JP2002241369A - 4-pyrimidinylaminoacetamide derivative and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful as a therapeutic agent for immune inflammatory diseases. SOLUTION: This 4-pyrimidinylaminoacetamide derivative is represented by the formula (I) (A means a lower alkyl or a cycloalkyl; R1 and R2 are same or different and each mean H or a lower alkyl; and X means a halogen).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel 4-pyrimidinylaminoacetamide derivative useful as a therapeutic agent for immune inflammatory diseases, and more particularly to 2-lower alkyl or cycloalkyl-6- (4-trifluoromethylphenyl).
The present invention relates to a 4-pyrimidinylaminoacetamide derivative and a pharmaceutical composition containing the same.

[0002]

2. Description of the Related Art WO 96-32383 discloses that an acetic acid amide derivative represented by the following formula 3 is a benzodiazepine ω.
_{It describes} that it selectively acts on ₃ receptors and has anxiolytic and antirheumatic effects and can be used for treating anxiety-related diseases and immune diseases.

[0003]

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[Wherein, X represents —O— or —NR ₄ —, R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group;
₂ represents a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, and the like, and R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group. Then R
₄ represents a hydrogen atom, a lower alkyl group, etc., and R ₅ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy (lower) alkyl group, an unsubstituted or substituted benzyloxy (lower) alkyl group, an acyloxy (lower) Alkyl group, lower alkoxy (lower) alkyl group, amino group, mono- or di-lower alkylamino group, acylamino group,
Amino (lower) alkyl, nitro, carbamoyl, mono- or di-lower alkylcarbamoyl, carboxyl, protected carboxyl, carboxy (lower) alkyl or protected carboxy (lower)
R ₆ represents a hydrogen atom, a lower alkyl group, a trifluoromethyl group or an unsubstituted or substituted phenyl group, or R ₅ and R ₆ together represent-(CH ₂ ) n- (Where n means 3, 4, 5 or 6), and R ₇ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, R ₈ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, which means a mono or di lower alkylamino group, a cyano group or a nitro group. ]

The compound of the formula (I) described below is clearly different from the compound of the above formula 3 in the substituent at the 2-position of the pyrimidine ring.

[0006]

SUMMARY OF THE INVENTION The present inventors have conducted intensive studies to obtain a compound which is more useful as a therapeutic agent for an immune inflammatory disease. As a result, 4-pyrimidinylamino represented by the following formula (I) was obtained. The present inventors have found that an acetamide derivative meets this purpose, and have completed the present invention.

[0007]

According to the present invention, the following formula (I)

[0008]

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Wherein A represents a lower alkyl group or a cycloalkyl group, and R ₁ and R ₂ are the same or different,
X represents a hydrogen atom or a lower alkyl group, and X represents a halogen atom. 4-pyrimidinylaminoacetamide derivative represented by formula (I), a pharmaceutical composition containing the same, and the following formula (II):

[0010]

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Wherein A represents a lower alkyl group or a cycloalkyl group; R ₁ and R ₂ are the same or different;
It means a hydrogen atom or a lower alkyl group. ) Are provided.

Since the compounds represented by the formulas (I) and (II) may exist in the form of hydrates and / or solvates, these hydrates and solvates are also included in the present invention. Included in the compound.

The compounds of the formulas (I) and (II) optionally have one or more asymmetric carbon atoms and can give rise to geometric isomerism. Thus, the compounds of formula (I) and formula (II) may optionally exist in more than one stereoisomeric form. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

The terms used in the present specification are explained below.

The lower alkyl group means a group having 1 to 6 carbon atoms unless otherwise specified, and may be linear or branched. Specific examples of "lower alkyl group" include:
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl. The "cycloalkyl group" means a group having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom and a bromine atom are preferred.

Preferred examples of the compounds of the present invention include those in which A in the formula (I) is an isopropyl group or a cyclopropyl group and R ₁ , R ₂ and X are the same as those described above. .

More preferably, among the compounds of the present invention, in formula (I), A is isopropyl or cyclopropyl, X is chlorine or bromine, and R is
Compounds in which ₁ and R ₂ are the same as described above are mentioned.

More preferably, A in formula (I) is isopropyl or cyclopropyl,
Compounds in which X is a chlorine atom or a bromine atom, R ₁ is a hydrogen atom or a methyl group, and R ₂ is a hydrogen atom, a methyl group, an ethyl group or a propyl group.

Particularly preferred compounds include, for example, the following compounds.

2- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-propylacetamide,

2- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-methylacetamide,

2- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-ethylacetamide,

2- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] acetamide,

2- [5-chloro-2-cyclopropyl-
6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] acetamide,

2- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide,

2- [5-chloro-2-cyclopropyl-
6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide;

2- [5-bromo-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide, and

2- [5-bromo-2-cyclopropyl-
6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide.

As specific examples of the compounds included in the present invention,
In addition to the compounds of Examples described later, the compounds of Table 1 represented by the following formula 6 can be mentioned.

The following abbreviations may be used for simplification of the description in Table 1 of the present specification and Reference Examples and Examples described later.

Me: methyl group, Et: ethyl group, Pr: propyl group, iPr: isopropyl group, cPr: cyclopropyl group, Bu: butyl group, cPentyl: cyclopentyl group.

[0032]

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[0033]

[Table 1] ━━━━━━━━━━━━━━━━━━━━ R ₁ R ₂ A X ━━━━━━━━━━━━━━━━━━━━ H Et iPr Br H Et cPr Br H Et cPr Cl H Pr cPr Br H Pr cPentyl Cl H Pr Et Cl H Pr Bu Cl Et Et iPr Cl Et Et iPr Br Et Et cPr Cl Et Et cPr Br ━━━━━━ ━━━━━━━━━━━━━━

The compound of the present invention can be produced, for example, by the following method.

The compound of the formula (I) has the following formula (II)

[0036]

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(Wherein A, R ₁ and R ₂ have the same meanings as described above), and can be produced by halogenating the compound.

As the halogenating agent in this reaction, N
Chlorinating agents such as chlorosuccinimide, bromine, N
-Brominating agents such as bromosuccinimide and iodinating agents such as iodine.

Specific examples of the solvent include halogenated hydrocarbons such as chloroform and methylene chloride, and acidic solvents such as acetic acid, hydrochloric acid and sulfuric acid. The reaction temperature is
The temperature is usually about 0 to about 150 ° C, preferably about 20 ° C to about 100 ° C, although it varies depending on the type of the starting compound, reaction conditions and the like.

On the other hand, the intermediate (II) can be produced by the following method.

Intermediate Production Method (a) : In the intermediate (II), the compound in which both R ₁ and R ₂ are not hydrogen atoms is represented by the following formula (III)

[0042]

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(Wherein Z represents a leaving atom or leaving group, and A represents the same as those described above), and a compound represented by the following formula (IV):

[0044]

Embedded image H ₂ N—CH ₂ —CON (R ₁₁ ) (R ₂₁ ) (IV)

Wherein R ₁₁ and R ₂₁ are each independently
It means the same thing as ₁ and R _2. However, R ₁₁ and R ₂₁
Except that both are hydrogen atoms. The compound represented by the formula: can be produced by reacting the compound.

The leaving atom or leaving group represented by Z in the formula (III) is an atom or a group capable of leaving in the form of HZ together with the hydrogen atom of the NH moiety of the compound of the formula (IV) under the reaction conditions. A halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyl And arylsulfonyloxy groups such as oxy.

The reaction between the compound represented by the formula (III) and the compound represented by the formula (IV) is carried out at normal pressure or under pressure in the absence of a solvent or in a suitable solvent.

Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene; ketones such as methyl ethyl ketone and methyl isobutyl ketone; dioxane;
Examples include ethers such as diglyme, alcohols such as ethanol, isopropanol and butanol, acetonitrile, dimethylformamide, and dimethylsulfoxide. This reaction is preferably performed in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and tribasic amines such as triethylamine. Triamines may be mentioned, but they may also serve as an excess of the compound of formula (IV). The reaction temperature varies depending on the type of the starting compounds, reaction conditions, etc.
To about 200 ° C, preferably from about 100 ° C to about 170 ° C.

The starting compound (III) is, for example, represented by the following formula (V)

[0050]

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(Wherein, Y represents an oxygen atom or a sulfur atom, and A represents the same as described above) by halogenating or sulfonylating the compound according to a conventional method. Can be.

The halogenation in this reaction is carried out, for example, by reacting a compound of the formula (V) with a halogenating agent (for example, phosphorus oxychloride, phosphorus tribromide).
In the sulfonylation, for example, a compound in which Y is an oxygen atom in the formula (V) is reacted with a sulfonylating agent (eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride). This is done by:

The starting material (V) is prepared in a manner known per se, for example
J. Am. Chem. Soc., 74 , 842 (1952), Chem. Ber., 95 ,
937 (1962) and J. Org. Chem., 29 , 2887 (1964) or a method analogous thereto.

