CN113582969A - Application of acylthiourea compound in preparation of anti-enterovirus drugs - Google Patents
Application of acylthiourea compound in preparation of anti-enterovirus drugs Download PDFInfo
- Publication number
- CN113582969A CN113582969A CN202110906629.2A CN202110906629A CN113582969A CN 113582969 A CN113582969 A CN 113582969A CN 202110906629 A CN202110906629 A CN 202110906629A CN 113582969 A CN113582969 A CN 113582969A
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- Prior art keywords
- tert
- butyl
- benzamide
- thiocarbamoyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 61
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 title claims description 97
- 229940079593 drug Drugs 0.000 title abstract description 14
- -1 acyl thiourea compounds Chemical class 0.000 claims abstract description 243
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 41
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 30
- 241000709661 Enterovirus Species 0.000 claims abstract description 18
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 10
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000758 substrate Substances 0.000 claims abstract description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 242
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 105
- 238000000034 method Methods 0.000 claims description 48
- 239000007787 solid Substances 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 30
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
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- 125000005843 halogen group Chemical group 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
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- 239000000706 filtrate Substances 0.000 claims description 3
- CJHNWMDPTZLVMD-UHFFFAOYSA-N n-[(4-acetamidophenyl)carbamothioyl]thiophene-2-carboxamide Chemical compound C1=CC(NC(=O)C)=CC=C1NC(=S)NC(=O)C1=CC=CS1 CJHNWMDPTZLVMD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- ZTTVQOKRWCVGMS-UHFFFAOYSA-N CC(C)(C)C(C=C1)=CC=C1C(N(C(CN1C(C=CC=C2)=C2F)=O)C1=S)=O Chemical compound CC(C)(C)C(C=C1)=CC=C1C(N(C(CN1C(C=CC=C2)=C2F)=O)C1=S)=O ZTTVQOKRWCVGMS-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
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- WHNQTHDJEZTVHS-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-yl)propanoic acid Chemical compound C1=CC=C2SC(CCC(=O)O)=NC2=C1 WHNQTHDJEZTVHS-UHFFFAOYSA-N 0.000 claims 1
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
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- 239000003443 antiviral agent Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 1
- CAYJBRBGZBCZKO-BHGBQCOSSA-N ethyl (e,4s)-4-[[(2r,5s)-2-[(4-fluorophenyl)methyl]-6-methyl-5-[(5-methyl-1,2-oxazole-3-carbonyl)amino]-4-oxoheptanoyl]amino]-5-[(3s)-2-oxopyrrolidin-3-yl]pent-2-enoate Chemical compound C([C@@H](/C=C/C(=O)OCC)NC(=O)[C@@H](CC(=O)[C@@H](NC(=O)C1=NOC(C)=C1)C(C)C)CC=1C=CC(F)=CC=1)[C@@H]1CCNC1=O CAYJBRBGZBCZKO-BHGBQCOSSA-N 0.000 description 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- 231100000956 nontoxicity Toxicity 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical group ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses an application of acyl thiourea compounds in preparation of anti-enterovirus drugs, and belongs to the technical field of medicines. The acyl thiourea compound has a structure shown in general formulas (I), (II) and (III), and is prepared by reacting substituted acyl chloride compounds, ammonium thiocyanate and amine compounds serving as raw materials to obtain the acyl thiourea compound shown in general formula (I); reacting acyl thiourea compound shown in general formula (I) and chloracetyl chloride in solvent to obtain acyl thiourea compound shown in general formula (II); acyl thiourea compounds shown in general formula (I) are used as raw materials to react with halogenated substrates in a solvent to obtain acyl thiourea compounds shown in general formula (III). The acyl thiourea compound has the activity of resisting the enterovirus and can be used for preparing medicines for resisting the enterovirus.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an application of acyl thiourea compounds in preparation of anti-enterovirus medicines.
Background
The enterovirus is a non-enveloped single-stranded RNA virus of picornaviridae, and has high mutability. Enteroviruses include human enteroviruses (A, B, C, D) and non-human enteroviruses. Among them, Enterovirus71 (EV-A71), Enterovirus 68 (EV-D68), Coxsackie virus A16(CVA16) and poliovirus belonging to the family Enterovirus pose serious threats to the health and safety of human life and property in the history of social development. Although poliovirus has been eliminated at present, the enterovirus type 71, which is prevalent in China, and the enterovirus type 68, which is prevalent in North America, continue to be significant threats to the life health and safety of infants and young children worldwide.
Hand-foot-and-mouth disease (HFMD) is a common infectious disease of infants and young children mainly caused by infection with Enterovirus71 (Enterovirus 71) and coxsackievirus a16(CVA16), and the virus can be transmitted through a feces-mouth route or droplet transmission to cause infection. The clinical symptoms of the traditional Chinese medicine include fever, sore throat, and blister rash of hands, feet, tongue and oral mucosa. The hand-foot-and-mouth disease caused by enterovirus is more serious and is often closely related to nervous system diseases, such as meningitis, Japanese encephalitis and acute paralysis, and even death can be caused. Furthermore, EV-D68 also causes major damage to the infant nervous system.
In the case of enterovirus type 71, the enterovirus contains approximately 7400 nucleotides, which in turn constitute four capsid proteins (VP1-VP4) and seven nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, 3D), which play important roles in the adsorption, invasion, uncoating, and replication processes of the virus, each of which can serve as a target for antiviral drugs. For example, the viral capsid protein inhibitor pleconaril (proconrally), the 3C protease inhibitor rupintrivir (loprazvir), the 3D polymerase inhibitor gemcitabine (gemcitabine) and the PI4KB inhibitor enviroxime (enviroxime) all reach the preclinical or early clinical development stage, but due to the limited efficacy or safety problems of antiviral effect, they are stopped at the clinical research stage and cannot be really applied to the market. Therefore, it is necessary to synthesize a series of enterovirus small-molecule inhibitors with novel structural frameworks.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide an acyl thiourea compound and application thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, there is provided an acylthiourea compound represented by the following general formula (I), (II), (III) or a pharmacologically or physiologically acceptable salt thereof,
R1the substituent group can be an alkyl substituent group, a halogen substituent group, an alkoxy substituent group and a heteroalkyl substituent group, and comprises various free combination modes of single substitution, multi-substitution and the like of the substituent groups;
R2the substituent group can be an alkyl substituent group, a halogen substituent group, an alkoxy substituent group and a heteroalkyl substituent group, and comprises various free combination modes of single substitution, multi-substitution and the like of the substituent groups;
R3is mono-or polysubstituted alkyl substituent, halogen substituent, alkoxy substituent, heteroalkyl substituent;
R4the substituent group can be an alkyl substituent group, an alkoxy substituent group, a heteroalkyl substituent group, an acyl substituent group, or a benzene ring and an aromatic heterocyclic ring structure with different substituent groups, wherein the substituent groups can be an alkyl substituent group, a halogen substituent group, an alkoxy substituent group and a heteroalkyl substituent group, and comprise various free combination modes of single substitution, multiple substitution and the like of the substituent groups;
x is a sulfur atom or an oxygen atom;
y is a nitrogen atom, a sulfur atom or an oxygen atom.
