WO2021196949A1 - 一种glp-1受体激动剂的晶型a及其制备方法 - Google Patents

一种glp-1受体激动剂的晶型a及其制备方法 Download PDF

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WO2021196949A1
WO2021196949A1 PCT/CN2021/078622 CN2021078622W WO2021196949A1 WO 2021196949 A1 WO2021196949 A1 WO 2021196949A1 CN 2021078622 W CN2021078622 W CN 2021078622W WO 2021196949 A1 WO2021196949 A1 WO 2021196949A1
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phenyl
crystal form
oad2
hexahydro
isoquinoline
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PCT/CN2021/078622
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English (en)
French (fr)
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胡海文
方丽
胡范
陈芬芬
周鑫洁
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杭州中美华东制药有限公司
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Priority to EP21780934.2A priority Critical patent/EP4130005A4/en
Priority to CN202180023642.1A priority patent/CN115461344B/zh
Priority to US17/995,090 priority patent/US20230174546A1/en
Priority to JP2022560234A priority patent/JP2023528565A/ja
Publication of WO2021196949A1 publication Critical patent/WO2021196949A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention belongs to the technical field of medicine, and relates to (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropane) Group)-2,3,6,7,8,9-hexahydro-[1,4]-dioxeno[2,3-g]isoquinoline-8-carboxamido)-3 -(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid (“OAD2”) crystalline form A and its preparation method.
  • Form A can be used to treat various metabolic-related disorders, including but not limited to type II diabetes.
  • OAD2 dihydrochloride is a non-peptide, oral glucagon-like peptide-1 receptor (GLP-1r) agonist.
  • OAD2 dihydrochloride is easy to absorb moisture, and post-processing operations such as filtration and drying are difficult, which has a serious impact on its quality. Therefore, it is necessary to carry out in-depth research on OAD2 to meet the requirements for the quality, purity, stability and form of the active ingredients in the development of new drugs.
  • This application provides an OAD2 crystal form A with high purity and good stability and a preparation method thereof.
  • the present application also provides OAD2 in a solid state form, wherein the solid state form includes crystal form A of OAD2.
  • the application also provides the use of the solid-state form of OAD2 comprising crystal form A in the preparation of a medicament for the treatment of diseases or conditions that benefit from the activation of the GLP-1 receptor.
  • This application further provides a method for preparing crystal form A of OAD2.
  • the application also provides a method for preparing a solid state form of OAD2 containing crystal form A.
  • the application also provides a pharmaceutical composition comprising crystal form A of OAD2, wherein the pharmaceutical composition comprises a therapeutically effective amount of crystal form A of OAD2, and optionally a pharmaceutically acceptable carrier.
  • the composition can be prepared according to methods known in the art.
  • the application also provides a pharmaceutical composition comprising a solid state form of OAD2, wherein the solid state form includes crystal form A.
  • the present application also provides a method for preparing a pharmaceutical composition in a solid form comprising OAD2, wherein the solid form OAD2 includes crystal form A of OAD2.
  • the application also provides the use of the crystal form A of OAD2 in the preparation of GLP-1 receptor agonists.
  • the application also provides the use of the crystal form A of OAD2 in the preparation of medicines.
  • drugs can be used to treat diabetes.
  • the application also provides a treatment method, which comprises administering a therapeutically effective amount of OAD2 in a solid state form to a subject in need, wherein the OAD2 in a solid state form includes crystal form A.
  • This method of treatment can be used to treat diseases that benefit from the activation of GLP-1 receptors.
  • Figure 1 is a powder X-ray diffraction pattern of the crystal form A of OAD2 of the application.
  • Figure 2 is a DSC thermal analysis and thermogravimetric analysis TGA diagram of the crystal form A of OAD2 of the application.
  • crystal or “crystal form” is confirmed by the X-ray powder diffraction pattern characterization shown.
  • the experimental error of the characterization data depends on the condition of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray powder diffraction pattern usually changes with the conditions of the instrument.
  • the relative intensity of the X-ray powder diffraction pattern may also vary with the experimental conditions, so the peak intensity cannot be the only or decisive factor.
  • the experimental error of the peak angle is usually 5%% or less, and an error of ⁇ 0.2 is usually allowed.
  • the obtained value should be understood to be within the range of ⁇ 3.0°C, preferably within the range of ⁇ 1.0°C.
  • the term "therapeutically effective amount” refers to the amount of OAD2 that elicits the therapeutic response sought by the subject.
