JPH1129480A - Pharmaceutical composition containing fused pyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical composition useful as a painkiller having little side effect, a nitric oxide synthetic enzyme inhibitor, etc., by including a fused pyrimidine derivative as an active ingredient. SOLUTION: This composition contains a fused pyrimidine derivative of the formula [R<1> is an alkyl or phenyl; R<2> is furyl, thienyl, pyridyl, naphthyl or phenyl (optionally having a substitution group); R<3> is H, a lower alkyl or (CO)R<2> ; X is N, CH or C-Ph (Ph is phenyl); when X is N, Y is CH and Z is CH, C-CN or C(CO)NH2 , and when X is CO or C Ph, both Y and Z are N], which is a new compound. The compound is exemplified by 5-n-butyl-7-(3,4,5- trimethoxybenzoylamino)-1,2,4-triazolo[1,5-a]pyrimidine. The daily dose of the preparation is 0.5-20 mg/kg. The composition is effective for treatment and prevention of septicemia, endotoxin shock, chronic arthrorheumatism, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing a novel condensed pyrimidine derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION The fused pyrimidine derivative as an active ingredient in the present invention is a novel compound which has not been described in any literature.

[0003]

The object of the present invention is to provide a pharmaceutical composition containing the above-mentioned novel compound as an active ingredient, such as an analgesic or a nitric oxide synthase inhibitor, which is useful as a pharmaceutical, as described later. Aim.

[0004]

According to the present invention, there is provided a pharmaceutical composition comprising a fused pyrimidine derivative represented by the following formula (1) as an active ingredient.

[0005]

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Wherein R ¹ represents an alkyl group or a phenyl group, and R ² represents a furyl group, a thienyl group, a pyridyl group, a naphthyl group or a lower alkyl group, a lower alkoxy group, a halogen atom, a halogen-substituted lower alkyl group as a substituent. Group, nitro group, phenyl lower alkoxy group, phenoxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, halogen-substituted lower alkoxy group,
Lower alkoxycarbonyl group, cyano group, phenyl group,
1 to 1 of groups selected from di-lower alkoxyphosphoryl lower alkyl groups, N- (tri-lower alkoxybenzoyl) amino groups, lower alkanoyloxy groups and hydroxyl groups
R ³ is a hydrogen atom, a lower alkyl group or — (CO) R ² (R ² is the same as above), X is a nitrogen atom, CH or C-Ph (Ph is A phenyl group), and Y and Z represent the following when X is a nitrogen atom:
Y is CH and Z is CH, C-CN or C (CO) NH ₂
And when X is CH or C-Ph, Y and Z each represent a nitrogen atom. The fused pyrimidine derivative represented by the general formula (1) is
It is useful as an active pharmaceutical ingredient. In particular, the above derivatives include analgesics (postoperative pain, migraine, gout, chronic pain, neuropathic pain, cancer pain, etc.), anti-inflammatory agents, antibacterial agents, hypoglycemic agents, lipid-lowering agents, blood pressure-lowering agents It is useful as an anticancer drug and the like, and is particularly preferably used as an analgesic, which has characteristics that do not show the side effects seen in conventional analgesics.

[0007] The above-mentioned derivative has an action of selectively inhibiting inducible nitric oxide synthase. As an inhibitor of the enzyme, for example, treatment and prevention of sepsis, endotoxin shock, rheumatoid arthritis and the like. It is effective for
In particular, such nitric oxide synthase inhibitors have the advantage of having very few side effects as seen in the prior art.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The following groups can be exemplified as the groups defined in the general formula (1) representing the above-mentioned derivatives as active ingredients in the present invention. In addition, the term "lower" used in these groups means 1 to 6 carbon atoms.

The lower alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te
Examples thereof include straight-chain or branched lower alkyl groups such as rt-butyl, pentyl, and hexyl groups. Examples of the alkyl group include a heptyl, octyl, nonyl, decyl group and the like in addition to the lower alkyl group.

The lower alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.

The halogen atom includes a fluorine atom, a chlorine atom,
Bromine and iodine atoms are included.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, and tridecafluorohexyl.

The furyl group includes 2-furyl and 3-furyl groups.

The thienyl group includes 2-thienyl and 3-thienyl groups.

The pyridyl group includes 2-pyridyl, 3-pyridyl and 4-pyridyl groups.

The naphthyl group includes 1-naphthyl and 2-naphthyl groups.

Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy and the like.

Examples of the lower alkylthio group include a methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio group and the like.

Examples of the lower alkylsulfinyl group include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like.

Examples of the lower alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

The halogen-substituted lower alkoxy group includes
Examples thereof include trifluoromethoxy, pentafluoroethoxy, heptafluoropropoxy, nonafluorobutoxy, undecafluoropentyloxy, and tridecafluorohexyloxy groups.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

Examples of the di-lower alkoxyphosphoryl lower alkyl group include dimethoxyphosphorylmethyl, diethoxyphosphorylmethyl, dipropoxyphosphorylmethyl, dibutoxyphosphorylmethyl, dipentyloxyphosphorylmethyl, dihexyloxyphosphorylmethyl, and 2-hexyloxyphosphorylmethyl.
(Dimethoxyphosphoryl) ethyl, 2- (diethoxyphosphoryl) ethyl, 3- (diethoxyphosphoryl) propyl, 4- (diethoxyphosphoryl) butyl, 5- (diethoxyphosphoryl) pentyl, 6- (diethoxyphosphoryl) hexyl And the like.

Examples of the N- (tri-lower alkoxybenzoyl) amino group include N- (3,4,5-trimethoxybenzoyl) amino, N- (3,4,5-triethoxybenzoyl) amino and N- (3 , 4,5-tripropoxybenzoyl) amino, N- (2,3,4-trimethoxybenzoyl) amino, N- (2,4,5-trimethoxybenzoyl) amino and the like.

As a substituent, a lower alkyl group, a lower alkoxy group, a halogen atom, a halogen-substituted lower alkyl group,
Nitro group, phenyl lower alkoxy group, phenoxy group,
Lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, halogen-substituted lower alkoxy, lower alkoxycarbonyl, cyano, phenyl, di-lower alkoxyphosphoryl lower alkyl, N-
Examples of the phenyl group which may have 1 to 3 groups selected from a (tri-lower alkoxybenzoyl) amino group, a lower alkanoyloxy group and a hydroxyl group include the following substituted phenyl groups in addition to an unsubstituted phenyl group. Can be illustrated.

