CN1138334A - 具有生长激素释放特性的化合物 - Google Patents
具有生长激素释放特性的化合物 Download PDFInfo
- Publication number
- CN1138334A CN1138334A CN94194588A CN94194588A CN1138334A CN 1138334 A CN1138334 A CN 1138334A CN 94194588 A CN94194588 A CN 94194588A CN 94194588 A CN94194588 A CN 94194588A CN 1138334 A CN1138334 A CN 1138334A
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- Prior art keywords
- ala
- trp
- phe
- 2nal
- imidazolyl
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Abstract
通式A-B-C-D-E-(F)p的合成肽类,其中p为0或1,因为用氨基亚甲基(-CH2NH-)取代了酰胺键(-CONH-),或是引入了N-芳烷基甘氨酸,它具有改善了的对蛋白酶解降解作用的抵抗力,以及用于激发垂体释放生长激素的药用组合物。
Description
本发明涉及新的肽衍生物,含有该衍生物的组合物及其用于治疗因生长激素缺乏所致的医学疾病的用途。
生长激素是一种能激发所有能生长的组织生长的激素。此外,还知道生长激素对代谢过程有许多作用,例如激发蛋白质合成和游离脂肪酸活动,并引起从碳水化合物到脂肪酸代谢的能量代谢的转换。生长激素的缺乏会导致许多严重的医学疾病,如侏儒。
生长激素是从垂体中释放出来的。而释放过程受到多种激素和神经递质直接或间接地严格控制。生长激素的释放可用生长激素释放激素(GHRH)激发,并用生长激素抑制素抑制。在两种情况下该激素都是从下丘脑中释放出的,但其作用主要是通过位于垂体中的特异受体进行调节。可激发垂体释放生长激素的其它化合物也已公开。如精氨酸、L-3,4-二羟苯丙氨酸(L-Dopa)、胰高血糖素、加压素、PACAP(垂体腺苷酰环化酶活化肽)、蕈毒受体激动剂和一种合成的六肽,GHRP(生长激素释放肽)通过直接作用于垂体或通过影响下丘脑释放GHRH和/或生长激素抑制素而释放内源生长激素。
对需要提高生长激素的水平的疾病或症状来说,由于生长激素的蛋白质性质,使得除肠胃外使用的任何用法都没有活性。另外,其它直接作用的天然促分泌素如GHRH和DACAP是较长的多肽,因此,口服这类化合物也是没有活性的。
在本发明之前,已经有人提出用较短的肽来提高哺乳动物的生长激素水平,例如以下的专利文件:EP18072,EP83864,WO89/07110,WO89/01711,WO89/10933,WO88/9780,WO83/02272,WO 91/18016,WO92/01711和WO93/04081。
生长激素释放肽或肽衍生物的组成,对于其生长激素释放能力及其生物利用率来说是重要的。因此,本发明的目的是提供具有生长激素释放特性的肽,相对同一类型的已知肽而言,它具有改善了的性能。
因此,本发明涉及一种如通式I所示的化合物:
A-B-C-D-E(-F)P
其中
P为0或1;
A为咪唑基-C1-6链烷酸,咪唑基-C1-6链烯酸,氨基-C1 -6链烷酸或氨基-C1-6链烯酸或从下列H-His、H-Ala、H-D-Ala、H-(β-丙氨酸)、H-Aib、肌氨酸和Gly几种氨基酸中选择出的一种L-或D-α-氨基酸;
B为D-Trp,D-Nal或D-Phe;
C为Ala、Ser或Gly;
D为Trp、Phe、β-(2-噻吩基)-丙氨酸或芳烷基甘氨酸;
当p为1时E为D-Phe,当p为0时E为-NH-CH(CH2-R 3 )-CO-R 4 或-NH-CH(CH2-R3)-CH2-R4,其中,
R3为苯基,
而R4为哌嗪基(piperazino)、吗啉代、哌啶子基、OH或-N(R5)R6,其中R5和R6各自独立地为氢或低级烷基;
当p为1时,F为-NH-CH(R10)-(CH2)v-R7)
其中
v为0或1-8之间的一个整数,而
而R10为-H、-COOH、-CO-R11、CH2-R11或-CH2-OH,其中R11为哌嗪基、吗啉代、哌啶子基或-N(R12)-R13,其中R12和R13各自独立地为氢或低级烷基;
附带条件是,A与B、B与C、C与D、D与E、或p为1时E与F之间的至少一个酰胺键被氨基亚甲基取代,或者当p为0时,E为-NH-CH(CH2-R3)-CH2-R4,或者当p为1时,R10为CH2-R11;
或其可以药用的盐。
据信,式I的肽衍生物对于胃肠酶或血浆酶的蛋白酶解降解作用有较好的抵抗作用,因为用氨基亚甲基(-CH2NH)取代了酰胺键(-CONH-)或是引入了N-芳烷基甘氨酸。与现有文献中推荐的肽的生物利用率相比,本发明肽衍生物对蛋白酶解降解作用抵抗力的提高,可望能改善其生物利用率。
在本文中,“低级烷基”一词用于表示具有1-6个碳原子的烷基,具体来说有甲基、乙基、丙基、异丙基、丁基、戊基或己基。
在式I化合物的一个优选实施方案中,p为1。在式I化合物的另一个优选实施方案中,A为His、D-Ala或咪唑基丙酸。B最好为D-Trp或D-2Nal。C最好为Ala。当D表示N-芳烷基甘氨酸时,它最好是N-苄基甘氨酸。D最好为Trp。E最好为D-Phe。在F的含义内,v最好为3-6,而R7最好为-NH2。R10最好为-CONH2,-CH2OH。
本发明发特殊化合物的例子如下:
H-HisΨ(CH2NH)D-Trp-Ala-Trp-D-Phe-Lys-NH2
H-His-D-TrpΨ(CH2NH)Ala-Trp-D-Phe-Lys-NH2
H-His-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-Lys-NH2
H-His-D-Trp-Ala-TrpΨ(CH2NH)D-Phe-Lys-NH2
H-His-D-Trp-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-Lys-NH2
H-D-Ala-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
(3-(4-咪唑基)丙酰基)-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-OH
(3-(4-咪唑基)(丙酰基)-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
