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WO2018014277A1 - 罗替戈汀山嵛酸酯及其制备方法和用途 - Google Patents

罗替戈汀山嵛酸酯及其制备方法和用途 Download PDF

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Publication number
WO2018014277A1
WO2018014277A1 PCT/CN2016/090803 CN2016090803W WO2018014277A1 WO 2018014277 A1 WO2018014277 A1 WO 2018014277A1 CN 2016090803 W CN2016090803 W CN 2016090803W WO 2018014277 A1 WO2018014277 A1 WO 2018014277A1
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Prior art keywords
rotigotine
rotigotine behenate
behenate
degrees
crystal form
Prior art date
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PCT/CN2016/090803
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English (en)
French (fr)
Inventor
杨米娜
姜永涛
孟莹
王涛
徐钱钱
邵馨
沙春洁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong Luye Pharmaceutical Co Ltd
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Shandong Luye Pharmaceutical Co Ltd
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Priority to PL16909205T priority Critical patent/PL3489227T3/pl
Priority to CA3030043A priority patent/CA3030043C/en
Priority to SG11201811543XA priority patent/SG11201811543XA/en
Priority to JP2019524492A priority patent/JP6751208B2/ja
Priority to PCT/CN2016/090803 priority patent/WO2018014277A1/zh
Priority to RU2018146096A priority patent/RU2717542C9/ru
Priority to EP16909205.3A priority patent/EP3489227B1/en
Priority to MYPI2018002909A priority patent/MY195897A/en
Priority to AU2016415408A priority patent/AU2016415408B2/en
Priority to BR112019001035-1A priority patent/BR112019001035A2/pt
Priority to CN201680087177.7A priority patent/CN109415335B/zh
Priority to US16/309,807 priority patent/US10669249B2/en
Application filed by Shandong Luye Pharmaceutical Co Ltd filed Critical Shandong Luye Pharmaceutical Co Ltd
Priority to ES16909205T priority patent/ES2855976T3/es
Priority to KR1020197005257A priority patent/KR20190031314A/ko
Publication of WO2018014277A1 publication Critical patent/WO2018014277A1/zh
Priority to PH12018550212A priority patent/PH12018550212A1/en
Anticipated expiration legal-status Critical
Priority to US16/860,037 priority patent/US11111227B2/en
Ceased legal-status Critical Current

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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
    • C07D333/10—Thiophene
    • 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

Definitions

  • the invention relates to a rotigotine derivative, a preparation method and a use thereof, in particular to a rotigotine long-chain ester, a preparation method thereof and use thereof.
  • Rotigotine is a non-ergot-type selective dopamine receptor agonist that produces an anti-Parkinson effect by activating D3/D2/D1. Due to the first-pass effect of rotigotine, the oral bioavailability is extremely low (about 1%-5%), so it is not suitable for oral administration. At present, because Parkinson's disease can not be completely cured, it needs to rely on long-term treatment of drugs. Therefore, it is of great clinical significance to develop a simple preparation process, low cost, long-term stable release, and increased drug accessibility.
  • WO 2012068783 discloses a rotigotine microsphere preparation capable of maintaining an effective blood concentration for more than two weeks. Although the microsphere preparation can achieve the purpose of sustained stable release, there are problems in that the preparation process of the preparation is complicated and the product cost is high.
  • WO 2016014242 discloses a series of modified compounds of rotigotine, including a derivative of rotigotine and a saturated long-chain ester of 16 carbon or less, which solves the low blood concentration of rotigotine for oral administration.
  • the defect, but oral administration can not achieve the purpose of sustained stable release for more than two weeks.
  • the inventors have found through experiments that the rotigotine saturated long-chain esters such as rotigottin caprylate and Rotigo disclosed in WO 2016014242 are found.
  • the palmitate injection is administered, the blood concentration fluctuates greatly, and the effective blood concentration is maintained for a short period of time, and the long-term stable release of the drug cannot be achieved.
  • the inventors conducted intensive studies on other saturated and unsaturated long-chain esters of rotigotine, and surprisingly found that only rotigotine twenty-two carbon-saturated long-chain esters have both long-lasting effective blood concentration and bioavailability. High and long-term stable release, while saturated or unsaturated rotigotine long-chain esters with more or less than twenty-two carbons do not have the above-mentioned good effects.
  • the invention provides a rotigotine behenate and a preparation method and use thereof.
  • the rotigotine behenate provided by the present invention has the following structural formula:
  • the invention provides a method for preparing rotigotine behenate: reacting benyl chloride with rotigotine to obtain rotigotine behenate; or reacting behenic acid with rotigotine to obtain Rotigotine behenate; or the reaction of behenic anhydride with rotigotine to give rotigotine behenate.
  • the invention provides a method for preparing rotigotine behenate: adding rotigotine to a mixed solution of triethylamine and dichloromethane (DCM) under nitrogen protection at room temperature, and then adding hawthorn Acid chloride, complete reaction, washing, evaporation of solvent under reduced pressure, purification, to obtain rotigotine behenate; or behenic acid, rotigotine and dimethylaminopyridine p-methylbenzene under nitrogen protection at room temperature
  • DPTS sulfonate
  • DCM dichloromethane
  • DCC dicyclohexylcarbodiimide
  • Gentin behenate; or under the protection of nitrogen, behenic anhydride and rotigotine are dissolved in anhydrous tetrahydrofuran (THF), a catalytic amount of triethylamine is added, heated in an oil bath, and the reaction is completed, and steamed under reduced pressure.
  • dichloromethane (DCM) was added, and the mixture was washed with sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure and purified to give the s.
  • the rotigotine behenate crystal form (type I) has a powder X-ray diffraction pattern substantially as shown in FIG.
  • the rotigotine behenate crystal form (type I) has a TGA/DSC pattern substantially as shown in Figure 6.
  • the invention also provides a preparation method of rotigotine behenate crystal form (type I): dissolving rotigotine behenate in an organic solvent, cooling crystallization, suction filtration, washing,
  • the organic solvent is selected from one or more of ethyl acetate, ethanol, methanol, cyclohexane, n-hexane, petroleum ether, tetrahydrofuran, acetone, n-heptane.
