CN113717125B - Aromatic heterocyclic amine derivative, and preparation method and application thereof - Google Patents
Aromatic heterocyclic amine derivative, and preparation method and application thereof Download PDFInfo
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- CN113717125B CN113717125B CN202111194629.0A CN202111194629A CN113717125B CN 113717125 B CN113717125 B CN 113717125B CN 202111194629 A CN202111194629 A CN 202111194629A CN 113717125 B CN113717125 B CN 113717125B
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- -1 Aromatic heterocyclic amine Chemical class 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 238000001035 drying Methods 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- 238000005406 washing Methods 0.000 claims description 18
- 241000700721 Hepatitis B virus Species 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 229940125898 compound 5 Drugs 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 150000004780 naphthols Chemical class 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 2
- 229910000027 potassium carbonate Chemical class 0.000 claims description 2
- 230000010076 replication Effects 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 230000008685 targeting Effects 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 230000007246 mechanism Effects 0.000 abstract description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 2
- 230000002797 proteolythic effect Effects 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- 150000001408 amides Chemical group 0.000 abstract 1
- 125000001246 bromo group Chemical group Br* 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000011529 RT qPCR Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000007405 data analysis Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 208000002672 hepatitis B Diseases 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 241000700605 Viruses Species 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 238000013207 serial dilution Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 2
- 108020005202 Viral DNA Proteins 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 210000000234 capsid Anatomy 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229940127073 nucleoside analogue Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 101710142246 External core antigen Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 229940124765 capsid inhibitor Drugs 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000012094 cell viability reagent Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 231100000012 chronic liver injury Toxicity 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960005311 telbivudine Drugs 0.000 description 1
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (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
The application discloses an aromatic heterocyclic amine derivative, a preparation method and application thereof. The structural formula of the aromatic heterocyclic amine derivative is shown as a formula (I), wherein R 1 Selected from chlorine, methoxy, nitro, hydroxy or amino; r is R 2 Selected from 3, 5-dimethylisoxazolyl or bromo; the application provides an aromatic heterocyclic amine derivative compound which has good water solubility and high patentability. Similarly, the compound has an amide structure, and has good anti-HBV activity; the compound has hydroxyl and amino in the structure, can be designed and synthesized into a novel inhibitor based on a proteolytic targeting chimeric mechanism, and has a wide application prospect.
Description
Technical Field
The application relates to the technical field of compound synthesis, in particular to an aromatic heterocyclic amine derivative, a preparation method and application thereof.
Background
Hepatitis B Virus (HBV) is a common double-stranded hepadnavirus, infection of which causes acute and chronic liver injury, and long-term infection of which may cause hepatitis, cirrhosis and even liver cancer. The current drugs for treating hepatitis B mainly comprise interferon and nucleoside analogues (lamivudine, entecavir, telbivudine and the like). The interferon plays an anti-HBV role through immunomodulation, and needs long-term injection, which has the disadvantages of inconvenience and high cost. Nucleoside analogues act by inhibiting the reverse transcriptase of hepatitis b virus, which has the disadvantage of being susceptible to drug resistance. In addition, viral hepatitis B can be treated with non-nucleoside analogs, such as nucleocapsid inhibitors targeting HBV capsid assembly.
Chinese patent CN108610301a discloses chiral aromatic amine derivatives, which are nuclear capsid inhibitors targeting HBV capsid assembly, but aromatic amine derivatives having a p-methoxyl benzamide structure at the end have poor water solubility, poor patentability, and low or no anti-HBV activity of most compounds.
Disclosure of Invention
The application aims to overcome the defects and the shortcomings in the prior art and provide an aromatic heterocyclic amine derivative.
The second object of the application is to provide a preparation method of the aromatic heterocyclic amine derivatives.
A third object of the present application is to provide the use of said class of aromatic heteroamine derivatives.