(3-(4-咪唑基)丙烯酰)-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
H-D-Ala-D-Phe-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
(2R)-(H-D-Ala-D-Phe-Ala-Trp-NH)-3-苯丙胺
(2S)-(H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-氨基己醇
H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-NH2
4-(H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-NH)丁胺
(2R)-(H-D-Ala-D-2Nal-Ala-Trp-NH)-3-苯丙胺
((2R)-(H-D-Ala-D-2Nal-Ala-Trp-NH)-3-苯丙氨基己胺
(2R)-(H-D-2Nal-Ala-N-Bzl-Gly-NH)-3-苯丙胺
(2R)-(H-D-Ala-D-2Nal-Ala-N-Bzl-Gly-NH)-3-苯丙胺
H-Aib-D-2Nal-Ala-N-Bzl-Gly-D-PheΨ(CH2NH)Lys-NH2
(2S)-((3-(4-咪唑基)丙酰基)Ψ(CH2NH)D-Phe-Ala-Trp-D-Phe-NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-PheΨ(CH2NH)Ala-Trp-D-Phe-NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-Phe-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-TrpΨ(CH2NH)D-Phe-NH)-6-氨基己醇
(2S)-(2R)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-Trp-NH)-3-苯丙氨基)-6-氨基己醇
3-((3-(4-咪唑基(丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)丙胺
(2S)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-Trp-D-PheΨ(CH2NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-氨基己醇
3-((3-(4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)丙胺
H-D-Ala-D-2Nal-Ala-N-Bzl-Gly-D-PheΨ(CH2NH)Lys-NH2
H-Aib-D-2Nal-Ala-N-Bzl-Gly-D-PheΨ(CH2NH2)
缩略语
D-2Nal:D-2-萘基丙氨酸
N-Bzl:N-苄基甘氨酸
H-Aib:H-氨基异丁酸
式I的化合物可用常规的液相或固相肽合成方法进行制备。例如,固相合成可大致按Stewart和Young所公开的方法进行(Solid Phase PeptideSynthesis,2nd.Ed.Rockford,Illinosi,USA,1976)。而液相肽合成则可大致按Bodansky等人的方法进行(PeptideSynthesis,2nd.Ed.New York,New York,USA,1976)。
可按照Y.Sasaki和D.H.Coy所公开的方法(Peptides8(1),1987,pp.119-121),将氨基亚甲基作为酰胺键的取代基引入。
含有由氨基-或二-吡喃己糖衍生的氨基的肽衍生物,可用Amadori重排法进行制备,该方法基本上是R.Albert等人所公开的方法(Life Sciences 53,1993,pp.517-525)。一或二吡喃己糖的适当例子有:葡萄糖、半乳糖、麦芽糖、乳糖或纤维二糖。用作上述合成原料的衍生物可以由商业渠道获得,如有必要,还可引入适当的保护基。
式I化合物的可以药用的酸加成盐,包括将这种肽与无机酸或有机酸反应所生成的盐,例如,可选用的酸有氢氯酸、氢溴酸、硫酸、乙酸、磷酸、乳酸、马来酸、邻苯二甲酸、柠檬酸、戊二酸、葡糖酸、甲磺酸、水杨酸、丁二酸、酒石酸、甲苯磺酸、三氟乙酸、氨基磺酸和富马酸。
另外,本发明涉及一种药用组合物,它含有作为活性成分的通式I的化合物或其可以药用的盐,以及可以药用的载体或稀释剂。
含有本发明化合物的药用组合物可用常规技术制备,如在Remington’s Pharmaceutical Sciences(1985)中所公开的方法。可将该组合物制成常规剂型,如胶囊、片剂、烟雾剂、溶液、悬浮液或局部用药。
所用的药用载体或稀释剂,可以是常规的固体或液体载体。固体载体的例子有乳糖、石膏粉、蔗糖、环糊精、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸或纤维素的低级烷基醚。液体载体的例子有糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯和水。
同样地,所述载体或稀释剂可包括本领域任何已知缓释材料,如单硬脂酸甘油酯或二硬脂酸甘油脂,单独使用或与蜡混合后使用。
如果将固体载体用于口服,可将该制剂压片、以粉状或粒状形式放在硬明胶囊中,或制成片剂或锭剂。固体载体的用量可以有较大的变化,但通常为约25mg-约1g。
用常规的压片技术制成的典型片剂可包括:
芯部:
活性化合物(游离化合物或其盐) 100mg
胶态SiO2(Aerosil) 1.5mg
纤维素,微晶纤维素(Avicel) 70mg
改性纤维素胶(Ac-Di-Sol) 7.5mg
硬脂酸镁
涂层:
HPMC 约9mg
*Mywacett 9-40T 约0.9mg
*将酰化的单酸甘油脂用作涂膜的增塑剂。
如果采用的是液体载体,可将该制剂制成糖浆、乳剂、软明胶囊或无菌注射液,如水成或非水成液体悬浮液或溶液。
为了鼻用,该制剂可含有溶于或悬浮于液体载体,尤其是水成载体中的式I化合物,用作烟雾剂。所述载体可含有诸如增溶剂,如丙二醇;表面活性剂,如胆汁酸盐或聚氧乙烯高级醇醚;吸收增强剂,如卵磷脂(磷脂酰胆碱)或环糊精;或防腐剂,如对羟基苯甲酸酯之类的添加剂。
通常,本发明的化合物被分成单位剂量形式,每单位剂量含有0.0001-100mg的活性成份和药用载体。
本发明化合物的适用剂量为1-500mg/天,例如,当作为药物给患者,如病人使用时,每剂约100mg。
业已证实,通式I的化合物具有在体内释放内源生长激素的能力。因此,可将该化合物用于治疗需要提高血浆生长激素含量的疾病,如生长激素缺乏的病人或老年患者或牲畜。
因此,一方面,本发明涉及一种用于激发垂体释放生长激素的药用组合物,该组合物包括作为活性成分的通式I的化合物或其可以药用的盐,以及可以药用的载体或释释剂。
另一方面,本发明涉及一种激发垂体释放生长激素的方法,该方法包括给需要用药的对象使用有效剂量的通式I化合物或其可以药用的盐。
再一方面,本发明涉及将通式I的化合物或其可以药用的盐用于制备用来激发垂体释放生长激素的药物的用途。
本领域技术人员都知道,生长激素在人体上的现有和潜在的用途是变化的和多种多样的。假定式I的化合物可用于激发垂体释放生长激素的目的那么它就具有与生长激素本身类似的作用或用途。生长激素的用途可总结为如下几方面:激发老年人释放生长激素;预防糖皮质激素的代谢副作用,治疗骨质疏松症,激活免疫系统,加快伤口愈合,加快骨折的恢复,治疗生长停滞,治疗因生长停滞所致的肾衰竭或肾机能不全,治疗生理性身材矮小,包括生长激素缺乏的儿童和因慢性病造成的身材矮小,治疗肥胖及与肥胖相关的生长停滞,治疗与Prader-Willi综合症和Turner’s综合症相关的生长停滞;加速烧伤病人的恢复并缩短住院治疗时间;治疗子宫生长停滞,骨骼发育异常,肾上腺皮质机能亢进和Cushing’s综合症;诱导脉冲式生长激素释放;恢复紧张病人的生长激素,治疗骨软骨发育不良,Noonan’s综合症,精神分裂症,压抑,Alzheimer’s病,延迟的伤口愈合和精神失常,治疗肺机能障碍和呼吸器依赖症,减轻大手术之后的蛋白质代谢反应,减轻由慢性病如癌症或AIDS引起的恶病质和蛋白质减少;治疗胰岛素过多症,包括在胰岛素细胞增殖症,用于排卵诱导的辅助治疗;激发胸腺发育并防止与年龄相关的胸腺机能下降,治疗免疫抑制患者,改善肌肉强度和肌肉活动性,保持皮肤厚度,代谢的体内平衡,虚弱老年人的肾内环境稳定,激活成骨细胞,骨重塑和软骨生长,激发伴生动物的免疫系统并治疗伴生动物的衰老疾病,牲畜的生长促进和激发绵羊的羊毛生长。
对于上述治疗而言,剂量取决于所采用的式I化合物、使用方式和期望的治疗。不过,给病人或动物使用的一般剂量为每天0.0001-100mg/kg体重,以获得内源生长激素的有效释放。通常适于口服或鼻用的剂型包括与可以药用的载体或稀释剂混合的约0.0001-100mg,最好是约0.001-50mg的式I化合物。
式I化合物能以可以药用的酸加成盐形式或必要时碱金属或碱土金属或低级烷基铵盐形式使用。据认为,这种盐形物具有与游离碱相近似的活性。
或者,本发明的药用组合物也可含有与一种或多种具有不同活性的化合物,如抗菌素或其它药理活性材料混合的式I化合物。它可以是另一种促分泌素,如GHRP(1或6)或GHRH或其类似物,生长激素或其类似物或生长调节素,如IGF-1或IGF-2。
使用途径可以是任何能把所述活性化合物有效地输送到适当的或期望的作用位点的途径,如经口、鼻或肠胃外使用,口服最佳。
式I化合物除药用之外,还可将其用作研究生长激素释放调节的体外工具。
式I化合物还可被用作评估垂体的生长激素释放能力的体内工具。例如,在对人体使用这种化合物之前和之后提取血清样品,可以分析生长激素。通过比较各血清样品中的生长激素可直接测出患者垂体释放生长激素的能力。
可将式I化合物用于商业上重要的动物,以提高其生长速度和程度,并用于提高产乳量。
药理方法
可在体外评估式I化合物对初生大鼠亲躯体细胞释放生长激素影响的效力和能力。
可基本上按照以前公开的方法(Chen等,Endocrinology1991,129,3337-3342和Chen等,Endocrinology.1989,124,2791-2798)制备大鼠初生亲躯体细胞。简言之,通过断头杀死大鼠。迅速取出垂体。所得到的垂体用溶于Hanks平衡盐溶液中的0.2%的胶原酶和0.2%的透明质酸酶消化。将细胞悬浮于含有0.37%NaHCO3、10%马血清、2.5%胎牛血清、1%非必需氨基酸、1%谷氨酰胺和1%青霉素/链霉素的Dulbecco改进的Eagle培养基中,并调整至1.5×105细胞/ml。将1ml的该悬浮液放入24眼浅盘的每个眼中,并在进行释放实验之前放置2-3天。
在该实验的第一天,用含有25mM HEPES,pH7.4的上述培养基洗涤细胞两次。通过加入含有25mM HEPES和试验化合物的培养基引发生长激素的释放。在37℃培养15分钟。培养之后通过标准的RIA测定释放到培养基里的生长激素。
可按照以前公开的方法(Bercu等,Endocrinology1991,129,2592-2598),通过其对戊巴比妥麻醉的雌性大鼠生长激素释放的体内影响评价式I化合物在体内的作用。简而言之,以50mg/kg戊巴比妥的剂量ip麻醉成年雌性Sprague-Dawley大鼠。待大鼠完全麻醉之后,将气管插管和导管植入其颈动脉和颈静脉中。经过15分钟的恢复之后,在0计时提取血样。iv使用垂体促分泌素,并将动脉血样在冰上放置15分钟,然后以12,000×g离心2分钟。倒出血清并用标准RIA测定生长激素的含量。
下面的实施例将对本发明做进一步说明,但从任何意义上讲都不是对要求保护的发明范围的限定。
在本说明书中,使用了如下的缩略语:
H-His-D-TrpΨ(CH2NH)Ala-Trp-D-Phe-Lys-NH2
按照Fmoc方法,用生产商提供的FastMoc UV方案在AppliedBiosystems 431A肽合成仪上以0.25mmol的规模合成肽树脂H-Ala-Trp-D-Phe-Lys-Res in,所采用的是HBTU(2-(1H-苯并三唑-1-基)-1,1,3,3四甲基脲六氟磷酸)介导的在NMP(N-甲基吡咯烷酮)里的偶联,并UV监测Fmoc保护基的去保护。用于上述合成的原始树脂为470mg具有0.53mmol/g取代度的4-(2’,4’-二甲氧苯基-Fmoc-氨甲基)-苯氧基树脂(Novabiochem AG Switzerland,cat.#:01-64-0013)。所用的被保护的氨基酸衍生物是Fmoc-Lys(Boc)-OH,Fmoc-D-Phe-OH,Fmoc-Trp-OH和Fmoc-Ala-OH。
按照Sasaki,Y.和Coy,D.H.的方法(PEPTIDES8(1)119-121,1987)将-CH2NH-肽键等配物引入。
Fmoc-D-Trp-醛是按照Fehrentz,J.A.和Castro.B.的方法(SYNTHESIS 676-678,1983),
用399mg相应的N,O-异羟肟酸二甲酯制备而成的。将粗制的醛溶于用DMF(二甲基甲酰胺)配制的8ml 1%乙酸中,并分成两部分。将第一部分在室温下加入溶于8ml用DMF配制的1%乙酸溶液中的400mg(约0.2mmol)H-Ala-Trp-D-Phe-Lys(Boc)-Resin的搅动的浆体中。然后在60分钟内加入溶于1ml DMF中的40mg NaCNBH3(纯度85%),并再持续搅拌60分钟。此后,分离树脂,并经过滤漏斗用由DMF配制的1%乙酸洗涤。将所得树脂重新悬浮于5ml用DMF配制的1%乙酸中,并加入另一部分Fmoc-Ala-醛。同样在室温下,在60分钟之内加入溶于1ml DMF中的40mg NaCNBH3(纯度85%),并将该混合物搅拌18小时。
在这一还原性烷基化步骤之后,分离所述肽树脂,并在过滤漏斗上用溶于DMF中的1%的乙酸洗涤,按照上述方法,用保护的氨基酸衍生物Fmoc-His(Trt)-OH,通过肽合成仪完成链延长。
通过将所述肽树脂与由3ml TFA(三氟乙酸)、225mg苯酚、75μl乙二硫醇、150μl苯硫基甲烷和150μl H2O组成的混合物一起在室温下搅拌240分钟,将肽从其上面裂解下来。将裂解混合物过滤,并用氮气流将滤液浓缩成油状。用45ml乙醚将粗制的肽从该油状物中沉淀,并用45ml的乙醚洗涤3次。
通过在装有7μC-18二氧化硅的25mm×250mm的柱上进行半制备HPLC,纯化上述粗制肽。该柱用溶于0.05M(NH4)2SO4的、并用4M H2SO4调至pH2.5的21%CH3CN平衡。将干燥后的粗制肽溶于5ml溶于H2O中的70%CH3CN/0.1%TFA中,并用水稀释至50ml。将20ml的该溶液稀释至90ml,并加注到柱上,在40℃温度下,在47分钟之内以10ml/分的流速,用溶于0.05M(NH4)2SO4中的21%-31%CH3CN(pH2.5)梯度溶液将其从柱上洗脱。收集含有肽的部分,并用3倍体积的H2O稀释,然后通过用0.1%TFA平衡过的Sep-Dak C18柱(Waters Part#:51910)。然后用含有0.1%TFA的70%CH3CN进行洗脱,并在用水对洗脱液进行稀释之后分离提纯的肽。产量为6.55mg。
通过氨基酸分析(肽含量和氨基酸组成)、分析RP-HPLC(保留时间)和PDMS(等离子体解吸质谱)(分子量)鉴定所得到的最终产物。在该方法的实验误差(PDMS:±0.9amu,氨基酸分析±10%)之内,氨基酸分析和PDMS与期待的结构相符合。
采用214nm的UV检测和一个Vydac 218TP54 4.6×250mm 5μC-18二氧化硅柱(The Separation Group,Hesperia,USA)进行RP-HPLC分析,并在42℃以1ml/分钟的速度洗脱。采用两种不同的洗脱条件:
A1:用溶于由0.1M(NH4)2SO4组成的缓冲液中、并用浓硫酸调至pH2.5的5%CH3CN平衡层析柱,并在50分钟之内,用溶于同一缓冲液中的5%-60%的CH3CN梯度液进行洗脱。
B1:用5%CH3CN/0.1%TFA/H2O平衡层析柱,并在50分钟之内,用5%CH3CN/0.1%TFA/H2O至60%CH3CN/0.1%TFA/H2O梯度液洗脱。
发现采用洗脱条件A1和B1的保留时间分别为22.01分钟和23.08分钟。
例2
H-His-D-Trp-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
H-Lys(2-Cl-Z)-Resin是按照Boc方法,用生产商提供的单偶联方案,以0.5mmol的规模,在Applied Biosystems 430A肽合成仪上,用660mg具有0.72mmol/g取代度的4-甲基BHA树脂(Bissendorf Biochemicals,Hannover,Germany.cat.#:RMIS50)和B-Lys(Cl-Z)-OH合成的,采用的是与预先制成的溶于DMF中的对称酐的单偶联。该方案被修改成具有60分钟的偶联时间。
采用与例1类似的方法引入-CH2NH-肽键等配物。使用675mg H-Lys(Cl-Z)树脂和由616mg相应的N,O-异羟肟酸二甲酯制成的Boc-D-Phe-醛。
在这一还原性烷基化步骤之后,分离树脂并在过滤漏斗上用溶于DMF中的1%的乙酸洗涤。按照上述方法,用保护的氨基酸衍生物Boc-Trp(For)-OH,Boc-Ala-OH、Boc-D-Trp(For)-OH和Boc-His(Bom)-OH通过肽合成仪完成链延长。
通过与5ml HF和500μl m-甲酚组成的混合物搅拌75分钟,将肽从391mg的肽树脂上裂解下来。在0℃用氮气流将HF蒸发掉。用50ml乙醚将肽与树脂一起从残余的油中沉淀出来,用50ml乙醚洗涤2次,用2×2mlTFA从树脂中提取,并用50ml乙醚从合并的TFA提取液中沉淀,再用50ml的乙醚洗涤2次。
干燥之后,通过将所述肽溶于含有4ml乙醇胺的64ml 6M盐酸胍中,并在0℃搅拌5分钟切除色氨酸上的甲酰基。此后,通过加入4ml的乙酸中和该混合物,然后用140ml的H2O稀释。
采用与例1相同的方法,通过将该反应混合物直接加注到层析柱上对所得到的粗制肽进行半制备HPLC。产量为20.6mg。
按照例1所述方法对最终产物进行鉴定。
采用A1和B1条件的RP-HPLC分析所得到的保留时间分别为21.28分钟和23.17分钟。
例3-5
例 | 肽 | 用类似于以下实施例的方法进行制备 | RP-HLPC保留时间 | |
条件A1(例1) | 条件B1(例1) | |||
3 | H-HisΨ(CH2NH)D-Trp-Ala-Trp-D-Phe-Lys-NH2 | 2 | 20.42 | 22.9 |
4 | H-His-D-Trp-Ala-TrpΨ(CH2NH)D-Phe-Lys-NH2 | 1 | 18.97 | 21.3 |
5 | H-His-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-Lys-NH2 | 2 | 18.87 | 21.08 |
例6
(2R)-(H-D-Ala-D-2Nal-Ala-Trp-NH)-3-苯丙胺
按照Fehrentz,J.-A.和Castro.B.的方法(SYNTHESIS 676-678,1983),由385mg的相应N,O-异羟肟酸二甲酯制成Fmoc-D-Phe-醛。
用溶于DMF中的20%哌啶,对取代度为0.43mmol/g的580mg4-(2’,4’-二甲氧苯基-Fmoc-氨基甲基)-苯氧基树脂(Novabiochem AG Switzerland,Cat.#:01-64-0013)进行去保护20分钟,并用DMF和溶于DMF中的1%乙酸洗涤。
将第一部分Fmoc-D-Phe-醛和溶于1ml DMF中的58mgNaCNBH3(纯度85%)溶液加入脱保护的树脂中,并在室温下将该浆体搅拌75分钟。此后,在过滤漏斗上分离该树脂,并用溶于DMF中的1%乙酸洗涤。将第二部分Fmoc-D-Phe-醛和溶于1ml DMF中的58mg NaCNBH3(纯度85%)一起加入树脂中,并在室温下搅拌该混合物18小时,在过滤漏斗上分离树脂,并用溶于DMF中的1%乙酸、DMF、6∶4的DCM/甲醇和DCM(二氯甲烷)洗涤。