  • the organic solvent is selected from one or more of ethyl acetate, ethanol, methanol, cyclohexane, n-hexane, petroleum ether, tetrahydrofuran, acetone, n-heptane.
  • methanol is added, the crystals are cooled, suction filtered, and washed with an appropriate amount of methanol.
  • Rotigotine behenate crystal form type II
  • the rotigotine behenate crystal form (type II) has a powder X-ray diffraction pattern substantially as shown in FIG.
  • the rotigotine behenate crystal form (Form II) has a TGA/DSC pattern substantially as shown in Figure 7.
  • the invention also provides a preparation method of rotigotine behenate crystal form (type II): placing rotigotine behenate in a mixed solvent of tetrahydrofuran and methanol, and suspending at 40 ° C Stirred.
  • the present invention provides a pharmaceutical composition comprising rotigotine behenate.
  • the pharmaceutical compositions provided herein are administered in a parenteral form, preferably by injection, more preferably intramuscularly or subcutaneously.
  • the rotigotine behenate pharmaceutical composition provided by the present invention can achieve a dosing interval of at least about two weeks.
  • the present invention provides a use of rotigotine behenate in the manufacture of a medicament for treating a disease associated with a dopamine receptor.
  • the rotigotine behenate provided by the present invention has a daily dose of 1 mg to 1000 mg in the treatment of the above related diseases.
  • the rotigotine behenate provided by the invention can reduce the fluctuation of blood concentration, improve the bioavailability of the drug in vivo, and achieve the effect of smooth release for more than two weeks.
  • FIG. 7 Example 4 Rotigotine behenate crystal form (type II) TGA/DSC pattern
  • Figure 8 Time-lapse plasma concentration-time curve of rotigotine after injection in rats of test example 1.
  • Example 2 After the rotigotine behenate prepared in Example 1 was thermally dissolved in ethyl acetate, methanol was added thereto, and the crystals were cooled, suction-filtered, and the filter cake was washed with an appropriate amount of methanol to obtain a white solid, which was determined by the following measurement method:
  • Test instrument PANalytical Empyrean X-ray powder diffraction analyzer.
  • Test conditions CuK ⁇ radiation, K ⁇ 1 :1.540598, K ⁇ 2 :1.544426 K ⁇ 2/K ⁇ 1; Intensity ratio: 0.50 X-ray tube setting: 45kV 40mA, divergence slit: automatic, scanning mode: continuous, scanning range (°2TH) 3°-40° scanning step (°2TH) 0.013 Scan rate (°/min) is approximately 10
  • TA Q200/Q2000 Differential Scanning Calorimeter method provided by TA Instruments: The sample was placed in an aluminum pan, and the cap was heated from room temperature to a set temperature at a rate of 10 ° C/min under N2 protection.
  • the XRPD data of the rotigotine behenate crystal form (type I) are shown in Table 1, the powder X-ray diffraction pattern is shown in Fig. 4, and the TGA/DSC is shown in Fig. 6.
  • the rotigotine behenate prepared in excess of the preparation of Example 1 was placed in a mixed solvent of 1:19 (v/v) tetrahydrofuran and methanol, and suspended and stirred at 40 ° C for 5 days to obtain Rotego. Tingshan phthalate crystal form (type II).
  • the TGA results showed that the weight loss was 3.1% when the sample was heated to 100 ° C, and three endothermic peaks were observed in the DSC chart, which were 30.9 ° C, 41.7 ° C, and 46.7 ° C (peak), respectively.
  • the XRPD data for the rotigotine behenate crystal form (type II) is shown in Table 2, the powder X-ray diffraction results are shown in Figure 5, and the TGA/DSC chart is shown in Figure 7.
  • the residue is purified by column chromatography to ethyl acetate: 1:3 (v/v) -
  • the petroleum ether system is a rinsing agent, yielding a white solid, 36.2 g, yield 65.3%, melting point 27-30 °C.
  • Test Example 1 Pharmacokinetic behavior of rotigotine octanoate injection in rats
  • the mean blood concentration (ng/mL) of rotigotine in rats at different time points is shown in Table 3.
  • the time-course blood concentration-time curve of rotigotine after injection in rats is shown in Figure 8. Show.
  • Test Example 2 Pharmacokinetic behavior of each drug injection in rats
  • HPMC HPMC was configured as a 1% concentration solvent, and other rotigotine oleate, rotigotine palmitate, and rotigotine stearate were separately formulated into a 10 mg/ml suspension (with rotigotine).
  • the rotigotine hydrochloride was formulated as a 0.36 mg/ml injection (calculated as rotigotine) in physiological saline.
  • mice were randomly divided into rotigotine oleate group (A), rotigotine palmitate group (B), rotigotine stearate group (C) and rotigotine hydrochloride group (D).
  • 3 rats in each group rats in group A, B, and C were intramuscularly injected with the corresponding drug 2ml/kg, and rats in group D were injected intravenously with the corresponding drug 2ml/kg.
  • Groups A, B, and C were given before administration (0h) and 0.25h, 1h, 6h, 1d, 2d, 3d, 5d, 7d, 9d, 11d, 14d, 16d, 18d, 21d, 24d after administration.
  • the blood was taken from the eyelids of 28 days, placed in heparinized EP tubes, and immediately centrifuged (3000 rpm) for 10 min. The plasma was separated and stored at -35 ° C for testing.
  • Group D drugs were given before administration (0h) and 3min, 10min, 0.25h, 0.5h, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h after administration, and the heparinized EP tube was taken. Medium, immediately centrifuged (3000 rpm) for 10 min, plasma was separated, and stored at -35 ° C for testing.
  • the blood concentration (ng/mL) of rotigotine in rats at different time points is shown in Table 4 and Table 5.
  • the time-dependent blood concentration-time curve of rotigotine after injection in rats is shown in the attached figure. 9 is shown.
  • Test Example 3 Pharmacokinetic behavior of each drug administered in a rat
  • Rotigotine arachidonic acid prepared according to Comparative Example 5;
  • Rotigotine behenate prepared according to Example 1;
  • HPMC was configured as a 1% solvent, and rotigotine oleate, rotigotine palmitate, and rotigotine stearate were formulated as a 10 mg/ml suspension (based on rotigotine) ).
