JPH09291089A - New 5-thiazolyluracil derivative or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 5-thiazolyluracil derivative, effective for treatment of diseases that an adenosine A3 receptor participates and useful for treatment of low blood pressure, coronary thrombosis and allergy as an adenosine A3 receptor antagonist. SOLUTION: This derivative is a new 5-thiazolyluracil derivative (salt) of formula I [R<1> and R<2> are each H, a (substituted) lower alkyl, a (substituted) lower alkenyl, a (substituted) lower alkynyl and a (cross-linked) cycloalkyl; R<3> and R<4> are each H, a substituted lower alkyl, carboxyl, a lower acyl and a carbamoyl] useful for prevention and treatment of low blood pressure in shock or the like, circulation paralysis, ischemia disease, allergy disease and inflammatory disease as an adenosine A3 receptor antagonist. This compound is obtained by reacting a nitrile derivative of formula II (R<2> ' is a group except H in R<2> ) derived from an N-substituted urea with hydrogen sulfide to convert it to a thioamide derivative followed by reacting it with ethyl bromopyruvate or the like to form a thiazole ring.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, especially adenovirus.
Shin A_Three5-thiazolyluracil derivative or
The pharmaceutically acceptable salt, and those active ingredients
Adenosine A _ThreeIt relates to a receptor antagonist.

[0002]

2. Description of the Related Art Adenosine receptors are widely distributed in the living body and are known to be involved in various physiological reactions.
Many xanthine derivatives such as theophylline have been reported as compounds that antagonize adenosine receptors. They have a stimulatory effect on the central nervous system and myocardium, a diuretic effect on the kidneys, and a relaxing effect on smooth muscles, especially bronchial muscles (Trends in
Pharmacol. Sci. , 1 , 129-132
(1980); Life Sci. , 28 , 2083-
2097 (1981); Biochem. Pharma
col. , 30 , 325-333 (1981); Pro.
c. Natl. Acad. Sci. , 80 , 2077-
2080 (1983); European Patent No. 92398, Japanese Unexamined Patent Publication No. 62-42986, and many others).

On the other hand, research on adenosine receptor subtypes has also progressed, and A ₁ and A ₂ subtypes have been reported (J. Neu.
rochem. , 33 , 999-1003 (197).
9)), and it was further found that A ₂ is divided into A _2a and A _2b (Mol. Pharmacol., 29 , 331-3).
46 (1986)). Of these, the A ₁ receptor is c
It is known that the suppression of AMP production and the A _2a and A _2b receptors induce various physiological reactions through the enhancement of cAMP production. For example, it has been reported that a xanthine derivative which is an A ₁ receptor antagonist has a diuretic action, hypertension, renal failure, renal protection action, bronchodilation action and brain function improving action (J. Med. Chem., 36 ( 25), 401
5 (1993); European Patent Publication No. 449175;
JP-A-3-173889; JP-A-270222, etc.).

In recent years, the A ₃ receptor has been discovered in studies of its subtype (FEBS Let.
t. , 284 , 155-160 (1991); PNAS.
USA, 89 , 7432-36 (1992)), its pharmacological activity has been gradually elucidated, and it has been reported to be involved in various diseases. For example, activation of the A ₃ receptors have been reported to A ₃ receptor antagonists than to cause hypotension are useful for hypotension, improvement of circulatory insufficiency in the shock or the like (Drug Deve
Lopment Res. 30 , 147-152 (19
93); British J. et al. of Pharmaco
logy, 109 , 3-5 (1993); Europe.
an J. of Pharmacology, 252 ,
R5-R6 (1994)). Also, mast cells have only A ₃ receptors as adenosine receptors, and it is considered that mast cell degranulation is promoted by activation of A ₃ receptors.
Selective A ₃ receptor antagonists are useful for the preventive treatment of various diseases associated with mast cell degranulation due to A ₃ receptor activation, such as ischemic diseases, allergic diseases, and inflammatory diseases. A possibility has been reported (J. Biol. Ch.
em. , 268 , 16887-16890 (199
3); Cardiovasc. Res. , 28 , 105
7-1061 (1994); Pharmacol. , 4
7 , 194-199 (1993); Tips, 15 , 2
98-306 (August 1994)). Furthermore, A
_It is suggested that the A ₃ receptor antagonist may have an immunopotentiating effect because the ₃ agonist suppresses the adhesion of lymphocytes to tumor cells (Cancer Res., 54 , 35).
21-3526 (1994); Int. J. Clin.
Lab. Res. , 22 , 235-242 (199
2); Cell. Immunol. , 159 , 85-9
3 (1994)).

Recently, the human A ₃ receptor has been cloned, and an assay method for agonists or antagonists using the same has been reported (UK Patent Publication 226494).
No. 8). Furthermore, although reports of A ₃ receptor antagonists have been made, all of them relate to xanthine derivatives such as theophylline (Europe).
ean J. of Pharmacol. , 252 , R
5-R6 (1994); WO95 / 11681).

[0006]

However, xanthane
Chin derivatives are nausea, vomiting, increased heart rate, arrhythmias and convulsions
It is known to have side effects of (pharmacy45
(1), 621-624 (1994); Can. J. P
hysiol. Pharmacol. ,57, 917
(1979) etc. )), Or A_ThreeSelective antagonism of receptors
Compounds that do not know other than xanthine derivatives
Yes. Therefore, it has a new skeleton that does not take a xanthine structure.
Adenosine receptors that are useful without these side effects
It is expected to be an adenosine receptor antagonist. this
Therefore, the inventors of the present invention_ThreeSelective antagonism of receptors
As a result of the screening of compounds that
5-thiazolyluracil derivative having the above activity
They have found the present invention and completed the present invention.