  • the therapeutic response can be obtained by activating the GLP-1 receptor.
  • the bis-hydrochloride of OAD2 can be obtained according to the method described in patent CN102378574B or related international publication WO2010/114824, which is incorporated herein by reference in its entirety.
  • This application provides OAD2 crystal form A.
  • the X-ray powder diffraction (XRPD) pattern of this crystal form A has characteristic peaks at the following diffraction angles (2 ⁇ ): 9.53°, 12.32°, 13.80°, 17.84°, 18.56°, 19.40 °, 20.38°, 20.99°, 21.78°, 24.69° ( ⁇ 0.2).
  • the present application provides crystal form A of OAD2 with an XRPD pattern including characteristic peaks at the following diffraction angles (2 ⁇ ): 17.84°, 19.40° and 20.38° ( ⁇ 0.2).
  • the present application provides crystal form A of OAD2 with an XRPD pattern including characteristic peaks at the following diffraction angles (2 ⁇ ): 13.80° and 24.69° ( ⁇ 0.2). In other embodiments, the present application provides crystal form A of OAD2 with an XRPD pattern including characteristic peaks at the following diffraction angles (2 ⁇ ): 12.32°, 18.56°, 20.99° and 21.78° ( ⁇ 0.2). In other embodiments, the present application provides crystal form A of OAD2, which is characterized by having an XRPD pattern as shown in FIG. 1.
  • the DSC thermogram shows that the melting point of the crystal form A of OAD2 is 240.8°C.
  • the present application provides crystalline form A, which is characterized by an endothermic peak at 240.8°C measured by DSC.
  • the present application provides crystal form A, which is characterized by having a DSC curve as shown in FIG. 2.
  • the TGA thermogram shows that when heated to 150° C., the crystal form A of OAD2 has a weight loss of 1.1%.
  • the present application provides crystal form A, which is characterized in that its weight loss between room temperature and 150°C is about 1.1% as measured by TGA.
  • the present application provides crystal form A, which is characterized by having a TGA curve as shown in FIG. 2.
  • the crystal form A of OAD2 has the characteristic diffraction angle (2 ⁇ ), interplanar spacing (d) and relative intensity (%) listed in Table 1.
  • Table 1 XRPD characterization data of OAD2 crystal form A
  • the present application provides crystal form A of OAD2, which is characterized by at least two of the following characteristics:
  • the XRPD pattern has characteristic peaks at the following diffraction angles (2 ⁇ ): 17.84°, 19.40° and 20.38° ( ⁇ 0.2);
  • the application also provides a pharmaceutical composition comprising crystal form A of OAD2, wherein the pharmaceutical composition comprises a therapeutically effective amount of crystal form A of OAD2, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be prepared according to methods known in the art.
  • the crystal form A of OAD2 is 0.001% to 99% by weight of the pharmaceutical composition.
  • the application also provides a pharmaceutical composition comprising a solid state form of OAD2, wherein the solid state form includes crystal form A.
  • the present application also provides a method for preparing a pharmaceutical composition in a solid form comprising OAD2, wherein the solid form OAD2 includes crystal form A of OAD2.
  • the crystalline form A of OAD2 is combined with one or more pharmaceutically acceptable carriers and formulated into any dosage form suitable for human or non-human animals.
  • This application further provides a method for preparing OAD2 crystal form A: dissolving OAD2 bis-hydrochloride in a mixed solvent of organic solvent and water, neutralizing the mixture with a solution of alkali, stirring to crystallize, and separating the precipitated The crystal is obtained OAD2 crystal form A.
  • the organic solvent is one or two or more selected from 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile and acetone, preferably 2-methyltetrahydrofuran.
  • the mixing ratio of the organic solvent and water is 1:1.
  • the total volume of the organic solvent and water and the weight of the OAD2 dihydrochloride have a volume/weight ratio of 4 to 8:1, where the volume is in L and the weight is in kg.
  • the alkali is one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, preferably sodium hydroxide.
  • the temperature of the neutralization reaction and crystallization is 10-30°C.
  • the present application provides a pharmaceutical composition comprising a therapeutically effective amount of OAD2, said therapeutically effective amount of OAD2 including a sufficient amount of active ingredients for the treatment of diseases that benefit from the activation of GLP-1 receptors.
  • the present application also provides a treatment method, the treatment method comprising administering a therapeutically effective amount of OAD2 in a solid form to a subject in need, wherein the OAD2 in a solid form includes OAD2 crystal form A.
