CN1092193C - 脯氨酰内肽酶抑制剂 - Google Patents
脯氨酰内肽酶抑制剂 Download PDFInfo
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Abstract
本发明涉及新的通式(I)的脯氨酰内肽酶抑制剂。
Description
本发明涉及新的通式(I)化合物，含有它们的药物组合物，及制备这些化合物的方法。本发明的进一步的方面是新的通式(I)化合物通过抑制本文下面描述的一些酶来治疗CNS疾病的用途。
由于伴随记忆缺失，痴呆和识别及智力功能的逐渐下降，例如早老性痴呆，艾滋病痴呆，各种起源的老年痴呆(缺氧，缺血)的中枢神经系统疾病的发病率和社会原因，急需新的药物治疗和预防上述疾病。
脯氨酰内肽酶(prolyl endopeptides)PE或PEP是后脯氨酸裂解酶(PPCE)。其广泛分布于各种哺乳动物中并且可在身体的各种器官中发现。这种酶在脑，睾丸和骨骼的肌肉中水平最高(Yoshimoto T.，Ogita K.，Walter，R.，Koida M.，and Tsuru D.：Biochem.Biophys.Acta，569，(1979)，184-192)。
PEP在记忆过程起重要作用是基于其底物是生物活性的神经肽(物质P，促甲状腺素-释放激素，Arg8-加压素)的事实。这些神经肽对中枢神经系统显示有特征性药理作用：它们能够改变动物和人的学习和记忆方面的行为(Toide K.，Iwamoto Z.，Fujiwara T.，and Abe H.：《药理实验与治疗杂志》(J.Pharm.Therapeutics)，274，(1995)，1370-1380；Riedel W.and Jolles《药物与衰老杂志》(J.，Drugs & Aging)，8，(1996)，245-274)。神经肽物质P抑制β-淀粉样蛋白诱发大脑皮层中的神经元损失和Alz-50蛋白的表达(Kowall N.，Beal M.F.，Busciglio J.，and Duffy L.K.：Proc.Natl.Acad.Sci.，88，(1991)7247-7251)。在早老性痴呆患者的大脑中，已知大脑ACh含量降低并且大脑功能遭受严重损伤(O′Leary R.andO′Connor B.：《神经化学杂志》(J.Neurochem.)，65，(1995)953-963)。PEP抑制剂通过增加TRH水平能够诱发ACh在大脑中的释放，其结果导致更好的识别能力。可以预期高效PEP抑制剂将被证明对治疗神经变性疾病中的中枢神经疾病是有用的。
作为新药的新PEP抑制剂应当是1.具有提高记忆力和抗痴呆作用的促智(nootropic)药，并且可用于治疗与年龄相关的识别下降；2.用于治疗以下疾病的神经保护剂a.，急性发病(缺血/缺氧)b.，渐进神经变性疾病-早老性痴呆(Alz heimer′s disease)-艾滋病痴呆-亨廷顿舞蹈病。
对于人口老年化，老年痴呆和早老性痴呆症成为严重和快速增长的问题，因此PEP抑制剂可用于上述严重疾病的一般治疗。
我们的任务是制备显示优异特性并作为新药活性成分的新的PEP抑制剂。我们要求其具有强的PEP抑制剂效果，有选择性，容易通过血脑屏障，长半衰期，利于口服吸收，好的化学和生物稳定性及优越治疗性能，包括低毒和尽可能低的副作用。
在合成和生物鉴定大量新的化合物过程中，我们发现新的通式(I)化合物，其中A表示单或多取代的或未取代的含第一个游离价的一个氮原子并且任意含有一个或多个选自氮原子，硫原子或氧原子的其它杂原子的有机环状基团，特别是具有下列通式的基团：(1)，(1a)，(2)，(2a)，(3)，(3a)，(4)，(5)，(6)，(7)，(8)，(9)，(10)，(11a)，(11b)，(12)，(12a)，(12b)，(13)，(13a)，(14)，(15)，(16)，(17)，(18)，(19)，(19a)，(20)，(20a)，(21)，(22)，(23)，(23a)，(23b)，(24)，(25)，(25a)，(26)，(27)，(28)，(28a)，(28b)，(29)，(29a)，(30)，(31)，(32)，(32a)，(33)，(34)，(35)，(36)-其中R代表氢原子，1-4个碳原子的烷基或6-12个碳原子的芳基或芳烷基；R1，R2，R3和R4各自独立地代表氢原子，卤原子，羟基，1-6个碳原子的直链或支链烷基或烯基或炔基或烷氧基或烯氧基或炔氧基，硝基，氨基，1-12个碳原子单烷氨基或单酰氨基，2-24个碳原子的二烷氨基或二酰氨基，一其中酰基是烷基，芳烷基，环烷基或芳基一，氰基，巯基，羧基，2-7个碳原子的酯化羧基，1-6个碳原子的羟基烷基，1-7个碳原子的酰基，1-7个碳原子的酰氧基，苯基或苄基，苯胺基，苯甲酰基，苯氧基，苄氧基，异氰酸根合，异硫氰酸根合，1-6个碳原子的烷硫基，磺氨基或氨磺酰，硫氰酸根合或氰酸根合；R5和R6各自独立地代表氢原子，羟基，苯基或1-4个碳原子的烷基，或R5和R6一起代表氧基；R7代表1-6个碳原子的烷基；R8代表氢原子或1-6个碳原子的烷基或7-10个碳原子的芳烷基；虚线代表任意的化学键；n是0，1，2或3；X代表-CH2-基团，-NH-基团，碳原子，氢原子，氧原子或氨基；或A代表R-Y-N＝基团或R′-Y-NR9-其中R′代表1-6个碳原子的烷基，7-10个碳原子的芳烷基，二苯基甲基，烷氧基，7-10个碳原子的芳烷氧基，或任意被卤原子或1-4个碳原子的烷基或硝基取代的苯基或苯氧基或含7-10个碳原子的苯基烷基或含7-10个碳原子的苯基烷氧基；Y代表化学键或氧，磺酰基或亚磺酰基，R9代表氢原子或1-4个碳原子的烷基；条件是式(20)和(33)中X不代表-CH2-基团，-NH-基团，氧原子或硫原子，式(30)和(31)中X不代表-CH2-基团，氧原子或硫原子或氨基；B代表
其中m是1-21的整数；或
其中p是1-3的整数；或其中R9，R10，R11，R12，R13和R14各自独立地代表氢原子，1-6个碳原子烷基或烷氧基，卤素，任意被一个或两个1-6个碳原子的烷基取代的氨基；或苯基，苯氧基，7-12个碳原子的芳基-烷基或7-12个碳原子的芳基-烷氧基，其中每个任意含有1，2或3个相同或不同的取代基R1，R2，R3或R4；或R9，R10，R11，R12，R13和R14中的两个一起代表氧或环氧基或其它化学键，或其中4个一起代表两个其它化学键，其余的基团代表氢原子；或R9，R10，R11，R12，R13和R14与链碳原子一起代表饱和或不饱和的含有3-8个碳原子的碳环，或饱和或不饱和的含2-7个碳原子及氮或硫或氧原子的杂环，它们可与任意的6-10个碳原子的芳香环稠合；及w是0或1；C代表脯氨酰或式(37)，(38)，(39)，(40)或(41)之一，其中n是0或1或2，Hlg代表氟，氯，溴，或碘原子；R5和R6各自独立地代表氢原子，羟基，苯基或1-4个碳原子的烷基，或R5和R6一起代表氧基；R16代表1-4个碳原子的烷氧基，或-NH-CH2-CN基团，或-NH-CH2-CO2R7基团，其中R7定义如上；或D或L代表结构单元；或式(42)或(43)或(43a)之一，其中虚线代表任意存在的化学键，s是1，2或3或式(44)基团，其中R15代表氢原子，1-6个碳原子的烷基，苯基或萘基；或式(45)基团，其中Z代表NH-基团，氧原子或硫原子；D代表共价化学键或脯氨酰或硫代脯氨酰，或式(37)或(38)，(39)，(40)或(41)基团之一；L代表任意被一个卤原子，通常被两个卤原子取代的吡咯烷并基(pyrrolilino)或2-氰基吡咯烷并基，噻唑烷并基(thiazolidino)或2-氰基-噻唑烷并基或哌啶子基；或式(46)基团，其中R17代表氢原子或氰基，n是0，1或2；或式(47)或(48)或(49)基团；及及其＝所述通式化合物的光学，顺-反，几何异构体，差向异构体，互变异构体，盐，前药和它们的人和哺乳动物的代谢物，它们具有显著的脯氨酰内肽酶抑制效果，并且它们显示一种或多种上述优点。一组优选的通式(I)化合物是在权利要求3，8和9中定义的那些。
在A的定义中“单或多取代或未取代的含带一个游离价的一个氮原子及任意一个或多个其它选自氮原子，硫原子或氧原子的杂原子的有机环状基团”包括所有满足上述定义的单环或多环基团。
对于多环，环可以是稠合的和/或可以是螺环。上述环的一些代表为下列通式：(1)，(1a)，(2)，(2a)，(3)，(3a)，(4)，(5)，(6)，(7)，(8)，(9)，(10)，(11a)，(11b)，(12)，(12a)，(12b)，(13)，(13a)，(14)，(15)，(16)，(17)，(18)，(19)，(19a)，(20)，(20a)，(21)，(22)，(23)，(23a)，(23b)，(24)，(25)，(25a)，(26)，(27)，(28)，(28a)，(28b)，(29)，(29a)，(30)，(31)，(32)，(32a)，(33)，(34)，(35)，(36).
在通式(I)的定义中，“1-6个碳原子的烷基”代表具有1-6个碳原子的直链或支链烷基，如甲基，乙基，丙基，丁基，异丁基，仲丁基，叔丁基，戊基，新戊基和己基。“6-10个碳原子的芳基”代表例如苯基，甲苯基或萘基。
“6-10个碳原子的芳烷基”代表例如苄基，1-苯基乙基，2-苯基乙基，1-苯基丙基。1-6个碳原子的烯基代表直链或支链烯基，如乙烯基，烯丙基，甲基烯丙基(methaorlyl)，丁烯基，3-丁烯基，2-戊烯基，4-戊烯基，2-己烯基，5-己烯基。“1-6个碳原子的炔基”代表直链或支链炔基，如乙炔基，炔丙基，2-丁炔基，3-丁炔基，2-戊炔基，4-戊炔基，2-己炔基，5-己炔基，4-甲基己炔基。
“1-12个碳原子的酰基”的环烷基部分代表例如环丙基，环丁基，环戊基，环己基，环庚基或环辛基。
这些定义适用于烷氧基，烯氧基，炔氧基，芳氧基，芳烷氧基，苯基烷氧基或烷氨基或酰氨基情况。
使用下列方法我们测定了PEP抑制活性和式(I)代表的化合物的生物稳定性。鼠脑堤取物中的PEP活性测定
除去小脑后，将雄性鼠(Sprague-Dawley，180-200g)整个脑在两倍体积的0.1M Tris-HCl，1mM EDTA的缓冲液，pH＝5(PEP缓冲液)中均化。将均浆在4℃，40000g离心30分钟并收集含有酶的上清液。将颗粒再悬浮于上述相同体积的缓冲液中并在相同条件下离心。合并两次的上清液等分为1ml储存在-70℃(至少3个月)。在测定活性之前融化上清液并用1∶15的PEP缓冲液稀释。用J.R.Atack等人(《欧洲药理学杂志》(EurJ.Pharmacol.)，205，(1991)，157-163)所述荧光(flurometric)法测定酶活性。酶反应在室温和作为高效合成PEP的底物的62.5μM Z-甘氨酰-脯氨酰-7-氨基-4-甲基-香豆素(Bachem Biochem.)存在下进行15分钟。在相同条件下在100-0.001nM化合物存在下试验化合物的抑制作用。用分光荧光法在激发波长370nm和发射波长440nm检测7-氨基-4-甲基-香豆素的形成。用Hill-公式通过酶的％抑制对抑制剂浓度(M)的曲线拟合计算化合物的50％抑制浓度(IC50)。通式(I)化合物的IC50值的范围为100nM-1pM。猪脑PEP活性测定
纯化的猪脑脯氨酰内肽酶是Laszlo Pogar(Enzymology Institute ofthe Hungarian Academy of Sciences)提供的。酶溶液用反应混合物稀释400000倍。测定在体外鼠脑制剂测定相同的条件下进行。通式(I)化合物显示对猪脑PEP活性也是活性的。体外代谢研究
在小鼠，大鼠和人(匈牙利科学院化学研究中心的肝微粒体制剂(Central Chemistry Institute of The Hungarian Academy of Sciences)制备的)中研究脯氨酰内肽酶抑制剂的生物稳定性。将小鼠和大鼠的肝合并并在4倍体积含有1.15％ KCl和1mM EDTA的Tris-HCl缓冲液(pH7.4)中均化。将均浆在10000g离心30分钟，将上清液在105000g再超声离心1小时。将颗粒再均化并重复超声离心。将颗粒再均化并用缓冲液稀释至最终体积为0.5g肝/ml。将样品等分为2ml冷冻在-80℃。该制剂被表征为细胞色素P450异构酶活性。
在下列条件下试验新的通式(I)化合物：反应混合物含有2mg肝微粒体蛋白，0.1M Tris-HCl缓冲液(pH＝7.4)，2mM NADP，20mM葡萄糖-6-磷酸酯二钠盐，10mM MgCl2，5U葡萄糖-6-磷酸酯脱氢酶和50μM PEP抑制剂，最终体积为1.5ml。在0，10，20，40分钟温育后，加入乙腈终止反应。将样品在3000rpm离心1分钟。用HPLC(Supelcosil C18)分析上清液。测定未变化的底物量并且计算化合物的半衰期。
一些通式(I)化合物在人肝微粒体中的半衰期超过7小时。这种良好的生物稳定性有利于体内维持长效并且优于其它已知生物不稳定的肽型PEP抑制剂。
公开的欧洲申请No 0232 849 A2描述了许多PEP-抑制剂包括SUAM-1221(N-[N-(γ-苯基)丁酰基-L-脯氨酰]吡咯烷)。通式(I)化合物对脯氨酰内肽酶显示了高的抑制活性并且在上述试验系统测定其优于上述参考化合物SUAM-1221。
化合物 在鼠脑提取液中的IC50(M)
实施例123 2,78×10-10
实施例31 3,60×10-10
实施例171 4,51×10-10
SUAM-1221 3,12×10-8
通式(I)化合物的制备可用文献中的已知方法或用与肽类物质合成化学上明显等价方法进行。
通式A-B-C-D-L(I)(其中A，B，C，D，和L定义如上)中的A和B单元与适当的酸酐或其它活性酸衍生物及胺偶合反应，产生通式(II)化合物，其中A和B定义如上。单元C和D也与适当活性酸衍生物例如酸酐和胺进行偶合。单元CD和L偶合产生通式(III)化合物(其中CD和L定义如上)是通过适当的混合酐和胺，相应的酯和金属有机化合物反应进行的。
相应的单元A，B，C，D，和L的起始化合物为商品或用形成它们的已知方法或如《药物化学通讯》(Chem Pharm.Bulletin)，41(9)p1583-1588(1993)所述方法容易制备。
通式(I)化合物通过通式(II)化合物的活性衍生物与通式(III)化合物在一般肽化学中的酰胺偶合条件下反应制备。通式(II)化合物的活性衍生物可以是，例如酰氯(可使用卤化剂(例如亚硫酰氯)合成)。活性酯可通过1-羟基-苯并三唑在N，N′-二环己基碳化二亚胺的存在下产生(Chem.Ber.103，788/1970)。混合酐可通过氯甲酸酯或戊酰氯产生(Methoden der Organischen Chemie(Houben-Weyl) Band XV/2Syntheses von Peptiden，Georg Thieme Verlag，Stuttgart，1974)。
偶合反应优选在有机溶剂(优选温度在-25℃和反应混合物的沸点之间)中进行。使用酸结合剂例如有机胺有利于反应。
如果需要，通过常规纯化技术可纯化通式(I)化合物，如果需要，通过常规分离技术可分离其异构体，并且如果需要，将其与可药用酸转化为其加成盐。
可药用酸可是，例如盐酸，硫酸，酒石酸，富马酸，甲磺酸等。
本发明另一个目的是含有至少一种通式(I)化合物作为活性成分的或与可药用酸形成的加成盐之一或与一种或多种惰性，无毒赋形剂或载体结合的药物组合物。
本发明药物组合物可具体制成适于口服，非肠道或鼻内给药，简单或糖包衣片剂，舌下片剂，可注射组合物，滴注剂，包装剂(packets)，明胶胶囊，栓剂，乳膏，软膏，皮肤凝胶等。
剂量根据患者的年龄和体重，疾病的性质和严重程度和给药途径变化。
给药途径可以是口服，鼻内，肠道或非肠道。单位剂量通常在0.1-50mg/kg体重之间变化，每24小时治疗1-3次。
附图说明
附图1-5表示式(I)、(II)和(III)的结构及用带括号的数字和带括号的数字加符号表示的基团的相应结构。
本发明将通过下列表格式非限定性实施例和实施例4中描述的方法更详细说明。根据本说明书或这里公开的本发明实例，本发明其它实施方案对于本领域技术人员是显而易见的。实施例实施例4(表1)中所列化合物的制备描述
在-15℃和搅拌下，向由1.17g(5.0mM)4-邻苯二甲酰亚氨基-丁酸和0.56g(5.5mM)三乙胺溶解在20ml氯仿中制备的溶液中滴加0.61g(5.0mM)戊酰氯。将反应混合物在上述温度下搅拌1小时，向其中滴加由1.03g(5.0mM)L-脯氨酰-吡咯烷-盐酸盐溶解在5ml氯仿和1.5ml(1.1g，11.0mM)三乙胺的混合物制备的溶液。将反应混合物在室温搅拌4小时，依次用水，30％cc.柠檬酸溶液，饱和碳酸氢钠水溶液，水和饱和氯化钠水溶液洗涤。有机相用煅烧的硫酸镁干燥然后蒸发。从5ml氯仿和10ml石油醚中结晶剩余物，产生1.1g(53％)N-(4-邻苯二甲酰亚氨基-丁酰基)-L-脯氨酰-吡咯烷，熔点148-149℃。通式(I)混合物通过上述方法由相应的通式(II)和(III)化合物为起始原料进行合成。
一些新的通式(I)化合物的结构和物理常数列在表1中。表1
差向异构体的初始转向a，d，c，d可逆转。洗脱剂缩写：A CM201 氯仿∶甲醇＝20∶1B BM 41 苯∶甲醇＝4∶1C CM 41 氯仿∶甲醇＝4∶1D DM101 二氯甲烷∶甲醇＝10∶1E CM955 氯仿∶甲醇＝95∶5F CM 91 氯仿∶甲醇＝9∶1G DM 91 二氯甲烷∶甲醇＝9∶1I HA 21 正己烷∶丙酮＝2∶1H HA 31 正己烷∶丙酮＝3∶1K CA 101 氯仿∶丙酮＝10∶1
Claims (11)
1. 通式(I)化合物，及其光学、顺-反、几何异构体，差向异构体，互变异构体，盐，
R1，R2，R3和R4各自独立地代表氢原子，卤原子，羟基，氰基，硝基，氨基，苯胺基，巯基，羧基，苯基，苯氧基，苄基，苄氧基，苯甲酰基，氰酸根合，异氰酸机合，硫氰酸根合，异硫氰酸根合，1-6个碳原子烷硫基，磺氨基或氨磺酰，含1-6个碳原子的直链或支链烷基、烯基、炔基、烷氧基、烯氧基或炔氧基，含1-12个碳原子的单烷氨基或单酰氨基，含2-24个碳原子的二烷氨基或二酰氨基，其中酰基是烷基、芳烷基，环烷基或芳基型酰基，含2-7个碳原子的酯化羧基，含1-6个碳原子的羟烷基，含1-7个碳原子的酰基或含1-7个碳原子的酰氧基；
B代表
-(CH2)m-CO-，
其中m是2-6的整数；
C代表脯氨酰基或
或
Hal是F，Cl，Br或I，
L代表任意或选择性被一个卤原子或通常被两个卤原子取代的吡咯烷并基，2-氰基吡咯烷并基。
2.权利要求1的式(I)化合物及其光学，顺-反，几何异构体，差向异构体，互变异构体及盐
B代表 -(CH2)m-CO-，
其中m是是2或3；
C代表脯氨酰或
L代表吡咯烷并基。
3.制备权利要求1或2定义的通式(I)化合物，其特征在于将通式(II)化合物
其中R1-R4和B如权利要求1或2定义，转化成酰卤，活性酯，混合酸酐或碳化二亚胺，及
得到的化合物与通式(III)H-C-L的外消旋或光活性化合物或它们的盐反应，其中C和L如权利要求1或2定义。
4.根据权利要求1或2的方法，其特征在于式(I)化合物从其盐中释放出来。
5.权利要求3的方法，其特征在于使用通式(III)化合物的酸加成盐。
6.权利要求3或5的方法，其特征在于活性混合酐是由通式(II)化合物和戊酰氯形成的。
7.权利要求3，5或6的方法，其特征在于该反应在有机溶剂中进行。
8.权利要求3，5，6或7的方法，其特征在于该反应在-25℃至反应混合物的沸点之间的温度下进行。
9.根据权利要求3，5，6，7或8的方法，其特征在于该反应在酸结合剂存在下进行。
10.药物组合物，其含有一或多个权利要求1或2的式(I)化合物，有用载体和/或辅料。
11.权利要求1或2的式(I)化合物用于制备用于抑制包括人类的哺乳动物中脯氨酰内肽酶的药物组合物。
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| EP1824846A2 (en) | 2003-11-03 | 2007-08-29 | Probiodrug AG | Novel compounds for the treatment of neurological disorders |
| ES2477868T3 (es) * | 2005-04-22 | 2014-07-18 | Alantos Pharmaceuticals Holding, Inc. | Inhibidores de dipeptidil peptidasa-IV |
| EP2730571A1 (en) * | 2012-11-12 | 2014-05-14 | Universitat De Barcelona | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
| US9392814B2 (en) | 2014-06-06 | 2016-07-19 | Nicholas J. Singer | Delivery system for drinks |
| USD773313S1 (en) | 2015-06-23 | 2016-12-06 | Nicholas J. Singer | Package |
| JOP20170113B1 (ar) * | 2016-05-09 | 2023-03-28 | Bayer Pharma AG | مركبات 5، 6، 7، 8-رباعي هيدرو [1، 2، 4] تريازولو [4، 3-أ] بيريدين 3(2h)-ون مستبدلة ومركبات 2، 5، 6، 7-رباعي هيدرو-3h-بيرولو [2، 1-ج] [1، 2، 4] تريازول-3-ون واستخداماتها |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0419683A1 (en) * | 1989-04-13 | 1991-04-03 | Japan Tobacco Inc. | New amino acid derivatives having prolylendopeptidase inhibitor activity |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1320734C (en) | 1986-02-04 | 1993-07-27 | Suntory Limited | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
| CA2004028C (en) * | 1988-12-08 | 1998-09-22 | Motoki Torizuka | Condensed benzene derivative |
| EP0468469A2 (en) * | 1990-07-27 | 1992-01-29 | Japan Tobacco Inc. | Proline derivatives |
-
1995
- 1995-08-17 HU HU9502426A patent/HUT76640A/hu unknown
-
1996
- 1996-07-26 CA CA002235677A patent/CA2235677A1/en not_active Abandoned
- 1996-07-26 US US09/011,703 patent/US6191161B1/en not_active Expired - Fee Related
- 1996-07-26 MX MX9801190A patent/MX9801190A/es unknown
- 1996-07-26 EP EP96925926A patent/EP0861246B1/en not_active Expired - Lifetime
- 1996-07-26 WO PCT/HU1996/000041 patent/WO1997007116A1/en not_active Ceased
- 1996-07-26 DE DE69630391T patent/DE69630391T2/de not_active Expired - Fee Related
- 1996-07-26 NZ NZ313751A patent/NZ313751A/xx unknown
- 1996-07-26 EE EE9800044A patent/EE9800044A/xx unknown
- 1996-07-26 AU AU66279/96A patent/AU725429B2/en not_active Ceased
- 1996-07-26 BR BR9610075A patent/BR9610075A/pt unknown
- 1996-07-26 EA EA199800200A patent/EA001399B1/ru not_active IP Right Cessation
- 1996-07-26 IL IL12326896A patent/IL123268A0/xx unknown
- 1996-07-26 SK SK189-98A patent/SK18998A3/sk unknown
- 1996-07-26 JP JP9509080A patent/JPH11514970A/ja not_active Ceased
- 1996-07-26 PL PL96325013A patent/PL325013A1/xx unknown
- 1996-07-26 CN CN96197030A patent/CN1092193C/zh not_active Expired - Fee Related
- 1996-07-26 AT AT96925926T patent/ATE252096T1/de not_active IP Right Cessation
- 1996-07-26 TR TR1998/00243T patent/TR199800243T1/xx unknown
- 1996-07-26 KR KR1019980701148A patent/KR19990037669A/ko not_active Ceased
- 1996-07-26 CZ CZ98457A patent/CZ45798A3/cs unknown
- 1996-08-01 ZA ZA9606554A patent/ZA966554B/xx unknown
- 1996-08-13 HR HR960375A patent/HRP960375B1/xx not_active IP Right Cessation
- 1996-08-15 TW TW085109928A patent/TW486476B/zh active
- 1996-08-15 YU YU47096A patent/YU47096A/sh unknown
- 1996-08-16 AR ARP960104018A patent/AR009225A1/es unknown
-
1998
- 1998-02-16 NO NO980643A patent/NO980643L/no not_active Application Discontinuation
- 1998-02-16 IS IS4668A patent/IS4668A/is unknown
- 1998-03-12 BG BG102323A patent/BG102323A/bg unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0419683A1 (en) * | 1989-04-13 | 1991-04-03 | Japan Tobacco Inc. | New amino acid derivatives having prolylendopeptidase inhibitor activity |
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Correction item: Inventor Correct: K*Carnegie|S*Eduo|A Sapupanuosi|J Adams|I Hemaici|G*Tsvoboda|Batori Sandor|G Hejia|Baluoge M|Lehr Philipp|J West Persia|B, V, Bata|Z Pakanyi|It 'V.|P - mornas False: K*Carnegie|S*Eduo|A Sapupanuosi|J Adams|I Hemaici|G*Tsvoboda|Batori Sandor|G Hejia Number: 42 Page: 102 Volume: 14 |
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Correction item: Inventor Correct: K*Carnegie|S*Eduo|A Sapupanuosi|J Adams|I Hemaici|G*Tsvoboda|Batori Sandor|G Hejia|Baluoge M|Attila Horvath|J West Persia|B, V, Bata|Z Pakanyi|It 'V.|P - mornas False: K*Carnegie|S*Eduo|A Sapupanuosi|J Adams|I Hemaici|G*Tsvoboda|Batori Sandor|G Hejia Number: 42 Page: 102 Volume: 14 |
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