TW202304915A - Pharmaceutical salt of lumateperone, preparation method, pharmaceutical composition and use thereof - Google Patents

Abstract

The present disclosure provides a pharmaceutical salt of Lumateperone, preparation method, pharmaceutical composition and use thereof. The pharmaceutical salt of Lumateperone is formed from the free base of Lumateperone and an organic acid with six carbons or more. The pharmaceutical salt of Lumateperone prepared according to the present disclosure has low solubility and thus is suitable for sustained-release administration. Also, it has high stability and is convenient to prepare, so that it is suitable for large-scale industrial production.

Description

盧美哌隆藥用鹽、製備方法、含其的藥物組合物及應用Medicinal salt of lumepirone, preparation method, pharmaceutical composition containing it and application

本發明屬於醫藥技術領域，具體涉及盧美哌隆藥用鹽、製備方法、含其的藥物組合物及應用。The invention belongs to the technical field of medicine, and in particular relates to a medicinal salt of lumepirone, a preparation method, a pharmaceutical composition containing the lumepirone and its application.

本申請要求2021年3月26日向中國國家知識產權局提交的，專利申請號為202110322805.8，發明名稱為“盧美哌隆藥用鹽、製備方法、含其的藥物組合物及應用”在先申請的優先權。該申請的全文通過引用的方式結合於本申請中。This application claims to be submitted to the State Intellectual Property Office of China on March 26, 2021. The patent application number is 202110322805.8, and the invention name is "lumiperone medicinal salt, preparation method, pharmaceutical composition containing it and application". priority. The entirety of this application is incorporated by reference into this application.

2019年12月23日Intra-Cellular Therapies宣佈該公司旗下抗精神病藥盧美哌隆（Lumateperone，商品名 Caplyta）獲美國食品藥物監督管理局（FDA）批准上市，用於成人精神***症的治療。盧美哌隆是精神***症治療領域的首創新藥，通過協同調節中樞5-HT、DA及谷胺酸能系統發揮療效。目前，該藥品尚未在國內上市。On December 23, 2019, Intra-Cellular Therapies announced that its antipsychotic drug Lumateperone (trade name Caplyta) has been approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia in adults. Lumepirone is the first innovative drug in the field of schizophrenia treatment. It exerts its curative effect by synergistically regulating the central 5-HT, DA and glutaminergic systems. At present, the drug has not yet been marketed in China.

盧美哌隆化學名稱為1- (4-氟苯基)-4- [ (6bR ,10aS) -2,3,6b,9,10,10a-六氫化-3-甲基-1H-吡啶並[3',4':4,5]吡咯並[1,2,3-de]喹喔啉-8 (7H)-基]1-丁酮，其化學結構式如下所示：

。 The chemical name of lumepirone is 1-(4-fluorophenyl)-4-[(6bR ,10aS)-2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl]1-butanone, its chemical structure is as follows:

.

盧美哌隆是5-HT _2A受體配體，對多巴胺D2受體和血清素轉運蛋白具有強親和力，但與抗精神病藥物的認知和代謝副作用相關的受體的結合可以忽略不計。 Lumepirone is a 5- _HT2A receptor ligand with strong affinity for dopamine D2 receptors and serotonin transporters, but binding to receptors associated with cognitive and metabolic side effects of antipsychotics is negligible.

盧美哌隆的工業化生產仍面臨挑戰。游離鹼形式盧美哌隆是油性、黏性固體。專利文獻CN112384218A記載了製備該化合物的鹽異常困難。美國專利文獻US7,183,282中揭露了盧美哌隆鹽酸鹽形式，其通過從***中沉澱得到，但是這種特定的鹽形式具有吸濕性並且顯示出差的穩定性。專利文獻WO 2009/114181和US 2011/0112105中揭露了盧美哌隆的甲苯磺酸鹽。The industrial production of lumepirone still faces challenges. The free base form of lumepirone is an oily, viscous solid. Patent document CN112384218A records that it is extremely difficult to prepare the salt of this compound. US Pat. No. 7,183,282 discloses the form of lumepirone hydrochloride, which is obtained by precipitation from diethyl ether, but this particular salt form is hygroscopic and shows poor stability. Patent documents WO 2009/114181 and US 2011/0112105 disclose the tosylate salt of lumepirone.

目前上市的是盧美哌隆對甲苯磺酸鹽膠囊，該產品為口服製劑，需要每日給藥，以維持其血藥濃度。但由於需要頻繁給藥，使得患者的用藥依從性差。因此，急需開發一種在水或不同pH介質中溶解度低，適宜緩釋給藥，且物理和化學性質穩定的盧美哌隆藥學上可接受的鹽。Lumepirone p-toluenesulfonate capsules are currently on the market. This product is an oral preparation and needs to be administered daily to maintain its blood drug concentration. However, due to the need for frequent administration, the patient's medication compliance is poor. Therefore, there is an urgent need to develop a pharmaceutically acceptable salt of lumepirone that has low solubility in water or different pH media, is suitable for sustained-release administration, and has stable physical and chemical properties.

為改善上述問題，本發明提供盧美哌隆藥用鹽，其為盧美哌隆游離鹼與六個碳以上的有機酸形成的鹽。In order to improve the above problems, the present invention provides lumepirone medicinal salt, which is a salt formed of lumepirone free base and an organic acid with more than six carbons.