  • the treatment methods provided in this application can be used to treat diseases or conditions that benefit from activation of GLP 1 receptor, such as but not limited to diseases or conditions selected from the group consisting of metabolic syndrome, glucose intolerance, hyperglycemia, dyslipidemia, I Type 2 diabetes, type II diabetes, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, other cardiovascular diseases, hypertension, benefit from Metabolic disorders that activate GLP-1 receptors, etc., as well as complications caused by or related to diabetes, including but not limited to neurological diseases, retinopathy, nephropathy, and poor wound healing.
  • the condition treated by the method of treatment is type II diabetes.
  • the OAD2 in the solid form of the present application can be administered at a certain dosage level, and the dosage of OAD2 is 1 mg to 100 mg per day.
  • the clinician can personalize the dosage according to the specific clinical condition of the subject being treated. Therefore, the specific dosage level for any particular subject depends on a variety of factors, including the activity of the specific compound used, the subject’s age, weight, general health, gender, diet, time of administration, and administration. The route, the rate of drug excretion, the combination of drugs, and the severity of the specific disease being treated.
  • the crystal form A of OAD2 has a number of improved properties.
  • the crystalline form A of OAD2 does not gain weight due to water absorption for 5 days under the experimental conditions, while the OAD2 bishydrochloride salt shows a weight increase of 8.3% due to moisture absorption for 5 days under similar conditions.
  • the method of purifying OAD2 can be simpler and lower in cost than the method of purifying OAD2 dihydrochloride.
  • X-ray powder diffraction (XRPD): Empyrean, test conditions: power 40kV ⁇ 250mA, CuK ⁇ radiation, scanning range 3 ⁇ 40°(2 ⁇ ), step width 0.02°, scanning speed 5°/min, scanning method: continuous scanning
  • TGA and DSC Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC): TGA and DSC graphs were collected on TA Q5000/5500 thermogravimetric analyzer and TA Q200/Q2000/2500 differential scanning calorimeter respectively, listed in Table 2 The test parameters.
  • Example 1 (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2 ,3,6,7,8,9-hexahydro-[1,4]-dioxeno[2,3-g]isoquinoline-8-carboxamido)-3-(4- Preparation of (2,3-dimethylpyridin-4-yl)phenyl)propionic acid (i.e. OAD2) crystalline form A
