WO2022011752A1 - 一种沃诺拉赞盐及其制备方法与用途 - Google Patents

一种沃诺拉赞盐及其制备方法与用途 Download PDF

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WO2022011752A1
WO2022011752A1 PCT/CN2020/106149 CN2020106149W WO2022011752A1 WO 2022011752 A1 WO2022011752 A1 WO 2022011752A1 CN 2020106149 W CN2020106149 W CN 2020106149W WO 2022011752 A1 WO2022011752 A1 WO 2022011752A1
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bismuth
complex
salt
acid
vonoprazan
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PCT/CN2020/106149
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French (fr)
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刘军华
蒋海港
王衡新
邓俐丽
宋志林
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天地恒一制药股份有限公司
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Priority to CN202080001418.8A priority Critical patent/CN112839934B/zh
Publication of WO2022011752A1 publication Critical patent/WO2022011752A1/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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

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  • the invention belongs to the field of chemical drugs, in particular to a salt of a pyrrole compound with proton pump inhibitory effect, more particularly to a salt formed by vonoprazan and a complex of an organic acid and bismuth, and a preparation method and application thereof .
  • Gastric acid-related diseases are a class of diseases caused by excessive gastric acid secretion or sensitivity to gastric acid, such as peptic ulcer, gastroesophageal reflux, and digestive system diseases caused by non-steroidal anti-inflammatory drugs.
  • PPIs proton pump inhibitors
  • omeprazole omeprazole
  • lansoprazole lansoprazole
  • P-CAB potassium ion-competitive acid blocker
  • Vonolazan whose chemical name is 1-[5-(2-fluorophenyl)-1-(pyrrol-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, The structural formula is shown in formula I.
  • Vonolazan developed by Takeda Pharmaceuticals, is the world's first reversible potassium-competitive acid blocker (P-CAB). In February 2015, Vonorazan was approved for marketing in Japan.
  • the marketed salt form is fumarate and the marketed dosage form is tablet.
  • Chinese patent application with publication number CN105693693A discloses various organic or inorganic acid salts of vonoprazan, such as fumarate, acetate, mesylate, sulfate, phosphate, L-apple acid, citrate.
  • Chinese patent application with publication number CN107759568A discloses vonoprazan dihydrochloride, bisphosphonate, benzene sulfonate, 1,4-succinic acid sulfonic acid half salt, 2-hydroxyethane sulfonate and L -Tartrate etc.
  • the present invention further studies the salt of vonolazan, and provides a salt formed by the complex of vonolazan and an organic acid and bismuth, which is compatible with the existing vonolazan salt. Compared with the salt, the bioavailability is improved.
  • the salt formed by the complex of vonoprazan with an organic acid and bismuth provided by the present invention has good solubility and stability, and has the effect of synergistically increasing the drug efficacy and the like.
  • a method for preparing a salt formed by a complex of vonoprazan with an organic acid and bismuth is provided.
  • an application of vonoprazan salt in preparing a medicine for treating gastric acid-related diseases is also provided.
  • the vonorazan salt of the present invention is a salt formed by a complex of vonorazan, an organic acid and bismuth.
  • the complex of organic acid and bismuth is a complex of citric acid and bismuth, or the complex of organic acid and bismuth is a complex of tartaric acid and bismuth.
  • the preparation method of the Vonorazan salt of the present invention comprises the following steps:
  • Step 1 add the complex of organic acid and bismuth and vonolazan to solvent I, heat and stir to dissolve completely;
  • Step 2 remove solvent I to obtain oil
  • Step 3 Add the oily substance obtained in Step 2 into solvent II for beating, to separate out a white solid, and filter with suction to obtain Voronorazan salt.
  • the complex of citric acid and bismuth, or the complex of tartaric acid and bismuth has a relatively large molecular weight, is weak acid, and is insoluble; Vonorazan is a weak base, which forms a salt with an organic acid, especially a weak organic acid , the acid-base neutralization is weak, the steric hindrance is relatively large, and the reaction is relatively difficult. Therefore, at present, there is no report on complexing the pyrrole compound Vonolazan with proton pump inhibitory effect with organic acid bismuth to form a salt in the prior art.
  • the present invention breaks this technical barrier in the prior art, and prepares a salt formed by a complex of vonoprazan, an organic acid and bismuth.
  • the solvent I in the step 1 is a mixed solvent of alcohols and water.
  • the solvent II in step 3 is a mixed solvent of ethyl acetate and alcohols.
  • the alcohols include at least one of methanol, ethanol, propanol or isopropanol.
  • the molar ratio of the organic acid and bismuth complex to Voronolazan is 1:1.1 to 3.0 (preferably 1:1.2 to 2.5).
  • the volume ratio of alcohols and water is 1:0.2-1 (more preferably 1:0.3-0.5).
