JPH07179456A - Alkylbenzofuran derivative and angiotensin ii antagonist - Google Patents

Abstract

PURPOSE:To provide a new alkylbenzofuran derivative having angiotension II antagonism and useful for circulatory diseases such as hypertension, heart- failure, cerebral apoplexy and arteriosclerosis. CONSTITUTION:A benzofuran derivative of formula I {A is a group of formula II [R<1> and R<2> each is H, a lower alkyl, a lower alkenyl, etc.; R<3> is a lower alkyl, a hydroxy-lower alkyl, a halogen, etc.; X is O, NH, etc.; (m) is an integer of 1-2] or a group of formula III; R<4> is H, a lower alkyl, a lower alkoxy, etc.; B is carboxy or tetrazolyl; (n) is an integer of 1-2} or its salt, e.g. 4-[3- bromo-2-[2'-(triphenylmethyl tetrazol-5-yl)phenyl]benzofuran-5-yl]methoxy-5-(4- methoxy-carbonylbenzyl)-6-methyl-2-propylpyrimidine. The compound of formula I is obtained by reacting, e.g. a compound of formula IV with a compound of formula V (Y is a halogen, an alkyl-sulfonyloxy, etc.).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel alkylbenzofuran derivative and an angiotensin II antagonist containing the alkylbenzofuran derivative as an active ingredient. Since the novel alkylbenzofuran derivative according to the present invention has angiotensin II antagonistic activity, it is useful for various cardiovascular diseases such as hypertension, heart disease, stroke or arteriosclerosis.

[0002]

BACKGROUND OF THE INVENTION The renin-angiotensin system is known as a major pressor factor in the living body. That is,
Activated renin (proteolytic enzyme) secreted from the kidney acts on the renin substrate (angiotensinogen) produced in the liver to produce angiotensin I (AI). It is considered that this AI becomes angiotensin II (AII) by the angiotensin converting enzyme (ACE) produced in the lung, and this AII shows a strong pressor activity. Therefore, AII antagonists can be used for treating cardiovascular diseases such as hypertension caused by AII.

So far, [Sar ¹ , Ala ⁸ ] AII
It has been reported that many angiotensin II analogs such as (salalacin) have an AII antagonistic action, but these peptide-type AII antagonists have a short action time and have a drawback that they are not effective in oral administration. It was As the non-peptidic AII antagonist, benzofuran derivatives are disclosed in, for example, JP-A-4-217975 and JP-A-5-1864.
No. 62 and Japanese Unexamined Patent Publication No. 5-262768.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that
As a result of earnest research to obtain a non-peptide AII antagonist which has an II-antagonistic action and is orally administrable and has high safety, a group of alkylbenzofuran derivatives having a chemical structure different from those of the above-mentioned conventionally known benzofuran derivatives Have a strong AII antagonism. The present invention is based on these findings.

[0005]

Accordingly, the present invention provides a compound represented by the general formula (I):

[Chemical 4] [In the formula, A is (I-1):

[Chemical 5] [In the formula, R ¹ and R ² may be the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkenyl group,
A lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a phenyl group or a substituted phenyl group, R ³ represents a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, A sulfone group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxyalkoxycarbonyl group, a lower alkanoyloxyalkoxycarbonyl group, a tetrazolyl group, or a protected tetrazolyl group, or a compound represented by the formula —CH ₂ OR ⁵ (wherein R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an acetyl group, a phenyl group or a substituted phenyl group), and X represents O, NH or S (O ) P (in the formula, p represents an integer of 0 to 2), and m Represents an integer of 1 to 2] or is represented by the general formula (I-2):

[Chemical 6] (Wherein R ¹ , R ² , R ³ , X and m have the same meanings as described above), R ⁴ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a carboxyl group. Group, a lower alkoxycarbonyl group, B is a carboxyl group, a lower alkoxycarbonyl group, a tetrazolyl group or a protected tetrazolyl group, and n is 1
To an integer of 2] or a salt thereof. The present invention also provides an angiotensin containing a benzofuran derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
It also relates to II antagonists.

In the present specification, the lower alkyl group means
For example, it means a linear or branched alkyl group having 1 to 6 carbon atoms (particularly 1 to 4), such as a methyl group, an ethyl group,
Propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, t-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2
-Dimethylpropyl group, hexyl group, isohexyl group,
1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-
Dimethylbutyl group, 1,3-dimethylbutyl group, 2,2
-Dimethylbutyl group, 2,3-dimethylbutyl group, 3,
3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,
Examples include 2,2-trimethylpropyl group and 1-ethyl-2-methylpropyl group.

The lower alkenyl group has, for example, 2 carbon atoms.
To 6 (particularly 2 to 4) linear or branched alkenyl group, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3- Butenyl group, 1-methyl-1-propenyl group,
2-methyl-1-propenyl group, 1-methylallyl group,
2-methylallyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1
-Methyl-3-butenyl group, 2-methyl-1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3-butenyl group, 3-methyl-1-butenyl group, 3-methyl-
2-butenyl group, 3-methyl-3-butenyl group, 1,1
-Dimethylallyl group, 1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-hexenyl group, Examples thereof include a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group and a 5-hexenyl group.

Examples of the lower alkynyl group include linear or branched alkynyl groups having 2 to 6 carbon atoms (particularly 2 to 4), such as ethynyl group, 1-propynyl group, 2-propynyl group and 1-butynyl group. , 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 1 -Methyl-3
-Butynyl group, 2-methyl-3-butynyl group, 3-methyl-1-butynyl group, 1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4- Hexynyl group, 5-hexynyl group and the like can be mentioned.

As the lower alkoxy group, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms (particularly 1 to 4), for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n- Examples thereof include butoxy group, isobutoxy group, t-butoxy group, n-pentyloxy group and n-hexanoxy group. Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms (particularly 1 to 4), such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group,
n-butylthio group, isobutylthio group, sec-butylthio group, t-butylthio group, n-pentylthio group, n-
Hexylthio group and the like can be mentioned. Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

Examples of the substituent of the substituted phenyl group include a lower alkyl group having 1 to 6 carbon atoms (particularly 1 to 4) and a lower alkoxy group having 1 to 6 carbon atoms (particularly 1 to 4). , Halogen atom, nitro group, trifluoromethyl group, carboxyl group, lower alkoxycarbonyl group and the like.

The lower alkoxycarbonyl group is, for example, an alkoxycarbonyl group having 2 to 6 carbon atoms (particularly 2 to 4), such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n. -Butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, t
Examples include -butoxycarbonyl group and n-pentyloxycarbonyl group. Examples of the lower alkoxycarbonyloxyalkoxycarbonyl group include a 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl group. Examples of the lower alkanoyloxyalkoxycarbonyl group include a bivaloyloxymethoxycarbonyl group. Examples of the protecting group of the protected tetrazolyl group include a trityl group,
Examples thereof include p-nitrobenzyl group, 1-ethoxyethyl group and t-butoxycarbonyl group.

