WO2021110135A1 - 作为acc1和acc2抑制剂的晶型及其制备方法和应用 - Google Patents

作为acc1和acc2抑制剂的晶型及其制备方法和应用 Download PDF

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WO2021110135A1
WO2021110135A1 PCT/CN2020/133892 CN2020133892W WO2021110135A1 WO 2021110135 A1 WO2021110135 A1 WO 2021110135A1 CN 2020133892 W CN2020133892 W CN 2020133892W WO 2021110135 A1 WO2021110135 A1 WO 2021110135A1
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crystal form
compound
preparation
add
reaction solution
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PCT/CN2020/133892
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French (fr)
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洪绯
黄进明
林锦霞
庄毅超
罗志毅
郑晓平
江志赶
贺海鹰
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漳州片仔癀药业股份有限公司
南京明德新药研发有限公司
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Priority to EP20896844.6A priority Critical patent/EP4071154B1/en
Priority to JP2022534284A priority patent/JP7265681B2/ja
Priority to CN202080084236.1A priority patent/CN114746426B/zh
Priority to US17/781,839 priority patent/US11578081B1/en
Priority to ES20896844T priority patent/ES2965380T3/es
Publication of WO2021110135A1 publication Critical patent/WO2021110135A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • 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 invention relates to a crystal form as an inhibitor of ACC1 and ACC2, a preparation method thereof, and application in the preparation of a medicine as an inhibitor of ACC1 and ACC2.
  • Fatty acid metabolism disorder caused by increased fatty acid synthesis, decreased fatty acid oxidation, or both is a sign of a variety of metabolic disorders, including insulin resistance, hepatic steatosis, dyslipidemia, obesity, metabolic syndrome (MetSyn), non-alcoholic Fatty liver (NAFLD) and so on. At the same time, it may lead to the development of type 2 diabetes (T2DM), as well as non-alcoholic steatohepatitis (NASH), atherosclerosis and other vascular diseases. Disorders of fatty acid metabolism are also a sign of cancer, which can lead to abnormal and persistent malignant tumor cell proliferation. Therefore, inhibiting fatty acid synthesis and/or stimulating fatty acid oxidative metabolism may be beneficial to these diseases (PNAS, 2016, E1796-E1805).
  • Acetyl-CoA carboxylase catalyzes the conversion of acetyl-CoA to malonyl-CoA, which is the first step in fatty acid synthesis, and it is also the speed-determining step.
  • ACC1 is mainly distributed in liver and adipose tissue
  • ACC2 is mainly distributed in liver, heart and muscle tissue.
  • malonyl-CoA catalyzed by ACC1 in the cytoplasm
  • ACC2 on the surface of mitochondria
  • the oxidative metabolism of fatty acids PNAS, 2016, E1796-E1805). Therefore, inhibiting the two subtypes of ACC at the same time can reduce the synthesis of fatty acids and stimulate the oxidative metabolism of fatty acids.
  • WO2013071169A1 discloses the application of ACC inhibitor I-181 in the treatment of related diseases.
  • the present invention provides the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) with characteristic diffraction peaks at the following 2 ⁇ angles: 8.54 ⁇ 0.20°, 17.64 ⁇ 0.20° and 24.81 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.54 ⁇ 0.20°, 10.87 ⁇ 0.20°, 15.55 ⁇ 0.20°, 16.56 ⁇ 0.20°, 17.64 ⁇ 0.20°, 21.32 ⁇ 0.20°, 23.53 ⁇ 0.20° and 24.81 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) has characteristic diffraction at the following 2 ⁇ angles: 6.91°, 8.54°, 8.80°, 9.51°, 10.87°, 11.30°, 12.38°, 12.81°, 13.84°, 14.10°, 15.55°, 16.56°, 17.64°, 17.99°, 18.76°, 19.07°, 20.27°, 20.63°, 21.32°, 22.19°, 22.71°, 23.53°, 24.07° , 24.81°, 26.80°, 27.40°, 27.79°, 28.34°, 29.94°, 30.86°, 30.86°, 31.34°, 31.98°, 33.17°, 33.69°, 35.21°, 35.64°, 36.25°, 36.75°, 37.79 ° and 38.98 °.
  • the XRPD pattern of the crystal form A of the compound of formula (I) is shown in FIG. 1.
  • the XRPD pattern analysis data of the above-mentioned crystal form A is shown in Table 1:
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has the starting point of the endothermic peak at 234.9°C.
  • the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A has a weight loss of 0.86% at 200.0 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form A is shown in FIG. 3.
  • the crystal form A of the compound of the formula (I) of the present invention is stable and is less affected by light, heat and humidity; and the compound of the formula (I) and the crystal form A of the present invention have good drug efficacy in vivo and have broad prospects for preparing medicines.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following acronyms: EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for p-toluenesulfonic acid; mp stands for melting point; EtSO 3 H stands for ethanesulfonic acid; MeSO 3 H stands for methanesulfonic acid; THF stands for tetrahydrofuran; EtOAc stands for ethyl acetate; RuPhos stands for 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl; AcCl stands for acetyl chloride; DCM stands for dichloromethane; DMSO stands for dimethyl sulfide Sulfone.
