WO2018227429A1 - 一种晶ii型物质及其制备方法、药物组合物与用途 - Google Patents

一种晶ii型物质及其制备方法、药物组合物与用途 Download PDF

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WO2018227429A1
WO2018227429A1 PCT/CN2017/088251 CN2017088251W WO2018227429A1 WO 2018227429 A1 WO2018227429 A1 WO 2018227429A1 CN 2017088251 W CN2017088251 W CN 2017088251W WO 2018227429 A1 WO2018227429 A1 WO 2018227429A1
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crystalline form
pharmaceutical composition
compound
preparation
substance
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李润涛
吕扬
崔景荣
杜冠华
葛泽梅
杨世颖
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北京大学
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/21—Radicals derived from sulfur analogues of carbonic acid

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  • the present invention relates to 1-piperazine dithiocarbazin-3-cyano-3,3-diphenylpropyl ester hydrochloride (abbreviated as "Compound A” in the entire text of the present invention) which is present in a solid state.
  • the seed crystal type II substance, the preparation method thereof, the pharmaceutical composition, and the crystal type II substance of the compound A as an active ingredient are used in the preparation of a medicament for anti-tumor and tumor prevention diseases, and belong to the field of medical technology.
  • the compound A has the following structure:
  • Aminodithioformate compounds are widely used in many fields, especially in the field of pesticides. However, there have been few studies on the antitumor activity of such compounds.
  • Gerhauser C et al. isolated an aminodithioformate Brassinium from cruciferous plants, which has a strong tumor preventive effect (Cancer Research 1997, 57, 272-278). Based on this work, we have found a piperazinyl dithioformate compound with remarkable anti-tumor effect.
  • Chinese patent CN 1328999A Publication No.
  • the "piperazinyl dithiocarboxylic acid" of the invention of Peking University Li Runtao et al. Esters their preparation and their use in antitumor drugs.
  • a piperazinyl dithioformate compound, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same are disclosed, and the compound is useful for inhibiting tumor growth, and the compound A is one of the most excellent compounds.
  • a first aspect of the invention provides a crystalline Form II material of Compound A.
  • a second aspect of the invention provides a process for the preparation of a compound A crystalline Form II material.
  • a third aspect of the invention provides a composition comprising a compound A crystalline Form II material.
  • a fourth aspect of the invention provides the use of a Compound A crystalline Form II material for the manufacture of a medicament for the treatment and prevention of a tumor.
  • the present inventors have found that the crystalline VII type solid substance of Compound A has an absorption advantage in a living body and can increase the blood drug concentration in a living body, thereby completing the present invention.
  • Figure 1 is an X-ray diffraction pattern of a powder of a Compound A crystal Form II sample.
  • Figure 2 is an infrared spectrum of a Compound A crystal Form II sample.
  • Figure 3 is a differential scanning calorimetry map of Compound A crystal Form II sample.
  • Figure 4 is a graph showing the blood concentration of a Compound A crystal Form II sample after oral absorption in a rat.
  • the compound A crystalline Form II material of the present invention behaves as: diffraction peak position 2-Theta value (°), d value ( ), the peak intensity of the diffraction peak (Height%), and the peak area value (Area%) have the following characteristic peaks (Table 1, Figure 1):
  • the compound A crystalline Form II material of the present invention behaved as 2997, 2957, 2914, 2743, 2699, 2648, 2620, 2432, 2241, 1571, 1491, 1469, 1448, 1402, 1383. , 1362, 1339, 1311, 1257, 1243, 1202, 1158, 1141, 1077, 1057, 1027, 1016, 1000, 980, 912, 893, 870, 852, 810, 776, 766, 752, 729, 698 cm -1 There are characteristic peaks of the infrared spectrum, and the allowable deviation of the characteristic peaks of the infrared spectrum is ⁇ 2 cm -1 (Fig. 2).
  • the compound A crystalline Form II material of the present invention exhibits a Peak endotherm at 202 ° C ⁇ 3 ° C in a DSC pattern at a heating rate of 10 ° C per minute. Peak ( Figure 3).
  • the melting point is 201 ° C ⁇ 2 ° C.
  • the compound A crystal form of the present invention is prepared by completely dissolving the compound A sample by using a mixed solvent of tetrahydrofuran and ethyl acetate (for example, a volume ratio of 1:1 to 2:1), and the ambient temperature is 10 ° C to 80 ° C.
