CN117384091B - 一类酰胺衍生物、合成方法及用途 - Google Patents
一类酰胺衍生物、合成方法及用途 Download PDFInfo
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- CN117384091B CN117384091B CN202311676796.8A CN202311676796A CN117384091B CN 117384091 B CN117384091 B CN 117384091B CN 202311676796 A CN202311676796 A CN 202311676796A CN 117384091 B CN117384091 B CN 117384091B
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Classifications
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Landscapes
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- Organic Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一类酰胺衍生物、合成方法及用途,属于药物合成技术领域。在本发明中,以苯甲酸酯类化合物与硝基苯甲醛类化合物为原料,进行一些系列特定反应后,得到一类酰胺衍生物,属于Nav1.7抑制剂,可用于治疗慢性疼痛。具有良好的镇痛活性,非成瘾性,起效快,镇痛时间长,为开发外周非成瘾性镇痛药物提供了参考,具有良好的应用前景。
Description
技术领域
本发明涉及一类酰胺衍生物、合成方法及用途,属于药物合成技术领域。
背景技术
疼痛是许多医学问题的常见症状,通常表明组织损伤的发生,持续3个月以上的疼痛即为慢性疼痛。相比于具有生存价值和治疗作用的急性疼痛,慢性疼痛的病理现象,严重影响患者的生活质量,更是一种负担。据统计,全球疼痛的发病率约为35-45%,成人慢性疼痛的发病率约为30%。
现有的镇痛药物大多难以对症,导致其治疗效果不理想,且伴有严重的不良反应。例如:在治疗中度到重度的疼痛中,阿片类药物起着重要作用,但其具有很高的成瘾和滥用风险;而非甾体类抗炎药、三环类抗抑郁药,具有中等的镇痛效果,同时,会引发一系列的不良反应,包括急性肾损伤、胃十二指肠毒性和心脏毒性等。因此,慢性疼痛的治疗是一个未被满足的卫生问题,迫切需要治疗或缓解该疼痛的方法。
疼痛的发生与钠离子通道的功能密切相关,钠离子通道负责可兴奋细胞中动作电位的起始和增值。由于钠离子通道的不同亚型的主要序列、组织分布和门控特征有所区别,非选择性抑制钠离子通道用于镇痛会产生不良反应,例如,局麻药-利多卡因和抗惊厥药物表现出良好的镇痛效果,但抑制了中枢神经系统(CNS)和心脏中的钠通道,治疗窗口很窄。因此,开发能够治疗慢性疼痛的亚型选择性抑制剂,将副作用降到最低是很有必要的。
Nav1.7是电压门控钠离子通道家族中α亚基由基因SCN9A编码的成员,免疫细胞化学和电生理记录的证据表明,Nav1.7的表达与神经元的大小和传导速度成反比,表明Nav1.7在传递痛觉的C纤维和Aδ纤维中优先表达。最初,通过遗传学研究发现Nav1.7的功能缺失性突变的个体会出现先天性无痛症(congenital insensitivity to pain,CIP),功能获得性突变与多种先天性疼痛综合征有关,如原发性红斑性肢痛症(primaryerythromelalgia,PE)和阵发性极度疼痛障碍(paroxysmal extreme pain disorder,PEPD)等,这表明Nav1.7在疼痛过程中起重要作用。Nav1.7优先在外周神经系统表达,在痛觉感受器中充当阈值通道,放大由其他通道引起的小的去极化以产生动作电位,提高敏感性,在痛觉信号的放大中起了重要作用,是经过基因验证的镇痛药物靶点。
目前,并没有选择性Nav1.7抑制剂应用于临床,因此,开发新的Nav1.7抑制剂仍然有着广阔的前景,也十分必要。
发明内容
本发明针对现有技术的不足,提出了一类酰胺衍生物、合成方法及用途。其中,发明人团队发现该酰胺衍生物在镇痛方面具有起效快、镇痛效果良好、药效持续时间长等优势,为此,将其用于治疗慢性疼痛,即用于制备出具有镇痛的非成瘾性产品,为临床上慢性疼痛的治疗提供更多选择。