在一些實施方式中，所述六個碳以上的有機酸為C ₆-C ₃₀的有機酸，包括但不限於：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、十一烷酸、月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕櫚酸、十七烷酸、硬脂酸、十九烷酸、二十烷酸、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸、甘油三乙酸、木質酸、雙羥萘酸、1-羥基-2萘甲酸、雙羥萘酸（又可稱為「帕莫酸」）和萘酸衍生物。所述的「萘酸衍生物」包括但不限於萘酸酯，例如包含羧基和額外的酯基官能團的萘酸。 In some embodiments, the organic acid with more than six carbons is a C ₆ -C ₃₀ organic acid, including but not limited to: hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, Alkanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, oleic acid, eicosanoic acid , docosanoic acid, tricosanoic acid, tetracosanoic acid, pentadecanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, three Decanoic acid, glyceryl triacetic acid, ligninic acid, pamoic acid, 1-hydroxy-2 naphthoic acid, pamoic acid (also known as "pamoic acid") and naphthoic acid derivatives. The "naphthoic acid derivatives" include but not limited to naphthoic acid esters, such as naphthoic acid containing carboxyl and additional ester functional groups.

在一些實施方式中，所述盧美哌隆藥用鹽為盧美哌隆半雙羥萘酸鹽，即盧美哌隆的雙羥萘酸鹽，其中盧美哌隆與雙羥萘酸以莫耳比1:0.5進行複合成鹽。In some embodiments, the pharmaceutically acceptable salt of lumepirone is lumepirone hemipamoate, that is, the pamoate salt of lumepirone, wherein lumepirone and pamoic acid are expressed in the form of The molar ratio is 1:0.5 for complex salt formation.

在一些實施方式中，所述雙羥萘酸又稱帕莫酸（Pamoic acid），CAS No. 130-85-8。In some embodiments, the pamoic acid is also called Pamoic acid, CAS No. 130-85-8.

根據本發明的實施方案，所述盧美哌隆雙羥萘酸鹽為無定型。According to an embodiment of the present invention, said lumepirone pamoate is amorphous.

本發明中所述無定型是指無定形固體（非晶體）的形式。The term "amorphous" in the present invention refers to the form of an amorphous solid (non-crystal).

在一些實施方式中，所述盧美哌隆半雙羥萘酸鹽無定型的X射線粉末繞射圖為沒有特徵峰的彌散圖，基本如圖3所示。In some embodiments, the X-ray powder diffraction pattern of the amorphous lumepirone hemipamoate is a scatter pattern without characteristic peaks, which is basically shown in FIG. 3 .

在一些實施方式中，所述盧美哌隆半雙羥萘酸鹽無定型的差式掃描量熱分析圖顯示其沒有明顯的熔融峰，如圖4所示。In some embodiments, the differential scanning calorimetry diagram of the amorphous lumepirone hemipamoate shows no obvious melting peak, as shown in FIG. 4 .

在一些實施方式中，所述盧美哌隆半雙羥萘酸鹽無定型的核磁圖顯示盧美哌隆與雙羥萘酸以莫耳比1:0.5成鹽，如圖5所示。In some embodiments, the NMR of the amorphous lumepirone hemipamoate salt shows that lumepirone and pamoic acid form a salt at a molar ratio of 1:0.5, as shown in FIG. 5 .

本發明還提供如上所述盧美哌隆藥用鹽的製備方法，包括以下步驟：將盧美哌隆游離鹼與如上所述六個碳以上的有機酸進行成鹽反應。The present invention also provides a method for preparing the pharmaceutically acceptable salt of lumepirone as described above, comprising the following steps: performing a salt-forming reaction with the free base of lumepirone and the above-mentioned organic acid with more than six carbons.

在一些實施方式中，所述盧美哌隆半雙羥萘酸鹽無定型的製備方法包括如下步驟： 方法(1)：將盧美哌隆對甲苯磺酸鹽溶於乙醇中得溶液A，將雙羥萘酸溶於氫氧化鈉乙醇溶液得溶液B，將溶液B加入溶液A中進行攪拌；或 方法(2)：將盧美哌隆與雙羥萘酸溶於DMSO，加入反溶劑水，攪拌析出。 In some embodiments, the preparation method of the amorphous form of lumepirone hemipamoate comprises the following steps: Method (1): dissolving lumepirone p-toluenesulfonate in ethanol to obtain solution A, dissolving pamoic acid in sodium hydroxide ethanol solution to obtain solution B, adding solution B to solution A and stirring; or Method (2): Dissolve lumepirone and pamoic acid in DMSO, add anti-solvent water, and stir to precipitate.

在一些實施方式中，方法(1)和(2)中攪拌在0~30 ℃下進行。In some embodiments, stirring in methods (1) and (2) is performed at 0-30°C.

在一些實施方式中，方法(2)中，所述盧美哌隆為盧美哌隆對甲苯磺酸鹽溶於二氯甲烷中，攪拌條件下加入0.2 N的氫氧化鈉水溶液得到的盧美哌隆游離鹼。In some embodiments, in the method (2), the lumepirone is lumepirone p-toluenesulfonate dissolved in dichloromethane, and a 0.2 N sodium hydroxide aqueous solution is added under stirring conditions. Piperone free base.

本發明還提供如上所述盧美哌隆藥用鹽在製備治療和/或預防成人精神***症、雙相性障礙以及急性躁狂症的藥物中的用途。The present invention also provides the use of the pharmaceutically acceptable salt of lumepirone as described above in the preparation of medicaments for treating and/or preventing adult schizophrenia, bipolar disorder and acute mania.