[0007]

The present invention relates to a 5-thiazolyluracil derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0008]

Embedded image

(However, the symbols in the formulas have the following meanings: R ¹ and R ^{2 are the} same or different and each is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkenyl group. , An optionally substituted lower alkynyl group or an optionally bridged cycloalkyl group, R ³ , R ⁴ : the same or different, a hydrogen atom, an optionally substituted lower alkyl group, a carboxyl group, a lower alkoxy Carbonyl group, lower acyl group, carbamoyl group, or mono- or di-lower alkylcarbamoyl group)

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the general formula (I) is further described as follows. In addition, in the present specification, unless otherwise specified in the definition of the general formula, the term “lower” means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms.

Therefore, the "lower alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group , Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3- Dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,
Examples include 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, and 1-ethyl-2-methylpropyl group, and R ² is A methyl group, an ethyl group or an isopropyl group is particularly preferable.

Specific substituents of "optionally substituted lower alkyl group", "optionally substituted lower alkenyl group" and "optionally substituted lower alkynyl group" of R ¹ and R ^2. Examples thereof include an optionally substituted aryl group, an optionally bridged cycloalkyl group, a carboxyl group, a lower alkoxycarbonyl group, a heterocyclic group and the like. Specific examples of the substituent of the “optionally substituted lower alkyl group” for R ³ and R ⁴ include a halogen atom, a nitro group, a cyano group, a trihalogenomethyl group, an amino group, a mono- or di-lower alkyl group. Examples thereof include an amino group, a hydroxyl group, a mercapto group and a lower alkoxy group.

"Halogen atom" means a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom.

The "lower alkoxy group" has a carbon number of 1 to 1.
6 is an alkoxy group, specifically, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group,
Butoxy group, isobutoxy group, sec-butoxy group, t
ert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, hexyloxy group, iso Hexyloxy group, 1-methylpentoxyoxy group, 2-methylpentoxyoxy group, 3-methylpentoxyoxy group, 1,1-dimethylbutoxy group, 1,2
-Dimethylbutoxy group, 2,2-dimethylbutoxy group,
1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1,1,2-trimethylpropoxy group, 1,2, 2-trimethylpropoxy group,
1-ethyl-1-methylpropoxy group, 1-ethyl-2
-Methylpropoxy group and the like.

"Alkyl group which may be substituted"
Means an unsubstituted aryl group or a substituted aryl group, and the aryl group means an aromatic hydrocarbon ring group, and preferably has 6 to 14 carbon atoms. In particular,
Examples thereof include a phenyl group, a naphthyl group, an anthryl group and a phenanthryl group, with a phenyl group being particularly preferred.
As the substituent of the "substituted aryl group", specifically, a halogen atom, a nitro group, a cyano group, a trihalogenomethyl group, an amino group, a mono- or di-lower alkylamino group, a hydroxyl group, a mercapto group, A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group and the like can be mentioned. Of these groups, a halogen atom, a nitro group, an amino group, a hydroxyl group, a lower alkyl group and a lower alkoxy group are particularly preferable.

As the "heterocyclic group", 1 or 2
4 to 8-membered ring group containing oxygen atom, nitrogen atom or sulfur atom as a hetero atom, specifically, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an isothiazolyl group, an isoxazolyl group, Pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, indolyl group, indazolyl group, indolizinyl group, quinolyl group, quinazolinyl group, quinolidinyl group, quinoxalinyl group, cinnolinyl group, benzimidazolyl group, imidazopyridyl group, benzofuranyl group, dihydrobenzofuran group Examples thereof include a nyl group, naphthyridinyl group, 1,2-benzisoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxazolopyridyl group, isothiazolopyridyl group and benzothienyl group. Of these groups, the pyridyl group is particularly preferred.

Examples of the "lower acyl group" include formyl group, acetyl group, propionyl group, butyryl group, valeryl group, pivaloyl group and the like.

The "lower alkenyl group" has 2 to 6 carbon atoms.
Alkenyl groups, specifically vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-
1-propenyl group, 2-methylallyl group, 1-methyl-
Examples thereof include 1-propenyl group, 1-methylallyl group, 1,1-dimethylvinyl group, 1-pentenyl group, and among these groups, allyl group is particularly preferable.

The "lower alkynyl group" has 2 carbon atoms.
To 6 linear or branched alkynyl groups, specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1- Examples thereof include a methyl-2-propynyl group and a 1-pentynyl group.

The "cycloalkyl group" preferably has 3 to 8 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. The cyclopropyl group is particularly preferable.
Specific examples of those having a crosslink include an adamantyl group and a noradamantyl group.

Further, the "lower alkoxycarbonyl group" is
A carbonyl group substituted with a lower alkoxy group, specifically, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-
Butoxycarbonyl group, pentyloxycarbonyl group,
An ester was formed from a carbonyl group and a linear or branched alcohol having 1 to 6 carbon atoms such as an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a tert-pentyloxycarbonyl group, and a hexyloxycarbonyl group. A group can be mentioned. Of these, an ethoxycarbonyl group is particularly preferable.

The "mono- or di-lower alkylcarbamoyl group" is a carbamoyl group mono- or di-substituted with the above lower alkyl group. In the compound of the present invention, the combination of groups R ^{1 to} R ⁴ is appropriately determined,
Preferred R ¹ is an optionally substituted lower alkyl group, and among these, the optionally substituted lower alkyl group has a substituent, which may be an aryl group or an optionally bridged group. A cyclic group such as a cycloalkyl group or a heterocyclic group is particularly preferable. Preferred R ² is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or the like having 1 to 6 carbon chains. One of R ³ and R ⁴ is preferably a hydrogen atom, and particularly preferably R ⁴ is a hydrogen atom. Further, regarding the groups of R ³ and R ^4, a carboxyl group and a lower alkoxycarbonyl group are more preferable.