2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-t-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy Phenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4
-Dimethoxyphenyl, 3,5-dimethoxyphenyl,
2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-
Trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-
Chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,
3-dichlorophenyl, 2,4-dichlorophenyl,
2,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4-dichloro-5-fluorophenyl, 2
-Trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl, 4-nonafluorobutylphenyl, 4-
Undecafluoropentylphenyl, 4-tridecafluorohexylphenyl, 2,3-bis (trifluoromethyl) phenyl, 2,4-bis (trifluoromethyl)
Phenyl, 3,4-bis (trifluoromethyl) phenyl, 3,5-bis (trifluoromethyl) phenyl,
3,4,5-tris (trifluoromethyl) phenyl,
2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 4-nitrophenyl
(2-phenylethoxy) phenyl, 4- (3-phenylpropoxy) phenyl, 4- (4-phenylbutoxy) phenyl, 4- (5-phenylpentyloxy) phenyl, 4- (6-phenylhexyloxy) phenyl, 2,4-dibenzyloxyphenyl, 3,5-dibenzyloxyphenyl, 4-benzyloxy-3,5-
Dimethoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 4-ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl , 4-pentylthiophenyl, 4-hexylthiophenyl, 2,4-dimethylthiophenyl, 3,4-dimethylthiophenyl,
3,5-dimethylthiophenyl, 2-methylsulfinylphenyl, 3-methylsulfinylphenyl, 4-methylsulfinylphenyl, 4-ethylsulfinylphenyl, 4-propylsulfinylphenyl, 4-butylsulfinylphenyl, 4-pentylsulfinylphenyl, 4-hexylsulfinylphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 4-propylsulfonylphenyl, 4-
Butylsulfonylphenyl, 4-pentylsulfonylphenyl, 4-hexylsulfonylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-pentafluoroethoxyphenyl, 4-heptafluoropropoxyphenyl , 4-nonafluorobutoxyphenyl,
4-undecafluoropentyloxyphenyl, 4-tridecafluorohexyloxyphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-propoxycarbonylphenyl, 4- Butoxycarbonylphenyl, 4-pentyloxycarbonylphenyl, 4-hexyloxycarbonylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, (1,1'-biphenyl)-
4-yl, (1,1′-biphenyl) -3-yl,
(1,1'-biphenyl) -2-yl, 2- (diethoxyphosphorylmethyl) phenyl, 3- (diethoxyphosphorylmethyl) phenyl, 4- (diethoxyphosphorylmethyl) phenyl, 4- (dimethoxyphosphorylmethyl) Phenyl, 4- (dipropoxyphosphorylmethyl)
Phenyl, 4- (dibutoxyphosphorylmethyl) phenyl, 4- (dipentyloxyphosphorylmethyl) phenyl, 4- (dihexyloxyphosphorylmethyl) phenyl, 4- [2- (dimethoxyphosphoryl) ethyl] phenyl, 4- [2- (Diethoxyphosphoryl) ethyl] phenyl, 4- [N- (3,4,5-trimethoxybenzoyl) amino] phenyl, 3- [N- (3,4,5-trimethoxybenzoyl) amino] phenyl, -[N-
(3,4,5-trimethoxybenzoyl) amino] phenyl, 4- [N- (3,4,5-triethoxybenzoyl) amino] phenyl, 4- [N- (3,4,5-tripropoxybenzoyl) ) Amino] phenyl, 4- [N-
(2,3,4-trimethoxybenzoyl) amino] phenyl, 4- [N- (2,4,6-trimethoxybenzoyl) amino] phenyl, 2-acetoxyphenyl, 3-
Acetoxyphenyl, 4-acetoxyphenyl, 4-propionyloxyphenyl, 4-butyryloxyphenyl, 4-valeryloxyphenyl, 4-pivaloyloxyphenyl, 4-hexanoyloxyphenyl, 4-heptanoyloxyphenyl, 2,3-diacetoxyphenyl, 2,4-diacetoxyphenyl, 3,4-diacetoxyphenyl, 3,5-diacetoxyphenyl, 3,
4,5-triacetoxyphenyl, 4-acetoxy-
3,5-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5
-Dihydroxyphenyl, 3,4,5-trihydroxyphenyl.

Among the derivatives represented by the general formula (1), those which are preferable as the active ingredient of the medicament of the present invention include those in which R ¹ is an alkyl group and X is CH or C—
Ph and compounds wherein X is a nitrogen atom and Z is C-CN or C (CO) NH ₂ , wherein R ¹ is an alkyl group and R ³ is a hydrogen atom are more preferred. . Among these preferred condensed pyrimidine derivatives, R ² further comprises a lower alkyl group, a lower alkylthio group, a halogen-substituted lower alkyl group, a phenyl group having 1 to 2 halogen atoms or 3 lower alkoxy groups as substituents. Alternatively, those which are naphthyl groups are preferred.

In the pharmaceutical composition of the present invention, one of the most preferable examples of the active ingredient is 5-n-butyl-7.
-(3,4,5-trimethoxybenzoylamino)-
1,2,4-triazolo [1,5-a] pyrimidine, 2
-N-butyl-8-cyano-4- (2,4-dichlorobenzoylamino) imidazo [1,5-a] pyrimidine and 2-n-butyl-8-cyano-4- (3,4,5-tri Methoxybenzoylamino) imidazo [1,5-a]
Pyrimidine can be exemplified.

The fused pyrimidine derivative as an active ingredient in the present invention can be produced by various methods. Specific examples thereof will be described in detail below with reference to reaction schemes.

[0030]

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Wherein R ¹ , R ² , X, Y and Z are as defined above. R ^3a is a group — (CO) R ² (R ² is as defined above)
And A represents a halogen atom. In the above reaction scheme 1, the ring condensation reaction between the nitrile derivative (2) and the compound (3) is performed in an inert solvent such as benzene, toluene, xylene, acetic acid, and ethanol in the range of room temperature to reflux temperature. It takes about 3 to 50 hours below. The ratio of the two compounds used is generally about equimolar.

The compound (4) obtained by the above reaction is
Then, this is reacted with an acid halide (5) to convert it into the active ingredient compound (1a) of the present invention.
In this case, the compound (1b) may be obtained as a by-product in some cases. This reaction can be carried out in a suitable solvent in the presence of a deoxidizing agent. Here, examples of the solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ether, and chain or cyclic ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran (THF) and 1,4-dioxane. And ketones such as acetone, ethyl methyl ketone and acetophenone, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Examples of the deoxidizing agent include tertiary amines such as triethylamine, N, N-diethylaniline, N-methylmorpholine, pyridine and 4-dimethylaminopyridine, and alkali metal hydrides such as sodium hydride and potassium hydride. And the like can be preferably exemplified.