在一些實施方式中，所述盧美哌隆藥用鹽為盧美哌隆半雙羥萘酸鹽。In some embodiments, the pharmaceutically acceptable salt of lumepirone is lumepirone hemipamoate.

本發明還提供一種藥物組合物，其包括如上所述盧美哌隆藥用鹽。The present invention also provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of lumepirone as described above.

在一些實施方式中，所述盧美哌隆藥用鹽為盧美哌隆半雙羥萘酸鹽。In some embodiments, the pharmaceutically acceptable salt of lumepirone is lumepirone hemipamoate.

在一些實施方式中，所述藥物組合物還可以包括藥學上可接受的輔料。In some embodiments, the pharmaceutical composition may further include pharmaceutically acceptable excipients.

在一些實施方式中，所述藥學上可接受的輔料包括生理或藥學上可接受的載體、稀釋劑、媒介物和/或賦形劑中的一種，兩種或更多種。In some embodiments, the pharmaceutically acceptable adjuvant includes one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.

本發明還提供了一種盧美哌隆藥物製劑，其包括如上所述盧美哌隆藥用鹽或藥物組合物。The present invention also provides a pharmaceutical preparation of lumepirone, which comprises the pharmaceutically acceptable salt of lumepirone or the pharmaceutical composition as described above.

在一些實施方式中，所述盧美哌隆藥物製劑的劑型包括但不限於片劑、膠囊、溶液劑、混懸劑和半固體製劑。In some embodiments, the dosage form of the lumepirone pharmaceutical preparation includes but not limited to tablet, capsule, solution, suspension and semi-solid preparation.

本發明中，所述藥學上可接受的輔料是指如下物質：其在正常的醫學判斷範圍內適用於與患者的組織接觸而不會有不適當毒性、刺激性、過敏反應等，具有合理的利弊比，且能有效用於其目的用途。In the present invention, the pharmaceutically acceptable excipient refers to the following substances: it is suitable for contacting with the patient's tissue within the scope of normal medical judgment without undue toxicity, irritation, allergic reaction, etc., and has a reasonable advantages and disadvantages, and can be effectively used for its intended use.

本發明還提供一種治療和/或預防成人精神***症、雙相性障礙以及急性躁狂症的方法，包括將如上所述盧美哌隆藥用鹽，或其藥物組合物，或盧美哌隆藥物製劑施用於有此需要的客體。The present invention also provides a method for treating and/or preventing adult schizophrenia, bipolar disorder and acute mania, comprising the above-mentioned lumepirone pharmaceutical salt, or its pharmaceutical composition, or lumepirone Pharmaceutical formulations are administered to a subject in need thereof.

有益效果Beneficial effect

本發明製得的盧美哌隆藥用鹽在不同pH的介質中溶解度低，且溶解度差異小，表明該鹽型本身就具有緩釋作用，且釋放速度可以最小程度地依賴於pH，從而避免在體內不同區域的pH環境中對其釋藥速率的影響，造成突釋現象或體內局部區域血藥濃度過高，以及降低了個體間釋藥差異性。因此，其適合用於製備長效製劑，可減少用藥次數，提高患者用藥依從性，市場化前景良好。此外，盧美哌隆藥用鹽穩定性高，製備方便，適合於大規模工業化生產。The medicinal salt of lumepirone prepared by the present invention has low solubility in media of different pH, and the solubility difference is small, indicating that the salt type itself has a slow-release effect, and the release rate can be minimally dependent on pH, thereby avoiding The influence of the pH environment in different regions of the body on its drug release rate, resulting in a burst release phenomenon or an excessively high blood drug concentration in a local area of the body, and reduces the variability in drug release between individuals. Therefore, it is suitable for the preparation of long-acting preparations, can reduce the number of medications, improve medication compliance of patients, and has a good market prospect. In addition, the pharmaceutical salt of lumepirone has high stability, is convenient to prepare, and is suitable for large-scale industrial production.

而且，本發明採用盧美哌隆對甲苯磺酸鹽作為初始原料進行後續反應操作，可以有效避免單獨使用為油狀物，且穩定性不好的游離鹼對最終產物造成影響。操作過程更簡單，且重複性好。Moreover, the present invention uses lumepirone p-toluenesulfonate as the initial raw material for subsequent reaction operations, which can effectively avoid the free base used alone as an oil, and the free base with poor stability will affect the final product. The operation process is simpler and has good repeatability.

下文將結合具體實施例對本發明的技術方案做更進一步的詳細說明。應當理解，下列實施例僅為示例性地說明和解釋本發明，而不應被解釋為對本發明保護範圍的限制。凡基於本發明上述內容所實現的技術均涵蓋在本發明旨在保護的範圍內。The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

除非另有說明，以下實施例中使用的原料和試劑均為市售商品，或者可以通過已知方法製備。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

