CN1032253C - 用作抑制脯氨酸羟化酶的药物的制备方法 - Google Patents

用作抑制脯氨酸羟化酶的药物的制备方法 Download PDF

Info

Publication number
CN1032253C
CN1032253C CN91103013A CN91103013A CN1032253C CN 1032253 C CN1032253 C CN 1032253C CN 91103013 A CN91103013 A CN 91103013A CN 91103013 A CN91103013 A CN 91103013A CN 1032253 C CN1032253 C CN 1032253C
Authority
CN
China
Prior art keywords
alkyl
hydrogen
compound
methyl
preparation
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.)
Expired - Fee Related
Application number
CN91103013A
Other languages
English (en)
Other versions
CN1056683A (zh
Inventor
埃柯哈德·巴得
哈拉得·布利哈德
沃科马·古泽勒-浦卡尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Publication of CN1056683A publication Critical patent/CN1056683A/zh
Application granted granted Critical
Publication of CN1032253C publication Critical patent/CN1032253C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Transplantation (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Materials For Medical Uses (AREA)

Abstract

本发明涉及用作影响胶原和类胺原物质代谢或胶原合成的药物的制备方法，其包括将式I化合物，它们的D-及L-型为主的化合物及其药用盐与药用赋形剂混合物。

Description

用作抑制脯氨酸羟化酶的药物的制备方法
草酰氨基酸衍生物是已知的，例如，在FR-A2，010，601，JP43/10614或生物化学(Bio chemistry)，27(8)，2934-2943(1988)中叙述过。然而，这些化合物用作药物，以前并未叙述过。现已发现式I的草酰氨基酸衍生物和其主要以钝D—型和L-型的化合物及其药用盐是脯氨酸羟化酶和赖氨酸羟化酶的良好抑制物，
Figure C9110301300041
其中R和R1是相同或不同的C1—C6烷基或H，R1是H或C1-C4—烷基，R2是H，C1—C6—烷基，C1—C3—烷氧基，羧基，C1—C6—烷
氧羰基，芳基，SH，NH2或卤素，这里的烷基是未被取代或者被
芳基，OH，SH，或NH2基团取代，或者R1和R2一起构成C2—C4—亚烷基链。
本发明涉及上述化合物作为药物的用途，特别是用作影响胶原和类胶原物质的代谢或生物合成的药物。
本发明尤其涉及式I中如下取代时的那些化合物的应用，其中R和R1是相同或不同的C1—C3—烷基，Na或K，R1是氢，甲基或乙基，R2是氢或C1—C4—烷基，这里的烷基是未取代或被苯基或SH取代或R1和R2一起形成C2—或C3—亚烷基链。
