JP2001220389A - 6-Heteroaryl-2- (4-trifluoromethylphenyl) pyrimidine derivative and pharmaceutical composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To exhibit an excellent anti-rheumatic effect, and to exhibit rheumatic diseases such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, and self-induced diseases such as multiple sclerosis, systemic lupus erythematosus, and Sjogren's syndrome. Provided are compounds useful as therapeutic and prophylactic agents for immune inflammatory diseases such as immune inflammatory diseases. SOLUTION: A 6-heteroaryl-2- (4-trifluoromethylphenyl) pyrimidine derivative represented by the following formula 1 and a pharmaceutical composition containing the same. Embedded image [Wherein, R ₁ represents a hydrogen atom, a lower alkyl group, or the like;
R ₂ represents a lower alkyl group, a cycloalkyl group or the like;
R ₃ represents a hydrogen atom or a lower alkyl group, R ₄ represents a halogen atom, and R ₅ represents an unsubstituted or substituted heteroaryl group. ]

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 6-heteroaryl-2- (4-trifluoromethylphenyl) pyrimidine derivative useful as a therapeutic or prophylactic agent for an immune inflammatory disease, and more particularly to a pyrimidine ring 4 6-heteroaryl-2-substituted amino group substituted with acetic acid amide
The present invention relates to a (4-trifluoromethylphenyl) pyrimidine derivative.

[0002]

2. Description of the Related Art WO96 / 32383 and JP-A-10-130150 disclose that an acetate amide derivative represented by the following formula 2 acts selectively on a benzodiazepine ω ₃ receptor and has an anxiolytic and antirheumatic effect. Has,
It is described that it can be used for treating anxiety-related diseases and immune diseases.

[0003]

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Wherein X represents —O— or —NR ₄ —, and R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group;
R 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. Means, R ₄
Represents a hydrogen atom, a lower alkyl group, etc., R ₅ represents a hydrogen atom, a lower alkyl group, a halogen atom, etc., and 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 form — (CH ₂ ) _n — where n means 3, 4, 5 or 6;
₇ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, etc., and R ₈ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.

[0005] WO 98/09960 discloses that
Acid amide derivative represented by the following formula 3, which acts selectively on benzodiazepine omega ₃ receptors have been described.

[0006]

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Wherein X represents —O— or —NR ₄ —, and R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group;
R 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. Means, R ⁴
Represents a hydrogen atom, a lower alkyl group, R ⁵ represents a hydrogen atom, a lower alkyl group, a halogen atom, etc., and R ⁶ represents a hydrogen atom, a lower alkyl group and a trifluoromethyl group, a halogen atom, a lower alkoxy group, A hydroxy (lower) alkyl group or the like, or R ₅ and R _{6 taken} together are-(CH ₂ ) _n- (where n is 3,
4, 5 or 6), and A represents an unsubstituted or substituted heteroaryl group or the like]

[0008] WO 99/59980 discloses that
[2-Alkyl-5-halogeno-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] acetamide derivative has an antirheumatic effect and can be used as a therapeutic or prophylactic agent for immune inflammatory disease. Have been.

The above chemical formulas 2, 3 and WO 99/59980
The compound of the publication is different from the compound of the formula (I) described below in that the compound does not have a heteroaryl group at the 6-position of the pyrimidine ring.

[0010]

SUMMARY OF THE INVENTION Immune inflammatory diseases such as rheumatoid arthritis (hereinafter sometimes referred to as "rheumatic"), Sjogren's syndrome, Behcet's disease and ankylosing spondylitis are diseases that develop in specific organs. Or a disease that develops systemically, but in any case they are common in that they are intractable diseases of unknown cause. Therefore, at present, the treatment has to rely on non-specific anti-inflammatory therapy or immunosuppressive therapy. For example, in the treatment of rheumatism, non-steroidal anti-inflammatory drugs and steroids have been used in the past, but in recent years it has been revealed that abnormalities in the immune response are involved in the pathology of rheumatism. The use of immunosuppressants such as methotrexate and mizoribine and immunomodulators such as sulfasalazine, D-penicillamine, and oral gold preparations has been increasingly used for the treatment of rheumatism. However, each of these drugs has serious side effects, and the follow-up of the side effects is very important in treatment. In addition, many of the immunomodulators have a problem in clinical use that their effects are attenuated or lost by continuous use. Against this background, there is a strong demand for the development of highly effective and safe therapeutic agents and immunomodulators for immunoinflammatory diseases.

