CN1182418A - 一种新形态的(e)－3－[6－[[(2,6－二氯苯基)－硫代]甲基]－3－(2－苯基乙氧基)－2－吡啶基]－2－丙烯酸 - Google Patents

一种新形态的(e)－3－[6－[[(2,6－二氯苯基)－硫代]甲基]－3－(2－苯基乙氧基)－2－吡啶基]－2－丙烯酸 Download PDF

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CN1182418A
CN1182418A CN96193405A CN96193405A CN1182418A CN 1182418 A CN1182418 A CN 1182418A CN 96193405 A CN96193405 A CN 96193405A CN 96193405 A CN96193405 A CN 96193405A CN 1182418 A CN1182418 A CN 1182418A
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dichlorophenyl
methyl
sulfo
pyridyl
vinylformic acid
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V·W·雅克伊维克茨
M·A·哈里斯
R·K·安德森
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SmithKline Beecham Ltd
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/63—One oxygen atom
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters

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Abstract

本发明公开了一种新的物理形态的(E)－3－[6－[[(2,6－二氯苯基)－硫代]甲基]－3－(2－苯基乙氧基)－2－吡啶基]－2－丙烯酸及其在医疗中的用途。

Description

一种新形态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基] -3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸
本发明涉及一种新的物理形态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸，包含该物质的药用组合物及它在医疗中的用途。
(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸，也就是说，具有下述结构的化合物：在本领域中，已知是一种用作白三烯拮抗物的化合物。具体说，WO 94/00437中公开了该化合物，用于治疗牛皮癣。牛皮癣患者需经常暴露在日光下，这是他们医疗中的一部分，这类暴光可潜在性地引起药用活性成分的降解，因而，需要有一种含有这种在暴露于日光时具有抗性的化合物的局部用制剂。
(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸可以以多种不同的物理形态存在(也称为多晶型物)。
因而，本发明的第一方面是提供了具有由下述特征鉴别的形态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸：
·红外线吸收谱在约697、743和884cm-1；
·用差示扫描量热器鉴定时，单一的熔化吸收热，并且在约140℃(最小在142.2℃)开始；
·X-射线衍射散射(Cu源)在9.2、16.4、23.3、26.8和27.3度。
在本文的以下部分中，具有上述这些特征的形态将被称作(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2.-吡啶基]-2-丙烯酸形态II。
为避免疑惑，上述的这些红外吸收谱均采用医用石蜡研糊测得。
WO 94/00437中公开的多晶型的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸具有以下物理特征：
·红外吸收谱在约704、758、和896cm-1
·一小的吸收热，之后是温度在118℃-138℃间的一小的放热，然后是熔化吸热，并且约在140℃开始，这一结果是由差示扫描量热器鉴定出的。
·X-射线衍射散射角度为10.1、20.0、23.0、24.0和25.4度(Cu源)。
·具有以上特征的多晶形态指定为形态I。
(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸形态II与前面所述的物理形态相比具有令人惊喜的优点，如该种物质的形态II较多晶形态I显示出非常大的光稳定性。
本发明还提供了(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸的晶形II在医疗方面的应用，尤其是治疗牛皮癣病。医疗应用时，利用熟知的药物领域的技术，(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸形态II可制成典型的药学组合物。
在另一方面，本发明提供了一种药物组合物，其中包括与药用载体相结合的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸形态II。
对于本领域的技术人员来说，非常明显的是，包含了基本纯净形式的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸形态II的药物组合物将会显示出上述优点。“基本纯净形式”意味着最少50％的纯度，优选的是80-90％的纯度，最优选纯度高于95％。
包含形态I和形态II多种晶形混合物的组合物是本发明的另一个方面。
在又一方面，本发明提供了(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸形态II在治疗牛皮癣病的药物生产中的用途。本发明还提供了治疗牛皮癣病的方法，其中包括给需要者服用有效量的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸形态II。
服用本发明化合物的每日剂量范围约为5-1000mg，优选每日约10到约200mg。治疗牛皮癣时的局部使用剂量应依照感染面积的大小和疾病的严重程度而定。
按照本发明用药时，本发明中的组合物没有不可接受的毒素效应。
以下实例用以说明本发明：
例1：
用一盖有箔片的50ml锥形瓶，内盛(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2丙烯酸粗品5.0g(依WO/95/00487公开的方法制得)和丙-2-醇25ml，对该悬浮液加热至回流，将所得溶液在减压条件下通过(滤)纸过滤，滤液收集在一内含磁性附件的箔片覆盖的小瓶内。密封小瓶，搅拌其中的滤液3小时，使温度降至周围环境温度。滤出白色固体，充分沥干，用乙醚(3ml)(见注释)由顶部洗并真空干燥，由此获得(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)2-吡啶基]-2-丙烯酸，为雪白色固体(4.36g，回收率88％)。
注释：乙醚是用于帮助真空干燥，该步可被省略或代之以用冷的丙-2-醇洗，不会影响回收量。
所得产品具有以下特征：
·红外吸收谱约为697、743和884cm-1
·有单一的熔化吸收热，并在约140℃(最少142.2℃)开始，此是经差示扫描量热器鉴别的。
·X-射线衍射散射(Cu源)角度为9.2、16.4、23.3、26.8和27.3度。
例2：
不同晶形的光稳定性比较
晶形I和晶形II的样品被放置在Heraeus Sun Test CPS光箱中，曝露在氙灯(85,000lux)4小时。用HPLC测定曝光前后各样品的相对反应和不纯度曲线。
样品   相对响应值(较未曝光)   主峰面积(％)   二聚物面积(％)
未曝光晶形I曝光晶形I     100％0.7％     99.5％1.1％     0.1％75.8％
未曝光晶形II曝光晶形II     100％96.5％     97.7％98.1％     nd＜0.1％
nd＝未检测到。
表中的二聚物是指(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸的环丁烷二聚物，是形态I化合物的主要降解产物。(表中的)结果显示，暴露在氙灯下时，形态II的稳定程度明显高于形态I。曝光四小时后，形态I几乎全部降解。

Claims (5)

1.具有以下特征的一种形态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸：
·红外吸收谱约为697、743、884cm-1；
·经差示扫描量热器测定，有单一的熔化吸收热，并且在约140℃(最少在142.2℃)开始；
·X-射线衍射散射(Cu源)角度为9.2、16.4、23.3、26.8和27.3度。
2.一种药用组合物，包括权利要求1中所描述形态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸和与之结合的一种药物学可接受载体。
3.权利要求1所描述形态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸用于医疗。
4.权利要求1所描述形态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸用于牛皮癣病的治疗或预防。
5.一种药用组合物，其中包括形态I和形态II两种状态的(E)-3-[6-[[(2，6-二氯苯基)-硫代]甲基]-3-(2-苯基乙氧基)-2-吡啶基]-2-丙烯酸以及与之相结合的可药用载体。
CN96193405A 1995-04-21 1996-04-02 一种新形态的(e)－3－[6－[[(2,6－二氯苯基)－硫代]甲基]－3－(2－苯基乙氧基)－2－吡啶基]－2－丙烯酸 Pending CN1182418A (zh)

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GBGB9508137.8A GB9508137D0 (en) 1995-04-21 1995-04-21 Formulation
GB9508137.8 1995-04-21

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US (1) US6093828A (zh)
EP (1) EP0821673B1 (zh)
JP (1) JPH11503737A (zh)
KR (1) KR19990007900A (zh)
CN (1) CN1182418A (zh)
AT (1) ATE198883T1 (zh)
AU (1) AU707089B2 (zh)
BR (1) BR9608003A (zh)
CA (1) CA2218322A1 (zh)
CZ (1) CZ333797A3 (zh)
DE (1) DE69611670T2 (zh)
DK (1) DK0821673T3 (zh)
ES (1) ES2154818T3 (zh)
GB (1) GB9508137D0 (zh)
GR (1) GR3035494T3 (zh)
HU (1) HUP9801574A3 (zh)
NO (1) NO309767B1 (zh)
NZ (1) NZ307493A (zh)
PL (1) PL322897A1 (zh)
PT (1) PT821673E (zh)
TR (1) TR199701213T1 (zh)
WO (1) WO1996033174A1 (zh)
ZA (1) ZA963134B (zh)

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GB9602675D0 (en) * 1996-02-09 1996-04-10 Smithkline Beecham Plc Process

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AU2573592A (en) * 1991-09-19 1993-04-27 Smithkline Beecham Corporation Pyridine compounds for treating leukotriene-related diseases
MA22926A1 (fr) * 1992-06-30 1994-04-01 Smithkline Beecham Corp Procede pour la preparation de nouveaux composes.
WO1994000433A1 (en) * 1992-06-30 1994-01-06 Smithkline Beecham Corporation Process for making phenylthiomethylpyridinylalkenoates
GB9313145D0 (en) * 1993-06-25 1993-08-11 Smithkline Beecham Plc Process

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ATE198883T1 (de) 2001-02-15
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CA2218322A1 (en) 1996-10-24
EP0821673B1 (en) 2001-01-24
HUP9801574A3 (en) 1998-12-28
PL322897A1 (en) 1998-03-02
DE69611670D1 (en) 2001-03-01
AU5685996A (en) 1996-11-07
KR19990007900A (ko) 1999-01-25
NO974840D0 (no) 1997-10-20
PT821673E (pt) 2001-05-31
DK0821673T3 (da) 2001-06-18
GR3035494T3 (en) 2001-05-31
NO309767B1 (no) 2001-03-26
ES2154818T3 (es) 2001-04-16
ZA963134B (en) 1997-02-14
GB9508137D0 (en) 1995-06-07
TR199701213T1 (zh) 1998-03-21
AU707089B2 (en) 1999-07-01
JPH11503737A (ja) 1999-03-30
NZ307493A (en) 1998-07-28
CZ333797A3 (cs) 1999-01-13
EP0821673A1 (en) 1998-02-04
HUP9801574A2 (hu) 1998-11-30
WO1996033174A1 (en) 1996-10-24
NO974840L (no) 1997-10-20
US6093828A (en) 2000-07-25

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