WO2009003307A1 - Phthiobuzonum derivatives and preparation, pharmaceutical composition and use thereof - Google Patents

Abstract

A new phthiobuzonum derivatives, its preparation, pharmaceutical composition comprising them and use as drugs, especially as antiviral drugs.

Description

 酞丁安 derivative, its preparation method and its pharmaceutical composition and use

 The present invention relates to a novel class of agmatine derivatives, a process for their preparation, pharmaceutical compositions containing them, and their use as medicaments, especially as antiviral drugs. Background technique

 酞丁安 (TDA,) is a bis-thiosemicarbazone compound, chemical name is 3-phthalimide -2-oxo-n-butyraldehyde bis-semicarbazone, and its structure is shown in Figure 1.

 Figure 1. The structure of Kenting

 Antiviral studies have shown that 酞丁安 has a significant inhibitory effect on the replication of herpes simplex virus type I (HSV-1) and type II (HSV-2) in tissue culture cells, and local administration of 酞丁安 preparation can prevent guinea pig HSV- I cell lesions. Clinical trials have shown that 酞丁安 has a good effect on the skin diseases of herpes simplex and herpes zoster virus and the virulence-transmitted disease caused by human papillomavirus-condyloma acuminata (genital warts). In October 1984, it was the first antiviral chemotherapeutic drug created in China. Later, in order to solve the problem of water solubility and improve the curative effect of 酞丁安, further structural modification was carried out, and various 酞丁安 derivatives were synthesized. Summary of the invention

 In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a novel agmatine derivative; another object of the present invention is to provide a process for preparing a novel agmatine derivative;

Another object of the present invention is to provide a novel butyl butyl derivative and a composition thereof as a pharmaceutical application; one aspect of the present invention relates to a pharmaceutical composition comprising the general formula (I), (π), απ as an active ingredient , (iv), (V) (VI), and optical isomers thereof, and carriers commonly used in the pharmaceutical field. The present invention relates to a compound of the formula (I)

 (I)

Wherein, and independently selected from the group consisting of hydrogen, - ₈ alkyl, halogenated d- ₈ alkyl, aryl substituted. ^ mercapto, allyl, -8 fluorenyl substituted aryl, monohalogenated or polyhalogenated aryl, halo-8 fluorenyl substituted aryl, amino substituted aryl, ammonia Cr ₈ alkyl substituted aryl, But and can't be hydrogen at the same time;

Preferred halogens are selected from the group consisting of fluorine, chlorine, and bromine;

Preferred aryl groups are selected from phenyl;

Preferred substituents on the phenyl group are: .5 fluorenyl, fluoro, chloro, bromo, trifluoromethyl, amino;

More preferably, independently selected from the group consisting of d- ₅ alkyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluorophenyl, 3, 4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3,4- Dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl,

4-fluoro-4-chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,

5-trifluoromethylphenyl, 3,5-bistrifluoromethylphenyl;

The most preferred compound of (I) is selected from

 3-phthalimide-2-oxo-n-butyraldehyde bis(4,4-dimethyl)-3-aminothiourea

 3-phthalimide -2-oxo-n-butyraldehyde bis-(4-propylpropyl)-3-aminothiourea

 3-phthalimide -2-oxo-n-butyric acid bis(4-isopropyl)-3-aminothiourea

^3- phthalimide-2-oxo-n-butyraldehyde bis-[4-(4-bromophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyl ketone double-shrink [4-(3,4-dichlorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde bis- [4-(2-fluorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde bis- [4-(4-fluorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde bis-[4-(4-chlorophenyl)-3-aminothiourea]

³ -phthalimido-2-oxo-n-butyraldehyde bis-[4-(3,5-bistrifluoromethylphenyl)-3-aminothiourea] The invention also relates to a compound of the formula (Π)

其中， 和 ，独立的选自氢、 -8垸基、 卤代 -8垸基、 芳基取代 -₈烷基、 烯丙 基、 -8垸基取代芳基、 单卤代或多卤代芳基、 卤代 d-₈烧基取代芳基、 氨基取代芳 基、 氨 c ₈烷基取代芳基、 但是 和 ，不能同时为氢；

Wherein, and independently selected from hydrogen, -8 fluorenyl, halo-8 fluorenyl, aryl substituted- ₈ alkyl, allyl, -8 fluorenyl substituted aryl, monohalogenated or polyhalogenated aromatic a halogenated d- ₈ alkyl substituted aryl group, an amino substituted aryl group, an amino c ₈ alkyl substituted aryl group, but not simultaneously hydrogen;

Preferred halogens are selected from the group consisting of fluorine, chlorine, and bromine;

Preferred aryl groups are selected from phenyl;

Preferred substituents on the phenyl group are: C _1-5 fluorenyl, fluoro, chloro, bromo, trifluoromethyl, amino;

More preferably and R ₂ , independently selected from C _1-5 alkyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluoro Phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl , 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl,

4-fluoro-4-chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-Dibromophenyl, 3,5-dibromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,

5-trifluoromethylphenyl, 3,5-bistrifluoromethylphenyl;

The most preferred (Π) compound is selected from

 3-phthalimide -2-oxo-n-butyraldehyde mono- (4,4-dimethyl)-3-aminothiourea

 3-phthalimide -2-oxo-n-butyraldehyde mono- (4- propyl)-3-thiosemicarbazide

 3-phthalimide -2-oxo-n-butyraldehyde mono- (4-isopropyl)-3-aminothiourea

 3-phthalimide-2-oxo-n-butyraldehyde monocondensation [4-(4-bromophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde monocondensation [4-(3,4-dichlorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde monocondensation [4-(2-fluorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde monocondensation [4-(4-fluorophenyl)-3-aminothiourea]

3-phthalimide -2-oxo-n-butyraldehyde monocondensation [4-(4-chlorophenyl)-3-aminothiourea]

3-phthalimido-2-oxo-n-butyraldehyde mono[4-(3,5-bistrifluoromethylphenyl)-3-aminothiourea] The invention also relates to a compound of the formula (III)

R _{3 is} selected from the group consisting of: hydrogen, halogen, -5 fluorenyl, Q.5 decyloxy, halo d. ₅ alkyl, hydroxy, d- ₅ fluorenyl C00, cyano, aldehyde, nitro, amino, carboxy, Acylhydrazino, C _1:5 alkyl alkoxycarbonyl, d- ₅ decyloxycarbonylamino, d. ₅ alkylalkylaminomethyl.

More preferably R _{3 is} selected from the group consisting of: C _M decyl, C _M alkoxy, fluorine, chlorine, bromine.

More preferably R _{3 is} selected from the group consisting of: C _w thiol, fluorine, chlorine, bromine.

The most preferred compound (III) is selected from

 1-[4-(3-methoxyphenyl) piperazine-1-yl]-3-indolimide-2-butanone

1-[4-(4-chlorophenyl)piperazine small group]-3-phthalimide-2-butanone

1-[4-(3-chlorophenyl)piperazine-1-yl]-3-indolimide-2-butanone

1-[4-(4-fluorophenyl)piperazine small group]-3-phthalimide-2-butene

1-[4-(3,4-Dimethylphenyl)piperazine-1-yl]-3-phthalimide-2-butanone The present invention also relates to a compound of the formula (IV)

Selected from: hydrogen, halogen, C _1-5 alkyl, -5 alkoxy, halogenated d- ₅ alkyl, hydroxy, d- ₅ fluorenyl C00, cyano, aldehyde, nitro, amino, carboxyl, hydrazide group, D_ ₅ alkyl alkoxycarbonyl, firing D- ₅ alkoxycarbonylamino group, _{5-aminomethyl-alkyl} alkoxy.

More preferably selected from the group consisting of: C _M alkyl, C ₁₄ alkoxy, fluorine, chlorine, bromine. More preferably selected from the group consisting of: C _M alkyl, fluorine, chlorine, .3,5-bistrifluoromethyl.