  • the stability of OAD2 crystal form A was studied. Determine the chemical stability and crystal stability of crystal form A in H 2 O, SGF (artificial gastric juice), FeSSIF (artificial intestinal fluid under fed state) and FaSSIF (artificial intestinal fluid under fasting state), and characterize the chemistry by HPLC purity Stability, observe whether the crystal form of crystal form A has changed with XRPD. The results are shown in Table 3.
  • the free base crystal form A has good chemical stability, does not change its crystal form under various conditions, is not easy to absorb moisture, and has the advantage of being more suitable for preparation of medicines.

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  • Public Health (AREA)
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Abstract

本发明涉及一种GLP-1受体激动剂的晶型A及其制备方法，具体地涉及一种纯度高、稳定性好的(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸("OAD2")的晶型A及其制备方法。晶型A可用于治疗各种代谢相关的疾病及病症，包括但不限于II型糖尿病。

Description

一种GLP-1受体激动剂的晶型A及其制备方法 技术领域
本发明属于医药技术领域，涉及(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸(“OAD2”)的晶型A及其制备方法。晶型A可用于治疗各种代谢相关的病症，包括但不限于II型糖尿病。
背景技术
(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸双盐酸盐(以下简称“OAD2双盐酸盐”)，分子式：C 50H 49Cl 4N 3O 6，分子量：929.76，其化学结构式如下所示：
Figure PCTCN2021078622-appb-000001
OAD2双盐酸盐是一种非肽类、口服胰高血糖素样肽-1受体(GLP-1r)激动剂。
尽管发明专利CN102378574B公开了(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸游离碱(以下简称“OAD2”)的结构，但并未系统研究OAD2的晶型。
经过研究发现，OAD2双盐酸盐易吸湿，过滤、干燥等后处理操作难度大，对其质量产生严重影响。因此，有必要针对OAD2开展深入的研究，满足新药开发中对于有效成分的质量、纯度、稳定性和形态的要求。
发明内容
本申请提供了一种纯度高、稳定性好的OAD2晶型A及其制备方法。本申请还提供了固态形式的OAD2，其中固态形式包括OAD2的晶型A。
本申请还提供了包含晶型A的OAD2的固态形式在制备用于治疗受益于GLP-1受体的激活的疾病或病症的药物中的用途。
本申请进一步提供了一种制备OAD2的晶型A的方法。本申请还提供了制备包含晶型A的OAD2固态形式的方法。
本申请还提供了包含OAD2的晶型A的药物组合物，其中所述药物组合物包含治疗有效量的OAD2的晶型A，以及任选存在的药学上可接受的载体。所述的组合物可以根据本领域已知的方法来制备。本申请还提供了包含OAD2的固态形式的药物组合物，其中该固态形式包括晶形A。本申请还提供了一种制备包含OAD2的固态形式的药物组合物的方法，其中固态形式OAD2包括OAD2的晶形A。
本申请还提供了OAD2的晶型A在制备GLP-1受体激动剂中的用途。
本申请还提供了OAD2的晶型A在制备药物中的用途。在一些实施方案中，药物可以用于治疗糖尿病。
本申请还提供了一种治疗方法，该方法包括向有需要的受试者给药治疗有效量的固态形式的OAD2，其中所述固态形式的OAD2包括晶型A。该治疗方法可用于治疗受益于GLP-1受体的激活的疾病。
附图说明
图1为本申请的OAD2的晶型A的粉末X-射线衍射图。
图2为本申请的OAD2的晶型A的DSC热分析及热重分析TGA图。
本申请如下的具体实施方式部分将更详细地描述本申请的各种实施方案。
发明详述
