PREVENTIVE OR THERAPEUTIC AGENT FOR DISEASE RELATED TO VIRUS OF HERPES
Field of the Invention The present invention is directed to a medicament, particularly a medicament useful for preventing or treating diseases associated with herpes viruses. Background of the Invention Viruses belong to the family of Herpesviridae, originating various infectious diseases in humans and animals. For example, it is known that the varicella zoster virus
(VZV), causes varicella and herpes zoster, and herpes simplex viruses type 1 and type 2 (HS V-1 and HSV-2) cause infections such as cold sores, genital herpes, etc., respectively.
In addition, in recent years, the infectious diseases originating from DOG herpes viruses have been explained, such as cytomegalovirus (CMV), EB virus (Epstein-Barr virus, EBV), human herpes viruses 6, 7 and 8, etc. . Currently, drugs based on nucleic acid, called "polymerase inhibitor", such as acyclovir (ACV) and its prodrugs, for example, valaciclovir (VCV), famciclovir (FCV), etc., are used con agents against herpes viruses such as VZV and HSV. These nucleic acid series drugs are mono-phosphorylated in nucleoside monophosphates via viral thymidine kinase encoded by VZV
or HSV and are subsequently converted to triphosphate compounds by cellular enzymes. Finally, the tri-phosphorylated nucleoside analogs are incorporated during replication of the viral genomes by herpes virus DNA polyperase, to suppress the extension reaction of the strains of
Viral DNA Since the reaction mechanism of existing herpes anti-viral agents is based on the effect of "competitive inhibition" towards deoxynucleoside triphosphate, as described above, it is necessary to use these drugs in a high concentration. of its antiviral effects. Actually, these anti-herpes virus drugs of the nucleic acid series are administered clinically in a dose as high as several hundred, s of mg up to several grams per day. Since these drugs of nucleic acid series can be incorporated into the genome DNA of a host through the host DNA polymer, in addition, the mutagenicity thereof has inconvenient aspects. On the other hand, several pharmaceutical drugs have recently been reported with a non-nucleic acid base and with anti-virus erp activity. For example, an amide or sulphonamide derivative is described which suppresses the HSV helicase-cousin enzyme complex showing anti-HSV-1 activity and anti-CMV activity, 1 as represented by the following formula (G ), where the N-atom is substituted with a thiazolylphenylcarbamoylmethyl group or the like (see Reference for
Patent reference 2: International Publication No. 00/29399 Patent reference 3: International Publication No. 02/38554 Patent reference 4: International Publication No. 03/95435 Patent reference 5: International Publication No. 05/014559 Patent reference 6: Publication of German Patent Application Specification No. 1012971 Brief Description of the Invention Problems to be Resolved in the Present Invention To date, it has been mandated the development of a herpes anti-virus agent that has high security Means to solve the problem The inventors of the present invention have carried out extensive studies with respect to agents to prevent and treat diseases associated with viruses and herpes, and as a result, they discovered two or more compounds having anti-herpes virus activity based on the inhibitory activity of helicase-primase. Furthermore, when its inhibition of helicase-primase was used concomitantly with a polymerase inhibitor generally used as an anti-herpes virus anti-virus, it was unexpectedly discovered that they have a synergistic effect, resulting in this way the achievement of the present invention. That is, the present invention relates to (1) an herpes virus agent characterized by combining a helicase-primase inhibitor, compound N-. { 2 - [(4-substituted phenyl) to mino] -2-oxq eti l} tetrahydro-2H-thiopy n-4-
