WO1999043678A1

WO1999043678A1 - Remedies/preventives for parkinson's disease

Info

Publication number: WO1999043678A1
Application number: PCT/JP1999/000828
Authority: WO
Inventors: Hiroshi Tsumuki; Akiko Nakamura; Shizuo Shiozaki; Michio Ichimura; Yoshihisa Kuwana; Junichi Shimada
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 1998-02-24
Filing date: 1999-02-24
Publication date: 1999-09-02
Also published as: AU2639299A

Abstract

Drugs for treating and/or preventing diseases induced by the hyperenergia of adenosine A2A receptor such as Parkinson's diseases which contain as the active ingredient [1,2,4]triazolo[1,5-a]pyrimidine derivatives represented by general formula (I) or physiologically acceptable salts thereof, wherein Z represents oxygen or sulfur; and R represents formula (a) (wherein Y represents oxygen, sulfur, etc.; n is an integer of from 0 to 5; and X?1, X2, and X3¿ represent each hydrogen, halogeno, lower alkyl, etc.

Description

Description Treatment and prevention of Parkinson's disease Technical field

The present invention relates to a medicament having an antagonistic action on adenosine _A2A receptor and useful for, for example, treating and / or preventing Parkinson's disease. The present invention also relates to a novel [1,2,4] triazolo [1,5-a] pyrimidine derivative or salt useful as an active ingredient of the above-mentioned medicament. Background art

Adenosine, adenosine A _2A receptor via known to attenuate the effects of the neurotransmitter [® sip Bien 'journal O Bed & Famako port G. (Eur. J. Pharmacol.), 168, 285 (1989)]. Thus, substances having an antagonistic action against the adenosine A _2A receptor, each species diseases resulting from hyperactivity of adenosine A _2A receptors, such as Parkinson's disease, dementia, or as therapeutic and Z or pre Bozai for such depression Is expected to be useful.

On the other hand, as [1,2,4] triazolo [l, 5-a] pyrimidine derivatives, compounds having an inhibitory effect on atherosclerotic vascular hypertrophy (JP-A-4-99775 and JP-A-3-118383) Gazette), a compound having a vasodilatory effect, a hypotensive effect, a platelet aggregation inhibitory effect, and a cholesterol lowering effect (JP-A-57-35592), and a compound having an antitumor effect (JP-A-55-51089) ) And compounds useful as therapeutic agents for cardiovascular diseases, especially cerebral cardiovascular diseases (JP-A-2-212488). However, the antagonism of adenosine receptors of [1,2,4] triazolo [1,5-a] pyrimidine derivatives and their effects on the central nervous system have not been known. In addition, as a triazolopyrimidine derivative showing efficacy against No. Kinson's disease, the specification of W095 / 03806 describes [1,2,4] triazolo [1,5-c] pyrimidine derivative. Te, ru <

Disclosure of the invention

An object of the present invention is to have a strong adenosine A _2A receptor antagonistic effect, and to be effective in treating and / or preventing Z- or prophylaxis of a disease derived from hyperactivity of adenosine A _2A receptor, preferably Parkinson's disease [1, 2, [4] It is an object of the present invention to provide a medicament comprising a triazolo [1,5-a] pyrimidine derivative or a physiologically acceptable salt thereof as an active ingredient. Another object of the present invention is to provide a novel [1,2,4] triazolo [l, 5-a] pyrimidine derivative or a salt thereof having the above characteristics.

The present inventors have conducted intensive studies to solve the above-mentioned problems, and found that [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the following general formula is a powerful adenosine derivative. It has an _A2A receptor antagonistic activity and has been found to be useful as an active ingredient of a medicament for treating and / or preventing Parkinson's disease. The present invention has been completed based on the above findings.

That is, the present invention provides the following formula (I):

(I)

[Wherein, Z represents an oxygen atom or a sulfur atom; R is the following formula

Wherein, Upsilon represents an oxygen atom, (wherein, R 'represents a hydrogen atom or a lower alkyl group) a sulfur atom, NR ^1, or a single bond; eta represents an integer of 0 to 5; X ¹ , X ² , and X ³ Each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, a substituted or unsubstituted arylo group, substituted or unsubstituted Which represents a substituted or unsubstituted heterocyclic group, a hydroxyl group or a nitro group, or a group represented by the following formula:

[Wherein, m represents an integer of 0 to 5; k represents an integer of 0 to 5; Q represents an oxygen atom, a sulfur atom, -NH-, or a methylene group; R ² represents a hydrogen atom, lower alkyl. Group, hydroxy lower alkyl group, amino lower alkyl group, lower alkoxy group, lower alkylthio group, mono- or di-lower alkylamino group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic group, or I represents a group represented by CO—R ³ (wherein, R ³ represents a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group) [1,2,4] triazolo [l, 5-a] pyrimidine derivative represented by the formula: and physiologically acceptable salts thereof, and hydrates and solvents thereof Substance selected from the group consisting of Japanese There is provided a medicament for the treatment及beauty / or prevention of diseases resulting from hyperactivity of adenosine A _2A receptor comprising as an active ingredient. According to a preferred aspect of the present invention, there is provided the above medicament wherein the disease is Parkinson's disease.

In another aspect of the present invention, a [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the formula (I) for the production of the above-mentioned medicament and a physiologically acceptable Use of a substance selected from the group consisting of salts thereof, and hydrates and solvates thereof; in a method for treating and / or preventing a disease derived from hyperactivity of adenosine A _2A receptor, preferably Parkinson's disease. The [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the above formula (I), a physiologically acceptable salt thereof, and hydrates and hydrates thereof And administering to a human a therapeutically and / or prophylactically effective amount of a substance selected from the group consisting of a solvate and a solvate; and [1, 2, 4] triazolo represented by the formula (I) [ 1, 5-A] Pyrimidine derivatives and physiologically acceptable salts thereof, and adenosine _A2A antagonists comprising a substance selected from the group consisting of hydrates and solvates thereof are provided. In still another aspect of the present invention, in the above formula (I), Z is an oxygen atom or a sulfur atom; Y is an oxygen atom, a sulfur atom, one NR ¹ — (wherein, R ¹ is a hydrogen atom or Represents a lower alkyl group) or a single bond; n is an integer of 0 to 5; X ¹ , X ² and X ³ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group Group, lower alkylthio group, amino group, mono- or di-lower alkylamino group, lower alkanoyl group, substituted or unsubstituted arylo group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic group, hydroxyl group, or A nitro group (except when X ¹ , X ² , and X ³ are both hydrogen atoms); 111 is an integer from 1 to 5; k is an integer from 0 to 5; , Sulfur atom,-NH- Or be a methylene group; R ² Gahi Dorokishi lower alkyl group, Amino lower alkyl groups, lower-grade alkoxy group, a lower alkylthio group, a mono- or di-lower alkylamino group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted A heterocyclic group or one CO—R ³ (wherein R ³ represents a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group) ( However, when k is 0, R ² is not an unsubstituted aryl group.) The [1,2,4] triazo [1,5-a] pyrimidine derivative or a salt thereof is Provided as a new substance.

The meanings of the terms used in the present specification are as follows.

A lower alkyl group or a substituent containing a lower alkyl moiety (for example, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoyl group, a hydroxy lower alkyl group, or an amino lower alkyl group; And the like. The lower alkyl moiety in, for example, may be straight-chain or branched, and includes, for example, an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Can be used. More specifically, as lower alkyl group, use methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, or tert-butyl group, pentyl group, neopentyl group, hexyl group, etc. In the substituent having a lower alkyl moiety, it is preferable that these lower alkyl groups constitute the alkyl moiety.

Examples of the “lower alkoxy group” include, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, and a tert-butoxy group. Examples of the "alkylthio group" include a methylthio group, an ethylthio group, and a propylthio group.Examples of the "mono-lower alkylamino group" include a methylamino group, an ethylamino group, a propylamino group, and an n-amino group. Examples of the “di-lower alkylamino group” include a dimethylamino group, a getylamino group, and an ethylmethylamino group.

Examples of the "lower alkanoyl group" include, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, bivaloyl group, hexanoyl group, and the like.Examples of the "aroyl group" Examples thereof include a benzoyl group and a naphthoyl group. However, these substituents are not limited to the above specific examples. The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The two alkyl groups in the di-lower alkylamino group may be the same or different. In the hydroxy lower alkyl group or amino lower alkyl group, the substitution position of the hydroxyl group or amino group present in each group is not particularly limited. The number of hydroxyl groups or amino groups is not particularly limited, but is preferably one.

As an aryl group in an aryl group or a substituent containing an aryl group (for example, an aryl group), for example, a 5- to 14-membered monocyclic, bicyclic, or tricyclic aryl group is used. Can be. More specifically, as an aryl group, a phenyl group, a naphthyl group, an indenyl group, an anthryl group, and the like can be used. In the substituent containing an aryl group, it is preferable that these aryl groups constitute the aryl group.

As the heterocyclic group, a 5- to 14-membered heterocyclic group containing one or more hetero atoms (for example, an oxygen atom, a nitrogen atom, a sulfur atom, etc.) as a ring-constituting atom can be used. . As the heterocyclic group, for example, a monocyclic, bicyclic, or tricyclic heterocyclic group can be used, and in addition to an aromatic heterocyclic group, a partially saturated heterocyclic group can also be used. . More specifically, a furyl group, a cyenyl group, a pyrrolyl group, a vinylil group, a thiopyranyl group, a pyridyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrimidinyl group, a triazinyl group, an indolyl group, a quinolyl group, and prynyl A benzoxazolyl group, a benzothiazolyl group, a benzoimidazolyl group, or the like.

In the definition of the above formula (I), when a substituent is referred to as “substituted or unsubstituted”, the substituent is further substituted with one or more, preferably one to three functional groups. It means that it may be substituted. When the substituent has two or more functional groups, those functional groups may be the same or different. Examples of such a functional group include a lower alkyl group, a halogenated lower alkyl group (such as a chloromethyl group and a trifluoromethyl group), a hydroxy lower alkyl group (such as a hydroxymethyl group), a lower alkoxy group, and a lower alkoxy group. Alkenyl group, lower alkynyl group, hydroxyl group, halogen atom, carboxyl group, lower alkyloxycarbonyl group, lower alkanol group, halogenated lower alkanol group (such as trifluoroacetyl group), aryl group, aralkyl group (benzyl group, triphenyl group) , 2-phenyl, 2-phenylpropyl, diphenylmethyl, naphthinomethyl, etc.), aryloxy, aralkyloxy, aroyl, heterocyclic, amino, mono- or di-lower alkylamino, sorbamoyl, Toro group, Shiano group, Mechirenjiokishi group, a lower alkylsulfinyl group, lower alkyl Rusuruhoniru group, a thiol group, or a lower alkylthio group, but such Ru can be exemplified, without being limited thereto. In addition, these functional groups are It may have a group. Specific examples of such a compound include a phenyl group, a methylcarbamoyl group, a benzyl group, and an alkoxybenzyl group.

In the above formula (I), Z represents an oxygen atom or a sulfur atom, Y represents an oxygen atom, a sulfur atom, —NR ¹ — (wherein R ¹ represents a hydrogen atom or a lower alkyl group), or a single bond Is shown. When Y represents a single bond, it means that [1,2,4] triazolo [l, 5-a] pyrimidine and a group represented by one (CH ₂ ) „— are directly bonded. N is 0 or an integer from 5 to 5, but when n is 0, it means that the benzene ring substituted by X ¹ , X ² , and X ³ is directly bonded to Y. When Y represents a single bond and n is 0, the benzene ring substituted by X ¹ , X ² , and X ³ is [1,2,4] triazolo [l, 5-a] It means that it is directly bonded to pyrimidine The substitution positions of X ¹ , X ² , and X ³ are not particularly limited, and each can be substituted at an arbitrary position.

Further, in the above formula (I), m represents an integer of 0 to 5, and Q represents an oxygen atom, a sulfur atom, -NH-, or a methylene group. It means that the ring is a five-membered ring. The group represented by 1 (CH ₂ ) _k — R ² is directly bonded to any of the ring-constituting atoms of the ring containing Q (however, [1, 2, 4] triazolo [1, 5-a] pyrimidine skeleton And k represents an integer of 0 to 5. When k is 0, it means that a ring-constituting atom of the ring containing Q (excluding the above-mentioned nitrogen atom) is directly bonded to R ² . Among these, it is preferable that a group represented by one (CH ₂ ) _k — is bonded to Q.

Examples of the physiologically acceptable salt of the compound represented by the formula (I) include a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, an acid addition salt and the like. Examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and the like. Examples of the ammonium salt include ammonium and tetra Salts such as methylammonium can be mentioned. Physiologically acceptable organic amine addition salts include, for example, the addition of bases such as morpholine and piperidine. The physiologically acceptable amino acid addition salts include, for example, addition salts of amino acids such as lysine, glycine, and phenylalanine. Physiologically acceptable acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate and phosphate, and organic acids such as acetate, maleate, fumarate, tartrate, citrate and the like. Salts may be mentioned.

The compound represented by the above formula (I) can be produced, for example, according to the method disclosed in the scheme shown below.

(Μ)

(IV)

(Ι-Β)

(In the scheme, X ¹ , χ ² , χ · \ and Ζ are as defined above.)

The compound (I-II) shown in the above scheme 1 can be produced according to the above steps 1 and 2. The compound (IV) can be obtained by reacting the compound (II) with 2 to 10 equivalents of the compound (III) in an inert solvent in the presence of 1 to 10 equivalents of the base (Step 1). The reaction is completed, for example, at a temperature of 0 ° C to 200 ° C, preferably at room temperature for about 10 minutes to 50 hours. The type of the solvent inert to the reaction is not particularly limited, but examples thereof include dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methizoletetrahydrofuran, and dioxane. , Detinole, Tenzene, Benzene, Toluene, Xylene, Ethyl acetate Acetonitrile, Pyridine, Dichloro Methane, dichloroethane, ethanol, methanol, prono. No./butanone, or any mixture thereof can be used, and preferably, dimethylformamide, tetrahydrofuran, or the like can be used. The base may be sodium carbonate, carbon dioxide, hydrogen hydride, hydrogen hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropyl pyrethylamine, or 1, 8- Diazabicyclo [4,5,0] pande-7-ene (DBU) or the like can be used, and preferably, sodium hydride, potassium carbonate, or DBU can be used.