为了实现上述技术目的,提出如下技术方案:
本技术方案的第一目的,在于提供:一类酰胺衍生物,用如下的通式(Ⅰ)表示:
(Ⅰ);
其中,R1为氢基、卤素、氰基、巯基、酯基、三氟甲基或硝基;
R2为氢基、C1-C3烷氧基、卤素、氰基、羟基、三氟甲基或硝基;
R3为氢基、甲氧基、卤素、氰基、羟基、三氟甲基或硝基;
R4为氢基、C1-C3的烷基、C1-C3的烷氧基、卤素、氰基、羟基或三氟甲基;
R5为氢基、甲氧基、甲基、乙基、异丙基或卤素。
R6为氢基、甲氧基、甲基、乙基、异丙基或卤素。
更为具体的,酰胺衍生物包括如下通式Ⅱ表示的化合物:
(Ⅱ)。
更为具体的,酰胺衍生物包括如下通式Ⅲ表示的化合物:
(Ⅲ)。
更为具体的,酰胺衍生物包选自如下结构式:
、、
、、
、、
、、
、、
、
、、
、、
、、
和。
本技术方案的第二目的,在于提供:一类酰胺衍生物的合成方法,包括如下步骤:
S1:将苯甲酸酯类化合物A与硝基苯甲醛类化合物B在强碱条件下反应,得到中间体C;
S2:将中间体C进行还原反应,得到中间体D;
S3:将中间体D与甲醛水溶液进行曼尼希反应,得到中间体E;
S4:中间体E与溴乙酰溴在碱性条件下发生取代反应,得到中间体F;
S5:中间体F在碱性条件下水解,得到中间体G;
S6:中间体G与胺缩合剂发生缩合反应,即得酰胺衍生物;
涉及的合成路线如下:
其中,R1为氢基、卤素、氰基、巯基、酯基、三氟甲基或硝基;
R2为氢基、C1-C3烷氧基、卤素、氰基、羟基、三氟甲基或硝基;
R3为氢基、甲氧基、卤素、氰基、羟基、三氟甲基或硝基;
R4为氢基、C1-C3的烷基、C1-C3的烷氧基、卤素、氰基、羟基或三氟甲基;
R5为氢基、甲氧基、甲基、乙基、异丙基或卤素;
R6为氢基、甲氧基、甲基、乙基、异丙基或卤素。
此外,在步骤S1中,所述强碱为甲醇钠、乙醇钠、二(三甲基硅基)氨基锂、二(异丙基)氨基锂、NaH、正丁基锂或正己基锂中一种或任意两种以上的混合。
在步骤S2中,采用的还原剂包括:在酸性条件下的铁、锌或锡;或者,在碱性条件下的硫化铵或硫氢化钠;或者,在中性条件下的钯或镍。
在步骤S3中,采用的溶剂包括:甲醇、乙醇、丙醇、异丙醇、乙酸或水。
在步骤S4中,采用的碱包括:NaH、二(三甲基硅基)氨基锂、正丁基锂、正己基锂、碳酸钾、碳酸铯、叔丁醇钾、甲醇钠或乙醇钠。
在步骤S5中,采用的碱包括:氢氧化锂、氢氧化钾或氢氧化钠。
在步骤S6中,所述胺缩合剂包括:EDCI、T3P、EMPA、SOCl2、三氯氧磷、DDC、DBU、HOBt、HATU或TCT。
本技术方案的第三目的,在于提供:一种所述的酰胺衍生物的用途,包括用于制备镇痛的非成瘾性制品,其中,镇痛包括慢性炎性疼痛镇痛和慢性神经病理性疼痛镇痛。
本技术方案的第四目的,在于提供:一种药物组合物,包括所述的酰胺衍生物或其药学上可用的盐为活性成分,以及药学上可接受的载体、稀释剂和赋形剂,其中,药物组合物是用于治疗慢性疼痛的非成瘾性药物组合物。
在发明中,提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或 CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本发明没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。其中:
“取代”是指分子中的氢原子被其它不同的原子或分子所替换;
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,“C1-C3烷基”是指包含1-3个碳原子的烷基;
“烷基”是指具有指定数目的成员原子的饱和烃链。例如,“C1-C3烷基”是指具有1-3个成员原子的烷基基团。烷基基团可以是直链或支链,烷基基团可任选地被一个或多个如本发明所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基);
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基,除非另有规定。烷氧基的例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基。
“卤素”为氟、氯、溴或碘;