  • the main reason for choosing the mixed solvent of alcohol and water is that the complex of organic acid and bismuth is insoluble in the mixed solvent of alcohol and water, but the salt formed by the complex of vonoprazan and organic acid and bismuth can Dissolving in this mixed solvent and choosing this mixed solvent is helpful for judging whether the reaction is completed (after the organic acid and bismuth complex reacts completely, it is no longer suspended in the mixed solvent, and the dissolution is complete, indicating that it is the end of the reaction). And alcohol and water are also easy to remove, and it is safer to use.
  • step 1 the organic acid and bismuth complex and vonoprazan are added to solvent I, and heated to above 30°C (preferably 32-50°C, more preferably 35°C).
  • the reaction is performed for more than 2 hours, and more preferably, the reaction is performed for 3 to 5 hours.
  • the volume ratio of ethyl acetate to alcohols is 1:0.5-3, preferably 1:1-1.5.
  • the mixed solvent of ethyl acetate and alcohols is selected for beating, the purpose is to remove excess vonoprazan; by adjusting the ratio of ethyl acetate and alcohols, it can not only remove excess vonoprazan, but also reduce the product Loss.
  • the beating time is 0.5 to 3 hours, more preferably 1 hour.
  • the strong acid is at least one of sulfuric acid, nitric acid, hydrochloric acid and the like.
  • the synthetic method of the complex of tartaric acid and bismuth specifically comprises the following steps:
  • the bismuth nitrate was added to the water, the aqueous solution of the strong alkali was added dropwise to make the pH be 2 ⁇ 3, the white solid was obtained by suction filtration, the white solid was added to the water, the aqueous solution of the strong alkali was added dropwise, the pH of the reaction system was adjusted to be 8 ⁇ 9, and the suction filtration was carried out. , the filter cake is washed with water, the gained white solid is added to the water, then the compound VI ammonium tartrate is added, the temperature is raised, and the pH is adjusted to 9 to 10 with an aqueous solution of strong base after the reaction is completed.
  • the strong base is potassium hydroxide, preferably the aqueous solution mass concentration of the strong base is 20-30%; the molar ratio of bismuth nitrate to ammonium tartrate is 1:3-4 (preferably 1:3.1-3.5).
  • the compound VII potassium bismuth tartrate is added to the water, and after dissolving, the pH is adjusted to 2 ⁇ 3 with a strong acid, a white solid is separated out, and suction filtration is performed to obtain a white solid product, which is the complex compound of compound VIII tartaric acid and bismuth.
  • the strong acid is at least one of sulfuric acid, nitric acid, hydrochloric acid and the like.
  • the vonoprazan salt of the present invention can be used to prepare medicines for preventing or treating gastric acid diseases, such as related diseases caused by hyperacidity, including erosive esophagitis, gastric ulcer, duodenal ulcer, pylorus Helicobacter disease, etc.
  • gastric acid diseases such as related diseases caused by hyperacidity, including erosive esophagitis, gastric ulcer, duodenal ulcer, pylorus Helicobacter disease, etc.
  • the novel salt of Vonorazan prepared by the invention is a salt formed by the complex of Vonorazan and organic acid and bismuth, especially the complex of Vonorazan and citric acid and bismuth or tartaric acid and bismuth.
  • the salt formed by the complex of bismuth is a new compound, which is completely different from the mixture obtained by simple physical mixing of two active ingredients.
  • the new salt has unique physicochemical properties and the ability to inhibit gastric acid secretion and protect mucosa. Dual action, with good water solubility.
  • the salt formed by the complex of vonoprazan with tartaric acid and bismuth in this application has a saturated solubility in water of 2.40 mg/mL (25°C), while the physical The mixture barely dissolves.
  • Fig. 1 is the C-T curve of different drugs orally administered to rats in Example 3 of the present invention.
  • This example prepares the salt formed by the complex of vonoprazan with citric acid and bismuth.
  • Vonorazan can be obtained through commercially available channels or synthesized through existing technologies.
  • Compound IX is the fumarate salt of vonoprazan.
  • DCM is dichloromethane.
  • the synthetic method of compound I vonoprazan is as follows:
  • compound IV potassium bismuth citrate (5.00g, 7.1mmol, 1.0eq) was added to 20mL of water, and the pH was adjusted to 2 with 2M (mol/L) sulfuric acid, and a white solid was precipitated, After suction filtration, 3.50 g of white solid product was obtained. After the mother liquor was placed for 2 hours, some white solids were precipitated, and 0.50 g of white product was obtained by suction filtration, and the yield was 95.5%.
  • This example prepares the salt formed by the complex of vonoprazan with tartaric acid and bismuth.
  • Compound VII potassium bismuth tartrate (1.0g, 1.3mmol, 1.0eq) was added to 8mL of water, after dissolving, the pH was adjusted to 2 with 2M (mol/L) sulfuric acid, a white solid was separated out, and suction filtration was performed to obtain a white solid product 0.35g , which is the complex of compound VIII tartaric acid and bismuth, and the yield is 41.1%.