The amounts of the acid halide (5) and the deoxidizing agent to be used in the above reaction with respect to the compound (4) are not particularly limited, but the acid halide is usually about equimolar and the deoxidizing agent is usually equimolar. The reaction is completed in about 0.5 to 20 hours under conditions ranging from room temperature to reflux temperature. In general, when the amount of the acid halide used is increased, the yield of the compound (1b) tends to increase.

When the compound (1a) is reacted again with the acid halide (5) in the same manner as described above, the compound (1b) can be obtained.

Here, the intermediate compound (4) in the above reaction scheme-1 can also be produced, for example, by the method shown in the following reaction scheme-2.

[0036]

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Wherein R ¹ , X, Y and Z are as defined above. E represents a lower alkyl group, and Q represents a halogen atom. The condensation reaction between the compound (6) and the compound (3) in the above-mentioned reaction step formula-2 is carried out in a suitable inert solvent at a temperature ranging from room temperature to the boiling point of the solvent. Examples of the inert solvent used here include acetic acid, ethanol, benzene, toluene, xylene, THF, and the like.
In general, the ratio of the compound (6) to the compound (3) used is preferably about equimolar, and the reaction is completed in about 2 to 5 hours.

The halogenation reaction of the compound (7) obtained as described above can be carried out using a suitable halogenating agent, for example, phosphorus oxychloride, phosphorus oxybromide and the like. Since the halogenating agent also serves as a solvent, it is not necessary to use a solvent in the reaction, but other inert solvents such as benzene, toluene, and xylene can be used. If necessary, N, N-dimethylaniline, N, N
-Use a deoxidizing agent such as diethylaniline, triethylamine, etc.
It can be added in a molar amount of 10 to 10 times. Reaction is at room temperature
It is carried out under a temperature condition of about 150 degrees for about 0.5 to 12 hours.

The halide (8) obtained by the above reaction can be converted to the compound (4) by treating it with aqueous ammonia. This treatment does not require a solvent, and can be usually carried out by heating the compound (8) together with an excess amount of aqueous ammonia at about 100 to 150 ° C. for about 1 to 12 hours.

[0040]

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Wherein R ¹ , R ² , A, Q, X, Y and Z are as defined above. R ^3b represents a lower alkyl group. The active ingredient compound (1c) of the present invention is obtained by the above reaction scheme-
3 can be produced. That is, first, the compound (8) and the amine (9) are heated in an inert solvent such as methanol or ethanol in the presence of a deoxidizing agent such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate at a temperature of about the reflux temperature. The compound (10) is treated for about 1 to 6 hours to obtain a compound (10), which is reacted with an acid halide (5) to give a compound (1c).

The reaction of the above compound (10) with the acid halide (5) can be carried out according to the method shown in the above reaction scheme 1.

[0043]

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Wherein R ¹ , X, Y and Z are as defined above. R ^2a has a lower alkanoyloxy group as a substituent, and further has a lower alkyl group, a lower alkoxy group, a halogen atom, a halogen-substituted lower alkyl group, a nitro group, a phenyl lower alkoxy group, a phenoxy group, a halogen-substituted lower alkoxy group, and a cyano group. R ^3c is a hydrogen atom, a lower alkyl group or a group — (CO) —R ^2a (R ^2a is the same as defined above), which may have 1 to 2 groups selected from a group, a phenyl group and a lower alkanoyloxy group. The same ^applies to R ^2b , R ^2b is a substituted phenyl group defined as R ^2a , wherein the site corresponding to the lower alkanoyloxy group is a hydroxyl group, and R ^3d is a hydrogen atom, a lower alkyl group or a group — (C
O) -R ^2b the (R ^2b are the same), respectively. The active ingredient compound (1d) of the present invention can be converted into the active ingredient compound (1e) of the present invention by hydrolyzing it. The hydrolysis reaction is performed in an inert solvent such as methanol or ethanol, an aqueous sodium hydroxide solution,
It can be carried out by treating with an aqueous solution of potassium hydroxide. The reaction is generally completed in 10 minutes to 3 hours under a temperature condition of 0 ° C. to room temperature.

[0045]

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Wherein R ¹ , X, Y and Z are as defined above. R ^2c has a lower alkylthio group as a substituent, and further has a lower alkyl group, a lower alkoxy group, a halogen atom,
A halogen-substituted lower alkyl group, a nitro group, a phenyl lower alkoxy group, a phenoxy group, a halogen-substituted lower alkoxy group, a cyano group, a phenyl group which may have one or two groups selected from a phenyl group and a lower alkylthio group, R ^3e represents a hydrogen atom, a lower alkyl group or a group — (C
O) -R ^2c (R ^2c is as defined above), and R ^2d is a substituted phenyl group defined by R ^{2c in} which the portion corresponding to the lower alkylthio group is a lower alkylsulfinyl group or a lower alkylsulfonyl group. , R ^3f represents a hydrogen atom, a lower alkyl group or a group — (CO) —R ^2d (R ^2d is the same as above). The oxidation reaction of the compound (1f) is performed using acetic acid, dichloromethane,
In an inert solvent such as carbon tetrachloride, the reaction is carried out using an aqueous solution of hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate or the like as an oxidizing agent.

When the above oxidation reaction is limited to lower alkylsulfinyl groups, the amount of the oxidizing agent used is 1 to a small excess equivalent, and the oxidizing agent is used at a temperature of about 0 ° C. to room temperature.
The reaction may be carried out for minutes to 2 hours.

On the other hand, when the oxidation reaction proceeds to a lower alkylsulfonyl group, the amount of the oxidizing agent used is 2
To an excess equivalent, and if necessary, a catalyst such as sodium tungstate is added.
The reaction is preferably performed for 5 minutes to 2 hours. The sulfonyl compound can also be produced by re-oxidizing the sulfinyl compound. In that case, the reaction conditions may be any of the above two conditions.

The compound of the present invention can be converted into a pharmaceutically acceptable acid addition salt by subjecting it to a suitable acidic compound according to a conventional method to form a pharmaceutically acceptable acid addition salt. Also includes such acid addition salts. The acid addition salt has the same pharmacological activity as the compound in the free form, and can be similarly used as an active pharmaceutical ingredient.

Examples of the acidic compounds capable of forming the above-mentioned acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid. And organic acids such as benzenesulfonic acid.