分別採用核磁共振（ ¹H-NMR）、X-射線粉末繞射（XRPD）、差示掃描量熱法（DSC）、高效液相色譜（HPLC）對實施例和對比例的鹽型化合物進行測試，測試使用的儀器參數如下： （1） ¹H-NMR測試在布魯克型號為Bruker Advance III 500 M核磁共振譜儀中進行，測量頻率為400 Mz，使用的溶劑為氘代DMSO。 （2）DSC測量在TA Instruments型號為Q2000的密封盤裝置進行，測試方法為：將樣品（約1-2 mg）在鋁盤中稱量，轉移至儀器中進行測量。測試參數如下：儀器在30 ℃平衡，以10 ℃/min的速率升溫至300 ℃，實驗氣氛為氮氣。 （3）XRPD測量在布魯克型號為D8 Advance X-射線粉末繞射儀上進行，並使用圓形零背景的單晶矽樣品台。掃描參數如下：電壓40 kv，電流40 mA，掃描範圍3°~45°，掃描步長0.02°，掃描模式為連續掃描。 （4）HPLC含量和有關物質檢測使用的儀器和相關檢測參數 含量測試： 儀器 高效液相色譜 管柱層析 Welch Xtimate C18  4.6×150 mm，5 μm      檢測波長 214 nm 流速 1.0 mL/min 柱溫 30 ℃ 進樣量 5 μL 流動相A 體積分率0.05%三氟乙酸水溶液 流動相B 乙腈 溶劑 體積分率為60%的乙腈水溶液 含量梯度洗脫程序表： 時間（min） 流動相A（體積分率%） 流動相B（體積分率%） 0.0 90 10 8.0 10 90 12.0 10 90 12.1 90 10 15.0 90 10 有關物質測試： 儀器 高效液相色譜 管柱層析 Welch Xtimate C18  4.6×150 mm，5 μm 檢測波長 214 nm 流速 1.0 mL/min 柱溫 30 ℃ 進樣量 10 μL 流動相A 體積分率0.05%三氟乙酸水溶液 流動相B 乙腈 溶劑 體積分率為60%的乙腈水溶液 有關梯度洗脫程序表： 時間（min） 流動相A（體積分率%） 流動相B（體積分率%） 0.0 90 10 10.0 20 80 15.0 20 80 15.1 90 10 25.0 90 10 The salt compounds of Examples and Comparative Examples were tested by nuclear magnetic resonance ( ¹ H-NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and high-performance liquid chromatography (HPLC) respectively. , the instrument parameters used in the test are as follows: (1) ^{The 1} H-NMR test was carried out in a Bruker Advance III 500 M nuclear magnetic resonance spectrometer with a measurement frequency of 400 Mz, and the solvent used was deuterated DMSO. (2) DSC measurement was carried out in a TA Instruments model Q2000 sealed pan device. The test method was as follows: the sample (about 1-2 mg) was weighed in an aluminum pan and transferred to the instrument for measurement. The test parameters are as follows: the instrument is balanced at 30 °C, the temperature is raised to 300 °C at a rate of 10 °C/min, and the experimental atmosphere is nitrogen. (3) The XRPD measurement was carried out on a Bruker model D8 Advance X-ray powder diffractometer, and a circular zero-background single-crystal silicon sample stage was used. The scan parameters are as follows: voltage 40 kv, current 40 mA, scan range 3°-45°, scan step size 0.02°, scan mode is continuous scan. (4) Instruments used for HPLC content and related substances detection and related detection parameters content test: instrument HPLC Column chromatography Welch Xtimate C18 4.6×150 mm, 5 μm Detection wavelength 214 nm flow rate 1.0 mL/min Column temperature 30°C Injection volume 5 μL mobile phase A Volume fraction 0.05% trifluoroacetic acid aqueous solution mobile phase B Acetonitrile solvent The volume fraction is 60% acetonitrile aqueous solution Content gradient elution schedule: time (min) Mobile phase A (volume fraction%) Mobile phase B (volume fraction%) 0.0 90 10 8.0 10 90 12.0 10 90 12.1 90 10 15.0 90 10 Related Substance Test: instrument HPLC Column chromatography Welch Xtimate C18 4.6×150 mm, 5 μm Detection wavelength 214 nm flow rate 1.0 mL/min Column temperature 30°C Injection volume 10 μL mobile phase A Volume fraction 0.05% trifluoroacetic acid aqueous solution mobile phase B Acetonitrile solvent The volume fraction is 60% acetonitrile aqueous solution For gradient elution schedule table: time (min) Mobile phase A (volume fraction%) Mobile phase B (volume fraction%) 0.0 90 10 10.0 20 80 15.0 20 80 15.1 90 10 25.0 90 10

對比例comparative example 11 盧美哌隆對甲苯磺酸鹽固相表徵檢測Solid phase characterization and detection of lumepirone p-toluenesulfonate

將市售的盧美哌隆對甲苯磺酸鹽進行固相表徵檢測，測試項目為 ¹H-NMR，DSC和XRPD。 ¹H-NMR（400MHz, DMSO- d ₆ ）：δ9.10（s, 1H），8.07-8.03（m, 2H），7.48（d, 2H），7.37（t, 3H），7.11（d, 2H），6.60（t, 1H），6.51（d, 2H），6.42（d, 2H），3.61-3.57（m, 1H），3.47-3.39（m, 3H），3.23-2.98（m, 6H），2.81（s, 3H），2.74-2.68（m, 1H），2.64-2.53（m, 1H），2.26（d, 4H），2.12-1.97（m, 3H）。 The commercially available lumepirone p-toluenesulfonate was subjected to solid-phase characterization and detection, and the test items were ¹ H-NMR, DSC and XRPD. ¹ H-NMR (400MHz, DMSO- d ₆ ): δ9.10 (s, 1H), 8.07-8.03 (m, 2H), 7.48 (d, 2H), 7.37 (t, 3H), 7.11 (d, 2H ), 6.60 (t, 1H), 6.51 (d, 2H), 6.42 (d, 2H), 3.61-3.57 (m, 1H), 3.47-3.39 (m, 3H), 3.23-2.98 (m, 6H), 2.81 (s, 3H), 2.74-2.68 (m, 1H), 2.64-2.53 (m, 1H), 2.26 (d, 4H), 2.12-1.97 (m, 3H).