Preferably, the acylthiourea compound is selected from the compounds in the following table 1:
TABLE 1
Still further, the acylthiourea compound is selected from the following compounds: 4- (tert-butyl) -N- ((2-chlorophenyl) thiocarbamoyl) benzamide (V-6), 4- (tert-butyl) -N- ((2-bromophenyl) thiocarbamoyl) benzamide (V-7), 4- (tert-butyl) -N- ((2-methylphenyl) thiocarbamoyl) benzamide (V-8), 4- (tert-butyl) -N- ((2-methoxyphenyl) thiocarbamoyl) benzamide (V-9), 4- (tert-butyl) -N- ((4-aminophenyl) thiocarbamoyl) benzamide (V-16), 4- (tert-butyl) -N- (pyridin-2-ylcarbamoyl) benzamide (V-17), 4- (tert-butyl) -N- (quinoline-2-carbonothioyl) benzamide (V-18), N- ((4-propionylaminophenyl) thiocarbamoyl) -4-tert-butylbenzamide (V-19), 4- (tert-butyl) -N- ((4-neopentylamide) thiocarbamoyl) benzamide (V-20), 4- (tert-butyl) -N- ((4- (ethylsulfonamido) phenyl) thiocarbamoyl) benzamide (V-21), N- ((4-benzoylaminophenyl) thiocarbamoyl) -4- (tert-butyl) benzamide (V-22), N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -2-methoxyldi-nyl Phenylbenzamide (V-23), N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -3-methoxybenzamide (V-24), N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -4-methoxybenzamide (V-25), 4- (tert-butyl) -N- ((4- (4-methylbenzamido) phenyl) thiocarbamoyl) benzamide (V-26), 4- (tert-butyl) -N- ((4- (4-ethylbenzamido) phenyl) thiocarbamoyl) benzamide (V-27), 4- (tert-butyl) -N- ((4- (4-fluorobenzamido) phenyl) thiocarbamoyl) benzamide (V-27) ) Benzamide (V-28), 4- (tert-butyl) -N- ((4- (4-chlorobenzoylamino) phenyl) thiocarbamoyl) benzamide (V-29), 4- (tert-butyl) -N- ((4- (4-bromobenzoylamino) phenyl) thiocarbamoyl) benzamide (V-30), 4- (tert-butyl) -N- ((4- (4-tert-butylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-31), 4- (tert-butyl) -N- ((4- (4-propylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-32), 4- (tert-butyl) -N- ((4- (4-butylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-32) ) Benzamide (V-33), 4- (tert-butyl) -N- ((4- (4-pentylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-34), carbonic acid (((4- (3- (4- (4- (tert-butyl) benzoyl) thioureido) phenoxy ] [ hydroxy) phosphoryl ] oxy) methylisopropyl (V-41), (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) boronic acid (V-43), 4- (tert-butyl) -N- ((4-phenoxyphenyl) aminomonoyl) benzamide (V-48), 4- (tert-butyl) -N- (((4- (4-fluoro-3-methylphenoxy) -2-methylphenyl) aminomonoyl) benzamide (V-34) Amide (V-49), N- ((4-amino-2-chlorophenyl) aminomonoyl) -4- (tert-butyl) benzamide (V-50), 4- (tert-butyl) -N- ((4- (2- (2- (2-hydroxyethoxy) ethoxy) phenyl) aminomonoyl) benzamide (V-55), 4- (tert-butyl) -N- (((4- (phenylamino) phenyl) aminomonoyl) benzamide (V-65), 4- (tert-butyl) -N- (((4- ((3-methoxyphenyl) amino) phenyl) aminomonoyl) benzamide (V-68).
In a second aspect, the present invention provides an application of any one of the above acylthiourea compounds or pharmacologically or physiologically acceptable salts thereof in preparing an anti-enterovirus drug.
In a third aspect, the present invention provides an anti-enterovirus drug, which comprises the above acyl thiourea compound or its pharmacologically or physiologically acceptable salt, and a pharmaceutically acceptable carrier or excipient.
The invention also provides a preparation method of the acyl thiourea compound, which divides the acyl thiourea compound into a series I acyl thiourea compound (general formula (I)), a series II acyl thiourea compound (general formula (II)) and a series III acyl thiourea compound (general formula (III)).
The preparation of the acyl thiourea compound of the series I is carried out by the following method (1) or (2):
the method (1) comprises the following steps: reacting acyl chloride compound with ammonium thiocyanate in a solvent; filtering the obtained reaction liquid, and adding an amine compound into the filtrate to react to obtain the acyl thiourea compound of the series I. Wherein, the solvent is preferably acetonitrile, and the reaction condition of the acyl chloride compound and the ammonium thiocyanate in the solvent is preferably 0-40 ℃ for 1-4 hours; the reaction condition after adding the amine compound is preferably 0-40 ℃ for 4-12 h.
The method (2) comprises the following steps: reacting acyl chloride compound with ammonia water in a first solvent; filtering the obtained reaction liquid to obtain a solid, dissolving the solid by using a solvent II, and slowly adding oxalyl chloride for reaction; concentrating and spin-drying the obtained reaction liquid, dissolving the reaction liquid by using a solvent III, and then adding an amine compound to react to obtain the acyl urea compound of the series I. Wherein, the solvent I is preferably dichloromethane, and the reaction condition of the acyl chloride compound and ammonia water in the solvent I is preferably 0-40 ℃ for 2-4 h; the second solvent is preferably dichloromethane, and the reaction condition after adding oxalyl chloride is preferably 60-80 ℃ for 6-12 h; the solvent III is preferably methanol, and the condition for adding the amine compound for reaction is preferably 0-40 ℃ for 2-24 h.
Synthetic route of acyl thiourea compounds of series I
The preparation of the acyl thiourea compound of the series II comprises the following steps: a series of I compounds and chloroacetyl chloride are used as raw materials and react in a solvent in the presence of an acid-binding agent to obtain a series of II acyl thiourea compounds. Wherein the acid-binding agent is preferably triethylamine, the solvent is preferably dichloromethane, and the reaction condition is preferably 0-40 ℃ for 2-24 h.
Synthetic route of series II acyl thiourea compounds
The preparation of the acyl thiourea compound in the series III comprises the following steps: the series III acyl thiourea compound is obtained by taking a series I compound and a halogenated substrate as raw materials and reacting in a solvent. The solvent is preferably DCM or DMF, and the reaction condition is preferably 20-110 ℃ for 2-24 h.
Synthetic route of series II acyl thiourea compounds
Wherein R is1、R2、R3、R4The substituent groups are as described above; x is a sulfur atom or an oxygen atom; y is a sulfur atom, a nitrogen atom or an oxygen atom; z is a halogen atom.
The acyl thiourea compound provided by the invention can effectively inhibit the activity of enteroviruses, and the enteroviruses comprise poliovirus, coxsackievirus, echovirus and novel enterovirus, have low toxicity to cells, and can be used for preparing medicines for resisting the enteroviruses.
Drawings
FIG. 1 is a graph showing the results of evaluation of the pharmacological effects of acylthiourea compounds in mice.
FIG. 2 is a graph showing the results of safety studies on acylthiourea compounds.
Detailed Description
Further features and advantages of the present invention will be understood from the following detailed description. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way.
[ example 1 ] preparation of acylthiourea compounds of series I
The acyl thiourea compound of the series I is synthesized by the reaction shown in the following formulas I and ii.
Taking a synthesis example of 4- (tert-butyl) -N- ((4-aminophenyl) thiocarbamoyl) benzamide V-16, the following steps are carried out: a50 mL single-neck flask was charged with ammonium thiocyanate (305.5mg, 4.0mmol) and 20mL acetonitrile, and 4-tert-butylbenzoyl chloride (0.8mL, 4.0mmol) was added under ice-cooling and reacted for 1h under ice-cooling. After filtration, p-phenylenediamine (432.4mg, 4.0mmol) was added to the filtrate, and the mixture was reacted at room temperature overnight. TLC confirmed the reaction was complete, concentrated and purified on silica gel column using mobile phase petroleum ether and ethyl acetate (V/V ═ 6/1) to give 4- (tert-butyl) -N- ((4-aminophenyl) thiocarbamoyl) benzamide V-16.
The preparation method of other series I acyl thiourea compounds is the same as the above.
[ example 2 ] preparation of acylureas of series I
The acyl thiourea compound of the series I is synthesized by the reaction shown in the following formulas iii, iv and v.
