CN114716384B - 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 - Google Patents
一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 Download PDFInfo
- Publication number
- CN114716384B CN114716384B CN202210234067.6A CN202210234067A CN114716384B CN 114716384 B CN114716384 B CN 114716384B CN 202210234067 A CN202210234067 A CN 202210234067A CN 114716384 B CN114716384 B CN 114716384B
- Authority
- CN
- China
- Prior art keywords
- nmr
- mercaptoacetyl
- mer
- chloroform
- pleuromutilin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical class C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title claims abstract description 44
- 125000000714 pyrimidinyl group Chemical group 0.000 title claims abstract description 11
- OKGNMRKOGWTADH-UHFFFAOYSA-N 1,4-dihydropyrimidine Chemical compound C1C=CNC=N1 OKGNMRKOGWTADH-UHFFFAOYSA-N 0.000 title abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 15
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 14
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims abstract description 12
- 229960003085 meticillin Drugs 0.000 claims abstract description 12
- 241000193996 Streptococcus pyogenes Species 0.000 claims abstract description 9
- 241000894006 Bacteria Species 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 32
- 230000000694 effects Effects 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 238000005481 NMR spectroscopy Methods 0.000 description 39
- -1 diterpenoid compounds Chemical class 0.000 description 37
- 241000272186 Falco columbarius Species 0.000 description 11
- 102000007517 Neurofibromin 2 Human genes 0.000 description 11
- 108010085839 Neurofibromin 2 Proteins 0.000 description 11
- 229960004885 tiamulin Drugs 0.000 description 8
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 description 8
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 7
- 229940124350 antibacterial drug Drugs 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 229950008166 valnemulin Drugs 0.000 description 4
- LLYYNOVSVPBRGV-MVNKZKPCSA-N valnemulin Chemical compound CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 LLYYNOVSVPBRGV-MVNKZKPCSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 3
- SFAYBQDGCKZKMH-UHFFFAOYSA-N BNCC Chemical compound BNCC SFAYBQDGCKZKMH-UHFFFAOYSA-N 0.000 description 2
- 108010077805 Bacterial Proteins Proteins 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- JBLLRCOZJMVOAE-HSQYWUDLSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methoxy-1h-indole-2-carboxamide Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)C=1NC=2C=CC=C(C=2C=1)OC)C(=O)C=1SC2=CC=CC=C2N=1)[C@@H]1CCNC1=O JBLLRCOZJMVOAE-HSQYWUDLSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003230 pyrimidines Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KPVIXBKIJXZQJX-FCEONZPQSA-N 21904a5386 Chemical compound O([C@H]1[C@@]2(C)[C@@H]3C(=O)CC[C@]3([C@H]([C@H](O)[C@](C)(C=C)C1)C)CC[C@H]2C)C(=O)CS[C@@H]1CC[C@@H](N)C[C@H]1O KPVIXBKIJXZQJX-FCEONZPQSA-N 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 241000589893 Brachyspira hyodysenteriae Species 0.000 description 1
- 241001572230 Clitopilus passeckerianus Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- AKQOBHZKBDHWQI-BZEFIUHZSA-N O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O Chemical compound O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O AKQOBHZKBDHWQI-BZEFIUHZSA-N 0.000 description 1
- 241000222350 Pleurotus Species 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000010983 kinetics study Methods 0.000 description 1
- 229950010255 lefamulin Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于抗菌活性化合物技术领域，尤其涉及一种含有3,4‑二氢嘧啶和嘧啶侧链的截短侧耳素类衍生物及其应用。本发明公开了一种含有3,4‑二氢嘧啶侧链或嘧啶侧链的截短侧耳素类衍生物，所述含有3,4‑二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物对多种阳性菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌等具有非常显著的抑制作用，可应用于制备耐药菌药物。
Description
技术领域
本发明属于抗菌活性化合物技术领域，尤其涉及一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其应用。
背景技术
截短侧耳素是上世纪50年代首次从高等真菌Pleurotus multilus(Fr.)Sacc.和Pleurotus Passecke-rianus Pilat中分离出的一种具有抗菌活性的双萜类化合物。尽管截短侧耳素抑菌活性较低，但通过对该化合物经过结构改造，尤其在C-14位酯基上连接一个硫醚基的侧链，可显著提高该类化合物的抑菌活性。截短侧耳素及其衍生物是在核糖体水平上抑制细菌蛋白质的合成，该类化合物结合在核糖体肽基转移酶(PTC)的V结构域，其中，三元母核结合于A位点的活性口袋中，而侧链部分覆盖了tRNA与核糖体结合的P位点，通过抑制细菌蛋白质的合成而达到抑菌目的。正是由于这种特殊的作用机制，截短侧耳素及其衍生物在体内和体外均有着良好的抗阳性耐药菌的活性，以及较好的药代动力学性质和较低的耐药性。
