CN1308629A - 粒度减小形式的1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪 - Google Patents
粒度减小形式的1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪 Download PDFInfo
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- CN1308629A CN1308629A CN99808217A CN99808217A CN1308629A CN 1308629 A CN1308629 A CN 1308629A CN 99808217 A CN99808217 A CN 99808217A CN 99808217 A CN99808217 A CN 99808217A CN 1308629 A CN1308629 A CN 1308629A
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- pyridyl
- benzoyl
- piperazine
- chloronaphthalene
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
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- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪的可药用盐和粒度减小形式的该化合物或其可药用盐,它们具有抗血栓形成性和抗凝血性并因此可用在治疗人或动物疾病的方法中。本发明也涉及制备上述化合物可药用盐及其粒度减小形式的方法,涉及包含它们的可药用组合物及其在生产用于在人体产生抗血栓形成作用和抗凝血作用的药物中的应用。
Description
本发明涉及1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪的可药用盐和粒度减小形式的该化合物或其可药用盐,它们具有抗血栓形成性和抗凝血性并因此可用在治疗人或动物疾病的方法中。本发明也涉及制备上述化合物可药用盐及其粒度减小形式的方法,涉及包含它们的可药用组合物及其在生产用于在人体产生抗血栓形成作用和抗凝血作用的药物中的应用。
相信,由本发明化合物产生的抗血栓形成作用和抗凝血作用可归于它们对已知称作因子Xa的激活凝固蛋白酶强烈的抑制作用。因子Xa是在复杂的血凝固过程中涉及的蛋白酶系列中的一个。已知称作凝血酶的蛋白酶是所述蛋白酶系列中的最后一个并且因子Xa是能够使凝血酶原分裂开产生凝血酶的前面的蛋白酶。
已知某些化合物具有因子Xa的抑制特性并且R.B.Wallis在Current Opinion in Therapeutic Patents,1993,1173-1179中评论了该方面。因此知道,两种蛋白质,一种称作抗抑制素并且另一种称作蜱抗凝蛋白(TAP),是特异性因子Xa抑制剂,它在各种血栓形成疾病动物模型中具有抗血栓形成性。
也已知,某些非肽化合物具有因子Xa抑制活性。在R.B.Wallis的评论中所提到的低分子量抑制剂都具有强碱性基团如脒苯基或脒萘基。
我们已经发现,1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪(下文称作化合物1)在不抑制或在较小程度上抑制所述凝血酶的浓度下具有因子Xa的抑制活性,其中所凝血酶也是血凝固酶系列中的一员。
在PCT申请号GB97/03033的实施例7中公开了化合物1的三氟乙酸加成盐。
化合物1具有治疗或预防各种需要抗凝剂治疗的内科疾病的活性,例如具有治疗或预防血栓形成性疾病如冠状动脉和脑血管疾病的活性。所述内科疾病的其他实例包括各种心血管和脑血管疾病如心肌梗塞、动脉粥样硬化蚀斑的形成、静脉或动脉血栓形成、凝固综合症、血管损伤(包括在血管成形术和冠状动脉搭桥术后的再闭塞和再狭窄、在进行血管外科手术技术后或在进行一般外科手术如髋部置换手术后引起的血栓形成、采用人工心脏瓣膜或当血液再循环时)、脑梗塞、脑血栓形成、中风、脑栓塞、肺栓塞、局部出血和心绞痛(包括不稳定型心绞痛)。
化合物1也用作体外情形的血凝固抑制剂,所述体外情形如全血或其他怀疑含有因子Xa(其中凝固是有害的)的生物样品的贮存。
我们发现,当口服给予化合物1,即游离碱时,其水溶性和生物利用度受限制。我们已经研究了化合物1的可药用盐并且也研究了为了改善化合物1的物理性质而粒度减小的固体形式的化合物1和化合物1的可药用盐。
我们的研究者已经指出,化合物1的可药用盐和粒度减小形式的化合物1及其可药用盐显示改善的物理性质。特别是化合物1的可药用盐显示改善物理性质如水溶性和口服生物利用度。特别是当与化合物1比较时,粒度减小形式的化合物1的可药用盐显示改善的水溶出速度、口服生物利用度,并且显示口服生物利用度的可变性降低。
因此,本发明提供:
(a)、粒度减小形式的化合物1的可药用盐或其溶剂化物;
(b)、粒度减小形式的化合物1或其溶剂化物;和
(c)、化合物1的可药用盐或其溶剂化物。
本文所使用的术语“本发明化合物”是指上述式(a)、(b)或(c)中的任一化合物。
本文所使用的术语“粒度减小的”是指通过适宜的加工技术变成较小粒度和较大表面积固体的固体化合物1、或其可药用盐、或其溶剂化物。制药领域已知的任一加工技术都可以用于减小固体粒度,如研磨、碾磨和微粉化,参见Remington:The Science and Practiseof Pharmacy,19thEd.,Page 1598-1602,其中有更详细的评论。
本发明优选的粒度范围递增优选从中度细粉、细粉、极细粉、微细粉到最优选超细粉。
上述有关粒度的参考是从英国药典1993,第II卷,附录XVIIB,A193中获得的,并且在下面重述供参考。中度细粉
一种粉末,其中所有粒子都能通过标称孔径为355μm的筛并且不超过重量40.0%的粒子通过标称孔径为250μm的筛。细粉
一种粉末,其中所有粒子都能通过标称孔径为180μm的筛并且不超过重量40.0%的粒子通过标称孔径为125μm的筛。极细粉
一种粉末,其中所有粒子都能通过标称孔径为125μm的筛并且不超过重量40.0%的粒子通过标称孔径为45μm的筛。微细粉
一种粉末,其中不低于重量90%的粒子能通过标称孔径为45μm的筛。超细粉
一种粉末,其中不低于重量90%的粒子能通过标称孔径为10μm的筛。
用于测定粒度的粒子筛描述于英国药典1993,第II卷,附录XVIIB,A193-A194中,将该部分引入本文供参考。
可通过将化合物1的碱基部分与任一可药用有机或无机酸反应并将所形成的盐从溶液中沉淀出来来制备可药用盐。优选的化合物1的可药用盐是盐酸盐。更优选地,化合物1的盐酸盐是溶剂化物,优选水合物,并且特别优选半水合物形式。
本发明的一个特征是提供在内科治疗中应用的上述本发明化合物。
本发明的另一特征是提供一种包含上述本发明化合物和可药用稀释剂或载体的药物组合物。
所述组合物可以是适用于口服应用的形式,例如片剂、胶囊剂、水或油溶液、悬浮液或乳浊液;局部应用的形式,例如霜剂、软膏剂、凝胶或水或油溶液或悬浮液;鼻应用的形式,例如嗅剂、鼻喷雾剂或滴鼻剂;阴道的或直肠应用的形式,例如栓剂;通过吸入给药的形式,例如细碎的粉剂如干粉、微晶形式或液体气雾剂;舌下或口腔应用的形式,例如片剂或胶囊剂;或者非肠道(包括静脉内、皮下、肌肉内、血管内或输注)应用的形式,例如灭菌水或油溶液或悬浮液。大多数上述组合物可通过常规方法,使用常规赋形剂制备。
与一种或多种赋形剂组合制备单一剂量形式的上述本发明化合物的量将依赖于所治疗宿主和特定给药途径而改变。例如,希望口服给予人的制剂通常包含0.5mg-2g与适宜量赋形剂组合的活性剂,其中所述赋形剂可占组合物总重量的大约5-98%。剂量单位形式通常包含大约1mg-500mg活性组分。
本发明也包括利用上述本发明化合物来生产一种药物,所述药物用于:
(i)、产生因子Xa的抑制作用;
(ii)、产生抗凝作用;
(iii)、产生抗血栓形成作用;
(iv)、治疗因子Xa介导的疾病或内科疾病;
(v)、治疗血栓形成介导的疾病或内科疾病;
(vi)、治疗凝结性疾病;和/或
(vii)、治疗与因子Xa介导的凝结有关的血栓形成或栓塞。
本发明也包括产生上述定义的作用或治疗上述定义的疾病的方法,它包括给予需要该治疗的温血动物有效量上述本发明化合物形式。
按照公知的用药原则,用于治疗或预防目的的上述本发明化合物形式的剂量大小将依赖于所述内科疾病的性质和严重性、所治疗动物或病人的年龄和性别以及给药途径而改变。在本发明化合物的使用中,通常给予本发明化合物使得每日口服剂量在,例如0.1-50mg/kg体重/天,如果需要以均分剂量形式给予。通常,当使用非肠道途径时,将给予较低的剂量,例如,静脉内给药通常使用0.01-10mg/kg体重/天的剂量。例如,优选的每日口服剂量包括0.1-10mg/kg体重/天。优选的口服或非肠道给药的剂量范围为0.01-10mg/kg体重/天。
可通过将(4-吡啶基)苯甲酸或其反应衍生物,例如酰氯衍生物,与1-(6-氯萘-2-基磺酰基)哌嗪或其盐,例如盐酸盐反应很方便地制备化合物1。该反应可在适宜的碱存在下方便地进行,所述碱如碱金属或碱土金属碳酸盐、醇化物、氢氧化物或氢化物,例如碳酸钠、碳酸钾、乙醇钠、丁醇钾、氢氧化钠、氢氧化钾、氢化钠或氢化钾,或有机金属碱如烷基锂,例如正丁基锂或二烷基氨基锂,例如二异丙基氨基锂,或有机胺,例如吡啶、2,6-二甲基吡啶、三甲吡啶、4-二甲基氨基吡啶、三乙胺、吗啉或二氮杂二环[5.4.0]十一碳-7-烯。优选地,该反应也可以在适宜的惰性溶剂或稀释剂如二氯甲烷、氯仿、四氯化碳、四氢呋喃、1,2-二甲氧基乙烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷-2-酮、二甲基亚砜或丙酮存在下并且在温度,例如-78-150℃,方便地在室温或接近室温下进行。
在PCT申请号PCT/GB97/03033中可找到准备上述两种中间体以及化合物1的方法。
化合物1或本发明化合物可作为单独的治疗剂给予或者它们可以与其他药理学活性剂如溶栓剂,例如组织纤溶酶原激活剂或其衍生物或链激酶一起给予。例如,本发明化合物也可以与已知的血小板聚集抑制剂(例如阿司匹林、血栓烷拮抗剂或血栓烷合成酶抑制剂)、已知的降脂剂(hypolipidaemic agent)或已知的抗高血压剂一起给予。
用英国药典1998附录XIID A189-A191中所描述的类似的方法测定物质的溶出速度。
下列实施例用于说明本发明。
实施例1从游离碱制备1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪盐酸盐:
将1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪游离碱(54.8g)溶解在二氯甲烷(800ml)中并在搅拌下加入HCl的乙酸乙酯(3.1M,50ml,1.1eq)溶液;将该混合物搅拌1小时,得到很多沉淀。真空除掉溶剂并将所得到的无色固体在高真空下干燥。向该固体中加入热甲醇(2.5升),将该悬浮液回流(在该步骤得到溶液)、过滤,然后在蒸汽浴下将体积减少到开始出现结晶;将该溶液从蒸汽浴上移去并放置使之结晶得到46.6g无色结晶固体形式的1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪盐酸盐的半水合物。
M.p.250℃
1H NMR(d6-DMSO):2.9-3.2(宽s,4H),3.3-3.8(宽s,4H),7.4(d,2H),7.7(m,3H),7.8(m,3H),8.2(d,1H),8.3(m,2H),8.5(s,1H),8.7(d,2H)
微量分析,实测值:C,57.9;H,4.5;N,7.7;S,6.2;Cl,13.0%;C26H23N3O3ClS.1.0HCl.0.5H2O要求:C,58.0;H,4.7;N,7.8;S,6.0;Cl,13.2%
质谱(+ive ESP)m/z 492/494(M+H+)。
实施例2制备粒度减小形式的实施例1
将化合物1的半水合物盐酸盐(实施例1)以可控速度加入流能磨(粉碎机)中,在所述流能磨中,所述盐受到高能蒸汽的作用引起自身磨损。将产生的微粒连续分类,通过滤器收集所述细粉。
所产生的固体测定为“超细粉”(参考:英国药典1993,第2卷,附录A193)。
实施例3
适用于提供治疗或预防应用的本发明化合物的药物剂量形式包括下列片剂和胶囊剂制剂,它们可通过制药领域公知的常规方法获得并且适用于人的治疗应用:
(a)、片剂I mg/片
化合物Z* 1.0
乳糖Ph.Eur. 93.25
交联羧甲基纤维素钠 4.0
玉米淀粉糊(5%w/v的含水糊剂) 0.75
硬脂酸镁 1.0
(b)、片剂II mg/片
化合物Z* 50
乳糖Ph.Eur. 223.75
交联羧甲基纤维素钠 6.0
玉米淀粉 15.0
聚乙烯吡咯烷酮(5%w/v的含水糊剂) 2.25
硬脂酸镁 3.0
(c)、片剂III mg/片
化合物Z* 100
乳糖Ph.Eur. 182.75
交联羧甲基纤维素钠 12.0
玉米淀粉糊(5%w/v的含水糊剂) 2.25
硬脂酸镁 3.0
(d)、胶囊剂 mg/胶囊
化合物Z* 10
乳糖Ph.Eur. 488.5
硬脂酸镁 1.5注意:
*活性组分化合物Z是上述本发明化合物。例如,所述片剂组成(a)-(c)可以通过常规方法,例如用邻苯二甲酸酯乙酸酯纤维素进行肠包衣。
Claims (9)
1.粒度减小形式的1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪或1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪的可药用盐或其溶剂化物。
2.1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪盐酸盐或其溶剂化物。
3.1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪盐酸盐半水合物。
4.1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪或1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪的可药用盐或其溶剂化物的超细粉。
5.1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪或1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪的可药用盐或其溶剂化物的微细粉。
6.1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪或1-(6-氯萘-2-基磺酰基)-4-[4-(4-吡啶基)苯甲酰基]哌嗪的可药用盐或其溶剂化物的极细粉。
7.权利要求1-7所定义的任一物质在医药治疗中的应用。
8.包含权利要求1-7所定义的任一物质和可药用稀释剂或载体的药物组合物。
9.权利要求1-7所定义的任一物质在生产用于治疗因子Xa所介导的疾病或内科疾病的药物中的应用。
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GBGB9809350.3A GB9809350D0 (en) | 1998-05-02 | 1998-05-02 | Novel salt |
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1998
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GB9809350D0 (en) | 1998-07-01 |
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EE200000638A (et) | 2002-04-15 |
NO20005498L (no) | 2000-11-01 |
KR20010043216A (ko) | 2001-05-25 |
HUP0102394A3 (en) | 2003-01-28 |
WO1999057112A1 (en) | 1999-11-11 |
PL343705A1 (en) | 2001-08-27 |
IL139405A0 (en) | 2001-11-25 |
EP1084118A1 (en) | 2001-03-21 |
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AU3719699A (en) | 1999-11-23 |
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