Abstract:
Novel triazolopyrimidine compounds represented by the formula (I) and physiologically acceptable salts thereof are disclosed. These compounds have an excellent anti-allergic activity in oral administration and are useful for treatment and prophylaxis of allergic diseases such as bronchial asthma, allergic gastro-intestinal disorders, allergic rhinitis, hay fever, urticaria and the like.

Description:
FIELD OF THE INVENTION 
     This invention relates to triazolopyrimidine derivatives and physiologically acceptable salts thereof which are useful as anti-allergic agent. 
     BACKGROUND OF THE INVENTION 
     It is well known that a chemical mediator released by antigen-antibody reaction, e.g., histamine, plays an important role in inducing allergy. Typical known agents having an inhibitory activity on release of chemical mediators include sodium cromoglycate as disclosed in British Pat. No. 1,144,906. This compound, however, is not effective in oral administration and is generally administered by inhalation or by other topical applications as an aqueous solution thereof. Apparently, the inhalation has difficulty in administering the compound to infants or children and, moreover, can not be administered to patients sensitive to irritation caused by powder, and the topical application of aqueous solution is limited only to nasal cavity. Thus, development of excellent anti-allergic agents which can be administered orally has long been desired. 
     As a result of extensive studies on compounds having an anti-allergic activity, the present inventors found that the triazolopyrimidine derivatives of the present invention represented by the formula (I) below exhibit an excellent anti-allergic activity. 
     The condensed ring included in the compounds of this invention, i.e., thiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidine and [1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidine, are novel condensed ring which have been first synthesized by the present inventors, and the compounds represented by the formula (I) having various substituents thereon are novel compounds. 
     The compounds represented by the formula (I) of this invention have the following characteristics: 
     (a) These compounds exhibit an inhibitory activity on release of chemical mediators induced by the antigen-antibody reaction, not only release of histamine which has been well known as a chemical mediator, but also release of a so-called &#34;slow reacting substance of anaphylaxis&#34; (SRS-A) which has recently been known to play an important role as a chemical mediator in the attack of asthma. 
     (b) These compounds exhibit such inhibitory activity in oral administration. 
     SUMMARY OF THE INVENTION 
     An object of this invention is therefore to provide a novel type of compounds having an anti-allergic activity. 
     Another object of the present invention is to provide a novel type of compounds which are useful for treatment and prophylaxis of allergic diseases such as bronchial asthma, allergic gastro-intestinal disorders, allergic rhinitis, hay fever, urticaria and the like. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The triazolopyrimidine compounds according to the present invention are represented by the formula (I) ##STR1## wherein: A represents CH or N; 
     R represents an aryl group or a heterocyclic group, each of which may be substituted with one or more substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkylene group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylenedioxy group having 1 to 8 carbon atoms and a halogen atom; and 
     X represents a single bond, an alkylene group having 1 to 10 carbon atoms or an alkenylene group having 2 to 10 carbon atoms, each of which may be bonded to the substituent R or the condensed ring via an oxygen atom or a sulfur atom and may be substituted with one or more substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an aryl group and a heterocyclic group; 
     and physiologically acceptable salts thereof. 
     Examples of alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl groups and the like. 
     Examples of aryl group include phenyl, biphenyl, naphthyl groups and the like. 
     Examples of heterocyclic group include furyl, thienyl, pyridyl, isochromanyl, chromanyl, chromenyl, benzodioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrimidinyl, morpholinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, oxazolinyl, oxazolidinyl, tetrazolyl, thiazolidinyl, indolyl, quinolyl, naphthyridinyl, quinazolinyl, pteridinyl, isobenzofuranyl, carbazolyl, acridinyl, xanthenyl, phenoxazinyl, perimidinyl group and the like. 
     The term &#34;alkylene group&#34; as used herein means a methylene or polymethylene group which may be substituted with one or more alkyl groups, and examples thereof include methylene, ethylene, trimethylene, heptamethylene, decamethylene, propylene, butylene, amylene, hexylene groups and the like. 
     Examples of cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups and the like, which may be substituted with one or more alkyl groups, and the like. 
     The term &#34;alkenylene group&#34; as used herein means a group formed by removing two hydrogen atoms from alkene, and examples thereof include vinylene, propenylene, butenylene, 1-pentenylene, 2-pentenylene, 2-methyl-1-butenylene, 2-methyl-2-butenylene, 1-hexenylene, 2,3-dimethyl-2-butenylene groups and the like. 
     Of the compounds according to the present invention, compounds of the formula (I) wherein X represents an alkylene group and R represents a phenyl group which may be substituted with one or more substituents selected from the group consisting of an alkyl group, an alkoxy group and a halogen atom are preferred from the standpoint of their anti-allergic activity. Most preferred compounds are those of the formula (I) wherein X represents an ethylene group and R represents a phenyl group, a halophenyl group or an alkylphenyl group. 
     Although the compounds of the formula (I) are represented as their 1H-9-oxo compounds for the sake of convenience, it is to be understood that these compounds have the following tautomers (I&#39;), (I&#34;) and (I&#34;&#39;), which are within the scope of this invention. ##STR2## 
     The compounds of the formula (I) can be prepared according to the following reaction scheme: ##STR3## wherein A, R and X are as defined above. 
     The compound of the formula (I) can be prepared by diazotizing a compound of the formula (II) or a salt thereof with a nitrite in an acid. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid and the like, organic acids such as acetic acid, propionic acid and the like, and a mixture thereof. Examples of the nitrite include sodium nitrite, potassium nitrite, etc. In the diazotizing reaction, the nitrite is used in at least an equimolar amount to the compound of the formula (II), and the acid is usually used in a large excess amount to the compound of the formula (II). The reaction can be generally carried out under ice-cooling or at a temperature up to room temperature (about 1° to 30° C.) for a period of from about 30 minutes to about 10 hours. 
     Alternatively, the above diazotization can be carried out by reacting a compound of the formula (II) with a nitrous acid ester such as isoamyl nitrite, tert-butyl nitrite, etc. in a solvent such as dimethylformamide, etc. 
     The compounds of the formula (I) can also be prepared according to the following reaction scheme: ##STR4## wherein A, R and X are as defined above. In this process, the compound of the formula (I) can be prepared by reacting a compound of the formula (III) or a tautomer thereof represented by the formula (IV) or a mixture thereof with a cyanoacetic acid ester such as methyl cyanoacetate, ethyl cyanoacetate and the like, in a solvent such as methanol, ethanol, etc. in the presence of an alkali such as sodium alkoxide, i.e., sodium methoxide or sodium ethoxide. The reaction can be carried out at a temperature in the range of from room temperature to a boiling point of the solvent used for a period of from about 30 minutes to about 10 hours. 
     The starting materials of the formulae (II), (III) and (IV) used in the above-described processes are novel compounds and can be prepared by the following processes: ##STR5## wherein A, R and X are as defined above. 
     Some of the compounds represented by the formula (V) are also novel compounds which can be prepared according to a known procedure for preparing thiadiazole derivatives as disclosed in, for example, Japanese Patent Application (OPI) No. 177997/83 (the term &#34;OPI&#34; as used herein means an unexamined published patent application) or a known procedure for preparing thiazole derivatives as disclosed in, for example, Ya. G. Balon, M. D. Shul&#39;man, N. V. Kuznetsov; Zh. Org. Khim., Vol. 15, No. 11, p2351, 1979. 
     The above processes for preparing the starting materials are hereinafter described in detail. 
     The compound of the formula (VI) can be prepared by reacting a compound of the formula (V) with a malonic acid ester, preferably 2,4,6-trichlorophenyl malonate, in the presence or absence of an inert solvent, for example, Dowtherm A, etc. The reaction can be carried out at a temperature of from about 100° to about 250° C. for a period of from about 30 minutes to about 10 hours. 
     The compound of the formula (VII) can be prepared by reacting the compound of the formula (VI) with fuming nitric acid in the presence or absence of an inert solvent, for example, acetic acid, diethyl ether, etc. The reaction can be carried out under ice cooling or at a temperature up to about 80° C. for a period of from about 30 minutes to about 15 hours. 
     The compound of the formula (VIII) can be prepared by reacting the compound of the formula (VII) with phosphorus oxychloride in the presence of an acid acceptor and in the presence or absence of a solvent. Preferred acid acceptors include an organic base such as dimethylaniline, diethylaniline, tripropylamine, etc. The reaction can be carried out at a temperature of from room temperature to about 100° C. for a period of from about 30 minutes to about 5 hours. 
     The compound of the formula (IX) can be prepared by reacting the compound of the formula (VIII) with ammonia in the presence or absence of a solvent, for example, an alcohol, dimethylformamide, dioxane and the like. The reaction can be carried out under ice cooling or at a temperature up to about 80° C. for a period of from about 30 minutes to about 5 hours. 
     The starting compound of the formula (II) can be prepared by subjecting the compound of the formula (IX) to a usual reduction reaction, for example, catalytic reduction using palladium or reduction using a metal and an acid such as tin and hydrochloric acid. 
     The starting materials of the formulae (III) and (IV) which exist as tautomers can be prepared by reacting the compound of the formula (V) with an alkali and p-toluenesulfonyl azide in the presence or absence of a solvent such as dichloromethane. 
     Examples of salts of the compounds represented by the formula (I) include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salt, and amine salts such as ammonium, tris(hydroxymethyl)aminomethane and N-methylglucamine salts, and the like. 
     The excellent anti-allergic activity of the compounds of this invention has been confirmed by evaluating an inhibitory activity on release of histamine and SRS-A induced by passive peritoneal anaphylaxis (PPA) reaction in rat as well as an inhibitory activity on passive cutaneous anaphylaxis (PCA) reaction in rats. As a result of these tests, it has been found that the compounds of this invention inhibit not only the release of histamine but also the release of SRS-A to a significant degree in the PPA reaction, and also inhibit the PCA reaction to a significant degree in oral administration of the compounds. Thus, the compounds of this invention have been found to possess a strong anti-allergic activity and, therefore, are useful as anti-allergic agent in oral administration. 
     In contrast, sodium cromoglycate which has been known as an anti-allergic agent having an inhibitory activity on release of chemical mediators did not inhibit the release of SRS-A in the PPA reaction and also did not inhibit the PCA reaction in oral administration. 
     These anti-allergic activities are described in more detail in Test Examples hereinafter described. 
     The compounds of the formula (I) and the salts thereof can be generally administered orally at a dose level of from about 150 mg to about 600 mg, 2 to 3 times per day for adult human, in a form of pharmaceutical preparation such as tablets, capsules, syrups and the like. 
     The compounds of the formula (I) are relatively of low toxicity, and LD 50  values determined in rats by oral administration are higher than 2 g/kg for the compounds of Examples 1, 9, 17, 18, 20, 21, 23, 42, 47, 48, 49, 50, 53, 54 and 55. 
    
