CN1052731C - 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
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- CN1052731C CN1052731C CN94194590A CN94194590A CN1052731C CN 1052731 C CN1052731 C CN 1052731C CN 94194590 A CN94194590 A CN 94194590A CN 94194590 A CN94194590 A CN 94194590A CN 1052731 C CN1052731 C CN 1052731C
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Abstract
通式A-B-C-D-(E)P的合成肽，其中p为0或1，由于具有相邻氨基酸，并有选择的结合以用(Y-N-R18)，如氨基亚甲基(-CH2NH-)取代酰胺键和/或改进该肽的N-或C-末端，它具有改善了的对蛋白酶解降作用的抵抗力。该肽衍生物可以激发垂体释放生长激素。
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介导。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PACAP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，WO91/18016，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)P
其中
P为0或1；
A为氢或R1-(CH2)q-(X)r-(CH2)s-CO，其中
q为0或1-5之间的一个整数；
r为0或1；
S为0或1-5之间的一个整数；
R1为氨、咪唑基、胍基、哌嗪基、吗啉代或N(R2)-R3，其中，R2和R3各自独立地为氢或有选择地被一个或多个羟基、吡啶基或呋喃基取代过的低级烷基；而
当r为1时，X是-NH-，-CH2-，-CH＝CH-
或
其中，R16和R17各自独立地为氢或低级烷基；
B是(G)t-(H)u，其中
t为0或1；
u为0或1；
G和H是从天然L-氨基酸或其相应的D-异构体或者非天然氨基酸中选择的氨基酸残基，如1，4-二氨基丁酸、氨基并丁酸、1，3-二氨基丙酸、4-氨基苯丙氨酸、3-吡啶丙氨酸、1，2，3，4-四氢异喹啉-3-羧酸、1，2，3，4-四氢norharman-3-羧酸、N-甲基氨茴酸、氨茴酸、N-苄基甘氨酸、3-氨基-3-甲基苯甲酸、3-氨基-3-甲基丁酸、肌氨酸、3-哌啶甲酸或并哌啶甲酸；
其中，当t和u都为1时，G和H之间的酰胺键可有选择地被
取代，其中，Y是
或
，而R18为氢、低级烷基或低级芳烷基；
C为式-NH-CH((CH2)w-R4)-CO-的D-氨基酸，其中
w为0、1或2，而
R4选自下列基团或
其中的每一个基团有选择地被卤基、低级烷基、低级烷氧基、低级烷氨基、氨基或羟基取代；
当p为1时，D是式-NH-CH((CH2)k-R5)-CO-的D-氨基酸，或当p为0时，D是-NH-CH-((CH2)1-R5)-CH2-R6或-NH-CH((CH2)m-R5)-CO-R6，其中
R为0、1或2；
l为0、1或2；
m为0、1或2；
R5选自下列基团
或
其中每个基团有选择地被卤基、烷基、烷氧氨基或羟基所取代；而
R6为哌嗪基、吗啉代、哌啶子基、-OH或-N(R7)-R8，其中R7和R8各自独立地为氢或低级烷基；
当p为1时，E是-NH-CH(R10)-(CH2)v-R9，其中
r为0或1-8之间的一个整数；
R9为氢、咪唑基、胍基、哌嗪基、吗啉代、哌啶子基，
其中n为0、1或2，而R19是氢或低级烷基，
式
其中o为1-3之间的整数，
或N(R11)-R12，其中R11和R12各自独立地为氢或低级烷基，或或
每个基团有选择地被卤基、烷基、烷氧基、氨基、烷氨基、羟基、或氨基与吡喃己糖或吡喃己糖基吡喃己糖的Amadori重排产物所取代
和
当p为1时，R10是选自-H、-COOH、-CH2-R13、-CO-R13或-CH2-OH的基团，其中
R13为哌嗪基、吗啉代、哌啶子基、-OH或-N(R14)-
R 15 ，其中R14和R15各自独立地为氢或低级烷基；
B与C之间的酰胺键，或者当t和u为0时A与C之间的酰胺键有选择地被
或者，当p为1时，D与E之间的酰胺键有选择地被-Y-所取代，其中Y和R18如上所述；
或其可以药用的盐。
据认为，式I的肽衍生物具有改善了的对由酶引起的蛋白酶解降解作用的抗性，由于该肽序列中相邻D-氨基酸的存在，并有选择地结合上述的用
取代酰胺键(-CO-NH-)，例如氨基亚甲基(-CO2-NH-)和/或对该肽的N-或C-末端进行改性。对蛋白酶解降解作用抵抗能力的提高，并结合本发明肽衍生物大小的下降，可望改善其相对现有文献中提出的肽的生物利用率。
在本文中，“低级烷基”一词表示具有1-6个碳原子的烷基，具体有甲基、乙基、丙基、并丙基、丁基、戊基或己基。“卤基”一词包括Cl、F、Br和I。在术语“低级烷氧基”、“低级芳烷基”和“低级烷氨基”中，低级烷基部分具有上述含义。
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是氢或R1-(CH2)q-(X)r-(CH 2 ) s-CO-，其中R1是3-咪唑基，q为2，r为0，s为0；或者，其中R1是NH2，q为1，r为1，X是二取代的苯，最好是在1和3位取代的苯，而且s为0；或者，其中R1是NH2，q为1，r为1，X是二取代的噻吩，最好是在3和2位上取代的噻吩，而且S为0。当t为1时，式I化合物中的G最好是Ala、Gly、Aib、肌氨酸、3-哌啶甲酸或异哌啶甲酸。当u为1时，H最好是His、Phe、Tic、Phe(4-NH2)、3-Pyal、Gly、Ala、Sar、Pro、Tyr、Arg、Orn、3-氨甲基苯甲酸或D-Phe。式I化合物中的C最好是D-2-萘丙氨酸(D-2Nal)、D-1-萘丙氨酸(D-1Nal)、D-Phe或D-Trp。式I化合物中的D最好是D-Phe、D-1Nal、D-2Nal、D-Trp、3-Pyal、D-Phe(4F)、D-Tyr或Phe-NH2。
式1化合物中的E最好是Lys-NH2、NH-(2-(1-哌嗪基)乙基)、NH-(2-(1-吗啉代)丙基)、NH-(2-氨乙基)、NH-(4-氨甲基苄基)、NH-(苄基)、Lys-OH、NH-(1-羟基-6-氨基-2S-己基)、NH-(2-(1-甲基-2-吡咯烷基)乙基)，或
式I化合物中的R4最好是2-萘基。R5最好是苯基。v最好是2-6，而R9是NH2、吗啉代乙基、吗啉代丙基或(1-甲基吡咯烷基)乙基。R10最好是-COOH、-CH2-OH、-H、CONH2或-CON(CH3)2。
本发明具体化合物的例子有：
H-Ala-Hisψ(CH2NH)D-2Nal-D-Phe-Lys-NH2
H-Ala-Ala-D-2Nal-D-Phe-Lys-NH2
H-His-D-2Nal-D-Phe-Lys-NH2
(3-(4-咪唑基)丙酰基)-D-2Nal-D-Phe-Lys-NH2
H-D-Lys-D-2Nal-D-Phe-Lys-NH2
H-5Apent-His-D-2Nal-D-Phe-Lys-NH2
H-D-Ala-D-2Nal-D-Phe-Lys-NH2
H-5Apent-D-2Nal-D-Phe-Lys-NH2
(正丙基)-His-D-2Nal-D-Phe-Lys-NH2
H-Ala-3Pyal-D-2Nal-D-Phe-Lys-NH2
H-Ala-Phe(4-NH2)-D-2Nal-D-Phe-Lys-NH2
H-D-Ala-His-D-2Nal-D-Phe-Lys-NH2
(2-(4-咪唑基)乙酰基)-D-2Nal-D-Phe-Lys-NH2
(3-(4-咪唑基)丙烯酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨基苯乙酰)-D-2Nal-D-Phe-Lys-NH2
(4-氨基苯乙酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨基丁烯酰)-D-2Nal-D-Phe-Lys-NH2
(4-哌啶子基-羧基)-D-2Nal-D-Phe-Lys-NH2
H-Ala-His-D-2Nal-D-Phe-NH2
(H-Ala-His-D-2Nal-D-Phe-NH)己烷
6-(H-Ala-His-D-2Nal-D-Phe-NH)己胺
5-(H-Ala-His-D-2Nal-D-Phe-NH)戊胺
H-Ala-His-D-2Nal-D-Pheψ(CH2NH)Lys-NH2
H-Ala-His-D-2Nal-D-Phe-Lys-OH
(2S)-(H-Ala-His-D-2Nal-D-Phe-NH)-6-氨基己醇
(2-(H-Ala-His-D-2Nal-D-Phe-NH)乙基)苯
2-(H-Ala-His-D-2Nal-D-Phe-NH)乙胺
4-((H-Ala-His-D-2Nal-D-Phe-NH)甲基)苄胺
H-Ala-His-D-2Nal-D-Phe-Lys(麦芽糖基)-NH2
H-Ala-His-D-2Nal-D-Phe-Phe-NH2
H-Ala-His-D-2Nal-D-Phe-D-Phe-NH2
H-Ala-His-D-Phe-D-Phe-Lys-NH2
H-Ala-His-D-Trp-D-Phe-Lys-NH2
H-His-D-2Nal-D-Trp-Lys-NH2
H-Ala-His-D-1Nal-D-Phe-Lys-NH2
H-Ala-Phe-D-2Nal-D-Phe-Lys-NH2
H-Ala-His-D-2Nal-D-Phe-Lys(麦芽糖基)-NH2
(2R)-(H-Ala-His-D-2Nal-D-Phe-Lys-NH)-3苯丙胺
H-Ala-N-Me-(2-氨基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(3-(甲基氨甲基)苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(4-(氨甲基)苯甲酰)-D-2Nal-D-Phe-Lys-NH2
H-His-Ala-D-2Nal-D-Phe-Lys-NH2
4-(H-Ala-His-D-2Nal-D-Phe-NH)丁胺