除非另有规定,本发明所描绘的结构也意味着包括该结构的所有异构(例如对映异构、非对映异构和几何异构(或构象异构))形式;例如,每一不对称中心的R与S构型,(Z)与 (E)双键异构体,和(Z)与(E)构象异构体。因此,这些化合物的单一立体化学异构体以及对映异构、非对映异构和几何异构(或构象异构)混合物都属于本发明的范围。除非另有规定,本发明化合物的所有互变异构形式都属于本发明的范围。
除非另有规定,本发明所描绘的结构也意味着包括该结构的溶剂化物,溶剂化物指本发明化合物与一个或多个溶剂分子的物理缔合;该物理缔合涉及各种程度的离子键和共价键,其包括氢键;合适的溶剂非限制性实例包括但不限于异丙醇、乙醇、甲醇、聚乙二醇、DMSO、乙酸乙酯、乙酸和乙醇胺等;“水合物”为其中溶剂分子为H2O的溶剂化物;
术语“药学上可接受的”是指某载体、赋形剂、稀释剂、辅料,和/或可用的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“药学上可用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
此外,本发明化合物可以以任何便利的使用形式被施用,如片剂、粉末、胶囊、溶液、分散体、悬浮液、糖浆剂、喷雾剂、栓剂、凝胶剂、乳剂、贴剂等。此类组合物可以包含药物制剂中常规的组分,如稀释剂、载体、pH调节剂、增甜剂、增色剂、填充剂、粘合剂、和另外的活性剂;
本发明化合物可以通过任何合适的方式施用,包括口服、局部(包括颊部和舌下)、直肠、阴道、透皮、肠胃外、皮下、腹膜内、肺内和皮肤内,并且,如果需要用于局部治疗,病灶内施用。肠胃外输注包括肌肉内、静脉内、动脉内、腹膜内、眼内、病灶内或皮下施用。
采用本技术方案,带来的有益技术效果为:
本发明提出一类酰胺衍生物及其合成方法,该类酰胺衍生物用于治疗慢性疼痛,具有非成瘾性,起效快,镇痛时间长,这为设计新型非成瘾性慢性镇痛药物提供理论基础,同时为新药研究提供一条新途径,有利于药物开发和临床研究,创造对应的经济价值;
此外,本发明中合成的酰胺衍生物对Navl.7具有抑制活性,属于Nav1.7抑制剂,具有良好的镇痛活性,可用于广泛疼痛治疗,并为开发外周非成瘾性镇痛药物提供了参考,具有良好的应用前景。
附图说明
图1为本发明讨论例1中化合物1-4在CFA疼痛模型中的机械疼痛阈值-时间曲线;
图2为本发明讨论例1中化合物5-8在CFA疼痛模型中的机械疼痛阈值-时间曲线;
图3为本发明讨论例1中化合物1-8在CFA疼痛模型中的机械疼痛阈值-时间曲线的曲线下面积(AUC);
图4为本发明讨论例2中化合物1对Nav1.7电流的抑制率及时间-电流反应曲线(静息态);
图5为本发明讨论例2中化合物1对Nav1.7电流的抑制率及时间-电流反应曲线(半失活态)。
具体实施方式
下面通过对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。除非另行定义,本文所用的术语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。在下述实施例中,对于所涉及的原料和试剂,均通过市售购买获得。
其中,化合物的结构通过核磁共振(NMR)和/或质谱(MS)来确定的,NMR位移(δ)以HT6(ppm)的单位给出,NMR的测定采用fcuker NEO(400MHz)核磁仪,溶剂为氘代氯仿(CDCl3),内标为四甲基硅烷(TMS);MS的测定采用Waters Q-TOF-Premier。高效液相(HPLC)分析采用岛津的LC-20AD。
实施例1
本实施例提供一类酰胺衍生物的合成方法,合成路线如下:
涉及的合成条件如下:
步骤1、NaH,THF,0-40℃,16 h;
步骤2、H2,Pb,CH3OH,rt,16 h;
步骤3、CH3OH,rt,16 h;
步骤4、K2CO3,MeCN,80℃,Reflux;
步骤5、LiOH⋅H2O,MeOH/H2O,60℃,2 h;
步骤6、EDCI,DMAP,DCM,rt,18 h。
涉及的具体合成过程如下:
步骤1:中间体1a的制备
将4-甲基苯甲酸乙酯(1g,36mmol)和2-硝基苯乙酮(993 mg,6mmol)混合在60 mL四氢呋喃中;0℃下,滴加NaH悬浮液(60 %质量分数,720 mg,18.0mmol),搅拌1小时;在氮气保护下移置40℃条件下,搅拌反应16h;减压去除溶剂,在残留的固体糊中加水(40 ml)、加入1M HCl溶液调节pH至中性,用乙酸乙酯(3×30mL)萃取水相,无水MgSO4干燥,过滤,滤液在减压条件下浓缩,后在乙醇中重结晶提纯,得1.3g的中间体1a,为白色,产率76 %。ESI[M+H]+:284.1345。
步骤2:中间体1b的制备
将钯碳(lg,10mass%)加入到中间体1a(1g,3.53mmol)的MeOH(60mL)溶液中,氢气保护,室温搅拌反应过夜,过滤,滤饼用DCM/MeOH(10/1,100mL×2)淋洗,滤液减压浓缩至干,然后柱层析纯化(MeOH/DCM(v/v)=1/34)得到中间体1b,为白色固体(650 mg,65 %)。ESI[M+H]+:254.0987。
步骤3:中间体1c的制备
将中间体1b(640 mg,2.53mmol)溶于30mL甲醇中,加入甲醛水溶液(37%,12.63mmol),室温下搅拌16 h,TLC监测反应完全。过滤,用甲基叔丁基醚洗涤得粗产品。用硅胶柱柱层析纯化(EA/PE= 0-50%),得450mg的中间体1c,为无色油状物,产率70%。ESI[M+H]+:266.2201。
步骤4:中间体1d的制备
将中间体1c(450 mg,1.70mmol)溶解于适量乙腈中,向其中依次加入K2CO3(703mg,5.09mmol)、原料溴乙酸乙酯(340mg,2.04mmol),加热至80℃回流反应;TLC监测反应完全后,减压浓缩反应液;将残留物溶于适量DCM中,水洗有机相除去无机物,分离、合并有机相并通过无水硫酸钠干燥;用柱层析纯化(PE:EA=3:1)得到500 mg中间体1d,淡黄色油状物,产率84 %。ESI[M+H]+:352.1519。
步骤5:中间体1e的制备
向中间体1d (500 mg,1.42mmol)的四氢呋喃(10mL)溶液中加入20mL的MeOH/H2O(5/1,v/v)和LiOH⋅H2O(300 mg,7.11mmol),于60℃下反应2 h;反应完全后,加入乙酸乙酯萃取,水相用1M盐酸调节pH至5左右,再用乙酸乙酯萃取,所得有机相用饱和盐水洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩后得白色固体中间体1e(420 mg,收率91 %)。该产品直接用于下一步,无需进一步纯化。ESI[M+H]+:326.2345。
步骤6:化合物1的制备
将中间体1e (100 mg,0.31mmol)、EDCI(99.8 mg,0.47mmol)、3,4-二甲基苯胺(44.69 mg,0.37mmol)和DMAP(8 mg,0.031mmol)在DCM(30.0mL)中室温搅拌过夜,然后冷却至室温,再加入水(10mL),混合物在DCM和水之间分配;分离的有机层用盐水(10mL×2)洗涤,在Na2SO4上干燥,抽滤,减压干燥;粗产物经柱层析洗脱纯化(PE:EA=2:1),得到80 mg白色固体化合物,产率61 %。
对于化合物1:1H NMR(500 MHz, Chloroform-d)δ9.38 (s, 1H), 7.87 – 7.81(m, 2H), 7.76 (dd, J = 7.9, 2.1 Hz, 1H), 7.41(dd, J= 7.9, 2.2 Hz, 1H), 7.36 –7.20(m, 5H), 7.06 – 6.97 (m, 2H), 4.60 (t, J = 5.4 Hz, 1H), 4.28 (d, J = 1.6Hz, 2H), 4.05(dd, J = 12.4,5.4 Hz, 1H), 3.92 (dd, J = 12.4, 5.4 Hz, 1H), 2.39(d, J = 1.8 Hz, 3H),2.28 – 2.21(m,6H). ESI[M+H]+:429.1827。
实施例2
在实施例1的基础上,本实施例进行化合物2的制备,具体如下:
将实施例1中的中间体1e(100 mg,0.31mmol)、EDCI(99.8 mg,0.47mmol)、4-异丙基苯胺(49.87 mg,0.37mmol)和DMAP(8 mg,0.031mmol)在DCM(30.0mL)中室温搅拌过夜,然后冷却至室温,再加入水(10mL),混合物在DCM和水之间分配;分离的有机层用饱和盐水(10mL ×2)洗涤,Na2SO4干燥,抽滤,减压干燥。粗产物经柱层析洗脱纯化(PE:EA=2:1),得到95 mg白色固体化合物,产率70 %。
对于化合物2:1H NMR(500 MHz, Chloroform-d) δ 9.71 (s, 1H), 7.87 – 7.81(m, 2H), 7.76 (dd, J = 7.9, 2.1 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.36 – 7.27 (m,2H), 7.24 (dq, J = 8.0, 1.1 Hz, 2H),7.20 – 7.14 (m, 2H), 7.00 (dd, J = 6.9,1.9 Hz, 1H), 4.60 (t, J= 5.4 Hz, 1H), 4.28 (d, J = 1.6 Hz, 2H), 4.05 (dd, J=12.4, 5.4 Hz, 1H), 3.92 (dd, J = 12.4, 5.4 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.39(d, J = 1.8 Hz,3H), 1.30 (d, J = 6.6 Hz, 3H), 1.25 (d, J= 6.6 Hz, 3H). ESI[M+H]+:443.3156。
实施例3
在实施例1的基础上,本实施例进行化合物3的制备,具体如下:
将实施例1中的中间体1e(100 mg,0.31 mmol)、EDCI(99.8 mg,0.47 mmol)、3,4-二氟苯胺(47.91mg,0.37mmol)和DMAP(8mg,0.031mmol)在DCM(30.0mL)中室温搅拌过夜,然后冷却至室温,再加入水(10mL),混合物在DCM和水之间分配;分离的有机层用饱和盐水(10mL ×2)洗涤,Na2SO4干燥,抽滤,减压干燥。粗产物经柱层析洗脱纯化(PE:EA=2:1),得到75 mg白色固体化合物,产率56 %。
对于化合物3:1H NMR (500 MHz, Chloroform-d) δ 9.54 (s, 1H), 7.87 –7.81 (m, 2H), 7.76 (dd, J = 7.9, 2.1 Hz, 1H),7.50 (ddd, J = 8.1, 5.0, 2.2 Hz,1H), 7.36 – 7.26 (m, 3H), 7.26 – 7.19 (m, 3H), 7.00 (dd, J = 6.9, 1.9 Hz,1H), 4.60 (t, J= 5.4 Hz, 1H), 4.28 (d, J = 1.6 Hz, 2H), 4.05 (dd, J= 12.4,5.4 Hz, 1H), 3.92 (dd, J = 12.4, 5.4 Hz, 1H), 2.39 (d, J = 1.8 Hz, 3H). ESI[M+H]+:435.0423。
实施例4
本实施例另提供一类酰胺衍生物的合成方法,合成路线如下:
涉及的合成条件如下:
步骤1、NaH,THF,0-40℃,16 h;
步骤2、H2,Pb,CH3OH,rt,16 h;
步骤3、CH3OH,rt,16 h;
步骤4、K2CO3,MeCN,80 ℃,Reflux;
步骤5、LiOH·H2O,MeOH/H2O,60 ℃,2h;
步骤6、EDCI,DMAP,DCM,rt,18 h;
涉及的具体合成过程如下:
步骤1:中间体4a的制备
将4-甲基苯甲酸乙酯(1g,36mmol)和2-硝基-4-三氟甲基苯乙酮(1.4 g,6mmol)混合在60mL四氢呋喃中,0℃下滴加NaH悬浮液(60 %质量分数,720 mg, 18.0mmol),搅拌1小时;在氮气保护下移置40℃条件下,搅拌反应16小时,减压去除溶剂,在残留的固体糊中加水(40ml);加入1M的HCl溶液调节pH至中性,用乙酸乙酯(3×30mL)萃取水相,无水MgSO4干燥,过滤,滤液在减压条件下浓缩,后在乙醇中重结晶提纯,得1.7g白色中间体4a,产率81%。ESI[M+H]+:352.1178。
步骤2:中间体4b的制备
将钯碳(lg,10mass%)加入到中间体4a(1g,2.85mmol)的MeOH(60mL)溶液中,氢气保护,室温搅拌反应过夜,过滤,滤饼用DCM/MeOH(10/1,100mL ×2)淋洗,滤液减压浓缩至干,然后柱层析纯化(MeOH/DCM(v/v)=1/34)得到中间体4b为白色固体(720 mg,72 %)。ESI[M+H]+:322.0967。
步骤3:中间体4c的制备
将中间体4b(720 mg,2.24mmol)溶于30mL甲醇中,加入甲醛水溶液(37 %,11.2mmol),室温下搅拌16 h,TLC监测反应完全,过滤,用甲基叔丁基醚洗涤得粗产品,用硅胶柱柱层析纯化(EA/PE= 0-50%),得540 mg无色油状的中间体4c,产率72 %。ESI[M+H]+:334.1015。
步骤4:中间体4d的制备