  • the content of vonoprazan in the purchased vonoprazan fumarate was determined by HPLC to be 74.87% (theoretical value 69.4%), and the same method was used to measure the vonoprazan in compound III.
  • the content is 35.51% (the theoretical value of 1:1 salt formation is 34.48%).
  • Test test drugs HYH2002001 (control group 1, commercially available Vonorazan fumarate), HYH2002002 (Example 1, the salt formed by the complex of Vonorazan with citric acid and bismuth), HYH2002004 ( Embodiment 2, the salt formed by the complex of Vonorazan and tartaric acid and bismuth), HYH2002005 (control group 2, commercially available potassium bismuth citrate and Vonorazan fumarate according to the mole of 1:1 than performing physical mixing);
  • AUCINF_pred (h*ng/mL) represents the area under the time from the start of dosing to theoretically extrapolated infinity.
  • the AUClast (h*ng/mL) of HYH2002001, HYH2002002, HYH2002004 and HYH2002005 are 116.5, 172.5, 178.6 and 133.7 respectively.
  • the AUC of HYH2002002 is increased by 48%, the AUC0 of HYH2002004 by 053.5%
  • HYH2002002, HYH2002004 and HYH2002005 all improved the pharmacokinetic properties and increased the bioavailability of vonorazan, especially HYH2002002, HYH2002004 significantly improved vonorazan bioavailability.
  • High temperature stability investigation steps Put fumarate, bismuth citrate, and bismuth tartrate at a high temperature of 60°C, respectively, and then detect their peak areas and activities at 0h, 4h, 8h, and 24h at a high temperature of 60°C.
  • Component content active component content is based on the detection data at 0h of fumarate, set as 100), the results are shown in Table 2.
  • Illumination stability investigation steps Put fumarate, bismuth citrate and bismuth tartrate under illumination (4500Lux) respectively, and then detect their peak areas under illumination (4500Lux) for 0h, 4h, 8h, and 24h respectively. And active ingredient content (active ingredient content is based on the detection data at the time of fumarate 0h, set as 100), the results are shown in Table 2.
  • Fumarate means the fumarate of vonoprazan.
  • the bismuth citrate salt represents a salt formed by the vonoprazan of the present invention with a complex of citric acid and bismuth.
  • the bismuth tartrate salt represents a salt formed by the vonoprazan of the present invention with a complex of tartaric acid and bismuth.

