CN116891447A - 一类trpv1拮抗剂、制备方法及其在制备治疗疼痛药物中的应用 - Google Patents
一类trpv1拮抗剂、制备方法及其在制备治疗疼痛药物中的应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一类TRPV1拮抗剂或其药学上可接受的盐,其结构通式如下所示:R1和R2各自独立选自苯环、烷基、或环烷基;X1和X2各自独立选自O、S、NH或SO2NH。本发明还提供了该拮抗剂的制备方法及含其的药物组合物作为制备治疗疼痛药物的用途。所述化合物对TRPV1具有较强的抑制活性,同时具有优异的体内镇痛活性,可用于制备治疗疼痛的药物。
Description
技术领域
本发明属于药物化学及药物治疗学技术领域,具体涉及一类TRPV1拮抗剂、其制备方法,以该类化合物为活性成分的药物组合物,以及它们在制备治疗疼痛药物中的应用。
背景技术
疼痛是常见临床症状,每年大约有5亿人遭受着各种各样疼痛的困扰。目前,临床上应用最多的镇痛药主要分为两类:一类是直接激活阿片受体的麻醉性镇痛药,另一类是以非甾体抗炎药(NSAIDs)为代表的解热镇痛药。这些药物虽然临床效果较好,但是也有明显的副作用,如阿片类药物的成瘾性,非甾体抗炎药的胃肠副反应等。此外,慢性及神经性疼痛使用现有药物也无法得到有效控制。
近年来,随着相关学科的发展及新技术的应用,对各种与疼痛传导相关的受体及其选择性配体的研究取得了一定进展。TRPV1在初级感觉神经元高度表达,是一种非特异性阳离子通道,能被氢离子(pH<5.5)、高温(>42℃)以及其他内源性和外源性配体等激活,在机体对温度和疼痛的感知中发挥重要作用。TRPV1激活后,引起钙离子内流,导致神经末梢释放P物质和降钙素基因相关肽等,从而引发疼痛。下调TRPV1表达或使用TRPV1拮抗剂可以有效阻止TRPV1激活,抑制疼痛信号从外周神经到中枢神经的传导,缓解多种神经损伤带来的疼痛。TRPV1拮抗剂的研究已经成为目前最有前景的镇痛药研究方向之一。
发明内容
本发明目的在于克服现有技术缺陷,提供一类TRPV1拮抗剂、其制备方法,以该类化合物为活性成分的药物组合物,以及它们在制备镇痛药物或治疗疼痛药物中的应用。
为实现上述目的,本发明采用如下技术方案:
一类TRPV1拮抗剂或其药学上可接受的盐,其结构通式如下式(I)所示:
R1和R2各自独立选自苯环、烷基、或环烷基等;
X1和X2各自独立选自O、S、NH或SO2NH等。
进一步的,所述苯环、烷基、环烷基任选被一个或多个选自卤素的基团所取代。
进一步优选的,所述TRPV1拮抗剂或其药学上可接受的盐为下述任意一种化合物:
2-(3-((4-(叔丁基)苄基)氧基)亚苄基)-6-乙氧基苯丙呋喃-3(2H)-酮(I-1);
6-乙氧基-2-(3-((4-异丙基苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-2);
6-乙氧基-2-(3-((4-(三氟甲基)苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-3);
6-乙氧基-2-(3-((2,4,6-三甲基苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-4);
2-(3-乙氧基亚苄基)-6-((4-(三氟甲基)苄基)氧基)苯并呋喃-3(2H)-酮(I-5);
6-((4-(叔丁基)苄基)氧基)-2-(3-乙氧基亚苄基)苯并呋喃-3(2H)-酮(I-6)。
一种药物组合物,其含有治疗有效量的所述TRPV1拮抗剂或其药学上可接受的盐,以及适量的载体、稀释剂或赋形剂。载体、稀释剂或赋形剂采用本领域常规技术即可。
本发明提供了上述TRPV1拮抗剂或其药学上可接受的盐在制备镇痛药物或治疗疼痛药物中的应用。
本发明还提供了上述药物组合物在制备镇痛药物或治疗疼痛药物中的应用。
除非另有说明,否则下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指饱和的脂族烃基团,包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基,较优选含有1至6个碳原子的烷基,更优选含有1至3个碳原子的烷基,最优选为甲基。非限制性实施例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等,及其各种支链异构体等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自卤素、羟基、氰基、硝基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的基团所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,其包括3至20个碳原子,优选包括3至12个碳原子,更优选环烷基环包含3至10个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本发明所述化合物或其可药用的盐,或其前药与其他化学组分的混合物,其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收,利于活性成分在生物体内发挥生物活性。
和现有技术相比,本发明的有益效果如下:
本发明发现了一类新型的TRPV1拮抗剂,并研究给出了其制备方法,其合成过程简单易操作,原料低廉易得,适合规模化生产。本发明还提供了以该类化合物为活性成分的药物组合物,以及它们在制备镇痛药物或治疗疼痛药物中的应用。试验验证:本发明TRPV1拮抗剂具有较好的镇痛效果,可用作镇痛药物或治疗疼痛药物。
具体实施方式
以下结合实施例对本发明的技术方案作进一步地详细介绍,但本发明的保护范围并不局限于此。
下述实施例中,如无特殊说明,所用原料均为可以直接购买的普通市售产品或者可以采用本领域常规方法制备获得。室温指代25±5℃。
实施例1(E)-6-乙氧基-2-(3-羟基亚苄基)苯丙呋喃-3(2H)-酮
第一步:原料Ⅱ-1 6-羟基苯并呋喃酮(0.2g,1.33mmol)溶于20ml乙腈中,加入溴乙烷(0.173g,1.60mmol),无水碳酸钾(0.46g,3.325mmol),0.1g催化量KI,加热至60℃反应8h,过滤,减压蒸除溶剂得到0.24g黄色油状物II-2,未经纯化直接用于下步反应。
第二步:上步得到的化合物II-2溶于20ml甲醇中,加入II-3 3-羟基苯甲醛(0.178g,1.463mmol),甲醇钠(0.18g,3.325mmol),室温下反应6h,减压蒸除溶剂,残余物溶于30ml水中,加入乙酸调pH至酸性(pH=2-3),乙酸乙酯(20ml×3)萃取,合并有机相,以饱和食盐水(15ml×2)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化,得0.26g白色固体II-4,熔点163-165℃,产率65%。
实施例2 2-(3-((4-(叔丁基)苄基)氧基)亚苄基)-6-乙氧基苯丙呋喃-3(2H)-酮(I-1)
第一步:原料III-1对叔丁基苯甲醛(0.2g,1.23mmol)溶于20ml混合溶剂中(四氢呋喃/甲醇,1:1,v/v),冰浴下缓慢加入硼氢化钠(0.085g,2.26mmol),冰浴下反应半小时,反应结束后,加20ml水淬灭反应,乙酸乙酯萃取(30ml×3),合并有机相,以饱和NaCl溶液(20ml×2)洗涤,所得有机相用无水硫酸钠干燥,抽滤,滤液减压蒸除溶剂,未经纯化直接用于下步反应。
第二步:上步得到的化合物溶于20ml二氯甲烷中,缓慢滴入0.5ml氯化亚砜,加入50ul的DMF,室温反应2小时,反应结束后减压蒸除溶剂,得到淡黄色油状物III-2(0.21g,1.23mmol)。上步得到的化合物III-2溶于20ml乙腈中,加入II-4(0.416g,1.48mmol),无水碳酸钾(0.425g,3.075mmol),0.1g催化量KI,加热至60℃反应8h,反应结束后,过滤,减压蒸除溶剂,得到0.44g黄色油状物,残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化得0.31g白色固体I-1,产率58.8%。图谱数据如下。
1H NMR(400MHz,Chloroform-d)δ7.71–7.56(m,1H),7.49(t,J=2.0Hz,1H),7.42–7.23(m,6H),6.93(dd,J=8.2,2.5Hz,1H),6.75–6.58(m,3H),5.01(s,2H),4.06(q,J=7.0Hz,2H),1.39(t,J=7.0Hz,3H),1.26(s,9H).13C NMR(101MHz,Chloroform-d)δ183.02,168.63,166.91,159.10,151.25,147.98,133.70,129.79,127.66,125.82,124.29,117.28,116.15,114.59,112.67,111.67,97.02,70.02,64.56,34.65,31.37,29.69,14.58.ESI-MSm/z:429.5[M+H]+;元素分析计算值:For C28H28O4:C,78.48;H,6.59;实测值:C,78.47;H,6.61。
实施例3 6-乙氧基-2-(3-((4-异丙基苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-2)
合成方法参照实施例2,不同之处在于:将起始原料III-1替换为对异丙基苯甲醛,得白色固体0.28g,熔点165-167℃,产率70%。图谱数据如下。
1H NMR(400MHz,Chloroform-d)δ7.64–7.56(m,1H),7.34(dd,J=13.3,8.0Hz,3H),7.27(t,J=8.0Hz,1H),7.22–7.15(m,3H),6.97–6.90(m,1H),6.69(s,1H),6.67–6.62(m,2H),5.00(s,2H),4.06(q,J=7.0Hz,2H),2.85(hept,J=6.9Hz,1H),1.40(d,J=7.0Hz,3H),1.19(d,J=7.0Hz,6H).13C NMR(101MHz,Chloroform-d)δ183.02,168.63,166.91,159.09,148.99,148.01,133.70,129.79,127.93,126.78,125.89,124.30,117.27,116.23,114.58,112.74,111.66,97.00,70.11,68.57,64.56,33.95,29.69,24.03,14.58.ESI-MSm/z:415.5[M+H]+;元素分析计算值:For C27H26O4:C,78.24;H,6.32;实测值:C,78.26;H,6.31。
实施例4 6-乙氧基-2-(3-((4-(三氟甲基)苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-3)
合成方法参照实施例2,不同之处在于:将起始原料III-1替换为对三氟甲基苯甲醛,得白色固体0.16g,熔点179-181℃,产率63%。图谱数据如下。
1H NMR(400MHz,Chloroform-d)δ7.61–7.55(m,2H),7.51(d,J=8.1Hz,2H),7.48–7.32(m,2H),7.28(t,J=7.9Hz,1H),6.91(dd,J=8.2,2.6Hz,1H),6.73–6.53(m,3H),5.11(s,2H),4.06(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H).13C NMR(101MHz,Chloroform-d)δ182.95,168.60,166.96,158.58,148.04,140.90,133.87,130.40,128.13,127.49,125.86,125.67,124.65,122.72,117.16,116.12,114.53,112.65,111.33,97.02,69.25,64.57,29.73,14.56.ESI-MS m/z:441.4[M+H]+;元素分析计算值:For C25H19F3O4:C,68.18;H,4.35;实测值:C,68.16;H,4.33。
实施例5 6-乙氧基-2-(3-((2,4,6-三甲基苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-4)
合成方法参照实施例2,不同之处在于:将起始原料III-1替换为2,4,6-三甲基苯甲醛,得白色固体0.23g,熔点181-183℃,产率68%。图谱数据如下。
1H NMR(400MHz,Chloroform-d)δ7.64–7.53(m,2H),7.37(d,J=7.7Hz,1H),7.30(t,J=7.9Hz,1H),6.98(dd,J=8.1,2.6Hz,1H),6.86(s,2H),6.78(s,1H),6.71(s,1H),6.65(d,J=8.3Hz,2H),4.99(s,2H),4.06(q,J=7.0Hz,2H),2.31(d,J=1.9Hz,9H),1.39(t,J=7.0Hz,3H).13C NMR(101MHz,Chloroform-d)δ183.06,168.67,166.93,159.59,159.01,148.02,138.58,138.55,138.13,137.95,137.71,133.75,129.80,129.22,128.86,127.07,125.82,124.29,118.02,117.26,115.75,114.89,112.78,100.36,96.97,68.99,64.57,59.20,31.67,29.74,29.68,21.10,19.55,19.50,14.63.ESI-MS m/z:415.5[M+H]+;元素分析计算值:For C27H26O4:C,78.24;H,6.32;实测值:C,78.25;H,6.33。
实施例6 2-(3-乙氧基亚苄基)-6-((4-(三氟甲基)苄基)氧基)苯并呋喃-3(2H)-酮(I-5)
第一步:原料IV-1对三氟甲基苯甲醛(0.2g,1.14mmol)溶于20ml混合溶剂中(四氢呋喃/甲醇,1:1,v/v),冰浴下缓慢加入硼氢化钠(0.086g,2.28mmol),冰浴下反应半小时,反应结束后,加20ml水淬灭反应,乙酸乙酯萃取(30ml×3),合并有机相,以饱和NaCl溶液(20ml×2)洗涤,所得有机相用无水硫酸钠干燥,抽滤,滤液减压蒸除溶剂,未经纯化直接用于下步反应。
第二步:上步得到的化合物溶于20ml二氯甲烷中,缓慢滴入0.5ml氯化亚砜,加入50ul的DMF,室温反应2小时,反应结束后减压蒸除溶剂得到0.259g淡黄色油状物IV-2。上步得到的化合物IV-2(0.259g,1.33mmol)溶于20ml乙腈中,加入II-1(0.2g,1.33mmol),无水碳酸钾(0.425g,3.075mmol),0.1g催化量KI,加热至60℃反应8h,反应结束后,过滤,减压蒸除溶剂,得到0.24g黄色油状物,残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化,得0.372g浅黄色固体IV-3。
第三步:原料II-3 3-羟基苯甲醛(0.178g,1.463mmol)溶于20ml乙腈中,加入溴乙烷(0.190g,1.76mmol),无水碳酸钾(0.46g,3.325mmol),0.1g催化量KI,加热至60℃反应8h,过滤,减压蒸除溶剂,得到0.22g黄色油状物IV-4,未经纯化直接用于下步反应。
第四步:第二步得到的IV-3(0.372g,1.207mmol)溶于20ml甲醇中,加入IV-4(0.22g,1.463mmol),甲醇钠(0.130g,2.414mmol),室温下反应6h,反应结束后,减压蒸除溶剂,残余物溶于30ml水中,加入乙酸调至pH至酸性(pH=2-3),乙酸乙酯(20ml×3)萃取,合并有机相,用饱和食盐水(15ml×2)洗涤,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化,得0.36g白色固体I-5,熔点163-165℃,产率68%。图谱数据如下。
1H NMR(400MHz,Chloroform-d)δ7.63(dd,J=15.3,8.5Hz,3H),7.50(d,J=8.0Hz,2H),7.37(dd,J=4.8,2.4Hz,2H),7.27(t,J=8.1Hz,1H),6.86(dd,J=8.2,2.5Hz,1H),6.80–6.65(m,3H),5.16(s,2H),4.02(q,J=7.0Hz,2H),1.38(t,J=7.0Hz,3H).13C NMR(101MHz,Chloroform-d)δ182.98,168.37,165.94,159.12,147.77,139.56,133.49,130.80,130.48,129.79,127.45,126.06,125.84,124.00,122.61,117.14,115.94,112.58,97.75,69.78,63.58,14.86.ESI-MS m/z:441.4[M+H]+;元素分析计算值:For C25H19F3O4:C,68.18;H,4.35;实测值:C,68.17;H,4.33。
实施例7 6-((4-(叔丁基)苄基)氧基)-2-(3-乙氧基亚苄基)苯并呋喃-3(2H)-酮(I-6)
合成方法参照实施例6,不同之处在于:将起始原料IV-1替换为对叔丁基苯甲醛,得白色固体0.27g,熔点183-187℃,产率56%。图谱数据如下。
1H NMR(400MHz,Chloroform-d)δ7.63(d,J=8.2Hz,1H),7.37(d,J=7.2Hz,4H),7.35–7.22(m,3H),6.85(dd,J=8.1,2.2Hz,1H),6.76(d,J=5.2Hz,1H),6.70(s,1H),5.06(s,2H),4.02(q,J=6.8Hz,2H),1.38(t,J=6.7Hz,3H),1.26(s,9H).13C NMR(101MHz,Chloroform-d)δ183.08,168.53,166.66,159.12,151.67,147.91,133.61,132.44,129.78,127.56,125.90,123.99,117.04,115.93,114.94,112.85,111.95,97.62,70.71,63.57,34.69,31.34,14.88.ESI-MS m/z:429.5[M+H]+;元素分析计算值:For C28H28O4:C,78.48;H,6.59;实测值:C,78.47;H,6.58。
镇痛活性试验
本发明中化合物的TRPV1抑制活性及体内镇痛活性可以通过使用如下所述的测定系统测定。以下生物学测试实施例描述解释本发明。
本发明测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常用试剂。
测试例1本发明化合物对hTRPV1-HEK293稳转细胞的激动活性
本发明使用以下方法测定本发明化合物的hTRPV1抑制活性:
hTRPV1-HEK293稳转细胞以2.5×104/孔的密度接种至96孔黑板上,置于37℃、5%CO2的细胞培养箱中过夜培养;在室温下装载Fluo-3AM钙离子荧光探针,首先配制2mM钙离子荧光探针Fluro-3AM的DMSO母液,向Fluo-3AM/DMSO溶液中加16.5mg Pluronic F127,防止Fluo-3AM在HBSS(Hank’s平衡盐溶液)中聚合并能帮助其进入细胞。用HBSS稀释Fluo-3AM溶液,制备5μM的Fluo-3AM工作液,将上述工作液加入细胞板中,每孔10μL,37℃培养30分钟。每孔加入50μL含有1%胎牛血清的HBSS,继续培养40分钟。用台式液洗涤细胞4次,每孔加入40μL不同浓度的样品,每个样品浓度设置3个复孔,阳性对照组加入等量的N-(4-(叔丁基)苯基)-4-(3-氯吡啶-2-基)哌嗪-1-甲酰胺(BCTC),阴性对照组加入台氏液(英文全称Tyrode's solution)。37℃孵育30分钟后给予辣椒碱刺激(50nM),随后检测辣椒碱刺激前后λex=488nm和λex=540nm吸光度值来表征胞浆钙离子浓度,结果见表1。
抑制率=(空白组差值-实验组差值)/空白组差值(差值=给辣椒碱前后荧光值的差)
表1:hTRPV1受体抑制活性
表1中化合物代号对应的化学结构同实施例。
表1的测试结果表明,本发明所有化合物在不同浓度下对TRPV1具有明显的抑制活性,在10μM浓度下抑制率均大于50%,其中化合物I-6具有较强的抑制活性,与阳性对照BCTC相当。
测试例2本发明化合物的体内镇痛活性可以通过使用如下所述的两种小鼠疼痛模型测定系统测定:
(1)醋酸诱导扭体实验
10周龄昆明种清洁级小鼠,体重22~25 g,雄性,按照体重随机分组,每组6只。测试前30 min灌胃给药本发明化合物,剂量均为30 mg/kg,空白对照组给予等体积的0.5%的羧甲基纤维素钠溶液。测试时小鼠腹腔注射0.6%醋酸溶液,记录小鼠15分钟内出现扭体反应(腹部内凹、伸展后肢、臀部抬高)的次数,结果见表2。
(2)福尔马林致痛模型实验
8周龄清洁级ICR小鼠进行适应性喂养后,按照体重随机分组,每组6只。实验开始前,小鼠灌胃给药本发明化合物,实验组给药剂量均为30 mg/kg,空白对照组给予等体积的0.5%的羧甲基纤维素钠溶液。1 h后,右后侧脚趾皮下注射福尔马林溶液,分别记录I相(0-5 min)和II相(15-45 min)反应舔足时间。
表2:部分化合物对醋酸及福尔马林诱导的小鼠扭体的影响
注:*P≤0.05为相对于空白对照组的Student’s t检验结果。
表2测试结果表明,本发明所有化合物均可显著抑制醋酸诱导的疼痛反应,其中化合物I-6镇痛活性最强,与阳性对照BCTC相当。此外,化合物I-6还可显著抑制福尔马林诱导的炎症性疼痛。
实施例8
含活性成分I-6的片剂:
片剂的制备采用本领域常规技术即可,如可参考:将活性成分I-6、预胶化淀粉和微晶纤维素过筛,充分混合,加入聚乙烯吡咯烷酮与适量乙醇,混合,制软材,过筛,制湿颗粒,于50-60℃干燥,将羧甲基淀粉钠盐、硬脂酸镁和滑石粉过筛加入至上述颗粒中压片成型。
经试验验证,上述组合物片剂也具有良好的体内镇痛活性。
Claims (6)
1.一类TRPV1拮抗剂或其药学上可接受的盐,其特征在于,结构通式如下所示:
R1和R2各自独立选自苯环、烷基、或环烷基;
X1和X2各自独立选自O、S、NH或SO2NH。
2.如权利要求1所述TRPV1拮抗剂或其药学上可接受的盐,其特征在于,所述苯环、烷基、环烷基任选被一个或多个选自卤素的基团所取代。
3.如权利要求1所述TRPV1拮抗剂或其药学上可接受的盐,其特征在于,所述TRPV1拮抗剂或其药学上可接受的盐为下述任意一种化合物:
2-(3-((4-(叔丁基)苄基)氧基)亚苄基)-6-乙氧基苯丙呋喃-3(2H)-酮(I-1);
6-乙氧基-2-(3-((4-异丙基苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-2);
6-乙氧基-2-(3-((4-(三氟甲基)苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-3);
6-乙氧基-2-(3-((2,4,6-三甲基苄基)氧基)亚苄基)苯并呋喃-3(2H)-酮(I-4);
2-(3-乙氧基亚苄基)-6-((4-(三氟甲基)苄基)氧基)苯并呋喃-3(2H)-酮(I-5);
6-((4-(叔丁基)苄基)氧基)-2-(3-乙氧基亚苄基)苯并呋喃-3(2H)-酮(I-6)。
4.一种药物组合物,其特征在于,含有治疗有效量的权利要求1所述TRPV1拮抗剂或其药学上可接受的盐,以及适量的载体或赋形剂。
5.权利要求1所述TRPV1拮抗剂或其药学上可接受的盐在制备镇痛药物或治疗疼痛药物中的应用。
6.权利要求4所述药物组合物在制备镇痛药物或治疗疼痛药物中的应用。
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