按照例1所述方法及保护的氨基酸衍生物Fmoc-Trp-OH、Fmoc-Ala-OH、Fmoc-D-2Nal-OH和Fmoc-D-Ala-OH,用上述树脂在肽合成仪上完成链延长。
将肽从600mg所得肽树脂上切下来。将所得粗制肽溶于50mlH2O中,并通过半制备HPLC提纯25ml的上述溶液,再用与例1相似的方法进行鉴定。产量为10.9mg。
用A1和B1条件进行RP-HPLC分析所得到的保留时间分别为27.98分钟和29.45分钟。
例7-12
例 | 肽 | 用类似于以下实施例的方法进行制备 | RP-HIPC保留时间 | |
条件A1(例1) | 条件B1(例1) | |||
7 | H-D-Ala-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2 | 1 | 26.00 | 27.02 |
8 | H-D-Ala-D-Phe-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2 | 1 | 22.02 | 23.30 |
9 | 3-(4-咪唑基)丙酰基-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2 | 1 | 26.33 | 27.70 |
10 | 3-(4-咪唑基)丙烯酰-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2 | 1 | 26.93 | 28.15 |
11 | (2S)-(H-D-Ala-D-2Nal-Ala-Trp-D-Phe-NH)-6-氨基己胺 | 6 | 25.33 | 26.08 |
12 | H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-Lys-NH2 | 1 | 23.62 | 25.07 |
例13
(2S)-((3-(4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-氨基己醇
采用类似于例1所述的方法,以1mmol的规模合成肽树脂3-(1-Adoc-4-咪唑基)丙酰基-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-Lys(Boc)-Sasrin树脂(Adoc是1-金刚烷基-羰氧基的缩写),所不同的是,采用具有0.87mmol/g取代能力的Sasrin树脂(2-甲氧基-4-烷氧苄基醇树脂)(Bachem,Bubendorf,Switzerland cat.#:D-1295)10 20mg,用于将第一个氨基酸残基与树脂偶联的方案是由生产商提供的4-二甲基氨基吡啶催化的预先制备的对称酐的偶联,随后再用苯甲酸酐对树脂上的残留-OH进行封端。
通过与由10.8ml THF(四氢呋喃)、1.8ml乙醇、211mg LiBr和92mg NaBH4组成的混合物一起,在室温下将所述肽树脂搅拌24小时,把保护肽(2S)-((3-1-Adoc-4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-(Boc-氨基)-己醇从1800mg的3-(1-Adoc-4-咪唑基)丙酰基-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-Lys(Boc)-Sasrin树脂上切下来。然后将2mlH2O和2ml乙酸滴加进去。过滤除去树脂珠,并用25ml的乙醇洗涤。通过抽真空浓缩上述滤液,用50ml H2O稀释残余的油状物并冷冻干燥。按例1所述方法用TFA对所得粉状物进行裂解。按照例1所述方法对所得粗制肽的1/5进行提纯,产量为28.54mg。
按照例1所述的方法对最终产物进行鉴定。采用洗脱条件A1时的保留时间为20.4分钟。
例14
3-((3-(4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)丙胺
采用类似于例1所述的方法以1mmol的规模合成肽树脂(3-(1-Adoc-4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-Sasrin树脂,所不同的是,采用的是取代能力为0.87mmol/g的1000mg Sasrin树脂(2-甲氧基-4-烷氧苄基醇树脂)(Bachem,Bubendorf,Switzerland cat.#:D-1295),而且,用于将第一个氨基酸残基与树脂偶联的方案是由生产商提供的4-二甲基氨基吡啶催化的预先制备的对称酐的偶联,随后再用苯甲酸酐对树脂上的残留-OH基进行封端。
通过在室温下与10ml 1,3-二氨基丙烷一起搅拌20小时,将肽3-((3-(1-Adoc-4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)丙胺从1000mg的(3-(1-Adoc-4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-Sasrin树脂上切下来。滤去废树脂,并用5ml DMF提取。在搅拌条件下,将合并的滤液和提取液缓慢加入240ml 1M的氢氯酸中。然后用H2O将混合物稀释至500ml,并过滤。
用与例1类似的方法,在9个实验中将滤液直接加注到9×1/9’th的层析柱上,通过半制备HPLC对粗制肽进行提纯。产量为73.53mg。
按照例1所述方法对最终产物进行鉴定。
采用洗脱条件A1和B1时的保留时间分别为21.5分钟和22.7分钟。
例15-18
例 | 肽 | 用类似于以下实施例的方法进行制备 | RP-HPLC保留时间 | |
条件A1(例1) | 条件B1(例1) | |||
15 | (2R)-(H-D-2Nal-Ala-N-Bzl-Gly-NH)-3-苯丙胺 | 6 | 29.6 | 31.2 |
16 | (2R)-(H-D-Ala-D-2Nal-Ala-N-Bzl-Gly-NH)-3-苯丙胺 | 6 | 29.4 | 31.1 |
17 | H-D-Ala-D-2Nal-Ala-N-Bzl-Gly-D-PheΨ(CH2NH)Lys-NH2 | 2 | 30.4 | 31.7 |
18 | (2R)-(H-Aib-D-2Nal-Ala-N-Bzl-Gly-NH)-3-苯丙胺 | 6 | 28.1 | 29.2 |
本发明代表性化合物的结构如下:
(2S)-((2R)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-Trp-NH)-3苯丙氨基)-6-氨基己醇
例19
用大鼠垂体细胞建立一个体外分析,以研究不同的GH促分泌素的作用。从雌性大鼠的垂体前叶中分离混合的垂体细胞培养物,并培养3天。洗涤之后,刺激细胞15分钟,并测定培养物上清液中所分泌的GH量。
大鼠垂体细胞的提取方法为Sartor,O。等人方法(Endocrinology 116,1985,pp.952-957)的改进方法。断头之后,从250mg的雌性Sprague-Dawley大鼠体内分离垂体。除去垂体中叶,将其余部分放入补充了0.25%葡萄糖、2×非必须氨基酸和1%BSA的Gey’s培养基(提取缓冲液)中。将腺体切成小片并转移到盛3ml添加有11.5mg胰蛋白酶和1000μg DNase的提取缓冲液的三角瓶中,并在37℃,以95%O2和70rpm的转速培养35分钟。通过在提取缓冲液中沉淀将片段洗涤3次,并用巴氏吸管将其抽吸成单细胞。分散之后通过尼龙滤膜(160μm)对细胞进行过滤,以除去未消化的组织。用补充了胰蛋白酶抑制剂(0.75mg/ml)提取缓冲液将细胞洗涤3次,并再悬浮于培养基(补充25mM HEPES、4mM谷氨酰胺、0.75%NaHCO3、2.5%FCS、3%马血清、10%大鼠血清、InM T3和40μg/L地塞米松的DMEM)中,使密度为2×105细胞/ml。将细胞接种到微量滴定板上,200μl/眼,并在37℃,8%CO2条件下培养3天。
在上述培养阶段之后,用激发缓冲液(补充了1%BSA、0.25%D-葡萄糖和25mM HEPES的HBSS)洗涤细胞2次,并预培养1小时。然后除去缓冲液,并加入含有本发明化合物的新激发缓冲液,在37℃和5%CO2条件下将上述滴定板温育15分钟。收集缓冲液,并在以下的闪烁亲近分析(SPA)中分析大鼠生长激素(rGH)的含量(SPA,基本上如以下文献所公开的方法:US4,568,649,Hart和Greenwalt,Mol.Immunol.16,1979,pp.265-269,或Udenfriend等,Proc.Natl.Acad.Sci.USA 82,1985,pp.8672-8676)。
rGH分析是在适于在Packards Topcount(β-闪烁计数器)上直接计数的Opti Plates(96眼板)上进行。
分析方案:
40μl缓冲液
10μl样品(培养的激发缓冲液)
50μl125I-rGH
50μl兔抗-rGH
50μlSPA试剂(与氟微球体结合的抗兔抗体)
将板密封,并放在板摇床上摇动30分钟,接着再培养10小时,在10-15℃沉降并计数。
在该SPA中,与抗-GH兔抗体(初级抗体)结合的rGH和与氟微球体(SPA Type II RIA,购自Amersham)结合的次级抗体反应。任何放射性标记的与初级抗体结合的rGH都能固定在该氟微球体上,然后就能够发光。在β-闪烁计数器上测量,可以计算出放射性标记的rGH量。随着样品中rGH含量的增加,与氟微球体结合的放射性标记的rGH量减少。
化合物 | EC50(nM) | Emax(%GHRP-6) |
H-His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 | 2.0 | 100 |
H-D-Ala-D-2Nal-Ala-Trp-D-Phe-Lys-NH2 | 1.8 | 85 |
H-His-DTrp-Ala-Trp-DPhe-Ψ(CH2NH)Lys-NH2 | 0.5 | 100 |
H-DAla-D2Nal-Gly-Trp-DPhe-Lys-NH2 | 0.8 | 75 |
(2S)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-Trp-D-PheΨ(CH2NH)-6-氨基己醇 | 5 | 80 |
Claims (16)
1.一种通式I所示的化合物
A-B-C-D-E(-F)p
其中
p为0或1;
A是咪唑基-C1-6链烷酸、咪唑基-C1-6链烯酸、氨基-C1 -6链烷酸或氨基-C1-6链烯酸或从下列氨基酸中选出的一种L-或D-α-氨基酸:H-His、H-Ala、H-D-Ala、H-β-丙氨酸、H-氨基异丁酸、肌氨酸和Gly;
B是D-Trp、D-2Nal或D-Phe;
C是Ala、Ser或Gly;
D是Trp、Phe、β-(2-噻吩基)-丙氨酸或N-芳烷基甘氨酸;
当p为1时,E是D-Phe,当p为0时,E是-NH-CH(CH2-R3)-CO-R4或-NH-CH(CH2-R3)-CH2-R4,其中
R3为苯基,
而R4为哌嗪基、吗啉代、哌啶子基、-OH或-N(R5)R6,其中R5和R6各自独立地为氢 或低级烷基;
当p为1时,F是-NH-CH(R10)-(CH2)v-R7)-,其中
v为0或1-8之间的一个整数,而
而R10为-H、-COOH、-CO-R11、CH2-R11或-CH2-OH,其中,R11为哌嗪基、吗啉代、哌啶子基或-N(R12)-R13,其中R12和R13各自独立地为氢或低级烷基;
附带条件是,A与B、B与C、C与D、D与E、或p为1时E与F之间的至少一个酰胺键被氨基亚甲基取代,或者当p为0时,E是-NH-CH(CH2-R3)-CH2-R4,或者当p为1时,R10是CH2-R11;
或其可以药用的盐。
2.如权利要求1所述的化合物,其特征在于p为1。
3.如权利要求1所述的化合物,其特征在于A为His、D-Ala或咪唑基丙酸。
4.如权利要求1所述的化合物,其特征在于B为D-Trp或D-2Nal。
5.如权利要求1所述的化合物,其特征在于C为Ala。
6.如权利要求1所述的化合物,其特征在于D为N-苄基甘氨酸或Trp。
7.如权利要求1所述的化合物,其特征在于E为D-Phe。
8.如权利要求1所述的化合物,其特征在于v=6,而R7=-NH2。
9.如权利要求1所述的化合物,其特征在于R10为-CONH2、-CH2-OH。
10.如上述权利要求中任一项所述的化合物,选自下列化合物:
H-HisΨ(CH2NH)D-Trp-Ala-Trp-D-Phe-Lys-NH2
H-His-D-TrpΨ(CH2NH)Ala-Trp-D-Phe-Lys-NH2
H-His-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-Lys-NH2
H-His-D-Trp-Ala-TrpΨ(CH2NH)D-Phe-Lys-NH2
H-His-D-Trp-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-Lys-NH2
H-D-Ala-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
(3-(4-咪唑基)丙酰基)-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-OH
(3-(4-咪唑基)(丙酰基)-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
(3-(4-咪唑基)丙烯酰)-D-2Nal-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
H-D-Ala-D-Phe-Ala-Trp-D-PheΨ(CH2NH)Lys-NH2
(2R)-(H-D-Ala-D-Phe-Ala-Trp-NH)-3-苯丙胺
(2S)-(H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-氨基己醇
H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-NH2
4-(H-D-Ala-D-2Nal-AlaΨ(CH2NH)Trp-D-Phe-NH)丁胺
(2R)-(H-D-Ala-D-2Nal-Ala-Trp-NH)-3-苯丙胺
((2R)-(H-D-Ala-D-2Nal-Ala-Trp-NH)-3-苯丙氨基)己胺
(2R)-(H-D-2Nal-Ala-N-Bzl-Gly-NH)-3-苯丙胺
(2R)-(H-D-Ala-D-2Nal-Ala-N-Bzl-Gly-NH)-3-苯丙胺
H-Aib-D-2Nal-Ala-N-Bzl-Gly-D-PheΨ(CH2NH)Lys-NH2
(2S)-((3-(4-咪唑基)丙酰基)Ψ(CH2NH)D-Phe-Ala-Trp-D-Phe-NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-PheΨ(CH2NH)Ala-Trp-D-Phe-NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-Phe-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-TrpΨ(CH2NH)D-Phe-NH)-6-氨基己醇
(2S)-(2R)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-Trp-NH)-3-苯丙氨基)-6-氨基己醇
3-((3-(4-咪唑基(丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)丙胺
(2S)-((3-(4-咪唑基)丙酰基)-D-Phe-Ala-Trp-D-PheΨ(CH2NH)NH)-6-氨基己醇
(2S)-((3-(4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)-6-氨基己醇
3-((3-(4-咪唑基)丙酰基)-D-Trp-AlaΨ(CH2NH)Trp-D-Phe-NH)丙胺
H-D-Ala-D-2Nal-Ala-N-Bzl-Gly-D-PheΨ(CH2NH)Lys-NH2
H-Aib-D-2Nal-Ala-N-Bzl-Gly-D-PheΨ(CH2NH2)
11.一种药用组合物,包括作为活性成分的通式I的化合物或其可以药用的盐以及可以药用的载体或稀释剂。
12.如权利要求11所述的组合物,其单位剂量形式含有约10-约200mg通式I的化合物或其可以药用的盐。
13.一种用于激发垂体释放生长激素的药用组合物,该组合物包括作为活性成分的通式I的化合物或其可以药用的盐以及可以药用的载体或稀释剂。
14.一种激发垂体释放生长激素的方法,该方法包括给需要治疗的对象使用有效剂量的通式I的化合物或其可以药用的盐。
15.如权利要求14所述的方法,其特征在于通式I的化合物或其可以药用的盐或其酯的有效剂量的范围为每天约0.0001-约100mg/kg体重,最好为每天约0.001-约50mg/kg体重。
16.将通式I的化合物或其可以药用的盐用于制备用来激发垂体释放生长激素的药物的用途。
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US20170121385A1 (en) | 2015-10-28 | 2017-05-04 | Oxeia Biopharmaceuticals, Inc. | Methods of treating neurodegenerative conditions |
WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
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US4803261A (en) * | 1986-06-27 | 1989-02-07 | The Administrators Of The Tulane Educational Fund | Method for synthesizing a peptide containing a non-peptide |
US5480869A (en) * | 1990-01-09 | 1996-01-02 | The Regents Of The University Of California | Anti-inflammatory peptide analogs and treatment to inhibit vascular leakage in injured tissues |
US5486505A (en) * | 1990-07-24 | 1996-01-23 | Polygen Holding Corporation | Polypeptide compounds having growth hormone releasing activity |
IL98910A0 (en) * | 1990-07-24 | 1992-07-15 | Polygen Holding Corp | Polypeptide compounds having growth hormone releasing activity and pharmaceutical compositions containing them |
US5663146A (en) * | 1991-08-22 | 1997-09-02 | Administrators Of The Tulane Educational Fund | Polypeptide analogues having growth hormone releasing activity |
US5470753A (en) * | 1992-09-03 | 1995-11-28 | Selectide Corporation | Peptide sequencing using mass spectrometry |