The salt of the compound (I) of the present invention includes alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, methylamine salt, ethylamine salt, triethylamine salt, pyridine salt and the like. Organic amine salts, basic amino acid salts such as lysine and arginine, ammonium salts and the like. The compound (I) of the present invention may have geometrical isomers, optical isomers or tautomers, and any single isomer or any mixture thereof is included in the present invention. .

The compound (I) of the present invention can be produced, for example, by the following various methods. (1) Reaction (a): General formula (II-1):

[Chemical 7] (Wherein R ¹ , R ² , R ³ , X and m have the same meanings as described above), or the general formula (II-2):

[Chemical 8] (Wherein R ¹ , R ² , R ³ , X and m have the same meanings as described above), and a compound represented by the general formula (III):

[Chemical 9] (Wherein Y represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, and R ⁴ , B and n have the same meanings as described above), and the above-mentioned compound of the present invention is reacted. (I) can be prepared.

In this reaction (a), the compound represented by the general formula (II-1) or (II-2) is reacted with the compound represented by the general formula (III) in the presence of a base. Thus, the compound (I) of the present invention is obtained. As the base used in the reaction, sodium hydroxide, potassium hydroxide,
Sodium hydride, sodium methoxide, sodium ethoxide, alkali metal compounds such as potassium t-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, alkali metal carbonates such as potassium hydrogen carbonate, triethylamine, diisopropylethylamine,
Organic amines such as pyridine and N, N-dimethylaminopyridine may be mentioned. Any solvent may be used as long as it does not participate in the reaction, and examples thereof include organic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dioxane, tetrahydrofuran, acetone and alcohol, or these solvents and water. Mixed solvent of. The reaction temperature is -20 to
The temperature is in the range of 200 ° C, preferably 0 to 100 ° C, and the reaction is usually completed in 1 to 48 hours.

(2) Reaction (b-1) General formula (IV-1):

[Chemical 10] (In the formula, R ⁶ represents an optionally substituted lower alkyl group, and R ² , R ³ and m have the same meanings as described above), and a compound represented by the general formula (V-1):

[Chemical 11] (Wherein R ¹ , R ⁴ , B and n have the same meanings as described above), the group A in the general formula (I) is replaced by the general formula (I-1). The present invention compound (I), that is, the present invention compound (I) in which the alkylbenzofuran moiety is bonded to the nitrogen atom of the pyrimidine ring can be prepared. This reaction (b-1)
Is a compound represented by the general formula (IV
It can be carried out by reacting the compound represented by -1) with the compound represented by the general formula (V-1) in the presence of the same base as described above.

(3) Reaction (b-2) General formula (IV-2):

[Chemical 12] (In the formula, W represents a halogen atom, and R ¹ , R ² , R ³ and m have the same meanings as described above), and a compound represented by the general formula (V-2):

[Chemical 13] (In the formula, Z represents a hydroxyl group, an amino group or a sulfhydryl group, and R ⁴ , B and n have the same meanings as described above), and a compound represented by the formula (I) It is possible to prepare the compound (I) of the present invention in which A is the general formula (I-2), that is, the compound (I) of the present invention in which the alkylbenzofuran moiety is bonded to the pyrimidine moiety via the group X. This reaction (b-2)
Is a compound represented by the general formula (IV
It can be carried out by reacting the compound represented by -2) with the compound represented by the general formula (V-2) in the presence of the same base as described above.

(4) Reaction (c): A compound in which the group B is a cyano group in the above general formula (I) is used as a starting material, and the starting material is reacted with various azides in an organic solvent, Compounds in which the group B in the general formula (I) is a tetrazolyl group can be prepared. In this reaction (c), about 1 to 3 mol of an azide compound is used with respect to 1 mol of the starting material, and usually, it can be carried out in a solvent such as N, N-dimethylformamide, dimethylacetamide, toluene or benzene. . As an azide compound,
Trialkyltin azide or triphenyltin azide, hydrazoic acid, etc. can be used.

When an organic tin azide compound is used, it can be reacted in toluene or benzene while heating under reflux for about 10 to 30 hours. When hydrazoic acid is reacted, sodium azide and ammonium chloride are used in an amount of about 2 times the molar amount of the starting material, and the reaction is performed in dimethylformamide at about 100 to 130 ° C. for about 1 to 3 days. You can During this period, it is preferable to accelerate the reaction by adding appropriate amounts of sodium azide and ammonium chloride.

(5) Reaction (d): converting the compound of the general formula (I) in which the group B is a lower alkoxycarbonyl group into a compound of the general formula (I) in which the group B is a free carboxyl group. You can In this reaction (d), a carboxylic acid ester compound is hydrolyzed in the presence of an alkali to obtain a free carboxylic acid compound. Using 1 to 3 mol of alkali to 1 mol of the carboxylic acid ester compound as a starting material, usually,
It can be carried out in a solvent such as alcohols including water (eg, methanol, ethanol, methyl cellosolve, etc.). As the alkali, sodium hydroxide, potassium hydroxide or the like can be used. The reaction temperature is
The temperature is in the range of room temperature to 100 ° C., and the reaction is usually preferably performed for about 1 to 10 hours.

(6) Reaction (e): In the general formula (I), the group B is a protecting group (eg, trityl group, p-nitrobenzyl group, p-methoxybenzyl group, methoxymethyl group, 1-ethoxyethyl group). Group, 2-cyanoethyl group or t
The compound which is a tetrazolyl group substituted with —butoxycarbonyl group) can be converted to a compound in which the group B is a tetrazolyl group in the general formula (I) by removing the protecting group. Deprotection of this reaction (e) is
It can be performed in the presence of an acid. The reaction is usually 0.5 to
It is preferably carried out in a hydroalcohol containing about 2N hydrochloric acid or acetic acid (eg, methanol, ethanol, etc.) or in trifluoroacetic acid at room temperature to about 50 ° C. for about 1 to 10 hours.

(7) Reaction (f): Conversion from the compound of the general formula (I) in which the group R ³ is a lower alkoxycarbonyl group to the compound of the general formula (I) in which the group R ³ is a free carboxyl group. can do. In this reaction (f), a carboxylic acid ester compound is hydrolyzed in the presence of an alkali to obtain a free carboxylic acid compound. Using about 1 to 3 mol of alkali with respect to 1 mol of the carboxylic acid ester compound as a starting material, and usually performed in a solvent such as alcohols containing water (eg, methanol, ethanol, methyl cellosolve, etc.) You can As the alkali, sodium hydroxide, potassium hydroxide or the like can be used. The reaction temperature is
The temperature is in the range of room temperature to 100 ° C., and the reaction is usually preferably performed for about 1 to 10 hours.

(8) Reaction (g): Conversion from a compound in which the group R ³ is a lower alkoxycarbonyl group in the above general formula (I) to a compound in which the group R ³ in the above general formula (I) is a hydroxymethyl group. can do. In this reaction (g), a hydroxymethyl compound is obtained by reducing a carboxylic acid ester compound. The reaction is carried out by a known method, for example, K. Soai et al., Bull. C
hem. Soc. Jpn. 57.1948 (198
4), G.I. Kototos, Synthesis. 29
9 (1990) and the like.