The above object of the present application is achieved by the following technical solutions:
an aromatic heterocyclic amine derivative is characterized in that the chemical structural formula is shown as formula (I):
wherein R is 1 Selected from the group consisting ofR 2 Selected from->
Preferably, said R 1 Selected from the group consisting ofR 2 Selected from->
Preferably, said R 1 Selected from the group consisting ofR 2 Selected from->
Preferably, said R 1 Selected from the group consisting ofR 2 Selected from->
Preferably, said R 1 Selected from the group consisting ofR 2 Selected from->
Preferably, said R 1 Selected from the group consisting ofR 2 Selected from->
The application also provides a preparation method of the aromatic heterocyclic amine derivative, which is characterized by comprising the following steps:
s1, dissolving 2-aminothiazole and di-tert-butyl dicarbonate in anhydrous tetrahydrofuran, reacting overnight at room temperature, spin-drying, separating and purifying to obtain a compound 2;
s2, adding anhydrous tetrahydrofuran into the compound 2 under the protection of inert gas for dissolution, cooling to-76 to-80 ℃, slowly adding n-butyllithium for reaction, then slowly adding tetrahydrofuran solution for continuous reaction, adding a quencher after the reaction is finished, heating to room temperature, extracting, spin-drying, separating and purifying to obtain a compound 3;
s3, dissolving the compound 3 in anhydrous dichloromethane, and adding thionyl chloride into the solutionReflux reaction at 78-82 deg.c in inert atmosphere, cooling to room temperature, decompression drying solvent, and further adding substituted naphthol and K 2 CO 3 Reflux-reacting in dichloromethane at 78-82 ℃, spin-drying the solvent after the reaction, extracting, washing, spin-drying, separating and purifying to obtain a compound 4;
s4, dissolving the compound 4 in anhydrous dichloromethane, adding trifluoroacetic acid, reacting at room temperature overnight, decompressing, spin-drying the solvent, adjusting the pH value to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 5;
s5, dissolving the compound 5 and the p-methoxybenzoyl chloride in anhydrous dichloromethane, adding pyridine, reacting at room temperature overnight, spin-drying the solvent after the reaction is finished, adjusting the pH to 3-5, extracting, washing, spin-drying, separating and purifying to obtain a compound 6;
s7, dissolving the compound 6 in anhydrous dichloromethane, cooling to-76 to-80 ℃, slowly adding excessive boron tribromide for reaction, then heating to room temperature for reaction, adjusting the pH to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 7;
or reflux-reacting compound 6, excessive iron powder and ammonium chloride with ethanol/water (3:1) as solvent at 88-92 ℃ overnight, cooling to room temperature, adjusting pH to 7-9, extracting, washing, spin-drying, separating and purifying to obtain compound 7;
the structural formulas of the compounds 2, 3, 4, 5, 6 and 7 are as follows:
wherein X is selected from->Y is selected from->Z is selected from->
The aromatic heterocyclic amine derivative provided by the application can inhibit the assembly of hepatitis B virus nucleocapsids, and improves the water solubility and the drug property on the basis of maintaining the activity of the existing aromatic heterocyclic amine derivative. Therefore, the application also provides the application of the aromatic heterocyclic amine derivative in preparing the medicament for inhibiting the assembly of the hepatitis B virus nucleocapsid; and the application of the aromatic heterocyclic amine derivative in preparing medicaments for inhibiting replication of hepatitis B virus.
Compared with the prior art, the application has the following beneficial effects:
the application synthesizes a novel aromatic heterocyclic amine derivative, which has better water solubility, good patentability and good anti-hepatitis B virus activity on the basis of maintaining the activity of the aromatic heterocyclic amine derivative with the p-methoxyl benzamide structure at the tail end; meanwhile, the novel compound has hydroxyl and amino in the structure, so that the novel inhibitor based on a proteolytic targeting chimeric mechanism can be designed and synthesized, and the novel inhibitor has a wide application prospect.
Drawings
FIG. 1 is a HBV viral copy number standard curve.
Detailed Description
The application is further illustrated in the following drawings and specific examples, which are not intended to limit the application in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present application are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
The preparation method of the novel aromatic heterocyclic amine derivative comprises the following basic synthetic route:
a: to a 100mL round bottom flask was added 2-aminothiazole (compound 1) (2 g,20mmol,1.0 eq) and di-tert-butyl dicarbonate (6.268 g,30mmol,1.5 eq) in sequence, followed by anhydrous tetrahydrofuran to dissolve and reaction at room temperature overnight. Tetrahydrofuran was dried by spin-drying under reduced pressure and column chromatography to give compound 2 (3902 mg, 97.55%).