Herpes for a patient who is administered a polymerase inhibitor, wherein the agent comprises an effective amount of a compound of the general formula (I). Effect of the Invention By combining a pblimerase inhibitor in the form of a conventional herpes anti-virus agent with a helicase-primase inhibitor having a different mechanism of action, the herpes anti-herpesvirus agent of the present invention achieved an extremely superior anti-herpes virus activity compared to the administration of a polymerase inhibitor alone. Accordingly, it is particularly effective in a case in which a sufficiently therapeutic effect can not be achieved with only a polymerase inhibitor. In addition, since the doses of both agents can be kept low through their concomitant use, it is possible to obtain a therapeutic effect which is my own, greater in the case of a single administration, together with the decrease of the undesirable actions of both agents to which it refers. Accordingly, the herpes anti-herpesvirus agent of the present invention is useful as an herpesvirus ant ti agent which has particularly high safety for the prevention or treatment of various herpes virus infections such as chicken pox associated with VZV infection, herpes zoster associated with recurrent infection with latent VZV, herpes labialis and herpes encephalitis associated with HSV-1 infection, herpes
a helicase-primase inhibitor with a polymerase inhibitor of the present invention includes a pharmaceutical preparation for preventing or treating a disease associated with herpes virus, which comprises an effective amount of a helicase-primase inhibitor and an effective amount of a polymerase inhibitor (mixture in editions), and a kit comprising two pharmaceutical preparations; ur anti-herpes virus agent in the form of a first pharmaceutical preparation comprising a helicase-primase inhibitor in the form of its ingredient active agent and another herpes anti-virus agent in the form of a second pharmaceutical preparation comprising a polymerase inhibitor as its active ingredient In this connection, pharmaceutical preparations are administered via the same route or a different administration route simultaneously or separately The "equipment comprising two pharmaceutical preparations" above In this case, it includes two pharmaceutical preparations each of which contain respective active ingredients for the therapy of concomitant use of these active ingredients and its example includes a package that may contain a supplementary pharmaceutical preparation, such as placebo, etc., which facilitates the administp a. in response to their period of administration on demand occasions or in a deployment element. Also the term "simultaneously" means that the first preparation! pharmaceutical ca and the second preparation
Pharmaceutical is administered through the same route of administration, and the term "separately" means that the first pharmaceutical preparation and the second pharmaceutical preparation are administered separately through the same route or a different administration route. in the same or different frequency of administration or administration interval. Preferably, they are administered simultaneously or separately under suitable administration conditions for respective pharmaceutical preparations which relate to the preparation formulation of the pharmaceutical preparation, route of administration, frequency of administration and simi lar, taking into consideration the bioavailability , stability and similarities of each pharmaceutical preparation. In addition, the phrase "medication for anti-herpes virus treatment, which comprises (a) a pharmaceutical preparation comprising a helicase-primase inhibitor as an active ingredient and (b) a package insert which indicates that the The pharmaceutical preparation is used in an adjuvant manner with an anti-herpes virus treatment agent comprising a polymerase inhibitor as the active ingredient., means a packaged medicine for the anti-vir treatment of herpes comprising an effective amount of the pharmaceutical preparation comprising the helicase-primase inhibitor as the active ingredient, shown as mediant (a), the end of the package that is
refers to the aforementioned pharmaceutical preparation (a), which indicates that the pharmaceutical preparation. It is used concomitantly with an anti-herpes virus treatment agent comprising a polymerase inhibitor as the active ingredient, shown by (b). Subsequently, the helicase-primase inhibitor of the medicine of the present invention, the compound N-. { 2 - [(4-substituted phenyl) amino] -2-oxoetyl-1-tetrahydro-2H-thiopyran-4-carboxamide represented by the general formula (I) is described further. In the present invention, the atoms F, Cl, Br and I can be exemplified as a "halogen atom". The compound N-. { 2 - [(4-substituted phenyl) amino] -2-oxoethyl} tetrahydro-2H-thiopyran-4-carbolxamide represented by the general formula (I), may be its hydrates, various species of solvates and polymorphic substances. Particularly, the following compounds are recommended, in the form of the; s compounds represented by the general formula (I). (1) Compound A, wherein Z is a group 1, 2,4-oxadiazol-3-yl. (2) Compound A, where Z 3s is a 4-oxazolyl group. (3) Compound A, (wherein A is a phenyl group which is substituted by at least one methyl group and may additionally have one or two substituents selected from the group