That is, it can be carried out by using an excess of the reducing agent in an amount of about 1 to 5 mol per 1 mol of the carboxylic acid ester compound as the starting material. Examples of the reducing reagent used in the reaction include lithium aluminum hydride, sodium borohydride, and homologues thereof, and in some cases, a suitable Lewis acid (eg, aluminum chloride or cesium chloride) may coexist. Any solvent may be used as long as it does not participate in the reduction, and examples thereof include tetrahydrofuran, diethyl ether, dioxane, methanol, ethanol, dichloromethane and the like. The reaction temperature is in the range of -20 to 100 ° C, preferably -10 to 60 ° C, and the reaction is usually completed in 30 minutes to 5 hours.

(9) Reaction (h): The compound represented by the general formula (I) wherein the group R ³ is a hydroxymethyl group is subjected to alkylation in the presence of a base to act an alkylating agent. It is possible to prepare compounds in (I) in which the group R ³ is a lower alkoxymethyl group.

In this reaction (h), 1 to 3 mol of a base and 1 to 3 mol of an alkylating agent are used per 1 mol of a hydroxymethyl compound as a starting material, and usually N, N-dimethylformamide or dimethyl is used. It can be carried out in a solvent such as sulfoxide, acetonitrile, acetone or ethyl methyl ketone. As the base, for example, sodium hydride, potassium t-butoxy, potassium carbonate, sodium carbonate and the like can be used. As the alkylating agent, an alkyl halide (eg, alkyl chloride, alkyl bromide or iodide), a substituted sulfonic acid alkyl ester (eg, methyl p-toluenesulfonate, etc.) and the like can be used. The reaction conditions will differ depending on the combination of the base and alkylating agent used, but it is generally preferable to carry out under ice cooling to room temperature for about 1 to 48 hours.

The starting compounds used in the above various reaction steps are known compounds or can be synthesized according to known methods. For example, general formulas (II-1) and (II-
The pyrimidine derivative represented by 2) is disclosed in JP-A-3-13
It can be manufactured according to the method described in Japanese Patent No. 3964. Further, the benzofuran derivative represented by the general formula (III) can be produced according to the method described in JP-A-4-217975. The compound of the present invention represented by the general formula (I) synthesized by the above-mentioned synthetic method is purified by a conventional purification method such as recrystallization, reprecipitation, solvent extraction, silica gel column chromatography, column chromatography with an adsorptive resin and the like. can do.

Since the compound (I) of the present invention has an excellent angiotensin II antagonistic action and is highly safe, it can be used as an angiotensin II antagonist for the treatment of various cardiovascular diseases. Examples of the cardiovascular disease include hypertension, heart disease, stroke or arteriosclerosis, and are also useful as therapeutic agents for ocular hypertension.

The angiotensin II antagonist containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is orally or parenterally (eg, intramuscular injection, intravenous injection, subcutaneous injection, rectal injection). Administration, transdermal administration, etc.), and by incorporating a pharmaceutically acceptable auxiliary agent, tablets, capsules, granules, powders, pills, fine granules, injections, rectal administration agents, suppositories, etc. Can be Pharmaceutically acceptable auxiliary agents include excipients, binders, disintegrating agents, lubricants, buffers, preservatives, solubilizing agents, preservatives, flavoring agents, soothing agents, stabilizers, and coloring agents. And the like, and these can be appropriately combined and used according to a conventional method.

The excipients are lactose, sucrose, glucose, sorbitol, corn starch, crystalline cellulose and the like, the binders are cellulose derivatives, gum arabic, gelatin, polyvinyl alcohol, polyvinyl ether and the like, and the disintegrants are carboxymethyl cellulose calcium. As a lubricant, talc, magnesium stearate, polyethylene glycol, etc., and as a preservative, methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, etc. Polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, maglogol, etc. as flavoring agents, cocoa powder, peppermint oil, cinnamon powder, etc. Sodium sulfite as a stabilizing agent, sodium metabisulfite, etc. ethers.

The angiotensin II antagonist of the present invention comprises a compound represented by the above-mentioned general formula (I) which is an active ingredient or a pharmacologically acceptable salt thereof, and angiotensin II
It is contained in an amount effective for antagonistic activity, for example, 5 to 100% by weight, preferably 25 to 100% by weight. The dose varies depending on the age, weight, sex, symptoms, administration method, administration period, therapeutic effect, etc., but in the case of oral administration, it is usually 1 to 1000 mg, preferably 5 to 200 mg per day for an adult, and this is usually It is administered in 1 to 3 divided doses.

[0031]

The present invention will be described in detail below with reference to examples, but these do not limit the scope of the present invention. Reference Example 1: 5- (4-methoxycarbonylbenzyl)-
6-methyl-2-propylpyrimidine-4 (3H) -o
Preparation of sodium methoxide 2.70 g anhydrous methanol 60
Dissolved in ml, 6.13 g of n-propylamidine hydrochloride
Was added and the mixture was stirred at room temperature for 10 minutes, then 6.13 g of ethyl 2- (4-methoxycarbonylbenzyl) -3-oxobutanoate and 60 ml of anhydrous methanol were added, and the mixture was heated to 50 ° C.
Stirred overnight. The solvent was distilled off under reduced pressure, water was added, and 1
The mixture was made weakly acidic with N hydrochloric acid and then extracted twice with ethyl acetate.
The ethyl acetate extract layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with n-hexane to give the title compound 4.6.
9 g was obtained. Yield: 63% Melting point: 210 ° C (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, t,
J = 7.4 Hz), 1.70-1.85 (2H, m),
2.34 (3H, s), 2.56-2.63 (2H,
m), 3.89 (3H, s), 3.94 (2H, s),
7.32 (2H, d, J = 8.6Hz), 7.93 (2
H, d, J = 8.6 Hz) IR (KBr) cm ⁻¹ : 1725, 1660, 160
5,1275 MS (FAB) m / z: 301 (M + 1)

Reference Examples 2-5 Based on the method of Reference Example 1, the following compounds shown in Reference Examples 2-5 were prepared. Reference Example 2: 2-butyl-5- (4-methoxycarbonyl)
Benzyl) -6-methylpyrimidin-4 (3H) -one Yield: 60% Melting point: 195-197 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t,
J = 7.3 Hz), 1.30-1.44 (2H, m),
1.67-1.80 (2H, m), 2.32 (3H,
s), 2.61 (2H, t, J = 7.8Hz), 3.8
9 (3H, s), 3.94 (2H, s), 7.32 (2
H, d, J = 8.1 Hz), 7.93 (2H, d, J =
8.1 Hz) IR (KBr) cm ^-1 : 1725, 1660, 160
5,1275 MS (FAB) m / z: 315 (M + 1)