  • Group A, B, and C drugs before administration (0h) and 0.25h, 1h, 6h, 1d, 2d, 3d, 5d, 7d, 9d, 11d, 14d, 16d, 18d, 21d, 25d, 28d after administration
  • Blood was taken from the eyelids of rats, 30d, 35d, 39d and 42d, placed in heparinized EP tubes, immediately centrifuged (3000 rpm) for 10 min, plasma was separated, and stored at -35 ° C for testing.
  • the blood concentration (ng/mL) of rotigotine in rats at different time points is shown in Table 6.
  • the time-course blood concentration-time curve of rotigotine after injection in rats is shown in Figure 10. .
  • the absolute bioavailability of Gottin lignin ester is 65.2%; the release of rotigotine behenate in vivo has no delay time, the effective blood concentration is stable and the maintenance time can reach more than two weeks, and the absolute bioavailability of intramuscular injection in rats The degree is 91.1%.
  • the rotigotine unsaturated acid ester such as oleate has a peak time in the body, a large fluctuation in blood concentration, and a short duration of effective blood concentration.
  • the octyl octanoate in rotigotine saturated acid ester peaks in the body in 1 hour, and the effective blood concentration in the body is kept short; the blood of rotigotine palmitate and stearate in other saturated long-chain esters
  • the concentration fluctuation is large, the effective blood concentration in the body is maintained for a short time, and the effective blood concentration cannot be maintained for more than two weeks.
  • the blood concentration of rotigotine arachidate and lignin ester is not fluctuating, it cannot be effective.
  • the plasma concentration is maintained for more than two weeks; and the absolute bioavailability of these rotigotine saturated or unsaturated long-chain esters is less than 70%; only the absolute bioavailability of rotigotine behenate is greater than 90%,
  • the fluctuation of blood drug concentration in the body is small, and the effective blood drug concentration maintenance time can reach more than two weeks, which can reduce the fluctuation of blood drug concentration, improve the bioavailability of the drug in vivo, and achieve the effect of smooth release for more than two weeks.

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Abstract

本发明涉及罗替戈汀山嵛酸酯及其制备方法和用途，并提供了罗替戈汀山嵛酸酯的制备方法，以及罗替戈汀山嵛酸酯化合物在治疗与多巴胺受体有关疾病的用途。罗替戈汀山嵛酸酯具体结构如下式Ｉ所示，罗替戈汀山嵛酸酯体内血药浓度波动小，有效血药浓度维持时间长，生物利用度高，可以达到长效平稳释放的效果。

Description

罗替戈汀山嵛酸酯及其制备方法和用途 技术领域
本发明涉及一种罗替戈汀衍生物及其制备方法和用途，具体涉及一种罗替戈汀长链酯及其制备方法和用途。
背景技术
罗替戈汀是一种非麦角类选择性多巴胺受体激动剂，通过激动D3/D2/D1而产生抗帕金森作用。由于罗替戈汀肝首过效应，口服生物利用度极低(约1％-5％)，所以不适合口服给药。目前由于帕金森病尚不能彻底治愈，需要依靠药物长期治疗，因此开发一种制备工艺简单，成本低，且长期稳定释放，增加药物可及性具有重要的临床意义。
WO 2012068783中公开一种有效血药浓度能够维持二周以上的罗替戈汀微球制剂，虽然该微球制剂可以达到持续稳定释放的目的，但存在制剂的制备工艺复杂，产品成本高等问题。