Further, among the active ingredient compounds of the present invention, R
Those in which ³ is a hydrogen atom can be converted into an alkali metal salt, such as a sodium salt, a potassium salt, or the like, or an alkaline earth metal salt, such as a calcium salt, a magnesium salt, or the like, or a copper salt, according to a conventional method. These salts are also included in the active ingredients of the present invention, and can be used as similar active pharmaceutical ingredients.

The target compound obtained in each of the above steps can be easily isolated and purified by ordinary separation means. Examples of the separation means include various commonly used methods, for example, a solvent extraction method, a recrystallization method, column chromatography, ion exchange chromatography and the like.

The pharmaceutical composition of the present invention is put to practical use in the form of a general pharmaceutical preparation by using the above-mentioned active ingredient compound together with a suitable nontoxic pharmaceutical carrier. Examples of the pharmaceutical carrier include diluents or excipients such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant, and a lubricant which are usually used depending on the use form of the pharmaceutical. These can be appropriately selected and used depending on the dosage unit form of the obtained preparation.

As the dosage unit form of the pharmaceutical composition (pharmaceutical preparation) of the present invention, various forms can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions and suspensions. Emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments and the like.

In the case of molding into a tablet form, the above-mentioned preparation carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and potassium phosphate;
Binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone; sodium carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, dried Disintegrants such as starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride; sucrose, stearin, cocoa butter; Disintegration inhibitors such as hydrogenated oil; Absorption accelerators such as quaternary ammonium bases and sodium lauryl sulfate; Glycerin, starch and the like Moisturizers; starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid; purified talc, stearates, boric acid powder may be used a lubricant such as polyethylene glycol.

Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

In the case of molding into the form of pills, pharmaceutical carriers such as glucose, lactose, starch, cocoa butter,
Excipients such as hardened vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; disintegrating agents such as laminaran and agar can be used.

For shaping in the form of suppositories, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride and the like can be used as pharmaceutical carriers.

Capsules are prepared according to a conventional method, usually by mixing the active ingredient compound of the present invention with the various pharmaceutical carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like.

When the pharmaceutical agent of the present invention is prepared as an injection, such as a liquid, emulsion, or suspension, it is preferably sterilized and isotonic with blood. As a diluent, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to adjust the isotonic solution may be contained in the drug of the present invention, and ordinary solubilizers, buffers, soothing agents and the like are added. May be.

Further, the pharmaceutical agent of the present invention may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like and other pharmaceuticals, if necessary.

For molding into the form of an ointment such as a paste, cream or gel, for example, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as a diluent.

The amount of the active ingredient compound represented by the general formula (1) to be contained in the medicament of the present invention is not particularly limited and may be appropriately selected from a wide range. %.

The method of administration of the pharmaceutical preparation of the present invention is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, degree of disease, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered, and injections are administered intravenously, alone or as a mixture with ordinary replenishers such as glucose and amino acids. Intramuscularly, intradermally, subcutaneously or intraperitoneally, and suppositories may be administered rectally alone.

The dose of the above pharmaceutical preparation is appropriately selected depending on the usage, age and sex of the patient, other conditions, the degree of the disease, etc. Usually, the amount of the active ingredient compound is about 0,1 kg / kg body weight per day. About 5 to 20 mg, preferably 1 to 1
The dosage is preferably about 0 mg, and the preparation can be administered in 1 to 4 times a day.

[0066]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, a production example of a starting compound for producing a compound as an active ingredient in the present invention will be described as a reference example, and then a production example of an active ingredient compound will be described as an example. Examples of pharmacological tests performed using the active ingredient compounds and examples of preparations of the pharmaceutical composition of the present invention are also described.

[0067]

Reference Example 1 Production of 4-amino-8-cyano-2-phenylimidazo [1,5-a] pyrimidine 1.9 g of 5-amino-4-cyanoimidazole and 2.6 g of benzoylacetonitrile were dissolved in 5 ml of acetic acid.
Stirred at 100 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure, chloroform-ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration, washed sequentially with water and ethyl acetate, and recrystallized from ethanol to obtain 630 mg of the desired compound (melting point: 314-
316 ° C).

[0068]

Reference Examples 2 to 10 The following starting compounds were produced in the same manner as in Reference Example 1.

(2) 4-amino-2-n-butyl-8-
Cyanoimidazo [1,5-a] pyrimidine (melting point: 25
(6 to 258 ° C) (3) 7-amino-5-ethyl-1,2,4-triazolo [1,5-a] pyrimidine (melting point: 194 to 197)
° C, recrystallization solvent: ethanol-n-hexane) (4) 7-amino-5-n-propyl-1,2,4-triazolo [1,5-a] pyrimidine (melting point: 139-1)
42 ° C., recrystallization solvent: ethanol-n-hexane) (5) 7-amino-5-n-butyl-1,2,4-triazolo [1,5-a] pyrimidine (melting point: 149 to 15)
1 ° C, recrystallization solvent: chloroform-n-hexane) (6) 7-amino-5-n-pentyl-1,2,4-triazolo [1,5-a] pyrimidine (melting point: 178-1)
81 ° C., recrystallization solvent: ethanol-n-hexane) (7) 7-amino-5-n-octyl-1,2,4-triazolo [1,5-a] pyrimidine (melting point: 148 to 1)
50 ° C, recrystallization solvent: ethanol-n-hexane) (8) 4-amino-2-n-butyl-8-carbamoylimidazo [1,5-a] pyrimidine (9) 7-amino-5-n-butyl -2-phenyl-
1,2,4-triazolo [1,5-a] pyrimidine (melting point: 211 to 213 ° C., recrystallization solvent: ethanol-n-
Hexane) (10) 7-amino-5-ethyl-2-phenyl-1,
2,4-triazolo [1,5-a] pyrimidine (melting point:
224 to 226 ° C, recrystallization solvent: ethanol-n-hexane)

[0070]

Reference Example 11 7-amino-5-n-butyl-1,
Production of 2,4-triazolo [1,5-a] pyrimidine Step (1) 34.6 g of 3-amino-1,2,4-triazole and 3
A solution of 6-5.0 g of -oxoheptanoic acid methyl ester in 40 ml of toluene was refluxed with heating at 110 ° C for 3 hours. After cooling, toluene was distilled off under reduced pressure, and the residue was recrystallized from ethanol-n-hexane to give 5-n-butyl-7-hydroxy-1,2,4-triazolo [1,5-a] pyrimidine colorless. 63.9 g of crystals were obtained.

