JPH08165292A - Adenine derivative,its production and application - Google Patents

Abstract

PURPOSE: To provide a new adenine derivative producible e.g. by the reaction of a specific adenine compound with a cyanophenylbenzyl halide, etc., followed by hydrolysis of the product, having angiotensin II antagonistic action and useful e.g. for the treatment and prevention of hypertension, cardiac insufficiency, etc.

CONSTITUTION: This new adenine derivative having angiotensin II antagonistic action and useful e.g. for the treatment and prevention of hypertension, cardiac insufficiency, etc., is expressed by the formula I [R¹ is R (R is a 1-14C hydrocarbon residue) or RS; R² is amino or mono- or di-substituted amino; R³ is H or a lower alkyl; R⁴ is carboxyl, an esterified carboxyl or tetrazol-5-yl which may have a protection group at 1-site]. The adenine derivative can be produced by reacting a 9H-adenine derivative (salt) of the formula II with a 4-(2- cyanophenyl)benzyl halide of the formula III (X is an eliminable group), etc., and hydrolyzing the resultant compound of the formula IV with an acid or an alkali.

COPYRIGHT: (C)1996,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an adenine derivative, a method for producing the same, and uses thereof.

[0002]

BACKGROUND OF THE INVENTION Angiotensin II has an arterial vasoconstrictor effect by acting specifically on a receptor present in smooth muscle of blood vessels, and at the same time, mediated by vasomotor centers. To exert a pressor effect. Angiotensin II antagonists are useful for the treatment and prevention of hypertension, heart failure, etc. by suppressing these vasoconstriction and blood pressure increase. A large number of compounds having an adenine skeleton and having an angiotensin II antagonistic activity have been reported (for example, JP-A-4-234391).
JP-A-5-97851, JP-A-4-327586
No.). However, the development of more effective angiotensin II antagonists is desired. As a result of diligent research by producing a compound having a substituent at the 2-position and a side chain at the 9-position of the adenine ring, a compound having a strong antagonistic action against angiotensin II was found.

[0003]

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

[0004]

[Chemical 11] [In the formula, R ¹ represents an R- or RS- group (R represents a carbon number of 1 to 1).
14 hydrocarbon groups), R ² is an amino group or a mono- or di-substituted amino group, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ is a carboxyl group or an esterified carboxyl group or is protected at the 1-position. A tetrazin-5-yl group which may have a group] and a pharmacologically acceptable salt thereof are provided. Further provided are methods for producing the above compounds and pharmaceutical compositions containing them.

In the above formula (I), the lower alkyl group represented by R ³ has a linear or branched carbon number of 1 to
6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert.
-Butyl, pentyl, isopentyl, neopentyl, hexyl and the like, or a cyclic alkyl group having 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclohexyl and the like.

In the formula (I), the number of carbon atoms represented by R is 1
Examples of the hydrocarbon residue of to 14 include an alkyl group, an aralkyl group, an alkenyl group, an aryl group, and the like, and the alkyl group may be a linear or branched alkyl group,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, etc., or a cyclic alkyl group. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Examples of the aralkyl group include phenyl-C such as benzyl, phenethyl and 3-phenylpropyl.
_1-4 alkyl is mentioned. The alkenyl group preferably has 2 to 10 carbon atoms, such as vinyl,
Allyl, crotyl, 2-penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 3-methyl-2-buten-1-yl and the like can be mentioned. To be

The above aryl group includes a C _6-14 aryl group, for example, optionally substituted phenyl or naphthyl. Examples of the substituent in the optionally substituted phenyl group include halogen (eg, chlorine, bromine,
Fluorine, etc.), alkyl groups (eg, methyl, ethyl, propyl, butyl, etc.), hydroxy groups, alkoxy groups (eg,
Methoxy, ethoxy, propoxy, etc.), a substituted carboxy group (eg, methylcarboxy, ethylcarboxy, etc.), an amino group, a substituted amino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.). In formula (I), a mono-represented by R ²
Alternatively, specific examples of the di-substituted amino group include methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like.

In formula (I), the esterified carboxyl group represented by R ⁴ is, for example, methyl,
Examples thereof include a carboxyl group substituted with C _1-6 alkyl such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. In formula (I), examples of the protecting group for the tetrazol-5-yl group, which may have a protecting group at the 1-position represented by R ⁴ , include trityl, 2-tetrahydropyranyl, methoxymethyl, ethoxymethyl and the like. Named
A trityl group is preferred.

