WO2016078594A1 - 含吡咯环质子泵抑制剂的半富马酸盐及其晶型、中间体和医药用途 - Google Patents

含吡咯环质子泵抑制剂的半富马酸盐及其晶型、中间体和医药用途 Download PDF

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WO2016078594A1
WO2016078594A1 PCT/CN2015/094958 CN2015094958W WO2016078594A1 WO 2016078594 A1 WO2016078594 A1 WO 2016078594A1 CN 2015094958 W CN2015094958 W CN 2015094958W WO 2016078594 A1 WO2016078594 A1 WO 2016078594A1
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methyl
fluorophenyl
methylamino
sulfonyl
pyrrol
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PCT/CN2015/094958
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English (en)
French (fr)
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余俊
朱强
杨宝海
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江苏豪森药业集团有限公司
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Priority claimed from CN201410665883.8A external-priority patent/CN104447491B/zh
Priority claimed from CN201410664394.0A external-priority patent/CN104447490B/zh
Application filed by 江苏豪森药业集团有限公司 filed Critical 江苏豪森药业集团有限公司
Priority to CN201580059766.XA priority Critical patent/CN107001262A/zh
Publication of WO2016078594A1 publication Critical patent/WO2016078594A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms

Definitions

  • the present invention relates to the field of medical biology, and in particular to 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)benzene Oxy)-N-methylacetamide hemi-fumarate and its crystal form, as well as a preparation method, an intermediate, a pharmaceutical composition and medical use thereof.
  • Peptic ulcer refers to tissue damage caused by the digestive digestion of the gastrointestinal mucosa by the digestive juice of the stomach. It can occur in any part of the digestive tract.
  • the stomach and duodenum are the most common, namely gastric ulcer and twelve.
  • Intestinal ulcers, the etiology, clinical symptoms and treatment methods are basically similar, and the diagnosis is mainly based on gastroscopy.
  • Gastric ulcer is the most common type of peptic ulcer, mainly refers to tissue damage caused by gastric mucosa being digested by gastric digestive juice itself.
  • Gastric ulcer is one of the common and frequently-occurring diseases in Chinese population.
  • the geographical distribution of gastric ulcer generally has an upward trend in the north, and occurs in the winter and spring seasons with large climate change.
  • the incidence of males is significantly higher than that of females, which may be closely related to smoking, irregular living and eating, work and external stress, and mental and psychological factors.
  • the incidence of gastric ulcer has begun to decline, but it is still one of the most common diseases of digestive diseases. Its occurrence is mainly related to the imbalance between the damage factors of the gastric duodenal mucosa and the mucosal self-defense repair factors. H.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • gastric ulcer is more likely to occur in the stomach horn and small antrum of the antrum. It is more common in elderly male patients, and its incidence has a certain relationship with seasonal changes.
  • gastric acid and pepsin are important digestive substances in gastric juice.
  • Gastric acid is a strong acid substance and is highly aggressive; pepsin has the function of hydrolyzing proteins and can destroy proteins on the stomach wall.
  • the gastrointestinal tract can still resist and maintain mucosal integrity.
  • duodenal mucosa also has a series of defense and repair mechanisms.
  • We will harm the stomach acid and pepsin sexuality is called the injury mechanism, and the defense and repair mechanism that the gastrointestinal tract itself has is called the protection mechanism. It is currently believed that the protective mechanism of the gastric duodenal mucosa of normal people is sufficient to resist the erosion of gastric acid and pepsin.
  • H2-RA H2 receptor antagonists
  • PPIs proton pump inhibitors
  • H2-RA inhibits basic and stimulating gastric acid secretion, such as cimetidine, ranitidine, famotidine and nizatidine
  • PPI acts as a key enzyme in the terminal steps of gastric acid secretion.
  • -K+ATPase which makes it irreversibly inactivated, and has a stronger acid-suppressing effect and a long-lasting effect.
  • PPI promotes ulcer healing faster and has a higher healing rate. It is suitable for the treatment of patients with various refractory ulcers or NSAID ulcers who can not stop NSAID. It can also be used together with antibiotics to eradicate Helicobacter pylori treatment. It is the first choice for gastric ulcer.
