CN1274713C - 激肽释放酶抑制剂 - Google Patents
激肽释放酶抑制剂 Download PDFInfo
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- CN1274713C CN1274713C CNB038054019A CN03805401A CN1274713C CN 1274713 C CN1274713 C CN 1274713C CN B038054019 A CNB038054019 A CN B038054019A CN 03805401 A CN03805401 A CN 03805401A CN 1274713 C CN1274713 C CN 1274713C
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- China
- Prior art keywords
- propionyl amino
- amino
- piperidines
- carbonamidine
- phenyl
- Prior art date
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Abstract
通式1的化合物，或其药学上可接受的盐，其中，R1选自H、低级烷基、R4-CO、R4-O2CCH2、R5-OCO和R5-SO2；R2选自低级烷基、任选地被烷基或烷氧基取代的环烷基、任选地被烷基或烷氧基取代的(C5-C12)环烷基烷基、任选地被最多三个选自F、Cl、Br、I、OH、低级烷基、O-(低级烷基)、O-苄基、NH2、NO2、NH-酰基、CN和CF3的基团所取代的芳烷基、任选地被最多三个选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的芳烷基氧甲基；或者，R1和R2一起构成任选地在芳环上被选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的邻-亚二甲苯基；R3选自H、OH和O-(低级烷基)；R4选自H、低级烷基和苯基；以及R5选自低级烷基、苯基和苄基。所述化合物可用作药物组合物。
Description
本发明涉及一系列新的化合物，它们是酶血浆激肽释放酶的选择性抑制剂，涉及包含这些抑制剂的药物组合物，以及这种组合物在治疗人类疾病中的应用。
背景
酶血浆激肽释放酶，按分类也称为EC.3.4.21.34，是胰蛋白酶样丝氨酸蛋白酶家族的成员，该家族还包括组织激肽释放酶、凝血酶、胰蛋白酶和纤溶酶。在血浆中它以无活性的酶原存在，并被因子XIIa所激活。该酶具有广谱的活性。血浆激肽释放酶通过切断Lys-Arg和Arg-Ser键从大分子量的激肽原释放出血管作用的缓激肽。同样的肽也可在中性白细胞弹性蛋白酶存在下从低分子量的激肽原释放。它还能够激活尿激酶原和纤溶酶原，还认为它参与了从凝乳酶原到血管紧张肽原酶的转化。血浆激肽释放酶是体内的血液凝结级联反应的必需组分，虽然它的作用不涉及缓激肽的释放或酶催化的断裂。高分子量的激肽原是血浆激肽释放酶的优选的底物，对于在该级联反应中的激活作用是必需的(K.D.Bhoola等，Pharm.Rev.，1992，44，1-80)。
血浆激肽释放酶的生理作用看来是从激肽原的蛋白水解断裂以释放激肽或其它底物如生长因子前体产生的。激肽如缓激肽是发炎的强力介体。此外，它们还影响细胞功能，如血压、局部血流、葡萄糖运输和细胞增殖。这些细胞活动通过二级信使(如血小板激活因子、白三烯、前列腺素、P物质、乙酰胆碱和去甲肾上腺素)的释放来调节。
有几个小组已经公开了血浆激肽释放酶的合成的抑制剂。这些包括精氨酸酮亚甲基衍生物(WO92/04371和D.M.Evans等，Immunopharmacology，1996，32，115-116)、去甲胍基丁胺和胍基丁胺衍生物(WO 95/07291，WO 94/29335)、苯脒衍生物(J.Sturzbecher等，Brazilian J.Med.Biol.Res.，1994，27，1929-1934)、硼酸衍生物(US 5187157)和氨基甲基环己酰基衍生物(N.Teno等，Chem.Pharm.Bull.，1993，41，1079-1090)。氨基甲基环己酰基衍生物在小鼠的胶原蛋白诱导的关节炎模型中(Y.Fujimora等，Agents Actions，1993，39，42-48)以及在大鼠的内毒素诱导的播散性的血管内凝结(DIC)中(S.Okamoto等，Agents Actions(增补本)，1992，38(第一部分)，198-205)表现出活性。硼酸衍生物在炎性肠病模型(A.Stadnicki等，Digestive Diseases and Sciences，1996，41，912-920和FASEB，1998，12，325-333)中是有活性的。
关于胰蛋白酶样丝氨酸蛋白酶的其它成员的选择性还是一个重要的争议。显示弱血浆激肽释放酶活性的组织激肽释放酶的抑制剂过去也已经有报道(M.Szelke等，Brazilian J.Med.Biol.Res.，1994，27，1935和D.M.Evans等，Immunopharmacology，1996，32，117)，但仍存在对能选择性地抑制血浆激肽释放酶而不抑制组织激肽释放酶的化合物的需求。
发明简述
本发明涉及一系列酰基氨基哌啶-1-甲脒(acylaminopiperidine-1-carboxamidine)，它们是血浆激肽释放酶的抑制剂。这些化合物显示对血浆激肽释放酶的良好的选择性，并在炎性肠病、关节炎、炎症、败血性休克、低血压、癌症、成年人呼吸窘迫综合症、播散性血管内凝结、心肺旁路外科和手术后出血的治疗中有潜在的应用。本发明还涉及该抑制剂的药物组合物，涉及该抑制剂的药物组合物，涉及该组合物作为治疗籍的应用以及涉及用该组合物的治疗方法。
发明详述
本发明的第一方面包含通式1的一系列新的4-(二肽基氨基)-哌啶-甲脒。
在通式1中，R1代表选自下列基团的基团：氢原子(H)、低级烷基、式R4-CO的基团、式R4-O2CCH2的基团、式R5-OCO的基团和式R5-SO2的基团。R2代表选自下列基团的基团：低级烷基、环烷基、或(C5-C12)环烷基烷基(它们可任选地被烷基或烷氧基取代)、芳烷基(它可任选地被最多三个选自F、Cl、Br、I、OH、低级烷基、O-(低级烷基)、O-苄基、NH2、NO2、NH-酰基、CN和CF3的基团所取代)、芳烷基氧甲基(它可任选地被最多三个选自F、Cl、Br、OH和O-(低级烷基)的基团所取代)。或者，R1和R2一起构成邻-亚二甲苯基(o-C6H4(CH2)2)。该亚二甲苯基的芳环可任选地被选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代。
R3代表选自H、OH和O-(低级烷基)的基团。
R4代表选自H、低级烷基和苯基的基团。
R5代表选自低级烷基、苯基和苄基的基团。
在本发明的内容中，术语“烷基”和“低级烷基”可交换使用，表示具有1-8个碳原子的线形和分支的饱和烃基，如甲基、乙基、异丙基、叔丁基、新戊基和异辛基。
术语“环烷基”表示具有3-12个碳原子的单环或多环的饱和烃基，如环丙基、环己基、二环[4.4.0]癸基(即十氢萘基)和金刚烷基。
术语“环烷基烷基”表示带有环烷基作为取代基的烷基，如环己基甲基和1-(环戊基)乙基。当带有限制性说明时，如(Ca-Cb)-环烷基烷基，则代表该环烷基部分具有a-b个碳原子。
术语“烷氧基”表示O-(烷基)基团。
术语“酰基”表示甲酰基(H-CO)和烷基-CO基团。
术语“芳烷基”表示带有芳基作为取代基的烷基，如苄基和1-萘基甲基。术语“芳基”包括苯基、萘基、呋喃基、噻吩基、吡咯基和吡啶基。
术语“芳烷基氧甲基”表示芳烷基-OCH2基团。
本发明化合物都具有胍官能团因此能与酸形成加成盐。只要这些酸是药学上可接受的，这些盐就在本发明的范围之内。合适的酸的例子包括乙酸、三氟乙酸、富马酸、苹果酸、柠檬酸、苯甲酸、苯磺酸、盐酸、硫酸和磷酸。本发明的某些化合物具有酸官能团，因此能与碱金属和碱土金属形成盐。同样，只要这些是药学上可接受的，它们就都包括在本发明的范围内。这些盐的例子包括钠、钾和钙盐。