b: to a 100mL round bottom flask was added compound 2 (3 mmol,1.0 eq), placed on a vacuum pump for thirty minutes, protected with argon, dissolved in an appropriate amount of anhydrous tetrahydrofuran, and placed in a low temperature reaction bath at-78 ℃. N-butyllithium (12 mmol,4.0 eq) was slowly added over a period of 30 minutes after cooling to-78 ℃. Then the corresponding substituted benzaldehyde (4.5 mmol,1.5 eq) in anhydrous tetrahydrofuran was slowly added over 30 minutes as well and the reaction was continued at-78℃for 5 hours, the whole reaction being protected with argon. After the reaction, the remaining n-butyllithium was quenched with 1M HCl, then warmed to room temperature, extracted with ethyl acetate, washed with saturated sodium chloride solution, and the organic layer was dried under reduced pressure and separated by column chromatography to give compound 3.
c: to a 100mL round bottom flask was added compound 3 (1.0 eq), dissolved in anhydrous dichloromethane, and then added with an appropriate amount of thionyl chloride, and reacted overnight under argon at 80 ℃. Cooled to room temperature, the solvent was dried under reduced pressure, substituted naphthol (1.2 eq) and potassium carbonate (3.0 eq) were added, and the mixture was reacted with dichloromethane as a solvent at 80℃under reflux for 4 hours. After the reaction, the dichloromethane was dried under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride solution, and the organic layer was dried under reduced pressure, followed by column chromatography to give compound 4.
d: to a 50mL round bottom flask was added compound 4, dissolved in anhydrous dichloromethane, and then added with an appropriate amount of trifluoroacetic acid, and reacted overnight at room temperature. The dichloromethane was dried under reduced pressure, the pH was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, and the organic layer was dried under reduced pressure and separated by column chromatography to give Compound 5.
e: to a 25mL round bottom flask was added the corresponding compound 5 (1.0 eq) and p-methoxybenzoyl chloride (1.2 eq), dissolved in anhydrous dichloromethane, and pyridine (4.0 eq) was added and reacted overnight at room temperature. The dichloromethane was dried under reduced pressure, the pH was adjusted to about 4 with 1mol/L hydrochloric acid, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying the organic layer under reduced pressure, and column chromatography to give Compound 6.
The synthesis method of the compound 7 comprises the following steps:
f (a) methoxy becomes hydroxy: to a 50mL round bottom flask was added the corresponding compound 6, dissolved in anhydrous dichloromethane, and placed in a-78℃low temperature reaction bath. After cooling to-78 ℃, adding excessive boron tribromide slowly, continuing to react for 2.5 hours at-78 ℃, and then raising the temperature to room temperature for 4 hours. The pH was adjusted to about 8 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, spin-drying the organic layer under reduced pressure, and column chromatography to give the corresponding compound 7.
f (b) reduction of nitro to amino: to a 50mL round bottom flask was added the corresponding compound 6 (1.0 eq), excess iron powder and ammonium chloride, ethanol/water (3:1) as solvent and reacted at 90℃under reflux overnight. Cooling to room temperature, regulating pH to about 8 with saturated sodium bicarbonate solution, extracting with ethyl acetate, washing with saturated sodium chloride solution, drying under reduced pressure, and separating by column chromatography to obtain the corresponding compound 7.
Example 1
Synthesis of aromatic heterocyclic amine derivative shown in chemical formula (II)
Taking the corresponding compound 5 (X isY is->) (230 mg,0.5 mmol), p-methoxybenzoyl chloride (102 mg,0.6 mmol) was dissolved in anhydrous dichloromethane, pyridine (158 mg,2 mmol) was added, and the reaction was carried out at room temperature overnight. The dichloromethane was dried under reduced pressure, the pH was adjusted to about 4 with 1mol/L hydrochloric acid, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying the organic layer under reduced pressure, and column chromatography to give the compound.
Data analysis: 1 h NMR (Bruker 500or 400MHz, solvent deuterated methanol, deuterated chloroform orDeuterated DMSO), mass spectrum (ESI, thermofisher LCQ or QE), data are shown below:
1 H NMR(500MHz,DMSO)δ12.29(s,1H),10.16(s,1H),8.14(s,1H),8.03(d,J=8.9Hz,2H),7.87–7.81(m,2H),7.41(d,J=13.9Hz,2H),7.33(d,J=8.6Hz,2H),7.24(d,J=8.6Hz,3H),7.03(d,J=9.0Hz,2H),6.66(s,1H),3.81(s,3H),2.43(s,3H),2.26(s,3H).
