WO2023011395A1 - Glp-1r激动剂化合物的盐及其制备方法和医药用途 - Google Patents

Glp-1r激动剂化合物的盐及其制备方法和医药用途 Download PDF

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WO2023011395A1
WO2023011395A1 PCT/CN2022/109367 CN2022109367W WO2023011395A1 WO 2023011395 A1 WO2023011395 A1 WO 2023011395A1 CN 2022109367 W CN2022109367 W CN 2022109367W WO 2023011395 A1 WO2023011395 A1 WO 2023011395A1
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salt
glp
salts
agonist compound
compound according
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English (en)
French (fr)
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吴俊军
陆银锁
连小磊
李亲泽
李松
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深圳信立泰药业股份有限公司
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Priority to CN202280051627.2A priority Critical patent/CN117693504A/zh
Publication of WO2023011395A1 publication Critical patent/WO2023011395A1/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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • 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

Definitions

  • the invention belongs to the technical field of chemical medicine and provides a series of salts of GLP-1R agonist compounds.
  • the present invention also relates to pharmaceutical compositions containing the salts of these compounds and the use of the compounds in medicines for treating diseases such as diabetes.
  • Diabetes affects millions of people worldwide and is considered one of the major threats to human mortality in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. Worldwide, the socioeconomic burden of diabetes is high.
  • Type I diabetes is characterized by insulin deficiency, which is mainly caused by autoimmune-mediated destruction of pancreatic ⁇ cells
  • type II diabetes is characterized by abnormal insulin secretion and subsequent insulin resistance.
  • type 1 diabetes must ingest exogenous insulin to survive.
  • type 2 diabetics are not as dependent on exogenous insulin as type 1 diabetics, they may require exogenous insulin to control blood sugar levels.
  • GLP-1 receptor belongs to the subfamily of G protein-coupled receptors. When GLP-1 binds to GLP-1 receptor, it triggers a series of biological effects. Studies have shown that GLP-1 promotes insulin secretion in a glucose-dependent manner, that is, when the blood sugar concentration in the human body rises, GLP-1 stimulates islet cells, increases insulin secretion, and lowers blood sugar.
  • GLP-1 receptor agonist is a new type of hypoglycemic drug, which can effectively control blood sugar levels without causing hypoglycemia; it can also increase satiety, delay gastric emptying, suppress appetite and reduce fat. Accumulation, etc., can effectively reduce body weight and achieve the goal of weight loss.
  • peptide drugs liraglutide, exenatide, and semaglutide based on GLP-1 receptor agonists have been used in obese patients with type II diabetes and simply obese or overweight patients. Significantly reduce weight, but often accompanied by nausea, vomiting and other gastrointestinal adverse reactions. Oral non-peptide drugs have been tried by research institutions for the treatment of type II diabetes and weight loss drugs, but because small molecules are difficult to mimic the interaction between receptors and peptides, small molecule drugs for glucagon-like peptide-1 receptor are limited discovery.
  • patent applications disclosing non-polypeptide GLP-1 receptor agonists include WO2009/111700, WO2010/114824, WO2011/114271, WO2013/090454, WO2018/056453, WO2018/109607, WO2019239319, WO2019239571, WO20201038, etc.
  • vTv's TTP-273 and Pfizer's PF-06882961 have entered phase II clinical research.
  • the invention provides a series of salts of oxopyridazinamide derivatives, their preparation method and their application in medicine.
  • the present invention provides a salt of a GLP-1R agonist compound represented by formula (I),
  • n 0.3-3;
  • M forms a salt with a carboxyl group, and the salt is selected from at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt or ammonium salt; or the salt is selected from methyl Amine salts, dimethylamine salts, trimethylamine salts, ethylamine salts, diethylamine salts, triethylamine salts, isopropylamine salts, 2-ethylaminoethanol salts, pyridinium salts, picoline salts, ethanolamine salts, diethanolamine salt, ammonium salt, tetramethylammonium salt, tetraethylammonium salt, triethanolamine salt, piperidinium salt, piperazine salt, morpholine salt, lysine salt, L-lysine salt, arginine salt, L-Arginine Salt, Histidine Salt, L-Histidine Salt, Meglumine Salt, Dimethyl Glucamine Salt, Ethyl Gluc
  • the structure of the GLP-1R agonist compound is as follows:
  • the salt is selected from sodium salts, potassium salts, trihydroxymethylaminomethane salts, calcium salts, and magnesium salts.
  • the salt is selected from:
  • the salt is selected from:
  • more than one hydrogen atom of the compound is replaced by isotope deuterium.
  • the present invention further provides a pharmaceutical composition, comprising the aforementioned salt, and more than one pharmaceutically acceptable carrier.
  • the present invention further provides the use of the salt in the preparation of medicines for treating GLP-1R-related diseases, preferably the use of medicines for diabetes-related diseases.
  • salts of the compounds of the present invention refer to "pharmaceutically acceptable salts", which are prepared from the compounds with specific substituents found in the present invention and pharmaceutically acceptable acids or bases.
  • Salts of certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the atoms of the compound molecules of the present invention are isotopes, and the isotope derivatization can usually prolong the half-life, reduce the clearance rate, stabilize metabolism and improve the activity in vivo. Also, an embodiment is included wherein at least one atom is replaced by an atom having the same atomic number (proton number) and different mass number (sum of protons and neutrons).