The most preferred compound (IV) is selected from

 1-[4-(4-fluorophenyl)-3-aminothiourea-1-yl]-3-indolimide-2-butanone

1-[4-(4-chlorophenyl)-3-aminothiourea small group]-3-phthalimide-2-butanone

1-[4-(4-bromophenyl)-3-aminothiourea small group]-3-phthalimide-2-butanone

1-[4-(3,5-bistrifluoromethylphenyl)-thiosemicarbazide] -3-phthalimide-2-butanone The present invention also relates to a compound of the formula (V)

R5 is selected from the group consisting of hydroxy, _-8 alkyl, haloQ-8 fluorenyl, aryl substituted _-8 alkyl, allyl, Q- ₈ alkyl substituted aryl, monohalogenated or polyhalogenated aryl, halogenated -8 alkyl substituted aryl, amino substituted aryl, ammonia. ^alkyl substituted aryl;

Preferred R5 is selected from the group consisting of hydroxyl, decyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluorophenyl, 3,4-difluoro Phenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3,4-dichlorophenyl , 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 4-fluoro-4-chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2- Trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 3,5-bistrifluoromethylphenyl;

The most preferred compound (V) is selected from

 3-phthalimido-2-oxo-n-butyraldehyde bis-[1-(4-oxo-4,5-dihydrothiazole-2-yl)anthracene]

3-phthalimido-2-oxo-n-butyraldehyde bis-[1-(5-phenylthiazol-2-yl)anthracene]. The invention also relates to a compound of the formula (VI)

 (VI)

, and, independently selected from hydrogen, d- ₈ fluorenyl, halogenated C _r8 alkyl, aryl substituted alkyl, allyl, d- ₈ alkyl substituted aryl, monohalogenated or polyhalogenated aromatic a halogenated d- ₈ alkyl substituted aryl group, an amino substituted aryl group, an amino _Cr8 alkyl substituted aryl group;

Preferred halogens are selected from the group consisting of fluorine, chlorine, and bromine;

Preferred aryl groups are selected from phenyl;

Preferred substituents on the phenyl group are: Cw alkyl, fluoro, chloro, bromo, trifluoromethyl, amino;

More preferably, and, independently selected from the group consisting of hydrogen, Cw alkyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluorophenyl , 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3 ,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 4-fluoro-4-chlorophenyl, 5-fluoro 4-chlorophenyl, 2-bromophenyl, 3-diphenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-dibromophenyl, 3,5- Dibromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 3,5-bistrifluoromethyl Phenyl group;

 Re is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, halogenated lower alkyl, hydroxy, RCOO, cyano, aldehyde, nitro, amino, carboxy, hydrazide, lower methoxycarbonyl, lower alkane Oxycarbonylamino, lower alkylaminomethyl. The invention also provides methods of preparing the compounds of the invention.

Preparation of starting materials

甲基酮 (化合物 0-1)和溴酮 (化合物 0-2)是酞丁安中间体， 是在合成酞丁安过程中得到 的中间产物， 它们的制备可参阅文献方法合成。 酞丁安中间体（化合物 0-1或 0-2) 用二甲亚砜（DMSO) 或者二氧化硒 （Se(¾)氧化,得到氧化产物 (1,2-二羰基化合物， 化合物 0— 3)。

Methyl ketone (compound 0-1) and bromoketone (compound 0-2) are intermediates of acetonide, which are intermediates obtained in the synthesis of butyl butyl hydride. Their preparation can be synthesized by reference to literature methods. Anthracene intermediate (compound 0-1 or 0-2) is oxidized with dimethyl sulfoxide (DMSO) or selenium dioxide (Se(3⁄4) to give an oxidation product (1,2-dicarbonyl compound, compound 0-1) ).

1. Preparation method of compound (I):

 0-3

The oxidation product of the butyl butyl intermediate (compound 0-3) is prepared by condensation of the corresponding substituted thiosemicarbazide.

Starting materials: 3-phthalimide-1-bromobutanone, 4--4-, thiosemicarbazide;

Proportion: 3-phthalimide-1-bromobutanone: 4- -4-,-thiosemicarbazide molar ratio = 1:2-3, preferred molar ratio = 1:2;

Solvent: ^R^-Rr-thiosemicarbazide is dissolved in water, ethanol, ethanol and water, and can be heated to facilitate dissolution;

Reaction temperature: may be a temperature from room temperature to reflux of the solvent, preferably a temperature at which the solvent is refluxed;

Reaction time: 0.5-8 hours, preferably 1-4 hours, most preferably 2 hours, gradually forming a precipitate during the reaction;

Post-treatment: After the reaction is completed, the reflux is stopped, and the mixture is cooled. Optionally, an appropriate amount of water can be added, and the mixture is filtered to obtain a crude product. The refining of the crude product can be carried out by a conventional method. For example, washing with a solvent to remove impurities, preferably washing and dissolving The agent is selected from the group consisting of chloroform, absolute ethanol, water, dichloromethane, chloroform, and methanol. Or using column chromatography: the crude product is dissolved in a small amount of chloroform, and subjected to silica gel column chromatography, eluting with different gradients of chloroform and ethyl acetate, petroleum ether and ethyl acetate. The main spot is collected, concentrated, and dried to obtain the desired product. . It can also be refined by recrystallization, for example, the crude product is recrystallized from 95% ethanol.

2. Preparation method of compound (II):

酞丁安中间体的氧化产物 (化合物 0-3)和相应的取代氨基硫脲缩合而制备的。

The oxidation product of the butyl butyl intermediate (compound 0-3) and the corresponding substituted thiosemicarbazide are prepared by condensation.

Starting materials: 3-phthalimide small bromobutanone, 4-R ₂ -4-R ₂ ,-thiosemicarbazide;

Proportion: 3-phthalimide-1-bromobutanone: 4-R ₂ -4-R ₂ , -thiosemicarbazide molar ratio = 0.5-1:1, preferred molar ratio = 1:1;

Solvent: 4- -4-,-thiosemicarbazide is dissolved in water, ethanol, ethanol and water, and can be heated to facilitate dissolution;

Reaction temperature: It may be a temperature from room temperature to reflux of the solvent, preferably a temperature at which the solvent is refluxed.

Reaction time: 0.5-8 hours, preferably 1-4 hours, most preferably 2 hours, gradually forming a precipitate during the reaction;

Post-treatment: After the reaction is completed, the reflux is stopped, and the mixture is cooled. Optionally, an appropriate amount of water can be added and filtered to obtain a crude product. The refining of the crude product can be carried out by a conventional method. For example, the impurities are washed with a solvent, and the preferred lacquer solvent is selected from the group consisting of chloroform, absolute ethanol, water, dichloromethane, chloroform, and methanol. Or use column chromatography: The crude product is dissolved in a small amount of chloroform, and subjected to silica gel column chromatography, eluting with a gradient of chloroform and ethyl acetate, petroleum ether and ethyl acetate. The main spot is collected, concentrated, and dried to give the desired product. It can also be refined by recrystallization, for example, the crude product is recrystallized from 95% ethanol.

3. Preparation method of compound (III):

 m

The bromoketone (compound 0-2) and the substituted amine are obtained by thiolation.

Starting material: 1-(R ₃ -phenyl)piperazine hydrochloride, bromoketone (compound 0-2);

Proportion: molar ratio of 1-(R ₃ -phenyl)piperazine hydrochloride, bromoketone = 1:1.2-1.6, preferred molar ratio = 1:1.4; Conditions: The reaction is preferably carried out under basic conditions, preferably Providing alkaline conditions with NaHC0 ₃ ;

Solvent: The preferred solvent is ethanol;

Reaction temperature: may be a temperature from room temperature to reflux of the solvent, preferably a temperature at which the solvent is refluxed;

The reaction time is 2 to 24 hours, preferably 4 to 8 hours, and most preferably 6 hours, and a precipitate is gradually formed during the reaction. After stopping heating, stir overnight;

Post-treatment: The crude product was dissolved in a small amount of acetone, and subjected to silica gel column chromatography, eluting with a gradient of petroleum ether and acetone, petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried to give the desired product.

4. Preparation method of compound (IV):

 IV

The bromoketone (compound 0-2) and the substituted amine are obtained by thiolation.

Starting materials: 4-substituted phenyl-3-aminothiourea, bromoketone (compound 0-2);

Proportion: molar ratio of 4-substituted phenyl-3-aminothiourea and bromoketone = 1 : 1.2-1.6, preferred molar ratio = 1:1.5-1.6;

Conditions: The reaction is preferably carried out under basic conditions, preferably basic conditions to provide with NaHC0 _3; preferably carried out in the presence of KI;

Solvent: The preferred solvent is acetonitrile;

Reaction temperature: may be room temperature to the reflux temperature of the solvent, and the preferred temperature is room temperature;

Reaction time: 1-4 hours, preferably 2-3 hours;

Post-treatment: The residue was applied to a dry column, eluting with a gradient of petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried. 5. Preparation method of compound (V)

 The cyclization reaction was carried out using 酞丁安 as a raw material.