盧美哌隆對甲苯磺酸鹽晶型X射線粉末繞射圖如圖1所示，具體地，該X射線粉末繞射圖中在2θ大約為 5.643º，8.428º，11.310º，12.077º，13.284º，15.787º，16.041º，16.421º，17.030º，17.507º， 18.173º，18.985º， 19.243º，19.873º，20.742º，21.650º，22.594º，22.812º，23.429º，23.740º，24.294º，25.656º，26.007º，26.941º，27.269º，29.700º，31.594º，34.869º，37.551º和39.523º處有繞射峰，誤差範圍為±0.2 º。The X-ray powder diffraction pattern of lumepirone p-toluenesulfonate crystal form is shown in Figure 1. Specifically, the X-ray powder diffraction pattern is about 5.643º, 8.428º, 11.310º, 12.077º at 2θ, 13.284º, 15.787º, 16.041º, 16.421º, 17.030º, 17.507º, 18.173º, 18.985º, 19.243º, 19.873º, 20.742º, 21.650º, 22.594º, 22.812º, 23.429º2.09º, 23.429º2.09º, 23.7º , 25.656º, 26.007º, 26.941º, 27.269º, 29.700º, 31.594º, 34.869º, 37.551º and 39.523º have diffraction peaks, and the error range is ±0.2º.

差式掃描量熱曲線（DSC）顯示盧美哌隆對甲苯磺酸鹽晶型吸熱峰峰頂值為179.03 ℃，具體測試結果見圖2。The differential scanning calorimetry curve (DSC) showed that the peak value of the endothermic peak of lumepirone p-toluenesulfonate crystalline form was 179.03 °C, and the specific test results are shown in Figure 2.

實施例Example 11 盧美哌隆半雙羥萘酸鹽的製備方法Preparation method of lumepirone hemipamoate 11

將100 mg（0.175 mmol）盧美哌隆對甲苯磺酸鹽溶於3 mL乙醇中，將34 mg（0.088 mmol）雙羥萘酸溶於0.92 mL氫氧化鈉濃度為 7.5 mg/mL的90%乙醇-水溶液中得到澄清的雙羥萘酸氫氧化鈉溶液（氫氧化鈉濃度為 7.5 mg/mL的90%乙醇-水溶液採用如下方式製備：將乙醇和水以9/1的體積比配成體積分率為90%的乙醇水溶液，再將氫氧化鈉溶解於該溶液中，配成7.5 mg/mL的濃度）。將0.92 mL雙羥萘酸氫氧化鈉溶液於室溫攪拌條件下加入3 mL盧美哌隆對甲苯磺酸溶液中，過濾分離產物並用水沖洗，得到灰色固體濾餅。將濾餅置於真空乾燥箱內40 ℃乾燥12小時，所得樣品進行 ¹H-NMR，XRPD和DSC檢測。 ¹H-NMR結果顯示，得到的樣品為盧美哌隆半雙羥萘酸鹽（鹼：酸莫耳比為1:0.5），核磁測試結果如下： ¹H-NMR（400MHz, DMSO- d ₆ ）：δ8.19（d, 2H），8.04-8.02（m, 2H），7.65（d, 1H），7.32（t, 2H），7.13-7.11（m, 1H），7.01（t, 1H），6.59（s, 1H），6.51（d, 1H），6.41（d, 1H），4.69（s, 1H），3.12（t, 3H），2.80（s, 3H），2.71（t, 1H），2.17（s, 1H），2.08（s, 1H），2.01（s, 2H）。 Dissolve 100 mg (0.175 mmol) of lumiperone p-toluenesulfonate in 3 mL of ethanol and 34 mg (0.088 mmol) of pamoic acid in 0.92 mL of sodium hydroxide at a concentration of 7.5 mg/mL 90% A clear pamoic acid sodium hydroxide solution was obtained in the ethanol-water solution (90% ethanol-water solution with a sodium hydroxide concentration of 7.5 mg/mL was prepared in the following manner: the volume ratio of ethanol and water was 9/1 to form a volume The fraction is 90% ethanol aqueous solution, and then sodium hydroxide is dissolved in the solution to make a concentration of 7.5 mg/mL). Add 0.92 mL pamoic acid sodium hydroxide solution to 3 mL lumepirone p-toluenesulfonic acid solution under stirring at room temperature, filter and separate the product and wash it with water to obtain a gray solid filter cake. The filter cake was dried in a vacuum oven at 40° C. for 12 hours, and the resulting sample was detected by ¹ H-NMR, XRPD and DSC. ^{The 1} H-NMR results showed that the obtained sample was lumepirone hemipamoate (alkaline:acid molar ratio was 1:0.5), and the NMR test results were as follows: ¹ H-NMR (400MHz, DMSO- d ₆ ): δ8.19 (d, 2H), 8.04-8.02 (m, 2H), 7.65 (d, 1H), 7.32 (t, 2H), 7.13-7.11 (m, 1H), 7.01 (t, 1H), 6.59 (s, 1H), 6.51 (d, 1H), 6.41 (d, 1H), 4.69 (s, 1H), 3.12 (t, 3H), 2.80 (s, 3H), 2.71 (t, 1H), 2.17 (s, 1H), 2.08 (s, 1H), 2.01 (s, 2H).

盧美哌隆半雙羥萘酸鹽的XRPD和DSC圖譜分別見圖3和4，結果顯示盧美哌隆半雙羥萘酸鹽為無定型。The XRPD and DSC patterns of lumepirone hemi-pamoate are shown in Figures 3 and 4, respectively, and the results show that lumepirone hemi-pamoate is amorphous.