WO 2016014242中公开了一系列罗替戈汀的改构化合物，其中包括罗替戈汀与16个碳以下的饱和长链酯构成的衍生物，解决了罗替戈汀口服给药血药浓度低的缺陷，但口服给药无法实现二周以上持续稳定释放的目的，发明人经过试验，发现将WO 2016014242中披露的罗替戈汀饱和长链酯如罗替戈汀辛酸酯和罗替戈汀棕榈酸酯注射给药，其血药浓度波动大，维持有效血药浓度时间短，仍无法实现药物的长效稳定释放。
发明人针对罗替戈汀其他饱和与不饱和长链酯进行深入研究，惊奇地发现，只有罗替戈汀二十二个碳饱和长链酯同时具备有效血药浓度维持时间长、生物利用度高和长效稳定释放，而多于或少于二十二个碳的饱和或不饱和罗替戈汀长链酯均不同时具备上述良好效果。
发明内容
本发明提供了一种罗替戈汀山嵛酸酯及其制备方法和用途。
本发明提供的罗替戈汀山嵛酸酯，结构式如下所示：
Figure PCTCN2016090803-appb-000001
本发明提供的罗替戈汀山嵛酸酯的制备方法：将山嵛酰氯和罗替戈汀反应，得罗替戈汀山嵛酸酯；或者将山嵛酸和罗替戈汀反应，得罗替戈汀山嵛酸酯；或者将山嵛酸酐和罗替戈汀反应，得罗替戈汀山嵛酸酯。
本发明提供的一种罗替戈汀山嵛酸酯的制备方法：在室温氮气保护下，将罗替戈汀加入到三乙胺和二氯甲烷(DCM)的混合溶液中，再加入山嵛酰氯，反应完全，洗涤，减压蒸除溶剂，纯化，得罗替戈汀山嵛酸酯；或者在室温氮气保护下，将山嵛酸、罗替戈汀和二甲氨基吡啶对甲基苯磺酸盐(DPTS)溶于二氯甲烷(DCM)中，滴加二环己基碳二亚胺(DCC)至上述混合溶液，反应完成后抽滤，减压蒸除溶剂，纯化，得罗替戈汀山嵛酸酯；或者在氮气保护下，将山嵛酸酐和罗替戈汀溶于无水四氢呋喃(THF)中，加入催化量三乙胺，油浴加热，反应完全后，减压蒸除溶剂，加入二氯甲烷(DCM)，以碳酸氢钠溶液洗涤，减压蒸除溶剂，纯化，得罗替戈汀山嵛酸酯。
本发明提供了一种罗替戈汀山嵛酸酯晶型(I型)，其通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838(±0.2度2θ)处具有特征峰。
罗替戈汀山嵛酸酯晶型(I型)，其通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838、16.154、19.403、11.749、14.518和17.875(±0.2度2θ)处具有特征峰。
罗替戈汀山嵛酸酯晶型(I型)，其通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838、16.154、19.403、11.749、14.518、17.875、19.729、20.299、13.583、11.962、22.949、23.772、16.424、15.749、12.586和22.430(±0.2度2θ)处具有特征峰。
罗替戈汀山嵛酸酯晶型(I型)，其通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838、16.154、19.403、11.749、14.518、17.875、19.729、20.299、13.583、11.962、22.949、23.772、16.424、15.749、12.586、22.430、12.238、23.995、18.626、16.614、28.574、24.530、25.169、27.044、36.329、27.764、29.127和31.490(±0.2度2θ)处具有特征峰。
罗替戈汀山嵛酸酯晶型(I型)具有基本如图4所示的粉末X射线衍射图谱。
罗替戈汀山嵛酸酯晶型(I型)具有基本如图6所示的TGA/DSC图谱。
本发明还提供了一种罗替戈汀山嵛酸酯晶型(I型)的制备方法：将罗替戈汀山嵛酸酯在有机溶剂中溶解、冷却结晶、抽滤、洗涤制得，其中所述有机溶剂选自乙酸乙酯、乙醇、甲醇、环己烷、正己烷、石油醚、四氢呋喃、丙酮、正庚烷中一种或多种。优选地，将罗替戈汀山嵛酸酯以乙酸乙酯热溶解后，加入甲醇，冷却结晶，抽滤，再以适量甲醇洗涤制得。
本发明提供了一种罗替戈汀山嵛酸酯晶型(II型),其通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.481、23.887(±0.2度2θ)处具有特征峰。
罗替戈汀山嵛酸酯晶型(II型)，其通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝3.274、21.481、23.887(±0.2度2θ)处具有特征峰。
罗替戈汀山嵛酸酯晶型(II型)具有基本如图5所示的粉末X射线衍射图谱。
罗替戈汀山嵛酸酯晶型(II型)具有基本如图7所示的TGA/DSC图谱。
本发明还提供了一种罗替戈汀山嵛酸酯晶型(II型)的制备方法：将罗替戈汀山嵛酸酯置于四氢呋喃和甲醇的混合溶剂中，在40℃条件下悬浮搅拌制得。
本发明提供了一种含有罗替戈汀山嵛酸酯的药物组合物。特别地，本发明提供的药物组合物以胃肠外形式给药，优选为注射给药，更优选为肌肉注射或皮下注射。
本发明提供的罗替戈汀山嵛酸酯药物组合物可以实现至少约二周的给药间隔。
本发明提供了一种罗替戈汀山嵛酸酯在制备治疗与多巴胺受体有关疾病的药物中的用途。特别是罗替戈汀山嵛酸酯在制备治疗帕金森氏病的药物中的用途。
本发明提供的罗替戈汀山嵛酸酯在治疗上述有关疾病时，每日剂量为1mg至1000mg。
本发明提供的罗替戈汀山嵛酸酯能够减少血药浓度波动，提高药物的体内生物利用度、达到两周以上平稳释放的效果。
附图说明
图1：实施例1罗替戈汀山嵛酸酯1H核磁图谱
图2：实施例1罗替戈汀山嵛酸酯13C核磁图谱
图3：实施例1罗替戈汀山嵛酸酯红外图谱
图4：实施例3罗替戈汀山嵛酸酯晶型(I型)粉末X射线衍射图
图5：实施例4罗替戈汀山嵛酸酯晶型(II型)粉末X射线衍射图
图6：实施例3罗替戈汀山嵛酸酯晶型(I型)TGA/DSC图谱
图7：实施例4罗替戈汀山嵛酸酯晶型(II型)TGA/DSC图谱
图8：试验例1大鼠注射给药后罗替戈汀的经时血药浓度-时间曲线
图9：试验例2大鼠注射给药后罗替戈汀的经时血药浓度-时间曲线
图10：试验例3大鼠注射给药后罗替戈汀的经时血药浓度-时间曲线
具体实施方式
以下实施例用以更详细地说明本发明，但不以任何形式限制本发明。
实施例1：罗替戈汀山嵛酸酯
Figure PCTCN2016090803-appb-000002
室温氮气保护下,将34.1g(0.1mol)山嵛酸溶于300ml二氯甲烷(DCM)中，滴加12.7g(0.1mol)草酰氯至混和溶液，待反应完全，为溶液1；将31.5g(0.1mol)罗替戈汀溶于15.2g(0.15mol)三乙胺和300ml二氯甲烷(DCM)的混合溶液，为溶液2；滴加溶液1至溶液2中；待反应完全后，用等体积水洗涤上述反应液，有机相减压蒸除溶剂；剩余物经过柱层析纯化，以1:3(v/v)乙酸乙酯-石油醚体系为淋洗剂，得类白色固体44.2g，熔点48-52℃，收率69.0％。图1和图2分别是化合物的1H核磁图谱、13C核磁图谱，图3是化合物的红外图谱。
Figure PCTCN2016090803-appb-000003
核磁共振图谱归属
1H NMR(CDCl3,400MHz)δH:7.12(m,2H,H-7&H-14),6.98(d,J＝7.40Hz,1H,H-6),6.92(q,J＝3.44,5.04Hz,1H,H-15),6.82(d,J＝7.28Hz,2H,H-8&H-13),3.01(m 4H,H-1&H-4),2.81(m,4H,H-19&H-20),2.54(m,5H,H-2,H-16&H-22),2.08(m,1H,H-3),1.76(m,2H,H-23),1.58(m,1H,H-3),1.39(m,2H,H-41),1.26(m,36H,H-17,H-24～H-40),0.88(m,6H,H-18&H-42)。
13C NMR(CDCl3,100MHz)δC:172.0(C-21),148.9(C-5),143.1(C-12),138.8(C-9),128.7(C-10),127.1(C-15),126.5(C-7),126.2(C-13),124.5(C-14),123.1(C-8),119.0(C-6),56.4(C-2),52.6(2C,C-19&C-16),34.2(C-22),32.1(C-40),31.9(C-20),30.1(C-1),29.2-29.7(C-24～C-39),25.3(C-3),25.1(C-23),24.1(C-4),22.7(C-41),22.3(C-17),14.1(C-42),11.9(C-18)
实施例2：罗替戈汀山嵛酸酯
Figure PCTCN2016090803-appb-000004
0℃氮气保护下，将3.4g(0.01mol)山嵛酸、3.1g(0.01mol)罗替戈汀和1.4g(0.005mol)二甲氨基吡啶对甲基苯磺酸盐(DPTS)溶于20ml二氯甲烷(DCM)中，滴加2.7g(13mmol)二环己基碳二亚胺(DCC)至上述混合体系，待反应完全，抽滤，滤饼以适量二氯甲烷(DCM)洗涤后合并滤液，减压蒸除二氯甲烷(DCM)，剩余物经过柱层析纯化，以1:3(v/v)乙酸乙酯-石油醚体系为淋洗剂，得类白色固体4.3g，熔点48-52℃，收率67％。核磁检测、红外检测结果同实施例1。
实施例3罗替戈汀山嵛酸酯晶型(I型)
将实施例1制备的罗替戈汀山嵛酸酯以乙酸乙酯热溶解后，加入甲醇，冷却结晶，抽滤，滤饼以适量甲醇洗涤得类白色固体，按照以下测定方法进行测定：
试验仪器：PANalytical Empyrean X射线粉末衍射分析仪。
试验条件：CuKα辐射,Kα1
Figure PCTCN2016090803-appb-000005
:1.540598,Kα2
Figure PCTCN2016090803-appb-000006
:1.544426 Kα2/Kα1；强度比例:0.50X射线光管设定:45kV 40mA,发散狭缝:自动,扫描模式:连续,扫描范围(°2TH)3°-40°扫描步长(°2TH)0.013扫描速率(°/min)大约10
差示扫描量热(DSC)
仪器：TA Instruments提供的TA Q200/Q2000差示扫描量热仪方法：样品置于铝盘中，压盖后在N2保护下以10℃/min的速度从室温升温至设定温度。
热重分析(TGA)
仪器：TA Instruments提供的TA Q500/Q5000热重分析仪方法：样品置于合金盘中，敞口在N2保护下以10℃/min的速度从室温升温至设定温度。
测定结果：罗替戈汀山嵛酸酯晶型(I型)的XRPD数据如表1所示，粉末X射线衍射图谱见附图4，TGA/DSC见附图6。
表1罗替戈汀山嵛酸酯晶型(I型)XRPD数据
Figure PCTCN2016090803-appb-000007
Figure PCTCN2016090803-appb-000008
实施例4罗替戈汀山嵛酸酯晶型(II型)
通过将过量实施例1制备得到的罗替戈汀山嵛酸酯置于1:19(v/v)四氢呋喃和甲醇的混合溶剂中，在40℃条件下悬浮搅拌5天，即得罗替戈汀山嵛酸酯晶型(II型)。
按照实施例3所述测定方法进行测定。
TGA结果显示在样品加热至100℃时失重为3.1％，DSC图中观察到3个吸热峰，分别为30.9℃、41.7℃和46.7℃(峰值)。
罗替戈汀山嵛酸酯晶型(II型)的XRPD数据如表2所示，粉末X射线衍射结果见附图5，TGA/DSC图见附图7。
表2罗替戈汀山嵛酸酯晶型(II型)XRPD数据
Figure PCTCN2016090803-appb-000009
Figure PCTCN2016090803-appb-000010
对照例1罗替戈汀辛酸酯
Figure PCTCN2016090803-appb-000011
室温氮气保护下，将14.4g(0.1mol)辛酸溶于300ml二氯甲烷DCM，30min内滴加12.7g(0.1mol)草酰氯至上述混和溶液，室温反应完全,为溶液1；将31.5g(0.1mol)罗替戈汀溶于15.2g(0.15mol)三乙胺和300ml二氯甲烷DCM的混合溶液中，为溶液2；滴加溶液1至溶液2中，待混合体系反应完全后，以等体积水洗涤上述反应液，有机相减压蒸除溶剂，剩余物经过柱层析纯化，以1:3(v/v)乙酸乙酯-石油醚体系为淋洗剂，得浅黄色油状物31.8g，收率72.1％。
Figure PCTCN2016090803-appb-000012
1H NMR(CDCl3,400MHz)δH:7.01(m,2H,H-7&H-14),6.88(d,J＝7.56Hz,1H,H-6),6.81(t,J＝3.46Hz,1H,H-15),6.72(t,J＝2.78Hz,2H,H-8&H-13),2.92(m 4H,H-1&H-4),2.78(m,4H,H-19&H-20),2.49(m,5H,H-2,H-22&H-16),2.04(m,1H,H-3),1.77(m,2H,H-23),1.58(m,1H,H-3),1.39(m,2H,H-17),1.23(m,8H,H-24～H-27),0.96(m,6H,H-18&H-28)。
对照例2罗替戈汀油酸酯
Figure PCTCN2016090803-appb-000013
室温氮气保护下，将28.3g(0.1mol)油酸和300ml二氯甲烷(DCM)混合均匀，30min 内滴加12.7g(0.1mol)草酰氯至上述混和溶液中，室温反应完全，为溶液1；将31.5g(0.1mol)罗替戈汀溶于15.2g(0.15mol)三乙胺和300ml二氯甲烷(DCM)的混合溶液中，为溶液2；滴加溶液1至溶液2中，待混合体系反应完全后，用等体积水洗涤上述反应液，有机相减压蒸除溶剂，剩余物经过柱层析纯化，以1:3(v/v)乙酸乙酯-石油醚为淋洗剂，得浅黄色油状物40.1g，收率69.1％。
Figure PCTCN2016090803-appb-000014
1H NMR(CDCl3,400MHz)δH:7.10(m,2H,H-7&H-14),6.98(d,J＝7.58Hz,1H,H-6),6.91(t,J＝3.48Hz,1H,H-15),6.81(t,J＝2.80Hz,2H,H-8&H-13),5.42(m 4H,H-29&H-30),2.94(m 4H,H-1&H-4),2.80(m,4H,H-19&H-20),2.53(m,5H,H-2,H-22&H-16),2.04(m,5H,H-3,H-28&H-31),1.77(m,2H,H-23),1.58(m,1H,H-3),1.51(m,2H,H-37),1.39(m,2H,H-17),1.28(m,18H,H-24～H-27&H-32～H-36),0.89(m,6H,H-18&H-38)。
对照例3罗替戈汀棕榈酸酯
Figure PCTCN2016090803-appb-000015
室温氮气保护下，将31.5g(0.1mol)罗替戈汀溶于15.2g(0.15mol)三乙胺和300ml二氯甲烷(DCM)的混合溶液中，滴加27.49g(0.1mol)棕榈酰氯和200ml二氯甲烷(DCM)的混合溶液，待反应完全后以等体积水洗涤，有机相减压蒸除溶剂，剩余物经过柱层析纯化，以1:3(v/v)乙酸乙酯-石油醚体系为淋洗剂，得类白色固体36.2g，收率65.3％，熔点27-30℃。
Figure PCTCN2016090803-appb-000016
1H NMR(CDCl3,400MHz)δH:7.11(m,2H,H-7&H-14),6.97(d,J＝7.64Hz,1H,H-6),6.91(t,J＝3.52Hz,1H,H-15),6.80(t,J＝2.84Hz,2H,H-8&H-13),2.92(m 4H,H-1&H-4),2.79(m,4H,H-19&H-20),2.53(m,5H,H-2,H-22&H-16),2.03(m,1H,H-3),1.76(m,2H,H-23),1.55(m,1H,H-3),1.49(m,2H,H-35),1.38(m,2H,H-17),1.26(m,22H,H-24～H-34),0.88(m,6H,H-18&H-36)。
对照例4：罗替戈汀硬脂酸酯
Figure PCTCN2016090803-appb-000017
室温氮气保护下，将31.5g(0.1mol)罗替戈汀溶于15.2g(0.15mol)三乙胺和300ml二氯甲烷(DCM)的混合溶液，再滴加入30.29g(0.1mol)硬脂酰氯和200ml二氯甲烷(DCM)的混合溶液，待反应完全后以等体积水洗涤，有机相减压蒸除溶剂，剩余物经过柱层析纯化，以1:3(v/v)乙酸乙酯-石油醚体系为淋洗剂，得类白色固体38.4g，收率66.0％，熔点24-26℃。
Figure PCTCN2016090803-appb-000018
1H NMR(CDCl3,400MHz)δH:7.10(m,2H,H-7&H-14),6.98(d,J＝7.58Hz,1H,H-6),6.91(t,J＝3.48Hz,1H,H-15),6.81(t,J＝2.80Hz,2H,H-8&H-13),2.94(m 4H,H-1&H-4),2.80(m,4H,H-19&H-20),2.53(m,5H,H-2,H-22&H-16),2.04(m,1H,H-3),1.77(m, 2H,H-23),1.58(m,1H,H-3),1.51(m,2H,H-37),1.39(m,2H,H-17),1.28(m,26H,H-24～H-36),0.89(m,6H,H-18&H-38)。
对照例5：罗替戈汀花生酸酯
Figure PCTCN2016090803-appb-000019
室温氮气保护下，将31.2g(0.1mol)花生酸溶于300ml二氯甲烷(DCM)中，滴加12.7g(0.1mol)草酰氯，反应完全,为溶液1；将31.5g(0.1mol)罗替戈汀溶于15.2g(0.15mol)三乙胺和300ml二氯甲烷(DCM)的混合溶液中，为溶液2；滴加溶液1至溶液2中；待混合体系反应完全后以等体积水洗涤上述反应液，有机相减压蒸除溶剂，得油状物，冷却后为白色固体；以适量乙醇洗涤过滤，得类白色湿固体；将上述湿固体以乙酸乙酯热溶解后，加入甲醇，得澄清溶液，冷却结晶完全；抽滤，滤饼以适量甲醇洗涤得类白色固体43.3g，熔点30-33℃,收率70.0％。
Figure PCTCN2016090803-appb-000020
1H NMR(CDCl3,400MHz)δH:7.10(m,2H,H-7&H-14),6.96(d,J＝7.56Hz,1H,H-6),6.91(q,J＝3.40,5.08Hz,1H,H-15),6.80(t,J＝3.92Hz,2H,H-8&H-13),2.94(m 4H,H-1&H-4),2.81(m,4H,H-19&H-20),2.53(m,5H,H-2,H-16&H-22),2.03(m,1H,H-3),1.76(m,2H,H-23),1.56(m,1H,H-3),1.49(m,2H,H-39),1.38(m,2H,H-17),1.26(m,30H,H-24～H-38),0.88(m,6H,H-18&H-40)
对照例6：罗替戈汀木质素酸酯
Figure PCTCN2016090803-appb-000021
室温氮气保护下，将36.8g(0.1mol)木质素酸溶于300ml二氯甲烷(DCM)中，滴加12.7g(0.1mol)草酰氯，反应完全，为溶液1；将31.5g(0.1mol)罗替戈汀溶于15.2g(0.15mol)三乙胺和300ml二氯甲烷(DCM)的混合溶液中，为溶液2；滴加溶液1至溶液2中；待混合体系反应完全后以等体积水洗涤上述反应液，有机相减压蒸除溶剂，得油状物，冷却后为白色固体；以适量乙醇洗涤过滤，得类白色湿固体；将上述湿固体以乙酸乙酯热溶解后，加入甲醇，得澄清溶液，冷却结晶完全；抽滤，滤饼以适量甲醇洗涤得类白色固体46.6g，收率70.0％，熔点47-49℃。
Figure PCTCN2016090803-appb-000022
1H NMR(CDCl3,400MHz)δH:7.11(m,2H,H-7&H-14),6.96(d,J＝7.36Hz,1H,H-6),6.91(q,J＝3.42,5.02Hz,1H,H-15),6.81(d,J＝7.24Hz,2H,H-8&H-13),2.98(m 4H,H-1&H-4),2.81(m,4H,H-19&H-20),2.53(m,5H,H-2,H-16&H-22),2.03(m,1H,H-3),1.77(m,2H,H-23),1.58(m,1H,H-3),1.38(m,2H,H-43),1.28(m,40H,H-17,H-24～H-42),0.89(m,6H,H-18&H-44)。
试验例1：罗替戈汀辛酸酯注射给药在大鼠体内的药动学行为
样品：
罗替戈汀辛酸酯：根据对照例1制备
HPMC：上海卡乐康包衣技术有限公司 批号PD341942
试验动物：
雄性SD大鼠(山东绿叶制药有限公司提供)，体重190～280g，3只。
试验过程及结果：
取HPMC配置成1％浓度溶媒，另取罗替戈汀辛酸酯配置成10mg/ml混悬液(以罗替戈汀 计)，3只大鼠分别肌肉注射药物2ml/kg，于给药前(0h)及给药后0.25h,1h,6h,1d,2d,3d,5d,7d,9d,11d,14d,16d,18d,21d,24d,28d大鼠眼眶取血，置肝素化EP管中，立刻离心(3000rpm)10min，分离血浆，–35℃保存待测。
不同时间点大鼠体内罗替戈汀的血药浓度(ng/mL)均值见表3所示，大鼠注射给药后罗替戈汀的经时血药浓度-时间曲线见附图8所示。
表3：不同时间点体内罗替戈汀的血药浓度
Figure PCTCN2016090803-appb-000023
结论
由表3及附图8可以看出，大鼠肌肉注射罗替戈汀辛酸酯在体内1小时即达峰，血药浓度波动大，有效血药浓度维持时间短，无法实现长效稳定释放。
试验例2：各药物注射给药在大鼠体内的药动学行为
样品：
罗替戈汀油酸酯：根据对照例2制备；
罗替戈汀棕榈酸酯：根据对照例3制备；
罗替戈汀硬脂酸酯：根据对照例4制备；
罗替戈汀盐酸盐：纯度99.83％
HPMC：上海卡乐康包衣技术有限公司 批号PD341942
试验动物：
雄性SD大鼠(山东绿叶制药有限公司提供)，体重190～280g，12只，每组3只。
试验过程及结果：
取HPMC配置成1％浓度溶媒，另取罗替戈汀油酸酯、罗替戈汀棕榈酸酯、罗替戈汀硬脂酸酯分别配置成10mg/ml混悬液(以罗替戈汀计)，罗替戈汀盐酸盐以生理盐水配置成0.36mg/ml注射液(以罗替戈汀计)。
动物随机分成罗替戈汀油酸酯组(A)、罗替戈汀棕榈酸酯组(B)、罗替戈汀硬脂酸酯组(C)和罗替戈汀盐酸盐组(D)，每组3只，A、B、C组大鼠分别肌肉注射相应药物2ml/kg，D组大鼠静脉注射相应药物2ml/kg。
A、B、C各组药物于给药前(0h)及给药后0.25h,1h,6h,1d,2d,3d,5d,7d,9d,11d,14d,16d,18d,21d,24d,28d大鼠眼眶取血，置肝素化EP管中，立刻离心(3000rpm)10min，分离血浆，–35℃保存待测。
D组药物于给药前(0h)及给药后3min,10min,0.25h,0.5h,1h,1.5h,2h,4h,6h,8h,12h,大鼠眼眶取血，置肝素化EP管中，立刻离心(3000rpm)10min，分离血浆，–35℃保存待测。
不同时间点大鼠体内罗替戈汀的血药浓度(ng/mL)见表4和表5所示，大鼠注射给药后罗替戈汀的经时血药浓度-时间曲线见附图9所示。
表4：不同时间点体内罗替戈汀的血药浓度
Figure PCTCN2016090803-appb-000024
Figure PCTCN2016090803-appb-000025
表5：不同时间点大鼠体内的血药浓度
Figure PCTCN2016090803-appb-000026
结论
由表4、表5及附图9可以看出，大鼠肌肉注射相应药物后，各组药物在体内达峰时间早，血药浓度波动大，有效血药浓度维持时间短，无法实现二周以上的长期稳定释放；同时绝对生物利用度低，其中罗替戈汀油酸酯绝对生物利用度为54.3％，罗替戈汀棕榈酸酯为51.3％，罗替戈汀硬脂酸酯为38.2％。
试验例3：各药物注射给药在大鼠体内的药动学行为
样品：
罗替戈汀花生酸脂：根据对照例5制备；
罗替戈汀山嵛酸酯：根据实施例1制备；
罗替戈汀木质素酯：根据对照例6制备；
HPMC：上海卡乐康包衣技术有限公司 批号PD341942
试验动物：
雄性SD大鼠(山东绿叶制药有限公司提供)，体重190～280g，12只，每组3只。
试验过程及结果：
取HPMC配置成1％浓度溶媒，另取罗替戈汀油酸酯、罗替戈汀棕榈酸酯、罗替戈汀硬脂酸酯配置成10mg/ml混悬液(以罗替戈汀计)。
动物随机分成罗替戈汀花生酸酯组(A)、罗替戈汀山嵛酸酯组(B)和罗替戈汀木质素酸酯组(C)，每组3只，A、B、C组分别肌肉注射相应药物2ml/kg。
A、B、C组药物于给药前(0h)及给药后0.25h、1h、6h、1d、2d、3d、5d、7d、9d、11d、14d、16d、18d、21d、25d、28d、30d、35d、39d和42d大鼠眼眶取血，置肝素化EP管中，立刻离心(3000rpm)10min，分离血浆，–35℃保存待测。
不同时间点大鼠体内罗替戈汀的血药浓度(ng/mL)见表6所示，大鼠注射给药后罗替戈汀的经时血药浓度-时间曲线见附图10所示。
表6：不同时间点体内罗替戈汀的血药浓度
Figure PCTCN2016090803-appb-000027
Figure PCTCN2016090803-appb-000028
结论
由表6、表5及附图10可以看出，大鼠肌肉注射相应药物后，罗替戈汀花生酸酯在体内前期释放量大，释放周期内血药浓度低，有效血药浓度维持时间短，大鼠肌肉注射罗替戈汀花生酸酯绝对生物利用度为33.1％；罗替戈汀木质素酸酯在体内前期释放量小，前期无法获得有效血药浓度，大鼠肌肉注射罗替戈汀木质素酸酯绝对生物利用度为65.2％；罗替戈汀山嵛酸酯在体内释放没有延迟时间，有效血药浓度平稳且维持时间能达到二周以上，大鼠肌肉注射绝对生物利用度为91.1％。
综上试验例1、试验例2和试验例3的结果，可知罗替戈汀不饱和酸酯如油酸酯，在体内达峰时间早，血药浓度波动大，有效血药浓度维持时间短；罗替戈汀饱和酸酯中辛酸酯在体内1小时即达峰，体内有效血药浓度维持时间短；其他饱和长链酯中罗替戈汀棕榈酸酯和硬脂酸酯的血药浓度波动大，体内有效血药浓度维持时间短，无法实现有效血药浓度维持二周以上的效果；罗替戈汀花生酸酯和木质素酸酯血药浓度虽然波动不大，但无法实现有效血药浓度维持二周以上的效果；并且这些罗替戈汀饱和或不饱和长链酯绝对生物利用度均低于70％；只有罗替戈汀山嵛酸酯绝对生物利用度大于90％，体内血药浓度波动小，有效血药浓度维持时间能达到二周以上，可以实现减少血药浓度波动，提高药物的体内生物利用度、达到两周以上平稳释放的效果。

Claims (18)

  1. 罗替戈汀山嵛酸酯，结构式如下所示：
    Figure PCTCN2016090803-appb-100001
  2. 权利要求1所述罗替戈汀山嵛酸酯的制备方法，其特征为：将山嵛酰氯和罗替戈汀反应，得罗替戈汀山嵛酸酯；或者将山嵛酸和罗替戈汀反应，得罗替戈汀山嵛酸酯；或者将山嵛酸酐和罗替戈汀反应，得罗替戈汀山嵛酸酯。
  3. 根据权利要求2所述的制备方法，其特征为：在室温氮气保护下，将罗替戈汀加入到三乙胺和二氯甲烷的混合溶液中，再加入山嵛酰氯，反应完全，洗涤，减压蒸除溶剂，纯化，得罗替戈汀山嵛酸酯；或者在室温氮气保护下，将山嵛酸、罗替戈汀和二甲氨基吡啶对甲基苯磺酸盐溶于二氯甲烷中，滴加二环己基碳二亚胺至上述混合溶液，反应完成后抽滤，减压蒸除溶剂，纯化，得罗替戈汀山嵛酸酯；或者在氮气保护下，将山嵛酸酐和罗替戈汀溶于无水四氢呋喃中，加入催化量三乙胺，油浴加热，反应完全后，减压蒸除溶剂，加入二氯甲烷，以碳酸氢钠溶液洗涤，减压蒸除溶剂，纯化，得罗替戈汀山嵛酸酯。
  4. 权利要求1所述的罗替戈汀山嵛酸酯的晶型(I型)，其特征为：通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838(±0.2度2θ)处具有特征峰。
  5. 根据权利要求4所述的罗替戈汀山嵛酸酯晶型(I型)，其特征为：通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838、16.154、19.403、11.749、14.518和17.875(±0.2度2θ)处具有特征峰。
  6. 根据权利要求5所述的罗替戈汀山嵛酸酯晶型(I型)，其特征为：通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838、16.154、19.403、11.749、14.518、17.875、19.729、20.299、13.583、11.962、22.949、23.772、16.424、15.749、12.586和22.430(±0.2度2θ)处具有特征峰。
  7. 根据权利要求6所述的罗替戈汀山嵛酸酯晶型(I型)，其特征为：通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.563、21.156、23.295、21.955、20.838、16.154、19.403、11.749、14.518、17.875、19.729、20.299、13.583、11.962、22.949、 23.772、16.424、15.749、12.586、22.430、12.238、23.995、18.626、16.614、28.574、24.530、25.169、27.044、36.329、27.764、29.127和31.490(±0.2度2θ)处具有特征峰。
  8. 根据权利要求7所述的罗替戈汀山嵛酸酯晶型(I型)，其特征为：基本具有图4所示的粉末X射线衍射图谱。
  9. 权利要求4-8任一所述的罗替戈汀山嵛酸酯晶型(I型)的制备方法，其特征为：将罗替戈汀山嵛酸酯在有机溶剂中溶解、冷却结晶、抽滤、洗涤制得，其中所述有机溶剂选自乙酸乙酯、乙醇、甲醇、环己烷、正己烷、石油醚、四氢呋喃、丙酮、正庚烷中一种或多种。
  10. 根据权利要求9所述的罗替戈汀山嵛酸酯晶型(I型)的制备方法，其特征为：将罗替戈汀山嵛酸酯以乙酸乙酯热溶解后，加入甲醇，冷却结晶，抽滤，再以适量甲醇洗涤制得。
  11. 权利要求1所述的罗替戈汀山嵛酸酯晶型(II型)，其特征为：通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝21.481、23.887(±0.2度2θ)处具有特征峰。
  12. 根据权利要求11所述的罗替戈汀山嵛酸酯晶型(II型)，其特征为：通过CuKα辐射得到的粉末X射线衍射图谱在2θ(2θ(度))＝3.274、21.481、23.887(±0.2度2θ)处具有特征峰。
  13. 根据权利要求12所述的罗替戈汀山嵛酸酯晶型(II型)，其特征为：基本具有图5所示的粉末X射线衍射图谱。
  14. 权利要求11-13任一所述的罗替戈汀山嵛酸酯晶型(II型)的制备方法，其特征为：将罗替戈汀山嵛酸酯置于四氢呋喃和甲醇的混合溶剂中，在40℃条件下悬浮搅拌制得。
  15. 含有权利要求1所述罗替戈汀山嵛酸酯的药物组合物。
  16. 根据权利要求15所述的药物组合物，其特征为：其以胃肠外形式给药。
  17. 罗替戈汀山嵛酸酯在制备治疗与多巴胺受体有关疾病的药物中的用途。
  18. 罗替戈汀山嵛酸酯在制备治疗帕金森氏病的药物中的用途。
PCT/CN2016/090803 2016-07-21 2016-07-21 罗替戈汀山嵛酸酯及其制备方法和用途 Ceased WO2018014277A1 (zh)

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US20200255396A1 (en) 2020-08-13
RU2717542C1 (ru) 2020-03-24
JP2019523297A (ja) 2019-08-22
EP3489227A1 (en) 2019-05-29
EP3489227A4 (en) 2020-01-22
US10669249B2 (en) 2020-06-02
CA3030043A1 (en) 2018-01-25
CN109415335A (zh) 2019-03-01
PL3489227T3 (pl) 2021-05-04
US11111227B2 (en) 2021-09-07
RU2717542C9 (ru) 2020-08-12

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