Then, the compound (IV) is reacted with 1 equivalent to a large excess, preferably a large excess of ammonia saturated with a suitable solvent to obtain the compound (IB) (Step 2). As the solvent, water, methanol, ethanol, propanol, isopropanol, butanol, acetonitrile, pyridine, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethyl acetate, or any mixture thereof can be used. Preferably, ethanol or acetonitrile can be used. This reaction is completed in about 10 minutes to 50 hours at a temperature of, for example, 0 ° C to 100 ° C.

Scheme 2>

) m

Process 3

(l-C)

I-B1

(In the scheme, k, m, Q, R ² , and Z are as defined above.)

A compound (I-B ¹ ) in which X ¹ , X ² , and X ³ are each independently a hydrogen atom, a halogen atom, or a nitro group;

The compound (IC) can be obtained by reacting with (V) (Step 3). This reaction is carried out without solvent or in the presence of 1 to 10 equivalents of a base as necessary. The reaction can be performed in an active solvent, for example, at a temperature of 0 ° C. to 200 ° C. in about 10 minutes to 50 hours. The type of the inert solvent is not particularly limited, but includes, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetyl ether, benzene, tonolene, Xylene, ethyl acetate, acetonitrinole, pyridine, dichloromethane, dichloroethane, ethanolanol, methanolol, and phenol. For example, phenol, butanol, or any mixture thereof can be used. Preferably, dimethylformamide, tetrahydrofuran, or the like can be used. As the base, for example, sodium carbonate, carbonated lime, sodium hydride, hydrogenated hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, or DBU can be used. Preferably, hydrogenated sodium or DBU can be used.

Ar— (CH-,) — COCH ₂ C0 ₂ Et

Process 5

(IX) (l-D)

(In the scheme, Ar represents a phenyl group substituted with X ′, X ² , and X ³ , and n and Z, and Χ ′, Χ, and X ³ have the same meanings as defined above.)

Compound (VI) and a substantially equivalent amount of compound (VII) are mixed in an acidic solvent such as formic acid, acetic acid, or propionic acid, preferably in acetic acid, for example, at a temperature from room temperature to reflux, preferably under reflux. The compound (VIII) can be obtained by allowing the reaction to proceed for 10 minutes to 50 hours (step 4). Then, compound (VIII) is converted to an oxysalt Compound (IX) can be obtained by treating with a chlorinating agent such as phosphorus chloride or thionyl chloride, preferably phosphorus oxychloride (Step 5). This reaction can be carried out without solvent or in an inert solvent, and is completed using 15 equivalents of phosphorus oxychloride, for example, at a temperature from room temperature to 100 ° C in about 10 minutes to 24 hours. Examples of the inert solvent include tetrahydrofuran, dioxane, dichloromethane, chloroform, benzene, tonolen, xylene, ethynole acetate, triethynoleamine, pyridine, NN-dimethylaniline, and any mixture thereof. Etc. can be used. Subsequently, the compound (IX) is reacted with 1 equivalent to a large excess, preferably a large excess of ammonia saturated with an appropriate solvent to obtain a compound (ID) (Step 6). This reaction is completed in about 10 minutes to 50 hours at a temperature of, for example, 0 ° C to 100 ° C. Examples of the reaction solvent include water, methanol, ethanol, propanol, isoprono, and the like. Nore, butanol, acetonitrile, pyridine, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethyl acetate, etc., preferably ethanol, acetonitrile, or any mixture thereof can be used. .

(I-F) (Ι-Ε)

(In the scheme, Hal represents a halogen atom, and k,, and Z are as defined above.)

The compound (I-E) can be obtained by reacting the compound (IF) with 1 to 20 equivalents of the compound (X) in a solvent-free or inert solvent (Step 7). The reaction can be carried out in the presence of 15 equivalents of a base depending on the case. For example, the reaction is completed in about 10 minutes to 50 hours at 0 ° C and 150 ° C. The type of the inert solvent is not particularly limited. For example, dimethylformamide, dimethylacetamide, N-methylbiamide Lolidone, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethyl ether, benzene, toluene, xylene, ethyl acetate, acetonitrile, pyridine, dichloromethane, dichloroethane, ethanol, methanol, propanol , Butanol, or any mixture thereof, and the like, and preferably dimethylformamide, pyridine, dichloromethane, and the like can be used. Examples of the base include cesium carbonate, sodium carbonate, sodium carbonate, sodium hydride, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, disopropylethylamine, and DBU. Preferably, triethylamine or the like can be used.

X, NH,

ΝΗ ₂

, _N (XI) x ¹ ,

And. X ^2- (ΟΗ _{2) Π} . _{Υ Ν} Λ _Ν

Process 8

(Ι-Β1) (I-G)

(Scheme, _eta, gamma, and Ζ is. Compounds representing the same meaning as defined above (that put in ^{I-B 1) Χ ι '} , Χ 2', and X ³ 'are each independently a hydrogen atom, a halogen atom, Or X ¹ , X ² , and X ³ in the compound (XI) and the compound (IG) are as defined in the formula (I).)

The compound (I-G) can be obtained by reacting the compound (I-B1) with 1 equivalent to a large excess of the compound (XI). This reaction can be performed, for example, in a solvent-free or inert solvent in the presence of 1 to 5 equivalents of a base, if necessary, at a temperature from room temperature to 200 ° C, for about 10 minutes to 50 hours. Complete with Although the type of the inert solvent is not particularly limited, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dixan, getinole Athenole, benzene, tonole, xylene, Examples include ethyl sulphate, acetate nitrinole, pyridine, ethanol, methanol, propanol, and butanol. Preferably, dimethylformamide, dimethyl sulfoxide, or any mixture thereof can be used. Examples of the base include sodium methoxide, sodium methoxide, carbon dioxide lime, sodium hydride, hydrogen hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, and DBU. And preferably hydrogenated sodium.

The compound represented by the formula (I) can also be produced, for example, by the method disclosed in the scheme shown below.

Scheme 6>

(XV) (I)

(In the scheme, Z and R are as defined above.)

Compound (I) can be produced according to Step 9, Step 10 and Step 11 described above. That is, the compound (II) and 1 to 5 equivalents of 3,4-dimethoxybenzylamine (XII) are usually used without solvent or in a solvent inert to the reaction, usually Ot: to 100 ° C, preferably 0 ° C. Compound (XIII) can be obtained by reacting at room temperature for 10 minutes to 24 hours (step 9). In this reaction, in some cases, 0.1 to 5 equivalents, preferably 1 equivalent, of a base may be added. Examples of the base to be added include triethylamine, diisopropylethyl / reamine, DBU, N, N-dimethyl. Anilin, Pi Lysine, quinoline, carbonated sodium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium hydride and the like. The type of solvent inert to the reaction is not particularly limited.Examples include ethanol, methanol, propanol, butanol, water, dimethyl honolem amide, dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. , Tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, getyl ether, benzene, tonolen, xylene, ethynole acetate, acetonitrile, pyridine, dichloromethane, dichloroethane, etc., and any mixture thereof can be used. Preferably, ethanol or dimethylformamide can be used.

Then, the compound (XIII) and 1 equivalent to a large excess, preferably 2 to 4 equivalents of a compound (XIV) represented by RH (wherein R is as defined above) are mixed with a solvent-free or The compound (XV) can be obtained by reacting in a solvent inert to the reaction, usually at room temperature to 150 ° C. for 10 minutes to 24 hours (Step 10). In some cases, this reaction is carried out by adding 0.5 to 10 equivalents, preferably 2 to 4 equivalents of a base. Examples of the base to be added include triethylamine, diisopropylethylamine, DBU, N, N-dimethylaniline, pyridine, quinoline, potassium carbonate, sodium carbonate, sodium bicarbonate, hydroxylated sodium, sodium hydroxide, potassium tert-butoxide, butyllithium, sodium hydride, potassium hydride, etc. And preferably DBU, potassium carbonate and sodium hydride. The type of the solvent inert to the reaction is not particularly limited.Examples include ethanol, methanol, propanol, butanol, water, dimethyl honolemamide, dimethyl acetate, N-methylpyrrolidone, dimethyl sulfoxide, and tetrahydrofura. , 2-methinolete trahydrofuran, dioxane, ethynoleatenole, benzene, toluene, xylene, ethynole acetate, acetonitrile, pyridine, dichloromethane, dichloroethane, etc., and any mixture thereof can be used, preferably Is ethanol, dimethyl sulfoxide or dimethylformamide, etc. Can be used.

Subsequently, the compound (I) is treated by treating the compound (XV) with 1 equivalent to a large excess of a strong acid in a solvent or in a suitable solvent, or treating with 1 equivalent to a large excess of a suitable oxidizing agent. Can be obtained (step 11). In the case of treating with a strong acid, examples of the strong acid used include trifluoromethanesulfonic acid, naphion (Nafion®), trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., and preferably trifluoromethanesulfonic acid, nafion, etc. 6 equivalents can be used. The reaction is usually carried out at room temperature to 100 ° C, preferably at room temperature to 60 ° C, and is completed in about 10 minutes to 24 hours. At this time, it is advisable to add 1 equivalent to a large excess of anisol, dimethoxybenzene or trimethoxybenzene. Suitable solvents to be used include acetic acid, trifluoroacetic acid, trifluoroacetic acid, dichloroacetic acid, methanesnolephonic acid, ethanol, methanol, propanol, butanol, benzene, tonolene, xylene, chlorophonolem, dichloromethane, dichloroethane, carbon tetrachloride, and tetrachloromethane. Examples thereof include drofuran, getyl ether, dioxane, ethyl acetate, ethyl methyl ketone, and dimethylformamide. An arbitrary mixture thereof can be used, and trifluoroacetic acid can be preferably used. In the case of treatment with an oxidizing agent, examples of the oxidizing agent to be used include 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), Kuguchi Rael and the like. The reaction can be usually performed at 0 ° C to 100 ° C, preferably at room temperature, and is completed in about 10 minutes to 24 hours. Suitable solvents used are benzene, toluene, xylene, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, tetrahydrofuran, getyl ether, dioxane, ethyl acetate, ethynole methyl ketone, and dimethylform. Amide, acetate nitrile and the like can be mentioned, and an arbitrary mixture thereof can be used.

Further, the compound represented by the formula (I) can also be produced, for example, by the method disclosed in the scheme shown below. Scheme 7>

(In the scheme, Z and R are as defined above.)

The compound (XIII) obtained in Step 9 is subjected to the same treatment as in Step 11 to lead to the compound (I-H) (Step 12), and the compound (I-H) is used in Step 10 Compound (I) can be obtained by performing the same operation as in (Step 13).

The intermediates and target compounds in each of the above production methods are separated and purified by methods commonly used in the field of synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of mouth chromatography, etc. Can be isolated and purified. Further, the production intermediate can be subjected to the next reaction without purification. When a salt of the compound represented by the formula (I) is produced, if the final product is obtained in the form of a salt in the above reaction step, it may be purified as it is, and the final product may be converted into a free form. When the compound is obtained as a compound, the compound may be dissolved or suspended in an appropriate solvent, an acid or a base may be added to form a salt, and then the desired product may be isolated and purified. Further, the final product obtained in the form of a salt may be converted into a compound in a free form and then further converted into a target salt.

Among the compounds included in the above formula (I), specific examples of the compounds suitable as the active ingredient of the medicament of the present invention are shown in the following Tables 1 to 4, and the compounds used in the present invention are shown below. It is not limited (in the table, Me represents a methyl group). Table 1

Table 1 continued

Table 1 continued

Table 1 continued

In addition, among the compounds included in the above formula (I), Z is an oxygen atom or a sulfur atom; Y is an oxygen atom, a sulfur atom, NR ¹ (wherein, R ¹ is a hydrogen atom or a lower alkyl group. N) is an integer of 0 to 5; X ¹ , X ² , and X ³ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, An amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, a substituted or unsubstituted arylo group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group ( Provided that m is an integer of 1 to 5 except that X ¹ , X ² , and X ³ are simultaneously hydrogen atoms. Ri; k is located at 5 integer from 0; Q is an oxygen atom, a sulfur atom, - NH -, or is methylene group; R ² Gahi Dorokishi lower alkyl group, Amino lower alkyl group, a lower alkoxy group, a lower An alkylthio group, a mono- or di-lower alkylamino group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, or —CO—R ³ (wherein R ³ is a lower alkyl group, a lower alkoxy group, A lower alkylthio group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group (however, when k is 0, R ² is not an unsubstituted aryl group) Is a new compound.

The use of these novel compounds provided by the present invention is not limited to the use as an active ingredient of the medicament of the present invention, but may be used as an active ingredient of another medicament or an intermediate for producing another compound. Can be used. It goes without saying that the scope of the present invention relating to the novel compound includes such other uses. In addition, as for the above-mentioned novel compounds, any hydrates or solvates as well as any salts such as the above-mentioned physiologically acceptable salts are also included in the scope of the present invention. The type of the solvent that forms the solvate is not particularly limited, and examples thereof include ethanol, tetrahydrofuran, and dioxane. Further, when one or more asymmetric carbons are present, the present invention also includes pure optical isomers, pure isomers such as diastereoisomers, arbitrary mixtures of isomers, and racemic isomers. Is included in the range.

The medicament of the present invention comprises a [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the formula (I) and a physiologically acceptable salt thereof, and a hydrate and a hydrate thereof. a substance selected from the group consisting of a solvate is characterized by containing as an active ingredient, various diseases resulting from hyperactivity of adenosine emissions a _2A receptor, for example, Parkinson's disease, senile dementia, such as depression It can be used for treatment and / or prevention. A particularly preferred subject of the medicament of the present invention is Parkinson's disease. As the medicament of the present invention, the above-mentioned substance which is an active ingredient may be administered as it is, but generally, a pharmaceutical composition comprising the above-mentioned substance which is an active ingredient and one or more pharmaceutical additives It is desirable to administer in the form of Such a pharmaceutical composition is known or commonly used in the field of pharmaceuticals. It can be manufactured according to the method. The medicament of the present invention in the form of a pharmaceutical composition may contain one or more active ingredients of another medicament. The medicament of the present invention is applicable to mammals including human.

