JPH0841053A - Pyrimidine derivative bearing heteroarylalkyl group and angiotensin ii antagonist containing the same - Google Patents

Abstract

PURPOSE:To obtain a pyrimidine derivative which has a heteroarylalkyl group represented by a specific formula and is safe and useful as a therapeutic agent for circulatory diseases such as hypertension, heart diseases, cerebral apoplexy, or arteriosclerosis because it has excellent angiotensin II antagonistic action. CONSTITUTION:The derivative of formula I [R<1>, R<2> are each H, a lower alkyl, a lower alkenyl, a lower alkynyl, a lower alkoxy, a lower alkylthio, a halogen, a (substituted) phenyl; Het is (substituted) heteroaryl; X is O, NH, S(O)p (p is 0-2); A is carboxy, a lower alkoxylcarbonyl, cyano, (protected) tetrazolyl; m, n are each 1-2], for example, 2,6-diethyl-5-(2- pyridylmethyl)-4-[2'-(triphenyltetrazol-5-yl)biphenyl-4-yl]methoxyprim idine. It is preferably prepared, for example, by reaction of a compound of formula II with a compound of formula III in the presence of a suitable base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pyrimidine derivative having a novel heteroarylalkyl group having angiotensin II antagonistic activity. Furthermore, the present invention provides angiotensin II containing the pyrimidine derivative as an active ingredient.
Regarding antagonists. This angiotensin II antagonist is useful as a therapeutic agent for diseases caused by excessive AII, for example, cardiovascular diseases such as hypertension, heart disease, stroke and arteriosclerosis.

[0002]

BACKGROUND OF THE INVENTION The renin-angiotensin system is known as a major blood pressure-increasing factor in the living body. Angiotensin II (AII) is a substance having a particularly strong pressor action in this system. AII is a peptide consisting of 8 amino acids, and its biosynthesis is considered to be carried out as follows. First, activated renin secreted from the kidney acts on a renin substrate (angiotensinogen) produced in the liver to produce angiotensin I (AI). This AI is
It is converted to angiotensin II (AII) by angiotensin converting enzyme (ACE) produced in the lung. The pressor activity of AII produced is believed to begin with AII binding to the AII receptor.

The above-mentioned action of AII in the living body is caused by a compound that suppresses the production of AII or the activity of AII, which causes circulatory system such as hypertension, heart disease, stroke and arteriosclerosis caused by excessive AII. It shows that the disease can be treated.

Many drugs have been clinically used to treat these cardiovascular diseases by inhibiting ACE and suppressing the production of AII. But ACE
The inhibitor has a side effect of dry cough, and there is a problem that it deprives the physical strength of cardiovascular disease patients, which are often elderly.

Therefore, in recent years, by not inhibiting the production of AII, but inhibiting AII-AII receptor binding,
Development of a drug that suppresses the activity of II (AII antagonist) has begun.

First, it was reported that many AII analogs such as [Sar ¹ , Ala ⁸ ] AII (salalacin) have an AII antagonistic action. However, these peptidic AII antagonists have a shortcoming that they are not effective because they are rapidly degraded in vivo and their action time is short, and when they are orally administered, they are metabolized in the liver. Therefore, recently, development of non-peptide AII antagonists has been mainly conducted. For example, the above-mentioned imidazole derivatives having an AII antagonistic action are disclosed in JP-A-56-71074, JP-A-57-98270, JP-A-58-157768 and JP-A-63-2.
It is disclosed in Japanese Patent No. 3868, Japanese Patent Laid-Open No. 1-287071, and the like. Further, a pyrimidine derivative having an AII antagonistic action is disclosed in EP-0407342 and JP-A-3-1339.
No. 64, No. 3-197466, No. 4
-120072, JP 4-230370, JP 4-261156, and JP 4-330.
No. 073, EP-0445811.

However, none of them describes a pyrimidine derivative having a structure different from that of the compound of the present invention and having a substituted heteroarylalkyl group at the 5-position.