13 C NMR(126MHz,DMSO)δ165.55(s),163.06(s),158.81(s),153.65(s),135.44–133.50(m),132.67(d,J=148.4Hz),130.93(s),130.58–129.67(m),129.17(s),128.48(s),124.27(s),120.33(s),119.63(s),116.15(s),114.30(s),55.96(s),26.81(s),11.92(s),11.09(s).
example 2
Synthesis of aromatic heterocyclic amine derivative shown in chemical structural formula (III)
Taking the corresponding compound 5 (X isY is->) (376 mg,0.85 mmol), p-methoxybenzoyl chloride (145 mg,0.85 mmol) was dissolved in anhydrous dichloromethane, pyridine (135 mg,1.7 mmol) was added thereto, and the reaction was carried out at room temperature overnight. The dichloromethane was dried under reduced pressure, the pH was adjusted to about 4 with 1mol/L hydrochloric acid, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying the organic layer under reduced pressure, and column chromatography to give the compound.
Data analysis: 1 h NMR (Bruker 500or 400mhz, solvent deuterated methanol, deuterated chloroform or deuterated DMSO), mass spectrometry (ESI, thermofisher LCQ or QE), data as follows:
1 H NMR(500MHz,DMSO)δ12.29(s,1H),10.21(s,1H),8.06(d,J=2.1Hz,1H),8.02(d,J=8.9Hz,2H),7.93–7.82(m,1H),7.75(d,J=8.9Hz,1H),7.41(d,J=8.8Hz,1H),7.26(d,J=8.9Hz,1H),7.22(s,1H),7.15(d,J=8.6Hz,2H),7.02(d,J=9.0Hz,2H),6.84(d,J=8.8Hz,2H),6.57(s,1H),3.81(s,3H),3.70(s,3H).
13 C NMR(126MHz,DMSO)δ163.03(s),158.03(s),153.75(s),134.57(d,J=38.8Hz),131.63(s),130.82(s),130.55(s),129.17(s),128.83(s),124.66(s),120.98(s),120.10(s),115.61(s),114.65–114.43(m),114.18(d,J=25.1Hz),55.95(s),55.46(s),26.80(s).
example 3
The chemical structural formula is shown in the formula (IV) and is synthesized by aromatic heterocyclic amine derivatives:
taking the corresponding compound 5 (X isY is->) (432 mg,0.95 mmol), p-methoxybenzoyl chloride (162 mg,0.95 mmol) was dissolved in anhydrous dichloromethane, pyridine (150 mg,1.9 mmol) was added thereto, and the reaction was carried out overnight at room temperature. The dichloromethane was dried under reduced pressure, the pH was adjusted to about 4 with 1mol/L hydrochloric acid, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, drying the organic layer under reduced pressure, and column chromatography to give the compound.
Data analysis: 1 h NMR (Bruker 500or 400mhz, solvent deuterated methanol, deuterated chloroform or deuterated DMSO), mass spectrometry (ESI, thermofisher LCQ or QE), data as follows:
1 H NMR(500MHz,DMSO)δ12.36(s,1H),10.36(s,1H),8.14(d,J=8.9Hz,2H),8.11(d,J=2.1Hz,1H),8.07–8.01(m,3H),7.80(d,J=8.9Hz,1H),7.52(d,J=9.4Hz,2H),7.39(d,J=8.6Hz,2H),7.24(d,J=8.9Hz,1H),7.03(d,J=9.0Hz,2H),6.76(s,1H),3.82(s,3H).
13 C NMR(126MHz,DMSO)δ163.08(s),153.73(s),152.22(s),146.14(s),131.63(s),130.96(s),130.95(s),130.44(d,J=34.3Hz),129.79(s),129.33(s),128.88(s),123.77(s),120.24(s),115.88(s),114.30(s),55.96(s).
example 4
The chemical structural formula is shown in the formula (V) and is synthesized by aromatic heterocyclic amine derivatives:
to a 50mL round bottom flask was added the compound of formula (III) (190 mg,0.33 mmol), dissolved in anhydrous dichloromethane, and placed in a low temperature reaction bath at-78 ℃. After cooling to-78 ℃, adding excessive boron tribromide slowly, continuing to react for 2.5 hours at-78 ℃, and then raising the temperature to room temperature for 4 hours. The pH was adjusted to about 8 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, washing with saturated sodium chloride solution, spin-drying the organic layer under reduced pressure, and column chromatography to give the compound.