本申请中，“晶体”或“晶型”是由所示的X射线粉末衍射图表征所证实的。本领域技术人员能够理解，其中的表征数据实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是本领域技术人员公知，X射线粉末衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线粉 末衍射图的相对强度也可能随着实验条件而变化，所以峰强度不能作为唯一或决定性因素。峰角度的实验误差通常在5％％或更少，通常允许有±0.2的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本申请的X射线粉末衍射图谱的特征峰相同或相似的晶型均属于本发明的范畴。DSC热分析图中的熔点，所得的值应理解为在该值的±3.0℃度的范围内，较好是在该值的±1.0℃的范围内。
本申请中，术语“治疗有效量”是表示引起治疗对象所寻求的治疗反应的OAD2的量。在一些实施方案中，治疗反应可以是通过激活GLP-1受体来获得。
OAD2的双盐酸盐可以根据专利CN102378574B或相关国际公开WO2010/114824中描述的方法获得，该专利文献在此全文引入作为参考。
晶型A
本申请提供了OAD2晶型A。使用Cu-Kα辐射测定，该晶型A的X-射线粉末衍射(XRPD)图具有在以下衍射角(2θ)处的特征峰：9.53°、12.32°、13.80°、17.84°、18.56°、19.40°、20.38°、20.99°、21.78°、24.69°(±0.2)。在一些实施方案中，本申请提供了具有XRPD图的OAD2的晶型A，该XRPD图包括在以下衍射角(2θ)处的特征峰：17.84°，19.40°和20.38°(±0.2)。在另一些实施方案中，本申请提供了具有XRPD图的OAD2的晶型A，该XRPD图包括在以下衍射角(2θ)处的特征峰：13.80°和24.69°(±0.2)。在另一些实施方案中，本申请提供了具有XRPD图的OAD2的晶型A，该XRPD图包括在以下衍射角(2θ)处的特征峰：12.32°，18.56°，20.99°和21.78°(±0.2)。在另一些实施方案中，本申请提供了OAD2的晶型A，其特征在于具有如图1所示的XRPD图。
作为一些具体的实施方案，DSC热分析图显示OAD2的晶型A的熔点为240.8℃。在另一些实施方案中，本申请提供了晶型A，其特征在于通过DSC测定的在240.8℃的吸热峰。在另一些实施方案中，本申请提供了晶形A，其特征在于具有如图2所示的DSC曲线。
作为一些具体的实施方案，TGA热分析图表明，当加热至150℃时，OAD2的晶型A具有1.1％的重量损失。在另一些实施方案中，本申请提供 了晶型A，其特征在于，通过TGA测定，其在室温至150℃之间的重量损失约为1.1％。在另一些实施方案中，本申请提供了晶型A，其特征在于具有如图2所示的TGA曲线。
作为一些特定的实施方案，OAD2的晶型A具有表1所列的特征衍射角(2θ)，晶面间距(d)和相对强度(％)。
表1：OAD2晶型A的XRPD表征数据
Figure PCTCN2021078622-appb-000002
在另一些实施方案中，本申请提供了OAD2的晶型A，其特征在于以下特征中的至少两个：
i)XRPD图具有在以下衍射角(2θ)处的特征峰：17.84°，19.40°和20.38°(±0.2)；
ii)DSC曲线，如图2所示；或者
iii)TGA曲线，如图2所示。
药物组合物
本申请还提供了包含OAD2的晶型A的药物组合物，其中所述药物组合物包含治疗有效量的OAD2的晶型A，以及任选存在的药学上可接受的载体。可以根据本领域已知的方法制备药物组合物。优选地，OAD2的晶型A为药物组合物重量的0.001％～99％。本申请还提供了包含OAD2的固态形式的药物组合物，其中该固态形式包括晶形A。本申请还提供了一种制备包含OAD2的固态形式的药物组合物的方法，其中固态形式OAD2包括OAD2的晶形A。
作为一些具体的实施方案，将OAD2的晶型A与一种或多种药学上可接受的载体组合，并配制成适合用于人类或非人类动物的任何剂型。
制备方法
本申请进一步提供了一种制备OAD2晶型A的方法：将OAD2双盐酸盐溶解在有机溶剂和水的混合溶剂中，用碱的溶液中和该混合物，搅拌以结晶，并分离出沉淀的晶体以得OAD2的晶型A。
作为具体的实施方案，所述的有机溶剂是选自2-甲基四氢呋喃，四氢呋喃，乙腈和丙酮中的一种或两种以上，优选为2-甲基四氢呋喃。
作为具体的实施方案，有机溶剂和水的混合比例为1∶1。在另一些实施方案中，有机溶剂和水的总体积和OAD2双盐酸盐的重量具有4～8:1的体积/重量比，其中体积以L为单位，重量以kg为单位。
作为具体的实施方案，在中和反应步骤中，所述的碱是选自氢氧化锂，氢氧化钠，氢氧化钾，碳酸钠和碳酸钾中的一种，优选为氢氧化钠。
作为一些具体的实施方案，中和反应及结晶的温度为10～30℃。
治疗方法
在另一方面，本申请提供了药物组合物，其包含治疗有效量的OAD2，所述的治疗有效量的OAD2包括足够量的活性成分用于治疗受益于GLP-1受体的激活的疾病。
在另一方面，本申请还提供了治疗方法，所述的治疗方法包括向有需要的受试者施用治疗有效量的固态形式的OAD2，其中所述固态形式的OAD2包括OAD2晶型A。本申请提供的治疗方法可用于治疗受益于激活GLP 1受体的疾病或病症，例如但不限于选自以下的疾病或病症：代谢综合征，葡萄糖耐受不良，高血糖症，血脂异常，I型糖尿病，II型糖尿病，X综合征，胰岛素抵抗，糖耐量减低(IGT)，肥胖，糖尿病血脂异常，高脂血症，动脉硬化，动脉粥样硬化，其他心血管疾病，高血压，受益于激活GLP-1受体的代谢紊乱等，以及由糖尿病引起或与之相关的并发症，包括但不限于神经疾病，视网膜病变，肾病和伤口愈合不良等。在一些实施方案中，所述的治疗方法治疗的病症是II型糖尿病。
本申请的固态形式的OAD2可以一定的剂量水平施用，所述的OAD2施用量为每天1mg至100mg。临床医生可以根据治疗受试者的具体临床状况来个性化剂量。因此，任何特定受试者的具体剂量水平取决于多种因素，所述的因素包括所用具体化合物的活性，受试者年龄，体重，总体健康情况，性别，饮食情况，给药时间，给药途径，药物排泄速率，药物组合以及接受治疗的特定疾病的严重程度。
有益效果
相对于OAD2双盐酸盐，OAD2的晶型A具有多项改进的性质。例如，OAD2的晶型A在实验条件下5天不会因吸水而增重，而OAD2双盐酸盐在相似条件下5天实验表现出因吸湿而重量增加8.3％。此外，纯化OAD2的方法可以比纯化OAD2双盐酸盐的方法更简单且成本更低。
实施例
下面结合具体实施例对本发明作进一步的详细说明。以下实施例用于理解本发明的方法和核心思想，对于本领域的技术人员来说，在不脱离本发明构思的前提下，进行任何可能的变化或替换，均属于本发明的保护范 围。本发明的实施例中未注明具体条件的实验方法，通常为常规条件，或按照原料或商品制造厂商所建议的条件；未注明来源的试剂，通常为通过商业途径可购得的常规试剂。
仪器信息和方法：
X射线粉末衍射(XRPD)：Empyrean，测试条件：功率40kV×250mA，CuK α辐射，扫描范围3～40°(2θ)，步宽0.02°，扫描速度5°/min，扫描方式：连续扫描
热重分析(TGA)和差示扫描量热(DSC)：TGA和DSC图分别在TA Q5000/5500热重分析仪和TA Q200/Q2000/2500差示扫描量热仪上采集，表2列出了测试参数。
表2：DSC和TGA测试参数
Figure PCTCN2021078622-appb-000003
实施例1：(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸(即OAD2)的晶型A的制备
在1L三口瓶中，加入100g OAD2双盐酸盐(HPLC纯度：97.87％)，加入2-甲基四氢呋喃:水(质量比为1:1，各0.4kg)，搅拌溶清，保持20℃条件，加入将9克氢氧化钠溶于水中配成的2N氢氧化钠溶液，加完后在20℃搅拌析晶6小时，过滤，真空干燥，得游离碱晶型A，收率：88.4％。HPLC检测纯度：99.50％。
实施例2：OAD2晶型A的制备
在1L三口瓶中，加入100g的OAD2双盐酸盐(HPLC纯度：97.57％)，加入乙腈:水(质量比为1:1，各0.8kg)，搅拌溶清，保持30℃条件，加入将9克氢氧化钠溶于水中配成的2N氢氧化钠溶液，加完后在30℃搅拌析 晶6小时，过滤，真空干燥，得游离碱晶型A，收率：84.6％。HPLC检测纯度：99.0％。
实施例3：稳定性研究
对OAD2晶型A进行了稳定性研究。测定晶型A在H 2O，SGF(人工胃液)，FeSSIF(进食状态下的人工肠液)和FaSSIF(空腹状态下的人工肠液)中的化学稳定性及晶型稳定性，以HPLC纯度表征化学稳定性，以XRPD观察晶型A的晶型是否发生变化。结果如表3所示，游离碱晶型A的化学稳定性好，在各种条件下未发生晶型变化，且不易吸湿，具有更适宜于成药的优点。
表3：OAD2晶型A的稳定性研究
Figure PCTCN2021078622-appb-000004
1OAD2晶型A于25℃/75±5％RH放置5天(d)，样品吸湿增重1.4％。
2OAD2双盐酸盐于25℃/75±5％RH放置5d，样品吸湿增重8.3％。

Claims (8)

  1. 一种(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸的晶型A，其特征在于，该晶型A的粉末X-射线衍射图谱具有在以下衍射角(2θ)处的衍射峰：9.53±0.2°、12.32±0.2°、13.80±0.2°、17.84±0.2°、18.56±0.2°、19.40±0.2°、20.38±0.2°、20.99±0.2°、21.78±0.2°、24.69±0.2°。
  2. 根据权利要求1所述的(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸的晶型A，其特征在于，其粉末X射线衍射图的峰与图1中显示的衍射角(2θ)处的峰基本上相同。
  3. 一种(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸的晶型A的制备方法，其特征在于，使(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸的双盐酸盐溶解在水和有机溶剂中，再加入碱的溶液以进行中和反应，结晶析出固体，过滤，得游离碱晶型A。
  4. 根据权利要求3所述的制备方法，其特征在于，所述有机溶剂是选自2-甲基四氢呋喃，四氢呋喃，乙腈和丙酮中的一种或两种；和/或
    有机溶剂和水的混合比例为1:1；和/或
    有机溶剂与水的总体积与(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸双盐酸盐的体积/质量比为4～8:1。
  5. 根据权利要求3所述的制备方法，其特征在于，在中和反应中，所 述碱是选自氢氧化锂，氢氧化钠，氢氧化钾，碳酸钠和碳酸钾中的一种，优选氢氧化钠；和/或
    中和反应及结晶温度为10～30℃。
  6. 一种药物组合物，其特征在于，含有重量百分比为0.001％～99％的根据权利要求1或2所述的晶型A，以及任选存在的药学上可接受的载体。
  7. 根据权利要求1或2所述的(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸的晶型A在制备GLP-1受体激动剂中的应用。
  8. 根据权利要求1或2所述的(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸的晶型A制备治疗糖尿病的药物中的应用。
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