CN1572789A - 1-(2,6-二氟苄基)-1h-1,2,3-三唑-4-甲酰胺的结晶改良体及其用作抗癲痫药的用途 - Google Patents
1-(2,6-二氟苄基)-1h-1,2,3-三唑-4-甲酰胺的结晶改良体及其用作抗癲痫药的用途 Download PDFInfo
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Abstract
本发明涉及新的式(I)所示的化合物1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的改良体C,它治疗癫痫的用途以及含有这些结晶改良体的药物制剂。
Description
本申请是申请号为98805675.5、申请日为1998年6月8日、发明名称为“1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的结晶改良体及其用作抗癫痫药的用途”的中国专利申请的分案申请。
技术领域
本发明涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的结晶改良体及其用作抗癫痫药的用途。
背景技术
下式所示的化合物1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺:
已在欧洲专利申请公开No.0 199 262 A2(EP 199262)中有所描述,例如实施例4。该化合物显示出有价值的药理学特性;因此可将它用作例如抗癫痫药。化合物1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺是按照EP199262中的方法、以2,6-二氟苄基叠氮化物为起始反应物并通过形成1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-羧酸而制得,该方法类似于实施例2。
EP199262中没有记载任何关于获得可能的结晶改良体的内容。若按照实施例4所述的方法并结合实施例2,制备的1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺粗产物最终是以乙醇重结晶。然而,EP199262中并未明确这种重结晶是要特别采用或需在特定条件下进行。现惊奇地发现,通过对具体选择的反应条件进行选择,例如选择适宜的重结晶溶剂和重结晶时间,可制备特征如下的不同结晶改良体(同质多晶)。
发明内容
所得1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺可以新的结晶改良体-A、A’、B和C形式获得。这些结晶改良体的区别在于:它们的热力学稳定性、如IR和拉曼光谱吸收图谱等物理学参数、X-射线结构分析以及它们的制备方法。
本发明涉及新的B和C结晶改良体、它们的制备方法以及在含有该结晶改良体的药物制剂中的应用。
与A相比,改良体A’在其晶格中有缺陷。这可通过例如X-射线分析的方法对它们进行测定,例如通过对谱线间距的减小以及其他基本相同的谱线或谱带进行分析。
1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的新结晶改良体A在242℃(239-245℃)下熔化。
在FT红外(FT-IR)光谱(KBr压片-透射法)中,改良体A或A’在许多谱带的形状和相对强度上与改良体B和C明显不同。其特有的在改良体B和C的FT-IR光谱中不曾存在的特征是:3412cm-1和3092cm-1处的谱带[参见:附图1]。在4000-600cm-1范围内,由改良体A测得下列特征谱带:3412、3189、3092、1634、1560、1473、1397、1325、1300、1284、1235、1125、1053、1036、1014、885、840、799、781、723、688和640cm-1。可使用例如IFS 88(Bruker)仪器来记录各改良体的FT-IR光谱。
在FT拉曼光谱(粉末-反射法180°)中,改良体A或A’在许多谱带的形状和相对强度上与改良体B和C明显不同。其特有的在改良体B和C的拉曼光谱中不曾存在的特征是:1080cm-1处的谱带[参见:附图2]。在3400-300cm-1范围内,由改良体A测得下列特征谱带:3093、2972、1628、1614、1558、1465、1446、1393、1279、1245、1147、1080、1061、1036、1014、840、724、691、667、550、499、437和368cm-1。可使用例如RFS 100(Bruker)仪器来记录各改良体的FT拉曼光谱。
新改良体A在其X-射线粉末图谱中具有面间距(d值)为:
10.5,5.14,4.84,4.55,4.34,4.07,3.51,3.48,3.25,3.19,3.15,3.07,2.81的特征谱线[参见附表1]。该测量可以以例如透射几何学的方式、使用由Enraf-Nonius,Delft(荷兰)生产的FR 552纪尼叶照相机并利用铜Kα1射线(波长=1.54060)来完成。记录在X-射线胶片上的图谱可用Johannsson,Taby(瑞典)生产的LS-18线性扫描器进行测量并用Scanpi软件(P.E.Werner,Stockholm大学)进行计算。
新改良体A的特征在于其由差示扫描量热法测得的热分析图。在该图的230-260℃范围间显示一个吸热峰。该峰值温度为239-245℃并且该吸热信号为209J/g+/-10J/g。测量是利用Perkin Elmer DSC 7、在一个封闭盘内并以20K/分钟的加热速度来完成。标准样品量约为4mg。作为不同于改良体B和C的典型区别特征是:改良体A的热分析图中没有其他热信号。
改良体A’的结晶具有与改良体A相同的晶体结构。但它与改良体A在X-射线粉末图谱中的区别是:其特征谱线对之间的线间距微微减小。它们是具有下列面间距的谱线对:3.68和3.64、3.51和3.48、3.19和3.15。
在FT-IR(KBr压片-透射法)光谱中,改良体B在许多谱带的形状和相对强度上与改良体A、A’和C明显不同,其特征在于1678cm-1处的谱带[参见:附图1],这在改良体A和C的相应图谱中未发现。在4000-600cm-1之间,由改良体B获得下列特征谱带:3404,3199,3125,1678,1635,1560,1475,1393,1357,1322,1286,1237,1051,1036,1028,889,837,800,719,667和645cm-1.。可使用如IFS 85(Bruker)仪来记录各改良体的FT-IR光谱。
在FT-拉曼光谱(粉末-反射法180°)中,改良体B在许多谱带的形状和相对强度上与改良体A、A′和C明显不同,其特征在于3166cm-1和1086cm-1处的谱带[参见:附图2],这在改良体A和C的拉曼图谱中并不存在。在3400-300cm-1之间,由改良体B获得下列特征谱带:3166,3089,2970,1678,1628,1614,1559,1464,1441,1391,1275,1244,1147,1086,1062,1036,1014,839,773,724,690,668,595,549,500,493,430和365cm-1.
可使用如RFS 100(Bruker)仪来记录各改良体的FT-拉曼光谱。
改良体B在其X-射线粉末图谱中具有面间距(d值)为:11.0,8.3,5.18,4.88,4.80,4.42,4.33,4.19,4.12,3.81,3.50,3.41,3.36,3.32,3.28,3.24,3.05,2.83的特征谱线[参见:附表1]。
在差示扫描量热法测得的热分析图中,改良体B除在230-260℃范围内有一个吸热信号(峰值温度239-245℃)外,在205℃(180-220℃)处还有一个弱的热信号并且该信号成为不同于改良体A或A’和C的典型区别特征。
在FT-IR(KBr压片-透射法)光谱中,改良体C在许多谱带的形状和相对强度上与改良体A、A’和B明显不同。其特征在于3137cm-1处的谱带[参见:附图1],这在改良体A和B的相应图谱中并未发现。
在4000-600cm-1之间,由改良体C获得下列特征谱带:C:3396,3287,3137,1657,1631,1602,1559,1475,1392,1323,1287,1237,1122,1104,1047,1035,1012,876,839,797,773,729和653cm-1。可使用如IFS 85(Bruker)仪器来记录各改良体的FT-IR光谱。
在FT-拉曼光谱(粉末-反射法180°)中,改良体C在许多谱带的形状和相对强度上与改良体A或A’和B明显不同。其特有的在改良体A和B的拉曼光谱中不曾存在的特征是:3137和1602cm-1处的谱带[参见:附图2]。在3400-300cm-1之间,由改良体C获得下列特征谱带:3137,3080,3012,2971,1673,1629,1602,1561,1436,1271,1248,1105,1065,1035,1013,839,800,767,726,690,672,593,549,500,492,435和370cm-1。可使用例如RFS100(Bruker)仪来记录各改良体的FT拉曼光谱。
改良体C在其X-射线粉末图谱中具有面间距(d值)为:9.0,4.73,4.65,3.75,3.54,3.42,3.25的特征谱线[参见附表1]。在差示扫描量热法测得的热分析图中,改良体C除在230-260℃范围内有一个吸热信号(峰值温度为239-245℃)外,其在180℃区域内还有一个不同于改良体A或A’和B的很宽并较弱的放热信号。
表1:改良体A、B和C(X-射线粉末图谱)的特征
改良体A: | 改良体B: | 改良体C: | |||
d[] | 强度 | d[] | 强度 | d[] | 强度 |
10.9 | 弱 | 11.0 | 中等 | 9.0 | 中等 |
10.5 | 中等 | 8.3 | 中等 | 7.0 | 弱 |
6.6 | 弱 | 8.1 | 很弱 | 5.49 | 弱 |
5.63 | 弱 | 5.68 | 很弱 | 5.11 | 很弱 |
5.25 | 弱 | 5.18 | 很强 | 4.80 | 弱 |
5.14 | 中等 | 5.11 | 弱 | 4.73 | 强 |
4.94 | 弱 | 4.88 | 中等 | 4.65 | 很强 |
4.84 | 很强 | 4.80 | 强 | 4.47 | 很弱 |
4.55 | 强 | 4.71 | 很弱 | 4.19 | 很弱 |
4.42 | 很弱 | 4.61 | 弱 | 4.11 | 很弱 |
4.34 | 中等 | 4.45 | 弱 | 3.98 | 很弱 |
4.23 | 很弱 | 4.42 | 强 | 3.83 | 很弱 |
4.16 | 弱 | 4.33 | 很强 | 3.75 | 强 |
4.07 | 中等 | 4.19 | 中等 | 3.73 | 弱 |
4.01 | 弱 | 4.12 | 强 | 3.54 | 中等 |
3.68 | 很弱 | 4.09 | 弱 | 3.50 | 弱 |
3.64 | 很弱 | 3.99 | 很弱 | 3.42 | 强 |
3.60 | 弱 | 3.95 | 很弱 | 3.25 | 中等 |
3.56 | 弱 | 3.84 | 弱 | 2.88 | 很弱 |
3.51 | 中等 | 3.81 | 中等 | 2.80 | 很弱 |
3.48 | 中等 | 3.65 | 弱 | 2.74 | 很弱 |
3.38 | 很弱 | 3.61 | 很弱 | 2.67 | 很弱 |
3.25 | 强 | 3.58 | 很弱 | 2.64 | 弱 |
3.19 | 中等 | 3.54 | 弱 |
3.15 | 中等 | 3.50 | 中等 | ||
3.11 | 弱 | 3.47 | 很弱 | ||
3.07 | 中等 | 3.41 | 中等 | ||
2.93 | 很弱 | 3.36 | 很强 | ||
2.87 | 很弱 | 3.32 | 强 | ||
2.81 | 中等 | 3.28 | 中等 | ||
2.76 | 弱 | 3.24 | 中等 | ||
2.73 | 很弱 | 3.10 | 弱 | ||
2.68 | 弱 | 3.07 | 弱 | ||
2.62 | 很弱 | 3.05 | 中等 | ||
2.53 | 弱 | 2.93 | 弱 | ||
2.43 | 弱 | 2.88 | 弱 | ||
2.40 | 很弱 | 2.87 | 很弱 | ||
2.83 | 中等 | ||||
2.66 | 弱 | ||||
2.63 | 很弱 | ||||
2.55 | 弱 | ||||
2.50 | 弱 | ||||
2.46 | 弱 | ||||
2.44 | 弱 | ||||
2.37 | 弱 | ||||
2.35 | 弱 |
单晶X-射线分析:
改良体A、B和C的晶体质量和单位晶胞将通过韦森堡和徘循照相进行鉴定。用四轴Nonius CAD-4衍射仪测量强度。用SHELXS-97解析晶体结构并以SHELXL-97软件进行精确化。
改良体A
空间群:Pan21-斜方晶的
晶胞大小:
a=24.756(5) b=23.069(4) c=5.386(1)
v=3075.9 Z=12 Dx=1.543gcm-3
V/分子式: Vz=256.33
9011个特征反射;其中有2479个反射具有I>2σ(I)的显著性。精确了557个参数。
通过差示傅里叶图确定并按各向同性方式精算出所有H原子的位置。可靠性指数R1:3.65%(所有9011反射的wR2:11.34%)。
改良体B
空间群:P-1-三斜晶的
晶胞大小:
a=5.326(1) b=11.976(2) c=17.355(3)
α=107.22(3)° β=92.17(3)° γ=102.11(3)°
v=1027.93 Z=4 Dx=1.539gcm-3
V/分子式 Vz=257.03
4934个特征反射;其中有834个具有I>2σ(I)的显著性。精确了232个参数。
通过差示傅里叶图确定并按各向同性方式精算出所有H原子的位置。可靠性指数R1:4.20%(所有4934反射的wR2:7.93%)
改良体C
空间群:P21/C-单斜晶的
晶胞大小:
a=10.982(2) b=5.350(1) c=17.945(3)
β=91.59(1)°
v=1053.93 Z=4 Dx=1.501gcm-3
V/分子式: Vz=263.53
3073个特征反射;其中有1071个具有I>2σ(I)的显著性。精确了187个参数。
通过差示傅里叶图确定并按各向同性方式精算出所有H原子位置。可靠性指数R1:5.02%(所有3073反射的wR2:14.55%)
与改良体A或A’相比,改良体B和C具有有价值的药理学特性;尤其可将它们用于癫痫的治疗。
与改良A或A’相比,改良体B和C具有突出的优越性。
我们发现,例如,改良体B与改良体A或A’相比在水和胃液中的溶解速率较快。因此改良体B用于治疗时可以达到快速起作用的效果,这一点对于如急性癫痫发作是特别有利的。
本发明涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的改良体B,其特征在于其在红外图谱(KBr压片-透射法)中具有下列吸收:1678cm-1谱带。
本发明涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的改良体B,其特征在于:由X-射线粉末图谱法测定的具有11.0,8.3,5.18,4.88,4.80,4.42,4.33,4.19,4.12,3.81,3.50,3.41,3.36,3.32,3.28,3.24,3.05和2.83,面间距(d值)的特征谱线。
本发明涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的改良体B,其特征在于具有如表1所示面间距(d值)的特征谱线。
本发明涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的改良体B,它在差示扫描量热法热分析图中除在230-260℃范围内有一个吸热信号(峰值温度239-245℃)外,在205℃(180-220℃)处还有一个弱的热信号。
本发明涉及1-(2,6-二氟苄基)-1H,-1,2,3-三唑-4-甲酰胺的改良体C,它在红外图谱(KB1压片-透射法)中具有下列吸收:3137cm-1谱带。
本发明涉及1-(2,6-二氟苄基)-1H,-1,2,3-三唑-4-甲酰胺的改良体C,其特征在于其X-射线粉末图谱中具有面间距(d值)为:9.0,4.73,4.65,3.75,3.54,3.42,3.25。
本发明涉及1-(2,6-二氟苄基)-1H,-1,2,3-三唑-4-甲酰胺的改良体C,其特征在于具有如表1所示面间距(d值)的特征谱线。
本发明涉及1-(2,6-二氟苄基)-1H,-1,2,3-三唑-4-甲酰胺的改良体C,它在差示扫描量热法热分析图中除在230-260℃范围内有一个吸热信号(峰值温度239-249℃)外,在180℃区域内还有一个很宽并较弱的放热信号。
本发明涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的基本纯的改良体B和C。术语“基本纯”是指以改良体B和C计的纯度>95%,优选>98%,最佳>99%。
本发明涉及含有1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体B和C的药物制剂。本发明特别涉及适于治疗癫痫及其继发病症的药物制剂。本发明还涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体B和C在制备药物制剂中的应用,尤其是在制备治疗癫痫及其继发病症药物制剂中的应用。
新的1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体B和C可以以例如含有有效治疗量活性组分的药物制剂形式来使用,如果需要可结合无机或有机的、固体或液体的、适宜肠胃内(如口服)或肠胃外给药的可药用载体。此外,新的1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体B和C可以采用肠胃外给药或输注溶液的制剂形式给药。上述药物制剂可以经灭菌处理和/或包含例如防腐剂、稳定剂、湿润剂和/或乳化剂、增溶剂、渗透压调节用盐和/或缓冲剂的赋形剂。本发明药物制剂含有约0.1-100%、优选约1-50%的冻干品至约100%的活性组分。
本发明还涉及1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体B和C的用途,尤其是在药物制剂中的用途。所用剂量将取决于多种因素,例如给药方式、物种、患者年龄和/或个体状况。口服给药情况下的每日给药剂量介于约0.25-10mg/kg,并且对于体重约为70Kg的温血物种而言优选介于约20-50mg范围内。
附图说明
附图1是结晶改良体A、B和C的KBr压片的FT-IR光谱图示。
附图2是改良体A、B和C的粉末的FT-拉曼光谱图示。
在两个附图中,改良体A用符号*表示,改良体B用符号**表示而改良体C以符号***表示。
具体实施方式
改良体B和C的制备可通过例如下列实施方式来完成。
实施例1:改良体B
在搅拌和58-63℃下将1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺(18.29kg)溶解在甲酸(89.3kg)中。将上述溶液在20℃至0℃下、以30分钟的时间加入到搅拌的甲醇(105.5升)中然后用甲酸(6.1kg)洗涤,以形成一悬浮液。产物经过滤立即得以分离,用冷甲醇(150升,约4℃)洗涤。于约60℃真空干燥,得到产物改良体B,产率约为94%。
实施例2:改良体C
在搅拌和约90℃下将1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺(15.0g)溶于乙酸(120ml)中。在约8分钟期间内将溶液冷却至20℃,形成悬浮液。产物经过滤立即得以分离,用甲苯(120ml)洗涤,于约60℃真空干燥。得到产物改良体C。产率67.3%。
制剂实施例1:
每剂量单位分别含有100、200或400mg的1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体B或C和下列组分的膜包衣片剂:
芯材 mg mg mg
活性组分 100.00 200.00 400.00
无水、胶体二氧化硅 0.88 1.75 3.5
微晶纤维素 36.62 73.25 146.50
羟丙基甲基纤维素 5.00 10.00 20.00
乳糖 20.00 40.00 80.00
硬脂酸镁 2.00 4.00 8.00
玉米淀粉 10.00 20.00 40.00
羧甲基纤维素钠 5.00 10.00 20.00
十二烷基硫酸钠 0.50 1.00 2.00
包衣膜 mg mg mg
羟丙基甲基纤维素 3.22 6.43 12.87
红氧化铁 0.04 0.09 0.18
聚乙二醇8000 0.58 1.16 2.32
絮片体
滑石 2.33 4.66 9.31
二氧化钛 0.83 1.66 3.32
将活性组分和去离子水一起制粒。然后将研碎的乳糖、玉米淀粉、Avicel PH 102、纤维素-HP-M-603和十二烷基硫酸钠加入到上述混合物中并与去离子水进一步制粒。
将所得湿材干燥并磨碎。加入其余组分后将匀质的混合物压制以制得具有上述活性组分含量的片剂内芯。
将片剂内芯用由适宜组分组成的包膜物进行包衣,后者是溶解或悬浮于水或少量含有5%异丙醇的乙醇中。
Claims (5)
1.下列化合物1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺的改良体C,
其特征在于:
-以X-射线粉末图谱方法测定的面间距(d值)为9.0、4.73、4.65、3.75、3.54、3.42、3.25;
-其红外光谱(KBr压片-透射法)具有下列吸收:3396,3287,3137,1657,1631,1602,1559,1475,1392,1323,1287,1237,1122,1104,1047,1035,1012,876,839,797,773,729和653cm-1;
-FT-拉曼光谱(粉末-反射法180°)具有下列吸收:3137,3080,3012,2971,1673,1629,1602,1561,1436,1271,1248,1105,1065,1035,1013,839,800,767,726,690,672,593,549,500,492,435和370cm-1;
-它在差示扫描量热法热分析图中除在230-260℃范围内有吸热信号(峰值温度239-245℃)外,在180℃区域有一很宽的弱放热信号。
2.权利要求1中的改良体C,其特征在于X-射线粉末图谱具有下列面间距(d值)特征谱线:9.0(中等),7.0(弱),5.49(弱),5.11(很弱),4.80(弱),4.73(强),4.65(很强),4.47(很弱),4.19(很弱),4.11(很弱),3.98(很弱),3.83(很弱),3.75(强),3.73(弱),3.54(中等),3.50(弱),3.42(强),3.25(中等),2.88(很弱),2.80(很弱),2.74(很弱),2.67(很弱),2.64(弱)。
3.权利要求1或2的改良体C,其纯度大于95%。
4.药物制剂,该制剂含有权利要求1或2的1-( 2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体C以及可药用赋形剂和添加剂。
5.权利要求1或2的1-(2,6-二氟苄基)-1H-1,2,3-三唑-4-甲酰胺改良体C用于制备治疗癫痫及其继发病症的药物制剂的用途。
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US6096779A (en) | 1995-02-22 | 2000-08-01 | Hoechst Pharmaceuticals & Chemicals K.K. | Amorphous piretanide, piretanide polymorphs, process for their preparation and their use |
NZ333505A (en) * | 1996-07-11 | 2000-06-23 | Novartis Ag | Preparing 1-substituted 4-cyano-1,2,3-triazoles using 4-cyano-1-(2,6-difuorobenzyl)-1H-1,2,3-triazole |
TW526195B (en) | 1997-06-10 | 2003-04-01 | Novartis Ag | Crystal modifications of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and their use |
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