通过对截短侧耳素结构改造，已研发出泰妙菌素、沃尼妙林、瑞他莫林和Lefamulin四种药物。其中，前两种作为兽用药物用于治疗或预防由Brachyspirahyodysenteriae和Mycoplasma spp.引起的疾病。后两种作为人用药物，分别治疗由葡萄球菌和链状球菌引起的伤口感染皮肤感染和社区获得性细菌性肺炎。而开发抑菌活性更好的截短侧耳素衍生物，对于抗菌药物的研发及其重要。
发明内容
本发明的目的在于提供一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其应用，所提供的截短侧耳素类衍生物具有显著的抑菌活性。
为实现上述目的，本发明采用的技术方案是：
第一方面，本发明提供了一种截短侧耳素类衍生物或其药学上可接受的盐，所述截短侧耳素类衍生物为式(I)所示的含有取代3,4-二氢嘧啶侧链的截短侧耳素类衍生物，或式(II)所示的含有取代嘧啶侧链的截短侧耳素类衍生物：
其中，R1选自烷基或烷氧基；R2选自直链或支链烷基。
优选地，所述R1选自-CH3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH＝CH2；R2选自-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CHCH(CH3)2、或-CH(CH2CH3)2。
优选地，所述截短侧耳素类衍生物为式(II)所示的含有取代嘧啶侧链的截短侧耳素类衍生物。
优选地，所述R1为-OCH3，R2为-CH3。
优选地，所述R1为-CH3，R2为-CH3。
优选地，所述R1为-OCH2CH3，R2为-CH3。
第二方面，本发明提供了上述第一方面所述的截短侧耳素类衍生物或其药学上可接受的盐在制备抗菌药物中的应用。
优选地，所述抗菌药物为抗耐药菌的药物。
优选地，所述耐药菌包括金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌。
第三方面，本发明提供了上述第一方面所述的截短侧耳素类衍生物或其药学上可接受的盐加入药学上可接受的载体或辅料制成药学上可接受的任一剂型。
相比于现有技术的缺点和不足，本发明具有以下有益效果：
相较于已有的截短侧耳素类衍生物，本发明提供的含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物，对多种阳性菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌等，具有显著的抑制作用，因此，本发明的截短侧耳素衍生物可以进一步研发为抗菌药物，尤其是抗耐药菌药物；本发明涉及到的截短侧耳素类衍生物的制备原料主要是乙酰乙酸乙酯、醛和硫脲，与泰妙菌素、沃尼妙林、瑞他莫林和利发姆林等截短侧耳素类药物相比，具有原料易得、成本低廉，工艺简单，绿色环保等优点；而且相较于现有已知的泰妙菌素、沃尼妙林、瑞他莫林和利发姆林等截短侧耳素类衍生物，本发明所述的截短侧耳素类衍生物5a、5g和5h对MRSA、MRSE和S.aureus的MIC均小于或等于0.0313μg/mL，对化脓链球菌也有中等的抑菌活性，抑菌效果更显著。
附图说明
图1化合物5a、5g和5h的1×和6×MIC浓度进行了杀菌动力学结果；
图2化合物5h治疗感染MRSA小鼠的死亡率及ED50，其中A为死亡率；B为ED50。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明所述的含有3,4-二氢嘧啶和嘧啶侧链的截短侧耳素类衍生物，通过以下技术路线实施制备：
本发明制得的侧链含有3,4-二氢嘧啶和嘧啶的截短侧耳素类衍生物采用IR、NMR和HRMS对其进行结构表征。
实施例1 14-O-[(5-甲氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4a所示的化合物，即14-O-[(5-甲氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3175,3111,2964,1933,2874,1714,1653,1587,1479,1435,1375,1332,1267,1183,1133,1110,1081,785,760cm-1；1H NMR(400MHz,Chloroform-d)δ6.49–6.36(m,1H),5.79–5.64(m,1H),5.31–5.26(m,1H),5.23–5.11(m,1H),4.48(d,J＝6.5Hz,1H),3.79–3.59(m,5H),3.34(dd,J＝10.3,6.4Hz,1H),2.34–2.24(m,2H),2.22(s,3H),2.12–2.03(m,2H),1.78–1.70(m,1H),1.67–1.60(m,2H),1.54(d,J＝11.1Hz,2H),1.43(s,4H),1.37–1.32(m,2H),1.24(d,J＝7.1Hz,1H),1.20–1.13(m,3H),1.11–1.00(m,4H),0.85(d,J＝6.9Hz,3H),0.71(t,J＝5.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.02,168.07,167.99,167.14,138.92,138.90,117.16,74.58,70.12,60.38,58.13,50.97,45.45,44.43,43.97,41.88,36.77,36.74,36.02,34.46,33.74,33.70,30.42,26.86,26.39,24.83,22.24,16.77,14.89,11.45；HRMS(ES)calcd[M+H]+for C30H44N2O6S 561.2993,found 561.3056.
实施例2 14-O-[(5-甲氧羰基-4-乙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4b所示的化合物，即14-O-[(5-甲氧羰基-4-乙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3489,3311,2956,2877,1731,1655,1458,1375,1341,1277,1246,1184,1117,1012,917cm-1；1H NMR(400MHz,Chloroform-d)δ6.39(ddd,J＝17.6,11.1,6.9Hz,1H),5.74–5.60(m,1H),5.31–5.21(m,1H),5.21–5.07(m,1H),4.35(s,1H),3.74–3.66(m,1H),3.63(s,3H),3.29(dd,J＝10.6,6.4Hz,1H),2.24(s,1H),2.18(s,3H),2.15(s,1H),2.01(d,J＝25.7Hz,3H),1.70(dd,J＝14.7,3.2Hz,1H),1.64–1.54(m,2H),1.52–1.46(m,1H),1.46–1.42(m,2H),1.39(s,3H),1.37(d,J＝7.5Hz,2H),1.30(d,J＝15.8Hz,2H),1.19(t,J＝7.2Hz,2H),1.09(d,J＝6.1Hz,3H),1.05(d,J＝10.1Hz,1H),0.87–0.72(m,6H),0.67(dd,J＝7.0,3.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.01,168.12,168.03,167.38,138.90,138.86,117.20,74.59,70.12,60.39,58.13,50.95,45.45,44.49,44.39,43.96,41.87,36.74,36.02,34.47,33.74,30.42,26.87,26.36,24.83,14.88,11.47；HRMS(ES)calcd[M+H]+for C31H46N2O6S 575.3149,found 575.3173.
实施例3 14-O-[(5-甲氧羰基-4-丙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4c所示的化合物，即14-O-[(5-甲氧羰基-4-丙基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3363,2953,2871,1701,1652,1491,1436,1422,1381,1299,1214,1141,1083,1052,1012cm-1；1H NMR(400MHz,Chloroform-d)δ6.38(ddd,J＝17.2,11.0,3.7Hz,1H),5.67(dd,J＝8.4,4.3Hz,1H),5.26–5.19(m,1H),5.12(dd,J＝17.5,4.3Hz,1H),4.41(s,1H),3.71(d,J＝10.7Hz,2H),3.63(d,J＝5.1Hz,3H),3.28(d,J＝7.0Hz,1H),2.31–2.22(m,2H),2.17(d,J＝6.8Hz,3H),2.03(s,2H),1.73–1.66(m,1H),1.58(dt,J＝12.3,4.8Hz,2H),1.53–1.44(m,2H),1.39(s,4H),1.35–1.31(m,2H),1.26–1.15(m,3H),1.09(d,J＝6.4Hz,4H),0.85(d,J＝6.7Hz,5H),0.80(s,3H),0.66(dd,J＝7.0,4.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.97,168.58,168.04,167.22,139.54,138.93,117.16,74.58,70.25,59.11,58.12,50.87,45.44,44.41,43.98,41.87,39.24,36.73,36.03,34.45,33.80,32.84,30.41,26.86,26.42,24.83,22.51,19.31,16.78,14.86,13.95,11.45；HRMS(ES)calcd[M+H]+for C32H48N2O6S 589.3306,found 589.3368.
实施例4 14-O-[(5-甲氧羰基-4-丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4d所示的化合物，即14-O-[(5-甲氧羰基-4-丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3369,2954,2867,1734,1701,1491,1459,1434,1375,1274,1220,1171,1118,1088,1015,954,917,776cm-1；1H NMR(400MHz,Chloroform-d)δ6.47–6.28(m,1H),5.75–5.59(m,1H),5.30–5.22(m,1H),5.12(dd,J＝16.5,4.1Hz,1H),4.41(s,1H),3.64(s,2H),3.63(s,3H),3.34–3.24(m,1H),2.23(d,J＝9.6Hz,2H),2.17(d,J＝6.1Hz,3H),2.04(d,J＝8.4Hz,2H),1.71–1.67(m,1H),1.60(s,2H),1.56(d,J＝6.8Hz,2H),1.42–1.38(m,4H),1.36–1.26(m,5H),1.19(dd,J＝16.4,10.6Hz,6H),1.09(d,J＝5.9Hz,4H),0.90(d,J＝7.1Hz,1H),0.85(d,J＝6.7Hz,3H),0.79(d,J＝6.3Hz,3H),0.67(dd,J＝7.1,4.6Hz,3H)；13CNMR(101MHz,Chloroform-d)δ216.58,167.54,167.10,166.27,138.42,137.83,116.21,74.10,73.58,58.09,57.12,49.89,44.43,44.05,42.96,40.85,35.81,35.56,35.01,33.45,31.85,29.38,25.82,25.32,23.82,21.52,18.42,17.17,15.80,13.86,13.05,12.41,10.46；HRMS(ES)calcd[M+H]+for C33H50N2O6S 603.3462,found 603.3455.
实施例5 14-O-[(5-甲氧羰基-4-异丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4e所示的化合物，即14-O-[(5-甲氧羰基-4-异丁基-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3315,2953,2867,1733,1655,1458,1437,1375,1285,1224,1176,1118,1089,1017,981,917,775cm-1；1H NMR(400MHz,Chloroform-d)δ6.43–6.32(m,1H),5.67(dd,J＝8.4,3.2Hz,1H),5.31–5.20(m,1H),5.18–5.06(m,1H),4.41(s,1H),3.66(s,2H),3.63(d,J＝5.7Hz,3H),3.28(d,J＝7.2Hz,1H),2.29–2.18(m,2H),2.16(d,J＝10.7Hz,3H),2.05–1.95(m,2H),1.72–1.67(m,1H),1.59(dd,J＝7.0,3.5Hz,2H),1.41(d,J＝2.7Hz,2H),1.39(s,4H),1.30(d,J＝7.6Hz,2H),1.22–1.14(m,3H),1.09(d,J＝6.6Hz,4H),0.84(ddd,J＝12.9,5.6,2.2Hz,7H),0.79(d,J＝5.8Hz,3H),0.66(dd,J＝7.0,4.1Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.05,168.24,168.09,167.23,138.89,138.85,117.20,74.59,70.11,65.04,58.14,50.94,45.45,44.51,43.98,41.87,36.76,36.73,36.02,34.47,33.82,30.41,26.91,26.86,26.38,24.83,23.53,18.43,16.79,14.88,11.48；HRMS(ES)calcd[M+H]+for C33H50N2O6S 603.3462,found 603.3457.
实施例6 14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4f所示的化合物，即14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3313,2957,2936,2873,1733,1663,1491,1458,1376,1270,1168,1114,1082,1016,981,917cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(td,J＝11.3,5.5Hz,1H),5.71(d,J＝8.5Hz,1H),5.33–5.25(m,1H),5.22–5.11(m,1H),4.58(s,1H),3.70(d,J＝4.2Hz,2H),3.67(s,3H),3.37–3.28(m,1H),2.29(t,J＝6.6Hz,1H),2.22(s,3H),2.18(d,J＝9.4Hz,1H),2.09–1.99(m,2H),1.75(dd,J＝14.5,3.2Hz,1H),1.63(dd,J＝7.4,3.5Hz,2H),1.56–1.49(m,2H),1.42(d,J＝14.2Hz,4H),1.33(d,J＝5.5Hz,2H),1.23(t,J＝6.0Hz,2H),1.14(d,J＝6.2Hz,4H),0.91(td,J＝7.6,7.1,2.9Hz,4H),0.83(dt,J＝13.5,7.1Hz,9H),0.70(dd,J＝7.0,4.2Hz,3H)；13C NMR(101MHz,Chloroform-d)217.00,168.21,168.01,167.69,138.97,138.92,117.15,74.59,70.05,60.37,58.15,50.83,45.44,44.53,43.96,41.87,36.75,36.73,36.02,34.45,33.51,30.41,26.90,26.86,26.41,24.83,22.63,16.77,14.86,11.73,11.67,11.45；HRMS(ES)calcd[M+H]+for C34H52N2O6S 617.3619,found617.3752.
实施例7 14-O-[(5-乙酰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4g所示的化合物，即14-O-[(5-乙酰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3279,2960,2865,1728,1616,1473,1375,1255,1192,1117,1080,1016,955,916cm-1；1H NMR(400MHz,Chloroform-d)δ6.39(ddd,J＝17.5,11.0,2.7Hz,1H),5.68(dd,J＝8.5,5.0Hz,1H),5.25(d,J＝9.3Hz,1H),5.13(dd,J＝17.5,1.6Hz,1H),4.52(q,J＝6.4Hz,1H),3.79(d,J＝16.4Hz,1H),3.61(dd,J＝16.3,7.0Hz,1H),3.31(dd,J＝10.2,6.3Hz,1H),2.24(d,J＝1.6Hz,3H),2.18(s,6H),2.07–1.95(m,3H),1.70(dd,J＝14.5,3.0Hz,1H),1.62–1.51(m,3H),1.46(dd,J＝13.9,3.3Hz,1H),1.39(s,3H),1.30(dd,J＝16.2,4.0Hz,2H),1.19(t,J＝6.2Hz,2H),1.10(d,J＝4.1Hz,3H),1.03(t,J＝6.1Hz,3H),0.81(d,J＝7.0Hz,3H),0.73–0.63(m,3H)；13C NMR(101MHz,Chloroform-d)δ217.11,175.45,168.08,167.97,142.12,138.96,117.20,74.56,70.30,60.43,58.11,48.36,45.45,44.42,43.97,41.87,36.71,36.01,34.48,33.89,30.40,26.86,26.45,24.83,22.77,22.02,16.82,14.89,14.19,11.50；HRMS(ES)calcd[M+H]+for C30H44N2O5S545.3044,found 545.3041.
