CN1384822A - 2－(4,6－二甲基嘧啶基－2－氧基)－3－[2－(3,4－二甲氧基苯基)乙氧基]－3,3－二苯基丙酸钠及其作为内皮素拮抗剂的用途 - Google Patents
2－(4,6－二甲基嘧啶基－2－氧基)－3－[2－(3,4－二甲氧基苯基)乙氧基]－3,3－二苯基丙酸钠及其作为内皮素拮抗剂的用途 Download PDFInfo
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- CN1384822A CN1384822A CN00814871A CN00814871A CN1384822A CN 1384822 A CN1384822 A CN 1384822A CN 00814871 A CN00814871 A CN 00814871A CN 00814871 A CN00814871 A CN 00814871A CN 1384822 A CN1384822 A CN 1384822A
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Abstract
2－(4,6－二甲基嘧啶基－2－氧基)－3－[2－(3,4－二甲氧基苯基)乙氧基]－3,3－二苯基丙酸钠及其作为内皮素拮抗剂的用途固体结晶形式的式(I)化合物,及其作为药物的用途。
Description
本发明涉及式(I)化合物的固体结晶形式：
WO 98/09953中描述了通式(A)的吖嗪基氧基-和苯氧基-二芳基羧酸衍生物：
及其作为混合ETA/ETB内皮素受体拮抗剂的用途。表2描述了一种具有极好的ETA和ETB受体亲合性，以外消旋物且，特别是，以S-对映体形式的化合物(I-445)。I-445的结构由式(B)给出。
在实施例14中描述了I-445的合成。此物质的提纯包括在乙醚中溶解该游离酸并用1 M NaOH水溶液提取，而后再用1 M HCl转变为游离酸并结晶。
然而，人们发现化合物(I-445)很难在工业规模进行制备，尽管其具有极好的药理作用。为达到制药目的要求的超过99.5％的高纯度是很困难的。此外，人们发现该物质在干燥期间可形成特别高的静电电荷。
因而本发明的目的在于提供一种具有类似于I-445所显示的药理学内皮素拮抗效果，但不具有I-445在提纯和加工中的缺点的化合物。
现在我们发现式(I)的化合物2-(4，6-二甲基嘧啶基-2-氧基)-3-[2-(3，4-二甲氧基苯基)乙氧基]-3，3-二苯基丙酸钠可实现此目的。
式(I)的化合物具有与I-445相同的活体外对ETA和ETB受体的受体亲合性。这里，S-构型为更有效的对映体，因此构成发明的优选实施方案。
化合物(I)可以通过本领域技术人员所熟知的方法由已知化合物I-445获得。关于I-445的制备可参照文献WO 98/09953，其内容在此引入作为参考。通过羧酸与适当的强碱进行脱质子化而引入钠作为平衡离子可取得良好的结果。尤其适宜的是氢氧化钠。做为选择也可以使用醇钠，结果类似。
可以使钠盐结晶的适当的溶剂为醇类，在其中可加入其它极性稍小的溶剂，例如，异丙醇与MTB醚的混合物。
可以在-20至+100℃的温度范围进行盐形成反应，优选在室温至60℃的温度范围。超出此范围的反应温度不会在某种程度上使产率提高。因此可在-20℃和室温的温度之间进行结晶。此范围之外的温度并不会带来特别有利之处。
化合物(I)为一种易于加工的固体结晶物质，可得到非常高的纯度，且非常适合于盖仑制剂方法。在此化合物(I)上没有观察到在固体游离酸(I-445)上发现的静电电荷。
本发明还涉及化合物(I)作为药品的用途。因而可以制备有效用于治疗由内皮素所引起的疾病的药物。
具体地，这些疾病为张力过高，肺高压，心肌梗塞，心绞痛，心律失常，急性/慢性肾衰竭，慢性心功能不全，肾机能不全，脑血管痉挛，脑缺血，蛛网膜下出血，偏头痛，哮喘，ateriosclerosis，内毒素性休克，器官的内毒素诱导障碍，血管内血凝固，血管成形术和旁路术后再狭窄，良性的前列腺肥大，缺血性的和毒素引起的肾机能不全或压力过高，癌症和间质肿瘤的生长，对比物质引起的肾机能不全，胰腺炎，胃肠溃疡，和勃起机能障碍。本发明更进一步涉及式I的内皮素受体拮抗剂与肾素-血管-张力蛋白体系抑制剂的组合物。肾素-血管-张力蛋白体系抑制剂为肾素抑制剂，血管张力蛋白-II拮抗剂和血管张力蛋白转化酶(ACE)抑制剂。优选将式I的内皮素受体拮抗剂与ACE抑制剂联合。
化合物(I)可以以常规的方式口服或胃肠外给药。剂量取决于病人的年龄，状况，以及体重，以及取决于所使用的给药方法。通常，活性组分的日剂量口服通常为约0.5-50毫克/公斤体重，肠胃外给药为约0.1-10毫克/公斤体重。
化合物(I)可以以固体或液态形式使用通常的方法给药，例如作为片剂，包衣片剂，胶囊，粉末，粒剂，糖衣丸，栓剂，溶液，油膏，乳剂或喷雾剂使用。这些制剂是用常规的方式制造的。这些活性物质可以与常规的医学填充剂结合，例如片剂粘合剂，填料，防腐剂，片剂崩解剂，流动调节剂，增塑剂，润湿剂，分散剂，乳化剂，溶剂，阻滞剂，抗氧化剂；和/或燃料气(参见H.Sucker等人：Pharmazeutische Technologie，Thieme Verlag，Stuttgart，1991)。得到的给药形式通常包含按重量计0.1到90wt％浓度的活性组分。
实施例
在容量400L的反应器中放入18.8kg S-2-羟基-3-[2-(3，4-二甲氧基苯基)乙氧基]-3，3-二苯基丙酸，向其中加入80L DMF，将混合物冷却至10℃。
在10-21℃的温度下向该溶液中于30分钟内加入3kg氨基锂。
然后加入10kg 4，6-二甲基嘧啶基-2-甲基砜，且将混合物在35℃搅拌23小时。
反应完成后，冷却混合物至10℃，然后加入240L软化水。
向此溶液中加入70L MTB，而后加入40L 20％浓度的盐酸。水相的pH值为2-3。
接着分去水相，用70L软化水再次洗涤有机相而后将其排放到一个大桶中。
在第二个容量400L的反应器中，向280L异丙醇中加入3.2kg50％浓度的氢氧化钠溶液，在50℃下将混合物搅拌2小时。然后冷却混合物至20-25℃。
在将其加入到上述异丙醇化的NaOH溶液中之前，将上述大桶中的MTB相用玻璃料过滤澄清。
在20-25℃下搅拌一小时，然后在45-50℃下搅拌一小时，最后在20-25℃的温度下搅拌13小时。
通过过滤分离产物，将残余物在过滤机上用50L异丙醇洗涤，而后在过滤机上于夹套温度为50℃下用氮气干燥。
得到19.2kg微晶的产物，纯度通过HPLC测定为99.7％。
Claims (5)
1.固体结晶形式的式(I)化合物：
2.如权利要求1定义的化合物，其为S-对映体形式。
3.一种使用如权利要求1和权利要求2中所定义的化合物用于药物生产的方法。
4.权利要求3中定义的方法，为用于治疗哮喘的药物的生产方法。
5.一种含有权利要求1或权利要求2所定义的化合物作为活性物质的药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19951671A DE19951671A1 (de) | 1999-10-27 | 1999-10-27 | 2-(4,6-Dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionssäure-Natriumsalz und seine Verwendung als Endothelinantagonist |
| DE19951671.5 | 1999-10-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1384822A true CN1384822A (zh) | 2002-12-11 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00814871A Pending CN1384822A (zh) | 1999-10-27 | 2000-10-17 | 2－(4,6－二甲基嘧啶基－2－氧基)－3－[2－(3,4－二甲氧基苯基)乙氧基]－3,3－二苯基丙酸钠及其作为内皮素拮抗剂的用途 |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1228047A1 (zh) |
| JP (1) | JP2003512460A (zh) |
| KR (1) | KR20020047301A (zh) |
| CN (1) | CN1384822A (zh) |
| AU (1) | AU1272701A (zh) |
| BG (1) | BG106700A (zh) |
| BR (1) | BR0015112A (zh) |
| CA (1) | CA2389012A1 (zh) |
| CZ (1) | CZ20021485A3 (zh) |
| DE (1) | DE19951671A1 (zh) |
| HU (1) | HUP0203476A3 (zh) |
| IL (1) | IL149312A0 (zh) |
| MX (1) | MXPA02004071A (zh) |
| NO (1) | NO20021986D0 (zh) |
| SK (1) | SK5962002A3 (zh) |
| TR (1) | TR200201169T2 (zh) |
| WO (1) | WO2001030767A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2656017T3 (es) | 2004-06-24 | 2018-02-22 | Vertex Pharmaceuticals Incorporated | Moduladores de transportadores del casete de unión a ATP |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19636046A1 (de) * | 1996-09-05 | 1998-03-12 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶A¶/ET¶B¶-Rezeptorantagonisten |
-
1999
- 1999-10-27 DE DE19951671A patent/DE19951671A1/de not_active Withdrawn
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2000
- 2000-10-17 IL IL14931200A patent/IL149312A0/xx unknown
- 2000-10-17 CN CN00814871A patent/CN1384822A/zh active Pending
- 2000-10-17 HU HU0203476A patent/HUP0203476A3/hu unknown
- 2000-10-17 WO PCT/EP2000/010202 patent/WO2001030767A1/de not_active Application Discontinuation
- 2000-10-17 BR BR0015112-2A patent/BR0015112A/pt not_active IP Right Cessation
- 2000-10-17 JP JP2001533121A patent/JP2003512460A/ja not_active Abandoned
- 2000-10-17 AU AU12727/01A patent/AU1272701A/en not_active Abandoned
- 2000-10-17 CA CA002389012A patent/CA2389012A1/en not_active Abandoned
- 2000-10-17 MX MXPA02004071A patent/MXPA02004071A/es unknown
- 2000-10-17 KR KR1020027005457A patent/KR20020047301A/ko not_active Application Discontinuation
- 2000-10-17 CZ CZ20021485A patent/CZ20021485A3/cs unknown
- 2000-10-17 EP EP00974404A patent/EP1228047A1/de not_active Withdrawn
- 2000-10-17 TR TR2002/01169T patent/TR200201169T2/xx unknown
- 2000-10-17 SK SK596-2002A patent/SK5962002A3/sk unknown
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2002
- 2002-04-26 NO NO20021986A patent/NO20021986D0/no not_active Application Discontinuation
- 2002-05-14 BG BG106700A patent/BG106700A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BG106700A (en) | 2003-02-28 |
| AU1272701A (en) | 2001-05-08 |
| CA2389012A1 (en) | 2001-05-03 |
| NO20021986L (no) | 2002-04-26 |
| HUP0203476A2 (en) | 2003-05-28 |
| SK5962002A3 (en) | 2002-09-10 |
| KR20020047301A (ko) | 2002-06-21 |
| IL149312A0 (en) | 2002-11-10 |
| DE19951671A1 (de) | 2001-05-03 |
| BR0015112A (pt) | 2002-10-29 |
| CZ20021485A3 (cs) | 2003-06-18 |
| TR200201169T2 (tr) | 2002-09-23 |
| WO2001030767A1 (de) | 2001-05-03 |
| JP2003512460A (ja) | 2003-04-02 |
| HUP0203476A3 (en) | 2003-07-28 |
| EP1228047A1 (de) | 2002-08-07 |
| MXPA02004071A (es) | 2002-10-11 |
| NO20021986D0 (no) | 2002-04-26 |
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