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Abstract

本发明公开了一种沃诺拉赞盐及其制备方法与用途，本发明之沃诺拉赞盐，为沃诺拉赞与有机酸和铋的络合物所形成的盐。本发明还包括沃诺拉赞盐的制备方法及沃诺拉赞盐在制备治疗胃酸疾病药物方面的应用。本发明之沃诺拉赞与有机酸和铋的络合物所形成的盐与现有沃诺拉赞的盐相比，具有许多令人满意的优点，比如溶解性和稳定性良好、提高了生物利用度和协同增加药效等。

Description

一种沃诺拉赞盐及其制备方法与用途 技术领域
本发明属于化学药物领域，具体涉及一种具有质子泵抑制作用的吡咯化合物的盐，更具体的涉及沃诺拉赞与有机酸和铋的络合物所形成的盐，及其制备方法与用途。
背景技术
胃酸相关性疾病是一类由于胃酸分泌过多或对胃酸特别敏感而引起的疾病，如消化性溃疡、胃食管返流及非甾体类抗炎药物引起的消化系统病等。目前治疗胃酸分泌过多的最强药物是质子泵抑制剂(PPI)，例如奥美拉唑、兰索拉唑等。但该类药物存在着严重缺陷：夜间会发生酸反跳现象，影响治疗效果。钾离子竞争性酸阻滞剂(P-CAB)类药物(如沃诺拉赞)的出现很好的解决了这一类问题，通过竞争性抑制质子泵(H +，K +-ATPase)中K +而起作用，临床上可明显减少夜间酸反跳现象的发生。
沃诺拉赞，其化学名为1-[5-(2-氟苯基)-1-(吡咯-3-基磺酰基)-1H-吡咯-3-基]-N-甲基甲胺，结构式如式I所示。沃诺拉赞由武田制药公司研制，是全球第一个可逆的钾离子竞争性酸阻滞剂(P-CAB)。2015年2月，沃诺拉赞在日本批准上市，上市盐型为富马酸盐，上市剂型为片剂。
Figure PCTCN2020106149-appb-000001
体外实验研究表明沃诺拉赞抑制质子泵的能力是常规质子泵抑制剂兰索拉唑的400倍，其相对于Na +、K +-ATPase的抑制选择性在1000倍以上，可有效地抑制胃酸分泌。沃诺拉赞具有抑制胃酸分泌强劲、持久、起效快等特点，是新一代的抗胃酸分泌药物。但现上市药物沃诺拉赞富马酸盐的水溶性差，动物口服生物利用度仅10％，限制了该化合物发挥其抑酸和治疗胃酸相关性疾病的作用。因此人们尝试合成式I化合 物的盐，希望能改善其水溶性及提高其生物利用度，以便更好的发挥该化合物的临床应用价值。公开号为CN105693693A的中国专利申请，公开了沃诺拉赞的各种有机酸或无机酸的盐，如富马酸盐、醋酸盐、甲磺酸盐、硫酸盐、磷酸盐、L-苹果酸盐、枸橼酸盐。公开号为CN107759568A的中国专利申请，公开了沃诺拉赞双盐酸盐、双磷酸盐、苯磺酸盐、1，4-丁二酸磺酸半盐、2-羟基乙磺酸盐和L-酒石酸盐等。上述专利申请对不同的沃诺拉赞酸盐的溶解度和稳定性进行了考察，但并没有对各盐的生物活性及其生物利用度进行研究。由于化合物的生物活性及生物利用度将直接影响到药物剂型的开发和临床应用，因此开发一种沃诺拉赞的新型盐以提高其生物利用度是十分必要的。
发明内容
为解决上述技术问题，本发明进一步对沃诺拉赞成盐进行了研究，提供了一种沃诺拉赞与有机酸和铋的络合物所形成的盐，其与现有的沃诺拉赞的盐相比，提高了生物利用度。
进一步，本发明提供的沃诺拉赞与有机酸和铋的络合物所形成的盐，溶解性和稳定性良好，具有协同增加药效的作用等。
根据本发明的另一个方面，提供一种沃诺拉赞与有机酸和铋的络合物所形成的盐的制备方法。
根据本发明的另一方面，还提供一种沃诺拉赞盐在制备治疗胃酸相关疾病药物方面的应用。
本发明之沃诺拉赞盐，为沃诺拉赞与有机酸和铋的络合物所形成的盐。
进一步，所述有机酸和铋的络合物为枸橼酸和铋的络合物，或有机酸和铋的络合物为酒石酸和铋的络合物。
沃诺拉赞与枸橼酸和铋的络合物所形成的盐，其结构式如下式II所示：
Figure PCTCN2020106149-appb-000002
沃诺拉赞与酒石酸和铋的络合物所形成的盐，其结构式如下式III所示：
Figure PCTCN2020106149-appb-000003
本发明之沃诺拉赞盐的制备方法，包括以下步骤：
步骤一：将有机酸和铋的络合物和沃诺拉赞加入到溶剂I中，加热搅拌至完全溶解；
步骤二：除去溶剂I，得到油状物；
步骤三：将步骤二中得到的油状物再加入溶剂II中进行打浆，析出白色固体，抽滤，得沃诺拉赞盐。
枸橼酸和铋的络合物、或酒石酸和铋的络合物，分子量较大，又为弱酸，且难溶；沃诺拉赞为弱碱，其与有机酸特别是弱有机酸成盐，酸碱中和作用较弱，空间位阻比较大，反应难度比较大。因此，目前现有技术中没有任何关于将具有质子泵抑制作用的吡咯化合物沃诺拉赞与有机酸铋络合成盐的报道。而本发明打破了现有技术中这一技术壁垒，制得一种沃诺拉赞与有机酸和铋的络合物所形成的盐。
进一步，步骤一中的溶剂I为醇类与水的混合溶剂。步骤三中的溶剂II为乙酸乙酯与醇类的混合溶剂。醇类包括甲醇、乙醇、丙醇或异丙醇中的至少一种。
进一步，有机酸和铋的络合物，与沃诺拉赞的摩尔比为1:1.1～3.0(优选1:1.2～2.5)。
研究表明，沃诺拉赞的加入量越多，反应越快，但是多余的沃诺拉赞是通过用溶剂II打浆除掉的，沃诺拉赞加得太多，反应快速，但是会造成原料的浪费，后处理打浆次数多才能除去；沃诺拉赞加得少，反应速度较慢，但是原料浪费少，打浆纯化更容易。
进一步，溶剂I中，醇类与水的体积比为1：0.2～1(更优选1：0.3～0.5)。