[0008]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and a novel pyrimidine derivative having an excellent AII antagonistic activity, and an orally administrable and safe composition containing the pyrimidine derivative as an active ingredient. The purpose of the present invention is to provide a circulatory agent for high circulation.

[0009]

Means and Action for Solving the Problems The present inventors have
As a result of earnest research to solve the above problems, a group of heteroarylalkyl derivatives among the pyrimidine derivatives was found to have a strong AII antagonistic effect, and the present invention was completed.

The present invention provides a pyrimidine derivative having a heteroarylalkyl group represented by the following general formula (I), a pharmacologically acceptable salt thereof, and an angiotensin II antagonist containing them as an active ingredient. Is.

[0011]

Embedded image

However, in the formula (I), R ¹ , R ² and H
Each of et, X, A, m and n represents the following.

R ¹ and R ² : may be the same or different,
Each independently represents 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 or an optionally substituted phenyl group. Het: represents a heteroaryl group which may be substituted. X: O, NH or S (O) _p (wherein p represents an integer of 0 to 2) is shown. A: represents a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a tetrazolyl group or a protected tetrazolyl group. m and n: each represents an integer of 1 to 2.

The details of the present invention will be described below together with the operation. <Inventive Compound> First, the compound of the present invention will be described in detail. In the substituents R ¹ and R ² of the compound of the present invention, the lower alkyl group means a carbon number of 1 to 6 (preferably 1
To 4) are linear or branched alkyl groups. Examples thereof include methyl group, 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,
Examples include 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group and the like.

The lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms (preferably 2 to 4 carbon atoms). Examples thereof include 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-
A propenyl group, a 1-hexenyl group, a 2-hexenyl group,
Examples thereof include a 3-hexenyl group, a 4-hexenyl group and a 5-hexenyl group.

The lower alkynyl group means a straight or branched alkynyl group having 2 to 6 carbon atoms (preferably 2 to 4). Examples thereof include an ethynyl group, a 1-propynyl group,
2-propynyl group, 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-
Examples include 2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, and 5-hexynyl group.

The lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4). Examples thereof include methoxy group, ethoxy group, n-
Examples thereof include a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a t-butoxy group, an n-pentyloxy group and an n-hexanoxy group.

The lower alkylthio group has 1 to 6 carbon atoms.
(Preferably 1 to 4) means a linear or branched alkylthio group. Examples thereof include methylthio group, ethylthio group, n-propylthio group, isopropylthio group,
Examples thereof include n-butylthio group, isobutylthio group, sec-butylthio group, t-butylthio group, n-pentylthio group and n-hexylthio group.

The halogen atom means a typical element belonging to Group 7 of the periodic table, and includes, for example, fluorine, chlorine, bromine and iodine.

Examples of the substituent of the phenyl group which may be substituted include a lower alkyl group having 1 to 6 carbon atoms (preferably 1 to 4) and a lower alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4). Group, halogen atom, nitro group, trifluoromethyl group, carboxyl group, lower alkoxycarbonyl group and the like.

The heteroaryl group of the optionally substituted heteroaryl group means a 5- or 6-membered heterocyclic group. Examples thereof include 2-furyl group, 3-furyl group, 2
-Thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-
Pyrrolyl group, 3-pyrrolyl group, 2-oxazolyl group, 4
-Oxazolyl group, 5-oxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1-imidazolyl group, 2-imidazolyl group, 4
-Imidazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 5-pyridyl group, 6-pyridyl group, 3-pyridazyl group, 4-pyridazyl group, 2 -Pyrimidyl group, 4-pyrimidyl group, 5-pyrimidyl group, 2-pyrazyl group, 3-pyrazyl group and the like can be mentioned.

Examples of the substituent of the heteroaryl group include a lower alkyl group having 1 to 6 carbon atoms (preferably 1 to 4), a lower alkoxy group having 1 to 6 carbon atoms (preferably 1 to 4), and halogen. An atom, a nitro group, a trifluoromethyl group, a carboxyl group, a lower alkoxycarbonyl group and the like can be mentioned.