實施例Example 22 盧美哌隆半雙羥萘酸鹽的製備方法Preparation method of lumepirone hemipamoate 22

將1.44 g（2.546 mmol）盧美哌隆對甲苯磺酸鹽溶於15 mL二氯甲烷中，攪拌條件下加入0.2 N的氫氧化鈉水溶液，分層，棄去水層，減壓濃縮除去溶劑得到盧美哌隆游離鹼。將上述盧美哌隆游離鹼與0.49 g（1.273 mmol）雙羥萘酸溶於20 mL DMSO中，超音波溶解，加入50 mL水，析出固體，攪拌，抽濾，大量水洗，減壓乾燥處理得1.33 g淡黃色固體，收率為89.26%。Dissolve 1.44 g (2.546 mmol) of lumiperone p-toluenesulfonate in 15 mL of dichloromethane, add 0.2 N aqueous sodium hydroxide solution under stirring conditions, separate layers, discard the water layer, and concentrate under reduced pressure to remove the solvent Lumepirone free base was obtained. Dissolve the above-mentioned lumepirone free base and 0.49 g (1.273 mmol) pamoic acid in 20 mL DMSO, dissolve by ultrasonic wave, add 50 mL water, precipitate solid, stir, filter with suction, wash with a large amount of water, and dry under reduced pressure 1.33 g of a light yellow solid was obtained, and the yield was 89.26%.

所得樣品進行 ¹H-NMR和XRPD檢測， ¹H-NMR結果顯示得到的樣品為盧美哌隆半雙羥萘酸鹽（鹼：酸莫耳比為1:0.5），結果如下： ¹H-NMR（400MHz, DMSO- d ₆ ）：δ8.22-8.18（t, 2H），8.05-8.01（m, 2H），7.67-7.65（d, 1H），7.34-7.29（t, 2H），7.16-7.12（t, 1H），7.04-7.00（t, 1H），6.61-6.57（t, 1H），6.53-6.51（d, 1H），6.42-6.40（d, 1H），4.70（s, 1H），3.50-3.44（m, 2H），3.41-3.30（m, 7H），3.23（s, 1H），3.15-3.12（t, 3H），2.80（s, 3H），2.18-1.98（m, 4H）。 The obtained sample was tested by ¹ H-NMR and XRPD, and the result of ¹ H-NMR showed that the obtained sample was lumepirone hemipamoate (base:acid molar ratio was 1:0.5), and the results were as follows: ¹ H- NMR (400MHz, DMSO- d ₆ ): δ8.22-8.18 (t, 2H), 8.05-8.01 (m, 2H), 7.67-7.65 (d, 1H), 7.34-7.29 (t, 2H), 7.16- 7.12 (t, 1H), 7.04-7.00 (t, 1H), 6.61-6.57 (t, 1H), 6.53-6.51 (d, 1H), 6.42-6.40 (d, 1H), 4.70 (s, 1H), 3.50-3.44 (m, 2H), 3.41-3.30 (m, 7H), 3.23 (s, 1H), 3.15-3.12 (t, 3H), 2.80 (s, 3H), 2.18-1.98 (m, 4H).

核磁測試結果顯示盧美哌隆與雙羥萘酸以莫耳比1:0.5成鹽。NMR test results showed that lumepirone and pamoic acid formed a salt with a molar ratio of 1:0.5.

其X射線粉末繞射圖如圖6所示，圖6表明盧美哌隆半雙羥萘酸鹽為無定型。Its X-ray powder diffraction pattern is shown in Figure 6, which shows that lumepirone hemipamoate is amorphous.

實施例Example 33 溶解度對比Solubility comparison

分別取對比例1的盧美哌隆對甲苯磺酸鹽與實施例1和2獲得的盧美哌隆半雙羥萘酸鹽，將三種物質分別加入到相應介質中（測試結果見表1，其中pH3為醋酸緩衝溶液，pH5、pH7和pH9均為磷酸緩衝溶液），將所得溶液在37 ℃條件下振盪24小時，使用0.45 µm水相濾膜過濾，收集濾液。採用高效液相色譜測定三種物質在測試介質中的溶解度。Take the lumepirone p-toluenesulfonate of Comparative Example 1 and the lumepirone hemipamoate obtained in Examples 1 and 2 respectively, and add the three substances to the corresponding medium respectively (see Table 1 for test results, Among them, pH3 is acetic acid buffer solution, pH5, pH7 and pH9 are all phosphate buffer solutions), the resulting solution was shaken at 37 °C for 24 hours, filtered through a 0.45 μm aqueous phase filter membrane, and the filtrate was collected. The solubility of the three substances in the test medium was determined by high performance liquid chromatography.

表1顯示本發明製得的盧美哌隆半雙羥萘酸鹽在水和不同pH介質中的溶解度顯著低於盧美哌隆對甲苯磺酸鹽，盧美哌隆半雙羥萘酸鹽在水中的溶解度為7~8 µg/ mL，這相當於盧美哌隆對甲苯磺酸鹽的約1/200。並且在各pH介質中盧美哌隆半雙羥萘酸鹽溶解度均較低，且溶解度差異小，表明該鹽型本身就具有緩釋作用，且釋放速度可以最小程度地依賴於pH，從而避免在體內不同區域的pH環境中對其釋藥速率的影響，造成突釋現象或體內局部區域血藥濃度過高，以及降低了個體間釋藥差異性，因此適合用於製備長效製劑，可減少用藥次數，提高患者用藥依從性，市場化前景良好。 表1溶解度對比結果 介質 溶解度（µg/mL） 對比例1 實施例1 實施例2 水 1463.01 8.04 7.30 pH 3 1280.88 47.37 29.72 pH 5 1504.91 11.80 10.77 pH7 462.59 13.94 11.81 pH 9 57.63 14.45 13.04 Table 1 shows that the solubility of lumepirone semi-pamoate obtained in the present invention in water and different pH media is significantly lower than that of lumepirone p-toluenesulfonate, lumepirone semi-pamoate The solubility in water is 7~8 µg/mL, which is equivalent to about 1/200 of lumepirone p-toluenesulfonate. And in each pH medium, the solubility of lumepirone hemipamoate is low, and the solubility difference is small, indicating that the salt type itself has a sustained release effect, and the release rate can be minimally dependent on pH, thereby avoiding The influence of the pH environment in different regions of the body on its drug release rate, resulting in a burst release phenomenon or excessively high blood drug concentration in a local area of the body, and reduces the variability in drug release between individuals, so it is suitable for the preparation of long-acting preparations. Reduce the number of medications, improve patient compliance, and have a good market prospect. Table 1 Solubility comparison results medium Solubility (µg/mL) Comparative example 1 Example 1 Example 2 water 1463.01 8.04 7.30 pH 3 1280.88 47.37 29.72 pH 5 1504.91 11.80 10.77 pH7 462.59 13.94 11.81 pH 9 57.63 14.45 13.04

實施例Example 44 有關物質含量與穩定性對比Content and stability comparison of related substances

取盧美哌隆對甲苯磺酸鹽與實施例2獲得的盧美哌隆半雙羥萘酸鹽於加速條件下（40 ℃/75 %RH）放置，分別於0天、1月以及3.5月取樣進行有關物質檢測。Lumepirone p-toluenesulfonate and Lumepirone hemipamoate obtained in Example 2 were placed under accelerated conditions (40 ° C / 75 % RH), respectively at 0 days, 1 month and 3.5 months Sampling for related substance testing.

加速條件下有關物質檢測結果見表2。表2顯示本發明的盧美哌隆半雙羥萘酸鹽與市售盧美哌隆對甲苯磺酸鹽在1個月時，雜質類型及雜質含量增長量相當，但在3.5月時有關物質RRT0.83和RRT1.06含量及總雜含量變化上，本發明的盧美哌隆半雙羥萘酸鹽較市售盧美哌隆對甲苯磺酸鹽存在明顯優勢，即本發明的盧美哌隆半雙羥萘酸鹽穩定性更好。 表2 有關物質檢測結果 名稱 時間 有關物質(%) RRT0.83 RRT1.06 總變化 盧美哌隆對甲苯磺酸鹽 0天 ND 0.07 0 1月 0.07 0.06 0.08 3.5月 0.13 0.18 2.17 盧美哌隆半雙羥萘酸鹽 0天 ND ND 0 1月 ND 0.05 0.07 3.5月 0.07 0.06 0.97 注意：ND= 未檢出；最後一列「總變化」是有關物質含量相對於第0天時的增量。 The test results of related substances under accelerated conditions are shown in Table 2. Table 2 shows that the lumepirone hemipamoate of the present invention and the commercially available lumepirone p-toluenesulfonate have the same impurity types and impurity content growth in 1 month, but the related substances in 3.5 months In terms of RRT0.83 and RRT1.06 content and total impurity content changes, Lumepirone hemipamoate of the present invention has obvious advantages over commercially available Lumepirone p-toluenesulfonate, that is, Lumepirone of the present invention Pironone hemipamoate is more stable. Table 2 Test results of related substances name time relative substance(%) RRT0.83 RRT1.06 total change Lumepirone p-toluenesulfonate 0 days ND 0.07 0 January 0.07 0.06 0.08 3.5 months 0.13 0.18 2.17 Lumepirone hemipamoate 0 days ND ND 0 January ND 0.05 0.07 3.5 months 0.07 0.06 0.97 Note: ND=not detected; the last column "total change" is the increment of the content of the relevant substance relative to day 0.

無none

[圖1]為對比例1盧美哌隆對甲苯磺酸鹽XRPD圖譜。 [圖2]為對比例1盧美哌隆對甲苯磺酸鹽DSC圖譜。 [圖3]為實施例1盧美哌隆半雙羥萘酸鹽XRPD圖譜。 [圖4]為實施例1盧美哌隆半雙羥萘酸鹽DSC圖譜。 [圖5]為實施例2盧美哌隆半雙羥萘酸鹽 ¹H-NMR圖譜。 [圖6]為實施例2盧美哌隆半雙羥萘酸鹽XRPD圖譜。 [Fig. 1] is the XRPD pattern of Lumepirone p-toluenesulfonate in Comparative Example 1. [Fig. 2] is the DSC spectrum of lumepirone p-toluenesulfonate in Comparative Example 1. [ Fig. 3 ] is the XRPD pattern of Lumepirone hemipamoate in Example 1. [ Fig. 4 ] is the DSC spectrum of Lumepirone hemipamoate in Example 1. [ Fig. 5 ] is the ¹ H-NMR spectrum of lumepirone hemipamoate in Example 2. [ Fig. 6 ] is the XRPD pattern of Lumepirone hemipamoate in Example 2.

