CN113717125A - Aromatic hetero amine derivatives, and preparation method and application thereof - Google Patents
Aromatic hetero amine derivatives, and preparation method and application thereof Download PDFInfo
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- -1 Aromatic hetero amine Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
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- 239000003814 drug Substances 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 238000001035 drying Methods 0.000 claims description 37
- 238000005406 washing Methods 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- 241000700721 Hepatitis B virus Species 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 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
- 238000010992 reflux Methods 0.000 claims description 7
- 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
- 230000002401 inhibitory effect Effects 0.000 claims description 6
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- 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
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
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- 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
- 150000003935 benzaldehydes Chemical class 0.000 claims description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- 230000017854 proteolysis Effects 0.000 abstract description 2
- 230000008685 targeting 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
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- 210000004027 cell Anatomy 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 4
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- GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical group COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
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- 125000003277 amino group Chemical group 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 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
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- 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
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- 125000005241 heteroarylamino group Chemical group 0.000 description 1
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- 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
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- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
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- 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 invention discloses an aromatic heterocyclic amine derivative and a preparation method and application thereof. The structural formula of the aromatic hetero amine derivative is shown as a formula (I), wherein R1Selected from chlorine, methoxy, nitro, hydroxyl or amino; r2Selected from 3, 5-dimethylisoxazolyl or bromo; the invention provides the aromatic heterocyclic amine derivative compound which has good water solubility and high patent drug property. Similarly, the compound has an amide structure, and the anti-hepatitis B virus activity of the compound discovered by the invention is good; and the structure of the compound has hydroxyl and amino, so that a novel inhibitor based on a proteolysis targeting chimeric mechanism can be designed and synthesized, and the application prospect is wide.
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to an aromatic hetero amine derivative and 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 damage, and long-term infection of which may cause hepatitis, cirrhosis and even liver cancer. The existing medicines for treating hepatitis B mainly comprise interferon and nucleoside analogs (lamivudine, entecavir, telbivudine and the like). Among them, interferon exerts an anti-HBV effect through immune regulation, and needs to be administered by injection for a long time, and has the disadvantages of inconvenience and high cost. The nucleoside analogue plays a role by inhibiting the reverse transcriptase of hepatitis B virus, and has the defect of easy generation of drug resistance. In addition, viral hepatitis B can be treated with non-nucleoside analogs, such as nucleocapsid inhibitors that target HBV capsid assembly.
Chinese patent CN108610301A discloses a chiral aromatic-heteroaromatic amine derivative, which is a nucleocapsid inhibitor taking HBV capsid assembly as a target spot, however, the aromatic-heteroaromatic amine derivative compound with a p-methoxybenzamide structure at the end has poor water solubility and drug forming property, and the anti-hepatitis B virus activity of most compounds is low or even none.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide an aromatic hetero amine derivative.
The second purpose of the invention is to provide a preparation method of the aromatic hetero amine derivatives.
The third purpose of the invention is to provide the application of the aromatic hetero amine derivatives.
The above object of the present invention is achieved by the following technical solutions:
an aromatic hetero amine derivative is characterized in that the chemical structural formula is shown as the formula (I):
wherein R is1Is selected from
R2Is selected from
Preferably, said R is1Is selected from
R2Is selected from
Preferably, said R is1Is selected from
R2Is selected from
Preferably, said R is1Is selected from
R2Is selected from
Preferably, said R is1Is selected from
R2Is selected from
Preferably, said R is1Is selected from
R2Is selected from
The invention also provides a preparation method of the aromatic-hetero 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 dissolving, cooling to-76-80 ℃, slowly adding n-butyllithium for reaction, slowly adding a tetrahydrofuran solution of substituted benzaldehyde for continuous reaction, adding a quenching agent 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 to perform reflux reaction at 78-82 ℃ in an inert atmosphere, cooling to room temperature, performing reduced pressure spin drying on the solvent, and continuously adding substituted naphthol and K2CO3Carrying out reflux reaction in dichloromethane at 78-82 ℃, and after the reaction is finished, spin-drying the solvent, 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, performing reduced pressure spin-drying on the solvent, adjusting the pH to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 5;
s5, dissolving the compound 5 and 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 value 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-76-80 ℃, slowly adding excessive boron tribromide for reaction, heating to room temperature for reaction, adjusting the pH value to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 7;
or carrying out reflux reaction on the compound 6, excessive iron powder and ammonium chloride with ethanol/water (3: 1) as a solvent at 88-92 ℃ overnight, cooling to room temperature, adjusting the pH value 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 aromatic heterocyclic amine derivative provided by the invention can inhibit the assembly of hepatitis B virus nucleocapsid, 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 invention also provides the application of the aromatic heterocyclic amine derivative in preparing the medicament for inhibiting the assembly of hepatitis B virus nucleocapsid; and the application of the aromatic heterocyclic amine derivative in preparing the medicament for inhibiting the replication of the hepatitis B virus.
Compared with the prior art, the invention has the following beneficial effects:
the invention synthesizes a kind of novel aromatic heterocyclic amine derivatives, which have better water solubility and pharmacy and good anti-hepatitis B virus activity on the basis of maintaining the activity of the aromatic heterocyclic amine derivatives with the p-methoxy benzamide structure at the tail end; meanwhile, the novel compound has hydroxyl and amino in the structure, can be designed and synthesized according to the structure to form a novel inhibitor based on a proteolysis targeting chimeric mechanism, and has a wide application prospect.
Drawings
FIG. 1 is a standard curve of HBV viral copy number.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
The preparation method of the novel aromatic heterocyclic amine derivatives comprises the following basic synthetic route:
a: 2-aminothiazole (Compound 1) (2g,20mmol,1.0eq) and di-tert-butyl dicarbonate (6.548g,30mmol,1.5eq) were added in this order to a 100mL round-bottomed flask, and then dissolved in anhydrous tetrahydrofuran, followed by reaction at room temperature overnight. Tetrahydrofuran was dried by spin-drying under reduced pressure, and column chromatography gave compound 2(3902mg, 97.55%).
b: compound 2(3mmol,1.0eq) was added to a 100mL round bottom flask, vacuum pumped for thirty minutes, then under argon protection, dissolved in an appropriate amount of anhydrous tetrahydrofuran, and placed in a low temperature reaction bath at-78 ℃. After cooling to-78 deg.C, n-butyllithium (12mmol,4.0eq) was added slowly over a period of 30 minutes. The corresponding substituted benzaldehyde (4.5mmol,1.5eq) dissolved in dry tetrahydrofuran was then added slowly over the course of 30 minutes and the reaction was continued at-78 ℃ for 5 hours, the reaction being continued under argon. After the reaction is finished, quenching the residual n-butyllithium in 1M HCl, then heating to room temperature, extracting with ethyl acetate, washing with saturated sodium chloride solution, carrying out reduced pressure spin-drying on an organic layer, and carrying out column chromatography separation to obtain a compound 3.
c: to a 100mL round bottom flask was added compound 3(1.0eq), dissolved in anhydrous dichloromethane, and added an appropriate amount of thionyl chloride, and the reaction was refluxed at 80 ℃ under argon atmosphere overnight. Cooled to room temperature, the solvent was spin-dried under reduced pressure, and substituted naphthol (1.2eq) and potassium carbonate (3.0eq) were added to conduct reflux reaction at 80 ℃ for 4 hours using methylene chloride as a solvent. After the reaction is finished, decompressing and spin-drying dichloromethane, extracting by using ethyl acetate, washing by using a saturated sodium chloride solution, decompressing and spin-drying an organic layer, and separating by using a column chromatography to obtain a compound 4.
d: to a 50mL round-bottom flask, Compound 4 was added, dissolved in anhydrous dichloromethane, and then an appropriate amount of trifluoroacetic acid was added, and the mixture was reacted overnight at room temperature. Decompressing and spin-drying dichloromethane, adjusting pH to about 8 by using saturated sodium bicarbonate solution, extracting by using ethyl acetate, washing by using saturated sodium chloride solution, decompressing and spin-drying an organic layer, and separating by using column chromatography to obtain a compound 5.
e: to a 25mL round-bottomed flask, the corresponding compound 5(1.0eq) and p-methoxybenzoyl chloride (1.2eq) were added, dissolved in anhydrous dichloromethane, and then pyridine (4.0eq) was added to react at room temperature overnight. Decompressing and spin-drying dichloromethane, adjusting pH to about 4 by using 1mol/L hydrochloric acid, extracting by using ethyl acetate, washing by using saturated sodium chloride solution, decompressing and spin-drying an organic layer, and separating by using column chromatography to obtain a compound 6.
The synthesis method of the compound 7 comprises the following steps:
f (a) methoxy to hydroxy: to a 50mL round-bottom flask was added the corresponding Compound 6, dissolved by adding anhydrous dichloromethane, and placed in a low temperature reaction bath at-78 ℃. When the temperature is cooled to-78 ℃, excessive boron tribromide is slowly added, the reaction is continued for 2.5 hours at-78 ℃, then the temperature is raised to the room temperature, and the reaction is carried out for 4 hours. Adjusting pH to about 8 with saturated sodium bicarbonate solution, extracting with ethyl acetate, washing with saturated sodium chloride solution, spin-drying organic layer under reduced pressure, and separating with column chromatography to obtain corresponding compound 7.
(b) reduction of nitro groups to amino groups: a50 mL round-bottomed flask was charged with the corresponding compound 6(1.0eq), excess iron powder and ammonium chloride, in ethanol/water (3: 1) as a solvent, and refluxed at 90 ℃ overnight. Cooling to room temperature, adjusting pH to about 8 with saturated sodium bicarbonate solution, extracting with ethyl acetate, washing with saturated sodium chloride solution, spin-drying organic layer under reduced pressure, and separating by column chromatography to obtain compound 7.
Example 1
Synthesis of heteroaryl amine derivative with chemical structural formula shown as formula (II)
Taking the corresponding compound 5(X is
Y is
) (230mg,0.5mmol) and p-methoxybenzoyl chloride (102mg,0.6mmol) were dissolved in anhydrous dichloromethane, followed by addition of pyridine (158mg,2mmol) and reaction at room temperature overnight. Decompressing and spin-drying dichloromethane, adjusting pH to about 4 by using 1mol/L hydrochloric acid, extracting by using ethyl acetate, washing by using saturated sodium chloride solution, decompressing and spin-drying an organic layer, and separating by using column chromatography to obtain the compound.
And (3) data analysis:1h NMR (Bruker 500or 400MHz with deuterated methanol, deuterated chloroform or deuterated DMSO as solvent), mass spectrometry (ESI, Thermofisiher LCQ or QE) with the following data:
1H 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).
13C 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 aryl-hetero amine derivatives with chemical structural formula shown as formula (III)
Taking the corresponding compound 5(X is
Y is
) (376mg,0.85mmol) and p-methoxybenzoyl chloride (145mg,0.85mmol) were dissolved in anhydrous dichloromethane, followed by addition of pyridine (135mg,1.7mmol) and reaction at room temperature overnight. Decompressing and spin-drying dichloromethane, adjusting pH to about 4 by using 1mol/L hydrochloric acid, extracting by using ethyl acetate, washing by using saturated sodium chloride solution, decompressing and spin-drying an organic layer, and separating by using column chromatography to obtain the compound.
And (3) data analysis:1h NMR (Bruker 500or 400MHz with deuterated methanol, deuterated chloroform or deuterated DMSO as solvent), mass spectrometry (ESI, Thermofisiher LCQ or QE) with the following data:
1H 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).
13C 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
Synthesizing the aromatic hetero amine derivative with the chemical structural formula shown as the formula (IV):
taking the corresponding compound 5(X is
Y is
) (432mg,0.95mmol) and p-methoxybenzoyl chloride (162mg,0.95mmol) were dissolved in anhydrous dichloromethane, followed by addition of pyridine (150mg,1.9mmol) and reaction at room temperature overnight. The dichloromethane is dried by spinning under reduced pressure and 1mol/L hydrochloric acid is usedAdjusting pH to about 4, extracting with ethyl acetate, washing with saturated sodium chloride solution, spin-drying organic layer under reduced pressure, and separating by column chromatography to obtain the compound.
And (3) data analysis:1h NMR (Bruker 500or 400MHz with deuterated methanol, deuterated chloroform or deuterated DMSO as solvent), mass spectrometry (ESI, Thermofisiher LCQ or QE) with the following data:
1H 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).
13C 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
Synthesizing the aromatic heterocyclic amine derivative with the chemical structural formula shown as the formula (V):
a50 mL round-bottomed flask was charged with the compound represented by the formula (III) (190mg,0.33mmol), dissolved in anhydrous dichloromethane, and placed in a low-temperature reaction bath at-78 ℃. When the temperature is cooled to-78 ℃, excessive boron tribromide is slowly added, the reaction is continued for 2.5 hours at-78 ℃, then the temperature is raised to the room temperature, and the reaction is carried out for 4 hours. Adjusting pH to about 8 with saturated sodium bicarbonate solution, extracting with ethyl acetate, washing with saturated sodium chloride solution, spin-drying organic layer under reduced pressure, and separating by column chromatography to obtain the compound.
And (3) data analysis:1h NMR (Bruker 500or 400MHz with deuterated methanol, deuterated chloroform or deuterated DMSO as solvent), mass spectrometry (ESI, Thermofisiher LCQ or QE) with the following data:
1H 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).
13C 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 synthesis of the aromatic hetero amine derivative with the chemical structural formula shown as the formula (VI):
a50 mL round-bottomed flask was charged with the compound represented by the formula (IV) (230mg,0.39mmol), an excess of iron powder and ammonium chloride, ethanol/water (3: 1) as a solvent, and reacted at 90 ℃ under reflux overnight. Cooling to room temperature, adjusting pH to about 8 with saturated sodium bicarbonate solution, extracting with ethyl acetate, washing with saturated sodium chloride solution, spinning dry organic layer under reduced pressure, and separating by column chromatography to obtain the compound.
And (3) data analysis:1h NMR (Bruker 500or 400MHz with deuterated methanol, deuterated chloroform or deuterated DMSO as solvent), mass spectrometry (ESI, Thermofisiher LCQ or QE) with the following data:
1H 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).
13C 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 example
anti-HBV effect detection experiment
HepG2.2.15 cells have integrated complete HBV genome in their chromosomes and stably express viral DNA and viral proteins. HepG2.2.15 cells secrete mature hepatitis B virus particles, HBsAg and HBeAg into the culture medium. Virion DNA secreted by hepg2.2.15 cells can be quantified by qPCR methods and the effect of compounds on viral replication can be detected therefrom. The method specifically comprises the following steps:
1. compound treatment of HepG2.2.15 cells
(1) HepG2.2.15 cells are plated in 96-well cell culture plates (Greiner 655098) at 20000 cells per well, 200. mu.L cell culture medium per well;
(2) at 37 ℃ 5% CO2Culturing in a cell culture box for 3 days until the cells grow to be full of pores;
(3) on test day 0, old media was discarded and 200 μ Ι _ of fresh assay media (2% FBS) was added;
(4) compound formulation and cell treatment in antiviral experiments: compounds were dissolved to 30mM in DMSO, further compounds were diluted to 4mM in DMSO, then 5-fold dilutions of 8 dilutions were made, with the highest concentration being 4 mM. Add 1. mu.L of serially diluted compound per well to the cell plate prepared in step c, with the highest final concentration tested being 20. mu.M (200-fold dilution). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) was used as a positive control compound at a maximum concentration of 1 μ M. The negative control wells were loaded with 1. mu.L DMSO to a final concentration of 0.5%, and the positive control wells were loaded with TDF to a final concentration of 1. mu.M.
(5) 96-well cell assay plate CO at 37 deg.C2Incubate for 7 days in the incubator, change the solution (2% FBS) every other day (days 2, 4, 6) and add 1 μ L of freshly prepared compound, as described in steps (3) and (4).
(6) At day 7, 150. mu.L of supernatant per well was taken for qPCR detection of viral DNA.
2. Compound preparation and cell treatment in cytotoxicity experiment
Serial dilutions of the compounds were made with Bravo liquid handling system, 11 dilutions, 3-fold dilutions, with a maximum concentration of 30 mM. Add 0.25. mu.L of serially diluted Compound to 384 well cytotoxic cellsIn plates (Greiner 781098), 50 μ L hepg2.2.15 cells (5000 cells/well) were added per well, with the highest final concentration of the experiment being 150 μ M (200-fold dilution). CO at 37 deg.C2The cytotoxicity test was performed after 4 days of incubation in the incubator.
3. qPCR method for detecting virus genome DNA
(1) Preparing a qPCR reaction system 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) ABI ViiA7 qPCR instrument was set up as follows
Stage 1: reps: 95 ℃,30 s, one cycle; and (2) stage: reps: 40 cycles of 95 ℃, 5s and 60 ℃, 34 s; the dissolution profile was added.
4. Lumi-Glo reagent for detecting cytotoxic effect of compound
a. The Lumi-Glow cell viability reagent was equilibrated to room temperature.
b. The 384-well cytotoxic assay plate was equilibrated for about 20 minutes to room temperature.
c. Add 10. mu.L Lumi-Glo reagent per well.
d. Shake on a plate shaker for 2 minutes.
e. Equilibrate for 10 minutes at room temperature in the dark.
f. Read on an Envision plate reader (0.1 sec/well)
As a result: with a plasmid containing the HBV genome (viral copy number: 2X 10E)6，2×10E5，2×10E4，2×10E3) Making a standard curve, as shown in FIG. 1; and calculating the virus copy number by a standard curve. The effect of a compound on viral replication is calculated by the following formula: the inhibitory effect (%) was 100- (detection value-positive control well mean)/(negative control well mean-positive control well mean) × 100. The detection value is the virus copy number (ge/muL), the mean value of the negative control wells is the mean value of the DMSO-treated wells, and the mean value of the positive control wells is the mean value of the TDF-treated wells. Concentration-inhibition (%) data were processed with Graphpad Prism 5 software and the EC of compounds on viral replication was calculated by a four-parameter non-linear regression model50. Compound cytotoxicity was calculated using the following formula: cytotoxicity (%) ═ 100- (mean value of assay/DMSO control wells × 100). Concentration-cytotoxicity (%) data were processed with Graphpad Prism 5 software and CC was calculated by a four-parameter non-linear regression model50。
TABLE 15 information on the test Compounds
TABLE 2 summary of mean values for compounds EC50 and CC50
TABLE 3 antiviral Activity of Prior Art CN108610301A Arhetamine derivatives
The results show that the aromatic heterocyclic amine derivatives with the brand-new structures provided by the invention have anti-hepatitis B virus activity.
Second, solubility determination
Two identical sample solutions were prepared from 10mM stock solutions of compound, and after evaporation of DMSO by a centrifugal vacuum evaporator, the compound was dissolved in 0.05M phosphate buffer (pH 6.5), stirred for 1h, and then shaken for 2 h. The next day, the solution was filtered using a microtiter plate. The filtrate and the 10-fold diluted filtrate were then analyzed by HPLC-UV. In addition, four-point calibration curves were prepared for solubility determination of compounds using 10mM storage solutions. The unit of the results is μ g/mL. If the percentage of the sample volume measured after evaporation of DMSO divided by the maximum sample volume calculated theoretically is greater than 80%, then solubility greater than this maximum can be reported.
TABLE 4 solubility of the Compounds of the invention
TABLE 5 solubility of Prior Art CN108610301A Arhetamine derivatives
The results show that the arylamine derivatives with the brand-new structures provided by the invention have better water solubility and druggability, and particularly the water solubility and druggability of the compounds in the formulas (V) and (VI) are obviously improved compared with those of the existing compounds.
Claims (9)
1. An aromatic hetero amine derivative is characterized in that the chemical structural formula is shown as the formula (I):
wherein R is1Is selected from
R2Is selected from
2. The heteroaralamine derivative according to claim 1, wherein R is1Is selected from
R2Is selected from
3. The heteroaralamine derivative according to claim 1, wherein R is1Is selected from
R2Is selected from
4. The heteroaralamine derivative according to claim 1, wherein R is1Is selected from
R2Is selected from
5. The heteroaralamine derivative according to claim 1, wherein R is1Is selected from
R2Is selected from
6. The heteroaralamine derivative according to claim 1, wherein R is1Is selected from
R2Is selected from
7. A process for the preparation of the arylheteramine derivative of 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 dissolving, cooling to-76-80 ℃, slowly adding n-butyllithium for reaction, slowly adding a tetrahydrofuran solution of substituted benzaldehyde for continuous reaction, adding a quenching agent 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 into the anhydrous dichloromethane, and placing the mixture in an inert atmosphere of 78-82 DEGReflux reaction at room temperature, cooling to room temperature, vacuum drying, adding substituted naphthol and K2CO3Carrying out reflux reaction in dichloromethane at 78-82 ℃, and after the reaction is finished, spin-drying the solvent, 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, performing reduced pressure spin-drying on the solvent, adjusting the pH to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 5;
s5, dissolving the compound 5 and 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 value 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-76-80 ℃, slowly adding excessive boron tribromide for reaction, heating to room temperature for reaction, adjusting the pH value to 7-9, extracting, washing, spin-drying, separating and purifying to obtain a compound 7;
or carrying out reflux reaction on the compound 6, excessive iron powder and ammonium chloride with ethanol/water (3: 1) as a solvent at 88-92 ℃ overnight, cooling to room temperature, adjusting the pH value 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:
8. Use of the arylhetero amine derivatives of any of claims 1 to 6 for the preparation of a medicament for inhibiting the nucleocapsid assembly of hepatitis b virus.
9. The use of the arylhetero amine derivatives of any of claims 1 to 6 for 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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| 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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| 刘莹 等: "《有机化学》", 30 September 2017, 电子科技大学出版社 * |
| 岳宝珍 等: "《有机合成基础》", 31 October 2000, 北京医科大学出版社 * |
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