The protective group for the optionally protected tetrazolyl group includes, for example, triphenylmethyl group, p-nitrobenzyl group, 1-ethoxyethyl group, t-butoxycarbonyl group and the like.

The pharmacologically acceptable salts of the compound (I) of the present invention include inorganic salts such as hydrochlorides, sulfates and nitrates, acetates, oxalates, tartrates, citrates and maleates. Organic acid salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, organic amine salts such as methylamine salts, ethylamine salts, triethylamine salts and pyridine salts, lysine and arginine And basic amino acid salts, ammonium salts and the like.

In the compound (I) of the present invention, geometric isomers, optical isomers, and tautomers may be present in some cases.
The compound (I) of the present invention also includes these individual isomers and any mixture thereof.

<Production Method> The compound (I) of the present invention can be produced, for example, as shown in the following five reactions (a) to (e).

[0027]

Embedded image

[0028]

[Chemical 4]

[0029]

Embedded image

[0030]

[Chemical 6]

[0031]

[Chemical 7]

However, the above formulas (I) (Ia) (Ib) (Ic)
R ¹ , R in (Id) (Ie) (II) (III) (IV) (V)
² , Het, A, X, m and n have the same meanings as described above, and Y, W, Z, R ³ and R ⁴ each represent the following.

Y: represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. W: Indicates a halogen atom. Z: shows a hydroxyl group, an amino group or a sulfhydryl group. R ³ : represents an optionally substituted lower alkyl group. R ^4: triphenylmethyl group, p- nitrobenzyl group,
A p-methoxybenzyl group, a methoxymethyl group, a 1-ethoxyethyl group, a 2-cyanoethyl group or a t-butoxycarbonyl group is shown.

The reaction (a) is an example of a method for obtaining the compound (I) of the present invention by reacting the compound (II) with the compound (III) in the presence of a suitable base.

Suitable bases used in the above reaction (a) include, for example, alkali hydroxide, alkali hydride, alkali metal alcoholate, alkali metal carbonate and organic amine. Examples of the alkali hydroxide include sodium hydroxide and potassium hydroxide. Examples of the alkali hydride include sodium hydride and potassium hydride. Examples of alkali metal alcoholates include:
Sodium methoxide, sodium ethoxide, potassium t-butoxide can be mentioned. Examples of alkali metal carbonates include, for example, sodium carbonate, potassium carbonate,
Examples thereof include sodium hydrogen carbonate and potassium hydrogen carbonate.
Examples of organic amines include triethylamine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine. The solvent used in the reaction is not particularly limited as long as it does not participate in the reaction. Examples thereof include organic solvents such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, dioxane, tetrahydrofuran, acetone and alcohol, or a mixed solvent of these solvents and water. The reaction temperature is in the range of -20 to 200 ° C, preferably 0 to 100 ° C, and the reaction is usually completed in 1 to 48 hours.

Further, according to the same method as the above-mentioned reaction (a), the reaction (b) in which the compound (IV) and the compound (V) are reacted in the presence of a suitable base is also used to carry out the present invention. Compound (I) can be obtained.

In the reaction (c), the compound (Ia) in which the group A is a cyano group among the compounds of the general formula (I) is reacted with various azides in an organic solvent to give tetrazole. It transforms into the body (Ib). In this reaction, 1 to 3 mol of the compound (Ia) is used in an amount of about 1 to 3 mol of an azide compound, and is usually performed in a solvent. Examples of the azide compound used in this reaction include trialkyltin azide or triphenyltin azide and hydrazoic acid. The solvent used also includes, for example, N, N-dimethylformamide, dimethylacetamide, toluene,
Examples include benzene. When using an organotin azide compound, heat and reflux in toluene or benzene 1
React for about 0 to 30 hours. Further, when the hydrazoic acid is reacted, sodium azide and ammonium chloride are used in an amount about 2 times the mole of the compound (Ia), and the reaction is carried out in dimethylformamide at about 100 to 130 ° C. for about 1 to 3 days. During this period, it is preferable to accelerate the reaction by adding appropriate amounts of sodium azide and ammonium chloride.