    
     The present invention is further described in more detail by the following Examples, Reference Examples and Test Examples, but the present invention is not limited thereto. 
     EXAMPLE 1 
     6-(4-tert-Butylphenyl)-[1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one 
     1.0 of 6,7-diamino-2-(4-tert-butylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in a mixture of 20 ml of concentrated hydrochloric acid and 20 ml of water, and 2 ml of an aqueous solution containing 0.70 g of sodium nitrite was added dropwise thereto while cooling below 5° C. and stirring. The mixture was stirred at that temperature for 1.5 hours and then diluted with water. The resulting precipitate was filtered and recrystallized from chloroform-ethanol to obtain 0.88 g of the titled compound as pale yellow prisms. Melting Point: 293°-296° C. (decomposition). 
     In the same manner as described in Example 1, each of the following compounds represented by the formula (I) of Examples 2 to 8 was prepared. 
     
         ______________________________________ExampleNo.    A      RX               Melting point (°C.)______________________________________2      N          ##STR6##        269-2713      N          ##STR7##        285-2874      N          ##STR8##        &gt;3005      CH          ##STR9##        305-3076      CH          ##STR10##       &gt;3007      CH          ##STR11##       &gt;3008      CH          ##STR12##       &gt;300______________________________________ 
    
     EXAMPLE 9 
     6-(2-Phenylethyl)-[1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one 
     10.7 g of 7-amino-6-nitro-2-(2-phenylethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in 130 ml of dioxane, and 18 g of tin powder was added thereto. Then, 22 ml of concentrated hydrochloric acid was added dropwise to the gentle refluxing suspension. The gentle refluxing was further continued and, after confirming disappearance of the starting material, any insoluble material was removed by filtration. The filtrate was concentrated, and the precipitate was separated by filtration and suspended in 300 ml of concentrated hydrochloric acid-water (1:1 by volume). 20 ml of an aqueous solution containing 6.2 g of sodium nitrite was then added dropwise to the suspension at a temperature below 5° C. and, after stirring the mixture at 5° C. for 3 hours, the precipitate was separated by filtration. After washing with water and drying, the precipitate was recrystallized from chloroform-ethanol to obtain 5.3 g of the titled compound. Melting point: 295°-296° C. 
     In the same manner as described in Example 9, each of the following compounds represented by the formula (I) of Examples 10 to 79 was prepared. 
     