3-(H-Ala-His-D-2Nal-D-Phe-NH)丙胺
(3-(二甲基氨甲基)苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨基-3-甲基丁酰基)-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-hPhe-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)ψ(CH2NH)D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-hPhe-Lys-NH2
(3-氨基-3-甲基丁酰基)-His-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-N-Bzl-Gly-Lys-NH2
(2S)-(3-氨甲基苯甲酰)ψ(CH2NH)-D-2Nal-D-Phe-NH)-6-氨基己醇
(2S)((3-氨甲基苯甲酰)-D-2Nal-D-Phe-NH)-6-氨基己醇
(3-氨甲基苯甲酰)-D-2Nal-D-Thial-Lys-NH2
(2S)-(H-Aib-Hisψ(CH2NH)-D-2Nal-D-Phe-NH)-6-氨基己醇
(3-氨甲基苯甲酰)-D-2Nal-D-3Pyal-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe(4-F)-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe(4-OMe)-Lys-NH2
(2-氨甲基苯乙酰)-D-2Nal-D-Phe-Lys-NH2
(2-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
2-(H-Aib-His-D-2Nal-D-Phe-NH)-(4-吡啶基)乙烷
H-Aib-Phe-D-2Nal-D-Phe-Lys-NH2
2-(H-Aib-His-D-2Nal-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-(H-Aib-His-D-2Nal-D-Phe-NH)-(4-吡啶基)乙烷
H-Aib-Hisψ(CH2NH)-D-2Nal-D-Phe-Lys-OH
(3-氨甲基苯甲酰)-D-2Nal-N-Me-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-Gly-NH2
H-Aib-His-D-2Nal-D-Phe-Ala-NH2
H-Aib-His-D-2Nal-D-Phe-Orn-NH2
(5-氨甲基噻吩基)-2-羰基)-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-D-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-Dab-NH2
H-Aib-His-D-2Nal-D-Pheψ(CH2NH)-Lys-NH2
H-Aib-His-N-Me-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-N-Me-Lys-NH2
(3-氨甲基噻吩基-2-羰基)-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-N-Me-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-Lys-N(Me)2
(3R)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(3S)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-1Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Trp-Lys-NH2
(糠基)-Aib-His-D-2Nal-D-Phe-Lys-NH2
(2-吡啶甲基)-Aib-His-D-2Nal-D-Phe-Lys-NH2
H-Aib-(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
H-Aib-3Pyal-D-2Nal-D-Phe-Lys-NH2
(3S)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(3R)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(2-(H-Aib-His-D-2Nal-NH)乙基)苯
N，N-二(2R-羟丙基)-(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(2R-羟丙基)-Aib-His-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Pheψ(CH2NH)Lys-NH2
(3-氨甲基苯甲酰)-N-Me-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe-N-Me-Lys-NH2
H-D-Thr-His-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-N-(苯乙基)-Gly-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-N-(苯乙基)-Gly-Lys-NH2
H-Hyp-His-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-N-Me-D-2Nal-N-(苯乙基)-Gly-Lys-NH2
H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Pheψ(CH2N(Me))-Lys-NH2
3-(H-Aib-His-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
2-(H-Aib-His-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
(3R)-哌啶羰基-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH2
3-((氨甲基苯甲酰)-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
2-(H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-(3R)-哌啶羰基-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-(3-氨甲基苯甲酰)-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
3-(H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
3-((3R)-哌啶羰基-N-Me-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
3-((3-氨甲基苯甲酰)-N-Me-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
H-Aib-His-D-2Nal-N-Me-D-Phe-Hyp-NH2
2-((3-氨甲基苯甲酰)-D-2Nal-N-Me-D-Pbe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-((3R)哌啶羰基-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
缩略语：D-2Nal＝D-2萘丙氨酸
5Apent＝5-氨基戊酸
3Pyal＝3-吡啶基丙氨酸
Aib＝H-氨基并丁酸
Thial＝噻吩基丙氨酸
hPhe＝高苯丙氨酸
N-Bzl-Gly＝N-苄基甘氨酸
4-F＝4-氟
4-OMe＝4-甲氧基
Orn＝鸟氨酸
Dab＝2，4-二氨基丁酸
Hyp＝羟脯氨酸
Tic＝1，2，3，4-四氢异喹啉-3-羧酸
可用常规的液相或固相肽合成法制备式I的化合物。例如，固相合成可基本上按Steward和Young所公开的方法(SolidPhase Peptide Synthesis，2nd Ed.Rockford，Illinois，USA，1976)进行。液相合成则可大致按Bodansky等所公开的方法(PeptideSynthesis，2nd Ed.，New York，USA，1976)进行。
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。可通过Amadori重排法制备含有由一或二-吡喃己糖衍生的氨基的肽衍生物，该方法基本上是R.Albert等所公开的方法(LifeSciences 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、乳糖和纤维二糖。用作上述合成的原料的衍生物可通过商业渠道获得，而且，必要时提供适当的保护基，或者，也可以通过已知方法制备用于制备通式I的“A”部分的原料，并用已知方法有选择地加以保护。
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
*Mywacett9-40T 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。预计式I的化合物可用于激发垂体释放生长激素的目的，而且还将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0.0001mg-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。
在本说明书中和实施例中所采用的缩略语是指以下结构：
用于非天然氨基酸残基的缩略语： 用于肽键取代基的缩略语：用于保护基的缩略语：
在以下实施例中所制备的化合物都是作为三氟乙酸(TFA)的盐分离的。
例1
H-Ala-His-D-2Nal-D-Trp-Lys-NH2
按照Fmoc方法，采用生产商提供的FastMoc UV方案以0.22mmol的规模在Applied Biosystems 431A肽合成仪上合成标题中的肽，使用的是在NMP(N-甲基吡咯烷酮)中由HBTU(2-(1H-苯并三唑-1-基)-1，1，3，3-四甲基脲六氟磷酸)介导的偶联，并用UV监测Fmoc保护基的去保护。用于该合成的原始树脂是取代能力为0.39mmol/g的559mg4-((2’，4’-二甲氧基苯基)-(Fmoc-氨基)甲基)-苯氧基树脂(Novabio-Chem，Bad Soden，Germany.Cat.#01-64-0013)。所使用的保护氨基酸衍生物是Fmoc-Lys(Boc)-OH、Fmoc-D-Trp-OH，Fmoc-2Nal-OH、Fmoc-His(Trt)和Fmoc-Ala-OH。
通过在室温下与由4ml TFA(三氟乙酸)、300mg苯酚、100μl乙二硫醇、200μl苯硫基甲烷和200μl H2O组成的混合物一起搅拌180分钟，将肽从434mg的肽树脂上切下来。过滤裂解混合物，并用氮气流将滤液浓缩至1ml。用45ml乙醚将粗制肽从该油状物中沉淀，并用50ml乙醚洗涤3次。
干燥粗制的肽，并通过在装有7μc-18SiO2的20mm×250mm层析柱上进行半制备HPLC提纯。该柱用溶于0.05M(NH4)2SO4的、并用4MH2SO4调至pH2.5的15％CH3CN预平衡过。将粗制肽溶于2ml溶解在H2O中的70％CN3CN/0.1％TFA中，并用水稀释至100ml。将该溶液分成相等的两个部分，将每一部分在两个独立的实验中加注到层析柱上。在40℃，在47分钟内以10ml/分的速度，用溶于0.05M(NH4)2SO4中的15-25％CH3CN(pH2.5)梯度溶液洗脱。收集含肽部分，用3倍体积的水稀释并上用0.1％TFA平衡过的Sep-PakC18柱(Waters pait.#：51910)。然后用含有0.1％TFA的70％CH3CN将肽从Sep-Pak柱上洗脱，用水稀释后通过冷冻干燥法将肽从洗脱物中分离出来。产量为19.0mg。
通过分析RP-HPLC(保留时间)和等离子体解吸质谱(分子量)鉴定所得到的最终产物。质谱结果在该方法允许的误差范围内(质谱±0.9amu)与预期的结构符合。
采用214nm的UV检测并用一个Vydac 218TP54 4.6mm×250mm5μC-18SiO2柱(The Separation Group，Hesperia)进行RP-HPLC分析，在42℃以1ml/分的速度洗脱。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4MH2SO4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梯度液洗脱。
B1：用5％CH3CN/0.1％TFA/H2O平衡层析柱，并在50分钟内，用5％CH3CN/0.1％TFA/H2O～60％CH3CN/0.1％TFA/H2O梯度液洗脱。
采用洗脱条件A1和B1的保留时间分别为17.88分钟和20.15分钟。
例2
H-Ala-His-D-2Nal-D-Phe-Lys-OH
采用与例1类似的方法合成标题中的肽，所不同的是，将取代能力为0.49mmol/g的450mg Fmoc-Lys(Boc)-Wang树脂(Novabiochem.Bad Soden，Germany.cat.#：04-12-2014)用作原料树脂。当采用例1所述方法将560mg肽树脂裂解并对所得到的1/2的粗制肽进行提纯时，获得了25.9mg的产量。
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的保留时间分别为18.30分钟和20.15分钟。
例3
5-(H-Ala-His-D-2Nal-D-Phe-NH)氨基戊烷
采用与例1类似的方法合成肽树脂H-Ala-His(Trt)-D-2Nal-D-Phe-Sasrin树脂，所不同的是，采用的是取代能力为0.96mmol/g的262mg Sasrin树脂(2-甲氨基-4-烷氧苄基醇树脂)(Bachem，Bubendorf，Switzerland，cat.#：D-1295)，而将第一个氨基酸残基偶联到该树脂上的方案是由4-二甲氨基吡啶催化的预先制备的对称酐的偶联，随后用苯甲酸酐对树脂上的残余-OH基进行封端。
通过在室温下与0.5ml1，5-二氨基戊烷一起搅拌20小时，将被部分保护的肽5-(H-Ala-His(Trt)-D-2Nal-D-Phe-NH)氨基戊烷从56mg的H-Ala-His(Trt)-D-2Nal-D-Phe-Sasrin树脂上裂解下来。滤去废树脂，并用1mlDMF提取。在搅拌条件下将合并的滤液和提取物缓慢加入由2.5mlCH3CN和10ml1M氢氯酸组成的混合物中，在用25％CH3CN稀释至50ml后，将混合物在4℃下放置100小时(用于裂解组氨酸上的三苯甲基保护)。然后用水将该混合物稀释至200ml并过滤。
用与例1类似的方法将1/2的滤液直接加注到层析柱上，通过半制备HPLC将粗制肽提纯。所得产量为4.5mg。
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18.43分钟和20.75分钟。
例4
(2S)-(H-Ala-His-D-2Nal-D-Phe-NH)-6-氨基己醇
用与例3类似的方法，由取代能力为0.96mmol/g的Sasrin树脂合成肽树脂H-Ala-His(Trt)-D-2Nal-D-Phe-Lys(Boc)-Sasrin树脂。
通过在室温下与由1.2mlTHF(四氢呋喃)、0.2ml乙醇、23mg LiBr和10mg NaBH4组成的混合物一起将肽树脂搅拌20小时，将被部分保护起来的肽(2S)-(H-Ala-His(Trt)-D-2Nal-D-Phe-NH)-6-氨基己醇从200mg的H-Ala-His(Trt)-D-2Nal-D-Phe-Lys(Boc)-Sasrin树脂上裂解下来。然后加入200μl H2O、200μl乙酸和4ml乙醇。过滤除去树脂珠，用50ml H2O稀释滤液并冷冻干燥。将所得到的粉状物进行TFA裂解并按例1方法提纯。为了获得足够纯的产品，必须重复提纯，获得5.8mg的产量。
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的保留时间分别为17.82分钟和20.02分钟。
例5
H-Ala-Hisψ(CH2NH)D-2Nal-D-Phe-Lys-NH2
采用与例1类似的方法，以取代能力为0.34mmol/g的556mg4-((2’，4’-二甲氧苯基)-(Fmoc-氨基)甲基)-苯氧基树脂(Novabiochem AG Switzerland，cat.#：01-64-0013)为原料合成肽树脂H-D-2Nal-D-Phe-Lys-(Boc)Resin.采用以下的保护氨基酸衍生物：Fmoc-Lys-(Boc)-OH、Fmoc-D-Phe-OH和Fmoc-2Nal-OH。
按照Sasaki，Y.和Coy，D.H.的方法(Peptides 8(1)，119-121，1987)引入-CH2NH-肽键等排物。
按照Fehrentz，J.-A.和Castro.B.的方法(Systhesis 676-678，1983)，由820mg相应的N，O-异羟肟酸二甲酯制备Fmoc-His(Trt)-醛。将粗制的醛溶于8ml DMF中并分成两份。在室温下将第一部分加入溶于DMF中10ml 1％乙酸中的610mgH-D-2Nal-D-Phe-Lys-Resin的搅拌浆体中。然后加入溶于1mlDMF中的57mg NaCNBH3(纯度85％)，并继续搅拌60分钟。此后，过滤分离肽树脂，并用溶于DMF中的1％乙酸洗涤。将肽树脂重新悬浮于10ml溶于DMF中的1％乙酸中，并加入另一部分Fmoc-His(Trt)-醛。在室温下再次加入溶于1ml DMF中的57mg NaCNBH3(纯度85％)，并搅拌混合物18小时。
在该还原性烷基化步骤之后，过滤分离肽树脂并用溶于DMF的1％乙酸洗涤，按照上述方法，用保护的氨基酸衍生物Fmoc-Ala-OH、采用肽合成仪完成链延长。
将肽从550mg的肽树脂上裂解下来，并用与例1类似的方法通过半制备HPLC提纯粗制肽。获得11.3mg的产量。
按照例1所述方法鉴定最终产物。采用洗脱条件A1和B1的保留时间分别为13.35分钟和17.38分钟。
例6
(正丙基)-His-D-2Nal-D-Phe-Lys-NH2和(正丙基)2-His-D-2-Nal-D-Phe-Lys-NH2
用与例1类似的方法，以取代能力为0.34mmol/g的4-((2’，4’-二甲氧苯基)-(Fmoc-氨基)甲基)-苯氧基树脂(Novabiochem AG Switzerland，cat.#：01-64-0013)为原料合成肽树脂H-His(Trt)-D-2Nal-D-Phe-Lys(Boc)-Resin。所用保护的氨基酸衍生物是Fmoc-Lys(Boc)-OH、Fmoc-D-Phe-OH、Fmoc-2Nal-OH和Fmoc-His(Trt)-OH。
在室温下，将13μl正丙醇加入溶于3.3ml由DMF配制的1％乙酸中的150mg的H-His(Trt)-D-2Nal-D-Phe-Lys-Resin的搅拌浆体中。然后加入16.8mg溶于0.5ml DMF中的NaCNBH3(纯度85％)，并继续搅拌6小时。在该还原性烷基化步骤之后，分离肽树脂，用DMF和CH2Cl2在过滤漏斗上洗涤并真空干燥。
将所得到的两种肽树脂混合，并将未烷基化的一正丙基和二正丙基肽从所得到的300mg肽树脂上裂解下来。用与例1类似的方法通过半制备HPLC分离并提纯肽。得到6.54mg正丙基-His-D-2Nal-D-Phe-Lys-NH2和5.59mg(正丙基)2-His-D-2Nal-D-Phe-Lys-NH2。
按照例1所述方法对最终产物进行鉴定。对(正丙基)-His-D-2Nal-D-Phe-Lys-NH2而言，采用洗脱条件A1和B1的保留时间分别为16.45分钟和19.92分钟。
例7
H-Ala-Tic-D-2Nal-D-Phe-Lys-NH2
用生产商提供的0.5mmol规模的单偶联方案，以取代能力为0.72mmol/g的620mg4-甲基BHA树脂(BissenderfBiochemicals，Hannover，Gernany，cat.#：RMIS50)为原料，按照Boc方法在Applied Biosystems 430A肽合成仪上合成标题中的肽，采用的是在DMF中与预先制备的对称酐的单偶联。该方案调整到60分钟联偶时间。将2×60分钟的双偶联时间用于N-末端Ala。用于该合成的保护的氨基酸衍生物是Boc-Lys(2-氯-Z)-OH、Boc-D-Phe-OH，Boc-D-2Nal-OH，Boc-Tic-OH和Boc-Ala-OH。