Taking the preparation of compound 4- (tert-butyl) -N- ((2-fluorophenyl) carbamoyl) benzamide V-39 as an example, the procedure was as follows: 4-tert-butylbenzoyl chloride (0.4mL, 2.0mmol) was dissolved in dichloromethane, excess ammonia was added under ice bath, the ice bath was removed, and reaction was carried out at room temperature for 3 h. The solid obtained by filtration was dried under vacuum and dissolved in dichloromethane, oxalyl chloride (507.7mg, 4.0mmol) was added under ice-bath, reacted at 75 ℃ for 6h, concentrated and dried. After spin-drying, the crude product was dissolved in methanol, followed by addition of 2-fluoroaniline (222.2mg, 2.0mmol) and reaction at room temperature overnight. TLC confirmed the reaction was complete, concentrated and purified on silica gel column using mobile phase petroleum ether and ethyl acetate (V/V ═ 10/1) to give 4- (tert-butyl) -N- ((2-fluorophenyl) carbamoyl) benzamide V-39.
The preparation method of the acyl urea compounds of other series I is the same as the preparation method.
Example 3 preparation of the series II acylthiourea Compounds
The acyl thiourea compound of the series II is synthesized by the reaction shown in the following formula vi.
Taking as an example the preparation of the compound 3- (4- (tert-butyl) benzoyl) -1- (2-fluorophenyl) -2-thioxooxoimidazolidin-4-one V-45, the procedure was as follows: the compound 4- (tert-butyl) -N- ((2-fluorophenyl) thiocarbamoyl) benzamide V-4(100mg, 0.3mmol) was dissolved in DCM, and triethylamine (61.4mg, 0.6mmol) and chloroacetyl chloride (0.05mL, 0.6mmol) were sequentially added under ice bath to react at room temperature overnight. After confirming completion of the reaction by TLC, it was quenched with water and extracted with DCM. After concentration, purification on silica gel column using mobile phase petroleum ether and ethyl acetate (V/V ═ 6/1) gave 3- (4- (tert-butyl) benzoyl) -1- (2-fluorophenyl) -2-thioxoimidazolin-4-one V-45.
The preparation method of other series II acyl thiourea compounds is the same as the above.
Example 4 preparation of the series III acylthiourea Compounds
The acyl thiourea compound of the series III is synthesized by the reaction shown in the following formula vii.
Taking the preparation of 4- (tert-butyl) -N- ((4- (ethylsulfonamido) phenyl) thiocarbamoyl) benzamide V-21 as an example, the procedure was as follows: the 4- (tert-butyl) -N- ((4-aminophenyl) thiocarbamoyl) benzamide V-16(150mg, 0.46mmol) prepared in example 2 was weighed out into a 25mL one-necked flask and dissolved by adding DCM. Triethylamine (0.07mL, 0.55mmol) and ethylsulfonyl chloride (0.05mL, 0.55mmol) were added under ice-cooling, and the mixture was reacted at room temperature overnight. After TLC confirmed the reaction was complete, concentration was performed and purified by silica gel column using mobile phase petroleum ether and ethyl acetate (V/V ═ 6/1) to give 4- (tert-butyl) -N- ((4- (ethanesulfonamide) phenyl) thiocarbamoyl) benzamide V-21.
The preparation method of other series III acyl thiourea compounds is the same as the above.
(1) Preparation of N- ((4-acetamidophenyl) thiocarbamoyl) benzo [ b ] thiophene-2-carboxamide (V-1)
With R1The aromatic formyl chloride derivative is benzothiophene-2-formyl chloride, R2The substituted heteroaromatic amine derivative was 4-aminoacetanilide, and the title compound was prepared in 30% yield as a yellow solid according to the procedure in example 1.
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.85(s,1H),10.07(s,1H),8.77(s,1H),8.10(d,J＝8.0Hz,1H),8.02(d,J＝7.8Hz,1H),7.72–7.43(m,6H),2.06(s,3H).13C NMR(100MHz,DMSO-d6)δ178.78,168.79,163.02,141.89,139.42,137.98,136.97,133.31,130.40,128.01,126.73,125.82,125.37,123.41,119.41,24.46.
(2) Preparation of N- ((4-acetamidophenyl) thiocarbamoyl) thiophene-2-carboxamide (V-2)
With R1The aromatic formyl chloride derivative is 2-thiophenecarbonyl chloride, R2The substituted heteroaromatic amine derivative was 4-aminoacetanilide, and the objective compound was prepared in the same manner as in example 1, and the product was a white solid with a yield of 67%.
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),11.63(s,1H),10.09(s,1H),8.40(d,J＝3.4Hz,1H),8.06(d,J＝4.8Hz,1H),7.97(s,1H),7.46(d,J＝7.1Hz,1H),7.33(d,J＝7.6Hz,2H),7.29–7.22(m,1H),2.06(s,3H).13C NMR(100MHz,DMSO-d6)δ179.10,168.93,162.52,140.10,138.71,137.15,135.81,133.18,129.32,129.21,119.32,117.33,115.29,24.51.
(3) Preparation of N- ((4-acetamidophenyl) thiocarbamoyl) -4-tert-butylbenzamide (V-3)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 4-aminoacetanilide, and the target compound was prepared in the white solid at a yield of 59% by referring to the procedure in example 1.
1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),11.48(s,1H),10.10(s,1H),8.31–7.71(m,3H),7.57(d,J＝8.4Hz,2H),7.50–7.25(m,3H),2.07(s,3H),1.32(s,9H).13C NMR(100MHz,DMSO-d6)δ179.42,168.93,168.61,156.76,140.14,138.70,129.72,129.33,129.13,125.77,119.18,117.28,115.14,35.33,31.28,24.52.
(4) Preparation of 4- (tert-butyl) -N- ((2-fluorophenyl) thiocarbamoyl) benzamide (V-4)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative is 2-fluoroaniline, see example 1The procedure produced the title compound in 78% yield as a white solid.
1H NMR(400MHz,CDCl3)δ12.79(s,1H),9.24(s,1H),8.47–8.40(m,1H),7.86(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.27–7.16(m,3H),1.37(s,9H).13C NMR(100MHz,CDCl3)δ178.77,166.90,157.86,156.30,153.83,128.50,127.59,126.22,125.40,124.01,115.72,115.53,35.27,31.05.
(5) Preparation of 4- (tert-butyl) -N- ((3-fluorophenyl) thiocarbamoyl) benzamide (V-5)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 3-fluoroaniline, and the target compound was prepared in 78% yield as a white solid according to the method in example 1.
1H NMR(400MHz,CDCl3)δ12.81(s,1H),9.18(s,1H),7.85(d,J＝8.5Hz,2H),7.78(d,J＝10.4Hz,1H),7.57(d,J＝8.5Hz,2H),7.45–7.33(m,2H),7.00(d,J＝7.2Hz,1H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.33,167.03,163.77,161.32,157.96,139.13,130.01,128.45,127.55,126.27,119.38,113.67,113.46,111.32,111.06,35.29,31.05.
(6) Preparation of 4- (tert-butyl) -N- ((2-chlorophenyl) thiocarbamoyl) benzamide (V-6)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2-chloroaniline, and the target compound was prepared in the same manner as in example 1, and the product was a white solid with a yield of 72%.
1H NMR(400MHz,CDCl3)δ12.82(s,1H),9.23(s,1H),8.44(d,J＝1.1Hz,1H),7.88(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,2H),7.53–7.47(m,1H),7.37(t,J＝7.7Hz,1H),7.31–7.20(m,1H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.89,166.71,157.88,135.13,129.68,128.50,128.03,127.67,127.61,126.90,126.27,126.23,35.28,31.06.
(7) Preparation of 4- (tert-butyl) -N- ((2-bromophenyl) thiocarbamoyl) benzamide (V-7)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The title compound was prepared in 66% yield as a white solid according to the procedure in example 1 using 2-bromoaniline as the substituted heteroaromatic amine derivative.
1H NMR(400MHz,CDCl3)δ12.68(s,1H),9.24(s,1H),8.29–8.25(m,1H),7.88(d,J＝8.6Hz,2H),7.70–7.66(m,1H),7.57(d,J＝8.6Hz,2H),7.45–7.37(m,1H),7.19(m,1H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ179.22,166.66,157.89,136.55,132.96,128.51,128.24,127.63,127.56,127.22,126.23,118.71,35.29,31.07.
(8) Preparation of 4- (tert-butyl) -N- ((2-methylphenyl) thiocarbamoyl) benzamide (V-8)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2-methylaniline, and the title compound was prepared in 70% yield as a white solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ12.34(s,1H),9.24(s,1H),7.90–7.85(m,2H),7.79(d,J＝7.7Hz,1H),7.61–7.55(m,2H),7.36–7.23(m,3H),2.40(s,3H),1.39(s,9H).13C NMR(100MHz,CDCl3)δ179.54,166.99,157.81,136.47,133.34,130.80,128.65,127.66,127.56,126.47,126.23,35.28,31.08,18.08.
(9) Preparation of 4- (tert-butyl) -N- ((2-methoxyphenyl) thiocarbamoyl) benzamide (V-9)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2-methoxyaniline, and the target compound was prepared in 74% yield as a white solid according to the method in example 1.
1H NMR(400MHz,CDCl3)δ12.94(s,1H),9.15(s,1H),8.92–8.63(m,1H),7.87(d,J＝8.5Hz,2H),7.55(d,J＝8.5Hz,2H),7.26–7.22(m,1H),7.12–6.94(m,2H),3.97(s,3H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ176.87,166.48,157.54,150.79,128.89,127.52,127.26,126.77,126.14,123.05,120.22,110.65,56.08,35.24,31.08.
(10) Preparation of 4- (tert-butyl) -N- ((2, 6-dibromophenyl) thiocarbamoyl) benzamide (V-10)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2, 6-dibromoaniline and the title compound was prepared in 60% yield as a white solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ12.16(s,1H),9.39(s,1H),7.88(d,J＝8.4Hz,2H),7.65(d,J＝8.1Hz,2H),7.56(d,J＝8.4Hz,2H),7.13(t,J＝8.1Hz,1H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ180.62,166.93,157.92,136.21,132.44,130.46,128.34,127.74,126.21,124.32,35.30,31.09.
(11) Preparation of 4- (tert-butyl) -N- ((2, 4-bistrifluoromethylphenyl) thiocarbamoyl) benzamide (V-11)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2, 4-bistrifluoromethylaniline and the title compound was prepared according to the procedure in example 1 in the form of a white solid with a yield of 65%.
1H NMR(400MHz,CDCl3)δ12.82(s,1H),9.36(s,1H),8.42(s,1H),7.88(d,J＝8.5Hz,3H),7.70(d,J＝8.2Hz,1H),7.58(d,J＝8.5Hz,2H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ180.89,167.07,158.23,136.53,134.27,128.13,127.69,127.26,127.21,127.16,127.11,127.01,126.97,126.93,126.90,126.29,123.95,121.60,121.29,35.31,31.01.
(12) Preparation of 4- (tert-butyl) -N- ((2, 4-dimethylphenyl) thiocarbamoyl) benzamide (V-12)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2, 4-dimethylaniline and the title compound was prepared in 73% yield as a white solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ12.25(s,1H),9.28(s,1H),7.87(d,J＝8.5Hz,2H),7.58(t,J＝8.3Hz,3H),7.12(d,J＝11.6Hz,2H),2.36(d,J＝8.8Hz,6H),1.39(s,9H).13C NMR(100MHz,CDCl3)δ179.70,166.98,157.74,137.53,133.92,133.22,131.51,128.69,127.58,127.17,126.19,35.28,31.09,21.17,18.00.
(13) Preparation of 4- (tert-butyl) -N- ((2-bromo-4-methylphenyl) thiocarbamoyl) benzamide (V-13)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2-bromo-4-methylaniline and the title compound was prepared in 71% yield as a white solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ12.56(s,1H),9.21(s,1H),8.05(d,J＝8.2Hz,1H),7.87(d,J＝8.5Hz,2H),7.57(d,J＝8.5Hz,2H),7.50(s,1H),7.21(d,J＝8.3Hz,1H),2.38(s,3H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ179.29,166.64,157.85,138.74,133.92,133.28,128.54,128.36,127.59,127.05,126.23,118.61,35.28,31.07,20.88.
(14) Preparation of 4- (tert-butyl) -N- ((3, 4-difluorophenyl) thiocarbamoyl) benzamide (V-14)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 3, 4-difluoroaniline and the title compound was prepared in 63% yield as a white solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ12.72(s,1H),9.18(s,1H),7.91–7.77(m,3H),7.57(d,J＝8.5Hz,2H),7.36–7.31(m,1H),7.26–7.12(m,1H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.81,167.09,158.08,151.06,149.85,148.59,147.38,134.08,128.35,127.53,126.29,120.27,117.33,117.15,113.91,113.70,35.30,31.03.
(15) Preparation of 4- (tert-butyl) -N- ((2,4, 6-trichlorophenyl) thiocarbamoyl) benzamide (V-15)
With R1The aromatic formyl chloride derivative is 4-tert-butylButyl carbonyl chloride, R2The substituted heteroaromatic amine derivative was 2,4, 6-trichloroaniline and the title compound was prepared in 52% yield as a white solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ12.08(s,1H),9.44(s,1H),7.85(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,2H),7.45(s,2H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ180.96,167.03,158.07,135.09,134.65,132.48,128.64,128.20,127.70,126.23,35.31,31.06.
(16) Preparation of 4- (tert-butyl) -N- ((4-aminophenyl) thiocarbamoyl) benzamide (V-16)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was p-phenylenediamine and the title compound was prepared in 40% yield as a yellow solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ12.41(s,1H),9.16(s,1H),7.84(d,J＝8.5Hz,2H),7.55(d,J＝8.5Hz,2H),7.44(d,J＝8.6Hz,2H),6.73(d,J＝8.7Hz,2H),3.81(s,2H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.46,166.83,157.66,145.41,128.78,127.43,126.19,125.73,115.07,35.25,31.06.
(17) Preparation of 4- (tert-butyl) -N- (pyridin-2-ylcarbamoylthio) benzamide (V-17)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2-aminopyridine and the title compound was prepared in 69% yield as a white solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ13.20(s,1H),9.10(s,1H),8.84(d,J＝8.3Hz,1H),8.46(d,J＝3.9Hz,1H),7.95–7.69(m,3H),7.56(d,J＝8.4Hz,2H),7.20–7.16(m,1H),1.37(s,9H).13C NMR(100MHz,CDCl3)δ177.18,166.38,157.79,151.32,148.63,137.68,128.67,127.54,126.21,121.45,116.10,35.26,31.05.
(18) Preparation of 4- (tert-butyl) -N- (quinoline-2-aminothiocarbonyl) benzamide (V-18)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2-aminoquinoline and the title compound was prepared in 51% yield as a yellow solid according to the procedure in example 1.
1H NMR(400MHz,CDCl3)δ13.29(s,1H),9.18(s,1H),8.87(d,J＝8.9Hz,1H),8.24(d,J＝8.9Hz,1H),8.01(d,J＝8.4Hz,1H),7.89(d,J＝8.3Hz,2H),7.84(d,J＝8.1Hz,1H),7.72(t,J＝7.6Hz,1H),7.60–7.51(m,3H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.11,166.48,157.87,150.59,146.97,137.66,130.05,128.62,128.45,127.56,126.99,126.26,116.13,35.28,31.06.
(19) Preparation of N- ((4-propionylaminophenyl) thiocarbamoyl) -4-tert-butylbenzamide (V-19)
The acyl thiourea compound of the series I is V-16, R4The title compound was prepared in 44% yield as a white solid according to the procedure in example 4, substituting the acid chloride derivative as propionyl chloride.
1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),11.45(s,1H),10.00(s,1H),7.95(d,J＝8.3Hz,2H),7.70–7.50(m,6H),2.34(q,J＝7.5Hz,2H),1.32(s,9H),1.10(t,J＝7.5Hz,3H).13C NMR(100MHz,DMSO-d6)δ179.37,172.45,168.53,156.75,138.00,133.24,129.75,129.08,125.77,125.16,119.47,35.32,31.28,29.99,10.12.
(20) Preparation of 4- (tert-butyl) -N- ((4-neopentyl amide) thiocarbamoyl) benzamide (V-20)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was pivaloyl chloride, and the title compound was prepared in 28% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.62(s,1H),9.13(s,1H),7.85(d,J＝7.9Hz,2H),7.68(d,J＝8.3Hz,2H),7.62(d,J＝8.5Hz,2H),7.57(d,J＝7.8Hz,2H),7.44(s,1H),1.36(d,J＝14.9Hz,18H).13C NMR(100MHz,CDCl3)δ178.43,176.61,166.90,157.83,136.66,133.55,128.62,127.46,126.25,124.82,120.14,39.68,35.28,31.06,27.63.
(21) Preparation of 4- (tert-butyl) -N- ((4- (ethylsulfonamido) phenyl) thiocarbamoyl) benzamide (V-21)
Taking the preparation of 4- (tert-butyl) -N- ((4- (ethylsulfonamido) phenyl) thiocarbamoyl) benzamide V-21 as an example, the procedure was as follows: the 4- (tert-butyl) -N- ((4-aminophenyl) thiocarbamoyl) benzamide V-16(150mg, 0.46mmol) prepared in example 1 was weighed out into a 25mL one-necked flask and dissolved by adding DCM. Triethylamine (0.07mL, 0.55mmol) and ethylsulfonyl chloride (0.05mL, 0.55mmol) were added under ice-cooling, and the mixture was reacted at room temperature overnight. After TLC confirmed the reaction was complete, concentration was purified by column chromatography on silica gel using a mobile phase ratio of petroleum ether and ethyl acetate (V/V-6/1) to give V-21 as a white solid in 29% yield.
1H NMR(400MHz,CDCl3)δ12.70(s,1H),9.20(s,1H),7.86(d,J＝8.5Hz,2H),7.71(d,J＝8.8Hz,2H),7.57(d,J＝8.5Hz,2H),7.36–7.27(m,2H),7.24(s,1H),3.19(q,J＝7.4Hz,2H),1.50–1.32(m,12H).13C NMR(100MHz,CDCl3)δ178.60,167.11,157.96,135.36,134.55,128.49,127.55,126.26,125.47,120.56,46.11,35.29,31.05,8.25.
(22) Preparation of N- ((4-benzoylaminophenyl) thiocarbamoyl) -4- (tert-butyl) benzamide (V-22)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was benzoyl chloride, and the title compound was prepared in 36% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.65(s,1H),9.14(s,1H),8.12(s,1H),7.88(d,J＝7.4Hz,2H),7.84(d,J＝8.4Hz,2H),7.77–7.65(m,4H),7.55(t,J＝7.6Hz,3H),7.48(t,J＝7.4Hz,2H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.38,166.95,165.83,157.84,136.56,134.75,133.85,131.96,128.81,128.62,127.50,127.13,126.24,124.84,120.49,35.28,31.06.
(23) Preparation of N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -2-methoxybenzamide (V-23)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 2-methoxybenzoyl chloride, and the title compound was prepared in 33% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.65(s,1H),9.92(s,1H),9.16(s,1H),8.32–8.28m,1H),7.85(d,J＝8.5Hz,2H),7.81–7.69(m,4H),7.62–7.47(m,3H),7.15(t,J＝7.2Hz,1H),7.05(d,J＝8.3Hz,1H),4.07(s,3H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.33,166.91,163.23,157.81,157.22,137.02,133.50,133.41,132.55,128.65,127.48,126.25,124.80,121.73,121.58,120.59,111.58,56.30,35.28,31.06.
(24) Preparation of N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -3-methoxybenzamide (V-24)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 3-methoxybenzoyl chloride, and the title compound was prepared in 29% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.65(s,1H),9.13(s,1H),8.09(s,1H),7.84(d,J＝8.5Hz,2H),7.76–7.68(m,4H),7.56(d,J＝8.5Hz,2H),7.49–7.32(m,3H),7.13–7.00(m,1H),3.86(s,3H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.36,166.92,165.62,159.96,157.85,136.53,136.24,133.86,129.79,128.61,127.48,126.24,124.82,120.43,118.81,118.16,112.51,55.51,35.28,31.05.
(25) Preparation of N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -4-methoxybenzamide (V-25)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-methoxybenzoyl chloride, and the title compound was prepared in 39% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.64(s,1H),9.13(s,1H),8.08(s,1H),7.85(t,J＝8.6Hz,4H),7.77–7.62(m,4H),7.56(d,J＝8.4Hz,2H),6.95(d,J＝8.7Hz,2H),3.86(s,3H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.31,166.92,165.36,162.52,157.81,136.81,133.58,129.07,128.60,127.49,126.88,126.23,124.78,120.45,113.94,55.48,35.27,31.06.
(26) Preparation of 4- (tert-butyl) -N- ((4- (4-methylbenzamido) phenyl) thiocarbamoyl) benzamide (V-26)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-methylbenzoyl chloride, and the title compound was prepared in a white solid with a yield of 30% by referring to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.64(s,1H),9.14(s,1H),8.11(s,1H),7.84(d,J＝8.5Hz,2H),7.78(d,J＝8.1Hz,2H),7.74–7.65(m,4H),7.56(d,J＝8.5Hz,2H),7.26(d,J＝8.0Hz,2H),2.41(s,3H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.28,166.90,165.79,157.80,142.45,136.72,133.67,131.86,129.90,129.41,128.62,127.49,127.18,126.22,124.74,120.46,35.27,31.06,21.51.
(27) Preparation of 4- (tert-butyl) -N- ((4- (4-ethylbenzamido) phenyl) thiocarbamoyl) benzamide (V-27)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-ethylbenzoyl chloride, and the title compound was prepared in 38% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.64(s,1H),9.13(s,1H),8.10(s,1H),7.86–7.78(m,4H),7.75–7.66(m,4H),7.56(d,J＝8.4Hz,2H),7.29(d,J＝8.0Hz,2H),2.71(q,J＝7.6Hz,2H),1.38(s,9H),1.27(t,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3)δ178.32,166.92,165.83,157.80,148.67,136.73,133.68,132.09,128.62,128.24,127.50,127.28,126.23,124.78,120.48,35.27,31.06,28.81,15.30.
(28) Preparation of 4- (tert-butyl) -N- ((4- (4-fluorobenzamido) phenyl) thiocarbamoyl) benzamide (V-28)
The acyl thiourea compound of the series I is V-16, R4The substituted acyl chloride derivative is 4-fluorobenzoyl chloride,the title compound was prepared in 33% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.63(s,1H),9.14(s,1H),8.16(s,1H),7.94–7.79(m,4H),7.68(s,4H),7.56(d,J＝8.4Hz,2H),7.13(t,J＝8.5Hz,2H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.37,166.95,157.86,136.43,133.92,130.88,129.65,129.56,128.58,127.49,126.24,124.81,120.66,115.90,115.69,35.27,31.05.
(29) Preparation of 4- (tert-butyl) -N- ((4- (4-chlorobenzoylamino) phenyl) thiocarbamoyl) benzamide (V-29)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-chlorobenzoyl chloride, and the title compound was prepared in 29% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.64(s,1H),9.14(s,1H),8.21(s,1H),7.82(t,J＝8.7Hz,4H),7.68(s,4H),7.56(d,J＝8.5Hz,2H),7.41(d,J＝8.3Hz,2H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.36,166.96,164.84,157.87,138.18,136.33,133.97,133.06,128.98,128.65,127.49,126.25,124.81,120.65,35.28,31.05.
(30) Preparation of 4- (tert-butyl) -N- ((4- (4-bromobenzoylamino) phenyl) thiocarbamoyl) benzamide (V-30)
The acyl thiourea compound of the series I is V-16, R4The title compound was prepared in 21% yield as a white solid by reference to the procedure in example 4 using 4-bromobenzoyl chloride as the substituted acid chloride derivative.
1H NMR(400MHz,CDCl3)δ12.64(s,1H),9.14(s,1H),8.19(s,1H),7.84(d,J＝8.5Hz,2H),7.74(d,J＝8.5Hz,2H),7.69(s,4H),7.57(t,J＝8.6Hz,4H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ178.35,166.95,164.93,157.87,136.31,133.99,133.53,131.96,128.80,128.57,127.49,126.67,126.25,124.81,120.64,35.28,31.06.
(31) Preparation of 4- (tert-butyl) -N- ((4- (4-tert-butylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-31)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-ethylbenzoyl chloride, and the title compound was prepared in 36% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.65(s,1H),9.15(s,1H),8.11(s,1H),7.88–7.80(m,4H),7.78–7.66(m,4H),7.56(d,J＝8.4Hz,2H),7.50(d,J＝8.3Hz,2H),1.37(d,J＝7.4Hz,18H).13C NMR(100MHz,CDCl3)δ178.34,166.90,165.71,157.81,155.54,136.70,133.74,131.85,128.64,127.49,126.99,126.24,125.74,124.81,120.43,35.27,35.01,31.17,31.06.
(32) Preparation of 4- (tert-butyl) -N- ((4- (4-propylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-32)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-propylbenzoyl chloride, and the title compound was prepared in 34% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.64(s,1H),9.13(s,1H),8.08(s,1H),7.85–7.81(m,4H),7.76–7.67(m,4H),7.56(d,J＝8.4Hz,2H),7.28(d,J＝8.0Hz,2H),2.75–2.54(m,2H),1.70–1.66(m,2H),1.38(s,9H),0.97(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ178.34,166.91,165.77,157.82,147.20,136.70,133.72,132.14,128.87,128.63,127.48,127.13,126.24,124.80120.41,37.90,35.27,31.06,24.30,13.77.
(33) Preparation of 4- (tert-butyl) -N- ((4- (4-butylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-33)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-butylbenzoyl chloride, and the title compound was prepared in 30% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.65(s,1H),9.10(s,1H),7.98(s,1H),7.87–7.81(m,4H),7.73(s,4H),7.57(d,J＝8.5Hz,2H),7.35–7.26(m,2H),2.73–2.66(m,2H),2.72–1.58(m,5H),1.70–1.60(m,2H),1.45–1.34(m,11H),0.96(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ178.33,166.88,165.70,157.84,147.48,136.68,133.75,132.11,128.85,128.64,127.46,127.11,126.25,124.81,120.35,35.56,35.28,33.33,31.05,22.31,13.92.
(34) Preparation of 4- (tert-butyl) -N- ((4- (4-pentylbenzoylamino) phenyl) thiocarbamoyl) benzamide (V-34)
The acyl thiourea compound of the series I is V-16, R4The substituted acid chloride derivative was 4-pentylbenzoyl chloride, and the title compound was prepared in 31% yield as a white solid according to the procedure in example 4.
1H NMR(400MHz,CDCl3)δ12.64(s,1H),9.11(s,1H),8.09(s,1H),7.86–7.78(m,4H),7.76–7.67(m,4H),7.56(d,J＝8.4Hz,2H),7.28(d,J＝8.1Hz,2H),2.72–2.60(m,2H),1.72–1.58(m,2H),1.45–1.27(m,13H),0.92(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ178.30,166.89,165.78,157.81,147.46,136.71,133.70,132.08,128.80,128.63,127.48,127.17,126.23,124.78,120.43,35.83,35.27,31.44,31.06,30.87,22.52,14.05.
(35) Preparation of 4- (tert-butyl) -N- ((2-fluorophenyl) carbamoyl) benzamide (V-39)
With R1The aromatic formyl chloride derivative is 4-tert-butyl formyl chloride, R2The substituted heteroaromatic amine derivative was 2-fluoroaniline, and the target compound was prepared in the same manner as in example 2 in a white solid at a yield of 66%.
1H NMR(400MHz,CDCl3)δ11.43(s,1H),10.45(s,1H),8.33(dd,J＝10.6,4.9Hz,1H),8.11(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.23-7.10(m,3H),1.40(s,9H).13C NMR(100MHz,CDCl3)δ168.58,157.26,154.33,152.40,151.89,129.08,128.16,126.09,125.98,125.78,124.57,124.49,124.19,124.15,121.91,115.29,115.10,35.19,31.13.
(36) Preparation of 3- (4- (tert-butyl) benzoyl) -1- (2-fluorophenyl) -2-thioxooxoimidazolidin-4-one (V-45)
The acylthiourea compound of series I was V-4 and the title compound was prepared in the form of a pale yellow solid with a yield of 31% by reference to the procedure in example 3.
1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.5Hz,2H),7.61–7.51(m,1H),7.43–7.33(m,5H),4.04(q,J＝18.3Hz,2H),1.32(s,9H).13C NMR(100MHz,CDCl3)δ177.19,171.55,170.73,158.77,157.08,156.25,132.20,131.48,131.41,130.03,129.93,125.37,124.71,124.68,122.56,122.43,116.83,116.64,35.15,33.21,31.09.
[ example 5 ] testing of biological Activity of acylthiourea Compounds
(1) Determination of cytotoxicity of acylthiourea compounds:
yellow thiazole blue, MTT for short, can penetrate through cell membranes to enter cells, amber dehydrogenase in mitochondria of living cells can enable exogenous MTT to be reduced into water-insoluble needle-shaped Formazan crystals and deposited in the cells, the crystals can be dissolved by 20 percent (mass to volume) SDS, an enzyme linked immunosorbent detector is used for measuring the light absorption value at 595nm wavelength, and the cell number can be indirectly reflected.
For the experiments, RD cells were administered at 2X 10 per well4The density of (2) was transferred to a 96-well plate, and after 24 hours of incubation at 37 ℃, the medium was aspirated and cell culture medium (DMEM + 5% serum) containing various concentration gradient compounds was added to each well. After 24 hours, 5mg/mL MTT solution was added per well and the cell plates were incubated at 37 ℃ CO2Culturing in incubator for 4 h. And measuring the OD value at 595nm by using an enzyme-labeling instrument. Inhibition ratio (%) of compound [1- (E-N)/(P-N)]X 100, wherein "E" represents the OD value of the administered group, "P" represents the OD value of the non-administered group, and "N" represents the OD value of the blank group. Median inhibitory concentration (CC) of the Compound50) As an indicator of the cytotoxicity of the compound.
(2) The in vitro anti-enterovirus activity of the acyl thiourea compound is as follows:
antiviral activity of the compounds was assessed by a viral plaque reduction assay. Inoculating enterovirus into 6-well plate with RD cells, removing virus-containing culture medium 40 min later, adding culture medium containing drug to be tested with specific concentration, and culturingThe medium contained TPCK-trypsin at a final concentration of 2. mu.g/mL and 0.5% agarose. At 37 deg.C, 5% CO2After 48-72 hours of incubation under conditions, the cells were fixed with 3% formalin, stained with 0.5% crystal violet and the number of viral plaques was counted. EC (EC)50Refers to the concentration of the particular drug required to effectively inhibit the number of plaques produced by the virus to 50% of the control wells.
The enteroviruses involved in the present example include poliovirus, echovirus, coxsackievirus, and enteroviruses EV-D68, EV-A-71, rhinovirus, and the like.
The invention uses Envir oxime as control, checks the cytotoxicity and anti-enterovirus activity of 72 synthesized compounds, calculates the selectivity index SI of the compound, and the result is shown in Table 2.
TABLE 2 results of the anti-Enterovirus EV71 activity and cytotoxicity of the synthesized compound V1-72 of the present invention
TABLE 3 broad spectrum anti-enterovirus activity results for the compounds synthesized according to the invention
The above experimental results show that: most of the acyl thiourea compounds synthesized have good anti-enterovirus activity, such as compounds V-6, V-8, V-9, V-16, V-19, V-20, V-22, V-23, V-26, V-27, V-28, V-29, V-30, V-31, V-32, V-33, V-34, V-49, V-50, V-65, V-66, V-67, V-68, V-69 and the like, especially compounds V-16, V-20, V-22, V-23, V-26, V-27, V-28, V-29, V-30, V-31, V-32, V-3, V-65, V-22, V-23, V-26, V-27, V-28, V-29, V-30, V-31, V-32, V-3, V-65, V-69 and the like, V-66, V-67, V-68, and V-69 all showed low nanomolar levels of anti-enterovirus activity and high selectivity.
[ example 6 ] testing of Activity of acylthiourea Compounds in animals
(1) Evaluation of efficacy of acylthiourea compounds in mice
Firstly, the experimental mice related to the invention are two-week KM mice purchased from the provincial center of Hubei, and all related experimental operations conform to the animal welfare guidelines. Taking the compound V-31 as an example, the experimental group of the mice is a blank group (no toxicity attacking group, NC) is not administrated, a negative control group (only toxicity attacking and no medicine group, Mock) and an experimental group (toxicity attacking and administrating group, V-31) are three groups, and each group comprises 8 mice. The dose of the negative control group mouse challenge (EV-A71) is 0.8X 108pfu (lethal dose), by nasal drip; the mice in the experimental group are administrated 6 hours before the toxin counteracting, the administration concentration is 0.6mg/kg, and the toxin counteracting dose is 0.8 multiplied by 108pfu (lethal dose), administered orally at a dose of 0.6mg/kg for 4 consecutive days after challenge. The behavior, body weight of three groups of mice were monitored and recorded daily for 10 days. As shown in FIG. 1, the control group showed dead or nearly dead state after the sixth day, while the compound V-31 showed excellent protective effect on virus-infected mice up to 80% at a dosage of 0.6mg/kg, and was suitable for further development as a clinical candidate drug.
(2) Safety study of acylthiourea compounds
The experimental mice were divided into 5 groups, a blank group (non-administration and non-administration group, Mock), a negative control group (only administration and non-administration group, EV71), an experimental group (administration group, EV71+ V-310.6 mg/kg), and only administration groups (two concentrations, V-315mg/kg, V-3110 mg/kg). Wherein the dosage of the toxic materials is 0.8 × 108pfu; the administration mode of the compound is oral administration 6 hours before the detoxificationThe medicine is continuously administrated for four days after toxin counteracting. The behavior and body weight of each group of mice were monitored and recorded daily for 10 days, and the results are shown in fig. 2. As can be seen from figure 2, compound V-31 does not show a significant weight reduction trend when administered alone at a dose of up to 10mg/kg (more than 15 times the amount administered in the laboratory), thus indicating that the compound is safe and has no significant toxic or side effects on mice, and is suitable for further development as a clinical candidate drug.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. An acylthiourea compound, characterized in that: the acyl thiourea compound is a compound with a structure shown in a general formula (I), (II) or (III):
R1the substituent is alkyl or a benzene ring or an aromatic heterocyclic structure with different substituents, wherein the substituents are alkyl substituents, halogen substituents, alkoxy substituents and heteroalkyl substituents, and the substituent comprises a single-substituted and multi-substituted free combination mode of the substituents;
R2the substituent is alkyl or a benzene ring or an aromatic heterocyclic structure with different substituents, wherein the substituents are alkyl substituents, halogen substituents, alkoxy substituents and heteroalkyl substituents, and the substituent comprises a single-substituted and multi-substituted free combination mode of the substituents;
R3is mono-or polysubstituted alkyl substituent, halogen substituent, alkoxy substituent, heteroalkyl substituent;
R4is alkyl substituent, alkoxy substituent, heteroalkyl substituent, acyl substituentOr a benzene ring and an aromatic heterocyclic structure with different substituents, wherein the substituents are alkyl substituents, halogen substituents, alkoxy substituents and heteroalkyl substituents, and the substituent comprises a single-substituted and multi-substituted free combination mode of the substituents;
x is a sulfur atom or an oxygen atom;
y is a nitrogen atom, a sulfur atom or an oxygen atom.
2. The acylthiourea-based compound of claim 1, wherein: comprising the following compounds: n- ((4-acetylaminophenyl) thiocarbamoyl) benzothiophene-2-carboxamide, N- ((4-acetylaminophenyl) thiocarbamoyl) thiophene-2-carboxamide, N- ((4-acetylaminophenyl) thiocarbamoyl) -4-tert-butylbenzoamide, 4- (tert-butyl) -N- ((2-fluorophenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((3-fluorophenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2-chlorophenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2-bromophenyl) thiocarbamoyl) benzamide, and a pharmaceutically acceptable salt thereof, 4- (tert-butyl) -N- ((2-methylphenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2-methoxyphenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2, 6-dibromophenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2, 4-bistrifluoromethylphenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2, 4-dimethylphenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2-bromo-4-methylphenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((3, 4-difluorophenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((2,4, 6-trichlorophenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((4-aminophenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- (pyridin-2-ylcarbamoyl) benzamide, 4- (tert-butyl) -N- (quinoline-2-carbonothioyl) benzamide, N- ((4-propionylaminophenyl) thiocarbamoyl) -4-tert-butylbenzamide, 4- (tert-butyl) -N- ((4-neopentylamide) thiocarbamoyl) benzamide, N- ((N, N-phenylthiocarbamoyl) benzamide, N-phenylthiocarbamoyl-N, N- (tert-butyl) -N- ((4-neopentylamide) thiocarbamoyl) benzamide, N-phenylthiocarbamoyl-N, N-phenylthiocarbamoyl-4-phenylcarbamoyl-4-phenylthiocarbamoyl-amide, N-phenylthiocarbamoyl-phenylcarbamoyl-4-phenylformamide, N, S, 4- (tert-butyl) -N- ((4- (ethylsulfonamido) phenyl) thiocarbamoyl) benzamide, N- ((4-benzoylaminophenyl) thiocarbamoyl) -4- (tert-butyl) benzamide, N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -2-methoxybenzamide, N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -3-methoxybenzamide, N- (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) -4-methoxybenzamide, 4- (tert-butyl) -N- ((4- (4-methylbenzamido) phenyl) thiocarbamoyl) benzoyl) benzene Formamide, 4- (tert-butyl) -N- ((4- (4-ethylbenzamido) phenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((4- (4-fluorobenzamido) phenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((4- (4-chlorobenzamido) phenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((4- (4-bromobenzoamido) phenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((4- (4-tert-butylbenzoamido) phenyl) thiocarbamoyl) benzamide, and, 4- (tert-butyl) -N- ((4- (4-propylbenzoylamino) phenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((4- (4-butylbenzoylamino) phenyl) thiocarbamoyl) benzamide, 4- (tert-butyl) -N- ((4- (4-pentylbenzoylamino) phenyl) thiocarbamoyl) benzamide, N- ((4-acetamidophenyl) aminomonoyl) -4-chlorobenzamide, N- ((4-acetamidophenyl) aminomonoyl) -4- (dimethylamino) benzamide, N- ((4-acetamidophenyl) aminomonoyl) -4-methoxybenzamide, N-tert-butyl-N- ((4- (4-propylbenzoylamino) phenyl) thiocarbamoyl) benzamide, N-tert-butyl-N- ((4- (4-pentylbenzoylamino) phenyl) thiocarbamoyl) benzamide, N-methylcarbamoyl-4-chlorobenzamide, N-methylcarbamoyl-4-chlorobenzamide, N-methylcarbamoylamino-4-methylcarbamoyl-4-chlorobenzamide, N-methylcarbamoyl-4-methylcarbamoyl-phenylcarbamate, N-methylcarbamoyl-4-phenylcarbamate, N-methylcarbamoyl-4-N-methylcarbamoyl-N-methylcarbamoyl-N-methylcarbamoyl-N-p-N-p-N-p-m-p-amide, N-p-, N- ((4-acetamidophenyl) aminomonoyl) -2, 6-dichlorobenzamide, 4- (tert-butyl) -N- ((2-fluorophenyl) carbamoyl) benzamide, 4- (3- (4- (tert-butyl) benzoyl) thioureido) phenylphosphonic acid dihydrogen, carbonic acid (((4- (3- (4- (4- (4- (tert-butyl) benzoyl) thioureido) phenoxy ] [ hydroxy) phosphoryl ] oxy) methylisopropyl, 4- (tert-butyl) -N- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) aminomonoyl) benzamide, (4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl) boronic acid, and mixtures thereof, N- ((4- (1H-1,2, 4-triazol-1-yl) phenyl) aminomonoyl) -4- (tert-butyl) benzamide, 3- (4- (tert-butyl) benzoyl) -1- (2-fluorophenyl) -2-thioxoimidazolidin-4-one, N- (((4H-1,2, 4-triazol-4-yl) aminomonoyl) -4- (tert-butyl) benzamide, 4- (3- (4- (tert-butyl) benzoyl) thioureido) phenyl 4- (tert-butyl) benzoate, 4- (tert-butyl) -N- ((4-phenoxyphenyl) aminomonoyl) benzamide, and mixtures thereof, 4- (tert-butyl) -N- (((4- (4-fluoro-3-methylphenoxy) -2-methylphenyl) aminomonoyl) benzamide, N- ((4-amino-2-chlorophenyl) aminomonoyl) -4- (tert-butyl) benzamide, 4- (tert-butyl) -N- ((2-chloro-4- (ethylamino) phenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- (((2-chloro-4-ethoxyphenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- ((4- (2-methoxyethoxy) phenyl) aminomonoyl) benzamide, and mixtures thereof, 4- (tert-butyl) -N- ((4- (2-hydroxyethoxy) phenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- ((4- (2- (2- (2-hydroxyethoxy) ethoxy) phenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- ((4- (2- (2- (2- (2-hydroxyethoxy) ethoxy) phenyl) aminomonoyl) benzamide, N- ((4-aminophenyl) aminomonoyl) acetamide, 4- (tert-butyl) -N- (ethylaminomethionyl) benzamide, 4- (tert-butyl) -N- ((2- (methylamino) ethyl) aminomonoyl) benzamide, and mixtures thereof, 1- (4-aminophenyl) -3- (4- (tert-butyl) benzoyl) -2-thioxooxoimidazolidin-butan-4-one, N- (4- (3- (4- (tert-butyl) benzoyl) -4-oxo-2-thioxooxoimidazolidin-1-yl) -2-fluorophenyl) acetamide, 4- (tert-butyl) -N- ((4- (ethylamino) -2-methylphenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- ((4- (((2-hydroxyethyl) amino) phenyl) aminomonoyl) benzamide, 2- (2- (((4- (3- (4- (4- (4- (tert-butyl) benzoyl) thioureido) phenyl) amino) ) Ethoxy) acetic acid tert-butyl ester, 4- (tert-butyl) -N- (((4- (phenylamino) phenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- ((4- (p-tolylmethylamino) phenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- ((4- (phenylthiophenyl) aminomonoyl) benzamide, 4- (tert-butyl) -N- (((4- ((3-methoxyphenyl) amino) phenyl) aminomonoyl) benzamide, N- (4- (3- (4- (4- (tert-butyl) benzoyl) thioureido) -3-methylphenyl) -3-fluorobenzamide, and mixtures thereof, N- ((4-Acylaminophenyl) aminomethylsulfonyl) -4- ((trifluoromethyl) thio) cyclohexa-1, 5-diene-1-carboxamide, N- ((4-benzoylaminophenyl) carbamoyl) -4- (tert-butyl) benzamide, N- ((2-bromo-4-methylphenyl) carbamoyl) -4- (tert-butyl) benzamide.
3. A method for producing an acylthiourea compound as claimed in claim 1 or 2, characterized in that:
the preparation method of the compound with the structure shown in the general formula (I) is the following method (1) or (2):
the method (1) comprises the following steps: reacting acyl chloride compound with ammonium thiocyanate in a solvent; filtering the obtained reaction solution, adding an amine compound into the filtrate to react to obtain a compound with a structure shown in a general formula (I);
the method (2) comprises the following steps: reacting acyl chloride compound with ammonia water in a first solvent; filtering the obtained reaction liquid to obtain a solid, dissolving the solid by using a solvent II, and slowly adding oxalyl chloride for reaction; concentrating and spin-drying the obtained reaction liquid, dissolving the reaction liquid by using a solvent III, and then adding an amine compound to react to obtain a compound with a structure shown in a general formula (I);
the preparation method of the compound with the structure shown in the general formula (II) comprises the following steps: taking a compound with a structure shown in a general formula (I) and chloroacetyl chloride as raw materials, and reacting in a solvent in the presence of an acid-binding agent to obtain a compound with a structure shown in a general formula (II);
the preparation method of the compound with the structure shown in the general formula (II) comprises the following steps: taking a compound with a structure shown in a general formula (I) and a halogenated substrate as raw materials, and reacting in a solvent to obtain a compound with a structure shown in a general formula (II).
4. The method for producing an acylthiourea-based compound according to claim 3, characterized in that:
in the method (1) for preparing the compound with the structure shown in the general formula (I), the solvent is acetonitrile, and the reaction condition of the acyl chloride compound and the ammonium thiocyanate in the solvent is 0-40 ℃ for 1-4 hours; the reaction condition after the amine compound is added is that the reaction is carried out for 4 to 12 hours at the temperature of between 0 and 40 ℃;
in the method (2) for preparing the compound with the structure shown in the general formula (I), the solvent I is dichloromethane, and the reaction condition of the acyl chloride compound and ammonia water in the solvent I is 0-40 ℃ for 2-4 h; the second solvent is dichloromethane, and the reaction condition after adding oxalyl chloride is 60-80 ℃ for 6-12 h; the third solvent is methanol, and the amine compound is added for reaction under the condition of 0-40 ℃ for 2-24 h;
in the method for preparing the compound with the structure shown in the general formula (II), the acid-binding agent is triethylamine, the solvent is dichloromethane, and the reaction condition is 0-40 ℃ for 2-24 h;
in the method for preparing the compound with the structure shown in the general formula (III), the solvent is DCM or DMF, and the reaction condition is that the reaction is carried out for 2-24h at 20-110 ℃.
5. A pharmacologically or physiologically acceptable salt of an acylthiourea compound as claimed in claim 1 or 2.
6. Use of an acylthiourea compound according to claim 1 or 2 or a pharmacologically or physiologically acceptable salt according to claim 5 for the preparation of an anti-enterovirus medicament.
7. An anti-enterovirus medicament characterized by: comprising an acylthiourea-based compound of claim 1 or 2 or a pharmacologically or physiologically acceptable salt of claim 5.
8. The anti-enterovirus agent of claim 7, wherein: comprising an acylthiourea compound of claim 1 or 2 or a pharmacologically or physiologically acceptable salt pharmaceutically acceptable carrier or excipient of claim 5.
9. The anti-enterovirus agent of claim 7 or 8, wherein: the enteroviruses comprise poliovirus, Coxsackie virus, echovirus and different types of enteroviruses.
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