CN111518047B - Magl抑制剂及制备方法和用途 - Google Patents
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- CN111518047B CN111518047B CN202010058256.3A CN202010058256A CN111518047B CN 111518047 B CN111518047 B CN 111518047B CN 202010058256 A CN202010058256 A CN 202010058256A CN 111518047 B CN111518047 B CN 111518047B
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Abstract
本发明属于药物领域,涉及一种化合物及其药学上可接受的盐;其制备方法;用于制备其的中间体;及含有这样的化合物或盐的组合物;及其用于治疗MAGL介导的疾病及病症(包括例如疼痛、炎症性病症、创伤性脑损伤、抑郁症、焦虑症、阿尔茨海默病、代谢紊乱、中风或癌症)的用途。
Description
技术领域
本发明涉及药物领域,特别涉及一种MAGL抑制剂及其制备方法和用途。
背景领域
单酰基甘油脂肪酸酶(Monoacylglycerol Lipase,MAGL),又称甘油一酯酶,是一类促进脂肪分解成甘油和脂肪酸的丝氨酸水解酶,是α/β水解酶超家族的成员之一,系丝氨酸水解酶,在人侵袭性肿瘤细胞和原发性肿瘤细胞内高表达。MAGL广泛表达于脂肪组织、肌肉、肾、卵巢、睾丸和肝中。在脂质代谢组织中,MAGL可协同激素敏感性脂解酶将储存的三酰甘油分解为脂肪酸和甘油,为机体供能。在中枢神经系统中,MAGL可将2-花生四烯酸甘油(2-AG)水解成花生四烯酸和甘油,调节内源性大麻素系统。
发明内容:
本发明提供式I化合物或其药学上可接受的盐:
其中,X1为H,F,Cl中的一种;
R为甲基,叔丁基,环己基,苯中的一种;
X2为H,甲氧基,羟基,氟,氯中的一种或多种。
在一些实施例中,R为甲基,叔丁基或环己基,X2为H。
在一些实施例中,R为苯时,X2为H,甲氧基,羟基,氟,氯中的一种或多种,取代基位置任意。
本发明提供一种如式I化合物的合成方法,具体步骤如下:
a和b反应生成I,其中,X1为H,F,Cl中的一种;
R为甲基,叔丁基,环己基,苯中的一种;
X2为H,甲氧基,羟基,氟,氯中的一种或多种。
在一些实施例中,R为甲基,叔丁基或环己基,X2为H。
在一些实施例中,R为苯时,X2为H,甲氧基,羟基,氟,氯中的一种或多种,取代基位置任意。
其中,b由反应而得;所述R为甲基,叔丁基,环己基,苯中的一种;
X2为H,甲氧基,羟基,氟,氯中的一种或多种。
在一些实施例中,R为甲基,叔丁基或环己基,X2为H。
在一些实施例中,R为苯时,X2为H,甲氧基,羟基,氟,氯中的一种或多种,取代基位置任意。
所述的a由反应而得;其中,所述的X1为H,F,Cl中的一种。
具体的,在一些实施例中,采用如下路线进行I的合成:
未经特别说明,本发明上述或下述的各步反应所选用的溶剂为本领域常规溶剂,其选用原则是溶解反应物但不参与反应,萃取产物或使相应产物在其中结晶与杂质分离,如水、卤代烷烃、烷胺、脂肪烃类、酯类、醇类、芳香烃类、醚类、杂环类溶剂;具体选自,但不限于这些溶剂:甲醇、乙醇、丙醇、异丙醇、乙醚、乙酸乙酯、乙酸、环己烷、二氯甲烷、三氯甲烷、四氢呋喃、吡啶、二乙胺、三乙胺、二甲基甲酰胺、甲苯及其中至少两种的混合。
本发明所用a,b等编号是为了叙述通式方便采用的编号,它们在具体实施例中可以将其变形为其它编号,如1,2,3等,均是为了方便叙述,不影响其结构式及其反应方程式的实质属于通式及通式反应方程式的表达。本领域技术人员能够判断上述所有合成路线中的各中间体的取代基均根据目标化合物的结构而定。
通式I目标化合物通式所涵盖的化合物及其具体物质代表中的手性异构或顺反异构体及异构体间以任何比例的混合物亦涵盖在通式I目标化合物通式所涵盖的化合物及其具体物质代表范围内。
未经特别说明,本发明上述或下述的各步反应所选用的溶剂为本领域常规溶剂,其选用原则是溶解反应物但不参与反应,萃取产物或使相应产物在其中结晶与杂质分离,如水、卤代烷烃、烷胺、脂肪烃类、酯类、醇类、芳香烃类、醚类、杂环类溶剂;具体选自,但不限于这些溶剂:甲醇、乙醇、丙醇、异丙醇、乙醚、乙酸乙酯、乙酸、环己烷、二氯甲烷、三氯甲烷、四氢呋喃、吡啶、二乙胺、三乙胺、二甲基甲酰胺、甲苯及其中至少两种的混合。
未经特别说明,本发明上述或下述的各反应中,当反应物有过量时,反应终止可采用加入可与过量反应物反应的物质进行淬灭反应。如有的实施例中可采用水淬灭或采用饱和氯化铵淬灭。
未经特别说明,本发明上述或下述的各反应中,各步反应中的产物的纯化方式选自萃取、结晶、除溶剂、柱层析;其操作均为本领域常规技术,本领域技术人员能够根据具体情况进行处理。
本发明的通式以及通式合成方法可以衍生出不限于这些具体物质,且在本发明的通式和通式合成方法的指导下,本领域技术人员不需要付出创造性劳动即可得到的具体化合物,均在本发明范围内。
虽然本文已经显示和描述了本发明的优选实施方案,但对本领域技术人员显而易见的是,此类实施方案仅通过举例的方式提供。现在,本领域技术人员会想到不背离本发明的许多改变、变化和替代。应理解的是,对本发明所述的本发明实施方案的各种替代可用于实施本发明。所附权利要求旨在限定本发明范围,并且由此覆盖了在这些权利要求范围内的方法和结构及其等同形式。
本发明提供药物组合物,包含上述化合物,即I目标化合物通式所涵盖的化合物及其具体物质代表,或其药学上可接受的盐,和一种或多种药学上可接受的药用辅料。
本申请提供了一种药物组合物,其包含本申请所述的化合物或其药学可接受的盐和药学可接受的载体。所述药物组合物包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。所述组合物可以是液体、固体、半固体、凝胶或气溶胶形式。在一些实施方式中,所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液,用于胃肠外注射的无菌溶液、悬浮液或乳液,用于外用的软膏或乳膏,或者用于直肠给药的栓剂。在其它实施方式中,所述药物组合物为适合单次施予精确剂量的单位剂型。
本发明提供了上述所有化合物或其药学上可接受的盐及其药物组合物,其作为单酰基甘油酯酶抑制剂的用途;或其用于制备治疗具有单酰基甘油酯酶代谢途径的病理学特征的疾病或病症的药物的用途。
本发明提供了上述所有化合物或其药学上可接受的盐及其药物组合物用于抑制单酰基甘油酯酶的方法。该方法包括体内和体外抑制单酰基甘油酯酶的方法。还提供了上述所有化合物或其药学上可接受的盐及其药物组合物用于治疗单酰基甘油酯酶介导的疾病或病症的方法。
其中所述病症选自:代谢紊乱(例如肥胖症);肾病(例如急性炎症性肾损伤及糖尿病肾病);呕吐或涌吐(例如化学疗法诱导的呕吐);恶心(例如难治性恶心或化学疗法诱导的恶心);进食障碍(例如厌食症或贪食症);神经病变(例如糖尿病神经病变、糙皮病性神经病变、酒精性神经病变、脚气病神经病变);神经变性病症[多发性硬化(MS)、帕金森病(PD)、亨廷顿病、痴呆、阿尔茨海默病、肌萎缩侧索硬化(ALS)、癫痫、额颞叶痴呆、睡眠障碍、克雅氏病(CJD)或朊病毒病];精神分裂症;抑郁症;双相障碍;震颤;运动障碍;张力失常;痉挛状态;图雷特氏综合征;戒断综合征[戒酒综合征、抗抑郁药停药综合征、抗精神病药停药综合征、苯并二氮停药综合征、大麻戒断、新生儿戒断、尼古丁戒断或阿片类戒断];外伤性脑损伤;非外伤性脑损伤;脊髓损伤;癫痫发作;与异常细胞生长或增殖有关的病症[例如良性肿瘤或癌症,例如良性皮肤肿瘤、脑瘤、乳头状瘤、前列腺肿瘤、脑肿瘤(胶质母细胞瘤、髓上皮瘤、髓母细胞瘤、神经母细胞瘤、星形细胞瘤、星形母细胞瘤、室管膜瘤、少突神经胶质瘤、丛肿瘤、神经上皮瘤、骨骺肿瘤、室管膜母细胞瘤、恶性脑膜瘤、肉瘤病、黑色素瘤、神经鞘瘤)、黑色素瘤、转移性肿瘤、肾癌、膀胱癌、脑癌、胶质母细胞瘤(GBM)、胃肠癌、白血病或血癌];炎症性病症[例如阑尾炎、滑囊炎、结肠炎、膀胱炎、皮炎、静脉炎、鼻炎、肌腱炎、扁桃体炎、血管炎、寻常痤疮、慢性前列腺炎、肾小球肾炎、超敏反应、IBS、盆腔炎性疾病、结节病、HIV脑炎、狂犬病、脑脓肿、神经炎症、中枢神经系统(CNS)炎症];免疫系统病症(例如移植排斥或乳糜泻);创伤后应激障碍(PTSD);急性应激障碍;惊恐障碍;物质诱导性焦虑;强迫症(OCD);广场恐怖症;特定恐怖症;社交恐怖症;焦虑症;注意缺陷障碍(ADD);注意缺陷多动障碍(ADHD);疼痛[例如急性疼痛;慢性疼痛;炎症性疼痛;内脏痛;手术后疼痛;偏头痛;下腰痛;关节疼痛;腹痛;胸痛;乳房切除术后疼痛综合征;月经疼痛;子宫内膜异位症疼痛;由物理创伤所致的疼痛;头痛;窦性头痛;紧张性头痛、蛛网膜炎、疱疹病毒疼痛、糖尿病性疼痛;由选自以下的病症所致的疼痛:骨关节炎、类风湿性关节炎、骨关节炎、脊椎炎、痛风、阵痛、肌骨骼疾病、皮肤病、牙痛、胃灼热、烧伤、晒伤、蛇咬伤、毒蛇咬伤、蜘蛛咬伤、昆虫叮咬、神经源性膀胱、间质性膀胱炎、尿路感染(UTI)、鼻炎、接触性皮炎/超敏反应、发痒、湿疹、咽炎、黏膜炎、肠炎、肠易激综合征(IBS)、胆囊炎及胰腺炎;神经性疼痛(例如神经性腰痛、复杂性区域疼痛综合征、支柱三叉神经痛、灼性神经痛、中毒性神经病、反射性交感神经营养不良、糖尿病神经病变、化学治疗剂所致的慢性神经病变或坐骨神经痛疼痛)];脱髓鞘病[例如多发性硬化(MS)、德维克氏病、CNS神经病变、脑桥中央髓鞘溶解、梅毒性脊髓病、脑白质病、脑白质营养不良症、格林-巴利综合征、慢性炎症性脱髓鞘性多神经病、抗髓磷脂相关糖蛋白(MAG)周围神经病变、夏科-马里-图思病、周围神经病变、脊髓病变、视神经病变、进展性炎症性神经病变、视神经炎、横贯性脊髓炎];及认知损害[例如与唐氏综合征有关的认知损害;与阿尔茨海默病有关的认知损害;与PD有关的认知损害;轻度认知损害(MCI)、痴呆、化学疗法后认知损害(PCCI)、手术后认知功能障碍(POCD)]。本文所用术语“药学可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力,并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学可以接受的盐。药学可接受的盐是指把母体化合物中的碱基基团转换成盐的形式。药学可接受的盐包括,但不仅限于,碱基基团例如胺(氨)基的无机或有机酸盐类。本申请药学可接受的盐可以由母体化合物合成,即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remingtong’sPharmaceutical Scicences,17th ed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中。
除特别指示外,本申请中的盐指用有机酸/无机酸形成的酸式盐,以及用有机碱/无机碱形成的碱式盐。另外,当通式化合物的碱性官能团是吡啶或咪唑(但不限制于吡啶或咪唑),酸性官能团是羧酸(但不限制于羧酸)时就会形成两性离子(内盐),内盐也包括在本申请中的盐内。
具体实施方式:
本发明的具体化合物代表均可以通过本发明公开的通式合成方法合成出来。下面结合具体的实施方式对本发明做进一步描述,但本发明并不受其限制。且在本发明的通式、通式合成方法及具体的实施方式的指导下,本领域技术人员不需要付出创造性劳动即可得到的其它具体化合物,均在本发明范围内。
实施例1
中间体a的制备:
10ml二氯甲烷中加入3-甲酰基苯硼酸(449.8mg,3mmol,1.5eq),对氟苯酚(224.2mg,2mmol,1eq),醋酸铜(399.3mg,2mmol,1eq),吡啶(0.32ml,4mmol,2eq),室温搅拌12h,停止反应,抽滤除去醋酸铜,滤液经柱层析分离纯化(石油醚:乙酸乙酯=32:1)得到中间体a黄色油状物192.3mg(59.3%)
实施例2
中间体b的制备:
冰浴下,7mlTHF,8ml水中,加入氢氧化钠(240mg,6mmol,1.2eq),碳酸钠(636mg,6mmol,1.2eq),甘氨酸(375.35mg,5mmol,1eq)。10min内缓慢滴加环己甲酰氯(溶于1mlTHF中)(0.67ml,5mmol,1eq),撤去冰浴,室温搅拌14h。滴加0.1M稀盐酸至PH=2,减压蒸馏除去THF,加入10ml水,乙酸乙酯萃取3次,无水硫酸钠干燥,减压蒸馏除去溶剂,得到中间体b白色固体709mg(76.6%)。
实施例3
MAGLZ-III-02的制备:
1ml醋酐中加入N-乙酰甘氨酸(156.3mg,1.335mmol,1.5eq),醋酸钠(94.9mg,1.157mmol,1.3eq),中间体a(192.3mg,0.89mmol,1eq),130℃搅拌1.5h。停止反应,加入饱和碳酸氢钠溶液淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗3次,无水硫酸钠干燥,经柱层析分离纯化(石油醚:乙酸乙酯=100:1)得到目标化合物黄色粉末143.4mg(54.2%)。
实施例4
MAGLZ-III-15的制备:
1.5ml醋酐中加入中间体b(277.8mg,1.5mmol,1.5eq),醋酸钠(106.6mg,1.3mmol,1.3eq),间苯氧基苯甲醛(0.173ml,1mmol,1eq),130℃搅拌1.5h。停止反应,加入饱和碳酸氢钠溶液淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗3次,无水硫酸钠干燥,经柱层析分离纯化(石油醚:乙酸乙酯=100:1)得到目标化合物白色粉末37.8mg(10.9%)。
1HNMR(DMSOd6)δ(ppm):8.02(s,1H),7.72-7.80(m,1H),7.39-7.54(m,3H),7.14-7.24(m,3H),7.06-7.13(m,2H),2.56-2.70(m,1H),1.80-1.95(m,2H),1.58-1.78(m,3H),1.21-1.44(m,5H).
实施例5-9参照实施例1-4的制备过程,合成以下各目标产物,各目标产物的MS结果均与理论值相当,列其NMR数据于下表:
实施例A:MAGL酶分析
采用Cayman的MAGL抑制剂筛选试剂盒,根据其说明书,以4-硝基苯乙酸的乙醇溶液作为MAGL的底物,底物的终浓度为236UM.96孔板中每孔加入150微升的1Xassay buffer,10微升的重组人MAGL蛋白,以及10微升的不同浓度的MAGL inhibitor(1nM-1000nM间的六个点).JZL195(阳性对照抑制剂)作为阳性对照孔,室温孵育5min后,每孔加入10微升的MAGL底物,将86孔震荡10秒,室温下放置10min,检测410nm的吸光值。其中,还要设置100%抑制对照孔(96孔板中每孔加入150微升的1Xassay buffer,10微升的MAGL,以及10微升的DMSO,设置三个复孔),背景孔(每孔加入160微升的1Xassay buffer以及10微升的DMSO,设置三个复孔)。然后采用graphad prism 5.0计算拟合各抑制剂的IC50曲线,具体值见表2。
表2活性数据
化合物编号 | IC50(μM) |
MAGLZ-III-01 | 2.687 |
MAGLZ-III-02 | 33.54 |
MAGLZ-III-03 | 4.466 |
MAGLZ-III-04 | 12.62 |
MAGLZ-III-13 | 2.369 |
MAGLZ-III-15 | ND |
MAGLZ-III-17 | 4.085 |
注:N.D.=未测定
实施例B:动物试验
1材料与方法
1.1实验动物
体重18~22g雄性ICR小鼠。动物在正常的12h光照,12h黑暗时间表下活动。环境温度和相对湿度分别保持在22±1℃和55±5%。
1.2实验方法
1.2.1动物分组和给药方法
6组实验小鼠,每组10只,设为对照组(生理盐水组),阳性对照组(盐酸氟西汀胶囊,5mg/kg),5个MAGLZ-III系列给药处理组:分别为MAGLZ-III-01、MAGLZ-III-03、MAGLZ-III-13、MAGLZ-III-17,给药浓度为5mg/kg。
所有药物通过灌胃以20mL/kg体重的剂量使用,1次/天,持续10天。最后一次给药1h后,开始进行动物行为学的检测。
1.2.2小鼠强迫游泳试验
小鼠强迫游泳实验根据Porsolt(Porsalt R D.Behavioural despair in mice:Aprimary screening test for antidepressants[J].Arch.Int.Pharmacolodyn.1977,229)建立的方法进行检测。小鼠单独在开放的圆柱形容器(直径10cm,高25cm)中强迫游泳,该容器水温25±1℃,水深19cm,每只动物在6分钟的过程中保持不动的总时间被记录为不动时间(以秒为单位)。每只小鼠在停止挣扎时被判定为不动,并且在水中保持悬浮不动,只做出必要的动作以保持头部高于水面。不动时间的减少表明具有抗抑郁作用。
1.2.3小鼠悬尾试验
尾部悬浮试验(TST)根据Porsolt等(Porsolt R D,Le Pichon M,JalfreM.Depression:a new animal model sensitive to antidepressant treatments[J].Nature,1977,266(5604):730-732)建立的方法进行检测。使用悬尾夹子,在距离盒子(250mm×250mm×300mm)尾部10mm,头部距离底部5cm处将小鼠分别悬挂在尾部。在具有最小背景的黑暗房间中测试噪声,每只小鼠悬挂6分钟,在最后4分钟间隔记录不动时间。判定标准是小鼠停止挣扎,完全静止不动。
1.2.4数据处理
所有数据以x±SD表示,组间比较采用单因素方差分析。
2结果
2.1MAGLZ-III系列化合物对小鼠强迫游泳行为的影响
MAGLZ-III系列化合物对小鼠强迫游泳行为影响实验表明阳性对照药盐酸氟西汀、MAGLZ-III系列化合物组均能明显缩短小鼠强迫游泳累积不动时间(P<0.05)(表3)。
表3 MAGLZ-III系列化合物对小鼠强迫游泳行为的影响
注:与对照组比较,P<0.1,P<0.05。
2.2 MAGLZ-III系列化合物对小鼠悬尾行为的影响
与对照组相比,MAGLZ-III系列化合物MAGLZ-III系列各化合物组能明显缩短悬尾小鼠的累计不动时间(P<0.1)(表4)。
表4 MAGLZ-III系列化合物对小鼠悬尾行为的影响
注:与对照组比较,P<0.1,P<0.05。
3讨论
小鼠强迫游泳和小鼠悬尾是较为常用的、经典的抑郁症动物模型。模型所体现出的小鼠绝望、行为扭曲等状态是体外模拟抑郁症的显著特征,同时由于其对抗抑郁药物比较敏感且便于操作,因此是抗抑郁药物常用的筛选模型。本研究采用这两种经典的抑郁动物模型对MAGLZ-III系列化合物的抗抑郁活性进行进一步的评价与验证。结果表明,MAGLZ-III系列化合物能显著缩短小鼠强迫游泳和小鼠悬尾的累积不动时间,表明MAGLZ-III系列化合物具有明确的抗抑郁作用。
Claims (8)
1.式I化合物或其药学上可接受的盐: ,
其中,X1为F;
R为甲基,叔丁基,环己基,苯中的一种;
X2为H,甲基,二甲基,甲氧基,羟基,氟,氯中的一种或多种,取代基位置任意;或X1为Cl中的一种;
R为甲基,叔丁基,环己基,苯中的一种;
X2为H,甲基,二甲基,甲氧基,羟基,氯中的一种或多种,取代基位置任意;
或X1为H,
R为叔丁基,环己基中的一种,
X2为H,甲基,二甲基,甲氧基,羟基,氟,氯中的一种或多种,取代基位置任意;
或X1为H,
R为甲基,
X2为甲基,二甲基,甲氧基,羟基,氟,氯中的一种或多种,取代基位置任意。
2.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述X1为H,F或Cl,R为叔丁基或环己基,X2为H。
3.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,X1为F,R为苯,X2为H,甲氧基,羟基,氟,氯中的一种或多种,取代基位置任意;或 X1为Cl,R为苯,X2为H,甲氧基,羟基,氯中的一种或多种,取代基位置任意。
4.如权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于,具体结构式选自,,/>,,/>,/>。
5.如权利要求1的化合物或其药学上可接受的盐,其为或其药学上可接受的盐。
6.一种药物组合物,其包含权利要求1至5中任一项的化合物或药学上可接受的盐及药学上可接受的载体。
7.权利要求1至5中任一项的化合物或或 />或其药学上可接受的盐在制备治疗MAGL介导的疾病或病症的药物中的用途。
8.如权利要求7所述的用途,其中所述病症选自:代谢紊乱,肾病,呕吐或涌吐或恶心,进食障碍,神经病变,精神分裂症,抑郁症,双相障碍,震颤,运动障碍,戒断综合征,外伤性脑损伤,非外伤性脑损伤,脊髓损伤,癫痫发作,与异常细胞生长或增殖有关的病症,炎症性病症,免疫系统病症,急性应激障碍,物质诱导性焦虑,强迫症,焦虑症,注意缺陷多动障碍,疼痛脱髓鞘病,及认知损害。
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GB2184120A (en) * | 1985-12-06 | 1987-06-17 | Budapesti Vegyimuevek | Novel azlactone derivatives, process for the preparation thereof and pesticides containing these compounds as active ingredient |
CN1120533A (zh) * | 1994-05-02 | 1996-04-17 | 赫彻斯特股份公司 | N-酰基-α-氨基酸衍生物的制备方法 |
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