  • Commonly used PPIs are omeprazole, lansoprazole, rabeprazole, esomeprazole, and iprazol.
  • Amide hemifumarate is a proton pump inhibitor containing a pyrrole ring, which has the advantages of remarkable efficacy and small side effects, and has great potential in the treatment of gastric ulcer drugs.
  • the object of the present invention is to provide a hemifumarate represented by the formula (I), which is a proton pump inhibitor containing a pyrrole ring for treating gastroesophageal reflux, peptic ulcer, gastric ulcer, twelve fingers Intestinal bulb ulcer, esophagitis, etc.
  • the present invention provides a 2-(3-((2-(2-fluorophenyl)-4-)-(()-) Crystal form of amino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide hemifumarate.
  • the XRD pattern of the crystal form has a characteristic peak of 2.858, 9.456, 13.202, 14.836, 15.59, 15.749, 15.050, 19.948 at 2 ⁇ angle ( ⁇ 0.2°), and preferably also contains a 2 ⁇ angle ( ⁇ 0.2°) of 19.901. Characteristic peaks of 20.922, 22.423, 24.867, and particularly preferably, the XRD pattern of the crystal form is shown in FIG.
  • Another object of the present invention is to provide a process for preparing a hemifumarate crystal form represented by formula (I) by (2) 2-(3-((2-(2-fluorophenyl))-4) -((Methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-methylacetamide is obtained by salting out fumaric acid in an organic solvent.
  • the preparation method comprises the following steps:
  • the organic solvent is an alcohol solvent.
  • the alcohol solvent is selected from the group consisting of isopropanol or/and anhydrous ethanol.
  • the alcohol solvent is a mixed solvent of isopropyl alcohol/anhydrous ethanol
  • the ratio of isopropyl alcohol is 0.1% to 100%.
  • the alcohol solvent is a mixed solvent system of isopropanol/anhydrous ethanol, and the volume ratio of isopropanol to absolute ethanol is from 1 to 8:1, more preferably from 3 to 5:1, and most preferably 4: 1.
  • the fumaric acid solution is a solution of fumaric acid in ethanol.
  • the molar equivalent of the fumaric acid added is 0.4 to 0.5 equivalents, more preferably 0.45 to 0.47 equivalents, of the compound of the formula (II).
  • the temperature of the step (2) stirring and heating is 50 to 82 ° C, more preferably reflux temperature.
  • Another object of the present invention is to provide a 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl) sulfonate.
  • the composition is in the form of a tablet or capsule.
  • Another object of the present invention is to provide the 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl) a phenoxy)-N-methylacetamide hemi-fumarate or a crystalline form thereof and the pharmaceutical composition for the treatment of gastroesophageal reflux, peptic ulcer, gastric ulcer, duodenal ulcer or Use in esophagitis drugs.
  • Another object of the present invention is to provide a preparation of 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrole) represented by the formula (III).
  • Another object of the present invention is to provide a process for the preparation of said intermediate comprising the addition of tert-butyl((5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbonic acid
  • the ester is obtained by condensation of 3-(2-(methylamino)-2-oxoethoxy)phenyl-1-sulfonyl chloride in an organic solvent.
  • the organic solvent is selected from the group consisting of benzene, toluene, xylene, acetonitrile or DMF.
  • Another object of the present invention is to provide a process for preparing the intermediate free base which comprises passing the compound of the formula (III) into a hydrochloric acid gas and adjusting the pH to a basic state with a basic substance.
  • the basic substance is selected from the group consisting of sodium hydrogencarbonate, sodium hydroxide or sodium carbonate.
  • the hemifumarate of the present invention has better stability, exhibits excellent biological activity, and has good gastric acid inhibition.
  • the crystal form of the compound is obtained for the first time, and the obtained crystal form is stable in properties, and is very suitable for pharmaceutical preparation applications, and has good market prospect.
  • Figure 1 2-(3-((2-(2-Fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N- 1H-NMR spectrum of methyl acetamide hemifumarate.
  • Figure 2 2-(3-((2-(2-Fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N- 13C-NMR spectrum of methyl acetamide hemifumarate.
  • Figure 3 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)- XRD pattern of the crystal form of N-methylacetamide hemifumarate.