         ______________________________________                              MeltingExample                            PointNo.    A      RX                   (°C.)______________________________________10     N          ##STR13##           &gt;30011     N          ##STR14##           276-27812     N          ##STR15##           &gt;30013     N          ##STR16##           296-29814     N          ##STR17##           290-29215     N          ##STR18##           296-29916     N          ##STR19##           &gt;30017     N          ##STR20##           &gt;30018     N          ##STR21##           &gt;30019     N          ##STR22##           &gt;30020     N          ##STR23##           &gt;30021     N          ##STR24##           &gt;30022     N          ##STR25##           &gt;30023     N          ##STR26##           &gt;30024     N          ##STR27##           &gt;30025     N          ##STR28##           280-28326     N          ##STR29##           295-29727     N          ##STR30##           &gt;30028     N          ##STR31##           253-25629     N          ##STR32##           225-23030     N          ##STR33##           &gt;30031     N          ##STR34##           270-27332     N          ##STR35##           &gt;30033     N          ##STR36##           &gt;30034     N          ##STR37##           &gt;30035     N          ##STR38##           &gt;30036     N          ##STR39##           298-30337     N          ##STR40##           297-30038     N          ##STR41##           &gt;30039     N          ##STR42##           &gt;30040     N          ##STR43##           260-280 (not clear)41     N          ##STR44##           &gt;30042     N          ##STR45##           &gt;30043     N          ##STR46##           267 (decompo- sition) (not clear)44     N          ##STR47##           &gt;30045     N          ##STR48##           285-28846     N          ##STR49##           &gt;30047     N          ##STR50##           &gt;30048     N          ##STR51##           277-27949     N          ##STR52##           276-27850     N          ##STR53##           284-28551     N          ##STR54##           285-28752     N          ##STR55##           270-27253     N          ##STR56##           284-28654     N          ##STR57##           277-27955     N          ##STR58##           290-29256     N          ##STR59##           295-29757     N          ##STR60##           265-26758     N          ##STR61##           276-27859     N          ##STR62##           297-30260     N          ##STR63##           265-26761     N          ##STR64##           279-28162     N          ##STR65##           &gt;30063     N          ##STR66##           &gt;30064     N          ##STR67##           &gt;30065     N          ##STR68##           &gt;30066     N          ##STR69##           283-28567     N          ##STR70##           &gt;30068     N          ##STR71##           &gt;30069     N          ##STR72##           245-248 (decompo- sition)70     N          ##STR73##           249-25171     N          ##STR74##           288-29072     N          ##STR75##           228-23073     CH          ##STR76##           270-27574     CH          ##STR77##           &gt;30075     CH          ##STR78##           &gt;30076     CH          ##STR79##           250-253 (decompo- sition)77     CH          ##STR80##           232-233 (decompo- sition)78     N          ##STR81##           273-27679     N          ##STR82##           212-214______________________________________ 
    
     EXAMPLE 80 
     6-(4-Methylphenyl)-[1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one monohydrate 
     3.12 g of ethyl cyanoacetate was added to 15 ml of an ethanol solution containing 1.88 g of sodium ethoxide and, after stirring, 3.0 g of 2-azido-5-(4-methylphenyl)-1,3,4-thiadiazole was added to the solution. The mixture was stirred at room temperature for 20 minutes and then gently refluxed for 2 hours. After allowing to cool, the precipitate was separated by filtration, washed with ethanol and added to dilute hydrochloric acid. The resulting precipitate was separated by filtration and washed with water to obtain 2.54 g of the titled compound as a colorless powder. Melting Point: higher than 300° C. 
     In the same manner as described in Example 80, each of the following compounds represented by the formula (I) of Examples 81 to 84 was prepared. 
     
         ______________________________________ExampleNo.    A      RX               Melting Point (°C.)______________________________________81     N          ##STR83##       &gt;30082     N          ##STR84##       250-25383     N          ##STR85##       284-28784     CH          ##STR86##       &gt;300______________________________________ 
    
     EXAMPLE 85 
     6-(4-tert-Butylphenyl)-[1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one tris(hydroxymethyl)aminomethane salt. 
     A mixture of 0.80 g of the product obtained in Example 1 and 0.296 g of tris(hydroxymethyl)aminomethane was heated in ethanol. After allowing the mixture to cool, the resulting precipitate was separated by filtration to obtain 0.861 g of the titled compound. Melting Point: 160°-165° C. (not clear). 
     EXAMPLE 86 
     6-(4-Methoxyphenyl)-[1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one tris(hydroxymethyl)aminomethane salt. 
     In the same manner as described in Example 85, the titled compound was prepared from the product obtained in Example 3 and tris(hydroxymethyl)aminomethane. Melting Point: 160°-165° C. (not clear). 
     EXAMPLE 87 
     6-(2-Phenylethyl)-[1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one sodium salt monohydrate 
     22.35 g of the product obtained in Example 9 was suspended in 300 ml of water, and 79 ml of a 1N aqueous solution of sodium hydroxide was added to the suspension, followed by stirring for 1 hour. Any insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure to a volume of about 100 ml. 500 ml of isopropanol was added to the concentrate and, after allowing the mixture to stand under ice-cooling, the precipitate formed was separated by filtration, washed with isopropanol and dried under reduced pressure at 80° C. for 4 hours to obtain 19.4 g of the titled compound as a pale yellow substance. Melting Point: higher than 300° C. (with loss of water of crystallization at about 150° C.). 
     NMR (δ in D 2  O): 2.6-3.3 (4H, m), 6.90 (5H, s). 
     EXAMPLE 88 
     6-(2-Phenylethyl)-[1,3,4]thiadiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one potassium salt sesquihydrate 
     The titled compound was obtained in the same manner as described in Example 87 using the product obtained in Example 9 and a 1N aqueous solution of potassium hydroxide, but air-drying the product for 3 days. Melting Point: higher than 300° C. (with loss of water of crystallization at about 90° C.). 
     NMR (δ in D 2  O): 2.6-3.3 (4H, m), 6.90 (5H, s). 
     EXAMPLE 89 
     6-(2-Phenylethyl)-[1,3,4[thiadiazolo[3,2-a][1,2,3]triazolo[4,5-]pyrimidin-9(1H)-one lithium salt dihydrate 
     The titled compound was obtained in the same manner as described in Example 87 using the product obtained in Example 9 and a 1N aqueous solution of lithium hydroxide, but air-drying the product for 3 days. Melting Point: 247°-255° C. (decomposition and with loss of water of crystallization at about 150° C.). 
     NMR (δ in D 2  O): 2.6-3.3 (4H, m), 6.90 (5H, s). 
     Syntheses of the starting materials of the formulae (II), (III), (IV) and (IX) used in the above Examples are described in the following Reference Examples. In these Reference Examples, the substituents A, R and X of the starting materials are identical to those in the compounds of the formula (I) of Examples having the corresponding number. 
     SYNTHESIS OF STARTING COMPOUND OF FORMULA (II) 
     REFERENCE EXAMPLE 1 
     6,7-Diamino-2-(4-tert-butylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 
     (i) A mixture of 9.3 g of 2-amino-5-(4-tert-butylphenyl)-1,3,4-thiadiazole, 20 g of 2,4,6-trichlorophenyl malonate and 50 ml of Dowtherm A was heated at a temperature of 120° to 130° C. for 2 hours. After allowing the mixture to cool, the precipitate was separated by filtration, washed successively with isopropanol and diethyl ether to obtain 11.6 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a colorless, crystalline powder having a melting point of 265° to 268° C. (decomposition). 
     Elemental Analysis for C 15  H 15  N 3  O 2  S: Calc&#39;d: C: 59.78; H: 5.02; N: 13.94. Found: C: 60.19; H: 5.34; N: 13.62. 
     (ii) 10.0 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in 100 ml of acetic acid, and 15 ml of fuming nitric acid was added dropwise to the suspension while maintaining the temperature at 80° C. After completion of the reaction, the mixture was cooled and the precipitate was separated by filtration to obtain 7.1 g of 2-(4-tert-butylphenyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as pale yellow prisms having a melting point of 245° to 246° C. (decomposition). 
     Elemental Analysis for C 15  H 14  N 4  O 4  S: Calc&#39;d: C: 52.01; H: 4.07; N: 16.18.  Found: C: 52.08; H: 4.43; N: 16.18. 
     (iii) 6.0 g of 2-(4-tert-butylphenyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was added to a mixture of 25 ml of phosphorus oxychloride and 4 ml of diethylaniline, and the resulting mixture was heated at a temperature of 70° to 80° C. for 2 hours. After cooling, the precipitate formed was filtered, washed successively with water, isopropanol and diethyl ether to obtain 4.3 g of 2-(4-tert-butylphenyl)-7-chloro-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as crystals having a melting point of 245° to 248° C. 
     Elemental Analysis for C 15  H 13  ClN 4  O 3  S: Calc&#39;d: C: 49.38; H: 3.32; N: 15.36. Found: C: 49.02; H: 3.27; N: 15.48. 
     (iv) 1.9 g of 2-(4-tert-butylphenyl)-7-chloro-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was suspended in a mixture of 20 ml of ethanol and 10 ml of dimethylformamide, and 5 ml of concentrated aqueous ammonia was added dropwise to the suspension while maintaining at a temperature of 60° C. to 70° C. After heating at that temperature for 2 hours, the mixture was cooled and the precipitate formed was separated by filtration to obtain 1.3 g of 7-amino-2-(4-tert-butylphenyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as pale yellow prisms having a melting point higher than 300° C. 
     Elemental Analysis for C 15  H 15  N 5  O 3  S: Calc&#39;d: C: 52.16; H: 4.38; N: 20.28. Found: C: 51.23; H: 4.62; N: 20.37. 
     (v) 2.75 g of 7-amino-2-(4-tert-butylphenyl)-6-nitro-5H-[1,3,4] thiadiazolo[3,2-a]pyrimidin-5-one was dissolved in 200 ml of warmed dimethylformamide, and 20 ml of acetic acid and 2.0 g of 5% palladium-carbon were added to the solution. Catalytic reduction was carried out at a temperature of 40° to 60° C. After the calculated amount of hydrogen was absorbed, the catalyst was removed by filtration while hot, and the filtrate was concentrated under reduced pressure. The precipitate formed was separated by filtration to obtain 2.0 g of 6,7-diamino-2-(4-tert-butylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as yellow needles. 
     Elemental Analysis for C 15  H 17  N 5  OS: Calc&#39;d: C: 57.12; H: 5.43; N: 22.21. Found: C: 57.06; H: 5.33; N: 22.21. 
     In the same manner as described in Reference Example 1, each of the compounds represented by the formula (II) of Reference Examples 2 to 7 was prepared. In these compounds of the formula (II), the substituents A, R and X are the same as those of Examples 2 to 7, respectively. 
     