  • isotopes included in the compounds of the present invention include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, which respectively include 2H, 3H, 13C, 14C, 15N, 17O, 18O , 31P, 32P, 35S, 18F, 36Cl.
  • radioisotopes such as3H or14C, which emit radiation as they decay, are useful in the topographical examination of pharmaceutical preparations or compounds in vivo.
  • Stable isotopes neither decay nor change with their amount, nor are they radioactive, so they are safe to use.
  • the isotopes can be converted according to general methods by substituting reagents used in the synthesis with reagents containing the corresponding isotopes.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium (2H), iodine-125 (125I) or C-14 (14C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • one or more hydrogen atoms of the compound of the present invention are substituted by the isotope deuterium (2H).
  • the compound of the present invention After deuterated, the compound of the present invention has the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism and improving activity in vivo.
  • the preparation method of the isotopic derivative generally includes: a phase transfer catalytic method.
  • a preferred deuteration method employs a phase transfer catalyst (eg, tetraalkylammonium salt, NBu4HSO4).
  • a phase transfer catalyst eg, tetraalkylammonium salt, NBu4HSO4
  • the use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher rate than that with a deuterated silane (e.g. triethyldeuterosilane) or with a Lewis acid such as trichlorosilane in the presence of an acid (e.g. methanesulfonic acid).
  • Aluminum is reduced with sodium deuterated borate to introduce higher deuterium.
  • pharmaceutically acceptable carrier refers to any preparation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil , vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • terapéutica refers to a chemical entity that is effective in the treatment of the targeted disorder, disease or condition.
  • the 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 the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
  • HPLC High-performance liquid chromatography
  • the CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
  • the thin-layer chromatography silica gel plate uses Yantai Yinlong HSGF254 or GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.17mm ⁇ 0.23mm, and the specification of the thin-layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.
  • Step A Synthesis of tert-butyl 4-(6-chloropyridin-2-yl)piperazine-1-carboxylate
  • Step B Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylate
  • Step D Synthesis of 2-(1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3- Methyl (((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate
  • Step E Synthesis of 2-((S)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl )-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound A-a) and 2-(( R)-1-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)ethyl)-3-(((S )-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound A-b)
  • Embodiment 5 The solubility investigation of compound of the present invention
  • solubility is measured.
  • the compound prepared in the embodiment of the present invention is ground into a fine powder, and the sample is weighed and placed in a solvent with a certain capacity at 25°C ⁇ 2°C. , Shake vigorously for 30 seconds every 5 minutes; observe the dissolution within 30 minutes, if there are no visible solute particles or droplets, it is considered completely dissolved.
  • Very soluble means that 1g (mL) of solute can be dissolved in less than 1mL of solvent;
  • Soluble means that 1 g (mL) of solute can be dissolved in 1 to less than 10 mL of solvent;
  • Dissolution means that 1 g (mL) of solute can be dissolved in 10 to less than 30 mL of solvent;
  • Slightly soluble means that 1 g (mL) of solute can be dissolved in 30 to less than 100 mL of solvent;
  • Slightly soluble means that 1 g (mL) of solute can be dissolved in 100 to less than 1000 mL of solvent;
  • Slightly soluble means that 1g (mL) of solute can be dissolved in 1000-less than 10000mL of solvent;
  • Example 1 Compound A-a Example 2
  • Example 4 pH4.5 ⁇ 1mg/ml >34mg/ml >168mg/ml pH6.8 >1mg/ml, ⁇ 10mg/ml >35mg/ml >168mg/ml
  • Embodiment 6 the stability investigation of compound of the present invention
  • Stability determination was carried out in accordance with the guidance on stability of the fourth part of the "Chinese Pharmacopoeia” 2020 edition "Guiding Principles for Stability Testing of Raw Materials and Preparations”. Appropriately weigh the test sample (about 50mg) of the compound prepared by the embodiment of the present invention and place it in a 10ml vial, press the cap and seal it, pack several samples in this way, and then place the samples at 30°C ⁇ 2°C, 65% ⁇ In a constant temperature and humidity chamber under the condition of 5% RH and 20°C ⁇ 2°C, 60% ⁇ 5% RH, take out the sample after 10 days, measure the moisture and related substances, and compare with the test results of moisture and related substances on day 0.
  • the sodium salt, potassium salt and tris-hydroxymethylaminomethane salt of the compound of the present invention are more stable under various humidity/temperature conditions than the free acid of compound A-a.
  • Embodiment 7 The rat pharmacokinetic characteristic investigation of compound of the present invention
  • SD rats male, 180-250 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • CMC-Na sodium carboxymethylcellulose
  • TPGS batch number CSN10842-002, CSNpharm
  • DMSO Dimethyl sulfoxide
  • PEG-400 polyethylene glycol 400
  • acetonitrile formic acid
  • propranolol internal standard
  • Mobile phase A water (0.1% formic acid)
  • mobile phase B acetonitrile
  • flow rate 0.5mL/min
  • gradient elution gradient elution:
  • Pentagastrin (sigma, batch number SLCC6419), No. 0 gelatin empty capsule, ammonium hydroxide (ACS reagent, 28.0-30.0% NH 3 , Alan (Shanghai) Chemical Technology Co., Ltd., batch number CEC1070004), LC-MS instrument (Thermo Fisher Ultimate 3000 UPLC, TSQ QUANTUM ULTRA triple quadrupole mass spectrometer).
  • LC-MS detection conditions are as follows:
  • Mobile phase A water (0.1% formic acid)
  • mobile phase B acetonitrile
  • flow rate 0.5mL/min
  • gradient elution gradient elution:
  • the oral solid absorption exposure of the sodium salt of the compound of the present invention, potassium salt, and trishydroxymethylaminomethane salt in the Beagle dog body is significantly better than that of the compound A-a free acid, indicating that it is more effective than the compound A-a free acid. good absorption.
  • Embodiment 9 Pharmacokinetic study of compound of the present invention in rats
  • SD rats male, 180-250 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • DMSO dimethyl sulfoxide
  • PEG-400 polyethylene glycol 400
  • normal saline normal saline
  • heparin normal saline
  • acetonitrile formic acid
  • propranolol internal standard
  • Example 4A-1 and 10A-77 dissolve in DMSO-PEG-400-saline (5:60:35, v/v/v) system
  • 200 ⁇ L of venous blood was collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h (additional collection of 5 min in the IV group) into heparinized EP tubes, centrifuged at 12,000 rpm for 2 min, and plasma Freeze at -80°C until testing.
  • LC-MS detection conditions are as follows:
  • Chromatographic column Thermo Fisherman HYPERSIL GOLD C-18 UPLC column, 100*2.1mm, 1.7 ⁇ m.

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Abstract

一系列GLP-1R激动剂化合物的盐，包含这些化合物的盐的药物组合物以及使用该化合物治疗糖尿病等疾病的药物中的用途。

Description

GLP-1R激动剂化合物的盐及其制备方法和医药用途 技术领域
本发明属于化学药物技术领域，提供了一系列的GLP-1R激动剂化合物的盐。本发明还涉及包含这些化合物的盐的药物组合物以及使用该化合物治疗糖尿病等疾病的药物中的用途。
背景技术
糖尿病影响全世界数百万人，被认为是21世纪人类死亡的主要威胁之一。随着时间推移，不被控制的糖尿病能损坏身体系统，包括心脏、血管、眼、肾和神经。在全世界范围，糖尿病的社会经济负担很沉重。
有两种主要类型的糖尿病，命名为I型和II型，其中II型糖尿病(T2DM)占全世界所有糖尿病的超过90％。I型糖尿病特征为胰岛素缺乏，主要由自身免疫介导的胰岛β细胞破坏引起，II型糖尿病特征为胰岛素分泌异常和随之而来的胰岛素耐受。为预防引起酮酸中毒，患有I型糖尿病的患者必须摄取外源胰岛素以存活。尽管II型糖尿病患者不像I型糖尿病患者那样依赖于外源胰岛素，他们可能需要外源胰岛素以控制血糖水平。
胰高血糖素样肽-1(GLP-1)是肠促胰素的一种，由肠道上皮L细胞分泌，通过与其受体结合发挥生理效应。GLP-1受体(GLP-1R)属于G蛋白耦联受体亚家族，当GLP-1与GLP-1受体相结合后，引发一系列的生物学效应。有研究表明，GLP-1是以葡萄糖依赖的方式促进胰岛素分泌，即当人体内血糖浓度升高时，GLP-1刺激胰岛细胞，增加胰岛素分泌，降低血糖。GLP-1受体激动剂是一种新型的降糖药物，既可在不引起低血糖的情况下，有效控制血糖水平；又可通过增加饱腹感、延缓胃排空、抑制食欲及减少脂肪堆积等，有效减轻体质量，达到减肥的目的。
目前，以GLP-1受体激动剂为基础的多肽类药物利拉鲁肽、艾塞那肽、索马鲁肽等已经应用于肥胖的II型糖尿病患者以及单纯肥胖或超重患者，均显示出明显地减轻体质量作用，但常伴有恶心、呕吐等胃肠道不良反应。口服非多肽类药物一直是研究机构尝试用于治疗II型糖尿病及减肥的药物，但由于小分子难以模拟受体与多肽的相互作用，限制了胰高血糖素样肽-1受体小分子药物的发现。
目前公开非多肽类GLP-1受体激动剂的专利申请有WO2009/111700、WO2010/114824、WO2011/114271、WO2013/090454、WO2018/056453、WO2018/109607、WO2019239319、WO2019239371、WO2020103815等。其中，目前仅有vTv公司的TTP-273和辉瑞公司的PF-06882961进入了临床二期研究。
申请人在前期申请CN202110415182.9中申请了包括下式所示的化合物A的一系列GLP-1R激动剂化合物：
Figure PCTCN2022109367-appb-000001
发明内容
本发明提供了一系列的氧代哒嗪酰胺类衍生物的盐、其制备方法及其在医药上的应用。
具体而言，本发明提供式(I)所示GLP-1R激动剂化合物的盐，
Figure PCTCN2022109367-appb-000002
其中：
n为0.3-3；