将中间体4c(540 mg,1.62mmol)溶解于适量乙腈中,向其中依次加入K2CO3(671mg,4.86mmol)、原料溴乙酸乙酯(325 mg,1.94mmol),加热至80 ℃回流反应,TLC监测反应完全后,减压浓缩反应液;将残留物溶于适量DCM中,水洗有机相除去无机物,分离、合并有机相并通过无水硫酸钠干燥;用柱层析纯化(PE:EA=3:1)得到580 mg中间体4d,淡黄色油状物,产率85 %。ESI[M+H]+:420.1104。
步骤5:中间体4e的制备
向中间体4d(580 mg,1.38mmol)的四氢呋喃(10mL)溶液中加入20mL MeOH/H2O(5/1,v/v)和LiOH·H2O(290mg,6.91mmol),于60℃下反应2h。反应完全后,加入乙酸乙酯萃取,水相用1M盐酸调节pH至5左右,再用乙酸乙酯萃取,所得有机相用饱和盐水洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩后得白色固体中间体4e(520mg,收率96 %)。该产品直接用于下一步,无需进一步纯化。ESI[M+H]+:392.0978。
步骤6:化合物4的制备
将中间体4e (100 mg,0.26mmol)、EDCI (97.9 mg,0.41mmol)、3,4-二甲基苯胺(39.69 mg,0.31mmol)和DMAP(6 mg,0.026mmol)在DCM(30.0mL)中室温搅拌过夜,然后冷却至室温,再加入水(10mL),混合物在DCM和水之间分配;分离的有机层用盐水(10mL ×2)洗涤,在Na2SO4上干燥,抽滤,减压干燥。粗产物经柱层析洗脱纯化(PE:EA=2:1),得到95 mg白色固体化合物,产率65 %。
实施例5
在实施例4的基础上,本实施例进行化合物5的制备,具体如下:
将实施例4中的中间体4e(100mg,0.26mmol)、EDCI(97.9mg,0.41mmol)、4-氟苯胺(34.07mg,0.31mmol)和DMAP(6mg,0.026mmol)在DCM(30.0mL)中室温搅拌过夜,然后冷却至室温,再加入水(10mL),混合物在DCM和水之间分配;分离的有机层用盐水(10mL ×2)洗涤,在Na2SO4上干燥,抽滤,减压干燥。粗产物经柱层析洗脱纯化(PE:EA=2:1),得到85mg白色固体化合物,产率75 %。
实施例6
本实施例提供一类酰胺衍生物的合成方法,合成路线如下:
涉及的合成条件如下:
步骤1、NaH,THF,0-40℃,16 h;
步骤2、H2,Pb,CH3OH,rt,16 h;
步骤3、CH3OH,rt,16 h;
步骤4、K2CO3,MeCN,80℃,Reflux;
步骤5、LiOH·H2O,MeOH/H2O,60 ℃,2 h;
步骤6、EDCI,DMAP,DCM,rt,18 h。
涉及的具体合成过程如下:
步骤1:中间体6a的制备
将3,5-二甲氧基苯甲酸乙酯(1g,4.76mmol)和2-硝基-苯乙酮(786 mg,6mmol)混合在60mL四氢呋喃中;0℃下,滴加NaH悬浮液(60 %质量分数,720 mg,18.0mmol),搅拌1小时;在氮气保护下移置40℃的条件下,搅拌反应16小时,减压去除溶剂,在残留的固体糊中加水(40 ml),加入1M的HCl溶液调节pH至中性,用乙酸乙酯(3×30mL)萃取水相,无水MgSO4干燥,过滤,滤液在减压条件下浓缩,后在乙醇中重结晶提纯,得1.3 g白色中间体6a,产率81 %。ESI[M+H]+:330.1003。
步骤2:中间体6b的制备
将钯碳(lg,10%)加入到中间体6a(1g,2.85mmol)的MeOH(60mL)溶液中,氢气保护,室温搅拌反应过夜,过滤,滤饼用DCM/MeOH(10/1,100mL ×2)淋洗,滤液减压浓缩至干,然后柱层析纯化(MeOH/DCM(v/v) =1/34)得到中间体6b为白色固体(680 mg,68 %)。ESI[M+H]+:300.2659。
步骤3:中间体6c的制备
将中间体6b(680 mg,2.27mmol)溶于30mL甲醇中,加入甲醛水溶液(37 %,11.4mmol),室温下搅拌16h,TLC监测反应完全,过滤,用甲基叔丁基醚洗涤得粗产品;用硅胶柱柱层析纯化(EA/PE=0-50%),得590mg无色油状的中间体6c,产率83%。ESI[M+H]+:312.1228。
步骤4:中间体6d的制备
将中间体6c(590mg,1.9mmol)溶解于适量乙腈中,向其中依次加入K2CO3(786mg,5.69mmol)、原料溴乙酸乙酯(380mg,2.27mmol),加热至80 ℃回流反应;TLC监测反应完全后,减压浓缩反应液;将残留物溶于适量DCM中,水洗有机相除去无机物,分离、合并有机相并通过无水硫酸钠干燥;用柱层析纯化(PE:EA=3:1)得到650 mg中间体6d,淡黄色油状物,产率86 %。ESI[M+H]+:398.1600。
步骤5:中间体6e的制备
向中间体6d (650 mg,1.64mmol)的四氢呋喃(10mL)溶液中加入20mL MeOH/H2O(5/1,v/v)和LiOH·H2O(342 mg,8.18mmol),于60℃下反应2h;反应完全后,加入乙酸乙酯萃取,水相用1M盐酸调节pH至5左右,再用乙酸乙酯萃取,所得有机相用饱和盐水洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩后得白色固体中间体6e(535mg,收率88%)。该产品直接用于下一步,无需进一步纯化。ESI[M+H]+:370.1022。
步骤6:化合物6的制备
将中间体6e (100 mg,0.27mmol)、EDCI (97.9 mg,0.41mmol)、3,4-二甲基苯胺(39.37 mg,0.32mmol)和DMAP(6mg,0.027mmol)在DCM(30.0mL)中室温搅拌过夜,然后冷却至室温,再加入水(10mL),混合物在DCM和水之间分配;分离的有机层用盐水(10mL ×2)洗涤,在Na2SO4上干燥,抽滤,减压干燥;粗产物经柱层析洗脱纯化(PE:EA=2:1),得到95 mg白色固体化合物,产率75 %。
实施例7
在实施例6的基础上,本实施例进行化合物7的制备,具体如下:
将实施例6中的中间体6e(100mg,0.27mmol)、EDCI(97.9mg,0.41mmol)、3,4-二氟苯胺(41.94mg,0.32mmol)和DMAP(6mg,0.027mmol)在DCM(30.0mL)中室温搅拌过夜,然后冷却至室温,再加入水(10mL),混合物在DCM和水之间分配;分离的有机层用盐水(10mL ×2)洗涤,在Na2SO4上干燥,抽滤,减压干燥。粗产物经柱层析洗脱纯化(PE:EA=2:1),得到85 mg白色固体化合物,产率65 %。
对于化合物7:1H NMR (500 MHz, Chloroform-d) δ 9.54 (s, 1H), 7.76 (dd,J = 7.9, 2.0Hz, 1H), 7.50 (ddd, J = 8.2, 5.1, 2.3 Hz, 1H), 7.36 – 7.26 (m,3H), 7.26 – 7.22 (m, 1H), 7.20 (s, 2H), 7.00 (dd, J = 6.9, 1.9 Hz, 1H),6.62(t, J = 2.3 Hz, 1H), 4.64 (t, J = 5.4 Hz, 1H), 4.28 (d, J= 1.6 Hz, 2H), 4.05(dd, J = 12.5, 5.3 Hz, 1H), 3.92 (dd, J = 12.4, 5.4 Hz,1H), 3.81 (s, 6H).ESI[M+H]+:481.1336。
实施例8
在实施例6的基础上,本实施例进行化合物8的制备,具体如下:
将实施例6中的中间体6e(100 mg,0.27 mmol)、EDCI(97.9 mg,0.41 mmol)、苯胺(30.58 mg,0.32 mmol)和DMAP(6 mg,0.027 mmol)在DCM(30.0 mL)中室温搅拌过夜,然后冷却至室温,再加入水(10 mL),混合物在DCM和水之间分配;分离的有机层用盐水(10 mL×2)洗涤,在Na2SO4上干燥,抽滤,减压干燥;粗产物经柱层析洗脱纯化(PE:EA=2:1),得到70mg白色固体化合物,产率58 %。
讨论例1
本讨论例将经实施例1-8所得的化合物1-8在CFA疼痛模型中的镇痛活性进行研究,以对本发明做进一步的说明。
一、将ICR小鼠(购自成都达硕实验动物有限公司,6-8周龄,体重约25g,雄性,在实验环境适应三天)随机分成sham组、model组、阳性对照组及药物组,每组6只。sham组小鼠的左足底给20微升的生理盐水,其他组小鼠的左足底给20微升的CFA,造模,触发炎性疼痛;
二、造模一天后,用电子测痛仪测量给药前各组的造模机械疼痛阈值,采用DMSO:吐温80:生理盐水=1:1:8的溶剂组合,进行对应药物的溶解;
其中,药物组:采用上述的溶剂组合分别溶解化合物1-8,然后,用13mM、0.2mL的剂量进行腹腔注射给药;