SE9300012D0 (sv) * | 1993-01-05 | 1993-01-05 | Astra Ab | New peptides |
US5559209A (en) * | 1993-02-18 | 1996-09-24 | The General Hospital Corporation | Regulator regions of G proteins |
US5767085A (en) * | 1993-12-23 | 1998-06-16 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
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1994
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- 1994-12-22 PL PL94315114A patent/PL181286B1/pl not_active IP Right Cessation
- 1994-12-22 CZ CZ19961833A patent/CZ291382B6/cs not_active IP Right Cessation
- 1994-12-22 CA CA002179598A patent/CA2179598A1/en not_active Abandoned
- 1994-12-22 US US08/464,679 patent/US5854211A/en not_active Expired - Fee Related
- 1994-12-22 WO PCT/DK1994/000486 patent/WO1995017422A1/en active IP Right Grant
- 1994-12-22 EP EP95904405A patent/EP0736038B1/en not_active Expired - Lifetime
- 1994-12-22 RU RU96115195/04A patent/RU2167881C2/ru not_active IP Right Cessation
- 1994-12-22 HU HU9601740A patent/HU221092B1/hu not_active IP Right Cessation
- 1994-12-22 JP JP51711095A patent/JP3759748B2/ja not_active Expired - Fee Related
- 1994-12-22 IL IL11211194A patent/IL112111A/xx not_active IP Right Cessation
- 1994-12-22 UA UA96062484A patent/UA45962C2/uk unknown
- 1994-12-22 AT AT95904405T patent/ATE202785T1/de active
- 1994-12-22 DE DE69427650T patent/DE69427650T2/de not_active Expired - Fee Related
- 1994-12-22 CN CN94194588A patent/CN1052730C/zh not_active Expired - Fee Related
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1995
- 1995-01-13 TW TW084100272A patent/TW438810B/zh active
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1996
- 1996-06-20 FI FI962591A patent/FI962591A0/fi not_active IP Right Cessation
- 1996-06-21 NO NO19962664A patent/NO315611B1/no not_active IP Right Cessation
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HU221092B1 (en) | 2002-08-28 |
PL181286B1 (pl) | 2001-07-31 |
AU683121B2 (en) | 1997-10-30 |
HU9601740D0 (en) | 1996-08-28 |
HUT74820A (en) | 1997-02-28 |
CN1052730C (zh) | 2000-05-24 |
IL112111A (en) | 2000-07-16 |
UA45962C2 (uk) | 2002-05-15 |
DE69427650T2 (de) | 2001-11-22 |
RU2167881C2 (ru) | 2001-05-27 |
TW438810B (en) | 2001-06-07 |
FI962591A (fi) | 1996-06-20 |
CZ291382B6 (cs) | 2003-02-12 |
NO962664L (no) | 1996-08-23 |
CA2179598A1 (en) | 1995-06-29 |
AU1310695A (en) | 1995-07-10 |
DE69427650D1 (de) | 2001-08-09 |
JP3759748B2 (ja) | 2006-03-29 |
PL315114A1 (en) | 1996-10-14 |
JPH09506873A (ja) | 1997-07-08 |
FI962591A0 (fi) | 1996-06-20 |
WO1995017422A1 (en) | 1995-06-29 |
EP0736038B1 (en) | 2001-07-04 |
NO962664D0 (no) | 1996-06-21 |
IL112111A0 (en) | 1995-03-15 |
CZ183396A3 (en) | 1997-02-12 |
EP0736038A1 (en) | 1996-10-09 |
US5854211A (en) | 1998-12-29 |
NO315611B1 (no) | 2003-09-29 |
ATE202785T1 (de) | 2001-07-15 |
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