In the reaction (d), the carboxylic acid (Id) is hydrolyzed in the presence of an alkali to hydrolyze the group R ³ of the compound (Ic) in which the group A of the general formula (I) is a carboxylic acid ester. I will get it. In this reaction, about 1 to 3 mol of alkali is used with respect to 1 mol of compound (Ic), and it is usually carried out in a solvent such as alcohols containing water (eg, methanol, ethanol, methyl cellosolve, etc.). Examples of the alkali used in this reaction include sodium hydroxide and potassium hydroxide. 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.

The reaction (e) is a compound (Ie) in which the group A of the general formula (I) is a tetrazolyl group protected with a protecting group.
Is deprotected to obtain a tetrazole compound (Ib). For example, when the protecting group is a triphenylmethyl group, it can be deprotected in the presence of a suitable acid. In this case, the reaction is usually carried out at room temperature to 50 in hydrous alcohols containing hydrochloric acid or acetic acid of about 0.5 to 2N (eg, methanol, ethanol, etc.) or in trifluoroacetic acid.
It is preferable to carry out the treatment at about C for about 1 to 10 hours.

The raw material compounds can be synthesized according to known methods or known methods. For example, the pyrimidine derivative represented by the general formula (II) is disclosed in JP-A-3-133964.
It can be produced from an amidine derivative and a β-ketoester derivative according to the method described in the publication. In addition, the biphenyl derivative represented by the general formula (III) is represented by WO
O-anisic acid can be used as a raw material according to the method described in JP-A-89 / 06233 and JP-A-1-117876.

The compound represented by the general formula (I) synthesized by the above-mentioned synthetic method can be purified by usual purification methods such as recrystallization, reprecipitation, solvent extraction, silica gel column chromatography,
It can be purified by column chromatography using an adsorptive resin.

<Pharmacological Test and Toxicity> Next, the pharmacological action of the compound of the present invention will be described. The pharmacological action of the compound of the present invention was determined by AII receptor binding test (AII antagonistic action).
It can be confirmed as follows.

First, a radioligand ([ ³ H] -AII) is bound to an AII receptor preparation prepared from rat liver. The specific binding of this radioligand to the AII receptor is
It is inhibited by adding and replacing the compound of the present invention. The AII receptor preparations are incubated with the radioligand, a compound of the invention or a control compound or buffer (compound absence control) for a time sufficient for this displacement to reach equilibrium. After that, the unbound ligand is separated and removed by the filter, and the radiation dose remaining on the filter (when compound is present: Y, when compound is not present: T)
To measure. The test compound is used after being diluted in several steps, and the bound radiation dose at each concentration is determined. On the other hand, the absence compound, a large excess with ^[3 H] -AII the same concentration (about 1
( ³ times) non-radioactive ligand (AII) was added to the receptor preparation and reacted in the same manner, and the radiation dose for non-specific binding (NS)
Ask for. Y-NS and T-NS are radiation doses for specific binding.

Using these values, the% inhibition of AII receptor binding at each compound concentration is determined by the following formula.

(% Inhibition of AII receptor binding) = (1- (Y-
NS) / (T-NS)) x 100

The graph of logarithm of compound concentration and% inhibition is a sigmoidal curve. Compound concentration (D) and combined radiation dose (Y above) at the measurement point closest to the inflection point
And combined radiation dose in the absence of compound (T above)
And the radiation dose of nonspecific binding (S: said T-NS), RF Bruns, et. Al., Molecular Pharmacol
50% according to the following relational expression described in ogy, 29, p331-346, 1986
The binding inhibition concentration IC ₅₀ value (K) can be determined. I
The smaller the C ₅₀ value is, the higher the antagonism of the compound to the AII receptor is, and the higher the effect is evaluated.