Further, the compound of the present invention may be capable of forming a salt with an acid or a base, and these salts also have an adenosine A ₃ inhibitory action. Suitable salts are, for example, acid addition salts with inorganic acids or organic acids, or salts with inorganic or organic bases, and are pharmaceutically acceptable. Specific examples of these salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid. , Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, organic acids such as methanesulfonic acid or ethanesulfonic acid, or acid addition salts with acidic amino acids such as aspartic acid or glutamic acid, sodium, potassium, magnesium, Examples thereof include inorganic bases such as calcium and aluminum, organic bases such as methylamine, ethylamine and ethanolamine, and salts with basic amino acids such as lysine and ornithine. Further, it may be a quaternary ammonium salt. The quaternary ammonium salt is specifically a salt obtained by a reaction with a lower alkyl halide, a lower alkyl triflate, a lower alkyl tosylate, a benzyl halide or the like, and preferably a salt with a methyl iodide or a benzyl chloride.

The compound represented by the general formula (I) includes a compound having a keto-enol type tautomer. The compound of the present invention includes a keto type compound, an enol type compound or a mixture thereof.

The compound of the general formula (I) may have an optical isomer based on an asymmetric carbon atom or a geometric isomer based on a double bond or a cyclohexane ring. The present invention includes a mixture of various isomers such as these geometrical isomers and optical isomers and separated ones. Further, the compound of the general formula (I) includes hydrates thereof, various solvates and the like. Further, the compound of the general formula (I) includes a compound having a crystal polymorph and includes all the crystal forms.

(Production Method) The compound of the present invention and a salt thereof can be produced by applying various synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. At that time, depending on the kind of the functional group, when it is effective in manufacturing technology to replace the functional group with an appropriate protecting group at the stage of the raw material or the intermediate, that is, a group which can be easily converted into the functional group. There is. After that, the protecting group can be removed by a usual operation, if necessary, to obtain the desired compound. As such a functional group, for example, green (G
Reene) and Wuts, “Prote
ctive Groupsin Organic Sy
The protective groups described in "Nesis", 2nd edition can be mentioned, and these may be appropriately used depending on the reaction conditions.

Typical methods for producing the compound of the present invention will be illustrated below.

[0028]

Embedded image

(The symbols in the formula have the same meanings as described above. X represents a halogen atom.)

Among the compounds (I) of the present invention, the compound (I ′) in which either R ³ or R ⁴ is a hydrogen atom is obtained by converting the compound represented by the general formula (II) into hydrogen sulfide or dithiophosphoric acid 0, It can be produced by converting it to a compound represented by the general formula (III) by reacting with 0-diethyl, and then reacting with an α-halocarbonyl compound (for example, bromopyruvic acid or a lower alkyl ester thereof).

The reaction with hydrogen sulfide is carried out at 0 ° C. to room temperature using a basic solvent such as a pyridine-triethylamine mixed solvent. The reaction with 0,0-diethyl dithiophosphate is carried out under acidic conditions such as a solution of hydrochloric acid in ethyl acetate or dioxane as a solvent at a temperature of 0 ° C to 50 ° C.

In the reaction with the α-halocarbonyl compound, dioxane, acetone, alcohol or the like is used as a solvent, and if necessary, in the presence of a base such as triethylamine or sodium hydrogencarbonate, the reaction time and the reaction temperature are appropriately adjusted. It is carried out selectively, but it is preferably carried out under heating.

Next, a typical method for producing the compound represented by the general formula (II) will be illustrated.

(First production method)

Embedded image

(In the formula, R represents a lower alkyl group. R ^{2 '}
Represents a group other than a hydrogen atom in R ² . R ¹ , R ² and X
Has the same meaning as described above. )

Compound (II) wherein R ² is hydrogen, 3-alkyl-4-imino-2-oxo-1,2,
3,4-Tetrahydropyrimidine-5-carbonitrile (II-a) reacts with monosubstituted urea (IV) with malononitrile to give 1-alkyl-3- (2,2-dicyanovinyl) -urea (V). It can be produced by reacting with a metal alkoxide and treating with an acid.
In addition, the compound (II-b) in which R ² is other than a hydrogen atom in the compound (II) can be produced by reacting the compound (II-a) with an alkylating agent or the like.

The reaction of monosubstituted urea (IV) with malononitrile is carried out by using alcohol, toluene, dimethylformamide, acetone, chloroform or the like as a solvent,
The reaction time and the reaction temperature are appropriately selected in the presence of trialkoxymethane, but it is preferably carried out under heating under reflux.

The reaction of the compound (V) with the metal alkoxide is carried out by using alcohol as a solvent at 0 ° C. to room temperature,
Alternatively, it is carried out at room temperature or under heating under reflux.

The reaction of the compound (II-a) with an alkylating agent and the like is carried out using tetrahydrofuran, dioxane, dimethylformamide and the like as a solvent in the presence of sodium hydride or potassium carbonate at a temperature condition of 0 ° C to 50 ° C. Done. Examples of the alkylating agent used for the substitution of R2 include alkylating agents well known to those skilled in the art.
Specifically, methyl iodide, ethyl bromide, α-bromopropionic acid, α-bromoacetic acid, ethyl α-bromopropionate, benzyl bromide, alkyl halides (or phenylalkyl halides) such as phenethyl iodide, or Dimethylsulfate, diethylsulfate, etc. are used.

(Second manufacturing method)

[0041]

Embedded image

(In the formula, R ^{1 ′} represents a lower alkyl group. R
² and X have the same meaning as described above. )

Compound (II) wherein R ¹ is hydrogen, 1-alkyl-2,4-dioxo-1,2,3,4
-Tetrahydropyrimidine-5-carbonitrile (II
-C) is obtained by reacting cyanoacetylcarbamic acid ethyl ester (VIII) obtained by reacting cyanoacetic acid (VI) with carbamic acid ethyl ester (VII) with ethyl orthoformate (2-cyano-3-ethoxy). Acroyl) carbamic acid ethyl ester (IX),
Further, it can be obtained by reacting with various alkylamines. In addition, the compound (II-d) in which R ¹ is an alkyl group in the compound (II) can be produced by reacting the compound (II-c) with an alkyl halide.

