CN1067431A - 脒基苯丙氨酸衍生物，它们的制备方法，它们的应用和含有它们的组合物 - Google Patents
脒基苯丙氨酸衍生物，它们的制备方法，它们的应用和含有它们的组合物 Download PDFInfo
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- CN1067431A CN1067431A CN92102446A CN92102446A CN1067431A CN 1067431 A CN1067431 A CN 1067431A CN 92102446 A CN92102446 A CN 92102446A CN 92102446 A CN92102446 A CN 92102446A CN 1067431 A CN1067431 A CN 1067431A
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- CN
- China
- Prior art keywords
- carbon atoms
- betanaphthyl
- form piperidines
- piperidines together
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明描述了脒基苯丙氨酸衍生物、它们的制备
方法、它们的应用和含有这些化合物的药物组合物。
Description
本发明涉及脒基苯丙氨酸衍生物，它们的制备方法，它们的应用和含有这些化合物的药物组合物。
已知许多病理生理学状况会导致血浆中最重要的凝血酶抑制剂-抗凝血酶Ⅲ（AT Ⅲ）的消耗。AT Ⅲ的减少可异致血栓形成的危险增加也是已知的，特别是从先天性缺乏AT Ⅲ的病例中可以得知。AT Ⅲ减少到低于正常值的75%将导致血栓栓塞并发症。这些并发症常常在手术后和在休克状态下以弥漫性血管内凝血形式出现。在许多病例中，会出现威胁生命的血凝块。为了治疗和预防血栓形成性疾病，到目前为止已将具有不同作用方式的抗凝血剂用于临床。为了紧急控制血栓形成的危险，像AT Ⅲ，肝素以及最近开发的水蛭素等物质已被使用。已使用香豆素和2，3-二氢-1，3-茚二酮衍生物进行长期预防。但所说的抗凝血剂在某些情况下受很多不利条件影响。
例如肝素由于它的多糖结构故只能经肠胃道外途径使用，而且它的作用尚须依赖于功能性抗凝血酶Ⅲ的水平。香豆素直接阻碍蛋白质的生物合成，这样便不再能得到足够的维生素K依赖性凝血因子Ⅱ，Ⅶ，Ⅸ和Ⅹ，因而使凝血潜力降低。由此造成其作用的短暂延缓。已知的副作用有出血性皮肤坏死、恶心及毛发脱落。
相比之下，低分子量凝血酶抑制剂的优点在于它们以不依赖于辅助因子的方式通过直接与活性中心结合而直接作用于凝血酶。从而暂时封闭酶。由于它们的化学结构，这些物质口服给药并可立刻发挥其作用。
基于精氨酸或脒基苯丙氨酸的氨基酸衍生物已受到特殊的关注。第一组中包括D-苯丙氨酰-L-脯氨酰-精氨酸醛和（2R，4R）-4-甲基-1-〔N2-（3-甲基-1，2，3，4-四氢-8-喹啉磺酰-L-精氨酰〕-4-哌啶羧酸-水合物（“MD805”）等化合物。MD805是一种已在治疗上使用的特异竞争性凝血酶抑制剂。另一种已知的脒基苯丙氨酸衍生物是β-萘磺酰-甘氨酰-R，S-4-脒基苯丙氨酰哌啶（NAPAP）。EP0，236，163和EP0，236，164中描述了NAPAP衍生物。在这些衍生物中，甘氨酸被一个结构为NH2-CHR1-COOH的氨基酸所取代，其中R1是低级烷基，低级羟烷基，苯基或4-羟基苯基。4-脒基苯丙氨酸（Aph）可被N-甲基化，得到N-甲基-Aph。另外，描述了在芳磺酰基、“桥接”甘氨酸和哌啶环上NAPAP的各种衍生作用。因此，最合适的是N-末端上为α-或β-萘磺酰基，而相反杂芳磺酰基如8-喹啉磺酰基要比α-或β-萘磺酰基差数十倍。天然氨基酸作为疏水性萘基与Aph之间的桥接成员的缺点是连接Aph的酰胺键可受酶的作用而断裂。这个缺点在口服给药情况下特别有影响。然而，用另一种桥接成员如β-丙氨酸代替甘氨酸会异致凝血酶抑制活性的明显丧失。即使是用亚氨基酸如脯氨酸进行取代也会使其作用丧失。
因此，本发明的目的是提供基于脒基苯丙氨酸的新化合物，它们在抗血栓形成活性上优于已知的化合物，同时对酶促裂群作用具有高度抗性，从而提高了可耐受性。
本发明涉及下示通式Ⅰ的化合物：
其中R′是可被1-3个至多含有3个碳原子的烷氧基或被至多5个含有1-2个碳原子的烷基衍化的萘基或苯基，或可被至多5个甲基衍化的苯并二氢呋喃基，
R1是氢、至多有4个碳原子的低级烷基、羟烷基、至多有7个碳原子的芳烷基或至多有4个碳原子的羧烷基，
R2和R3相同或不同，各自代表至多有4个碳原子的烷基、R2和R3与氮原子一起可形成一个环，该环可被至多有3个碳原子的羧基、羟基或羟烷基基团衍化，
＊以R或S构型存在，但最好以R构型存在。
与已知结构的实质性区别在于与其R键合的原子是氮原子，而不是碳原子。
NAPAP具有下列结构：
令人惊奇的是，用氮杂氨基酸残基代替NAPAP中的甘氨酸可能大大增强抗血栓形成活性。氮杂氨基酸残基是可由下式表示的已知化合物：
氮杂氨基酸的结构要素可形成如上述式Ⅰ所代表的结构。
令人惊奇的是，β-萘磺酰氮杂甘氨酰-D-脒基苯丙氨酰-哌啶的活性超过甘氨酸化合物的活性达5倍。氮杂氨基酸与式Ⅰ中的疏水残基R′结合可生成KI和IC50值在微微摩尔范围内的化合物。而且，含有氮杂氨基酸的化合物显示出对酶促降解作用的抗性，因此本发明的化合物特征在于除了作用显著增强以外还提高了稳定性。
本发明的化合物可用已知的方法制备，例如在Houben-Weyl，“Methoden der organischen chemie”（Methods of Organic Chemistry），Volume 15（1+2），Georg Thieme Verlag Stuttgart，1974，by Erich Wiinsch或在Pharmazie 39，228（1984）中所述的方法。
最好首先使Boc-氰基苯丙氨基与“胺成分”偶联。所用的胺成分最好是环状胺例如哌啶，甲基哌啶或羟甲基哌啶。用普通的标准方法形成肽键，最好在羟苯并三唑存在下，在二甲基甲酰胺或类似溶剂中与碳化二亚胺反应。分离N-α-保护的化合物后，通过酸解脱去保护基，在此情况下是借助酸解作用脱去Boc基团。为此，最好用三氟乙酸，并根据需要可在溶剂如二氯甲烷中或在HCl/乙酸中进行裂解。
也可使用已知的方法，例如活性酯法偶联氮杂氨基酸，其中被保护的肼衍生物与氯甲酸酯反应得到活性酯。具体地说，所使用的活性酯是对位硝基苯酯。作为进一步的可能性，可活化氰苯基残基上的氨基以得到异氰酸酯，然后便有可能与肼衍生物进行反应。在反应过程中可用已知的保护基封闭肼的Nβ官能团，为此目的可使用苄氧羰基，特别是叔丁氧羰基。酸解脱去保护基之后，加入碱如N-甲基吗啉、三乙胺或二异丙基乙胺，使芳香、杂芳香或杂环磺酰氯在溶剂如四氢呋喃、二噁烷、二氯甲烷或DMF中偶联。然而常见的是，先使磺酰氯衍生物与肼衍生物偶联更为有利。这样可避免保护基的引入。可用已知的反应方法使氰基转变为脒基官能团。最好在几天之内用硫化氢处理溶于三乙胺/吡啶中的相应的氰基苯丙氨酸衍生物。分离以这种方法形成的硫代酰胺并使用甲基化剂如甲基碘将其转变为硫代亚氨酸甲酯化合物。通过用铵化合物例如乙酸铵，最好在用甲酸作为溶剂情况下进行处理，可得到所需的酰氨基苯丙氨酸化合物。
用常规的方法纯化这些化合物。最好是使用凝胶渗透层析法（在诸如RSephadex LH-20等材料上）或离子交换层析法（在诸如羧甲基纤维素等材料上），且最好使用乙酸盐缓冲液。用薄层层析法和HPLC检验本发明所述化合物的纯度。借助元素分析和NMR检验其特性。
按照各种标准检测本发明所述抑制剂的活性，最好是在体内和体外测定KI值、IC50值或部分组织促凝血酶原激酶时间（PTT）。由此可知本发明要求专利保护的化合物是特异的、并且是有显著抗血栓形成能力的高活性凝血酶抑制剂，其活性明显地超过了此前已知的低分子量抑制剂。
本发明还涉及具有抗血栓形成作用，含有所述的抑制剂的诊断组合物或治疗组合物，和这些化合物作为诊断剂或在制备具有抗血栓形成作用的药物中的应用。
下列实施例将更详细地描述本发明。
实施例1
β-萘磺酰基-氮杂甘氨酰-D-对位脒基苯丙氨酰-哌啶
1.Boc-D-对位氰基苯丙氨酰-哌啶
将50g（255mmol）对位氰基苄基溴、55g（255mmol）乙酰胺基丙二酸二乙酯和2g碘化钾在250ml无水二噁烷中加热至沸腾。在3小时内将新鲜配制的6g（260mmol）钠在乙醇中的溶液滴加到该混合物中。在回流下再沸腾3小时之后，将混合物冷却至80℃并在3小时内加入170ml氢氧化钠溶液。将混合物加热至95℃保持4小时。冷却后，用6N HCl将其pH调到1并蒸发除去二噁烷。滤除所沉积的任何沉淀物。用氢氧化钠溶液将混合物的pH调到9并用乙酸乙酯萃取两次。再用盐酸将水相pH调到1，从而结晶出N-乙酰氰基苯丙氨酸。收集结晶，用水洗数次并在高真空下干燥之。
产率：47g（理论值的79.2%）
纯度检验：TLC Rf＝0.5（氯仿/甲醇/冰乙酸体积比为50∶10∶2.5）。
加入3N氢氧化钠溶液使24g该产物溶于3升水中并调节pH至6-6.5。将500mg酰基转移酶加到该混合物中并将其在37℃下保温4天。此后，通过超滤除去溶液中的酰基转移酶。然后浓缩至1升。调节pH至1之后，用乙酸乙酯萃取混合物数次。用不太浓的氯化钠溶液洗涤有机相并用硫酸钠干燥之，蒸发除去溶剂后得到8.2gN-乙酰-D-氰基苯丙氨酸（理论值的82%）。
将含在40ml水中的22ml冰乙酸和4.3ml浓盐酸加到8g该化合物中并将混合物加热煮沸24小时。蒸发解离溶液后，用甲醇夹带走附着的痕量酸，然后用甲醇/二乙醚溶解并重新沉淀该产物。
产率：6.6g（理论值的85%）
加入7.5ml二异丙基乙胺使5gD-氰基苯丙氨酸盐酸盐溶于14ml水中。将6g叔丁氧基羰基-肟基-2-苯基乙腈在17ml二噁烷中的溶液加到该混合物中并搅拌过夜。加入40ml水和50ml乙酸乙酯。分离出水相并用1M碳酸氢钾再次萃取有机相。合并水相，再用10ml二乙醚洗涤，然后用盐酸将pH调到3。用乙酸乙酯萃取3次，并用氯化钠溶液洗涤有机相，然后用硫酸钠干燥之。蒸发溶剂后，得到5.6g（78%）Boc-D-氰基苯丙氨酸。
将3.26g（10mmol）Boc-D-氰基苯丙氨酸，1.49g（11mmol）HOBt和2.42g（12mmol）DCCI溶解于50mlDMF中并将该溶液搅拌1小时。加入1ml吡啶并将混合物搅拌过夜。滤出沉淀的二环己基脲，蒸馏除去DMF并用乙酸乙酯浸溶残余物。分别用碳酸氢钾、1M硫酸氢钾和饱和氯化钠溶液将该溶液各洗3次。用硫酸钠干燥有机相并蒸馏除去溶剂之后，得到3.16g（80%）Boc-D-氰基苯丙氨酰-哌啶。
纯度检验：TLC：Rf＝0.27（氯仿）
2.D-氰基苯丙氨酰-哌啶盐酸盐
将3gBoc-保护的化合物溶解于50ml加在冰醋酸中的1.2NHCl中并在室温下将混合物搅拌30分钟。真空蒸馏除去解离试剂，然后用甲苯夹带走溶剂并用少量二乙醚研制残余物。收集结晶并真空干燥之。
产率：2.2g。
3.Boc-氮杂甘氨酰-D-氰基苯丙氨酰-哌啶
将2.08g（7mmol）Boc-氮杂甘氨酰-对位硝基苯基酯和2.06g（7mmol）氰基苯丙氨酰-哌啶溶于50mlDMF中。加入2.4ml（14mmol）二异丙基乙胺后，在室温下暗处搅拌混合物1天。真空蒸馏除去溶剂，用乙酸乙酯浸溶残余物并用1M硫酸氢钾溶液洗涤该溶液3次、用碳酸氢钾溶液洗涤3次、用浓氯化钠溶液洗涤两次。用硫酸钠干燥有机相并蒸发掉溶剂。将残余物与二异丙醚一起搅拌，收集并干燥结晶，得到2.29gBoc-氮杂甘氨酰-D-氰基苯丙氨酰-哌啶。
4.β-萘磺酰-氮杂甘氨酰-D-氰基苯丙氨酰-哌啶
将2.08g（5mmol）Boc-氮杂甘氨酰-D-氰基苯丙氨酰-哌啶溶于50ml加在冰醋酸内的1.2NHCl中并在室温下将混合物搅拌30分钟。蒸发解离试剂并在真空下用甲苯夹带除去之，然后用乙醚研制残余物并收集结晶。将结晶溶于50ml二氯甲烷并加入1.7ml（10mmol）二异丙基乙胺。将1.134gβ-萘磺酰氯加到该混合物中并在室温下搅拌过夜。蒸馏除去溶剂，用乙酸乙酯浸溶残余物，用1M硫酸氢钾溶液洗涤该溶液3次、用碳酸氢钾溶液洗涤3次并用浓氯化钠溶液洗涤两次。用硫酸钠干燥有机相并蒸发除去溶剂，得到1.75gβ-萘磺酰-氮杂甘氨酰-D-氰基苯丙氨酰-哌啶。
5.β-萘磺酰-氮杂甘氨酰-D-脒基-苯丙氨酰哌啶
将1g在步骤4中制得的化合物溶于30ml无水吡啶中，加入1ml三乙胺后，通入硫化氢气体3小时。室温下放置3天之后，将溶液倒在100g冰和50ml浓盐酸的混合物上。抽滤并用水洗涤沉淀物。干燥后，用50ml丙酮浸溶硫代酰胺，并用1.5ml甲基碘处理该溶液。将它在回流下煮沸30分钟。冷却后，用二乙醚进行沉淀。将沉淀物溶于二氯甲烷并用水洗涤两次。用硫酸钠干燥有机相并除去溶剂之后，用30ml无水甲醇浸溶残余物并加入200mg乙酸铵。将混合物加热至60℃保持3小时。真空蒸发溶剂。在加有甲醇的RSephadex LH-20上对产物进行层析纯化。
产率：590mg
纯度检验：熔点182℃
TLC：Rf＝0.48〔氯仿50/甲醇10/冰乙酸2.5（体积比）〕
特性检验：
分子量测定（快原子轰击）MH+523
实施例2
Pmc-氮杂甘氨酰-D-对位脒基苯丙氨酰哌啶
步骤1-3与前面的实施例相同。
4.Pmc-氮杂甘氨酰-D-氰基苯丙氨酰哌啶
将1.67g（4mmol）Boc-氮杂甘氨酰-D-氰基苯丙氨酰-哌啶溶于50ml加在冰醋酸内的1.2NHCl中并将混合物在室温下搅拌30分钟。蒸发解离剂并在真空下用甲苯夹带除去之后，用乙醚研制残余物并收集结晶。将结晶溶于加入了1.36ml（8mmol）二异丙基乙胺的50ml二氯甲烷中。将1.35gPmc氯化物加到该混合物中并在室温下搅拌过夜。蒸馏除去溶剂之后，用乙酸乙酯浸溶残余物并用1M硫酸氢钾溶液洗涤该溶液3次，用碳酸氢钾溶液洗涤3次，再用浓氯化钠溶液洗涤两次。用硫酸钠干燥有机相并蒸发除去溶剂，得到1.95gPmc-氮杂甘氨酰-D-氰基苯丙氨酰哌啶。
5.Pmc-氮杂甘氨酰-D-脒基苯丙氨酰哌啶
将1.5g在步骤4中制得的化合物溶于30ml无水吡啶，加入1ml三乙胺之后，通入硫化氢气体3小时。在室温下放置3天后，将溶液倒在100g冰和50ml浓盐酸的混合物上。抽滤并用水洗涤沉淀物。干燥后，用50ml丙酮浸溶硫代酰胺并用1.5ml甲基碘处理之。将混合物在回流下煮沸30分钟。冷却后，用二乙醚进行沉淀之。将沉淀物溶解于二氯甲烷中并用水洗两次。用硫酸钠干燥有机相并除去溶剂之后，用30ml无水甲醇浸溶残余物并加入300mg乙酸铵。将混合物加热至60°保持3小时。真空蒸发溶剂。在加有甲醇的RSephadex LH-20上对产物进行层析纯化。产率：990mg。
纯度检验：熔点149-155℃（烧结，乙酸盐）
TLC：Rf＝0.52〔氯仿50/甲醇10/冰乙酸2.5（体积比）〕
凝血酶抑制剂IC50值的测定：
在0.1MTris-HCl缓冲液/0.15MNaCl（pH8.2）中以递增的浓度将这些化合物与人凝血酶一起保温。1小时后，通过加入底物Chromozym TH（Tos-Gly-Pro-Arg-pNA，5×10 M/l）开始酶促反应。1小时后用光度计在405nm处测定pNA的释放，检测结果以光密度的增加表示。将导致50%酶活性抑制的抑制剂浓度定为ID50值（100%相当于不受抑制的酶反应）。
凝血酶K值的测定：
用上述凝血酶溶液测定所研究之化合物的KI值。为此目的，将凝血酶与抑制剂一起保温，其中抑制剂的浓度大致相当于在上述试验中所测得的IC50值。加入各种不同浓度的底物ChromozymRTH（0.7-45×10-5mol/l）后开始反应。按照Lin eweaver和Burk所述的方法（J.Amer.Chem.Soc.，56658-666，1934）测定抑制的类型和KI值。
表Ⅰ
化合物 凝血酶抑制作用
IC50（mol/l） KI（mol/l）
Pmc-Gly- 1.4×10-91.3×10-9
Aph-Pip
Nas-AGly- 1.3×10-92.6×10-9
Aph-Pip
Pmc-AGly- 1.6×10-129.2×10-11
Aph-Pip
NAPAP 2.8×10-91.4×10-9
缩写：
BOC：叔丁氧基羰基
TLC：薄层层析法
Rf：滞留因子
HOBt：羟基苯并三唑
DCCI：二环己基碳化二亚胺
DMF：二甲基甲酰胺
Pmc：2，2，5，7，8-五甲基苯并二氢吡喃-6-磺酰。
Claims (12)
1、制备式(Ⅰ)所示化合物的方法
其中R′是可被1-3个至多含有3个碳原子的烷氧基或被至多5个含有1-2个碳原子的烷基衍化的萘基或苯基，或可被至多5个甲基衍化的苯并二氢呋喃基，
R1是氢、至多有4个碳原子的低级烷基、羟烷基、至多有7个碳原子的芳烷基或至多有4个碳原子的羟烷基，
R2和R3相同或不同，各自代表至多有4个碳原子的烷基、R2和R3与氮原子一起可形成一个环，该环可被至多有3个碳原子的羟基、羟基或羟烷基基团衍化，
*以R或S构型存在，但最好以R构型存在，
该方法包括使式R′-SO2-NH-NHR1的肼衍生物，其中R′和R1具有在式Ⅰ中所示的含意一与羰基化剂在溶液中进行反应并使反应产物与对-脒基苯基二烷基酰胺反应，其中烷基基团具有式Ⅰ中指出的R2和R3的含意。
2、根据权利要求1所述的方法，其中所用的羰基化剂是对位硝基苯基氯甲酸酯。
3、根据权利要求1所述的方法，其中制得的化合物中R′是β-萘基，R1是氢，R2和R3一起形成哌啶。
4、根据权利要求1所述的方法，其中R′是2，2，5，7，8-五甲基苯并二氢吡喃，R1是氢，R2和R3一起形成哌啶。
5、根据权利要求1所述的方法，其中R′是β-萘基，R1是-CH2-COOH，R2和R3一起形成哌啶。
6、根据权利要求1所述的方法，其中R′是β-萘基，R1是甲基，R2和R3一起形成哌啶。
7、根据权利要求1所述的方法，其中R′是6，7-二甲氧基-β-萘基，R1是H，R2和R3一起形成哌啶。
8、根据权利要求1所述的方法，其中R′是5-甲氧基-α-萘基，R1是甲基，R2和R3一起形成哌啶。
9、根据权利要求1所述的方法，其中R′是β-萘基，R1是H，R2和R3一起形成哌啶。
10、根据权利要求1所述的方法，其中R′是5，6，7，8-四氢-β-萘基，R1是CH2-COOH，R2和R3一起形成哌啶。
11、根据权利要求1所述的方法，其中R′是甲氧基三苯甲基。
12、根据权利要求1所述的方法，其中R′是五甲基苯基，R1是H，R2和R3一起形成哌啶。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4111394.2 | 1991-04-09 | ||
| DE4111394A DE4111394A1 (de) | 1991-04-09 | 1991-04-09 | Amidinophenylalaninderivate, verfahren zu deren herstellung, deren verwendung und diese enthaltende mittel |
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| CN1067431A true CN1067431A (zh) | 1992-12-30 |
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| CN92102446A Pending CN1067431A (zh) | 1991-04-09 | 1992-04-07 | 脒基苯丙氨酸衍生物，它们的制备方法，它们的应用和含有它们的组合物 |
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| Country | Link |
|---|---|
| US (1) | US5274098A (zh) |
| EP (1) | EP0508220B1 (zh) |
| JP (1) | JPH0597793A (zh) |
| KR (1) | KR920019738A (zh) |
| CN (1) | CN1067431A (zh) |
| AT (1) | ATE125549T1 (zh) |
| AU (1) | AU650526B2 (zh) |
| BG (1) | BG60683B1 (zh) |
| BR (1) | BR9201253A (zh) |
| CA (1) | CA2065585A1 (zh) |
| CS (1) | CS106492A3 (zh) |
| DE (2) | DE4111394A1 (zh) |
| DK (1) | DK0508220T3 (zh) |
| ES (1) | ES2076595T3 (zh) |
| FI (1) | FI921525A (zh) |
| GR (1) | GR3017107T3 (zh) |
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| IE (1) | IE67347B1 (zh) |
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| MA (1) | MA22495A1 (zh) |
| MX (1) | MX9201642A (zh) |
| NO (1) | NO921382L (zh) |
| NZ (1) | NZ242246A (zh) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7153963B2 (en) | 2000-08-18 | 2006-12-26 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
| US7345049B2 (en) | 2003-12-22 | 2008-03-18 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| DE4115468A1 (de) * | 1991-05-11 | 1992-11-12 | Behringwerke Ag | Amidinophenylalaninderivate, verfahren zu deren herstellung, deren verwendung und diese enthaltende mittel als antikoagulantien |
| DE4242655A1 (de) * | 1992-12-17 | 1994-06-23 | Behringwerke Ag | Verwendung von Thrombin-Inhibitoren zur Inhibition okularer Fibrinbildung |
| DE4342154A1 (de) * | 1993-12-10 | 1995-06-14 | Behringwerke Ag | Amidinophenylalaninderivate, Verfahren zu deren Herstellung, deren Verwendung und diese enthaltende Mittel als Antikoagulantien |
| AU3107795A (en) * | 1994-08-09 | 1996-03-07 | Pentapharm Ag | Inhibitors of the benzamidine type |
| US5525617A (en) * | 1994-08-24 | 1996-06-11 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| DE19517198C1 (de) * | 1995-05-11 | 1996-10-10 | Samson Ag | Verfahren zur Führung der Hubstellung eines Stellgliedes |
| US5766932A (en) * | 1995-12-20 | 1998-06-16 | Hoechst Marion Roussel, Inc. | Process for preparing N-acetyl(L)-4-cyanophenylalanine from a mixture of the corresponding D,L ethyl esters using subtilisin |
| US5840733A (en) * | 1996-07-01 | 1998-11-24 | Redcell, Canada, Inc. | Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes |
| KR19990074598A (ko) * | 1998-03-12 | 1999-10-05 | 성재갑 | 고체상 반응을 이용한 벤즈아미딘 유도체의 신규한 제조방법 |
| SI21137A (sl) * | 2002-01-24 | 2003-08-31 | LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d. | Derivati azafenilalanina |
| DE10330900B4 (de) * | 2003-07-01 | 2006-09-14 | Leibniz-Institut Für Polymerforschung Dresden E.V. | Biomaterial mit einem modularen Beschichtungssystem zur Anwendung in Medizinprodukten mit direktem Blutkontakt |
| EP1827446A4 (en) * | 2004-12-06 | 2011-01-12 | Siga Technologies Inc | SULFONYL SEMICARBAZIDES, SEMICARBAZIDES AND URETINS, PHARMACEUTICAL COMPOSITIONS THEREOF AND METHOD FOR TREATING HEMORRHAGIC FEVER VIRUSES, INCLUDING INFECTIONS WITH ARENA VIRUSES |
| US7994221B2 (en) | 2004-12-06 | 2011-08-09 | Siga Technologies, Inc. | Sulfonyl semicarbazides, carbonyl semicarbazides, semicarbazides and ureas, pharmaceutical compositions thereof, and methods for treating hemorrhagic fever viruses, including infections associated with arenaviruses |
| US8410149B2 (en) | 2004-12-06 | 2013-04-02 | Siga Technologies Inc. | Sulfonyl semicarbazides, semicarbazides and ureas, pharmaceutical compositions thereof, and methods for treating hemorrhagic fever viruses, including infections associated with arenaviruses |
| CN101034257B (zh) * | 2007-04-06 | 2010-09-08 | 上海复旦天臣新技术有限公司 | 用于全息记录的感光薄膜及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4028380A (en) * | 1974-06-01 | 1977-06-07 | Akzona Incorporated | Hydrazino-imidazole derivatives |
| DD155954B1 (de) * | 1981-02-03 | 1988-11-09 | Wagner Guenter | Verfahren zur herstellung von n tief alpha arly-bzw. n tief alpha heteroarylsulfonylaminoacylierten amidinophenylalaninamiden |
| DD235866B1 (de) * | 1985-03-29 | 1988-12-28 | Univ Leipzig | Verfahren zur herstellung von n alpha (2-naphthyl)-sulfonylaminoacylierten amidinophenylalanisamiden |
| PT84171B (pt) * | 1986-01-24 | 1989-03-30 | Sanofi Sa | Processo para a preparacao de derivados das n alfa-aril-sulfonilamiminoacil-p- -amidinofenil-alaninamidas, bem como dos seus derivados de sintese e das composicoes farmaceuticas que os contem |
| PT84170B (pt) * | 1986-01-24 | 1989-03-30 | Sanofi Sa | Processo para a preparacao de derivados n alfa-substituidos das n alfa-aril-sulfonilaminoacil d-amidinofenil-alaninamidas |
-
1991
- 1991-04-09 DE DE4111394A patent/DE4111394A1/de not_active Withdrawn
-
1992
- 1992-03-25 DK DK92105138.9T patent/DK0508220T3/da active
- 1992-03-25 DE DE59203006T patent/DE59203006D1/de not_active Expired - Fee Related
- 1992-03-25 AT AT92105138T patent/ATE125549T1/de not_active IP Right Cessation
- 1992-03-25 ES ES92105138T patent/ES2076595T3/es not_active Expired - Lifetime
- 1992-03-25 EP EP92105138A patent/EP0508220B1/de not_active Expired - Lifetime
- 1992-04-02 BG BG96171A patent/BG60683B1/bg unknown
- 1992-04-06 NZ NZ242246A patent/NZ242246A/en unknown
- 1992-04-06 UY UY23395A patent/UY23395A1/es unknown
- 1992-04-07 CN CN92102446A patent/CN1067431A/zh active Pending
- 1992-04-07 US US07/864,547 patent/US5274098A/en not_active Expired - Fee Related
- 1992-04-07 TW TW081102613A patent/TW214542B/zh active
- 1992-04-07 FI FI921525A patent/FI921525A/fi not_active Application Discontinuation
- 1992-04-07 RO RO92-200477A patent/RO109197B1/ro unknown
- 1992-04-07 MA MA22776A patent/MA22495A1/fr unknown
- 1992-04-08 NO NO92921382A patent/NO921382L/no unknown
- 1992-04-08 IE IE921123A patent/IE67347B1/en not_active IP Right Cessation
- 1992-04-08 JP JP4085807A patent/JPH0597793A/ja active Pending
- 1992-04-08 ZA ZA922535A patent/ZA922535B/xx unknown
- 1992-04-08 KR KR1019920005804A patent/KR920019738A/ko not_active Application Discontinuation
- 1992-04-08 HU HU9201189A patent/HUT65359A/hu unknown
- 1992-04-08 BR BR929201253A patent/BR9201253A/pt not_active Application Discontinuation
- 1992-04-08 AU AU14703/92A patent/AU650526B2/en not_active Ceased
- 1992-04-08 PL PL29414892A patent/PL294148A1/xx unknown
- 1992-04-08 IL IL10152992A patent/IL101529A/en not_active IP Right Cessation
- 1992-04-08 CA CA002065585A patent/CA2065585A1/en not_active Abandoned
- 1992-04-08 CS CS921064A patent/CS106492A3/cs unknown
- 1992-04-09 MX MX9201642A patent/MX9201642A/es not_active IP Right Cessation
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1995
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7153963B2 (en) | 2000-08-18 | 2006-12-26 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
| US7872125B2 (en) | 2000-08-18 | 2011-01-18 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
| US8222405B2 (en) | 2000-08-18 | 2012-07-17 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
| US8426588B2 (en) | 2000-08-18 | 2013-04-23 | Ajinomoto Co, Inc. | Phenylalanine derivatives |
| US7345049B2 (en) | 2003-12-22 | 2008-03-18 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
| US8309561B2 (en) | 2003-12-22 | 2012-11-13 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
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