M与羧基成盐，所述盐选自锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铁盐、锌盐或铵盐中的至少一种；或所述盐选自甲胺盐、二甲胺盐、三甲胺盐、乙胺盐、二乙胺盐、三乙胺盐、异丙胺盐、2-乙氨基乙醇盐、吡啶盐、甲基吡啶盐、乙醇胺盐、二乙醇胺盐、铵盐、四甲基铵盐、四乙基铵盐、三乙醇胺盐、哌啶盐、哌嗪盐、吗啉盐、赖氨酸盐、L-赖氨酸盐、精氨酸盐、L-精氨酸盐、组氨酸盐、L-组氨酸盐、葡甲胺盐、二甲基葡糖胺盐、乙基葡糖胺盐、二环己基胺盐、1,6-己二胺盐、葡糖胺盐、肌氨酸盐、丝氨醇盐、三羟基甲基氨基甲烷盐、氨基丙二醇盐、鸟氨酸盐或胆碱盐中的至少一种。
作为本发明的一种优选技术方案，所述GLP-1R激动剂化合物结构如下：
Figure PCTCN2022109367-appb-000003
作为本发明的一种优选技术方案，n为0.33、0.5、1、1.5、2、2.5或3，特别优选n＝1或者0.5。
作为本发明的一种优选技术方案，所述的盐选自钠盐、钾盐、三羟基甲基氨基甲烷盐、钙盐、镁盐。
作为本发明的一种优选技术方案，所述的盐选自钠盐、n＝1；钾盐、n＝1；三羟基甲基氨基甲烷盐、n＝1；钙盐、n＝0.5；镁盐、n＝0.5。
作为本发明的一种优选技术方案，所述的盐选自：
Figure PCTCN2022109367-appb-000004
作为本发明的一种优选技术方案，所述的盐选自：
Figure PCTCN2022109367-appb-000005
作为本发明的一种优选技术方案，所述化合物的一个以上的氢原子上被同位素氘取代。
本发明进一步提供了一种药物组合物，包括前述盐，和一种以上药学上可接受的载体。
本发明进一步提供了所述盐在制备用于制备治疗GLP-1R相关疾病的药物用途，优选糖尿病相关疾病的药物用途。
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短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。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
本发明化合物的盐是指“药学上可接受的盐”，由本发明发现的具有特定取代基的化合物与药学上可接受的酸或碱制备。
本发明的某些化合物的盐可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体，以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明化合物分子的原子是同位素，通过同位素衍生化通常可以延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。并且，包括一个实施方案，其中至少一个原子被具有相同原子数(质子数)和不同质量数(质子和中子和)的原子取代。本发明化合物中包括的同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子、氯原子，其分别包括2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl。特别的是，随其衰退而发射辐射的放射性同位素例如3H或14C可用于药物制剂或者体内化合物的局部解剖学检验。稳定的同位素既不随其量衰减或变化，也不具有放射性，因此其可以安全使用。当构成本发明化合物分子的原子是同位素时，通过用包含相应同位素的试剂替代合成中所用的试剂，可以根据通用方法转化同位素。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
进一步地，本发明的化合物一个或多个氢原子上被同位素氘(2H)取代，本发明化合物氘代后，具有延长半衰期、降低清除率、代谢稳定和提高体内活性等效果。
所述同位素衍生物的制备方法通常包括：相转移催化方法。例如，优选的氘化方法采用相转移催化剂(例如，四烷基铵盐，NBu4HSO4)。使用相转移催化剂交换二苯基甲烷化合物的亚甲基质子，导致比在酸(例如，甲磺酸)存在下用氘化硅烷(例如三乙基氘化甲硅烷)或用路易斯酸如三氯化铝采用氘化硼酸钠还原而引入较高的氘。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“治疗”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
本发明的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。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-III核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。
MS的测定用ISQ EC质谱仪(生产商:Thermo,型号:ISQ EC)。
高效液相色谱法(HPLC)分析使用Thermo U3000 HPLC DAD高效液相色谱仪。
CombiFlash快速制备仪使用CombiFlash Rf+LUMEN(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台银龙HSGF254或GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.17mm～0.23mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用乳山上邦硅胶100～200目硅胶为载体。
实施例1
合成2-((S)-(1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸
合成2-((R)-(1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸
Figure PCTCN2022109367-appb-000006
具体合成路线如下：
步骤A：合成4-(6-氯吡啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022109367-appb-000007
将哌嗪-1-羧酸叔丁酯(300.0毫克,1.61毫摩尔)溶于1,4-二氧六环(12.0毫升)中，加入2,6-二氯吡啶(262.0毫克,1.77毫摩尔)，甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(135.4毫克,0.16毫摩尔)和碳酸铯(788.5毫克,2.42毫摩尔)。氮气保护下，升温至100摄氏度，搅拌反应5小时。旋干溶剂，柱层析分离(乙酸乙酯：正己烷＝1：10)，得150.0毫克米黄色固4-(6-氯吡啶-2-基)哌嗪-1-羧酸叔丁酯(收率：31.3％)。LC-MS：RT＝1.82min,[M- tBu+H] +＝242.36。
步骤B：合成4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022109367-appb-000008
将4-(6-氯吡啶-2-基)哌嗪-1-羧酸叔丁酯(150.0毫克，0.51毫摩尔)溶于1,4-二氧六环(5.0毫升)中，加入3-氟-4-(羟甲基)苯甲腈(76.3毫克，0.51毫摩尔)，甲烷磺酸(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(43.2毫克，0.05毫摩尔)和碳酸铯(246.8毫克，0.76毫摩尔)。氮气保护下，升温至100摄氏度，搅拌反应15小时。旋干溶剂，柱层析分离(乙酸乙酯：正己烷＝1：10)，得102.0毫克米黄色固体4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(收率：49.1％)。LC-MS：RT＝2.23min,[M- tBu+H] +＝357.23。
步骤C：合成3-氟-4-(((6-(哌嗪-1-基)吡啶-2-基)氧基)甲基)苯甲腈
Figure PCTCN2022109367-appb-000009
将4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(102.0毫克，0.25毫摩尔)溶于甲醇(2.0毫升)中，加入盐酸/1,4-二氧六环溶液(0.5毫升，2.0毫摩尔)。室温条件下，搅拌反应3小时。旋干溶剂，得73.7毫克白色固体3-氟-4-(((6-(哌嗪-1-基)吡啶-2-基)氧基)甲基)苄腈(收率：73.5％)。LC-MS：RT＝1.68min,[M+H] +＝313.25。
步骤D：合成2-(1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯
Figure PCTCN2022109367-appb-000010
25摄氏度下，向含有4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪盐酸盐(652毫克,2.09毫摩尔)的乙腈(8.0毫升)中，加入N,N-二异丙基乙胺(1.0毫升)、碘化钾(420毫克，3.13毫摩尔)和碳酸钾(577毫克，4.18毫摩尔)加入N,N-二甲基甲酰胺(10.0毫升)中，最后加入2-((S)-1-氯乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(650毫克,2.09毫摩尔)，N 2保护下，60摄氏度反应3.0小时。
反应结束，加水淬灭，乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/正己烷＝2/1。得到690毫克黄色固体2-(1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(收率：56.4％，dr＝66％)。LC-MS:RT＝1.93min,[M+H] +＝586.26。
步骤E：合成2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物A-a)和2-((R)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶 -5-羧酸(化合物A-b)
Figure PCTCN2022109367-appb-000011
零摄氏度下，向含有2-(1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(690毫克,1.18毫摩尔)的四氢呋喃(3毫升)和甲醇(1毫升)混合溶液中，滴加氢氧化锂(198毫克,4.72毫摩尔)的水溶液(1毫升)，于25摄氏度下反应30分钟。
反应结束，加水淬灭，乙酸乙酯(30毫升×2次)萃取，合并有机相，饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/10。得到290毫克白色固体2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物A-a)(收率：43.0％)和59毫克白色固体2-((R)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物A-b)(收率8.7％)。粗产品用制备型高效液相色谱纯化。分离条件如下：色谱柱：Agilent 5 Prep-C 18100mm×30mm 5μM；流动相：水(含有0.1％的氨水)和乙腈洗脱；流速：20毫升/分钟；梯度：由21％乙腈在10.12分钟及12.17分钟分别洗脱出来化合物A-a和化合物A-b，检测波长：254nm。
化合物A-a:HPLC:RT＝10.12min。LC-MS:RT＝1.79min,[M+H] +＝572.30。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝8.2Hz,1H),7.97(d,J＝8.2Hz,1H),7.87(dd,J＝10.0,1.5Hz,1H),7.69(dd,J＝7.9,1.4Hz,1H),7.64(t,J＝7.6Hz,1H),7.45(t,J＝8.0Hz,1H),6.30(d,J＝8.1Hz,1H),6.10(d,J＝7.8Hz,1H),5.38(s,2H),5.30–5.24(m,1H),4.82–4.70(m,2H),4.63–4.58(m,1H),4.44–4.39(m,1H),4.11–4.06(m,1H),3.43–3.33(m,4H),2.64–2.58(m,1H),2.56–2.52(m,4H),2.39–2.30(m,1H),1.45(d,J＝6.7Hz,3H)。
化合物A-b:HPLC:RT＝12.17min。LC-MS:RT＝1.79min,[M+H] +＝572.30。 1H NMR(400MHz,DMSO)δ8.09(d,J＝8.2Hz,1H),7.95(d,J＝8.2Hz,1H),7.87(dd,J＝10.0,1.4Hz,1H),7.69(dd,J＝7.9,1.5Hz,1H),7.67–7.61(m,1H),7.46(t,J＝8.0Hz,1H),6.31(d,J＝8.1Hz,1H),6.11(d,J＝7.8Hz,1H),5.39(s,2H),5.07–5.00(m,2H),4.69–4.49(m,4H),3.47–3.37(m,4H),2.79–2.70(m,1H),2.66–2.52(m,5H),1.42(d,J＝6.8Hz,3H)。
实施例2
合成2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸钠盐
Figure PCTCN2022109367-appb-000012
将2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(1克，1.75毫摩尔)溶解于20毫升水中得到混悬液，冰浴条件下滴加氢氧化钠水溶液(0.175毫摩尔/毫升，10毫升，1.75毫摩尔)，溶液变澄清，保持冰浴条件继续搅拌1小时，样品直接冻干得钠盐样品。
1H NMR(400MHz,DMSO-d 6)δ7.96(d,J＝8.2Hz,1H),7.91(d,J＝8.2Hz,1H),7.88(dd,J＝9.9,1.5Hz,1H),7.70(dd,J＝7.9,1.5Hz,1H),7.64(t,J＝7.5Hz,1H),7.45(t,J＝8.0Hz,1H),6.30(d,J＝8.1Hz,1H),6.11(d,J＝7.8Hz,1H),5.39(s,2H),5.22(tt,J＝7.6,3.9Hz,1H),4.83–4.69(m,2H),4.52(q,J＝6.7Hz,1H),4.41(td,J＝8.0,5.7Hz,1H),4.07(dt,J＝9.2,5.7Hz,1H),3.45–2.53(m,4H),2.58–2.53(m,5H),2.41–2.32(m,1H),1.44(d,J＝6.7Hz,3H)。
实施例3
合成2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸钾盐
Figure PCTCN2022109367-appb-000013
将2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(1克，1.75毫摩尔)溶解于20毫升水中得到混悬液，冰浴条件下滴加氢氧化钾水溶液(0.175毫摩尔/毫升，10毫升，1.75毫摩尔)，溶液变澄清，保持冰浴条件继续搅拌1小时，样品直接冻干得钾盐样品。
1H NMR(400MHz,DMSO-d6)δ7.91(d,J＝8.2Hz,1H),7.88(dd,J＝10.0,1.5Hz,1H),7.84(d,J＝8.2Hz,2H),7.70(dd,J＝7.9,1.5Hz,1H),7.65(t,J＝7.5Hz,1H),7.45(t,J＝8.0Hz,1H),6.30(d,J＝8.2Hz,1H),6.10(d,J＝7.8Hz,1H),5.39(s,2H),5.29–5.23(m,1H),4.70(dd,J＝15.0,4.1Hz,1H),4.69(dd,J＝15.0,4.1Hz,1H),4.57(q,J＝6.7Hz,1H),4.41(td,J＝8.1,5.8Hz,1H),4.06(dt,J＝9.1,5.9Hz,1H),3.50–3.30(m,5H),2.61–2.50(m,4H),2.40–2.31(m,1H),1.44(d,J＝6.7Hz,3H)。
实施例4
合成2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸三羟基甲基氨基甲烷盐
Figure PCTCN2022109367-appb-000014
将2-((S)-1-(4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)乙基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(599.9毫克，1.05毫摩尔)溶解于10毫升甲醇得到混悬液，室温条件下加入三羟甲基氨基甲烷水溶液(2毫摩尔/毫升，524.9微升，1.05毫摩尔)，室温搅拌10分钟后溶液变澄清，室温条件下继续搅拌2小时，将澄清样品转移至室温下真空干燥，向干燥所得固体样品中加入10毫升甲基叔丁基醚得混悬液，将混悬液在温度循环下(50℃～5℃，0.1℃/min)搅拌24小时，将混悬液离心，固体在50℃下真空干燥得三羟基甲基氨基甲烷盐样品。 1H NMR(400MHz,MeOD)δ8.10–8.02(m,2H),7.62(t,J＝7.5Hz,1H),7.56–7.51(m,2H),7.42(t,J＝8.0Hz,1H),6.25(d,J＝8.1Hz,1H),6.12(d,J＝7.8Hz,1H),5.42(s,2H),5.41–5.33(m,1H),4.97(dd,J＝15.2,3.8Hz,1H),4.87(dd,J＝15.2,3.6Hz,1H),4.66(q,J＝6.7Hz,1H),4.53(td,J＝8.0,6.0Hz,1H),4.11(dt,J＝9.3,5.9Hz,1H),3.67(s,6H),3.51–3.37(m,4H),2.72–2.56(m,5H),2.44–2.32(m,1H),1.56(d,J＝6.8Hz,3H)。
实施例5本发明化合物的溶解度考察
按照《中国药典》2020版第四部凡例对溶解度的指导进行溶解度测定，取本发明实施例制备得到的化合物，研成细粉，称取样品，置于25℃±2℃一定容量的溶剂中，每隔5分钟强力振摇30秒钟；观察30分钟内的溶解情况，如无目视可见的溶质颗粒或液滴时，即视为完全溶解。
药品的近似溶解度以下名词术语表示：
极易溶解系指溶质1g(mL)能在溶剂不到1mL中溶解；
易溶系指溶质1g(mL)能在溶剂1～不到10mL中溶解；
溶解系指溶质1g(mL)能在溶剂10～不到30mL中溶解；
略溶系指溶质1g(mL)能在溶剂30～不到100mL中溶解；
微溶系指溶质1g(mL)能在溶剂100～不到1000mL中溶解；
