CN106414479B - 作为催产素激动剂的肽 - Google Patents
作为催产素激动剂的肽 Download PDFInfo
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- CN106414479B CN106414479B CN201580027370.7A CN201580027370A CN106414479B CN 106414479 B CN106414479 B CN 106414479B CN 201580027370 A CN201580027370 A CN 201580027370A CN 106414479 B CN106414479 B CN 106414479B
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Abstract
本发明涉及式(I)的化合物，其中R1是氢、低级烷基或环烷基；R2是氢或R1和R2可以与它们连接的N和C原子一起形成任选地被一个或两个F原子或被羟基取代的吡咯烷环，或可以形成氮杂环丁烷或哌嗪环；R3是氢、低级烷基、被羟基取代的低级烷基、‑(CH2)2C(O)NH2、苄基、苯基、‑CH2‑五元芳族杂环基、CH2‑吲哚基、‑CH2‑环烷基、环烷基或‑(CH2)2‑S‑低级烷基；R3’是氢或低级烷基；或X是‑C(O)‑CHR4‑CHR4’‑C(O)‑NH‑CH2‑R4/R4’是氢或R4或R4’之一是氨基：o是0或1；或涉及其药用酸加成盐、外消旋混合物或其相应对映异构体和/或光学异构体。已经发现，本发明的化合物是催产素受体激动剂，用于治疗孤独症，精神紧张，包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症，精神分裂症，精神障碍和记忆丧失，酒精戒断，药物成瘾和用于治疗普拉德‑威利综合征。
Description
本发明涉及式I的化合物
其中
R1是氢、低级烷基或环烷基；
R2是氢或
R1和R2可以与它们连接的N和C原子一起形成任选地被一个或两个F原子或被羟基取代的吡咯烷环，或可以形成氮杂环丁烷或哌嗪环；
R3是氢、低级烷基、被羟基取代的低级烷基、-(CH2)2C(O)NH2、苄基、苯基、-CH2-五元芳族杂环基、CH2-吲哚基、-CH2-环烷基、环烷基或-(CH2)2-S-低级烷基；
R3’是氢或低级烷基；或
X是–C(O)-CHR4-CHR4’-C(O)-NH-CH2-
R4/R4’是氢或R4或R4’之一是氨基:
o是0或1；
或其药用酸加成盐、外消旋混合物或它们的相应对映异构体和/或光学异构体。
已经发现，本发明的化合物是催产素(oxytocin)受体激动剂，该化合物是保留催产素生物活性的催产素类似物。这种类似物分子能够以类似于内源性催产素的方式作用，包括结合催产素受体。催产素的类似物具有全新的分子结构。
催产素是九氨基酸环肽激素，具有在位置1和6之间形成二硫键的两个半胱氨酸残基。人催产素包含序列Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly。
肽已经作为商业相关类型的药物出现，相对传统小分子药物，其提供更好特异性和效力以及更低毒性性质的优势。它们为很多疾病提供有希望的治疗选择，比如糖尿病、HIV、肝炎、癌症等，并且医生和患者变得更接受基于肽的药物。本发明涉及肽催产素受体激动剂，其还包括天然激素催产素和卡贝缩宫素(carbetocin)。
催产素是有效的子宫收缩剂，用于控制宫缩无力和失血过多，临床上用以引起分娩，并且已经显示促进泌乳的开始和维持(Gimpl等人，Physiol.Rev.，81，(2001)，629–683，Ruis等人,BMJ，283，(1981)，340–342)。卡贝缩宫素(1-脱氨基-1-卡巴(carba)-2-酪氨酸(O-甲基)-催产素)也是有效的子宫收缩剂，临床上用于控制宫缩无力和失血过多。
肽类催产素激动剂可以用于治疗普拉德-威利综合征(Prader-Willi Syndrom)，其是在25.000个儿童中影响一个的罕见遗传病。
进一步研究表明，催产素激动剂可用于治疗炎症和疼痛，包括腹部和背部疼痛(Yang，Spine，19，1994，867-71)，男性性功能障碍(Lidberg等人，Pharmakopsychiat.，10，1977，21–25)和女性性功能障碍(Anderson-Hunt，等人，BMJ，309，1994，929)，肠易激综合征(IBS，Louvel等人，Gut，39，1996，741–47)，便秘和胃肠道梗阻(Ohlsson等人，Neurogastroenterol.Motil.，17，2005，697–704)，孤独症(Hollander等人，Neuropsychopharm.，28，2008，193–98)，精神紧张，包括创伤后精神紧张性障碍(PTSD)(Pitman等人，Psychiatry Research，48，107–117)，焦虑，包括焦虑症和抑郁症(Kirsch等人，J.Neurosci.，25，49，11489–93，Waldherr等人，PNAS，104，2007，16681–84)，手术失血或产后出血的控制(Fujimoto等人，Acta Obstet.Gynecol.，85，2006，1310-14)，引产和维持(Flamm等人，Obstet.Gynecol.，70，1987，70–12)，伤口愈合和感染，乳腺炎和胎盘娩出，以及骨质疏松症。此外，催产素激动剂可以用于诊断癌症和胎盘机能不全。
此外，论文“Intranasal Oxytocin blocks alcohol withdrawal in humansubjects”(Alcohol Clin Exp Res，Vol，No.2012)和“Breaking the loop：Oxytocin as apotential treatment for drug addiction”(Hormones and Behavior，61，2012，331-339)建议用催产素激动剂治疗酒精戒断(alcohol withdrawel)和药物成瘾。
催产素和其受体存在于精神分裂症的症状密切相关的脑区域中，比如伏隔核和海马。催产素受体激动剂可以用于治疗孤独症，精神紧张(stress)，包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症，精神分裂症，阿尔茨海默病，精神障碍，记忆丧失和代谢性疾病(WO2012/016229)。
本发明的目标是式I的新化合物和式I的化合物和其药用盐用于治疗与催产素受体相关的CNS疾病的用途，所述疾病是孤独症，精神紧张，包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症，精神分裂症，精神障碍和记忆丧失，酒精戒断，药物成瘾和用于治疗普拉德-威利综合征。
进一步的目标是制备式I的新化合物和含有它们的药物。
本发明可以提供选择性的，有效的化合物，在某些CNS疾病包括孤独症，精神紧张，包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症，精神分裂症，精神障碍和记忆丧失，酒精戒断，药物成瘾的治疗方面和普拉德-威利综合征的治疗方面提供替代和/或改善。
已经显示，目前的肽对后叶加压素受体V1a和V2具有非常好的选择性，如表中所示。这对于用作药物以避免副作用可以具有较大优势。在旨在治疗中枢神经系统疾病的情况下，这些生理效果可以被认为是不希望的副作用。因此，希望的是获得相对于后叶加压素受体对催产素受体有选择性的药物。
如本文中使用的，术语“低级烷基”表示含有1至7个碳原子的饱和直链或支链基团，例如，甲基，乙基，丙基，异丙基，正丁基，异丁基，2-丁基，叔丁基等。
术语“被羟基取代的低级烷基”表示如上文所定义的低级烷基，其中至少一个氢原子被羟基替代。
术语“环烷基”表示含有3至6个碳原子的环烷基链。
如本文使用的，术语“五元芳族杂环基团”表示咪唑基，噻吩基，呋喃基，吡咯基，吡唑基，
唑基，
二唑基或异
唑基。
术语“药用酸加成盐”包括与无机或有机酸的盐，比如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等。
优选的五元杂环是咪唑环。
优选的是式I的化合物，其中o是0。
其他实施方案是式I的化合物，其中R1是甲基或环丙基。
其他实施方案是式I的化合物，其中R1和R2可以与它们连接的N和C原子一起形成吡咯烷环。
已经制备了以下具体化合物并且测试了它们对催产素受体的激动活性：
通过使用Fmoc和Boc方法的固相肽化学中的标准方法合成本文中的化合物。手工进行的反应在室温进行，而微波辅助的肽合成在升高的温度进行。
一般合成描述：
环肽可以通过珠上(on-bead)环化(烯丙基/烯丙基氧羰基(Aloc)策略方法A)或通过溶液相环化以完全脱保护的线性肽(方法B)产生。
参考例如：Kates和Albericio编辑，“Solid Phase Synthesis：A practicalguide”，Marcel Decker，New York，Basel，2000，手工或使用微波技术通过现有固相合成方案(Fmoc-化学)合成线性肽。作为固相载体，使用TentaGel-S-RAM树脂(0.24meq/g)。在用HOBT/HBTU 1：1(0.5mol/L于DMF中)和4当量的DIPEA(2mol/L于NMP中)活化之后，所有Fmoc-氨基酸以4-倍过量加入。用DMF中的20％哌啶实现Fmoc-切割。
烯丙基/烯丙基氧羰基-切割和内酰胺-环化:
方法A:将树脂连接的肽手工用20当量苯基硅烷在DCM中的溶液和0.05当量的四三苯基膦钯在RT处理30min。重复该步骤。将树脂用0.5％的二硫代氨基甲酸钠在DMF中的溶液洗涤。对于珠上内酰胺形成，再次将活化剂加入至树脂并且在RT振荡另外8h。通过茚三酮试验验证环化完成。
方法B:在脱保护和从树脂切割以及标准后处理后，将肽在溶液中环化。将粗制肽用DMF中的标准肽活化剂处理。通过HPLC监测环化。
切割和后处理:
将三氟乙酸、三异丙基硅烷和水(95/2.5/2.5)的切割-混合物加入至树脂并且在RT振荡1h。将切割的肽在冷乙醚(-18℃)中沉淀。将肽离心并且将残留物用冷乙醚洗涤两次。将残留物再次溶解在水/乙腈中并冻干。
纯化：
使用反相高效液相色谱(RP-HPLC)纯化肽，使用Reprospher 100C18-T柱(100x4.6mm，5u粒径)作为固定相和水/乙腈作为洗脱剂(1-50％MeCN梯度，历时30min)。收集级分并且通过LC/MS分析。将纯产物样品合并并冻干。获得所有肽，为白色粉末，纯度>85％。通过质谱获得产品鉴定。
所有标准氨基酸购自CEM。Fmoc-SAR-OH和Fmoc-N-环丙基-甘氨酸分别购自Bachem和Enamine。琥珀酸单叔丁酯来自Sigma-Aldrich
琥珀酸单烯丙酯的合成:
将46mmol的4-叔丁氧基-4-氧代丁酸(Sigma-Aldrich)在70ml THF和92mmolDIPEA中的溶液在0℃冷却。现在将55mmol的3-碘丙-1-烯(Fluka)在6ml THF中的溶液逐滴加入并且加温至室温并且搅拌过夜。将反应混合物用碳酸氢盐水溶液萃取，经硫酸钠干燥并将溶剂蒸发。获得3.7g的棕色油状物。经Kieselgel色谱纯化粗制材料，获得3.4g二酯。将中间体溶解在10ml DCM中并且在室温加入5ml的TFA并搅拌过夜。将溶剂和TFA蒸发，获得1.6g终产物。
提供实施例1的合成详细描述，以进一步说明合成条件：
肽合成：
使用CEM微波技术，以每个氨基酸5分钟的偶联时间在升高的温度(78℃)并且以0.25mmol的规模合成肽。使用TentalGel-S RAM树脂作为固体载体(0.24meq/g)进行合成。将所有使用的氨基酸溶解在DMF中至0.2mol浓度。使用HOBT/HBTU 1：1(0.5mol/L)4当量和DIPEA 4当量的混合物活化氨基酸。用DMF中的哌啶(20％)实现Fmoc-切割3min。重复Fmoc-切割。
烯丙基氧羰基-&烯丙基-切割：
用20当量苯基硅烷和0.05当量的四三苯基膦钯在DCM(5ml)中的溶液在RT手工处理树脂30min。重复该步骤。将树脂用0.5％二硫代氨基甲酸钠在DMF中的溶液洗涤两次。用DCM重复洗涤步骤。
珠上环化(方法A)：
再次将偶联试剂(4ml的0.5mol/L溶液HOBT/HBTU(1：1)和1ml的DMF中的DIPEA(4当量)加入至树脂。将浆在RT振荡约8h。将树脂用DMF和DCM洗涤两次。通过茚三酮试验验证环化的完成。
从树脂切割：
将10ml的切割-混合物(TFA；TIS；水(95/2.5/2.5))加入至树脂并且在RT振荡1h。将切割的肽在冷乙醚(-18℃)中沉淀。将肽离心并且将沉淀用冷乙醚洗涤两次。将沉淀溶解在H2O/乙腈中并且冻干，获得210mg白色粉末。
所有其他类似物基于使用珠下(off-bead)环化策略的方法B产生。
珠下环化策略(方法B):
将粗制肽溶解在DMF(15ml)中。加入DMF中的1当量的偶联剂PyaOP(0.5mol/L)和NMP中的DIPEA(2mol/l)。将反应混合物在室温搅拌1h。反应完成(LCMS控制)后，将DMF含量浓缩至约2ml。将残留物在冷的(-18℃)二乙醚(40ml)中沉淀。将肽离心并且将沉淀用冷的乙醚洗涤。
纯化：
将粗制肽通过制备型HPLC在Reprospher 100C18-T柱(100x 4.6mm，5um粒径)上纯化。作为洗脱系统，在0-30min内以0-50％乙腈梯度使用0.1％TFA/水/乙腈的混合物。收集级分并且通过分析型HPLC检查。将含有纯产物的级分合并并冻干。获得7.2mg白色粉末。
相应合成下文列出的所有其他肽。
缩写:
Fmoc:9-芴基甲氧基羰基
tBu:叔丁基
Gly:甘氨酸
Phe:苯丙氨酸
Cha:环己基丙氨酸
Chg:环己基甘氨酸
CyclopropGly:N-环丙基甘氨酸
Sar:肌氨酸
Ile:异亮氨酸
Leu:亮氨酸
Nle:正亮氨酸
Nva:正缬氨酸
Aib:氨基异丁酸
Pro:脯氨酸
Ala:丙氨酸
Val:缬氨酸
homoVal:高缬氨酸
MeVal:L-α-甲基-缬氨酸
His(Trt):侧链保护的(三苯甲基)组氨酸
Asn(Trt):侧链保护的(三苯甲基)天冬酰胺
Gln(Trt):侧链保护的(三苯甲基)谷氨酰胺
Ser(tBu):侧链保护的(叔丁基)丝氨酸
Tyr(tBu):侧链保护的(tBu)酪氨酸
Thr(tBu):侧链保护的(tBu)苏氨酸
HOBT:N-羟基苯并三唑
COMU:1-[(1-(氰基-2-乙氧基-2-氧代亚乙基氨基氧基)二甲基氨基吗啉代)]脲
六氟磷酸盐
PyoAP:(7-氮杂苯并三唑-1-基氧基)三吡咯烷子基-
六氟磷酸盐
HBTU：O-苯并三唑-N,N,N′,N′-四甲基-脲
-六氟磷酸盐
DMF：N,N-二甲基甲酰胺
NMP：N-甲基吡咯烷酮
DIPEA：N,N-二异丙基胺
DCM：二氯甲烷
MeCN：乙腈
实施例1
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Leu-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期971.1；观察到971.2
实施例2
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Leu-OH，Fmoc-Sar-OH，Fmoc-Dap(Aloc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和Fmoc-Asp(烯丙基)-OH。MS(M+H+):预期960.0；观察到960.8
实施例3
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Leu-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期945.0；观察到945.5
实施例4
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Leu-OH，Fmoc-SAR-OH，Fmoc-Dap(Aloc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH，Fmoc-D-AspO烯丙基。MS(M+H+):预期960.0；观察到960.8
实施例5
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Val-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期931.0；观察到931.1
实施例6
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Nva-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期945.0；观察到945.2
实施例7
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-MeVal-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期985.0；观察到985.2
实施例8
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Met-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期989.1；观察到989.5
实施例9
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Ile-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期971.0；观察到971.5
实施例10
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Thr(tBu)-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期959.0；观察到959.5
实施例11
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Ser(tBu)-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期945.0；观察到945.5
实施例12
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Val-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期957.0；观察到957.6
实施例13
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Gln(Trt)-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期986.0；观察到986.5
实施例14
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-PheOH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期1005.0；观察到1006.8
实施例15
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-His(Trt)OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期995.0；观察到996.7
实施例16
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Trp(Boc)-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期1044.10；观察到1045.4
实施例17
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Nva-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期957.0；观察到957.5
实施例18
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Cha-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期1011.1；观察到1011.5
实施例19
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Phg-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期991.0；观察到991.5
实施例20
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Chg-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期997.0；观察到997.5
实施例21
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Thi-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期1011.1；观察到1011.4
实施例22
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-homoLeu-OH，Fmoc-Pro-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期985.1；观察到985.5
实施例23
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-MeLeu-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期959.0；观察到959.5
实施例24
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Chg-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期971.0；观察到971.2
实施例25
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-homoLeu-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期959.0；观察到959.1
实施例26
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Met-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期963.1；观察到963.6
实施例27
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Nva-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期931.0；观察到931.5
实施例28
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Ile-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期945.0；观察到945.5
实施例29
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Thr(tBu)-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期933.0；观察到933.6
实施例30
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Ser(tBu)-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期919.0；观察到919.4
实施例31
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Cha-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期985.1；观察到985.6
实施例32
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Gln(Trt)-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期960.0；观察到960.8
实施例33
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Phe-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期979.0；观察到979.3
实施例34
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Thi-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期985.1；观察到985.6
实施例35
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-His(Trt)-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期969.0；观察到969.9
实施例36
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Trp(Boc)-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期1018.0；观察到1018.6
实施例37
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Phg-OH，Fmoc-Sar-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期965.0；观察到965.2
实施例38
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Leu-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期971.1；观察到971.8
实施例39
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-MeVal-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期985.1；观察到985.6
实施例40
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Val-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期957.0；观察到957.5
实施例41
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Aib-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期943.0；观察到943.5
实施例42
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Ile-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期971.1；观察到971.6
实施例43
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Chg-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期997.1；观察到997.6
实施例44
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Thr(tBu)-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期959.0；观察到959.5
实施例45
使用以下氨基酸:Fmoc-Gly-OH，Fmoc-Ser(tBu)-OH，Fmoc-CyclopropGly-OH，Fmoc-Dap(Boc)-OH，Fmoc-Asn(Trt)-OH，Fmoc-Gln(Trt)-OH，Fmoc-Ile-OH，Fmoc-Tyr(tBu)-OH和琥珀酸单叔丁酯。MS(M+H+):预期945.0；观察到945.5
材料和方法
细胞培养和稳定克隆制备
将中国仓鼠卵巢(CHO)细胞用编码人V1a、人催产素(OTR)或人V2受体的表达质粒转染，后者与嵌合Gqs5 G蛋白组合，以重新定向针对钙流的信号。通过有限稀释克隆稳定细胞，获得表达人V1a，人V2+Gqs5或人OTR受体的单克隆细胞系并且基于在检测受体活化后细胞中钙流的荧光成像平板读数器(FLIPR)上检测的功能性响应来选择。将稳定细胞系在含有10％胎牛血清(FBS)，1％青霉素-链霉素，1％L-谷氨酸盐，200ug/ml遗传霉素的F-12K营养混合物(Kaighns Modification)中，在37℃，在10％CO2培养箱中以95％湿度培养。
使用荧光成像(荧光成像平板读数器，FLIPR)的钙流测定
在测定之前的下午，将细胞以50,000个细胞/孔的密度铺在黑色96孔板中，所述96孔板具有清晰的底部，以允许从各个孔的底部检查细胞和测量荧光。细胞的密度足以在次日获得铺满的单层。对于各个实验，新鲜制备无酚红、含有20mM HEPES(pH 7.3)和2.5mM丙磺舒的Hanks平衡的盐溶液(测定缓冲液)。使用Beckman Biomek 2000实验室自动化工作站在含有1％DMSO的测定缓冲液中进行化合物稀释。染料-上样缓冲液由测定缓冲液中的终浓度2μM的Fluo-4-AM(溶解于DMSO和普流尼克酸(pluronic acid))组成。从孔中移除已有的培养基并且向每孔加入100μl的染料-上样缓冲液并且在37℃在5％CO2温箱中在95％湿度孵育大约60min。染料一加载完，在Embla细胞清洗器上将细胞用测定缓冲液彻底清洗，以去除任何未结合的染料。每孔精确地留下100μl测定缓冲液。
将每个含有染料加载的细胞的96孔板置于FLIPR机器中并且将激光强度设置到合适水平，以检测低的基底荧光。为了测试作为激动剂的化合物，将25μl稀释的化合物加入至平板，10秒进入荧光测量并且记录荧光响应5分钟。将荧光数据归一化为内源性完全激动剂剂量响应，对于最大响应设为100％并且对于最小设为0％。使用四参数逻辑方程用Microsoft Excel XLFit如下构建各个激动剂浓度-响应曲线：Y＝最小+((最大–最小)/(1+10(LogEC50-X)nH))，其中y是％归一化荧光，最小是最小y，最大是最大y，logEC50是产生最大引发荧光的50％的log10浓度，x是激动剂化合物浓度的log10并且H是曲线的斜率(希尔系数)。最大值以百分数给出激动剂测试化合物的功效。产生半数-最大响应的激动剂浓度由EC50值表示，其对数获得pEC50值。
可以与对于hV1a和hV2的比较数据一起，提供对于具体肽的以下EC50(nM)，和功效(％)：
式I化合物和式I化合物的药用盐可以用作药物，例如以药物制剂的形式用作药物。所述药物制剂可以优选经皮，鼻内，皮下或静脉内(iv)给药。
经皮是一种给药途径，其中活性成分跨皮肤递送用以系统分布。实例包括用于药物递送的经皮贴片，和用于医学或美学目的的经皮移植物。
经鼻给药可以用以递送药物而产生局部或系统性效应，用于局部效果的鼻喷雾非常常见。肽药物可以以鼻喷雾给药，以避免口服给药后的药物降解。
对于肽药物给药，皮下注射也是常见的。肌肉内注射是直接将物质注射入肌肉内。其是药物给药的多种替代方法的一种。其常用于特定形式的以小量给药的药物。该注射应该在皮肤下给予。
静脉内途径是直接将液体物质灌注到静脉中。与其它给药途径相比，静脉内途径是将流体和药物递送遍及身体的最快方式。
此外，所述药物制剂可以含有防腐剂、增溶剂、稳定剂、湿润剂、乳化剂、甜味剂、着色剂、香料、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其它治疗上有价值的物质。
含有式I化合物或其药用盐和治疗惰性载体的药物也是本发明的目标，作为其制备方法，所述方法包括将一种以上式I的化合物和/或药用酸加成盐和，如果需要，一种以上其它治疗上有价值的物质与一种以上治疗上惰性的载体纳入盖伦给药形式。
根据本发明的最优选的适应症是包括中枢神经系统疾病的那些，例如治疗或预防孤独症，精神紧张,包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症,精神分裂症，精神障碍和记忆丧失，酒精戒断，药物成瘾和用于治疗普拉德-威利综合征。
剂量可以在宽的限度内变化，并且当然在各个特定情况中必须被调整至个体需求。对于成人的剂量可以在每天约0.01mg至约1000mg的通式I的化合物或相应量的其药用盐之间变化。每日剂量可以以单个剂量施用或以分开的剂量施用，此外，当发现需要时，也可以超过上限。
Claims (6)
1.化合物，其中所述化合物是
或其药用酸加成盐，外消旋混合物或其相应对映异构体和/或光学异构体。
2.一种药物组合物，所述药物组合物包含根据权利要求1所述的化合物和药用载体和/或辅剂。
3.一种药物组合物，所述药物组合物包含根据权利要求1所述的化合物和药用载体和/或辅剂，所述药物组合物用于治疗孤独症，精神紧张，包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症，精神分裂症，精神障碍和记忆丧失，酒精戒断，药物成瘾和用于治疗普拉德-威利综合征。
4.根据权利要求1所述的化合物，所述化合物用作治疗活性物质。
5.根据权利要求1所述的化合物，所述化合物在以下疾病的治疗中用作治疗活性物质：孤独症，精神紧张，包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症，精神分裂症，精神障碍和记忆丧失，酒精戒断，药物成瘾和普拉德-威利综合征。
6.根据权利要求1所述的化合物用于制备药物的用途，所述药物用于治疗和/或预防性治疗孤独症，精神紧张，包括创伤后精神紧张性障碍，焦虑，包括焦虑症和抑郁症，精神分裂症，精神障碍和记忆丧失，酒精戒断，药物成瘾和用于治疗普拉德-威利综合征。
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| WO2020061414A1 (en) * | 2018-09-20 | 2020-03-26 | Levo Therapeutics, Inc. | Stable intranasal formulations of carbetocin |
| TW202034899A (zh) | 2018-09-20 | 2020-10-01 | 克里斯托弗 Ｓ 布萊恩特 | 卡貝縮宮素藥品及其製備方法 |
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| IL248553A0 (en) | 2016-12-29 |
| PH12016502232A1 (en) | 2017-01-09 |
| EA201692404A1 (ru) | 2017-05-31 |
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| SG11201610073PA (en) | 2016-12-29 |
| WO2015185467A1 (en) | 2015-12-10 |
| CA2949173A1 (en) | 2015-12-10 |
| CR20160563A (es) | 2017-01-06 |
| JP6412170B2 (ja) | 2018-10-24 |
| JP2017518311A (ja) | 2017-07-06 |
| CN106414479A (zh) | 2017-02-15 |
| EP3151849B1 (en) | 2018-10-10 |
| US9957298B2 (en) | 2018-05-01 |
| US20170081369A1 (en) | 2017-03-23 |
| KR20170004013A (ko) | 2017-01-10 |
| MX2016015873A (es) | 2017-03-27 |
| CL2016003095A1 (es) | 2017-06-16 |
| EA030091B1 (ru) | 2018-06-29 |
| EP3151849A1 (en) | 2017-04-12 |
| PE20161559A1 (es) | 2017-01-12 |
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