Step (2): 80 ml of phosphorus oxybase was added to 19.2 g of the crystals obtained in the above step (1), and the mixture was heated under reflux for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was poured into ice water, the mixture was neutralized with anhydrous sodium acetate, extracted with dichloromethane, and the organic layer was collected. This was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 2) to give 5-n-butyl-7-chloro-1,2,4-triazolo [1,5 -A] Pyrimidine pale red oil 1
4.9 g were obtained.

8.8 g of the compound obtained in the above step and 25
% Ammonia water was sealed in a stainless steel sealed tube and heated at 120 ° C. for 22 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, and recrystallized from methanol-n-hexane to give 3.7 g of the target compound as colorless crystals. This was the same as the compound shown in Reference Example 5 (5).

[0073]

Example 1 8-cyano-2-phenyl-4- (3,
Preparation of 4,5-trimethoxybenzoylamino) imidazo [1,5-a] pyrimidine Crystal 300 obtained in Reference Example 1 in 3.0 ml of pyridine
Then, 294 mg of 3,4,5-trimethoxybenzoyl chloride was added under ice-cooling and stirring. The suspension was stirred at 0 ° C. for 1 hour and then at room temperature for 10 hours. Chloroform was added to the reaction mixture, and the precipitated crystals were collected by filtration.
The crystals were washed sequentially with water, ethanol and chloroform to obtain 100 mg of crystals of the target compound. Table 1 shows the structure and melting point of the obtained compound.

[0074]

Examples 2 to 13 The compounds shown in Table 1 were prepared in the same manner as in Example 1.

[0075]

[Table 1]

[0076]

[Table 2]

[0077]

Examples 14 to 39 Using the appropriate starting materials and carrying out the same reactions as in the above Reference Examples and Examples, the following compounds can be produced. It can be used as an active ingredient.

Example 14 4-benzoylamino-2-
n-Butyl-8-cyanoimidazo [1,5-a] pyrimidine.

Example 15 2-n-butyl-8-cyano-4- (2-trifluoromethylbenzoylamino) imidazo [1,5-a] pyrimidine.

(Melting point: 192 to 195 ° C., recrystallization solvent:
Example 16: 2-n-butyl-8-cyano-4- (2-
Methylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 17 2-n-butyl-4- (2-
(Chlorobenzoylamino) -8-cyanoimidazo [1,
5-a] Pyrimidine.

(Melting point: 205-207 ° C., recrystallization solvent:
Example 18 ... 8-cyano-2-ethyl-4- (3,4,
5-trimethoxybenzoylamino) imidazo [1,5
-A] pyrimidine.

Example 19 8-cyano-2-n-octyl-4- (3,4,5-trimethoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 20 2-n-butyl-4- (3,3
4,5-Trimethoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 21 2-ethyl-4- (3,4,
5-trimethoxybenzoylamino) imidazo [1,5
-A] pyrimidine.

Example 22 2-N-octyl-4-
(3,4,5-trimethoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 23 2-n-butyl-4- (2-
Trifluoromethylbenzoylamino) imidazo [1,
5-a] Pyrimidine.

Example 24 2-N-butyl-4- (2-
Methylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 25 2-n-butyl-4- (2-
Chlorobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 26 5-methyl-7- (3,4,
5-trimethoxybenzoylamino) -1,2,4-triazolo [1,5-a] pyrimidine.

Example 27 5-phenyl-7- (3,3
4,5-trimethoxybenzoylamino) -1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 28 7-benzoylamino-5
Phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 29 7- (2-Methylbenzoylamino) -5-phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 30 7- (2-chlorobenzoylamino) -5-phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 31 5-phenyl-7- (2-trifluoromethylbenzoylamino) -1,2,4-triazolo [1,5-a] pyrimidine

Example 32: 5-n-butyl-7- (3,
4,5-triethoxybenzoylamino) -1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 33: 5-n-butyl-7- (2-
Pentafluoroethylbenzoylamino) -1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 34 5-N-hexyl-7-
(3,4,5-trimethoxybenzoylamino) -1,
2,4-triazolo [1,5-a] pyrimidine.

Example 35 5-N-heptyl-7-
(3,4,5-trimethoxybenzoylamino) -1,
2,4-triazolo [1,5-a] pyrimidine.

Example 36: 5-n-nonyl-7- (3,
4,5-trimethoxybenzoylamino) -1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 37: 5-n-decyl-7- (3,
4,5-trimethoxybenzoylamino) -1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 38: 5-n-butyl-7- (2,
3,4-trimethoxybenzoylamino) -1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 39 5-n-butyl-7- (2,
4,5-trimethoxybenzoylamino) -1,2,4
-Triazolo [1,5-a] pyrimidine.

[0104]

Examples 40 and 41 2-n-butyl-8-cyano-4- (2-methoxybenzoylamino) imidazo [1,5-a] pyrimidine and 2-n-butyl-8-cyano-4- [N , N-bis (2-methoxybenzoyl)
Production of Amino] imidazo [1,5-a] pyrimidine Using the compound obtained in Reference Example 2 and 2-methoxybenzoyl chloride, the same reaction as in Example 1 was carried out,
The crude product was recrystallized from dichloromethane-diethyl ether to obtain colorless crystals of 2-n-butyl-8-cyano-4- (2-methoxybenzoylamino) imidazo [1,5-a] pyrimidine. Next, the recrystallized mother liquor was concentrated, and the residue was recrystallized from ethyl acetate to give 2-n-butyl-8-cyano-4- [N, N-bis (2-methoxybenzoyl) amino] imidazo [1 Colorless crystals of [, 5-a] pyrimidine were obtained. Table 2 shows the structures and melting points of the obtained compounds.

[0105]

Examples 42 to 54 In the same manner as in Example 1, the compounds shown in Table 2 were produced.

[0106]

Example 55 Preparation of 5-n-butyl-7- (2-methylsulfinylbenzoylamino) -1,2,4-triazolo [1,5-a] pyrimidine 1.0 g of the compound obtained in Example 54 0.4 g of a 30% aqueous hydrogen peroxide solution was added to a 20 ml solution of acetic acid, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: chloroform: ethyl acetate = 1: 2 → chloroform: methanol = 10: 1).
And recrystallized from ethanol-n-hexane to obtain 0.76 g of the target compound as colorless crystals. Table 2 shows the structure and melting point of the obtained compound.

[0107]

Example 56 Preparation of 5-n-butyl-7- (2-methylsulfonylbenzoylamino) -1,2,4-triazolo [1,5-a] pyrimidine 1.0 g of the compound obtained in Example 54 0.8 g of a 30% aqueous hydrogen peroxide solution was added to a solution of acetic acid in 20 ml, and the mixture was stirred at 80 ° C. for 2 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: ethyl acetate = 1: 2 → chloroform: methanol = 10:
Purification in 1) and further recrystallization from ethanol-n-hexane gave 0.67 g of the target compound as colorless crystals. Table 2 shows the structure and melting point of the obtained compound.

