WO2003095435A1

WO2003095435A1 - Amide derivatives

Info

Publication number: WO2003095435A1
Application number: PCT/JP2003/005756
Authority: WO
Inventors: Toru Kontani; Junji Miyata; Wataru Hamaguchi; Yoji Miyazaki; Osamu Yamamoto; Hiroshi Suzuki; Kenji Sudo
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.; Rational Drug Design Laboratories
Priority date: 2002-05-09
Filing date: 2003-05-08
Publication date: 2003-11-20
Also published as: AU2003235889A1; AU2003235889A8

Abstract

Novel amide derivatives characterized in that, in an N-({[4-(substituted thiazol-4-yl)phenyl]carbamoyl}methyl)amide derivative, the N atom of the amide group is directly substituted by an aromatic ring group (an aryl or a heteroaryl group). Because of having an excellent anti-herpesvirus activity, these amide derivatives are useful as medicines and antiviral agents, in particular, preventives or remedies for various diseases from infection with viruses belonging to Herpesviridae, i.e., herpesvirus infections such as varicella (chicken pox) from infection with varicella-zoster virus, herpes zoster from recurrent infection with latent varicella-zoster virus, herpes labialis and herpes encephalitis from HSV-1 infection and herpes genitalis from HSV-2 infection.

Description

Specification

Amid inducer

Technical field

The present invention relates to a novel amide derivative or a salt thereof, which is useful for the prevention and treatment of a disease associated with a medicament, an antiviral agent, particularly a herpes virus such as varicella-zoster virus. Background art

Herpesviruses cause a variety of infections in humans and animals. For example, varicella zoster virus (VZV) causes varicella and shingles, and herpes simplex virus type-1 and -2; HSV-1 and herpes simplex virus type-2. HSV-2) is known to cause infectious diseases such as cold sores and genital herpes. In recent years, cytomegalovirus (CMV), EB virus (Epstein-Barr virus; EBV), and human herpesvirus 6, 7, 8 (human herpesvirus 6, 7,

Infectious diseases caused by herpes virus such as 8) have been clarified.

Currently, nucleic acid-based drugs such as acyclovir (ACV) and its prodrugs valacyclovir (VCV) and fancyclovir (FCV) are used as anti-herpesvirus drugs for VZV and HSV. These nucleic acid-based drugs are monophosphorylated to nucleoside monophosphate by viral thymidine kinase encoded by VZV or HSV, and then converted into triphosphates by cellular enzymes. Eventually, the triphosphorylated nucleoside analog is incorporated during the replication of the viral genome by Herpesvirus DNA polymerase, inhibiting the elongation of the viral DNA strand. Thus, the mechanism of action of existing anti-viral viruses is based on the “competitive inhibition” effect on deoxynucleoside triphosphates, so that high concentrations of drugs are required to exert antiviral effects. Is required. In fact, clinical dosages of these nucleic acid-based antiherpes drugs are currently in the range of hundreds of mg to several g per day. Furthermore, since nucleic acid-based drugs can be incorporated into host genomic DNA by the host DNA polymerase, their mutagenicity is a concern. —On the other hand, recently, several non-nucleic acid drugs that exhibit anti-herpesvirus activity have been reported. For example, W097 / 24343 discloses that an N atom represented by the following formula (G) having an anti-HSV-1 activity and an anti-CMV activity by suppressing an HSV helicase-primase enzyme complex, Amide or sulfonamide derivatives substituted by r-dilcal / dimethylmethyl group and the like are disclosed. However, there is no specific disclosure about the anti-VZV activity of these compounds. (G)

(Where R is hydrogen, lower alkyl, amino, lower alkylamino, etc., R ² is hydrogen or lower alkyl, Q is absent or methylene, R ³ is hydrogen, lower alkyl, etc., R ⁴ is unsubstituted or substituted. substituted phenyl (lower) alkyl, 1-Indaniru, 2- Indaniru, (lower consequent opening alkyl) - (lower alkyl), (Het) - (lower alkyl) or the like, R ⁵ is phenylalanine sulfonyl, 1- or 2 - naphthyl sulfonyl, (Het) - sulfonyl, (unsubstituted or substituted phenylene _{Honoré) -Y- (CH 2) nC (} 0), (Het) - (CH 2) nC (O) or the like, Y is 0 or S , N is 0, 1, 2. See the gazette for details.)