通过在0℃与由4.5ml HF和500μl m-甲酚组成的混合物一起搅拌75分钟，将肽从486mg肽树脂上裂解下来。在0℃用氮气流将HF蒸发掉。用50ml乙醚将肽从残余的油状物和废树脂中沉淀出来，并用50ml乙醚洗涤2次。干燥之后，用加有4滴乙酸的10ml H2O将肽提取沉淀。用水将提取物稀释至100ml。
用与例1类似的方法，通过两套半制备HPLC从2×18ml的稀释提取液中提纯粗制肽。产量为17.3mg。
按照例1所述方法鉴定最终产物。
采用条件A1和B1进行RP-HPLC分析所得到的保留时间分别为27.37分钟和29.50分钟。
例8
(2R)-(H-Ala-His-D-2Nal-NH)-3-苯丙胺
通过用溶于NMP中的20％哌啶处理20分钟，除去580mg取代能力为0.43mmol/g的4-((2’，4’-二甲氧苯基)-(Fmoc-氨基)甲基)-苯氧基(Novabiochem AG Switzerland cat.#：01-64-0013)上的Fmoc基团。用DMF和CH2Cl2洗涤树脂，并用例5所述的烷基化方法用Fmoc-D-Phe-醛进行烷基化。
此后，过滤分离肽树脂，在过滤斗漏上用溶于DMF中的1％乙酸洗涤，并采用例1中的肽合成仪完成链延长。所用保护的氨基酸衍生物是Fmoc-D-2Nal-OH、Fmoc-His(Trt)-OH和Fmoc-Ala-OH。
用与例1类似的方法将肽从肽树脂上裂解下来并通过半制备HPLC提纯粗制肽。产量为23.92mg。
按照例1所述方法鉴定最终产物。采用洗脱条件A1和B1的保留时间分别为19.33分钟和21.77分钟。
例9-54
| 例 | 肽 | 用类似于以下实施例的方法进行制备 | 条件A1的RP-HPLC保留时间 | 条件B1的RP-HPLC保留时间 |
| 9 | H-Ala-His-D-Phe-D-Phe-Lys-NH2 | 1 | 12.53 | 15.43 |
| 10 | H-Ala-Phe-D-2Nal-D-Phe-Lys-NH2 | 1 | 28.13 | 29.62 |
| 11 | H-His-D-2Nal-D-Phe-Lys-NH2 | 1 | 18.02 | 20.15 |
| 12 | H-Ala-His-D-2Nal-D-Phe-Phe-NH2 | 1 | 28.48 | 29.48 |
| 13 | H-Ala-His-D-2Nal-D-Phe-D-Phe-NH2 | 1 | 26.65 | 27.75 |
| 14 | H-Ala-His-D-2Nal-Phe-Lys-NH2 | 1 | 21.85 | 23.12 |
| 15 | (3-(4-咪唑基)丙酰基)-D-2Nal-D-Phe-Lys-NH2 | 1 | 20.7 |
| 16 | (丙酰基)-His-D-2Nal-D-Phe-Lys-NH2 | 1 | 22.2 | 23.77 |
| 17 | H-Ala-His-D-2Nal-D-Phe-NH2 | 1 | 21.7 | 23.08 |
| 18 | (H-Ala-His-D-2Nal-D-Phe-NH)己烷 | 3 | 34.11 | 35.78 |
| 19 | H-Ala-His-D-Trp-D-Phe-Lys-NH2 | 1 | 14.52 | 16.7 |
| 20 | H-Ala-Ala-D-2Nal-D-Phe-Lys-NH2 | 1 | 21.97 | 23.23 |
| 21 | ((丙酰基)-His-D-2Nal-D-Phe-NH)己烷 | 3 | 37.17 | 39.47 |
| 22 | 6-(H-Ala-His-D-2Nal-D-Phe-NH)己胺 | 3 | 19.3 | 21.57 |
| 23 | H-D-2Nal-D-Phc-Lys-NH2 | 1 | 15.88 | 18.25 |
| 24 | (5-氨基戊酰)-His-D-2Nal-D-Phe-Lys-NH2 | 1 | 17.8 | 19.98 |
| 25 | H-D-Lys-D-2Nal-D-Phe-Lys-NH2 | 1 | 17.07 | 19.62 |
| 26 | H-Ala-His-D-2Nal-D-Tic-Lys-NH2 | 1 | 19.12 | 20.78 |
| 27 | H-D-Lys-Phe-2Nal-D-His-D-Ala-NH2 | 1 | 18.15 | 20.48 |
| 28 | (5-氨基戊酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 20.67 | 22.45 |
| 29 | H-D-Ala-D-2Nal-D-Phe-Lys-NH2 | 1 | 19.57 | 21.53 |
| 30 | (丙酰基)-D-2Nal-D-Phe-Lys-NH2 | 1 | 26.7 | 27.92 |
| 31 | H-D-Ala-His-D-2Nal-D-Phe-Lys-NH2 | 1 | 17.83 | 20.3 |
| 32 | H-Ala-3-Pyal-D-2Nal-D-Phe-Lys-NH2 | 1 | 18.15 | 20.18 |
| 33 | (正丁基)-Ala-His-D-2Nal-D-Phe-Lys-NH2 | 6 | 19.55 |
| 34 | (正辛基)-Ala-His-D-2Nal-D-Phe-Lys-NH2 | 6 | 27.88 | 24.52 |
| 35 | H-Ala-His-D-2Nal-D-Pheψ(CH2NH)Lys-NH2 | 5 | 17.97 | 20.83 |
| 36 | (3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 22.42 | 24.13 |
| 37 | (3-氨基苯乙酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 23.62 | 23.97 |
| 38 | ((4-咪唑基)-乙酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 20.42 | 22.22 |
| 39 | (3-(4-咪唑基)-丙烯酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 21.25 | 23.32 |
| 40 | (4-氨基苯乙酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 22.45 | |
| 41 | (trans-4-氨甲基环己酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 22.07 | 23.67 |
| 42 | 2-(H-Ala-His-D-2Nal-D-Phe-NH)-乙胺 | 3 | 18.6 | 20.25 |
| 43 | (2-(H-Ala-His-D-2Nal-D-Phe-NH)乙基)苯 | 3 | 30.18 | 32.18 |
| 44 | 4-((H-Ala-His-D-2Nal-D-Phe-NH)甲基)苄胺 | 3 | 19.63 | 21.55 |
| 45 | (2R)-(H-Ala-His-D-2Nal-NH)-3-苯丙胺 | 4 | 21.55 | 23.57 |
| 46 | 2-(H-Ala-His-D-2Nal-NH)乙胺 | 3 | 25.52 | |
| 47 | H-D-Phe-Ala-D-2Nal-D-Phe-Lys-NH2 | 1 | 27.82 | 29.43 |
| 48 | H-Ala-D-Phe-D-2Nal-D-Phe-Lys-NH2 | 1 | 25.62 | 27.22 |
| 49 | H-Ala-(2-氨基苯甲酰)-D-2Nal-D-Phe-Lys-NH2 | 7 | 26.42 | 24.93 |
| 50 | H-Aib-His-D-2Nal-D-Phe-Lys-NH2 | 1 | 17.42 | 20.13 |
| 51 | H-Aib-His-D-1Nal-D-Phe-Lys-NH2 | 1 | 17.55 | 19.8 |
| 52 | H-Tyr-Ala-His-D-2Nal-D-Phe-Lys-NH2 | 1 | 19.9 | 21.22 |
| 53 | (哌啶-4-羰基)-D-2Nal-D-Phe-Lys-NH2 | 1 | 20.4 | 22.32 |
| 54 | H-Ala-Phe(4-NH2)-D-2Nal-D-Phe-Lys-NH2 | 1 | 19.20 | - |
例55
((丙酰基)-D-2Nal-D-Phe-NH)己烷
用与例3类似的方法，由取代能力为0.96mmol/g的Sasrin树脂合成肽树脂(丙酰基)-D-2Nal-D-Phe-Sasrin树脂。
对所得到的105mg树脂进行氨解作用。
通过在室温下与1ml正己胺一起搅拌20小时，将肽((丙酰基)-D-2Nal-D-Phe-NH)己烷从105mg的丙酰基-D-2Nal-D-Phe-Sasrin树脂上裂解下来。滤去废树脂并用1ml DMF提取。将合并的滤液和提取液在搅拌条件下加入8ml 1M氢氯酸中。通过加入约70ml CH3CN将所得沉淀物重新溶解，然后加入20ml H2O进行再沉淀。滤出沉淀物，用水洗涤并干燥。产量为12mg。
按照例1所述方法对产物进行鉴定，所不同的是，用类似于B1的条件仅进行一个HPLC分析，与B1条件不同的是用0.1％TFA/H2O-90％CH3NH/0.1％TFA/H2O梯度液在50分钟内洗脱。保留时间为35.73分钟。
例56
(3-甲基氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
用类似于例7的方法，由取代能力为0.72mmol/g的MBHA树脂合成肽树脂(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys(Cl-Z)-MBHA。
按照Kaljuste，K.和Unden，A.的方法(Int.J.Peptide ProteinRes.42118-124，1993)将所得到的肽树脂甲基化。将300mg树脂与由8ml DCM、150μl DIEA(二乙基异丙胺)和39mg4，4’-二甲氧基二苯甲基氯(DOD-Cl)组成的混合物一起搅拌2小时，然后过滤分离并用DCM和DMF洗涤。将DOD保护的肽树脂与18ml溶于DMF中的3.7％甲醛溶液一起搅拌，加入0.18ml乙酸和180mg Na CNBH3并继续搅拌18小时。通过过滤分离树脂，并用DMF和DCM洗涤。通过用2×3ml DCM/TFA1∶1分别处理5分钟和30分钟去除DOD保护，用DCM洗涤肽树脂，然后在真空中干燥。
用类似于例7的方法将所得N-甲基化的肽从370mg树脂上裂解下来，并按照例1所述方法提纯和鉴定。产量为17.3mg。
用条件A1和B1进行RP-HPLC分析所得到的保留时间分别为22.83分钟和24.60分钟。
例57
(3-二甲基氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
用类似于例7的方法，由取代能力为0.72mmol/g的MBHA树脂合成肽树脂(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys(Cl-Z)-MBHA树脂。
将650mg所得肽树脂与20ml溶于DMF中的1％乙酸和45μl溶于DMF中的3.7％甲醛溶液一起搅拌。然后加入55mgNaCNBH3(85％)，并继续搅拌18小时。通过过滤分离树脂，并用DMF、DCM/MeOH，6∶4和DCM洗涤。
用类似于例7的方法将所得到的N，N-二甲基化肽的混合物从631mg树脂上裂解下来，并按照例1所述方法进行提纯和鉴定。产量为8.58mg。
用条件A1和B1进行RP-HPLC分析所得到的保留时间分别为31.58分钟和33.00分钟。
例58
(3-氨基-3-甲基丁酰)-D-2Nal-D-Phe-Lys-NH2
用类似于例1的方法，由2g取代能力为0.39mmol/g的4-((2’，4’-二甲氧苯基)-(Fmoc-氨基)甲基)-苯氧基树脂(Rink树脂)(Novabiochem，Bad Soden，Germany，cat.#：01-64-0013)合成肽树脂H-D-2Nal-D-Phe-Lys(Boc)-Rink树脂。
将所得到的500mg肽树脂(0.15mmol)悬浮于4mlDCM/MeOH1∶1中。加入42μl三乙胺(0.3mmol)，并在冷却至0℃以后在搅拌条件下加入31mg(0.158mmol)2，2-二甲基-4-氧-氮杂环丁烷-1-磺酰氯。在0℃继续搅拌20分钟，并在室温下搅拌90分钟。在用DCM/MeOH6∶4洗涤树脂并真空干燥之后，用类似于例1的方法将粗肽从树脂上裂解下来并提纯。产量为41.81mg。
用A1和B1条件进行RP-HPLC分析所得保留时间分别为21.35分钟和22.95分钟。
例59
(2S)-((3-氨甲基苯甲酰)ψ(CH2NH)D-2Nal-D-Phe-NH)-6-氨基己醇
用类似于例3的方法，由取代能力为0.87mmol/g的980mgSasrin树脂合成肽树脂H-D-2Nal-D-Phe-Lys(Boc)-Sasrin树脂。
用Boc-3-氨甲基苯甲醛对1.4g上述树脂进行还原性烷基化，并将肽从1.0g所得树脂上裂解下来，用类似于例5的方法对一半粗制产物进行提纯。产量为18.46mg。
用A1和B1条件进行RP-HPLC分析所得到的保留时间分别为14.78分钟和17.40分钟。
例60
(2-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
用类似于例1的方法，由取代能力为0.39mmol/g的2g4-(2’，4’-二甲氧苯基)-(Fmoc-氨基)甲基)-苯氧基树脂(Rink树脂)(Novabiochem，Bad Soden，Germany，cat.#：01-64-0013)合成肽树脂H-D-2Nal-D-Phe-Lys(Boc)-Rink树脂。
在10ml DMF中将300mg所得肽树脂(0.096mmol)与54mg邻苯二甲酰-2-氨甲基-苯甲酸(0.192mmol)、182mg HBTU(0.480mmol)和164μl DIEA(0.96mmol)一起搅拌18小时。
在用DMF、DCM/MeOH6∶4和DCM洗涤树脂，并真空干燥之后，通过在室温下与由3ml TFA、225mg苯酚、75μl乙二硫醇、150μl苯硫基甲烷和150μl H2O组成的混合物一起搅拌180分钟，将(邻苯二甲酰-2-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2从290mg肽树脂裂解下来。过滤裂解混合物，用1mlTFA洗涤残余的树脂，并通过氮气流将滤液浓缩至1ml。用50μl乙醚将粗制肽从上述油状物中沉淀出来，并用50ml乙醚洗涤3遍。然后将沉淀物溶于50μl H2O中并冷冻干燥。在70℃温度下，在5ml乙醇中将所得粉状物与0.5ml水合肼一起搅拌6小时，然后用50ml H2O稀释并冷冻干燥。
通过加入2ml乙酸、2ml乙醇和100ml H2O溶解冷冻干燥产物，并用类似于例1的方法提纯。产量9.43mg。
用条件A1和B1进行RP-HPLC分析所得保留时间分别为23.22分钟和25.05分钟。
例61
H-Aib-Hisψ(CH2NH)D-2Nal-D-Phe-Lys-OH
用类似于例5的方法合成标题中的肽，不同的是，将1050mg取代能力为0.87mmol/g的Sasrin树脂(2-甲氧基-4-烷氧苄基醇树脂)(Bachem，Bubendorf，Switzerland，cat.#：D-1295)用于合成，而且用于将第一个氨基酸残基与树脂偶联的方案是，由4-二甲基氨基吡啶催化的预先制备的对称酐的偶联，随后用苯甲酸酐对树脂上的残余-OH基进行封端。在将752mg肽树脂裂解并按例1所述方法将7/10所得的粗制产物提纯之后，获得36.76mg产物。
按例1所述方法对最终产物进行鉴定。采用洗脱条件A1和B1的保留时间分别为13.90分钟和17.42分钟。
例62
H-Aib-His-N-Me-D-2Nal-D-Phe-Lys-NH2
用类似于例56的方法，由取代能力为0.72mmmol/g的MBHA树脂合成肽树脂H-N-Me-D-2Nal-D-Phe-Lys(Cl-Z)-MBHA树脂。
通过与Boc-His(Bom)-OH和Boc-Aib-OH偶联，将458mg的上述树脂用于合成H-Aib-His(Bom)-N-Me-D-2Nal-D-Phe-Lys(Cl-Z)-MBHA。然后将N-甲基化的肽从469mg所得树脂上裂解下来，并按例1所述方法对1/2粗制肽进行提纯和鉴定。产量为23.5mg。
用条件A1和B1进行RP-HPLC所得到的保留时间分别为17.62分钟和19.95分钟。
例63
(糠基)-Aib-His-D-2Nal-D-Phe-Lys-NH2
用类似于例1的方法，由取代能力为0.43mmol/g的4-((2’4’-二甲氧苯基)-(Fmoc-氨基)甲基)-苯氧基在树脂(Rink树脂)(Novabiochem，Bad Soden，Ger-many，cat.#：01-64-0013)合成肽树脂H-Aib-His(Trt)-D-Nal-D-Phe-Lys(Boc)-Rink树脂。
然后将所得300mg肽树脂与5ml溶于DMF的1％乙酸和410μl呋喃-2-醛搅拌。在15分钟和180分钟之后加入231mgNaCNBH3(85％)。持续搅拌18小时。过滤分离树脂，并用DMF、DCM/MeOH6∶4和DCM洗涤。
将N-烷基化的肽从所得319mg树脂上裂解下来，按照例1所述方法提纯和鉴定。产量为44.8mg。
采用条件A1和B1进行RP-HPLC分析所得到的保留时间分别为19.45分钟和22.23分钟。
例64
N，N-二-(2R-羟基-丙基)-3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
用类似于例7的方法，由取代能力为0.72mmol/g的4-甲基二苯甲基胺(MBHA)树脂(Biss-endorfBiochemicals，Hannover，Germany，cat.#：RMIS50)合成肽树脂(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys(Cl-Z)-MBHA树脂。
然后，将所得500mg肽树脂与12.5ml溶于DMF中的1％乙酸和410μl2(R)-(四氢吡喃-2(R，S)-基氧丙醛一起搅拌。5分钟后加入213mg NaCNBH3(85％)。继续搅拌18小时。过滤分离树脂，并用DMF、DCM/MeOH6∶4和DCM洗涤。
将N，N-二烷基化肽从所得到的490mg树脂上裂解下来，并按照例7所述方法进行提纯和鉴定。产量为20.72mg。
用条件A1和B1进行RP-HPLC分析所得到的保留时间分别为23.4分钟和25.33分钟。
例65-110
N，N-(2R-羟丙基)-(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2 
3-(4-咪唑基)丙酰基)-D-2Nal-D-Phe-Lys-NH2 
H-Ala-3Pyal-D-2Nal-D-Phe-Lys-NH2 
| 例 | 肽 | 用类似于以下实施例的方法进行制备 | 条件A1的RP-HPLC保留时间(例1) | 条件B1的RP-HPLC保留时间(例1) |
| 65 | H-Ala-N-Me-(2-氨基甲酰)-D-2Nal-D-Phe-Lys-NH2 | 7 | 24.47 | 26.27 |
| 66 | (4-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2 | 1 | 22.22 | 23.5 |
| 67 | H-His-Ala-D-2Nal-D-Phe-Lys-NH2 | 1 | 19.90 | 21.45 |
| 68 | (2S)-(H-Ala-His-D-2Nal-D-Phe-NH)-1，6-二氨基己烷 | 8 | 17.05 | 19.07 |
| 69 | 4-(H-Ala-His-D-2Nal-D-Phe-NH)丁胺 | 3 | 18.65 | 20.08 |
| 70 | 3-(H-Ala-His-D-2Nal-D-Phe-NH)丙胺 | 3 | 18.42 | 19.80 |
| 71 | (3-氨甲基苯甲酰)-D-hPhe-D-Phe-Lys-NH2 | 7 | 20.33 | 21.95 |
| 72 | (3-氨甲基苯甲酰)ψ(CH2NH)D-2Nal-D-Phe-Lys-NH2 | 5 | 14.17 | 17.23 |
| 73 | (3-氨甲基苯甲酰)-D-2Nal-D-hPhe-Lys-NH2 | 7 | 25.30 | 26.58 |
| 74 | (3-氨基-3-甲基丁酰)-His-D-2Nal-D-Phe-Lys-NH2 | 58 | 18.12 | 20.20 |
| 75 | (3-氨甲基苯甲酰)-D-2Nal-N-Bzl-Gly-Lys-NH2 | 7 | 25.33 | 26.70 |
| 76 | (2S)-((3-氨甲基苯甲酰)-D-2Nal-D-Phe-NH)-6-氨基己醇 | 4 | 22.95 | 24.32 |
| 77 | (3-氨甲基苯甲酰)-D-2Nal-D-Thial-Lys-NH2 | 7 | 22.13 | 23.23 |
| 78 | (2S)-(H-Aib-Hisψ(CH2NH)D-2Nal-D-Phe-NH)-6-氨基己醇 | 59 | 12.83 | 17.27 |
| 79 | (3-氨甲基苯甲酰)-D-2Nal-D-3Pyal-Lys-NH2 | 1 | 15.10 | 16.87 |
| 80 | (3-氨甲基苯甲酰)-D-2Nal-D-Phe(4-F)-Lys-NH2 | 7 | 23.40 | 24.63 |
| 81 | (3-氨甲基苯甲酰)-D-2Nal-D-Phe(4-OMe)-Lys-NH2 | 7 | 22.50 | 23.90 |
| 82 | 2-(H-Aib-His-D-2Nal-D-Phe-NH)乙烷 | 3 | 18.30 | 20.47 |
| 83 | H-Aib-Phe-D-2Nal-D-Phe-Lys-NH2 | 1 | 29.25 | 30.55 |
| 84 | 2-(H-Aib-His-D-2Nal-D-Phe-NH-(1-甲基-2-吡咯烷基)乙烷 | 3 | 18.70 | 20.80 |
| 85 | 2-(H-Aib-His-D-2Nal-D-Phe-NH)-(2-吡啶基)乙烷 | 3 | 19.20 | 20.83 |
| 86 | (3-氨甲基苯甲酰)-D-2Nal-N-Me-D-Phe-Lys-NH2 | 1 | 26.78 | 27.88 |
| 87 | H-Aib-His-D-2Nal-D-Phe-Gly-NH2 | 1 | 20.48 | 22.23 |
| 88 | H-Aib-His-D-2Nal-D-Phe-Ala-NH2 | 1 | 21.65 | 23.38 |
| 89 | H-Aib-His-D-2Nal-D-Phe-Orn-NH2 | 1 | 18.43 | 20.05 |
| 90 | (5-氨甲基噻吩基-2-羰基)-D-2Nal-D-Phe-Lys-NH2 | 1 | 22.32 | 23.65 |
| 91 | H-Aib-His-D-2Nal-D-Phe-D-Lys-NH2 | 1 | 18.50 | 20.00 |
| 92 | H-Aib-His-D-2Nal-D-Phe-Dab-NH2 | 1 | 17.75 | 19.48 |
| 93 | H-Aib-His-D-2Nal-D-Pheψ(CH2NH)Lys-NH2 | 5 | 18.57 | 20.62 |
| 94 | H-Aib-His-D-2Nal-D-Phe-N-Me-Lys-NH2 | 62 | 18.03 | 20.60 |
| 95 | (3-氨甲基噻吩基-2-羰基)-D-2Nal-D-Phe-Lys-NH2 | 1 | 23.23 | 24.78 |
| 96 | H-Aib-His-D-2Nal-N-Me-D-Phe-Lys-NH2 | 1 | 21.78 | 23.53 |
| 97 | H-Aib-His-D-2Nal-D-Phe-Lys-N(Me)2 | 3 | 18.70 | 21.07 |
| 98 | (3-氨甲基苯甲酰)-D-1Nal-D-Phe-Lys-NH2 | 1 | 22.67 | 24.23 |
| 99 | H-Aib-His-D-2Nal-D-Trp-Lys-NH2 | 1 | 18.17 | 20.40 |
| 100 | (2-吡啶甲基)-Aib-His-D-2Nal-D-Phe-Lys-NH2 | 63 | 19.07 | 21.73 |
| 101 | H-Aib-(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2 | 7 | 23.95 | 25.38 |
| 102 | H-Aib-3Pyal-D-2Nal-D-Phe-Lys-NH2 | 1 | 18.53 | 20.38 |
| 103 | (3R)-哌啶羰基)-D-2Nal-D-Phe-Lys-NH2 | 1 | 21.52 | 22.97 |
| 104 | (2-(H-Aib-His-D-2Nal-NH)乙基)苯 | 3 | 25.55 | 27.85 |
| 105 | (2R-羟丙基)-Aib-His-D-2Nal-D-Phe-Lys-NH2 | 64 | 18.15 | 20.28 |
| 106 | (3-氨甲基苯甲酰)-D-2Nal-D-Pheψ(CH2NH)Lys-NH2 | 5 | 22.00 | 23.95 |
| 107 | (3-氨甲基苯甲酰)-N-Me-D-2Nal-D-Phe-Lys-NH2 | 62 | 23.27 | 24.72 |
| 108 | (3-氨甲基苯甲酰)-D-2Nal-D-Phe-N-Me-Lys-NH2 | 67 | 22.60 | 23.98 |
| 109 | H-D-Thr-His-D-2Nal-D-Phe-Lys-NH2 | 7 | 17.75 | 19.83 |
| 110 | H-Hyp-His-D-2Nal-D-Phe-Lys-NH2 | 7 | 17.58 | 19.37 |
(反-4-氨甲基环己酰)-D-2Nal-D-Phe-Lys-NH2 H-Ala-(2-氨基苯甲酰)-D-2Nal-D-Phe-Lys-NH2 
(3R)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2 
H-Ala-N-Me-(2-氨基苯甲酰)-D-2Nal-D-Phe-Lys-NH2 
(2S)-(H-Aib-Hisψ(CH2NH)D-2Nal-D-Phe-NH)-6-氨基己醇
2-(H-Aib-His-D-2Nal-D-Phe-NH)(1-甲基-2-吡咯烷基)乙烷
(5-氨甲基噻吩基-2-羰基)-D-2Nal-D-Phe-Lys-NH2 
(3-氨甲基-噻吩基-2-羰基)-D-2Nal-D-Phe-Lys-NH2 
(3-氨甲基苯甲酰)-D-2Nal-N-(苯乙基)-Gly-Lys-NH2 
例116
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1000μgDNase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(补充了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4μg/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，并加入含有本发明肽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。测定法收集缓冲液，并在以下的闪烁亲近测定法(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
50μl SPA试剂(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。
| 例 | 化合物 | EC50(nM) | Emax(％GHRP-6) |
| 3 | H-Ala-His-D-2Nal-D-Phe-NH-(CH2)5NH2 | 20 | 100 |
| 10 | H-Ala-Phe-D-2Nal-D-Phe-Lys-NH2 | 2 | 90 |
| 51 | H-Ala-His-D-1Nal-D-Phe-Lys-NH2 | 10 | 85 |
| 76 | (2S)-((3-(氨甲基苯甲酰)-D2Nal-D-Phe-NH)-6+氨基己醇 | 26 | 65 |
| 83 | H-Aib-Phe-D-2Nal-D-Phe-Lys-NH2 | 8 | 75 |
| 88 | H-Aib-His-D-2Nal-D-Phe-Ala-Nh2 | 11 | 80 |
| 104 | (2-(H-Aib-His-D-2Nal-NH)乙基)苯 | 58 | 85 |
Claims (17)
1.一种通式I所述的化合物
A-B-C-D-(-E)p
其中
p为0或1；
A为氢或R1-(CH2)q-(X)r-(CH2)s-CO-，其中
q为0或1-5之间的一个整数；
r为0或1；
s为0或1-5之间的一个整数；
R1为氢、咪唑基、胍基、哌嗪基、吗啉代、哌啶子基或N(R2)-R3，其中，R2和R3各自独立地为氢或有选择地被一个或多个羟基、吡啶基或呋喃基取代过的低级烷基；而
当r为1时，X是-NH-，-CH2-，-CH＝CH-，
或
其中，R16和R17各自独立地为氢或低级烷基；
B是(G)t-(H)u，其中
t为或0或1；
u为或0或1；
G和H是从天然L-氨基酸或其相应的D-异构体或者非天然氨基酸中选择的氨基酸残基，
其中，当t和u都为1时，G和H之间的酰胺键可有选择地被
代，其中，Y是
或
，而R18为氢、低级烷基或低级芳烷基；
C为式-NH-CH((CH2)w-R4)-CO-的D-氨基酸，其中
w为0、1或2；而
R4选自下列基团
或
其中的每一个基团有选择地被卤基、低级烷基、低级烷氧基、低级烷氨基、氨基或羟基取代；
当p为1时，D是式-NH-CH((CH2)k-R5)-CO-的D-氨基酸，或当p为0时，D是-NH-CH((CH2)1-R5)-CH2-R6或-NH-CH((CH2)mR5)-CO-R6，其中
k为0、1或2；
l为0、1或2；
m为0、1或2；
R5选自下列基团
或
其中每个基团有选择地被卤基、烷基、烷氧氨基或羟基所取代；而
R6为哌嗪基、吗啉代、哌啶子基、-OH或-N(R7)-R8，其中R7和R8各自独立地为氢或低级烷基；
当p为1时，E是-NH-CH(R10)-(CH2)v-R9，其中
v为0或1-8之间的一个整数；
R9为氢、咪唑基、胍基、哌嗪基、吗啉代、哌啶子基，
其中n为0、1或2，而R19是氢或低级烷基，或
其中o为1-3之间的整数，
或N(R11)-R12，其中R11和R12各自独立地为氢或低级烷基，或
或
每个基团有选择地被卤基、烷基、烷氧基、氨基、烷氨基、羟基、或氨基与吡喃己糖或吡喃己糖基吡喃己糖的Amadori重排产物所取代
和
当p为1时，R10是选自-H、-COOH、-CH2-R13、-CO-R13或-CH2-OH
的基团，其中
R13为哌嗪基、吗啉代、哌啶子基、-OH或-N(R14)-R15，其中R14和R15各自独立地为氢或低级烷基；
B与C之间的酰胺键，或者当t和u为0时A与C之间的酰胺键有选择地被
或者，当p为1时，D与E之间的酰胺键有选择地被
取代，其中Y和R18如上所述；
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为氢。
4.如权利要求1所述的化合物，其中G和H是1，4-二氨基丁酸、氨基异丁酸、1，3-二氨基丙酸、4-氨基苯丙氨酸、3-吡啶丙氨酸、1，2，3，4-四氢异喹啉-3-羧酸、1，2，3，4-四氢norharman-3-羧酸、N-甲基氨茴酸、氨茴酸、N-苄基甘氨酸、3-氨基甲基苯甲酸、3-氨基-3-甲基丁酸、肌氨酸、3-哌啶甲酸或异哌啶甲酸。
5.如权利要求1所述的化合物，其特征在于A是R1-(CH2)
q -(X) r -(CH 2 ) s-CO-，其中R1为3-咪唑基，q为2，r为0，s为0；或者R1为NH2，q为1，r为1，X是双取代的苯，而s为0；或者R1为NH，q为1，r为1，X是双取代的噻吩，而s为0。
6.如权利要求5所述的化合物，其中R1为NH2，q为1，r为1，X为1，3-二取代的苯，而s为0；或者其中R1为NH，q为1，r为1，X为2，3-二取代的噻吩，而s为0。
7.如权利要求1所述的化合物，其特征在于当t为1时，G是Ala、Gly、Aib、肌氨酸、3-哌啶甲酸或异哌啶甲酸。
8.如权利要求1所述的化合物，其特征在于，当u为1时，H是His、Phe、Tic、3Pyal、Gly、Ala、Phe(4-NH2)、Sar、Pro、Tyr、Arg、Orn、3-氨基甲基苯甲酸或D-Phe。
9.如权利要求1所述的化合物，其特征在于R4是2-萘基。
10.如权利要求1所述的化合物，其特征在于R5是苯基。
11.如权利要求2所述的化合物，其特征在于v是2-6，R9是-NH2、吗啉代丙基、吗啉代乙基或(1-甲基吡咯烷基)乙基。
12.如权利要求2所述的化合物，其特征在于R10是-COOH、CH2-OH、-H或CONH2。
13.如权利要求1所述的化合物，选自下列诸化合物：
H-Ala-Hisψ(CH2NH)D-2Nal-D-Phe-Lys-NH2
H-Ala-Ala-D-2Nal-D-Phe-Lys-NH2
H-His-D-2Nal-D-Phe-Lys-NH2
(3-(4-咪唑基)丙酰基)-D-2Nal-D-Phe-Lys-NH2
H-D-Lys-D-2Nal-D-Phe-Lys-NH2
H-5Apent-His-D-2Nal-D-Phe-Lys-NH2
H-D-Ala-D-2Nal-D-Phe-Lys-NH2
H-5Apent-D-2Nal-D-Phe-Lys-NH2
(正丙基)-His-D-2Nal-D-Phe-Lys-NH2
H-Ala-3Pyal-D-2Nal-D-Phe-Lys-NH2
H-Ala-Phe(4-NH2)-D-2Nal-D-Phe-Lys-NH2
H-D-Ala-His-D-2Nal-D-Phe-Lys-NH2
(2-(4-咪唑基)乙酰基)-D-2Nal-D-Phe-Lys-NH2
(3-(4-咪唑基)丙烯酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨基苯乙酰)-D-2Nal-D-Phe-Lys-NH2
(4-氨基苯乙酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨基丁烯酰)-D-2Nal-D-Phe-Lys-NH2
(4-哌啶子基-羧基)-D-2Nal-D-Phe-Lys-NH2
H-Ala-His-D-2Nal-D-Phe-NH2
(H-Ala-His-D-2Nal-D-Phe-NH)己烷
6-(H-Ala-His-D-2Nal-D-Phe-NH)己胺
5-(H-Ala-His-D-2Nal-D-Phe-NH)戊胺
H-Ala-His-D-2Nal-D-Pheψ(CH2NH)Lys-NH2
H-Ala-His-D-2Nal-D-Phe-Lys-OH
(2S)-(H-Ala-His-D-2Nal-D-Phe-NH)-6-氨基己醇
(2-(H-Ala-His-D-2Nal-D-Phe-NH)乙基)苯
2-(H-Ala-His-D-2Nal-D-Phe-NH)乙胺
4-((H-Ala-His-D-2Nal-D-Phe-NH)甲基)苄胺
H-Ala-His-D-2Nal-D-Phe-Lys(麦芽糖基)-NH2
H-Ala-His-D-2Nal-D-Phe-Phe-NH2
H-Ala-His-D-2Nal-D-Phe-D-Phe-NH2
H-Ala-His-D-Phe-D-Phe-Lys-NH2
H-Ala-His-D-Trp-D-Phe-Lys-NH2
H-His-D-2Nal-D-Trp-Lys-NH2
H-Ala-His-D-1Nal-D-Phe-Lys-NH2
H-Ala-Phe-D-2Nal-D-Phe-Lys-NH2
H-Ala-His-D-2Nal-D-Phe-Lys(麦芽糖基)-NH2
(2R)-(H-Ala-His-D-2Nal-D-Phe-Lys-NH)-3苯丙胺
H-Ala-N-Me-(2-氨基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(3-(甲基氨甲基)苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(4-(氨甲基)苯甲酰)-D-2Nal-D-Phe-Lys-NH2
H-His-Ala-D-2Nal-D-Phe-Lys-NH2
4-(H-Ala-His-D-2Nal-D-Phe-NH)丁胺
3-(H-Ala-His-D-2Nal-D-Phe-NH)丙胺
(3-(二甲基氨甲基)苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(3-氨基-3-甲基丁酰基)-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-hPhe-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)ψ(CH2NH)D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-hPhe-Lys-NH2
(3-氨基-3-甲基丁酰基)-His-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-N-Bzl-Gly-Lys-NH2
(2S)-(3-氨甲基苯甲酰)ψ(CH2NH)-D-2Nal-D-Phe-NH)-6-氨基己醇
(2S)((3-氨甲基苯甲酰)-D-2Nal-D-Phe-NH)-6-氨基己醇
(3-氨甲基苯甲酰)-D-2Nal-D-Thial-Lys-NH2
(2S)-(H-Aib-Hisψ(CH2NH)-D-2Nal-D-Phe-NH)-6-氨基己醇
(3-氨甲基苯甲酰)-D-2Nal-D-3Pyal-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe(4-F)-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe(4-OMe)-Lys-NH2
(2-氨甲基苯乙酰)-D-2Nal-D-Phe-Lys-NH2
(2-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
2-(H-Aib-His-D-2Nal-D-Phe-NH)-(4-吡啶基)乙烷
H-Aib-Phe-D-2Nal-D-Phe-Lys-NH2
2-(H-Aib-His-D-2Nal-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-(H-Aib-His-D-2Nal-D-Phe-NH)-(4-吡啶基)乙烷
H-Aib-Hisψ(CH2NH)-D-2Nal-D-Phe-Lys-OH
(3-氨甲基苯甲酰)-D-2Nal-N-Me-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-Gly-NH2
H-Aib-His-D-2Nal-D-Phe-Ala-NH2
H-Aib-His-D-2Nal-D-Phe-Orn-NH2
(5-氨甲基噻吩基)-2-羰基)-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-D-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-Dab-NH2
H-Aib-His-D-2Nal-D-Pheψ(CH2NH)-Lys-NH2
H-Aib-His-N-Me-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-N-Me-Lys-NH2
(3-氨甲基噻吩基-2-羰基)-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-N-Me-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Phe-Lys-N(Me)2
(3R)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(3S)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-1Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Trp-Lys-NH2
(糠基)-Aib-His-D-2Nal-D-Phe-Lys-NH2
(2-吡啶甲基)-Aib-His-D-2Nal-D-Phe-Lys-NH2