The reaction between cyanoacetic acid (VI) and carbamic acid ethyl ester (VII) is carried out in the presence of a solvent such as phosphorus oxychloride by appropriately selecting the reaction time and the reaction temperature, but it may be carried out under heating. preferable.

The reaction of the compound (VIII) with ethyl orthoformate is carried out in the presence of a solvent such as acetic anhydride by appropriately selecting the reaction time and the reaction temperature, but it is preferably carried out under heating under reflux.

The reaction of compound (IX) with an alkylamine is carried out in the presence of a solvent such as alcohol or dioxane by appropriately selecting the reaction time and the reaction temperature, but it is preferably carried out under heating.

The reaction between the compound (II-c) and the alkylating agent is carried out under the same conditions as described above.

The reaction products obtained by the above-mentioned production methods are
It is isolated and purified as various solvates such as free compounds, salts or hydrates thereof. The salt can be produced by subjecting it to an ordinary salt-forming reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.

[0049]

The present invention compounds according to the present invention are adenosine A ₃ receptor specifically antagonize the adenosine A ₃ receptors inhibit various physiological reactions mediated. Therefore, conditions or diseases that A ₃ receptor is involved, for example, low blood pressure in shock or the like due to the activation of the A ₃ receptor, circulatory failure, etc., degranulation of mast cells caused by A ₃ receptor involvement Diseases, for example, tissue damage in ischemic diseases, specifically coronary artery occlusion, cerebrovascular accident, postoperative ischemic renal failure, etc., or allergic diseases, specifically asthma, rhinitis, dermatitis , Useful as a prophylactic / therapeutic agent for conjunctivitis, food allergy, etc. Furthermore, the compound of the present invention is expected to inhibit the suppression of adhesion of lymphocytes involved in A ₃ receptors to tumor cells, and can be expected to be useful as an immunopotentiator in cancer treatment. Further, the compound of the present invention can be used as an agent for elucidating the mechanism of a disease involving the A ₃ receptor or as a diagnostic agent. Furthermore, the compound of the present invention does not have a xanthine skeleton,
It is possible to avoid the side effects of conventional adenosine receptors having a xanthine skeleton and is expected to be useful.

The pharmacological action of the compound of the present invention will be described below.
An example will be posted and described. (experimental method)Adenosine receptor inhibition test (1) Human adenosine A_ThreeEstablishment of receptor-high expressing cells Human adenosine A_ThreeReceptor cDNA expression vector (G
(from Arvan Inc.)15
(3), 73-79 (1993).
Introduced into CHO-K1 cells by the fectamine method,
Drug resistant clones were selected using G418. Ade
Nosin A_ThreeWith the receptor agonist I-AB-MECA
A based on the binding test_ThreeHigh receptor expressing cells were isolated.

(2) Preparation of cell membrane A cell membrane was prepared from CHO-K1 cells expressing human adenosine A ₃ receptor. Cell membranes were similarly prepared from CHO-K1 cells expressing human adenosine A ₁ receptor (obtained from Garvan). After culturing the cells in a Petri dish for adherent cells (surface area: 500 cm ² ), the cells are peeled off using a cell scrubber, and Phosphate-buf
It was suspended in ferred saline (PBS). This is centrifuged at 2000 rpm for 5 minutes, and the sediment is again in PBS.
It was suspended in water, washed, and then centrifuged again to obtain a precipitate. 5 of this sediment
0 mM Tris-HCl (pH 7.4), 10 mM
The cells were suspended in MgCl ₂ and 250 mM sucrose, disrupted by ultrasonic waves, and then centrifuged at 2000 rpm for 5 minutes to obtain a supernatant. The supernatant was centrifuged at 35,000 g for 25 minutes, and the precipitate was used as a cell membrane fraction. Cell membrane fraction is 50 mM
Tris-HCl (pH 7.4), 10 mM MgCl
₂ , suspended in 250 mM sucrose to obtain a cell membrane solution.

(3) Receptor binding experiment A sample was dissolved in DMSO so as to have a concentration of 1 mg / ml, diluted with DMSO and diluted with 0.1, 0.01, 0.
A 001 mg / ml solution was prepared. Cell membrane is 50 mM
Tris-HCl (pH 7.4), 10 mM MgC
It was used by suspending it in ₁₂ to 100 μg / ml. [ ¹²⁵ I] AB-MECA (Amersham 2
000 Ci / mmol, 50 nM) to 50 mM Tri
It was dissolved in s-HCl (pH 7.4) and 10 mM MgCl ₂ to prepare a 1 nM solution.

2 samples in 48 well plate
[ ¹²⁵ I] AB-MECA (1 nM) 100 μl, cell membrane suspension (100 μg / ml, pro
100 μl of tein condensation)
In addition, the mixture was incubated at 25 ° C for 60 minutes. After the reaction was completed, the cell membrane was adsorbed on a glass filter (GF / B) using a cell harvester, and 50 mM Tris-HC was used.
1 (pH 7.4), 10 mM MgCl ₂ , 0.01%
After washing with CHAPS, the glass filter was dried and the radioactivity adsorbed on the filter was measured. Total b
DMSO for indexing, non-specific
10 μMI-AB-MECA was used for c binding. Based on the measured radioactivity, binding inhibitory activity and IC ₅₀ value were calculated. As a result, the compound of the present invention specifically bound to the human adenosine A ₃ receptor.

A pharmaceutical composition containing, as an active ingredient, one or more compounds such as a compound represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof is usually used. Using carriers, excipients and other additives for the formulation,
It is adjusted to tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches and the like, and is orally or parenterally administered.

The clinical dose is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which it is applied, but it is usually 0.1 to 500 mg orally per day for an adult and 0.0 or less per parenteral.
The dose is 1 to 100 mg, which is administered once or divided into several times. Since the dose varies under various conditions, a dose smaller than the above dose range may be sufficient.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances are at least one inert diluent such as lactose,
It is mixed with mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid, magnesium aluminate. According to a conventional method, the composition comprises an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing or solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents, For example, it contains purified water and ethyl alcohol. This composition contains, in addition to an inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, aromatic agents,
It may contain a preservative.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (trade name). Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving in sterile water or a sterile injection solvent before use.

Formulation examples for preparing the compound of the present invention into injections and tablets are shown below.

Prescription Example 1 Injection (Composition) Compound of the present invention 1.5 mg Lactic acid 0.2 mg Lactose 200 mg Water for injection Total 2.0 ml To 0.15 g of the present compound, 0.1 g of lactic acid and about 300 ml of water for injection were added. A liquid prepared by dissolving 100 g of lactose in about 500 ml of water for injection is added to the liquid and stirred. 60 parts of this liquid
Heat and dissolve each time. After cooling to room temperature, add 1
000 ml. After filtering with a membrane filter, the mixture was filled in an ampoule of 2 ml and sterilized to prepare an injection containing 1.5 mg of the present compound.

Formulation Example 2 Film-coated tablet (composition) [tablet] Compound of the present invention 5.0 mg Lactic acid 73.2 Corn starch 18.3 Hydroxypropyl cellulose 3.0 Magnesium stearate 0.5 Subtotal 100 mg [Coat] Hydroxypropyl Methylcellulose 2910 2.5 mg Polyethylene glycol 6000 0.5 Talc 0.7 Titanium oxide 0.3 Subtotal 4 mg Total 104 mg

After mixing 25 g of the compound of the present invention and 366 g of lactose, the mixture was ground with a sample mill (manufactured by Hosokawa Micron). 391g of this mixed pulverized product and corn starch 91.5
g was uniformly mixed in a fluidized granulation coating apparatus (manufactured by Okawara Seisakusho), and then 150 g of a 10% hydroxypropylcellulose aqueous solution was sprayed to granulate. After drying, it is passed through a 24 misch screen, 2.5 g of magnesium stearate is added to it, and 1 tablet per tablet is produced using a rotary tableting machine (manufactured by Hata Tekko Co., Ltd.) with a 6.5 mmφ x 7.8 R pestle.
It was a tablet of 00 mg. Using a coating device (manufactured by Freund Sangyo), 12.5 g of hydroxypropyl cellulose and polyethylene glycol 6000 were applied to the tablets.
An aqueous coating solution (154 g) containing 2.5 g, talc (3.5 g) and titanium oxide (1.5 g) was sprayed to coat 4 mg per tablet to give a film-coated tablet containing 5.0 mg of the present compound.

[0063]

EXAMPLES The present invention will be described in more detail below with reference to examples. Needless to say, the present invention is not limited to the compounds of Examples. Further, when the raw material used in the present invention is novel, it will be described as a reference example.

Reference Example 1 30.0 g of benzylurea
(200 mmol), 12.6 ml of malononitrile (2
00 mmol) and 33.3 ml of triethoxymethane
(200 mmol) were mixed and heated under reflux for 2 hours. After cooling to room temperature, the resulting precipitate was collected by filtration and washed with diethyl ether to obtain a crude product. Recrystallize from ethyl acetate to give 1-benzyl-3- (2,2-dicyano-vinyl)
-18.3 g of urea was obtained.

Physicochemical properties Mass spectrometric value (FAB, Pos., M / z): 227
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.38 (2H, d, J = 5.5 Hz), 7.26
-7.37 (5H, m), 7.61 (1H, t, J =
5.5 Hz), 8.37 (1 H, s), 10.7 (1
H, s).

Reference Example 2 18.4 g of sodium (80
0 mmol) was dissolved in 500 ml of ethanol to prepare an ethanol solution of sodium ethoxide, and 1-benzyl-3- (2,2-dicyano-vinyl) -urea 1 was added.
8.3g (80.4mmol) was added and it heated and refluxed for 1 hour. After distilling off the solvent, 300 ml of water was added to the residue,
Further, 120 ml of 6N HCl was added under ice cooling. The formed precipitate was collected by filtration and washed with water to obtain a crude product. Recrystallization from dimethylformamide-water gave 12.2 g of 3-benzyl-4-imino-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile as colorless needle crystals.

Physicochemical properties Melting point 260-263 ° C. Elemental analysis value (as C ₁₂ H ₁₀ N ₄ O) C (%) H (%) N (%) Calculated value 63.71 4.46 24.76 Experimental value 63 .94 4.38 24.83 Mass spectrum (FAB, Pos., M / z): 227
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO, TMS internal standard) δ: 5.19 (2H, s), 7.17 (2H, d, J =
7.3 Hz), 7.27 (1H, t, J = 7.3H)
z), 7.34 (2H, t, J = 7.9Hz), 8.3.
3-8.39 (3H, m).

Reference Example 3 3-benzyl-4-imino-
2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile 12.0 g (53.0 mmo
30 ml of 12% hydrochloric acid was added to 1) and the mixture was heated under reflux for 4 hours. After cooling to room temperature, the formed precipitate was collected by filtration,
Wash sequentially with water, ethanol, and diethyl ether, and then 3-
10.8 g of benzyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile were obtained.

Physicochemical properties Melting point 250-255 ° C. Elemental analysis value (as C ₁₂ H ₉ N ₃ O ₂ ) C (%) H (%) N (%) Calculated value 63.43 3.99 18.49 Experimental value 63.35 3.97 18.44 Mass spectrum (FAB, Pos., M / z): 228
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO, TMS internal standard) δ: 4.94 (2H, s), 7.25-7.33 (5
H, m), 8.53 (1H, s), 12.37 (1H,
s).