  • the crystallizing type II substance of the compound A is obtained by a recrystallization preparation process at ° C and an ambient humidity of 10% to 75%.
  • the pharmaceutical composition of the present invention contains a crystalline Form II substance of Compound A or a mixed crystalline solid substance containing Compound A crystalline Form II substance in an effective amount, and contains a pharmaceutically acceptable carrier.
  • the effective dose is equivalent to 1-piperazin dithiocarbazin-3-cyano-3,3-diphenylpropyl ester hydrochloride. 300 mg/kg body weight, preferably 10 to 100 mg/kg body weight.
  • the pharmaceutical composition of the present invention may be a tablet, a capsule, a pill, an injection, a sustained release preparation or a controlled release preparation.
  • the present invention also relates to the use of a Compound A crystalline Form II substance or a pharmaceutical composition comprising a Compound A crystalline Form II substance for the preparation of a medicament for the prevention and treatment of a tumor.
  • the present invention relates to a biological absorption effect of a drug developed by using a compound A crystal form II substance as an active ingredient and a pharmaceutical composition thereof, which is characterized by using a compound A crystal form type II as described in the claims of the present invention.
  • the substance acts as an active ingredient and exerts a dominant effect in the prevention and treatment of diseases by rapidly reaching the maximum concentration value in the gastrointestinal tract or blood (Fig. 4).
  • a pure product of the compound A crystal form II substance or a mixed crystal solid substance containing the compound A crystal form II substance is used as a raw material drug, and a tablet containing 10 to 300 mg of each tablet is prepared by using several excipients. 2 gives the formulation of the tablet:
  • the excipients and the raw materials in each formula are mixed uniformly according to the dosage, and the appropriate amount of 1% hydroxymethylcellulose sodium solution is added to prepare a soft material, sieving and granulating, drying the wet granules, sieving the granules, adding the hard
  • the magnesium oleate and talc powder are evenly mixed and compressed.
  • a pure product of the compound A crystal form II substance or a mixed crystal solid substance containing the compound A crystal form II substance is used as a raw material drug, and each of the capsules having a drug content of 10 to 300 mg is prepared by using several excipients, Table 3
  • Table 3 The formulation of the capsule is given:
  • the SPF-class SD rats weighing 190-210 g were fed with normal feeding conditions, freely drinking water, and fasted for 12 hours.
  • the drugs were administered orally at 150 mg/kg, before administration and 45 min, 2 h, 4 h, 6 h, 8 h after administration.
  • blood was taken from the eye in heparinized tubes, centrifuged, and 0.15 mL of plasma was taken.
  • the solution was reconstituted with 100 ⁇ L of the mobile phase. 20 ⁇ L of the sample was applied for HPLC detection, and the ratio of the sample to the internal standard peak area was used for quantitative analysis.
  • the HPLC detection system was an Aligent 1200 HPLC system with Agilent Zorbax SB-C 18 (4.6 ⁇ 250 mm, 5 ⁇ m), a gradient elution mobile phase system (see Table 4), injection volume 20 ⁇ L, flow rate It was 1 mL/min, the detection wavelength was 254 nm, and the column temperature was 30 °C. The results showed that the oral compound A crystal form II sample was able to detect the active ingredient in the blood after 4 hours (see Table 5).
  • Example 5 Administration dose of a drug of Form II of Compound A as an active ingredient
  • Compound A is administered at a daily dose of 300 mg/kg body weight, and can be prepared 3 times a day/one tablet 100 mg each time. /kg body weight ordinary tablets, 2 times a day / 1 piece of 150mg / kg body weight of ordinary tablets or 1 time / 1 piece of 300mg / kg body weight of the tablet type.
  • the pharmaceutical composition of the compound A crystalline Form II substance according to the present invention has many factors influencing the dosage of the active ingredient, for example, the use of the dosage for daily use for prevention and treatment is different. Different; the nature of the disease is different from the severity of the disease, resulting in daily dose The difference in the patient's gender, age, body surface area, the route of administration, the number of doses, and the purpose of treatment, resulting in different daily doses; in addition, the absorption and blood concentration between the crystal samples are different, etc.
  • the daily suitable dosage range for the use of the crystalline Form II component of the present invention in the present invention is from 1 to 300 mg/kg body weight, preferably from 1 to 100 mg/kg body weight.