本发化合物都具有至少两个立构中心(不对称碳原子)，因此能以光学异构体存在，如对映体、非对映体和端基异构体。所有这些异构体都包括在本发明的范围内。这些异构体的混合物，包括(但不限于)外消旋混合物也包括在本发明的范围内。
在一个优选的实施方案中，本发明包含通式1的化合物，其中R1选自H、低级烷基和R4-O2CCH2。
在另一个优选的实施方案中，本发明包含通式1的化合物，其中R2选自(C6-C10)环烷基烷基、任选地被最多三个选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的苄基、任选地被最多三个选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的苯乙基和任选地被最多三个选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的苄氧基甲基。更优选R2选自环己基甲基、十氢萘-2-基甲基、苄基、4-氟苄基、4-氯苄基、4-羟基苄基、4-(低级烷基)氧苄基、α-羟基苄基、α-甲氧基苄基、苯乙基和苄氧基甲基。
在另一个优选的实施方案中，本发明包含通式1的化合物，其中的绝对立体化学如通式1A所表示。更优选地，绝对立体化学如通式1B所表示。
在另一个优选的实施方案中，本发明包含的化合物选自：
(2’S，2”R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(3”-(4-乙氧基苯基)-2”-(甲氧基羰基甲基氨基)-(丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-氨基-3”-苯基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-苯基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-(甲氧基羰基甲基氨基)-3”-苯基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-氨基-3”-十氢萘-2-基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-十氢萘-2-基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(3”-十氢萘-2-基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-氨基-3”-环己基丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(2”-羧甲基氨基-3”-环己基丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(2”-羧甲基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒；和
(2’S，2”R，3’R)-4-(2’-(3”-(4-乙氧基苯基)-2”-(甲氧基羰基甲基氨基)-丙酰基氨基)-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒。
本发明的化合物可通过本领域公知的方法制备，特别是那些用在肽化学领域的方法。有用的起始材料是4-氨基-1-苄基哌啶(2)。用叔丁氧基羰基(Boc)保护伯胺得到3，氢解得到哌啶衍生物4。它可用异硫脲衍生物5处理产生甲脒基哌啶衍生物6，其中的胺和胍官能团是用不同的保护基保护的。
甲脒基哌啶衍生物6然后可选择性地脱保护，与N-保护的氨基酸7偶合，得到中间体8。
中间体8产生最终产物的反应在某些程度上取决于R1的性质。当R1是R5-OCO时，合成可方便地通过中间体9进行。
当R1是H、R4-CO、R4-O2CCH2、或R5-SO2时，反应可方便地通过中间体10和11进行。
胍官能团的脱保护给出通式1的化合物，其中R1是H。在胍脱保护之前将伯胺衍生化给出R1的其它实施方案的方法。
中间体12、13和14然后脱保护，产生相应的通式1的化合物。
当R1是烷基，或当R1和R2一起形成亚二甲苯基时，合成可方便地通过中间体15进行。
然后两个脱保护步骤给出通式1的化合物。
本发明化合物是强力的和选择性的血浆激肽释放酶的抑制剂。因此它们可用来治疗那些血浆激肽释放酶的过度活性是致病因子的疾病。一般，为了在这样的治疗中使用，化合物需要经过配方来给予病人。药物配方可以是固体的或液体的，如药片、胶囊、溶液或悬浮液。制备这些配方的方法是制药行业所公知的。
组合物要在护理医生的监督下给予病人。
实施例
使用以下的缩写：
AcOH 乙酸
Boc-Dcha-OH N-(叔丁氧基羰基)-3-环己基-D-丙氨酸
Boc-Dtyr(Et)-OH N-(叔丁氧基羰基)-O-乙基-D-酪氨酸
Boc-Phe-ONSu N-(叔丁氧基羰基)-苯丙氨酸琥珀酰亚氨酸酯
DMF 二甲基甲酰胺
H-thPse-OH 苏式-3-苯基丝氨酸
Mplc 中压液相色谱
TFA 三氟乙酸
“Celite”是Celite公司的注册商标
“Vydac”是W.R.Grace & Co.的注册商标
实施例1
(2’S，2”R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
1A.1-苄基-4-(叔丁氧基羰基氨基)哌啶
4-氨基-1-苄基哌啶(3.2g，16.8mmol)溶解在二氯甲烷(100mL)中。加入二碳酸二叔丁酯(3.7g，17.0mmol)和N，N-二异丙基乙基胺(1.9g，19mmol)。混合物室温搅拌18小时，真空除去溶剂，残渣中加入乙酸乙酯(150mL)。该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，干燥(Na2SO4)，真空蒸发，给出黄色油，用硅胶快速色谱纯化(洗脱液：70％氯仿，30％环己烷)，给出黄色固体，鉴定为1-苄基-4-(叔丁氧基羰基氨基)哌啶(4.9g，18.9mmol，100％)。
1B.4-(叔丁氧基羰基氨基)哌啶
1-苄基-4-(叔丁氧基羰基氨基)哌啶(4.9g，18.9mmol)溶解在乙醇(100mL)中。该溶液用10％Pd/C在60psi氢化。室温18小时后，混合物Celite过滤，残渣用乙醇(100mL)洗涤。合并的滤液真空蒸发，给出白色固体，鉴定为.4-(叔丁氧基羰基氨基)哌啶(2.3g，7.1mmol，51％)。
1C.N，N’-二(苄氧基羰基)-4-(叔丁氧基羰基氨基)哌啶-1-甲脒
4-(叔丁氧基羰基氨基)哌啶(1.5g，7.5mmol)溶解在乙醇(100mL)中。加入N，N’-二(苄氧基羰基)-S-甲基异硫脲(3.1g，8.7mmol)和氧化汞(1.9g，8.8mmol)。混合物在40℃搅拌4小时，然后滤出固体，用乙醇(50mL)洗涤。合并的滤液真空蒸发，给出无色油，用硅胶快速色谱纯化，得到无色油，鉴定为N，N’-二(苄氧基羰基)-4-(叔丁氧基羰基氨基)哌啶-1-甲脒(3.3g，6.6mmol，87％)。
1D.(2’S)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒
N，N’-二(苄氧基羰基)-4-(叔丁氧基羰基氨基)哌啶-1-甲脒(3.1g，6.1mmol)溶解在4M HCl/二噁烷(70mL)中。室温30分钟后，真空蒸发溶剂，残渣溶解在二氯甲烷(60mL)中。将该溶液冷却到0℃，加入Boc-Phe-ONSu(2.2g，6.1mmol)，pH用N-甲基吗啉调节到9。混合物室温搅拌4小时，真空蒸发溶剂，残渣溶解在乙酸乙酯(200mL)中。该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，干燥(Na2SO4)，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：70％氯仿，30％环己烷)，给出白色固体，鉴定为(2’S)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒(3.56g，5.4mmol，89％)。
