CN117886714A - 丙氨酸衍生物、其制备方法及医药用途 - Google Patents
丙氨酸衍生物、其制备方法及医药用途 Download PDFInfo
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- CN117886714A CN117886714A CN202410064706.8A CN202410064706A CN117886714A CN 117886714 A CN117886714 A CN 117886714A CN 202410064706 A CN202410064706 A CN 202410064706A CN 117886714 A CN117886714 A CN 117886714A
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- compound
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- pharmaceutically acceptable
- alkyl
- phenyl
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Abstract
本发明公开了丙氨酸衍生物、其制备方法及医药用途,如通式(I)所示的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N‑氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐。本发明公开了一类对P2Y14受体有抑制作用的丙氨酸衍生物及其可药用盐,该类化合物通过药理学实验证实,其对P2Y14受体具有显著的抑制作用,尤其可以作为治疗包括痛风性关节炎和腹膜炎在内的炎症疾病药物。
Description
技术领域
本发明属于药物化学领域,涉及化合物及其制法和用途,具体涉及一类新型丙氨酸衍生物以及含有这类化合物的药物组合物、其制备方法以及作为治疗剂特别是P2Y14受体拮抗剂的医药用途。
背景技术
当身体受到压力或损伤时,各种重要的细胞内分子,如腺苷-5′-三磷酸(ATP)和尿苷-5′-三磷酸(UTP),会被特定的组织或器官释放到细胞外液中。这些核苷酸具有通过与细胞表面受体结合来调节先天和适应性免疫反应的能力,被结合的受体被鉴定为嘌呤能受体,主要分为腺苷(P1)和核苷酸(P2)受体。P2家族进一步被分为两个亚家族,P2X受体和P2Y受体(P2YRs)。P2YRs属于G蛋白偶联受体(GPCRs)家族,由P2Y1样受体(P2Y1,2,4,6,11)和P2Y12样(P2Y12,13,14)组成。已经报道的G蛋白偶联受体的P2Y受体家族包含8种亚型(P2Y1、2、4、6、11、12、13、14),广泛分布于各种细胞和组织中,而且各亚型之间同源性比较低,因此不同的亚型对配体具有很高的选择性。其中P2Y1、2、4、6受体结合Gq并激活PLC途径;P2Y12、13、14受体结合Gi抑制腺苷酸环化酶的活性;P2Y4受体偶联Gq/Gi两种G蛋白;P2Y11偶联Gq/Gs两种G蛋白。P2Y受体介导免疫调节、血小板聚集、平滑肌细胞增殖等一系列生物学效应。
P2Y14受体被至少四种自然存在的UDP糖,特别是UDP葡萄糖(UDPG)激活。P2Y14受体已被发现在一系列人类组织中广泛表达,包括大脑、心脏、脂肪组织、胎盘、肠道和造血干细胞。P2Y14受体通过激活与其偶联的Gi蛋白,抑制腺苷酸环化酶(AC),减少细胞内3′,5′环磷酸腺苷(cAMP)的产生及相应的生物学效应。
P2Y14受体已被证明是先天免疫炎症性疾病的潜在靶点,如糖尿病、囊性纤维化、肾无菌性炎症、急性痛风性关节炎和过敏性疾病。P2Y14受体可促进中性粒细胞和巨噬细胞的招募和趋化,释放促炎细胞因子、趋化因子和肥大细胞介质。在COVID-19引起的重症病例中,很大一部分严重病程是由系统性炎症引起的,称为“细胞因子风暴”。基于P2Y14受体对中性粒细胞的作用和COVID-19致重症患者中发现的高水平UDPG,一种通过P2Y14受体拮抗剂防止中性粒细胞趋化失控的机制被提出,以避免细胞因子风暴和全身炎症,从而降低患者死亡率。此外,P2Y14受体基因被敲除可抑制巨噬细胞的募集和组织炎症,减轻高脂肪饮食诱导的胰岛素抵抗。另一项研究表明,糖原代谢也会增加巨噬细胞中UDPG的水平和P2Y14受体的数量,阻断这一糖原代谢途径可有效抑制脂多糖(LPS)诱导的急性腹膜炎。综上所述,P2Y14受体可能是先天性免疫系统疾病的潜在治疗靶点。