式I中的化合物的用途在如下的情况时是特别好的，其中，R和R1是相同的甲基，乙基，Na或K，R1是氢或甲基，R2是氢，C1—C3—烷基，苄基或硫甲基，或R1和R2一起形成亚乙基链。
有3个或更多碳的烷基可以是直链和支链。芳基其含意可理解为芳香烃类，特别是苯基和萘基。卤素可认为是F，Cl，Br和I，特别是Cl和Br。
式(I)的化合物的制备是已知的，例如在FR-A2,010,601中所述。其制备方法只不过是将1-3当量的氨基酸酯氢卤酸盐，(最好是盐酸盐)和1-5当量的碱合并，这里使用的碱例如碳酸盐或碳酸氢盐，如碳酸钠或碳酸钾，或碳酸氢钠或碳酸氢钾，或者为叔胺，如三乙胺，三丁胺，乙基二异丙胺，或者为杂环胺如N-烷基吗啉，吡啶，喹啉或二烷基苯胺。
如果需要，许多碱可同时使用。反应温度是-30℃到150℃，以20℃到100℃较好。如果需要，反应也可在溶剂中进行，如乙醚或二甲氧基乙烷或四氢呋喃，氯化烃类如二氯甲烷，氯仿，三或四氯乙烯，苯，甲苯以及极性溶剂如二甲基甲酰胺，丙酮，醇类如甲醇或乙醇或二甲基亚砜。然后在-78℃和100℃之间，最好是在-20℃和+20℃之间慢慢加1-3当量草酸酯酰氯。如果需要，该反应也可在上述溶剂中进行。用薄层层析检测反应是否完全。
如果需要，可用例如提取或者用硅胶层析处理产物，分离的产物可用重结晶纯化。
式I的R和/或R1为碱金属，例如Na或K的化合物可以用如下方法制备，例如由式I的R和/或R1为C1—C4—烷氧基的相应化合物在碱性介质中水解；如NaOH或KOH，溶剂为低分子量醇中如甲醇或乙醇，或者在醚中如二甲氧基乙烷或四氢呋喃，如果需要可有水存在。所得盐的金属阳离子可用常规的方法通过离子交换剂酸化，以任何所需的阳离子取代。为此，例如将酸通过装有阳离子交换剂的柱子，这种交换剂例如是基于聚苯乙烯/二乙烯苯(AmberliteCG-150或Dowex-CCR-2)的树脂。阳离子交换剂载有所要的阳离子，例如铵离子，是由伯胺、仲胺或叔胺产生的。洗脱液经蒸发可得所要的盐。
由伯，仲或叔胺产生的酸的铵盐也可用下法制备，即向游离酸的醇溶液加等摩尔量的适当的胺，然后蒸掉溶剂即可。
由外消旋物制备以D-或L-对映体为主的纯化合物，同样可用文献已知的方法进行，例如，用分步结晶法或用酶处理法进行。另外一种可行的方法是由适当的D-或L-前体(起始物)直接合成纯的对映体化合物。
本发明的物质作为可逆的抑制剂对脯氨酸羟化酶是有效的。因此，这些物质选择性地抑制胶原特异的羟化反应，在该反应过程中，脯氨酸羟化酶羟化结合于蛋白中的脯氨酸。该反应在抑制剂的作用下，形成无功能的、羟化不全的胶原分子，该类分子只有少量释放入细胞间隙中。羟化不全的胶原不能另外参入到胶原基质中，而很容易发生蛋白水解性的降解过程。由于这些作用，细胞外沉积的胶原总量减少。因此，脯氨酸羟化酶抑制剂在治疗主要由于胶原沉积引起的征候群方面是适宜的手段。其中特别包括肺、肝和皮肤(硬皮病)的纤维化以及动脉粥样硬化。
另外，用已知的抑制剂如α，α1—联吡啶对脯氨酸羟化酶的抑制导致巨噬细胞的生物合成胶原的抑制也是已知的(W.Muller etal，FEBS Lett，90,218以及下列等等(et seq)(1978))。结果不能发生补体活化经典的途径；因此，脯氨酸羟化酶抑制剂在像免疫综合症方面也起免疫抑制剂的作用。
因此，本发明的物质可用作纤维化抑制剂，免疫抑制剂及抗动脉粥样硬化剂。