  • Example 1 On the basis of Example 1, the target crystal form was obtained, and it was named as Form 1, and weighed 9.8 g, and the mass yield was 98%.
  • the 1H-NMR spectrum is shown in Fig. 1, and the XRD pattern is shown in Fig. 3.
  • Example 2 On the basis of Example 2, the target crystal form was obtained, which was named as Form 1 and weighed 9.6 g. The mass yield was 96%.
  • the 1H-NMR spectrum was basically the same as that in Figure 1.
  • the XRD pattern was basically consistent with Figure 3. Form 1 features.
  • the compound III (4.5 g) was dissolved in 15 mL of ethyl acetate, and the temperature of the reaction mixture was cooled to 10 ° C in an ice bath, and hydrochloric acid gas was added thereto, and the reaction was stirred for 1 hour.
  • the hemifumarate of the present invention can inhibit gastric mucosal ulcer bleeding caused by indomethacin in a dose-dependent manner, and has a tendency to inhibit at a dose of 1 mg/kg, and 3 mg/kg and 9 mg/kg can significantly inhibit gastric ulcer. Hemorrhage (p less than 0.01 and 0.001, respectively), and the inhibition effect was significantly stronger than 20 mg / kg of omeprazole (p ⁇ 0.05).
  • test compound the compound of Example 1
  • rat histamine stimulation model The gastric acid inhibition of the test compound (the compound of Example 1) in the rat histamine stimulation model was evaluated.
  • Control solvents and different doses of test compounds were administered at specific time points (4 hours prior to collection of gastric juice) according to experimental design.
  • the animals were anesthetized with diethyl ether 1 hour after administration, the abdominal cavity was opened, the pylorus was ligated, and the animal was injected subcutaneously with a histamine phosphate solution (administered at a dose of 30 mg/kg). After 3 hours of injection of histamine phosphate, the animals were anesthetized, the cardia were ligated, and gastric juice was collected.
  • Rat gastric juice was collected from 1 hour to 4 hours after administration. After diluting a certain amount of gastric acid sample to the detection volume, the potentiometric titration was carried out by using an automatic titrator using NaOH standard solution (0.1036 mol/L, 0.1006 mol/L), the acid content was determined, and the total acid was calculated according to the total volume of the sample. value.
  • Acid discharge (mmol) total volume of gastric acid / volume of gastric acid for titration ⁇ volume of NaOH standard solution ⁇ concentration of NaOH standard solution
  • Gastric acid secretion inhibition rate (I%) [acid discharge amount (solvent group) - acid discharge amount (compound group)] / acid discharge amount (solvent group) ⁇ 100%
  • test compound the compound of Example 1
  • the test compound the compound of Example 1
  • the inhibition rate of gastric acid secretion compared with the solvent group (p ⁇ 0.05 and 0.01, respectively). It can reach 62.4%, 90.3% and 99.7% respectively.
  • the crystal form 1 (prepared in Example 1-1) of the present invention was subjected to a three-month accelerated stability (sampling conditions of 40 ° C ⁇ 2 ° C, RH 75 ⁇ 5%).
  • the sample was provided by Jiangsu Haosen Pharmaceutical Co., Ltd.
  • the three batches of crystal products were named VP-130401, VP-130402 and VP-130403, respectively.
  • Table 1-2 The stability of related substances is shown in Table 3.

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Abstract

本发明公开了含吡咯环质子泵抑制剂的半富马酸盐、晶型及其中间体和医药用途。具体地，本发明涉及一种含有吡咯环的质子泵抑制剂的半富马酸盐、晶型形式、中间体及其制备方法和医药用途，即式(I)所示2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐，以及通过2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺与富马酸的成盐方法，并表征了半富马酸盐晶型。本发明的半富马酸盐及其晶型稳定性更好，且表现出了优异的生物活性，具有良好的胃酸抑制作用。

Description

含吡咯环质子泵抑制剂的半富马酸盐及其晶型、中间体和医药用途 技术领域
本发明涉及医药生物领域，具体涉及2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐及其晶型以及制备方法、中间体、药物组合物及其医药用途。
背景技术
消化性溃疡指胃肠黏膜被胃消化液自身消化而造成的超过粘膜肌层的组织损伤，可发生于消化道的任何部位，其中以胃及十二指肠最为常见，即胃溃疡和十二指肠溃疡，其病因、临床症状及治疗方法基本相似，明确诊断主要靠胃镜检查。胃溃疡是消化性溃疡中最常见的一种，主要是指胃黏膜被胃消化液自身消化而造成的超过粘膜肌层的组织损伤。
胃溃疡是我国人群中常见病、多发病之一。作为消化性溃疡中的常见类型，胃溃疡的地理分布大致有北方向南方升高趋势，且好发于气候变化较大的冬春两季。此外，男性发病率明显高于女性，可能与吸烟、生活及饮食不规律、工作及外界压力以及精神心理因素密切相关。近年来，胃溃疡的发病率开始呈下降趋势，然而其仍属消化系统疾病中最常见的疾病之一。其发生主要与胃十二指肠黏膜的损害因素和黏膜自身防御修复因素之间失平衡有关。幽门螺杆菌(H.pylori)感染、非甾体抗炎药(NSAID，如阿司匹林)、胃酸分泌异常是引起溃疡的常见病因。典型的溃疡疼痛具有长期性、周期性和节律性的特点。其中，胃溃疡多好发于在胃角和胃窦小弯，多见于老年男性患者，其发病与季节变化有一定关系。
胃腔内，胃酸和胃蛋白酶是胃液中重要的消化物质。胃酸为强酸性物质，具有较强的侵蚀性；胃蛋白酶具有水解蛋白质的作用，可破坏胃壁上的蛋白质，然而，在这些侵蚀因素的存在下，胃肠道仍能抵抗而维持黏膜的完整性及自身的功能，其主要是因为胃、十二指肠黏膜还具有一系列防御和修复机制。我们将胃酸及胃蛋白酶的有害侵蚀 性称之为损伤机制，而将胃肠道自身具有的防御和修复机制称之为保护机制。目前认为，正常人的胃十二指肠黏膜的保护机制，足以抵抗胃酸及胃蛋白酶的侵蚀。但是，当某些因素损害了保护机制中的某个环节就可能发生胃酸及蛋白酶侵蚀自身黏膜而导致溃疡的形成。当过度胃酸分泌远远超过黏膜的防御和修复作用也可能导致溃疡发生。近年的研究已经表明，幽门螺杆菌和非甾体抗炎药是损害胃肠保护机制导致溃疡发病的最常见病因，胃酸在溃疡形成中起关键作用。此外，药物，应激，激素也可导致溃疡的产生，各种心理因素及不良的饮食生活习惯可诱发溃疡的出现。
目前临床上主要有H2受体拮抗剂(H2-RA)及质子泵抑制剂(PPI)。H2-RA可抑制基础及刺激的胃酸分泌，常用的如西咪替丁、雷尼替丁、法莫替丁和尼扎替丁；PPI作用于壁细胞胃酸分泌终末步骤中的关键酶H+-K+ATP酶，使其不可逆失活，抑酸作用更强且作用持久。PPI促进溃疡愈合的速度较快、愈合率较高，适用于各种难治性溃疡或NSAID溃疡患者不能停用NSAID时的治疗，还可与抗生素的协同作用可用于根除幽门螺杆菌治疗，因此是胃溃疡的首选用药。常用的PPI有奥美拉唑、兰索拉唑、雷贝拉唑、埃索美拉唑、艾普拉唑等。
2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐是一种含有吡咯环的质子泵抑制剂，具有药效显著，副作用小等优点，在治疗胃溃疡药物中具有巨大的潜力。
发明内容
本发明的目的在于提供一种式(I)所示的半富马酸盐，是一种含有吡咯环的质子泵抑制剂，用治疗胃食管反流，消化性溃疡，胃溃疡，十二指肠球部溃疡，食管炎等。
Figure PCTCN2015094958-appb-000001
式(I)
优选的，本发明提供了一种式(1)所示的2-(3-((2-(2-氟苯基)-4-((甲 胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐的晶型。
所述晶型的XRD图谱具有2θ角(±0.2°)为7.858，9.456，13.202，14.836，15.099，15.749，15.050，19.948的特征峰，优选的，还含有2θ角(±0.2°)为19.901，20.922，22.423，24.867的特征峰，特别优选的，所述晶型的XRD图谱如图3所示。
本发明的另外一个目的在于提供一种式(I)所示的半富马酸盐晶型的制备方法，通过(2)2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺与富马酸在有机溶剂里成盐析晶得到。
Figure PCTCN2015094958-appb-000002
优选的，所述制备方法包括如下步骤：
(1)将式(II)化合物2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺溶于有机溶剂，加入富马酸盐固体或者富马酸溶液；
(2)将上述反应液搅拌加热；
(3)降温析晶得到式(I)化合物。
优选的，所述有机溶剂为醇类溶剂。
优选的，所述醇类溶剂选自异丙醇或/和无水乙醇。
优选的，当醇类溶剂为异丙醇/无水乙醇混合溶剂时，其中异丙醇的比例为0.1％～100％。
优选的，所述醇类溶剂为异丙醇/无水乙醇的混合溶剂体系，异丙醇/无水乙醇的体积比为1～8∶1，更优选3～5∶1，最优选4∶1。
优选的，所述富马酸溶液是富马酸的乙醇溶液。
优选的，加入富马酸的摩尔当量为式(II)化合物的0.4～0.5当量，更优选为0.45～0.47当量。
优选的，所述步骤(2)搅拌加热的温度为50～82℃，更优选回流 温度。
本发明的另一目的还在于提供一种包含2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐及药学上可接受载体的药物组合物。
优选的，该组合物的存在形式是片剂或胶囊。
本发明的另一目的还在于提供所述2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐或其晶型及所述药物组合物在制备治疗胃食管反流，消化性溃疡，胃溃疡，十二指肠球部溃疡或食管炎药物中的用途。
本发明的另一目的还在于提供一种式(III)所示制备2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐的中间体
Figure PCTCN2015094958-appb-000003
本发明的另一目的还在于提供制备所述中间体的方法，包括将叔丁基((5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)碳酸酯与3-(2-(甲氨基)-2-氧代乙氧基)苯基-1-磺酰氯在有机溶剂中缩合制得。
优选的，所述有机溶剂选自苯、甲苯、二甲苯、乙腈或DMF。
本发明的另一目的还在于提供一种制备所述中间体游离碱的方法，包括将所述式(III)化合物通入盐酸气，用碱性物质调节pH至碱性。
优选的，所述碱性物质选自碳酸氢钠、氢氧化钠或碳酸钠。
本发明的半富马酸盐稳定性更好，且表现出了优异的生物活性，具有良好的胃酸抑制作用。本发明首次制得该化合物晶型，所得晶型性质稳定，非常适合药物制剂应用，具有良好的市场前景。
附图说明
图1：2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐的1H-NMR图谱。
图2：2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐的13C-NMR图谱。
图3：本发明2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐晶型的XRD图谱。
具体实施方式
实施例1：
将2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺10g，溶于异丙醇(80ml)和无水乙醇(20ml)的混合溶剂中，在搅拌的条件下加入富马酸1.26g，之后加热至50℃回流30分钟，在搅拌的条件下自然冷却至室温，搅拌2小时，过滤，干燥得到2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐。
实施例1-1
在实施例1的基础上，得到目标晶型，命名为晶型1，称重9.8g，质量收率98％，其1H-NMR图谱如图1所示，XRD图谱如图3所示。
实施例2：
将2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺10g，溶于异丙醇(80ml)，加入富马酸的乙醇溶液(1.26g/20ml)，加热至回流，固体全部溶解，搅拌的条件下自然冷却至室温，搅拌2小时，过滤，干燥得到2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐。
实施例2-1
在实施例2的基础上，得到目标晶型，命名为晶型1，称重9.6g，质量收率96％，其1H-NMR图谱基本与图1相同，XRD图谱基本与图3吻合，符合晶型1特征。
实施例3：2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐中间体以及游离碱的制备
Figure PCTCN2015094958-appb-000004
第一步
将叔丁基((5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)碳酸酯(3.0g，10mmol)和3-(2-(甲氨基)-2-氧代乙氧基)苯基-1-磺酰氯(2.64mg，10mmol)，加入乙腈中，加入DIEA搅拌反应2～5小时。反应液降温，加入稀盐酸调节pH至4～5，加入纯化水析晶，得化合物III，4.9g，产率：92.3％。
第二步
将化合物III(4.5g)溶解于15mL的乙酸乙酯中，冰浴冷却反应液温度至10℃，投入盐酸气，搅拌反应1小时。用于碳酸氢钠调节pH至碱性，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B(正己烷和乙酸乙酯体系)纯化所得残余物，得到2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺(3.0g，无色油状物)，产率：82.2％。
实验例1、产品稳定性研究
参照本发明实施例1的方法制备得到2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐，其中富马酸含量11.80％。
参考本发明实施例1的方法制备2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺富马酸盐，区别在于使用甲醇/乙酸乙酯替换实施例1中的成盐体系，所得产品中富马酸含量为21.10％。
表1 上述两种盐在不同影响因素条件下考察结果如下：
Figure PCTCN2015094958-appb-000005
Figure PCTCN2015094958-appb-000006
实验例2、大鼠吲哚美辛致胃溃疡模型评价半富马酸盐的抗溃疡作用
将健康成年SD大鼠，雌雄兼用，随机分组，禁食48小时后开始造模，动物禁食过程中允许自由饮水。根据实验设计分别给予对照溶剂、阳性对照药和受试化合物。给药后30min，除非模型组外，经腹腔注射吲哚美辛(剂量为20mg/kg体重)造模。造模成功后，分别按照1mg/kg、3mg/kg和9mg/kg注射实施例1制得的半富马酸盐，5小时后计算胃粘膜溃疡出血点数目和溃疡抑制百分率。结果如下：
表2 大鼠吲哚美辛致胃溃疡模型--抑制百分率(％)
Figure PCTCN2015094958-appb-000007
试验结果：本发明的半富马酸盐能够剂量依赖性地抑制吲哚美辛导致的胃粘膜溃疡出血，1mg/kg剂量下有抑制趋势，3mg/kg和9mg/kg都能明显抑制胃溃疡出血(p分别小于0.01和0.001)，且抑制效果明显强于20mg/kg的奥美拉唑(p＜0.05)。
实验例3、大鼠组胺刺激模型评价受试化合物的胃酸抑制作用
实验目的：
评价受试化合物(实施例1化合物)在大鼠组胺刺激模型中的胃酸抑制作用。
试验方法：
根据实验设计分别在特定时间点(收集胃液前4小时)给予对照溶剂和不同剂量的受试化合物。给药后1小时用乙醚将动物麻醉，打开腹腔，结扎幽门，动物皮下注射磷酸组织胺溶液(给药剂量为30mg/kg)。注射磷酸组胺3小时后麻醉动物，结扎贲门，收集胃液。
表3 实验分组与剂量
Figure PCTCN2015094958-appb-000008
检测指标
收集给药后1小时至4小时的大鼠胃液。将一定量的胃酸样品稀释到检测体积后，用自动滴定仪采用NaOH标准液(0.1036mol/L、0.1006mol/L)进行电位滴定，测定其含酸量，并根据该样品总体积计算总酸值。
酸排出量(mmol)＝胃酸总体积/滴定用胃酸体积×消耗NaOH标准液体积×NaOH标准液浓度
胃酸分泌抑制率(I％)＝[酸排出量(溶剂组)-酸排出量(化合物组)]/酸排出量(溶剂组)×100％
表4.大鼠组胺刺激模型胃酸量测定(Mean±SEM)
Figure PCTCN2015094958-appb-000009
Figure PCTCN2015094958-appb-000010
表5.大鼠组胺刺激模型--胃酸和胃液抑制百分率(％)
Figure PCTCN2015094958-appb-000011
实验结果
实验结果如下所示：给药后4小时，与溶剂组相比，不同剂量下的受试化合物(实施例1化合物)能够显著(p分别小于0.05和0.01)减少胃酸量，且胃酸分泌抑制率可分别达62.4％、90.3％和99.7％。
实验例4、晶型的稳定性考察：
对本发明晶型1(实施例1-1制得)进行3个月加速稳定性(放样条件为40℃±2℃，RH75±5％)试验考察，样品由江苏豪森药业股份有限公司提供，三个批次的晶型产品分别命名为VP-130401、VP-130402和VP-130403，与样品初始X-射线粉末衍射数据对比见下表1～2，有关物质稳定性见表3。
表1.加速稳定性X-射线粉末衍射数据对比(-2θ)
Figure PCTCN2015094958-appb-000012
Figure PCTCN2015094958-appb-000013
表2.加速稳定性X-射线粉末衍射数据对比(-d)
Figure PCTCN2015094958-appb-000014
表3.加速稳定性质量数据对比
Figure PCTCN2015094958-appb-000015
上述3个月加速稳定性数据表明，晶型1具有良好的稳定。

Claims (18)

  1. 一种式(I)所示2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐，
    Figure PCTCN2015094958-appb-100001
  2. 一种2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐晶型，
    其XRD图谱特征峰具有2θ角(±0.2°)为7.858，9.456，13.202，14.836，15.099，15.749，15.050，19.948，优选的，还含有2θ角(±0.2°)为19.901，20.922，22.423，24.867的特征峰，特别优选的，所述晶型的XRD图谱如图3所示。
  3. 制备根据权利要求1所述的式(I)所示2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐或权利要求2所述晶型的方法，包括由式(II)所示2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺与富马酸在有机溶剂里成盐析晶制得，
    Figure PCTCN2015094958-appb-100002
  4. 根据权利要求3所述的制备方法，包括如下步骤：
    1)将式(II)化合物2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺溶于有机溶剂，加入富马酸盐固体或者富马酸溶液；
    2)将上述反应液搅拌加热；
    3)降温析晶得到式(I)化合物。
  5. 根据权利要求3或4所述的制备方法，其特征在于，所述有机溶剂为醇类溶剂。
  6. 根据权利要求5所述的制备方法，其特征在于，所述醇类溶剂选自异丙醇或/和无水乙醇，优选的，当醇类溶剂为异丙醇/无水乙醇混合溶剂时，其中异丙醇的比例为0.1％～100％。
  7. 根据权利要求6所述的制备方法，其特征在于，所述醇类溶剂为异丙醇/无水乙醇的混合溶剂体系，异丙醇/无水乙醇的体积比为1～8∶1，优选3～5∶1，最优选4∶1。
  8. 根据权利要求4所述的制备方法，其特征在于，所述富马酸溶液是富马酸的乙醇溶液。
  9. 根据权利要求3或4所述的制备方法，其特征在于，加入富马酸的摩尔当量为式(II)化合物的0.4～0.5当量，优选为0.45～0.47当量。
  10. 根据权利要求4所述的制备方法，其特征在于，所述步骤2)搅拌加热的温度为50～82℃，优选回流温度。
  11. 包含2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐或其晶型及药学上可接受载体的药物组合物。
  12. 根据权利要求11所述的药物组合物，该组合物的存在形式是片剂或胶囊。
  13. 根据权利要求1所述的式(I)所示2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐或其晶型及权利要求11所述药物组合物在制备治疗胃食管反流，消化性溃疡，胃溃疡，十二指肠球部溃疡或食管炎药物中的用途。
  14. 式(III)所示的制备2-(3-((2-(2-氟苯基)-4-((甲胺基)甲基)-1H-吡咯-1-基)磺酰基)苯氧基)-N-甲基乙酰胺半富马酸盐的中间体，
    Figure PCTCN2015094958-appb-100003
  15. 制备根据权利要求14所述的中间体的方法，包括将叔丁基((5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)碳酸酯与3-(2-(甲氨基)-2-氧代乙氧基)苯基-1-磺酰氯在有机溶剂中缩合制得。
  16. 根据权利要求14所述的制备方法，其特征在于，所述有机溶剂选自苯、甲苯、二甲苯、乙腈或DMF。
  17. 制备根据权利要求14所述的中间体的游离碱的方法，包括将所述式(III)化合物通入盐酸气，用碱性物质调节pH至碱性。
  18. 根据权利要求17所述的制备方法，其特征在于，所述碱性物质选自碳酸氢钠、氢氧化钠或碳酸钠。
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CN115594623A (zh) * 2021-07-09 2023-01-13 天地恒一制药股份有限公司（Cn） 一种吡咯磺酰类衍生物、及其制备方法与应用

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