目前对P2Y14受体拮抗剂的研究仅仅报道了4种结构类型的化合物(嘧啶并哌啶类、2-萘酸类、3-取代苯甲酸类和吡唑-3-羧酸类),但还都在临床前研究阶段。其中活性和选择性最高的为2-萘酸类,然而目前报道的2-萘酸类结构的拮抗剂存在溶解性差、口服生物利用度低、合成纯化难度大等缺陷,给进一步讨论构效关系及生物学评价带来了较大的困难。因此寻找新结构类型的P2Y14受体拮抗剂,改善2-萘酸类拮抗剂存在的成药性差等问题,成为发现活性强、选择性好的P2Y14受体拮抗剂的新策略。
发明内容
发明目的:本发明的目的在于提供一类结构新颖的且具有P2Y14受体拮抗作用的丙氨酸衍生物及其可药用盐。本发明的另一个目的是提供一种上述丙氨酸衍生物的制备方法。本发明还有一个目的是提供一种上述丙氨酸衍生物在包括痛风性关节炎和腹膜炎在内的治疗炎症性疾病方面的应用。
技术方案:本发明所述的通式(I)所示的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐:
R1选自:H、C1-4烷基、
R2选自:
R3选自:
苯基、C3-6环烷基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R3基团可独立地任选地被1至5个下列的取代基取代:C1-6烷基、卤素、氰基、羧基、乙酰基、甲磺酰基、卤代C1-4烷基、卤代C1-4烷氧基、OH、NO2、醛基、C1-6烷氧基、氨基、二甲氨基;
R4选自:H、C3-6环烷基、苯基、甲氨基、二甲氨基、-OCOC1-16烷基、C1-16烷基、(OCH2CH2)1-4OCH3;
R5选自:
苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R5基团可独立地任选地被1至5个下列的取代基取代:C1-4烷基、卤素、氰基、羧基、乙酰基、甲磺酰基、卤代C1-4烷基、卤代C1-4烷氧基、OH、NO2、醛基、C1-4烷氧基、氨基、二甲氨基;
所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐,
R3选自:
苯基、C5-6环烷基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R3基团可独立地任选地被1至2个下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基;
R4选自:H、C5-6环烷基、苯基、二甲氨基、-OCOC1-16烷基、C1-16烷基、(OCH2CH2)1-4OCH3;
R5选自:
苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R5基团可独立地任选地被1至2个下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基;
所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐,
其中手性中心为D型氨基酸骨架;
R3选自:
苯基、环己烷、吡啶基、噻吩基、呋喃基;上述R3基团可独立地任选地被1个下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基;
R4选自:H、环己烷、苯基、二甲氨基、甲基、正十六烷基、-OCOCH3、(OCH2CH2) 4OCH3;
R5选自:
苯基、吡啶基、噻吩基、呋喃基;上述R5基团可独立地任选地被1个选自下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基;
所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐,通式(I)化合物选自如下化合物:
所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐的制备方法,包括如下步骤:
(1)通式化合物A通过酯化反应制得通式B化合物;
(2)通式化合物B与不同羧酸衍生物进行缩合反应制得通式化合物C;
(3)通式化合物C可经脱保护基反应制得通式化合物D;
(4)通式化合物D可经取代反应制得通式化合物E
化合物E即通式(I)化合物,R1、R2、R3同上所述。
药物组合物,其中含有权利要求1所述的通式(I)化合物或其药学上可接受的盐及药学上可接受的辅料。
所述的通式(I)化合物或其药学上可接受的盐、或所述的药物组合物在制备P2Y14受体拮抗剂药物中的用途。
所述的通式(I)化合物或其药学上可接受的盐或所述的药物组合物在制备治疗炎症疾病药物中的用途。
所述的用途,所述炎症疾病包括痛风性关节炎和腹膜炎。
所述的用途,所述药物添加药学上可接受的辅料制成不同剂型。
本领域普通技术人员应了解,当备选取代基列表包括因其化合价要求或其他原因无法用于取代特定基团成员时,意在按本领域普通技术人员的知识来参阅该列表以仅纳入那些适于取代该特定集团的列表成员。这同样适用于在一个基团上的可能的取代基的数目。
本发明中所用化合物可呈药学上可接受的盐或溶剂合物形式。术语“药学上可接受的盐”指由药学上可接受的无毒碱或酸(包括无机碱或酸及有机碱或酸)制备的盐。倘若本发明化合物含有一或多个酸性或碱性基团,则本发明亦包含其相应药学上或毒理学上可接受的盐,具体而言其药学上可利用的盐。因此,根据本发明,含有酸性基团的本发明化合物可按例如碱金属盐、碱土金属盐或铵盐形式使用。这些盐的更具体的实例包括钠盐、钾盐、钙盐、镁盐或与氨或有机胺(例如,乙胺、乙醇胺、三乙胺或氨基酸)形成的盐。根据本发明,含有一或多个碱性基团(即可质子化得基团)的本发明化合物可以按它们的无机酸或有机酸的加成盐形式使用。适合的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸及本领域普通技术人员已知的酸。若本发明化合物在分子中同时含有酸性或碱性基团,则本发明除所提及的盐形式外亦包括内盐或甜菜碱(两性离子)。各种盐可通过本领域普通技术人员已知的通常方法获得,例如,通过在溶剂或分散剂中使这些物质与有机或无机酸或碱反应或通过与其他盐进行阴离子交换或阳离子交换。本发明亦包括所有因低生理相容性无法直接适用于药物但可例如作为中间体用于化学反应或用于制备药学上可接受的盐的本发明化合物的盐。
本发明所述药学上可接受的辅料,是指制备不同剂型时加入所需的各种常规辅料,例如稀释剂、黏合剂、崩解剂、助流剂、润滑剂、矫味剂、包合材料、吸附材料等以常规的制剂方法制备成任何一种常用的口服制剂,例如可以是颗粒剂、散剂、片剂、胶囊剂、丸剂、口服液、汤剂、滴丸剂等。
有益效果:本发明与现有技术相比,具有如下优点:本发明公开了一类对P2Y14受体有抑制作用的丙氨酸衍生物及其可药用盐,该类化合物通过药理学实验证实,其对P2Y14受体具有显著的抑制作用,尤其可以作为治疗炎症疾病药物。
附图说明
图1是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白表达;
图2是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白NLRP3相对表达,其中,数据是平均值土标准差(n=4),用one-way anova进行方差分析(####代表与正常组比较P<0.0001,*代表与模型对照组比较P<0.05,#代表与模型对照组比较P<0.01,***代表与模型对照组比较P<0.001,****代表与模型对照组比较P<0.0001);
图3是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白ASC相对表达,其中,数据是平均值土标准差(n=4),用one-way anova进行方差分析(####代表与正常组比较P<0.0001,*代表与模型对照组比较P<0.05,#代表与模型对照组比较P<0.01,***代表与模型对照组比较P<0.001,****代表与模型对照组比较P<0.0001);
图4是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白Caspase-1 p20相对表达,其中,数据是平均值土标准差(n=4),用one-way anova进行方差分析(####代表与正常组比较P<0.0001,*代表与模型对照组比较P<0.05,#代表与模型对照组比较P<0.01,***代表与模型对照组比较P<0.001,****代表与模型对照组比较P<0.0001);
图5是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白IL-1β相对表达,其中,数据是平均值土标准差(n=4),用one-way anova进行方差分析(####代表与正常组比较P<0.0001,*代表与模型对照组比较P<0.05,#代表与模型对照组比较P<0.01,***代表与模型对照组比较P<0.001,****代表与模型对照组比较P<0.0001);
图6是THP-I细胞培养基上清液中IL-1β水平,其中,数据是平均值土标准差,用one-way anova进行方差分析(####代表与正常组比较P<0.0001,*代表与模型对照组比较P<0.05,#代表与模型对照组比较P<0.01,***代表与模型对照组比较P<0.001,****代表与模型对照组比较P<0.0001);
图7是LSP诱导的腹膜炎模型中小鼠血清各指标的水平,其中数据是平均值土标准差,用one-way anova进行方差分析(####代表与正常组比较P<0.0001,*代表与模型对照组比较P<0.05,#代表与模型对照组比较P<0.01,***代表与模型对照组比较P<0.001,****代表与模型对照组比较P<0.0001);
图8是MSU诱导的急性痛风性关节炎模型中小鼠关节周径,其中数据是平均值土标准差,用one-way anova进行方差分析(####代表与正常组比较P<0.0001,*代表与模型对照组比较P<0.05,#代表与模型对照组比较P<0.01,***代表与模型对照组比较P<0.001,****代表与模型对照组比较P<0.0001);以及小鼠滑膜组织病理变化。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好的阐述本发明,并不是用来限制本发明的范围。
实施例1
步骤一:(R)-2-氨基-3-(4-氟苯基)丙酸甲酯(1a)
将(R)-2-氨基-3-(4-氟苯基)丙酸(5.0g)悬浮于100mL甲醇中,搅拌下缓慢滴加三甲基氯硅烷(13mL),滴加过程中混悬液逐渐澄清,加毕于室温反应12h。TLC监测,反应完全后,减压浓缩至干燥状态,得到白色固体4.67g,产率为87%。1H NMR(300MHz,DMSO-d6)δ(ppm)8.69(s,3H),7.29(dd,J=8.6,5.7Hz,2H),7.16(t,J=8.9Hz,2H),4.26(t,J=6.6Hz,1H),3.67(s,3H),3.24-3.05(m,2H)。
步骤二:(R)-3-(4-氟苯基)-2-(3-(对甲苯基)丙酰胺基)丙酸甲酯(1b)
将(R)-2-氨基-3-(4-氟苯基)丙酸甲酯(1.0g)溶于10mL乙腈中,之后加入3-(4-甲苯)丙酸(0.91g),N-甲基咪唑(1.32g)和N,N,N′,N′-四甲基氯甲脒六氟磷酸盐(1.55g),室温下搅拌混合物12h。TLC监测,反应完全后,加水,乙酸乙酯萃取(3次)。合并有机相,用饱和食盐水洗涤,无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯=10∶1),得到淡黄色固体1.32g,产率77.51%。1H NMR(300MHz,Chloroform-d)δ(ppm)8.36(d,J=7.8Hz,1H),7.26-7.17(m,2H),7.15-6.98(m,7H),4.52-4.41(m,1H),3.61(s,3H),3.01(dd,J=13.8,5.5Hz,1H),2.86(dd,J=13.8,9.4Hz,1H),2.69(t,J=7.6Hz,2H),2.35(dd,J=8.6,6.8Hz,2H),2.27(s,3H).
步骤三:(R)-3-(4-氟苯基)-2-(3-(对甲苯基)丙酰胺基)丙酸(1)
将(R)-3-(4-氟苯基)-2-(3-(对甲苯基)丙酰胺基)丙酸甲酯(500mg)溶于甲醇/四氢呋喃(1/1)(10ml)混合溶剂中,加入4mol/L的LiOH溶液(5mL),加毕,室温搅拌反应5h。反应完全后,加入1N的HCl调至溶液pH=2,过滤,得到白色固体450.6mg,产率为90.8%。1HNMR(300MHz,DMSO-d6)δ(ppm)8.24(d,J=8.1Hz,1H),7.25-7.14(m,2H),7.12-6.95(m,6H),4.46-4.37(m,1H),3.07-2.75(m,2H),2.66(t,J=7.7Hz,2H),2.33(dd,J=8.7,6.7Hz,2H),2.23(s,3H).
如实施例1方法类似地制备下列化合物:
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实施例50
步骤一:(R)-3-(4-氟苯基)-2-(3-(对甲苯基)丙酰胺基)丙酸乙酯
将(R)-3-(4-氟苯基)-2-(3-(对甲苯基)丙酰胺基)丙酸(0.5g)溶于5mLDMF中,搅拌下缓慢加入氯乙烷(0.18g)和碳酸钾(0.39g),升温至50℃,反应12h。TLC监测,反应完全后,加水稀释,乙酸乙酯萃取(3次)。合并有机相,用饱和食盐水洗涤,无水Na2SO4干燥。之后过滤无水Na2SO4,将滤液减压蒸发,得到类白色固体0.45g,产率为83.45%。
如实施例50方法类似地制备下列化合物:
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本发明中通式I的化合物的药理学实验及结果如下:
实验方法:
稳转P2Y14受体的HEK293细胞株培养于DMEM培养基中(含10%胎牛血清、100U/ml青霉素和100μg/ml链霉素),实验前接种至培养板,改用无血清培养基,接种密度为1×105个细胞/孔,细胞于37℃、95%O2、5%CO2湿度条件下培养。加入IBMX抑制PDEs活性,以保证cAMP在一个较高的水平上。采用AC激动剂Forskolin(30μM)刺激细胞cAMP的产生,预先加入不同浓度的受试化合物(0.01、0.1、1、10、100nm),以PPTN作为阳性对照。随后加入1μM的P2Y14受体激动剂UDPG,4h后cAMP GloTMAssay试剂盒(PROMEGA Co.Ltd,美国)检测细胞内cAMP的含量。根据cAMP含量计算其抑制率值。
表1全部化合物在细胞水平对P2Y14受体的抑制率值:
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受试化合物抑制LPS诱导的巨噬细胞炎性反应的药理研究实验方法
(1)将THP-1细胞按照1×106个/mL的密度接种至6孔板,每孔加入2mL含100μg/mLPMA和10%胎牛血清的RPMI 1640完全培养基,置于37℃、含5%CO2,饱和湿度的恒温培养箱中培养72h后,显微镜下观察到细胞呈梭形贴壁生长,多数细胞伸出伪足,说明细胞已分化为巨噬细胞。
(2)细胞分化后,将细胞分为6组:Control组、LPS组、LPS+PPTN(100nM)、LPS+受试化合物14(1000nM)、LPS+受试化合物14(100nM)、LPS+受试化合物14(10nM),每组设三个复孔。弃去培养基,每孔加入2mL RPMI 1640不完全培养基并给药,1h后除Control组,每孔按100ng/mL加入LPS刺激,置于37℃、含5%CO2,饱和湿度的恒温培养箱中培养24h。
Western Blot法检测细胞中UDPG/P2Y14受体信号通路下游蛋白的表达,结果如图1-5所示,LPS造成THP-1细胞的P2Y14受体下游相关蛋白表达显著升高,提示造模成功;不同剂量受试化合物能够不同程度的下调P2Y14受体下游相关蛋白表达,与模型对照组比较均体现出显著性差异;PPTN也体现出了预期的效果,表明实验结果真实可信;
按ELISA试剂盒(深圳欣博盛)方法检测细胞培养基上清液中IL-1β的水平,结果如图6所示,LPS造成THP-1细胞培养基上清液中IL-1β水平显著升高,提示造模成功;不同剂量受试化合物能够不同程度的下调细胞培养基上清液中IL-1β水平,与模型对照组比较均体现出显著性差异;PPTN也体现出了预期的效果,表明实验结果真实可信。
受试化合物在整体动物水平对急性腹膜炎的治疗作用的药理实验研究方法
在8周龄雄性C57小鼠腹部注射LPS(10mg/kg)的磷酸盐缓冲溶液(PBS,pH7.4),刺激产生炎症,模拟急性腹膜炎。在LPS诱导前1小时将测试化合物经腹腔注射(5和10mg/kg)注入腹腔中,对照小鼠注射等体积PBS(pH 7.4)。注射后24h后取血,在3000×g离心条件下离心15min,取血清,置于-80℃保存备用,检测如下指标:
(1)按试剂盒(南京建成)方法检测血清中ALT和ASR的水平。
(2)按ELISA试剂盒(深圳欣博盛)方法检测血清中TNF-α,IL-6和IL-1β的水平。
结果如图7所示,LPS造成小鼠血清中各指标水平显著升高,提示造模成功;不同剂量受试化合物能够不同程度的下调血清中各指标的水平,与模型对照组比较均体现出显著性差异;地塞米松也体现出了预期的效果,表明实验结果真实可信。
受试化合物在整体动物水平对急性痛风性关节炎的治疗作用的药理实验研究方法
雄性清洁级SD大鼠,体重200±20g,自由水食,每天12h照明,环境温度为25±2℃。动物分为若干组:正常对照组、模型对照组、给药组(地塞米松和受试化合物14),采用一次性关节腔注射MSU诱导急性痛风性关节炎模型,而正常对照组和正常给药各组采用等量的生理盐水注射入关节腔。各给药组通过关节腔注射给予受试化合物14(50μM),地塞米松作为阳性药进行对照。采用缚线法检测大鼠关节周径,测定时间点选择0h、2h、4h、8h、12h、24h,24h后,24h后断颈处死动物,在冰台上快速分取关节滑膜组织,检测滑膜组织病理学改变。结果如图8所示,MSU造成小鼠关节周径显著增加,提示造模成功;受试化合物能够降低小鼠关节周径,与模型对照组比较体现出显著性差异;地塞米松也体现出了预期的效果,表明实验结果真实可信。
Claims (10)
1.通式(I)所示的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐:
R1选自:H、C1-4烷基、
R2选自:
R3选自:
苯基、C3-6环烷基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R3基团可独立地任选地被1至5个下列的取代基取代:C1-6烷基、卤素、氰基、羧基、乙酰基、甲磺酰基、卤代C1-4烷基、卤代C1-4烷氧基、OH、NO2、醛基、C1-6烷氧基、氨基、二甲氨基;
R4选自:H、C3-6环烷基、苯基、甲氨基、二甲氨基、-OCOC1-16烷基、C1-16烷基、(OCH2CH2)1- 4OCH3;
R5选自:
苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R5基团可独立地任选地被1至5个下列的取代基取代:C1-4烷基、卤素、氰基、羧基、乙酰基、甲磺酰基、卤代C1-4烷基、卤代C1-4烷氧基、OH、NO2、醛基、C1-4烷氧基、氨基、二甲氨基。
2.根据权利要求1所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐,其特征在于,
R3选自:
苯基、C5-6环烷基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R3基团可独立地任选地被1至2个下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基;
R4选自:H、C5-6环烷基、苯基、二甲氨基、-OCOC1-16烷基、C1-16烷基、(OCH2CH2)1-4OCH3;
R5选自:
苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基;上述R5基团可独立地任选地被1至2个下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基。
3.根据权利要求1所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐,其特征在于,
其中手性中心为D型氨基酸骨架;
R3选自:
苯基、环己烷、吡啶基、噻吩基、呋喃基;上述R3基团可独立地任选地被1个下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基;
R4选自:H、环己烷、苯基、二甲氨基、甲基、正十六烷基、-OCOCH3、(OCH2CH2)4OCH3;
R5选自:
苯基、吡啶基、噻吩基、呋喃基;上述R5基团可独立地任选地被1个选自下列的取代基取代:卤素、氰基、羧基、乙酰基、甲磺酰基、硝基、醛基、羟基、氨基、三氟甲基,三氟甲氧基、甲基、乙基、正丙基、异丙基、叔丁基。
4.根据权利要求1所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐,其特征在于,通式(I)化合物选自如下化合物:
5.一种权利要求1所述的丙氨酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐的制备方法,其特征在于,包括如下步骤:
(1)通式化合物A通过酯化反应制得通式B化合物;
(2)通式化合物B与不同羧酸衍生物进行缩合反应制得通式化合物C;
(3)通式化合物C可经脱保护基反应制得通式化合物D;
(4)通式化合物D可经取代反应制得通式化合物E
化合物E即通式(I)化合物,R1、R2、R3同权利要求1所述。
6.一种药物组合物,其特征在于,其中含有权利要求1所述的通式(I)化合物或其药学上可接受的盐及药学上可接受的辅料。
7.权利要求1所述的通式(I)化合物或其药学上可接受的盐、或权利要求7所述的药物组合物在制备P2Y14受体拮抗剂药物中的用途。
8.权利要求1所述的通式(I)化合物或其药学上可接受的盐或权利要求7所述的药物组合物在制备治疗炎症疾病药物中的用途。
9.根据权利要求8所述的用途,其特征在于,所述炎症疾病包括痛风性关节炎和腹膜炎。
10.根据权利要求7或8所述的用途,其特征在于,所述药物添加药学上可接受的辅料制成不同剂型。
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