The compound of the formula (IV), which is the other starting compound in the present production method, can be produced by a method known per se, for example, the method described in JP-A-2-32058 or a method analogous thereto. .

Intermediate Production Method (b) -A compound in which both R ₁ and R ₂ are hydrogen atoms in the intermediate (II) is represented by the following formula (VI)

[0056]

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(Wherein R represents a lower alkyl group;
Means the same as above. ) Can be produced by reacting the compound represented by the formula (2) with ammonia.

In this reaction, ammonia is used as an aqueous solution, and ethanol may be added thereto. Also, if necessary, add ammonium chloride to this,
This reaction can proceed smoothly. The reaction temperature is usually
About 0 ° C to about 100 ° C, preferably about 0 ° C to about 40 ° C.

The compound represented by the above formula (VI) can be obtained by adding the compound of the above formula (II) to the following formula (VII)

[0060]

Embedded image H ₂ N—CH ₂ —COOR (VII)

(Wherein, R represents the same as described above) and can be produced by reacting the compound represented by the formula (a) with the intermediate described above.

The compound of the formula (VII) is commercially available or can be produced by a method known per se.

The product obtained by each of the above-mentioned production methods is isolated by a conventional method such as chromatography, recrystallization and reprecipitation.
It can be purified.

Various stereoisomers of the compound of the formula (I) can be separated and purified according to a conventional method such as chromatography.

[0065]

The test results of representative compounds of the present invention are shown below, and the characteristics of the pharmacological action of the compounds of the present invention will be described.

Test Example 1 —Collagen-induced arthritis inhibition test—

The collagen-induced arthritis inhibition test was performed by Trethan,
Experimental rheumatoid model reported by DE et al. (See J. Exp. Med., 146 , 857 (1977)), followed by Kaki
moto, K. et al. show that the collagen-induced arthritis inhibition test is useful not only for anti-inflammatory drugs but also as an evaluation system for immunosuppressants and immunomodulators from the mechanism of its development (J. Immunol. , 140 , 78-83 (1988)].

The collagen-induced arthritis inhibition test was performed using Kakimo
(Kakimoto, K. et al., supra). That is, the solubilized bovine cartilage-derived type II collagen (manufactured by Elastin Products, USA) is mixed with Freund's complete adjuvant (Freund's complete adjuvant;
DIFCO Lab., USA) to obtain a uniform emulsion. 150 μg of this emulsion was injected into the base of the tail of DBA / IJ male mice (6 weeks old; manufactured by Charles River Japan, Japan) to perform the first sensitization. Twenty-one days later, 150 μg of the emulsion prepared in the same manner as above was injected again into the base of the tail to perform a booster immunization to induce arthritis. The test compound was orally administered 5 days a week except Saturday and Sunday from the day before the first sensitization to the end of the test. From day 7 after the booster immunization, the degree of arthritis was visually observed, and Wood,
FD et al. [Int. Arch.Allergy Appl. Immunol.,
35 , 456-467 (1969)]. The sum of the scores of the four forelimbs and both hindlimbs was defined as the arthritis score, and the point at which score 1 was obtained was defined as the date of onset.

[0069]

[Table 2]

51 days after first sensitization (52 days after occasion)
The inhibition rate was determined by comparing the arthritis score in the above with the control group, and the results are shown in Table 3.

[0071]

[Table 3] ^* : Measured on the 52nd day.

As is clear from the results of Table 3 in Test Example 1, the compounds of Examples 1 to 6, 8 and 9 showed 3 mg / mg in the collagen-induced arthritis inhibition test which is a model of immune inflammatory diseases such as rheumatism. A strong inhibitory effect of 40% or more was observed in kg. In the vehicle control group, arthritis developed from day 28 of the first sensitization, whereas in the group administered with 10 mg / kg of the compounds of Examples 6 and 8, none of the cases developed on the 51st day at the end of the test. And completely suppressed the development of arthritis.

As is clear from the above pharmacological test results,
The compound of the formula (I) (hereinafter sometimes referred to as “the compound of the present invention”) has an excellent antirheumatic effect in an in vivo test, and is therefore useful as a therapeutic or prophylactic agent for immune inflammatory diseases such as rheumatism. Useful.