The administration route of the medicament of the present invention is not particularly limited, and the most effective administration route for treatment and / or prevention can be appropriately selected from oral or parenteral administration. Oral or parenteral such as oral, respiratory, rectal, subcutaneous, intramuscular and intravenous. Examples of preparations suitable for oral administration include, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, and suspensions. Preparations suitable for parenteral administration Examples thereof include injections, drops, inhalants, sprays, suppositories, transdermal absorbers, transmucosal absorbers, and the like.

For the production of liquid preparations suitable for oral administration, for example, sugars such as water, sucrose, sorbitol, fructose; glycols such as polyethylene glycol and propylene d'alicol; Preservatives such as p-hydroxybenzoic acid esters; and additives for pharmaceutical preparations such as flavors such as strobe leaf flavor and peppermint. For the production of solid preparations such as capsules, tablets, powders, or granules, excipients such as lactose, glucose, sucrose, and mannite; disintegrants such as starch and sodium alginate; magnesium stearate; And binders such as polyvinyl alcohol, hydroxypropylcellulose and gelatin; surfactants such as fatty acid esters; and plasticizers such as glycerin.

Among preparations suitable for parenteral administration, preparations for intravascular administration such as injections and drops can be prepared preferably using an aqueous medium isotonic with human blood. For example, the propellant is prepared as a solution, suspension, or dispersion using an aqueous medium selected from a salt solution, a glucose solution, or a mixture of a salt water and a glucose solution with an appropriate auxiliary according to a conventional method. can do. Suppositories for enteral administration can be prepared using carriers such as cocoa butter, hydrogenated fats or hydrogenated carboxylic acids. The propellant is It can be prepared using a carrier that does not irritate the oral cavity and respiratory tract mucosa of humans and that can promote absorption by dispersing the above-mentioned substance as an active ingredient as fine particles. As such a carrier, for example, lactose or glycerin can be used. Depending on the nature of the substance and the carrier used as the active ingredient, it can be prepared as a preparation in the form of an aerosol or a dry powder. For the preparation of parenteral preparations, for example, one or more selected from diluents, fragrances, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Pharmaceutical additives can be used.

The dose and frequency of administration of the medicament of the present invention are not particularly limited, and the kind of the substance as the active ingredient, the administration route, the purpose of treatment and prevention or prevention, the age and weight of the patient, the nature and severity of symptoms It can be appropriately selected according to various conditions such as. For example, it is preferable to administer 1 to 50 mgZkg per adult daily in 3 to 4 divided doses. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to these Examples. The numbers of the compounds in the following Examples correspond to the numbers of the compounds exemplified as preferable compounds in Tables 1 to 4 (EtOH represents ethanol). Example 1 (Reference example): 5,7-dihydroxy-2- (2-furyl) [1,2,4] triazolo [1,5-a] pyrimidine [Compound (1)]

3.2 g (80 mmol) of sodium hydride was slowly added to 100 ml of ethanol at 0 ° C. Then, 12.2 ml (80 mmol) of getyl malonate was added to the suspension, and 3-amino-3- (2-furyl) -1,2,4 synthesized by the method described in JP-A-5-97855. After addition of 12 g (80 ml) of triazole, the mixture was heated under reflux for 7 hours. The reaction product was returned to room temperature, ether was added, and the precipitated solid was collected by filtration. The obtained solid was washed with ether, dried, and dissolved in 200 ml of water. To this solution, add concentrated hydrochloric acid to adjust the pH. Was adjusted to about 4. The mixture was allowed to stand at 0 ° C for a while, and the precipitated solid was collected by filtration. The obtained solid was washed with water and ether, and then dried to obtain 12.4 g of the title compound (1).

(Yield: 71%) as a white solid.

Ή negation _{R (DMS0- d 6, δ ppm} ): 7.90-7.75 (m, 1H), 7.08-6.79 (m, 1H), 6.70- 6.57 (m, 1H), 5.08 (s (br), 1H)

MS (m / e): 218 (M ⁺ ) Example 2 (Reference example): 5,7-dichloro-2- (2-furyl) [1,2,4] triazolo [1,5-a] pyrimidine [Compound (2)]

20 g (91.7 ol) of the compound (1) obtained in Example 1 was heated to reflux in 50 ml of phosphorus oxychloride for 4 hours. The reaction was returned to room temperature, the solvent was distilled off under reduced pressure, and the residue was poured into ice water. The precipitated solid was collected by filtration, washed with water, and dried to obtain 15.1 g (yield: 73%) of the title compound (2) as a pale brown solid.

_{¾ NMR (CDC1 3, δ ppm} ): 7.66 (t, J = l.0Hz, 1H), 7.35 (t, J = 3.5Hz, 1H), 7.22 (s, 1H), 6.62 (dd, J = 3.5Hz , 1.5Hz, 1H)

MS (m / e): 256, 254 (M ⁺ ) Example 3 (Reference example): 2- (2-furyl) -5,7-diphenoxy [1,2,4] triazolo [1,5-a] pi Limidine [Compound (3)]

13.8 g (147 mmol) of phenol was dissolved in tetrahydrofuran (THF), and 5.88 g (147 mmol) of sodium hydride was slowly added to this solution. Then, 15 g of compound (2) obtained in Example 2 ( 58.8 Marauders ₀ 1) were added and the mixture was heated and refluxed for 4 hours. The reaction was returned to room temperature, ether was added, and the precipitated solid was collected by filtration. The obtained solid was washed with ether and water, and then dried to give the title compound (3) (26.8 g, yield: quantitative) as a white solid.

_{Ή NMR (DMS0- d 6, δ} ppm): 7.65-7.13 (m, 12H), 6.59 - 6.54 (m, 1H), 5.82 (s, 1H) MS (m / e): 370 (M ⁺ ) Example 4 (Reference example): 7-amino-2- (2-furyl) -5-phenoxy [1,2,4] triazolo [1,5-a] Pyrimidine [Compound (4)]

To 500 mg (1.39 mmol) of the compound (3) obtained in Example 3, 10 ml of acetonitrile and 10 ml of ammonia water were added, and the mixture was stirred at 40 ° C for 5 hours. The solvent was distilled off, and the residue was extracted with chloroform and water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain 255 mg (yield: 62%) of the title compound (4) as a white solid.

_{'Η NMR (DMS0 - d 6} , δ ppm): 8.10 (s (br), 2H), 7.88 (d, J = 0.7Hz, 1H), 7.50- 7.21 (m, 5H), 7.06 (t, J = l.0Hz, 1H), 6.68 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.79 (s, 1H)

MS (m / e) 293 (M ⁺ )

IR (KBr; cm " ¹ ): 1649, 1600, 1585, 1564, 1461, 1322

Melting point: 208.9-210.5 ° C Example 5 (Reference example): 2- (2-furyl) -5,7-bis (2,4-dichlorophenoxy) [1, 2,4] triazolo [1, 5] -a] Pyrimidine [Compound (5)]

Using the compound (2) obtained in Example 2 and 2,4-dichlorophenol, the title compound (5) (yield: 58%) was obtained as a pale brown solid in the same manner as in Example 3.

_{Ή NMR (CDC1 3, δ ppm} ): 7.65-7.15 (m, 8H), 6.55 (dd, J = 3.5Hz, 2.0Hz, 1H), 5.81 (s, 1H)

MS (m / e): 507 (M ⁺ ) Example 6 (Example): 7-amino-5- (2,4-dichlorophenoxy) -2- (2-furyl) [1,2,4 ] Triazolo [1,5-a] pyrimidine [Compound (6)]

Using the compound (5) obtained in Example 5, the title compound (6) (yield (95%) as a pale yellow solid.

'Η NMR (DMSO—d ₆ , δ ppm): 8.22 (s (br), 2H), 7.88 (d, J = 1.5 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.53 ( dd, J = 9.1Hz, 2.5Hz, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.05 (d, J = 3.0Hz, 1H), 6.68 (dd, J = 3.5Hz, 2.0Hz, 1H) ), 5.91 (s, 1H)

MS (m / e): 361 (M +)

IR (KBr; cm " ¹ ): 1654, 1604, 1571, 1459

Melting point:> 290 ° C Example 7 (Reference example): 2- (2-furyl) -5,7-bis (2,4,6-trichloromouth phenoxy) [1,2,4] triazolo [1,5- a] Pyrimidine [Compound (7)]

Using the compound (2) obtained in Example 2 and 2,4,6-trichlorophenol, the title compound (7) (yield: 49%) was obtained as a pale brown solid in the same manner as in Example 3.

_{¾ NMR (DMSO- d 6, δ} ppm): 7.65-7.15 (m, 8H), 6.55 (dd, J = 3.5Hz, 2.0Hz, 1H), 5.81 (s, 1H)

MS (m / e): 577 (M +) Example 8 (Example): 7-Amino-2- (2-furyl) -5- (2,4,6-triclonal mouth) [1,2,4] triazolo [1,5-a] pyrimidine [compound (8)]

The title compound (8) (yield: 59%) was obtained as a pale yellow solid using the compound (7) obtained in Example 7 in the same manner as in Example 4.

¾ NMR (DMSO- d ₆ , δ ppm): 8.51 (s (br), 2H), 7.92 (d, J = l.0Hz, 1H), 7.18 (d,

J = 3.5Hz, 1H), 6.71 (dd, J = 3.5Hz, 2.0Hz, 1H), 6.27 (s, 1H)

MS (m / e): 395 (M ⁺ )

IR (KBr; cm " ¹ ): 1645, 1594, 1326

Melting point:> 290 ° C Example 9 (Reference example): 2- (2-furyl) -7-hydroxy-5-phenyl [1,2,4] triazolo [1,5-a] pyrimidine [compound (9)]

3-Amino-5- (2-furyl) -1,2,4-triazole (3 g, 20 mmol) and benzoyl acetate ethyl 3.64 ml (21 ol) were dissolved in 30 ml of acetic acid at 120 ° C. Stir for 12 hours. The reaction mixture was returned to room temperature, and extracted with chloroform and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 2.78 g (yield: 50%) of the title compound (9).

Ή NMR (DMS0-d ₆ , δ ppm): 7.95-7.86 (m, 3H), 7.60-7.52 (m, 3H), 7.16 (s (br), 1H), 6.72 (s (br), 1H), 6.34 (s, 1H)

MS (m / e): 278 (M ⁺ ) Example 10 (Reference example): 7-chloro-2- (2-furyl) -5-phenyl [1,2,4] triazolo [1,5-a] pyri Midine [Compound (10)]

1.3 g (4.67 benzyl) of the compound (9) obtained in Example 9 was heated to reflux in 15 ml of phosphorus oxychloride. The reaction product was returned to room temperature, poured into ice water, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried to obtain 1.27 g (yield: 92%) of the title compound (10). Ή NMR (DMS0-d ₆ , δ ppm): 8.40-8.31 (m, 3H), 7.99 (d, J = 1.0 Hz, 1H), 7.63-7.58 (m, 3H), 7.32 (d, J = 3.5 Hz, 1H), 6.76 (dd, J = 3.5Hz, 2.0Hz, 1H)

MS (m / e): 298, 296 (M ⁺ ) Example 11 (Reference Example): 7-amino-2- (2-furyl) -5-phenyl [1,2,4] triazolo [1,5-a ] Pyrimidine [Compound (11)]

690 mg (2.33 mmol) of the compound (10) obtained in Example 10 was heated and refluxed in ethanol saturated with ammonia for 3 hours. After the solvent was distilled off, chloroform and water were added to the residue for extraction. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain 380 mg (yield: 59%) of the title compound (11). _{¾ NMR (DMS0- d 6, δ} ppm): 8.23 (s (br), 2H), 8.08-8.04 (m, 2H), 7.93 (t, Jl.0Hz, 1H), 7.59-7.49 (m, 3H) , 7.18 (d, J = 3.0Hz, 1H), 6.79 (s, 1H), 6.72 (dd, J = 3.5Hz, 1.5Hz, 1H)

MS (m / e): 277 (M ⁺ )

IR (KBr; cm: 1643, 1637, 1592, 1968, 1384)

Melting point:> 270 ° C (decomposition) Example 12 (Example): 7-amino-5- (3,4-dimethoxyphenyloxy) -2- (2-furyl) [1,2,4 ] Triazolo [1,5-a] pyrimidine [Compound (12)]

17 g (7.58 mmol) of 3,4-dimethyloxyphenol L was dissolved in 15 ml of dimethylformamide (DMF), and 404 mg (10.12 mmol) of sodium hydride was slowly added at 0 ° C. Next, to this mixture was added 1.0 g (2.53 mmol) of the compound (8) obtained in Example 8, and the mixture was stirred at 100 ° C for 4 hours. The reaction was cooled to room temperature, and extracted by adding water and then chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (elution solvent: pore-form). The obtained solid was washed with ethanol to obtain 1.0 g (yield: quantitative) of the title compound (12).

'Η NMR (DMS0-d ₆₎ δ ppm): 8.08 (s (br), 1H), 7.89 (d, J = l.0Hz, 1H), 7.08-6.67 (m, 5H), 5.73 (s, 1H ), 3.79 (s, 3H), 3.75 (s, 3H)

MS (m / e): 353 (M ⁺ )

IR (KBr; cm " ¹ ): 1637, 1589, 1564, 1461, 1400

Melting point: 263.5-264.5 ° C Example 13 (Example): 7-Amino-2- (2-furyl) -5- (4-fuyruphenoxy) [1,2,4] triazolo [1,5-a] Pyrimidine [Compound (13)]

1.29 g (7.59 mmol) of 4-phenylphenol was dissolved in 15 ml of DMF, and 404 mg (10.12 mmol) of sodium hydride was slowly added at 0 ° C. Next, to this mixture was added 1.0 g (2.53 mmol) of the compound (8) obtained in Example 8, and the mixture was stirred at 100 ° C for 3 hours. The reaction mixture was returned to room temperature, and water and then chloroform were added for extraction. Organic The layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue obtained was recrystallized from DMF-water to obtain 580 mg (yield: 62%) of the title compound (13).