Relational expression Y = T-S * D / (D + K)

The IC ₅₀ values of the Example compounds prepared in Examples 2 to 11 were measured in Example 12. As shown in Table 1,
In most of the example compounds, the compounds of EP-0407342 used as control compounds and other pyrimidine derivatives having a benzyl group at the 5-position showed a comparable or higher competitive inhibitory effect on the AII receptor. . Among them, the example compounds shown in Examples 2, 4 and 5 exhibited 1.6 to 2.2 times the antagonism of the control substance, and were particularly effective.

The toxicity of the compound of the present invention is 4-5 weeks of IC.
It can be evaluated by intraperitoneal administration of R male mouse 300 mg / kg. As shown in Example 13, with the example compounds produced in Examples 2, 4 and 5, no deaths were observed in any of the administration groups.

<Usage (including preparation), dose> A of the present invention
The II antagonist contains the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient. The administration route is not particularly limited, and oral administration or parenteral administration (for example, intramuscular injection, intravenous injection, subcutaneous injection, rectal administration, transdermal administration) can be performed. Regarding the dosage form (formulation), a pharmaceutically acceptable auxiliary agent is blended into tablets, capsules, granules, powders, pills, fine granules, injections, rectal preparations, suppositories, etc. be able to. Examples of pharmaceutically acceptable adjuvants include excipients, binders, disintegrants, lubricants, buffers, preservatives, diluents, solubilizers, preservatives, flavoring agents, soothing agents, and stabilizers. Agents, coloring agents, etc., which can be used in appropriate combination by a conventional method.

Examples of the excipient include lactose, sucrose, glucose, sorbitol, corn starch and crystalline cellulose. Examples of binders include cellulose derivatives, gum arabic, gelatin, polyvinyl alcohol, polyvinyl ether. An example of a disintegrant is carboxymethyl cellulose calcium. Examples of lubricants include talc, magnesium stearate, polyethylene glycol. Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate,
Examples include sorbic acid, phenol, cresol and chlorocresol. Examples of the diluent include sterile water and sterile physiological saline. Examples of solubilizers include:
Polyoxyethylene hydrogenated castor oil, polysorbate 8
0, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, and maglogol. Examples of the flavoring agent include cocoa powder, peppermint oil, and cinnamon powder. Examples of stabilizers include sodium sulfite, sodium metasulfite, and ether. Example 14
The formulation examples of the compound of the present invention using Example Compounds 1 to 4 are shown in.

The dose of the AII antagonist of the present invention varies depending on the age, body weight, sex, symptoms, administration method, administration period, therapeutic effect, etc., but in the case of oral administration, it is converted into the amount of the compound of the present invention. Usually, it is 1 to 1000 mg, preferably 5 to 200 mg per day for an adult, and this may be administered in 1 to 3 divided doses per day.

[0053]

[Examples] The present invention will be described in more detail below with reference to Reference Examples for the synthesis of starting compounds and intermediates used in the production of the compounds of the present invention and Examples for the production of the compounds of the present invention and their pharmacological tests. However, the present invention is not limited thereto.

Reference Example 1: Synthesis of starting material compound (II) As one example of the compound (II), R ¹ = ethyl group, R ²
= Ethyl group, X = O, Het = 2-pyridyl group, m = 1
Is 2,6-diethyl-5- (2-pyridylmethyl)
Pyrimidin-4 (3H) -one was prepared.

First, 1.06 g of sodium methoxide was dissolved in 30 ml of anhydrous methanol, 2.14 g of ethylamidine hydrochloride was added, and the mixture was stirred at room temperature for 10 minutes. afterwards,
Ethyl 2- (2-pyridylmethyl) -3-oxovalerate (2.88 g) and anhydrous methanol (30 ml) were added, and the mixture was stirred at 50 ° C overnight. The solvent was evaporated under reduced pressure, water was added, the mixture was neutralized with 1N hydrochloric acid, and then extracted twice with chloroform. The chloroform extract layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with n-hexane to give 1.95 g of the title compound.
I got

Yield: 86% Melting point: 151-153 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.6Hz), 1.28 (3H, t, J =
7.6Hz), 2.63 (2H, q, J = 7.6Hz), 2.68 (2H, q, J = 7.6Hz), 4.10
(2H, s), 7.07-7.11 (1H, m), 7.21-7.27 (1H, m), 7.51-7.58 (1
H, m), 8.49-8.50 (1H, m) IR (KBr) cm ^-1 : 2980,2870,1660,1610 MS (FAB) m / z 244 (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: Synthesis of raw material compound (II) As one example of the compound (II), R ¹ = methyl group, R ²
= Methyl group, X = O, Het = 2-pyridyl group, m = 1
2,6-dimethyl-5- (2-pyridylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 29% Melting point: 207-208 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H, s), 2.38 (3H, s), 4.09 (2H,
s), 7.07-7.12 (1H, m), 7.21 (1H, d, J = 7.8Hz), 7.52-7.59 (1
H, m), 8.48-8.51 (1H, m) IR (KBr) cm ^-1 : 3600-3300,1660,1610,1435 MS (FAB) m / z 216 (M + 1)

Reference Example 3: Synthesis of starting material compound (II) As an example of the compound (II), R ¹ = ethyl group, R ²
= Methyl group, X = O, Het = 2-pyridyl group, m = 1
2-ethyl-6-methyl-5- (2-pyridylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 55% Melting point: 176-178 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.7Hz), 2.37 (3H, s),
2.63 (2H, q, J = 7.7Hz), 4.09 (2H, s), 7.07-7.12 (1H, m), 7.21
-7.27 (1H, m), 7.52-7.58 (1H, m), 8.48-8.51 (1H, m) IR (KBr) cm ^-1 : 1645,1610,1590,1440 MS (FAB) m / z: 230 ( (M + 1)

Reference Example 4: Synthesis of raw material compound (II) As one example of the compound (II), R ¹ = methyl group, R ²
= Ethyl group, X = O, Het = 2-pyridyl group, m = 1
6-ethyl-2-methyl-5- (2-pyridylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 52% Melting point: 175-177 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.6Hz), 2.38 (3H, s),
2.66 (2H, q, J = 7.6Hz), 4.10 (2H, s), 7.07-7.12 (1H, m), 7.21
-7.27 (1H, m), 7.52-7.59 (1H, m), 8.49-8.51 (1H, m) IR (KBr) cm ^-1 : 2840,1665,1610,1590 MS (FAB) m / z: 230 ( (M + 1)

Reference Example 5: Synthesis of starting material compound (II) As an example of the compound (II), R ¹ = propyl group, R
² = methyl group, X = O, Het = 2-pyridyl group, m =
1-6-methyl-2-propyl-5- (2-pyridylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 40% Melting point: 168-169 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.60-1.70 (2
H, m), 2.19 (3H, s), 2.46 (2H, t, J = 7.6Hz), 3.90 (2H, m), 7.12
-7.19 (2H, m), 7.60-7.64 (1H, m), 8.40-8.43 (1H, m) IR (KBr) cm ^-1 : 2960,2870,1665,1605 MS (FAB) m / z 244 ( (M + 1)

Reference Example 6: Synthesis of starting material compound (II) As one example of the compound (II), R ¹ = propyl group, R
² = methyl group, X = O, Het = 3-pyridyl group, m =
1-6-methyl-2-propyl-5- (3-pyridylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 65% Melting point: 165-166 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.3Hz), 1.71-1.85 (2
H, m), 2.36 (3H, s), 2.59 (2H, t, J = 7.7Hz), 3.87 (2H, s), 7.18
(1H, dd, J = 7.8Hz, 4.6Hz), 7.58 (1H, dt, J = 7.8Hz, 1.7Hz), 8.
44 (1H, dd, J = 4.6Hz, 1.7Hz), 8.55 (1H, d, J = 1.7Hz) IR (KBr) cm ^-1 : 3200-2600,1655,1605,1420 MS (FAB) m / z : 244 (M + 1)