Reference Example 4 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5
-Carbonitrile 15.0 g (66.0 mmol) and triethylamine 73.2 ml in pyridine solution 600 ml
Hydrogen sulfide gas was introduced into the flask under ice cooling for 2 hours. 4 at room temperature
After stirring for one day, the solvent was distilled off to obtain a crude product. Recrystallization from chloroform gave 12.5 g of 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbothioamide.

Physicochemical properties Melting point 240-243 ° C. Elemental analysis value (as C ₁₂ H ₁₁ N ₃ O ₂ S) C (%) H (%) N (%) S (%) Calculated value 55.16 4.24 16.08 12.27 Experimental value 54.84 4.05 15.90 12.87 Mass spectrum value (FAB, Pos., M / z): 262
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO, TMS internal standard) δ: 5.01 (2H, s), 7.24-7.40 (5
H, m), 8.84 (1H, s), 9.87 (1H, b
rs), 10.20 (1H, brs).

Reference Example 5 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5
-To a 1,4-dioxane solution (350 ml) of 7.85 g (30.0 mmol) of carbothioamide was added 4.19 ml (30.0 mmol) of ethyl bromopyruvate, and the mixture was stirred at 80 ° C for 18 hours. After cooling to room temperature,
The insoluble material was filtered off and concentrated under reduced pressure. Chloroform was added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium hydrogen carbonate, and the solvent was distilled off to give 2- (3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro). 7.52 g of -pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester was obtained.

Physicochemical properties Melting point 275-278 ° C. Elemental analysis value (as C ₁₇ H ₁₅ N ₃ O ₄ S) C (%) H (%) N (%) S (%) Calculated value 57.13 4.23 11.76 8.97 Experimental value 56.96 4.16 11.66 8.90 Mass spectrum value (EI, m / z): 358 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.42 (3H, t, J = 7.3Hz), 4.44
(2H, q, J = 7.3 Hz), 5.20 (2H,
s), 7.26-7.34 (3H, m), 7.51 (2)
H, d, J = 6.7 Hz), 8.16 (1H, s),
8.63 (1H, d, J = 13Hz), 10.01 (1
H, brs).

Reference Example 6 17.0 g of cyanoacetic acid, 17.8 g of ethyl carbamic acid and 9.4 ml of phosphorus oxychloride were mixed and stirred at 70 ° C. for 1 hour. The mixture was cooled to room temperature, water was added, and the insoluble matter was collected by filtration. Recrystallization from ethanol gave 16.6 g of cyanoacetylcarbamic acid ethyl ester.

Physicochemical properties Mass spectrometric value: (EI, m / s) 156 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.22 (3H, t, J = 7. 2Hz), 4.09
(2H, s), 4.13 (2H, q, J = 7.2H
z), 10.97 (1H, brs).

(Reference Example 7) 16.5 g of ethyl cyanoacetylcarbamic acid was added to 17.6 g of ethyl orthoformate.
mg and 40 ml of acetic anhydride were added, and the mixture was heated under reflux for 1 hr.
After cooling to room temperature, the resulting precipitate was collected by filtration and washed with diethyl edel to obtain (2-cyano-3-ethoxyacroyl) carbamic acid ethyl ester (15.3 g).

Physicochemical properties Mass spectrometric value: (FAB (Pos), m / s) 213
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.24 (3H, t, J = 7.0 Hz), 1.34
(3H, t, J = 7.0Hz), 4.14 (2H, q,
J = 7.0 Hz), 4.39 (2H, q, J = 7.0H)
z), 8.39 (1H, s), 10.55 (1H, br
s).

Reference Example 8 N- (Ethoxycarbonyl)
To a solution of 12.38 g of 2-cyano-3-ethoxyacrylic acid ethyl ester in 80 ml of ethanol was added 4.4 ml of allylamine, and the mixture was stirred at room temperature for 1 hour. The mixture was further stirred with heating under reflux for 1 hour, cooled to room temperature, and the obtained white precipitate was collected by filtration to give 1-allyl-2,4-dioxo-1,
7.47 g of 2,3,4-tetrahydropyrimidine-5-carbonitrile was obtained.

Physicochemical properties Mass spectrometric value: (FAB, Pos., M / z): 178
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.33-4.35 (2H, m), 5.20-5.
25 (2H, m), 5.85-5.95 (1H, m),
8.66 (1H, s), 12.00 (1H, brs).

Reference Example 9 1-allyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-
Carbonitrile (11.93 g) was used and subjected to the same reaction as in Reference Example 4 to give 1-allyl-2,4-dioxo-1,2,2.
15.1 g of 3,4-tetrahydro-pyrimidine-5-carbothioamide was obtained.

Physicochemical properties Mass spectrometric value: (FAB, Pos., M / z): 212
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 4.54-4.61 (2H, m), 5.18-5.
40 (2H, m), 5.70-6.20 (1H, m),
9.01 (1H, s), 9.54 (0.5H, s),
9.64 (0.5H, s).

Reference Example 10 1-allyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5
-Using 15.1 g of carbothioamide, the same reaction as in Reference Example 5 was performed, and then the crude product was subjected to column chromatography, and the fractions eluted with chloroform-ethyl acetate (4: 1) were collected and reduced in pressure. The lower solvent was distilled off to obtain 8.23 g of 2- (1-allyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester. Obtained.

Physicochemical properties Mass spectrometry value: (FAB, Pos., M / z): 308
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.31 (3H, t, J = 7.2 Hz), 4.33
(2H, q, J = 7.2 Hz), 4.43-4.60
(2H, m), 5.16-5.35 (2H, m), 5.
70-6.20 (1H, m), 8.41 (1H, s),
8.61 (1H, S), 12.02 (1H, brs).