实施例8 14-O-[(5-乙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4h所示的化合物，即14-O-[(5-乙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3307,2958,2865,1733,1651,1602,1487,1374,1340,1260,1180,1116,1016,915,776cm-1；1H NMR(400MHz,Chloroform-d)δ6.38(td,J＝12.8,6.5Hz,1H),5.66(d,J＝7.1Hz,1H),5.23(d,J＝8.5Hz,1H),5.11(d,J＝17.3Hz,1H),4.44(s,1H),4.07(dtq,J＝14.6,7.4,4.1Hz,3H),3.72(d,J＝16.3Hz,1H),3.58(d,J＝16.2Hz,1H),3.30(d,J＝6.4Hz,1H),2.24(d,J＝6.6Hz,1H),2.17(d,J＝3.3Hz,4H),2.05(s,1H),1.97(d,J＝3.4Hz,3H),1.70(d,J＝14.7Hz,1H),1.59(d,J＝11.2Hz,2H),1.46(d,J＝13.0Hz,1H),1.41–1.37(m,3H),1.34–1.25(m,2H),1.19(dt,J＝11.3,6.5Hz,5H),1.13–1.07(m,3H),1.03(dt,J＝8.7,4.8Hz,3H),0.81(d,J＝6.9Hz,3H),0.66(dt,J＝7.2,3.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.27,170.25,167.00,165.82,137.97,137.93,116.14,73.56,69.04,59.45,58.68,57.15,44.47,43.38,42.97,40.88,35.75,35.03,33.50,32.69,29.42,25.86,25.48,23.84,21.24,20.06,15.78,13.91,13.37,13.19,10.50；HRMS(ES)calcd[M+H]+for C31H46N2O6S 575.3149,found 575.3161.
实施例9 14-O-[(5-丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4i所示的化合物，即14-O-[(5-丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3307,3128,2962,2864,1732,1655,1459,1399,1336,1268,1174,1152,1116,1069,1016,980,781cm-1；1H NMR(400MHz,Chloroform-d)δ6.45–6.32(m,1H),5.72–5.62(m,1H),5.30–5.21(m,1H),5.12(d,J＝17.5Hz,1H),4.46(d,J＝7.1Hz,1H),4.00(dt,J＝6.5,3.3Hz,2H),3.71(s,1H),3.59(dd,J＝16.2,1.9Hz,1H),3.29(dd,J＝10.3,6.4Hz,1H),2.28–2.21(m,1H),2.21–2.13(m,4H),2.04(d,J＝2.7Hz,1H),1.97(d,J＝1.7Hz,2H),1.70(dd,J＝14.7,3.2Hz,1H),1.58(td,J＝12.9,11.9,5.6Hz,4H),1.52–1.45(m,1H),1.38(d,J＝15.2Hz,5H),1.34–1.27(m,2H),1.19(t,J＝7.2Hz,2H),1.09(d,J＝4.0Hz,3H),1.05(t,J＝5.5Hz,3H),0.92–0.87(m,3H),0.81(d,J＝6.9Hz,3H),0.67(dd,J＝7.1,4.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.05,168.12,168.05,166.74,138.88,138.86,117.25,74.58,70.12,65.47,60.41,58.13,45.45,44.53,44.41,43.96,41.87,36.74,36.01,34.47,33.79,33.73,30.42,26.91,26.86,26.35,24.83,22.11,16.91,16.82,14.90,14.20,11.49,10.68；HRMS(ES)calcd[M+H]+for C32H48N2O6S 589.3306,found589.3278.
实施例10 14-O-[(5-烯丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成4j所示的化合物，即14-O-[(5-烯丙氧羰基-4,6-二甲基-1,4-二氢嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,3313,3088,2933,2864,1732,1655,1599,1456,1375,1226,1176,1036,937,815,775cm-1；1H NMR(400MHz,Chloroform-d)δ6.44–6.29(m,1H),5.94–5.75(m,1H),5.73–5.62(m,1H),5.26(s,1H),5.23(s,2H),5.11(d,J＝16.4Hz,1H),4.56(d,J＝4.7Hz,1H),4.49(d,J＝7.0Hz,1H),4.41(s,1H),4.05(qd,J＝7.1,2.4Hz,1H),3.79–3.55(m,1H),3.29(s,1H),2.38(s,1H),2.21(dd,J＝12.5,5.1Hz,3H),2.15(d,J＝7.6Hz,1H),2.04–1.94(m,3H),1.71(s,1H),1.60–1.53(m,2H),1.47(s,1H),1.42–1.31(m,6H),1.18(td,J＝7.2,2.7Hz,3H),1.07(d,J＝8.7Hz,6H),0.80(d,J＝7.1Hz,3H),0.71–0.55(m,3H)；13C NMR(101MHz,Chloroform-d)δ216.83,167.93,166.11,164.87,138.71,132.62,129.92,128.09,117.36,74.55,70.30,65.05,64.50,60.40,58.10,53.46,45.44,44.50,43.97,41.84,36.54,36.03,34.46,30.40,26.77,26.39,24.82,21.69,16.53,14.88,14.19,11.49；HRMS(ES)calcd[M+H]+for C32H46N2O6S 587.3149,found 587.3146.
实施例11 14-O-[(5-甲氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5a所示的化合物，即14-O-[(5-甲氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3535,2973,2930,2870,1728,1545,1457,1446,1380,1295,1158,1118,1089,1018,978,914,886cm-1；1H NMR(400MHz,Chloroform-d)δ6.45(dd,J＝17.3,11.0Hz,1H),5.73(d,J＝8.5Hz,1H),5.28(d,J＝11.0Hz,1H),5.15(d,J＝17.4Hz,1H),3.90(d,J＝2.8Hz,3H),3.86(d,J＝2.3Hz,2H),3.32(s,1H),2.43(d,J＝2.9Hz,6H),2.28(d,J＝6.9Hz,1H),2.23–2.12(m,2H),2.07–1.97(m,2H),1.77–1.70(m,1H),1.62(dd,J＝11.1,3.2Hz,2H),1.49(d,J＝3.5Hz,2H),1.40(d,J＝3.0Hz,3H),1.34(s,1H),1.27(d,J＝15.8Hz,2H),1.12(d,J＝3.5Hz,3H),1.11–1.05(m,1H),0.84(d,J＝6.9Hz,3H),0.72(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.98,170.21,167.65,165.33,138.99,121.75,117.16,74.54,69.70,58.12,52.44,45.43,44.58,43.93,41.86,36.75,35.99,34.45,34.02,30.41,26.85,26.35,24.81,23.14,16.88,14.86,11.44；HRMS(ES)calcd[M+H]+forC30H42N2O6S 559.2836,found 559.2824.
实施例12 14-O-[(5-甲氧羰基-4-乙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5b所示的化合物，即14-O-[(5-甲氧羰基-4-乙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3539,2973,2931,2871,1728,1541,1458,1413,1377,1296,1229,1173,1117,1091,1018,978,916,888cm-1；1H NMR(400MHz,Chloroform-d)δ6.41(dd,J＝17.4,11.0Hz,1H),5.68(d,J＝8.4Hz,1H),5.24(dd,J＝11.0,1.6Hz,1H),5.10(dd,J＝17.4,1.6Hz,1H),3.85(s,4H),3.64(q,J＝7.0Hz,1H),3.27(d,J＝6.4Hz,1H),2.64(q,J＝7.5,7.0Hz,2H),2.36(s,3H),2.27–2.22(m,1H),2.19–2.10(m,2H),2.04–1.94(m,2H),1.69(dd,J＝14.7,3.1Hz,1H),1.61–1.54(m,2H),1.46(dd,J＝13.7,3.5Hz,2H),1.40(d,J＝3.3Hz,1H),1.36(s,3H),1.29(d,J＝3.5Hz,2H),1.18–1.14(m,3H),1.07(d,J＝4.5Hz,3H),1.02(d,J＝4.5Hz,1H),0.79(d,J＝7.0Hz,3H),0.67(d,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.02,170.24,169.41,167.86,167.73,165.03,138.96,121.60,117.17,74.54,69.72,58.13,52.50,45.44,44.60,43.93,41.88,36.75,35.98,34.46,34.02,30.41,29.17,26.85,26.30,24.81,22.92,16.87,14.86,12.74,11.44；HRMS(ES)calcd[M+H]+for C31H44N2O6S 573.2993,found 573.2988.
实施例13 14-O-[(5-甲氧羰基-4-丙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5c所示的化合物，即14-O-[(5-甲氧羰基-4-丙基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,2956,2868,1732,1541,1497,1457,1375,1286,1223,1152,1116,1098,1017,980,917,814,554cm-1；1H NMR(400MHz,Chloroform-d)δ6.47(dd,J＝17.5,10.9Hz,1H),5.73(d,J＝8.5Hz,1H),5.33–5.26(m,1H),5.17(dd,J＝17.4,1.7Hz,1H),3.90(d,J＝7.8Hz,3H),3.33(d,J＝4.1Hz,1H),2.78–2.55(m,2H),2.43(d,J＝8.9Hz,3H),2.29(d,J＝6.8Hz,1H),2.25–2.18(m,2H),2.08–2.01(m,2H),1.73(s,1H),1.69–1.64(m,2H),1.55(d,J＝11.3Hz,2H),1.41(s,4H),1.35(s,2H),1.25(s,2H),1.14(d,J＝4.9Hz,4H),0.97–0.91(m,3H),0.85(d,J＝6.8Hz,3H),0.73(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.00,170.12,168.35,167.89,167.74,167.01,138.96,121.98,117.18,74.55,69.72,58.13,52.48,45.44,44.61,43.94,41.88,36.76,35.99,34.46,34.01,30.42,26.91,26.86,26.30,24.82,22.95,21.96,16.88,14.86,13.98,11.45；HRMS(ES)calcd[M+H]+for C32H46N2O6S 587.3149,found 587.3143.
实施例14 14-O-[(5-甲氧羰基-4-丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5d所示的化合物，即14-O-[(5-甲氧羰基-4-丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3448,2956,2864,1732,1541,1458,1434,1376,1288,1233,1152,1116,1080,1017,980,916cm-1；1H NMR(400MHz,Chloroform-d)δ6.49(dd,J＝17.4,11.0Hz,1H),5.76(d,J＝8.5Hz,1H),5.33(dd,J＝11.0,1.6Hz,1H),5.19(dd,J＝17.4,1.6Hz,1H),3.93(s,3H),3.92–3.79(m,2H),3.35(s,1H),2.69(dd,J＝9.0,6.7Hz,2H),2.44(s,3H),2.32(d,J＝6.9Hz,1H),2.27–2.19(m,2H),2.11–2.02(m,2H),1.75(d,J＝2.8Hz,1H),1.65(dtd,J＝9.5,7.3,6.4,3.6Hz,4H),1.44(s,4H),1.37(dd,J＝8.7,6.3Hz,4H),1.28(d,J＝6.9Hz,2H),1.16(d,J＝4.6Hz,4H),0.94(d,J＝7.4Hz,3H),0.87(d,J＝5.0Hz,3H),0.75(d,J＝6.9Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.01,170.11,168.62,167.90,167.75,165.02,138.97,121.90,117.19,74.56,69.72,58.13,52.47,45.44,44.62,43.94,41.88,36.76,35.99,35.59,34.47,34.01,30.76,30.42,26.86,26.31,24.82,22.95,22.54,16.89,14.86,13.80,11.45；HRMS(ES)calcd[M+H]+for C33H48N2O6S 601.3306,found601.3288.
