-(叔丁氧基羰基)金刚烷-1-基)氨基)-2-氯嘧啶-5-羧酸(1d)
4-((3-(tert-butoxycarbonyl)adamantan-1-yl)amino)-2-chloropyrimidine-5-carboxylicacid
将化合物1c(15g，34.41mmol)溶解于四氢呋喃200mL，水200mL中，加入氢氧化锂(1.65g,68.82mmol)，室温搅拌1h。TLC监测反应完全，浓缩除去四氢呋喃，用6N盐酸调pH为5，有白色固体析出，过滤，滤饼用石油醚洗两次，搜集固体得到标题化合物1d(白色固体，14g，产率99.75％)。
1H NMR(400MHz,DMSO-d 6)δ8.65(s,1H),8.58(s,1H),2.01–2.17(m,8H),1.57–1.77(m,6H),1.38(s,9H)。
LC-MS m/z(ESI)＝408.10[M+1]。
第四步：
3-(2-氯-8-氧代8,9-二氢-7氢-嘌呤-9-基)金刚烷-1-羧酸叔丁酯(1e)
tert-butyl-3-(2-chloro-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate
将化合物1d(15g,36.77mmol)溶于N,N-二甲基乙酰胺(150mL)中，冰浴加入叠氮磷酸二苯酯(7.91mL,36.77mmol)和三乙胺(5.11mL,36.77mmol)，将反应液室温搅拌1h后升温至120℃继续反应3h。TLC监测反应完全(二氯甲烷/甲醇(v/v)＝4/1)，将反应液自然冷却至室温，缓慢倒入600mL冰水中，出现大量固体，过滤，收集固体，且用乙酸乙酯(150mL)打浆，真空干燥得到目标化合物1e(白色固体,7.0g,产率47.02％)。
1H NMR(400MHz,DMSO-d 6)δ11.56(s,1H),8.07(s,1H),2.44–2.57(m,6H),2.23(s,2H),1.58–1.80(m,6H),1.39(s,9H)。
第五步：
叔丁基3-(2-氯-8-氧代-8,9-二氢-7氢-嘌呤-9-基)金刚烷-1-羧酸叔丁酯(1f)
tert-butyl3-(2-chloro-7-methyl-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate
将化合物1e(5g,12.35mmol)溶于二甲基甲酰胺(40mL)中，在0℃下加入碳酸铯(6.04g,18.52mL)和硫酸二甲酯(1.4mL,14.82mmol),室温反应2h。TLC监测至反应完全，加入100ml水，析出固体，过滤，干燥得到目标化合物1f(白色固体，5.0g,产率96.64％)。
1H NMR(400MHz,DMSO-d 6)δ8.31(s,1H),3.29(s,3H),2.43–2.56(m,6H),2.24(s,2H),1.54–1.80(m,6H),1.38(s,9H)。
第六步：
叔丁基3-(7-甲基-2-[(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基]-8-氧代-8,9-二氢-7氢-嘌呤-9-基)金刚烷-1-羧酸叔丁酯(1g)
tert-butyl3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate
将7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-胺(500mg，3.37mmol)、化合物1f(1.41g，3.37mmol)、碳酸铯(2.31g，7.08mmol)、[(2-二-环己基膦基-3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯基)-2-(2′-氨基-1,1′-联苯基)]甲磺酸钯(II)甲磺酸酯(310mg，0.34mmol)溶解于二氧六环(10mL)，氮气保护并换气，在100℃搅拌4h。TLC监测反应结束，将反应液倒入冰水中，搜集固体，将固体用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝100/1)，得到目标化合物1g(白色固体，1.4g,产率78.29％)。
1H NMR(400MHz,DMSO-d 6)δ9.08(s,1H),8.58(s,1H),8.36(s,1H),8.10(s,1H),7.68(s,1H),3.24(s,3H),2.33-2.61(m,6H),2.14(s,2H),1.51-1.67(m,6H),1.32(s,9H)。
LC-MS m/z(ESI)＝531.3[M+1]。
第七步：
3-(7-甲基-2-((7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基]氨基]氨基)-8-氧代-7,8-二氢-9H-嘌呤-9-基)金刚烷-1-羧酸(1h)
3-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylic acid
将化合物1g(1.4g，2.64mmol)溶于4N盐酸二氧六环溶液(100mL),混合物室温反应16h后，浓缩，经中压制备后得到目标化合物1h(浅黄色固体,1.4g,产率99％)。