_{Ή NMR (DMS0- d 6, δ} pm): 8.15 (s (br), 2H), 7.89 (t, J = l.0Hz, 1H), 7.77-

7.69 (m, 4H), 7.52-7.30 (m, 5H), 7.07 (d, J = 3.3Hz, 1H), 6.68 (dd, J = 3.6Hz,

2.0Hz, 1H), 5.84 (s, 1H)

MS (m / e): 369 (M ⁺ )

IR (KBr; cm " ¹ ): 1662, 1654, 1604, 1560, 1216

Melting point:> 290 ° C Example 14 (Reference example): 7-Amino-5-benzyloxy-2- (2-furyl) [1, 2, 4] triazolo [l, 5-a] pyrimidine [Compound (14) ]

Using 0.8 g of the compound (8) obtained in Example 8 and 0.63 ml of benzyl alcohol, the title compound (14) (yield: 90%) was obtained in the same manner as in Example 12.

¾ NMR (DMS0-d ₆₎ δ ppm): 7.89 (s (br), 2H), 7.48-7.31 (m, 6H), 7.09 (d, J = 3.3Hz, 1H), 6.70 (dd, J = 3.3 Hz, 1.7Hz, 1H), 5.68 (s, 1H), 5.40 (s, 2H) MS (m / e): 307 (M ⁺ )

IR (KBr; cm— ¹ ): 1654, 1608, 1473, 1336

Melting point: 251.5-253.0 ° C Example 15 (Reference example): 7-amino-2- (2-furyl) -5-morpholino [1,2,4] triazolo [1,5-a] pyri Midine [Compound (14)]

0.8 g (2.73 ol) of the compound (4) obtained in Example 4 was dissolved in 5 ml of morpholine, 0.45 ml of DBU was added, and the mixture was heated under reflux overnight. After the solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was washed with ether and recrystallized from ethanol to obtain the title compound (15) (yield: 52%).

_{lH NMR (DMSO- d 6, δ} ppm): 7.85 (. t, J = l OHz, 1H), 7.52 (s (br), 2H), 7.02 (d, J = 4.0Hz, 1H), 6.66 (dd , J = 3.5Hz, 2.OHz, 1H), 5.66 (s, 1H), 3.69 (t, J = 4.0Hz, 4H), 3.52 (t, J = 4.6Hz, 4H)

MS (m / e): 286 (M ⁺ )

IR (KBr; cm " ¹ ): 1654, 1604, 1569, 1490

Melting point:> 290 ° C Example 16 (Reference example): 7-Amino-2- (2-furyl) -5- (4-methylbiperazinyl) [1,2,4] triazolo [1, 5- a] Pyrimidine hydrochloride [Compound (16)]

Using 1.0 g (3.41 mmol) of the compound (4) obtained in Example 4 and 5 ml of N-methylbiperazine, 7-amino-2- (2-furyl) -5- (4-methylbiperazinyl) in the same manner as in Example 15. ) [1, 2,4] Triazo mouth [1,5-a] pyrimidine 600 mg (yield: 59%) was obtained. The obtained 7-amino-2- (2-furyl) -5- (4-methylbiperazinyl) [1,2,4] triazolo [l, 5_a] pyrimidine 600 mg (2.10 mmol) was added to 4N The mixture was stirred in ethyl acetate monohydrochloride for 30 minutes. The solvent was distilled off, and ether was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was dried to obtain 303 mg (yield: 25%, 2 steps) of the title compound (16).

¾ NMR (DMS0-d ₆₎ δ ppm): 7.90 (d, J = 1.5Hz, 1H), 7.81 (s (br), 2H), 7.13 (d, J = 3.5Hz, 1H), 6.69 (dd , J = 3.5Hz, 1.5Hz, 1H), 5.81 (s, 1H), 4.40-4.34 (m, 2H), 3.58-3.38 (m, 4H), 3.16-3.03 (m, 2H), 2.76 (d ( br), J = 4.0Hz, 3H)

MS (m / e): 299 (W)

IR (KBr; cm " ¹ ): 1647, 1604, 1575, 1519

Melting point: 224.0-226.5 ° C Example 17 (Reference example): 7-Amino-2- (2-furyl) -5- (4-phenylbiperazinyl) [1, 2,4] triazolo [1, 5-a] pyrimidine [compound (17)]

800 mg (2.21 mmol) of the compound (6) obtained in Example 6 was dissolved in 5 ml of dimethyl sulfoxide (DMS0), and 1.07 ml (6.65 mmol) of N-phenylbiperazine and 0.3 ml (2.21 bandol) of DBU were added. And stirred at 140 ° C for 6 hours. The reaction mixture was returned to room temperature, and extracted by adding chloroform and 1N aqueous sodium hydroxide solution. Organic layer After drying over anhydrous magnesium sulfate and evaporating the solvent, the residue obtained was purified by silica gel column chromatography, and the obtained purified product was recrystallized from ethanol to give 430 mg of the title compound (17) (yield) : 54%).

_{Ή NMR (DMS0 - d 6,} δ ppm): 7.86 (s, 1H), 7.52 (s (br), 2H), 7.28- 7.21 (m, 2H), 7.04-6.97 (m, 3H), 6.81 (t , J = 6.9Hz, 1H), 6.67 (dd, J = 3.3Hz, 1.7Hz, 1H),

5.71 (s, 1H), 3.79-3.69 (m, 4H), 3.28-3.21 (m, 4H) ''

MS (m / e): 361 (M +)

IR (KBr; cm-: 1658, 1598, 1502, 1490

Melting point: 277.5-280.0 ° C Example 18 (Reference example): 7-Amino-2- (2-furyl) -5-piperazinyl [1,2,4] triazolo [1,5-a] pyrimidine hydrochloride [Compound (18)]

To 2.03 g (5.27 mmol) of the compound (26) obtained in Example 26 was added 4N hydrochloric acid 1,4-dioxane, and the suspension was stirred at room temperature for 4 hours. After completion of the reaction, ether was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was washed with ether and dried under reduced pressure to obtain 1.70 g (yield: quantitative) of compound (18).

¾ NMR (DMSO— d ₆ , δ ppm): 7.93 (t, J = 0.7Hz, 1H), 7.16 (d, J = 3.3Hz, 1H),

6.73 (dd, J = l.7Hz, 0.7Hz, 1H), 5.76 (s, 1H), 3.91-3.81 (m, 4H), 3.24-3.15 (m, 4H)

MS (ra / e): 361 (M ⁺ ) Example 19 (Example): 7-amino-5- (4-benzylpiperazinyl) -2- (2-furyl) [1,2,4] triazolo [ 1,5-a] Pyrimidine [Compound (19)]

800 mg (2.21 mmol) of the compound (6) obtained in Example 6 was dissolved in 5 ml of DMSO, and 73 ml (9.94 mmol) of N-benzylbiperazine L and 0.33 ml (2.21 mmol) of DBU were added. Stirred overnight at ° C. The reaction mixture was returned to room temperature, and extracted by adding water and chloroform. The organic layer is washed with a saturated saline solution, and anhydrous sulfuric acid is added. And dried. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: 1% methanol / chloroform), and the obtained purified product was recrystallized from ethanol / isopropyl ether (1: 5). 275 mg (yield: 33%) of the title compound (19) was obtained as a brown solid.

ΐ 丽 R (CDC1 ,, δ ppm): 7.56 (d, J = 1.7 Hz, 1H), 7.35-7.30 (m, 5H), 7.17 (d, J = 3.3 Hz, 1H), 6.54 (d, J = 3.3Hz, 1H), 5.55 (s, 1H), 5.33 (s (br), 2H), 3.72 (s (br), 4H), 3.56 (s (br), 2H), 2.53 (s (br) , 4H)

MS (m / e): 375 (M ⁺ )

IR (KBr, cm " ¹ ): 2371, 1651, 1604, 1564, 1244

Melting point: ＞ 230 ° C (decomposition)

As _{_{_{C 20 H 21 N 7 0 0.2H}}} 2 0 0.3Et0H: Elemental analysis

Observed value (%): C 62.99, H 5.77, N 25.05

Calculated value (%): C 62.98, H 5.96, N 24.96 Example 20 (Example): 7-amino-2- (2-furyl) -5- (4-pyronylbiperazinyl) [1,2 , 4] triazolo [1,5-a] pyrimidine [compound (20)]

The title compound (20) was obtained as a brown solid (yield: 73%) in the same manner as in Example 19 using N-piperonylbiperazine.

_{Ή NMR (CDC1 3, δ ppm} ): 7.56 (d, J = l.7Hz, 1H), 7.35-7.30 (m, 5H), 7.17 (d, J = 3.3Hz, 1H), 6.54 (d, J = 3.3Hz, 1H), 5.55 (s, 1H), 5.33 (s (br), 2H), 3.72 (s (br), 4H), 3.56 (s (br), 2H), 2.53 (s (br), 4H)

MS (m / e): 419 (M ⁺ )

IR (KBr, cm " ¹ ): 3302, 2380, 1556, 1512, 1462, 1383

Melting point: 265.5-267.0 ° C

Elemental analysis: As C ₂₁ H ₂₁ N ₇ 0 ₃ 0.1¾0 0.2EtOH

Observed value (%): C 59.79, H 5.12, N 22.83

Calculated value (%): C 59.71, H 5.24, N 22.78 Example 21 (Example): 7-amino-5- [4- (3,4-dimethoxybenzyl) pidazur] -2-(2-furyl) [1,2,4] triazolo [1,5- a] Pyrimidine [Compound (21)]

Using N- (3,4-dimethoxybenzyl) pirazine, the title compound (21) (yield: 85%) was obtained as a yellow solid in the same manner as in Example 19.

_{lH NMR (CDC1 3, δ ppm} ): 7.56 (s, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.88 (s, 1H), 6.76 (s, 2H), 6.54 (dd, J = 3.3 Hz, 1.7Hz, 1H), 6.00 (s, 2H), 5.56 (s, 1H), 5.34 (s, 2H), 3.70-3.68 (m, 4H), 3.45 (s, 2H), 2.51-2.48 (m , 4H)

MS (m / e): 435 (M ⁺ )

IR (KBr, cm— ¹ ): 3446, 2366, 1649, 1560, 1230

Melting point: 223.4-224.5 ° C

As _{_{_{_{C 22 H 25 N 7 0 3}}}} : Elemental analysis

Observed value (%): C 60.38, H 5.92, N 22.12

Calculated value (%): C 60.68, H 5.79, N 22.51 Example 22 (Example) 7-amino-5- [4- (4-anisyl) pirazur] -2- (2-free ) [1,2,4] triazolo [1,5-a] pyrimidine [compound (22)]

The title compound (22) (yield: quantitative) was obtained as a yellow solid using N- (4-anisyl) pirazine in the same manner as in Example 19:

_{'Η NMR (CDC1 3, δ} ppm): 7.57 (s, 1H), 7.19 (d, J = 3.3Hz, 1H), 6.95-6.84 (m, 4H), 6.55 (dd, J = 3.3Hz, 1.7Hz , 1H), 5.63 (s, 1H), 5.41 (s (br), 2H), 3.89-3.85 (m, 4H), 3.78 (s, 3H), 3.16-3.12 (m, 4H)

MS (m / e): 391 (M ⁺ )

IR (KBr, cm " ¹ ): 3115, 2382, 1655, 1601, 1570, 1508

Melting point: 280.0-281.8 ° C

As _{_{_{_{C 20 H 21 N 7 0 2}}}} 0.2H 2 0: Elemental analysis

Observed value (%): C 61.02, H 5.50, N 24.52 Calculated value (%): C 60.81, H 5.46, N 24.82 Example 23 (Example): 7-amino-2- (2-furyl) -5- [4- (2-pyrimidinyl) piperajule] [ 1,2,4] Triazolo [l, 5-a] pyrimidine [Compound (23)]

Using N- (2-pyrimidinyl) pirazine, the title compound (23) (yield: 62%) was obtained as a brown solid in the same manner as in Example 19.

_{Ή NMR (CDC1 3, δ ppm} ): 8.34 (d, J = 4.6Hz, 2H), 7.57 (t, J = l.0Hz, 1H), 7.19 (d, J = 3.3Hz, 1H), 6.56-6.53 (m, 1H), 5.61 (s, 1H), 5.40 (s (br), 2H), 3.97-3.93 (m, 4H), 3.84-3.81 (m, 4H)

MS (m / e): 363 (M +)

IR (KBr, cm— '): 3157, 2382, 1650, 1589, 1489, 1238

Melting point:> 291 ° C Example 24 (Example): 7-Amino-2- (2-furyl) -5- [4- (2-methoxethyl) piperazinyl] [1,2,4] triazolo [1, 5-a] pyrimidine [compound (24)]

The title compound (24) (yield: 54%) was obtained as a yellow solid in the same manner as in Example 19, using N- (2-methoxethyl) pirazine.

Ή NMR (CDC13 ₎ δ ppm): 7.56 (s, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.55 (dd, J-3.3Hz, 1.7Hz, 1H), 5.58 (s, 1H) , 5.41 (s (br), 2H), 3.77 (s (br), 4H), 3.57 (t, J = 5.3Hz, 2H), 3.37 (s, 3H), 2.63 (s (br), 6H)

MS (m / e): 343 (M ⁺ )

IR (KBr, cm " ¹ ): 3160, 2384, 1661, 1606, 1560

Melting point: 163.5-165.5

Elemental analysis: C ₁₆ H ₂₁ N ₇ 0 ₂ 0.4H ₂ 0 0.1 As hexane

Observed value (%): C 55.19, H 6.61, N 27.49

Calculated value (%): C 55.51, H 6.51, N 27.30 Example 25 (Example): 7-amino-2- (2-furyl) -5- [4- (3-phenylpropyl) piperazinyl] [1,2,4] triazolo [1,5-a] pyrimidine [Compound (25)]

Using N- (3-phenylpropyl) pirazine, the title compound (25) (yield: 68%) was obtained as a brown solid in the same manner as in Example 19.