1E.(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒
(2’S)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧羰基基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒(2.5g，3.85mmol)溶解在4M HCl/二噁烷(70mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在二氯甲烷/DMF(9∶1，50mL)中。该溶液冷却到0℃，加入Boc-DTyr(Et)-OH(1.2g，3.84mmol)接着加入1-羟基苯并三唑水合物(680mg，5.0mmol)和水溶性碳二亚胺(1.0g，5.0mmoL)。15分钟后，用N-甲基吗啉将pH调节到8。混合物室温搅拌18小时。然后真空蒸发溶剂，残渣溶解在氯仿(200mL)中。该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，干燥(Na2SO4)，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：85％氯仿，15％环己烷)，给出白色固体，鉴定为(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒(2.47g，3.2mmol，65％)。
1F.(2’S，2”R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒(2.1g，2.7mmol)溶解在4MHCl/二噁烷(50mL)中。室温30分钟后，真空蒸发溶剂，残渣溶解在乙酸/水(95∶5，50mL)中。该溶液用10％Pd/C氢化。室温2小时后，混合物用Celite过滤，残渣用乙酸/水(9∶1，30mL)洗涤。合并的滤液真空蒸发，残渣用mplc在Vydac C18(15-25μ)，MeCN/H2O/TFA纯化，给出白色固体鉴定为H-DTyr(Et)-Phe-4-氨基-1-咪基哌啶三氟乙酸盐(1.12g)。[M+H]+＝480.6。
实施例2
(2’S，2”R)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒
2A.(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒
(2’S)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒(从实施例1D，1.9g，2.99mmol)溶解在4M HCl/二噁烷(70mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在二氯甲烷/DMF(9∶1，50mL)中。
该溶液冷却到0℃，加入Boc-DCha-OH(900mg，3.3mmol)接着加入1-羟基苯并三唑水合物(820mg，6.1mmol)和水溶性碳二亚胺(730mg，3.6mmoL)。15分钟后，用N-甲基吗啉将pH调节到8。混合物室温搅拌18小时。然后真空蒸发溶剂，残渣溶解在氯仿(200mL)中。该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，干燥(Na2SO4)，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：90％氯仿，10％环己烷)，给出白色固体，鉴定为(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.73g，2.14mmol，72％)。
2B.(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒
(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.73g，2.14mmol)溶解在4M HCl/二噁烷(50mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在乙腈(100mL)中。加入溴代乙酸甲酯(400mg，2.6mmol)和N，N-二异丙基乙基胺(440mg，4.4mmol)。混合物在60℃搅拌5小时，然后真空蒸发溶剂，残渣溶解在乙酸乙酯(200mlL)中。。该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，干燥(Na2SO4)，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：90％氯仿，10％环己烷)，给出白色固体，鉴定为(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.65g，2.11mmol，98％)。
2C.(2’S，2”R)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.62g，2.11mmol)溶解在乙酸/水(95∶5，50mL)中。该溶液用10％ Pd/C氢化。室温2小时后，混合物用Celite过滤，残渣用乙酸/水(9∶1，30mL)洗涤。合并的滤液真空蒸发，残渣用mplc在VydacC18(15-25μ)，MeCN/H2O/TFA纯化，给出白色固体鉴定为.(2’S，2”R)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐(570mg)。
[M+H]+＝515。
实施例3
(2’S，2”R)-4-(2’-(2”-(羧甲基氨基)-3”-环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
3A.(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(羧甲基氨基)-3”-环己基-丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒
(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒(从实施例2B，1.62g，2.1mmol)溶解在四氢呋喃(50mL)中。加入1M氢氧化锂(3mL，3mmol)。18小时后，溶剂真空蒸发，残渣用乙酸乙酯(150mL)溶解，用1M柠檬酸(1×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，硫酸钠干燥，真空蒸发，给出白色固体，鉴定为(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(羧甲基氨基)-3”-环己基-丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒(11.62g，2.11mmol，100％)。
3B.(2’S，2”R)-4-(2’-(2”-(羧甲基氨基)-3”-环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(羧甲基氨基)-3”-环己基-丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.62g，2.11mmol)溶解在乙酸/水(95∶5，50mL)中。该溶液用10％Pd/C氢化。室温2小时后，混合物用Celite过滤，残渣用乙酸/水(9∶1，30mL)洗涤。合并的滤液真空蒸发，残渣用mplc在Vydac C18(15-25μ)，MeCN/H2O/TFA纯化，给出白色固体鉴定为(2’S，2”R)-4-(2’-(2”-(羧甲基氨基)-3”-环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐(570mg)。
[M+H]+＝501
实施例4
(2’S，2”R)-4-(2’-(2”-(苯甲酰基氨基-3”-(4-乙氧基苯基)-3’-苯基丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
4A.(2’S，2”R)-4-(2’-(2”-(苯甲酰基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)-N，N’-二(苄氧基羰基)哌啶-1-甲脒
(2’S，2”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒(从实施例1F，100mg，0.12mmol)溶解在4MHCl/二噁烷(20mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在二氯甲烷(20mL)中。溶液冷却到0℃，加入苯甲酰氯(19.7mg，0.141mmol)和三乙胺(36mg，0.36mmol)。混合物室温搅拌18小时，真空蒸发溶剂，残渣溶解在乙酸乙酯(70mL)中，用0.3M KHSO4(2×20mL)，饱和NaHCO3(2×20mL)，水(2×20mL)和盐水(1×20mL)洗涤，硫酸钠干燥，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：85％氯仿，15％环己烷)，给出白色固体，鉴定为(2’S，2”R)-4-(2’-(2”-(苯甲酰基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)-N，N’-二(苄氧基羰基)哌啶-1-甲脒(65mg，0.072mmol，60％)。
4B.(2’S，2”R)-4-(2’-(2”-(苯甲酰基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
(2’S，2”R)-4-(2’-(2”-(苯甲酰基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)-N，N’-二(苄氧基羰基)哌啶-1-甲脒(65mg，0.072mmol)溶解在乙酸/水(95∶5，25mL)中。该溶液用10％ Pd/C氢化。室温1小时后，混合物用Celite过滤，残渣用乙酸/水(9∶1，20mL)洗涤。合并的滤液真空蒸发，残渣用mplc在VydacC18(15-25μ)，MeCN/H2O/TFA纯化，给出白色固体鉴定为(2’S，2”R)-4-(2’-(2”-(苯甲酰基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐(44mg)。
[M+H]+＝585
实施例5
(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-羟基-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
5A.(2S，3R)-2-(叔丁氧基羰基氨基)-3-羟基-3-苯基丙酸
H-thPse-OH(J.Biol.Chem.，1953，204，323)(1.4g，7.73mmol)溶解在二噁烷(75mL)中。加入氢氧化钠(820mg，9.6mmol)在水(75mL)中的溶液，接着加入二碳酸二叔丁酯(2.1g，9.6mmol)。混合物室温搅拌18小时，然后真空蒸发除去二噁烷，残渣用乙醚(1×100ml)洗涤，用1M HCl酸化到pH4，用氯仿(3×100mL)萃取。合并的萃取物用水(1×50mL)和盐水(1×50mL)洗涤，硫酸钠干燥，真空蒸发给出白色固体，鉴定为(2S，3R)-2-(叔丁氧基羰基氨基)-3-羟基-3-苯基丙酸(1.6g，5.7mmol，74％)。
5B.(2’S，3R’)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒
N，N’-二(苄氧基羰基)-4-(叔丁氧基羰基氨基)哌啶-1-甲脒(从实施例1C，2.3g，4.5mmol)溶解在4M HCl/二噁烷(70mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在CH2Cl2/DMF(9∶1，50mL)中。溶液冷却到0℃，加入(2S，3R)-2-(叔丁氧基羰基氨基)-3-羟基-3-苯基丙酸(1.6g，5.6mmol)，接着加入1-羟基苯并三唑水合物(1.1g，8.1mmol)和水溶性碳二亚胺(1.4g，75.0mmol)。15分钟后，用N-甲基吗啉将pH调节到8。混合物在室温搅拌18小时，然后真空蒸发溶剂，残渣溶解在乙酸乙酯(200mlL)中。该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，干燥(Na2SO4)，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：50％乙酸乙酯，50％石油醚)，给出白色固体，鉴定为(2’S，3R)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.1g，1.6mmol，36％)。
5C.(2’S，2”R，3”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒
(2’S，3’R)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.1g，1.6mmol)溶解在4M HCl/二噁烷(70mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在CH2Cl2/DMF(9∶1，50mL)中。溶液冷却到0℃，加入Boc-Dtyr(Et)-OH(620mg，2.0mmol)，接着加入1-羟基苯并三唑水合物(270mg，2.0mmol)和水溶性碳二亚胺(420mg，2.1mmol)。15分钟后，用N-甲基吗啉将pH调节到8。混合物在室温搅拌18小时，然后真空蒸发溶剂，残渣溶解在乙酸乙酯(200mlL)中。该溶液用0.3M KHSO4(2×30mL)、饱和NaHCO3(2×30mL)、水(2×30mL)和盐水(1×30mL)洗涤，干燥(Na2SO4)，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：60％乙酸乙酯，40％石油醚)，给出白色固体，鉴定为(2’S，2”R，3”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.2g，1.3mmol，80％)。
5D.(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-羟基-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
(2’S，2”R，3”R)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒(1.2g，1.3mmol)溶解在4MHCl/二噁烷(50mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在乙酸/水(95∶5，50mL)中。该溶液用10％ Pd/C氢化。室温2小时后，混合物用Celite过滤，残渣用乙酸/水(9∶1，30mL)洗涤。合并的滤液真空蒸发，残渣用mplc在VydacC18(15-25μ)，MeCN/H2O/TFA纯化，给出白色固体鉴定为(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-羟基-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐(540mg)。
[M+H]＝497.0
实施例6
(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-甲氧基-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
6A.(2’SR，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒
(2’SR，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒按照实施例5相同的方法制备，但是用外消旋的H-thPse-OH为原料。
6B.(2’SR，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒
(2’SR，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒(180mg，0.27mmol)溶解在CH2Cl2(30mL)中。加入碘甲烷(190mg，1.3mmol)和氧化银(132mg，0.8mmol)。60℃18小时后，过滤混合物，滤液真空蒸发，得到褐色油，用硅胶快速色谱纯化(洗脱液：50％乙酸乙酯，50％石油醚)，给出白色固体，鉴定为(2’SR，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒(112mg，0.16mmol，61％)。
6C.(2’SR，2’R，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒
(2’SR，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(叔丁氧基羰基氨基)-3”-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒(112mg，0.16mmol)溶解在4M HCl/二噁烷(20mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在CH2Cl2(30mL)中。溶液冷却到0℃，加入Boc-Dtyr(Et)-OH(50mg，0.16mmol)，接着加入PyBrop(76g，0.16mmol)。用N，N-二异丙基胺将pH调节到9。混合物在室温搅拌18小时，然后真空蒸发溶剂，残渣溶解在乙酸乙酯(70mL)中。该溶液用0.3M KHSO4(2×20mL)、饱和NaHCO3(2×20mL)、水(2×20mL)和盐水(1×20mL)洗涤，干燥(Na2SO4)，真空蒸发，给出白色固体，用硅胶快速色谱纯化(洗脱液：65％氯仿，15％己烷)，给出白色固体，鉴定为(2’SR，2’R，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒(108mg，0.12mmol，75％)。
6D.(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-甲氧基-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐
(2’SR，2’R，3’RS)-N，N’-二(苄氧基羰基)-4-(2’-(2”-(叔丁氧基羰基氨基)-3”-(4-乙氧基苯基)丙酰基氨基-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒(108mg，0.12mmol)溶解在4MHCl/二噁烷(20mL)中。室温30分钟后，溶剂真空蒸发，残渣溶解在乙酸/水(95∶5，20mL)中。该溶液用10％Pd/C氢化。室温2小时后，混合物用Celite过滤，残渣用乙酸/水(9∶1，30mL)洗涤。合并的滤液真空蒸发，残渣用mplc在Vydac C18(15-25μ)，MeCN/H2O/TFA纯化，给出白色固体鉴定为(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-甲氧基-3’-苯基-丙酰基氨基)哌啶-1-甲脒三氟乙酸盐(18mg)。
[M+H]＝511.3
用类似的方法制备以下的化合物。
实施例7-17
实施例18-52
| Ex. | R1 | S1 | S2 | S3 | S4 | m/e |
| 18 | H | H | H | H | H | 437.3 |
| 19 | H | H | H | CH3CH2CH2 | H | 479 |
| 20 | H | H | H | NO2 | H | 482.3 |
| 21 | H | H | H | NH2 | H | 452.3 |
| 22 | H | H | H | I | H | 563.1 |
| 23 | H | H | H | F | H | 455.2 |
| 24 | H | H | H | CN | H | 462.3 |
| 25 | H | H | H | Cl | H | 471.6 |
| 26 | H | H | H | CF3 | H | 505.3 |
| 27 | H | H | H | NHCOCH3 | H | 494.3 |
| 28 | H | H | F | H | H | 455 |
| 29 | H | H | Cl | Cl | H | 505.1 |
| 30 | H | Cl | H | Cl | H | 505.1 |
| 31 | H | H | H | OH | H | 453.3 |
| 32 | H | H | H | OCH2Ph | H | 543.5 |
| 33 | H | H | H | OC(CH3)3 | H | 509.3 |
| 34 | H | H | H | OCH2CH2CH3 | H | 495.4 |
| 35 | H | H | H | OCH3 | H | 467.3 |
| 36 | H | H | H | OCH(CH3)2 | H | 495.2 |
| 37 | H | H | H | OnC6H13 | H | 537.3 |
| 38 | H | H | I | OCH2CH3 | I | 733.1 |
| 39 | CH3 | H | H | OCH2CH3 | H | 493.3 |
| 40 | CH3SO2 | H | H | OCH2CH3 | H | 559.3 |
| 41 | CH3CH2SO2 | H | H | OCH2CH3 | H | 573.3 |
| 42 | PhSO2 | H | H | OCH2CH3 | H | 621 |
| 43 | CH3CO | H | H | OCH2CH3 | H | 523.3 |
| 44 | CH3CH2CH2CO | H | H | OCH2CH3 | H | 551 |
| 45 | CH3CH2CO | H | H | OCH2CH3 | H | 537 |
| 46 | PhCH2OCO | H | H | OCH2CH3 | H | 615 |
| 47 | MeO2CCH2 | H | H | OCH2CH3 | H | 553 |
| 48 | HO2CCH2 | H | H | OCH2CH3 | H | 539 |
| 49 | H | -CH＝CH-CH＝CH- | H | H | 487.4 | |
| 50 | H | H | -CH＝CH-CH＝CH- | H | 487.3 | |
| 51 | -CH2- | H | H | H | 449.3 | |
| 52 | -CH2- | H | OCH2CH3 | H | 493.3 | |
实施例53-54
| Ex. | R3 | m/e |
| 53 | OH | 497.4 |
| 54 | OMe | 511.3 |
实施例55-58
| Ex. | S1 | S2 | m/e |
| 55 | H | OH | 453.3 |
| 56 | H | OMe | 467.3 |
| 57 | OH | H | 453.3 |
| 58 | OMe | H | 467.3 |
实施例59
测定对血浆激肽释放酶的抑制常数Ki
用标准方法(见Johansen等，Int.J.Tiss.Reac.1986，8，185；shori等，Biochem.Pharmacol.，1992，43，1209；Sturzebecher等，Biol.Chem.Hoppe-Seyler，1992，373，1025)测定血浆激肽释放酶活性的体外抑制作用。人血浆激肽释放酶(Callbiochem)在37℃与三个不同浓度的生色底物S-2302(Chromogenix AB)和各种浓度的试验化合物共同培养。残留的酶活性(反应的初速度)通过测量在405nm处光吸收的改变来测定，试验化合物的抑制常数Ki从Dixon曲线确定(Dixon，Biochem.J.，1953，55，170)。典型的结果列在下表中。
| 实施例No.的化合物 | Ki(nM) | 实施例No.的化合物 | Ki(nM) |
| 1 | 4.5 | 34 | 7.0 |
| 2 | 66.0 | 39 | 15.0 |
| 3 | 3.0 | 40 | 9.0 |
| 4 | 1.4 | 42 | 4.5 |
| 5 | 6.6 | 43 | 7.3 |
| 6 | 25.0 | 44 | 4.1 |
| 14 | 2.6 | 45 | 3.0 |
| 15 | 19.0 | 52 | 18.0 |
| 32 | 5.5 |
实施例60
酶选择性的测定
选出的化合物按照实施例59的方法用适当的酶和生色底物(Chromogenix AB)进一步筛选对其它胰蛋白酶样的蛋白酶的抑制活性。代表性的结果列在下表中。选择性按下式计算：
选择性＝(对试验酶的Ki)/(对血浆激肽释放酶的Ki)
| 酶 | 底物 | 实施例No.的化合物 | Ki(nM) | 选择性 |
| 人组织激肽释放酶 | S-2266 | 1 | 45,000 | 10,000 |
| 3 | 6,000 | 2,000 | ||
| 4 | 18,500 | 13,000 | ||
| 5 | ＞70,000 | ＞10,000 | ||
| 39 | 14,000 | 930 | ||
| 40 | 1,950 | 210 | ||
| 42 | 6,800 | 1,500 | ||
| 43 | 69,000 | 9,400 | ||
| 45 | 49,000 | 16,000 |
| 凝血酶 | S-2238 | 3 | 310 | 100 |
| 40 | 16,500 | 1,800 | ||
| 纤溶酶 | S-2390 | 3 | 3,200 | 1,000 |
| 40 | 1,440 | 160 | ||
| 胰蛋白酶 | S-2222 | 3 | 825 | 270 |
| 40 | 3,500 | 380 |
Claims (11)
1.通式1的化合物，或其药学上可接受的盐
其中，
R1选自H、低级烷基、R4-CO、R4-O2CCH2、R5-OCO和R5-SO2；
R2选自低级烷基、任选地被烷基或烷氧基取代的环烷基、任选地被烷基或烷氧基取代的(C5-C12)环烷基烷基、任选地被最多三个选自F、Cl、Br、I、OH、低级烷基、O-(低级烷基)、O-苄基、NH2、NO2、NH-酰基、CN和CF3的基团所取代的芳烷基、任选地被最多三个选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的芳烷基氧甲基；或者，
R1和R2一起构成任选地在芳环上被选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的邻-亚二甲苯基；
R3选自H、OH和O-(低级烷基)；
R4选自H、低级烷基和苯基；以及
R5选自低级烷基、苯基和苄基。
2.如权利要求1所述的化合物，其中R1选自H、低级烷基和R4-O2CCH2。
3.如权利要求1或2所述的化合物，其中R2选自(C6-C10)环烷基甲基、任选地被最多三个选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的苄基、任选地被最多三个选自F、Cl、Br、OH、低级烷基、O-(低级烷基)的基团所取代的苯乙基和任选地被最多三个选自F、Cl、Br、OH、低级烷基和O-(低级烷基)的基团所取代的苄氧基甲基。
4.如权利要求1所述的化合物，其中R2选自环己基甲基、十氢萘-2-基甲基、苄基、4-氟苄基、4-氯苄基、4-羟基苄基、4-(低级烷基)氧苄基、α-羟基苄基、α-甲氧基苄基、苯乙基和苄氧基甲基。
5.如权利要求1所述的化合物，其中绝对立体化学如通式1A所描述
6.如权利要求1所述的化合物，其中绝对立体化学如通式1B所描述
7.如权利要求1所述的化合物，所述化合物选自；
(2’S，2”R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-(4-乙氧基苯基)丙酰基-氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(3”-(4-乙氧基苯基)-2”-(甲氧基羰基甲基氨基)-丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-氨基-3”-环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-环己基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-氨基-3”-苯基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-苯基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-(甲氧基羰基甲基氨基)-3”-苯基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-氨基-3”-十氢萘-2-基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(2”-羧甲基氨基-3”-十氢萘-2-基丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R)-4-(2’-(3”-十氢萘-2-基-2”-(甲氧基羰基甲基氨基)丙酰基氨基)-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-环己基丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(2”-羧甲基氨基-3”-环己基丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(3”-环己基-2”-(甲氧基羰基甲基氨基)-丙酰基氨基)-3’-羟基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(2”-氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
(2’S，2”R，3’R)-4-(2’-(2”-羧甲基氨基-3”-(4-乙氧基苯基)丙酰基氨基)-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒；和
(2’S，2”R，3’R)-4-(2’-(3”-(4-乙氧基苯基)-2”-(甲氧基羰基甲基氨基)-丙酰基氨基)-3’-甲氧基-3’-苯基丙酰基氨基)哌啶-1-甲脒；
或其药学上可接受的盐。
8.一种药物组合物，所述药物组合物包含权利要求1-7中任一项所述的化合物或其药学上可接受的盐。
9.如权利要求1-7中任一项所述的化合物在制造用于治疗人或动物疾病的药物中的应用。
10.如权利要求9所述的应用，其特征在于，所述药物用于治疗以血浆激肽释放酶的过度活性为致病因子的疾病。
11.如权利要求10所述的应用，其特征在于，所述药物用于治疗炎性肠病、关节炎、炎症、败血性休克、低血压、癌症、成年人呼吸窘迫综合症、播散性血管内凝结、心肺旁路外科和手术后出血。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0205527.5A GB0205527D0 (en) | 2002-03-08 | 2002-03-08 | Inhibitors |
| GB0205527.5 | 2002-03-08 |
Publications (2)
| Publication Number | Publication Date |
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| CN1639186A CN1639186A (zh) | 2005-07-13 |
| CN1274713C true CN1274713C (zh) | 2006-09-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB038054019A Expired - Fee Related CN1274713C (zh) | 2002-03-08 | 2003-03-04 | 激肽释放酶抑制剂 |
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| US (1) | US7649000B2 (zh) |
| EP (1) | EP1483284B1 (zh) |
| JP (1) | JP4330450B2 (zh) |
| KR (1) | KR100974633B1 (zh) |
| CN (1) | CN1274713C (zh) |
| AR (1) | AR039868A1 (zh) |
| AT (1) | ATE333463T1 (zh) |
| AU (1) | AU2003208471B2 (zh) |
| CA (1) | CA2478099C (zh) |
| DE (1) | DE60306904T2 (zh) |
| DK (1) | DK1483284T3 (zh) |
| EG (1) | EG25482A (zh) |
| ES (1) | ES2264523T3 (zh) |
| GB (1) | GB0205527D0 (zh) |
| HK (1) | HK1072265A1 (zh) |
| IL (2) | IL163710A0 (zh) |
| MX (1) | MXPA04008523A (zh) |
| MY (1) | MY130830A (zh) |
| NO (1) | NO332678B1 (zh) |
| NZ (1) | NZ534891A (zh) |
| PL (1) | PL209670B1 (zh) |
| PT (1) | PT1483284E (zh) |
| RU (1) | RU2301225C2 (zh) |
| TW (1) | TWI283685B (zh) |
| UY (1) | UY27699A1 (zh) |
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|---|---|---|---|---|
| CN103687846A (zh) * | 2011-07-07 | 2014-03-26 | 卡尔维斯塔制药有限公司 | 作为血浆激肽释放酶抑制剂的苄胺衍生物 |
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| WO2005095327A1 (ja) | 2004-03-31 | 2005-10-13 | Ajinomoto Co., Inc. | アニリン誘導体 |
| AU2008289005A1 (en) * | 2007-08-21 | 2009-02-26 | Genzyme Corporation | Treatment with kallikrein inhibitors |
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| US9290485B2 (en) | 2010-08-04 | 2016-03-22 | Novartis Ag | N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides |
| WO2013111108A1 (en) | 2012-01-27 | 2013-08-01 | Novartis Ag | 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors |
| EP2807156A1 (en) | 2012-01-27 | 2014-12-03 | Novartis AG | Aminopyridine derivatives as plasma kallikrein inhibitors |
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| IL239682B (en) | 2013-01-08 | 2018-10-31 | Kalvista Pharmaceuticals Ltd | History of benzylamine and 2-(aminomethyl)pyridine |
| GB201300304D0 (en) | 2013-01-08 | 2013-02-20 | Kalvista Pharmaceuticals Ltd | Benzylamine derivatives |
| GB2510407A (en) | 2013-02-04 | 2014-08-06 | Kalvista Pharmaceuticals Ltd | Aqueous suspensions of kallikrein inhibitors for parenteral administration |
| CA2912285C (en) | 2013-05-23 | 2021-07-13 | Kalvista Pharmaceuticals Limited | Fused 6,5 or 6,6-heteroaromatic bicyclic amide derivatives and pharmaceutical compositions thereof useful as plasma kallikrein inhibitor |
| GB2517908A (en) * | 2013-08-14 | 2015-03-11 | Kalvista Pharmaceuticals Ltd | Bicyclic inhibitors |
| TWI636047B (zh) | 2013-08-14 | 2018-09-21 | 英商卡爾維斯塔製藥有限公司 | 雜環衍生物 |
| CA2920815C (en) | 2013-08-14 | 2021-09-21 | Kalvista Pharmaceuticals Limited | Inhibitors of plasma kallikrein |
| EP3062823B1 (en) * | 2013-10-28 | 2018-12-12 | BicycleRD Limited | Novel polypeptides |
| ES2945905T3 (es) | 2014-02-07 | 2023-07-10 | Exithera Pharmaceuticals Inc | Compuestos y composiciones terapéuticos |
| GB201421088D0 (en) | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | New enzyme inhibitors |
| GB201421083D0 (en) | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | Enzyme inhibitors |
| GB201421085D0 (en) | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | New enzyme inhibitors |
| US11180484B2 (en) | 2016-05-31 | 2021-11-23 | Kalvista Pharmaceuticals Limited | Pyrazole derivatives as plasma kallikrein inhibitors |
| GB201609603D0 (en) | 2016-06-01 | 2016-07-13 | Kalvista Pharmaceuticals Ltd | Polymorphs of N-[(6-cyano-2-fluoro-3-methoxyphenyl)Methyl]-3-(methoxymethyl)-1-({4-[(2-ox opyridin-1-YL)Methyl]phenyl}methyl)pyrazole-4-carboxamide |
| GB201609607D0 (en) | 2016-06-01 | 2016-07-13 | Kalvista Pharmaceuticals Ltd | Polymorphs of N-(3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-({4-((2-oxopy ridin-1-yl)methyl)phenyl}methyl)pyrazole-4-carboxamide and salts |
| SI3716952T1 (sl) | 2017-11-29 | 2022-04-29 | Kalvista Pharmaceuticals Limited | Farmacevtske oblike, ki obsegajo zaviralec plazemskega kalikreina |
| GB201719881D0 (en) | 2017-11-29 | 2018-01-10 | Kalvista Pharmaceuticals Ltd | Solid forms of plasma kallikrein inhibitor and salts thereof |
| BR112021008462A2 (pt) | 2018-10-30 | 2021-08-03 | Exithera Pharmaceuticals, Inc. | compostos e composições terapêuticas |
| GB201910116D0 (en) | 2019-07-15 | 2019-08-28 | Kalvista Pharmaceuticals Ltd | Treatments of hereditary angioedema |
| GB201910125D0 (en) | 2019-07-15 | 2019-08-28 | Kalvista Pharmaceuticals Ltd | Treatments of angioedema |
| EP4010333A1 (en) | 2019-08-09 | 2022-06-15 | Kalvista Pharmaceuticals Limited | Plasma kallikrein inhibitors |
| GB201918994D0 (en) | 2019-12-20 | 2020-02-05 | Kalvista Pharmaceuticals Ltd | Treatments of diabetic macular edema and impaired visual acuity |
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| WO2021198534A1 (en) | 2020-04-04 | 2021-10-07 | Oxurion NV | Plasma kallikrein inhibitors for use in the treatment of coronaviral disease |
| WO2022079446A1 (en) | 2020-10-15 | 2022-04-21 | Kalvista Pharmaceuticals Limited | Treatments of angioedema |
| WO2022084693A1 (en) | 2020-10-23 | 2022-04-28 | Kalvista Pharmaceuticals Limited | Treatments of angioedema |
| WO2022172006A1 (en) | 2021-02-09 | 2022-08-18 | Kalvista Pharmaceuticals Limited | Treatments of hereditary angioedema |
| WO2023002219A1 (en) | 2021-07-23 | 2023-01-26 | Kalvista Pharmaceuticals Limited | Treatments of hereditary angioedema |
| WO2023144030A1 (en) | 2022-01-31 | 2023-08-03 | Oxurion NV | Plasma kallikrein inhibitor therapy for anti-vegf sensitization |
| WO2023148016A1 (en) | 2022-02-04 | 2023-08-10 | Oxurion NV | Biomarker for plasma kallikrein inhibitor therapy response |
| LT4288036T (lt) | 2022-04-27 | 2024-09-25 | Kalvista Pharmaceuticals Limited | Farmacinės plazmos kalikreino inhibitoriaus formos |
| WO2024180100A1 (en) | 2023-02-27 | 2024-09-06 | Kalvista Pharmaceuticals Limited | New solid form of a plasma kallikrein inhibitor |
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| GB9019558D0 (en) * | 1990-09-07 | 1990-10-24 | Szelke Michael | Enzyme inhibitors |
| WO1993008211A1 (en) * | 1991-10-23 | 1993-04-29 | The Procter & Gamble Company | Tripeptide derivative anti-inflammatory agents |
| SE9301911D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptide derivatives |
| GB9318637D0 (en) * | 1993-09-08 | 1993-10-27 | Ferring Res Ltd | Enzyme inhibitors |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103687846A (zh) * | 2011-07-07 | 2014-03-26 | 卡尔维斯塔制药有限公司 | 作为血浆激肽释放酶抑制剂的苄胺衍生物 |
| CN103687846B (zh) * | 2011-07-07 | 2016-06-22 | 卡尔维斯塔制药有限公司 | 作为血浆激肽释放酶抑制剂的苄胺衍生物 |
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