CN101168560B - N-取代肽酰胺，其药物组合物与用途 - Google Patents
N-取代肽酰胺，其药物组合物与用途 Download PDFInfo
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Abstract
本发明公开了一类新的肽酰胺化合物，这类化合物的制备方法，含有它们的药物组合物以及这类化合物在预防和/或治疗与免疫功能低下相关的疾患中的应用。
Description
技术领域
本发明为一类新的促进免疫功能、免疫双向调节的N-取代肽酰胺，涉及肽及有机小分子领域。
背景技术
文献报导及各国大量临床实践证明TP-5具有免疫双向调节功能。可诱导和促进人体的T淋巴细胞及其亚群分化、成熟和活化；调节T淋巴细胞的比例，使CD4 +/CD8 +趋于正常；增加多种淋巴因子，如a.、r干扰素、白介素2和白介素3的分泌；增强NK细胞活力等。但是TP-5在体内代谢太快，半衰期仅为此30秒的缺点
发明内容
针对现有技术中TP-5在体内代谢快，半衰期仅为此30秒的缺点，本发明提供一种新的促进免疫功能、免疫双向调节的N-取代肽酰胺。
为解决本发明的技术问题，采用如下的技术方案：
在Asp3及Val4处换成非天然结构的Ida及β-Ala；
在C末端引入不同取代的酰胺结构；
在Tyr5的羧基端引入Aca-Phe-Met片段；
使TP-5双链化。
本发明化合物的结构通式为：
R1-X1-X2-X3-X4-Tyr-R2
其中精氨酰、缬氨酰及酪氨酰保持不变。而原TP-5分子中的赖氨酰及天冬氨酰在多数改造物中也保持不变，只在个别的合成物中有所改变。详见下列描述：
X1选自精氨酰(Arg)，赖氨酰(Lys)、胍-硝基精氨酰(Arg(NO2))；
X2选自赖氨酰(Lys)，精氨酰(Arg)，N-甲基甘氨酰(Sar)、D-丙氨酰(D-Ala)；
X3选自天冬氨酰(Asp)，谷氨酰(Glu)、亚氨基二乙酸单酰(Ida)；
X4选自缬氨酰(Val)，亮氨酰(Leu)、β-丙氨酰(β-Ala)，Cys；
R1选自H、Cys；
R2选自NH2，NHMe，NHEt，NHBu，NH(CH2)2OH(Gol)，NH(CH2)2NH(CH2)2OH，NHC(CH3)2CH2OH、Aca-Phe-Met-R/[R/选自NHEt，Gol，NH(CH2)2NH(CH2)2OH及NHC(CH3)2CH2OH]、Lys-NHR (R＝H，C1～10烷基)。
根据本发明还提供了制备本发明化合物的方法。首先采用经典的固相肽合成策略，以氯甲基树脂(取代度：1mmol/g，交联度：1％，颗粒度：100-200目)为固相载体，经逐步法完成目标序列的组装。
缩合剂为N-羟基苯并三唑(HOBt)与二环己基碳二亚胺(DCC)的等摩尔混合物，或O-苯并三唑-N，N，N′，N′-四甲基六氟膦鎓盐(HBTU)与HOBt及NMM(N-甲基吗啉)的等摩尔混合物。每步缩合后均用茚三酮颜色反应监测缩合程度。
其中Tyr、Val及Arg均用Boc保护a-氨基，另二个氨基酸的保护形式为：Fmoc-Lys(Boc)-OH及Fmoc-Asp(OtBu)-OH。
Boc及tBu保护基由3.5N HCl/HOAc脱除，Fmoc保护基用20％哌啶/DMF脱除。
肽链序列组装完成后分别用不同的胺化合物进行氨解，完成从固相载体上释放出肽酰胺产物。粗产物经C-18快速滤层及溶剂重结晶(或重沉淀)进行纯化。全部终产物均经ESI-MS分析证明结构。
本发明因此还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是 水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.1-100mg/Kg体重，更优选为1-60mg/Kg体重，最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
药理实验证明本发明的化合物可以预防和/或治疗与免疫功能低下相关的疾患，如慢性乙型肝炎、各种原发性或继发性T细胞缺陷(如儿童先天性免疫缺陷病)、各种细胞免疫功能低下疾病(如重症病毒性肝炎、重度上呼吸道感染、顽固性口腔溃疡等)、肿瘤患者及HIV感染者的辅助治疗等方面的药物或配方组份。
本发明优点
本发明的化合物羧基末端的各种取代酰胺结构克服了TP-5原结构不能对抗羧肽酶降解的缺点，免除了体内羧肽酶对改造物的降解作用，因而提高了这类小肽化合物在体内的稳定性。
在C-末端引入三肽段及TP-5主链的双链化增加了分子量延缓在体内被清除的速度。
本发明的生物活性实验证明我们的改造物促进T细胞转移的活性比TP-5有明显提高，表明是一类很好的免疫调节剂。
在制备方法上简便可行，成本低廉。
此类化合物可望在临床上用于多种免疫缺陷病症的预防与治疗药物
总之，本发明的肽化合物具有更强的生物稳定性及免疫调节活性。
术语：
原料中保护基缩写及试剂、溶剂的缩写分别为：
Boc：叔丁氧羰酰，
Fmoc：芴甲氧羰酰，
tBu：叔丁基，
Aca：ω-氨基己酸，
Ida：亚氨基二乙酸单酰，
Gol：甘氨醇，
DMF：二甲基甲酰胺，
DCM：二氯甲烷，
THF：四氢呋喃，
TEA：三乙胺，
HOAc：乙酸
Arg：精氨酰，
Lys：赖氨酰，
Arg(NO2)：胍-硝基精氨酰，
Sar：N-甲基甘氨酰，
D-Ala：D-丙氨酰，
Asp：天冬氨酰，
Glu：谷氨酰，
Ida：亚氨基二乙酸单酰，
Val：缬氨酰，
Leu：亮氨酰，
β-Ala：β-丙氨酰
具体实施方式
下面的实施例进一步说明本发明，但不以任何方式限制本发明。
实施例1
H-Arg-Lys-Asp-Val-Tyr-Gol·2HCl(I)的合成
首先采用经典的固相肽合成策略，以氯甲基树脂(取代度：1mmol/g，交联度：1％，颗粒度：100-200目)为固相载体，经逐步法完成目标序列的组装。其中Tyr、Val及Arg均用Boc保护a-氨基，另二个氨基酸的保护形式为：Fmoc-Lys(Boc)-OH及Fmoc-Asp(OtBu)-OH。每步缩合后均用茚三酮颜色反应监测缩合程度。全部缩合完成后，用氨基乙醇(Gol)/H2O/DMF(2∶1∶3，v/v)溶液与全保护的肽树脂混合摇动30h。收集到的滤液与适当体积的蒸馏水混合，然后在减压下通过C-18滤层，全部过滤后再用适量体积的蒸馏水分次淋洗C-18滤层(除去过量的Gol及DMF)。抽干后用无水乙醚淋洗。最后用HOAc-EtOH(1∶2，v/v)洗脱产物，收集的滤液经减压浓缩得固体残留物。后者经EtOAc-石油醚研磨得粉状产物。后者经3.5N HCl/HOAc脱除Boc及tBu保护基，浓缩后经Et2O研磨得终产物I，
总收率为88.7％，
其结构由ESI-MS分析证明，分子峰为723.4(M+H)。
合成路线如下：
实施例2
H-Arg-Lys-Asp-Val-Tyr-NH(CH2)2NH(CH2)2OH·2HCl(II)的合成肽链序列的固相合成与实施例I相同，取不同在于，氨解用H2N(CH2)2NH(CH2)2OH为胺组分。
其他具体反应条件与实施例I亦同。
II的收率为87.5％，
其ESI-MS的分析结果为766.3(M+H)。
实施例3
H-Arg-Lys-Asp-βAla-Tyr-NHEt(III)的合成
肽链序列的固相合成中，C-端第二位用Boc-β-Ala-OH代替原来的Boc-Val-OH，其余条件与实施例I均同。另外，与实施例I的又一区别是在氨解前先行脱除Boc及tBu保护基，氨解后即得到游离产物IIIi：
III的收率为93.6％，其ESI-MS的结果为：679.4(M+H)。
实施例4
H-Arg-Lys-Ida-Val-Tyr-NHEt(IV)的合成及生物活性
固相合成条件及氨解条件与实施3相同。
IV 的收率为91.9％，
其ESI-MS的分析结果为707.4(M+H)。
实施例5
H-Arg-Lys-Asp-β-Ala-Tyr-Aca-Phe-Met-NHEt(V)的合成
固相合成、氨解条件及后处理与实施例3相同，
V的收率为78.7％，
其ESI-MS结果为1071.6(M+H)。
实施例6
H-Arg-Lys-Asp-β-Ala-Tyr-Aca-Phe-Met-NHCH(CH3)2(VI)的合成固相合成、氨解条件及后处理与实施例5相同，
VI的收率为75.3％，
ESI-MS结果为1084.6(M+H)。
实施例7
H-Lys-Arg-Asp-Val-Tyr-NHEt(VII)的合成及生物活性
固相合成、氨解条件及后处理与实施例3相同，
VII的收率为88.2％，
ESI-MS结果为707.5(M+H)。
实施例8
H-Lys-Arg-Ida-Val-Tyr-NHCH3(VIII)的合成及生物活性
此合成全部采用Boc保护的氨基酸，其缩合反应及氨解反应与实施例7相同。
VIII的收率为76.3％，
ESI-MS结果为693.4(M+H)。
实施例9
此合成首先用Boc-Lys(Boc)-OH在K2CO3及KI催化下与氯甲基树脂键合。脱除赖氨酰上的两个Boc保护基后进行双键平行的TP-5序列组装。反应条件与实施例1相同。乙胺解条件与实施例3相同。合成路线如下：
产物IX的收率为90.1％，
其ESI-MS的结果为1482.8(M+H)。
实施例10
固相肽合成条件与实施例9相同，最后一步半胱氨酸的缩合以Boc-Cys(Acm)-OH为原料。缩合完成后用I2/HOAc-DMF条件脱除Acm保护基，并完成二硫键的键合。氨解条件与实施例3相同，合成路线如下：
产物X的收率为89.3％，
其ESI-MS的结果为1630.7(M+H)。
药理实验
本发明的肽产物对T淋巴细胞转化的影响等活性按如下方法测定：
1、体外实验
取BALB/c小鼠10只，按常规方法，无菌取小鼠脾脏，剪碎研磨，过200目钢网，无血清1640培养液洗一次，1500rpm离心5分钟。采用双蒸双盐方法破坏红细胞，并除去脂肪组织，再次离心。细胞沉淀即为白细胞，用完全1640培养液调细胞浓度为5*106/ml100μl/孔，种于96孔板，同时加ConA(终浓度5μg/ml)或LPS(终浓度5μg/ml)，样品10μl/孔。另设空白对照孔(未加诱导剂)，阴性对照孔(加诱导剂
但未加样品)，37℃、5％CO2孵育72h，培养结束前4h，加MTT100μl(终浓度5μg/ml)，培养结束后，测定540nm OD值，并按下列公式计算淋巴细胞转化率。
体外实验结果如表1所示：
表1 部分合成肽对T淋巴细胞转化的影响
实验例2、体内实验
取BALB/c小鼠80只，分为正常对照组、模型(环磷酰胺)对照组、阳性(TP-5，0.22μmol/kg)对照组及各种N-取代肽酰胺(0.22μmol/kg)实验组。除正常组外，其余各组均用环磷酰胺100mg/Kg腹腔注射造模。造模次日开始给药，腹腔注射给药，每只0.2ml。连续7天，末次给药后次日，称体重，无菌取小鼠脾测T/B淋巴细胞转化率，取胸腺和脾脏称重，采血进行白细胞计数。具体的操作如下：
(1)对胸腺和脾脏重量的影响
取小鼠胸腺和脾脏，并与体重做比较，计算胸腺指数和脾脏指数
(2)对T/B淋巴细胞转化的影响
按常规方法，无菌取小鼠脾脏，剪碎研磨，过200目钢网，无血清1640洗一次，1500rpm离心5分钟。采用双蒸双盐方法破坏红细胞，并除去脂肪组织，再次离心。细胞沉淀即为白细胞，用完全1640培养液调细胞浓度为5*106/ml100μl/孔，种于96孔板，同时加Con A(终浓度5μg/ml)或LPS(终浓度5μg/ml)，100μl/孔。另设空白对照孔(未加诱导剂)，37℃、5％CO2孵育72h，培养结束前4h，加MTT100μl(终浓度5μg/ml)，培养结束后，测定540nm OD值，并按下列公式计算淋巴细胞刺激指数。
刺激指数＝实验孔OD值/对照孔OD值
(3)对白细胞计数的影响
采抗凝血，与白细胞计数仪上记血中白细胞数。
(4)统计：实验数据以 
表示，组间比较采用t检验。
体内实验结果如表2所示：
表2 部分合成肽(剂量：0.22μmol/kg)的体内活性
*P＜0.05，**P＜0.01
从体外、体内的实验结果可以看出，对TP-5分子内的Arg与Lys两残基进行互换，不影响原活性；用非天然的氨基酸Ida代替TP-5中的Val后仍能保持原有活性。由于Ida不是蛋白源性氨基酸，在体内可有效对抗蛋白酶的降解，因此本发明中含Ida结构的肽化合物可望具有更强的生物稳定性及免疫调节活性。
Claims (3)
1.一类化合物，其特征在于，选自如下群组：
H-Arg-Lys-Asp-Val-Tyr-Gol
H-Arg-Lys-Ida-Val-Tyr-NHEt
H-Lys-Arg-Asp-Val-Tyr-NHEt
H-Lys-Arg-Ida-Val-Tyr-NHCH3。
2.一种药物组合物，其特征在于含有药物有效剂量的如权利要求1所述的任一化合物及药用载体，所述的药物组合物是注射剂。
3.权利要求1中任一化合物在制备预防和/或治疗与免疫功能低下相关的疾患药物中的应用，其特征在于所述的免疫功能低下相关的疾患包括慢性乙型肝炎、原发性或继发性T细胞缺陷病、病毒性肝炎、呼吸道重度感染、顽固性口腔溃疡、术后虚弱、肿瘤及爱滋。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4298523A (en) * | 1980-06-17 | 1981-11-03 | Ortho Pharmaceutical Corporation | Methods and compositions for preparation of H-ARG-X-Z-Y-TYR-R |
| US4420424A (en) * | 1979-09-22 | 1983-12-13 | Hoechst Aktiengesellschaft | New peptides and a process for their preparation |
| US4505853A (en) * | 1983-11-18 | 1985-03-19 | Ortho Pharmaceutical Corporation | Enzyme-resistant immunomodulatory peptides |
| EP0166612A2 (en) * | 1984-06-27 | 1986-01-02 | Ortho Pharmaceutical Corporation | Potent thymopentin analogs |
-
2006
- 2006-10-23 CN CN200610113970A patent/CN101168560B/zh not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4420424A (en) * | 1979-09-22 | 1983-12-13 | Hoechst Aktiengesellschaft | New peptides and a process for their preparation |
| US4298523A (en) * | 1980-06-17 | 1981-11-03 | Ortho Pharmaceutical Corporation | Methods and compositions for preparation of H-ARG-X-Z-Y-TYR-R |
| US4505853A (en) * | 1983-11-18 | 1985-03-19 | Ortho Pharmaceutical Corporation | Enzyme-resistant immunomodulatory peptides |
| EP0166612A2 (en) * | 1984-06-27 | 1986-01-02 | Ortho Pharmaceutical Corporation | Potent thymopentin analogs |
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