抗纤维化的活性可用四氯化碳诱发的肝纤维变性模型测定。为此，用溶在橄榄油中的CCl4(1ml/Kg)处理大鼠每周两次。受试物质溶在适宜的溶剂每天给药，如果合适甚至可每天给两次，口服或腹腔注射。用组织学方法测定肝纤维变性的程度和用测定羟基脯氨酸分析肝中胶原的比例，如Kivirikkoetal。在(Anal、Biochem、19,249等等(1967))所述。纤维发生的活力可用放射免疫测定血清中的胶原组分和原胶原肽。本发明的化合物在浓度为1-100mg/kg时对这种模型是有效的。另一个评价抗生活性的模型是Kelley等(J.Lab、Clin、Med、96,954，(1980)叙述的博莱霉素诱发的肺纤维变性。为评价本发明化合物对肉芽发生组织的活性，可用Meier等在Experimentia6,469(1950)中叙述的棉球肉芽肿模型进行试验。
本发明用以下实例更详细的阐明
实例
制备实例1-6中化合物的通用方法。
在室温氮气下，将1当量氨基酸酯盐酸盐，2当量三乙胺和2当量N，N-二甲胺基吡啶先加到二氯甲烷中。然后在0℃-10℃慢慢滴加溶在二氯甲烷的1当量草酸酯酰氯。混合物在室温搅拌12小时，加入饱和碳酸氢钠溶液后提取。分出有机层，用氯化钠溶液洗涤，硫酸镁干燥并蒸发。得到的粗产物进行层析。
实例1(N-草酰基)-L-丙氨酸二甲基酯R＝R′＝CH3；R1＝H；R2＝CH3
由5gL-丙氨酸甲酯盐酸盐和3.3ml草酸甲酯酰氯得6g油状实例1的化合物(层析：EA/CH3OH5/1)
实例2(N-草酰基)-L-苯丙氨酸二甲酯R＝R′＝CH3；R1＝H；R2＝CH2C6H3
由5gL-苯丙氨酸甲酯盐酸盐和2.2ml草酸甲酯酰氯得6.5g实例2的油状化合物(层析：EA/CH3OH5/1)
实例3(N-草酰基)-L-甘氨酸二甲酯R＝R′＝CH3；R1＝H；R2＝H
由15g甘氨酸甲酯盐酸盐和11ml草酸单甲酯酰氯得到23g实例3的化合物；m.p.49℃(层析：EA)
实例4(N-草酰基)-L-脯氨酸二甲酯R＝R′＝CH3；R1＝CH2－CH2＝R2
由2gL-脯氨酸甲酯盐酸盐和2.9g草酸单甲酯酰氯得1.5g油状物(层析：EA)
实例5(N-草酰基)-L-缬氨酸二甲酯R＝R′＝CH3；R1＝H；R2＝-OH(CH3)2
由2gL-缬氨酸甲酯盐酸盐和2.8g草酸单甲酯酰氯得2g油状物(层析：CH/EA1/1)
实例6(N-草酰基)-L-半胱氨酸二甲酯R＝R′＝CH3；R1＝H；R2＝CH2SH
由2gL-半胱氨酸甲酯盐酸盐和3.9g草酸单甲酯酰氯得1.5g油状物(层析：CH/E1/1)
实例7(N-草酰基)-肌氨酸二乙酯R＝R′＝C2H5；R1＝CH3；R2＝H
先将2g肌氨酸乙酯盐酸盐加到50ml乙醇中，室温下滴加3.5ml(2当量)草酸二乙酯和1.8ml三乙胺在25ml乙醇中的溶液。在50℃搅拌5小时，然后回流2小时。溶液冷却并蒸发至干。用二氯甲烷溶解剩余物，水洗一次，有机相经硫酸镁干燥并蒸除溶剂。粗产物进行层析(EA/CH1/1)产量：0.35g制备实例8-14中的化合物的通用方法：
将1当量实例1-7的化合物在室温下溶于2当量的0.1N碱金属氢氧化物的醇溶液。混合物在室温搅拌12小时并蒸发干。剩余物用甲苯蒸发两次，用戊烷洗涤数次，然后在高真空中干燥。
实例8(N-草酰基)-L-丙氨酸二钾盐R＝R1＝K；R1＝H；R2＝CH3
300mg实例1的化合物与32.5ml 0.1N氢氧化钾乙醇溶液反应。产量：370mg白色结晶，m，p，：＞300℃
实例9(N-草酰基)-L-苯丙氨酸二钠盐R＝R′＝Na；R1＝H；R2＝CH2C6H5
420mg实例2的化合物与32.5ml 0.1N氢氧化钠甲醇溶液反应。产量：440mg白色结晶，m.p：＞300℃
实例10(N-草酰基)-L-甘氨酸二钾盐R＝R2＝K；R1＝H；R2＝H
5.5g实例3的化合物与314ml 0.1N氢氧化钾甲醇溶液反应。产量：5.4g白色结晶，m.p：＞300℃
实例11(N-草酰基)-L-脯氨酸二钠盐R＝R1＝Na；R1＝CH2 CH2＝R2
300mg实例4的化合物与1.5ml 0.1N的氢氧化钠乙醇溶液反应。产量：290mg白色结晶，m.p：＞300℃
实例12(N-草酰基)-L-缬氨酸二钠盐R＝R1＝Na；R1＝H；R2＝CH2SH
300mg实例6的化合物与13.7ml 0.1N氢氧化钠甲醇溶液反应。产量：300mg白色结晶，m.P：＞300℃
实例14(N-草酰基)-肌氨酸二钾盐R＝R’＝K；R1＝CH3；R2＝H
120mg实例7的化合物与11.4ml 0.1N氢氧化钾乙醇溶液反应。产量：130mg白色结晶，m.p：＞300℃实例1-14的化合物列于下表(表1)
Figure C9110301300121
表1
实施例  R       R′    R1       R2        M.p./油1      CH3    CH3    H         CH3           油2      CH3    CH3    H         CH2C6H5    油3      CH3    CH3    H         H              49℃4      CH3    CH3    CH2______CH2          Oil5      CH3    CH3    H         CH(CH3)2    Oil6      CH3    CH3    H         CH2SH        Oil7      C2H5  C2H5 CH3      H             Oil8      K        K       H         CH3         ＞300℃9      Na       Na      H         CH2C6H5  ＞300℃10     K        K       H         H            ＞300℃11     Na       Na      CH2______CH2        ＞300℃12     Na       Na      H         CH(CH3)2  ＞300℃13     Na       Na      H         CH2SH      ＞300℃14     K        K       CH3      H           ＞300℃本发明的化合物对酶活性的抑制测定类似于B.Peterkofsky和R.DiBlasio(Anal.Biochem.66，279-286，(1975))的方法。该试验是在二价铁离子，α-酮戊二酸和抗坏血酸的存在下，用酶法使脯氨酰羟化酶羟化那些羟化不全的胶原，以抑制酶活性80％(以Ki表示其值)来计算本发明化合物的抑制浓度实例8和10的化合物的结果列于表2。
               表2(盐类)
化合物                              Ki〔mM〕实施例8                              0.04实施例10                             0.01
也可用细胞或组织培养法测定抑制活性。为此，可应用成纤维细胞或其它产生胶原的细胞或颅盖，或者产生胶原的细官。本发明物质对颅盖培养基的抑制活性列于表3。用代谢标记14C的脯氨酸测定法使羟基脯氨酸/脯氨酸比值减少50％表示其抑制浓度(IC50)。
                   表3(酯类)
化合物                              IC50〔mM〕实施例1                               0.35实施例3                               0.002

Claims (3)

1.影响胶原和类胶原物质代谢胶或原生物合成的药物的制备方法，其包括将式I的化合物，和它们的以D—及L—型为主的化合物和其药用盐与药用赋形剂混合
Figure C9110301300021
式中R和R′是相同或不相同且为C1—C6的烷基或氢，R1是氢或C1—C4烷基，R2是氢或C1—C6烷基，C1—C3烷氧基，羟基，C1—C6烷氧羰基，芳基，SH，NH2或氢，这里烷基是未被取代或者被芳基，OH，SH或NH2取代，或R1和R2一起是C2—C4亚烷基链。
2.如权利要求1所要求的方法，其中R和R1是相同或不同的C1—C3烷基，Na或K，R1是氢，甲基或乙基，R2是氢或C1—C4烷基，这里烷基是未被取代或被苯基或SH取代或R1和R2一起形成C2或C3亚烷基链。
3.如权利要求1所要求的方法，其中，R和R1是相同的，为甲基，乙基，Na或K，R1是或甲基，R2是氢，C1—C3烷基，苄基或硫甲基，或R1和R2一起形成亚乙基链。
CN91103013A 1990-05-12 1991-05-11 用作抑制脯氨酸羟化酶的药物的制备方法 Expired - Fee Related CN1032253C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4015255.3 1990-05-12
DE4015255A DE4015255A1 (de) 1990-05-12 1990-05-12 Oxalyl-aminosaeurederivate, verfahren zu ihrer herstellung und ihrer verwendung als arzneimittel zur inhibierung der prolyl-hydroxylase

Publications (2)

Publication Number Publication Date
CN1056683A CN1056683A (zh) 1991-12-04
CN1032253C true CN1032253C (zh) 1996-07-10

Family

ID=6406245

Family Applications (1)

Application Number Title Priority Date Filing Date
CN91103013A Expired - Fee Related CN1032253C (zh) 1990-05-12 1991-05-11 用作抑制脯氨酸羟化酶的药物的制备方法

Country Status (28)

Country Link
US (1) US5204338A (zh)
EP (1) EP0457163B1 (zh)
JP (1) JP2504874B2 (zh)
KR (1) KR910019612A (zh)
CN (1) CN1032253C (zh)
AT (1) ATE108177T1 (zh)
AU (1) AU641760B2 (zh)
BR (1) BR9101927A (zh)
CA (1) CA2042282A1 (zh)
CZ (1) CZ279939B6 (zh)
DE (2) DE4015255A1 (zh)
DK (1) DK0457163T3 (zh)
EG (1) EG19762A (zh)
ES (1) ES2057655T3 (zh)
HR (1) HRP940695B1 (zh)
HU (1) HU217974B (zh)
IE (1) IE65298B1 (zh)
IL (1) IL98109A (zh)
LT (1) LT3953B (zh)
LV (1) LV10387B (zh)
MA (1) MA22152A1 (zh)
MX (1) MX25723A (zh)
MY (1) MY108608A (zh)
NZ (1) NZ238112A (zh)
PT (1) PT97642B (zh)
RU (1) RU2025123C1 (zh)
TW (1) TW225988B (zh)
ZA (1) ZA913538B (zh)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5192773A (en) * 1990-07-02 1993-03-09 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
DE69229782T2 (de) * 1991-05-09 2000-04-27 Vertex Pharmaceuticals Inc., Cambridge Neue immunsuppressive verbindungen
US5723459A (en) * 1991-05-09 1998-03-03 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
US5620971A (en) * 1991-05-09 1997-04-15 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
ATE149486T1 (de) 1993-11-02 1997-03-15 Hoechst Ag Substituierte heterocyclische carbonsäureamide, ihre herstellung und ihre verwendung als arzneimittel
EP0650960B1 (de) * 1993-11-02 1997-03-05 Hoechst Aktiengesellschaft Substituierte heterocyclische Carbonsäureamidester, ihre Herstellung und ihre Verwendung als Arzneimittel
NZ270267A (en) * 1993-12-30 1997-03-24 Hoechst Ag 3-hydroxypyridin-2yl (and -quinolin-2-yl) carboxamide derivatives and pharmaceutical compositions
US5543423A (en) * 1994-11-16 1996-08-06 Vertex Pharmaceuticals, Incorporated Amino acid derivatives with improved multi-drug resistance activity
US5789426A (en) * 1995-01-20 1998-08-04 Cornell Research Foundation, Inc. Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation
US6046219A (en) * 1995-01-20 2000-04-04 Cornell Research Foundation, Inc. Method for the treatment of conditions mediated by collagen formation together with cell proliferation by application of inhibitors of protein hydroxylation
US7056935B2 (en) 1995-06-07 2006-06-06 Gpi Nil Holdings, Inc. Rotamase enzyme activity inhibitors
US5859031A (en) 1995-06-07 1999-01-12 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
IL135495A (en) * 1995-09-28 2002-12-01 Hoechst Ag Intermediate compounds for the preparation of quinoline-converted amines - 2 - carboxylic acid
US5801197A (en) * 1995-10-31 1998-09-01 Gpi Nil Holdings, Inc. Rotamase enzyme activity inhibitors
US5717092A (en) * 1996-03-29 1998-02-10 Vertex Pharmaceuticals Inc. Compounds with improved multi-drug resistance activity
US6218424B1 (en) 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US5786378A (en) * 1996-09-25 1998-07-28 Gpi Nil Holdings, Inc. Heterocyclic thioesters
US5801187A (en) 1996-09-25 1998-09-01 Gpi-Nil Holdings, Inc. Heterocyclic esters and amides
DE19650215A1 (de) * 1996-12-04 1998-06-10 Hoechst Ag 3-Hydroxypyridin-2-carbonsäureamidester, ihre Herstellung und ihre Verwendung als Arzneimittel
US6187796B1 (en) 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Sulfone hair growth compositions and uses
US20010049381A1 (en) 1997-06-04 2001-12-06 Gpl Nil Holdings, Inc., Pyrrolidine derivative hair growth compositions and uses
US5945441A (en) 1997-06-04 1999-08-31 Gpi Nil Holdings, Inc. Pyrrolidine carboxylate hair revitalizing agents
US6274602B1 (en) 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses
US6271244B1 (en) 1998-06-03 2001-08-07 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6187784B1 (en) 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Pipecolic acid derivative hair growth compositions and uses
DE19746287A1 (de) * 1997-10-20 1999-04-22 Hoechst Marion Roussel De Gmbh Substituierte Isochinolin-2-Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
US6331537B1 (en) 1998-06-03 2001-12-18 Gpi Nil Holdings, Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
US6429215B1 (en) 1998-06-03 2002-08-06 Gpi Nil Holdings, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
CA2334204A1 (en) 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Heterocyclic ester and amide hair growth compositions and uses
US6172087B1 (en) 1998-06-03 2001-01-09 Gpi Nil Holding, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6335348B1 (en) 1998-08-14 2002-01-01 Gpi Nil Holdings, Inc. Nitrogen-containing linear and azepinyl/ compositions and uses for vision and memory disorders
US6506788B1 (en) 1998-08-14 2003-01-14 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders
US7338976B1 (en) 1998-08-14 2008-03-04 Gpi Nil Holdings, Inc. Heterocyclic esters or amides for vision and memory disorders
US6384056B1 (en) 1998-08-14 2002-05-07 Gpi Nil Holdings, Inc. Heterocyclic thioesters or ketones for vision and memory disorders
US6333340B1 (en) 1998-08-14 2001-12-25 Gpi Nil Holdings, Inc. Small molecule sulfonamides for vision and memory disorders
US6462072B1 (en) 1998-09-21 2002-10-08 Gpi Nil Holdings, Inc. Cyclic ester or amide derivatives
ES2414706T3 (es) * 2001-12-06 2013-07-22 Fibrogen, Inc. Métodos para aumentar la eritropoyetina endógena
WO2006134963A1 (ja) * 2005-06-15 2006-12-21 Nippon Zoki Pharmaceutical Co., Ltd. オキサルル酸誘導体を含有する線維性疾患用剤