         ______________________________________Compound ofReference Example           Melting Point (°C.)______________________________________2               279-2823               &gt;3004               293-296           (decomposition)5               255-2586               270-2757               265-275______________________________________ 
    
     REFERENCE EXAMPLE 8 
     6,7-Diamino-2-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one 
     (i) In the same manner as described in steps (i), (ii), (iii) and (iv) of Reference Example 1, 7-amino-6-nitro-2-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one having a melting point of 291°-294° C. was obtained. 
     (ii) 2.0 g of 7-amino-6-nitro-2-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one was suspended in 50 ml of 90% dioxane, and 3.0 g of tin powder and 5 ml of concentrated hydrochloric acid were added thereto, followed by stirring the mixture at 80° to 90° C. for 30 minutes. Any insoluble material was removed by filtration, and the filtrate was concentrated. After cooling, the precipitate formed was separated by filtration and added to concentrated aqueous ammonia. The precipitate was separated by filtration and recrystallized from dimethylformamide to obtain 6,7-diamino-2-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one as yellow needles having a melting point higher than 300° C. 
     Elemental Analysis for C 12  H 10  N 4  OS: Calc&#39;d: C: 55.80; H: 3.90; N: 21.69. Found: C: 56.01; H: 4.09; N: 21.60. 
     In the same manner as described in steps (i), (ii), (iii) and (iv) of Reference Example 1, each of the compounds represented by the formula (IX) of Reference Examples 9 to 79 was obtained. In these compounds, the substituents A, R and X are the same as those of Examples 9 to 79, respectively. 
     
         ______________________________________Compound ofReference Example           Melting Point (°C.)______________________________________ 9              268-27010              &gt;30011              279-28512              &gt;30013              &gt;30014              &gt;30015              &gt;29516              280-28617              &gt;30018              &gt;280           (not clear)19              282-28420              &gt;30021              &gt;30022              &gt;290           (not clear)23              &gt;30024              &gt;30025              292-29626              &gt;30027              &gt;30028              272-27529              281-28430              &gt;30031              &gt;30032              &gt;30033              &gt;30034              &gt;30035              &gt;30036              &gt;30037              240-24838              &gt;30039              &gt;30040              &gt;30041              &gt;30042              286-28943              258-26144              298-30045              285-28746              286-28747              &gt;30048              264-26849              262-26450              273-27451              264-26752              254- 25753              260-26454              248-24955              248-25056              272-27357              220-22258              252-260           (decomposition)59              &gt;30060              252-25561              249-25262              &gt;30063              287-29064              267-26865               274           (decomposition)66              249-25167              &gt;30068              269-27169               243           (decomposition)70              150-15571              200-20272              234-23773              &gt;30074               280           (decomposition)75              290-29776              218-22377              215-21878              235-24379              180-187           (not clear)______________________________________ 
    
     REFERENCE EXAMPLE 80 
     2-Azido-5-(4-methylphenyl)-1,2,4-thiadiazole 
     A mixture of 3.67 g of 2-amino-5-(4-methylphenyl)-1,3,4-thiadiazole, 3.89 g of p-toluenesulfonyl azide, 0.68 g of tetrabutylammonium hydrogensulfate, 40 ml of a 40% aqueous sodium hydroxide solution and 60 ml of dichloromethane was vigorously stirred at room temperature. After 2 hours, cold water and dichloromethane were added to the mixture, and any insoluble material was removed by filtration. The dichloromethane layer was washed with water, dried and dichloromethane was distilled off. The resulting residue was recrystallized from methanol to obtain 3.02 g of the titled compound as colorless crystals having a melting point of 129° to 130° C. (decomposition). 
     Elemental Analysis for C 9  H 7  N 5  S: Calc&#39;d: C: 49.76; H: 3.25; N: 32.24. Found: C: 49.96; H: 3.33; N: 32.51. 
     REFERENCE EXAMPLE 81 
     2-Azido-5-(3-pyridyl)-1,3,4-thiadiazole 
     The titled compound was obtained from 2-amino-5-(3-pyridyl)-1,3,4-thiadiazole in the same manner as described in Reference Example 80. Melting Point: 121°-123° C. (decomposition). 
     REFERENCE EXAMPLES 82 AND 83 
     In the same manner as described in Reference Example 80, each of the compounds represented by the formula (IV) of Reference Examples 82 and 83 was obtained. 
     
         ______________________________________Compound ofReference Example           Melting Point (°C.)______________________________________82              129-13183              113-114______________________________________ 
    
     REFERENCE EXAMPLE 84 
     2-Azido-5-styrylthiazole 
     The titled compound was prepared from 2-amino-5-styrylthiazole in the same manner as described in Reference Example 80. Melting Point: 112°-130° C. (decomposition). 
     Some of the starting compounds having the formula (V) are novel compounds and their melting points are identified as follows. The substituents A, R and X in the following compounds are identical to those in the compounds of the formula (I) of Examples having the corresponding number. 
     
         ______________________________________Starting Compound ofFormula (V)    Melting point (°C.)______________________________________ 2             215-217 5             175-180 6             198-200 7             -270          (not clear, decomposition)10             220-22218             237-23919             195-19920             273-27822             241-24325             221-22527             206-20928             203-20529             235-23930             237-23831             195-19732             207-20933             255-26034             251-25335             250-25336             265-27037             213-21538             263-26739             224-22640             172-17441             230-23343              22348             193-19449             173.5-174.550             -214          (not clear)51             167-16852             212-21354             170-17255             219-22156             199-20158             -230          (not clear)59             192-19465              21967             220-22368             205-20769              22271             167-16973             198-20674             81-8275             153-15676             135-13777             110-11178             196-19879             164-16583             181-18884             -254          (not clear)______________________________________ 
    
     Elemental analysis and infrared absorption specrum of the compounds of the formula (I) described in Examples are shown below. 
     
         __________________________________________________________________________Compound          Elemental Analysisof                % (calc&#39;d)/(found)                       IR Absorption SpectrumExample Formula     C  H   N  (KBr) cm.sup.-1__________________________________________________________________________ 1    C.sub.15 H.sub.14 N.sub.6 OS             55.20                4.32                    25.75                       3140                          3060                             2940                                1735                                   1690             55.39                4.54                    25.82                       1550                          1480                             1430                                1255                                   1190 2    C.sub.14 H.sub.12 N.sub.6 OS             53.83                3.87                    26.91                       3050                          2850                             1720                                1670                                   1550             54.27                4.08                    26.93                       1520                          1490                             1290                                1255                                   1190 3    C.sub.12 H.sub.8 N.sub.6 O.sub.2 S             45.69                3.83                    25.66                       3070                          1695                             1600                                1530                                   1495 C.sub.3 H.sub.7 NO.H.sub.2 O             45.40                3.56                    25.59                       1440                          1310                             1260                                1175                                   835 4    C.sub.10 H.sub.5 N.sub.7 OS             43.48                2.17                    35.50                       3080                          1700                             1565                                1515                                   1470 1/4H.sub.2 O             43.88                2.25                    34.97                       1455                          1430                             1235                                990                                   775 5    C.sub.15 H.sub.13 N.sub.5 OS             57.86                4.21                    22.50                       3160                          3100                             2950                                1690                                   1570             57.78                4.33                    22.33                       1520                          1470                             1240                                1150                                   770 6    C.sub.16 H.sub.15 N.sub.5 OS             58.25                4.74                    21.23                       3160                          3100                             2950                                1685                                   1570 1/4H.sub.2 O             58.73                5.16                    20.98                       1525                          1465                             1240                                1150                                   770 7    C.sub.18 H.sub.17 N.sub.5 OS             60.74                4.95                    19.67                       3160                          3100                             2910                                1685                                   1560 1/4H.sub.2 O             60.62                4.89                    19.35                       1520                          1460                             1240                                1150                                   755 8    C.sub.12 H.sub.7 N.sub.5 OS             53.01                3.46                    25.19                       3080                          2920                             2780                                1710                                   1565 1/2C.sub.3 H.sub.7 NO             53.02                3.79                    24.89                       1510                          1450                             1395                                1235                                   755 9    C.sub.13 H.sub.10 N.sub.6 OS             52.34                3.38                    28.17                       3140                          3080                             1700                                1565                                   1520             52.50                3.56                    28.20                       1470                          1265                             1000                                970                                   77010    C.sub.16 H.sub.14 N.sub.6 OS             56.79                4.17                    24.84                       3130                          3070                             2940                                1740                                   1700             56.51                4.31                    24.65                       1555                          1530                             1480                                1420                                   119011    C.sub.13 H.sub.10 N.sub.6 O.sub.3 S             47.27                3.05                    25.44                       1725                          1635                             1570                                1530                                   1510             47.18                3.34                    25.10                       1470                          1270                             1235                                1080                                   99012    C.sub.12 H.sub.6 N.sub.6 O.sub.3 S             46.51                3.38                    25.31                       3420                          1730                             1650                                1560                                   1525 C.sub.3 H.sub.7 NO             46.23                3.30                    25.22                       1485                          1445                             1270                                1245                                   103013    C.sub.11 H.sub.5 FN.sub.6 OS             45.83                1.75                    29.16                       3060                          1690                             1580                                1520                                   1470             46.29                2.24                    28.90                       1440                          1250                             895                                800                                   76014    C.sub.11 H.sub.5 ClN.sub.6 OS             43.36                1.65                    27.58                       3400                          3150                             1710                                1550                                   1525             43.85                1.94                    27.15                       1415                          1240                             1190                                1170                                   67015    C.sub.11 H.sub.5 ClN.sub.6 OS             43.36                1.65                    27.58                       2830                          1725                             1680                                1585                                   1550             43.47                1.95                    27.65                       1520                          1475                             1255                                1190                                   108016    C.sub.11 H.sub.4 Cl.sub.2 N.sub.6 OS             38.96                1.19                    24.78                       3060                          2850                             1725                                1685                                   1550             39.36                1.58                    24.72                       1520                          1470                             1195                                990                                   96517    C.sub.9 H.sub.4 N.sub.6 O.sub.2 S             41.54                1.55                    32.30                       3100                          1680                             1565                                1510                                   1470             41.69                1.92                    32.05                       1250                          1225                             870                                780                                   75018    C.sub.10 H.sub.6 N.sub.6 O.sub.2 S             44.13                2.67                    29.92                       2980                          2880                             1690                                1575                                   1530 1/4C.sub.3 H.sub.7 NO             44.12                2.76                    29.98                       1480                          1260                             1240                                1010                                   89519    C.sub.11 H.sub.8 N.sub.6 O.sub.2 S             45.83                2.80                    29.15                       3080                          1720                             1640                                1525                                   1470             45.97                2.99                    28.71                       1410                          1370                             1235                                750                                   73020    C.sub.13 H.sub.12 N.sub.6 O.sub. 2 S             49.98                3.87                    26.91                       3180                          3080                             1710                                1565                                   1530             49.37                3.96                    26.47                       1510                          1250                             1000                                890                                   80021    C.sub.9 H.sub.3 ClN.sub.6 O.sub.2 S             39.19                2.74                    26.66                       3090                          1735                             1665                                1600                                   1545 C.sub.3 H.sub.7 NO             39.53                2.82                    26.86                       1510                          1460                             1200                                1010                                   97022    C.sub.13 H.sub.10 N.sub.6 O.sub.2 S             49.67                3.21                    26.74                       3140                          3090                             2930                                1705                                   1570             49.30                3.26                    26.43                       1545                          1525                             1155                                1005                                   89023    C.sub.9 H.sub.4 N.sub.6 OS.sub.2             39.39                1.70                    29.80                       3000                          1695                             1565                                1530                                   1450 1/8C.sub.2 H.sub.5 OH             39.02                1.83                    29.81                       1410                          1245                             1230                                970                                   72024    C.sub.9 H.sub.4 N.sub.6 OS.sub.2             39.12                1.46                    30.42                       3060                          1680                             1570                                1520                                   1470             39.52                2.09                    30.23                       1405                          1235                             1230                                845                                   73025    C.sub.10 H.sub.6 N.sub.6 OS.sub.2             41.37                2.08                    28.95                       3400                          2760                             1710                                1560                                   1510             41.37                2.19                    29.00                       1480                          1450                             1410                                1245                                   117026    C.sub.10 H.sub.6 N.sub.6 OS.sub.2             41.37                2.08                    28.95                       3150                          3080                             1690                                1570                                   1530             41.49                2.50                    28.71                       1500                          1440                             1235                                875                                   75027    C.sub.11 H.sub.8 N.sub.6 OS.sub.2             43.41                2.65                    27.62                       3080                          2920                             1725                                1650                                   1580             43.50                3.26                    27.70                       1525                          1490                             1475                                1415                                   75028    C.sub.13 H.sub.12 N.sub.6 OS.sub.2             46.97                3.64                    25.29                       2940                          2850                             1720                                1670                                   1540             46.85                3.64                    24.96                       1520                          1490                             1430                                1250                                   116029    C.sub.13 H.sub.12 N.sub.6 OS.sub.2             46.97                3.64                    25.29                       2950                          2640                             1740                                1540                                   1270             47.46                3.98                    25.55                       1235                          1205                             1190                                1170                                   75030    C.sub.11 H.sub.8 N.sub.6 OS.sub.2             42.16                2.90                    26.82                       3480                          2720                             1720                                1570                                   1510 1/2H.sub.2 O             42.28                2.88                    26.82                       1475                          1235                             1170                                980                                   59031    C.sub.12 H.sub.10 N.sub.6 OS.sub.2             46.07                4.38                    25.05                       2920                          1735                             1650                                1570                                   1535 C.sub.3 H.sub.7 NO             46.11                4.39                    25.08                       1510                          1475                             1440                                1385                                   87032    C.sub.9 H.sub.3 ClN.sub.6 OS.sub.2             37.55                3.00                    25.54                       2700                          1730                             1640                                1580                                   1530 C.sub.3 H.sub.7 NO             37.84                2.83                    25.46                       1500                          1475                             1425                                1385                                   124033    C.sub.12 H.sub.8 N.sub.6 OS.sub.2             45.56                2.55                    26.57                       3180                          1710                             1565                                1530                                   1500             45.54                2.69                    26.22                       1475                          1435                             1415                                1230                                   116034    C.sub.14 H.sub.13 N.sub.5 O.sub.3 S.sub.2             47.58                3.71                    23.78                       3170                          3120                             1695                                1570                                   1540 1/2H.sub.2 O             47.53                3.56                    23.64                       1505                          1430                             1245                                1005                                   77035    C.sub.13 H.sub.10 N.sub.6 OS.sub.2             47.42                3.39                    24.58                       3170                          1710                             1690                                1560                                   1530 1/4C.sub.2 H.sub.5 OH             46.91                3.23                    24.50                       1510                          1470                             1440                                1230                                   73536    C.sub.14 H.sub.12 N.sub.6 OS.sub.2             48.84                3.82                    24.14                       3400                          2910                             1730                                1640                                   1555 1/4C.sub.3 H.sub.7 NO             48.89                4.31                    24.15                       1515                          1450                             1380                                1250                                   120537    C.sub.12 H.sub.11 N.sub.7 O.sub.2 S             42.98                3.91                    29.24                       3100                          2950                             1730                                1705                                   1570 H.sub.2 O   43.33                3.59                    29.28                       1550                          1530                             1450                                1230                                   91038    C.sub.14 H.sub.8 N.sub.6 O.sub.2 S             51.59                3.21                    25.23                       3050                          1730                             1635                                1555                                   1530 1/2C.sub.3 H.sub.7 NO             51.90                3.46                    25.11                       1510                          1470                             1450                                1230                                   75539    C.sub.14 H.sub.10 N.sub.6 O.sub.2 S             51.52                3.09                    25.76                       3050                          1735                             1555                                1530                                   1515             51.67                2.72                    25.55                       1470                          1450                             1270                                1235                                   75540    C.sub.14 H.sub.10 N.sub.6 O.sub.2 S             51.30                3.75                    25.09                       1705                          1560                             1520                                1260                                   1230 1/2 C.sub.3 H.sub.7 NO             51.55                3.52                    24.24                       1150                          1100                             995                                965                                   74541    C.sub.13 H.sub.8 N.sub.6 O.sub.3 S             47.73                3.18                    24.96                       3040                          1700                             1560                                1530                                   1490 1/2C.sub.3 H.sub.7 NO             47.93                3.06                    24.95                       1270                          1260                             1240                                1090                                   76542    C.sub.12 H.sub.8 N.sub.6 OS             50.69                2.84                    29.56                       3150                          1705                             1570                                1530                                   1490             50.59                2.93                    29.57                       1150                          970                             770                                695                                   61043    C.sub.16 H.sub.16 N.sub.6 OS             55.71                4.82                    24.36                       3155                          2950                             1720                                1710                                   1625 1/4H.sub.2 O             55.92                4.73                    24.25                       1575                          1530                             1480                                1130                                   77044    C.sub.13 H.sub.10 N.sub.6 O.sub.2 S             49.67                3.21                    26.74                       3150                          1710                             1570                                1530                                   1510             49.74                3.34                    26.63                       1470                          1250                             1140                                1020                                   97045    C.sub.12 H.sub.7 FN.sub.6 OS             47.68                2.33                    27.80                       3050                          1705                             1600                                1570                                   1525             47.85                2.44                    27.53                       1500                          1470                             1230                                1215                                   111046    C.sub.12 H.sub.7 ClN.sub.6 OS             45.21                2.21                    26.77                       3140                          1710                             1570                                1530                                   1490             45.29                2.37                    26.44                       1475                          1150                             970                                770                                   61047    C.sub.11 H.sub.6 N.sub.6 OS             48.88                2.24                    31.10                       3060                          3030                             1690                                1575                                   1520             48.79                2.55                    30.79                       1480                          1440                             1240                                990                                   77048    C.sub.14 H.sub.12 N.sub.6 OS             53.83                3.87                    26.91                       3180                          1700                             1560                                1515                                   1470             53.62                3.99                    26.43                       1450                          1140                             990                                770                                   74049    C.sub.14 H.sub.12 N.sub.6 OS             53.83                3.87                    26.91                       3140                          2900                             1710                                1570                                   1550             53.86                4.03                    26.88                       1530                          1475                             1210                                970                                   77050    C.sub.14 H.sub.12 N.sub.6 OS             53.83                3.87                    26.91                       3210                          1705                             1560                                1520                                   1470             53.76                4.18                    26.57                       1445                          1230                             1220                                995                                   77051    C.sub.14 H.sub.12 N.sub.6 O.sub.2 S             51.21                3.68                    25.59                       3150                          1710                             1590                                1570                                   1540             51.19                3.92                    25.31                       1525                          1270                             1250                                1160                                   103052    C.sub.14 H.sub.12 N.sub.6 O.sub.2 S             51.21                3.68                    25.59                       3150                          1700                             1560                                1520                                   1500             51.25                3.76                    25.48                       1470                          1260                             1235                                970                                   80053    C.sub.13 H.sub.9 FN.sub.6 OS             49.36                2.87                    26.57                       3160                          1690                             1550                                1510                                   1490             49.30                3.06                    26.63                       1210                          1045                             990                                810                                   75054    C.sub.13 H.sub.9 ClN.sub.6 OS             46.92                2.73                    25.26                       3060                          1710                             1570                                1550                                   1530             46.93                2.87                    25.30                       1475                          970                             890                                865                                   77055    C.sub.13 H.sub.9 ClN.sub.6 OS             46.92                2.73                    25.26                       3150                          1700                             1560                                1520                                   1480             46.68                2.99                    24.80                       1210                          1085                             970                                805                                   76556    C.sub.13 H.sub.8 Cl.sub.2 N.sub.6 OS             42.52                2.20                    22.89                       3130                          1700                             1560                                1520                                   1455             42.44                2.35                    22.83                       1210                          1125                             985                                970                                   82057    C.sub.19 H.sub.14 N.sub.6 OS             58.15                4.11                    21.42                       3170                          1715                             1700                                1555                                   1515 H.sub.2 O   58.66                3.89                    21.05                       1480                          1465                             740                                690                                   59058    C.sub.14 H.sub.12 N.sub.6 OS             53.83                3.87                    26.91                       3150                          1705                             1570                                1525                                   1490             53.88                3.96                    26.54                       1470                          1135                             980                                765                                   69559    C.sub.15 H.sub.14 N.sub.6 OS             55.20                4.32                    25.75                       3150                          2940                             1710                                1560                                   1515             55.56                4.38                    25.89                       1470                          1430                             1140                                760                                   69060    C.sub.14 H.sub.12 N.sub.6 OS             53.83                3.87                    26.91                       3130                          1710                             1570                                1525                                   1490             53.58                3.93                    24.48                       1470                          1445                             970                                770                                   74561    C.sub.15 H.sub.14 N.sub.6 OS             55.20                4.32                    25.75                       3140                          2920                             1700                                1560                                   1520             54.91                4.27                    25.36                       1485                          1470                             1445                                770                                   74562    C.sub.13 H.sub.8 N.sub.6 OS             52.49                3.12                    27.83                       3400                          3120                             3060                                1700                                   1610 1/4C.sub.3 H.sub. 7 NO             52.57                3.49                    27.25                       1565                          1520                             1470                                970                                   77063    C.sub.19 H.sub.12 N.sub.6 OS             60.54                3.34                    22.30                       3130                          1715                             1690                                1540                                   1490 1/4H.sub.2 O             60.28                3.54                    22.24                       1435                          1255                             1190                                1140                                   77064    C.sub.12 H.sub.8 N.sub.6 O.sub.2 S             48.07                3.09                    27.48                       3180                          1710                             1560                                1530                                   1485 1/4C.sub.3 H.sub.7 NO             47.77                2.93                    27.33                       1245                          1230                             1210                                1170                                   76065    C.sub.16 H.sub.16 N.sub.6 O.sub.2 S             53.92                4.53                    23.58                       2970                          1720                             1560                                1530                                   1510             54.74                4.90                    22.87                       1250                          1230                             1185                                1170                                   82566    C.sub.12 H.sub.7 FN.sub.6 O.sub.2 S             45.28                2.22                    26.41                       3200                          1730                             1565                                1400                                   1250             45.45                2.42                    26.57                       1230                          1205                             1170                                830                                   77067    C.sub.12 H.sub.7 ClN.sub.6 O.sub.2 S             43.05                2.11                    25.11                       3150                          1710                             1565                                1530                                   1490             43.47                2.53                    24.85                       1240                          1220                             1170                                1060                                   82068    C.sub.16 H.sub.14 N.sub.6 O.sub.2 S             54.22                3.98                    23.72                       3200                          1725                             1710                                1575                                   1565             53.98                4.06                    23.35                       1550                          1495                             1260                                1235                                   117069    C.sub.17 H.sub.18 N.sub.6 O.sub.2 S             54.59                5.33                    22.37                       2960                          1710                             1580                                1555                                   1530 1/2C.sub.3 H.sub.7 NO             54.15                4.94                    22.45                       1510                          1245                             1185                                1155                                   77570    C.sub.12 H.sub.8 N.sub.6 OS.sub.2             45.30                2.55                    26.57                       3130                          1690                             1550                                1515                                   1465             45.63                2.60                    26.41                       1430                          1225                             1210                                1000                                   76071    C.sub.16 H.sub.16 N.sub.6 OS.sub.2             51.59                4.33                    22.57                       3150                          2950                             1720                                1710                                   1565             51.58                4.26                    23.04                       1525                          1480                             1235                                1105                                   82572    C.sub.13 H.sub.10 N.sub.6 OS.sub.2             47.49                3.25                    24.62                       3400                          3130                             1700                                1600                                   1560 1/4C.sub.2 H.sub.5 OH             47.50                3.31                    24.54                       1520                          1470                             1425                                1225                                   73073    C.sub.13 H.sub.8 ClN.sub.5 O.sub.2 S             46.96                2.77                    20.29                       3080                          1720                             1710                                1635                                   1590 1/4C.sub.2 H.sub.5 OH             47.22                2.55                    20.20                       1520                          1490                             1460                                1280                                   126574    C.sub.10 H.sub.5 N.sub.5 O.sub.2 S             46.52                2.45                    26.50                       1695                          1575                             1525                                1485                                   1240 1/4C.sub.3 H.sub.7 NO             46.39                2.40                    26.26                       985                          965                             750                                740                                   59075    C.sub.10 H.sub.5 N.sub.5 OS.sub.2             43.97                2.28                    24.42                       3170                          3080                             1680                                1570                                   1520 1/4C.sub.2 H.sub.5 OH             43.53                2.12                    24.64                       1465                          1235                             1140                                765                                   73076    C.sub.14 H.sub.11 N.sub.5 OS             56.55                3.73                    23.55                       2730                          1725                             1570                                1520                                   1460             56.64                3.93                    23.28                       1345                          1330                             1040                                770                                   74077    C.sub.14 H.sub.10 ClN.sub.5 OS             50.68                3.04                    21.11                       3100                          1685                             1570                                1520                                   1460             50.57                3.18                    20.99                       1420                          1340                             1320                                1230                                   77078    C.sub.13 H.sub.9 ClN.sub.6 OS             46.92                2.72                    25.26                       3170                          1700                             1555                                1520                                   1475             47.15                3.04                    24.98                       1445                          1125                             1035                                770                                   74079    C.sub.19 H.sub.22 N.sub.6 O.sub.2 S             57.27                5.56                    21.09                       2950                          1705                             1575                                1530                                   1480             57.16                5.57                    21.11                       1450                          1265                             1120                                975                                   77580    C.sub.12 H.sub.8 N.sub.6 OS             47.68                3.33                    27.80                       3480                          1720                             1575                                1530                                   1500 H.sub.2 O   47.79                3.45                    27.85                       1475                          1230                             985                                745                                   60081    C.sub.10 H.sub.5 N.sub.7 OS             44.59                2.34                    35.08                       1730                          1675                             1600                                1570                                   1545 1/4H.sub.2 O             44.46                2.24                    35.32                       1525                          1480                             1240                                1170                                   74582    C.sub.15 H.sub.14 N.sub.6 OS             55.20                4.32                    25.75                       3100                          2960                             1735                                1580                                   1525             55.13                4.29                    26.03                       1470                          1240                             990                                750                                   63083    C.sub.15 H.sub.12 N.sub.6 OS             55.54                3.73                    25.91                       2930                          1710                             1560                                1525                                   1480             55.70                3.94                    25.50                       1420                          1240                             1160                                825                                   75084    C.sub.14 H.sub.9 N.sub.5 OS             56.94                3.07                    23.71                       3100                          2880                             1685                                1670                                   1545             56.64                3.32                    22.96                       1310                          1150                             940                                775                                   75085    C.sub.19 H.sub.25 N.sub.7 O.sub.4 S             49.99                5.74                    21.48 1/2H.sub.2 O             50.24                6.00                    21.2586    C.sub.16 H.sub.19 N.sub.7 O.sub.5 S             42.01                5.07                    21.14 2H.sub.2 O  42.01                4.64                    21.9787    C.sub.13 H.sub.9 NaN.sub.6 OS             46.15                3.28                    24.84 H.sub.2 O   45.86                3.40                    24.8088    C.sub.13 H.sub.9 KN.sub.6 OS1.5H.sub.2 O             42.96                3.33                    23.13             42.76                3.40                    23.2389    C.sub.13 H.sub.9 LiN.sub.6 OS             45.88                3.85                    24.70 2H.sub.2 O  45.58                3.80                    24.55__________________________________________________________________________ 
    
     The pharmacological test examples and the anti-allergic activity of the compounds of this invention are described hereinafter in detail. 
     TEST EXAMPLE 1 
     (i) Preparation of Antiserum 
     1 mg of egg albumin dissolved in 0.2 ml of saline was intramuscularly administered to each of Sprague-Dawley male rats weighing 300 to 350 g (Charles River Japan Inc.), and then 1 ml of a suspension of sterilized Bordetella pertussis (2×10 10  cells) in saline was administered intraperitoneally to the rats. After 14 days, blood was drawn from the rats to obtain an antiserum. The PCA titer of this serum was found to be about 1:64 to 128 when measured with the 48 hours PCA in rats. 
     (ii) Passive Peritoneal Anaphylaxis (PPA) Test 
     The test was conducted according to the method of Orange et al [Orange, R. P., Stechschulte, D. J., Austen, K. F., J. Immunol., 105, pp1087-1095 (1970)]. Sprague-Dawley male rats weighing 250 to 400 g (5 rats per group) were passively sensitized by administering 5 ml of 5-fold dilution antiserum (prepared by diluting the above antiserum with saline). 2 hours later, 5 ml of an egg albumin solution prepared by dissolving 2 mg of egg albumin in phosphate buffered saline containing 0.9 mM of calcium chloride was administered intraperitoneally to the rats. After 5  minutes, the rats were sacrificed by decapitation, and peritoneal fluid was pooled and centrifuged at 300×G at 4° C. for 10 minutes. Then, amounts of SRS-A and histamine in the supernatant were determined. 
     The quantitative determination of SRS-A was carried out according to the method of Stechschulte et al [Stechschulte, D. J., Auste, K. F., Bloch, K. J., J. Exp. Med., 125, pp127-147 (1967)] using a guinea pig ileum specimen in the presence of mepyramine and atropine. The amount of SRS-A was expressed in terms of unit, i.e., one unit of SRS-A activity was defined as the concentration required to produce a contraction of guinea pig ileum equal in amplitude to that produced by 5 ng of histamine, and the total released amount of SRS-A per rat (unit/rat) was calculated. 
     The quantitative determination of histamine was carried out according to the method of Shore et al [Shore, P. A., Bunkhalter, A. H., Cohn, V. H., J. Pharmacol. Exp. Ther., 127, pp182-186 (1959)], and the total released amount of histamine per rat (μg/rat) was calculated. 
     In this test, the test compound of this invention was administered as follows. 2 mg of a test compound was dissolved in 10 ml of phosphate buffered saline containing 0.9 mM of calcium chloride, an equimolar amount of sodium hydroxide to test compound, 2% of dimethyl sulfoxide and 2% of ethanol, and the solution was administered intraperitoneally to the rats at a dose of 1 mg/kg 30 seconds before the injection of egg albumin for inducing PPA. For a control group, the same solution without test compound and sodium hydroxide was administered. 
     The inhibitory activity on release of histamine and SRS-A by the PPA reaction in the treated group was calculated by the following formula: ##EQU1## wherein: a represents a mean value of released amount in the control group. 
     b represents a mean value of released amount in the treated group. 
     c represents a mean value of spontaneously released amount. 
     The inhibitory activities of the compounds of this invention determined by the above tests are shown in Table 1. 
     
                       TABLE 1______________________________________Compound of     Inhibition (%)Example         Histamine SRS-A______________________________________ 1              83        64 2              85        52 3              93        42 8              83        37 9              80        5011              89        6612              87        5217              82        5523              84        5127              81        6332              87        6333              82        7035              88        4536              83        4141              91        6242              99        5443              75        5944              81        7057              86        6162              94        5566              89        4780              91        4282              82        52DSCG*           93         0______________________________________ *DSCG Sodium Cromoglycate (administered at 1 mg/kg of body weight) 
    
     TEST EXAMPLE 2 
     PCA Test 
     In this test, the antiserum described in Test Example 1 was used after it was diluted with saline so as to provide a blue spot having a diameter of about 10 mm in the following control group. 
     Sprague-Dowley male rats weighing about 180 g (5 rats per group) were sensitized by injecting 0.05 ml of the diluted antiserum into the shaved dorsal skin. 48 hours later, the animals were challenged with 1 ml of saline containing 5 mg of egg albumin and 5 mg of Evans blue dye administered via a tail vein. 30 minutes later, the rats were sacrificed by decapitation. The dorsal skin was removed, and the long and short axis of the each wheal was measured. 
     In this test, the test compound was administered as follows. 20 mg of a test compound was suspended in a 0.5% CMC aqueous solution, and the suspension was administered to each of the rats in an amount of 20 mg/kg 30 minutes before the antigen challenge. For a control group, only a 0.5% CMC solution was administered. 
     The inhibitory activity on the PCA reaction in the treated group was calculated by the following formula: ##EQU2## wherein: a represents a mean value of blue spot area in the control group. 
     b represents a mean value of blue spot area in the treated group. 
     The inhibitory activity of the compounds of this invention determined by the above test are shown in Table 2. 
     
                       TABLE 2______________________________________Compound ofExample       Inhibition (%)______________________________________ 1            46 6            36 7            40 9            5211            3212            3613            3417            5021            3523            3124            4528            3429            3931            3232            3533            4735            4536            4039            3842            4845            5747            3864            3369            3473            4875            3280            3183            44DSCG*          8______________________________________ *DSCG Sodium Cromoglycate (administered at 100 mg/kg of body weight) 
    
     Example of preparations containing the compound of this invention are described hereinafter. 
     PREPARATION EXAMPLE 1 
     Tablets each containing 50 mg of the compound of the present invention are prepared from the following formulation. 
     
         ______________________________________Compound of Present Invention*                50     mgLactose              35     mgStarch               24.5   mgMagnesium Stearate   0.5    mgTotal                110    mg per tablet______________________________________ 
    
     PREPARATION EXAMPLE 2 
     A syrup preparation containing 10 mg of the compound of the present invention per ml was prepared from the following formulation. 
     
         ______________________________________Compound of Present Invention*                 1000    mgPolysolbate 80        1000    mgSyrup                  quantum sufficientTotal                 100     ml______________________________________ *6-(2-Phenylethyl)-[1,3,4]thiadiazolo[3,2a][1,2,3triazolo[4,5d]pyrimidin91H)-one 
    
     While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.