H-Aib-(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
H-Aib-3Pyal-D-2Nal-D-Phe-Lys-NH2
(3S)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(3R)-哌啶羰基-D-2Nal-D-Phe-Lys-NH2
(2-(H-Aib-His-D-2Nal-NH)乙基)苯
N，N-二(2R-羟丙基)-(3-氨甲基苯甲酰)-D-2Nal-D-Phe-Lys-NH2
(2R-羟丙基)-Aib-His-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Pheψ(CH2NH)Lys-NH2
(3-氨甲基苯甲酰)-N-Me-D-2Nal-D-Phe-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-D-Phe-N-Me-Lys-NH2
H-D-Thr-His-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-N-(苯乙基)-Gly-Lys-NH2
(3-氨甲基苯甲酰)-D-2Nal-N-(苯乙基)-Gly-Lys-NH2
H-Hyp-His-D-2Nal-D-Phe-Lys-NH2
H-Aib-His-N-Me-D-2Nal-N-(苯乙基)-Gly-Lys-NH2
H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH2
H-Aib-His-D-2Nal-D-Pheψ(CH2N(Me))-Lys-NH2
3-(H-Aib-His-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
2-(H-Aib-His-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
(3R)-哌啶羰基-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH2
3-((氨甲基苯甲酰)-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
2-(H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-(3R)-哌啶羰基-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-(3-氨甲基苯甲酰)-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
3-(H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
3-((3R)-哌啶羰基-N-Me-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
3-((3-氨甲基苯甲酰)-N-Me-D-2Nal-N-Me-D-Phe-NH)吗啉代丙烷
H-Aib-His-D-2Nal-N-Me-D-Phe-Hyp-NH2
2-((3-氨甲基苯甲酰)-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
2-((3R)哌啶羰基-D-2Nal-N-Me-D-Phe-NH)-(1-甲基-2-吡咯烷基)乙烷
H-Aib-His-D-2Nal-D-Phe-Lys-NH2
14.一种药用组合物，包括作为活性成分的通式I化合物或其可以药用的盐，以及可以药用的载体或稀释剂。
15.如权利要求14所述的单位剂形式的组合物，含有约10-约200mg的通式I的化合物或其可药用盐。
16.一种用于激发垂体释放生长激素的药用组合物，该组合物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。
17.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。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK143993A DK143993D0 (zh) | 1993-12-23 | 1993-12-23 | |
| DK1439/93 | 1993-12-23 | ||
| DK0121/94 | 1994-01-28 | ||
| DK12194 | 1994-01-28 | ||
| DK1191/94 | 1994-10-14 | ||
| DK119194 | 1994-10-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1138335A CN1138335A (zh) | 1996-12-18 |
| CN1052731C true CN1052731C (zh) | 2000-05-24 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| CN94194590A Expired - Fee Related CN1052731C (zh) | 1993-12-23 | 1994-12-22 | 具有生长激素释放特性的化合物 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US5767085A (zh) |
| EP (1) | EP0736039B1 (zh) |
| JP (1) | JP3181918B2 (zh) |
| KR (1) | KR100354897B1 (zh) |
| CN (1) | CN1052731C (zh) |
| AT (1) | ATE197158T1 (zh) |
| AU (1) | AU689181B2 (zh) |
| BR (1) | BR9408377A (zh) |
| CA (1) | CA2179597A1 (zh) |
| CZ (1) | CZ293113B6 (zh) |
| DE (1) | DE69426206T2 (zh) |
| DK (1) | DK0736039T3 (zh) |
| ES (1) | ES2153469T3 (zh) |
| FI (1) | FI962584A0 (zh) |
| GR (1) | GR3035150T3 (zh) |
| HU (1) | HU224345B1 (zh) |
| IL (1) | IL112112A (zh) |
| MX (1) | MX9500072A (zh) |
| NO (1) | NO315561B1 (zh) |
| NZ (1) | NZ277486A (zh) |
| PL (1) | PL181280B1 (zh) |
| PT (1) | PT736039E (zh) |
| RO (1) | RO115635B1 (zh) |
| SG (1) | SG55069A1 (zh) |
| SK (1) | SK281963B6 (zh) |
| UA (1) | UA42747C2 (zh) |
| WO (1) | WO1995017423A1 (zh) |
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- 1994-12-22 JP JP51710995A patent/JP3181918B2/ja not_active Expired - Lifetime
- 1994-12-22 DK DK95903774T patent/DK0736039T3/da active
- 1994-12-22 SK SK820-96A patent/SK281963B6/sk unknown
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- 1994-12-22 CZ CZ19961834A patent/CZ293113B6/cs not_active IP Right Cessation
- 1994-12-22 AT AT95903774T patent/ATE197158T1/de not_active IP Right Cessation
- 1994-12-22 CN CN94194590A patent/CN1052731C/zh not_active Expired - Fee Related
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- 1994-12-22 HU HU9501947A patent/HU224345B1/hu not_active IP Right Cessation
- 1994-12-22 AU AU12724/95A patent/AU689181B2/en not_active Ceased
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- 1994-12-22 EP EP95903774A patent/EP0736039B1/en not_active Expired - Lifetime
- 1994-12-22 RO RO96-01293A patent/RO115635B1/ro unknown
- 1994-12-22 UA UA96062486A patent/UA42747C2/uk unknown
- 1994-12-22 US US08/448,623 patent/US5767085A/en not_active Expired - Lifetime
- 1994-12-22 KR KR1019960703336A patent/KR100354897B1/ko not_active IP Right Cessation
- 1994-12-22 PL PL94315113A patent/PL181280B1/pl not_active IP Right Cessation
- 1994-12-22 WO PCT/DK1994/000485 patent/WO1995017423A1/en active IP Right Grant
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