极微溶解系指溶质1g(mL)能在溶剂1000～不到10000mL中溶解；
几乎不溶或不溶系指溶质1g(mL)在溶剂10000mL中不能完全溶解。
实验方法及结果如下：
表一：本发明化合物的溶解度考察
溶剂pH 实施例1化合物A-a 实施例2 实施例4
pH4.5 ＜1mg/ml ＞34mg/ml ＞168mg/ml
pH6.8 ＞1mg/ml,＜10mg/ml ＞35mg/ml ＞168mg/ml
从上述结果可见，本发明化合物的钠盐和三羟基甲基氨基甲烷盐相对于化合物A-a游离酸，溶解性有大幅的提高，有利于提高药物的成药性。
实施例6：本发明化合物的稳定性考察
按照《中国药典》2020版第四部《原料药物与制剂稳定性试验指导原则》对稳定性的指导进行稳定性测定。适量称取本发明实施例制备得到的化合物供试品(约50mg)置于10ml西林瓶中，压盖密封，如此包装若干份样品，然后将样品分别置于30℃±2℃、65％±5％RH条件和20℃±2℃、60％±5％RH条件的恒温恒湿箱中，10天之后取出样品，测定水分和有关物质，与0天水分、有关物质的检验结果进行对比。
实验结果如下表所示：
表二：本发明化合物的稳定性考察
Figure PCTCN2022109367-appb-000015
从上述结果可见，本发明化合物的钠盐、钾盐和三羟基甲基氨基甲烷盐相对于化合物A-a游离酸，在多种湿度/温度条件下更稳定。
实施例7本发明化合物的大鼠药代动力学特征考察
1、实验材料
SD大鼠：雄性，180-250g，购于北京维通利华实验动物技术有限公司。
试剂：羧甲基纤维素钠(CMC-Na，粘度：800-1200mpa.s，批号B1707016，阿拉丁)，维生素E聚乙二醇琥珀酸酯(TPGS，批号CSN10842-002，CSNpharm)，DMSO(二甲亚砜)，PEG-400(聚乙二醇400)，乙腈，甲酸，普萘洛尔(内标)均为市售可得。
仪器：赛默飞LC-MS(Ultimate 3000 UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。
2、给药溶媒的配制
14.3％(w/v)TPGS溶液
以配制100mL为例：称取14.3g TPGS于合适容器中，60℃水浴融化成液态。另取合适容器加入100mL超纯水置于磁力搅拌器上加热至60℃，边搅拌边缓缓滴入融化的TPGS，持续搅拌1小时左右使成澄清透明的浅黄色液体。
0.5％(w/v)CMC-Na溶液
以配制100mL为例：量取100mL超纯水至合适容器中，放入磁力搅拌子，称取0.5g CMC-Na，边搅拌边加入到上述容器中，持续搅拌均匀至澄清透明溶液。
3、给药制剂的配制
分别称取适量化合物A游离酸、钠盐和三羟基甲基氨基甲烷盐三种粉末于陶瓷研钵中，溶媒组成为30％TPGS(14.3％)-40％CMC-Na(0.5％)30％PEG(v/v/v)，先加入30％TPGS将药粉研磨至无明显大颗粒，再加入40％CMC-Na研磨至无肉眼可见颗粒，最后加入30％PEG-400研磨混合均匀，即得。
4、血样采集与生物分析
大鼠灌胃给药后，于15min、30min、1h、2h、5h、7h、24h采集静脉血200μL于含EDTA-K2抗凝剂采血管中，4000rpm，2～8℃离心5min分离血浆，-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各5μL，加入空白血浆45μL，涡旋混匀，配制成相当于血浆浓度为0.3、1、3、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取30μL血浆，加入内标普萘洛尔(50ng/mL)的乙腈溶液150μL，涡旋混匀后，加入100μL纯化水，再次涡旋混匀，4000rpm离心5min，取上清LC-MS分析。LC-MS检测条件如下：
色谱柱：Waters ACQUITYTM PREMIER HSS T3，50*2.1mm，1.8μm。
流动相A：水(0.1％甲酸)，流动相B：乙腈，流速：0.5mL/min，梯度洗脱：
时间(min) A(％) B(％)
0 95％ 5％
1 40％ 60％
2.5 5％ 95％
2.51 95％ 5％
2.8 95％ 5％
5、数据处理
LC-MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数，结果见表三。
表三：本发明化合物的大鼠药代动力学参数
Figure PCTCN2022109367-appb-000016
从上述结果可见，本发明化合物的钠盐和三羟基甲基氨基甲烷盐在大鼠体内的暴露量明显优于化合 物A-a游离酸，说明相对于化合物A-a游离酸有更好的吸收。
实施例8本发明化合物胶囊剂的比格犬药代动力学特征考察
1、试剂与仪器
五肽胃泌素(sigma，批号SLCC6419)，0号明胶空心胶囊，氢氧化铵(ACS试剂，28.0-30.0％NH 3，艾览(上海)化工科技有限公司，批号CEC1070004)，LC-MS仪器(赛默飞Ultimate 3000 UPLC，TSQ QUANTUM ULTRA三重四极杆质谱)。
2、实验动物
Beagle犬4只，雄性，体重5kg-7kg，购于北京玛斯生物技术有限公司。
3、制剂配制
精密称取五肽胃泌素溶于DMSO，配制成25mg/mL储备液，用生理盐水稀释100倍，再加入0.1％(v/v)的氢氧化铵使析出的沉淀完全溶解，最终浓度为0.25mg/mL。
4、血样采集与生物分析
精密称取化合物A-a游离酸、钾盐、钠盐和三羟基甲基氨基甲烷盐四种粉末，装进0号空心胶囊中，固定4只犬编号，每只犬口服一粒胶囊，每种盐型样品给药犬只为4只，第一次给完一种盐型后，间隔2-3天，给予另一种盐型。每只犬都于给药前肌注五肽胃泌素。
犬口服给药后，于15min、30min、1h、2h、4h、6h、8h、10h、24h分别用头皮针于前肢或后肢静脉采集血液约1mL，置于含EDTA-K2抗凝剂采血管中，4000rpm，2～8℃离心10min分离血浆，-80℃保存待测。
精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。储备液用乙腈:水(1:1)稀释至30000、10000、3000、1000、300、100、30、10、3ng/mL得到标准曲线工作溶液。取5μL工作溶液加到45μL空白犬血浆中，涡旋混匀，配制成相当于血浆浓度为3000、1000、300、100、30、10、3、1、0.3ng/mL的标曲样品。取30μL标曲样品和采集的血浆样品加入150μL普萘洛尔乙腈溶液(内标，50ng/mL)沉淀蛋白，再加100μL水涡旋混匀后，4000rpm离心5min，取上清液LC-MS分析。LC-MS检测条件如下：
色谱柱：Waters ACQUITYTM PREMIER HSS T3，50*2.1mm，1.8μm。
流动相A：水(0.1％甲酸)，流动相B：乙腈，流速：0.5mL/min，梯度洗脱：
时间(min) A(％) B(％)
0 95％ 5％
1 40％ 60％
2.5 5％ 95％
2.51 95％ 5％
2.8 95％ 5％
5、数据处理
LC-MS检测血药浓度后，采用WinNonlin 6.1软件的非房室模型计算比格犬给药后的药动学参数，结果见表四。
表四：本发明化合物的比格犬药代动力学参数
Figure PCTCN2022109367-appb-000017
从上述结果可见，本发明化合物的钠盐、钾盐、三羟基甲基氨基甲烷盐在比格犬体内的口服固体吸收暴露量明显优于化合物A-a游离酸，说明相对于化合物A-a游离酸有更好的吸收。
实施例9：本发明化合物大鼠药代动力学研究
1、实验材料
SD大鼠：雄性，180-250g，购于北京维通利华实验动物技术有限公司。
试剂：DMSO(二甲亚砜)，PEG-400(聚乙二醇400)，生理盐水，肝素，乙腈，甲酸，普萘洛尔(内标)均为市售可得。
仪器：赛默飞LC-MS(U300 UPLC，TSQ QUANTUMN ULTRA三重四级杆质谱)。
2、实验方法
称取实施例1化合物A-a及按照CN201780086550.1实施例4A-1和10A-77制备得到的相应化合物溶于DMSO-PEG-400-生理盐水(5：60：35，v/v/v)体系中，大鼠静脉或灌胃给药后，于15min、30min、1h、2h、5h、7h、24h(iv组加采5min)采集静脉血200μL于肝素化EP管中，12000rpm离心2min，取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL，作为储备液。准确吸取适量的化合物储备液，加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL，加入空白血浆180μL，涡旋混匀，配制成相当于血浆浓度为0.3、1、3、10、30、100、300、1000、3000ng/mL的血浆样品，每一浓度进行双样本分析，建立标准曲线。取30μL血浆(静脉给药5min、15min、30min、1h血浆稀释10倍)，加入内标普萘洛尔(50ng/mL)的乙腈溶液200μL，涡旋混匀后，加入100μL纯化水，再次涡旋混匀，4000rpm离心5min，取上清LC-MS分析。LC-MS检测条件如下：
色谱柱：赛默飞HYPERSIL GOLD C-18 UPLC柱，100*2.1mm，1.7μm。
流动相：水(0.1％甲酸)-乙腈按下表进行梯度洗脱
时间(min) 水(含0.1％甲酸) 乙腈
0 90％ 10％
0.6 90％ 10％
1 10％ 90％
2.6 10％ 90％
2.61 90％ 10％
4 90％ 10％
3、数据处理
LC-MS检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数,结果见表五。
表五：本发明化合物对大鼠药代动力学结果
Figure PCTCN2022109367-appb-000018
结论：从表五中可以看出本发明化合物在大鼠口服吸收较好，具有较高的暴露量和生物利用度。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 式(I)所示的GLP-1R激动剂化合物的盐，
    Figure PCTCN2022109367-appb-100001
    其中：
    n为0.3-3；
    M与羧基成盐，所述盐选自锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铁盐、锌盐或铵盐中的至少一种；或所述盐选自甲胺盐、二甲胺盐、三甲胺盐、乙胺盐、二乙胺盐、三乙胺盐、异丙胺盐、2-乙氨基乙醇盐、吡啶盐、甲基吡啶盐、乙醇胺盐、二乙醇胺盐、铵盐、四甲基铵盐、四乙基铵盐、三乙醇胺盐、哌啶盐、哌嗪盐、吗啉盐、赖氨酸盐、L-赖氨酸盐、精氨酸盐、L-精氨酸盐、组氨酸盐、L-组氨酸盐、葡甲胺盐、二甲基葡糖胺盐、乙基葡糖胺盐、二环己基胺盐、1,6-己二胺盐、葡糖胺盐、肌氨酸盐、丝氨醇盐、三羟基甲基氨基甲烷盐、氨基丙二醇盐、鸟氨酸盐或胆碱盐中的至少一种。
  2. 根据权利要求1所述GLP-1R激动剂化合物的盐，其特征在于，所述GLP-1R激动剂化合物结构如下：
    Figure PCTCN2022109367-appb-100002
  3. 根据权利要求1或2所述GLP-1R激动剂化合物的盐，其特征在于，n为0.33、0.5、1、1.5、2、2.5或3。
  4. 根据权利要求1或2所述GLP-1R激动剂化合物的盐，其特征在于，所述的盐选自钠盐、钾盐、三羟基甲基氨基甲烷盐、钙盐、镁盐。
  5. 根据权利要求1或2所述GLP-1R激动剂化合物的盐，其特征在于，所述的盐选自钠盐、n＝1；钾盐、n＝1；三羟基甲基氨基甲烷盐、n＝1；钙盐、n＝0.5；镁盐、n＝0.5。
  6. 根据权利要求1所述GLP-1R激动剂化合物的盐，其特征在于，所述的盐选自：
    Figure PCTCN2022109367-appb-100003
  7. 根据权利要求1或2所述GLP-1R激动剂化合物的盐，其特征在于，所述的盐选自：
    Figure PCTCN2022109367-appb-100004
  8. 根据权利要求1-7任一项所述GLP-1R激动剂化合物的盐，其特征在于：所述化合物的一个以上的氢原子上被同位素氘取代。
  9. 一种药物组合物，其特征在于，包括前述权利要求1-8任一项所述GLP-1R激动剂化合物的盐，和一种以上药学上可接受的载体。
  10. 根据权利要求1-8任一项所述GLP-1R激动剂化合物的盐在制备用于制备治疗GLP-1R相关疾病的药物用途，优选糖尿病相关疾病的药物用途。
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