_{¾ NMR (DMSO- d 6, δ} ppm): 7.84 (s, 1H), 7.45 (s (br), 2H), 7.28 - 7.17 (m, 5H), 7.01 (d, J-3.3Hz, 1H), 6.66 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.65 (s, 1H), 3.55 (s (br), 4H), 2.65-2.59 (m, 2H), 2.43 (s (br), 4H) , 2.35-2.30 (m, 2H), 1.77 (s (br), 2H)

MS (m / e): 403 (M ⁺ )

IR (KBr, cm " ¹ ): 3383, 2366, 1645, 1604, 1574

Melting point: 165.0-167.5 ° C Example 26 (Example): 7-amino-2- (2-furyl) -5- [4- (tert-butoxycarbonyl) piperazinyl] [1,2,4] triazolo [1 , 5-a] Pyrimidine [Compound (26)]

Using N- (tert-butoxycarbonyl) pirazine, the title compound (26) was obtained as a white solid in the same manner as in Example 19.

Yield: 44%

Ή NMR (DMS0-d ₆ , δ ppm): 7.85 (t, J = 1 OHz, 1H), 7.53 (s (br), 2H), 7.02 (d, J = 3.3 Hz, 1H), 6.67 (dd , J = 3.3Hz, 1.7Hz, 1H), 5.64 (s, 1H), 3.57 (s (br), 4H), 3.44 (s (br), 4H), 1.43 (s, 9H)

MS (FAB): 386 (M + l)

IR (KBr, cm " ¹ ): 3151, 2910, 2384, 1653, 1568, 1414, 1232

Melting point: 223.4-224.5 ° C

As _{_{_{_{C 8 H 23 N 7 0 3}}}} 0.1H 2 0: elemental _analysis!

Observed value (%): C 55.82, H 6.12, N 25.02

Calculated value (%): C 55.83, H 6.04, N 25.32 Example 27 (Example): 7-amino-2- (2-furyl) -5- {4- [2- (4-fluorobenzoyl) ethyl] piperazinyl} [1,2,4] triazolo [1 , 5-a] Pyrimidine [Compound (27)] Dissolve 500 mg (1.55 tmol) of compound (18) obtained in Example 18 in 10 ml of ethanol, and add 860 mg (6.22 bandol) of potassium carbonate to this solution. In addition, the mixture was stirred at room temperature for 5 minutes. Then, 870 mg (4.66 tmol) of N- [2- (4-fluorobenzoyl) ethyl] pidazine was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was extracted by adding chloroform and water. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue obtained was purified by silica gel gel chromatography (elution solvent: 4% methanol-chloroform) to obtain a purified product. Recrystallization from ethanol gave 151 mg (yield: 22%) of the title compound (27).

_{Ή MR (DMS0 - d 6,} δ ppm): 8.12- 8.01 (m, 2H), 7.85 (dd, J = l.7Hz, 1.0Hz, 1H), 7.48 (s (br), 2H), 7.39- 7.33 (m, 2H), 7.00 (d, J = 3.3Hz, 1H), 6.67 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.65 (s, 1H), 3.54 (s (br), 4H), 3.34 (s (br), 4H), 3.28-3.23 (m, 2H), 2.75—2.73 (m, 2H)

MS (FAB): 436 (M + l)

IR (KBr, cm " ¹ ): 3152, 2839, 2375, 1660, 1599, 1574

Melting point: 199.4-202.5 ° C

As _{_{_{_{C 22 H 22 N 7 0 2}}}} F 0.2H 2 0 0. lEtOH: Elemental analysis

Observed value (%): C 60.04, H 5.12, N 22.07

Calculated value (%): C 60.10, H 5.22, N 22.10 Example 28 (Example): 7-amino-2- (2-furyl) -5- {4- [4- (4-fluorobenzoyl) butyl] Tyl] piperazinyl} [1,2,4] triazolo [1,5-a] pyrimidine [compound (28)]

The title compound (28) (yield: 19%) was obtained as a pale yellow solid in the same manner as in Example 27 using N- [4- (4-fluorobenzoyl) butyl] pirazine.

_{¾ NMR (CDC1 3, δ ppm} ): 8.01-7.97 (m, 2H), 7.56 (. D, J = l OHz, 1H), 7.18- 7.01 (m, 3H), 6.54 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.56 (s, 1H), 5.33 (s (br), 1H), 3.71-3.01 (m, 4H), 2.99- 2.96 (m, 2H), 2.53-2.49 (m, 4H), 2.45-2.40 (m, 2H), 1.82-1.76 (m, 2H)

MS (m / e): 463 (M ⁺ )

IR (KBr, cm " ¹ ): 3295, 2955, 2384, 1647, 1599, 1560, 1232

Melting point: 204.3-206.0 ° C

As _{_{_{_{C 24 H 26 N 7 0 2}}}} F: Elemental analysis

Observed value (%): C 62.01, H 5.91, N 20.84

Calculated value (%): C 62.19, H 5.65, N 21.15 Example 29 (Reference example): 5-chloro-7- (3,4-dimethoxybenzylamino) -2- (2-furyl) [ 1,2,4] triazolo [1,5-a] pyrimidine [compound (29)]

17.4 g (68.3 mmol) of the compound (2) obtained in Example 2 was suspended in 180 ml of ethanol, and 30.9 ml of veratriluamine (205 ol) was added thereto while stirring at 0 ° C. The reaction was returned to room temperature and stirred for 2 hours. After evaporating the solvent under reduced pressure, chloroform was added and the mixture was washed with diluted hydrochloric acid and then with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 22.7 g (yield: 86%) of the title compound (29) as a white powder.

_{'H NMR (CDC1 3, δ} ppm): 7.58 (. T, J = l OHz, 1H), 7.25 (d, J two 3.6Hz, 1H), 6.95-6.85 (m , 3H), 6.70 - 6.64 (m , 1H), 6.56 (dd, J = 3.6, 2.OHz, 1H), 6.21 (s, 1H), 4.53 (d, J = 5.6Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H )

MS (m / e): 387, 385 (W) Example 30 (Reference example): 7- (3,4-Dimethoxybenzylamino) -5- [4- (4-Chlorophenyl) piperazinyl]- 2- (2-furyl) [1,2,4] triazolo [1,5-a] pyrimidine [compound (30)]

800 mg (2.08 mmol) of the compound (29) obtained in Example 29, 2.24 g (8.32 mmol) of 1- (4-chlorofu: ^ nil) piperazine.2 hydrochloride, and 2.31 ml (16.6 mmol) of DBU were added. It was dissolved in 35 ml of ethanol and heated under reflux overnight. The reaction product was returned to room temperature, extracted with a chloroform and water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: 20% ethyl hexane monoacetate) to obtain 638 mg (yield: 56%) of the title compound (32).

_{¾ NMR (CDC1 3, δ ppm} ): 7.54 (s, 1H), 7.26-7.17 (m, 3H), 6 · 94- 9.80 (m, 5H), 6.54 (dd, J = 3.6Hz, 2.0Hz, 1H ), 6.25 (t, J = 5.3Hz, 1H), 5.41 (s, 1H), 4.47 (d, J = 5.3Hz, 2H), 3.92-3.78 (m, 10H), 3.30-3.20 (m, 4H)

MS (m / e): 545, 543 (M ⁺ ) Example 31 (Reference example): 7- (3,4-Dimethoxybenzylamino) -5- [4- (3-chlorophenyl) pidazur ]-2- (2-furyl) [1,2,4] triazolo [1,5-a] pyrimidine [compound

(31)]

The same operation as in Example 30 using 800 mg (2.08 mmol) of the compound (29) obtained in Example 29, 23 g (5.29 mmol) of 1- (3-chlorophenyl) piperazine 'hydrochloride, and 1.15 ml (8.32 mmol) of DBU By this, 673 mg (yield: 59%) of the title compound (31) was obtained as a cream-colored powder.

¾ NMR (DMS0-d ₆ , δ ppm): 8.40-8.33 (m, 1H), 7.95 (d, J = l.0Hz, 1H), 7.38-6.85 (m, 8H), 6.77 (dd, J = 3.3 Hz, 1.7Hz, 1H), 5.89—5.88 (m, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.95-3.75 (m, 4H), 3.40-3.25 (m, 4H)

MS (m / e): 545 (M ⁺ ) Example 32 (Reference Example): 7- (3,4-dimethylbenzylamino) -5- [4- (2-chlorophenyl) pidazur] -2- (2-furyl) [1,2,4] triazolo [1,5-a] pyrimidine [compound

(32)]

Perform the same operation as in Example 30 using 800 mg (2.08 ol) of compound (29) obtained in Example 29, 1.23 g (6.24 mmol) of tri (2-chlorophenyl) piperazine, and 1.0 ml (7.30 mmol) of DBU. Thereby, 732 mg (yield: 64%) of the title compound (32) was obtained. Ή NMR (CDCI3, δ ppm): 7.54 (t, J = 1.0 Hz, 1H), 7.42-6.83 (m, 8H), 6.54 (dd, J = 3.3 Hz, 2.0 Hz, 1H), 6.25 (brt, J = 5.3Hz, 1H), 5.44 (s, 1H), 4.47 (d, J = 5.3Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.95-3.86 (m, 4H), 3.15-3.08 (m, 4H) Example 33 (Reference example): 7- (3,4-Dimethoxybenzylamino) -5- [4- (2-Methoxypheno) pirazur]-2- ( 2-furinole) [1,2,4] triazolo [1,5-a] pyrimidine [compound

(33)]

800 mg (2.08 ol) of the compound (29) obtained in Example 29 and 1.10 ml (6.24 mmol) of 1- (2-methoxyphenolinole) pidazine were heated and refluxed overnight in 30 ml of ethanol. The reaction product was returned to room temperature, extracted with chloroform and water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and silica gel column chromatography

(Eluent: 20% chloroform-hexane) to give 574 mg of the title compound (33)

(Yield: 51%) was obtained as a yellow powder.

Ή NMR (DMS0-d ₆ , δ ppm): 8.27 (brt, J = 6.3 Hz, 1H), 7.85 (d, J = 0.7 Hz, 1H), 7.15-6.86 (m, 8H), 6.68-6.66 (m, 1H), 5.78 (s, 1H), 4.50 (d, J = 6.3Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.82-3.69 ( m, 4H), 3.06-2.90 (m, 4H)

MS (m / e): 541 (M Example 34 (Reference Example): 7- (3,4-dimethoxybenzylamino) -5- [4- (4-fluorophenylinole) piperazinyl] -2-(2 -Furyl) [1,2,4] triazolo [1,5-a] pyrimidine [compound

(34)]

Represented by performing the same operation as in Example 33 using 200 mg (0.52 mmol) of the compound (29) obtained in Example 29 and 374 mg (2.08 ol) of 1- (4-fluorophenyl) pidazine 293 mg (yield: quantitative) of compound (34) was obtained as a white powder.

Ή NMR (CDC1,., Δ ppm): 7.54 (t, J = l.OHz, 1H), 7.18 (d, J = 3.3Hz, 1H), 7.02— 7.85 (m, 7H), 6.54 (dd, J = 3.3Hz, 2.0Hz, 1H), 6.25 (t, J = 5.6Hz, 1H), 5.43 (s, 1H), 4.47 (d, J = 5.6 Hz, 2H), 3.90- 3.75 (m, 10H), 3.20-3.06 (m, 4H)

MS (m / e): 529 (M) Example 35 (Reference example): 5- (4-bromophenoxy) -7- (3,4-dimethoxybenzylamino) -2- (2-furyl) [1, 2, 4] triazolo [1,5-a] pyrimidine [compound (35)]

675 mg (3.90 mmol) of p-bromophenol was dissolved in 15 ml of DMF, and 156 mg (3.90 tmol) of sodium hydride (containing 60%) was added with stirring. To this was added 500 mg (1.30 ol) of the compound (29) obtained in Example 29, and the mixture was stirred at 100 ° C overnight. The reaction product was returned to room temperature, water and chloroform were added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: 20% hexane / monochloroform) to obtain 260 mg (yield: 38%) of the title compound (35) as a yellow powder.

Ή NMR (CDC13 ₎ δ ppm): 7.56-7.55 (m, 1H), 7.49 (d, J = 8.6Hz, 2H), 7.18 (d, J = 3.3Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.95-6.87 (m, 3H), 6 · 56-6.53 (m, 2H),

5.79 (s, 1H), 4.52 (d, J = 5.6Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H)

MS (m / e): 523, 521 (M +) Example 36 (Reference example): 7- (3,4-Dimethoxybenzylamino) -2- (2-furyl) -5- (4-propoxyphenoxy) [1,2,4] triazolo [1,5-a] pyrimidine [compound (36)]

Using 890 mg (5.84 mmol) of p-propoxyphenol, 234 rag (5.84 mmol) of sodium hydride (containing 60%) and 750 mg (1.95 mmol) of the compound (29) obtained in Example 29 Perform the same operation as on 35 to give 330 mg of the title compound (36)

(Yield: 34%) was obtained as a yellow powder.

_{¾ NMR (CDC1 3, δ ppm} ): 7.55 (t, J = 0.7Hz, 1H), 7.16 (d, J = 3.3Hz, 1H), 7.10-

6.80 (m, 8H), 6.53-6.49 (m, 2H), 5.75 (s, 1H), 4.49 (d, J = 5.3Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.95 -3.80 (m, 2H), 1.87-1.75 (m, 2H), 1.08-0.98 (m, 3H) MS (m / e): 501 (M ⁺ ) Example 37 (Reference example): 5- (4-butoxyphenoxy) -7- (3,4-dimethoxybenzylamino) -2- (2-furyl) ) [1,2,4] Triazolo [1,5-a] pyrimidine [Compound (37)]

Using 1.04 g (6.23 bandol) of P-butoxyphenol, sodium hydride (containing 60%) 250 mg (6.23 tall ol), and 800 mg (2.08 mmol) of the compound (29) obtained in Example 29, By performing the same operation as in Example 35, 377 mg (yield: 35%) of the title compound (37) was obtained as a yellow powder.