Data analysis: 1 h NMR (Bruker 500or 400mhz, solvent deuterated methanol, deuterated chloroform or deuterated DMSO), mass spectrometry (ESI, thermofisher LCQ or QE), data as follows:
1 H NMR(500MHz,DMSO)δ12.28(s,1H),10.17(s,1H),9.25(s,1H),8.06(d,J=2.1Hz,1H),8.04–7.99(m,2H),7.84(s,1H),7.74(d,J=8.9Hz,1H),7.40(d,J=8.8Hz,1H),7.26(d,J=8.9Hz,1H),7.19(s,1H),7.05–7.00(m,4H),6.67(d,J=8.6Hz,2H),6.53(s,1H),3.81(s,3H).
13 C NMR(126MHz,DMSO)δ163.03(s),156.10(s),153.74(s),132.89(s),131.67(s),130.67(d,J=29.7Hz),129.06(d,J=26.2Hz),128.74(s),128.63–128.36(m),124.70(s),121.16(s),120.07(s),115.53(d,J=12.6Hz),114.29(s),55.95(s),26.81(s).
example 5
The chemical structural formula is shown in the formula (VI) and is synthesized by aromatic heterocyclic amine derivatives:
to a 50mL round bottom flask was added the compound of formula (IV) (230 mg,0.39 mmol), excess iron powder and ammonium chloride, ethanol/water (3:1) as solvent and the reaction was refluxed overnight at 90 ℃. Cooling to room temperature, regulating pH to about 8 with saturated sodium bicarbonate solution, extracting with ethyl acetate, washing with saturated sodium chloride solution, drying under reduced pressure, and separating by column chromatography.
Data analysis: 1 h NMR (Bruker 500or 400mhz, solvent deuterated methanol, deuterated chloroform or deuterated DMSO), mass spectrometry (ESI, thermofisher LCQ or QE), data as follows:
1 H NMR(500MHz,DMSO)δ12.28(s,1H),10.12(s,1H),8.07(d,J=2.1Hz,1H),8.06–8.00(m,3H),7.85(d,J=24.7Hz,1H),7.75(dd,J=15.4,8.9Hz,1H),7.39(t,J=9.4Hz,1H),7.26(d,J=8.7Hz,1H),7.13(d,J=7.3Hz,1H),7.02(d,J=8.9Hz,2H),6.90(d,J=8.3Hz,1H),6.57(d,J=8.4Hz,1H),6.47(d,J=8.4Hz,2H),4.93(s,2H),3.81(s,3H).
13 C NMR(126MHz,DMSO)δ163.03(s),153.67(s),147.35(s),131.72(s),130.73(s),130.55(s),129.50(s),128.68(d,J=25.5Hz),128.50–128.16(m),124.71(s),121.43(s),119.88(d,J=37.2Hz),115.53(s),114.25(d,J=7.8Hz),55.95(s),26.81(s).
test case
1. anti-HBV effect detection experiment
The chromosomes of hepg2.2.15 cells integrate the complete HBV genome and stably express viral DNA and viral proteins. HepG2.2.15 cells are able to secrete mature hepatitis B virus particles, HBsAg and HBeAg into the culture medium. The viral particle DNA secreted by hepg2.2.15 cells can be quantified by qPCR methods and the effect of the compound on viral replication is thereby detected. The method specifically comprises the following steps:
1. compound treatment of HepG2.2.15 cells
(1) HepG2.2.15 cells 20000 cells per well, 200. Mu.L cell culture medium per well, were plated in 96 well cell culture plates (Greiner 655098);
(2) At 37 ℃,5% CO 2 Culturing in a cell culture box for 3 days until cells grow to full holes;
(3) On test day 0, old medium was discarded and 200 μl of fresh detection medium (2% fbs) was added;
(4) Compound formulation and cell treatment in antiviral experiments: the compound was dissolved with DMSO to 30mM, further diluted with DMSO to 4mM, then 5-fold dilutions of 8 dilutions were performed, with a maximum concentration of 4mM. Serial dilutions of 1 μl of compound were added to the cell plates prepared in step c, with a final experimental concentration of 20 μΜ (200-fold dilution). TDF (tenofovir disoproxil fumarate, selleck, cat S1400) was used as a positive control compound at a maximum concentration of 1. Mu.M. 1. Mu.L of DMSO was added to the negative control wells at a final concentration of 0.5%, and TDF was added to the positive control wells at a final concentration of 1. Mu.M.