  • Test method Approximately 10 mg of sample is used for XRPD detection.
  • Light tube voltage 45kV
  • light tube current 40mA
  • the first solar slit 0.04rad
  • the second solar slit 0.04rad
  • Step width angle 0.0263deg(X'Pert 3 )/0.0167deg(Empyrean)
  • Step length 46.665 seconds (X'Pert 3 )/17.780 seconds (Empyrean)
  • Test method Take a sample ( ⁇ 1-5mg) and place it in a DSC aluminum pan for testing. Under the condition of 50mL/min N 2 and at a heating rate of 10°C/min, heat the sample from 25°C (room temperature) to before the sample is decomposed .
  • TGA Thermal Gravimetric Analyzer
  • Test method Take a sample ( ⁇ 1-5mg) and place it in a TGA aluminum pan for testing. Under the condition of 10mL/min N 2 and at a heating rate of 10°C/min, heat the sample from room temperature to 350°C.
  • Fig. 1 is an XRPD spectrum of Cu-K ⁇ radiation of crystal form A of the compound of formula (I).
  • Figure 2 is a DSC chart of the crystal form A of the compound of formula (I).
  • Figure 3 is a TGA spectrum of the crystal form A of the compound of formula (I).
  • the raw materials I-06 (3.0 kg, 15.0 mol) and DMF (15 L) were added to a dry 50 L reactor, and then NIS (2.5 kg, 11.1 mol) was added in batches (250 g per batch). After the feeding is completed, the reaction mixture is heated to 50° C. and stirred for 1.5 hours. The reaction solution was cooled to room temperature, and then poured into 45 L of an aqueous solution with 500 g of sodium bisulfite dissolved in it, and stirred for 5 minutes, a brown solid precipitated out, and it was filtered to obtain a brown crude product.
  • the filtrate was separated, the aqueous phase was extracted with ethyl acetate (8L ⁇ 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under pressure to obtain a residue.
  • the filter cake and the concentrated residue were combined, methanol (15 L) was added, stirred at room temperature for 1 hour, and then filtered.
  • the filtrate was concentrated under reduced pressure, n-heptane (5 L) was added to the residue, and the mixture was stirred for 1 hour. Pour out the n-heptane, add tert-butyl methyl ether (4L), heat to 60°C, stir quickly for 0.5 hours, lower the temperature to 25°C, continue stirring for 1 hour, and filter.
  • the floc contained product so continue to filter with Celite, wash the filter cake with ethyl acetate (10L), separate the aqueous phase; combine the organic phases and wash with saturated sodium chloride aqueous solution (15L), and concentrate the organic phase under reduced pressure
  • the purified solid was added to isopropanol (4L), heated to 50 ⁇ 55°C and stirred until the solid was completely dissolved, then stirred for 30 ⁇ 40 minutes, then naturally cooled to 25 ⁇ 30°C, stirred for 2.0 ⁇ 2.5 hours, Add n-heptane (4L) to the reaction solution and stir at 25 ⁇ 30°C for 12-13 hours, filter, and rinse the filter cake with n-heptane (2L) and drain the filter cake under reduced pressure to obtain a yellow solid I-11.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove ethanol; then adjusted pH to 2 ⁇ 3 with a 3M aqueous hydrochloric acid solution (10L) (internal temperature during the adjustment process was 15 ⁇ 25°C), filtered, and added 0.3M hydrochloric acid to the crude product obtained by filtration Deionized aqueous solution (10L), and stirred at 25-30°C for 50-60 minutes, filtered, the filtered solid was added with ethanol (2L), stirred for 15-20 minutes, then filtered, and the filtered solid was concentrated under reduced pressure to obtain White solid crude product of formula (I).
  • Example 2 Solid physical stability test of crystal form A under different temperature, humidity and light conditions
  • XRPD characterization was performed on the placed sample to detect the change of the crystal form; the results showed that the crystal form of the crystal form A did not change under all stability conditions.
  • Protein human acetyl-CoA carboxylase 1 (hACC1) and human acetyl-CoA carboxylase 2 (hACC2).
  • Cofactors Acetyl-CoA, ATP (adenosine triphosphate)
  • the compound of the present invention has strong inhibitory activity on human ACC1/ACC2 enzymes.
  • test compound 0.5 mg/ml 10% DMSO, 10% polyethylene glycol stearate, 80% water
  • the suspension or clear solution of the test compound (1mg/ml 10% PEG400, 90% (0.5% methylcellulose + 0.2% Tween 80)) was intragastrically administered to 4 male C57BL/6 mice (overnight fasting, 7-9 weeks old), the administration dose is 10 mg/kg.
  • Each group of two mice is cross-collected blood, and each mouse is collected at 4 to 5 time points.
  • intravenous or intragastric administration about 30 ⁇ L of blood was collected from saphenous vein puncture at 0.0833h (IV group only), 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h and 24h.
  • the plasma was separated by centrifugation.
  • the LC-MS/MS method was used to determine the blood drug concentration, and the WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters by the non-compartmental model linear logarithmic ladder method.
  • the compound of formula (I) of the present invention can significantly improve single or partial indicators of pharmacokinetics in mice.
  • the purpose of this study is to study the improvement effect of the compound on NASH and liver fibrosis in the HFD+CCl 4 mouse model, with I-181 as the reference compound.
  • I-181 is an Acetyl-CoA Carboxylase inhibitor and is currently undergoing a phase II clinical study of Non Alcoholic Fatty Liver Disease (NAFLD).
  • the HFD+CCl 4 mouse model used in this study is an animal model that simulates the progression of human non-alcoholic fatty liver disease to NASH.
  • High-fat diet causes fat to accumulate and degenerate in liver cells; CCl 4 (intraperitoneal injection, every time Twice a week) to simulate the "second blow" of liver injury.
  • This model is stable and reliable, and has a high similarity to the pathogenesis of human NASH. It has the main pathological characteristics of NASH, including steatosis, apoptosis, inflammation and fibrosis, and also shows increased plasma aminotransferase (ALT and AST) levels. high.
  • the model in this experiment includes two steps: high-fat feed and CCl 4 induction.
  • the injection time of CCl 4 should be more than 4 hours apart from the time point of the first administration of the day.
  • the experiment was divided into 6 groups, namely healthy control group, model group, reference compound group (GS-0976), and test compound group (compound of formula (I), three doses).
  • the healthy control group consisted of 10 normal mice. During the experiment, they were fed with ordinary feed without CCl 4 injection; 50 obese mice were used in the model group and the administration group, each group consisted of 10 mice. After grouping, the intraperitoneal injection of CCl was started. 4 and given different doses of drugs. The grouping and dosage design are shown in Table 4.

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Abstract

一种作为ACC1和ACC2抑制剂（I）的晶型及其制备方法，以及在制备作为ACC1和ACC2抑制剂的药物中的应用。

Description

作为ACC1和ACC2抑制剂的晶型及其制备方法和应用
本申请主张如下优先权：
CN201911235373.6，申请日2019.12.05。
技术领域
本发明涉及一种作为ACC1和ACC2抑制剂的晶型及其制备方法，以及在制备作为ACC1和ACC2抑制剂的药物中的应用。
背景技术
由脂肪酸合成增多、脂肪酸氧化降低，或者两者同时存在引起的脂肪酸代谢失调，是多种代谢紊乱的标志，包括胰岛素抵抗、肝脂肪变性、血脂异常、肥胖、代谢综合征(MetSyn)、非酒精性脂肪肝(NAFLD)等。同时可能导致2型糖尿病(T2DM)的发展，以及非酒精性脂肪肝炎(NASH)、动脉粥样硬化等血管疾病。脂肪酸代谢紊乱也是癌症的一个标志，可导致异常和持续的恶性肿瘤细胞增殖，因此抑制脂肪酸的合成和/或刺激脂肪酸的氧化代谢，有可能对这些疾病有利(PNAS,2016,E1796-E1805)。
乙酰辅酶A羧化酶(ACC)催化了乙酰辅酶A向丙二酰辅酶A的转化，这是脂肪酸合成的第一步，同时也是决速步。ACC存在两种亚型，ACC1和ACC2。ACC1主要分布于肝脏和脂肪组织中，ACC2则主要分布于肝脏、心脏及肌肉组织中。在肝脏中，由细胞质中的ACC1催化形成的丙二酰辅酶A，主要负责脂肪酸的合成及延长；由线粒体表面的ACC2催化形成的丙二酰辅酶A则主要通过抑制肉碱转移酶I，调节脂肪酸的氧化代谢(PNAS,2016,E1796-E1805)。因此，同时抑制ACC的两个亚型，可以降低脂肪酸的合成，并刺激脂肪酸的氧化代谢。
WO2013071169A1公开了ACC抑制剂I-181在治疗相关疾病中的应用。
Figure PCTCN2020133892-appb-000001
发明内容
本发明提供式(Ⅰ)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.54±0.20°、17.64±0.20°和24.81±0.2°；
Figure PCTCN2020133892-appb-000002
本发明的一些方案中，上述式(Ⅰ)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.54±0.20°、10.87±0.20°、15.55±0.20°、16.56±0.20°、17.64±0.20°、21.32±0.20°、23.53±0.20°和24.81±0.20°。
本发明的一些方案中，上述式(Ⅰ)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射：6.91°、8.54°、8.80°、9.51°、10.87°、11.30°、12.38°、12.81°、13.84°、14.10°、15.55°、16.56°、17.64°、17.99°、18.76°、19.07°、20.27°、20.63°、21.32°、22.19°、22.71°、23.53°、24.07°、24.81°、26.80°、27.40°、27.79°、28.34°、29.94°、30.86°、30.86°、31.34°、31.98°、33.17°、33.69°、35.21°、35.64°、36.25°、36.75°、37.79°和38.98°。
本发明的一些方案中，上述式(Ⅰ)化合物的A晶型，其XRPD图谱如图1所示。
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示：
表1.A晶型的XRPD图谱解析数据
Figure PCTCN2020133892-appb-000003
Figure PCTCN2020133892-appb-000004
本发明的一些方案中，上述A晶型的差示扫描量热曲线在234.9℃处具有吸热峰的起始点。
本发明的一些方案中，上述A晶型的DSC图谱如图2所示。
本发明的一些方案中，上述A晶型的热重分析曲线在200.0±3℃时失重达0.86％。
本发明的一些方案中，上述A晶型的TGA图谱如图3所示。
技术效果
本发明式(Ⅰ)化合物的A晶型稳定、受光热湿度影响小；且本发明式(Ⅰ)化合物及其A晶型具有良好的体内给药药效，成药前景广阔。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：EtOH代表乙醇；MeOH代表甲醇；TFA代表三氟乙酸；TsOH代表对甲苯磺酸；mp代表熔点；EtSO 3H代表乙磺酸；MeSO 3H代表甲磺酸；THF代表四氢呋喃；EtOAc代表乙酸乙酯；RuPhos代表2-双环已基膦-2',6'-二异丙氧基联苯；AcCl代表乙酰氯；DCM代表二氯甲烷；DMSO代表二甲基亚砜。
化合物经手工或者
Figure PCTCN2020133892-appb-000005
软件命名，市售化合物采用供应商目录名称。
本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法
仪器型号：PANalytical(帕纳科)公司的X’Pert 3/Empyrean型X-射线衍射仪
测试方法：大约10mg样品用于XRPD检测。
详细的XRPD参数如下：
射线源：Cu,kα(
Figure PCTCN2020133892-appb-000006
Kα2/Kα1强度比例：0.5)
光管电压：45kV，光管电流：40mA
发散狭缝：固定1/8deg
第一索拉狭缝：0.04rad,第二索拉狭缝：0.04rad
接收狭缝：无，防散射狭缝：7.5mm
测量时间：5min
扫描角度范围：3-40deg
步宽角度：0.0263deg(X’Pert 3)/0.0167deg(Empyrean)
步长：46.665秒(X’Pert 3)/17.780秒(Empyrean)
样品盘转速：15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号：TA Q2000/Discovery DSC 2500差示扫描量热仪