[0011]

Means for Solving the Problems The present inventors have conducted intensive studies to obtain compounds which are more useful as therapeutic or prophylactic agents for immune inflammatory diseases, and as a result, the compound represented by the following formula (I): -Heteroaryl-2- (4-trifluoromethylphenyl) pyrimidine derivatives have been found to be suitable for this purpose and the present invention has been completed.

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

[0013]

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[In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, and R ₂ represents a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl (lower) alkyl group, an unsubstituted or substituted means phenyl group or an unsubstituted or substituted heteroaryl group, R ₃
Represents a hydrogen atom or a lower alkyl group, R ₄ represents a halogen atom, and R ₅ represents an unsubstituted or substituted heteroaryl group. 6-heteroaryl-
A 2- (4-trifluoromethylphenyl) pyrimidine derivative, a physiologically acceptable acid addition salt thereof, and a pharmaceutical composition containing the compound are provided.

The physiologically acceptable acid addition salts of the compounds of the formula (I) are defined as the physiologically acceptable acid addition salts of the compounds of the formula (I) when they have a basicity sufficient to form acid addition salts. And the like; for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and maleate, fumarate and oxalic acid Organic salts such as salt, citrate, tartrate, lactate, benzoate, methanesulfonate and the like can be mentioned.

Since the compound represented by the formula (I) and the acid addition salt thereof may be present in the form of a hydrate and / or a solvate, these hydrates and / or solvates are also present. Included in the compounds of the invention.

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

The terms used in this specification are described below.

The lower alkyl group and the lower alkyl moiety are
Unless otherwise specified, it means one having 1 to 6 carbon atoms, which may be linear or branched.

Specific examples of the "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. As the lower alkyl group for R ₃ , those having 1 to 4 carbon atoms are preferable.

The term "lower alkenyl group" means a group having 3 to 6 carbon atoms having one double bond other than between the 1-2 position, and includes, for example, allyl and 2-butenyl.

"Cycloalkyl group" refers to a group having 3 to 3 carbon atoms.
8 means, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Halogen atom" means fluorine, chlorine, bromine or iodine.

"Unsubstituted or substituted phenyl group"
Halogen atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, amino, mono or di (C
₁ -C ₃₎ alkylamino means one or two optionally substituted by a phenyl group selected from cyano and nitro, for example phenyl; 2-, 3- or 4-chlorophenyl; 2-, 3- Or 4-bromophenyl; 2-, 3-
Or 4-fluorophenyl; 2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl;
-Or 4-methoxyphenyl; 2-, 3- or 4-trifluoromethylphenyl; 2-, 3- or 4-aminophenyl; 2-, 3- or 4-methylaminophenyl;
-, 3- or 4-dimethylaminophenyl; 2-, 3-
Or 4-cyanophenyl; 2-, 3- or 4-nitrophenyl.

The term "unsubstituted or substituted phenyl (lower) alkyl group" means an alkyl group having 1 to 4 carbon atoms which is substituted by the above "unsubstituted or substituted phenyl group", for example, benzyl, phenethyl, 3-phenylpropyl, 4-fluorophenylmethyl, 4-chlorophenylmethyl.

"Unsubstituted or substituted heteroaryl group"
Is a 5- to 6-membered monocyclic heteroaryl containing at least one nitrogen atom, oxygen atom or sulfur atom which may be substituted by C ₁ -C ₃ alkyl, halogen atom or trifluoromethyl. Or a 5- or 6-membered bicyclic heteroaryl group, such as 2-, 3- or 4-pyridyl; 2- or 3-thienyl; 2- or 3-furyl; Or 5-pyrimidinyl; 2- or 3-
Pyrazinyl; 1-pyrazolyl; 2-imidazolyl; 2-
Thiazolyl; 2-isoxazolyl; 5-methyl-3-isoxazolyl; 5-methyl-2-pyridyl; 5-methyl-3-pyridyl; 5-bromo-3-pyridyl; quinolyl; isoquinolyl.

Among the compounds of the present invention, preferred are those wherein R ₁ is a hydrogen atom or a lower alkyl group, R ₂ is a lower alkyl group or a cycloalkyl group in the formula (I), and R ₃ and R ₄ And R ₅ are the same as described above, and physiologically acceptable acid addition salts thereof.

Further preferred compounds of the present invention are those wherein R ₁ is a lower alkyl group in formula (I) and R _{2 is}
Is a lower alkyl group or a cycloalkyl group, R ₃ is a hydrogen atom, R ₄ and R ₅ are the same as described above, and a physiologically acceptable acid addition salt thereof.