(5) 96 well cell test plate was CO at 37 °c 2 Incubate for 7 days, change every other day (days 2,4, 6) with liquid (2% FBS) and add 1. Mu.L of freshly prepared compound, see steps (3) and (4).
(6) 150. Mu.L of supernatant was taken per well on day 7 for qPCR detection of viral DNA.
2. Compound formulation and cell handling in cytotoxic assays
Serial dilutions of the compound were made up with Bravo liquid handling system, 11 dilutions, 3-fold dilution, and a maximum concentration of 30mM. Serial dilutions of compound were added 0.25 μl per well to 384 well cytotoxic cell plates (Greiner 781098) and 50 μl of hepg2.2.15 cells per well (5000 cells/well) at a final concentration of 150 μΜ (200 fold dilution) at the assay. CO at 37 DEG C 2 The cytotoxicity test was performed after incubation in the incubator for 4 days.
3. qPCR method for detecting virus genome DNA
(1) The qPCR reaction system is prepared according to the following components:
TB Premix Ex TaqTM II(2×) | 5μL |
HBV-For-202(10μM) | 0.4μL |
HBV-Rev-315(10μM) | 0.4μL |
ROX Reference Dye(50×) | 0.2μL |
viral supernatant | 1μL |
Adding water to | 10μL |
(2) The ABI ViiA7 qPCR instrument was set up according to the following conditions
Stage 1: reps:95 ℃,30s, one cycle; stage 2: reps:95 ℃,5s and 60 ℃,34s,40 cycles; a dissolution profile was added.
4. Cytotoxic effects of Lumi-Glo reagent detection compounds
a. The Lumi-Glow cell viability reagent was equilibrated to room temperature.
b. The 384-well cytotoxic assay plate was equilibrated for approximately 20 minutes to room temperature.
c. mu.L of Lumi-Glo reagent was added to each well.
d. The plate vibrator was set up for 2 minutes.
e. Equilibrated at room temperature for 10 minutes in the dark.
f. Reading on Envision plate reader (0.1 seconds/well)
Results: with plasmids containing HBV genomes (viral copy number: 2X 10E) 6 ,2×10E 5 ,2×10E 4 ,2×10E 3 ) Making a standard curve, as shown in fig. 1; and virus copy number was calculated as a standard curve. The effect of a compound on viral replication is expressed by the following formula: inhibition effect (%) =100- (detection value-positive control Kong Junzhi)/(negative control Kong Junzhi-positive control Kong Junzhi). Times.100. The assay value was virus copy number (ge/. Mu.L), negative control Kong Junzhi was DMSO-treated Kong Junzhi, and positive control Kong Junzhi was TDF-treated well mean. Concentration-inhibition (%) data were processed with Graphpad Prism 5 software and EC of compound on viral replication was calculated by a four-parameter nonlinear regression model 50 . Compound cytotoxicity was calculated using the following formula: cytotoxicity (%) = 100- (assay/DMSO control well mean x 100). Concentration-cytotoxicity (%) data were processed with Graphpad Prism 5 software and CC was calculated by a four-parameter nonlinear regression model 50 。
Table 15 test compound information
TABLE 2 average concentration of EC50 and CC50 compounds
TABLE 3 antiviral Activity of prior art CN108610301A aryl heteroamines derivatives
The result shows that the aromatic heterocyclic amine derivatives with the brand new structure provided by the application have anti-hepatitis B virus activity.
2. Solubility determination
Two identical sample solutions were prepared from 10mM stock solution of compound, and after evaporation of DMSO by centrifugal vacuum evaporator, the compound was dissolved in 0.05M phosphate buffer (pH 6.5), stirred for 1h, and then shaken for 2h. The next day, the solution was filtered using a microtiter plate. The filtrate was then analyzed by HPLC-UV and diluted 10-fold. In addition, four-point calibration curves were prepared using 10mM stock solutions for compound solubility determination. The unit of the result is μg/mL. If the percentage of the measured sample amount after evaporation of DMSO divided by the theoretical calculated maximum sample amount is greater than 80%, then it can be reported that the solubility is greater than this maximum.
TABLE 4 solubility of the compounds of the application
TABLE 5 solubility of prior art CN108610301A aromatic heteroamine derivatives
/>
The result shows that the aromatic heterocyclic amine derivative with the brand new structure provided by the application has better water solubility and patentability, especially the compounds shown in the formula (V) and the formula (VI), and the water solubility and patentability of the aromatic heterocyclic amine derivative are obviously improved compared with the existing compounds.
Claims (7)
1. An aromatic heterocyclic amine derivative is characterized in that the chemical structural formula is shown as formula (I):
(I);
wherein R is 1 Selected from the group consisting of、/>Or->;R 2 Selected from->。
2. The aromatic heterocyclic amine derivative according to claim 1, wherein R 1 Selected from the group consisting of,R 2 Selected from->。
3. The aromatic heterocyclic amine derivative according to claim 1, wherein R 1 Selected from the group consisting of,R 2 Selected from->。
4. The aromatic heterocyclic amine derivative according to claim 1, wherein R 1 Selected from the group consisting of,R 2 Selected from->。
5. The process for producing an aromatic heterocyclic amine derivative according to claim 1, comprising the steps of:
s1, dissolving 2-aminothiazole and di-tert-butyl dicarbonate in anhydrous tetrahydrofuran, reacting overnight at room temperature, spin-drying, separating and purifying to obtain a compound 2;
s2, adding anhydrous tetrahydrofuran into the compound 2 under the protection of inert gas for dissolution, cooling to-76 to-80 ℃, slowly adding n-butyllithium for reaction, then slowly adding tetrahydrofuran solution for continuous reaction, adding a quencher after the reaction is finished, heating to room temperature, extracting, spin-drying, separating and purifying to obtain a compound 3;
s3, dissolving the compound 3 in anhydrous dichloromethane, adding thionyl chloride, carrying out reflux reaction at 78-82 ℃ in an inert atmosphere, cooling to room temperature, decompressing and spin-drying the solvent, continuously adding substituted naphthol and K2CO3, carrying out reflux reaction at 78-82 ℃ in dichloromethane, spin-drying the solvent after the reaction is finished, extracting, washing, spin-drying, separating and purifying to obtain a compound 4;
s4, dissolving the compound 4 in anhydrous dichloromethane, adding trifluoroacetic acid, reacting at room temperature overnight, decompressing, spin-drying the solvent, adjusting the pH value to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 5;
s5, dissolving the compound 5 and the p-methoxybenzoyl chloride in anhydrous dichloromethane, adding pyridine, reacting at room temperature overnight, spin-drying the solvent after the reaction is finished, adjusting the pH to 3-5, extracting, washing, spin-drying, separating and purifying to obtain a compound 6;
s7, dissolving the compound 6 in anhydrous dichloromethane, cooling to-76 to-80 ℃, slowly adding excessive boron tribromide for reaction, then heating to room temperature for reaction, adjusting the pH to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 7;
or compound 6, excess iron powder and ammonium chloride in ethanol/water 3:1 as solvent, reflux reacting overnight at 88-92 ℃, cooling to room temperature, adjusting pH to 7-9, extracting, washing, spin drying, separating and purifying to obtain a compound 7;
the structural formulas of the compounds 2, 3, 4, 5, 6 and 7 are as follows:
、/> 、/>、、/>the method comprises the steps of carrying out a first treatment on the surface of the Wherein X is selected from->Or->The method comprises the steps of carrying out a first treatment on the surface of the Y is selected from->The method comprises the steps of carrying out a first treatment on the surface of the Z is selected from->Or->。
6. Use of an aromatic heterocyclic amine derivative according to any one of claims 1 to 4 for the preparation of a medicament for inhibiting the assembly of a hepatitis b virus nucleocapsid.
7. The use of the aromatic heterocyclic amine derivative according to any one of claims 1 to 4 in the preparation of a medicament for inhibiting replication of hepatitis B virus.
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CN108610301A (en) * | 2016-12-12 | 2018-10-02 | 中山大学 | A kind of chiral fragrant miscellaneous amine derivant and its synthetic method and application |
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