1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),9.07(s,1H),8.57(s,1H),8.36(s,1H),8.09(s,1H),7.68(s,1H),3.24(s,3H),2.41-2.58(m,6H),2.38(s,3H),2.14(s,2H),1.56–1.71(m,6H)。
LC-MS m/z(ESI)＝475.20[M+1]。
第八步：
3-(7-甲基-2-[(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基]-8-氧代-8,9-二氢-7氢-嘌呤-9-基)金刚烷-1-甲酰胺(1i)
3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxamide
将化合物1h(0.5g,1.05mmol)，氯化铵(0.56g,10.50mmol)，三乙胺(0.73mL,5.25mmol)溶于N,N-二甲基甲酰胺(15mL),冰浴加入HATU(0.6g,1.58mmol),混合物室温反应1h，加水(30mL)淬灭反应，乙酸乙酯(30mL×3)萃取，有机相干燥浓缩得到目标化合物1i(白色固体，0.14g,产率28.16％)。
1H NMR(400MHz,DMSO-d 6)δ9.08(s,1H),8.56(s,1H),8.36(s,1H),8.08(s,1H),7.68(s,1H),6.97(s,1H),6.74(s,1H),3.24(s,3H),2.33-2.62(m,9H),2.15(s,2H),1.51-1.73(m,4H)。
LC-MS m/z(ESI)＝474.3[M+1]。
第九步：
3-(7-甲基-2-[(7-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)氨基]-8氧代-8,9-二氢-7氢-嘌呤-9-基)金刚烷-1-甲腈(化合物A)
3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydr o-7H-purin-9-yl)adamantane-1-carbonitrile
将化合物1i(130mg,0.27mmol)溶于二氯甲烷(20mL)，冰浴加入吡啶(90mg,1.08mmol)，三氟乙酸酐(170mg,0.81mmol)，保持温度继续反应1h，加入甲醇(20mL),浓缩粗品。将粗品复溶解于乙酸乙酯(50mL)，分别用15％NaHCO 3(50mL)，饱和食盐水(50mL)，干燥，浓缩得到化合物A(浅黄色固体,60mg,产率48.78％)。
1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),8.65(s,1H),8.37(s,1H),8.11(s,1H),7.70(s,1H),3.25(s,3H),2.75(s,2H),2.44-2.51(m,4H),2.38(s,3H),2.15(s,2H),1.91-1.94(m,4H),1.53-1.62(m,2H)。
LC-MS m/z(ESI)＝456.2[M+1]。
实施例2化合物A晶型I的制备
化合物A在二氯甲烷中重结晶，得到化合物A的晶型I样品。
实施例3化合物A晶型II的制备
化合物A在二氯甲烷/甲醇(体积比9/1)混合溶液中重结晶，得到化合物A的晶型II样品。
测试例1
将化合物A的晶型I和II用日本Rigbu xtalab协同衍射仪，室温下石墨单色Cu-Kα辐射(λ＝1.54)，电压45KV，电流40mA，扫描范围(2θ角)3°-60°，获得粉末衍射图。使用Olex2，结构通过SHELXT结构解析程序，采用SHELXL-97直接方法对数据包进行最小方差精析。
化合物A晶型I的X-射线粉末衍射数据如表1所示，化合物A晶型I的X-射线粉末衍射图如附图1所示。
表1化合物A晶型I的X-射线粉末衍射数据
峰号 2θ角(度) 晶面间距 峰高 半峰宽 相对峰高
1 4.7909 18.430 1715 0.2631 5.00
2 7.414 11.914 8298 0.289 26.21
3 9.4472 9.3540 35184 0.2743 100.00
4 10.404 8.496 1611 0.280 5.28
5 10.78 8.199 212 0.59 1.29
6 11.964 7.392 633 0.286 2.28
7 13.077 6.7646 6619 0.285 18.76
8 13.514 6.5466 6458 0.311 20.02
9 13.790 6.416 1732 0.32 5.44
10 14.096 6.278 1420 0.27 3.86
11 15.119 5.855 5685 0.34 20.31
12 15.43 5.738 5114 0.41 21.84
13 16.601 5.3357 5661 0.372 21.97
14 17.027 5.2031 4245 0.274 12.15
15 17.527 5.056 2258 0.49 11.48
16 18.01 4.921 1656 0.34 5.86
17 18.23 4.862 1212 0.28 3.48
18 18.836 4.7075 7500 0.462 36.15
19 19.702 4.5024 1669 0.261 4.54
20 20.471 4.335 566 0.20 1.20
21 21.389 4.1509 1832 0.48 9.24
22 22.064 4.0254 1835 0.300 5.75