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH474532A (fr) * 1966-08-08 1969-06-30 Ajinomoto Kk Procédé de préparation de dérivés d'oxazole
DE1645987A1 (de) * 1966-08-08 1971-01-21 Ajinomoto Kk Oxalzolderivate und Verfahren zu deren Herstellung
US3646061A (en) * 1968-06-10 1972-02-29 Ajinomoto Kk Method of preparing n-alkoxalyl and n-formyl derivatives of alpha-amino acid esters

Also Published As

Publication number Publication date
CN1056683A (zh) 1991-12-04
CZ279939B6 (cs) 1995-09-13
IE65298B1 (en) 1995-10-18
ES2057655T3 (es) 1994-10-16
JPH04226913A (ja) 1992-08-17
PT97642B (pt) 1998-08-31
RU2025123C1 (ru) 1994-12-30
HU217974B (hu) 2000-05-28
JP2504874B2 (ja) 1996-06-05
IE911608A1 (en) 1991-11-20
HRP940695B1 (en) 1999-04-30
LV10387B (en) 1996-02-20
CA2042282A1 (en) 1991-11-13
NZ238112A (en) 1993-12-23
EP0457163B1 (de) 1994-07-06
DE4015255A1 (de) 1991-11-14
LTIP1460A (en) 1995-05-25
IL98109A (en) 1995-07-31
KR910019612A (ko) 1991-12-19
MA22152A1 (fr) 1991-12-31
AU7622191A (en) 1991-11-14
TW225988B (zh) 1994-07-01
AU641760B2 (en) 1993-09-30
MX25723A (es) 1993-04-01
HRP940695A2 (en) 1997-02-28
DE59102102D1 (de) 1994-08-11
EP0457163A1 (de) 1991-11-21
HUT57581A (en) 1991-12-30
ATE108177T1 (de) 1994-07-15
BR9101927A (pt) 1991-12-17
PT97642A (pt) 1992-02-28
DK0457163T3 (da) 1994-10-17
IL98109A0 (en) 1992-06-21
ZA913538B (en) 1992-02-26
EG19762A (en) 1996-01-31
US5204338A (en) 1993-04-20
MY108608A (en) 1996-10-31
HU157291D0 (en) 1991-11-28
LV10387A (lv) 1995-02-20
LT3953B (en) 1996-05-27

Similar Documents

Publication Publication Date Title
CN1032253C (zh) 用作抑制脯氨酸羟化酶的药物的制备方法
EP0038758B1 (fr) Dérivés d'acides aminés et leur application thérapeutique
Gacel et al. Evidence of the preferential involvement of. mu.-receptors in analgesia using enkephalins highly selective for peripheral. mu. or. delta. receptors
AU582600B2 (en) Dipeptide compounds having pharmaceutical activity and compositions containing them
CA1103259A (en) Carboxyalkylacylamino acids
US4401677A (en) Enkephalinase inhibitors
GB2442148A (en) FK 228 derivates as HDAC inhibitors
Kovács et al. Inhibition of hepatocytic protein degradation by methylaminopurines and inhibitors of protein synthesis
BRPI0607207A2 (pt) método para triar compostos, composto, uso de bactérias da famìlia staphylococci, microorganismos, métodos para evitar mau odor no suor, para preparar um produto tendo a capacidade de reduzir o desenvolvimento de mau odor e para metabolizar um composto sob condições controladas
FI70208B (fi) Foerfarande foer framstaellning av nya terapeutiskt anvaendbara n-acetyl-para-aminofenyl-n'-acetylaminotioalkansyraesterderivat
Smith Metabolism of phosphonates
PT86380B (pt) Processo para a preparacao de isoxazolidinas substituidas nas posicoes 2 e 3 e de composicoes farmaceuticas que as contem
US4395402A (en) Analgesic agent
Fournie-Zaluski et al. New carboxyalkyl inhibitors of brain enkephalinase: Synthesis, biological activity and analgesic properties
PT1430045E (pt) Derivados de pirano como inibidores de ace e nep
JPS6136297A (ja) カルボキシアルキルジペプチドを製造する方法
Köhler et al. Phospholipase A2 inhibition by alkylbenzoylacrylic acids
Spencer et al. Role of the carboxyl group in intestinal amino acid transport
Venkatraman et al. Synthesis of Oxadiazolidinedione Derivatives as Quisqualic Acid Analogs and Their Evaluation at a Quisqualate-Sensitized Site in the Rat Hippocampus
SAKAUE et al. Protective effect of S-(1, 2-dicarboxyethyl) glutathione, an intrinsic tripeptide in liver, heart and lens, and its esters on acetaminophen-induced hepatotoxicity in rats
JPH01501227A (ja) アミノ―２―エタンチオール誘導体、その製造および治療用途
HU198446B (en) Process for production of new amids of buten acid and medical compositions containing such active substances
FR2537131A1 (fr) Nouveaux derives d'acides amines et leur application therapeutique
KR900001182B1 (ko) α-알레닉-α-아미노산의 제조방법
SAKAUE et al. Acetaminophen-Induced Hepatotoxicity in Rats

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C15 Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993)
OR01 Other related matters
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee