CN112154139B - 用于降低眼压的前列腺素F2α衍生物 - Google Patents
用于降低眼压的前列腺素F2α衍生物 Download PDFInfo
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- CN112154139B CN112154139B CN201980032896.2A CN201980032896A CN112154139B CN 112154139 B CN112154139 B CN 112154139B CN 201980032896 A CN201980032896 A CN 201980032896A CN 112154139 B CN112154139 B CN 112154139B
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- 230000003076 paracrine Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- PXGPLTODNUVGFL-YNNPMVKQSA-N prostaglandin F2alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 description 1
- 102000017953 prostanoid receptors Human genes 0.000 description 1
- 108050007059 prostanoid receptors Proteins 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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Abstract
本发明涉及医药化学，尤其涉及新的生物活性化合物‑前列腺素F2α的酰胺衍生物。所述化合物具有低细胞毒性，并且能够刺激哺乳动物细胞中内源性氮氧化物的形成。这些化合物的合成促进了能够降低眼内压的前列腺素F2α的生物活性衍生物的生物活性扩展。
Description
本发明涉及临床化学，尤其涉及新的生物活性化合物-前列腺素F2α的酰胺衍生物。
前列腺素是通过环氧合酶(СΟX)从花生四烯酸在生物体中合成的多功能生物活性物质家族。这些氧化的脂肪酸是自分泌和旁分泌的脂质介体，其特征是具有广谱的生理活性，例如，扩张剂(支气管平滑肌)、收缩剂(胃肠道平滑肌)、抗凝集剂(血小板)，降血压或升血压活性的组合[Nicolau A.在：生物活性脂质(Eds.Nicolau A.,Kokotos J.)//布里奇沃特:油性出版社(Bridgewater:Oily Press),2004.–197p]。前列腺素F2α在有机体中的形成：在生物合成的第一阶段由环氧合酶引起的花生四烯酸氧化代谢，和第二阶段的还原酶形成[Smith W.L.，Marnett L.J.，DeWitt D.L.前列腺素和血栓烷的生物合成//药理学和治疗学Prostaglandin and thromboxane biosynthesis//Pharmacology&Therapeutics.1991，V.49(3)，P.153-179]。它是G蛋-白偶联受体FP内源性配体，其激活导致细胞内钙动员[Toh H，Ichikawa A，NarumiyaS.类花生酸受体的分子进化(Molecularevolution of receptors for eicosanoids)//FEBS Lett.1995，V.361，P.17-21]。
前列腺素可用于治疗高血压、血栓形成、哮喘、胃和肠道溃疡、预防动脉粥样硬化，以及用于产科。FP受体激动剂在临床上用作降低眼内压的药物[Woodward D.F.，LawrenceR.A.，Fairbairn C.E.，Shan T.，Williams L.S.根据放射性配体结合研究，选择性前列腺素受体激动剂的眼压作用涉及不同的受体亚型(Intraocular pressure effects ofselective prostanoid receptor agonists involve different receptor subtypesaccording to radioligand binding studie).//J Lipid Mediat.1993，V.6(1-3)，第545-553页]
前列腺酰胺(前列腺素和乙醇胺的酰胺)是由环氧合酶2引起的花生四烯酸乙醇酰胺(anandamide)氧化而在生物体内形成的[Kozak K.R.，Crews B.C.，Ray J.L.，Tai H.H.，Morrow J.D.，Marnett L.J.在体外和体内代谢前列腺素甘油酯和前列腺素乙醇酰胺(Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamidesin vitro and in vivo).//J.Biol.Chem.2001，V.276(40)，P.36993-36998]。这些衍生物似乎能够降低眼内压。这类产品中最知名的产品是前列腺素F2-比马前列素的合成类似物，其中乙醇胺残基被乙胺残基取代，并且前列腺素烷基侧链通过引入苯基进行修饰[Woodward DF，Krauss AH，Chen J.，Lai RK，Spada CS，Burk RM，Andrews SW，Shi L.，Liang Y.，Kedzie KM，Chen R.，Gil DW，Kharlamb A.，Archeampong A.，Ling J.，MadhuC.，Ni J.，Rix P.，乌桑斯基J.，乌桑斯基H.，韦伯A.，Welty D.，杨W.，唐柳DD，加斯特ME，布拉尔B.，惠勒LA，卡普兰LJ比马前列素(Lumigan)的药理作用//Surv.眼药(Thepharmacology of bimatoprost(Lumigan)//Surv.Ophthalmol).2001，V.45，增刊4，P.S337-S345]。
已知有多种前列腺酰胺类似物，其中分子的前列腺素和乙醇胺部分被修饰。与要求保护的化合物最接近的是能够神经保护的前列腺酰胺[V.V.Bezuglov,M.Y.Bobrov,N.M.Gretskaya,I.V.Serkov,G.N.Zinchenko,M.G.Akimov.能够神经保护的前列腺酰胺及其类似物(Prostamides and their analogues capable of neuroprotection)/Ru专利号2474426，优先权于26.12.2011，公开日10.02.2013，第4号公告]。该专利描述了包含硝酰乙胺、甘氨酸、γ-氨基丁酸、羟乙胺、酪胺和多巴胺残基的前列腺酰胺E类似物。然而，该专利没有描述包含相同的乙醇胺修饰残基的前列腺酰胺F的类似物。
还已知前列腺素F2α的类似物，例如,专利[US专利号7,910,767]，其描述了具有修饰的烷基侧链的前列腺素F2α的醚、硫醚和酰胺，与已知的前列腺素F2α类似物(比马前列素、曲伏前列素等)相比，其生物学活性有所改善，其在医学领域得到了应用。
还已知包含硝基氧基的前列腺素F2α的类似物。
US专利号5,625,083描述了前列腺素的二硝基甘油醚，包括前列腺素F2α，其可以用作血管扩张剂，降压药剂或支气管扩张剂。
US专利号8,101,658描述了产生氮氧化物的前列腺酰胺，其可以用于治疗青光眼和眼内压升高。
但是，这些发明不包含本发明中公开的结构。
本发明的目的是扩展能够降低眼内压的前列腺素F2α的生物活性衍生物。通过合成前列腺素F2α的酰胺衍生物解决了该问题，其中酰胺部分由氨基酸、其硝基衍生物、环胺和取代的乙醇胺表示。
因此，本发明的主题是具有通式(1)的前列腺素F2α的酰胺衍生物：
通式所示的前列腺素F2α衍生物
R1＝H，其中n＝1-4或
R1＝H，其中
R3＝CHMe2，HNCH2CH2ONO2，OCH2CH2ONO2，OCH(CH2ONO2)2或
R1＝H，其中
R4＝H，CHMe2；R5＝H，OH；R6＝H，OH，ONO2，CH2OH，CH2ONO2或
R1＝H；R2＝CH2CH2OC(O)NHCH2CH2ONO2或
R1＝H；R2＝CH2CH2OC(O)OCH(CH2ONO2)2或
其中n＝1、2；
其中R1和R2独立地指氢、烷基、环烷基、羟烷基、氨基酸、氨基酸的醚和酰胺，并且R1+R2也可以指杂环(例如取代或未取代的哌啶、吡咯烷等)；以及具有游离羧基的通式(1)化合物的药学上可接受的盐；以及两种或多种具有通式(1)的化合物的不同比例的混合物。
这些物质具有低细胞毒性，并且能够刺激哺乳动物细胞中内源性一氧化氮的形成。
除非另有说明，否则本文中使用的所有技术和科学术语具有相同的含义，这在本领域中是常见的，并且本领域技术人员可以理解。
“取代的”是指特定的基团或残基包括一个或多个不同于氢原子的取代基。
“未取代的”是指特定基团或残基不包含不同于氢原子的取代基。
“烷基”是指具有1-6个碳原子的直链或支链的未取代的烷基。
“环烷基”是指具有3-6个环碳原子的环状饱和烃基(例如环丙基、环丁基等)。
“混合物”–两种或两种以上物质的共混物，没有化学键合，各组分的物理性质保持不变。
“药学上可接受的盐”是指与所要求保护的物质的羧基产生的盐组分，不会对人体造成伤害。
“药学上可接受的阳离子”是指该阳离子在成盐时不会对人体造成伤害。
通用形式的本发明物质可以通过化学领域中已知的技术来合成。在实施例中给出的图中说明了生产本发明特定物质的一些方法。
本发明物质的生物活性包括：直至浓度为100μΜ无细胞毒性；降低眼内压的能力、增加细胞内钙浓度的能力、增加氮氧化物产生的能力。
所要求保护的物质是天然前列腺素F2α的类似物，能够与特定的前列腺素受体FP相互作用，从而刺激细胞内钙动员。
本发明的意外结果是所要求保护的物质在哺乳动物细胞中诱导内源性一氧化氮合成的能力。对于任何前列腺素F2α衍生物都没有观察到这种性质。此外，不包含NO-供体基团的化合物，例如前列腺素F2α与丝氨酸异丙酯的酰胺(化合物3)，也具有这种特性。
因此，本发明的问题是通过合成具有通式(1)的新的前列腺素F2α酰胺衍生物来解决的，该衍生物能够诱导内源性合成氮氧化物，在药理作用机理上涉及内源性调节剂–氮氧化物从而显著地扩大了所要求保护的物质在医学上的应用机会。
给出以下实施例以举例说明本发明，并且不应以任何方式将其视为限制本发明的范围。
实施例1前列腺素F2α与丝氨酸及其衍生物、环丙胺和L-脯氨醇的酰胺
前列腺素F2α与L-亚硝基丝氨酸的酰胺(1)。
在氩气气氛下，将76μl(0.55μmol)的Et3N加入到150mg(0.42μmol)前列腺素F2α在2ml乙腈中的溶液中，混合5分钟，然后添加71μl(0.55μmol)氯甲酸异丁酯在500μl乙腈中的溶液。将反应混合物在4℃下于30分钟内混合，蒸发至一半体积，用50ml乙酸乙酯稀释，用水(2×20ml)和NaCl饱和水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液蒸发。用油泵真空干燥残留物。得到171mg混合酸酐，为黄色油油状物。
在氩气气氛下，在4℃下，将得到的混合酸酐在1ml DMF和52μl N-甲基吗啉中的溶液添加到104mg(0.49μmol)L-硝基丝氨酸硝酸盐在0.500ml DMF中的溶液中，并90分钟内混合的获得混合物。蒸发溶剂，用50ml乙酸乙酯稀释残余物，并用2MNaHSO4水溶液(20ml)和NaCl饱和水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液煮沸。获得162mg前列腺素F2α与L-硝基丝氨酸的酰胺，为淡黄色油状物，产率–70％。
PMR:0.90(3H),1.29(6H),1.53(3H),1.75(2H),2.18(7H),2.41(2H),2.71(1H),3.95(1H),4.14(2H),4.33(1H),4.88(2H),5.52(4H).质谱图：509.2832[M+Na]+,441.3282[M–NO2+Na+H]+,c＝1,EtOH.
前列腺素F2α与L-丝氨酸的酰胺(2)。
类似地，衍生自前列腺素F2α和L-丝氨酸。产率–51％。PMR:0.84(3H),1.3(6H),1.52(3H),1.95(3H),2.16(6H),2.33(2H),2.68(1H),3.89(2H),3.92(1H),4.19(1H),4.32(2Η),5.34(4H),7.8(1H).c＝1,EtOH:H2O,1:2.
前列腺素F2α与L-丝氨酸异丙醚的酰胺(3)。
类似地，衍生自前列腺素F2α和L-丝氨酸异丙醚盐酸盐。产率–57％。PMR:0.89(3H),1.22(6H),1.3(9H),1.76(3H),2.04(6H),2.39(2H),3.9(2H),4.03(2H),4.13(1H),4.63(1H),5.08(1H),5.45(4H),6.83(1H).c＝1,EtOH.
前列腺素F2α与D-丝氨酸异丙醚的酰胺(4)。
类似地，衍生自前列腺素F2α和D-丝氨酸异丙醚盐酸盐。产率–35％。PMR:0.89(3H),1.21(6H),1.3(9H),1.74(3H),2.01(6H),2.4(2H),3.9(2H),4.0(2H),4.1(1H),4.6(1H),5.1(1H),5.43(4H),6.9(1H).c＝1,EtOH.
前列腺素F2α与L-亚硝基丝氨酸异丙醚的酰胺(5)。
类似地，衍生自前列腺素F2α和L-亚硝基丝氨酸异丙醚。产率–64％。PMR:0.84(3H),1.16(6H),1.23(8H),1.51(4H),1.96(4H),2.12(4H),3.88(3H),4.52(1H),4.9(2H),5.34(5H),7.9(1H).
前列腺素F2α与环丙胺的酰胺(6)。
类似地，衍生自前列腺素F2α和环丙胺。产率–73％。PMR:0.50(2H),0.78(2H),0.90(3H),1.31(6H),1.61(4H),1.86(4H),2.06(4H),2.36(2H),2.70(1H),4.00(1H),4.09(1H),4.20(1H),5.41(1H),5.57(2H),5.78(2H).c＝1,EtOH.
前列腺素F2α与L-脯氨醇的酰胺(7)。
类似地，衍生自前列腺素F2α和L-脯氨醇。产率–61％。PMR:0.91(3H),1.36(6H),1.60(6H),1.89(6H),2.08(4H),2.39(1H),2.65(1H),3.2(1H),3.45(1H),3.57(1H),3.73(1H),3.90(1H),4.06(1H),4.21(2H),5.48(2H),5.69(2H).c＝1,EtOH.
实施例2前列腺素F2α和γ-氨基丁酸衍生物的酰胺。
前列腺素F2α与γ-氨基丁酸的酰胺。
将600μl N，O-双(三甲基甲硅烷基)三氟乙酰胺添加到103mg(1.00μmol)γ-氨基丁酸在1ml乙腈中的溶液中，并在23℃下搅拌18小时。
向284mg(0.8μmol)前列腺素F2α在3ml乙腈中的溶液中加入145μl(1.05μmol)的三乙胺和125μl(0.96μmol)的氯甲酸异丁酯，并在23℃下搅拌30分钟。将得到的混合酸酐添加到甲硅烷基化的γ-氨基丁酸溶液中，并在23℃下搅拌4小时。向反应混合物中加入甲醇(5ml)，搅拌20分钟，并在吸水泵真空下的旋转蒸发仪上蒸发。将残余物溶解在乙酸乙酯(20ml)中，并用2ΜNaHSO4水溶液(20ml)和NaCl饱和水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液煮沸。通过硅胶柱色谱法纯化残余物。获得132mg前列腺素F2α和γ-氨基丁酸酰胺，为清澈的油状物，产率–60％。质谱图：462.2888[M+Na]+。
前列腺素F2α与γ-氨基丁酸硝基乙醇酰胺的酰胺(8)。
在氩气气氛下，将30μl(0.23μmol)Et3N加入到80mg(0.18μmol)前列腺素F2α与γ--氨基丁酸的酰胺在3ml乙腈中的溶液中，搅拌5分钟，然后添加30μl(0.22μmol))氯甲酸异丁酯。在4℃下将反应混合物搅拌30分钟，加入38mg(0.37μmol)硝基乙醇胺硝酸盐和50μlEt3N在2ml二氯甲烷中的溶液，然后在23℃下搅拌12小时。蒸发溶剂，用20ml乙酸乙酯稀释残余物，并用2M NaHSO4水溶液(20ml)和NaCl饱和水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液煮沸。通过硅胶柱色谱法纯化残余物。获得35mg前列腺素F2α与γ-氨基丁酸硝基乙醇酰胺的酰胺(8)，产率–36％。PMR:0.88(3H),1.21(6H),1.65(3H),1.77(4H),2.11(7H),2.38(1H),2.62(1H),3.33(2H),3.55(2Η),3.97(1H),4.18(2H),4.53(2Η),4.68(2H),5.47(4H)c＝1,EtOH.
前列腺素F2α与γ-氨基丁酸硝基乙二醇醚的酰胺(9)。
将24mg(0.12μmol)的N-(3-二甲基氨基丙基)-N'-碳酸乙酯盐酸盐，3mg(0.02μmol)的二甲基氨基吡啶和45mg(0.1μmol)的前列腺素F2α与γ-氨基丁酸酰胺添加到14μl(0.12μmol)硝基乙二醇在1ml二氯甲烷中的溶液中，并在23℃下搅拌90分钟。用氯仿(20ml)稀释反应混合物，并用2M NaHSO4水溶液(20ml)、水(2×20ml)和饱和NaCl水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液煮沸。通过硅胶柱色谱法纯化残余物。获得20mg酰胺(9)，为白色油状物，产率–37％。
PMR:0.89(3H),1.38(11H),1.88(9H),2.27(2H),2.87(2H),3.22(2H),3.81(1Η),3.99(1H),4.07(1H),4.37(2H),4.67(2H),5.36(4H),7.57(1H).c＝1,EtOH.
前列腺素F2α与γ-氨基丁酸二硝基甘油酯的酰胺(10)。
在氩气气氛下，将44mg(0.43μmol)N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐在0.5ml二氯甲烷中、5mg(0.04μmol)N-二甲基氨基吡啶和42mg(0.22μmol)二硝酸甘油添加到84mg前列腺素F2α与γ-氨基丁酸的酰胺在1ml二氯甲烷(0.2μmol)中的溶液中，并在23℃下搅拌2小时。蒸发溶剂，用乙酸乙酯(20ml)稀释残余物，并用2M NaHSO4水溶液(20mL)、水(2х20ml)和饱和NaCl水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液煮沸。通过硅胶柱色谱法纯化残余物。获得38mg前列腺素F2α与γ-氨基丁酸二硝基甘油酯的酰胺(10)，产率–33％。PMR:0.84(3H),1.43(14H),1.98(8H),2.34(2H),3.04(2H),3.88(2H),4.31(1H),4.46(2H),4.77(2H),5.36(5H),7.75(1H).质谱图,m/z：626.2968[M+Na]+,586.3943[M+H–H2O]+.c＝1,EtOH
实施例3前列腺素F2α与2-氨基乙基-[2-(硝氧基)乙基]氨基甲酸酯(11)的酰胺。
将93mg(0.37μmol)的碳酸二琥珀酰亚胺酯和52μl(0.37μmol)的Et3N添加到150mg(0.37μmol)前列腺素F2α与乙醇胺的酰胺在3ml乙腈中的溶液中，在23℃搅拌1.5h。然后，加入62mg(0.37μmol)的硝酸硝基乙醇胺和37mg(0.37μmol)的Et3N，并在4℃下搅拌18小时。蒸发溶剂，用20ml乙酸乙酯稀释残余物，并用2M NaHSO4水溶液(20ml)和NaCl饱和水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液煮沸。通过硅胶柱色谱法纯化残余物。获得38mg酰胺(11)，为白色油状物，产率–19％。PMR:0.90(3H),1.31(6H),1.55(4H),1.76(3H),2.15(5H),2.53(2Η),3.34(2H),3.53(2H),4.01(1H),4.18(4H),4.56(2H),5.40(2H),5.57(2H),5.71(1H),6.25(1H).质谱图，m/z：552.2983[M+Na]+.c＝1,EtOH
前列腺素F2α与2-氨基乙基-2-(硝基)-1-[[(硝氧基)甲基]乙基]碳酸酯的酰胺(12)。
将32mg(0.12μmol)的碳酸二琥珀酰亚胺酯和20μl(0.14μmol)的Et3N加入55mg(0.14μmol)前列腺素F2α与乙醇胺的酰胺在1.5ml二氯甲烷中的溶液中，在23℃搅拌40min。然后，加入25mg(0.14μmol)的硝酸二甘油酯和16mg(0.14μmol)的N-二甲基氨基吡啶，并在4℃搅拌18小时。蒸发溶剂，用20ml乙酸乙酯稀释残余物，并用2M NaHSO4水溶液(20ml)和NaCl饱和水溶液(20ml)洗涤，并在无水Na2SO4上干燥。过滤干燥剂，在吸水泵真空下的旋转蒸发仪中将滤液煮沸。通过硅胶柱色谱法纯化残余物。获得20mg酰胺(12)，为白色油状物，产率–19％。PMR:0.84(3H),1.24-1.53(12H),2.01(8H),2.39(1H),2.51(1H),2.64(2H),3.64(2H),4.00(2H),4.18(1H),4.46(2H),4.81(2H),5.31(5H),7.95(1H).质谱图,m/z：628.2770[M+Na]+,588.2843[M+H-H2O]+.
实施例4前列腺素F2α衍生物的细胞毒活性。
将3T3-L1细胞在95％湿度，在5％СΟ2的气氛中于37℃孵育。在含有7％FСS，2Mm谷氨酰胺，100U/ml青霉素，100μg/ml链霉素和0.25μg/ml两性霉素B的DMEM培养基中进行培养。每48-72小时对细胞进行传代培养。为了悬浮，将细胞在Versene溶液中孵育1分钟，并在胰蛋白酶-EDTA溶液中孵育1分钟(0.25％)。
评估物质对细胞培养的影响
将3万个细胞接种到100μl培养基中的96孔板(单层)的孔中用于MTT测试。培养24小时后，将用于细胞培养的培养基中的100μl测试物质添加到细胞中，用新培养基代替培养基。将细胞与测试物质孵育24小时。将添加至100μl用于细胞培养的培养基中的细胞用作阳性对照。
使用MTT测试评估培养物中的细胞存活率
孵育后，从每个孔中除去培养基，然后将100μlMTT溶液添加到每个孔中(0.5mg/mlMTT，3.5mg/ml D-葡萄糖的Hanks溶液)。将该板置于СΟ2-培养箱(Ependorf,德国)中保持1.5小时。此后，除去MTT，向每个孔中添加100μl DMSO，并在振荡器内于550rpm混合2分钟。然后，使用读板仪(EFOS 9305，OAOΜZ Sapphir)在576nm和620nm的波长下确定溶液的光密度。
在浓度达100μΜ时，所有测试物质都没有明显的细胞毒性(表1)。
表1前列腺素F2α衍生物对培养的小鼠3Τ3-L1细胞的细胞毒性
| 化合物编号 | 细胞毒性，EC50μΜ |
| 1 | 226.4±2 |
| 2 | >200 |
| 3 | 143.6±3 |
| 5 | 195.2±2 |
| 6 | 124.4±2 |
| 7 | 104.4±2 |
| 8 | 193.9±4 |
| 11 | 184.5±3 |
| 12 | 137.5±1.5 |
实施例5前列腺素F2α衍生物引起的眼压降低。
该研究是在质量为2.5-3kg的栗鼠兔上进行的。通过自动手动兽用眼压计Tonovet(Icare，Finland)测量IOP。
使用两组兔测试每个样本：
5只动物以单剂量样品滴入两只眼睛。
5只动物以单剂量生理盐水滴入两只眼睛。
用一次性移液器将所有测试样品滴加2滴。在滴注之前以及之后的6小时内每小时测量一次IOP。结果在表2中给出。所有测试物质均能降低血压正常兔子的眼内压。对于化合物3和6，此效果更为突出。
表2滴注前列腺素衍生物溶液后降低血压正常兔子的眼压(最大值为5只动物的平均值)
| 化合物编号 | 眼压降低量，mm Hg |
| 3 | 3.20 |
| 5 | 1.20 |
| 6 | 3.30 |
| 8 | 2.00 |
| 11 | 1.50 |
| 12 | 1.90 |
实施例6前列腺素F2α衍生物引起的细胞内钙浓度增加。
在添加10％胎牛血清(FCS)，4mM L-谷氨酰胺，100U/ml青霉素，100μg/ml链霉素，2.5μg/ml两性霉素B的DMEM培养基中培养3T3-L1细胞。细胞在37℃，5％CO2的气氛，95％湿度下中培养。
实验时的细胞密度为96孔板的每孔7000个，钙绿色染料(1.5mΜ，在无BSA的孵育培养基中负载0.4％普朗尼克(Pluronic)F-62，在37℃处理1小时，负载后三次洗涤200μl孵育培养基)，孵育培养基：汉克斯(Hanks)溶液，1g/L的D-葡萄糖，1mg/ml的无脂肪BSA，将物质引入乙醇(终浓度<0.5％)，在25℃孵育，检测激发波长为485nm，发射波长为535nm。
结果
向3T3-L1细胞中添加测试物质会导致细胞内钙浓度升高。因此，在添加参考物质时：相对于对照，在10分钟内，67μΜ的前列腺素F2α和前列腺素F2(前列腺素F2α乙醇酰胺)的钙传感器的荧光分别增加195和185AU；而在物质3存在下，这种增加为405AU。
实施例7前列腺素F2α衍生物引起的氮氧化物的产生。
将3T3-L1细胞在95％湿度,5％СΟ2的气氛中于37℃孵育。在含有7％FCS，2mM谷氨酰胺，100U/ml青霉素，100μg/ml链霉素和0.25μg/ml两性霉素B的DMEM培养基中进行培养。每48-72小时对细胞进行传代培养。为了悬浮，将细胞在Versene溶液中孵育1分钟，并在胰蛋白酶-EDTA溶液中孵育1分钟(0.25％)。
NO生成水平的确定
在100μl培养基中，将3万个细胞接种到96孔板的孔(单层)中。与物质的孵育持续20小时。之后，从每个孔中取培养基等分试样，并通过改良的Griess方法测定NO浓度。将12.5μl的0.04％磺胺酰胺水溶液添加到用于EIA的96孔板的孔中的75μl测试培养基中，在室温下避光放置10分钟，然后加入在12.5μl的3ΜHCl中的2％萘乙二胺溶液，在室温下避光保存10分钟，然后在540nm的波长处测定光吸收。
在被测物质浓度为100μΜ时，大多数测试化合物观察到通过诱导生成一氧化氮而产生的最大活性。结果在表3中给出。
表3浓度为100μΜ的前列腺素F2α衍生物引起的小鼠3Τ3-L1细胞产生的一氧化氮(NO)。
| 化合物编号 | No生成量，相对对照％ |
| 1 | 7 |
| 2 | 25 |
| 3 | 15 |
| 6 | 5 |
| 7 | 15 |
| 8 | 22 |
| 11 | 28 |
| 12 | 57 |
但是，对于前列腺素F2α酰胺(3)，最有效的浓度为25μΜ。在此浓度下，3Τ3-L1细胞中的一氧化氮水平相对于图1中所示的对照增加了60％。
Claims (3)
1.通式(I)所示的化合物或其药学上可接受的盐：
R1＝H，其中n＝1-4或
R1＝H，其中
R3＝CHMe2，HNCH2CH2ONO2，OCH2CH2ONO2，OCH(CH2ONO2)2或
R1＝H，其中
R4＝H，CHMe2；R5＝H，OH；R6＝H，OH，ONO2，CH2OH，CH2ONO2或
R1＝H；R2＝CH2CH2OC(O)NHCH2CH2ONO2或
R1＝H；R2＝CH2CH2OC(O)OCH(CH2ONO2)2或其中n＝1、2。
2.如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
3.如权利要求1或2所述的化合物，其特征在于，能够降低眼内压。
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| Publication number | Publication date |
|---|---|
| EA202092736A1 (ru) | 2021-02-10 |
| JP2021524862A (ja) | 2021-09-16 |
| CA3101512A1 (en) | 2019-11-21 |
| WO2019221641A1 (ru) | 2019-11-21 |
| EP3795562A1 (en) | 2021-03-24 |
| CN112154139A (zh) | 2020-12-29 |
| AU2019268225A1 (en) | 2021-01-07 |
| KR20210020909A (ko) | 2021-02-24 |
| RU2018118157A (ru) | 2019-11-18 |
| US12012375B2 (en) | 2024-06-18 |
| EP3795562A4 (en) | 2022-03-16 |
| RU2718744C2 (ru) | 2020-04-14 |
| RU2018118157A3 (zh) | 2019-11-18 |
| US20210230111A1 (en) | 2021-07-29 |
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