JPH10231297A - New adenine-1-noxide derivative, and use of the same as medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative consisting of a specific adenine-1- N-oxide derivative having a function of preventing an inflammatory cell from attaching to a target organ cell, useful, e.g. as a medicine for immunological diseases, such as autoimmune, allergic and inflammatory diseases. SOLUTION: This new adenine-1-N-oxide derivative is shown by formula I (R1 is H or a 1-4C alkyl; R2 is H, a 1-4C alkyl or a 1-4C alkoxy; R3 is a (substituted)phenyl or naphthyl, which is not substituted or substituted with 1 to 3 groups, such as a 1-4C alkyl, a 1-4C alkoxy, trifluoromehyl, nitro, phenyl, a halogeno or the like), e.g. 9-(4-chlorobenzyl)adenine-1-N-oxide, and useful as a medicine or the like for immunological diseases in which an inflammatory cell is involved, e.g. autoimmune and allergic diseases. The compound is obtained by reacting a substituted adenine derivative shown by formula II with an arylmethyl halide shown by the formula R3 -CH2 -X (X is Cl, Br or I) in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel adenine compound.
A 1-N-oxide derivative or a pharmaceutically acceptable salt thereof,
In addition, the present invention relates to a therapeutic drug for immunological diseases containing the same as an active ingredient. In particular, the therapeutic drug for an immune disease of the present invention is useful for the treatment of various adhesion molecules or ligand molecules involved in a process essential for the progression of an immune disease in which inflammatory cells such as leukocytes adhere to diseased tissue cells. It has an inhibitory / suppressive effect on the expression of, and can be used as a therapeutic drug for various autoimmune diseases, allergic diseases, and other immune diseases involving inflammatory cells.

[0002]

2. Description of the Related Art Pharmaceutical treatments for autoimmune diseases such as rheumatism, nephritis, systemic lupus erythematosus (SLE), multiple sclerosis, ulcerative colitis and the like include immunization with cyclooxygenase inhibitors, steroids, azathioprine and the like. Inhibitors and the like are conventionally used. These immunosuppressive agents only have a cognitive effect, and, for example, cyclooxygenase inhibitors such as indomethacin inhibit not only the affected area of inflammation but also the cyclooxygenase of the gastrointestinal tract. In most cases, the therapeutic effect is not sufficiently separated from the side effects, such as those causing severe ulcers and further exhibiting serious side effects such as steroid therapy.

[0003] These autoimmune diseases, like other immune diseases, are inflammatory diseases caused by inflammatory cells such as leukocytes, particularly neutrophils and macrophages. That is, after these inflammatory cells adhere to target organ cells via various adhesion molecules such as ICAM-1 and selectin, they release inflammatory substances such as active oxygen and protease to induce inflammation.・ Amplify. It has been reported that inhibition and suppression of this adhesion process can suppress the progression of inflammation, and indeed, administration of antibodies to several adhesion molecules is effective in animal inflammation models (J. Immunology). , 147 , 4167-4171 (1991), etc.). However, since antibodies can hardly be expected to absorb gastrointestinal tract, as a pharmaceutical, intravenous administration, for example, inevitable injection, requires long-term and continuous administration of therapeutic agents, such as autoimmune diseases It is not suitable for the treatment of various chronic diseases.

Therefore, development of a low-molecular substance suitable for oral administration and capable of absorbing gastrointestinal tract and having an inhibitory effect on the function of adhesion molecules has been desired. In particular, a drug that inhibits or suppresses the expression of various adhesion molecules on the surface of a target cell of an affected area has no adverse effect on the immune system and can suppress inflammation at a target affected area, and is particularly expected. In addition, drugs that inhibit the adhesion of inflammatory cells to target organs, besides autoimmune diseases, allergic diseases such as asthma, hepatitis,
It is also expected to be effective in the treatment of immune diseases such as insulin-dependent diabetes mellitus, adult respiratory distress, sepsis, shock, reperfusion injury after myocardial infarction, and immune diseases having these chronic factors and characteristics.