(Example 1) Sodium hydride 37 mg
(0.92 mmol) in dimethylformamide solution,
2- (3-benzyl-2,4-dioxo-1,2,3,
4-Tetrahydro-pyrimidin-5-yl) -thiazol-5-carboxylic acid ethyl ester 300 mg (0.8
2.0 ml of a dimethylformamide solution of 4 mmol) was added, and the mixture was stirred at room temperature for 10 minutes, and then 55 μl (0.88 mmol) of methyl iodide was added under ice cooling. After stirring at room temperature for 7.5 hours, a saturated ammonium chloride aqueous solution was added under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, then the solvent was distilled off to obtain a crude product. Recrystallize from toluene-hexane to give 2- (3
-Benzyl-2,4-dioxo-1-methyl-1,2,
250 mg of 3,4-tetrahydro-pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester were obtained.

Physicochemical properties Melting point 174-177 ° C. Elemental analysis value (as C ₁₈ H ₁₇ N ₃ O ₄ S) C (%) H (%) N (%) S (%) Calculated value 58.21 4.61 11.31 8.63 Experimental value 57.89 4.56 11.20 8.65 Mass spectrum value (EI, m / z): 372 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.42 (3H, t, J = 6.7Hz), 3.55
(3H, s), 4.43 (2H, q, J = 6.7H
z), 5.23 (2H, s), 7.26-7.34 (3
H, m), 7.53 (2H, d, J = 6.7 Hz),
8.15 (1H, s), 8.62 (1H, s).

Example 2 Sodium hydride 37 mg
(0.92 mmol) in dimethylformamide solution,
2- (3-benzyl-2,4-dioxo-1,2,3,
4-Tetrahydro-pyrimidin-5-yl) -thiazol-5-carboxylic acid ethyl ester 300 mg (0.8
2.0 ml of a dimethylformamide solution of 4 mmol) was added, and the mixture was stirred at room temperature for 10 minutes, and then 72 μl (0.88 mmol) of ethyl iodide was added under ice cooling. After stirring at room temperature for 2 days, saturated aqueous ammonium chloride solution was added under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography with toluene-
A crude product was obtained from the fraction eluted with ethyl acetate (5: 1). Recrystallized from toluene-hexane to give 2- (3-benzyl-2,4-dioxo-1-ethyl-1,2,3,3
54 mg of 4-tetrahydro-pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester were obtained.

Physicochemical properties Melting point 149-152 ° C. Elemental analysis value (as C ₁₉ H ₁₉ N ₃ O ₄ S) C (%) H (%) N (%) S (%) Calculated value 59.21 4.97 10.90 8.32 Experimental value 59.10 4.94 10.81 8.21 Mass spectrometry value (EI, m / z): 385 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.23-1.43 (6H, m), 3.97 (2
H, q, J = 6.7 Hz), 4.43 (2H, q, J =
7.3 Hz), 5.23 (2H, s), 7.26-7.
34 (3H, m), 7.53 (2H, d, J = 6.7H
z), 8.15 (1H, s), 8.62 (1H, s).

Example 3 Sodium hydride 37 mg
(0.92 mmol) in dimethylformamide solution,
2- (3-benzyl-2,4-dioxo-1,2,3,
4-Tetrahydro-pyrimidin-5-yl) -thiazol-5-carboxylic acid ethyl ester 300 mg (0.8
2.0 ml of a dimethylformamide solution of 4 mmol) was added, and the mixture was stirred at room temperature for 10 minutes, and then 76 μl (0.88 mmol) of allyl bromide was added under ice cooling. 2 at room temperature
After stirring for 3 hours, the same treatment as in Example 2 was performed to give 2- (1
-Allyl-3-benzyl-2,4-dioxo-1,2,
135 mg of 3,4-tetrahydro-pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester were obtained.

Physicochemical properties Melting point 174-177 ° C. Elemental analysis value (as C ₂₀ H ₁₉ N ₃ O ₄ S) C (%) H (%) N (%) S (%) Calculated value 60.44 4.82 10.57 8.07 Experimental value 60.48 4.75 10.52 8.03 Mass spectrum value (EI, m / z): 398 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.42 (3H, t, J = 7.3Hz), 4.43
(2H, q, J = 7.3 Hz), 4.52 (2H, d,
J = 6.1 Hz), 5.31-5.35 (2H, m),
5.89-5.97 (1H, m), 7.26-7.34
(3H, m), 7.53 (2H, d, J = 7.3H
z), 8.15 (1H, s), 8.58 (1H, s).

Example 4 65 mg (1.62 mmol) of 60% sodium hydride
To 30 ml of the dimethylformamide solution of 2), 2- (3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl) -thiazol-5-carboxylic acid ethyl ester 524 mg (1.47 mmol )
2.0 ml of the dimethylformamide solution in Example 1 was added, and the mixture was stirred at room temperature for 10 minutes, and then propargyl bromide 0.
15 μl (1.54 mmol) was added. 23 at room temperature
After stirring for a period of time, the same treatment as in Example 2 was performed to give 2- (1-
(Propin-3-yl) -3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5
-Yl) -thiazole-5-carboxylic acid ethyl ester 330 mg was obtained.

Physicochemical properties Melting point 191-192 ° C. Elemental analysis value (as C ₂₀ H ₁₇ N ₃ O ₄ S) C (%) H (%) N (%) S (%) Calculated value 60.75 4.33 10.63 8.11 Found 60.46 4.23 10.39 8.00 Mass Spec (FAB, Pos., M / z): 396
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.33 (3H, t, J = 7.2 Hz), 3.55
(1H, t, J = 2.4 Hz), 4.33 (2H, q,
J = 7.2 Hz), 4.87 (2H, d, J = 2.4H)
z), 5.12 (2H, s), 7.18-7.53 (5
H, m), 8.47 (1H, s), 8.89 (1H,
s).