The object compound of the present invention and its salt can be produced, for example, by any of the following methods. The starting compound used here can be produced by a known method or a method known per se as described below. Method A

[0011]

[Chemical 12] [In the above formula, R ¹ , R ² , R ³ and R ′ have the same meanings as described above,
X represents a leaving group]

In the formula (III), the leaving group represented by X is halogen (eg, chlorine, bromine, iodine, etc.), a substituted sulfonyloxy group (eg, methanesulfonyloxy,
Benzenesulfonyloxy, p-toluenesulfonyloxy and the like). Method B

[0013]

[Chemical 13] [In the above formula, R ¹ , R ² , R ³ , R ″ and X have the same meanings as described above] Each step will be described in detail below. Hereinafter, the compound of the formula () is abbreviated as the compound ().

Method A Step 1 Compound (II) or a salt thereof is reacted with compound (III) to produce compound (I-1). The reaction is in an organic solvent,
It is carried out in the presence of a base. As the organic solvent, for example,
Examples thereof include dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile and ethylmethylketone. Also, as the base, lithium hydride,
Examples thereof include sodium hydride, potassium carbonate, sodium carbonate, potassium t-butylate, and the like, and potassium carbonate is particularly preferable. About 1 to 3 mol of the compound (III) and about 1 to 3 mol of the base are used with respect to 1 mol of the compound (II).
The reaction temperature will differ depending on the base used and the type of leaving group of compound (III), but it is usually under ice cooling to room temperature, and the reaction time is about 1 to 10 hours, preferably 1 to 4 hours.

In the compound (I), when R ⁴ is a carboxyl group, it is further subjected to a hydrolysis reaction with an acid or a base. This hydrolysis reaction is carried out according to a conventional method in a water-containing solvent in the presence of an acid or a base.

Method B Step 2 Compound (II) or a salt thereof is reacted with compound (VI) to produce compound (VII). This reaction can be carried out in exactly the same manner as in Method A, step 1. Step 3 Compound (VII) or a salt thereof is subjected to a usual hydrolysis reaction with an acid or a base to give compound (I-1) (in the formula,
R ′ = H) is obtained.

Step 4 Compound (I-2) is produced by reacting compound (VII) or a salt thereof with an azide. Examples of the azide include lithium azide, sodium azide, sodium azide and aluminum chloride, trimethylsilyl azide, trimethyltin azide, and tri-n-butyltin azide.
Particularly, trimethyltin azide and tri-n-butyltin azide are preferable. The reaction is carried out in a usual organic solvent. Examples of the organic solvent include dimethylformamide, dimethylacetamide, toluene, xylene and the like. The azide is used in an amount of about 1-5 mol per 1 mol of compound (VII). Especially when an organotin azide compound is used, it is about 1 to 4
Used in moles. The reaction temperature is about the boiling point of the solvent used, and the reaction time is about 1 to 4 days.

Step 5 Compound (II) or a salt thereof is reacted with compound (IX) to produce compound (I-3). Reaction is Method A, Step 1
Can be done in exactly the same way as. However, the compound (I
In X), when the tetrazolyl group has no protective group,
First, after adding a base to compound (II), compound (IX)
Add.

When the tetrazolyl group in the product (I-3) has a protecting group, it is further subjected to a deprotection reaction. In the deprotecting group reaction, the deprotecting reaction conditions differ depending on the type of the protecting group (R ′ ″). For example, when R '''is trityl, 2-tetrahydropyranyl, methoxymethyl or ethoxymethyl, it is used in an alcohol containing hydrochloric acid or acetic acid of about 0.5 to 2N (eg, methanol or ethanol) at room temperature. React for about 30 minutes to 1 hour.

The compound thus obtained is known per se, for example, filtration, concentration, concentration under reduced pressure, solvent extraction, phase transfer, liquid conversion, crystallization, recrystallization, distillation, sublimation, salting out, chromatography and the like. It can be isolated and purified by. Compounds (I-1) and (I-
2) and (I-3) may form a salt with a pharmacologically acceptable acid or base. Examples of such salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid,
And salts with organic acids such as methanesulfonic acid, p-tolylsulfonic acid, fumaric acid, lactic acid, citric acid and tartaric acid. When the compounds (I-1) and (I-2) have an acidic functional group (eg, carboxyl group), a salt with an inorganic base such as sodium salt, potassium salt, aluminum salt, calcium salt, Examples thereof include ammonium salts.

Further, not only pharmacologically acceptable salts but also other salts are useful, for example, when the product is isolated or purified. Further, the compounds (I-1) and (I-2) may be solvates combined with a solvent. As the solvent, water,
Examples include methanol and ethanol. The compound (I) of the present invention and its salt are excellent angiotensin compounds.
It has II antagonism and low toxicity.

Therefore, the compound (I) and its salt are
It is effective in treating or preventing angiotensin II-mediated diseases such as hypertension (essential hypertension, renal hypertension, etc.), chronic and acute heart failure, etc. by suppressing vasoconstriction and elevation of blood pressure. In addition, compound (I) and its salts are useful for treating heart diseases (eg angina, arrhythmia, myocardial infarction)
Expected to be useful as a therapeutic and / or prophylactic agent for hyperaldosteronemia, cerebral circulation disorders, senile dementia, eye diseases (eg, glaucoma, etc.), and as a diagnostic agent for testing the renin-angiotensin system. It

Thus, according to one aspect of the present invention, an angiotensin II antagonistic agent comprising the compound (I) of the present invention or a salt thereof (particularly a pharmacologically acceptable salt) as an active ingredient Will be provided. When the compound (I) of the present invention or a salt thereof is orally administered to treat hypertension, heart failure and the like, powders, granules, tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including soft capsules) ), Syrups, emulsions, suspensions and the like. Such a composition is produced by a method known per se and contains a carrier, an excipient or a diluent usually used in the field of formulation. For example, carriers for tablets, excipients, lactose, starch, sucrose, magnesium stearate, etc., binders,
Tragant gum, gum arabic, corn starch, gelatin, etc., as a crushing agent, corn starch, starch, alginic acid, etc., as a lubricant, magnesium stearate, etc., and as a sweetener, for example, sucrose, lactose or saccharin, as a flavoring agent, Examples include peppermint, orange or cherry flavors. In addition, an emulsifier, a preservative, an antioxidant and the like can be mixed if necessary.

When the compound (I) of the present invention or a salt thereof is used as a therapeutic agent for hypertension, the dose varies depending on the kind of compound, symptoms, age of patient, etc.
The daily dose for an adult is about 0.01 to 5 mg / kg body weight, preferably about
It is preferably 0.1 to 2 mg, and this amount is preferably divided into 1 to 3 times a day.

Among the starting compounds for producing the compound (I) of the present invention, the compound (II) is the compound of Journal of Organic Chemistry (J. Org. Chem.) Vol. 36,
It can be easily synthesized by the method described on page 3211 (1971) or a method analogous thereto. For example, the target compound can be produced in high yield by the method shown by the following reaction formula.

[0026]

Embedded image (In the formula, R ¹ and R ³ are defined as above)

Step 6 and Step 7 Oxazolopyrimidine (XI) synthesized by the method described in the above literature was subjected to a conventional acylation reaction to acylate the amino group at the 6-position to give compound (XII). Then, this is subjected to a reductive ring-closing reaction by catalytic reduction or a reducing agent (eg, zinc and acetic acid) to obtain an adenine derivative (II). The reaction conditions for this reductive ring-closure reaction vary depending on the reagents used, but in the case of catalytic reduction, it is carried out in the presence of a catalyst (palladium-carbon) in a suitable solvent under a hydrogen atmosphere at normal pressure to medium pressure. As the solvent, alcohols, acetic acid, etc. are used alone or as a mixed solution. Reaction temperature is room temperature to about 50
At C, the reaction time is about 1-40 hours.

Compounds (III), (IV) and (IX), which are one of the raw material compounds, are described in Journal Medical Chemistry (J. Med. Chem.) Vol. 34, 252.
5 (1991) or a method similar thereto.

[0029]

In order to demonstrate the usefulness of the compound (I) of the present invention, the pharmacological activity of typical compounds of the present invention is shown below.
[1] Test compound: 6-amino-8-butyl-9-[(2'-carboxybiphenyl-4-yl) methyl] -2-phenyl-9H-
Purine (compound) 6-amino-8-butyl-9-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]
-2-Phenyl-9H-purine (compound) 6-amino-8-butyl-9-[(2'-carboxybiphenyl-4-yl) methyl] -2-methylthio-9H
-Purine (compound) 6-amino-8-butyl-9-[(2'-1H-tetrazol-5-yl) biphenyl-4-yl) methyl]-
2-Methylthio-9H-purine (compound) [2] Inhibition of contractile response to angiotensin II in isolated guinea pig ileum by antagonists

Test method : A male guinea pig having a body weight of 300 to 500 g was bruised on the head to be sacrificed, and the ileum was immediately removed. A longitudinal section of the ileum (length: approx. 3 cm) was placed in a 20 ml organ bath filled with Tyrode's solution at 37 ° C., and a 0.5 g load was applied under aeration of mixed gas (95% O ₂ + 5% CO ₂ ). And isotonic contractions were recorded in an ink-writing recorder via an isotonic transducer. After the sample was put in the above-mentioned Tyrode's solution for 30 minutes to be stabilized, acetylcholine (3 × 10 ⁻⁸ M) was added to confirm that sufficient contraction was obtained. Then Angiotensin II
A reaction to (1 × 10 ⁻⁸ M) was obtained and the sample was washed several times. This operation was repeated several times, and after the contraction by angiotensin II was stabilized (control reaction), a reaction to angiotensin II (1 × 10 ⁻⁸ M) in the presence of the test compound was obtained. Test compound is angiotensin II 15
Added a minute ago. Inhibition of contraction by angiotensin II is expressed as a change rate (%) with respect to a control reaction, and
₅₀ (M) was determined. Test result :

[0031]

[Table 1] This Table 1 clearly demonstrates that the adenine derivative (I) or a salt thereof has an excellent angiotensin II antagonistic action.

[0032]

The present invention will be described in more detail with reference to Reference Examples, Examples and Formulation Examples, but the present invention should not be limited thereto. Reference Example 1 7-N-valerylamino-5-phenyl- [1,2,5]
Oxazolo [3,4-d] pyrimidine

[0033]

[Chemical 15]

7-amino-5-phenyl- [1,2,5]
Oxazolo [3,4-d] pyrimidine (2.15g) in pyridine solution (33ml) under ice cooling under valeryl chloride (1.4ml).
ml) was added slowly. After heating and stirring at 80 ° C. for 10 hours, the solvent was distilled off, the mixture was poured into a 0.5 N hydrochloric acid aqueous solution and extracted with chloroform, and the chloroform layer was washed successively with a saturated sodium carbonate aqueous solution and water and then dehydrated with magnesium sulfate. After the treatment with activated carbon, the solvent was distilled off to obtain a crude product of yellow crystals. The crude product was recrystallized from water-containing methanol to give the desired product as yellow crystals (1.73 g,
58%).

Elemental analysis Calculated value as C ₁₅ H ₁₅ N ₅ O ₂ C: 60.60%, H: 5.09%, N: 23.55%, measured value C: 60.79%, H: 5.13%, N: 23.60% ¹ H- NMR (CDCl ₃ ) δ: 1.02 (3H, t), 1.46-1.60 (2H, m), 1.80-
1.91 (2H, m), 3.18 (2H, t), 7.52-7.65 (3H, m), 8.54 (2H, d),
8.62 (1H, br) Reference Example 2 6-Amino-8-butyl-2-phenyl-9H-purine

[0036]

Embedded image

7-N-valerylamino-5-phenyl-
[1,2,5] Oxazolo [3,4-d] pyrimidine (1.0
10% Pd-carbon was added to an acetic acid solution (200 ml) of 5 g), the pressure was increased to 4 atm under a hydrogen atmosphere, and the mixture was stirred at room temperature for 4 hours. After removing excess hydrogen, the mixture is heated with stirring at 80 ° C. for 2 hours. After completion of the reaction, the product is filtered through Celite, and the solvent is distilled off to obtain a crude product. Recrystallize from the aqueous ethanol solution (0.8
g, 85%).

Elemental analysis Calculated value as C ₁₅ H ₁₇ N ₅ C: 67.39%, H: 6.41%, N: 26.20%, measured value C: 67.38%, H: 6.41%, N: 25.98% ¹ H-NMR ( DMSO-d ₆ ) δ: 0.93 (3H, t), 1.37-1.50 (2H, m), 1.70
-1.78 (2H, m), 2.75 (2H, t), 6.98 (2H, br), 7.38-7.46 (3H,
m), 8.28-8.31 (2H, m), 12.60 (1H, br) Reference Example 3 7-N-valerylamino-5-methylthio- [1,2,
5] -Production of Oxazolo (3,4-d] pyrimidine

[0039]

[Chemical 17]

7-amino-5-methylthio- [1,2,
5] Valeryl chloride (1.54 ml) was slowly added to a pyridine solution (35 ml) of oxazolo [3,4-d] pyrimidine (0.99 g) under ice cooling. After heating and stirring at 80 ° C. for 10 hours, the solvent was distilled off, the mixture was poured into a 0.5 N hydrochloric acid aqueous solution and extracted with chloroform, and the chloroform layer was washed successively with a saturated sodium carbonate aqueous solution and water and then dehydrated with magnesium sulfate. After the treatment with activated carbon, the solvent was distilled off to obtain a crude product of white crystals. The crude product was recrystallized from water-containing methanol to give the desired product as white crystals (0.
59 g, 41%).

Elemental analysis Calculated as C ₁₀ H ₁₃ N ₅ O ₂ S C: 44.93%, H: 4.90%, N: 26.20%, measured value C: 44.93%, H: 5.00%, N: 25.99% ¹ H -NMR (DMSO-d ₆ ) δ: 0.96 (3H, t), 1.39-1.53 (2H, m), 1.63
-1.68 (2H, m), 2.59 (3H, s), 2.74 (2H, t), 12.02 (1H, br) MS 267 (M ⁺ ), 183,85,57 Reference Example 4 5-Methylthio-7-N -Propionylamino- [1,
Production of 2,5] oxazolo [3,4-d] pyrimidine

[0042]

Embedded image

7-amino-5-methylthio- [1,2,
5] Oxazolo [3,4-d] pyrimidine (11.55 g)
Valeryl chloride (5.63 ml) was slowly added to the pyridine solution of (270 ml) under ice cooling. After heating and stirring at 80 ° C. for 10 hours, the solvent was distilled off, the mixture was poured into a 0.5 N hydrochloric acid aqueous solution and extracted with chloroform, and the chloroform layer was washed successively with a saturated sodium carbonate aqueous solution and water and then dehydrated with magnesium sulfate. After the treatment with activated carbon, the solvent was distilled off to obtain a crude product of white crystals. The crude product was recrystallized from hydrous methanol to give the desired product as white crystals (8.
106 g, 58%).

Elemental analysis Calculated value as C ₈ H ₉ N ₅ O ₂ S C: 40.16%, H: 3.79%, N: 29.27%, measured value C: 40.05%, H: 3.72%, N: 29.21% ¹ H -NMR (DMSO-d ₆ ) δ: 1.11 (3H, t), 2.50 (3H, s), 2.62-2.70
(2H, m), 11.98 (1H, br) MS 239 (M ⁺ ), 183 UV (in MeOH) 302 nm Reference Example 5 6-Amino-8-butyl-2-methylthio-9H-pre
Manufacturing

[0045]

[Chemical 19]

10% Pd-carbon was added to a solution of 7-N-valerylamino-5-methylthio- [1,2,5] oxazolo [3,4-d] pyrimidine (7.61 g) in acetic acid (500 ml) with 10% Pd-carbon. The pressure is increased to 4 atm under the atmosphere, and the mixture is stirred at room temperature for 4 hours. After removing excess hydrogen, the mixture is heated with stirring at 80 ° C. for 2 hours. After completion of the reaction, the product is filtered through Celite, and the solvent is distilled off to obtain a crude product. Recrystallization from aqueous ethanol solution (5.67
g, 84%).

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (3H, t), 1.34-1.4
5 (2H, m), 1.71-1.79 (2H, m), 2.49 (3H, s), 2.78 (2H, t), 7.08
(2H, br), 12.59 (1H, b) MS 237 (M ⁺ ), 195 UV (in MeOH) 276, 228nm Reference Example 6 6-Amino-8-ethyl-2-methylthio-9H-pri
Manufacturing

[0048]

Embedded image

10% Pd-carbon was added to an acetic acid solution (500 ml) of 7-N-propionylamino-5-methylthio- [1,2,5] oxazolo [3,4-d] pyrimidine (7.41 g), Pressurize to 4 atm under hydrogen atmosphere and stir at room temperature for 4 hours. After removing excess hydrogen, the mixture is heated with stirring at 80 ° C. for 2 hours. After completion of the reaction, the product is filtered through Celite, and the solvent is distilled off to obtain a crude product. Recrystallize from aqueous methanol (4.
36 g, 69%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (3H, t), 2.49 (3H, s), 2.76-2.84
(2H, m), 7.06 (2H, br), 12.56 (1H, br) MS 209 (M ⁺ ) UV (in MeOH) 275, 230 nm Example 1 6-Amino-8-butyl-9-[(2 ′ -Cyanobife
Nyl-4-yl) methyl] -2-phenyl-9H-pre
Manufacturing

[0050]

[Chemical 21]

A solution of 8-butyl-2-phenyl-9H-adenine (0.48 g) in dimethylformamide (hereinafter abbreviated as DMF) (20 ml) was cooled with ice while sodium hydride (60% oil, 70 mg) was added thereto. After stirring for 4 minutes, 4
-(2-Cyanophenyl) benzyl bromide (0.54g)
Was added and stirred for 4 hours. Water was added to the reaction solution, extracted with methylene chloride, washed with water, and concentrated under reduced pressure. The product was recrystallized from ethanol to obtain the desired product as white crystals (0.62 g, 75%).

Elemental analysis Calculated value as C ₂₉ H ₂₆ N ₆ C: 75.96%, H: 5.71%, N: 18.33%, measured value C: 75.97%, H: 5.83%, N: 18.16% ¹ H-NMR ( DMSO-d ₆ ) δ: 0.92 (3H, t), 1.37-1.45 (2H, m), 1.66
-1.78 (2H, m), 2.89 (2H, t), 5.64 (2H, s), 7.26 (2H, br), 7.46
-8.47 (13H, m) Example 2 6-amino-8-butyl-9-[(2'-carboxyme
Cylbiphenyl-4-yl) methyl] -2-phenyl-
Production of 9H-purine

[0053]

[Chemical formula 22]

8-butyl-2-phenyl-9H-adenine (1.34 g) in DMF solution (60 ml) was cooled with ice,
Sodium hydride (60% oil, 200 mg) was added, and the mixture was stirred for 30 min, 4- (2-carboxymethylphenyl) benzyl bromide (1.67 g) was added, and the mixture was stirred for 4 hr. Water was added to the reaction solution, extracted with methylene chloride, washed with water,
It was concentrated under reduced pressure. The product was recrystallized from ethanol to obtain the desired product as white crystals (1.83 g, 75%).

Elemental analysis Calculated as C ₃₀ H ₂₉ N ₅ O ₂ C: 73.30%, H: 5.95%, N: 14.25% Measured value C: 73.29%, H: 6.01%, N: 14.04% ¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t), 1.37-1.46 (2H, m), 1.58-
1.77 (2H, m), 2.78 (2H, t), 3.61 (3H, s), 5.42 (2H, br), 5.49
(2H, s), 7.26-8.47 (13H, m) Example 3 6-amino-8-butyl-9-[(2'-carboxybi
Phenyl-4-yl) methyl] -2-phenyl-9H-
Purine (compound) production

[0056]

[Chemical formula 23]

6-amino-8-butyl-9-[(2'-
Carboxymethylbiphenyl-4-yl) methyl] -2
-Phenyl-9H-purine (0.55g) with 10% NaOH
The solution (7 ml) and ethanol (15 ml) were heated to reflux for 4 hours. The reaction solution was filtered and concentrated, and the resulting residue was dissolved in water and acidified with 1N hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give white crystals (0.19 g, 36
%) Was obtained.

Elemental analysis Calculated as C ₂₉ H ₂₇ N ₅ O ₂ 0.6 HCl C: 69.74%, H: 5.57%, N: 14.02% Measured value C: 69.66%, H: 5.63%, N: 13.79% ¹ H -NMR (DMSO-d ₆ ) δ; 0.93 (3H, t), 1.38-1.46 (2H, m), 1.68
-1.78 (2H, m), 2.89 (2H, t), 5.60 (2H, s), 7.37-8.47 (13H,
m), 12.7 (1H, br) Example 4 6-amino-8-butyl-9-[[2 '-[(triphe
Nylmethyl) tetrazol-5-yl] biphenyl-4
Preparation of -yl] methyl] -2-phenyl-9H-purine

[0059]

[Chemical formula 24]

While cooling 8-butyl-2-phenyl-9H-adenine (1.34 g) in DMF (60 ml) with ice,
Sodium hydride (60% oil, 0.2 g) was added and the mixture was stirred for 30 minutes, and then 4-[[(triphenylmethyl) tetrazol-5-yl] phenyl] benzyl bromide (3.06
g) was added and stirred for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, and concentrated under reduced pressure. The product was purified by silica gel column chromatography to obtain the desired product as white crystals (2.60 g, 70%).

MS 743 (M ⁺ ), 420, 343, 268 Example 5 6-Amino-8-butyl-9-[(2 '-(1H-teto
Razol-5-yl) biphenyl-4-yl) methyl]
Preparation of 2-phenyl-9H-purine (compound)

[0062]

[Chemical 25]

6-amino-8-butyl-9-[[(2 '
-Triphenylmethyl) tetrazol-5-yl] biphenyl-4-yl] -2-phenyl-9H-purine (2.
23 g), 10% hydrochloric acid (100 ml) and tetrahydrofuran (hereinafter abbreviated as THF) (20 ml) were stirred at room temperature for 4 hours. An excess amount of 10% NaOH aqueous solution is added, the solvent is distilled off under reduced pressure, the residue is dissolved in water, and filtered to distill off triphenylmethanol. PH of filtrate with 3N hydrochloric acid
After adjusting to 3, the precipitated crystals are collected by filtration to obtain the desired product. Recrystallized from ethyl acetate to give white crystals (0.98%, 65%)
I got

Elemental analysis Calculated as C ₂₉ H ₂₇ N ₉ C: 69.44%, H: 5.43%, N: 25.13% Measured value C: 69.39%, H: 5.43%, N: 24.89% MS 501 (M ⁺ ). , 458, 416, 192, 179 Example 6 6-amino-8-butyl-9-[(2'-cyanobife
Nyl-4-yl) methyl] -2-methylthio-9H-propyl
Manufacture of phosphorus

[0065]

[Chemical formula 26]

Lithium hydride (19.5 mg) was added to a DMF solution (15 ml) of 8-butyl-2-methylthio-9H-adenine (0.484 g) while ice-cooling, and the mixture was stirred for 30 minutes, and then 4- (2- Cyanophenyl) benzyl bromide (0.61 g) was added, and the mixture was stirred for 12 hours. After distilling off the solvent, a crude product (0.75 g) is obtained by silica gel column chromatography (distillate; toluene; ethyl acetate = 1: 1). Recrystallization from aqueous methanol solution (0.69g, 79)
%).

¹ H-NMR (DMSO-d ₆ ) δ: 0.82 (3H, t), 1.22-1.3
4 (2H, m), 1.57-1.62 (2H, m), 2.49 (3H, d), 2.75 (2H, t), 5.41
(2H, d), 7.19 (2H, br), 7.19-7.94 (8H, m) MS 428 (M ⁺ ), 386, 192. UV (in MeOH) 268nm Example 7 6-Amino-8-butyl-9 -[(2'-Carboxyme
Cylbiphenyl-4-yl) methyl] -2-methylthio
-9H-purine production

[0068]

[Chemical 27]

While DMF solution (50 ml) of 8-butyl-2-methylthio-9H-adenine (1.64 g) was cooled with ice, potassium carbonate (500 mg) was added and stirred for 30 minutes, and then 4- (2-carboxymethyl). Phenyl) benzyl bromide (2.31 g) was added, and the mixture was stirred for 4 hours. Water was added to the reaction solution, extracted with methylene chloride, washed with water, and concentrated under reduced pressure. The product was purified by silica gel column chromatography to obtain the desired product as yellow crystals (2.89 g, 91%).

Elemental analysis Calculated value as C ₂₉ H ₂₇ N ₅ O ₂ S C: 65.05%, H: 5.90%, N: 15.17% Measured value C: 65.04%, H: 5.84%, N: 14.88% ¹ H- NMR (CDCl ₃ ) δ: 0.90 (3H, t), 1.31-1.47 (2H, m), 1.63-
1.78 (2H, m), 2.56 (3H, s), 2.73 (2H, t), 5.36 (2H, s), 7.20-
7.86 (10H, m) Example 8 6-Amino-8-butyl-9-[(2'-carboxybi
Phenyl-4-yl) methyl] -2-methylthio-9H
-Production of purines (compounds)

[0071]

[Chemical 28]

6-amino-8-butyl-9-[(2'-
Carboxymethylbiphenyl-4-yl) methyl] -2
-Methylthio-9H-purine (1.07 g) was added to 10% NaO
The mixture was heated under reflux for 16 hours in H solution (16 ml) and ethanol (31 ml). The reaction solution was filtered and concentrated, and the resulting residue was dissolved in water and acidified (pH 2) with 1N hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give white crystals (0.74 g, 69%).

Elemental analysis Calculated as C ₂₄ H ₂₅ N ₅ SO ₂ 0.5 HCl C: 61.82%, H: 5.62%, N: 15.02% Measured value C: 61.88%, H: 5.48%, N: 14.89% ¹ H -NMR (DMSO-d ₆ ) δ: 0.92 (3H, t), 1.36-1.47 (2H, m), 1.67
-1.77 (2H, m), 2.56 (3H, s), 2.83 (2H, t), 5.46 (2H, s), 7.29-
7.81 (10H, m), 12.7 (1H, br) Example 9 6-Amino-8-butyl-9-[[2 '-[(triphe
Nylmethyl) tetrazol-5-yl] biphenyl-4
Preparation of -yl] methyl] -2-methylthio-9H-purine
Construction

[0074]

[Chemical 29]

While DMF solution (50 ml) of 8-butyl-2-methylthio-9H-adenine (2.37 g) was cooled with ice, potassium carbonate (0.76 g) was added and stirred for 30 minutes, and then 4-[[(tri Phenylmethyl) tetrazole-5
-Yl] phenyl] benzyl bromide (6.14 g) was added and the mixture was stirred for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, and concentrated under reduced pressure. The product was purified by silica gel column chromatography to give the desired product as white crystals (4.59
g, 64%).

¹ H-NMR (CDCl ₃ ) δ; 0.90 (3H, t), 1.24-1.36
(2H, m), 1.67-1.77 (2H, m), 2.45 (3H, s), 2.73 (2H, t), 5.20
(2H, s), 5.43 (2H, br), 6.89-7.95 (23H, m) MS 713 (M ⁺ ), 657, 420 Example 10 6-amino-8-butyl-9-[[2 '-( 1H-Tet
Razol-5-yl) biphenyl-4-yl] methyl]
Preparation of 2-methylthio-9H-purine (compound)

[0077]

Embedded image

6-amino-8-butyl-9-[[(2 '
-Triphenylmethyl) tetrazol-5-yl] biphenyl-4-yl] -2-methylthio-9H-purine (6.40 g), 10% hydrochloric acid (60 ml) and THF (10 m).
l) was stirred at room temperature for 4 hours. Excessive 10% NaO
Aqueous H solution is added, the solvent is distilled off under reduced pressure, the residue is dissolved in water and filtered to distill off triphenylmethanol.
The filtrate was adjusted to pH 3 with 3N hydrochloric acid, and the precipitated crystals were collected by filtration to obtain the desired product. Recrystallization from ethyl acetate gave white crystals (1.64%, 54%). MS 471 (M ⁺ ), 428, 386, 192

Formulation Example 1 Tablet Compound of Example 3 (compound) 10.0 mg Lactose 100.0 mg Corn starch 50.0 mg Hydroxypropyl cellulose 7.0 mg Magnesium stearate 3.0 mg ────────────────── ───────────────── 170.0 mg

The compound (compound) obtained in Example 3, lactose and corn starch were granulated with a solution of hydroxypropyl cellulose, magnesium stearate was added,
The mixture was compressed into tablets.

Formulation Example 2 Coated tablet Compound of Example 3 (compound) 10.0 mg Lactose 60.0 mg Corn starch 35.0 mg Hydroxypropylcellulose 3.0 mg Magnesium stearate 2.0 mg ───────────────── ────────────────── 110.0 mg

A mixture of the compound (compound) obtained in Example 3, lactose and corn starch was granulated with a hydroxypropyl cellulose solution through a 1 mm mesh sieve, dried at 40 ° C. and sieved again. Magnesium stearate was mixed with the granules thus obtained and compressed. The obtained central tablets were sucrose, titanium oxide,
Coated with an aqueous suspension of talc and gum arabic. The coated tablets were polished with beeswax.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location C07D 473/34 361 (72) Inventor Yasuhiro Fujioka 1052, Taki, Koga-cho, Koga-gun, Shiga Prefecture (72) Inventor Seiji Ohara 844-1 Sanda-dong, Gifu-shi, Gifu Maison Shizu 4 E (72) Inventor Kim Jihan 990-63 Dabayashi-dong, Yeongdeungpo-gu, Seoul, Republic of Korea

Claims (8)

[Claims] 1. Formula (I): [In the formula, R ¹ represents an R- or RS- group (R represents a carbon number of 1 to 1).
14 hydrocarbon groups), R ² is an amino group or a mono- or di-substituted amino group, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ is a carboxyl group or an esterified carboxyl group or is protected at the 1-position. Group which may have a tetrazol-5-yl group] and a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, wherein the hydrocarbon group represented by R in the formula (I) is an alkyl group, an alkenyl group, an aralkyl group or an aryl group. 3. The compound according to claim 1, wherein in the formula (I), R ¹ is an aryl group or a lower alkylthio group. 4. The compound according to claim 1, wherein in the formula (I), R ⁴ is a carboxyl group or a tetrazolyl group. 5. In the formula (I), R ² is an amino group, R ³
The compound according to claim 1, wherein is a lower alkyl group. 6. 6-Amino-8-butyl-9-[(2 ′
-Carboxybiphenyl-4-yl) methyl] -2-phenyl-9H-purine, 6-amino-8-butyl-9-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl ]
-2-Phenyl-9H-purine, 6-amino-8-butyl-9-[(2'-carboxybiphenyl-4-yl) methyl] -2-methylthio-9H
-Purine, or 6-amino-8-butyl-9-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]
The compound according to claim 1, which is 2-methylthio-9H-purine or a pharmacologically acceptable salt thereof. 7. (1) Formula (II): (Wherein R ¹ , R ² and R ³ have the same meanings as defined in formula (I)) or a salt thereof, and a compound of formula (III): (In the formula, R ′ represents a hydrogen atom or a lower alkyl group, and X represents a leaving group), and the compound of the formula (I-1): A compound of formula (I)
^When a compound in which ⁴ is a carboxyl group is desired, it is subjected to hydrolysis with an acid or an alkali, or (2-a) a compound of the formula (II) or a salt thereof is added with a compound of the formula (V
I): [Chemical 5] (Wherein, X has the same meaning as above), and the resulting compound of formula (VII): (Wherein R ¹ , R ² , and R ³ have the same meanings as described above), the compound represented by the formula (I-1) (wherein R ′ is a hydrogen atom) is used for hydrolysis with an acid or an alkali. (2-b) The compound of formula (VII) is reacted with an azide to obtain a compound of formula (I-2): (Wherein Tet represents a tetrazolyl group), or (2-c) a compound of formula (II) or a salt thereof is added to formula (I
X): (Wherein R "represents a hydrogen atom or a protective group) is reacted to give a compound of the formula (I-3): (Wherein each symbol has the same meaning as described above), and further deprotecting the tetrazolyl group when there is a protecting group, the compound of formula (I) (Wherein each symbol has the same meaning as described above), and a method for producing a pharmacologically acceptable salt thereof. 8. An angiotensin II antagonistic agent comprising an adenine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.