WO00 / 29399 also discloses an amide or sulfonamide derivative having an anti-HSV-1 activity and an anti-CMV activity, in which the N atom represented by the following formula (H) is substituted with a thiazolylphenylcarbamoylmethyl group, There is no specific disclosure about the anti-VZV activity of these compounds. (Η)

(Wherein R ¹ is NH ₂ , R ² is H, R ³ is H, R ⁴ is CH ₂ Ph, CH _2- (4-pyridyl), CH ₂ -cyclohexyl, etc., and R ⁵ is CO- (Substituted phenyl), CO- (unsubstituted or substituted heterocycle), etc. For details, refer to the official gazette.)

Recently, various viral virus protease inhibitors (Waxman Lloyd et al., 2000, Antiviral Chemistry and Chemotherapy, 11, 1-22), and HSV primase inhibitors. There are reports of N- (carbonylphenyl) benzamide derivatives (WO00 / 58270). However, there is no disclosure of compounds having good anti-VZV activity in these documents and patent publications.

There is an urgent need to create an anti-herbetic virus agent that has sufficient anti-VZV activity, is non-nucleic acid, has a small dose, and is highly safe. Disclosure of the invention

The present inventors have conducted intensive studies on compounds having an anti-varicella-zoster virus (anti-VZV) activity, and as a result, as shown in the following general formula (I), an amide group having an N atom substituted with a thiazolylphenylcarbamoylmethyl group. A novel amide derivative (including a sulfonamide derivative) is characterized in that an aryl or heteroaryl group which is an aromatic ring group as the group A is directly substituted without an alkylene chain at the N atom of They discovered that they have anti-VZV activity, and filed a patent application earlier (see WO2002 / 38554). Furthermore, as a result of diligent search for the best compound as an anti-VZV agent, the novel compound combining the specific substituents shown in the table below shows good antiviral activity even at low dose oral administration, and The present invention has been completed by finding that it can be a useful drug.

That is, the present invention relates to novel amide derivatives or salts thereof shown in the following table.

table 1

Furthermore, the present invention relates to a pharmaceutical composition comprising the compound of the present invention or a salt thereof and a pharmaceutically acceptable carrier, and an anti-herpesvirus agent, particularly an anti-VZV agent. Among the compounds of the present invention shown in Table 2, preferred compounds are shown below.

(No.1) N-({[4- (2-Aminothiazol-4-yl) phenyl] -lubamoyl} methyl) -N-benzo [b] Thiophene-5-yltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide or a salt thereof,

(Νο · 2) Ν-({[4- (2-Aminothiazol-4-yl) phenyl] l-rubamoyl} methyl) -Ν- (2,6-Dimethylphenyl) tedrahydro-2Η-thiopyran-4- 1,2-dioxoxide or its salt,

(Νο · 3) Ν-({[4- (2-Aminothiazol-4-yl) phenyl] pothambamoyl} methyl) -Ν- (4-Bromo-2-methylphenyl) 亍 trahydro-2Η-thiopyran- 4-force lipoxamide 1,1-dioxide or a salt thereof,

(Νο.6) Ν-({[4- (2-Aminothiazol-4-yl) phenyl] l-rubamoyl} methyl) -Ν- (2,4-dimethylphenyl) tetrahydro-2Η-thiopyran-4- Carboxamide 1,1-dioxide or a salt thereof,

(Νο.8) Ν-({[4- (2-Aminothiazol-4-yl) phenyl] -lumbamoyl} methyl) -Ν- (3-Methylbenzo [b] thiophen-5-yl) tetrahydro -2H-thiopyran-4-carboxamide 1,1-dioxide or a salt thereof,