More preferred compounds include the compounds of formula (I ') and their physiologically acceptable acid addition salts.

[0030]

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(Wherein R ₁ ′ represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and R ₂ ′ represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or a cyclopropyl group. R ₄ ′ represents a chlorine atom or a bromine atom, and R ₅ ′ represents a pyridyl group, a thienyl group or a furyl group.)

In the above formula (I ′), a compound wherein R ₁ ′ and R ₂ ′ are both methyl groups, and R ₄ ′ and R ₅ ′ are the same as described above, and a physiologically acceptable acid addition salt thereof. Is particularly preferred.

Specific examples of the compound represented by the formula (I ') include the following compounds.

2- [5-chloro-6- (2-pyridyl)
-2- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide (the compound of Example 1),

2- [5-bromo-6- (2-pyridyl)
-2- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide (the compound of Example 2),

2- [5-chloro-6- (3-pyridyl)
-2- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide (compound of Example 3),

2- [5-bromo-6- (3-pyridyl)
-2- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide (the compound of Example 4) and

2- [5-chloro-6- (4-pyridyl)
-2- (4-Trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide (compound of Example 5).

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 and physiologically acceptable acid addition salts thereof can be mentioned.

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

Me: methyl group, Et: ethyl group, Pr: propyl group, i-Pr: isopropyl group, c-Pr: cyclopropyl group, Bu: butyl group, Ph: phenyl group.

Thus, for example, Ph-2-Cl represents a 2-chlorophenyl group.

[0043]

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[0044]

[Table 1]

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

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

[0047]

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(Wherein, R ₁ , R ₂ , R ₃ and R ₅ have the same meanings as described above) by halogenating a compound represented by the formula:

As the halogenating agent in this reaction, N
Chlorinating agents such as chlorosuccinimide, bromine, N
A brominating agent such as bromosuccinimide, iodine,
An iodinating agent such as N-iodosuccinimide is used.

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
Although it depends on the type of the starting compound, the reaction conditions and the like, it is usually about 0 ° C to about 150 ° C, preferably about 20 ° C to about 100 ° C.
It is.

The compound of the above formula (II) has the following formula (III)

[0052]

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(Wherein, Z represents a leaving atom or leaving group, and R ₅ has the same meaning as described above) and a compound represented by the following formula (IV):

[0054]

Embedded image HN (R ₃ ) —CH ₂ —CON (R ₁ ) (R ₂ ) (IV)

(Wherein, R ₁ , R ₂ and R ₃ have the same meanings as described above).

The leaving atom or leaving group represented by Z in the formula (III) is an atom or 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 can be mentioned, but they can also serve as excess of the compound of the formula (III). The reaction temperature varies depending on the type of the starting compound, the reaction conditions, etc., but is usually about 40 to
At 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)

[0060]

Embedded image

(Wherein, Y represents an oxygen atom or a sulfur atom, and R ₅ has the same meaning as described above) by halogenating or sulfonylating the compound according to a conventional method. be able to.

The halogenation is carried out, for example, by compounding a compound of the formula (V) with a halogenating agent (for example, phosphorus oxychloride, phosphorus tribromide)
And by reacting Sulfonylation is
For example, in the formula (V), a compound in which Y is an oxygen atom and a sulfonylating agent (for example, methanesulfonyl chloride, p
-Toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride).

The starting material (V) is commercially available or known in a manner known per se, for example, J. Am. Chem. Soc., 74, 842.
(1952), Chem. Ber., 95, 937 (1962), J. Org.
m., 29, 2887 (1964) and WO 96/32383, or a method analogous thereto.

The compound of formula (IV), which is the other starting compound in the present production method, can be prepared by a method known per se, for example, the method described in JP-A-2-32058 and WO 96/32383 or a method analogous thereto. Can be manufactured.

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

The compound of the formula (I) having a sufficient basicity to form an acid addition salt can be converted into an acid addition salt by treating with a variety of acids according to a conventional method.

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

The test results of typical compounds of the present invention are shown below, and the pharmacological properties of the compounds of the present invention will be described.

Test Example 1 Collagen-Induced Arthritis Inhibition Test In many cases of human rheumatoid arthritis, an autoimmune reaction to collagen as a connective tissue component has been established. Have been found to be able to develop arthritis much like rheumatoid arthritis. In particular, since genetic analysis has been advanced in mice, a collagen-induced arthritis model using mice is positioned as a useful model for both developing therapeutic agents for rheumatoid arthritis and understanding disease concepts.

The collagen-induced arthritis inhibition test was initially conducted using Tr
This is an experimental rheumatoid model reported by ethan, DE et al. [see J. Exp. Med., 146, 857 (1977)], and the collagen-induced arthritis inhibition test by Kakimoto, K. et al. It has been shown to be useful as an evaluation system for not only inflammatory drugs but also immunosuppressants and immunomodulators [see J. Immunol., 140, 78-83 (1988)].

The following collagen-induced arthritis inhibition test was carried out according to the method of Kakimoto, K. et al. (See the above-mentioned Kakimoto, K. et al. Reference). That is, solubilized bovine cartilage-derived type II collagen (Elastin Products, USA)
Freund's complete adj
uvant; DIFCO Lab., USA) to obtain a uniform emulsion. 150 μg of this emulsion was added to DBA /
IJ male mice (6 weeks old; manufactured by Charles River Japan,
The first sensitization was performed by injection into the base of the tail (Japan). 21
One day later, 150 μm of the emulsion prepared in the same manner as above.
g was again injected into the base of the tail to boost the immunity and induce arthritis. The test compound was orally administered 5 days a week except Saturday and Sunday from the day of the first sensitization to the end of the test. Eight days after the booster immunization, the degree of arthritis was visually observed daily, and the method of Wood, FD et al. [Int. Arch.
l. 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.

[0072]

[Table 2]

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

[0074]

[Table 3]

As is clear from the results of Table 3 in the above test examples, the compounds of Examples 1, 2 and 4 were 10 mg / kg in a collagen-induced arthritis inhibition test which is a model of immune inflammatory diseases such as rheumatoid arthritis. Showed an inhibitory effect of 70% or more at the dose of, and the compounds of Examples 1 and 2 exhibited a strong inhibitory effect of 50% or more even at a dose of 1 mg / kg.

As is clear from the above pharmacological test results,
The compound of the formula (I) or a physiologically acceptable acid addition salt thereof (hereinafter, sometimes referred to as "the compound of the present invention")
Shows excellent anti-rheumatic effects in in vivo tests, rheumatic diseases such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, and autoimmune inflammatory diseases such as multiple sclerosis, systemic lupus erythematosus, Sjogren's syndrome, etc. It is useful as a therapeutic or prophylactic agent for immune inflammatory diseases.

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 0.1 to 30 mg / kg / day, depending on age, etc.
Preferably it is 0.3 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.

[0081]

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.

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

To a mixture of 22 g of a 28% methanol solution of sodium methoxide and 100 ml of absolute ethanol,
4-trifluoromethylbenzamidine hydrochloride 1 at 5 ° C
4.9 g were added. After stirring this at room temperature for 15 minutes,
Again at 0-5 ° C, 10 g of ethyl picolinoyl acetate was slowly added dropwise. After the completion of the dropwise addition, the temperature was gradually raised and the mixture was heated and refluxed for 12 hours. The reaction mixture was ice-cooled, concentrated hydrochloric acid was added dropwise until pH 4, and the precipitate was collected by filtration, washed with water, then with diethyl ether and then with methanol-water to obtain 10 g of the desired product. Melting point> 300 ℃

Reference Examples 2-3 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the following compounds.

Reference Example 2 6- (3-pyridyl) -2- (4-trifluoromethylphenyl) -4 (3H) -pyrimidinone; melting point 282
~ 284 ° C

Reference Example 3 6- (4-pyridyl) -2- (4-trifluoromethylphenyl) -4 (3H) -pyrimidinone; melting point> 30
0 ° C

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

6- (2-pyridyl) -2- (4-trifluoromethylphenyl) -4 (3H) -pyrimidinone 1
0 g and phosphorus oxychloride 9.7 g at 75 ° C. for 5 hours.
Stirred for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, ice water was added and the mixture was stirred. After neutralization with an aqueous solution of sodium hydroxide (1 mol / L), the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropanol to obtain 7 g of the desired product. 111-113 ° C

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.

Reference Example 5 4-chloro-6- (3-pyridyl) -2- (4-trifluoromethylphenyl) pyrimidine; melting point 109-1
10 ° C (recrystallized from isopropanol)

Reference Example 6-4-chloro-6- (4-pyridyl) -2- (4-trifluoromethylphenyl) pyrimidine; melting point 124-1
25 ° C (recrystallized from isopropanol)

Reference Example 7 N-N-dimethyl-2- [6- (2-pyridyl) -2-
Production of (4-trifluorophenyl) -4-pyrimidinylamino] acetamide

4-chloro-6- (2-pyridyl) -2-
2 g of (4-trifluoromethylphenyl) pyrimidine,
A mixture of 1.1 g of 2-amino-N, N-dimethylacetamide and 0.7 g of triethylamine is stirred for 150 minutes.
The mixture was heated at reflux 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, and eluted with chloroform.
Purification and recrystallization from ethanol yielded 1.8 g of the desired product. 210-212 ° C

Reference Examples 8 to 9 The corresponding compounds were reacted and treated in the same manner as in Reference Example 7 to obtain the following compounds.

Reference Example 8 N-N-dimethyl-2- [6- (3-pyridyl) -2-
(4-trifluorophenyl) -4-pyrimidinylamino] acetamide; melting point 210-212 ° C (recrystallized from ethanol)

( Reference Example 9 )-N, N-dimethyl-2- [6- (4-pyridyl) -2-
(4-trifluorophenyl) -4-pyrimidinylamino] acetamide; melting point 251-253 ° C (recrystallized from ethanol)

Example 1 2- [5-chloro-6- (2-pyridyl) -2- (4-
Production of (trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide

N, N-dimethyl-2- [6- (2-pyridyl) -2- (4-trifluoromethylphenyl) -4
-Pyrimidinylamino] acetamide (0.8 g), N-chlorosuccinimide (0.3 g) and acetic acid (8 ml) were mixed with 9
Stirred at 0 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water and chloroform were added to the residue, and sodium hydroxide was added.
After neutralization with an aqueous solution (1 mol / L), the chloroform layer was separated. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from ethanol to obtain 0.7 g of the desired product. Melting point 169-171 ° C

Examples 2 to 5 The corresponding starting compounds were used and reacted and treated in the same manner as in Example 1 to obtain the compounds of Table 4 represented by Chemical Formula 11.

[0100]

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[0101]

[Table 4]

Formulation Example 1 Production of Tablets 2- [5-Chloro-6- (2-pyridyl) -2- (4-
Trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide (20 g), lactose (75 g), corn starch (20 g), crystalline cellulose (25 g), hydroxypropyl cellulose (3
g), light anhydrous silicic acid (0.7 g), and magnesium stearate (1.3 g).

The above components are mixed and granulated by a conventional method, and the mixture is tableted at 145 mg per tablet to produce 1,000 tablets.

Formulation Example 2 Production of Capsules 2- [5-chloro-6- (2-pyridyl) -2- (4-
[Trifluoromethylphenyl) -4-pyrimidinylamino] -N, N-dimethylacetamide (40 g), lactose (127 g), corn starch (25 g), hydroxypropylcellulose (3.5 g), light anhydrous silicic acid (1. 8 g), and magnesium stearate (2.7
g).

According to a conventional method, the above components are mixed and granulated, and 200 mg of the granules are filled in capsules to produce 1,000 capsules.

[0106]

The compound (I) of the present invention exhibits excellent antirheumatic activity in in vivo tests, and exhibits rheumatic diseases such as rheumatoid arthritis, Behcet's disease and ankylosing spondylitis, and also multiple sclerosis and systemic sclerosis. It is useful as a therapeutic or prophylactic for immune inflammatory diseases such as autoimmune inflammatory diseases such as lupus erythematosus and Sjogren's syndrome.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 405/04 C07D 405/04 409/04 409/04 F term (Reference) 4C063 AA01 BB01 CC29 CC75 CC92 DD12 DD29 EE01 4C086 AA01 AA02 AA03 BC42 GA02 GA04 GA08 MA04 NA14 ZA96 ZB07 ZB11 ZB15

Claims (2)

[Claims] 1. A 6-heteroaryl-2- (4-trifluoromethylphenyl) pyrimidine derivative represented by the following formula 1 or a physiologically acceptable acid addition salt thereof. Embedded image [Wherein, R ₁ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, R ₂ represents a lower alkyl group, a cycloalkyl group, an unsubstituted or substituted phenyl (lower) alkyl group, an unsubstituted or substituted phenyl group or An unsubstituted or substituted heteroaryl group, R ₃ represents a hydrogen atom or a lower alkyl group, R ₄ represents a halogen atom,
R ₅ represents an unsubstituted or substituted heteroaryl group. ] 2. A pharmaceutical composition comprising the 6-heteroarylpyrimidine derivative according to claim 1 or a physiologically acceptable acid addition salt thereof.