which consists of a methyl group and halogen atoms. (4) A compound in which A is a 5-indanyl group. (5) A compound selected because it consists of N (2,6-dimethyl-l-phenyl) -N- (2 { [4- (1,3-oxazol-4-yl) phenyl] amino 1,1-dioxide} -2-oxoethyl) tetrahydro-2H-thiopyran-4-carboxamide, 1,1-dioxide N- (4-methylphenyl) -N- (2 { [4- (1,3-oxazole-4 -yl) phenyl] amino.} -2-oxoethyl) tetrahydro-2 H-thiopyran-4-carboxamide, 1,1-N- (3-methyl-1-phenyl) -N- (2- { [ 4- (1, 3-oxazol-4-yl) phenyl] amino.} -2-oxoethyl) tetrahydro-2H thiopyano-4-carboxamide, 1,1-dioxide N- (2-methyl-phenyl) -N - (2- {[[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopyran-4-carboxamide, 1,1-N-dioxide ( 2,4-dimethyl-phenyl) -N- (2- {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) te trahydro-2H-thiopyran-4- carboxamide, 1,1-N (3,4-dimethyl phenyl) -N- (2 { [4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl dioxide ) you trahydro-2H thiopyran -4 -carboxamide, 1,1-dioxide N (2,3-dihydro-1H-inden-5-yl) -N- (2- { [4- (1,3- oxazol-4-yl) phenyl] amino.} -2-'-pxoethyl) tetrahydro-2H-thiopyran-4-carboxamide a, N- (4-chloro-3-methylphenyl) -N- (2-) 1,1-dioxide. { [4- (1, 3-oxazol-4-yl) phenyl] amine} -2-oxoethyl) jtetrahydro-2l H-thiopyran -4 -carboxamide, N- (3-fluoro-4-methylphenyl) -N- (2 { [4- (1,3-oxazole) 1,1-dioxide -4-yl) phenyl] amino.} -2-oxoethyl) tetrahydro-2 H-thiopyran-4-carboxamide, N- (3-fluoro-2,4-di-methylphenyl) -N- 1,1-dioxide (2- {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopyran-4-carboxamide,
1,1-N- (3,5-difluoro-4-methylphenyl) -N- (2 { [4- (1, 3-oxazol-4-yl) phenyl] amino] dioxide. -2Joxoethyl) tetr; ahydro-2H-thiopyran-4-carboxamide, N- (2-fluoro-4-methylphenyl) -N- (2 { [4- (1,3-oxazole-4,1-dioxide -yl) phenyl] amino.} -2-oxoeti) tetrahydro-2H-thiopyran-4-carboxamide, 1,1-N- (2 3 -dimethylhexyl) -N- (2- { [4- (1,2,4-oxadiazol-3-yl) phenyl] amino] -2-oxoethyl-itetrahydro-2H-thiopyanocarboxamide, 1,1-N- (2-dioxide) 4-di methylethyl l) -N- (2- {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl tetrahydro-2H-thiopyran-4- carboxamide, N- (2,6-dimethylphenyl) -N- (2 { [4- (1,2,4-oxadiazol-3-yl) phenyl] amino 1,1} dioxide. -oxoetir tetrahydro-2H-thiopyran -4 -carboxamide, N-4-fluoro-2,6-dimethylphenyl 1,1-dioxide) -N- (2 { [4- (1, 2,4 oxadiazole- 3-yl) phenyl] amino.} -2-oxoethyl) tetrahydro-2H-thiopyran-4-carboxamide, N- (2, 3-dihydro-H-inden-5-yl) -N-1,1-dioxide - (2- {[[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-t iopyran-4-carboxamide, N- (3-fluoro-4-methylphenyl) -N- (2-. { [4- (1,2,4-oxadiazol-3-yl) phenyl] amino} 2-oxoethyl) tet ra hydro-2-thiopy n-4-carboxamide, | N- (4-chloro-3-methylphenyl) -N- (2. {[[4- (1,2,4-oxadiazol-3-yl) phenyl] amino] -2-oxoethyl 1,1-dioxide ) tetrahydro-2H-thiopyran-4-carboxamide, and N- (d-fluoro-2,4-dimethylphenyl) -N- (2 { [4- (1,2,4-) 1,1-dioxide oxadistol-3-yl) phenyl] aminoH2-oxoetyl) tetrahydro-2H-t -opyran-4-
carboxamide. The anti-virulent herpes agent of the present invention characterized by combining a helicase-primase inhibitor with a polymeric inhibitor can be prepared as a medical mixture or as separate pharmaceutical preparations for a kit, starting from of one or two or more species of an effective amount of a helicase primase inhibitor, and one or two or more species of an effective inhibitor of polymerase, through a generally used method utilizing carriers, excipients and similar for medications generally used in this field. The administration thereof can be either oral via tab, pills, capsules, granules, powders, liquids, etc., or parenterally through injections such as intravenous injections, intramuscular injections, etc., external agents such as ointments, plasters, creams, jellies, more cataplas, sprays, lotions, eye drops, ointments for eyes, etc., suppositories, inhalation agents and the like. In the form of the solid pomposiciote for oral administration, tab, powders, granules and the like are used. In said solid composition, one or more active substances are mixed in at least one inert excipient, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium tetrasilicate aluminate, etc. According to general methods, the composition can be
contain inert additives such as lubricants, for example, magnesium stearate, e te; disintegrants, for example, sodium carboxymethyl starch, etc .; and age nte dissolving aids. Tab or pills can be coated with sugar coatings or soluble in the stomach or enteric coatings. Examples of the liquid composition for oral administration include pharmaceutically acceptable emulsion, liquid, suspensions, syrups, elixirs, etc. where inert solvents for general use such as purified water, ethanol, etc., can be incorporated. In addition to the inert solvents, the composition may also contain auxiliary agents such as solubilizing agents, wetting agents and suspending agents, sweetening agents; flavoring agents; aromatic and preservative agents. Examples of injections for parenteral administration include sterile aqueous or nonaqueous liquids, suspensions and emulsions. Aqueous solvents include, for example, distilled water for injections and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (in name in the Pharmacopoeia) and the like. Said compositions may further contain isotonic, anti-septic agents, wetting agents, emulsifying agents, dispersing agents, stabilizers and dissolving auxiliary agents. These will
sterilize filtering to t? birds of fi re that retain bacteria, incorporating sterilization agents or by irradiation,
Alternatively, they can be produced in a sterile solid composition and subsequently dissolved or suspended in sterile water or sterile solvents for injections before use. Examples of external agents include ointments, plasters, creams, jellies, more cataplas, sprays, lotions, eye drops, ointments for eyes and the like. The external agent generally contains ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions and the like. As the bases of a güento or oil, mention may be made as examples of polyethylene glycol, propylene glycol, white petrolatum, white beeswax, castor oil hardened with polyoxyethylene, glycerol monostearate, stearyl alcohol, cetyl alcohol, lauror? acrogol, sorbitan sesquioleate, similar carboxyvinyl polymer. When a compound known conventionally through the above-referenced reference is used as the helicase-primase inhibitor of the present invention, the appropriate dosage and administration form described in the reference may be employed. Preferably, a dose lower than the dose described in the refe- rence is used, because a sufficient combined effect can be obtained with a much smaller amount. Generally, I at the right dose of the compound
Novel (I) of the present invention, which is the active ingredient of the present invention, is from about 0.001 to 50 mg / kg / body weight, preferably 0.01 to 30 mg / kg / body weight, more preferably 0.05 at 10 mg / kg / body weight, for oral administration For intravenous administration, the daily dose is approximately 0.0001 to 10 mg / kg / body weight, preferably 0.001 to 1.0 mg / kg / body weight. The dose is administered once or in separate portions per day, and is determined appropriately depending on each case, in terms of the symptom, age, sex D and the like. When the compound (I) will be used as an external agent, the agent containing the compound of the present invention is desirable in an amount of 0.0001 to 20%, preferably 0.01 to 10%. The external agent is administered locally at once or in separate portions per day depending on the symptom. On the other hand, the polymerase inhibitor dose of the present invention is decided in response to the activity of the polymerase inhibitor that will be used. In the case of a polymerase inhibitor in which its clinically adequate dose and its frequency of administration are already known, it is desirable to administer it in said blister dose and frequency of administration. As an alternative, taking into account its synergistic effect with the helicase-primase inhibitor, it can be administered in a smaller amount to that. For example, in the case of ACV, VCV or FCV, daily dose is usually from
about 1 to 300 mq / kq preferably from 5 to 200 mg / kg, more preferably from 10 to 150 mg / kg per body weight in the case of oral administration, and its daily dose in the case of intravenous administration is 0.01 at 10 mg / kg, preferably 0.1 to 1.0 mg / kg, per body weight, respectively, and this is administered once a day by dividing it in two or more times. The dose is optionally decided taking into consideration the symptom, age, sex and the like in response to individual cases. Furthermore, when used as an external preparation, an external preparation containing 0.0001 to 20%, preferably 0.01 to 10%, of the compound (I) is desirable. This is administered topically from one to several times per day in response to the symptom. The pharmaceutical composition of the present invention, which comprises both the helicase-primase inhibitor and the polymerase inhibitor, is produced by preparing it in such a way that both of the components are contained in respective amounts corresponding to the aforementioned doses. The helicase-primase inhibitor of the present invention can be prepared by the method described in the aforementioned reference, and can be used in a commercially available product such as the polymerase inhibitor. Hereinafter, the typical production methods of the compound (I) in the form of the helicase-primase inhibitor of the
Compound (I) can be easily produced by subjecting the carboxylic acid compound (lili) and the Aniline Derivative
(II) to a reaction of amydation. The amid ation reaction can be carried out through general methods. For example, the method described in the publication in "Courses in Experimental Chemistry" edited by Sociedad Química de Jaónon, fourth edition (Maruzen), Vol. 22, pp. 137-173 may be apleable. Preferably, the reaction is carried out by converting the Carboxylic Acid Compound (III) into a reactive derivative such as acid (acid chloride) allyl or an acid anhydride, and subsequently reacting the resulting reactive derivative with the derivative thereof. aniline (II). In the case of using uip reactive derivative of carboxylic acid, a base (an organic base such as carbonate of potassium io, sodium hydroxide, etc.) or an organic base such as triethylamine (TEA), di-isopropylethylamine, is added. piridiiha, etc.) In addition, the amidation reaction can be carried out by reacting the carboxylic acid in the presence of a condensation people (1-ethyl-3- (3-dimethylaminopropyl) ca rbodi-imide (WSC), 1,1'- carbonylbis-1H-imidazole (CDl), etc). In this case additives such as 1-hydroxybenzotriazole (HOB t), etc., can be added. The reaction temperature can be selected, suitable depending on the compound or raw material used. The solvent used includes those that are inert to the reaction,
ability to form an ester residue such as a lower alkyl, an aralkyl, etc.) In the above reaction scheme, the amidation can be carried out in the same manner as in the first prior production method. The N-alkylation of the compound (VI) can be carried out using a Halogenated Alkyl compound (Vil) according to usual methods, for example, and the method described in the publication "Courses in Experimental Chemistry", before mentioned, the fourth edition (Maruz en), Vol. 20, pp. 279-318. The reaction can be carried out under the temperature from cooling to heating. Examples of the usable solvent include solvents inert to the reaction, for example those exemplified for amidation in the first production method, etc. The reaction was preferably carried out in the presence of a base such as potassium carbonate, sodium hydroxide, sodium hydride, etc. The amidation can be carried out in the same way as the first prior production method. In the present invention, the amidation can be carried out first and then the
N-alkylation. Deprotection to obtain the Acid Compound
Carboxylic (III) can be carried out by suitably applying a general method that deposits the ester type. In the case of alkyl esters such as ethyl ester, etc., the
Deprotection can be carried out preferably by treating them with a base such as aqueous sodium hydroxide solution, etc. In the case of estere; Aralkyl groups such as benzyl ester, etc., deprotection can be carried out by reducing it with palladium-carbon (Pd-C). Dajo an atmosphere of hydrogen. The reactions can be carried out according to the method described in the publication "Pr otective Groups in Organic Synthesis", third edition, previously mentioned. A compound of the desired unprocessed material can be produced by subjecting the computer with a certain substituent type to a substituent modification reaction known to those skilled in the art. The compound (I) of the present invention obtained in this form is isolated and purified in its free form or as a salt thereof after a salt formation process by a general method. Isolation and purification are carried out using general chemical methods such as extraction, concentration, evaporation, crystallization, filtration, re-crystallization, various chromatographic techniques and the like. EXAMPLES Effects were confirmed as the medicament of the present invention, through the following pharmacological tests. EXAMPLE 1 Inhibitory Activity of Helica-Primasa Using a Ba culovirus to express proteins
of UL5, UIÍ52 and UL8 which constitute a HSV-1 helicase-primase complex (obtained from Dr. Nigel D.
Stow, Medical Research Council, United Kingdom), a recombinant HSV-1 helicase-primase complex was prepared by a method described in a report by Crute and associates (JB C, 1991, Vol. 266 , p 21252-21256). Detection of activity A DNA dependent passage of the helicase-primase complex HSV-1 was carried out in reference to the method described in a report of the publication of Crute et al. (JB C, 1991, Vol. 266 , p.4444-4488). In synthesis, 520 ng of helicase-primase complex was left HSV-1 was allowed to pass through a reaction at a temperature of 30 ° C for 30 minutes in a reaction liquid containing 20 μg / ml of sperm DNA from bovine denatured with heat and 2 mM ATP, and subsequently the concorción of the phosphoric acid formed through the hydrolysis of ATP in ADP and monophosphate was determined by the activity of APTPase adding the same volume of reagent Malachite Gree n (0.03 % Malachite Green, 0.1% ammonium molybdate, 4. 8% sulfuric acid) and measuring the resulting absorbance at 650 nm. The 50% inhibition concentration (IC5o value) of each compound that will be tested for ATPase dependent on helicase-primase DNA HSV-1, was calculated as the concentration that divides the concentration of phosphoric acid at the mo Do not add the compound. The results are shown in the table that is
continuation. Table 1 Compounds that will be tested! Value IC50 (μM) Compounds of preparation 2 0.084 Compounds of preparation 27! 0.11
EXAMPLE 2 Model of HSV-1 Skin Infection Mouse (In vivo test) Using a mouse model of infection HSV-1 model according to the method of H. Machida and associates (Antiviral Res., 1992, 17, 133-143), the in vivo activity of the pharmaceutical composition of the present invention was tested. The skin of each HR-1 shaved mouse (female, 7 weeks old) was scratched lengthwise and widthwise several times using a needle and a suspension of virus was dripped into the scarred region (strain HSV-1 WT- 51, 1. 5 x 104 PFU / 15 μl) for infection, anesthetizing at the same time with diethyl ether. With respect to the compounds to be tested, VCV was used as the polymerase inhibitor and was made into a suspension of methylcellulose, the compound of preparation 2, 1, 1-N- (4-methyl phenyl) dioxide. -N- (2- {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) te: rahydro-2H thiopyran-4-carboxamide which will be described later, was used as the helicase-primase inhibitor was made into a suspension of
methylcellulose, and admired orally in the dose of the table below, twice a day for 5 days beginning after 3 hours of infection. The symptom of the skin lesion caused by HSV-1 infection was classified in the following grades lasting 17 days: Score 0: no signs of infection. Qualification 1: localized, v < small little perceptible particles. Qualification 2: look slightly dispersed. Qualification 3: large patches of vesicles formed. Qualification 4: vesicles zoste riformes. Qualification 5: large patches of ulcers formed. Grade 6: zosteriform with severe ulcers. Qualification 7: for lysis of ext rear rem or death. The val or AUC of each average disease score of the group was calculated, and the inhibitory proportion of the group's disease to which each test compound was administered to the placeb D group was calculated using the AUC. The results are shown in the table below. The group of concomitant use of VCV with the compound of preparation 2, showed good inhibitory activity of the lesion compared to the single administration group VCV, and the group of concomitant use of 30 mg / kg by VCV with 3 mg / kg of the compound of preparation 2, almost completely inhibited the lesions.
you can expect a stronger effect even in the same inhibitory dose of conventional polymerase, or you could expect the same effect or a higher effect in a smaller polymerase inhibitory dose than in the conventional case. Even in the case where you can not < and obtaining a sufficient activity through a mechanism, a good anti-herpes virus activity can be achieved through the concomitant use of both agents, based on its synergic effect through two mechanisms, so that it can be obtained different clinical effects (Preparations) The production examples of the compound (I), which is an active ingredient of the present invention, are shown below in the form of Preparations. In the present invention, many of the raw material compounds for use in the subsequent reactions are known in the pamphlet of Patent Reference 1 (International Publication WO 02/38554) and the like is, and therefore may be readily available according to methods described in these known references. The examples of production of the novel compounds among the raw materials are shown below in the Reference Examples. REFERENCE EXAMPLES 1: 5% palladium-carbon powder was added to a mixed suspension of ethanol-tetrahydrofuran of 4- (4-
nitrof in i I) - 1, 3-oxazole and stirred for 12 hours at room temperature in a hydrochloric atmosphere. The reaction solution was filtered through cel ta and the filter was evaporated under reduced pressure. The remaining crude product was purified with a silica gel column chromatography to obtain [4- (1,3-oxazol-4-yl) phenyl] amine (pale yellow solid). Impact of electrons -MS (M) +: 160. EXAMPLE OF REFERENCE 2: Carboxylate and ethyl bromoacetate were added to a DMF solution of 4-methylala ina and heated at the same time as he was agitated. The reaction mixture was added with water and ethyl acetate. After the organic layer was separated, washed and dried, the solvent was evaporated under reduced pressure to obtain a cross product. The crude product was dissolved in methylene chloride and added to the resulting solution and pyridine, 1,1-d, tetrahydro-2H-thiopyran-4-carbonyl chloride oxide was stirred. After the reaction solution was concentrated, 1M hydrochloric acid and chloroform were added. The separated organic layer was washed and dried and the solvent was evaporated under a reddish pressure. The resulting crude product was purified by silica gel column chromatography to obtain. { [(1,1-dioxotetrahydro-2H-thiopyran-4-yl) carbonyl] (4-methylphenyl) amino} ethyl acetate (oily product without color) FAB-MS [(M + H) +]: 354.
EXAMPLES OF REFERENCE 3 TO 15: The compounds of reference examples 3 to 15, which are described in! Table 4, below, were obtained in the same manner as reference example 2. Preparation 1: To a solution of ejtanol (10 μl) of. { (2,6-dimethylphenyl) [(1,1-dioxide tetrahydro-2H-thiopyran-4-yl) ca • bonyl] amino} ethyl acetate
(735 mg) was added an aqueous solution of 1M sodium hydroxide (2.3 ml). The mixture was stirred at room temperature for 5 hours. After 1M hydrochloric acid was added from the reaction mixture to make the acid solution, water and chloroform were added thereto to prepare the organic layer. Subsequently, the organic layer was dried over anhydrous sodium sulfate and filtered, and subsequently the solvent was evaporated under reduced pressure. After the resulting crude carboxylic acid product was dissolved in chloroform (15 ml), WSC HCI (422 mg) and [4- (1, 3-oxazol-4-yl) phenyl] amine (320 mg) were added in sequences. ) in sequences to the resulting solution, which was stirred at room temperature for 4 hours. After an aqueous solution of saturated sodium hydrogencarbonate and chloroform was added to the reaction solution, the organic layer was separated. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered, at which point the solvent was evaporated under reduced pressure.
reduced pressure. The resulting raw material was rinsed in hexane-ethyl acetate (3/2), and subsequently re-crystallized from ethanol, to obtain 1,1-N- (2,6-dimethylphenyl) dioxide. -N- (2- {[[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopi-4-carbo xamide, (colorless crystal) in a production of 610 mg Preparation 2-40: The compounds of the preparations 2 to 40 shown in Tables 5 to 12 below, were taken in the same manner as in preparation 1. The physical-chemical properties of the Compounds of the examples of references shown? in table 4, while tables 5 through 12 show the structures and physical-chemical properties of the compounds of the preparations. The abbreviations in the tables indicate what is written below. Ref: Reference example; Eg: preparation; DAt: physical-chemical properties. { F +: FAl B-MS [(M + H) +]; F-: FAB-MS
[(M + H) "]; N1: 1H-NMR (DMSO-d6, internal standard TMS); PF: melting point (° C), the solvent for crystallization is shown in the parentheses); Ph: phenyl; : methyl, Et: ethyl, and Pr: isopropyl Here, the number figure before each substituent indicates the position for its replacement, for example, the group 3,4- (CI) 2-5-F- Ph indicates 3,4-dichloro-5-fluorophenyl.
Table 9
Ta
of both agents to which reference is made. Accordingly, the anti-herpes virus of the present invention is useful as an anti-herpes virus agent which has particularly high safety for the prevention or treatment of various herpes virus infections such as chickenpox associated with VZV infection, herpes zoster associated with recurrent infection with latent VZV, cold sores and herpes encephalitis associated with HSV-1 infection, genital herpes associated with HSV-2 infection and the like.