(Example 5) 60% sodium hydride 25
2- (3-benzyl-2,4-dioxo-) was added to 20 ml of a dimethylformamide solution containing mg (0.62 mmol).
1,2,3,4-Tetrahydro-pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester 20
2.0 ml of a 0 mg (0.56 mmol) dimethylformamide solution was added, and the mixture was stirred at room temperature for 10 minutes, then, under ice-cooling, cyclopropylmethyl bromide 0.060 ml.
(0.65 mmol) was added. After stirring at room temperature for 23 hours, the same treatment as in Example 2 was carried out to give 2- (1- (cyclopropylmethyl) -3-benzyl-2,4-dioxo-
1,2,3,4-Tetrahydro-pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester 13
5 mg were obtained.

Physicochemical properties Melting point 174-175 ° C. Elemental analysis value (as C ₂₁ H ₂₁ N ₃ O ₄ S) C (%) H (%) N (%) Calculated value 61.30 5.14 10.21 Actual measurement Value 61.43 5.19 10.16 Mass spectrum (FAB, Pos., M / z): 412
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.37-0.44 (2H, m), 0.46-0.
55 (2H, m), 1.15-1.34 (1H, m),
1.32 (3H, t, J = 7.2Hz), 3.90 (2
H, d, J = 7.2 Hz), 4.32 (2H, q, J =
7.2 Hz), 5.13 (2H, s), 7.24-7.
35 (5H, m), 8.45 (1H, s), 8.84
(1H, s).

(Example 6) 60% sodium hydride 35
20 mg (0.90 mmol) of dimethylformamide
2- (1-allyl-2,4-dioxo-
1,2,3,4-Tetrahydro-pyrimidin-5-yl) -thiazole-5-carboxylic acid ethyl ester 19
9 mg (0.648 mmol) was added, and further cyclohexylmethyl bromide 0.10 ml (0.68 mmo
1) was added, and the mixture was stirred overnight at room temperature. Treated as in Example 2, 2- (1-allyl-3- (cyclohexylmethyl) -2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl) -thiazol-5 25 mg of carboxylic acid ethyl ester was obtained.

Physicochemical properties Melting point 158-159 ° C. Elemental analysis value (as C ₂₀ H ₂₅ N ₃ O ₄ S) C (%) H (%) N (%) S (%) Calculated value 59.53 6.24 10.41 7.95 Found 59.25 6.10 10.34 7.90 Mass Spec: (FAB, Pos., M / z): 404
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.97-1.05 (2H, m), 1.05-1.
20 (3H, m), 1.32 (3H, t, J = 7.2H
z), 1.50-1.80 (6H, m), 3.79 (2
H, d, J = 7.2 Hz), 4.32 (2H, q, J =
7.2 Hz), 4.61-4.64 (2H, m), 5.
23-5.28 (2H, m), 5.94-6.03 (1
H, m), 8.44 (1H, S), 8.68 (1H,
S).

(Example 7) 60% sodium hydride 78
20 mg of dimethylformamide (mg (1.6 mmol))
2- (1-allyl-2,4-dioxo-1,
2,3,4-Tetrahydro-pyrimidin-5-yl)-
Thiazole-5-carboxylic acid ethyl ester 200 mg
(0.65 mmol) and 3-pyridylmethyl chloride hydrochloride 112 mg (0.70 mmol) were added, and the mixture was stirred at room temperature overnight. The same process as in Example 2 is performed and 2- (1-
Allyl-3- (3-pyridylmethyl) -2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-
Iyl) -thiazole-5-carboxylic acid ethyl ester 3
7 mg were obtained.

Physicochemical properties Melting point 182-184 ° C. Elemental analysis value (as C ₁₉ H ₁₈ N ₄ O ₄ S) C (%) H (%) N (%) S (%) Calculated value 57.28 4.55 14.06 8.05 Found 57.05 4.80 14.02 7.94 Mass Spec: (FAB, Pos., M / s): 399
((M + 1) ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.32 (3H, t, J = 7.2 Hz), 4.32
(2H, q, J = 7.2 Hz), 4.63-4.66
(2H, m), 5.14 (2H, S), 5.23-5.
31 (2H, m), 5.94-6.04 (1H, m),
7.34-7.38 (1H, m), 7.73-7.76
(1H, m), 8.45 (1H, S), 8.47-8.
49 (1H, m), 8.60 (1H, S), 8.72
(1H, S).

Table 1 shows the chemical structural formulas of the compounds obtained in Examples 1 to 7.

[0099]

[Table 1]

The following compounds were similarly synthesized.

[0101]

[Table 2]

[0102]

[Table 3]

Further, the compounds shown in Tables 4 to 8 can be easily prepared in the same manner as in the above-mentioned production method and the method described in the Examples or by applying some modifications which are obvious to those skilled in the art. It can be manufactured.

[0104]

[Table 4]

[0105]

[Table 5]

[0106]

[Table 6]

[0107]

[Table 7]

[0108]

[Table 8]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 31/505 ABR A61K 31/505 ABR ABS ABS ABS ABV ACF ACF ACV ACV ADA ADA AED AED C07D 417 / 14 209 C07D 417/14 209 215 215 233 233 239 239 239 249 249 257 257 471/04 114 114 471/04 114A

Claims (3)

[Claims] 1. A 5-thiazolyluracil derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (However, the symbols in the formulas have the following meanings: R ¹ and R ² : the same or different, a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, and a substituted Optionally lower alkynyl group or optionally crosslinked cycloalkyl group, R ³ and R ⁴ : the same or different, a hydrogen atom, an optionally substituted lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, Lower acyl group, carbamoyl group, or mono- or di-lower alkylcarbamoyl group) 2. A medicament comprising the 5-thiazolyluracil derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 3. An adenosine A ₃ receptor antagonist, which comprises the 5-thiazolyluracil derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.