选择醇类与水的混合溶剂，主要原因是，有机酸和铋的络合物不溶于醇类与水的 混合溶剂，但沃诺拉赞与有机酸和铋的络合物所形成的盐能溶于此混合溶剂，选择此混合溶剂，有利于判断反应是否完成(有机酸和铋的络合物反应完全后，不再悬浮于混合溶剂中，溶解完全，提示为反应终点)。而且醇类与水也很容易除去，使用也较安全。
进一步，步骤一中，将有机酸和铋的络合物和沃诺拉赞加入到溶剂I中，加热到30℃以上(优选32～50℃，更优选35℃)。优选反应2h以上，更优选反应3～5h。
进一步，溶剂II中，乙酸乙酯与醇类的体积比为1:0.5～3，优选1：1～1.5。
选择乙酸乙酯和醇类的混合溶剂打浆，目的是除去过量的沃诺拉赞；通过调节乙酸乙酯和醇类的比例，既能很好的除去过量的沃诺拉赞，又能减少产品的损失。
进一步，步骤三中，打浆的时间为0.5～3小时，更优选1小时。
进一步，所述有机酸和铋的络合物为枸橼酸和铋的络合物时，其制备方法基于以下路线：
Figure PCTCN2020106149-appb-000004
具体包括以下步骤：
将枸橼酸铋钾IV加入水中，用强酸调节pH至2～3，搅拌析出白色固体，抽滤，得枸橼酸和铋的络合物V。
进一步，所述强酸为硫酸、硝酸、盐酸等中的至少一种。
进一步，所述有机酸和铋的络合物为酒石酸和铋的络合物时，其制备方法基于以下路线：
Figure PCTCN2020106149-appb-000005
酒石酸和铋的络合物的合成方法，具体包括以下步骤：
(一)化合物VII酒石酸铋钾的合成：
将硝酸铋加入到水中，滴加强碱的水溶液，使得pH为2～3，抽滤得白色固体，将白色固体加入到水中，滴加强碱的水溶液，调节反应体系pH为8～9，抽滤，滤饼用水洗，所得白色固态物加入到水中，再加入化合物VI酒石酸铵，升温反应，反应完毕后用强碱的水溶液调节pH为9～10，再加热反应，冷却抽滤，滤液加入乙醇中，搅拌，析出白色固体，即为化合物VII酒石酸铋钾；优选的，所述升温反应，升温到55～60℃反应2h以上；所述加热反应，加热温度控制在45～50℃反应1h以上；所述强碱为氢氧化钾，优选强碱的水溶液质量浓度为20～30％；硝酸铋与酒石酸铵的摩尔比为1：3～4(优选1：3.1～3.5)。
(二)化合物VIII酒石酸和铋的络合物的合成：
将化合物VII酒石酸铋钾加入到水中，溶解后用强酸调节pH为2～3，析出白色固体，抽滤，得白色固体产品，即为化合物VIII酒石酸和铋的络合物。优选地，所述强酸为硫酸、硝酸、盐酸等中的至少一种。
本发明之沃诺拉赞盐，可以应用于制备用于预防或治疗胃酸类疾病的药物，如胃酸过多而引起的相关疾病，包括糜烂性食管炎、胃溃疡、十二指肠溃疡、幽门螺杆菌病等。
本发明具有以下有益效果：
本发明制得的沃诺拉赞新型盐，为沃诺拉赞与有机酸和铋的络合物所形成的盐，尤其是沃诺拉赞与枸橼酸和铋的络合物或酒石酸和铋的络合物所形成的盐，是一种新的化合物，其与两种活性成分通过简单的物理混合得到的混合物截然不同，该新型盐具有独特的理化特性及抑制胃酸分泌和保护黏膜的双重作用，具有较好的水溶性，比如本申请中沃诺拉赞与酒石酸和铋的络合物所形成的盐在水中的饱和溶解度为2.40mg/mL(25℃)，而两者的物理混合物几乎不溶解。此外，其与现有的沃诺拉赞的盐相比，具有许多令人满意的优点，溶解性和稳定性良好、提高了生物利用度和协同增加药效等，比如与现有已上市的沃诺拉赞富马酸盐相比，本申请制得的沃诺拉赞新型盐生物利用度提高了48％以上。
除了上面所描述的目的、特征和优点之外，本发明还有其它的目的、特征和优点。下面将参照图，对本发明作进一步详细的说明。
附图说明
构成本申请的一部分的附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1是本发明实施例3的大鼠口服不同药物的C-T曲线。
具体实施方式
以下结合附图对本发明的实施例进行详细说明，但是本发明可以由下述所限定和覆盖的多种不同方式实施。
本说明书中，除另有说明的外，所述百分比均为质量百分比。
实施例1
本实施例制备沃诺拉赞与枸橼酸和铋的络合物所形成的盐。
1、沃诺拉赞与枸橼酸和铋的络合物所形成的盐的化学式为C 29H 29BiFN 3O 16S，分子量为935.59；其分子结构如下式II所示：
Figure PCTCN2020106149-appb-000006
2、本实施例之沃诺拉赞与枸橼酸和铋的络合物所形成的盐的制备方法，其合成路线如下：
Figure PCTCN2020106149-appb-000007
具体包括以下步骤：
(一)沃诺拉赞可通过市售途径取得，或通过现有技术合成得到。
化合物IX为沃诺拉赞的富马酸盐。DCM为二氯甲烷。
本实施例中化合物I沃诺拉赞的合成方法如下：
将化合物IX(4.0g，8.67mmol，1.0eq)加入到20mL水和20mL DCM的混合液中，保持温度为25℃，用饱和NaHCO 3溶液调节水相pH为8，分液，水相再用DCM萃取，每次20mL，萃取2次，有机相合并，用无水硫酸钠干燥，旋除溶剂，得淡黄色油状物沃诺拉赞2.99g。
结构表征： 1H NMR(400MHz,DMSO)δ8.86(dd,J＝4.8,1.3Hz,1H),8.57(d,J＝2.1Hz,1H),7.95–7.84(m,1H),7.61(dd,J＝8.1,4.9Hz,1H),7.56–7.41(m,2H),7.31–7.20(m,2H),7.14(td,J＝7.4,1.6Hz,1H),6.37(d,J＝1.4Hz,1H),3.46(s,2H),2.21(s,3H).
证明得到的是沃诺拉赞化合物。
(二)化合物V枸橼酸和铋的络合物的合成
在温度为25℃的条件下，将化合物IV枸橼酸铋钾(5.00g，7.1mmol，1.0eq)加入到20mL水中，用2M(mol/L)的硫酸调节pH到2，析出白色固体，抽滤，得白色固体产品3.50g，母液放置2h后，又析出一些白色固态，抽滤，得白色体产品0.50g，收率95.5％。 1H NMR(400MHz,D 2O)δ2.51(d,J＝47.2Hz,8H).
(三)化合物II沃诺拉赞与枸橼酸和铋的络合物所形成的盐的合成：
将化合物IV(1.40g，2.4mmol，1.0eq)和化合物I(1.00g，2.9mmol，1.22eq)加入到10mL乙醇和4mL水的混合溶剂中，加热到35℃反应2h，溶解完后再搅拌0.5h，旋除溶剂，加入6mL乙酸乙酯和6mL异丙醇的混合溶剂打浆1h，慢慢析出白色固体，抽滤，得白色固体产品1.50g，即为化合物II沃诺拉赞与枸橼酸和铋的络合物所形成的盐，收率67.6％。
结构表征： 1H NMR(400MHz,DMSO)δ8.88(d,J＝4.1Hz,1H),8.55(s,1H),7.90(d,J＝8.6Hz,1H),7.74(s,1H),7.68–7.60(m,1H),7.52(d,J＝6.2Hz,1H),7.22(t,J＝8.0Hz,2H),7.11(t,J＝6.9Hz,1H),6.49(s,1H),3.90(s,2H),2.54(d,J＝43.9Hz,8H),2.45(s,3H).通过将该核磁氢谱与沃诺拉赞氢谱对比，该成盐化合物具有非常明显的光谱峰的移动，成盐后氮原子旁边的亚甲基氢的位移值从3.46ppm移动到了3.90ppm，甲基氢的位移值从2.21ppm移到2.45ppm，说明此化合物已经成盐。
以沃诺拉赞作为标准品，通过HPLC测得购买的沃诺拉赞富马酸盐(1：1)中沃诺拉赞含量为74.87％(理论值69.4％)，采用同样的方法测得化合物II中沃诺拉赞含量为40.90％(1:1成盐理论值37.0％)。
实施例2
本实施例制备沃诺拉赞与酒石酸和铋的络合物所形成的盐。
1、沃诺拉赞与酒石酸和铋的络合物所形成的盐的化学式为C 29H 31BiFN 3O 20S，分子量为1001.61；其分子结构如下式III所示：
Figure PCTCN2020106149-appb-000008
2、本实施例之沃诺拉赞与酒石酸和铋的络合物所形成的盐的制备方法，其合成路线如下：
Figure PCTCN2020106149-appb-000009
具体包括以下步骤：
(一)化合物VII酒石酸铋钾的合成：
将硝酸铋(6.0g，15.2mmol，1.0eq)加入到30mL水中，搅拌30min，滴加25wt％KOH水溶液6.16g，测得pH为2，继续搅拌30min，抽滤得白色固体，将白色固体加入到20mL水中，滴加质量浓度为25wt％的KOH水溶液，调节反应体系pH为8，搅拌30min， 抽滤，滤饼用水洗，所得白色固态物加入到28mL水中，再加入化合物VI酒石酸铵(8.96g，48.6mmol，3.2eq)，升温到60℃反应2h，反应完毕后冷却到室温，用25wt％KOH水溶液调节pH为9，再在45℃反应1h，冷却抽滤，滤液加入80mL乙醇中，搅拌，析出大量白色固体，抽滤，干燥得白色固体产品9.25g，即为化合物VII酒石酸铋钾，收率79.0％， 1H NMR(400MHz,D 2O)δ4.36(s,6H).
(二)化合物VIII酒石酸和铋的络合物的合成：
将化合物VII酒石酸铋钾(1.0g，1.3mmol，1.0eq)加入到8mL水中，溶解后用2M(mol/L)的硫酸调节pH为2，析出白色固体，抽滤，得白色固体产品0.35g，即为化合物VIII酒石酸和铋的络合物，收率41.1％。
(三)化合物III沃诺拉赞与酒石酸和铋的络合物所形成的盐的合成
将化合物VIII酒石酸和铋的络合物(100mg，152umol，1.0eq)和化合物I沃诺拉赞(120mg，347umol，2.3eq)加入到5mL乙醇和2mL水的混合溶剂中，加热到35℃反应3h，溶解完全，旋除溶剂，加入5mL乙酸乙酯和5mL异丙醇的混合溶剂打浆1h，慢慢析出白色固体，抽滤，得白色固体产品120mg，即为化合物III沃诺拉赞与酒石酸和铋的络合物所形成的盐，收率78.9％。
结构表征： 1H NMR(400MHz,D2O)δ8.69(d,J＝4.7Hz,1H),8.41(s,1H),7.86(s,1H),7.47(dd,J＝20.8,13.6Hz,3H),7.18–7.02(m,3H),6.36(s,1H),4.27(s,6H),3.56(s,2H),2.23(s,3H).通过将该核磁氢谱与沃诺拉赞氢谱对比，该成盐化合物具有非常明显的光谱峰的移动，成盐后氮原子旁边的亚甲基氢的位移值从3.46ppm移动到了3.56ppm，甲基氢的位移值从2.21ppm移到2.23ppm，说明此化合物已经成盐。
以沃诺拉赞作为标准品，通过HPLC测得购买的沃诺拉赞富马酸盐中沃诺拉赞含量74.87％(理论值69.4％)，同样的方法测得化合物III中沃诺拉赞含量35.51％(1:1成盐理论值34.48％)。
实施例3
生物活性药代动力学测试
试验测试药物：HYH2002001(对照组1，市售沃诺拉赞富马酸盐)、HYH2002002(实施例1，沃诺拉赞与枸橼酸和铋的络合物所形成的盐)、HYH2002004(实施例2，沃诺拉赞与酒石酸和铋的络合物所形成的盐)、HYH2002005(对照组2，市售枸橼酸 铋钾与沃诺拉赞富马酸盐按照1：1的摩尔比进行物理混合)；
实验方法：雄性SD大鼠(200-250g)60只，随机分成四组，分别灌胃给予HYH2002001(8.4g·kg-1)、HYH2002002(15.4g·kg-1)、HYH2002004(17.7g·kg-1)，HYH2002005(23.4g·kg-1)，其中HYH2002001及HYH2002002、HYH2002004、HYH2002005为等摩尔沃诺拉赞给药，给药体积为5ml·kg-1。分别于给药后5min，15min，30min，45min，1h，1.5h，2h，4h，8h时间点取血，离心取血浆，检测血浆中沃诺拉赞浓度。实验结果见表1和图1。图1是本发明实施例3的大鼠口服不同药物的C-T曲线。纵座标表示检测得到的血浆中沃诺拉赞浓度。
表1 大鼠口服HYH2002001与HYH2002002、HYH2002004、HYH2002005的药代动力学参数(Mean±SD)
Figure PCTCN2020106149-appb-000010
AUCINF_pred(h*ng/mL)表示从给药开始到理论外推无穷远的时间下面积。
实验结论：根据实验结果得出以下结论1.HYH2002001与HYH2002002、HYH2002004、HYH2002005的半衰期相差不大,Tmax达峰时间和整体曲线走势一致，说明药物吸收代谢时间类似。
2.HYH2002001、HYH2002002、HYH2002004、HYH2002005的AUClast(h*ng/mL)分别为116.5、172.5、178.6、133.7，与HYH2002001相比，HYH2002002的AUC提高了48％，HYH2002004的AUC提高了53.3％，HYH2002005的AUC提高了14.8％，说明与HYH2002001相比，HYH2002002、HYH2002004和HYH2002005都改善了药代动力学性质，提高了沃诺拉赞的生物利用度，特别是HYH2002002、HYH2002004显著提高了沃诺拉赞的生物利 用度。
实施例4
高温稳定性考察步骤：将富马酸盐、枸橼酸铋盐、酒石酸铋盐分别置于高温60℃下，再分别检测其在高温60℃下0h、4h、8h、24h的峰面积和活性成份含量(活性成份含量以富马酸盐0h时候的检测数据为基准，定为100)，结果见表2。
光照稳定性考察步骤：将富马酸盐、枸橼酸铋盐、酒石酸铋盐分别置于光照(4500Lux)下，再分别检测其在光照(4500Lux)下0h、4h、8h、24h的峰面积和活性成份含量(活性成份含量以富马酸盐0h时候的检测数据为基准，定为100)，结果见表2。
计算方法：外标法。
富马酸盐表示沃诺拉赞的富马酸盐。
枸橼酸铋盐表示本发明的沃诺拉赞与枸橼酸和铋的络合物所形成的盐。
酒石酸铋盐表示本发明的沃诺拉赞与酒石酸和铋的络合物所形成的盐。
表2 稳定性测试结果
Figure PCTCN2020106149-appb-000011
结论：高温、光照不同时间点下，各样品均无明显新增杂质产生；以0h主峰面积为100％，外标法计算，不同时间点下沃诺拉赞主峰含量均无明显变化，说明主成分无明显降解。综上，在60℃高温或4500Lux光照条件下，各沃诺拉赞盐在24h内均保持稳定。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种沃诺拉赞盐，其特征在于，为沃诺拉赞与有机酸和铋的络合物所形成的盐。
  2. 根据权利要求1所述的沃诺拉赞盐，其特征在于，有机酸和铋的络合物为枸橼酸和铋的络合物，或有机酸和铋的络合物为酒石酸和铋的络合物。
  3. 根据权利要求2所述的沃诺拉赞盐，其特征在于，
    沃诺拉赞与枸橼酸和铋的络合物所形成的盐，其结构式如下式II所示：
    Figure PCTCN2020106149-appb-100001
  4. 根据权利要求2所述的沃诺拉赞盐，其特征在于，
    沃诺拉赞与酒石酸和铋的络合物所形成的盐，其结构式如下式III所示：
    Figure PCTCN2020106149-appb-100002
  5. 制备如权利要求1－4之一所述的沃诺拉赞盐的方法，其特征在于，包括以下步骤：
    步骤一：将有机酸和铋的络合物和沃诺拉赞加入到溶剂I中，加热搅拌至完全溶解；
    步骤二：除去溶剂I，得到油状物；
    步骤三：将步骤二中得到的油状物再加入溶剂II中进行打浆，析出白色固体，抽滤， 得沃诺拉赞盐。
  6. 根据权利要求5所述的制备沃诺拉赞盐的方法，其特征在于，所述步骤一中的溶剂I为醇类与水的混合溶剂，所述步骤三中的溶剂II为乙酸乙酯与醇类的混合溶剂。
  7. 根据权利要求6所述的制备沃诺拉赞盐的方法，其特征在于，醇类包括甲醇、乙醇、丙醇或异丙醇中的至少一种。
  8. 根据权利要求6或7所述的制备沃诺拉赞盐的方法，其特征在于，所述有机酸和铋的络合物为枸橼酸和铋的络合物，其制备方法基于以下路线：
    Figure PCTCN2020106149-appb-100003
    具体包括以下步骤：
    将枸橼酸铋钾IV加入水中，用强酸调节pH至2～3，搅拌析出白色固体，抽滤，得枸橼酸和铋的络合物V。
  9. 根据权利要求6或7所述的制备沃诺拉赞盐的方法，其特征在于，所述有机酸和铋的络合物为酒石酸和铋的络合物，其制备方法基于以下路线：
    Figure PCTCN2020106149-appb-100004
    酒石酸和铋的络合物的合成方法，具体包括以下步骤：
    (一)化合物VII酒石酸铋钾的合成：
    将硝酸铋加入到水中，滴加强碱的水溶液，使得pH为2～3，抽滤得白色固体，将白色固体加入到水中，滴加强碱的水溶液，调节反应体系pH为8～9，抽滤，滤饼用水洗，所得白色固态物加入到水中，再加入化合物VI酒石酸铵，升温反应，反应完毕后用强碱的水溶液调节pH为9～10，再加热反应，冷却抽滤，滤液加入乙醇中，搅拌，析出白色固体，即为化合物VII酒石酸铋钾；
    (二)化合物VIII酒石酸和铋的络合物的合成：
    将化合物VII酒石酸铋钾加入到水中，溶解后用强酸调节pH为2～3，析出白色固体，抽滤，得白色固体产品，即为化合物VIII酒石酸和铋的络合物。
  10. 如权利要求1－4之一所述的沃诺拉赞盐，其在制备用于预防或治疗胃酸类疾病药物中的用途。
PCT/CN2020/106149 2020-07-13 2020-07-31 一种沃诺拉赞盐及其制备方法与用途 WO2022011752A1 (zh)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN105693693A (zh) * 2014-11-27 2016-06-22 江苏柯菲平医药股份有限公司 一种吡咯类胃酸分泌和抑制剂化合物盐的制备
CN107759568A (zh) * 2016-08-22 2018-03-06 四川海思科制药有限公司 沃诺拉赞盐、晶型及其制备方法和用途
CN110366415A (zh) * 2017-10-15 2019-10-22 消化系统疾病中心 用于治疗、减轻和预防幽门螺杆菌感染的组合物和方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105693693A (zh) * 2014-11-27 2016-06-22 江苏柯菲平医药股份有限公司 一种吡咯类胃酸分泌和抑制剂化合物盐的制备
CN107759568A (zh) * 2016-08-22 2018-03-06 四川海思科制药有限公司 沃诺拉赞盐、晶型及其制备方法和用途
CN110366415A (zh) * 2017-10-15 2019-10-22 消化系统疾病中心 用于治疗、减轻和预防幽门螺杆菌感染的组合物和方法

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