JP2001139561A - 5-halogeno-6-(4-trifluoromethylphenyl)-4-amino-pyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which exhibits an excellent anti-rheumatic action and is useful as a medicine for treating and preventing immunologic inflammatory diseases, for example, rheumatic diseases such as chronic articular rheumatism, Behcet's disease and ankylosing spondylitis, and autoimmune inflam matory diseases such as multiple sclerosis, systemic lupus erythematous and Sjogren's syndromes. SOLUTION: A 5-halogeno-6-(4-trifluoromethylphenyl)-4-aminopyrimidine derivative is represented by the formula (I) [R1 is hydrogen atom, a lower alkyl or the like; R2 is a lower alkyl, a mono- or di-hydroxy (lower) alkyl, di- lower alkylamino (lower) alkyl or the like, or R1 and R2 are bound together with the adjacent nitrogen atom to form a cyclic group which may be substituted with R5 (R5 is hydroxy or the like): R3 is a halogen atom; R4 is a lower alkyl or a cycloalkyl].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 5-halogeno-6 useful as a therapeutic or prophylactic agent for immune inflammatory diseases.
-(4-trifluoromethylphenyl) -4-aminopyrimidine derivatives.

[0002]

2. Description of the Related Art WO 96/32383 and JP-A-10-130150 disclose that an amide amide derivative represented by the following formula selectively acts on a benzodiazepine ω ₃ receptor and has an anxiolytic effect and an antirheumatic effect. It is described that it can be used for treating anxiety-related diseases and immune diseases.

[0003]

Embedded image

[Wherein, X represents —O— or —NR ₄ —, R ₁ represents a hydrogen atom, a lower alkyl group, etc., and R ₂ represents a lower alkyl group, an unsubstituted or substituted phenyl group, etc. R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group; R ₄ represents a hydrogen atom, a lower alkyl group; or R ₃ and R ₄ represent a carbon atom to which they are bonded. And a nitrogen atom together with a pyrrolidine, piperidine ring, etc., and R ₅ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy (lower) alkyl group, an unsubstituted or substituted benzyloxy (lower) alkyl group, Acyloxy (lower) alkyl group, lower alkoxy (lower) alkyl group, trifluoromethyl group, halogen atom, amino group, mono- or di-lower alkylamino group, acylamino group, A mino (lower) alkyl group, nitro group, carbamoyl group, mono- or di-lower alkylcarbamoyl group, carboxyl group, protected carboxyl group, carboxy (lower) alkyl group or protected carboxy (lower) alkyl group, 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 is 3,
4, 5 or 6), wherein R ₇ is a hydrogen atom,
A halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, etc., and R ₈ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group]

The compounds of formula (I) described below are clearly different from the above compounds in that they do not have an amide side chain at the 4-position of the pyridine ring and a phenyl group at the 2-position of the pyrimidine ring.

[0006] WO 98/09960 discloses 2,4.
- disubstituted pyrimidine derivatives have anti-anxiety effect and anti-rheumatic effects as well as acts selectively on benzodiazepine omega ₃ receptors are described and can be used in the treatment of anxiety-related diseases and immune disorders. However, the compound described in WO98 / 09960 has a side chain of acetate amide at the 4-position of the pyrimidine ring, which is clearly different from the compound of the formula (I) described below, like the compound of the above formula (2).

[0007]

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.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to obtain compounds that are more useful as therapeutic or prophylactic agents for immune inflammatory diseases, and as a result, the compound represented by the following formula (I): The present inventors have found that a -halogeno-6- (4-trifluoromethylphenyl) -4-aminopyrimidine derivative is suitable for this purpose and completed the present invention.

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

[0010]

Embedded image

Wherein R ₁ is a hydrogen atom, a lower alkyl group, a mono or dihydroxy (lower) alkyl group, a mono or di lower alkoxy (lower) alkyl group,
(Lower) alkyl group or mono- or di-lower alkylamino (lower) alkyl group, unsubstituted or substituted phenyl
R ₂ represents a lower alkyl group, a mono or dihydroxy (lower) alkyl group, a mono or di lower alkoxy (lower) alkyl group, an amino (lower)
Means an alkyl group or a mono- or di-lower alkylamino (lower) alkyl group, an unsubstituted or substituted phenyl (lower) alkyl group, or R ₁ and R ₂ together with an adjacent nitrogen atom form R ₅ (here Wherein R ₅ is a hydroxy group, a lower alkoxy group, a lower alkyl group, a mono or dihydroxy (lower) alkyl group, a mono or di lower alkoxy (lower) alkyl group, an amino (lower) alkyl group, or a mono or di lower alkyl amino ( A lower alkylene group), R ₃ represents a halogen atom, and R ₄ represents a lower alkyl group or a cycloalkyl group. Halogeno-6- (4-trifluoromethylphenyl) -4-aminopyrimidine derivative and pharmaceutically acceptable acid addition thereof Provided are salts, pharmaceutical compositions containing the compound and intermediates of the compound.

The pharmaceutically acceptable acid addition salt of the compound represented by the formula (I) includes a pharmaceutically acceptable salt of the compound of the formula (I) having a basicity sufficient to form an acid addition salt. Meaning acid addition salts which are chemically acceptable, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and maleate and fumarate And organic acid salts such as oxalate, citrate, tartrate, lactate, benzoate and methanesulfonate. Equation (II)
Examples of the acid addition salt of the compound represented by the above include the pharmaceutically acceptable acid addition salts described above.

The compounds represented by the formulas (I) and (II) and the acid addition salts thereof may exist in the form of hydrates and / or solvates.
Alternatively, solvates are also included in the present invention.

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 present invention.

The terms used in the present specification are described below.

"Lower alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec- Butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1,2-dimethylpropyl, tert-pentyl, neopentyl, hexyl.

The "mono- or dihydroxy (lower) alkyl group" means the above-mentioned "lower alkyl group" substituted by one or two hydroxy groups (however, excluding acetal). 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,
3-hydroxybutyl, 2-hydroxybutyl, 2,3
-Dihydroxypropyl.

The "lower alkoxy group" has 1 to 6 carbon atoms.
Means a straight-chain or branched-chain alkoxy group. Specific examples thereof include methoxy, ethoxy, propoxy and isopropoxy.

The "mono or di lower alkoxy (lower) alkyl group" means the above "lower alkyl group" substituted by one or two "lower alkoxy groups" (however, excluding acetal). As a specific example, 2-
Examples include methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, and 2,3-dimethoxypropyl.

The term "amino (lower) alkyl group" means the above "lower alkyl group" substituted with an amino group, and specific examples thereof include 2-aminoethyl, 3-aminopropyl,
2-aminopropyl is exemplified.

The "mono- or di-lower alkylamino (lower) alkyl group" refers to the above "amino" wherein the nitrogen atom is substituted by one or two alkyl groups having 1 to 4 carbon atoms.
(Lower) alkyl group ", and specific examples thereof include N-isopropyl-2-aminoethyl and N, N-dimethyl-2.
-Aminoethyl, N, N-diethyl-2-aminoethyl, N, N-dipropyl-2-aminoethyl, N, N-
Diisopropyl-2-aminoethyl, N, N-dimethyl-2-amino-1-methylethyl, N, N-dimethyl-
2-aminopropyl, N, N-dimethyl-3-aminopropyl, N, N-diethyl-3-aminopropyl.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, but a chlorine atom and a bromine atom are preferred.

The "cycloalkyl group" has 3 to 8 carbon atoms.
And specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Unsubstituted or substituted phenyl group"
The above “halogen atom”, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a trifluoromethyl group, an amino group, the above “mono or di lower alkylamino group”, a cyano group and a nitro group Phenyl, 4-, 3- or 2-fluorophenyl, 4-, 3- or 2-chlorophenyl, 4-,
3- or 2-bromophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 4-, 3- or 2-methylphenyl, 4-, 3- or 2-methoxyphenyl, 4-, 3- Or 2-trifluoromethylphenyl, 4-, 3- or 2-aminophenyl, 4-,
3- or 2-dimethylaminophenyl, 4-, 3- or 2-cyanophenyl or 4-, 3- or 2-nitrophenyl.

The “unsubstituted or substituted phenyl (lower) alkyl group” is the above “unsubstituted or substituted phenyl group”
Represents an alkyl group having 1 to 4 carbon atoms, and specific examples thereof include benzyl, 4-, 3- or 2-fluorobenzyl, 4-, 3- or 2-chlorobenzyl, -Or 2-bromobenzyl, 4-methoxybenzyl, phenethyl, 2- (4-chlorophenyl)
Ethyl is mentioned.

The term "cyclic group" means a saturated heterocyclic group formed by a nitrogen atom and 3 to 7 carbon atoms, and specific examples thereof include 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, and 1H- Hexahydroazepin-1-yl or 1H-heptahydroazocin-1-yl.

Specific examples of the “cyclic group optionally substituted by R ₅ ” include 1-pyrrolidinyl, 1-piperidinyl,
Hydroxy-1-pyrrolidinyl, 3- or 4-hydroxy-1-piperidinyl, 2- or 3-hydroxymethyl-1-pyrrolidinyl, 2-, 3- or 4-hydroxymethyl-1-piperidinyl, 3-methylamino-1
-Pyrrolidinyl, 3-dimethylamino-1-pyrrolidinyl, 3-dimethylaminomethyl-1-pyrrolidinyl, 2
-Or 4-dimethylaminomethyl-1-piperidinyl.

Among the compounds of the present invention, preferred are those wherein R ₁ in the formula (I) is a hydrogen atom, a lower alkyl group,
A mono- or dihydroxy (lower) alkyl group, a mono- or di-lower alkoxy (lower) alkyl group or a di-lower alkylamino (lower) alkyl group, wherein R ₂ is a lower alkyl group, a mono- or di-hydroxy (lower) alkyl group, A di-lower alkoxy (lower) alkyl group or a mono- or di-lower alkylamino (lower) alkyl group, or R ₁ and R ₂ together with an adjacent nitrogen atom form R ₅ (where R ₅ is hydroxy A pyrrolidine or piperidine ring group which may be substituted with a group, mono- or dihydroxy (lower) alkyl group, wherein R ₃ is a halogen atom and R ₄ is the same as described above. .

More preferably, among the compounds of the present invention, R ₁ is a hydrogen atom, a lower alkyl group, a mono- or dihydroxy (lower) alkyl group and R ₂ is a lower alkyl group in the formula (I). Mono or dihydroxy (lower) alkyl group, di-lower alkylamino (lower)
Is an alkyl group, or R ₁ and R ₂ together with an adjacent nitrogen atom are R ₅ (where R ₅ represents a hydroxy group, a lower alkyl group, a mono- or dihydroxy (lower) alkyl group) To form a pyrrolidine or piperidine ring group which may be substituted, R ₃ is a halogen atom, and R ₄ is an isopropyl group or a cyclopropyl group.

Among the compounds of the present invention, more preferred are the compounds of the following formula (I-1) or pharmaceutically acceptable acid addition salts thereof.

[0031]

Embedded image

[0032] In the formula, R ₂₁ denotes a lower alkyl group, a mono- or dihydroxy (lower) alkyl group or a di-lower alkylamino (lower) alkyl, R ₃₁ means a chlorine atom or a bromine atom, R ₄₁ Represents an isopropyl group or a cyclopropyl group]

The compound represented by the above formula (I-1) includes, for example, the following compounds.

2- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] ethanol (the compound of Example 1),

1- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] -2-propanol (the compound of Example 2),

N- [5-chloro-2-isopropyl-6
-(4-trifluoromethylphenyl) -4-pyrimidinylamino] -N ', N'-dimethylethylenediamine
(Compound of Example 7), and

N- [5-chloro-2-cyclopropyl-
6- (4-Trifluoromethylphenyl) -4-pyrimidinylamino] -N ', N'-dimethylethylenediamine (compound of Example 8).

As specific examples of the compounds included in the present invention,
In addition to the compounds of the examples described later, the compounds shown in Table 1 below can be mentioned.

For simplicity of description in Tables 1 and 2 of the present specification and Reference Examples and Examples described later,
The following abbreviations may be used.

Me: methyl group, Et: ethyl group, Pr: propyl group, iPr: isopropyl group, cPr: cyclopropyl group, Ph: phenyl group.

[0041]

Embedded image

[0042]

[Table 1]

[0043]

[Table 2]

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

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

[0046]

Embedded image

(Wherein R ₁ , R ₂ and R ₄ have the same meanings as described above) by halogenating the compound.

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.

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

The compound of the intermediate (II) has the following formula (III):

[0052]

Embedded image

Wherein Z represents a leaving atom or a leaving group, and R ₄ has the same meaning as described above, and a compound represented by the following formula (IV):

[0054]

Embedded image R ₁ —NH—R ₂ (IV)

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

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 carried out in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, sodium hydrogencarbonate, alkali hydrogencarbonates such as potassium hydrogencarbonate, and alkali salts such as triethylamine. Triamines may be mentioned, but may also serve as excess of the compound of formula (IV). The reaction temperature varies depending on the type of the starting compound, reaction conditions, and the like, but is usually about 40 ° C.
To about 200C, preferably from about 100C to about 170C.

The starting compound (III) has, for example, the following formula (V):

[0060]

Embedded image

(Wherein Y represents an oxygen atom or a sulfur atom, and R ₄ represents the same as those described above) by halogenating or sulfonylating the compound according to a conventional method. Can be.

The halogenation in this reaction can be carried out, for example, by the following method:
Compound (V) and 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 (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride). This is done by:

The starting material (V) can be prepared by a method known per se,
Am. Chem. Soc., 74 , 842 (1952); Chem. Ber., 95 , 93.
7 (1962), J. Org. Chem., 29 , 2887 (1964) and WO
It can be produced by the method described in JP-A-96 / 32383 or a method analogous thereto.

The compound of the formula (IV), which is the other starting compound in the present production method, 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.

The compound of the formula (I) having a sufficient basicity to form an acid addition salt can be converted into the 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 : 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. It has now been found that arthritis, much like rheumatism, can develop. 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 3]

The inhibition rate was determined by comparing the arthritis score 52 days after the initial sensitization with the control group, and the results are shown in Table 4.

[0074]

[Table 4]

*: Corresponding to the compound of Example No.

As is clear from the results of Table 4 in the above test examples, the compounds of Examples 1, 2, 7 and 8 were used in an inhibition test of collagen-induced arthritis, which is a model of immune inflammatory diseases such as rheumatoid arthritis, in a dose of 10 mg. 60 / kg dose
%, A strong inhibitory effect of at least% was observed.

As is clear from the above pharmacological test results,
The compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof (hereinafter, may be 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,
Preferably it is 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, 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. Also tablets,
Granules may be coated by known methods. 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.

[0082]

EXAMPLES The present invention will be described more specifically with reference to Reference Examples and Examples below, but the present invention is not limited to these Examples. The compound is identified by elemental analysis,
The measurement was performed based on mass spectrum, IR spectrum, NMR spectrum and the like.

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

[Recrystallization solvent] A: ethanol, AC: acetone, AN: acetonitrile, E: diethyl ether, HX: n-hexane.

[NMR] J: coupling constant, s: singlet, d: doublet, dd: double doublet, t: triplet, sept: sevenfold, m: multiplet.

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, 20.7 g of isopropylcarbamidine hydrochloride was added 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 at 0 to 5 ° C while stirring until pH 4 was reached. The precipitate was collected by filtration, washed with water, washed with diethyl ether and recrystallized from isopropanol to obtain 30 g of the desired product. Melting point 241-243 ° C

Reference Example 2 : Production of 2-cyclopropyl-6- (4-trifluoromethylphenyl) -4 (3H) -pyrimidinone

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the desired compound. Melting point 219
-220 ° C (recrystallized from isopropanol)

Reference Example 3 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 an aqueous solution of sodium hydroxide (1 mol / L), the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
41 g of the desired product was obtained as an oil.

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

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 3 to obtain the target compound as an oil.

Example A : Preparation of 2- [2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] ethanol

4-Chloro-2-isopropyl-6- (4
-Trifluoromethylphenyl) pyrimidine 1.0 g, 2
-0.37 g of aminoethanol and 0.4 of triethylamine
The mixture of g was heated to 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 diethyl ether and n
Recrystallization from a mixed solvent of -hexane gave 1.0 g of the desired product. Melting point 100-101 ° C

Example BH : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example A to obtain the compounds shown in Table 5.

[0097]

Embedded image

[0098]

[Table 5]

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

2- [2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino]
A mixture of ethanol 1 g, N-chlorosuccinimide 0.5 g and acetic acid 10 ml 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 sodium hydroxide (1 mol / L) aqueous solution, and then 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, and eluted and purified with chloroform.
Recrystallization from n-hexane gave 0.9 g of the desired product. Melting point 108-109 ° C

Examples 2 to 8 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1. If necessary, the compounds were converted into hydrochlorides with ethanol hydrochloride to obtain the compounds shown in Table 6.

[0102]

Embedded image

[0103]

[Table 6]

*: The NMR spectra (deuterated chloroform) of the compounds of Examples 3 to 5 are shown below.

Example 3 : δ (ppm); 1.25 (6H, d, J = 7.0 Hz), 3.01 (1H, sept, J = 7.
0Hz), 3.90-3.95 (8H, m), 7.67 (2H, m), 7.77 (2H, m)

Example 4 : δ (ppm); 1.27 (6H, d, J = 6.6 Hz), 1.28 (6H, d, J = 6.8H)
z), 3.04 (1H, sept, J = 6.8Hz), 3.49 (1H, m), 3.62 (2H,
t, J = 4.7Hz), 3.73 (2H, m), 4.53 (1H, sept, J = 6.6H
z), 7.68 (2H, dd, J = 8.6, 0.39Hz), 7.78 (2H, dd, J = 8.
6, 0.54Hz)

Example 5 : δ (ppm); 1.29 (3H, d, J = 6.8 Hz), 1.31 (3H, d, J = 6.8H)
z), 1.73-1.92 (2H, m), 1.96-2.14 (2H, m), 3.03 (1H, s
ept, J = 6.8Hz), 3.70-3.80 (2H, m), 3.83-4.05 (2H, m),
4.68 (1H, m), 7.70 (2H, m), 7.77 (2H, m)

Formulation Example 1 : Production of tablets

[0109]

Table 7 1- [5-Chloro-2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -2-propanol 25 g lactose ········· 70 g corn starch ········· 20 g microcrystalline cellulose ... 25 g hydroxypropyl cellulose 3 g

After mixing and granulating the above components by a conventional method, light anhydrous silicic acid (0.7 g) and magnesium stearate were added.
(1.3 g), and tableted at 145 mg per tablet.
Make 000 tablets.

Formulation Example 2 : Production of capsules

[0112]

Table 8 1- [5-Chloro-2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -2-propanol 50 g lactose ·········· 117 g corn starch ·········· 25 g hydroxypropylcellulose 3.5 g Light Silicic Anhydride 1.8 g 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.

Formulation Example 3 : Production of powder

[0115]

Table 9 1- [5-Chloro-2-isopropyl-6- (4-trifluoromethylphenyl) -4-pyrimidinylamino] -2-propanol 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]

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. Compounds of formula (II) are useful as intermediates of compounds of formula (I).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 401/04 C07D 401/04 403/04 403/04 (72) Inventor Masayasu Tanaka 5 Asahigaoka, Yao-shi, Osaka No. 85, 117 Building No. 404, No. 404 (72) Inventor Mari Ito 5-7-12 Tsuundai, Suita-shi, Osaka F-term (reference) 4C063 AA01 BB02 CC29 DD03 DD10 EE01 4C086 AA01 AA02 AA03 BC42 GA07 MA04 NA14 ZB07 ZB11

Claims (5)

[Claims] (1) The following formula (I): Wherein R ₁ is a hydrogen atom, a lower alkyl group, a mono- or dihydroxy (lower) alkyl group, a mono- or di-lower alkoxy (lower) alkyl group, an amino (lower) alkyl group, or a mono- or di-lower alkylamino (lower) R ₂ represents a lower alkyl group, a mono or dihydroxy (lower) alkyl group, a mono or di lower alkoxy (lower) alkyl group, an amino (lower) alkyl group, an alkyl group, an unsubstituted or substituted phenyl (lower) alkyl group; Or a mono- or di-lower alkylamino (lower) alkyl group, an unsubstituted or substituted phenyl (lower) alkyl group, or R ₁ and R ₂ together with an adjacent nitrogen atom represent R ₅ (where R ₅ is a hydroxy group, a lower alkoxy group, a lower alkyl group, a mono- or dihydroxy (lower) alkyl group, Mono or di-lower alkoxy
A cyclic group which may be substituted by (lower) alkyl, amino (lower) alkyl or mono- or di-lower alkylamino (lower) alkylamino;
₃ represents a halogen atom, and R ₄ represents a lower alkyl group or a cycloalkyl group], or a pharmacologically-produced 5-halogeno-6- (4-trifluoromethylphenyl) -4-aminopyrimidine derivative Pharmaceutically acceptable acid addition salts. 2. A compound represented by the following formula (I-1): [Wherein, R ₂₁ represents a lower alkyl group, a mono- or dihydroxy (lower) alkyl group or a di-lower alkylamino (lower) alkyl group, R ₃₁ represents a chlorine atom or a bromine atom, and R ₄₁ represents an isopropyl group. Or a cyclopropyl group].
(4-trifluoromethylphenyl) -4-aminopyrimidine derivative or a pharmaceutically acceptable acid addition salt thereof. 3. A pharmaceutical composition comprising the 5-halogeno-6- (4-trifluoromethylphenyl) -4-aminopyrimidine derivative according to claim 1 or a pharmaceutically acceptable acid addition salt thereof. object. 4. The 5-halogeno-6- (4-trifluoromethylphenyl) -4-aminopyrimidine derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 1 or 2, as an active ingredient. Drug for treating or preventing immune inflammatory disease. 5. The following formula (II): Wherein R ₁ is a hydrogen atom, a lower alkyl group, a mono- or dihydroxy (lower) alkyl group, a mono- or di-lower alkoxy (lower) alkyl group, an amino (lower) alkyl group, or a mono- or di-lower alkylamino (lower) R ₂ represents a lower alkyl group, a mono or dihydroxy (lower) alkyl group, a mono or di lower alkoxy (lower) alkyl group, an amino (lower) alkyl group, an alkyl group, an unsubstituted or substituted phenyl (lower) alkyl group; Or a mono- or di-lower alkylamino (lower) alkyl group, an unsubstituted or substituted phenyl (lower) alkyl group, or R ₁ and R ₂ together with an adjacent nitrogen atom represent R ₅ (where R ₅ is a hydroxy group, a lower alkoxy group, a lower alkyl group, a mono- or dihydroxy (lower) alkyl group, Mono or di-lower alkoxy
A cyclic group which may be substituted by (lower) alkyl, amino (lower) alkyl or mono- or di-lower alkylamino (lower) alkylamino;
₄ represents a lower alkyl group or a cycloalkyl group], or a 5-halogeno-6- (4-trifluoromethylphenyl) -4-aminopyrimidine derivative or an acid addition salt thereof.