[0005] Heretofore, as agents having a cell adhesion inhibitory effect, for example, substituted benzoic anilides represented by 4-hydroxy-N- (2-hydroxyphenyl) benzoic amide (JP-A-7-330595) ), 2-amino-3- represented by 2-chloro-3- [4- (1-pyrrolidinyl) piperidino] -1,4-naphthoquinone
-Halogeno-1,4-naphthoquinone derivatives (JP-A-8-1
The present inventors have also proposed purine derivatives represented by 6-amino-9-benzyl-8-bromopurine (9-benzyl-8-bromoadenine). (See Japanese Patent Application Laid-Open No. 7-330770), however, there is a demand for a proposal of a new compound having a further excellent adhesion inhibiting action.

[0006]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems, and an object of the present invention is to provide continuous or long-term oral administration, and to provide a main pharmacological effect of target organ cells of inflammatory cells. It is an object of the present invention to provide a novel compound that inhibits / suppresses adhesion to a drug, and a therapeutic drug for an immune disease containing the compound as an active ingredient.

[0007]

Under these circumstances, the present inventors have created a novel compound having a main pharmacological effect of inhibiting or suppressing the adhesion of inflammatory cells to target organ cells. As a result of continued intensive studies, new adenine-1-N-oxide derivatives were created, and they were found to exhibit excellent adhesion-inhibiting effects, and the present invention was completed.

The compound of the present invention has the following general formula (I):

Embedded image (Wherein, R ₁ represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and R ₂ represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Group or carbon number 1
It represents to 4 straight-chain or branched alkoxy group, R ₃
Is an unsubstituted or straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group, a trifluoromethyl group, and a nitro group. Phenyl group, a substituted phenyl group having 1 to 3 substituents selected from the group consisting of a halogeno group, and a naphthyl group. Adenine-1-N-oxide derivative or a pharmaceutically acceptable salt thereof. The therapeutic drug for immunological diseases of the present invention is a pharmaceutical composition containing the novel adenine-1-N-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009]

DETAILED DESCRIPTION OF THE INVENTION First, the novel compound of the present invention, an adenine-1-N-oxide derivative, will be described. In the general formula (I), the linear or branched alkyl group having 1 to 4 carbon atoms has a linear methyl group, an ethyl group, a propyl group, a butyl group, and a branched chain. , Isopropyl group, sec-butyl group, tert-butyl group, having 1 carbon atom
The straight-chain or branched alkoxy group of ~ 4 means an alkyloxy group comprising the above-mentioned alkyl group. Also,
An alkoxycarbonyl group also means an alkyloxycarbonyl group consisting of this alkyl group. The halogeno group refers to a fluoro group, a chloro group, a bromo group, and an iodo group. When a halogeno group is selected as a substituent in the substituted phenyl group of R ₃ , a fluoro group, a chloro group, and a bromo group are preferable.

Adenine-1 represented by the above general formula (I)
-N-oxide derivative, adenine skeleton at position 2
It is preferable to select a hydrogen atom for either R ₁ or R _{2 at} the 8-position. More preferably, both R ₁ and R ₂ are hydrogen atoms. On the other hand, when selecting a substituted phenyl group for R ₃ , a substituent containing a halogeno group or a trifluoromethyl group is preferable. Further, among the halogeno groups, a bromo group is more preferable. That is, a substituted phenyl group containing a bromo group or a trifluoromethyl group as a substituent is more preferred. In the case of mono-substitution, the substitution position on the substituted phenyl group more preferably has a substituent at the meta position. When two or more substituents are present, those having two substituents are generally preferred over those having three substituents. When the number of substituents is 2, the substitution position is more preferably present at both the meta position and the ortho position.

In the adenine-1-N-oxide derivative of the present invention, examples of the pharmacologically acceptable salt include a salt with a pharmacologically acceptable acid such as hydrochloride and hydrogen bromide. Examples thereof include salts with inorganic acids such as acid salts, salts with carboxylic acids such as acetates, salts with organic sulfonic acids such as methanesulfonate and p-toluenesulfonate.

The process for producing the adenine-1-N-oxide derivative of the present invention will be outlined below. Step 1: Preparation of intermediate material; 9-substituted adenine derivative As a starting material, the following general formula (II):

Embedded image (Wherein, R _1, R ₂ are each the general formula (. Representing the R _1, R ₂ group having the same meaning as in I)) represented by the adenine derivatives having substituents unsubstituted or position 2,8 In the presence of a base, the following general formula (III):

Embedded image (Wherein, R ₃ represents a group having the same meaning as R _{3 in} formula (I);
X represents a chloro, bromo or iodo group. )
By reacting an arylmethyl halide represented by the following formula (IV):

Embedded image _{(Wherein, R 1, R 2, R} 3 is, R ₁ in each formula (I),
Represents a group having the same meaning as R ₂ and R ₃ . ) Is synthesized as an intermediate material. Examples of the base used include alkoxides such as potassium carbonate, sodium hydride, sodium methoxide, and sodium ethoxide. As the reaction solvent, dimethylformamide (DMF), tetrahydrofuran (THF), 1,4-dioxane and the like are preferable. The reaction temperature can be selected from the range from room temperature to the temperature at which the solvent is refluxed, and particularly preferably in the range of 60 to 80 ° C. In the step of introducing a substituent on the nitrogen atom at the ninth position, 7
7- in which a substituent is introduced on the nitrogen atom at the 3- or 3-position
Substitutes and 3-substitutes are also produced in trace amounts, but are removed by purification after the next step, so there is no need to purify at this stage.

The following general formula (V):

Embedded image (Wherein, R _1, R ₃ each represents a R _1, R ₃ group having the same meaning as in formula (I).) An intermediate material represented by can also be prepared by the following method. The following formula (VI):

Embedded image 5-amino-4-cyanoimidazole represented by the following general formula (VII):

Embedded image (. In the formula, R _1, representing the R ₁ group having the same meaning as in general formula (I)) in to ring closure and the amide compound represented by the following general formula (VIII):

Embedded image (Wherein, R ₁ represents a group having the same meaning as R _{1 in} formula (I)). The 2-substituted adenine represented by formula (I) can be prepared and used as a starting material.

Alternatively, the following general formula (IX):

Embedded image (Wherein, R ₃ represents a group having the same meaning as R _{3 in} formula (I);
R ₂ represents a linear or branched alkoxy group having 1 to 4 carbon atoms. The intermediate raw material represented by ()) can also be produced by the following method. First, adenine and the above-mentioned general formula (II
By reacting the arylmethyl halide represented by I), the following general formula (X):

Embedded image (Wherein R ₃ represents a group having the same meaning as R _{3 in} formula (I)). Then, the 9-substituted adenine is reacted with bromine to lead to an 8-bromo-9-substituted adenine, and the alcohol corresponding to the alkoxy group of R ₂ is reacted with sodium, and represented by the general formula (IX). The desired intermediate material, 8-alkoxy-9
-Substituted adenine derivatives can be prepared.

Further, the following general formula (XI):

Embedded image (Wherein, R ₃ represents a group having the same meaning as R _{3 in} formula (I);
R2 represents a linear or branched alkyl group having 1 to 4 carbon atoms. The intermediate material represented by ()) is described in, for example,
6-amino-9-benzyl- described in JP-A-330770
8-bromopurine (9-benzyl-8-bromoadenine)
Can be produced according to a method for producing a purine derivative represented by First, formula (XII):

Embedded image 5-amino-4,6-dichloropyrimidine represented by the following general formula (XIII):

Embedded image (Wherein, R ₃ represents a group having the same meaning as R _{3 in} formula (I)), and reacted with an arylmethylamine compound represented by the following formula (XIV):

Embedded image (Wherein, R ₃ is. Representing the R ₃ group having the same meaning as in general formula (I)) lead to 5-amino-6- (aryl-methyl) amino-4-chloropyrimidine derivative represented by the. Then, the following general formula (XV):

Embedded image (Wherein R ₂ represents a linear or branched alkyl group having 1 to 4 carbon atoms), and an orthoester represented by the following general formula: (XVI):

Embedded image (Wherein, R ₃ represents a group having the same meaning as R _{3 in} formula (I);
Represents a linear or branched alkyl group having 1 to 4 carbon atoms. 8-alkyl-9-arylmethyl-6 represented by the formula:
The 8-chloro-9-substituted adenine derivative represented by the general formula (XI) can be prepared by replacing the chloro group at the 6-position with ammonia as a -chloropurine derivative.

Step 2: Derivation to an Adenine-1-N-oxide Derivative Next, an oxidizing agent such as meta-chloroperbenzoic acid (m-CPBA) is added to the 9-substituted adenine derivative of the intermediate material represented by the general formula (IV). To give the desired adenine-1-N-oxide derivative of the general formula (I). As a reaction solvent, lower alcohols such as methanol and ethanol, as well as chloroform, dichloromethane and the like can be used. Thereafter, if necessary, purification may be performed by conventional means such as recrystallization.

The therapeutic drug for immunological diseases of the present invention is a pharmaceutical composition containing the above-mentioned adenine-1-N-oxide derivative as an active ingredient. As shown in the following Test Examples, its pharmacological effect is as follows. Because it is caused by the effect of inhibiting and suppressing the adhesion of inflammatory cells to target organ cells, rheumatism,
Nephritis, systemic lupus erythematosus (SLE: Systemic lupus)
erythematosus), treatment of autoimmune diseases such as multiple sclerosis and ulcerative colitis, as well as allergic diseases such as asthma, hepatitis, insulin-dependent diabetes mellitus, adult respiratory distress, sepsis, shock, post-myocardial infarction It is also effective in the treatment of immune diseases such as reperfusion disorder. In addition,
The therapeutic agent of the present invention can be a parenteral administration such as an injection suitable for intravascular administration, but is most suitably prepared into an oral administration preparation, tablets, capsules,
It is preferable to use a dosage form such as a powder. The preparation can be prepared by conventional means together with various additives commonly used in these preparations for oral administration, excipients such as lactose and glucose, and lubricants such as magnesium stearate and talc. Furthermore, it may be administered in another form suitable for oral administration, for example, as a liquid preparation. In addition, the effective dose and the number of administrations of the above-mentioned adenine-1-N-oxide derivative are determined according to the patient's weight, age, sex, and symptoms.
Alternatively, it is appropriately determined according to the purpose of administration, and is usually 0.01 to 100 mg / kg per day for an adult male.
Can be administered once to several times.

Hereinafter, the present invention will be described in more detail with reference to specific examples.

[0019]

Example 1 9- (4-chlorobenzyl) adenine, 1-N
-Oxide (Step 1-1; Preparation of intermediate material 9- (4-chlorobenzyl) adenine) Adenine 270 mg (2 mmol), potassium carbonate 280
mg (2 mmol), 4-chlorobenzyl chloride 350 mg (2.2
mmol) was added to 20 ml of DMF, and the mixture was heated with stirring at 80 ° C. for 16 hours. After the solvent was distilled off under reduced pressure, water was added and the mixture was subjected to ultrasonic treatment. The precipitated solid 9- (4-chlorobenzyl) adenine was collected by filtration and washed with toluene (yield 480 mg).

(Step 1-2: N-Oxidation of Intermediate Starting Material 9- (4-Chlorobenzyl) adenine) Intermediate Starting Material Obtained in Step 1-1; 9- (4-chlorobenzyl) adenine 190
mg (0.7 mmol) was taken and stirred with 270 mg (1.4 mmol) of m-CPBA in methanol for 3 days. The precipitated solid was collected by filtration and washed with a 10% sodium carbonate solution and then with water to obtain 110 mg of the title compound (yield: 54%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.40 (2H, s), 7.37 (4H, dd),
8.42 (1H, s), 8.61 (1H, s) Mass: 276 (M +)

[0021]

Example 2 9-benzyl-8-ethyladenine, 1-N
-Oxide The title compound was synthesized in the same manner as in Example 1 using 9-benzyl-8-ethyladenine as an intermediate raw material (yield: 87%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.13 (3H, m), 2.70 (2H, m),
5.31 (2H, d), 7.03-7.26 (5H, m), 8.53 (1H, s) Mass: 269 (M +)

[0022]

Example 3 9-benzyl-8-methoxyadenine, 1
-N-oxide Using 9-benzyl-8-methoxyadenine as an intermediate material,
The title compound was synthesized in the same manner as in Example 1 (yield: 27%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 4.13 (3H, s), 5.15 (2H, s),
7.23-7.36 (5H, m), 7.90 (2H, brs), 8.53 (1H, s) TOF-MS: 271 (M +)

[0023]

Example 4 9- (4-bromobenzyl) adenine, 1-N
-Oxide Using 9- (4-bromobenzyl) adenine as an intermediate raw material, the title compound was synthesized in the same manner as in Example 1 (yield: 85%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.38 (2H, s), 7.27 (2H, d),
7.55 (2H, d), 8.42 (1H, s), 8.61 (1H, s) Mass: 319 (M +) Elemental analysis: C ₁₂ H ₁₀ N ₅ OBr · 1H ₂ O Calcd. C: H: N = 42.62 : 3.58: 20.71 Found C: H: N = 42.65: 3.57: 20.57

[0024]

Example 5 9- (4-methylbenzyl) adenine, 1-N
-Oxide Using 9- (4-methylbenzyl) adenine as an intermediate material, the title compound was synthesized in the same manner as in Example 1 (yield: 98%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.26 (3H, s), 5.34 (2H, m),
7.18 (4H, dd), 8.40 (1H, s), 8.61 (1H, s) Mass: 255 (M +)

[0025]

Example 6 9- (4-methoxybenzyl) adenine, 1
Using -N-oxide intermediate material 9- (4-methoxybenzyl) adenine,
The title compound was synthesized in the same manner as in Example 1 (yield: 90%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.71 (3H, s), 5.31 (2H, s),
6.90 (2H, d), 7.30 (2H, d), 8.40 (1H, s), 8.62 (1H, s) Mass: 271 (M +)

[0026]

Example 7 9- (2,4-dichlorobenzyl) adenine,
1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (2,4-dichlorobenzyl) adenine as an intermediate raw material (yield: 69%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.48 (2H, s), 7.10 (2H, d),
7.41 (2H, d), 8.35 (1H, s), 8.60 (1H, s) Mass: 309 (M +) Elemental analysis: Calcd as _{C 12 H 9 N 5 OCl 2} C:. H: N = 46.47: 2.92: 22.58 Found C: H: N = 46.26: 2.99: 22.31

[0027]

Example 8 9- (2,4,6-trimethylbenzyl) adenine, 1-N-oxide The same operation as in Example 1 using 9- (2,4,6-trimethylbenzyl) adenine as an intermediate material To synthesize the title compound (yield: 40%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.23 (3H, s), 2.26 (6H, s),
5.30 (2H, s), 6.92 (2H, s), 7.83 (1H, s), 8.64 (1H, s) Mass: 283 (M +)

[0028]

Example 9 9- (4-tert-butylbenzyl) adenine, 1-N-oxide Using 9- (4-tert-butylbenzyl) adenine as an intermediate material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 95%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.23 (9H, s), 5.35 (2H, s),
7.25 (2H, d), 7.36 (2H, d), 8.43 (1H, s), 8.63 (1H, s) Mass: 297 (M +)

[0029]

Example 10 9- (4-trifluoromethylbenzyl)
Adenine, 1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (4-trifluoromethylbenzyl) adenine as an intermediate raw material (yield: 79%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.18 (3H, m), 4.10 (1H, m),
5.52 (2H, s), 7.49 (2H, d), 7.72 (2H, d), 8.46 (1H, s), 8.
61 (1H, s) Mass: 309 (M +)

[0030]

Example 11 9- (1-Naphthylmethyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (1-naphthylmethyl) adenine as an intermediate raw material (yield: 59%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.89 (2H, s), 7.20-8.25 (7H,
m), 8.35 (1H, s), 8.64 (1H, s) Mass: 291 (M +)

[0031]

Example 12 9- (3-chlorobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (3-chlorobenzyl) adenine as an intermediate raw material (yield: 76%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.41 (2H, s), 7.27 (1H, m),
7.37-7.43 (3H, m), 8.45 (1H, s), 8.63 (1H, s) Mass: 275 (M +)

[0032]

Example 13 9- (2-chlorobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (2-chlorobenzyl) adenine as an intermediate raw material (yield: 73%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.50 (2H, s), 7.03-7.07 (1H,
m), 7.30-7.42 (2H, m), 7.84-7.88 (1H, m), 8.36 (1H, s),
8.61 (1H, s) Mass: 275 (M +)

[0033]

Example 14 9- (4-Fluorobenzyl) adenine, 1
Using -N-oxide intermediate material 9- (4-fluorobenzyl) adenine,
The title compound was synthesized in the same manner as in Example 1 (yield: 90%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.38 (2H, s), 7.18 (2H, m),
7.39 (2H, m), 8.42 (1H, s), 8.62 (1H, s) Mass: 259 (M +)

[0034]

Example 15 9- (4-phenylbenzyl) adenine,
Using 1-N-oxide intermediate material 9- (4-phenylbenzyl) adenine,
The title compound was synthesized in the same manner as in Example 1 (yield: 40%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.45 (2H, s), 7.36-7.48 (5H,
m), 7.62-7.66 (4H, m), 8.48 (1H, s), 8.64 (1H, s) Mass: 317 (M +)

[0035]

Example 16 9- (4-methoxycarbonylbenzyl)
Adenine, 1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (4-methoxycarbonylbenzyl) adenine as an intermediate raw material (yield: 44%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.83 (3H, s), 5.50 (2H, s),
7.41 (2H, d), 7.93 (2H, d), 8.45 (1H, s), 8.61 (1H, s) Mass: 299 (M +)

[0036]

Example 17 9- (4-nitrobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (4-nitrobenzyl) adenine as an intermediate raw material (yield: 27%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.57 (2H, s), 7.53 (2H, d),
8.20 (2H, d), 8.47 (1H, s), 8.61 (1H, s) Mass: 286 (M +)

[0037]

Example 18 9- (2-Naphthylmethyl) adenine, 1
—N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (2-naphthylmethyl) adenine as an intermediate raw material (yield: 35%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.57 (2H, s), 7.49-7.89 (7H,
m), 8.48 (1H, s), 8.62 (1H, s) Mass: 291 (M +)

[0038]

Example 19 9- (2,3-Dichlorobenzyl) adenine, 1-N-oxide Using 9- (2,3-dichlorobenzyl) adenine as an intermediate material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 65%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.54 (2H, s), 6.97-6.99 (1H,
m), 7.30-7.35 (1H, m), 7.61-7.62 (1H, m), 8.37 (1H, s),
8.60 (1H, s) Mass: 310 (M +)

[0039]

Example 20 9- (3,4-Dichlorobenzyl) adenine, 1-N-oxide Using 9- (3,4-dichlorobenzyl) adenine as an intermediate material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 51%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.41 (2H, s), 7.26-7.30 (1H,
m), 7.59-7.66 (2H, m), 8.43 (1H, s), 8.62 (1H, s) Mass: 310 (M +)

[0040]

Example 21 9- (2,6-Dichlorobenzyl) adenine, 1-N-oxide Using 9- (2,6-dichlorobenzyl) adenine as an intermediate starting material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 36%). Mass: 310 (M +)

[0041]

Example 22 9- (3,5-Difluorobenzyl) adenine, 1-N-oxide Using 9- (3,5-difluorobenzyl) adenine as an intermediate starting material, the title compound was prepared in the same manner as in Example 1. It was synthesized (yield: 50%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.44 (11H, m), 7.06-7.08 (2
H, m), 7.18-7.25 (2H, m), 8.44 (1H, s), 8.64 (1H, s) Mass: 277 (M +)

[0042]

Example 23 9- (3-bromobenzyl) adenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (3-bromobenzyl) adenine as an intermediate material (yield: 83%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.40 (2H, s), 7.30 (2H, m),
7.49-7.57 (2H, m), 8.44 (1H, s), 8.62 (1H, s) Mass: 320 (M +)

[0043]

Example 24 9- (3-trifluoromethylbenzyl)
Adenine, 1-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9- (3-trifluoromethylbenzyl) adenine as an intermediate raw material (yield: 41%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.51 (2H, s), 7.57-7.76 (4H,
m), 8.47 (1H, s), 8.62 (1H, s) Mass: 309 (M +)

[0044]

Example 25 9- (2,3,4-trifluorobenzyl) adenine, 1-N-oxide Same as Example 1 except for using 9- (2,3,4-trifluorobenzyl) adenine as an intermediate raw material. The title compound was synthesized by the operation described above (yield: 38%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.45 (2H, s), 7.09-7.19 (1H,
m), 7.25-7.35 (1H, m), 8.14 (1H, s), 8.22 (1H, s) Mass: 295 (M +)

[0045]

Example 26 9- (2,4,6-trifluorobenzyl) adenine, 1-N-oxide Same as Example 1 using 9- (2,4,6-trifluorobenzyl) adenine as an intermediate material The title compound was synthesized by the operation described above (yield: 97%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 5.43 (2H, s), 7.26 (2H, t),
8.34 (1H, s), 8.59 (1H, s) Mass: 295 (M +)

[0046]

Example 27 9-benzyl-2-methyladenine, 1
-N-oxide The title compound was synthesized in the same manner as in Example 1 using 9-benzyl-2-methyladenine as an intermediate raw material (yield: 63%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.57 (3H, s), 5.37 (2H, s),
7.26-7.33 (5H, m), 8.31 (1H, s) Mass: 255 (M +)

[0047]

Example 28 9- (3,4,5-trimethoxybenzyl) adenine, 1-N-oxide Same as Example 1 using 9- (3,4,5-trimethoxybenzyl) adenine as an intermediate material The title compound was synthesized by the operation described above (yield: 59%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.61 (3H, s), 3.72 (6H, s),
5.29 (2H, s), 6.71 (2H, s), 8.39 (1H, s), 8.63 (1H, s) Mass: 331 (M +)

[0048]

Example 29 9- (2,3-Dichlorobenzyl) -2-methyladenine, 1-N-oxide Example 1 was prepared using 9- (2,3-dichlorobenzyl) -2-methyladenine as an intermediate material. The title compound was synthesized in the same manner as described above (yield: 89%). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.90 (3H, s), 5.50 (2H, s),
6.88 (1H, d), 7.31 (1H, t), 7.62 (1H, d), 8.26 (1H, s) Mass: 324 (M +)

[0049]

Example 30 Inhibitory Effect of ICAM-1 Molecule Expression The adenine N-oxide derivative of the present invention has excellent ICAM-
It was verified by the following test that it had a single molecule expression suppressing effect.

Test Method Human umbilical vein endothelial cells are seeded in each well of a 96-well plate and cultured until confluent. A predetermined concentration of the test substance and TNF-α (100 U / ml) are added, and the cells are cultured for 24 hours. After fixing the cells with 0.1% glutaraldehyde,
Block with PBS containing 0.1% BSA, 0.2% gelatin, 0.75% glysine. E using mouse anti-human ICAM-1 antibody
The amount of expressed ICAM-1 is quantified by the LISA method.
As a reference group, when no test substance is added, the amount of expressed ICAM-1 is quantified, and the inhibition rate is calculated based on that value.

Table 1 shows, by way of example, the addition concentration at which the inhibition rate obtained from the dependency of the inhibition rate on the test substance addition concentration exceeds 50%, ie, the lowest effective concentration, based on the results of the above test.

[0052]

[Table 1]

[0053]

Example 31 E-selectin Molecule Expression Inhibitory Effect The adenine N-oxide derivative of the present invention is an excellent E-sel
It was verified by the following test that it had an ectin molecule expression inhibitory effect.

Test Method Human umbilical vein endothelial cells are seeded in each well of a 96-well plate and cultured until confluent. A predetermined concentration of the test substance and TNF-α (100 U / ml) are added, and the cells are cultured for 3 hours. After fixing the cells with 0.1% glutaraldehyde, perform blocking with PBS containing 0.1% BSA, gelatin and 0.75% glysine. The amount of expressed E-selectin is quantified by an ELISA method using a mouse anti-human E-selectin antibody. As a reference group, when no test substance is added, the amount of expressed E-selectin is quantified, and the inhibition rate is calculated based on that value.

Table 2 shows, by way of example, the additive concentration at which the inhibition rate obtained from the dependence of the inhibition rate on the test substance addition concentration, based on the results of the above test, exceeds 50%, ie, the lowest effective concentration.

[0056]

[Table 2]

[0057]

Example 32 Cell Adhesion Inhibitory Effect The adenine N-oxide derivative of the present invention
It was verified by the following tests that the compound was excellent in suppressing the expression of adhesion molecules such as ICAM-1 molecule and E-selectin molecule and, as a result, also excellent in suppressing the adhesion process itself of inflammatory cells.

Test Method Human umbilical vein endothelial cells are seeded in each well of a 96-well plate and cultured until confluent. A predetermined concentration of the test substance and TNF-α (100 U / ml) are added, and the cells are cultured for 3 hours. Then, 2 ', 7'-bis- (2-carboxyethyl) -5,6-
A predetermined amount of HL-60 cells fluorescently labeled with dicarboxyfluoresce-acetoxymethylester is added, and cultured for 30 minutes. After suction-removing unadhered HL-60 cells, the adhered HL-60 cells are lysed and the fluorescence intensity is measured (excitation: 490 nm, fluorescence: 530 nm). As a reference group, when no test substance is added, the number of adherent HL-60 cells is similarly quantified, and the inhibition rate is calculated based on the value.

From the dependence of the inhibition rate on the concentration of the test substance added, the value of the added concentration IC50 at which the inhibition rate was 50% was determined. As an example of the results, the compound of Example 19 and Example 23 were respectively 0.179 [mu] M, IC ₅₀ values of 0.157 [mu] M.

[0060]

Example 32. Effect on adjuvant arthritis model The adenine N-oxide derivative of the present invention is excellent in the action of inhibiting the process of adhesion of inflammatory cells to diseased tissue cells itself, so that it can be used in actual immune diseases. The effect of alleviating inflammatory symptoms was verified by the following adjuvant arthritis model.

Test Method 0.6% Myob was subcutaneously injected into the right hind footpad of 8-week-old male SD rats.
Inject 0.1 ml of acterium butyricum liquid paraffin suspension. The test substance is suspended at a predetermined dose in a 0.5% CMC-Na solution for one day from the day of adjuvant administration (day 0).
Oral administration once for 17 days. Difference between the paw volume on day 17 and the paw volume on day 0; increase in paw volume due to edema 0
The ratio to paw volume on day is calculated as edema rate. On the last day (17th day of induction), blood is collected from the abdominal aorta under ether anesthesia, and the blood sedimentation rate in a Westergren tube of a mixed solution of 3.2% citric acid: blood = 1: 4 is measured.

Table 3 shows the results of the compound of Example 19 and the compound of Example 23 as an example. In the table, the edema rate of the right hind limb; the edema rate of the right hind limb; the edema rate of the left hind limb; The results obtained when a 0.5% CMC-Na solution containing no test substance was administered are shown as controls.

[0063]

[Table 3]

[0064]

Industrial Applicability The adenine N-oxide derivative of the present invention is excellent in inhibiting the expression of adhesion molecules on endothelial cells, so that the adhesion of inflammatory cells to the target organ / tissue can be suppressed. . Utilizing this distinctive adhesion molecule expression inhibitory activity, various inflammatory diseases, namely rheumatism,
It is a useful medicine for treating autoimmune diseases such as SLE and multiple sclerosis, other allergic diseases such as asthma, and immune diseases such as reperfusion disorder after myocardial infarction. In addition, since the adenine N-oxide derivative of the present invention is a low molecular compound, it can be administered orally, is suitable for long-term or continuous administration, and is suitable for treating the above-mentioned chronic diseases.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/52 ABS A61K 31/52 ABS ACD ACD ACE ACE ACS ACS ADP ADP ADZ ADZ ADZ

Claims (2)

[Claims] 1. The following general formula (I): (Wherein, R ₁ represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and R ₂ represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Group or carbon number 1
It represents to 4 straight-chain or branched alkoxy group, R ₃
Is an unsubstituted or straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group, a trifluoromethyl group, and a nitro group. Phenyl group, a substituted phenyl group having 1 to 3 substituents selected from the group consisting of a halogeno group, and a naphthyl group. Adenine-1-N-oxide derivative or a pharmaceutically acceptable salt thereof. 2. The novel adenine according to claim 1,
An agent for treating an immune disease, comprising a 1-N-oxide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.