CN1158622A - 含d-2-烷基色氨酸的能促进生长激素释放的多肽化合物 - Google Patents
含d-2-烷基色氨酸的能促进生长激素释放的多肽化合物 Download PDFInfo
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- CN1158622A CN1158622A CN95195323A CN95195323A CN1158622A CN 1158622 A CN1158622 A CN 1158622A CN 95195323 A CN95195323 A CN 95195323A CN 95195323 A CN95195323 A CN 95195323A CN 1158622 A CN1158622 A CN 1158622A
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Abstract
一种分子式为A-D-Mrp-(Ala)n-B-C的肽，其中A是任何天然L-氨基酸或其异构体，其前提是，如果B是Trp而C是D-Phe-Lys-NH2，则A不是His；或者A是咪唑乙酰基、异哌啶甲酰基、4-氨基丁酰基、4-(氨基甲基)环己烷羰基、Glu-Tyr-Ala-His、Tyr-Ala-His、Tyr-His、D-Thr-His；D为右旋异构体，Mrp是2-烷基色氨酸；n是0或1；B是L或D-Trp、Phe或D-β-萘基丙氨酸；C是NH2、D-Phe-LysNH2、D-Trp-LysNH2、D-Phe-Lys-NH2、Phe-Lys-NH2、D-Phe-Lys-ThrNH2、D-Phe-Lys-D-ThrNH2、OR，其中R是C1-C3烷基，以及所述多肽中的任一种与可以药用的有机酸或无机酸形成的加成盐。这些化合物能够促进生长激素的释放，并且口服时具有活性。
Description
本发明涉及含有D-2-烷基色氨酸的寡肽化合物，该化合物可以使亲躯体细胞(somatotrope)释放生长激素(GH)，而且口服时具有活性。
在给哺乳动物服用能诱导生长激素(GH)释放的化合物之后，动物体内的GH水平提高。在服药后如果获得足够高的GH水平的话，可使得动物的生长加快、产肉量增加、并能提高产乳量。而且，业已知道，给哺乳动物服用已知的生长激素释放剂，如生长激素释放激素(GHRH)，可以提高动物的生长激素水平。
给动物服用生长激素释放肽也可以提高其体内的生长激素水平，某些肽在以前已经公开，例如，可参考如下美国专利：US 4,223,019、US4,223,020、US 4,223,021、US 4,224,316、US 4,226,857、US4,228,155、US 4,228,156、US 4,228,157、US 4,228,158、US4,410,512、US 4,410,513、US 4,411,890和US 4,839,344。
因此，目前需要的是相当简单的、能够促进生长激素释放的短链多肽，这种多肽还要具备如下条件：制备起来简单、方便，易于纯化和配制，而且口服时具有活性。
多年来研究较多的生长激素释放肽(GHRP)之一是GHRP-6(C.Y.Bowers等，Endocrinology 114：1537(1984))，其结构式为His-D-Trp-Ala-Trp-D-Phe-Lys-NH2。GHRP-6在体外和体内都能释放生长激素，而且动物和人口服时都有活性。其分子机理业已被研究过，还有其类似物之一的七肽GHRP-1(Cheng等，Endocrinology 124：2791(1989)；M.S.Akman等，Endocrinology132：1286(1993))也已被研究过。业已发现，与天然GHRP相反，这些肽是通过不同的GH释放受体和不同的机制起作用，它们独立于cAMP，而且是通过其它的胞内途径，如供钙转移途径和依赖于蛋白激酶C(PKC)的过程起作用(L.Bresson-Bepoldin和L.Dufy-Barbe，Cell.Calcium 15，247，(1994))。
业已发现，在GHRP系列的寡肽中引入D-2-烷基色氨酸(2-Mrp)，可以全新的方式修饰已知的胞内GH释放机制。在某些场合，业已证实其能够明显提高鼠和人的脑垂体前叶中腺苷酸环化酶的活性，但其具体的机理尚有待彻底查明。
因此，通过在色氨酸的2-位(在其D-构型上)引入一个烷基所进行的修饰，除了有利于提高Trp残基的稳定性之外(R.DeghenghiWO 91/18016，公开日为1991年11月28日；R.Deghenghi等，LifeSciences 54，1321，(1994))，而且还能出人意料地彻底改变其胞内机制，使其独立于钙，有时依赖于腺苷酸环化酶，而且它更类似于GHRH，及其它肽激素(James D.Watson等，Molecular Biology of the Gene，4th版，The Benj arnin/Cummings Publishing Company，Inc.，Menlo Park，California，1987，P.60)。
本发明的其它意外的特殊特征是，某些五肽、六肽和七肽具有很高的效价和理想的口服活性/效价比，该系列较小的四肽也是如此。
本发明寡肽的分子式如下：
A-D-Mrp-(Ala)n-B-C，其中，A是任何天然L-氨基酸或其D-异构体，前提是，如果B是Trp而C是D-Phe-Lys-NH2的话，A不是His，或者A是咪唑乙酰基、异哌啶甲酰基(isonipecotyl)、4-氨基丁酰基，4-(氨基甲基)环己烷羰基、Glu-Tyr-Ala-His、Tyr-Ala-His、Tyr-His、D-Thr-His，更理想的是，A是D-Ala、D-Thr、Tyr；D为右旋异构体，Mrp是2-烷基色氨酸，最好是2-甲基色氨酸；n是0或1；B是L-或D-Trp、Phe或D-β-Nal；C是NH2、D-Phe-LysNH2、Phe-LysNH2、D-Trp-LysNH2、D-Phe-Lys-ThrNH2、D-Phe-Lys-D-ThrNH2、OR，其中R是C1-C3烷基，更理想的是，当B是Trp时，C是Phe-LysNH2或D-Phe-LysNH2，而当B是Phe时，C是D-Trp-LysNH2。
本发明基于如下发现：能够促进生长激素释放并提高动物血液中生长激素水平的不同短链多肽的特征是，所有这类多肽的肽链上都含有2-烷基色氨酸的D-异构体(D-2-Me-Trp或D-Mrp)。
属于本发明范围内的多肽的分子式为
A-D-Mrp-(Ala)n-B-C，其中，A是任何天然L-氨基酸或其D-异构体，前提是，如果B是Trp而C是D-Phe-Lys-NH2，则A不是His，或者A是咪唑乙酰基、异哌啶甲酰基、4-氨基丁酰基、4-(氨基甲基)环己烷羰基、Glu-Tyr-Ala-His、Tyr-Ala-His、Tyr-His、D-Thr-His，更理想的是，A是D-Ala、D-Thr，Tyr；D是右旋异构体，Mrp是2-烷基色氨酸，最好是2-甲基色氨酸；n是0或1；B是L-或D-Trp、或D-β-Nal；C是NH2、D-Phe-LysNH2、Phe-LysNH2、D-Trp-LysNH2、D-Phe-Lys-ThrNH2、D-Phe-Lys-D-ThrNH2、OR，其中R是C1-C3烷基，更理想的是，当B是Trp时，C是Phe-LysNH2或D-Phe-LysNH2，而当B是Phe时，C是D-Trp-LysNH2和由可以药用的有机酸或无机酸与所述多肽中任一种所形成的加成盐。
这里所采用的氨基酸残基的缩写与肽的标准命名一致：
Gly＝甘氨酸
Tyr＝L-酪氨酸
Ile＝L-异亮氨酸
Glu＝L-谷氨酸
Thr＝L-苏氨酸
Phe＝L-苯丙氨酸
Ala＝L-丙氨酸
Lys＝L-赖氨酸
Asp＝L-天冬氨酸
Cys＝半胱氨酸
Arg＝L-精氨酸
Gln＝L-谷氨酰胺
Pro＝L-脯氨酸
Leu＝L-亮氨酸
Met＝L-蛋氨酸
Ser＝L-丝氨酸
Asn＝L-天冬酰胺
His＝L-组氨酸
Trp＝L-色氨酸
Val＝L-缬氨酸
此外，
D-β-Nal＝D-β-萘基丙氨酸；
INIP＝异哌啶甲酰基；
IMA＝咪唑乙酰基；
GAB＝4-氨基丁酰基；
Mrp＝2-烷基色氨酸。
本发明中的烷基是含有1-3个碳原子的低级烷基，例如，甲基、乙基、丙基、异丙基。其中甲基最佳。
所有以“D”开头的氨基酸的3字母缩写表示该氨基酸残基的D-构型。
在本发明的实施方案中，优选的生长激素释放化合物有：
INIP-D-Mrp-D-Trp-Phe-Lys-NH2；
INIP-D-Mrp-D-β-Nal-Phe-Lys-NH2；
IMA-D-Mrp-D-Trp-Phe-Lys-NH2；
IMA-D-Mrp-D-β-Nal-Phe-Lys-NH2；
GAB-D-Mrp-D-Trp-Phe-Lys-NH2；
GAB-D-Mrp-D-β-Nal-Phe-Lys-NH2；
GAB-D-Mrp-D-β-Nal-NH2；
GAB-D-Mrp-D-β-Nal-OC2H5；
4-(氨基甲基)环己烷羰基-D-Mrp-D-Trp-Phe-Lys-NH2；
4-(aminomethyl)ciclohexanecarbonyl-D-Mrp-D-β-Nal-Phe-
Lys-NH2；
D-Ala-D-Mrp-Ala-Trp-D-Phe-LysNH2；
D-Thr-D-Mrp-Ala-Trp-D-Phe-LysNH2；
His-D-Mrp-Ala-Phe-D-Trp-LysNH2；
Tyr-His-D-Mrp-Ala-Trp-D-Phe-LysNH2；
His-D-Mrp-Ala-TrpNH2；
D-Thr-D-Mrp-Ala-TrpNH2；其中，Mrp是2-甲基色氨酸，而INIP、IMA和GAB的定义如上文所述，以及与上述多肽中任一种与可以药用的有机酸或无机酸形成的加成盐。
这些化合物可以肠胃外方式服用，但更常见的是鼻内服用和口服，或是配成控释系统，如可生物降解的微胶囊、微球、皮下植入物等。
本发明的肽化合物可按照肽化学的常用方法合成，如固相方法和在溶液中合成，或通过本领域已知的经典方法合成。固相合成从肽的C-末端开始。可通过如下方式制备合适的原料，例如，将需要保护的α-氨基酸连接在的氯甲基化树脂、羟甲基化树脂、二苯甲基胺树脂(BHA)或对甲基二苯甲基胺树脂(p-Me-BHA)上。例如，由BioRad实验室(Richmond，California)以BIOBEADSSx1为商标的一种氯甲基化树脂。羟甲基树脂的制备如Bodansky等所述(Chem.Ind.(London)38，15997，(1996))。BHA树脂由Pietta和Marshall所披露(Chem.Comm.，650(1970))，并且由Peninsula Laboratories Inc.(Belmont，California)将其商品化。
在开始结合以后，α-氨基酸的保护基可用不同的酸试剂除去，包括在室温下溶于有机溶剂中的三氟乙酸(TFA)或氢氯酸(HCl)。在除去α-氨基酸上的保护基之后，其余的保护氨基酸按所需顺序逐步连接在一起。每个保护氨基酸通常要使用约3倍以上的合适的羧基活化基进行反应，活化基有溶解在二氯甲烷(CH2Cl2)或二甲基甲酰胺(DMF)中的二环己基碳化二亚胺(DCC)或二异丙基碳化二亚胺(DIC)及其混合物。在合成所需的氨基酸序列后，可通过用一种诸如氟化氢(HF)之类的试剂处理的方法把所需的肽从支持树脂上切下来，它不仅能把肽从树脂上切下来，而且能切下侧链上更常见的保护基。当使用氯甲基化树脂或羟甲基化树脂时，用HF处理会导致游离形式酸肽的形成。当采用BHA或p-Me-BHA树脂时，用HF处理会直接导致游离形式酰胺肽的形成。
以上所述的固相方法在本领域中广为人知，并由Atherton和Sheppard所披露(Solid Phase Peptide Synthesis，IRL Press，Oxford，1989)。
某些可用于合成本发明的肽组成部分的液相方法由Bodansky等做了详细披露(Peptide Synthesis第二版，John Wiley&Sons，New York，N.Y.1976)，并可见于Jones的文章(The Chemical Synthesis ofPeptides，Clarendon Press，Oxford，1994)。
可以有效剂量给动物和人服用上述化合物，所述有效剂量可由本领域的专家很方便地加以确定，而且可随受治对象的种类、年龄、性别和体重加以调整。例如，对人来说，当通过静脉注射服用时，优选的剂量范围为约0.1～10μg总肽/公斤体重。当口服时通常需要更高的剂量。例如，由人口服时，剂量水平一般为约30～约1000μg多肽/公斤体重。实际剂量水平可根据以上说明由经验加以确定。
含有上述多肽的有机和无机加成盐的活性成分和其混合物、且有选择地与媒介物、稀释剂、基质或缓释包衣混合的组合物也属于本发明的范围。适于皮下植入的、含有可生物分解的基质的缓释药用形式特别理想。所述基质的例子披露在WO 9222600和WO9512629中。
生物活性
用10日龄大鼠确定上述化合物的体内活性，按照R.Deghenghi等的详细披露(Life Sciences 54，1321，(1994))，以300μg/kg的剂量或在剂量应答研究中以不同的剂量对大鼠进行皮下注射(s.c.)。结果归纳在下表中，在处理以后15分钟测定释放的GH。
GHRP-2(对照标准)的结构为D-Ala-D-β-Nal-Ala-Trp-D-Phe-Lys-NH2(Chen和Clarke，J.Neuroend.7，179(1995))。
表肽 皮下注射剂量，μg/kg GH对照 释放的GH
(ng/ml) (ng/ml)His-D-Mrp-Ala-Trp-DPhe- 300 31±8 176±20Lys-Thr-NH2His-D-Mrp-Ala-Trp-DPhe- 300 31±8 169±27Lys-D-Thr-NH2D-Thr-D-Mrp-Ala-Trp-D- 300 31±8 266±20Phe-Lys-D-Thr-NH2D-Thr-His-D-Mrp-Ala-Trp-D- 300 31±8 86±19Phe-Lys-NH2D-Ala-D-Mrp-Ala-Trp-D- 40 34±1 200±20Phe-Lys-NH2D-Ala-D-Mrp-Ala-Trp-D- 320 34±1 251±32Phe-Lys-NH2
续表肽 皮下注射剂量，μg/kg GH对照 释放的GH
(ng/ml) (ng/ml)His-D-Mrp-Ala-Trp-NH2 5000 69±14 124±37
咪唑乙酰基-D-Mrp- 300 20±3 159±27Ala-Trp-D-Phe-Lys-NH2INIP-D-Mrp-D-Trp-Phe- 300 15 155Lys-NH2INIP-D-Mrp-D-β-Nal- 300 15 150Phe-Lys-NH2GAB-D-Mrp-D-Trp-Phe-Lys-NH2 300 10 110(GHRP-2) 300 10 98.6
在获自重150克的大鼠的脑垂体前叶细胞中测定腺苷酸环化酶的体外活性，与肽D-Ala-D-Mrp-Ala-Trp-D-Phe-LysNH2的EC50＝0.23nm的基线相比，其活性增加了30％，而GHRP-6(His-D-Trp-Ala-Trp-D-Phe-LysNH2)表现为无活性。
下面的实施例对本发明做了进一步的说明。
例1
合成GAB-D-Mrp-D-Trp-Phe-Lys-NH2(Mrp-2-甲基色氨酸)
所述合成是通过采用9-芴甲氧羰基(Fmoc)-氨基酸的固相方法进行的，包括按照本领域技术人员已知的几种方法之一进行的树脂制备、在反应柱中组合，如E.Atherton和R.C.Sheppard在“Solid PhasePeptide Synthesis”(IRL Press在Oxford University的出版社，1989)中所公开的方法。保护氨基酸为Fmoc-Lys(Fmoc)-Opfp(Opfp＝五氟苯基酯)、Fmoc-Phe-Opfp、Fmoc-D-Trp-Opfp、Fmoc-2-MeTrp-Opfp和Fmoc-GAB-Opfp(GAB＝γ-氨基丁酸)。此外，将Castro’s试剂、BOP和PyBOP(见Le Nguyen和Castro(1988)，Peptide Chemistry 1987，P.231-238，Protein ResearchFoundation Qsaka；和Tetrahedron Letters 31，205(1990))用作直接连接剂也是有利的。
在切除并分离之后，将标题肽以乙酸盐的形式纯化。纯度(HPLC)：98％，MW(M+H+)＝764.3(理论值＝763.9)。
例2
按照例1所述方法制备以下的肽，并以乙酸盐的形式获得：INIP-D-Mrp-D-Trp-Phe-Lys-NH2；纯度(HPLC)＝99.0％，MW(M+H+＝790.4；理论值＝790.0)INIP-D-Mrp-D-β-Nal-Phe-Lys-NH2；纯度(HPLC)＝96.5％，MW(M+H+＝801.4；理论值＝801.0)IMA-D-Mrp-D-Trp-Phe-Lys-NH2；纯度(HPLC)＝99.2％，MW(M+H+＝786.5；理论值＝786.8)IMA-D-Mrp-D-β-Nal-Phe-Lys-NH2；纯度(HPLC)＝97.3％， MW(M+H+＝798.3；理论值＝797.9)GAB-D-Mrp-D-β-Nal-Phe-Lys-NH2；4-(氨基甲基)环己烷羰基-D-Mrp-D-Trp-Phe-Lys-NH2；4-(氨基甲基)环己烷羰基-D-Mrp-D-β-Nal-Phe-Lys-NH2；D-Ala-D-Mrp-Ala-Trp-D-Phe-LysNH2；D-Thr-D-Mrp-Ala-Trp-D-Phe-LysNH2；His-D-Mrp-Ala-Phe-D-Trp-LysNH2；Tyr-His-D-Mrp-Ala-Trp-D-Phe-LysNH2；His-D-Mrp-Ala-TrpNH2；D-Thr-D-Mrp-Ala-TrpNH2；其中，Mrp是2-甲基色氨酸，INIP、IMA和GAB如在上文中所定义的。
Claims (13)
1.一种肽，其分子式为：
A-D-Mrp-(Ala)n-B-C，其中，A是任何天然L-氨基酸或其D-异构体，前提是，如果B是Trp而且C是D-Lys-NH2的话，A不是His；或者A是咪唑乙酰基、异哌啶甲酰基、4-氨基丁酰基、4-(氨基甲基)环己烷羰基、Glu-Tyr-Ala-His、Tyr-Ala-His、Tyr-His、D-Thr-His；D是右旋异构体，Mrp是2-烷基色氨酸；n是0或1；B是L-或D-Trp、Phe或D-β-Nal；C是NH2、D-Trp-LysNH2、D-Phe-LysNH2、Phe-LysNH2、D-Phe-Lys-ThrNH2、D-Phe-Lys-D-ThrNH2、OR，其中R是C1-C3烷基，以及所述多肽中任一种与可以药用的有机酸或无机酸的加成盐。
2.如权利要求1的肽，其中Mrp选自2-甲基色氨酸、2-乙基色氨酸、2-丙基色氨酸、2-异丙基色氨酸。
3.如权利要求1的肽，其中Mrp是2-甲基色氨酸。
4.如权利要求1的肽，其中A是咪唑乙酰基、异哌啶基、4-氨基丁酰基、D-Ala、D-Thr、Tyr。
5.如权利要求1的肽，其中C是Phe-LysNH2、D-Trp-LysNH2、NH2、OR，其中R是C1-C3烷基。
6.如权利要求1的肽，其选自：IMA-D-Mrp-D-Trp-Phe-LysNH2；IMA-D-Mrp-D-β-Nal-Phe-LysNH2；INIP-D-Mrp-D-Trp-Phe-LysNH2；INIP-D-Mrp-D-β-Nal-Phe-LysNH2；GAB-D-Mrp-D-Trp-Phe-LysNH2；GAB-D-Mrp-D-β-Nal-Phe-LysNH2；GAB-D-Mrp-D-β-Nal-NH2；GAB-D-Mrp-D-β-Nal-OC2H5；
4-(氨基甲基)环己烷羰基 -D-Mrp-D-Trp-Phe-Lys-NH2；
4-(氨基甲基)环己烷羰基 -D-Mrp-D-β-Nal-Phe-Lys-NH2.
7.如权利要求1的肽，其选自：
咪唑乙酰基 -D-Mrp-Ala-Trp-D-Phe-LysNH2；
D-Ala-D-Mrp-Ala-Trp-D-Phe-LysNH2；
D-Thr-D-Mrp-Ala-Trp-D-Phe-LysNH2；
His-D-Mrp-Ala-TrpNH2；
D-Thr-D-Mrp-Ala-TrpNH2；
His-D-Mrp-Ala-Phe-D-Trp-LysNH2；
D-Thr-D-Mrp-Ala-Trp-D-Phe-Lys-D-ThrNH2；
D-Thr-His-D-Mrp-Ala-Trp-D-Phe-LysNH2；
His-D-Mrp-Ala-Trp-D-Phe-Lys-ThrNH2；
His-D-Mrp-Ala-Trp-D-Phe-Lys-D-ThrNH2
8.如权利要求6或7的肽，其中Mrp是2-甲基色氨酸。
9.将权利要求1-8的肽用于生产用于促进动物生长激素释放的药物的用途。
10.如权利要求9的用途，其中所述药物可用于人体治疗。
11.将权利要求7的肽用于生产用于促进腺苷酸环化酶胞内活性的提高的药物的用途。
12.药用组合物，包括有效剂量的权利要求1-8的至少一种肽作为活性成分，可选择性地与载体或赋形剂混合。
13.如权利要求12的组合物，该组合物为适于肠胃外服用、鼻内服用、口服、控释服用、皮下植入物的形式。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI941954A IT1270021B (it) | 1994-09-27 | 1994-09-27 | "composti polipeptidici contenenti d-2-metiltriptofano aventi attivita'sull'aumento del camp intracellulare" |
| ITMI94A001954 | 1994-09-27 | ||
| ITMI95A00129 | 1995-06-16 | ||
| IT95MI001293A IT1276734B1 (it) | 1995-06-16 | 1995-06-16 | Composti polipeptidici contenenti d-2-alchiltriptofano in grado di promuovere la liberazione dell'ormone della |
| ITMI95A001293 | 1995-06-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1158622A true CN1158622A (zh) | 1997-09-03 |
| CN1121413C CN1121413C (zh) | 2003-09-17 |
Family
ID=26331189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95195323A Expired - Fee Related CN1121413C (zh) | 1994-09-27 | 1995-09-13 | 含d－2－烷基色氨酸的能促进生长激素释放的多肽化合物 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5795957A (zh) |
| EP (1) | EP0783521B8 (zh) |
| JP (1) | JP3810083B2 (zh) |
| KR (1) | KR100369105B1 (zh) |
| CN (1) | CN1121413C (zh) |
| AT (1) | ATE225806T1 (zh) |
| AU (1) | AU700066B2 (zh) |
| CA (1) | CA2201122A1 (zh) |
| CZ (1) | CZ291798B6 (zh) |
| DE (1) | DE69528531T2 (zh) |
| DK (1) | DK0783521T3 (zh) |
| ES (1) | ES2186730T3 (zh) |
| HK (1) | HK1001207A1 (zh) |
| HU (1) | HU221481B (zh) |
| IL (1) | IL115381A (zh) |
| MX (1) | MX9702275A (zh) |
| PL (1) | PL181588B1 (zh) |
| PT (1) | PT783521E (zh) |
| RU (1) | RU2157378C2 (zh) |
| SK (1) | SK284550B6 (zh) |
| WO (1) | WO1996010040A1 (zh) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020111461A1 (en) | 1999-05-21 | 2002-08-15 | Todd C. Somers | Low molecular weight peptidomimetic growth hormone secretagogues |
| US5798337A (en) * | 1994-11-16 | 1998-08-25 | Genentech, Inc. | Low molecular weight peptidomimetic growth hormone secretagogues |
| IT1277113B1 (it) * | 1995-12-20 | 1997-11-04 | Romano Deghenghi | Composti oligopeptidici contenenti d-2-alchiltriptofano in grado di promuovere la liberazione dell'ormone della crescita |
| WO1999039730A1 (fr) * | 1998-02-09 | 1999-08-12 | Kaken Pharmaceutical Co., Ltd. | Preparation a administration orale contenant des peptides favorisant la secretion d'hormone de croissance |
| US5932548A (en) * | 1998-06-03 | 1999-08-03 | Deghenghi; Romano | Lysine containing peptides for treatment of heart disease |
| US6696063B1 (en) | 1998-12-30 | 2004-02-24 | Applied Research Systems Ars Holding N.V. | Treatment of HIV-associated dysmorphia/dysmetabolic syndrome (HADDS) with or without lipodystrophy |
| US6211156B1 (en) * | 1999-11-10 | 2001-04-03 | Asta Medica A.G. | Peptides for treatment of erectile dysfunction |
| TWI331922B (en) | 2002-08-09 | 2010-10-21 | Ipsen Pharma Sas | Growth hormone releasing peptides |
| WO2006078320A2 (en) | 2004-08-04 | 2006-07-27 | Brookwood Pharmaceuticals, Inc. | Methods for manufacturing delivery devices and devices thereof |
| GB0603295D0 (en) | 2006-02-18 | 2006-03-29 | Ardana Bioscience Ltd | Methods and kits |
| US8728528B2 (en) | 2007-12-20 | 2014-05-20 | Evonik Corporation | Process for preparing microparticles having a low residual solvent volume |
| US9119832B2 (en) | 2014-02-05 | 2015-09-01 | The Regents Of The University Of California | Methods of treating mild brain injury |
| WO2017075535A1 (en) | 2015-10-28 | 2017-05-04 | Oxeia Biopharmaceuticals, Inc. | Methods of treating neurodegenerative conditions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1080470A (en) * | 1963-12-31 | 1967-08-23 | Merck & Co Inc | Indole derivatives |
| US4411890A (en) * | 1981-04-14 | 1983-10-25 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4228156A (en) * | 1979-03-30 | 1980-10-14 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4228158A (en) * | 1979-03-30 | 1980-10-14 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4228155A (en) * | 1979-03-30 | 1980-10-14 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4223019A (en) * | 1979-03-30 | 1980-09-16 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4224316A (en) * | 1979-03-30 | 1980-09-23 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4223021A (en) * | 1979-03-30 | 1980-09-16 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4223020A (en) * | 1979-03-30 | 1980-09-16 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4226857A (en) * | 1979-03-30 | 1980-10-07 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4228157A (en) * | 1979-03-30 | 1980-10-14 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| BR8208035A (pt) * | 1981-12-28 | 1983-11-22 | Beckman Instruments Inc | Peptideos sinteticos tendo atividade liberadora de hormonio do crescimento da pituitaria |
| US4410512A (en) * | 1981-12-28 | 1983-10-18 | Beckman Instruments, Inc. | Combinations having synergistic pituitary growth hormone releasing activity |
| US4410513A (en) * | 1981-12-28 | 1983-10-18 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
| US4725577A (en) * | 1985-04-25 | 1988-02-16 | Administrators Of The Tulane Educational Fund | Biologically active lysine containing octapeptides |
| US4839344A (en) * | 1987-06-12 | 1989-06-13 | Eastman Kodak Company | Polypeptide compounds having growth hormone releasing activity |
| WO1989007110A1 (en) * | 1988-01-28 | 1989-08-10 | Eastman Kodak Company | Polypeptide compounds having growth hormone releasing activity |
| DE3915361A1 (de) * | 1989-05-11 | 1990-11-15 | Merck Patent Gmbh | Cyclopeptide |