测试方法：取样品(～1-5mg)置于DSC铝盘内进行测试，在50mL/min N 2条件下，以10℃/min的升温速率，加热样品从25℃(室温)到样品分解前。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号：TA Discovery TGA 5500热重分析仪
测试方法：取样品(～1-5mg)置于TGA铝盘内进行测试，在10mL/min N 2条件下，以10℃/min的升温速率，加热样品从室温到350℃。
附图说明
图1为式(Ⅰ)化合物的A晶型的Cu-Kα辐射的XRPD谱图。
图2为式(Ⅰ)化合物的A晶型的DSC谱图。
图3为式(Ⅰ)化合物的A晶型的TGA谱图。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1：式(I)化合物A晶型的制备
Figure PCTCN2020133892-appb-000007
第一步：化合物I-02的制备
在20℃下，向干燥的三口瓶中加入原料I-01(650g,6.62mol)和DCM(1.5L)。降温至0℃，快速滴加SO 2Cl 2(1.88kg,13.90mol)，1小时左右加完，保持温度在0-10℃。滴加完毕，混合物在15-20℃下继续搅拌16小时(滴加过程中溶液逐渐变黑，持续有气体冒出，用氢氧化钠水溶液吸收尾气)。将反应液在40℃下减压浓缩，得到黄色液体粗品I-02直接用于下一步。 1H NMR(400MHz,CDCl 3)δ6.62(s,1H),2.13(s,3H)。
第二步：化合物I-03的制备
向干燥的5L三口瓶中加入将化合物I-02(500g,2.99mol)，AcCl(481.6g,2.05eq)和DCM(2.5L)，降温至0℃。然后分批(每批100g左右)加入AlCl 3(478.4g,3.59mol)，控制内温在0-10℃，1小时左右加完。反应体系缓慢升温至20℃，继续搅拌12小时。将反应液缓慢倒入2公斤左右碎冰中淬灭，边倒边搅拌，保持体系中始终有大量碎冰存在。待冰全部融化后分液。水相用DCM(500mL×2)萃取。合并的有机相用水(1L×2)和饱和食盐水(1L×2)洗涤，无水硫酸钠干燥，减压浓缩得到黄色液体产物I-03。 1H NMR(400MHz,CDCl 3)δ2.53(s,3H),2.15(s,3H)。
第三步：化合物I-04的制备
在20℃下，向干燥的5L三口瓶中加入原料I-03(500g,2.39mol)和DMSO(2.5L)，然后快速滴加aq.HBr(1.45kg,7.17mol)，1小时左右滴加完毕(滴加过程温度升高，体系温度升至52℃)。 混合物缓慢升至60℃，继续搅拌12小时。将反应液缓慢倒入5公斤左右碎冰中淬灭，加入石油醚(1.5L)，快速搅拌20分钟左右，析出大量黄色固体，过滤。滤饼用石油醚(500mL×3)洗涤后，减压抽干得到黄色固体产物I-04，粗品直接用于下一步。
第四步：化合物I-05的制备
在20℃下，向干燥的5L三口瓶中加入原料I-04(300g,1.25mol)和2-MeTHF(3L)，然后加入HOAc(75g,1.25mol)和BocNHNH 2(165.2g,1.25mol)，混合物继续搅拌16小时。反应液依次用水(1L)，20％碳酸钾水溶液(500mL×2)和饱和食盐水(1L×2)洗，无水硫酸钠干燥，减压浓缩得到黑色油状液体产物I-05，粗品直接用于下一步。
第五步：化合物I-06的制备
在20℃下，向干燥的5L三口瓶中加入原料I-05(560g,1.66mol)和DMSO(2.5L)，然后加入K 2CO 3(229.5g,1.66mol)，混合物升温至100℃搅拌16小时。反应液冷却至室温，然后将其倒入水(4L)和石油醚乙酸乙酯(4/1，1L)的混合液里，搅拌5分钟，然后用饱和的硫酸氢钾水溶液调节pH至3，有沙状固体析出，过滤，得到黑色的粗产品固体。继续用乙腈(1L)室温搅拌1小时，得到棕色固体产物I-06，粗品直接用于下一步。 1H NMR(400MHz,d 6-DMSO)δ2.47(s,3H)。
第六步：化合物I-07的制备
在20℃下，向干燥的50L反应釜中加入原料I-06(3.0kg,15.0mol)和DMF(15L)，然后分批(每批250g)加入NIS(2.5kg,11.1mol)。投料完毕，然后将反应混合液升温至50℃下搅拌1.5小时。反应液冷却至室温，然后将其倒入45L溶解有500g亚硫酸氢钠的水溶液里，搅拌5分钟，有棕色固体析出，过滤，得到棕色的粗品。继续用乙腈(15L)室温搅拌1小时，过滤，滤饼真空干燥得到棕色固体产物I-07，粗品直接用于下一步。 1H NMR(400MHz,d 6-DMSO)δ2.47(s,3H)。
第七步：化合物I-08的制备
在20℃下，向干燥的50L夹套釜中加入DMF(25L)，开启搅拌，然后加入原料I-07(5.2kg,15.9mol)和I-09(4.0kg,12.7mol)和K 2CO 3(1.75kg,12.7mol)。投料完毕，升温至115℃下搅拌24小时。反应液冷却至室温。与另一批次(4.5kg原料I-07)合并后处理，将合并反应液加到水(37.5L)和乙酸乙酯(8L)的混合液里，有固体析出，过滤。滤液分液，水相用乙酸乙酯(8L×2)萃取，合并有机相用无水硫酸钠干燥、过滤、加压浓缩得到残余物。滤饼和浓缩残余物合并，加入甲醇(15L)，室温搅拌1小时后过滤。滤液减压浓缩，向残余物中加入正庚烷(5L)，搅拌1小时。倒出正庚烷，加入叔丁基甲醚(4L)，加热至60℃，快速搅拌0.5小时，降温至25℃，继续搅拌1小时后过滤。合并所有的滤饼，40℃真空干燥得到黄色固体产物I-08。 1H NMR(400MHz,d 6-DMSO)δ7.48-7.46(m,1H),7.36-7.33(m,1H),7.07-7.02(m,2H),5.30(dd,J＝9.2,3.6Hz,1H),4.41(dd,J＝14.4,3.6Hz,1H),4.17(dd,J＝14.4,9.2Hz,1H),3.85(s,3H),3.38-3.36(m,1H),3.35-3.24(m,2H),3.24-3.14(m,2H),2.45(s,3H),1.63-1.62(m,1H),1.56-1.54(m,1H),1.34-1.31(m,1H),1.05-1.00(m,1H)。