(No.9) N-({[4- (2-Aminothiazol-4-yl) phenyl] l-rubamoyl} methyl) -N- (2,4,6-trimethylphenyl) tedrahydro-2H-thiopyran- 4-carboxamide 1,1-dioxide or a salt thereof,

(No.11) trans-N-({[4- (2-aminothiazol-4-yl) phenyl] -lumbamoyl} methyl) -N-benzofuran-5-yl-4-cyanocyclohexanecarpo Oxamide or a salt thereof,

(No.13) N-({[4- (2-Aminothiazol-4-yl) phenyl] pothambamoyl} methyl) good (2-coguchi-6-methylphenyl) tetradoro-2H-thiopyran -4-carboxamide 1,1-dioxide or a salt thereof, and

(No.14) N-({[4- (2-Aminothiazole-4-yl) phenyl j-rubamoyl} methyl) -4-cyano-N- (4-methoxyphenyl) cyclohexanecarbo Xaamide or a salt thereof.

The salt of the compound of the present invention is a pharmaceutically acceptable salt. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, etc. Is mentioned.

The compound of the present invention includes compounds having isomers, and the present invention includes a mixture of these isomers and an isolated isomer. The present invention further includes various hydrates, solvates and polymorphs of the compound of the present invention or a salt thereof. The compounds of the present invention also include all compounds that are metabolized in vivo and converted to the compounds of the present invention or salts thereof, so-called prodrugs. The group forming the prodrug of the present invention is described in Prog. Med. 5: 2157-2161 (1985). Groups that have been used.

(Manufacturing method)

A typical method for producing the compound of the present invention will be described below.

In the following production method, depending on the type of the functional group, it is necessary to replace the functional group with an appropriate protecting group at the stage of a raw material or an intermediate, that is, a group that can be easily converted to the functional group. May be effective. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like. Examples of such a protecting group include Protective Groups in Organic Synthesis, 3rd edition (TW Green and Ρ · G. Μ. Wuts, published by JOHN WLY & SONS, INC.), And these may be appropriately used depending on the reaction conditions. For the introduction and deprotection of the protecting group, the method described in the reference book can be applied as appropriate. First manufacturing method

The compound (I) of the present invention can be easily produced by subjecting a carboxylic acid compound (III) and a thiazolylphenyl derivative (II) to an amidation reaction.

The amidation reaction can be carried out by a conventional method, for example, the method described in The Chemical Society of Japan, "Experimental Chemistry Course_", 4th Edition (Maruzen), Vol. 22, p. 137 to 173. Preferably, a carboxylic acid compound The reaction can be carried out by converting (III) into a reactive derivative, for example, an acid halide (acid chloride or the like) or an acid anhydride, and then reacting it with a thiazolylphenyl derivative (II). When an acidic derivative is used, it is preferable to add a base (an inorganic base such as sodium hydroxide or an organic base such as triethylamine (TEA), diisopropylethylamine, pyridine, etc.). The acid is reacted with a condensing agent (such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1'-l-pyrrolbis-1H-imidazole (CDI), etc.) In this case, an additive such as 1-hydroxybenzotriazole (HOBt) may be added.The reaction temperature can be appropriately selected depending on the starting compound. Active solvents, for example, aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane and chloroform, N, N Examples include amide solvents such as N-dimethylformamide (DMF) and N, N-dimethylacetamide, and basic solvents such as pyridine, etc. The solvent is appropriately selected according to the type of the starting compound, etc., and may be used alone or in combination of two These are used as a mixture. Second manufacturing method

(In the formula, hal represents halogen. The same applies hereinafter.)

This production method is a method for obtaining a compound (I) of the present invention by subjecting an -halogenated ketone represented by the general formula (IV) to a cyclization reaction with a compound (V). This cyclization reaction can be carried out by a conventional method. For example, Tetrahedron Lett., 9, 24, 1959, and The Chemistry of Heterocyclic Compounds "Thiazole and its Derivatives 1, 2" (丄 V. Metzger: John Eiley & Sons).

Preferably, the reaction can be carried out by reacting the starting compound -halogenated ketone (IV) with the compound (V) in a solvent or without using a solvent under cooling or heating. As the solvent, preferably used are alcohol solvents such as methanol, ethanol and isopropanol, carbonyl solvents such as acetone and methyl ethyl ketone, ether solvents mentioned above, halogenated hydrocarbon solvents and amide solvents. be able to. These solvents are used alone or in combination of two or more. The solvent should be appropriately selected according to the type of the starting compound and the like. During the reaction, the reaction may proceed smoothly by adding a base (potassium carbonate, sodium carbonate, TEA, etc.).

Third manufacturing method

This production method is a method for obtaining the compound (I) of the present invention by subjecting the amine compound represented by the general formula (VI) and a carboxylic acid or a sulfone oxide compound (VII) to an amidation reaction. Amidation can be performed in the same manner as in the first production method. Production method of raw material compounds

Each of the above-mentioned raw material compounds can be easily produced by using a known reaction, for example, a reaction described in “Experimental Chemistry Course” edited by The Chemical Society of Japan (Maruzen). Hereinafter _c compounds exhibiting the typical preparation method cyclization of (II)

(II)

Preparation of compound (110

Preparation of compound (VI)

(In the formula, R represents a group capable of forming an ester residue such as lower alkyl and aralkyl, and P represents an amino-group-protecting group such as fluorenylmethoxycarbonyl (Fmoc).) The amidation can be carried out in the same manner as in the first production method, and the cyclization can be carried out in the same manner as in the second production method.

The N-alkylation of the compound (X) is carried out by a conventional method using an alkyl halide compound (XI), For example, it can be carried out by the method described in the above-mentioned “Experimental Chemistry Course”, 4th edition (Maruzen), Volume 20, pages 279 to 318. The reaction can be carried out under cooling or heating, and the solvent includes a solvent inert to the reaction, for example, a solvent exemplified in the amidation in the first production method. The reaction is preferably carried out in the presence of a base such as carbonated sodium, sodium hydroxide and sodium hydride. Deprotection for obtaining the carboxylic acid compound (III) can be carried out by appropriately applying a conventional method according to the kind of the ester. Preferably, an alkyl ester such as ethyl ester is treated with a base such as aqueous sodium hydroxide, and an aralkyl ester such as benzyl ester is treated with palladium monocarbon (Pd-C) under a hydrogen atmosphere. It can be done by reducing with. The reaction can be performed according to the method described in the above-mentioned Protective Groups in Organic Synthesis, 3rd edition.

The α-halogenated ketone compound (IV) can be synthesized by halogenating the acyl compound (XV) by a conventional method. Examples of the halogenating reagent include chlorine, bromine, iodine, copper (ll) bromide, potassium iodate, benzyltrimethylammonium tribromide, phenyltrimethylammonium tribromide, and tribromide. Tetrabutylammonium bromide, sulfuryl chloride, trimethylsilyl chloride, trimethylsilyl bromide, 5,5-dibromobarbituric acid, and the like.Examples of the solvent include solvents inert to the reaction, such as acetic acid. And acidic solvents such as hydrobromic acid / sulfuric acid, and the above-mentioned alcohol solvents and ether solvents. The reaction can be carried out under cooling or heating.

Deprotection to obtain the amine compound (VI) is carried out by a conventional method as appropriate depending on the type of the protecting group. For example, the method described in the above-mentioned Protective Groups in Organic Synthesis, 3rd edition, pages 503 to 572 can be applied.

In addition, depending on the type of the substituent, a desired starting compound can be produced by further subjecting to a substituent modification reaction well known to those skilled in the art.

The compound of the present invention thus produced can be isolated or purified as it is or by subjecting it to a salt-forming treatment by a conventional method. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography. The various isomers can be isolated by a conventional method utilizing the difference in the physicochemical properties between the isomers, and can be separated by, for example, fractional crystallization or chromatography. Further, by using an appropriate starting compound, only one isomer can be produced. Industrial applicability

The compound of the present invention has a good anti-VZV action, and is used as a drug, especially as a virus agent such as an anti-herpesvirus agent, for chickenpox (varicella) associated with VZV infection and shingles associated with recurrent infection of latent VZV. It is useful for prevention or treatment of

Further, since the compound of the present invention also has an activity of suppressing the replication of other herpesviruses (HSV-1, HSV-2, etc.), it is possible to prevent lip virus and herpes virus associated with HSV-1 infection. It can be applied to the prevention or treatment of various viral infections such as genital herpes associated with encephalitis and HSV-2 infection, and is useful as a versatile anti-herpes virus agent.

The pharmacological action of the compound of the present invention was confirmed by the following pharmacological test.

Test Example 1 Anti-VZV activity test

The experiment was performed according to the method described in Shigeta S. The Journal of Infectious Diseases, 147, 3, 576-584, (1983). Specifically, 10,000 HEF cells were seeded on a 96-well microtiter plate using a growth medium. The cells were cultured under C, 5% C02 for 4 days until a monolayer was formed. After washing the cells with the maintenance medium, 100 / L wells of VZV (CaQu strain) diluted with the maintenance medium were inoculated at a concentration of 20 to 30 pfuZL. After centrifugation the plates at room temperature for 20 minutes at 2000 rpm, and incubated _{37 ° C, 5% C0 2} 3 hours under, were infected with VZV. After washing three times with 100 / iL / well of maintenance medium, an appropriate concentration of test agent IOP JUL diluted in the maintenance medium was added to each well. Cells After culturing for 3-4 days under _{2 37 ° C, 5% C0} , 10% formalin PBS 100 / L / Ueru added and fixed to 2-3 hours cells. After discarding the fixative and the culture supernatant, washing the plate with water, adding a staining solution (0.025% crystal violet) in 50 LZ tubes, staining for 2-3 minutes, washing with water, and washing the plate at 37 ° C. Let dry. HEF cells infected with VZV cause cell death, and HEF cells in monolayer A plaque consisting of dead cells is formed at the same time. Count the number of plaques with a microscope

The EC ₅₀ value was calculated as the concentration that inhibited this plaque by 50%.

The EC ₅₀ value (j (i M) of the compound of the present invention is shown in the following table. The compound of the present invention has a better VZV compared to acyclovir and the known thiazolylphenylcarbamoylmethyl-substituted amide derivatives (Comparative compounds a and b). It had an antiviral effect.

Table 2

ACV: acyclovir

Comparative compounds a and b: compounds of entry 1 Nos. 29 and 34 in Table 1 of W097 / 24343

(Comparative compound a) (Comparative compound b) Test example 2 HSV-1 skin infection mouse model (in vivo test)

The in vivo effects of the compounds of the present invention were tested using an HSV-1 skin infection mouse model according to the method of H. Machida et al. (Antiviral Res. 1992 7 133-143). A virus solution (HSV-1 WT-51 strain 1.5 × 10 ⁴ PFU) was dropped and penetrated into the site of HR-1 hairless mouse skin rubbed several times vertically and horizontally with a syringe needle to infect HSV-1. . The compound of Example 2, 6, 9, 13, or 14 (dose: 10 mg / kg) or the compound of Example 1 (dose: 12.5 mg / kg or 12.5 mg / kg) was added at 20% CremophorEL (Nacalai Tesque) No. 20% polyethylene glycol (PEG) 400Z60% H ₂ O solution was orally administered twice a day for 5 days. Symptoms of skin lesions due to HSV-1 infection were scored on a 7-point scale and evaluated for 21 days, and the number of surviving mice was also examined. As a result, in the placebo group, an increase in the score due to deterioration of the skin lesions was observed after the infection 4, and the average lesion score exceeded 6 after 7 days, and the number of surviving days was 10 days or less. . On the other hand, in the compound-administered group, the deterioration of the symptom of the lesion was well suppressed, and the average disease score did not exceed 2 during the evaluation period. In addition, prolongation of survival days was observed, and no deaths were observed during the evaluation period.

The compounds of Examples 2, 9, 13 or 14 (dose: 10 mg / kg) were similarly tested with placebo. The AUC value was calculated from the average lesion score of each group, and the lesion inhibition rate of each compound administration group with respect to placebo was calculated. As a result, the lesion inhibition rates of these compound-administered groups were about 80 to 95%.

As described above, it was confirmed that the compound of the present invention orally administered in an in vivo animal model had a good anti-herpesvirus activity when administered orally at a low dose. Since the compound of the present invention is not a nucleic acid-based compound and exhibits good antiviral activity at a low dose, it was expected that the compound could be a more safe antiherpesvirus agent. Among the compounds of the present invention, a compound having a particularly low drug interaction is advantageous for use in combination with another drug. The pharmaceutical composition of the present invention containing one or more of the compound of the present invention or a salt thereof as an active ingredient can be used usually by using pharmaceutical carriers, excipients, etc., which are generally used in the art. It can be prepared by the method described. Administration is oral using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections such as intravenous injections, intramuscular injections, suppositories, eye drops, eye ointments, inhalants, etc. Any of the above forms may be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances include at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with magnesium metasilicate and aluminate. In accordance with a conventional method, the composition may contain an inert additive such as a lubricant such as magnesium stearate or a disintegrating agent such as carboxymethyl starch sodium. And a solubilizing agent. If necessary, tablets or pills may be coated with sugar coating or gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water, ethanol and the like. including. The composition may contain, in addition to the inert solvent, auxiliaries such as solubilizing agents, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may further comprise a tonicity agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, solubilizer. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition, dissolving and suspending in sterile water or a sterile solvent for injection before use.

External preparations include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments and the like. It contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. No.

Usually, 1 dose of the compound of the present invention is, when administered orally, about 0.001 to 50 mg Z kg per body weight, preferably 0.01 to 3 O mg Z kg, administered intravenously. If appropriate, approximately 0.001 to 1 Omg Z kg per body weight is appropriate, and should be administered once a day or in multiple doses. The dosage depends on the individual case, taking into account symptoms, age, gender, etc. Is determined as appropriate. When used as an external preparation, an external preparation containing the compound (I) in an amount of 0.0001 to 20%, preferably 0.01 to 10 <½ is preferable. This should be administered once or several times locally depending on the symptoms.

The compound of the present invention may be appropriately used in combination with other drugs.

ACV, VCV, FCV, Penciclovir (PCV), Vidarabine (ara-A), BVDU (Promovinyl Deoxyduridine), Foscanet (PFA), Ganciclovir (GCV) and other anti-herbal virus agents; Amitriptyline (3 Analgesics for postherpetic neuralgia such as cyclic antidepressants), gabapentin (anticonvulsants), lidocaine and mexiletine (antiarrhythmic drugs), and capsaicin; anti-inflammatory analgesics such as indomethacin, ibuprofen, and celecoxib . BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail based on examples. Production examples of the starting compound of the compound of the present invention are shown in Reference Examples.

Reference Example 1: Potassium carbonate and ethyl bromoacetate were added to a DMF solution of aniline, and the mixture was heated and stirred. After water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed and dried, and the solvent was distilled off under reduced pressure to obtain a crude product. This was dissolved in chloroform and TEA, 4-fluorobenzoyl chloride and dimethylaminopyridine (DMAP) were added and stirred. 1 M hydrochloric acid was added to the reaction solution, the organic layer was separated, washed and dried, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain ethyl [(4-fluorobenzoyl) phenylamino] acetate (colorless oil). FAB-MS [(M + H) ⁺ ]: 302.

Reference Examples 2 to 15 _: Compounds of Reference Examples 2 to 15 shown in Table 3 below were obtained in the same manner as in Reference Example 1. Production Example 1: To a solution of ethyl [(4-fluorobenzoyl) phenylamino] acetate (599 mg) in ethanol (10 mL) was added a 1 M aqueous sodium hydroxide solution (2.3 mL). The mixture was stirred at room temperature for 5 hours. After 1 M hydrochloric acid was added to the reaction solution to make the solution acidic, water and chloroform were added to separate the organic layer. Further, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. After dissolving the obtained carboxylic acid crude product in DMF (15 mL), 4- (4-aminophenyl) thiazo-l-un-2- ^ peramine dihydroiodide (831 mg), pyridine (0.23 mL), HOBt (0.3 g) and WSC'HCI (0.42 g) were sequentially added, followed by stirring at room temperature for 22 hours. After a 1 M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, the organic layer was separated. Further, the organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (formaldehyde methanol = 97/3) to obtain 451 mg of a yellow foam. This was dissolved in chloroform-methanol (4 mL, 1 mL), 4 M hydrogen chloride monoethyl acetate (0.38 mL) was added, and the solvent was distilled off under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give N-({[4- (2-aminothiazole-41-yl) 'phenyl] -caprolumbyl} methyl) -4-fluoro-N-phenylpentazamide monohydrochloride (Light yellow crystal) 270 mg was obtained. Characteristic peak of ¹ H-NMR (DMSO-d ₆ , TMS internal standard) (5 ppm: 4.67 (2H, s), 7.01 -7.40 (1 OH, m), 7.69-7 · 77 (4Η, m), 10.50 (1 H, s).

Examples 1 to 14: The compounds of Examples 1 to 14 shown in Tables 4 to 5 below were obtained in the same manner as in Production Example 1.

Abbreviations in the table are: Ref: Reference example; Ex: Example; Str: Structural formula; Sal: Salt; and Dat: Physicochemical properties {F +: FAB-MS [(M + H) ⁺ ]; N1: 1 H-NMR (DMSO-d ₆ , TMS internal standard) characteristic peak S ppm} is shown.

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Claims

The scope of the claims

1. Amide derivatives or salts thereof shown in the following table.

2. N-({[4- (2-Aminothiazol-4-yl) phenyl] pothambamoyl} methyl) benzo [b] thiophen-5-yltetrahydro-2H-thiopyran-4-carboxamide 1 , 1-dioxide or its salt.

3. N-({[4- (2-Aminothiazol-4-yl) phenyl] pothambamoyl} methyl) -N- (2,6-dimethylphenyl) tedrahydro-2H-thiopyran-4-potoloxamide 1,1-dioxide or its Salt.

4. N-({[4- (2-Aminothiazol-4-yl) phenyl] caprolbamoyl} methyl) -N- (4-bromo-2-methylphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide or a salt thereof.

5. N-({[4- (2-Aminothiazol-4-yl) phenyl] pothambamoyl} methyl) -N- (2,4-dimethylphenyl) tetrahydro-2H-thiopyran-4-carboxamide 1, 1-dioxide or a salt thereof.

6. N-({[4- (2-Aminothiazol-4-yl) phenyl] pothamamoyl} methyl) -N- (3-methylbenzo [b] thiophen-5-yl) tetrahydro- 2H-thiopyran-4-caproloxamide 1,1-dioxide or a salt thereof.

7. N-({[4- (2-Aminothiazol-4-yl) phenyl] -rubamoyl} methyl) -N- (2,4,6-trimethylphenyl) tedrahydro-2H-thiopyran-4-carboxami De 1,1-dioxide or a salt thereof.

8. trans-N-({[4- (2-Aminothiazol-4-yl) phenyl] -lubamoyl} methyl) -N-benzofuran-5-yl-4-cyanocyclohexanecarboxamide or a salt thereof .

9. N-({[4- (2-Aminothiazol-4-yl) phenyl] pothambamoyl} methyl) -N- (2-octamethyl-6-methylphenyl) tetrahydro-2H-thiopyran-4- Carboxamide 1,1-dioxide or a salt thereof.

10. N-({[4- (2-Aminothiazol-4-yl) phenyl] caproluvyl} methyl) -4-cyano-N- (4-methoxyphenyl) cyclohexanecarboxamide or salt.

11. A pharmaceutical composition comprising the amide derivative or a salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, which is an anti-herpes virus agent.

13. The pharmaceutical composition according to claim 12, which is an anti-varicella-zoster virus agent.