Reference Example 3: 2,6-diethyl-5- (3-
Methoxycarbonylbenzyl) pyrimidine-4 (3H)
- one Yield: 70% ^{mp: 133~135 ℃ 1 H-NMR (} CDCl 3) δ: 1.15 (3H, t,
J = 7.6 Hz), 1.29 (3H, t, J = 7.4H
z), 2.58-2.66 (4H, m), 3.89 (3
H, s), 3.94 (2H, s), 7.26-7.46.
(2H, m), 7.84-7.93 (2H, m) IR (KBr) cm ^-1 : 1720,1660,160
0.1275 MS (FAB) m / z: 301 (M + 1)

Reference Example 4: 5- (3-methoxycarbonyl)
Benzyl) -6-methyl-2-propylpyrimidine-4
(3H) -one Yield: 65% Melting point: 161-162 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, t,
J = 7.3 Hz), 1.65-1.82 (2H, m),
2.34 (3H, s), 2.59 (2H, t, J = 7.
7Hz), 3.89 (3H, s), 3.93 (2H,
s), 7.26-7.48 (2H, m), 7.85-
7.92 (2H, m) IR (KBr) cm ^-1 : 1725,1670,160
0,1280 MS (FAB) m / z: 301 (M + 1)

Reference Example 5: 2-butyl-5- (3-methoxy)
Cycarbonylbenzyl) -6-methylpyrimidine-4
(3H) -one yield: 80% Melting point: 171-173 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t,
J = 7.3 Hz), 1.33-1.41 (2H, m),
1.68-1.79 (2H, m), 2.33 (3H,
s), 2.61 (2H, t, J = 7.8Hz), 3.8
9 (3H, s), 3.93 (2H, s), 7.26-
7.47 (2H, m), 7.85-7.92 (2H,
m) IR (KBr) cm ⁻¹ : 1720, 1660, 160
0,1280 MS (FAB) m / z: 315 (M + 1)

Example 1: 4- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methoxy-5- (4-
Methoxycarbonylbenzyl) -6-methyl-2-pro
Preparation of Pyrpyrimidine 0.72 g of the compound obtained in Reference Example 1, 1.62 g of 5-bromomethyl-2- [2 '-(triphenylmethyltetrazol-5-yl) phenyl] benzofuran and 0.34 g of potassium carbonate Was suspended in 20 ml of dry DMF (N, N-dimethylformamide), and the mixture was heated with stirring at 80 ° C. for 48 hours. After the reaction is completed, the reaction solution is concentrated,
20 ml of water was added, and the mixture was extracted twice with 100 ml of ethyl acetate. The ethyl acetate extract layer was washed with water and saturated saline,
It was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was added to n-hexane: ethyl acetate (3:
Purified by silica gel column chromatography eluting with system 1) to give the title compound 0.4 as amorphous.
6 g was obtained. Yield: 21% Melting point: 144-146 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t,
J = 7.3 Hz), 1.80-1.91 (2H, m),
2.40 (3H, s), 2.80 (2H, t, J = 7.
7Hz), 3.86 (3H, s), 3.99 (2H,
s), 5.50 (2H, s), 6.83-7.10 (6
H, m), 7.16 (2H, d, J = 8.1 Hz),
7.20-7.29 (11H, m), 7.44-7.7
2 (4H, m), 7.89 (2H, d, J = 8.1H
z), 8.19-8.23 (1H, m) IR (KBr) cm ^-1 : 1720, 1565, 128
0,750 MS (FAB) m / z: 897 (M + 2)

Example 2: 3- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methyl-5- (4-me
Toxycarbonylbenzyl) -6-methyl-2-propyi
Preparation of lupyrimidin-4-one In the purification of the reaction product of Example 1 by silica gel column chromatography, 0.49 g of the title compound was obtained from the eluate of n-hexane: ethyl acetate (2: 1) system. Yield: 23% Melting point: 105-107 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t,
J = 7.3 Hz), 1.64-1.74 (2H, m),
2.34 (3H, s), 2.58 (2H, t, J = 7.
7Hz), 3.88 (3H, s), 4.03 (2H,
s), 5.40 (2H, s), 6.83-6.97 (6)
H, m), 7.10-7.26 (12H, m), 7.3.
8 (2H, d, J = 8.6 Hz), 7.54-7.71
(3H, m), 7.95 (2H, d, J = 8.3H
z), 8.20-8.23 (1H, m) IR (KBr) cm ^-1 : 1720, 1655, 165.
0,1280 MS (FAB) m / z: 895 (M)

Examples 3 to 10 In accordance with the methods of Examples 1 and 2, the following Examples 3 to 1
0 compound was obtained.

Example 3: 4- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methoxy-2-butyl
-5- (4-methoxycarbonylbenzyl) -6-methyl
Le pyrimidine Yield: 20% Melting ^{point: 147~149 ℃ 1 H-NMR (} CDCl 3) δ: 0.97 (3H, t,
J = 7.3 Hz), 1.40-1.48 (2H, m),
1.77-1.88 (2H, m), 2.40 (3H,
s), 2.82 (2H, t, J = 7.8Hz), 3.8
6 (3H, s), 3.99 (2H, s), 5.51 (2
H, s), 6.83-6.87 (6H, m), 6.97.
-7.23 (12H, m), 7.44-7.72 (5
H, m), 7.87-7.91 (2H, m), 8.19.
-8.23 (1H, m) IR (KBr) cm ^-1 : 1720, 1575, 128
0,750 MS (FAB) m / z: 909 (M)

Example 4: 3- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methyl-2-butyl-
5- (4-methoxycarbonylbenzyl) -6-methyl
Pyrimidin-4-one Yield: 19% Melting point: 103-105 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t,
J = 7.3 Hz), 1.23 to 1.39 (2H, m),
1.63-1.71 (2H, m), 2.34 (3H,
s), 2.61 (2H, t, J = 7.8Hz), 3.8
8 (3H, s), 4.03 (2H, s), 5.40 (2
H, s), 6.83-6.98 (6H, m), 7.10.
-7.26 (12H, m), 7.38 (2H, d, J =
8.1 Hz), 7.54-7.71 (3H, m), 7.
95 (2H, d, J = 8.1Hz), 8.20-8.2
3 (1H, m) IR (KBr) cm ^-1 : 1720, 1650, 154
0,1280 MS (FAB) m / z: 909 (M)

Example 5: 4- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methoxy-2,6-di
Ethyl-5- (3-methoxycarbonylbenzyl) pyri
Midine yield: 18% Melting point: 73-75 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t,
J = 7.6 Hz), 1.26 (3H, t, J = 7.1H)
z), 2.71 (2H, q, J = 7.6Hz), 2.8
6 (2H, q, J = 7.6Hz), 3.85 (3H,
s), 4.00 (2H, s), 5.51 (2H, s),
6.83-6.88 (6H, m), 6.96-7.29
(14H, m), 7.44-7.84 (5H, m),
8.19-8.22 (1H, m) IR (KBr) cm ^-1 : 1720, 1445, 128
5,750 MS (FAB) m / z: 896 (M + 1)

Example 6: 3- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methyl-2,6-die
Cyl-5- (3-methoxycarbonylbenzyl) pyrimi
Zin-4-one Yield: 19% Melting point: 84-86 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t,
J = 7.3 Hz), 1.19 (3H, t, J = 7.4H)
z), 2.60 (2H, q, J = 7.3 Hz), 2.6
5 (2H, q, J = 7.6Hz), 3.88 (3H,
s), 4.05 (2H, s), 5.40 (2H, s),
6.80-6.94 (8H, m), 7.09-7.23
(5H, m), 7.26 (4H, s), 7.34-7.
70 (6H, m), 7.85-7.97 (2H, m),
8.20-8.23 (1H, m) IR (KBr) cm ^-1 : 1720, 1655, 145
0.1285 MS (FAB) m / z: 895 (M)

Example 7: 4- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methoxy-5- (3-
Methoxycarbonylbenzyl) -6-methyl-2-pro
Pill pyrimidine Yield: 20% Melting ^{point: 112~114 ℃ 1 H-NMR (} CDCl 3) δ: 1.02 (3H, t,
J = 7.5 Hz), 1.87 (2H, q, J = 7.6H)
z), 2.41 (3H, s), 2.80 (2H, t, J
= 7.6 Hz), 3.85 (3H, s), 3.98 (2
H, s), 5.52 (2H, s), 6.83-6.89.
(6H, m), 6.98-7.29 (12H, m),
7.42-7.72 (5H, m), 7.82-7.85
(2H, m), 8.19-8.22 (1H, m) IR (KBr) cm ^-1 : 1720, 1575, 144
5,1285 MS (FAB) m / z: 895 (M)

Example 8: 3- [3-Bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methyl-5- (3-me
Toxycarbonylbenzyl) -6-methyl-2-propyi
Lupyrimidin -4-one Yield: 15% Melting point: 106-108 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t,
J = 7.3 Hz), 1.70-1.80 (2H, m),
2.38 (3H, s), 2.60-2.69 (2H,
m), 3.88 (3H, s), 4.01 (2H, s),
5.40 (2H, s), 6.83-6.98 (6H,
m), 7.10-7.36 (12H, m), 7.50-
7.70 (5H, m), 7.85-7.96 (2H,
m), 8.19-8.22 (1H, m) IR (KBr) cm ^-1 : 1720, 1655, 144
5,1285 MS (FAB) m / z: 895 (M)

Example 9: 4- [3-bromo-2- [2 '
-(Triphenylmethyltetrazol-5-yl) phen
Nyl] benzofuran-5-yl] methoxy-2-butyl
-5- (3-methoxycarbonylbenzyl) -6-methyl
Lupyrimidine yield: 19% Melting point: 101-103 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t,
J = 7.3 Hz), 1.40-1.48 (2H, m),
1.77-1.88 (2H, m), 2.41 (3H,
s), 2.82 (2H, t, J = 7.8Hz), 3.8
5 (3H, s), 3.98 (2H, s), 5.52 (2
H, s), 6.83-6.86 (7H, m), 6.97.
-7.29 (12H, m), 7.45-7.72 (4
H, m), 7.82-7.85 (2H, m), 8.19.
-8.22 (1H, m) IR (KBr) cm ^-1 : 1720, 1445, 128
5,750 MS (FAB) m / z: 910 (M + 1)

Example 10: 3- [3-bromo-2-
[2 '-(triphenylmethyltetrazol-5-i
Lu) phenyl] benzofuran-5-yl] methyl-2-
Butyl-5- (3-methoxycarbonylbenzyl) -6
-Methylpyrimidin -4-one Yield: 18% Melting point: 90-92 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t,
J = 7.3 Hz), 1.23 to 1.38 (2H, m),
1.61-1.71 (2H, m), 2.35 (3H,
s), 2.60 (2H, t, J = 7.9Hz), 3.8
8 (3H, s), 4.02 (2H, s), 5.40 (2
H, s), 6.83-6.98 (6H, m), 7.05.
-7.36 (12H, m), 7.50-7.71 (5
H, m), 7.85-7.97 (2H, m), 8.19.
-8.22 (1H, m) IR (KBr) cm ^-1 : 1720, 1655, 144
5,1285 MS (FAB) m / z: 909 (M)

Example 11: 4- [3-bromo-2-
[2 '-(1H-tetrazol-5-yl) phenyl
Lu] benzofuran-5-yl] methoxy-5- (4-carboxyl)
Ruboxybenzyl) -6-methyl-2-propylpyrimy
Preparation of gin 0.42 g of the compound obtained in Example 1 above was dissolved in 10 ml of methanol, a few drops of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours. Then, 4.0 ml of 1N-NaOH was added,
The mixture was heated under reflux for 7 hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, 30 ml of water was added to the obtained residue, and the insoluble material was collected by filtration. The pH of the obtained aqueous solution was adjusted to 4 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration to give the title compound (0.1 mg) as a white powder.
27 g was obtained. Yield: 94% Melting point: 141-143 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H,
t, J = 7.3 Hz), 1.72-1.83 (2H,
m), 2.37 (3H, s), 2.73 (2H, t, J
= 7.6 Hz), 4.02 (2H, s), 5.57 (2
H, s), 7.23 (2H, d, J = 8.3 Hz),
7.36-7.45 (2H, m), 7.52-7.53
(1H, m), 7.83 (2H, d, J = 8.5H
z), 7.73-7.96 (4H, m) IR (KBr) cm ^-1 : 1610, 1570, 141
5,1350 MS (FAB) m / z: 641 (M + 2)

Examples 12 to 20 According to the method described in Example 11 above, the compounds described in Examples 12 to 20 below were obtained.

Example 12: 3- [3-Bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methyl-5- (4-carboxyl
Cibenzyl) -6-methyl-2-propylpyrimidine-
4-one yield: 94% melting point: 150-152 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.88 (3H,
t, J = 7.3 Hz), 1.60-1.68 (2H,
m), 2.25 (3H, s), 2.68 (2H, t, J
= 7.3 Hz), 3.94 (2H, s), 5.44 (2
H, s), 7.22-7.26 (2H, m), 7.34.
(2H, d, J = 8.3 Hz), 7.48 (1H, d,
J = 8.1 Hz), 7.73-7.96 (6H, m) IR (KBr) cm ^-1 : 2960,1705,165.
0.1540 MS (FAB) m / z: 639 (M)

Example 13: 4- [3-bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methoxy-2-butyl-5-
(4-Carboxybenzyl) -6-methylpyrimidine Yield: 98% Melting point: 135-137 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H,
t, J = 7.3 Hz), 1.28-1.42 (2H,
m), 1.68-1.79 (2H, m), 2.36 (3
H, s), 2.74 (2H, t, J = 7.6 Hz),
4.02 (2H, s), 5.56 (2H, s), 7.2
3 (2H, d, J = 8.3 Hz), 7.36-7.45
(2H, m), 7.51-7.52 (1H, m), 7.
83 (2H, d, J = 8.3 Hz), 7.73-7.9.
6 (4H, m) IR (KBr) cm ^-1 : 1610, 1575, 141
5,1350 MS (FAB) m / z: 655 (M + 2)

Example 14: 3- [3-Bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methyl-2-butyl-5-
(4-Carboxybenzyl) -6-methylpyrimidine-
4-one yield: 91% melting point: 143-145 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.82 (3H,
t, J = 7.3 Hz), 1.24-1.37 (2H,
m), 1.53 to 1.64 (2H, m), 2.25 (3
H, s), 2.70 (2H, t, J = 7.6 Hz),
3.94 (2H, s), 5.44 (2H, s), 7.2
3-7.27 (2H, m), 7.34 (2H, d, J =
8.3 Hz), 7.48 (1H, d, J = 8.3H)
z), 7.73-7.96 (6H, m) IR (KBr) cm ^-1 : 1710, 1650, 161.
0.1535 MS (FAB) m / z: 655 (M + 2)

Example 15: 4- [3-bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methoxy-5- (3-carbo
Xybenzyl) -2,6-diethylpyrimidine Yield: 98% Melting point: 120 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (3H,
t, J = 7.6 Hz), 1.18 (3H, t, J = 7.
1Hz), 2.69 (2H, q, J = 7.5Hz),
2.79 (2H, q, J = 7.6Hz), 4.03 (2
H, s), 5.56 (2H, s), 7.32-7.53.
(5H, m), 7.72-7.96 (6H, m) IR (KBr) cm < ^-1 >: 1610,1570,142.
0.1350 MS (FAB) m / z: 641 (M + 2)

Example 16: 3- [3-bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methyl-5- (3-carboxyl
Cibenzyl) -2,6-diethylpyrimidin-4-one Yield: 85% Melting point: 133-135 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.10 (3H,
t, J = 7.3 Hz), 1.15 (3H, t, J = 7.
1Hz), 2.57 (2H, q, J = 7.5Hz),
2.74 (2H, q, J = 7.2Hz), 3.96 (2
H, s), 5.45 (2H, s), 7.20-7.48.
(5H, m), 7.73-7.97 (6H, m) IR (KBr) cm ^-1 : 1705, 1635, 154
0.1450 MS (FAB) m / z: 641 (M + 2)

Example 17: 4- [3-Bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methoxy-5- (3-carbo
Xybenzyl) -6-methyl-2-propylpyrimidine Yield: 98% Melting point: 136-138 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H,
t, J = 7.3 Hz), 1.74-1.83 (2H,
m), 2.37 (3H, s), 2.69-2.75 (2
H, m), 4.01 (2H, s), 5.56 (2H,
s), 7.33-7.54 (5H, m), 7.73-
7.78 (4H, m), 7.85-7.90 (1H,
m), 7.94-7.98 (1H, m) IR (KBr) cm ^-1 : 1570, 1445, 142
0.1350 MS (FAB) m / z: 641 (M + 2)

Example 18: 3- [3-Bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methyl-5- (3-carboxyl
Cibenzyl) -6-methyl-2-propylpyrimidine-
4-one yield: 98% melting point: 168-170 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.88 (3H,
t, J = 7.3 Hz), 1.60-1.68 (2H,
m), 2.26 (3H, s), 2.65-2.74 (2
H, m), 3.94 (2H, s), 5.45 (2H,
s), 7.20-7.29 (2H, m), 7.35-
7.48 (3H, m), 7.72-7.77 (3H,
m), 7.83-7.87 (2H, m), 7.95-
7.98 (1H, m) IR (KBr) cm ^-1 : 1705, 1650, 154
0.1445 MS (FAB) m / z: 639 (M)

Example 19: 4- [3-bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methoxy-2-butyl-5-
(3-Carboxybenzyl) -6-methylpyrimidine Yield: 98% Melting point: 132-134 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H,
t, J = 7.3 Hz), 1.28-1.42 (2H,
m), 1.69-1.80 (2H, m), 2.39 (3
H, s), 2.76 (2H, t, J = 7.6 Hz),
4.02 (2H, s), 5.58 (2H, s), 7.3
3-7.53 (4H, m), 7.63-7.80 (5
H, m), 7.85-7.96 (2H, m) IR (KBr) cm ^-1 : 1575, 1445, 142
0.1350 MS (FAB) m / z: 655 (M + 2)

Example 20: 3- [3-Bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methyl-2-butyl-5-
(3-Carboxybenzyl) -6-methylpyrimidine-
4-one yield: 93% melting point: 143-145 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.81 (3H,
t, J = 7.3 Hz), 1.26-1.34 (2H,
m), 1.52-1.61 (2H, m), 2.25 (3
H, s), 2.69 (2H, t, J = 7.6 Hz),
3.93 (2H, s), 5.45 (2H, s), 7.2
1-7.48 (4H, m), 7.75-7.96 (7
H, m) IR (KBr) cm ^-1 : 1705, 1650, 154
0.1445 MS (FAB) m / z: 655 (M + 2)

Example 21: 4- [3-bromo-2-
[2 '-(triphenylmethyltetrazol-5-i
Lu) phenyl] benzofuran-5-yl] methoxy-5
-(3-Hydroxymethylbenzyl) -6-methyl-2
-Preparation of propylpyrimidine To a solution of 1.36 g of the compound obtained in Example 17 above in 50 ml of methylene chloride was added triphenylmethyl chloride.
65 g and triethylamine 0.53 ml were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off and the obtained residue was used in the next reaction without purification. The obtained N-trityl compound was dried with THF (tetrahydrofuran) 1
It was dissolved in 5 ml and stirred at -10 ° C for 10 minutes. Next, 0.28 ml of N-methylmorpholine and 0.27 ml of ethyl chloroformate were added at the same temperature, and the mixture was further stirred for 10 minutes. After stirring, 0.28 g of sodium borohydride was rapidly added at the same temperature, and the reaction solution was warmed to 0 ° C.
Then, 35 ml of dry methanol was gradually added dropwise to the reaction solution at the same temperature, and the mixture was stirred for 15 minutes. After completion of the reaction, the reaction solution was concentrated, 20 ml of water was added, and the mixture was extracted twice with 150 ml of ethyl acetate. The ethyl acetate extract layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography eluting with n-hexane: ethyl acetate (3: 2) system to obtain 0.71 g of the title compound as an amorphous substance. Yield: 39% Melting point: 83-85 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t,
J = 7.3 Hz), 1.80-1.91 (2H, m),
2.41 (3H, s), 2.80 (2H, t, J = 7.
7Hz), 3.95 (2H, s), 4.53 (2H,
s), 5.52 (2H, s), 6.85-6.89 (6)
H, m), 7.00-7.26 (15H, m), 7.4.
9-7.63 (3H, m), 7.69-7.72 (1
H, m), 8.18-8.21 (1H, m) IR (KBr) cm ^-1 : 3420, 1570, 144
5,700 MS (FAB) m / z: 869 (M + 2)

Example 22: 4- [3-bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methoxy-5- (3-hydro
Xymethylbenzyl) -6-methyl-2-propylpyri
Preparation of Midine 0.70 g of the compound obtained in Example 21 above was added to methanol.
It was dissolved in 10 ml of water, a few drops of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours. Then, 4 ml of 1N-NaOH was added, the reaction mixture was concentrated to dryness under reduced pressure, and 20 ml of water was added to the obtained residue.
Was added and the insoluble matter was collected by filtration. The pH of the obtained aqueous solution was adjusted to 4 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 0.36 g of the title compound as a white powder. Yield: 71% Melting point: 123-125 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H,
t, J = 7.3 Hz), 1.74-1.82 (2H,
m), 2.36 (3H, s), 2.69-2.74 (2
H, m), 3.93 (2H, s), 4.41 (2H,
s), 5.56 (2H, s), 6.95-6.98 (1
H, m), 7.10-7.20 (3H, m), 7.39.
-7.47 (2H, m), 7.58-7.59 (1H,
m), 7.73-7.80 (2H, m), 7.87-
7.96 (2H, m) IR (KBr) cm ^-1 : 1570, 1445, 142
0.1350 MS (FAB) m / z: 625 (M)

Example 23: 3- [3-Bromo-2-
[2 '-(triphenylmethyltetrazol-5-i
Lu) phenyl] benzofuran-5-yl] methyl-5-
(3-Hydroxymethylbenzyl) -6-methyl-2-
Preparation of propylpyrimidin-4-one To a solution of 1.00 g of the compound obtained in Example 18 above in 50 ml of methylene chloride was added triphenylmethyl chloride.
48 g and triethylamine 0.38 ml were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off and the obtained residue was used in the next reaction without purification. The obtained N-trityl compound is dried THF (tetrahydrofuran)
It was dissolved in 15 ml and stirred at -10 ° C for 10 minutes. Next, 0.21 ml of N-methylmorpholine and 0.20 ml of ethyl chloroformate were added at the same temperature, and the mixture was further stirred for 10 minutes. After stirring, 0.22 g of sodium borohydride was rapidly added at the same temperature, and the reaction solution was warmed to 0 ° C. Next, at the same temperature, 35m of dry methanol was added to the reaction
1 was gradually added dropwise and stirred for 15 minutes. After the reaction was completed, the reaction solution was concentrated, 20 ml of water was added, and 150 m of ethyl acetate was added.
Extracted twice with 1. The ethyl acetate extract layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography eluting with n-hexane: ethyl acetate (3: 2) system to obtain 0.63 g of the title compound as an amorphous substance. Yield: 45% Melting point: 99-101 ° C ¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t,
J = 7.3 Hz), 1.66-1.74 (2H, m),
2.35 (3H, s), 2.58 (2H, t, J = 7.
7 Hz), 3.98 (2H, s), 4.64 (2H,
s), 5.40 (2H, s), 6.83-6.86 (6
H, m), 6.98 (2H, s), 7.10-7.30.
(14H, m), 7.54-7.71 (3H, m),
8.19-8.22 (1H, m) IR (KBr) cm ^-1 : 3440,1650,154
0,700 MS (FAB) m / z: 867 (M)

Example 24: 3- [3-Bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methyl-5- (3-hydroxy
Cimethylbenzyl) -6-methyl-2-propylpyrimy
Preparation of Zin-4-one 0.62 g of the compound obtained in Example 23 above was treated with methano-
It was dissolved in 10 ml of water, a few drops of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours. Then, 4 ml of 1N-NaOH was added, the reaction mixture was concentrated to dryness under reduced pressure, and 20 ml of water was added to the obtained residue.
Was added and the insoluble matter was collected by filtration. The pH of the obtained aqueous solution was adjusted to 4 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 0.38 g of the title compound as a white powder. Yield: 84% Melting point: 108-110 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.88 (3H,
t, J = 7.3 Hz), 1.60-1.68 (2H,
m), 2.24 (3H, s), 2.64-2.70 (2
H, m), 3.86 (2H, s), 4.45 (2H,
s), 5.44 (2H, s), 7.05-7.30 (6)
H, m), 7.46-7.49 (1H, m), 7.73
-7.80 (2H, m), 7.86-7.96 (2H,
m) IR (KBr) cm ⁻¹ : 3430, 1650, 154
0.1445 MS (FAB) m / z: 625 (M)

Examples 25 to 27 According to the method described in Examples 23 and 24, the compounds described in Examples 25 to 27 below were obtained. Example 25: 4- [3-Bromo-2- [2 '-(1H-
Tetrazol-5-yl) phenyl] benzofuran-5
-Yl] methoxy-2-butyl-5- (3-hydroxy
Methylbenzyl ) -6-methylpyrimidine Yield: 52% Melting point: 112-114 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (3H,
t, J = 7.3 Hz), 1.30-1.38 (2H,
m), 1.68-1.76 (2H, m), 2.35 (3
H, s), 2.73 (2H, t, J = 7.3 Hz),
3.93 (2H, s), 4.41 (2H, s), 5.5
6 (2H, s), 6.95-7.17 (4H, m),
7.39-7.58 (2H, m), 7.73-7.96
(5H, m) IR (KBr) cm ^-1 : 1570, 1445, 142
0.1350 MS (FAB) m / z: 641 (M + 2)

Example 26: 3- [3-Bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methyl-2-butyl-5-
(3-Hydroxymethylbenzyl) -6-methylpyrimi
Zin-4-one yield: 73% Melting point: 119-121 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.81 (3H,
t, J = 7.3 Hz), 1.26-1.34 (2H,
m), 1.52-1.63 (2H, m), 2.23 (3
H, s), 2.69 (2H, t, J = 7.6 Hz),
3.86 (2H, s), 4.45 (2H, s), 5.4
5 (2H, s), 7.05-7.30 (6H, m),
7.46-7.49 (1H, m), 7.73-7.98
(4H, m) IR (KBr) cm ^-1 : 3430, 1650, 153
5,1445 MS (FAB) m / z: 639 (M)

Example 27: 4- [3-bromo-2-
[2 ′-(1H-tetrazol-5-yl) phenyl]
Benzofuran-5-yl] methoxy-2,6-diethyl
-5- (3-hydroxymethylbenzyl) pyrimidine
Potassium salt Yield: 54% mp: 110 ° C. ^{(decomposition) 1 H-NMR (DMSO-} d 6) δ: 1.11 (3H,
t, J = 7.5 Hz), 1.31 (3H, t, J = 7.
6Hz), 2.69 (2H, q, J = 7.4Hz),
2.80 (2H, q, J = 7.6Hz), 3.95 (2
H, s), 4.35 (2H, s), 5.57 (2H,
s), 6.98-7.03 (2H, m), 7.12-
7.18 (2H, m), 7.33-7.44 (4H,
m), 7.51-7.57 (2H, m), 8.06-
8.09 (1H, m) IR (KBr) cm ^-1 : 1570, 1455, 141
5,1350 MS (FAB) m / z: 665 (M + 2)

Pharmacological test example 1: Angiotensin II receptor
Binding test The affinity of the compounds of the present invention for the angiotensin II receptor was evaluated by displacement of radioligand specifically bound to an angiotensin II receptor preparation prepared from rat liver. (1) Preparation of Angiotensin II Receptor Specimen A liver was extracted from a 5-week-old male Wistar rat (Charles River Japan) and homogenized in the following homogenizing buffer to prepare a 10% homogenate. The homogenate was centrifuged at 3000 xg for 15 minutes and the supernatant was collected. Collected supernatant at 50,000 xg for 30
Centrifugation for minutes gave a pellet. 20 ml of a homogenizing buffer was added to the obtained pellet and resuspended to give an angiotensin II receptor sample, which was frozen and stored at -80 ° C.

Homogenizing buffer 10 mM HEPES (pH 7.4) (*) 0.2% Bovine serum albumin 10 μM pepstatin A 10 μM bestatin 10 μM leupeptin 10 μM captopril 100 μM Phenylmethanesulfonyl fluoride (*) HEPES = N- (2-hydroxyethyl) ) Piperazine-N'-2-ethanesulfonic acid

(2) Receptor binding test The above receptor preparation was thawed and the total protein content was 250 μm.
After diluting with the following assay buffer to give g / ml, 0.5 nM [ ³ H] -angiotensin was added.
II and various concentrations of test compounds were added and incubated at 25 ° C for 1 hour. The reaction is stopped by suction filtration of the reaction mixture through a glass fiber filter (Whatman GF / B filter), and [ ³ H] -angiotensin II bound to the receptor and free [ ³ H] -angiotensin II are bound. Separated. The filter is washed with a buffer (10 mM HEPES, pH 7.
After rinsing with 4), the radiation dose adsorbed on the filter was measured using a liquid scintillation counter (Beckman). Non-specific binding was measured by adding 10 ^-5 M unlabeled angiotensin II and reacting.

Assay buffer 10 mM HEPES (pH 7.4) 0.2% Bovine serum albumin 10 mM MgCl ₂

(3) Calculation of IC ₅₀ value Relational expression Y = T-SxD / (D + K) (RF Bruns, et. Al., Molecular)
ar Pharmacology, 29: 331-34.
6, 1986) was used to calculate the IC ₅₀ value. In this formula, Y is the binding radiation dose in the presence of the test compound, T is the binding radiation dose in the absence of the test compound, S is the specific binding radiation dose in the absence of the test compound, and D is the concentration of the test compound. ,
K indicates the IC ₅₀ value of the test compound. The test results are shown in Table 1.

[0070]

Table 1 Test compounds IC ₅₀ (M) Compound of Example 11 3.5 × 10 ⁻⁷ Compound of Example 12 2.5 × 10 ⁻⁷ Compound of Example 13 3.7 × 10 ⁻⁷ Example 14 Compound of Example 15 8.0 × 10 ^-7 compound of Example 15 2.6 × 10 ^-7 compound of Example 16 7.6 × 10 ^-7 compound of Example 17 5.2 × 10 ^-7 compound of Example 18 2.3 × 10 ⁻⁷ Compound of Example 19 3.9 × 10 ⁻⁷ Compound of Example 20 2.4 × 10 ⁻⁷ Compound of Example 22 1.1 × 10 ⁻⁷ Compound of Example 24 3. 3 × 10 ⁻⁸ Compound of Example 25 1.9 × 10 ⁻⁷ Compound of Example 26 2.9 × 10 ⁻⁸

Toxicity test Example 4 to 5 weeks old ICR male mice were subjected to Example 11,
When the compounds of 15, 18, 24 and 26 of 500 mg / kg were intraperitoneally administered, no deaths were observed in any of the administration groups.

Formulation Example 1 Compound of Example 18 20 g Lactose 100 g Corn starch 36 g Microcrystalline cellulose 30 g Carboxymethyl cellulose calcium 10 g Magnesium stearate 4 g The ingredients of the above composition were uniformly mixed, and one tablet 200 mg tablet did.

Formulation Example 2 Compound of Example 22 20 g Lactose 315 g Corn starch 125 g Microcrystalline cellulose 25 g The components of the above composition were uniformly mixed and then granulated to give a granule.

Formulation Example 3 Compound of Example 24 20 g Lactose 100 g Microcrystalline Cellulose 70 g Magnesium stearate 10 g After uniformly mixing the components of the above composition, the mixture is granulated and filled into a gelatin capsule, and the content of one capsule is 200 mg. It was used as a capsule.

Formulation Example 4 Sodium salt of the compound of Example 26 5 g Glucose 50 g Benzyl alcohol 10 g The components of the above composition were dissolved in distilled water for injection so that the total amount was 1000 ml, sealed in an ampoule and injected in an ampoule of 1 ml. I used it as an agent.

[0076]

INDUSTRIAL APPLICABILITY As described above, the compound (I) of the present invention has an excellent angiotensin II antagonistic action and is highly safe, and therefore, is useful as an excellent cardiovascular agent. Therefore, the compound of the present invention is useful as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease, stroke and arteriosclerosis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 405/12 239 405/14 239 // (C07D 405/06 239: 32 307: 78) (C07D 405/12 239: 32 307: 78) (C07D 405/14 239: 32 257: 04 307: 78) (72) Inventor Hiroaki Sato 1-2-1, Marunouchi, Chiyoda-ku, Tokyo (72) Tomoko Saigo Tomoko Saigo, 1-2 Marunouchi, Chiyoda-ku, Tokyo Nihon Steel Tube Co., Ltd. (72) Inventor Tadashi Mizuta 1-2-1 Marunouchi, Chiyoda-ku, Tokyo Nihon Steel Tube Co., Ltd.

Claims (2)

[Claims] 1. A compound represented by the general formula (I): [In the formula, A is (I-1): [In the formula, R ¹ and R ² may be the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkenyl group,
A lower alkynyl group, a lower alkoxy group, a lower alkylthio group, a halogen atom, a phenyl group or a substituted phenyl group, R ³ represents a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, A sulfone group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxyalkoxycarbonyl group, a lower alkanoyloxyalkoxycarbonyl group, a tetrazolyl group, or a protected tetrazolyl group, or a compound represented by the formula —CH ₂ OR ⁵ (wherein R ⁵ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an acetyl group, a phenyl group or a substituted phenyl group), and X represents O, NH or S (O ) P (in the formula, p represents an integer of 0 to 2), and m Represents an integer of 1 to 2] or is represented by the general formula (I-2): (Wherein R ¹ , R ² , R ³ , X and m have the same meanings as described above), R ⁴ is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a carboxyl group. Group, a lower alkoxycarbonyl group, B is a carboxyl group, a lower alkoxycarbonyl group, a tetrazolyl group or a protected tetrazolyl group, and n is 1
A benzofuran derivative or a salt thereof. 2. An angiotensin II antagonist comprising the alkylbenzofuran derivative represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.