The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration. The dosage depends on the type of compound, administration method,
Usually varies from 0.3 to 30 mg / kg / day, depending on age, etc.
Preferably it is 1 to 10 mg / kg / day.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch,
Partially pregelatinized starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low substitution Degree hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate,
Light silicic anhydride, magnesium stearate, talc,
Carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin,
Fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, water, ethanol, polyoxyethylene hydrogenated castor oil (HCO), sodium chloride,
Examples include sodium hydroxide, hydrochloric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, glutamic acid, benzyl alcohol, methyl paraoxybenzoate, ethyl paraoxybenzoate and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, the compound of the present invention is prepared by dissolving the compound in water. If necessary, the compound may be dissolved using an isotonic agent or a solubilizing agent. And a preservative may be added.

These preparations contain the compound of the present invention in an amount of 0.0
It can be contained at a rate of 1% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically effective ingredients.

[0078]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples, but the present invention is not limited to these Examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra, and the like.

In the following Reference Examples and Examples,
The following abbreviations may be used to simplify the description.

[Recrystallization solvent] HX: n-hexane, IP: isopropanol.

Reference Example 1 Production of 2-isopropyl-6- (4-trifluoromethylphenyl) -4 (3H) -pyrimidinone

To a mixture of 18.3 g of sodium methoxide and 250 ml of absolute ethanol was added 20.7 g of isopropylcarbamidine hydrochloride at room temperature. After stirring at room temperature for 30 minutes, ethyl 4- (trifluoromethyl) benzoylacetate
40 g was added dropwise at the same temperature. After the dropwise addition, the mixture was heated under reflux for 12 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and concentrated hydrochloric acid was added dropwise while stirring at 0-5 ° C until the pH reached 4. The precipitate was collected by filtration, washed with water and diethyl ether, and recrystallized from isopropanol to obtain 30 g of the desired product. Melting point 241-243 ° C

Reference Examples 2-3 Using and reacting the corresponding starting compounds in the same manner as in Reference Example 1, the following compounds were obtained.

Reference Example 2 2-cyclopropyl-6- (4-trifluoromethylphenyl) -4 (3H) -pyrimidinone; melting point 219
Up to 220 ° C (recrystallized from isopropanol)

Reference Example 3-2-methyl-6- (4-trifluoromethylphenyl)
-4 (3H) -pyrimidinone; melting point 226-227
° C (recrystallized from isopropanol)

Reference Example 4 Production of 4-chloro-2-isopropyl-6- (4-trifluoromethylphenyl) pyrimidine

A mixture of 40 g of 2-isopropyl-6- (4-trifluoromethylphenyl) -4 (3H) -pyrimidinone and 43.5 g of phosphorus oxychloride was stirred at 80 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, added to ice water and stirred. After neutralization with a 1N aqueous sodium hydroxide solution, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 41 g of the desired product
Was obtained as an oil.

Reference Examples 5 to 6 The corresponding starting materials were used and reacted and treated in the same manner as in Reference Example 4 to obtain the following compounds as oils.

Reference Example 5 4-chloro-2-cyclopropyl-6- (4-trifluoromethylphenyl) pyrimidine

Reference Example 6 4-chloro-2-methyl-6- (4-trifluoromethylphenyl) pyrimidine

The compounds of the intermediate (II) are shown in Examples A to J below.

Example A Production of 2- [2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-propylacetamide

4-Chloro-2-isopropyl-6- (4
-Trifluoromethylphenyl) pyrimidine 15 g, 2-
A mixture of 10 g of amino-N-propylacetamide and 6 g of triethylamine was heated under reflux at 150 ° C. for 3 hours. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 17 g of the desired product. 111-112 ° C

Examples BG -The corresponding starting materials were used and reacted and treated in the same manner as in Example A to obtain the compounds of Table 4 represented by Chemical Formula 13.

[0095]

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[0096]

[Table 4]

Example H --Production of 2- [2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] acetamide

(1) 4-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) pyrimidine 7 g
, 150 g of a mixture of 6.5 g of glycine ethyl ester hydrochloride
The mixture was heated and stirred at 2 ° C. for 2 hours. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform.
Purification gave 5 g of ethyl 2- [2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] acetate.

(2) 2 g of the above product, 50 parts of concentrated aqueous ammonia
A mixture of 15 ml of ethanol and 15 ml of ethanol was stirred at room temperature for 24 hours. The precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 1.5 g of the desired product. Melting point 224-226 ° C

Examples I to J The corresponding starting compounds were reacted and treated in the same manner as in Example H to obtain the following compounds.

( Example I )-2- [2-cyclopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] acetamide; melting point 267-269 ° C (recrystallized from ethanol)

( Example J )-2- [2-methyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] acetamide; melting point: 197 to 198 ° C (recrystallized from ethanol)

Example 1 2- [5-chloro-2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino]
Production of -N-propylacetamide

2- [2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino]
A mixture of 16 g of -N-propylacetamide, 6.3 g of N-chlorosuccinimide and 150 ml of acetic acid was stirred at 90 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, and the mixture was neutralized with a 1N aqueous sodium hydroxide solution, and the chloroform layer was separated. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from n-hexane to obtain 15 g of the desired product.
Melting point 100-102 ° C

Examples 2 to 13 : Corresponding starting compounds and N-chlorosuccinimide or N
Using a halogenating agent of -bromosuccinimide, the reaction and treatment were carried out in the same manner as in Example 1 to obtain a compound of Table 5 represented by Chemical Formula 14.

[0106]

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[0107]

[Table 5]

Formulation Example 1 : Production of tablets

[0109]

[Table 6] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ · 2- [5-chloro-2- Isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-propylacetamide 25 g Lactose・ ・ ・ 70 g ・ Corn starch ・ ・ ・ ・ ・ ・ ・ 20 g ・ Microcrystalline cellulose ・ ・ ・ ・ ・ ・ ・ ・ ・ ・25 g ・ Hydroxypropyl cellulose 3 g ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━

The above components were mixed and granulated by a conventional method, and then light anhydrous silicic acid (0.7 g) and magnesium stearate (1.3 g) were added.
Make tablets.

Formulation Example 2 : Production of capsules

[0112]

[Table 7] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ · 2- [5-chloro-2- Isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-propylacetamide 50 g lactose・ ・ ・ 117 g ・ Maize starch ・ ・ ・ ・ ・ ・ ・ 25 g ・ Hydroxypropylcellulose ・ ・ ・ ・ 3.5 g ・ Light anhydrous silica Acids ... 1.8 g ・ Magnesium stearate ... 2.7 g ━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

According to a conventional method, the above components are mixed and granulated.
Fill 200 mg into capsules to make 1000 capsules.

Formulation Example 3 : Production of powder

[0115]

[Table 8] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ · 2- [5-chloro-2- Isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-propylacetamide 200 g Lactose ...・ ・ ・ ・ 770 g ・ Hydroxypropylcellulose ・ ・ ・ ・ 25 g ・ Light anhydrous silicic acid ・ ・ ・ ・ ・ ・ ・ ・ ・ ・・ ・ 5 g ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

According to a conventional method, after mixing the above components, the mixture is made into a powder.

[0117]

As described above, the compound of the present invention represented by the formula (I) exhibits an excellent antirheumatic effect in an in vivo test. Useful as a prophylactic. Further, the compound of the present invention represented by the formula (II) is useful as an intermediate of the compound of the formula (I).

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Mari Ito 5-7-12 Tsuundai, Suita-shi, Osaka F-term (reference) 4C086 AA01 AA02 AA03 BC42 MA01 MA04 NA14 ZB01 ZB11 ZB15

Claims (7)

[Claims] 1. A compound represented by the following formula (I): (In the formula, A represents a lower alkyl group or a cycloalkyl group, R ₁ and R ₂ are the same or different and represent a hydrogen atom or a lower alkyl group, and X represents a halogen atom.) 4-pyrimidinylaminoacetamide derivatives. 2. The compound according to claim 1, wherein A is an isopropyl group or a cyclopropyl group. 3. The compound according to claim 1, wherein X is a chlorine atom or a bromine atom. 4. 2- [5-chloro-2-isopropyl-
6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N-propylacetamide, 2- [5-chloro-2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino]
-N-methylacetamide, 2- [5-chloro-2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino]
-N-ethylacetamide, 2- [5-chloro-2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino]
Acetamide, 2- [5-chloro-2-cyclopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] acetamide, 2- [5-chloro-2-isopropyl-6- (4-trifluoro Methylphenyl) -4-pyrimidinylamino]
-N, N-dimethylacetamide, 2- [5-chloro-2-cyclopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide, 2- [5-bromo -2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino]
Any one selected from -N, N-dimethylacetamide and 2- [5-bromo-2-cyclopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide Compound. 5. The method according to claim 1, wherein
-A pharmaceutical composition comprising a pyrimidinylaminoacetamide derivative. 6. The method according to claim 1, wherein
-An agent for treating an immune inflammatory disease, comprising a pyrimidinylaminoacetamide derivative as an active ingredient. 7. The following formula (II): (Wherein A represents a lower alkyl group or a cycloalkyl group, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group.) A 4-pyrimidinylaminoacetamide derivative represented by the formula: