CN114716327A - Cedrol derivative, preparation method and application thereof - Google Patents
Cedrol derivative, preparation method and application thereof Download PDFInfo
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- CN114716327A CN114716327A CN202210402007.0A CN202210402007A CN114716327A CN 114716327 A CN114716327 A CN 114716327A CN 202210402007 A CN202210402007 A CN 202210402007A CN 114716327 A CN114716327 A CN 114716327A
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- SVURIXNDRWRAFU-OGMFBOKVSA-N cedrol Chemical class C1[C@]23[C@H](C)CC[C@H]3C(C)(C)[C@@H]1[C@@](O)(C)CC2 SVURIXNDRWRAFU-OGMFBOKVSA-N 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 16
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 15
- 229940026455 cedrol Drugs 0.000 claims abstract description 13
- PCROEXHGMUJCDB-UHFFFAOYSA-N cedrol Natural products CC1CCC2C(C)(C)C3CC(C)(O)CC12C3 PCROEXHGMUJCDB-UHFFFAOYSA-N 0.000 claims abstract description 13
- SVURIXNDRWRAFU-UHFFFAOYSA-N juniperanol Natural products C1C23C(C)CCC3C(C)(C)C1C(O)(C)CC2 SVURIXNDRWRAFU-UHFFFAOYSA-N 0.000 claims abstract description 13
- 241000700605 Viruses Species 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000010791 quenching Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 239000012266 salt solution Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 230000000840 anti-viral effect Effects 0.000 claims description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 13
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 18
- 206010022000 influenza Diseases 0.000 description 17
- 239000000047 product Substances 0.000 description 12
- 230000008569 process Effects 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000012512 characterization method Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000011161 development Methods 0.000 description 5
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000003443 antiviral agent Substances 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000012054 celltiter-glo Methods 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 239000003205 fragrance Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 230000000120 cytopathologic effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000686 essence Substances 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 108700010900 influenza virus proteins Proteins 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 210000003771 C cell Anatomy 0.000 description 1
- 241000218645 Cedrus Species 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000256602 Isoptera Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000027645 antigenic variation Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960003971 influenza vaccine Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 229930004725 sesquiterpene Natural products 0.000 description 1
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 229940045872 sodium percarbonate Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/417—Saturated compounds containing a keto group being part of a ring polycyclic
- C07C49/423—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system
- C07C49/453—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system having three rings
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/93—Spiro compounds
- C07C2603/95—Spiro compounds containing "not free" spiro atoms
- C07C2603/98—Spiro compounds containing "not free" spiro atoms containing at least one ring with more than six ring members
-
- 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
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of synthetic drugs, and particularly relates to cedrol derivatives, and a preparation method and application thereof. Cedrol derivatives are of the following structural formula:
Description
The application case is a divisional application, the application date of a parent application is 12 months and 14 days 2020, the application number is CN202011475888.6, and the name is 'cedrol derivative, and a preparation method and application thereof'.
Technical Field
The invention relates to the technical field of synthetic drugs, and particularly relates to cedrol derivatives, and a preparation method and application thereof.
Background
Cedrol (cedrol), also known as cedrol, is a sesquiterpene alcohol which has a pleasant and persistent cedar aroma, is widely used in costustoot, spicy and oriental type essences, is also widely used as a fragrance enhancer for disinfectants and sanitary products and a fragrance fixative for essence, and is also an intermediate for synthesizing other fragrances. The research shows that cedrol has obvious inhibiting effect on colibacillus, staphylococcus aureus, bacillus subtilis, salmonella typhi and other bacteria. The cedrol has the pharmacological activity of resisting spasm, relieving pain, resisting inflammation, resisting cancer, resisting virus, resisting free radical oxidation, etc. In addition, cedrol accelerates the growth of skin fibroblasts in a dose-dependent manner and increases the production of collagen type I proteins and elastin. In addition, the inhalation of cedrol in healthy people can increase parasympathetic nerve excitation, reduce sympathetic nerve excitation, act on cardiovascular system, and reduce blood pressure. Cedrol also has termite resistance.
Influenza (flu) is an acute respiratory infectious disease caused by influenza virus, is mainly spread by air droplets, and has the characteristics of sudden outbreak, rapid spread and wide spread. Influenza pandemics worldwide, which have occurred in 3 outbreaks in the 20 th century, have caused death of millions of people. Even today, influenza still threatens human life and health, and the seasonal influenza worldwide causes 300 to 500 ten thousand severe cases and 29 to 65 ten thousand death cases each year according to the estimation of the World Health Organization (WHO). The influenza virus includes human influenza virus and animal influenza virus, the human influenza virus is divided into A (A), B (B) and C (C)3 types, and is a pathogen of influenza, wherein the A type influenza virus is easy to have antigenic variation and causes a worldwide influenza pandemic for many times. At present, the prevention and treatment of influenza mainly adopt the prevention of vaccination and the development of antiviral drugs and the prevention and treatment of the influenza are repeated. Although vaccination can prevent homoinfluenza infection, it is desirable to start production just before the onset of influenza infection. Accurate prediction of the upcoming influenza strains remains a serious challenge and influenza vaccines are regenerated every year due to antigenic shift and drift of influenza virus, which all pose great difficulties in vaccine production.
In view of the great threat of influenza, the research and development of antiviral drugs aiming at influenza become a research hotspot all the time, and the design of drugs based on structures, such as the neuraminidase inhibitors oseltamivir, peramivir and the like, has great success. However, with the variation of influenza virus, existing anti-influenza drugs face a severe drug resistance situation, and therefore, the development of novel anti-influenza drugs is urgently needed.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide cedrol derivatives, a preparation method and application thereof. The embodiment of the invention provides a series of novel cedrol derivatives, which have good antagonistic action on viruses, particularly influenza viruses, so that the application range of cedrol and derivatives thereof is expanded, and the types of cedrol derivatives are expanded.
The invention is realized by the following steps:
in a first aspect, the present invention provides a cedrol derivative having the following structural formula:
in a second aspect, the present invention provides a method for preparing cedrol derivatives according to the foregoing embodiments, which includes performing a chemical reaction using cedrol as a raw material to obtain cedrol derivatives.
In a third aspect, the present invention provides a use of cedrol derivatives according to the previous embodiments in the preparation of antiviral drugs.
The invention has the following beneficial effects: the cedrol derivative provided by the embodiment of the invention has a good therapeutic effect on viruses, particularly influenza viruses, and can be used for preparing drugs for treating diseases caused by viruses, so that the application range of the cedrol derivative is expanded, and the variety of the cedrol derivative is also expanded.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The embodiment of the invention provides a cedrol derivative which has the following structural formula:
the embodiment of the invention also provides application of the cedrol derivative in preparation of antiviral drugs, and particularly, the viruses are influenza viruses.
It should be noted that: adopted by the embodiment of the invention1H-and13C-NMR was determined by Bruker AVANCE III-600, DRX-500 or AM-400, with internal standard TMS, where1H NMR was measured at 400MHz, 500MHz and 600MHz,13c NMR measurements at 100MHz, 125MHz and 150 MHz; mass spectra HREI-MS and EI-MS are measured by a Finnigan-MAT 90 mass spectrometer; HRESI-MS and ESI-MS were measured by an API QSTAR Pulsar i mass spectrometer; rotating the evaporator: buchi R-200, R-201; DLSB 5110 model low temperature reaction coolant circulation pump, IKA RCT basic (safety control type) heating magnetic stirrer.
Column chromatography material: silica gel (80-100 meshes and 200-300 meshes) for column chromatography and preformed GF254TLC plates are all produced by Qingdao ocean factories; sephadex LH-20 is a product of Amersham Biosciences, Sweden; chromatorex C-18(40-75 μm) is a product of Fuji Silysia chemical company, Japan. HPLC: agilent 1100, Zorbax SB-C18 column, 5 μm, 4.6mm × 150 mm; Prep-HPLC: agilent 1200, Zorbox SB-C18 column, 5 μm, 9.4 mm. times.150 mm. The color development method is to observe fluorescence at 254 and 365nm under fluorescent lamp, I2Steam color development, heating color development after 10% sulfuric acid vanillin treatment.