实施例15 14-O-[(5-甲氧羰基-4-异丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5e所示的化合物，即14-O-[(5-甲氧羰基-4-异丁基-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3554,2955,2870,1732,1639,1541,1456,1374,1288,1223,1177,1116,1018,980,916,786cm-1；1H NMR(400MHz,Chloroform-d)δ6.46(dd,J＝17.6,11.0Hz,1H),5.74(t,J＝8.2Hz,1H),5.30(ddd,J＝10.9,4.4,1.6Hz,1H),5.16(dt,J＝17.5,2.1Hz,1H),4.10(q,J＝7.1Hz,1H),3.90(s,3H),3.69(t,J＝7.0Hz,1H),3.33(d,J＝6.5Hz,1H),2.55(d,J＝7.2Hz,1H),2.42(d,J＝9.7Hz,3H),2.35–2.26(m,1H),2.24–2.14(m,2H),2.05(d,J＝17.0Hz,3H),1.79–1.71(m,1H),1.62(td,J＝11.0,10.2,6.0Hz,4H),1.55–1.48(m,1H),1.40(d,J＝7.8Hz,4H),1.37–1.28(m,2H),1.22(t,J＝7.2Hz,3H),1.16–1.10(m,4H),0.88(d,J＝6.6Hz,3H),0.84(d,J＝6.5Hz,3H),0.72(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.03,169.97,167.75,167.68,164.95,164.87,138.96,122.53,117.18,74.54,69.72,58.13,52.46,45.44,44.60,43.94,41.87,36.76,35.98,34.46,34.00,30.41,28.38,26.85,26.31,24.81,22.95,22.46,18.42,16.88,14.85,14.19,11.45；HRMS(ES)calcd[M+H]+for C33H48N2O6S 601.3306,found 601.3295.
实施例16 14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5f所示的化合物，即14-O-[(5-甲氧羰基-4-(戊烷-3-基)-6-甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3567,2959,2928,2874,1735,1637,1541,1458,1403,1383,1286,1227,1151,1116,1016,917,781cm-1；1H NMR(400MHz,Chloroform-d)δ6.56–6.37(m,1H),5.73(d,J＝8.5Hz,1H),5.35–5.24(m,1H),5.18(d,J＝17.3Hz,1H),3.93(d,J＝6.6Hz,3H),3.90(s,1H),3.71(q,J＝7.0Hz,1H),3.35(d,J＝6.5Hz,1H),2.57–2.47(m,1H),2.41(s,2H),2.33–2.28(m,1H),2.24–2.14(m,2H),2.10–2.02(m,2H),1.79–1.73(m,2H),1.64(dtdd,J＝21.3,11.1,6.5,3.0Hz,6H),1.51(d,J＝3.4Hz,1H),1.43(s,3H),1.43–1.35(m,3H),1.33(d,J＝7.4Hz,1H),1.25(q,J＝8.1,7.1Hz,3H),1.15(d,J＝2.0Hz,3H),1.12(s,1H),0.86(d,J＝7.0Hz,3H),0.79–0.74(m,3H),0.72(dd,J＝4.9,2.6Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.01,171.04,170.12,168.09,167.83,164.30,138.95,123.81,117.16,74.54,69.76,58.12,52.45,47.92,45.44,44.65,43.95,41.89,36.76,35.97,34.46,33.96,30.41,27.59,26.84,26.28,24.80,22.74,16.92,14.85,12.05,11.45；HRMS(ES)calcd[M+H]+for C34H50N2O6S 615.3462,found 615.3463.
实施例17 14-O-[(5-乙酰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5g所示的化合物，即14-O-[(5-乙酰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,3084,2932,2864,1734,1698,1532,1455,1429,1353,1300,1215,1116,1017,980,915,774cm-1；1H NMR(400MHz,Chloroform-d)δ6.42(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝8.5Hz,1H),5.26–5.21(m,1H),5.11(dd,J＝17.4,1.7Hz,1H),3.81(d,J＝2.0Hz,2H),3.28(d,J＝6.4Hz,1H),2.43(s,3H),2.29(s,6H),2.22(s,1H),2.15(dd,J＝6.4,2.8Hz,2H),2.03–1.96(m,2H),1.71–1.65(m,1H),1.58(d,J＝10.9Hz,2H),1.47(dd,J＝13.7,3.3Hz,2H),1.42–1.38(m,1H),1.38–1.35(m,3H),1.25(s,1H),1.20(d,J＝9.5Hz,2H),1.07(s,3H),0.79(d,J＝6.9Hz,3H),0.69(d,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ216.99,203.49,169.43,167.72,162.25,139.03,130.41,117.16,74.53,69.67,58.12,45.43,44.59,43.92,41.85,36.74,35.98,34.45,33.95,32.12,30.40,26.85,26.32,24.80,22.33,16.90,14.86,11.43；HRMS(ES)calcd[M+H]+for C30H42N2O5S543.2887,found 543.2827.
实施例18 14-O-[(5-乙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5h所示的化合物，即14-O-[(5-乙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3533,3085,2973,2871,1719,1541,1466,1445,1380,1358,1229,1158,1117,1084,977,861,785cm-1；1H NMR(400MHz,Chloroform-d)δ6.41(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝8.5Hz,1H),5.28–5.19(m,1H),5.11(dd,J＝17.4,1.6Hz,1H),4.33(q,J＝7.1Hz,2H),3.82(d,J＝3.5Hz,2H),3.27(d,J＝6.4Hz,1H),2.39(s,6H),2.28–2.21(m,1H),2.18–2.08(m,2H),2.01(d,J＝2.6Hz,1H),1.99–1.92(m,1H),1.69(dd,J＝14.4,3.2Hz,1H),1.62–1.55(m,2H),1.47(dd,J＝13.7,3.4Hz,2H),1.40(d,J＝3.2Hz,1H),1.36(s,3H),1.34(s,1H),1.31(d,J＝7.1Hz,3H),1.22(d,J＝16.0Hz,2H),1.07(s,3H),0.79(d,J＝7.0Hz,3H),0.68(d,J＝7.0Hz,3H)；1313C NMR(101MHz,Chloroform-d)δ216.99,170.01,167.67,167.17,165.12,138.97,122.08,117.17,74.54,69.66,61.69,58.12,45.43,44.55,43.91,41.85,36.74,35.97,34.45,34.02,30.40,26.84,26.30,24.80,23.03,16.88,14.86,14.14,11.44；HRMS(ES)calcd[M+H]+for C31H44N2O6S 573.2993,found573.2948.
实施例19 14-O-[(5-丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5i所示的化合物，即14-O-[(5-丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3547,3128,2934,2881,1728,1545,1457,1421,1386,1308,1228,1152,1116,1017,917,884cm-1；1H NMR(400MHz,Chloroform-d)δ6.41(dd,J＝17.4,11.0Hz,1H),5.69(d,J＝8.5Hz,1H),5.24(dd,J＝10.8,1.6Hz,1H),5.11(dd,J＝17.4,1.6Hz,1H),4.22(t,J＝6.7Hz,2H),3.81(d,J＝3.0Hz,2H),3.27(d,J＝6.4Hz,1H),2.39(s,6H),2.29–2.22(m,1H),2.19–2.11(m,2H),2.00(dd,J＝12.9,4.1Hz,2H),1.75–1.69(m,2H),1.68–1.64(m,1H),1.61–1.54(m,2H),1.52–1.43(m,2H),1.40(d,J＝3.0Hz,1H),1.36(s,3H),1.27(d,J＝19.5Hz,2H),1.20(s,1H),1.08(d,J＝5.5Hz,3H),0.95(t,J＝7.4Hz,3H),0.79(d,J＝7.0Hz,3H),0.68(d,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ217.02,170.00,167.68,167.33,165.12,138.97,122.15,117.18,74.54,69.65,67.38,58.12,45.43,44.55,43.90,41.85,36.75,35.97,34.45,34.03,30.40,26.84,26.30,24.80,23.08,21.91,16.88,14.86,11.44,10.54；HRMS(ES)calcd[M+H]+for C32H46N2O6S 587.3149,found587.3087.
实施例20 14-O-[(5-烯丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林
根据上述技术路线合成5j所示的化合物，即14-O-[(5-烯丙氧羰基-4,6-二甲基嘧啶-2-基)巯乙酰基]姆体林。
IR(KBr):3553,3127,2934,2885,1731,1545,1456,1400,1374,1289,1177,1152,1117,1085,916,816cm-1；1H NMR(400MHz,Chloroform-d)δ6.43–6.33(m,1H),5.94(dd,J＝16.9,10.6Hz,1H),5.69(dd,J＝8.6,3.8Hz,1H),5.35(dd,J＝17.1,1.6Hz,1H),5.30–5.21(m,2H),5.16–5.09(m,1H),4.75(d,J＝5.8Hz,1H),4.41(s,1H),3.82(d,J＝3.3Hz,1H),3.27(d,J＝6.5Hz,1H),2.39(s,6H),2.23(dd,J＝6.8,4.2Hz,1H),2.19–2.13(m,2H),2.12(s,1H),2.02–1.97(m,2H),1.70–1.66(m,1H),1.58(dd,J＝10.7,3.2Hz,2H),1.48(dd,J＝13.8,10.6Hz,2H),1.41(s,1H),1.34(s,3H),1.24–1.17(m,2H),1.09(s,3H),1.03(d,J＝6.9Hz,1H),0.80(d,J＝6.5Hz,3H),0.68(d,J＝6.9Hz,2H),0.55(s,1H)；13C NMR(101MHz,Chloroform-d)δ217.00,170.19,167.65,166.89,165.27,164.87,138.95,129.90,128.08,117.19,74.53,69.67,66.32,65.02,58.12,45.42,44.56,43.91,41.82,36.74,35.97,34.39,30.40,26.84,26.29,24.80,23.12,16.88,14.86,11.44；HRMS(ES)calcd[M+H]+forC32H44N2O6S 585.2993,found 585.2925.
实施例21截短侧耳素衍生物的抑菌活性
本发明实施例1-20所制得的截短侧耳素衍生物采用琼脂稀释法测定其对金黄色葡萄球菌ATCC 25923(Staphylococcus aureus ATCC 25923，S.aureus)、耐甲氧西林的表皮球菌ATCC 51625(methicillin-resistant Staphylococcus epidermidis ATCC 51625，MRSE)、耐甲氧西林的金黄色葡萄球菌BNCC 337371(methicillin-resistantStaphylococcus aureus BNCC 337371，MRSA)、和化脓链球菌(Streptococcus pyogenes，S.pyogenes)的最小抑菌浓度(MIC)，结果如表1所示。结果表明，所制备的截短侧耳素类衍生物均具有良好的体外抑菌活性。除个别化合物外，多数化合物的MIC要低于对照药物泰妙菌素或瑞他莫林。其中侧链含嘧啶环的化合物的抑菌活性要优于侧链含3,4-二氢嘧啶类的化合物，尤其是化合物5a、5g和5h的活性最好，对MRSA、MRSE和S.aureus的MIC小于或等于0.0313μg/mL，对化脓链球菌也有中等的抑菌活性。
表1截短侧耳素类衍生物的体外最小抑菌浓度(μg/mL)
在MIC测定的基础上，进一步对化合物5a、5g和5h的1×和6×MIC浓度进行了杀菌动力学研究，结果如图1所示。结果表明，化合物5h的抑菌活性最好，6×MIC的5h能使MRSA和S.aureus的数量分别下降2.44和3.62个log10CFU，显著优于瑞他莫林。
对化合物5h进行了MRSA感染小鼠的治疗研究。昆明系小鼠射感染0.4mL的MRSA(108CFU/mL)后，应用不同剂量的化合物5h和对照药物泰妙菌素对小鼠进行腹腔注射，同时设阳性组和空白溶剂组。研究结果表明，与泰妙菌素相比，5h能显著提高感染了MRSA小鼠的死亡率(结果见图2中A)，其ED50为16.14mg/kg，显著低于对照药物泰妙菌素(图2中B，ED50为22.87mg/kg)。
本发明所述衍生物结构新颖，抑菌活性突出。尤其重要的是，本发明涉及到的截短侧耳素类衍生物的制备原料主要是乙酰乙酸乙酯、醛和硫脲；与泰妙菌素、沃尼妙林、瑞他莫林和利发姆林等截短侧耳素类药物相比，具有原料易得、成本低廉，工艺简单，绿色环保等优点。
上述测试说明，本发明制备的含有3,4-二氢嘧啶和嘧啶侧链的截短侧耳素类衍生物对多种阳性菌，如金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌等，具有显著的抑制作用。因此，本发明的截短侧耳素衍生物可以在制备抗菌药物，尤其是抗耐药菌药物中应用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (5)
1.一种截短侧耳素类衍生物或其药学上可接受的盐，所述截短侧耳素类衍生物为式(II)所示的含有取代嘧啶侧链的截短侧耳素类衍生物：
其中，
所述R1为-OCH3，R2为-CH3；或，
所述R1为-CH3，R2为-CH3；或，
所述R1为-OCH2CH3，R2为-CH3。
2.如权利要求1所述的截短侧耳素类衍生物或其药学上可接受的盐在制备抗菌药物中的应用。
3.如权利要求2所述的应用，其特征在于，所述抗菌药物为抗耐药菌的药物。
4.如权利要求3所述的应用，其特征在于，所述耐药菌包括金黄色葡萄球菌、耐甲氧西林的表皮球菌、耐甲氧西林的金黄色葡萄球菌、化脓链球菌。
5.如权利要求1所述的截短侧耳素类衍生物或其药学上可接受的盐加入药学上可接受的载体或辅料制成药学上可接受的任一剂型。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210234067.6A CN114716384B (zh) | 2022-03-10 | 2022-03-10 | 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210234067.6A CN114716384B (zh) | 2022-03-10 | 2022-03-10 | 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114716384A CN114716384A (zh) | 2022-07-08 |
| CN114716384B true CN114716384B (zh) | 2023-09-26 |
Family
ID=82238123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210234067.6A Active CN114716384B (zh) | 2022-03-10 | 2022-03-10 | 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114716384B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850137B (zh) * | 2022-11-12 | 2024-04-12 | 中国农业科学院兰州畜牧与兽药研究所 | 一种截短侧耳素衍生化合物及其制备方法与应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4428953A (en) * | 1979-01-12 | 1984-01-31 | Sandoz, Ltd. | Pleuromutilin derivatives, their production and use |
| WO2000027790A1 (en) * | 1998-11-11 | 2000-05-18 | Smithkline Beecham P.L.C. | Mutilin compounds |
| CN115413238A (zh) * | 2020-04-17 | 2022-11-29 | 纳布里瓦治疗有限责任公司 | 截短侧耳素类化合物的治疗用途 |
-
2022
- 2022-03-10 CN CN202210234067.6A patent/CN114716384B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4428953A (en) * | 1979-01-12 | 1984-01-31 | Sandoz, Ltd. | Pleuromutilin derivatives, their production and use |
| WO2000027790A1 (en) * | 1998-11-11 | 2000-05-18 | Smithkline Beecham P.L.C. | Mutilin compounds |
| CN115413238A (zh) * | 2020-04-17 | 2022-11-29 | 纳布里瓦治疗有限责任公司 | 截短侧耳素类化合物的治疗用途 |
Non-Patent Citations (3)
| Title |
|---|
| Antibacterial Activity and Structure Activity Relationship of a Series of Newly Synthesized Pleuromutilin Derivatives;Yun-Ge Li等;Chem. Biodiversity;第16卷;e1800560（1-12） * |
| Design,Synthesis, and Structure−Activity Relationship Studies of Novel Thioether Pleuromutilin Derivatives as Potent Antibacterial Agents;Chenyu Ling等;J.Med.Chem.;第57卷;4772−4795 * |
| 截短侧耳素类衍生物的合成、结构鉴定与生物活性研究;衣云鹏;中国博士学位论文全文数据库 农业科技辑;D050-145，第9-22、25-48、68-81页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114716384A (zh) | 2022-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR930002509B1 (ko) | 결정성 칼슘 슈도모네이트 제법 | |
| US20210053909A1 (en) | Novel antimicrobial compound and use thereof | |
| TW200932250A (en) | Antibiotic macrocycle compounds and methods of manufacture and use thereof | |
| EP0655066A1 (en) | Protein kinase inhibitors and related compounds combined with taxol | |
| CN114716384B (zh) | 一种含有3,4-二氢嘧啶或嘧啶侧链的截短侧耳素类衍生物及其制备与应用 | |
| US20070244089A1 (en) | 2- Arylmethylazetidine Carbapenem Derivatives and Preparation Thereof | |
| IL187551A (en) | Antimicrobial capuramycin derivatives and pharmaceutical compositions containing the same | |
| CN102731301B (zh) | 麝香草酚酯类衍生物、制备方法和用途 | |
| EP3156400B1 (en) | Dihydrooxadiazine compounds for treating infections and cancer | |
| US11976080B1 (en) | Benzofuro[3,2-c]chromen-6-one compounds as antibacterial agents | |
| JPH01104014A (ja) | ４−オキソ−４ｈ−キノリジン−３−カルボン酸及びその誘導体 | |
| JP2020507572A (ja) | プレウロムチリンの精製 | |
| CN111253322A (zh) | 含有n-烷基化嘧啶侧链的截短侧耳素类衍生物及其应用 | |
| JPH0717609B2 (ja) | ノルフロキサシンの水溶性付加物 | |
| JPH01153632A (ja) | 抗細菌性９−デオキソ―９ａ―アリルおよびプロパルギル―９ａ―アザ―９ａ―ホモエリスロマイシンＡ誘導体 | |
| CN104098588B (zh) | 一类三环喹诺酮衍生物及其制备方法和用途 | |
| CN103709177B (zh) | 利福霉素类沃尼妙林杂合抗生素及其制备方法 | |
| WO2011063615A1 (zh) | 大环酰胺化合物、其药物组合物、其制备方法与应用 | |
| JP4836629B2 (ja) | 抗菌活性または抗腫瘍活性を有する化合物およびその製造方法 | |
| JP2004292426A (ja) | 抗菌剤と抗ガン剤 | |
| JP7334927B2 (ja) | 抗がん剤 | |
| WO2003051806A1 (en) | Antibacterial compounds | |
| WO2022163843A1 (ja) | Ｐｉｍ２阻害剤 | |
| EP3404026B1 (en) | Pyrimido-isoquinolin-quinone derivative compounds, and pharmaceutically acceptable salts, isomers and tautomers thereof; pharmaceutical composition; preparation method; and use thereof in the treatment of diseases caused by bacteria and multidrug-resistant bacteria | |
| EP1960375B1 (en) | Novel macrolide compounds with antibiotic and antneoplastic properties |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |