CN108129486B - 嘧啶酮衍生物及其用途 - Google Patents
嘧啶酮衍生物及其用途 Download PDFInfo
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- CN108129486B CN108129486B CN201810075170.4A CN201810075170A CN108129486B CN 108129486 B CN108129486 B CN 108129486B CN 201810075170 A CN201810075170 A CN 201810075170A CN 108129486 B CN108129486 B CN 108129486B
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- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 claims abstract description 8
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 claims abstract description 8
- 241000223960 Plasmodium falciparum Species 0.000 claims abstract description 8
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种嘧啶酮衍生物及其用途。所述嘧啶酮衍生物为式I所示化合物，或其在药学上可接受的盐。通过活性抑制实验发现：本发明提供的嘧啶酮衍生物对恶性疟原虫的二氢乳清酸脱氢酶具有显著的活性抑制作用。本发明为制备新型抗疟药物奠定了基础。
式I中，R1为C1～C6的直链、支链或环状烷基，或氨基；A为5～6元的饱和或不饱和的碳环基。
Description
技术领域
本发明涉及一种嘧啶酮衍生物及其用途。
背景技术
疟疾是由寄生性的疟原虫所引起的严重危害人类健康的虫媒介传染病，至今依然是世界上最严重的寄生虫病之一。
迄今，临床上应用的抗疟药物主要有氯喹、蒿甲醚和蒿乙醚等青蒿素衍生物、乙胺嘧啶和磺胺多辛等，这类药物具有难以避免的毒副作用、选择性差、容易产生耐药性等缺点。随着生命科学技术的飞速发展，以某些与疟疾相关信号转导通路关键酶作为药物筛选靶点，开发治疗效果好、毒副作用小的抗药物已成为当今新型抗疟药物研究的一个重要方向。
发明内容
本发明设计并合成了一系列嘧啶酮衍生物。通过体外活性抑制实验发现：本发明设计的嘧啶酮衍生物对恶性疟原虫的二氢乳清酸脱氢酶具有显著的活性抑制作用，为制备新型抗疟药物奠定了基础。
本发明的一个目的在于，提供一种结构新颖的嘧啶酮衍生物。
本发明所述的嘧啶酮衍生物为式I所示化合物，或其在药学上可接受的盐：
式I中，R1为C1～C6的直链、支链或环状烷基，或氨基(NH2)；A为5～6元的饱和或不饱和的碳环基。
本发明另一个目的在于，提供一种组合物。
所述组合物包含式I所示化合物或其在药学上可接受的盐和合适的稀释剂或/和填料。
本发明再一个目的在于，揭示上述嘧啶酮衍生物(式I所示化合物或其在药学上可接受的盐)或其组合物的一种用途。即式I所示化合物或其在药学上可接受的盐在制备恶性疟原虫的二氢乳清酸脱氢酶抑制剂中的应用；或，
包含式I所示化合物或其在药学上可接受的盐和合适的稀释剂或填料的组合物在制备治疗由恶性疟原虫的二氢乳清酸脱氢酶介导的疾病的药物中的应用。
此外，本发明还有一个目的在于，提供一种制备式I所示化合物的方法。
所述方法包括下列步骤：
(1)以丙二酸二乙酯为起始原料，由丙二酸二乙酯和氯乙酰氯反应，制备式II所示化合物的步骤；
(2)由式II所示化合物与相应的芳胺
反应，得到式III所示化合物的步骤；
(3)式III所示化合物经水解反应，得到式IV所示化合物的步骤；
(4)式IV所示化合与R1-NH2反应，得到式V所示化合物的步骤；和，
(5)式V所示化合物与多聚甲醛经成环反应，得到目标物(式I所示化合物)的步骤。
其中，R1和A的定义与前文所述相同。
具体实施方式
在本发明一个优选的技术方案中，R1为C1～C3的直链、支链或环状烷基，或氨基(NH2)；
在更优选的技术方案中，R1为甲基，乙基，正丙基，环丙基或氨基(NH2)。
在本发明另一个优选的技术方案中，A为