_{'Η NMR (CDC1 3, δ} ppm): 7.55 (t, J = l.0Hz, 1H), 7.16 (d, J = 3.5Hz, 1H), 7.08 (d, J = 8.9Hz, 2H), 6.94- 6.83 (m, 5H), 6.57-6.52 (m, 2H), 5.81 (s, 1H),

4.49 (d, J = 5.9Hz, 2H), 3.96 (t, J = 6.4Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 1.83-1.72 (m, 2H), 1.55- 1.43 (m, 2H), 0.99 (t, J = 7.4Hz, 3H)

MS (m / e): 515 (M +) Example 38 (Reference example): 7- (3,4-Dimethoxybenzylamino) -2- (2-furyl) -5- (3,4,5- Limethoxyphenoxy) [1,2,4] Triazolo [1,5-a] pyrimidine [Compound (38)]

1.19 g (6.48 mmol) of 3,4,5-trimethoxyphenol, 260 mg (6.48 mmol) of sodium hydride (containing 60%), and 800 mg (2.08 mmol) of the compound obtained in Example 29 (29) mmol) and 530 mg (yield: 46%) of the title compound (38) was obtained as an ocher powder by performing the same operation as in Example 35.

Thigh _{(CDC1 3, δ ppm):} 7.56 (. T, J = l OHz, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.94- 6.85 (m, 3H), 6.54 (dd, J = 3.3 Hz, 1.7Hz, 1H), 6.57- 6.53 (m, 1H), 6.40 (s, 2H),

5.76 (s, 1H), 4.51 (d, J = 5.6Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.81 (s, 6H)

MS (m / e): 533 (M ⁺ ) Example 39 (Reference example): 7- (3,4-Dimethyloxybenzylamino) -2- (2-furyl) -5-piperidino [1,2,4] triazolo [1,5-a] pyrimidine [ Compound (39)]

Using 0.62 ml (6.23 mmol) of piperidine and 600 mg (1.56 mmol) of the compound (29) obtained in Example 29, 480 mg (yield: 71) of the title compound (39) was obtained in the same manner as in Example 33. %) Was obtained as a milky white powder.

_{Ή NMR (CDC1 3, δ ppm} ): 7.53 (t, J = l.0Hz, 1H), 7.16 (d, J = 3.3Hz, 1H), 6.95- 6.84 (m, 3H), 6.52 (dd, J = 3.3Hz, 1.7Hz, 1H), 6.15 (t, J = 5.6Hz, 1H), 5.38 (s, 1H), 4.44 (d, J = 5.6Hz, 2H), 3.90 (s, 3H), 3.88 (s , 3H), 3.70-3.63 (m, 4H), 1.70—1.55 (m, 6H)

MS (m / e): 434 (M ⁺ ) Example 40 (Reference example): 7- (3,4-Dimethoxybenzylamino) -2- (2-furinole) -5- (1-hexamethyleneimino) [1,2,4] triazolo [1,5-a] pyrimidine [compound (40)] hexamethyleneimine 0.54 ml (4.83 mmol) and the compound obtained in Example 29 (29) 620 mg (1.61 mmol) The title compound was obtained by performing the same operation as in Example 33 using

(40) 510 mg (yield: 71%) was obtained as a white powder.

Anonymous _{R (CDC1 3, δ ppm)} : 7.53 (. T, J = l OHz, 1H), 7.17 (d, J = 3.0Hz, 1H), 6.95- 6.83 (m, 3H), 6.52 (dd, J = 3.5Hz, 1.5Hz, 1H), 6.17 (t, J = 5.4Hz, 1H), 5.26 (s, 1H), 4.44 (d, J = 5.4Hz, 2H), 3.89 (s, 3H), 3.87 (s , 3H), 3.76-3.50 (m, 4H), 1.85- 1.70 (m, 4H), 1.55-1.48 (m, 4H)

MS (m / e): 448 (M +) Example 41 (Reference example): 5- (4-benzylpyridino) -7- (3,4-dimethoxybenzylamino) -2- (2-furyl) [1,2,4] triazolo [l, 5-a] pyrimidine [compound (41)]

4 - benzylpiperidine L 10 ml (6.23 mmol) and the compound obtained in Example 29 (29) using 800 mg (2.07 negation ₀ 1), title of compounds by the same procedure as Example 33 (41) 726 mg (yield: 67 ° /.). Ή NMR (CDCI3, δ ppm): 7.53 (t, J = 0.7Hz, 1H), 7.30-7.12 (m, 6H), 6.94-6.83 (m, 3H), 6.52 (dd, J = 3.3Hz, 2.0Hz , 1H), 6.15 (t, J = 5.6 Hz, 1H), 5.37 (s, 1H), 4.43 (d, J = 5.6 Hz, 4H), 3.89 (s, 3H), 3.87 (s, 3H), 2.90 -2.80 (m, 2H), 2.56-2.53 (m, 2H), 1.84- 1.62 (m, 3H), 1.13- 1.21 (m, 2H)

MS (m / e): 524 (M ⁺ ) Example 42 (Reference example): 5-benzylamino-7- (3,4-dimethoxybenzylamino) -2- (2-furyl) [1,2,4 ] Triazolo [1,5-a] pyrimidine [Compound (42)]

800 mg (2.07 mmol) of the compound (29) obtained in Example 29, 0.71 ml (6.50 tmol) of benzylamine and 0.29 ml (2.16 mmol) of DBU were dissolved in 30 ml of ethanol, and the mixture was heated under reflux overnight. The reaction product was returned to room temperature, extracted with chloroform and water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: black form) to give the title compound (42) 720 mg

(Yield: 73%) as a yellow powder.

_{Ή NMR (CDC1 3, δ ppm} ): 7.52 (t, J = 0.7Hz, 1H), 7.35- 7.14 (m, 6H), 6.87- 6.82 (m, 3H), 6.52 (dd, J = 3.3Hz, 1.7 Hz, 1H), 6.30-6.20 (m, 1H), 5.16 (s, 1H), 4.61 (d, J = 5.9Hz, 2H), 4.37 (d, J = 5.3Hz, 2H), 3.88 (s, 3H) ), 3.86 (s, 3H) MS (m / e): 456 (M ⁺ ) Example 43 (Reference example): 7- (3,4-Dimethoxybenzylamino) -2- (2-furyl) -5 -Phenylethylamino [1,2,4] triazolo [1,5-a] pyrimidine [Compound (43)]

Compound (43) obtained by performing the same operation as in Example 42 using 800 mg (2.07 marl ol), phenethylamine 0.78 ml (6.23 mmol), and DBU 0.28 ml (2.07 mmol) obtained in Example 29 (29) 620 mg (yield: 64%) was obtained as a yellow powder. _{Ή NMR (CDC1 3, δ ppm} ): 7.54 (. T, J = l OHz, 1H), 7.34-7.16 (m, 5H), 6.91- 6.82 (m, 3H), 6.53 (dd, J = 3.3Hz, 1.7Hz, 1H), 6.21-6.17 (m, 1H), 5.10 (s, 1H), 4.39 (d, J = 5.3Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.71 ( q, J = 6.6Hz, 2H), 2.93 (t, J = 6.6Hz, 2H)

MS (m / e): 470 (M ⁺ ) Example 44 (Reference Example): 7- (3,4-dimethylbenzylamino) -2- (2-furyl) -5- (3-phenylpropyla Mino) [1,2,4] Triazo [1,5-a] pyrimidine [Compound (44)] 800 mg (2.07 mmol) of compound (29) obtained in Example 29, and 0.92 ml of 3-phenylpropylamine The same operation as in Example 33 was performed using 6.47 mmol) to obtain 617 mg (yield: 59%) of the title compound (44).

_{Ή NMR (CDC1 3, δ ppm} ): 7.52 (. T, J = l OHz, 1H), 7.28-7.13 (m, 6H), 6.90- 6.80 (in, 3H), 6.53 (dd, J = 3.3Hz, 1.7Hz, 1H), 6.21-6.15 (m, 1H), 5.08 (s, 1H), 4.87-4.79 (m, 1H), 4.39 (d, J = 5.6Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.50-

3.40 (m, 2H), 2.70 (t, J = 7.6Hz, 2H), 1.95 (q, J = 7.3Hz, 2H)

MS (m / e): 484 (M Example 45 (Reference example): 7- (3,4-Dimethoxybenzylamino) -5- (3,4-Dimethoxyphenethylamino) -2- (2- Furyl) [1, 2, 4] triazolo [1, 5-a] pyrimidine [compound (45)]

The same procedure as in Example 33 was carried out using 800 mg (2.07 ol) of the compound (29) obtained in Example 29 and 1.09 ml (6.47 mmol) of 3,4-dimethoxyphenethylamine to give the title compound (45). 529 mg (yield: 48%) were obtained as a yellow powder.

_{Ή NMR (DMS0 - d 6,} δ ppm): 8.91 - 8.10 (m, 1H), 7.84 (s, 1Η), 7.30-7.20 (m, 1H), 7.06-6.62 (m, 8H), 5.32 (s, 1H), 4.37 (d, J = 5.6Hz, 2H), 3.75—3.42 (m, 14H), 2.74 (t, J = 7.6Hz, 2H)

MS (m / e): 530 (W) Example 46 (Example): 7-amino-5- [4- (4-chlorophenyl) piperazinyl] -2- (2-furyl) [1,2,4] Triazolo [1,5-a] pyrimidine [Compound (46)] 620 mg (1.14 mmol) of the compound (30) obtained in Example 30 was dissolved in 10 ml of trifluoroacetic acid, 0.5 ml of anisol and 1.2 g of naphion were added, and the mixture was heated under reflux for 1.5 hours. The reaction was returned to room temperature, the naphthion was filtered off, and the naphthion was thoroughly washed with a methylamine-methanol solution and then with methanol. After the filtrate and washings were distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: 0.2% triethylamine-3% methanol-single-mouthed form) and recrystallized from ethanol to give 205 mg of the title compound (46). (Yield: 45%) as a white powder.

_{'Η NMR (DMSO- d 6,} δ ppm): 7.85 (s, 1H), 7.50 (s (br), 2H), 7.26 (d, J = 9.4Hz, 2H), 7.02 (d, J = 3.3Hz , 1H), 7.00 (d, J = 9.4Hz, 2H), 6.66 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.71 (s, 1H), 3.78-3.66 (m, 4H), 3.30-3.22 (m, 4H)

MS (m / e): 395 (M

IR (KBr; cm- ¹ ): 1659, 1601, 1570, 1495, 1234

Melting point:> 270 ° C

As _{_{_{C 19 H 18 N 7 0C1 0.}}} lEtOH 0.2H 2 0: Elemental analysis

Observed value (%): C 57.12, H 4.64, N 24.20

Calculated value (%): C 57.07, H 4.74, N 24.27 Example 47 (Example): 7-amino-5- [4- (3-chlorophenyl) piperazinyl] -2- (2-furyl) [1 , 2,4] triazolo [1,5-a] pyrimidine [compound (47)]

The same operation as in Example 46 was carried out using 650 mg (1.20 ol) of the compound (31) obtained in Example 31 to obtain 118 mg (yield: 25%) of the title compound (47) as a white powder. .

¾ negation _{R (DMSO- d 6, δ ppm} ): 7.85 (s, 1H), 7.52 (s (br), 2H), 7.24 (t, J = 7.9Hz, 1H), 7.04-6.93 (m, 3H) , 6.81 (d, J = 7.9Hz, 1H), 6.66 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.70 (s, 1H), 3.74-3.67 (m, 4H), 3.35-3.26 (m, 4H)

MS (m / e): 395 (M ⁺ )

IR (KBr; cm " ¹ ): 1666, 1650, 1603, 1485 Melting point:> 300 ° C

Elemental _{_{_{analysis: C 19 H 18 N 7 0C1}}} 0.3EtOH 0.4H, 0

Observed value (%): C 56.40, H 4.66, N 23.40

Calculated value (%): C 56.47, H 4.98, N 23.52 Example 48 (Example): 7-amino-5- [4- (2-chlorophenyl) piperazinyl] -2- (2-furyl) [1,2 , 4] triazolo [1,5-a] pyrimidine [compound (48)]

The same operation as in Example 46 was carried out using 700 mg (1.28 mmol) of the compound (32) obtained in Example 32 to obtain 271 mg (yield: 53%) of the title compound (48) as a yellow powder.

_{¾ NMR (CDC1 3, 5 ppm} ): 7.56 (. D, J = l OHz, 1H), 7.40 (dd, J = 7.6Hz, 1.3Hz, 1H), 7.26-7.20 (m, 1H), 7.18 (d , J = 3.3Hz, 1H), 7.01-6.97 (m, 2H), 6.54 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.63 (s, 1H), 5.49 (s (br), 2H), 3.90-3.86 (m, 4H), 3.14-3.09 (m, 4H)

MS (m / e): 395 (M ⁺ )

IR (KBr; cm " ¹ ): 1654, 1605, 1483, 1443, 1331, 1225

Melting point: 255.2-256.4. C

As _{_{_{C 19 H 18 N 7 0C1 0.2EtOH}}} : Elemental analysis

Observed value (%): C 57.57, H 4.65, N 24.21

Calculated value (%): C 57.53, H 4.78, N 24.21 Example 49 (Example): 7-amino-2- (2-furyl) -5- [4- (2-methoxyphenyl) piperazinyl] [1, 2,4] triazolo [1,5-a] pyrimidine [compound (49)]

The same operation as in Example 46 was carried out using 574 mg (1.06 mmol) of the compound (33) obtained in Example 33 to obtain 188 mg (yield: 45%) of the title compound (49) as a white powder.

_{¾ NMR (CDC1 3, δ ppm} ): 7.56 (. D, J = l OHz, 1H), 7.19 (d, J = 3.3Hz, 1H), 7.08-6.87 (m, 4H), 6.55 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.63 (s, 1H), 5.44 (s (br), 2H), 3.90 (s, 3H), 3.91- 3.85 (m, 4H), 3.15-3.09 (m, 4H)

MS (m / e): 391 (M ⁺ )

IR (KBr; cm- ¹ ): 1659, 1655, 1605, 1488, 1240

Melting point: 269.8-271.2 ° C

As _{_{_{_{C 20 H 21 N 7 0 2}}}} 0.3Et0H: Elemental analysis

Observed value (%): C 61.08, H 5.61, N 24.16

Calculated value (%): C 61.05, H 5.67, N 24.19 Example 50 (Example): 7-amino-5- [4- (4-fluorophenyl) piperazinyl] -2- (2-furyl) [1,2 , 4] Triazolo [1,5-a] pyrimidine [compound (50)]

The same operation as in Example 46 was carried out using 620 mg (1.17 mmol) of the compound (34) obtained in Example 34 to obtain 193 mg (yield: 44%) of the title compound (50) as a yellow powder.

_{¾ NMR (DMS0- d 6, δ} ppm): 7.85 (t, J = l.0Hz, 1H), 7.49 (s (br), 1H), 7.13- 6.96 (m, 5H), 6.66 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.72 (s, 1H), 3.77-3.65 (m, 4H), 3.25-3.13 (m, 4H)

MS (m / e): 379 (M ⁺ )

IR (KBr; cm " ¹ ): 1659, 1651, 1605, 1568, 1508, 1230

Melting point:> 270 ° C

As _{_{_{C 19 H l8 N 7 0F 0.2EtOH}}} 0.7H 2 0: Elemental analysis

Observed value (%): C 58.10, H 4.79, N 24.24

Calculated value (° / o): C 58.08, H 5.17, N 24.44 Example 51 (Example): 7-amino-5- (4-bromophenoxy) -2- (2-furyl) [1,2,4] tri Azolo [1,5-a] pyrimidine [Compound (51)]

The same operation as in Example 46 was carried out using 710 mg (1.91 mmol) of the compound (35) obtained in Example 35. This gave 180 mg (yield: 25%) of the title compound (51) as a white powder.

_{Ή NMR (DMS0-d 6,} δ ppm): 8.15 (s (br), 2H), 7.88 (d, J = L0Hz, 1H), 7.64 (dd, J = 8.9Hz, 2.0Hz, 2H), 7.21 ( dd, J = 8.9Hz, 2.0Hz, 2H), 7.06 (d, J = 3.3Hz, 1H), 6.68 (dd, J 3.3Hz, 2.0Hz, 1H), 5.82 (s, 1H)

MS (m / e): 373, 371 (M +)

IR (KBr; cm " ¹ ): 1670, 1655, 1605, 1572, 1223

Melting point:> 270 ° C

As _{_{_{_{C I5 H 10 N 5 0 2}}}} Br 0.2EtOH: Elemental analysis

Observed value (%): C 48.46, H 2.89, N 18.31

Calculated value (%): C 48.50, H 2.96, N 18.36 Example 52 (Example): 7-amino-2- (2-furyl) -5- (4-propoxyphenoxy) [1, 2,4] triazolo [1,5-a] pyrimidine [compound (52)]

The same operation as in Example 46 was carried out using 600 mg (1.19 mmol) of the compound (36) obtained in Example 36 to obtain 196 mg (yield: 47%) of the title compound (52) as a white powder.

Ή NMR (DMSO-d ₆ , δ ppm): 8.05 (s (br), 2H), 7.87 (d, J = 1.0 Hz, 1H), 7.12 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 3.3Hz, 1H), 6.99 (d, J = 8.9Hz, 2H), 6.67 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.73 (s, 1H), 3.95 (t, J = 6.6Hz , 2H), 1.82-1.68 (ra, 2H), 1.00 (t, J = 7.3Hz, 3H)

MS (m / e): 351 (M ⁺ )

IR (KBr; cnf ¹ ): 1655, 1602, 1566, 1508, 1211

Melting point:> 270 ° C

As _{_{_{_{C 18 H 17 N 5 0 3}}}} 0.2EtOH: Elemental analysis

Observed value (%): C 61.44, H 5.11, N 19.40

Calculated value (%): C 61.29, H 5.09, 19.42 Example 53 (Example): 7-amino-5- (4-butoxyphenoxy) -2- (2-furyl) [1,2,4] triazolo [1,5-a] pyrimidine [compound ( Compound 53)]

The same operation as in Example 46 was carried out using 377 mg (0.73 ol) of the compound (37) obtained in Example 37 to obtain 300 mg (yield: 56%) of the title compound (53) as a pale brown powder. .

'Η NMR (DMS0-d ₆ δ ppm) 8.05 (s (br), 2H), 7.88 (t, J = L ΟΗζ, 1H 7.12 (dd, J = 9.0Hz, 2.3Hz, 2H 7.06 (d, J = 3.3Hz, 1H 6.99 (dd, J = 9.0Hz, 2.3Hz, 2H), 6.68 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.73 (s, 1H 3.99 (t, J = 6.3Hz, 2H) , 1.77- 1.66 (m, 2H), 1.53- 1.38 (m, 2H), 0.95 (t, J = 7.3Hz, 3H)

MS (m / e): 365 (M ⁺ )

^{IR (KBr; cm '1)} : 1660, 1651, 1603, 1564, 1506, 1456, 1209

Melting point: 257.5-258.4 ° C

Elemental analysis: C, ₉ H ₁₉ N ₅ 0 ₃ 0.3Et0H 0.1H ₂₀

Observed value (%): C 61.75, H 5.48, N 18.30

Calculated value (%): C 61.79, H 5.56, N 18.38 Example 54 (Example): 7-amino-2- (2-furyl) -5- (3,4,5-trimethoxyphenoxy) [1,2,4] triazolo [1,5-a] pyrimidine [compound (54)]

The same operation as in Example 46 was carried out using 450 mg (0.84 ol) of the compound (38) obtained in Example 38 to obtain 157 mg (yield: 49%) of the title compound (54) as a yellow powder.

¾ NMR (DMS0-d ₆ , δ ppm) 8.08 (s (br), 2H), 7.88 (d, J = 1.0 Hz, 1H), 7.07 (d, J = 3.5 Hz, 1H 6.68 (dd, J = 3.5Hz, 1.5Hz, 1H), 6.58 (s, 2H), 5.76 (s, 1H) MS (m / e) 383 (M ⁺ )

IR (KBr; cm " ¹ ): 1662, 1606, 1570, 1504, 1468

Melting point:> 270 ° C As _{_{_{_{C 18 H 17 N 5 0 5}}}} 0.2Et0H: Elemental analysis

Observed value (%): C 56.28, H 4.56, N 17.83

Calculated value (%): C 56.30, H 4.67, N 17.84 Example 55 (Reference example): 7-amino-2- (2-furyl) -5-piperidino [1,2,4] triazolo [1 , 5-a] Pyrimidine [compound (55)]

The same operation as in Example 46 was carried out using 700 mg (1.61 mmol) of the compound (39) obtained in Example 39 to obtain 399 mg (yield: 87%) of the title compound (55) as a pale yellow powder. .

Thigh _{(DMS0 - d 6, δ ppm} ): 7.83 (d, J = l.5Hz, 1H), 7.35 (s (br), 2H), 7.00 (d, J = 3.5Hz, 1H), 6.65 (dd, J = 3.5Hz, 1.5Hz, 1H), 5.65 (s, 1H), 3.57 (t (br), 4H), 1.68-1.48 (m, 6H)

MS (m / e): 284 (M ten)

^{IR (KBr; cm '1)} : 1659, 1605, 1558, 1236

Melting point:> 270 ° C

As _{_{_{C 14 H 16 N 6 0 0.}}} lEtOH: Elemental analysis

Observed value (%): C 59.00, H 5.90, N 28.97

Calculated value (%): C 59.03, H 5.79, N 29.09 Example 56 (Reference example): 7-amino-2- (2-furinole) -5- (trihexamethylene timino) [1,2,4] triazolo [ 1, 5-a] Pyrimidine hydrochloride [Compound (56)]

500 mg (1.12 mmol) of the compound (40) obtained in Example 40 was dissolved in 10 ml of trifluoroacetic acid, 0.5 ml of anisol and 1.5 g of naphion were added, and the mixture was heated under reflux for 1.5 hours. The reaction was returned to room temperature, the naphthion was filtered off, and the naphthion was thoroughly washed with a methylamine-methanol solution and then with methanol. After the filtrate and the washings were distilled off under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: 20% hexane-chloroform). The resulting 7-amino-2- (2-figure) -5- (1-hexamethyleneimid) D) To a crude product of [1,2,4] triazolo [i, 5-a] pyrimidine was added 10 ml of 4M ethyl acetate monohydrochloride and the mixture was stirred at room temperature for 1 hour. Then, 40 ml of ether was added, and the precipitated solid was collected by filtration and washed with ether to obtain 154 mg (yield: 41%) of the title compound (56) as a pale yellow powder.

Ή negation _{R (CDC1 3, δ ppm)} : 7.55 (. T, J = l OHz, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.53 (dd, J = 3.3Hz, 1.7Hz, 1H) , 5.47 (s, 1H), 5.34 (s (br), 2H), 3.90-3.55 (m, 4H), 1.82-1.50 (m, 8H)

MS (m / e): 298 (M ⁺ )

IR (KBr; cm " ¹ ): 1678, 1614, 1568, 1548

Melting point: 206.5-208.4 ° C

As _{_{_{C 15 H 18 N 6 0 1.0HC1}}} 1.0H 2 0: Elemental analysis

Observed value (%): C 51.11, H 6.01, N 23.85

Calculated value (%): C 51.06, H 6.00, N 23.82 Example 57 (Example): 7-amino-2- (2-furyl) -5- (4-benzylpiperidino) [1,2,4] Triazolo [1,5-a] pyrimidine [Compound (57)]

The same operation as in Example 46 was carried out using 650 mg (1.24 ramol) of the compound (41) obtained in Example 41 to obtain 351 mg (yield: 75%) of the title compound (57) as a yellow powder.

_{Ή NMR (DMS0 - d 6,} δ ppm): 7.83 (. D, Jl OHz, 1H), 7.37-7.17 (m, 7H), 7.00 (d, J = 3.3Hz, 1H), 6.65 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.65 (s, 1H), 4.32-4.21 (m, 2H), 2.90-2.80 (m, 2H), 2.54-2.49 (m, 2H), 1.85-1.60 (m, 3H ), 1.28-1.06 (m, 2H)

MS (m / e): 374 (M ⁺ )

IR (KBr; cm- ¹ ): 1655, 1606, 1558, 1490, 1236

Melting point:> 270 ° C

As _{_{_{C 2I H 22 N 6 0 0.2H}}} 2 0: Elemental analysis Observed value (%): C 66.88, H 6.09, N 21.85

Calculated value (%): C 66.72, H 5.97, N 22.23 Example 58 (Reference example): 7-amino-5-benzylamino-2- (2-furyl) [1,2,4] triazolo [l, 5_a] pyri Midine [Compound (58)]

The same operation as in Example 46 was carried out using 600 mg (1.31 mmol) of the compound (42) obtained in Example 42 to obtain 210 mg (yield: 52%) of the title compound (58) as a white powder.

Ή NMR (DMSO—d ₆ , δ ppm): 7.83 (s, 1H), 7.70 (t (br), J = 5.6 Hz, 1H), 7.35—7.22 (m, 5H), 6.98 (d, J = 3.3 Hz, 1H), 6.64 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.50 (s, 1H), 4.52 (d, J = 5.6Hz, 2H)

MS (m / e): 306 (M ⁺ )

IR (KBr; cm " ¹ ): 1678, 1662, 1606, 1575, 1542, 1523, 1336

Melting point: 244.5-245.0 ° C

As _{_{_{C 6 H 14 N 6 0 0.}}} lEtOH: elemental _analysis!

Observed value (%): C 62.11, H 4.51, N 27.05

Calculated value (%): C 62.58, H 4.73, N 27.03 Example 59 (Reference example): 7-amino-2- (2 furyl) -5-phenethylamino [1, 2, 4] triazo mouth [1, 5-a] ] Pyrimidine hydrochloride [Compound (59)]

The same operation as in Example 56 was carried out using 580 mg (1.23 mmol) of the compound (43) obtained in Example 43 to obtain 211 mg (yield: 46%) of the title compound (59) as a white powder.

_{Ή NMR (CDC1 3, δ ppm} ): 7.53 (. T, J = l OHz, 1H), 7.30- 7.12 (m, 6H), 6.52 (dd, J = 3.5Hz, 1.5Hz, 1H), 5.85 (s (br), 2H), 5.38 (s, 1H), 3.65-3.58 (m, 2H), 2.89 (t, J = 7.4Hz, 2H)

MS (m / e): 320 (NT) IR (KBr; cnf ¹ ): 1686, 1678, 1578, 1560

Melting point: 164.1-170.2. C

Elemental analysis: C _I7 H ₁₆ N ₆ 0 1.1HC1 0.9H ₂₀

Observed value (%): C 54.07, H 4.94, N 22.45

Calculated value (%): C 54.21, H 5.06, N 22.31 Example 60 (Reference example): 7-amino-2- (2-furyl) -5- (3-phenylpropylamino) [1 , 2,4] triazolo [1,5-a] pyrimidine [compound (60)]

The same operation as in Example 46 was carried out using 520 rag (1.07 mmol) of the compound (44) obtained in Example 44 to obtain 280 mg (yield: 78%) of the title compound (60) as a brown powder.

¾ NMR (DMSO— d ₆ , δ ppm): 7.92 (d (br), J = 1.0Hz, 1H), 7.77-7.55 (m, 2H), 7.38-7.13 (m, 6H), 6.71 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.53 (s, 1H), 3.35-3.25 (m, 2H), 2.66 (t, J = 7.6Hz, 2H), 1.85 (q, J = 7.6Hz, 2H)

MS (m / e): 334 (M +)

IR (KBr; cm— ¹ ): 1662, 1658, 1575, 1558

Melting point: 114.2-114.9 ° C

Elemental analysis: C ₁₈ H ₁₈ N ₆ 0 0.3H ₂ 0 0.3Et0H

Obtained value (%) C 63.17, H 5.66, N 23.58

Calculated value (<< ¾): C 63.18, H 5.81, N 23.77 Example 61 (Example): 7-amino-5- (3,4-dimethoxyphenethylamino) -2- (2-furyl) [1,2,4] triazolo [1,5-a] pyrimidine hydrochloride [Compound (61)]

The same operation as in Example 56 was carried out using 500 mg (0.94 mmol) of the compound (45) obtained in Example 45 to obtain 193 mg (yield: 47%) of the title compound (61) as a brown powder.

_{Ή MR (CDC1 3, δ ppm} ): 7.53 (s, 1H), 7.13 (d, J = 3.3Hz, 1H), 6.80- 6.68 (m, 3H), 6.53-6.51 (m, 1H), 5.86 (s (br), 2H), 5.40 (s, 1H), 5.26 (s (br), 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.65- 3.56 (m, 2H), 2.83 (t, J = 6.9Hz, 2H)

MS (m / e): 380 (M +)

IR (KBr; cm " ¹ ): 1682, 1620, 1583, 1516

Melting point: 125.4-127.6 ° C

As _{_{_{_{C 19 H 20 N 6 0 3}}}} 0.9HC1 1.1H 2 0: Elemental analysis

Observed value (%): C 52.81, H 5.39, N 19.19

Calculated value (%): C 52.70, H 5.38, N 19.41 Formulation example 1: Tablet

Compound 4 10 mg

Lactose 30 mg

Horse feces 15 mg

Polyvinyl alcohol 1.5 mg

Magnesium stearate 0.5 mg

A tablet having the above composition is produced by a conventional method. Formulation Example 2: Capsule

Compound 26 10 mg

Lactose 100 mg

Magnesium stearate 2.5 mg

These components are mixed by a conventional method and filled into a gelatin capsule to produce a capsule. Formulation Example 3: Injection

Compound 61 2 mg

Refined soybean oil 200 mg Purified egg yolk lecithin 24 mg

Glycerin for injection 50 mg

1.72 ml of distilled water for injection

An injection having the above composition is produced by a conventional method. Test Example 1: Adenosine receptor antagonism (Adenosine A _2A receptor binding test)

Using the method of Bruns et al. [Mole. Pharmacol., 29, 331 (1986)] with minor modifications, the effect of the medicament of the present invention on the adenosine receptor was evaluated. The rat striatum was suspended in ice-cold 50 mM Tris (hydroxymethyl) aminomethan hydrochloride (Tris'HCl) buffer (pH 7.7) using a Polytron homogenizer (Kinematica). . The suspension was centrifuged (50, OOOxg, 10 minutes), and the obtained precipitate was re-suspended with the same amount of 50 mM Tris'HCl buffer and centrifuged in the same manner. The final precipitate was added to a 50 mM Tris'HCl buffer [10 mM magnesium chloride, adenosine deaminase 0.02 unit tissue mg (Sigma) to a tissue concentration of 5 mM (wet weight) Zml. ) Was added to the suspension.

CGS 21680 [Adenosine A _2A receptor agonist: 1--2- [P- (2-carboxyethyl) phenylamino]]-5 '-(N-ethylca Levoxamide) Adenosine: 40 Curie / mmol; manufactured by New England Nuclear; The Giannareo lab Pharmacol 'and J. Pharmacol. Exp. Ther., 251, 888 (1989)] 50 ml (final concentration 4.0 nM) and 50 μl of the test compound suspension were added. The mixture was allowed to stand at 25 ° C for 120 minutes, filtered through a glass fiber filter (GF / C; manufactured by Whatman) with a rapid suction filter, and immediately cooled with 5 ml of ice-cold 50 mM Tris'HCl buffer. Washed three times. The glass fiber filter paper was transferred to a vial, a scintillator (EX-II; manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the radioactivity was measured with a liquid scintillation counter (manufactured by Packard).

Calculation of the inhibition rate for A _2A receptor binding of a test compound (¾- CGS 21680 binding) following It was determined by the PT JP formula. Inhibition rate = [11 (the amount of binding in the presence of the test compound-the amount of non-specific binding) Z (total amount of binding-the amount of non-specific binding)] x ioo in the presence drug; ³ H-CGS 21680 is a bond amount of radioactivity in; non-specific binding is 100 mM cyclopentyladenosine; be ³ H-CGS 21680 binding radioactivity in the presence (CPA Sigma Co.) Is the amount of ¾-CGS 21680 bound radioactivity in the presence of various concentrations of the test compound]. The results are shown in Table 2. All of the compounds included in the formula (I) have potent adenosine _A2A receptor antagonism, and the medicament of the present invention is useful for treating Parkinson's disease derived from hyperactivity of adenosine _A2A receptor, Or it was shown to be effective for prevention.

Table 2 A _{2 A} receptor inhibition rate (%)

Compound No. 10 ^"8 10 one ⁷ M

4 48 87

6 31 80

11 11 53

14 68 94

17 0 47

21 13 56

25 38 76

26 21 61

27 37 78

53 NT 47

56 NT 53

57 NT 45

58 NT 65

59 NT 81

60 NT 62

61 NT 70

NT: Not tested

Test Example 2: Effect on CGS 21680-induced catalepsy

Parkinson's disease is a motor dysfunction based on degenerative 'cell death of the nigrostriatal dopamine nerve. Intraventricular administration of CGS 21680, an adenosine A _2A receptor agonist GABAergic inhibitory synaptic transmission in the striatum medium sized spiny neurons is directly inhibited via the adenosine A _2A receptor [Journal of Ob 'Neuroscience (J. Neurosci. ), 16, 605 (1996)]. This result indicates that adenosine A _2A receptor functions to promote GABAergic nerve output from the striatum to the globus pallidum, and that catalepsy is induced by administration of CGS 21680. It suggests.

The experiment was conducted using 10 5-week-old male ddY mice (body weight: 22 to 25 g, Japan Sic) per group. Was dissolved CGS 21680 and (RBI Co., Ltd.) in physiological saline (Otsuka Pharmaceutical Co., Ltd.), a 10 μ _8/20 μΐ was injected into the room mouse brain. The test compound was used by suspending it in distilled water (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.3% Tween80 [polyoxylene (20) sorbitan monooleate]. A suspension containing the test compound or a solution containing no test compound [distilled water containing 0.3% Tween80: control] was orally administered 30 minutes before the injection of CGS 21680 into the ventricle (10 mg / kg). , 0.1 ml per 10 g of mouse weight). One hour after administration of the test compound, the mice were hung on both forelimbs only and hindlimbs in turn on a vertical acryl stand of 4.5 cm in height and 1.0 cm in width, one at a time. did.

The effect was determined by totaling the catalepsy score of 10 animals per group using the following criteria (a maximum of 50 points). When the total score was 40 points or less, it was judged to be effective. The number of catalepsy-remission animals showed the number of catalepsy scores of 4 or less out of 10 animals. The power remission rate was shown as a percentage of the total score of the test compound administration group relative to the total score of the control group. Table 3 shows the results. Kukatalepsy score>

"0": The duration of the posture is less than 5 seconds while both the forelimbs and the hindlimbs hang on the table;

“1”: The duration of the posture with the forelimb hung on the table is 5 seconds or more and less than 10 seconds, and the duration of the hindlimb is less than 5 seconds;

“2”: The posture of the forelimb hung on the platform is 10 seconds or more, and the hindlimb is 5 seconds or less;

"3": (1) Fore and hind limbs hung on a table, the duration of the posture is 5 seconds or more, 10 For less than 5 seconds, or (2) the duration of the posture with the forelimb hung on the table is less than 5 seconds, and the duration of the hindlimb is 5 seconds or more;

“4”: (1) The duration of the posture is 10 seconds or more with the forelimbs hung on the platform, and the duration on the hindlimbs is 5 seconds or more, less than 10 seconds, or (2) The forelimbs hung on the platform The duration of the posture is more than 5 seconds and less than 10 seconds, the duration of hind limbs is more than 10 seconds;

"5": Fore and hind limbs hung on the table for 10 seconds or more

Table 3

Compound number Number of animals used Total score Number of animals with remission Remission rate (%)

Control 10 48 2 4

(0.3% Tween80)

4 10 14 10 66

6 10 9 10 78

12 10 21 8 56

16 10 30 9 36

17 10 14 10 68

19 10 15 9 66

21 10 13 8 70

26 10 22 9 54

27 10 19 8 60

46 10 30 8 38

48 10 18 9 62

49 10 28 8 42

54 10 7 9 84

56 10 22 8 56

59 10 15 9 70

61 10 29 10 40 Test Example 3: Effect on haloperidol-induced catalepsy

Administration of haloperidol (a dopamine D1 / D2 antagonist) induces catalepsis by blocking postsynaptic D2 receptors. This haloperidol-induced catalepsy is known as a classical model for reproducing Parkinson's disease by drug administration [Eur. J. Pharmacol., 182, 327 (1990). ) And U.S. Pat. No. 3,991,207]]. According to the following method, The effect of the medicament of the present invention on oral peridol-induced catalepsy was examined.

The experiment was performed using 10 5-week-old male ddY mice (body weight: 22 to 24 g, Japan SIX) per group. Haloperidol (manufactured by Janssen) was suspended in 0.3% carboxymethylcellulose (CMC), and 1.0 mg / kg was intraperitoneally administered to the mouse. The test compound was used by suspending in distilled water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) to which Tween80 was added. L-Dopa (L-D0PA; Kyowa Hakko Kogyo) and benserazide hydrochloride (benserazide HC1; Kyowa Hakko Kogyo) were used as 0.3% CMC suspensions. Haroperi Doll intraperitoneal free suspension is suspension or test compound comprising the administration 1 hour after the test compound [T _wee n80 distilled water for injection was added (manufactured by Otsuka Pharmaceutical Co., Ltd.): control] were orally administered respectively ( 10 mg / kg, 0.1 ml per 10 g of mouse body weight), 1 hour after administration of the test compound, one mouse was placed on a table 4.5 cm high and 1.0 cm wide, with both forelimbs and only hind legs The force talpe was measured. L-dopa 100 mg / kg and benserazide 25 mg / kg (combined use) were administered intraperitoneally as control drugs. The effect was determined in the same manner as in Test Example 2 using the same criteria as in Test Example 2 above. The results are shown in Table 4. From the results of Test Example 2 and Test Example 3, it is clear that the medicament of the present invention has an excellent therapeutic or preventive effect on Parkinson's disease.

Table 4

Control 10 50 0 0

(0.3% Tween80)

4 10 15 9 70

17 10 35 5 30 Industrial applicability

The medicament of the present invention has an adenosine A _2A antagonistic activity and is useful for treatment and / or prevention of various diseases derived from _{augmentation of} adenosine {2 _} receptor function, such as Parkinson's disease.

Claims

The scope of the claims

The following equation (I)

(I)

[Wherein, Y represents an oxygen atom, a sulfur atom, one NR ¹ — (wherein R ¹ represents a hydrogen atom or a lower alkyl group)), or a single bond; n represents an integer of 0 to 5; X ¹ , X ² , and X ³ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, A substituted aryl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group], or a group represented by the following formula:

Wherein, m represents an integer of 0 Kakara 5; k represents an integer of 0 to 5; Q is oxygen atom, a sulfur atom, - NH -, or represents a methylene group; R ² is a hydrogen atom, Lower alkyl group, hydroxy lower alkyl group, amino lower alkyl group, lower alkoxy group, lower alkylthio group, mono- or di-lower alkylamino group, substituted or unsubstituted aryl group, substituted or unsubstituted complex A ring group, or one CO—R ³ , wherein R ³ is lower alkyl A lower alkoxy group, a lower alkylthio group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group). Contains, as an active ingredient, a substance selected from the group consisting of [1, 2, 4] triazolo [1, 5-a] pyrimidine derivatives and physiologically acceptable salts thereof, and hydrates and solvates thereof a medicament for the treatment and Z or prevention of diseases resulting from hyperactivity of adenosine a _a receptor.

2. The medicament according to claim 1, wherein the disease is Parkinson's disease.

3. The [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the formula (I) described in claim 1 and a physiologically acceptable salt thereof, and a salt thereof. An adenosine _A2A antagonist comprising a substance selected from the group consisting of hydrates and solvates.

4. A [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the formula (I) described in claim 1 and a physiologically acceptable salt thereof, and a salt thereof. 3. Use of a substance selected from the group consisting of hydrates and solvates for the manufacture of a medicament according to claim 1 or 2.

5. A method for treating and / or preventing a disease caused by a hyperactivity of adenosine A _2A receptor, or a method for preventing Z, wherein the [1, 2, 4] triazolo represented by the formula (I) according to claim 1 is provided. Administer to a patient a therapeutically and / or prophylactically effective amount of a substance selected from the group consisting of [1,5-a] pyrimidine derivatives and physiologically acceptable salts thereof, and hydrates and solvates thereof. A method comprising the steps of:

6. The method according to claim 5, wherein the disease is Parkinson's disease.

7. In the formula (I) according to claim 1, Z is an oxygen atom or a sulfur atom; Y is an oxygen atom, a sulfur atom, one NR ¹ — (wherein, R ¹ is a hydrogen atom or a lower An alkyl group) or a single bond; n is an integer of 0 to 5; X ′, X ² and X ³ are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower Alkylthio group, amino group, mono- or di-lower alkylamino group, lower alkanoyl group, substituted or unsubstituted arylo group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic group, hydroxyl group, or nitro group And (but X ^1, X ^2, and except when X ³ is a hydrogen atom simultaneously); m force; 1 from Ri integer der of 5; k is located at 5 integer from 0; Q is an oxygen atom, a sulfur atom, -NH- or a methylene group; R ² is a hydroxy lower alkyl group, an amino lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono- or di-lower alkylamino group, a substituted or unsubstituted aryl. Group, substituted or unsubstituted heterocyclic group, or —CO—R ³ (where R ³ is a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted (Where k is 0, R ² is not an unsubstituted aryl group) [1,2,4] triazolo [l, 5_a] pyrimidine derivative Or a salt thereof.