CN112457309B - 一种苯基取代吡啶并嘧啶胺类化合物及其作为抗菌药物的应用 - Google Patents
一种苯基取代吡啶并嘧啶胺类化合物及其作为抗菌药物的应用 Download PDFInfo
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- -1 Phenyl-substituted pyrido-pyrimidinamine compound Chemical class 0.000 title claims abstract description 16
- 229940124350 antibacterial drug Drugs 0.000 title claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003242 anti bacterial agent Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- HHAVGBXLGVYXFF-AWEZNQCLSA-N (2r)-n-[3-(heptylamino)-3-oxopropyl]-2,4-dihydroxy-3,3-dimethylbutanamide Chemical compound CCCCCCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO HHAVGBXLGVYXFF-AWEZNQCLSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract description 6
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- WZUYRUCXPBGUOM-UHFFFAOYSA-N pyrido[3,2-d]pyrimidin-2-amine Chemical class N1=CC=CC2=NC(N)=NC=C21 WZUYRUCXPBGUOM-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- 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
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Abstract
本发明涉及一种苯基取代吡啶并嘧啶胺类化合物及其作为抗菌药物的应用，所述苯基取代吡啶并嘧啶胺类化合物具有式I所示结构：
Description
技术领域
本发明属于药物化学领域，具体涉及一种苯基取代吡啶并嘧啶胺类化合物及其作为抗菌药物的应用。
背景技术
吡啶、嘧啶、胺类结构基团是医药、农药等有机合成中一类重要结构单元，该类化合物表现出多种生物活性，例如抗肿瘤、抗病毒、抗菌、杀虫等，被药学家、化学家们广泛关注。本发明提供一种苯基取代吡啶并嘧啶胺类化合物及其作为抗菌药物的应用。本发明提供的苯基取代吡啶并嘧啶胺类化合物对革兰氏阳性菌和阴性菌均表现出抗菌活性。
发明内容
本发明提供一种式I结构的苯基取代吡啶并嘧啶胺类化合物、其立体异构体、互变异构体或其药学上可接受的盐，其特征在于式I结构如下：
本发明的另一实施方案提供上述式I结构的苯基取代吡啶并嘧啶胺类化合物选自如下化合物1-2：
本发明的另一实施方案提供上述式I结构的苯基取代吡啶并嘧啶胺类化合物的制备方法，其特征在于包括如下步骤：
(1)有机溶剂中，式II化合物与间氯过氧苯甲酸(mCPBA)在室温下搅拌反应得式III化合物；
(2)式III化合物与RNH2于有机溶剂中，加热至100-120℃，反应得到式I化合物，R选自C1-C3烷基、C6-C10芳基、苯基取代的C1-C3烷基；优选苯基、苄基。
步骤(1)中有机溶剂优选二氯甲烷，氯仿、甲苯、THF等，mCPBA的摩尔用量为式II化合物3-5倍；
步骤(2)中有机溶剂优选醋酸、异丙醇等，RNH2的摩尔用量为式II化合物1.5-2.0倍，反应优选在封管中进行。
本发明的另一实施方案提供上述式I结构的苯基取代吡啶并嘧啶胺类化合物、其立体异构体、互变异构体或其药学上可接受的盐在制备抗菌药物中的应用。
本发明的另一实施方案提供一种抗菌药物，其特征在于所述抗菌药物以上述式I结构的苯基取代吡啶并嘧啶胺类化合物、其立体异构体、互变异构体或其药学上可接受的盐作为有效成分。该抗菌药物还任选包括其他抗菌药物和/或药学上可接受的辅料。
具体实施方式
为了便于对本发明的进一步理解，下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则，本发明的实施方式不限于以下内容。
实施例1
(1)将式II化合物(1.0mmol)与间氯过氧苯甲酸(mCPBA，5.0mmol)溶于二氯甲烷(15mL)中，室温下搅拌反应约4小时(TLC检测反应完全)后，加入10％的硫代硫酸钠溶液终止反应，反应液用二氯甲烷萃取、并用饱和氯化钠洗涤、无水硫酸钠干燥，有机相浓缩干燥后得白色固体(即为式III化合物)；
(2)将步骤(1)得到的式III化合物(未经纯化)与BnNH2(2.0mmol)于醋酸(5mL)中，封管加热至120℃，反应2小时(TLC检测反应完全)后，反应液用乙酸乙酯萃取，并用饱和碳酸氢钠、饱和氯化钠洗涤、无水硫酸钠干燥，有机相浓缩后，经硅胶柱层析得到化合物2(242.3mg，淡黄色固体)，HRMS m/z401.1596[M+H]+(calcd for C23H21N4O3,401.1608)，1HNMR(DMSO-d6,400MHz)δ:9.00(s,1H),8.80(t,6.5Hz,1H),8.38(s,1H),7.61(d,6.8Hz,3H),7.54(dd,7.6,2.3Hz,2H),7.29(d,6.4Hz,1H),7.18(dd,5.0,2.0Hz,2H),6.88(dd,6.6,3.0Hz,2H),4.20(q,7.0Hz,2H),4.12(d,6.4Hz,2H),1.25(t,7.0Hz,3H)；13C NMR(DMSO-d6,100MHz)δ:173.04,164.07,162.23,160.35,156.58,149.47,140.04,139.27,129.91,129.64,129.41,128.72,128.50,128.47,128.20,127.24,114.17,111.18,60.56,44.81,14.65。
实施例2
(1)将式II化合物(1.0mmol)与间氯过氧苯甲酸(mCPBA，3.0mmol)溶于二氯甲烷中(15mL)，室温下搅拌反应约6小时(TLC检测反应完全)后，加入10％的硫代硫酸钠溶液终止反应，反应液用二氯甲烷萃取、并用饱和氯化钠洗涤、无水硫酸钠干燥，有机相浓缩干燥后得白色固体(即为式III化合物)；
(2)将步骤(1)得到的式III化合物(未经纯化)与PhNH2(1.5mmol)于异丙醇(5mL)中，封管加热至100℃，反应1小时(TLC检测反应完全)后，将反应液浓缩，经硅胶柱层析得到化合物1(201.6mg，淡黄色固体)，HRMS m/z387.1443[M+H]+(calcd for C22H19N4O3,387.1452)，1H NMR(DMSO-d6,400MHz)δ:10.42(s,1H),9.21(s,1H),8.50(s,1H),7.78-7.72(m,5H),7.43(d,8.0Hz,2H),7.04(s,2H),6.92(t,7.2Hz,1H),4.24(q,7.0Hz,2H),1.32(t,7.0Hz,3H)。
实施例3
本发明式II化合物可通过商业定制购买或者采用如下方法合成获得。
(1)取式IV化合物(10mmol)、醋酐(40mmol)、原甲酸三乙酯(25mmol)加热至回流温度，反应3小时左右，自然冷却至室温，反应液减压浓缩后得浅褐色油状物；
(2)将步骤(1)得到的油状物，溶于THF(50mL)中，搅拌下加入苯胺(15mmol)室温下搅拌8小时后，将反应液浓缩后加入DMF(50mL)、碳酸钾(15mmol)，惰性气体保护下加热至110℃反应6小时左右，减压浓缩除去DMF，并用二氯甲烷萃取、依次用1M HCl、饱和碳酸氢钠、饱和氯化钠洗涤，有机相用无水硫酸钠干燥，浓缩后经硅胶柱层析即得式II化合物(两步总收率42.3％)，HRMS m/z 342.0901[M+H]+(calcd for C17H16N3O3S,342.0907)；1H NMR(DMSO-d6,400MHz)δ:9.22(s,1H),8.56(s,1H),7.70-7.52(m,5H),4.22(q,7.0Hz,2H),2.27(s,3H),1.26(t,7.0Hz,3H)。
实施例4
活性测试：本发明采用本领域常用的采用微量肉汤二倍稀释法测试本发明化合物1-2对金黄色葡萄球菌(S.aureus ATCC25923)和大肠杆菌(E.coli ATCC25922)的最小抑菌浓度(MIC，μg/mL)，以环丙沙星作为阳性对照。具体方法为：分别在96孔板中加入适量细菌培养液，然后再第1孔中加入128.0μg/mL药物母液混匀，从中吸取一半体积的培养液加入第2孔中混匀，如此一直稀释至第11孔(第1至11孔药物浓度分别为128、64、32、16、8、4、2、1、0.5、0.25、0.125μg/mL)，最后在第1至12孔加入菌液，第12孔不加药物作为对照。将96孔板放置37℃恒温箱中培养24小时后，观察每孔细菌的生长情况，取未长菌孔的药物浓度作为最小抑菌浓度(MIC，μg/mL)。结果见下表
| 化合物 | ATCC25923 | ATCC25922 |
| 1 | 0.5 | 4.0 |
| 2 | 4.0 | 32.0 |
| 环丙沙星 | 1.0 | 16.0 |
Claims (7)
1.一种式I结构的苯基取代吡啶并嘧啶胺类化合物或其药学上可接受的盐，
其特征在于式I结构如下：
2.权利要求1所述的式I结构的苯基取代吡啶并嘧啶胺类化合物的制备方法，其特征在于包括如下步骤：
(1)有机溶剂中，式II化合物与间氯过氧苯甲酸mCPBA在室温下搅拌反应得式III化合物；
(2)式III化合物与RNH2于有机溶剂中，加热至100-120℃，反应得到式I化合物，R选自苯基、苄基。
3.权利要求2所述的制备方法，其特征在于步骤(1)中有机溶剂选自二氯甲烷，氯仿、甲苯、THF，mCPBA的摩尔用量为式II化合物3-5倍。
4.权利要求2所述的制备方法，其特征在于步骤(2)中有机溶剂选自醋酸、异丙醇，RNH2的摩尔用量为式II化合物1.5-2.0倍，反应在封管中进行。
5.权利要求1所述的式I结构的苯基取代吡啶并嘧啶胺类化合物或其药学上可接受的盐在制备抗菌药物中的应用。
6.一种抗菌药物，其特征在于所述抗菌药物以权利要求1所述的式I结构的苯基取代吡啶并嘧啶胺类化合物或其药学上可接受的盐作为有效成分。
7.权利要求6所述的抗菌药物，其特征在于该抗菌药物还包括其他抗菌药物和/或药学上可接受的辅料。
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| WO2014164729A1 (en) * | 2013-03-12 | 2014-10-09 | Arqule, Inc. | Substituted tricyclic pyrazolo-pyrimidine compounds |
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| WO2008055013A2 (en) * | 2006-10-31 | 2008-05-08 | Janssen Pharmaceutica N.V. | 5-oxo-5,8 - dihydro - pyrido - pyrimidines as inhibitors of c-fms kinase |
| WO2014164729A1 (en) * | 2013-03-12 | 2014-10-09 | Arqule, Inc. | Substituted tricyclic pyrazolo-pyrimidine compounds |
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