第八步：化合物I-10的制备
向50L的反应釜内加入试剂甲苯(22L)和二环己基胺(1422.0mL,2eq)，氮气鼓泡5分钟，调节反应釜温度至-10～5℃，氮气保护下将丁基锂(2.86L,2eq)缓慢滴加入反应液内(内温控制在-10～5℃)，控制反应液内温在-10～5℃，搅拌50～70分钟；然后在氮气保护下将异丁酸甲酯(817.2mL,2eq)缓慢滴加入反应液内(内温控制在-10～5℃)，控制反应液内温在-10～5℃，搅拌50～70分钟。氮气鼓泡下将I-08(2001.6g,1eq)加入反应液内，然后在氮气保护下将Pd 2(dba) 3(32.4g,0.01eq)和PtBu 3(10％甲苯溶液，251.6mL,0.03eq)加入反应液内，反应液缓慢升温至20℃，然后在20℃下搅拌50～70分钟。
将水(8L)加入反应液内，分液分出水相，然后将盐酸水溶液(3M,5L)缓慢加入反应液内，调节pH至约为4～5，硅藻土过滤，滤饼用乙酸乙酯(15L)洗涤，将滤液静置分层，分出水相；有相用盐酸水溶液(1M,10L)洗涤，然后用碳酸钾水溶液(0.2M,10L)洗涤，分出水相，水相有大量絮状物包含产物，故继续垫硅藻土过滤，用乙酸乙酯(10L)洗涤滤饼，分液分出水相；合并有机相并用饱和氯化钠水溶液(15L)洗涤，有机相减压浓缩得到该批次粗产品(照此方法，另外投料2kg和1.4kg批次的反应，分别后处理得到粗产品)。所有批次粗产品合并，用乙酸乙酯和正庚烷做洗脱剂进行硅胶柱层析(正庚烷：乙酸乙酯＝10:1至3：1)分离纯化，得到黄色固体I-10。LCMS：[M+H] +＝431.3, 1HNMR(400MHz,CDCl 3)δppm 7.51(dd,J＝7.6,1.6Hz,1H),7.36-7.32(m,1H),7.05–7.02(m,1H),6.91(d,J＝8.0Hz,1H),5.44(dd,J＝8.8,3.2Hz,1H),4.35(dd,J＝14.0,3.2Hz,1H),4.06(dd,J＝14.0,8.8Hz,1H),3.87(s,3H),3.80-3.74(m,1H),3.68(s,3H),3.58-3.52(m,1H),3.43-3.23(m,3H),2.56(s,3H),1.76-1.72(m,1H),1.60–1.45(m,8H),1.28-1.20(m,1H).
第九步：化合物I-11的制备
向10L的三口反应瓶内依次加入2-甲基四氢呋喃(1L)和噁唑(96.0mL，4.0eq)，氮气鼓泡5分钟，调节反应瓶内温度至-30～-15℃，氮气保护下将TMPMgCl.LiCl(1.8L，4.8eq)缓慢滴加入反应液内(内温控制在-30～-15℃)，控制反应液内温在-30～-15℃，搅拌30～40分钟；然后在氮气保护下将ZnCl 2(1.5L，8eq)缓慢滴加入反应液内(内温控制在-30～-15℃)，滴加完毕，撤去冷浴，反应液搅拌缓慢升温至15～20℃，得到噁唑的锌试剂。
另取一个10L三口反应瓶，依次加入2-甲基四氢呋喃(2L)和中间体I-10(200g)，氮气鼓泡5分钟，氮气保护下将Pd 2(dba) 3(34.6g，0.1eq)和RuPhos(34.9g，0.3eq)加入反应瓶内，然后反应液升温至60～70℃，搅拌30～50分钟，然后将噁唑的锌试剂加入反应液内，反应液升温至90～95℃，继续在此温度下搅拌13～16小时。
合并5锅平行反应后处理；反应液冷却至室温，然后将反应液加入到盐酸水溶液(1M,20L，0-5℃)中，调节pH至3～4，分液分出水相，水相用乙酸乙酯(5L)萃取，合并有机相并用饱和氯化钠水溶液(10L×2)洗涤，有机相减压浓缩得到粗产品(照此方法，另外投料200g 15锅反应，分三批次后处理，每批1公斤，得到粗产品)，硅胶柱层析分离纯化。将纯化得到的固体加入至异丙醇(4L)中，升温至50～55℃搅拌至固体完全溶解，再搅拌30～40分钟，然后自然降温至25～30℃，搅拌2.0～2.5小时，将正庚烷(4L)加入反应液内，并在25～30℃下搅拌12～13小时， 过滤，并用正庚烷(2L)淋洗滤饼后抽干，将滤饼减压浓缩得到黄色固体I-11。LCMS:[M+H] +＝568.3, 1HNMR(400MHz,CDCl 3)δppm 7.75(s,1H),7.54(dd,J＝7.6,1.2Hz,1H),7.33(td,J＝7.8,1.6Hz,1H),7.26(s,1H),7.06-7.04(m,1H),6.91(d,J＝8.0Hz,1H),5.49(dd,J＝8.8,3.2Hz,1H),4.41(dd,J＝14.0,3.2Hz,1H),4.17(dd,J＝14.0,8.8Hz,1H),3.87(s,3H),4.23-4.12(m,1H),3.78-3.71(m,1H),3.70(s,3H),3.56-3.49(m,1H),3.45-3.21(m,3H),3.00(s,3H),1.71-1.70(m,1H),1.64–1.48(m,8H),1.27-1.21(m,1H).
第十步：化合物I粗品的制备
向50L的反应釜内依次加入乙醇(25L)和中间体I-11，升温至55～60℃，搅拌至固体完全溶解，将配好的NaOH(1091.1g)的水(5L)溶液加入反应釜内，反应釜升温至70～80℃后，继续在此温度搅拌17～19小时。
反应液降至室温，减压浓缩除去乙醇；然后用3M盐酸水溶液(10L)调节pH至2～3(调节过程内温为15～25℃)，过滤，过滤所得的粗产品内加入0.3M盐酸去离子水溶液(10L)，并且在25～30℃下搅拌50～60分钟，过滤，过滤所得固体加入乙醇(2L)搅拌15～20分钟，再过滤，并将过滤所得的固体减压浓缩得到类白色的固体式(I)化合物的粗品。LCMS:[M+H] +＝554.3, 1HNMR(400MHz,CDCl 3)δppm 7.76(s,1H),7.53(dd,J＝7.6,1.6Hz,1H),7.37-7.30(m,1H),7.27(s,1H),7.06-7.02(m,1H),6.90(d,J＝8.0Hz,1H),5.49(dd,J＝8.8,4.0Hz,1H),4.44(dd,J＝14.0,4.0Hz,1H),4.21(dd,J＝14.0,8.8Hz,1H),3.86(s,3H),3.79-3.70(m,1H),3.61-3.49(m,1H),3.47-3.20(m,3H),3.02(s,3H),1.74-1.70(m,1H),1.63–1.50(m,8H),1.28-1.20(m,1H)。
第十一步：式(Ⅰ)化合物的A晶型的制备
向10L的三口反应瓶内依次加入乙醇(2.5L)和式(Ⅰ)化合物的粗品(850.0g)，然后将反应液加热到75～80℃搅拌30～35分钟，然后自然冷却至室温(25～30℃)，过滤，用乙醇(300mL×4次)洗涤滤饼，滤饼减压浓缩，所得固体真空烘干至恒重，得到式(Ⅰ)化合物的A晶型。LCMS:[M+H] +＝554.2， 1HNMR(400MHz,CDCl 3)δppm 7.76(d,J＝0.8Hz,1H),7.53(dd,J＝7.2,1.2Hz,1H),7.35-7.31(m,1H),7.27(s,1H),7.06-7.02(m,J＝7.2Hz,1H),6.90(d,J＝8.0Hz,1H),5.49(dd,J＝8.8,4.0Hz,1H),4.44(dd,J＝14.0,4.0Hz,1H),4.21(dd,J＝14.0,8.8Hz,1H),3.86(s,3H),3.79-3.70(m,1H),3.59-3.49(m,1H),3.44-3.20(m,3H),3.02(s,3H),1.74-1.69(m,1H),1.64–1.50(m,8H),1.30-1.19(m,1H)。
实施例2：A晶型在不同温度和湿度及光照条件下固体物理稳定性试验
为评估A晶型的固体稳定性，对晶型A进行了影响因素(高温、高湿及光照)、加速条件稳定性及中间条件稳定性的考察。
将A晶型在高温(60℃，闭口)、高湿(室温，92.5％RH(相对湿度)，封口膜包裹并扎5～10个小孔)下放置5天、10天，按照ICH条件(可见光照度达到1.2E06Lux·hrs，紫外光照度达到200W·hrs/m 2)闭口放置在可见光及紫外光下(遮光对照组用锡箔纸包裹)，同时在加速条件稳定性(60℃/75％RH，封口膜包裹并扎5～10个小孔)下放置1、2个月，中间条件稳定性(40℃/75％RH，封 口膜包裹并扎5～10个小孔)下放置1、2、3个月。对放置后的样品进行XRPD表征，以检测晶型的变化；结果显示，晶型A在所有稳定性条件下，晶型均未发生变化。
实验例1：体外评价
实验目的：
通过测定IC 50值来评价受试化合物对乙酰辅酶A羧化酶(ACC)的抑制能力。
实验材料：
1.蛋白：人源乙酰辅酶A羧化酶1(hACC1)和人源乙酰辅酶A羧化酶2(hACC2)。
2.底物：NaHCO 3
3.辅因子：乙酰辅酶A，ATP(三磷酸腺苷)
4.激活剂：柠檬酸钾
实验方法：
1.在孔板的微孔中加入1倍的酶/底物/辅因子。
2.利用Acoustic技术，向上述酶的混合物中，加入化合物的DMSO溶液，预孵化15分钟。
3.向其中加入ATP引发反应，摇匀。
4.室温下孵化1小时。
5.淬灭反应后，继续孵化40分钟。
6.加入检测试剂，孵化30分钟。
7.测试荧光。
8.分析数据：基于ADP的标准曲线，将荧光信号转化成ADP产物浓度并计算酶活。利用Graphpad Prism软件拟合曲线，得到IC 50值。实验结果如表2所示。
表2.本发明化合物体外筛选试验结果
化合物 hACC1(nM) hACC2(nM)
式(Ⅰ)化合物 14.1 10.3
结论：本发明化合物对人源ACC1/ACC2酶很强的抑制活性。
实验例2：化合物的药代动力学评价
实验目的：
测试化合物在C57BL/6小鼠体内的药代动力学
实验材料：
C57BL/6小鼠(雄性,18-30g,7～9周龄，上海灵畅生物科技有限公司)
实验操作：
将试验化合物的澄清溶液(0.5mg/ml 10％DMSO、10％聚乙二醇硬脂酸酯、80％水)经尾静脉注射到4只雄性C57BL/6小鼠体内(过夜禁食，7-9周龄)，给药剂量为2.0mg/kg。将试验化合物的混悬液或澄清溶液(1mg/ml 10％PEG400、90％(0.5％甲基纤维素+0.2％Tween 80))灌胃给予4只雄性 C57BL/6小鼠(过夜禁食，7-9周龄)，给药剂量为10mg/kg。
每两只小鼠一组，交叉采血，每只小鼠采4～5个时间点。小鼠静脉或灌胃给药后于0.0833h(仅IV组)、0.25h、0.5h、1.0h、2.0h、4.0h、6.0h、8.0h和24h从隐静脉穿刺采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验结果如表3所示：
表3.药代动力学测试结果
Figure PCTCN2020133892-appb-000008
结论：本发明式(Ⅰ)化合物可以显著提高小鼠药代动力学单项或部分指标。
实验例3：HFD+CCl4诱导的NASH小鼠模型中的体内药效学研究
实验目的:
本研究的目的为研究化合物在HFD+CCl 4小鼠模型中对NASH及肝纤维化的改善作用，以I-181为参比化合物。
I-181为Acetyl-CoA Carboxylase抑制剂，目前正在进行非酒精性脂肪性肝疾病(Non Alcoholic Fatty Liver Disease，NAFLD)的临床II期研究。本研究所用的HFD+CCl 4小鼠模型是一种模拟人类非酒精性脂肪性肝病进展为NASH过程的动物模型，高脂饲料导致脂肪在肝细胞中堆积、变性；CCl 4(腹腔注射，每周两次)模拟肝损伤的“二次打击”。该模型稳定可靠，与人NASH的发病机制具有很高的相似性，具备了NASH主要病理特点，包括脂肪变、凋亡、炎症和纤维化，同时也表现出血浆转氨酶(ALT和AST)水平升高。
实验设计：
本试验的造模包括高脂饲料喂养和CCl 4诱导两个步骤，首先以高脂饲料喂养小鼠诱导产生非酒精性脂肪肝，挑选体重>38g的小鼠，继续饲喂高脂饲料的同时，腹腔注射给与25％CCl 4，0.5mg/kg，每周两次，共四周。将开始给CCl 4的当天定为第0天，开始CCl 4的时间定为第0小时，在开始给CCl 4的当天，开始灌胃给药，各组的给药体积为5mL/kg，每天一次，持续4周(28天)。CCl 4的注射时间应与当天的第一次给药时间点间隔4小时以上。实验一共分为6组，即健康对照组、模型组、参比化合物组(GS-0976)、受试化合物组(式(Ⅰ)化合物，三个剂量)。健康对照组为10只正常小鼠，实验期间给予普通饲料喂养，不注射CCl 4；50只肥胖小鼠用于模型组及给药组，每组为10只小鼠，分组后开始腹腔注射CCl 4并分别给予不同剂量的药物。分组和剂量设计如表4所示。
表4.动物分组及给药方案
Figure PCTCN2020133892-appb-000009
Figure PCTCN2020133892-appb-000010
实验结果:
在高脂饮食和CCl 4联合诱导的小鼠模型中，式(Ⅰ)化合物不论在NAS以及纤维化两个维度均达到与参比化合物更高剂量下相同的药效。

Claims (9)

  1. 式(Ⅰ)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.54±0.20°、17.64±0.20°和24.81±0.2°；
    Figure PCTCN2020133892-appb-100001
  2. 根据权利要求1所述A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.54±0.20°、10.87±0.20°、15.55±0.20°、16.56±0.20°、17.64±0.20°、21.32±0.20°、23.53±0.20°和24.81±0.20°。
  3. 根据权利要求2所述A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射：6.91°、8.54°、8.80°、9.51°、10.87°、11.30°、12.38°、12.81°、13.84°、14.10°、15.55°、16.56°、17.64°、17.99°、18.76°、19.07°、20.27°、20.63°、21.32°、22.19°、22.71°、23.53°、24.07°、24.81°、26.80°、27.40°、27.79°、28.34°、29.94°、30.86°、30.86°、31.34°、31.98°、33.17°、33.69°、35.21°、35.64°、36.25°、36.75°、37.79°和38.98°。
  4. 根据权利要求3所述A晶型，其XRPD图谱如图1所示。
  5. 根据权利要求1～4任意一项所述A晶型，其差示扫描量热曲线在234.9℃处具有吸热峰的起始点。
  6. 根据权利要求5所述A晶型，其DSC图谱如图2所示。
  7. 根据权利要求1～4任意一项所述A晶型，其热重分析曲线在200℃±3℃时失重达0.86％。
  8. 根据权利要求7所述A晶型，其TGA图谱如图3所示。
  9. 根据权利要求1～8任意一项所述A晶型在制备作为ACC1和ACC2抑制剂的药物中的应用。
PCT/CN2020/133892 2019-12-05 2020-12-04 作为acc1和acc2抑制剂的晶型及其制备方法和应用 WO2021110135A1 (zh)

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