Other reagents were obtained from Sigma Aldrich, J & K carbofuran, Beijing InonoKay or Annaiji reagent company, and were all commercially available analytical or chemical pure reagents, and the anhydrous reagents used in the experimental part of the present invention (e.g., anhydrous THF, DCM, Toluene, DMF, etc.) were prepared according to the standard procedures for anhydrous solvents.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This example provides a cedrol derivative (numbered compound 2) named: (3R,3aS,7S,8aS) -3,6,8, 8-tetramethyl-2, 3,4,7,8,8 a-hexahydro-1H-3 a, 7-cedrane, the structural formula of which is shown aS follows:
this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of cedrol (numbered as compound 1) and 0.1mmol of p-toluenesulfonic acid into a reaction vessel, then adding 2mL of acetonitrile, reacting at 50 ℃ for 0.5 hour, after the reaction is finished, adding water or saturated salt solution into the reaction solution, washing and quenching the reaction, then extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 96%.
Characterization data for compound 2 are as follows: colorless oil, 96%,1H NMR(600MHz,CDCl3)δ5.23-5.22(m,1H),2.19-2.15(m,1H),1.86-1.57(m,11H),1.40-1.34(m,3H),1.02(s,3H),0.95(s,3H),0.85(d,3H,J＝7.3Hz)；13C NMR(150MHz,CDCl3)δ140.59,119.21,58.92,54.80,53.85,48.17,41.45,40.65,38.81,36.06,27.67,25.61,24.79,15.45。
example 2
This example provides a cedrol derivative (compound No. 3) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-ol, which has the following structural formula:
this example provides a process for the preparation of the cedrol derivatives: 0.1mmol of the compound 2 prepared in example 1 was added to a reaction vessel, dissolved in 2mL of THF, and 0.5mmol of BH was added3After 4H of DMS reaction, 1eq of NaOH and H are then added2O2After the reaction is finished for 3 hours, adding water or saturated salt solution into the reaction solution to wash and quench the reaction, then extracting with an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and recrystallizing the crude product to obtain the target product with the yield of 81%.
Characterization data for compound 3 are as follows: white salt, 81% and m.p.143-145 ℃.1H NMR(600MHz,CDCl3)δ3.79-3.78(m,1H),1.99-1.95(m,1H),1.85-1.83(m,1H),1.75-1.71(m,3H),1.62-1.48(m,5H),1.40-1.24(m,3H),1.20-1.18(m,2H),1.16(d,3H,J＝7.4Hz),1.13(s,3H),0.94(s,3H),0.85(d,3H,J＝6.8Hz)；13C NMR(150MHz,CDCl3)δ72.16,57.28,54.11,53.92,45.87,45.27,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55。
Example 3
This example provides a cedrol derivative (numbered compound 4) named: (3R,3aR,6S,7S,8aS) -5- (difluoromethoxy) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane, which has the following structural formula:
this example provides a process for the preparation of the cedrol derivatives: to the reaction vessel was added 0.1mmol of compound 3 provided in example 2 dissolved in 2mL of dichloromethane: to water (1:1), 3.8mmol of TMSCF was added2Br and 7.6mmol KHF2Reacting for 2 hours at room temperature, after the reaction is finished, adding water or saturated salt solution into the reaction solution to wash and quench the reaction, then extracting with an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of about 72 percent.
Characterization data for compound 4 are as follows: white salt, 72%, m.p.135-136 ℃.1H NMR(600MHz,CDCl3)δ6.39-6.13(m,1H),4.26-4.21(m,1H),1.99-1.96(m,1H),1.85-1.82(m,1H),1.75-1.70(m,2H),1.68-1.66(m,2H),1.62-1.57(m,2H),1.52-1.49(m,2H),1.22-1.18(m,2H),1.15(d,3H,J＝6.9Hz),1.12(s,3H),0.94(s,3H),0.85(d,3H,J＝6.9Hz)；13C NMR(150MHz,CDCl3)δ117.11,115.40,113.69,72.14,57.28,54.11,53.92,45.88,45.26,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55。
Example 4
This example provides a cedrol derivative (compound 5, No.), named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethylhexahydro-1H-3 a, 7-cedrane-5 (4H) -one, the formula of which is aS follows:
this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of compound 3 into a reaction vessel, dissolving in 2mL of dichloromethane, adding 0.11mmol of PCC, reacting for 3h at room temperature, after the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of about 84%.
Characterization data for compound 5 are as follows: colorless oil, 84%,1H NMR(600MHz,CDCl3)δ2.67-2.65(m,1H),2.35(d,1H,J＝1.6.2Hz),2.22-2.18(m,1H),1.89-1.83(m,3H),1.73-1.66(m,2H),1.63-1.56(m,2H),1.44-1.27(m,2H),1.12(d,3H,J＝7.5Hz),0.97(s,3H),0.95(s,3H),0.83(d,3H,J＝6.9Hz)；13C NMR(150MHz,CDCl3)δ215.92,57.46,54.63,54.17,48.75,45.89,41.73,40.57,36.55,35.74,25.96,25.87,24.72,17.18,14.34.HR-EI-MS(positive)m/z 221.18999[M+H]+(calcd for C15H25O 221.18272)。
example 5
This example provides a cedrol derivative (numbered compound 6) named: (2aR,3R,5aS,7R) -3,6,6,7 a-tetramethyloctahydro-2H-2 a, 7-cedrane [5,6-b ]]Ethylene oxide, the structural formula of which is as follows:
this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of the compound 2 prepared in the embodiment 2 into a reaction vessel, dissolving in 2mL of acetic anhydride, adding 0.12mmol of sodium percarbonate, placing into an ultrasonic reactor, reacting for 8 hours at room temperature, slowly adding water into the reaction solution after the reaction is finished, quenching the reaction solution, extracting with an organic solvent, drying, distilling under reduced pressure, concentrating to remove the solvent, and separating the crude product by column chromatography to obtain a target product with the yield of 93%.
Characterization data for compound 6 are as follows: colorless oil, 93%,1H NMR(600MHz,CDCl3)δ3.00(d,1H,J＝4.6Hz),1.94-1.76(m,4H),1.68-1.56(m,5H),1.42-1.40(m,4H),1.30-1.23(m,2H),1.18(s,3H),0.99(s,3H),0.80(d,3H,J＝6.9Hz)；13C NMR(150MHz,CDCl3)δ61.10,60.94,58.37,53.66,52.03,43.08,41.50,36.78,35.92,35.82,30.12,27.51,25.02,23.74,15.58.HR-EI-MS(positive)m/z 221.18999[M+H]+(calcd for C15H25O 221.18272)。
example 6
This example provides a cedrol derivative (No. compound 7) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-yl 2,2, 2-trifluoroacetate of the formula:
this example provides a process for the preparation of cedrol derivatives: this example provides the same preparation of cedrol derivatives as provided in example 3, except that the starting material, TMSCF2Br and KHF2Replacement with trifluoroacetic anhydride and Et3N。
Characterization data for compound 7 are as follows: white salt, 86%, m.p.125-127 ℃.1H NMR(600MHz,CDCl3)δ5.25-5.21(m,1H),2.09-2.06(m,1H),1.99-1.96(m,1H),1.88-1.72(m,5H),1.58-1.55(m,1H),1.43-1.38(m,2H),1.33-1.26(m,2H),1.19(s,3H),1.07(d,3H,J＝7.0Hz),0.98(s,3H),0.86(d,3H,J＝7.6Hz)；13C NMR(150MHz,CDCl3)δ157.63,157.35,157.08,117.53,115.63,113.74,111.84,81.31,58.21,55.08,54.86,46.43,43.90,42.49,41.77,39.13,36.73,28.72,28.03,25.79,17.35,15.50。
Example 7
This example provides a cedrol derivative (No. compound 8) named: (3R,3aR,6S,7S,8aS) -5-allyl-3, 6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-ol, having the formula:
this example provides a process for the preparation of the cedrol derivatives: adding 0.1mmol of the compound 5 prepared in the example 4 into a reaction container, dissolving the compound in 2mL of anhydrous THF, adding 0.12mmol of allyl bromide test reagent at 0 ℃, reacting for 12h at room temperature after the addition is finished, and adding saturated NH into the reaction solution after the reaction is finished4Washing with Cl solution or saturated salt solution to quench reaction, extracting with organic solvent, drying, and steaming under reduced pressureDistilling and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of about 73%.
Characterization data for compound 8 are as follows: colorless oil, 73%,1H NMR(600MHz,CDCl3)δ5.89-5.82(m,1H),5.15-5.08(m,2H),2.48-2.45(m,1H),2.35-2.31(m,1H),2.10-2.07(m,1H),1.83-1.76(m,3H),1.70-1.59(m,2H),1.62-1.59(m,2H),1.51-1.49(m,1H),1.41-1.35(m,2H),1.29(s,3H),1.27-1.25(m,1H),1.13(d,3H,J＝7.6Hz),0.93(s,3H),0.81(d,3H,J＝6.9Hz)；13C NMR(150MHz,CDCl3)δ133.32,117.72,72.14,54.65,53.02,51.59,48.27,46.21,45.88,45.02,42.99,40.94,34.39,28.12,27.19,24.09,14.57,13.81。
example 8
This example provides a cedrol derivative (compound No. 9) named: (3R,3aR,6S,7S, E) -3,6,8, 8-tetramethylhexahydro-1H-3 a, 7-cedrane-5 (4H) -one oxime of the formula:
this example provides a process for the preparation of cedrol derivatives: adding 0.1mmol of compound 5 into a reaction container, dissolving in 2mL of ethanol, adding 0.12mmol of hydroxylamine hydrochloride, adjusting the pH value to be neutral by using 30% NaOH solution, reacting for 12 hours at room temperature after the addition is finished, adding water or saturated salt solution into the reaction solution after the reaction is finished, washing and quenching the reaction, extracting by using an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and separating the crude product by column chromatography to obtain a target product with the yield of about 56%.
Characterization data for compound 9 is as follows: white salt, 56%, m.p.101-103 ℃.1H NMR(600MHz,CDCl3)δ9.37-9.31(m,1H),3.18-3.15(m,1H),2.54-2.52(m,1H),1.89-1.86(m,2H),1.80-1.75(m,3H),1.63-1.60(m,1H),1.54-1.48(m,2H),1.37-1.33(m,2H),1.29(d,3H,J＝7.0Hz),1.11(s,3H),0.93(d,6H,J＝7.0Hz)；13C NMR(150MHz,CDCl3)δ161.86,59.89,56.14,54.65,46.56,43.97,43.76,42.21,37.25,34.34,28.40,27.94,25.76,16.64,15.55.HR-EI-MS(positive)m/z 236.20084[M+H]+(calcd for C15H26ON 236.19361)。
Example 9
This example provides a cedrol derivative (numbered compound 10) named: (3R,3aR,6S,7S,8aS) -3,6,8, 8-tetramethyloctahydro-1H-3 a, 7-cedrane-5-amine, which has the following structural formula:
this example provides a process for the preparation of cedrol derivatives: adding 0.1mmol of compound 9 into a reaction vessel, dissolving in 2mL of anhydrous THF, adding 0.1mmol of lithium aluminum hydride, heating and refluxing for 12h, slowly adding water into the reaction solution after the reaction is finished, quenching the reaction solution, extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the target product with the yield of 70%.
Characterization data for compound 10 are as follows: white salt, 70%, m.p.129-130 ℃.1H NMR(600MHz,CDCl3)δ2.09-2.08(m,1H),1.81-1.71(m,4H),1.67-1.65(m,1H),1.59-1.56(m,3H),1.39(s,3H),1.38-1.36(m,1H),1.27-1.25(m,3H),1.20(s,3H),0.97(s,3H),0.93-0.91(m,1H),0.76(d,3H,J＝7.3Hz)；13C NMR(150MHz,CDCl3)δ60.72,52.97,52.12,43.64,41.64,40.05,37.14,36.72,36.16,35.71,30.56,27.65,26.59,24.90,15.52.HR-EI-MS(positive)m/z 220.20576[M+H]+(calcd for C15H26N 220.21435)。
Examples of the experiments
The virus strain: the influenza virus strain H1N1 PR8 was expanded and stored in this laboratory.
Cell model: dog kidney cell line MDCK, passage preservation in this laboratory. The culture conditions are as follows: DMEM + 10% fetal bovine serum, 37 ℃ and 5% CO2。
The samples were tested for their toxic effects on cells using the CellTiter-GloTM (Promega) kit.
Cytotoxicity experimental principle: the CellTiter-Glo kit detects the number of viable cells in culture by quantitative determination of ATP. ATP can be generated by the respiration of metabolically active cells and other life processes, a stable glow-type signal generated by luciferase is used in the kit, and the luciferase needs the participation of ATP in the luminescence process. When CellTiter-Glo reagent is added into cell culture medium to measure luminous value, the light signal is in direct proportion to ATP amount in the system, and ATP amount is in positive correlation with the number of living cells, so that the light signal value can reflect the number of living cells.
Cytotoxicity test procedure: and inoculating the MDCK cells into a 96-well cell culture plate, and keeping the cells for later use after the cells are attached to the wall. Compounds 1-10 were serially diluted in DMEM medium with 8 gradients of 3-fold gradient from 2-fold maximum assay concentration. Adding the compound and appropriate amount of culture medium into cells, and adding CO at 37 deg.C2Culturing in an incubator. After adding drugs and culturing for 24h, observing cytopathic effect (CPE) caused by the drugs under a microscope, and adding CellTiter-Glo to detect the cell survival rate. The toxicity of a drug to a cell is expressed as the activity of the cell.
Calculating the formula: cell activity (%) -drug group value/cell control group mean value 100.
Experimental principle of antiviral activity: the experiment measures the level of influenza virus protein expression to detect the level of virus replication. The expression level of structural proteins of influenza viruses is directly proportional to the replication of the virus; the experiment adopts a high-sensitivity reagent to detect the expression of the influenza virus protein, and the expression is reflected by the change of the fluorescence intensity.
And (3) antiviral activity detection: MDCK cells are inoculated in a 96-well cell culture plate and cultured at 37 ℃ overnight for later use. The corresponding compound and H1N1 virus solution were added simultaneously to MDCK cells. Culturing in a 37 deg.C cell culture box for 24 hr, and collecting culture supernatant for detection.
The experiment was performed with a blank control well (normal cells), a virus control well (no drug added after virus infection), and a positive drug control well (ribavirin added after infection).
Inhibition (%) > 100- (sample well number-blank number)/(virus control number-blank number) × 100.
The results are shown in the following table.
According to the table, the series of cedrol derivatives provided by the embodiment of the invention have good antiviral effect, and can be used for preparing antiviral medicines.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A cedrol derivative is characterized by being represented by the following structural formula:
2. the method for preparing cedrol derivatives according to claim 1, comprising the steps of:
adding 0.1mmol of cedrol and 0.1mmol of p-toluenesulfonic acid into a reaction vessel, then adding 2mL of acetonitrile, reacting for 0.5 hour at 50 ℃, after the reaction is finished, adding water or saturated salt solution into the reaction solution to wash and quench the reaction, then extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain a compound 2;
adding 0.1mmol of compound 2 into a reaction vessel, dissolving in 2mL of THF, adding 0.5mmol of BH3After 4H of DMS reaction, 1eq of NaOH and H are then added2O2After the reaction is finished for 3 hours, adding water or saturated salt solution into the reaction solution to wash and quench the reaction, then extracting by using an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and recrystallizing a crude product to obtain the compoundCompound 3;
adding 0.1mmol of compound 3 into a reaction vessel, dissolving in 2mL of dichloromethane, adding 0.11mmol of PCC, reacting for 3 hours at room temperature, after the reaction is finished, carrying out reduced pressure distillation and concentration to remove the solvent, and separating a crude product through column chromatography to obtain a compound 5;
adding 0.1mmol of compound 5 into a reaction container, dissolving in 2mL of ethanol, adding 0.12mmol of hydroxylamine hydrochloride, adjusting the pH value to be neutral by using 30% NaOH solution, reacting for 12 hours at room temperature after the addition is finished, adding water or saturated salt solution into the reaction solution after the reaction is finished, washing and quenching the reaction, extracting by using an organic solvent, drying, distilling and concentrating under reduced pressure to remove the solvent, and separating the crude product by using column chromatography to obtain a compound 9;
adding 0.1mmol of compound 9 into a reaction vessel, dissolving in 2mL of anhydrous THF, adding 0.1mmol of lithium aluminum hydride, heating and refluxing for reaction for 12h, slowly adding water into the reaction solution after the reaction is finished, quenching the reaction solution for reaction, extracting with an organic solvent, drying, distilling under reduced pressure and concentrating to remove the solvent, and separating the crude product by column chromatography to obtain the cedrol derivative.
3. Use of cedrol derivative as claimed in claim 1 in the preparation of antiviral medicament; the virus is influenza virus.
4. The use as claimed in claim 3, wherein the cedrol derivative is present in the medicament in an amount of 0.1 to 99% by mass.
5. The use as claimed in claim 4, wherein the cedrol derivative is present in the medicament in an amount of 0.5 to 90% by mass.
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