其中曲线标注位为取代位，且 A与其相连的“母环”为“并”的关系。
在本发明又一个优选的技术方案中，所述的组合物还可包括合适的纤维素制剂或钙磷酸盐(例如磷酸三钙或磷酸氢钙等)，及合适的粘结剂(例如淀粉糊，玉米淀粉，小麦淀粉，大米淀粉或马铃薯淀粉等)。如果需要，还可增加崩解剂和/或以抵抗胃液的合适包衣剂等。
本发明提供的组合物可制成多种剂型，以口服或注射方式给药。
以下通过实施例对本发明作进一步阐述，其目的仅在于更好理解本发明的内容。因此，所举之例不以任何方式限制本发明的保护范围。
实施例1
3-甲基-1-(2-萘基)-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H,6H)-二酮(式Ia所示化合物)合成
(1)2-(2-萘胺基)-4-羰基-4,5-二氢呋喃-3-甲酸乙酯(式IIIa所示化合物)的合成：
在50mL烧瓶中加入3mmol的钠氢(纯度为60％)和1.8mL的无水四氢呋喃(THF)，冰水浴下滴加6mmol的丙二酸二乙酯的3mL无水THF溶液，10分钟后再滴加3mmol氯乙酰氯的3mL无水THF溶液，在40℃～45℃状态搅拌至少1小时；
在室温条件下，再向上述反应液中滴加2-萘胺，在45℃～55℃状态搅拌至少12小时，用 5％稀盐酸溶液调节反应液的pH至6-7，用乙酸乙酯萃取，饱和食盐水洗涤2次，有机层浓缩，干燥，硅胶柱柱层析(石油醚：乙酸乙酯＝1：1，v/v)得白色粉末(式IIIa所示化合物)，收率40％。
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.02-7.90(m,4H),7.63-7.51(m,3H),4.75(s, 2H),4.25(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H).
(2)2-(2-萘胺基)-4-羰基-4,5-二氢呋喃-3-羧酸(式IVa所示化合物)的合成
在冰浴条件下，将3mmol式IIIa所示化合物溶于甲醇：水＝5：1(总18mL)的混合溶液中，再加入15mmol的一水合氢氧化锂，搅拌半小时后撤去冰浴，加热至55℃～60℃，并在此状态保持至少12小时，旋干甲醇，加少许水和5％的稀盐酸调节反应液的pH值为4-5，析出大量米白色固体，抽滤和干燥得到式IVa所示化合物，收率80％。
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.55(s,1H),8.11-7.93(m,4H),7.72-7.41(m, 3H),4.68(s,2H).
(3)2-(2-萘胺基)-4-羰基-4,5-二氢呋喃-3-甲酰胺(式Va所示化合物)的合成
将1mmol的式IVa所示化合物，依次加入10mL二氯甲烷，1.2mmol的1-羟基苯并三唑， 1.2mmol的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和1.2mmol的甲胺水溶液置于圆底烧瓶中，室温搅拌过夜，依次加入饱和碳酸氢钠溶液，饱和食盐水洗涤，有机层浓缩，干燥，硅胶柱柱层析(石油醚：乙酸乙酯＝5：1，v/v)得白色固体(式Va所示化合物)，收率25％。
1H NMR(400MHz,CDCl3)δ12.71(s,1H),8.80(d,J＝5.6Hz,1H),8.05-7.95(m,4H),7.60-7.53(m,3H),3.90(s,2H),3.31(s,3H).
(4)目标化合物(式Ia所示化合物)的合成
将式Va所示化合物(100mg，1.0mmol)和多聚甲醛(10mg，1.2mmol)溶于无水乙醇(4mL) 中，并加入氢氧化钠(17mg，1.2mmol)。混合液在室温搅拌1小时，然后于70℃状态保持至少8小时，停止加热，抽滤，滤液减压浓缩并用硅胶柱柱层析分离(乙酸乙酯：石油醚＝1：3) 得到36mg白色固体(目标化合物，式Ia所示化合物)，产率34.6％。
1H NMR(400MHz,CDCl3):δ8.11-7.90(m,4H),7.51-7.33(m,3H),5.61(s,2H),4.73(s,2H), 3.27(s,3H).
13C NMR(100MHz,CDCl3)δ191.1,183.4,165.5,135.4,133.3,132.3,129.8,128.4,128.2, 127.5,127.2,124.2,123.6,97.6,86.3,77.8,38.5.
LC-MS(ESI)calcd for C17H14N2O3[M+H]+295.10,found 295.17.
实施例2
1-(2-萘基)-3-乙基-2,3-二氢呋喃[2,3-d]嘧啶-4,5-(1H、6H)-二酮(式Ib所示化合物)的合成：
除以乙胺水溶液替换实施例1中甲胺水溶液外(步骤(3)中)，其它条件及步骤与实施例1相同，得到白色固体(式Ib所示化合物)，产率37.3％。
1H NMR(400MHz,CDCl3):δ8.03-7.73(m,4H),7.60-7.42(m,3H),5.51(s,2H),4.88(s,2H), 3.05(q,J＝7.6 3H),1.33(t,J＝7.6 3H).
13C NMR(100MHz,CDCl3)δ193.6,182.4,162.3,135.4,133.3,132.3,131.8,128.4,128.2, 127.5,127.2,124.2,123.6,97.6,38.6,38.5,14.9.
LC-MS(ESI)calcd for C18H16N2O3[M+H]+309.02,found 309.09.
实施例3
1-(2,3-二氢-1H-茚-5-基)-3-乙基-2,3-二氢呋喃[2,3-d]嘧啶-4.5(1H、6H)-二酮(式Ic所示化合物)的合成：
除以式c所示化合物替换实施例1中2-萘胺(步骤(1)中)，及以乙胺水溶液替换实施例1中甲胺水溶液外(步骤(3)中)，其它条件及步骤与实施例1相同，得到白色固体(式 Ic所示化合物)，产率39.1％。
1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.0Hz,1H),7.27(s,1H),7.16(d,J＝8.0Hz,1H), 4.22(q,J＝7.2Hz,2H),4.17(s,2H),3.65(s,2H),2.89(t,J＝7.6Hz,4H),2.09-2.02(m,2H),1.26 (t,J＝7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ190.9,183.5,165.6,145.7,144.2,135.8,125.4,123.6,121.6, 97.1,88.3,59.7,38.4,32.8,32.4,25.7,14.9.
LC-MS(ESI)calcd for C17H18N2O3[M+H]+299.13,found 299.17.
实施例4
1-(2-萘基)-3-丙基-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H、6H)-二酮(式Id所示化合物)的合成：
除以正丙胺水溶液替换实施例1中甲胺水溶液外(步骤(3)中)，其它条件及步骤与实施例1相同，得到白色固体(式Id所示化合物)，产率27.6％。
1H NMR(400MHz,DMSO-d6):δ7.92-7.84(m,4H),7.56-7.29(m,3H),4.51(s,2H),3.57(s, 2H),3.05(q,J＝6.4,2H),1.69-1.63(m,2H),1.33(t,J＝7.2,3H)
13C NMR(100MHz,DMSO-d6)δ193.6,182.4,162.3,135.4,133.3,132.3,131.8,128.4,128.2, 127.5,127.2,124.2,123.6,97.6,38.6,38.5,14.9.
LC-MS(ESI)calcd for C17H18N2O3[M+H]+323.13,found 323.17.
实施例5
1-(2-萘基)-3-环丙基-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H、6H)-二酮(式Ie所示化合物)的合成：
除以环丙胺水溶液替换实施例1中甲胺水溶液外(步骤(3)中)，其它条件及步骤与实施例1相同，得到白色固体(式Ie所示化合物)，产率35.3％。
1H NMR(400MHz,DMSO-d6)δ8.08-7.93(m,4H),7.69-7.54(m,3H),3.89(s,2H),3.64(s, 2H),2.82-2.77(m,1H),0.78-0.73(m,2H),0.56-0.50(m,2H).
13C NMR(100MHz,CDCl3)δ193.7,181.2,167.5,134.9,133.4,131.8,129.9,127.9,127.2, 126.5,121.7,123.5,120.5,99.4,83.6,77.4,29.7,21.6,6.5.
LC-MS(ESI)calcd for C19H16N2O3[M+H]+321.10,found 321.13.
实施例6
1-(2-萘基)-3-氨基-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H、6H)-二酮(式If所示化合物)的合成：
(1)将1mmol的式IVa所示化合物，依次加入6mL二氯甲烷、1mmol的N，N'-羰基二咪唑(CDI)在室温下搅拌约1h。然后加入1.2mmol的80％水合肼溶液。反应结束后，过滤，干燥滤饼并通过柱层析纯化(EA：甲醇＝10:1，v/v)，产品为棕色固体，收率27％；
(2)将1mmol的式Vf所示化合物溶解于5mL无水乙醇中，加入1.2mmol氢氧化钠固体，混合液在室温搅拌1小时后，加入1.2mmol多聚甲醛，于70℃状态保持至少8小时，停止加热，抽滤，滤液减压浓缩并用硅胶柱柱层析分离(乙酸乙酯：石油醚＝1：3)得到白色固体(目标化合物，式If所示化合物)，产率13.2％。
1H NMR(400MHz,CDCl3):δ10.33(s,2H),7.83-7.67(m,4H),7.65-7.43(m,3H),5.51(s, 2H),4.88(s,2H).
13C NMR(100MHz,CDCl3)δ194.7,185.4,162.7,133.5,132.6,131.5,132.2,128.4,128.2, 127.5,127.2,124.2,120.3,87.3,79.9,76.2.
LC-MS(ESI)calcd for C16H13N3O3[M+H]+296.10,found 296.13.
实施例7
本发明提供的化合物对恶性疟原虫二氢乳清酸脱氢酶(PfDHODH)活性的体外抑制效果实验如下：
筛选方法：DHODH(二氢乳清酸脱氢酶)在一定条件下能催化其天然底物DHO(二氢乳清酸)氧化为Orotate。在DHODH的催化下，首先将底物DHO的两个H+及e-转移到辅酶 FMN上，随后还原态的FMNH2将电子传递给游离辅酶CoQ。游离辅酶CoQ最终将电子传递给显色底物DCIP，DCIP被还原。DCIP在600nm处有最大光吸收，而还原态的DCIP在600nm 处没有光吸收。根据吸光度的减弱程度即可判断底物DHO被氧化的程度。单位时间内底物 DHO被氧化程度即为酶促反应初速度。加入抑制剂后，酶促反应初速度降低。PfDHODH实验过程采用DSM1为阳性对照，每次实验至少设三个平行。IC50值使用Originpro 8.0计算。
根据上述筛选方法，测试式Ia～If所示化合物抑制PfDHODH活性的IC50(μM)，具体结果见表1。
表1
Claims (8)
1.一种嘧啶酮衍生物，为式I所示化合物，或其在药学上可接受的盐：
式I中，R1为C1～C6的直链、支链或环状烷基，或氨基；A为5～6元的饱和或不饱和的碳环基。
2.如权利要求1所述的嘧啶酮衍生物，其特征在于，其中R1为C1～C3的直链、支链或环状烷基，或氨基。
3.如权利要求2所述的嘧啶酮衍生物，其特征在于，其中R1为甲基，乙基，正丙基，环丙基或氨基。
4.如权利要求1所述的嘧啶酮衍生物，其特征在于，A为
5.一种嘧啶酮衍生物，其特征在于，所述嘧啶酮衍生物为3-甲基-1-(2-萘基)-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H,6H)-二酮，1-(2-萘基)-3-乙基-2,3-二氢呋喃[2,3-d]嘧啶-4,5-(1H、6H)-二酮，1-(2,3-二氢-1H-茚-5-基)-3-乙基-2,3-二氢呋喃[2,3-d]嘧啶-4.5(1H、6H)-二酮，1-(2-萘基)-3-丙基-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H、6H)-二酮，1-(2-萘基)-3-环丙基-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H、6H)-二酮，或1-(2-萘基)-3-氨基-2,3-二氢呋喃[2,3-d]嘧啶-4,5(1H、6H)-二酮。
6.一种组合物，其包括权利要求1～5中任意一项所述的嘧啶酮衍生物和稀释剂或/和填料。
7.如权利要求1～5中任意一项所述的嘧啶酮衍生物在制备恶性疟原虫的二氢乳清酸脱氢酶抑制剂中的应用。
8.如权利要求6所述的组合物在制备治疗由恶性疟原虫的二氢乳清酸脱氢酶介导的疾病的药物中的应用。
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