sham组、model组:给同样剂量的空白溶剂;
阳性对照组:采用上述的溶剂组合溶解吲哚美辛,然后,用13mM、0.2mL的剂量进行腹腔注射给药;
在给药后10 min、30 min、60 min、90min、120 min、180 min、240 min和300min,分别测量每只小鼠左足的机械疼痛阈值,每个时间点测量三次,取平均值计入统计数据;
结果如图1-2所示:化合物1、化合物2、化合物4、化合物6、化合物7的镇痛活性优于阳性对照吲哚美辛。其中,化合物1于给药后30 min,达最佳的镇痛效果,并可持续约5 h;化合物1相比较于吲哚美辛,其起效快,作用时间长,镇痛强度更高;并且,从图3可发现,化合物1的曲线下面积(Area under curve,AUC%)优于吲哚美辛。
因此,得出:化合物1在镇痛方面具有起效快、镇痛效果良好、药效持续时间长的优点。
讨论例2
本讨论例将经实施例1所得的化合物1对Nav1.7电流的影响,进行研究,以对本发明做进一步的说明。其中,以工具药PF-05089771作为阳性对照,通过手动膜片钳试验测定10 mM浓度下化合物1对Nav1.7电流的作用,具体过程如下:
1、在该电生理实验开始前,高表达Nav1.7的CHO细胞株应保持在对数生长期最大密度的70%以内;
2、所有试剂在使用前预热至37℃,待细胞贴壁良好后进行膜片钳检测实验;
3、采用Patchmaster软件通过EPC⁃10放大器在电脑上采集和存储Nav1.7钠电流数据;
4、用镊子将细胞爬片从细胞培养皿中取出,加入细胞外液,放置在倒置显微镜载物台上的浴槽内;
5、使用P-1000微电极拉制仪拉制玻璃微管,将细胞内液充灌1/3体积的玻璃微管(记录电极),安放于电极夹持器;
6、利用电动显微操作器(Scientifica-Double 1U)将记录电极接触到细胞表面,膜测试窗口显示的封接测试脉冲所代表的电流值下降,撤掉正压,并施以0.5cm H2O 负压,观察封接电阻迅速上升,直至达到吉欧封接。记录电极与细胞膜之间封接电阻>1GΩ后,给予负压破膜,形成全细胞记录模式,待破膜稳定后补偿膜电容(Cs)及串联电阻(Rs);
刺激程序为:(1)钳制电压为-120 mV,给予-120~-10mV、阶跃10 mV、持续时间8000 ms的方波串刺激,然后阶跃至-10 mV,时间为30 ms,最后恢复到-120mV。以膜电位为横坐标,相对电流I/Imax为纵坐标作图,采用Boltzmann程I/Imax=1/{1+exp [(V-V1/2)/k]}进行拟合,得到稳态失活曲线(V1/2为通道半数失活时的条件脉冲电压,k 为斜率因子);
(2)钳制电压为-120mV,去极化至0mV,时程为40ms,刺激出钠通道静息态电流,然后,阶跃至失活曲线V1/2通道半数失活时的条件脉冲电压,时程为8000ms,复极化到-120mV,时程30ms,然后去极化至0mV,时程40ms,刺激出钠通道半失活态电流,最后恢复至-120mV,每20 s记录一次电流。在室温下,记录加药前的Nav1.7钠通道电流,待对照电流值达到稳态后即最近的连续4个电流记录线重合后,依次检测阴性(0.1% DMSO)、工具药PF-05089771、化合物1对电流的影响;
在三次独立重复试验中,检测受试品化合物对Nav1.7通道抑制作用,从PatchMaster软件中提取原始数据Nav1.7电流峰值,电流抑制率的计算公式如下:峰值电流抑制率=(1-peak current compound/peak current vehicle),化合物1对Nav1.7电流的抑制率及时间-电流反应曲线见图4-5。其中,化合物1在10 mM浓度下对静息态Nav1.7电流抑制率为:22.62%±2.45%,对半失活态Nav1.7电流抑制率为:30.92%±4.21%。
Claims (4)
1.一类酰胺衍生物,其特征在于,所述酰胺衍生物选自如下结构式:
、、和
。
2.一类根据权利要求1所述的酰胺衍生物在制备镇痛的非成瘾性药品中的用途。
3.根据权利要求2所述的用途,其特征在于,所述镇痛包括慢性炎性疼痛镇痛和慢性神经病理性疼痛镇痛。
4.一种药物组合物,包括根据权利要求1所述的酰胺衍生物,或其药学上可用的盐为活性成分,以及药学上可接受的载体,其中,药物组合物是用于治疗慢性疼痛的非成瘾性药物组合物。
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