23 23.496 3.7832 8375 0.289 24.08
24 23.79 3.737 6576 0.60 39.02
25 24.55 3.623 1337 0.9 12.22
26 25.154 3.5375 3029 0.293 8.83
27 25.912 3.4357 2677 0.367 9.78
28 26.676 3.3390 1176 0.23 2.66
29 27.407 3.2516 4893 0.337 16.41
30 28.39 3.141 668 0.69 4.62
31 29.454 3.0301 662 0.41 2.71
32 31.46 2.842 486 0.48 2.33
33 31.92 2.801 262 0.46 1.19
34 32.480 2.7544 1100 0.303 3.32
35 32.997 2.7124 776 0.29 2.26
36 33.402 2.6805 338 0.29 0.96
37 34.26 2.6152 336 0.33 1.09
38 35.28 2.5418 195 0.30 0.60
39 36.47 2.462 301 0.62 1.92
40 37.87 2.3739 366 0.41 1.55
41 41.113 2.1938 179 0.21 0.38
42 41.74 2.1620 80 0.22 0.17
43 42.50 2.1254 135 0.27 0.36
44 43.14 2.095 164 0.66 1.09
45 44.11 2.0513 163 0.24 0.40
46 45.49 1.992 224 0.41 0.97
47 45.97 1.9724 93 0.26 0.26
48 48.02 1.893 114 0.75 0.87
49 48.83 1.8635 265 0.36 0.97
50 50.71 1.7988 124 0.29 0.36
51 52.13 1.7530 159 0.59 0.94
52 53.27 1.7181 78 0.56 0.43
53 57.93 1.5905 55 0.8 0.86
化合物A晶型II的X-射线粉末衍射数据如表2所示，化合物A晶型II的X-射线粉末衍射图如附图2所示。
表2化合物A晶型II的X-射线粉末衍射数据
峰号 2θ角(度) 晶面间距 峰高 半峰宽 相对峰高
1 4.01 22.0 37 0.94 1.69
2 4.860 18.17 291 0.203 2.86
3 5.50 16.06 85 0.40 1.64
4 7.8763 11.216 8195 0.2114 71.72
5 8.419 10.494 121 0.14 0.72
6 9.243 9.561 4450 0.198 34.85
7 9.624 9.183 1820 0.297 21.40
8 10.156 8.703 2964 0.205 24.06
9 10.912 8.102 3916 0.245 41.70
10 11.619 7.610 3444 0.335 50.28
11 13.019 6.794 3259 0.369 43.09
12 13.601 6.505 920 0.39 12.97
13 13.924 6.355 494 0.18 3.21
14 14.591 6.066 3074 0.293 32.32
15 14.828 5.9696 2286 0.170 13.95
16 15.075 5.872 1791 0.218 13.98
17 15.725 5.631 830 0.30 9.81
18 16.057 5.515 1519 0.21 12.49
19 16.633 5.325 4907 0.45 88.15
20 17.075 5.189 4877 0.298 57.80
21 18.059 4.908 5877 0.427 100.00
22 19.26 4.605 2245 0.26 23.17
23 19.52 4.543 842 0.18 6.02
24 20.38 4.354 843 0.22 6.52
25 20.6 4.32 992 0.29 10.34
26 21.553 4.120 1191 0.29 12.19
27 22.088 4.0211 3984 0.327 46.35
28 22.504 3.948 2719 0.33 31.68
29 22.88 3.883 1255 0.40 17.87
30 23.475 3.7866 4161 0.287 42.46
31 23.807 3.734 2391 0.33 27.78
32 25.080 3.548 2026 0.317 22.87
33 25.754 3.4564 1305 0.27 12.57
34 27.085 3.2895 6518 0.289 83.52
35 27.915 3.1935 2958 0.383 50.10
36 29.325 3.0431 223 0.29 2.28
37 31.639 2.8256 2103 0.142 18.64
38 32.57 2.747 119 0.22 1.47
39 33.960 2.6376 431 0.41 6.34
40 34.55 2.5940 483 0.48 8.29
41 35.74 2.510 118 0.23 1.38
42 36.40 2.466 243 0.72 8.94
43 39.05 2.305 139 0.28 2.12
44 42.82 2.110 280 1.28 14.97
45 45.353 1.9980 803 0.271 9.10
46 46.44 1.9536 164 0.42 2.88
47 48.34 1.881 88 0.33 1.04
48 50.10 1.819 91 0.37 1.43
49 50.68 1.800 99 0.44 1.81
50 52.62 1.738 64 0.38 0.87
51 56.450 1.62877 1675 0.073 6.17
测试例2
DNA-PK激酶抑制试验
通过DNA-PK激酶检测试剂盒(DNA-PK kinase assay kit)(购买自Promega公司，货号：V4107，批号：0000366495)检测化合物对DNA-PK激酶的抑制活性。利用化学发光对结果进行定量，具体实验方案如下：
i.按照试剂盒说明书构建不同浓度ADP-荧光标准曲线；
ii.于384孔白色板中制备5μL反应体系，每孔中分别加入1μL化合物A(分别设定浓度梯度1μM、200nM、40nM、8nM、1.6nM、0.32nM、0.064nM、0.013nM)、 20units DNA-PK激酶、0.2μg/μL底物、10μg/μL DNA、50μM ATP、1％DMSO；
iii.混匀，离心(1000rpm，30s)，37℃孵育60min；
iv.加入5μL ADP‐Glo TM Reagent终止反应，混匀，离心(1000rpm，30s)，室温孵育40min；
v.加入10μL Kinase Detection Reagent，震荡混匀，离心(1000rpm，30s)，室温孵育30min；
vi.利用酶标仪(Thermo fisher，Varioskan LUX)测定荧光值。利用GraphPad Prism8进行IC 50的计算，结果见表3。
表3化合物A对DNA-PK激酶抑制活性
化合物编号 IC 50(nM)
化合物A 0.08
对照例 100.20
注：对照例为J.Med.Chem(2020),63(7),3461-3471的化合物3，对照例按照其制备方法制备得到。
结果表明，与对照例相比，本发明化合物对DNA-PK激酶具有更显著的抑制效果。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。

Claims (12)

  1. 式(A)所示化合物的晶体：
    Figure PCTCN2022102452-appb-100001
  2. 根据权利要求1所述的晶体，其特征在于，晶型I使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：9.4472°±0.3°，18.836°±0.3°，23.79°±0.3°。
  3. 根据权利要求2所述的晶体，其特征在于，晶型I使用Cu-Kα辐射，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：7.414°±0.2°，13.514°±0.2°，15.119°±0.2°，15.43°±0.2°，16.601°±0.2°，23.496°±0.2°。
  4. 根据权利要求3所述的晶体，其特征在于，晶型I使用Cu-Kα辐射，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：13.077°±0.2°，17.027°±0.2°，17.527°±0.2°，24.55°±0.2°，27.407°±0.2°。
  5. 根据权利要求4所述的晶体，其特征在于，晶型I的X-射线粉末衍射图谱如图1所示。
  6. 根据权利要求1所述的晶体，其特征在于，晶型II使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：7.8763°±0.3°，16.633°±0.3°，18.059°±0.3°，27.085°±0.3°。
  7. 根据权利要求6所述的晶体，其特征在于，晶型II使用Cu-Kα辐射，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：11.619°±0.2°，17.075°±0.2°，22.088°±0.2°，27.915°±0.2°。
  8. 根据权利要求7所述的晶体，其特征在于，晶型II使用Cu-Kα辐射，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：9.243°±0.2°，10.912°±0.2°，13.019°±0.2°，14.591°±0.2°，22.504°±0.2°，23.475°±0.2°。
  9. 根据权利要求8所述的晶体，其特征在于，晶型II的X-射线粉末衍射图谱如 图2所示。
  10. 一种药物组合物，包含治疗有效量的权利要求1～9中任一项所述晶型，以及药学上可接受的载体或赋形剂。
  11. 权利要求1～9中任一项所述晶型，或权利要求10所述的药物组合物在制备DNA-PK抑制剂中的用途。
  12. 权利要求1～9中任一项所述晶型，或权利要求10所述的药物组合物在制备用于治疗与预防癌症的药物中的用途。
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