[0108]

Example 57 In the same manner as in Example 1, the compounds shown in Table 2 were produced.

[0109]

Example 58 The compounds shown in Table 2 were produced in the same manner as in Example 56.

[0110]

Examples 59 to 74 The compounds shown in Table 2 were prepared in the same manner as in Example 1.

[0111]

Example 75 The compounds shown in Table 2 were prepared in the same manner as in Example 55.

[0112]

Example 76 In the same manner as in Example 1, the compounds shown in Table 2 were produced.

[0113]

Example 77 5-n-butyl-7- (4-hydroxybenzoylamino) -1,2,4-triazolo [1,5
-A] Preparation of pyrimidine 1.41 g of the compound obtained in Example 76 in ethanol 2
The 0 ml suspension was cooled to 0 ° C, 5 ml of a 2N aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at 0 ° C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with water and washed with dichloromethane. The aqueous layer was acidified by adding hydrochloric acid, and the precipitated crude crystals were collected by filtration and recrystallized from ethanol-chloroform-n-hexane to give 1.12 g of the target compound as colorless crystals.
I got Table 2 shows the structure and melting point of the obtained compound.

[0114]

Example 78 5-n-butyl-7- [Nn-butyl-N- (3,4,5-trimethoxybenzoyl) amino] -1,2,4-triazolo [1,5-a] Production of pyrimidine 3.16 g of the compound obtained in Step (2) of Reference Example 11,
1.10 g of n-butylamine and 1.26 g of anhydrous sodium hydrogencarbonate were added to 20 ml of ethanol.
For 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 1: 2) and further recrystallized from n-hexane to give 5-n-butyl-7-.
n-butylamino-1,2,4-triazolo [1,5-
a) 2.72 g of pyrimidine were obtained. Next, in the same manner as in Example 1 using 1.12 g of the obtained compound and 1.08 g of 3,4,5-trimethoxybenzoyl chloride, 0.52 g of colorless crystals of the target compound were obtained. Table 2 shows the structure and melting point of the obtained compound.

[0115]

[Table 3]

[0116]

[Table 4]

[0117]

[Table 5]

[0118]

[Table 6]

[0119]

[Table 7]

[0120]

[Table 8]

[0121]

[Table 9]

[0122]

[Table 10]

[0123]

Examples 79 to 141 The following compounds can be prepared by using the appropriate starting materials and conducting the same reactions as in the Reference Examples and Examples, all of which are used as active ingredients in the present invention. be able to.

Example 79 7- (4-Benzyloxybenzoylamino) -5-n-butyl-2-phenyl-
1,2,4-triazolo [1,5-a] pyrimidine.

Example 80 7- (2-benzyloxybenzoylamino) -5-n-butyl-2-phenyl-
1,2,4-triazolo [1,5-a] pyrimidine.

Example 81: 5-n-butyl-7- (2-
Phenoxybenzoylamino) -2-phenyl-1,
2,4-triazolo [1,5-a] pyrimidine.

Example 82: 5-n-butyl-7- (2-
Methylthiobenzoylamino) -2-phenyl-1,
2,4-triazolo [1,5-a] pyrimidine.

Example 83: 5-n-butyl-7- (2-
Methylsulfinylbenzoylamino) -2-phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 84: 5-n-butyl-7- (2-
Methylsulfonylbenzoylamino) -2-phenyl-
1,2,4-triazolo [1,5-a] pyrimidine.

Example 85 5-n-butyl-7- (2-
Chlorobenzoylamino) -2-phenyl-1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 86: 5-n-butyl-7- (2,
4-dichloro-5-fluorobenzoylamino) -2-
Phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 87: 5-n-butyl-7- (2-
Nitrobenzoylamino) -2-phenyl-1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 88 5-N-butyl-2-phenyl-7- (2-trifluoromethylbenzoylamino)
-1,2,4-triazolo [1,5-a] pyrimidine.

Example 89 5-n-butyl-2-phenyl-7- (4-trifluoromethoxybenzoylamino) -1,2,4-triazolo [1,5-a] pyrimidine.

Example 90: 5-n-butyl-7- (4-
(Methoxycarbonylbenzoylamino) -2-phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 91 5-n-butyl-7- (4-
Cyanobenzoylamino) -2-phenyl-1,2,4
-Triazolo [1,5-a] pyrimidine.

Example 92 5-n-butyl-2-phenyl-7- (2-phenylbenzoylamino) -1,2,2
4-triazolo [1,5-a] pyrimidine.

Example 93: 5-n-butyl-7- (4-
Diethoxyphosphorylmethylbenzoylamino) -2-
Phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 94: 5-n-butyl-2-phenyl-7- [4- (3,4,5-trimethoxybenzoylamino) benzoylamino] -1,2,4-triazolo [1,5- a) Pyrimidine.

Example 95 5-n-butyl-7- (1-
Naphthoylamino) -2-phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 96: 5-n-butyl-7- (2-
Furoylamino) -2-phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 97 5-n-butyl-2-phenyl-7- (2-thenoylamino) -1,2,4-triazolo [1,5-a] pyrimidine.

Example 98 5-n-butyl-7- (isonicotinoylamino) -2-phenyl-1,2,4-triazolo [1,5-a] pyrimidine.

Example 99 7- (2-acetoxybenzoylamino) -5-n-butyl-2-phenyl-1,
2,4-triazolo [1,5-a] pyrimidine.

Example 100 5-n-butyl-7- (2
-Hydroxybenzoylamino) -2-phenyl-1,
2,4-triazolo [1,5-a] pyrimidine.

Example 101 2-n-butyl-4- (benzyloxybenzoylamino) -8-cyanoimidazo [1,5-a] pyrimidine.

Example 102 2-n-butyl-8-cyano-4- (2-phenoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 103 2-n-butyl-8-cyano-4- (2-methylthiobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 104 2-n-butyl-8-cyano-4- (2-methylsulfinylbenzoylamino)
Imidazo [1,5-a] pyrimidine.

Example 105 2-n-butyl-8-cyano-4- (2-methylsulfonylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 106 2-n-butyl-8-cyano-4- (4-trifluoromethoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 107 2-n-butyl-8-cyano-4- (4-methoxycarbonylbenzoylamino)
Imidazo [1,5-a] pyrimidine.

Example 108 2-n-butyl-8-cyano-4- (4-cyanobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 109 2-n-butyl-8-cyano-4- (2-phenylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 110 2-n-butyl-8-cyano-4- (4-diethoxyphosphorylmethylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 111 2-n-butyl-8-cyano-4- [4- (3,4,5-trimethoxybenzoylamino) benzoylamino] imidazo [1,5-a] pyrimidine.

Example 112 2-n-butyl-8-cyano-4- (2-furoylamino) imidazo [1,5-
a) Pyrimidine.

Example 113 2-n-butyl-8-cyano-4- (2-thenoylamino) imidazo [1,5-
a) Pyrimidine.

Example 114 2-n-butyl-8-cyano-4- (isonicotinoylamino) imidazo [1,5
-A] pyrimidine.

Example 115 4- (2-acetoxybenzoylamino) -2-n-butyl-8-cyanoimidazo [1,5-a] pyrimidine.

Example 116: 2-n-butyl-8-cyano-4- (2-hydroxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 117: 2-n-butyl-4- (2
-Benzyloxybenzoylamino) -8-carbamoylimidazo [1,5-a] pyrimidine.

Example 118 2-n-butyl-8-carbamoyl-4- (2-phenoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 119 ... 2-n-butyl-8-carbamoyl-4- (2-chlorobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 120 2-N-butyl-8-carbamoyl-4- (2,4-dichlorobenzoylamino)
Imidazo [1,5-a] pyrimidine.

Example 121 2-n-butyl-8-carbamoyl-4- (2-nitrobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 122 2-n-butyl-8-carbamoyl-4- (2-trifluoromethylbenzoylamino) -imidazo [1,5-a] pyrimidine.

Example 123 2-n-butyl-8-carbamoyl-4- (2-methylthiobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 124 2-n-butyl-8-carbamoyl-4- (2-methylsulfinylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 125 2-n-butyl-8-carbamoyl-4- (2-methylsulfonylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 126 2-n-butyl-8-carbamoyl-4- (4-trifluoromethoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 127 2-n-butyl-8-carbamoyl-4- (4-methoxycarbonylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 128 2-n-butyl-8-carbamoyl-4- (4-cyanobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 129 2-n-butyl-8-carbamoyl-4- (2-phenylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 130 2-n-butyl-8-carbamoyl-4- (4-diethoxyphosphorylmethylbenzoylamino) imidazo [1,5-a] pyrimidine.

Example 131 2-n-butyl-8-carbamoyl-4- [4- (3,4,5-trimethoxybenzoylamino) benzoylamino] imidazo [1,5-
a) Pyrimidine.

Example 132 2-n-butyl-8-carbamoyl-4- (1-naphthoylamino) imidazo [1,5-a] pyrimidine.

Example 133: 2-n-butyl-8-carbamoyl-4- (2-furoylamino) imidazo [1,
5-a] Pyrimidine.

Example 134 2-n-butyl-8-carbamoyl-4- (2-thenoylamino) imidazo [1,
5-a] Pyrimidine.

Example 135 ... 2-n-butyl-8-carbamoyl-4- (isonicotinoylamino) imidazo [1,5-a] pyrimidine.

Example 136 ... 4- (2-acetoxybenzoylamino) -2-n-butyl-8-carbamoylimidazo [1,5-a] pyrimidine.

Example 137: 2-n-butyl-8-carbamoyl-4- (2-hydroxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 138 2-N-butyl-8-carbamoyl-4- (2-methoxybenzoylamino) imidazo [1,5-a] pyrimidine.

Example 139 ... 2-n-butyl-4- (4
-T-butylbenzoylamino) -8-carbamoylimidazo [1,5-a] pyrimidine.

Example 140 2-n-butyl-8-carbamoyl-4- (2-bromobenzoylamino) imidazo [1,5-a] pyrimidine.

Example 141 2-n-butyl-8-carbamoyl-4- [N, N-bis (2-methoxybenzoyl) amino] imidazo [1,5-a] pyrimidine.

[0187]

[Pharmacological test example 1] D. First, the pain threshold of the left hind footpad of each rat was determined using a pressure-stimulated analgesic effect measuring device (manufactured by Unicom) using the Randall-Selit method [Randall, LO and Sellitto, JJ, Ar
ch.Int.Pharmacodyn., 111 , 409 (1957)]. The obtained value is referred to as “previous value”.

One hour after the measurement of the previous value, the experimental group contained:
A 5% gum arabic suspension of the active ingredient compound of the present invention and a 5% gum arabic suspension (without the active ingredient compound of the present invention) in a control group at a rate of 10 ml / kg (active ingredient dose of 1 mg) / Kg) orally,
One hour later, a physiological saline solution of substance P (25 ng / 0.1 ml) was injected subcutaneously into the left hind footpad of each rat.

Next, at a predetermined time after the substance P injection, the pain threshold value of the left hind footpad of each group of rats was measured in the same manner as described above, and this was defined as “post-value”.

The pain threshold recovery rate (%) was calculated from the measured value (post-value) and the pre-value of each group according to the following equation.

Pain threshold recovery rate (%) = [(average value of experimental group) − (average value of control group)] / [(average previous value of control group) −
(Average after control group)] × 100 The results obtained (maximum recovery rate) are shown in Table 3 below.

[0192]

[Table 11]

From the above Table 3, it is clear that the active ingredient compound of the present invention exhibits an excellent analgesic effect.

[0194]

[Pharmacological Test Example 2] Spraque Dawl
ey) Male rats (6-9 weeks old, 200-250 g) were sacrificed by cervical dislocation, and the thoracic aorta was immediately excised and the surrounding connective tissue was detached. Next, this was divided into 5 to 7 slices, each of which was cut vertically, and then the endothelial cells were removed by rubbing the vascular lumen with a cleaning swab in order to eliminate the influence of cNOS present in the vascular endothelial cells. Then, a specimen was prepared.

A Krebs-Henseleit solution (NaCl 11) to which a dimethyl sulfoxide solution of the active ingredient compound of the present invention (test compound) adjusted to a concentration of 30 μM and L-arginine to a concentration of 400 μM was further added.
8.3 mM, KCl 4.7 mM, CaCl ₂ 2.5 m
M, KH ₂ PO ₄ 1.2 mM, MgSO ₄ 1.2 mM,
NaHCO ₃ 25.0 mM and glucose 11.1 m
The sample was placed in M) and incubated at 37 ° C. for 30 minutes. Next, lipopolysaccharide (LPS)
Was added at a concentration of 1000 ng / ml and incubated at 37 ° C. for 24 hours (experimental group using test compounds, present invention group).

Next, the supernatant was placed in a 96-well plate and described in the literature [Shinogen Chemistry Experiment Course 10, Blood vessels, endothelium and smooth muscle, 135
Page, the Japanese Biochemical Society, Tokyo Kagaku Dojin, in accordance with NO ₂ measurement method described in 1993], the NO ₂ were developed with grease (Griess) solution, bio kinetics Chicks leader (Biokinet
ics reader, BIO-TEK Instruments, EL-340
And the amount of accumulated NO ₂ was calculated.

Further, a blood vessel piece of the specimen was dissolved in a 1N aqueous solution of sodium hydroxide, and a Bio-Rad DC protein assay kit (Bio-Rad DC protein assay kit, Bio-Rad
d Laboratories) and color spectrophotometer (Spectrophotometer, HITACHI, U-300)
0 type) to calculate the amount of protein. From these values, the amount of NO ₂ produced per mg of protein was determined.

On the other hand, the same test was repeated for a control group to which dimethyl sulfoxide was added instead of the test compound and a control group to which LPS was not added.

From the NO ₂ production amount per mg of protein in each group obtained as described above, the iNOS induction inhibition rate was calculated according to the following equation.

Inhibition rate (%) = ｛1-[(value of the present invention) −
(Control group value)] / [(Control group value)-(Control group value)]｝ × 100 The obtained results are shown in Table 4.

[0201]

[Table 12]

Table 4 shows that the active ingredient compound of the present invention
It is clear that it inhibits iNOS induction by PS.

[0203]

Formulation Example 1 Preparation of Tablet Using the compound obtained in Example 9 as an active ingredient, a tablet for oral administration (100 mg containing 5 mg per tablet)
0 tablets) were prepared according to the following formulation:

Compound obtained in Example 9 5 g Lactose (Japanese Pharmacopoeia product) 50 g Corn starch (Japanese Pharmacopoeia product) 25 g Microcrystalline cellulose (Japanese Pharmacopoeia product) 25 g Methylcellulose (Japanese Pharmacopoeia product) 1.5 g Magnesium stearate ( 1 g That is, the compound obtained in Example 9 according to the above-mentioned formulation, lactose,
Corn starch and microcrystalline cellulose are mixed well, and the mixture is granulated with a 5% aqueous solution of methylcellulose,
After carefully drying through a 00 mesh sieve, the dried granules were passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets to obtain the desired tablets.

[0205]

Formulation Example 2 Preparation of Capsules Using the compound obtained in Example 44 as an active ingredient, 2 capsules for oral administration containing 10 mg per capsule.
One-sided hard gelatin capsules (1000 pieces) were prepared according to the following formulation.

Compound obtained in Example 44 10 g Lactose (Japanese Pharmacopoeia product) 80 g Starch (Japanese Pharmacopoeia product) 30 g Talc (Japanese Pharmacopoeia product) 5 g Magnesium stearate (Japanese Pharmacopoeia product) 1 g After finely pulverizing each component and sufficiently stirring to form a uniform mixture, the mixture was filled into a capsule for oral administration having desired dimensions to obtain a desired capsule.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/505 ADU A61K 31/505 ADU ADZ ADZ C07D 487/04 144 C07D 487/04 144 146 146 (72) Inventor Tsuneo Yasuda Tokushima Hama 43, Benzaiten-ten, Naruto, Naruto, Japan (72) Inventor Takeshi Iwamoto, 83-1 Kuri, Taura-cho, Komatsushima, Tokushima Prefecture Kent Palace Tokushima Minami 606

Claims (10)

[Claims] 1. A compound of the general formula Wherein R ¹ is an alkyl group or a phenyl group; R ² is a furyl group, a thienyl group, a pyridyl group, a naphthyl group or a lower alkyl group, a lower alkoxy group, a halogen atom, a halogen-substituted lower alkyl group, Group, phenyl lower alkoxy group, phenoxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, halogen-substituted lower alkoxy group, lower alkoxycarbonyl group, cyano group, phenyl group, di-lower alkoxyphosphoryl lower alkyl group, N A phenyl group which may have 1 to 3 groups selected from a-(tri-lower alkoxybenzoyl) amino group, a lower alkanoyloxy group and a hydroxyl group, R ³ is a hydrogen atom, a lower alkyl group or-(CO) R ² (R ² is the same), X is a nitrogen atom, CH or -Ph (Ph is phenyl group), Y and Z, when X is a nitrogen atom, Y is Z in CH is CH, a C-CN or C (CO) NH _2, X is CH or C-Ph In the case, Y and Z each represent a nitrogen atom. A pharmaceutical composition comprising, as an active ingredient, a condensed pyrimidine derivative represented by the formula: 2. The compound according to claim 1, wherein R ¹ is an alkyl group and X is CH or C-Ph, and X is a nitrogen atom and Z is C-CN or C (CO). ) N
^2. The pharmaceutical composition according to claim 1, wherein the composition is selected from compounds that are H2. 3. The pharmaceutical composition according to claim 2, wherein the active ingredient is a compound in which R ¹ is an alkyl group and R ³ is a hydrogen atom in the general formula according to claim 1. 4. The active ingredient according to claim 1, wherein R ² is a lower alkyl group, a lower alkylthio group, a halogen-substituted lower alkyl group, one or two halogen atoms or a lower alkoxy group as a substituent. The pharmaceutical composition according to claim 3, which is a compound having a phenyl group or a naphthyl group having three of the following. 5. The method according to claim 5, wherein the active ingredient is 5-n-butyl-7-.
(3,4,5-trimethoxybenzoylamino) -1,
2,4-triazolo [1,5-a] pyrimidine, 2-n
-Butyl-8-cyano-4- (2,4-dichlorobenzoylamino) imidazo [1,5-a] pyrimidine and 2
The pharmaceutical composition according to claim 4, which is selected from -n-butyl-8-cyano-4- (3,4,5-trimethoxybenzoylamino) imidazo [1,5-a] pyrimidine. 6. The pharmaceutical composition according to claim 1, which is an analgesic. 7. The pharmaceutical composition according to claim 1, which is a nitric oxide synthase inhibitor. 8. The pharmaceutical composition according to claim 1, which is an inducible nitric oxide synthase inhibitor. 9. The method according to claim 1, which is an agent for preventing and treating sepsis.
6. The pharmaceutical composition according to any one of 5. 10. The pharmaceutical composition according to claim 1, which is an endotoxin shock ameliorating agent.