| IT1240643B (it) * | 1990-05-11 | 1993-12-17 | Mediolanum Farmaceutici Spa | Peptidi biologicamente attivi contenenti in catena 2-alchiltriptofano |
| EP0663834A4 (en) * | 1992-09-25 | 1996-01-24 | Smithkline Beecham Corp | GROWTH HORMONE RELEASING PEPTIDES. |
-
1995
- 1995-09-13 CA CA002201122A patent/CA2201122A1/en not_active Abandoned
- 1995-09-13 PT PT95932735T patent/PT783521E/pt unknown
- 1995-09-13 ES ES95932735T patent/ES2186730T3/es not_active Expired - Lifetime
- 1995-09-13 SK SK399-97A patent/SK284550B6/sk unknown
- 1995-09-13 DE DE69528531T patent/DE69528531T2/de not_active Expired - Fee Related
- 1995-09-13 KR KR1019970701987A patent/KR100369105B1/ko not_active IP Right Cessation
- 1995-09-13 DK DK95932735T patent/DK0783521T3/da active
- 1995-09-13 EP EP95932735A patent/EP0783521B8/en not_active Expired - Lifetime
- 1995-09-13 MX MX9702275A patent/MX9702275A/es not_active IP Right Cessation
- 1995-09-13 AU AU35668/95A patent/AU700066B2/en not_active Ceased
- 1995-09-13 CZ CZ1997914A patent/CZ291798B6/cs not_active IP Right Cessation
- 1995-09-13 RU RU97107089/04A patent/RU2157378C2/ru not_active IP Right Cessation
- 1995-09-13 JP JP51131596A patent/JP3810083B2/ja not_active Expired - Fee Related
- 1995-09-13 HU HU9800136A patent/HU221481B/hu not_active IP Right Cessation
- 1995-09-13 PL PL95319382A patent/PL181588B1/pl unknown
- 1995-09-13 AT AT95932735T patent/ATE225806T1/de not_active IP Right Cessation
- 1995-09-13 WO PCT/EP1995/003601 patent/WO1996010040A1/en active IP Right Grant
- 1995-09-13 CN CN95195323A patent/CN1121413C/zh not_active Expired - Fee Related
- 1995-09-20 US US08/530,853 patent/US5795957A/en not_active Expired - Fee Related
- 1995-09-21 IL IL11538195A patent/IL115381A/xx not_active IP Right Cessation
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1998
- 1998-01-02 HK HK98100002A patent/HK1001207A1/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IL115381A (en) | 2000-07-16 |
| US5795957A (en) | 1998-08-18 |
| KR100369105B1 (ko) | 2003-04-07 |
| EP0783521B1 (en) | 2002-10-09 |
| DE69528531T2 (de) | 2003-06-05 |
| ES2186730T3 (es) | 2003-05-16 |
| ATE225806T1 (de) | 2002-10-15 |
| WO1996010040A1 (en) | 1996-04-04 |
| JPH10506114A (ja) | 1998-06-16 |
| EP0783521A1 (en) | 1997-07-16 |
| DK0783521T3 (da) | 2003-01-27 |
| MX9702275A (es) | 1997-06-28 |
| CA2201122A1 (en) | 1996-04-04 |
| CZ91497A3 (en) | 1997-09-17 |
| AU700066B2 (en) | 1998-12-17 |
| PT783521E (pt) | 2003-02-28 |
| CZ291798B6 (cs) | 2003-05-14 |
| AU3566895A (en) | 1996-04-19 |
| CN1121413C (zh) | 2003-09-17 |
| JP3810083B2 (ja) | 2006-08-16 |
| HUT77525A (hu) | 1998-05-28 |
| DE69528531D1 (de) | 2002-11-14 |
| PL319382A1 (en) | 1997-08-04 |
| IL115381A0 (en) | 1995-12-31 |
| RU2157378C2 (ru) | 2000-10-10 |
| HU221481B (en) | 2002-10-28 |
| SK284550B6 (sk) | 2005-06-02 |
| PL181588B1 (pl) | 2001-08-31 |
| SK39997A3 (en) | 1997-09-10 |
| HK1001207A1 (en) | 1998-06-05 |
| KR970706305A (ko) | 1997-11-03 |
| EP0783521B8 (en) | 2003-04-09 |
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