Starting material: 酞丁安: X-CH ₂ -CO-R ₅ wherein X is an easy leaving group;

Proportion: 酞丁安: X-CH ₂ -CO-R ₅ molar ratio is 1: 2-3;

 Conditions: The reaction is preferably carried out under basic conditions, preferably with NaOAc to provide basic conditions;

 Solvent: The preferred solvent is ethanol;

 Reaction temperature: may be room temperature to the reflux temperature of the solvent, the preferred temperature is the temperature at which the solvent is refluxed; reaction time: 5-12 hours, preferably 7-9 hours;

 Post-treatment: The main spot was collected by silica gel column chromatography, eluting with petroleum ether and ethyl acetate gradient, concentrated, and dried. The compounds of the invention also comprise the following compound structures:

 19' 19

 Compound 19' is an enol form and its stable structure is a compound 19.

6. Preparation method of compound (VI)

将酞丁安或化合物 （1)， 在有水合肼的条件下开环， 再连上取代基即得。

The compound or the compound (1) is opened under the condition of hydrazine hydrate, and the substituent is obtained.

Reaction time: 1 hour.

Solvent: The preferred solvent is methanol;

Reaction temperature: may be room temperature to the reflux temperature of the solvent, and the preferred temperature is room temperature;

Reaction time: 0.5-4 hours, preferably 1-2 hours;

Post-treatment: The crude product can be refined using conventional methods. For example, the impurities are washed away with a solvent, and the preferred washing solvent is selected from the group consisting of chloroform, absolute ethanol, water, dichloromethane, chloroform, and methanol. The invention therefore also relates to a pharmaceutical composition comprising the compound of the invention as an active ingredient. The pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually from 0,1 to 95% by weight.

 The compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, 'lung And the respiratory tract, skin, vagina, rectum, etc.

 The dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including plain tablets, enteric tablets, tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.

 The compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.

 In order to form the compound of the present invention into tablets, various excipients well known in the art, including diluents, binders, wetting agents, disintegrating agents, lubricants, and glidants, can be widely used. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant may be water, ethanol, or different Propyl alcohol, etc.; the binder may be starch pulp, dextrin, sugarwood, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linking Polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; lubricant and help The flow agent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol or the like.

Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets. In order to prepare the administration unit as a capsule, the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule. A variety of diluents, binders, wetting agents, disintegrants, glidants useful in the preparation of tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention.

 In order to prepare the compound of the present invention as an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added. The solubilizer or co-solvent may be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.

 In addition, coloring agents, preservatives, perfumes, flavoring agents or other additives may also be added to the pharmaceutical preparations as needed.

 The pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.

 The pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like. In general, a suitable daily dose of the compound of the present invention is from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from Ι-100 mg/kg body weight. The above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

 The compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation. The compounds of the invention are treated by a suitable method of administration such as oral, parenteral administration such as IP, IV or topical treatment of the virus. Viral infections include herpes simplex viruses type I and type II, herpes zoster virus, trachoma virus, condyloma acuminata, flat warts and other viral diseases. Detailed Description of References

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Indian Journal of Chemistry, Vol.40B, 2001: 674-677

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The Institute of Materia Medica, Chinese Academy of Medical Sciences, the new antiviral chemotherapy drug Ding Ding identification data, August 1984. Example 1. 3-phthalimide-2-oxo-n-butyraldehyde bis(4,4-dimethyl)-3-aminothiourea (Compound 1)

 0.296 g (1.0 mmol) of 3-phthalimide small bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow. Into 1.5 mL of water, then add 1.5 mL of 95% ethanol to obtain a yellow transparent solution A; 0.238 g (2.0 mmol) of 4,4-dimethylthiosemicarbazide was dissolved in 1.5 mL of 80 ° C hot water, added In solution A. After heating under reflux for 1 hour, a precipitate gradually formed. The reflux was quenched, cooled, and 5 mL of water was added and filtered with suction to give a yellow precipitate, which was dried under vacuum overnight. The crude product was washed repeatedly with chloroform, washed with impurities, and dried. Yield: 30.6 %, mp 191-194. C.

1H wake up R (CDC1 ₃ , 300MHz): δ 1.67 (d, 3H, CH ₃ ), 3.43 (m, 12H, N(CH ₃ ) ₂ ), 5.21 (dd, IH, NCH), 7.72 (s, IH, -CH=N -), 7.79 (m, 4H, Ar-H), 9.36 (s, IH, NH), 12.23 (s, IH, NH) Example 2. 3-phthalimide-2-oxo Butyraldehyde bis(4-allyl)-3-aminothiourea (compound 2)

0.296 g (1.0 mmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction mixture gradually turned yellow. Add 1.5 mL of water, then add 1.5 mL of 95% ethanol to obtain a yellow transparent solution A; 0.262 g (2.0 mmol) 4-allyl-3-aminothiourea is dissolved in 1.8 mL of 80 ° C hot water, added to the solution A. Heating under reflux for 1 hour gradually formed a yellow precipitate. The reflux was stopped, cooled, suction filtered, and the precipitate was washed repeatedly with anhydrous ethanol to give a yellow precipitate which was dried under vacuum overnight to give Compound 2. Yield: 83.6 %, mp 184-186 ° C ₀ 1H NMR (CDC1 ₃ , 300 MHz): δ 1.74 (d, ₃ Η, CH ₃ ), 4.37 ( m, 4H, CH ₂ ), 5.34 (m, 5H, CH ₂ =C and NCH), 5.92 (m, 1H, C=CH) 7.39 (s, 1H, CH=N ), 7.79 (m, 4H, Ar-H ), 9.75 (s, 1H,-NH), 11.71 ( s, lH, -NH); MS (FAB): m/z 458 (M+l), 342, 327, 174. Example 3. 3-phthalimido-2-oxo-n-butyraldehyde bis(4-isopropyl)-3-aminothiourea (compound 3)

 0.296 g (1.0 mmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow. Add 1.5 mL of water, then add 1.5 mL of 95% ethanol to obtain a yellow transparent solution A; 0.266 g (2.0 mmol) of 4-isopropyl-3-aminothiourea is dissolved in 1.5 mL of 80 ° C hot water, added to the solution A. After heating under reflux for 1 hour, a precipitate gradually formed. The reflux was quenched, cooled, and 25 mL of water was added and filtered. The crude product was dissolved in 1 mL of chloroform and purified by silica gel column chromatography eluting with chloroform and ethyl acetate. The main spot was collected, concentrated, and dried to give the desired product. Yield: 18.5%, mp 110-114 °C.

1H MR (DMSO-d ₆ , 300MHz): δ 1.21 (m, 12H, C(CH ₃ ) ₂ ), 1.62 (d, 3H, CH ₃ ), 4.39 (m, 2H, CH(Me) ₂ ), 5.46 (dd, 1H, NCH), 7.86 (m, 4H, Ar-H), 7.66 (s, 1H, -CH=N-), 11.56 (s, 2H, -NH) c Example 4. 3-indoleyl Imino-2-oxo-n-butyraldehyde bis-[4-(4-bromophenyl)-3-aminothiourea] (Compound 4)

0.296 g (1.0 mmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow. Add 1.5 mL of water, then add 1.5 mL of 95% ethanol to obtain a yellow clear solution A; 0.492 g (2.0 mmol) of 4-(4-bromophenyl)-3-aminothiourea is dissolved in 10 mL of 95% ethanol. Add to solution A. The mixture was heated under reflux for 4 hours to gradually form a precipitate. The reflux was stopped, cooled, filtered, and a yellow precipitate was obtained. The crude product was dissolved in a small amount of chloroform, and subjected to column chromatography, eluting with a gradient of petroleum ether and ethyl acetate. The main spot was collected, the solvent was evaporated, and dried to give the desired product. Yield: 20.2 %, mp l 78-182 ° C. 1H NMR (DMSO-d ₆ , 300 ΜΗζ): δ 1.71 (d, 3 Η, C3⁄4), 5.66 (dd, 1H, NCH), 7.58 (m, 8H, Ar-H), 7.70 (m, 4H, Ar-H ), 8.03 (s, 1H, -CH=N-), 9.84 (s, 2H, =NNH-) , 12.03 (d, 2H, -NH -). Example 5. 3-phthalimido-2-oxo-n-butyraldehyde bis-[4-(3,4-dichlorophenyl)-3-aminothiourea] (Compound 5)

 0.296 g (1.0 mmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO, and placed at 30 Torr for 2 days, and the reaction mixture gradually turned yellow. Add 1.5 mL of water, then add 1.5 mL of 95% ethanol to obtain a yellow clear solution A; 0.472 g (2.0 mmol) of 4-(3,4-dichlorophenyl)-3-aminothiourea is dissolved in 5 mL of ethanol. , added to solution A. Heating under reflux for 2 hours gradually formed a yellow precipitate. The reflux was quenched, rotary evaporated to dryness without ethanol, suction filtered, and the precipitate was washed with water to give a yellow precipitate, which was dried overnight in vacuo to give crude material. The crude product was washed repeatedly with dichloromethane, and the residue was evaporated to give the desired product of EtOAc (yield: 40.6 %, mp 200-204 ° C).

lR NMR (DMSO-d ₆ , 400MHz): δ 1.71 (d, 3H, CH ₃ ), 5.66 (dd, 1H, NCH ), 7.79-7.8 l(m, 6H, Ar-H), 7.83 (m, 4H , Ar-H), 8.04 (s, 1H, -CH=N-), 9.97 (s, 2H, =NNH-), 12.15 (d, 2H, -NH-) o Example 6. 3-decanoyl Amine-2-oxo-n-butyraldehyde bis-[4-(2-fluorophenyl)-3-aminothiourea] (Compound 6)

 0.296 g (1.0 mmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow. Add 1.5 mL of water, then add 1.5 mL of 95% ethanol to obtain a yellow transparent solution A; 0.370 g (2.0 mmol) of 4-(2-fluorophenyl)-3-thiosemicarbazide was added to 4 mL of 95% ethanol, heated After dissolution, it is added to the solution A. The mixture was heated under reflux for 2 hours to gradually form a precipitate. The reflux was stopped, cooled, filtered, and dried with a red-brown, and dried under vacuum overnight. The crude product was recrystallized from 95% ethanol and dried to give the desired product. Yield: 40.2%, mp 180-184 °C.

_{^{! H NMR (DMSO-d 6}} , 400MHz): δ 1.70 (d, 3H, C¾), 5.64 (dd, 1H, NCH), 7.40 (m, 8H, Ar-H), 7.79 (m, 4H, Ar- H), 8.06 (s, 1H, -CH=N-), 9.41, 9.65 ( s, 2H, =NNH- ) , 12.03-12.13 (d, 2H, -NH-) o Example 7. 3-decanoyl Imine-2-oxo-n-butyraldehyde bis [4-(4-fluorophenyl)-3-aminothiourea] (Compound 7)

 0.296 g (1.0 mmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow. Add 1.5 mL of water, then add 1.5 mL of 95% ethanol to obtain a yellow transparent solution A; 0.370 g (2 mmol) of 4-(4-fluorophenyl)-3-thiosemicarbazide was added to 4 mL of 95% ethanol, dissolved by heating. It is then added to solution A. The mixture was heated under reflux for 2 hours to gradually form a precipitate. The reflux was stopped, cooled, filtered, and dried with orange-brown. The crude product was washed successively with chloroform and methanol, and dried to give the objective product. Yield: 21.5 %, mp 206-210 ° C.

1H MR (DMSO-d ₆ , 400ΜΗζ): δ 1.71 (d, 3H, C3⁄4), 5.65 (dd, 1H, NCH), 7.21-7.58 ( m, 8H, Ar-H), 7.84 (m, 4H, Ar -H), 8.03 (s, 1H, -CH=N-), 9.78(d, 2H, =NNH-) _? 11.98 (d, 2H, -NH -).

Example 8. 3-phthalimido-2-oxo-n-butyraldehyde bis-[4-(4-chlorophenyl)-3-aminothiourea] (Compound 8)

 0.296 g (lmmol) of 3-phthalimide-1-bromobutanone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow. The pressure was 1.5 mL 7j, then 1.5 mL 95% ethanol was added to obtain a yellow transparent solution A; 0.403 g (2 mmol) 4-(4-chlorophenyl)-3-thiosemicarbazide was added to 9 mL of 95% ethanol. After heating, it was added to the solution A. The mixture was heated under reflux for 2 hours to gradually form a precipitate. The reflux was stopped, cooled, filtered, and dried over orange-yellow, dried under vacuum overnight to give crude material. The crude product was dissolved in a small amount of chloroform, and subjected to column chromatography, eluting with a gradient of petroleum ether and ethyl acetate. The main spot was collected, and the solvent was evaporated to give the desired product. Yield: 20.2%, mp 145-150 °C.

实施例 9. 3-酞酰亚胺 -2-氧代正丁醛双缩【4-(3，5-双三氟甲基苯基) -3-氨基硫脲】（化合 物 9)

1H NMR (DMSO-d ₆ , 400 ΜΗζ): δ 1.72 (d, 3H, CH ₃ ), 5.66 (dd, 1H, NCH), 7.45-7.74 (m, 8H: Ar-H), 7.76 (m, 4H, Ar-H), 8.03 (s, 1H, -CH=N-), 9.85(d, 2H, = NH-), 12.03(d,

Example 9. 3-phthalimido-2-oxo-n-butyraldehyde bis-[4-(3,5-bistrifluoromethylphenyl)-3-aminothiourea] (Compound 9)

 0.296 g (1.0 mmol) of 3-phthalimide bromobutyl ketone was dissolved in 1.5 mL of DMSO and allowed to stand at 30 ° C for 2 days, and the reaction solution gradually turned yellow. Force B into 1.5 mL 7K, then add 1.5 mL of 95% ethanol to obtain a yellow transparent solution A; 0.606 g (2.0 mmol) 4-(4-3,5-bistrifluoromethylphenyl)-3-aminosulfide Urea was added to 4 mL of 95% ethanol, dissolved by heating, and added to Solution A. The mixture was heated under reflux for 2 hours to gradually form a precipitate. The reflux was stopped, cooled, suction filtered, and a red-yellow precipitate was obtained, which was dried overnight in vacuo to give crude material. The crude product was dissolved in a small amount of chloroform, and purified by column chromatography, eluting with a gradient of petroleum ether and ethyl acetate. The main spot was collected, the solvent was evaporated, and dried to give the desired product. Yield: 42.6 %, mp 196-200. C.

1H NMR (DMSO-d ₆ , 400MHz): δ 1.73 (d, 3H, CH ₃ -), 5.66 (dd, 1H, NCH), 8.02-8.47 ( m, 6H, Ar-H), 7.77 (m, 4H , Ar-H), 8.61 (s, 1H, -CH=N-), 9.75 (s, 1H, = NH-) , 10.05 (d, 1H, = NH-) , 10.34 (s, 1H, -NH- ), 12.32 (s, 2H, -NH -). Example 10. l-[4-(3-Methoxyphenyl)piperazine small group 1-3-phthalimide-2-butanone (Compound 10)

 1-(2-methoxyphenyl)piperazine hydrochloride 114.36 mg (0.5 mmol), bromoketone 207.3 mg (0.7 mmol),

NaHC0 ₃ 117.6 mg (1.4 mmol) and 6 mL of ethanol were added to a 50 mL round bottom flask, and the mixture was heated and refluxed for 6 h. The heating was stopped and stirred overnight. The solution was brown-yellow turbid. Rotate and dry to a crude product. The crude product was dissolved in propylene and filtered. The filtrate was applied to a silica gel column eluting with petroleum ether and acetone. The main spot was collected, concentrated, and dried. Yield: 44.6 %, mp 120-122 ° C.

1H NMR (DMSO-d ₆ , 400 ΜΗζ): δ 1.52 (d, ₃ Η, CH ₃ -), 2.4 l (m, 4H, C3⁄4 of the piperazine ring), 2.82 (m, 4H, CH _{2 of the} piperazine ring) , 3.30 (dd, 2H, CO-CH ₂ -) , 4.99 (dd, 1H, NCH), 6.89 (m, 4H, Ar-H), 7.88 (m, 4H, Ar-H). Example 11 L-[4-(4-Chlorophenyl)piperazin-1-yl]-3-phthalimido-2-butanone (Compound 11)

Add 1-(4-chlorophenyl)piperazine dihydrochloride 134.8 mg (0.5 mmol), bromoketone 207.3 mg (0.7 mmol), NaHC0 ₃ 117.6 mg (1.4 mmol), ethanol 6 mL to 50 mL round bottom In the flask, the mixture is heated to reflux Stir for 6 h, stop heating, stir overnight, and the solution was dark brown turbid. Rotate and dry to a crude product. The crude product was dissolved in acetone, filtered, and the filtrate was applied to a silica gel column eluting with petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried. Yield: 32.1 %, mp 105-109 ° C.

1H NMR (DMSO-d ₆ , 400 ΜΗζ): δ 1.22 (d, 3H, CH ₃ -) ₅ 2.41 (m, 4H, C3⁄4 of the piperazine ring), 2.99 (m, 4H, CH _{2 of the} piperazine ring), 3.30 (dd, 2H, CO-C3⁄4-), 4.98 (dd, 1H, NCH), 6.89-7.19 (m, 4H, Ar-H), 7.88 (m, 4H, Ar-H). Example 12. l -[4-(3-chlorophenyl)piperazin-1-yl1-3-phthalimido-2-butanone (Compound 12)

Add 1-(3-chlorophenyl)piperazine 98.5 mg (0.5 mmol), bromoketone 207.3 mg (0.7 mmol), NaHC0 ₃ 117.6 mg (1.4 mmol) ethanol 6 mL to a 50 mL round bottom flask, mixture The mixture was heated under reflux for 6 h, the heating was stopped, and the mixture was stirred overnight, and the solution was dark brown turbid. Rotate and dry to a crude product. The crude product was dissolved in chloroform, filtered, and the filtrate was applied to a silica gel column eluting with petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried. Yield: 30.6 %, mp 142-146 ° C.

1H NMR (DMSO-d ₆ , 400 ΜΗζ): δ 1.51 (d, 3H, CH ₃ -), 2.38 (m, 4H, C3⁄4 of the piperazine ring), 3.04 (m, 4H, CH _{2 of the} piperazine ring), 3.28 (dd, 2H, CO-CH ₂ -), 4.98 (dd, 1H, NCH), 6.76-7.19 ( m, 4H, Ar-H), 7.90 (m, 4H, Ar-H). Example 13 L-[4-(4-Fluorophenyl)piperazin-1-yl]-3-indolimide-2-butanone (Compound 13)

Add 1 -(4-fluorophenyl)piperazine dihydrochloride 134.8 mg (0.5 mmol), bromoketone 207.3 mg (0.7 mmol), NaHC0 ₃ 117.6 mg (1.4 mmol), ethanol 6 mL to 50 mL round bottom In the flask, the mixture was heated under reflux for 6 h, the heating was stopped, and the mixture was stirred overnight, and the solution was dark brown turbid. Rotate the steam to get a crude product. The crude product was dissolved in acetone, filtered, and the filtrate was applied to a silica gel column eluting with petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried. Yield: 32.1 %, mp 180-185 ° C.

1H NMR (DMSO-d ₆ , 400 ΜΗζ): δ 1.51 (d, 3H, CH ₃ -), 2.08, 2.14 (s, 6H, Ar-CH ₃ ), 2.99 (m, 4H, CH _{2 of the} piperazine ring), 3.30 (dd, 2H, CO-CH ₂ -), 4.98 (dd, 1H, NCH), 6.89-7.19 ( m, 4H, Ar-H), 7. 88 (m, 4H, Ar-H). Example 14. l-[4-(3,4-Dimethyl)piperazine small group] -3-phthalimido-2-butanone (Compound 14)

Add 1 -(3,4-dimethyl-phenyl)piperazine 95 mg (0.5 mmol), bromoketone 207.3 mg (0.7 mmol), NaHC0 ₃ 117.6 mg (1.4 mmol), and ethanol 6 mL to 50 mL round In the bottom flask, the mixture was heated under reflux and stirred for 8 h, the mixture was stirred and stirred overnight and the solution was brown. Rotate and dry to a crude product. The crude product was dissolved in 1 mL of chloroform. Yield: 32.1 %, mp 220-223 ° C.

1H NMR (DMSO-d ₆ , 400 ΜΗζ): δ 1.52 (d, 3H, CH ₃ -), 2.40 (m, 4H, CH _{2 of the} piperazine ring), 2.93 (m, 4H, CH _{2 of the} piperazine ring) , 3.30 ( dd, 2H, CO-CH ₂ -) , 4.98 (dd, 1H, NCH), 6.56-6.92 (m, 3H, Ar-H), 7.88 (m, 4H, Ar-H). Example 15. l-[4-(4-Fluorophenyl)-3-aminothiourea small group]-3-phthalimido-2-butanone (Compound 15)

4-(4-Fluorophenyl)-3-thiosemicarbazide 20 mg (0.1 mmol), bromone 48 mg (0.16 mmol), NaHC0 ₃ 30 mg (0.36 mmol), I 18 mg (0.1 mmol), acetonitrile 5 mL Add to a 50 mL round bottom flask and stir the reaction mixture at room temperature for 1 h. Rotate to dryness, dry residue on a column, elute with a gradient of petroleum ether and ethyl acetate, collect the main spot, concentrate, and dry. Yield: 69.4%, mp l65-168 °C.

1H NMR (CDC1 ₃ , 400ΜΗζ): δ 1.79 (d, 3Η, CH ₃ ), 3.35 (dd, 2H, CH ₂ ), 5.23 ( q, 4H, CH ), 6.85 (d, 2H, Ar-H), 6.95 (d, 2H, Ar-H), 7.69-7.77 (m, 2H, Ar-H), 7.84-7.89 (m, 2H, Ar-H), 8.8 (s, ΙΗ, 丽). Example 16. 1-[4-(4-Chlorophenyl)-3-aminothiourea-1-yl -3-phthalimido-2-butanone (Compound 16)

4-(4-Chlorophenyl)-3-thiosemicarbazide 40 mg (0.2 mmol), bromoketone 88 mg (0.3 mmol), NaHC0 ₃ 75 mg (0.75 mmol). KI 50 mg (0.3 mmol)^ acetonitrile 5 mL Add to a 50 mL round bottom flask and stir the mixture for 2 h at room temperature. The mixture was evaporated to dryness, and the residue was applied to dry crystals eluted eluting with EtOAc EtOAc Yield: 31.5 %, mp l 30-133 ° C.

1H NMR (CDC1 ₃ , 400MHz): δ 1.75 (d, 3H, CH ₃ ), 3.34 (dd, 2H, CH ₂ ), 5.23 (q, 4H, CH), 6.85 (d, 2H, Ar-H), 7.24(d, 2H, Ar-H), 7.45-7.77(m, 2H, Ar-H), 7.85-7.88(m, 2H, Ar-H), 8.8 (s, IH, - NH). Example 17. 1-[4-(4-Bromophenyl)-3-aminothiourea-1-yl]-3-indolimide-2-butanone (Compound 17)

4-(4-Bromophenyl)-3-thiosemicarbazide 40 mg (0.16 mmol), bromone 72 mg (0.24 mmol), NaHC0 ₃ 60 mg (0.6 mmol) > KI 30 mg (0.2 mmol), acetonitrile 5 mL Add to a 50 mL round bottom flask and stir the mixture at room temperature for 1.5 h. The mixture was evaporated to dryness, and the residue was applied to dry crystals, eluted eluting with petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried. Yield: 28.0%, mp 137-140

1H NMR (CDC1 ₃ , 400MHz): δ 1.75 (d, 3Η, CH ₃ ), 3.35 (dd, 2H, CH ₂ ), 5.23 ( q, 4H, CH ), 6.8 l(d, 2H, Ar-H) , 7.39 (d, 2H, Ar-H), 7.45-7.77 (m, 2H, Ar-H), 7.85-7.88 (m, 2H, Ar-H), 8.8 (s, lH, -NH Example 18. L-[4-(3,5-Bistrifluoromethylphenyl)-thiosemicarbazide-1-yl]-3-indolimide-2-butanone (Compound 18)

4-(3,5-bistrifluoromethylphenyl)-3-thiosemicarbazide 55 mg (0.18 mmol), bromone 81 mg (0.27 mmol), NaHC0 ₃ 70 mg (0.75 mmol), KI 50 mg ( 0.3 mmol), 5 mL of acetonitrile was added to a 50 mL round bottom flask, and the mixture was stirred at room temperature for 3 h. The mixture was evaporated to dryness, and the residue was applied to dry crystals, eluted eluting with petroleum ether and ethyl acetate. The main spot was collected, concentrated, and dried. Yield: 88.3 % (oil)

1H Li R (CDC1 ₃ , 400MHz): δ 1.76 (d, 3H, CH ₃ ), 3.41(dd, 2H, CH ₂ ), 5.24 ( q, 4H, CH ), 7.39(s, IH, Ar-H) , 7.60 (s, IH, Ar-H), 7.45-7.78 (m, 3H, Ar-H), 7.87-7.89 (m, 2H, Ar-H), 8.8 (s, lH, -NH Example 19.3 - Indole-2-oxo-n-butyraldehyde bis-[l-(4-oxo-4,5-dihydrothiazol-2-yl)indole] (Compound 19)

TDA 380 mg (1 mmol), chloroacetic acid 200 mg (2.1 mmol), NaOAc 200 mg (2.4 mmol), and ethanol 15 mL were added to a 50 mL round bottom flask and heated to reflux for 8 h. After cooling, the product was poured into 100 mL of water. Filtration, washing with water, drying, and the product was purified by column chromatography, eluting with petroleum ether and ethyl acetate, and the main spot was collected, concentrated, and dried. Yield: 32.6 °/o, mp 282-284 °C.

1H NMR (CDC1 ₃ , 400MHz): δ 1.74 (d, 3H, CH ₃ ), 3.78-3.89 (m, 4H, CH ₂ ), 5.42 (q, 4H, CH ): 7.79-7.87 (m, 4H, Ar -H), 8.56 (s, 1H, -CH=N-), 12.06 (m, 2H, -NH). Example 20. 3-phthalimido-2-oxo-n-butyraldehyde bis-[l-(5-phenylthiazol-2-yl)anthracene] (Compound 20)

 TDA 380 mg (1 mmol), 2-bromoacetophenone 450 mg (2.3 mmol), NaOAc 500 mg (6.1 mmol), and ethanol 25 mL were added to a lOO mL round bottom flask, and the mixture was heated to reflux for 7 h. After cooling, the product was poured into lOOmL of water, filtered, washed with water and dried. The product was separated by column chromatography eluting with a gradient of petroleum ether and ethyl acetate. The main spot was collected, concentrated and dried. Yield: 34.6 %, mp l 39-142 ° C.

1H NMR (CDC1 ₃ , 400MHz): δ 1.74 (d, 3H, CH ₃ ), 5.39 (q, 4H, CH), 7.28-7.4 l (m, 8H, Ar-H), 7.82-7.90 (m, 8H , Ar-H), 8.04 (s, 1H, -CH=N-), 12.26 (s, 1H, -NH), 12.51 (s, 1H, -NH). Example 21. 3-(2-Phenylformylbenzamide)-2-oxo-n-butyraldehyde bis-thiosemicarbazone (Compound 21)

 TDA 380 mg (1.0 mmol), 85% 7j combined with 10 drops, and 25 mL of methanol were added to a 100 mL round bottom flask, and the mixture was stirred at room temperature for 1 h. Filter and rinse with dichloromethane to give a pale yellow solid. Yield: 48.8 %, mp 198-201 ° C.

1H NMR (CDC1 ₃ , 400MHz): δ 1.37 (d, ₃ Η, CH ₃ ), 4.37 (s, 2H, NH ₂ ), 5.17 ( m, 4H, CH ), 7.41-7.48 (m, 4H, Ar-H ), 7.68 (s, 1H, -NH), 7.85 (s, 1H, -CH=N-), 8,19 (s, 1H, -NH), 8.48 (s, 1H, -NH), 8.58 (m) , 2H, NH ₂ ) , 9.52 (s, 1H, -NH), 11.36 (s, 2H, NH ₂ ). Pharmacological experiment

Experimental example 1. In vitro screening experiment

1. Materials and methods

 1.1 Cells: Vero cells (African green monkey kidney) This room is subcultured by itself.

1.2 Virus: HSV-1 (VR733), HSV-2 (SAV) 1.3 reagents, laboratory supplies and instruments

 1.4 Reagents: Eagles MEM dry powder, American GIBCO company products; Newborn bovine serum, Tianjin Chuanzhan Biochemical Products Co., Ltd.; sodium bicarbonate, Tianjin Amino Acid Company People's Pharmaceutical Factory; penicillin, streptomycin and kanamycin are North China Pharmaceutical factory products.

1.5 Experimental supplies and instruments: Culture flasks, produced by Jiangsu Jiangyin Science and Technology Glass Instrument Factory; culture plate 96-well plate, American Costa products; carbon dioxide incubator, US MALLINCKRODT products.

1.6 Cell culture medium and reagent preparation 100 mL of MEM medium: 10% of newborn bovine serum, 100 U/mL of glutamine, penicillin, streptomycin, and kanamycin, NaHC0 ₃ 5%; cell digestive juice: 0.25 % trypsin, formulated with Hanks' solution, 0.02% EDTA.

2. Experimental methods

Add 0.25% trypsin 0.2 mL, 0.02% EDTA 4 mL in a cell-filled flask, digest for 20-25 minutes at 37 °C, discard the digestive juice, add the culture solution, pass 1:3, over 3 days, prepare 20 to 300,000 cells per ml were inoculated into a 96-well cell culture plate, 0.1 mL per well, cultured at 37 ° C, 5% CO _{2 for} 24 hours, and the cells were grown into a single layer and then tested. The cells are overgrown with a single layer, the culture medium is discarded, and the appropriate amount of virus is added. After adsorption for 1-1.5 hours, the virus solution is discarded, and the culture solution containing the diluted drug at different concentrations is added, and the virus control group is set at 37 ° C, The cells were cultured in a 5% C0 ₂ incubator. When the virus control group reached 4 plus signs, the cell lesions were observed. Three wells of the cell control wells were set in each experiment. The results were calculated using the Reed-Muench method to calculate the half effective concentration IC ₅ o.

50 ― <50% percent inhibition (B)

IC ₅₀ = Antilog (B + C)

 >50% percent inhibition (A) - <50% percent inhibition (B)

A=log>50% drug concentration B=log<50% drug concentration C=log dilution factor

3. Experimental results

 Table 1 In vitro anti-HSV-1 activity of some butyl butyl derivatives

Compound TD ₅₀ ( g/mL) TD ₀ (|ig/mL) IC ₅₀ ( g/mL) SI ^a

 4 111.11 37.03 21.37 >5.20

7 64.15 37.03 8.56 7.49

8 77.04 37.03 2.85 27.03

9 53.41 12.34 >12.34 -

11 384.86 222.22 222.22 1.73

12 462.24 222.22 >222.22

13 1154.59 666.67 666.67 1.73 TDA 384.9 222.22 95.44 4.03

ACV ^b 0.998 - a.SI = TD ₅ o/IC ₅₀ ; b AC V: in vitro anti-HSV-2 activity of acyclovir

4.结论

4 Conclusion

 Preliminary results of in vitro antiviral experiments showed that the antiviral activity of derivatives 4, 7, 8, 9 was significantly better than that of 酞丁安, and the antiviral (HSV-2) activity of compounds 7, 8 was higher than that of acyclovir. Experimental Example 2. In vivo antiviral test

Test material

 1.1 drugs

 4-C1-TDA Cream (Compound 8),

 Formulation amount: 0.1g10g, 0.05g/10g, 0.025g/10gc

 1.2 blank matrix

 Cream base

 1.3 reference drug (1): 酞丁安Ointment, batch number: 060304.

 Provided by: Beijing Xiehe Pharmaceutical Factory.

 Formulation amount: 0.1 g/10 g.

 1.4 reference drug (2): acyclovir gel, trade name: Love, batch number: 060321.

 Provided by: Jiangsu Shengbaoluo Pharmaceutical Co., Ltd.

 Formulation amount: 0.1 g/10 g. .

 1.5 cells

 Type 3.2.1: Vero cell line.

3.2.2 Provided by: Cell Bank of Shanghai Institute of Cell Biology, Chinese Academy of Sciences. 1.6 virus

 3.3.1 type, strain: HSV-1 type quality control strain (Sm44 strain).

 3.3.2 Provided by: Ministry of Health Biological Products and Drug Control Institute.

1.7 animals:

 3.4.1 Species, strains, sources, permits: Albino guinea pigs, Tangshan Qinglongshan animal breeding ground in Jiangning District, Nanjing,

SCX (Su) 2002-0004.

 3.4.2 Weight: 230~280(g)

 3.4.3 Gender: ? Half.

 3.4.4 Number of animals in each group: 4 to 5 in each group.

 experiment method

 Type 2.1: In vivo test.

 2.2 Contents: After guinea pig skin infection HSV-1, topical treatment with different concentrations of 4-F-TDA cream, the drug efficacy was judged by scoring method. Treated with Weidingan ointment and acyclovir gel as a control drug.

 Dosage setting and administration method

3.1 Test drug: 4-C1-TDA cream.

 3.1.1 Concentration group: Set 3 concentration groups, namely O.lg/lOg (large concentration) group, 0.05g/10g (medium concentration) group-,: 0.025g/10g (small concentration) group.

 3.1.2 Routes and methods of administration: Topically apply the drug to the lesion. 2 times a day for 7 consecutive days.

 3.1.3 The test was set up as a matrix control group, and the application method was the same as that of the test drug group.

3.2 Reference drug: 酞丁安膏膏 and acyclovir gel.

 3.2.1 Concentration group: Test setting One concentration group was used as a control, both of which were 0.1g/10g group.

 3.2.2 Routes and methods of administration: Topically apply the drug to the lesion. 2 times a day for 7 consecutive days.

 The main steps

 .1 Preparation for inoculation of virus solution: Vero cells were used for routine culture in vitro, and obtained after 23 hours of exposure.

 For the virus solution, the TCID50 was measured to be 6.02.

 4.2 In vivo antiviral test: The skin on both sides of the back of the guinea pig is shaved (p4cm, broken. 0.1 ml of virus solution is inoculated on each side of d0. After inoculation of the virus for about 1 hour, each test substance or reference drug is administered locally according to the setting scheme. At the same time, the virus model control group (no drug control group) and the blank control group were set up. The lesions were observed and recorded day by day.

4.3 Observation indicators: There are erythema, redness, blisters, induration, erosion and crusting after the virus inoculation site. Judging method

 5.1 Skin disease scores for drug antiviral tests

 0: Normal, no lesions.

 0.5: Reddish.

 1 : erythema, redness, or scarring with skin lesions.

2: The erythema is enlarged, red and swollen, or has blisters, or scarring when the skin lesions subsided. 3: Severe redness, or bulging of the entire lesion, or induration, or with a face.

 4: The erythema, induration is severely enlarged, or with severe blisters or blemishes.

 5.2 Observation time: Continuous observation for 11 days, record the lesion scores on both sides of each animal.

 6. Calculation and statistical methods

 Using the Ridit analysis method, the cream matrix group and the virus model control group, the 4-F-TDA cream large, medium and small concentration groups and the matrix group, respectively, were determined by Ridit analysis. An ointment group and virus model control group, acyclovir gel and virus model control group, 4-F-TDA cream large, medium and small concentration group and Qidingan ointment group were compared.

 7. Test results

 7.1 From the results of the virus model control group, it can be seen that the incidence scores of d4 and d5 were the highest after infection, and began to decrease after d7~d8 days, and dl0~dll decreased to close to zero. The natural course is about 11 days. The results are shown in Table 1.

 7.2 Different concentrations of 4-C1-TDA cream and control drug Ding An ointment and acyclovir gel on guinea pigs

 The protective effects of testicular HSV-1 skin infection are shown in Table 1. Topical application of different doses of 4-F-TDA cream has a certain protective effect on skin lesions caused by HSV-1. After Ridit analysis, one of the highest time points of the disease score (d4) showed no significant difference between the matrix group and the virus model control group (>ft05). : The concentration of 4-C1-TDA cream (0.1g/10g) and medium concentration (0.05g/10g) was significantly different from that of the matrix group (all P<0.W), while the small concentration ( There was no difference between the 0.025 g/10 g) group and the matrix group (P>aft).

7.3 The control drug Ding'an ointment group did not show protective effect on skin lesions caused by HSV-1, and there was no significant difference (>ftO?) compared with the virus model control group. The inhibitory effect of the acyclovir gel group was significantly different from that of the virus model (control group) (P<0.01).

 7.4 Compared with the Qidingan ointment group, the concentration of the 4-C1-TDA cream group was significantly different from that of the Dingding ointment group (Ρ<(λΟ? and ?<0.05), while the concentration was small. There is no difference in the group.

 7.5 Although the statistical results show that there is no significant difference between the matrix group and the virus model group, it can be seen from the specific score values in Table 1, the grade distribution of the two component values is obviously different, and the excessive concentration of dimethyl sulfoxide in the matrix is presumed. May cause a pseudo-therapeutic effect. Moreover, excess dimethyl sulfoxide also showed mild skin irritation at a later stage.

 8. Preliminary conclusions:

 This test showed that the high- and medium-concentration 4-C1-TDA cream applied to the guinea pig skin infected with HSV-1 had a certain protective effect on skin lesions.

 Table 1 Different concentrations of 4-C1-TDA cream and control drug Ding An ointment and acyclovir gel

Protective effect on experimental HSV-1 skin infection in guinea pigs Score value of skin lesions per day after infection with virus, skin lesions d3 d4 d5 d6 d7 d8 d9 dlO dll

 0 0 0 0 0 0 0 3 6-C1-TDA group 0.5 0 0 0 0 0 1 5 5 2

(0.1g/10g) 4/8 1 6 8 8 8 8 7 3 0 0

 2 2 0 0 0 0 0 0 0 0

(large concentration group) 3 0 0 0 0 0 0 0 0 0

 4 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 1 4 8-C1-TDA group 0.5 0 0 0 0 0 1 3 6 2

(0.05g/10g) 5/10 1 5 8 6 6 10 9 6 0 0

 2 5 2 4 4 0 0 0 0 0

(medium concentration group) 3 0 0 0 0 0 0 0 0 0

 4 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 1 4 7-C1-TDA group 0.5 0 0 0 0 0 2 5 4 1

(0.025g/10g) 4/8 1 2 4 6 6 8 6 2 0 0

 2 6 4 2 2 0 0 0 0 0

(small concentration group) 3 0 0 0 0 0 0 0 0 0

 4 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 1 7 8

0.5 0 0 0 0 0 5 7 1 0 Cream base set 4/8 1 3 0 3 4 7 3 0 0 0

 2 5 8 5 4 1 0 0 0 0

3 0 0 0 0 0 0 0 0 0

4 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 1 3 6

0.5 0 0 0 0 0 2 2 4 2 酞丁安膏 group 4/8 1 0 1 2 2 8 6 5 1 0

(O.lg/lOg) 2 8 7 6 6 0 0 0 0 0

 3 0 0 0 0 0 0 0 0 0

4 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 1 Acyclovir 0.5 0 0 0 0 0 0 8 8 7 Gel group 4/8 1 8 7 7 7 8 8 0 0 0

(0.1g/10g) 2 0 1 1 1 0 0 0 0 0

 3 0 0 0 0 0 0 0 0 0

4 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0

0.5 0 0 0 0 0 0 0 7 8 Virus Model 4/8 1 0 0 0 4 4 8 8 1 0 Control 2 8 5 4 1 4 0 0 0 0

 3 0 3 4 3 0 0 0 0 0

4 0 0 0 0 0 0 0 0 0 Table 2 Comparison of Ridit analysis results of d4 scores in guinea pig skin infected with HSV-1 compared with virus model control group and stromal group compared with 酞丁安Ointment group

(n) u value corpse value u value P value u value P value

4-C1-TDA

 3.4669 ≤0.01 3.03 <0.01 large concentration group

 4-C1-TDA 2.92 ≤0.01 2.47 <0.05 medium concentration group

 4-C1-TDA 1.73 >0.05 1.30 >0.05 small concentration group

 Matrix group 0.243 >0.05

酞丁安膏膏 1.57 >0.05

 Acyclovir 2.75 <0.01

 Gel group

 Virus model

 Control group Note: Ridit analysis, u<1.96, p>0.05; u≥1.96, p≤0.05; u>2.58, p<0.01

Claims

Claims 1. A compound of the formula (I)

Wherein RBR _{r is} independently selected from the group consisting of hydrogen, d- ₈ fluorenyl, halogenated d- ₈ fluorenyl, aryl substituted d- ₈ alkyl, allyl, _-s decyl substituted aryl, monohalogenated or poly A halogenated aryl group, a halogenated d- ₈ fluorenyl substituted aryl group, an amino substituted aryl group, an ammonia- ₈ alkyl group substituted aryl fluorene, but, and cannot be simultaneously hydrogen. 2. A compound according to claim 1, characterized in that and independently selected from the group consisting of -5 fluorenyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorobenzene , 6-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 4-fluoro-4- Chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-dibromo Phenyl, 3,5-dibromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 3, 5-bistrifluoromethylphenyl. 3. A compound of the formula (II)

Wherein R ₂ and independently are selected from the group consisting of hydrogen, C _r8 fluorenyl, halogenated C _r8 fluorenyl, and aryl. ^Alkyl, allyl, C decyl substituted aryl, monohalogenated or polyhalogenated aryl, halo- ₈ alkyl substituted aryl, amino substituted aryl, ammonia. ^Alkyl substituted aryl, but and cannot be hydrogen at the same time. The compound according to claim 3, wherein R ₂ and R _{2 are} independently selected from the group consisting of Q ₅ alkyl groups and alkenes. Claims propyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorophenyl, 6-fluorophenyl, 3,4-difluoro-based, 3,5-di Fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorobenzene Base, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 4-fluoro-4-chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3- Bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2-trifluoromethylphenyl, 3 -trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 3,5-bistrifluoromethylphenyl. a compound of the formula (III)

 (III) Wherein R _{3 is} selected from the group consisting of: hydrogen, halogen, Cw fluorenyl, 'Cw methoxy, halogenated d-5 alkyl, hydroxy, C alkyl COO, cyano, aldehyde, nitro, amino, carboxy, acyl Sulfhydryl, d. ₅ mercaptoalkyloxy, C alkyl alkoxycarbonylamino, .5 fluorenylaminomethyl. 6. A compound of the formula (IV)

 (IV) Wherein, selected from the group consisting of: hydrogen, halogen, d- ₅ alkyl, d. ₅ alkoxy, halogenated d- ₅ alkyl, hydroxy, d. ₅ fluorenyl COO, cyano, aldehyde, nitro, amino, carboxy , hydrazide group, d_ ₅ fluorenyl oxycarbonyl, C _1-5 fluorenyl oxyamino group, C succinyl aminomethyl group. 7. A compound of the formula (IV)

Wherein R _{5 is} selected from the group consisting of hydroxy, -8 alkyl, halo C _R8 fluorenyl, aryl substituted d- ₈ alkyl, allyl, _-8 alkyl substituted aryl, monohalogenated or polyhalogenated aryl And halogenated C _R8 fluorenyl substituted aryl, amino substituted aryl, amino d- ₈ alkyl substituted aryl. 8. A compound according to claim 7, characterized in that R _{5 is} selected from the group consisting of hydroxyl, CL ₅ fluorenyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 5-fluorobenzene , 6-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorophenyl, 6-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl, 4-fluoro-4- Chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromophenyl, 3,4-dibromo Phenyl, 3,5-dibromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-trifluoromethylphenyl, 3, 5-bistrifluoromethylphenyl. 9. A compound of the formula (VI)

 (VI) , and, independently selected from hydrogen, d- ₈ alkyl, halogenated Q- ₈ fluorenyl, aryl substituted- ₈ fluorenyl, allyl, C _R8 fluorenyl substituted aryl, monohalogenated or polyhalogenated a aryl group, a halogenated C ₈ alkyl substituted aryl group, an amino substituted aryl group, an amino d- ₈ alkyl substituted aryl group; Selected from hydrogen, halogen, lower alkyl, lower decyloxy, halogenated lower fluorenyl, hydroxy, RCOO, cyano, Aldehyde, nitro, amino, carboxy, hydrazide, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkylaminomethyl. 10. A compound according to claim 9, characterized in that R ₆ , and, independently selected from hydrogen, d. ₅ alkyl, allyl, 2-fluorophenyl, 3-fluorophenyl, 4- Fluorophenyl, 5-fluorophenyl, 6-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorobenzene , 5-chlorophenyl, 6-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorobenzene Base, 4-fluoro-4-chlorophenyl, 5-fluoro-4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromophenyl, 6-bromobenzene , 3,4-dibromophenyl, 3,5-dibromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-tri Fluoromethylphenyl, 3,5-bistrifluoromethylphenyl. 11. A compound according to claim 1 - 10 wherein said compound is selected from the group consisting of:  3-phthalimide-2-oxo-n-butyraldehyde bis(4,4-dimethyl)-3-aminothiourea

 3-phthalimide -2-oxo-n-butyraldehyde bis-(4-allyl)-3-aminothiourea

 3-phthalimide -2-oxo-n-butyraldehyde bis-(4-isopropyl)-3-aminothiourea

^3- -imide- ² -oxo-n-butyraldehyde bis-[4-(4-bromophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde bis-[4-(3,4-dichlorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde bis- [4-(2-fluorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyric acid bis [4-(4-fluorophenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyl ketone double-shrink [4-(4-chlorophenyl)-3-aminothiourea]

3-phthalimido-2-oxo-n-butyraldehyde bis-[4-(3,5-bistrifluoromethylphenyl)-3-aminothiourea]

 3-phthalimide -2-oxo-n-butyraldehyde mono- (4,4-dimethyl)-3-aminothiourea  3-phthalimide -2-oxo-n-butyraldehyde mono- (4-allyl)-3-thiosemicarbazide  3-phthalimide -2-oxo-n-butyraldehyde mono- (4-isopropyl)-3-aminothiourea  3-phthalimide-2-oxo-n-butyraldehyde monocondensation [4-(4-bromophenyl)-3-aminothiourea]  3-phthalimide-2-oxo-n-butyraldehyde monocondensation [4-(3,4-dichlorophenyl)-3-aminothiourea] 3-phthalimide -2-oxo-n-butyraldehyde monocondensation [4-(2-fluorophenyl 3-aminothiourea]  3-phthalimide -2-oxo-n-butyraldehyde monocondensation [4-(4-fluorophenyl)-3-aminothiourea]  3-phthalimide -2-oxo-n-butyraldehyde monocondensation [4-(4-chlorophenyl)-3-aminothiourea]  3-phthalimide-2-oxo-n-butyraldehyde monocondensation [4-(3,5-bistrifluoromethylphenyl)-3-aminothiourea] 1-[4-(3-methoxyphenyl)piperazin-1-yl]-3-indolimide-2-butanone

1-[4-(4-chlorophenyl)piperazin-1-yl]-3-indolimide-2-butanone

 1-[4-(3-chlorophenyl)piperazine small group]-3-phthalimide-2-butanone

L-[4-(4-Fluorophenyl)piperazin-1-yl]-3-indolimide-2-butanone

L-[4-(3,4-Dimethylphenyl)piperazine small group]-3-phthalimide-2-butanone

 1-[4-(4-fluorophenyl)-3-aminothiourea small group]-3-phthalimide-2-butanone

 1-[4-(4-chlorophenyl)-3-aminothiourea small group]-3-phthalimide-2-butanone

 1-[4-(4-bromophenyl)-3-aminothiourea small group]-3-phthalimide-2-butanone

1-[4-(3,5-bistrifluoromethylphenyl)-thiosemicarbazide] -3-phthalimido-2-butanone

3-phthalimido-2-oxo-n-butyraldehyde bis-[l-(4-oxo-4,5-dihydrothiazol-2-yl)anthracene]

3-phthalimido-2-oxo-n-butyraldehyde bis-[1-(5-phenylthiazol-2-yl)anthracene] , the preparation method of the compound (I):

 0-3 , the preparation method of the compound (II):

 , the preparation of compound (III):

III 15. Preparation method of compound (IV):

 IV  16. Preparation method of compound (V)

 17. Preparation method of compound (VI)

 IV  18. A pharmaceutical composition comprising a pharmaceutically effective amount of any of the compounds of any of claims 1-11, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition is a tablet, a capsule, a pill, an injection, a sustained release preparation, a controlled release preparation, and various microparticle administration preparations. 20. Use of a compound according to claims 1-11 for the preparation of a prophylactic and I or therapeutic antiviral drug. 21. Use according to claim 20, characterized in that said viral infection comprises herpes simplex virus type I and type II, herpes zoster virus, trachoma virus, condyloma acuminata, flat prion.