  • the total dose of Compound A New Form II active ingredient should be formulated according to the actual needs of prevention and treatment, and can be divided into multiple or one-time administration.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

提供一种化合物A(化学名：1-哌嗪二硫代甲酸-3-氰基-3,3-二苯基丙酯盐酸盐)的晶II型物质及其制备方法、药物组合物与在制备用于治疗和预防肿瘤的药物中的用途。

Description

一种晶II型物质及其制备方法、药物组合物与用途 技术领域
本发明涉及1-哌嗪二硫代甲酸-3-氰基-3,3-二苯基丙酯盐酸盐(在本发明的全文中简称为“化合物A”)在固体状态下存在的一种晶II型物质及其制备方法、药物组合物，还涉及化合物A的晶II型物质作为活性成分在制备抗肿瘤和肿瘤预防疾病药物中的应用，属于医药技术领域。所述化合物A具有如下结构：
Figure PCTCN2017088251-appb-000001
背景技术
氨基二硫代甲酸酯类化合物在许多领域都有着广泛的应用，特别是在农药领域中常用作杀菌剂。然而，有关该类化合物的抗肿瘤活性方面的研究却很少。
Gerhauser C等人从十字花科植物中分离出一种氨基二硫代甲酸酯类化合物Brassinium，该化合物具有较强的肿瘤预防作用(Cancer Research 1997,57,272-278)。基于这一工作，我们发现了抗肿瘤作用显著的哌嗪基二硫代甲酸酯类化合物，在中国专利CN 1328999A(公开号)中记载了北京大学李润涛等发明的“哌嗪基二硫代甲酸酯类化合物，它们的制备方法和在抗肿瘤药物中的应用”。其中，涉及了哌嗪基二硫代甲酸酯类化合物及其可药用盐和包含该化合物的药用组合物，该类化合物可用于抑制肿瘤生长，化合物A是最优秀的化合物之一。
在中国专利CN 1727332A(公开号)中记载了北京大学李润涛等发明的“芳甲氨基二硫代甲酸酯类化合物及其制备方法和应用”。其中，涉及了一类结构具有抗肿瘤活性的氨基二硫代甲酸酯类化合物或其可药用盐及其包含该化合物的药物组合物。
上述文献和专利是从化合物的分离提取、合成纯化等制备方法和临床治疗作用方面进行描述，而本发明切入点与上述文献和专利存在本质差异，即是从化合物A的固体物质存在状态研究入手，通过多晶型筛选技术研究，在药物活性成分的原料层面上寻找、发现化合物A固体物质的新晶型种类与状态特征，并将晶型研究与临床和保健应用结合，为寻找、发现、开发具有最佳功效的化合物A物质状态提供基础科学研究数据。
发明内容
本发明的第一方面提供了化合物A的晶II型物质。
本发明的第二方面是提供了化合物A晶II型物质的制备方法。
本发明的第三方面提供了含有化合物A晶II型物质的药物其组合物。
本发明的第四方面提供了化合物A晶II型物质在制备用于治疗和预防肿瘤的药物中的用途。
本发明人发现，化合物A的晶VII型固体物质在生物体内具有吸收优势，能够提高生物体内血药浓度，从而完成了本发明。
附图说明
图1为化合物A晶II型样品的粉末的X射线衍射图谱。
图2为化合物A晶II型样品的红外图谱。
图3为化合物A晶II型样品的差示扫描量热图谱。
图4为化合物A晶II型样品经口服吸收后在大鼠体内的血药浓度曲线。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。
1.化合物A晶II型物质的形态特征：
1.1当使用粉末X射线衍射分析采用CuKα辐射实验条件时，本发明的化合物A晶II型物质表现为：衍射峰位置2-Theta值(°)、d值(
Figure PCTCN2017088251-appb-000002
)、衍射峰相对强度峰高值(Height％)、峰面积值(Area％)具有如下特征峰值(表1，图1)：
表1  化合物A晶II型样品的粉末X射线衍射特征峰值
Figure PCTCN2017088251-appb-000003
1.2当使用红外光谱技术分析时，本发明的化合物A晶II型物质表现为在2997、2957、2914、2743、2699、2648、2620、2432、2241、1571、1491、1469、1448、1402、1383、1362、1339、1311、1257、1243、1202、1158、1141、1077、1057、1027、1016、1000、980、912、893、870、852、810、776、766、752、729、698cm-1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2cm-1(图2)。
1.3在使用差示扫描量热技术分析时，本发明的化合物A晶II型物质表现为：在升温速率为每分钟10℃的DSC图谱中，在202℃±3℃处具有1个Peak吸热峰(图3)。
1.4当使用熔点仪进行样品分析(例如升温速率为每分钟1℃)时，其熔点值为201℃±2℃。
2.化合物A晶II型物质的制备方法特征：
本发明的化合物A晶II型的制备方法为：使用四氢呋喃和乙酸乙酯的混合溶剂(例如体积比为1:1至2:1)将化合物A样品完全溶解后，经环境温度10℃～80℃、环境湿度10％～75％下的重结晶制备工艺获得化合物A的晶II型物质。
3.化合物A的药物组合物及用途特征：
3.1本发明的药物组合物以有效剂量含有化合物A的晶II型物质或含有化合物A晶II型物质的混晶固体物质，并且含有药学上可接受的载体。
3.2在本发明的药物组合物中，所述有效剂量相当于1-哌嗪二硫代甲酸-3-氰基-3,3-二苯基丙酯盐酸盐的每日用药剂量为1-300mg/kg体重，优选为10～100mg/kg体重。
3.3本发明的药物组合物可以是片剂、胶囊、丸剂、针剂、缓释制剂或控释制剂。
3.4本发明还涉及化合物A晶II型物质或含有化合物A晶II型物质的药物组合物在制备用于预防和治疗肿瘤的药物中的用途。
4.化合物A晶II型物质的吸收特征：
本发明涉及使用了化合物A晶II型物质作为活性成分开发的药物及其药物组合物经口服后的生物学吸收作用，其特征在于使用了含有本发明权利要求中所述的化合物A晶II型物质作为活性成分，通过胃肠道或血液中迅速达到最大浓度值而在防治疾病中发挥的优势作用(图4)。
实施例
为更好说明本发明的技术方案，特给出以下实施例，对本发明进行详细描述，但本发明并不仅限于此。除非特别说明，以下实施例中所用到的试剂均为市售商品，所用到的操作均按常规方案进行。
实施例1  化合物A晶II型物质的制备方法
制备方法1：
使用60mL四氢呋喃溶剂在室温下将500mg的化合物A样品完全溶解后，再加入60mL乙酸乙酯，在室温条件下重结晶制备获得化合物A晶II型物质，其粉末X射线衍射图谱与图1一致。
制备方法2：
使用比例为2:1的四氢呋喃:乙酸乙酯混合溶剂在40℃下将500mg的化合物A样品完全溶解后，在40℃条件下重结晶制备获得化合物A晶II型物质，其粉末X射线衍射图谱与图1一致。
实施例2  药物组合物的制备方法1(片剂)：
将化合物A晶II型物质的纯品、或含有化合物A晶II型物质的混晶固体物质作为原料药，用几种赋形剂制成每片含药量在10～300mg的片剂，表2给出了片剂的配方：
表2  化合物A的药物组合物(片剂)的制备配方
Figure PCTCN2017088251-appb-000004
将各配方中的赋形剂与原料药按用量混合均匀，加入1％羟甲基纤维素钠溶液适量，制成软料，过筛制粒，湿粒烘干，过筛整粒，加入硬脂酸镁和滑石粉混合均匀，压片，即得。
实施例3  药物组合物的制备方法2(胶囊)
将化合物A晶II型物质的纯品、或含有化合物A晶II型物质的混晶固体物质作为原料药，用几种赋形剂制成每粒含药量在10～300mg的胶囊，表3给出了胶囊的配方：
表3  化合物A的药物组合物(胶囊)的制备配方
Figure PCTCN2017088251-appb-000005
将各种赋形剂与原料药按配方用量混合均匀，加入1％羟甲基纤维素钠溶液适量，制成湿粒，烘干，过筛整粒，加入硬脂酸镁，混合均匀，插入胶囊制得。或不使用制粒步骤，而直接将原料药与几种赋形剂混合均匀，过筛后，直接装入胶囊制得。
实施例4  化合物A的晶II型物质在大鼠体内吸收特征和血药浓度特征
采用体重190～210g的SPF级SD大鼠常规饲养条件饲养，自由饮水，禁食12h后，按150mg/kg灌胃给予药物，于给药前及给药后45min、2h、4h、6h、8h、10h、12h、13.5h、14.5h、16h和24h，由眼内眦取血于肝素化试管中，离心，取血浆0.15mL，加内标10μL混均后，加0.8mL乙酸乙酯，振荡混均3min，13,400rpm离心10min，取上清液氮气吹干，以流动相100μL复溶，上样20μL进行HPLC检测，用样品与内标峰面积比进行定量分析。HPLC检测系统为Aligent 1200高效液相色谱系统，色谱柱为Agilent Zorbax SB-C18(4.6×250mm,5μm)，采用梯度洗脱的流动相系统(见表4)，进样量为20μL，流速为1mL/min，检测波长为254nm，柱温为30℃。结果显示，大鼠口服化合物A晶II型样品在4h后血液中即可检测出活性成分(见表5)。
表4.梯度洗脱的流动相系统数据
Figure PCTCN2017088251-appb-000006
表5.大鼠口服化合物A晶II型样品后的药时曲线数据
Figure PCTCN2017088251-appb-000007
实施例5  化合物A的晶II型物质作为活性成分的药品给药剂量
对于使用化合物A的晶II型物质作为药物活性成分制备开发的药物片剂或其他制剂，化合物A每日给药剂量为300mg/kg体重，可分别制备成每日3次/每次1片100mg/kg体重普通片剂，每日2次/每次1片150mg/kg体重普通片剂或每日1次/每次1片300mg/kg体重的片剂类型。
需要说明的是，本发明涉及的化合物A晶II型物质的药物组合物在有效成分的给药剂量上存在有许多因素影响，例如：用于预防和治疗的用途不同而造成每日用药剂量的不同；患病性质与患病严重程度不同而造成每日用药剂量 的不同；患者性别、年龄、体表面积的不同，给药途径、给药次数、治疗目的不同而造成每日用药剂量的不同；此外，晶型样品间存在的吸收和血药浓度不同等，亦造成本发明在使用化合物A的晶II型成分的每日合适剂量范围为1～300mg/kg体重，优选为1～100mg/kg体重。使用时应根据实际的预防与治疗不同情况需求制定化合物A新晶II型有效成分总剂量方案，并可分为多次或一次给药方式完成。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。

Claims (10)

1-哌嗪二硫代甲酸-3-氰基-3,3-二苯基丙酯盐酸盐的晶II型物质，其特征在于，当使用粉末X射线衍射分析采用CuKα辐射实验条件时，衍射峰位置2-Theta值(°)、d值
Figure PCTCN2017088251-appb-100001
衍射峰相对强度峰高值(Height％)、峰面积值(Area％)具有如下特征：
Figure PCTCN2017088251-appb-100002
根据权利要求1所述的晶II型物质，其特征在于，使用红外光谱技术分析时，表现为2997、2957、2914、2743、2699、2648、2620、2432、2241、1571、1491、1469、1448、1402、1383、1362、1339、1311、1257、1243、1202、1158、1141、1077、1057、1027、1016、1000、980、912、893、870、852、810、776、766、752、729、698cm-1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2cm-1。
根据权利要求1所述的晶II型物质，其特征在于，使用差示扫描量热技术分析时，所述晶II型物质表现为：在升温速率为每分钟10℃的DSC图谱中，在202℃±3℃处具有1个吸热峰。
根据权利要求1所述的晶II型物质，其特征在于，当使用熔点仪进行样品分析时，其熔点值为201℃±2℃。
1-哌嗪二硫代甲酸-3-氰基-3,3-二苯基丙酯盐酸盐的混晶固体物质，其特征在于，所述混晶固体物质含有权利要求1-4任一所述的晶II型物质。
权利要求1-4任一所述的晶II型物质的制备方法，其特征在于，使用四氢呋喃和乙酸乙酯的混合溶剂(例如体积比为1:1至2:1)将化合物A样品完全溶解后，经环境温度10℃～80℃、环境湿度10％～75％下的重结晶制备工艺获得晶II型固体样品。
一种药物组合物，其特征在于，所述药物组合物以有效剂量含有权利要求1-4任一所述的晶II型物质或如权利要求5所述的混晶固体物质，并且含有药学上可接受的载体。
根据权利要求7的药物组合物，其特征在于，所述有效剂量相当于1-哌嗪二硫代甲酸-3-氰基-3,3-二苯基丙酯盐酸盐的每日用药剂量为1-300mg/kg体重，优选为10～100mg/kg体重。
根据权利要求7的药物组合物，其特征在于，所述的药物组合物是片剂、胶囊、丸剂、针剂、缓释制剂或控释制剂。
权利要求1-4任一所述的晶II型物质或权利要求7所述的药物组合物在制备用于治疗和预防肿瘤的药物中的用途。
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