Claims (10)

一種盧美哌隆藥用鹽，其中該盧美哌隆藥用鹽係為盧美哌隆游離鹼與六個碳以上的有機酸形成的鹽。A pharmaceutically acceptable salt of lumepirone, wherein the pharmaceutically acceptable salt of lumepirone is a salt formed of lumepirone free base and an organic acid with more than six carbons. 如請求項1所述之盧美哌隆藥用鹽，其中該「六個碳以上的有機酸」為C ₆-C ₃₀的有機酸；該「C ₆-C ₃₀的有機酸」選自：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、十一烷酸、月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕櫚酸、十七烷酸、硬脂酸、十九烷酸、二十烷酸、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸、甘油三乙酸、木質酸、雙羥萘酸、1-羥基-2萘甲酸、雙羥萘酸和萘酸衍生物。 The medicinal salt of lumepirone as described in claim 1, wherein the "organic acid with more than six carbons" is a C ₆ -C ₃₀ organic acid; the "C ₆ -C ₃₀ organic acid" is selected from: Caproic acid, heptanoic acid, caprylic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid Acid, nonadecanoic acid, eicosanoic acid, oleic acid, behenic acid, behenic acid, tricosanoic acid, lignoceric acid, pentadecanoic acid, hexacosanoic acid , Hecosanoic Acid, Octacosanoic Acid, Nonacosanoic Acid, Triacosanoic Acid, Glyceryl Triacetate, Ligninic Acid, Pamoic Acid, 1-Hydroxy-2 Naphthoic Acid, Pamoic Acid, and Naphthalene acid derivatives. 如請求項1所述之盧美哌隆藥用鹽，其中該盧美哌隆藥用鹽為盧美哌隆半雙羥萘酸鹽，其中盧美哌隆與雙羥萘酸以莫耳比1:0.5進行複合成鹽。The medicinal salt of lumiperone as described in claim 1, wherein the medicinal salt of lumiperone is lumiperone semi-pamoate, wherein the molar ratio of lumiperone and pamoic acid 1:0.5 for complex salt formation. 如請求項3所述之盧美哌隆藥用鹽，其中該盧美哌隆雙羥萘酸鹽為無定型； 優選地，該盧美哌隆半雙羥萘酸鹽無定型的X射線粉末繞射圖基本如圖3所示。 The medicinal salt of lumepirone as described in claim 3, wherein the lumepirone pamoate is amorphous; Preferably, the X-ray powder diffraction pattern of the amorphous lumepirone hemipamoate is basically as shown in FIG. 3 . 一種如請求項1至4中任一項所述之盧美哌隆藥用鹽的製備方法，其包括以下步驟：將盧美哌隆游離鹼與如上該六個碳以上的有機酸進行成鹽反應。A method for preparing the pharmaceutically acceptable salt of lumepirone as described in any one of claims 1 to 4, comprising the following steps: salt-forming lumepirone free base and the above organic acid with more than six carbons reaction. 如請求項5所述之製備方法，其中該盧美哌隆半雙羥萘酸鹽無定型的製備方法包括如下步驟： 方法(1)：將盧美哌隆對甲苯磺酸鹽溶於乙醇中得溶液A，將雙羥萘酸溶於氫氧化鈉乙醇溶液得溶液B，將溶液B加入溶液A中進行攪拌；或 方法(2)：將盧美哌隆與雙羥萘酸溶於DMSO，加入反溶劑水，攪拌析出。 The preparation method as described in claim item 5, wherein the preparation method of the amorphous lumepirone hemipamoate comprises the following steps: Method (1): dissolving lumepirone p-toluenesulfonate in ethanol to obtain solution A, dissolving pamoic acid in sodium hydroxide ethanol solution to obtain solution B, adding solution B to solution A and stirring; or Method (2): Dissolve lumepirone and pamoic acid in DMSO, add anti-solvent water, and stir to precipitate. 一種如請求項1至4中任一項所述之盧美哌隆藥用鹽用於製備治療和/或預防成人精神***症、雙相性障礙或急性躁狂症的藥物之用途。A use of lumepirone pharmaceutical salt as described in any one of claims 1 to 4 for preparing a medicament for treating and/or preventing adult schizophrenia, bipolar disorder or acute mania. 如請求項7所述之用途，其中該盧美哌隆藥用鹽為盧美哌隆半雙羥萘酸鹽。The use as described in Claim 7, wherein the pharmaceutically acceptable salt of lumepirone is lumepirone hemipamoate. 一種藥物組合物，其包括請求項1至4中任一項所述之盧美哌隆藥用鹽； 優選地，該藥物組合物包括藥學上可接受的輔料； 優選地，該藥學上可接受的輔料包括生理或藥學上可接受的載體、稀釋劑、媒介物和/或賦形劑中的一種，兩種或更多種。 A pharmaceutical composition comprising the pharmaceutically acceptable salt of lumepirone described in any one of claims 1 to 4; Preferably, the pharmaceutical composition includes pharmaceutically acceptable excipients; Preferably, the pharmaceutically acceptable adjuvant includes one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients. 一種盧美哌隆藥物製劑，其包括請求項1至4中任一項所述盧美哌隆藥用鹽； 優選地，該盧美哌隆藥物製劑的劑型選自片劑、膠囊、溶液劑、混懸劑和半固體製劑。 A pharmaceutical preparation of lumepirone, which includes the medicinal salt of lumepirone described in any one of claim items 1 to 4; Preferably, the dosage form of the lumepirone pharmaceutical preparation is selected from tablet, capsule, solution, suspension and semi-solid preparation.

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