Reference Example 7: Synthesis of raw material compound (II) As one example of the compound (II), R ¹ = propyl group, R
² = methyl group, X = O, Het = 4-pyridyl group, m =
1-6-methyl-2-propyl-5- (4-pyridylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 70% Melting point: 145-146 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.3Hz), 1.73-1.85 (2
H, m), 2.32 (3H, s), 2.58 (2H, t, J = 7.7Hz), 3.88 (2H, s), 7.17
(2H, dd, J = 4.4Hz, 1.7Hz), 8.48 (2H, dd, J = 4.4Hz, 1.7Hz) IR (KBr) cm ^-1 : 3600-3300,1670,1605,1420 MS (FAB) m / z: 244 (M + 1)

Reference Example 8: Synthesis of raw material compound (II) As one example of the compound (II), R ¹ = butyl group, R ²
= Methyl group, X = O, Het = 2-pyridyl group, m = 1
2-Butyl-6-methyl-5- (2-pyridylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 56% Melting point: 158-159 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.30-1.41 (2
H, m), 1.68-1.79 (2H, m), 2.37 (3H, s), 2.61 (2H, t, J = 7.8H
z), 4.09 (2H, s), 7.07-7.12 (1H, m), 7.23 (1H, d, J = 7.9Hz),
7.55 (1H, dt, J = 7.9Hz, 1.8Hz), 8.49-8.51 (1H, m) IR (KBr) cm ^-1 : 3200-2600,1660,1605,1440 MS (FAB) m / z 258 ( (M + 1)

Reference Example 9: Synthesis of starting material compound (II) As one example of the compound (II), R ¹ = ethyl group, R ²
= Methyl group, X = O, Het = 2-thienyl group, m = 1
2-ethyl-6-methyl-5- (2-thienylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 59% Melting point: 174-175 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.6Hz), 2.39 (3H, s),
2.68 (2H, q, J = 7.6Hz), 4.05 (2H, s), 6.87-6.90 (2H, m), 7.09
(1H, dd, J = 4.6Hz, 1.7Hz) IR (KBr) cm ^-1 : 3600-3300,2970,1655,1605 MS (FAB) m / z 235 (M + 1)

Reference Example 10: Synthesis of raw material compound (II) As one example of the compound (II), R ¹ = propyl group, R ² =
Methyl group, X = O 2, Het = 2-thienyl group, 6-methyl- with m = 1
2-Propyl-5- (2-thienylmethyl) pyrimidin-4 (3H) -one was prepared.

Yield: 63% Melting point: 168-169 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.3Hz), 1.77-1.85 (2
H, m), 2.41 (3H, s), 2.63 (2H, t, J = 7.7Hz), 4.05 (2H, s), 6.88
-6.91 (2H, m), 7.10 (1H, dd, J = 4.6Hz, 1.7Hz) IR (KBr) cm ^-1 : 3600-3300,2960,1665,1605 MS (FAB) m / z 249 (M +1)

Example 1 Synthesis of Compound (Ie) of the Present Invention As an example of compound (Ie) of the present invention, R ¹ = ethyl group,
R ² = ethyl group, X = O, Het = 2-pyridyl group, A
= Triphenylmethyltetrazole group, m = 1, n = 1
Is 2,6-diethyl-5- (2-pyridylmethyl)
-4- [2 '-(triphenylmethyltetrazole-5
-Yl) biphenyl-4-yl] methoxypyrimidine was prepared.

0.27 g of sodium methoxide was dried on DM
It was suspended in 20 ml of F (N, N-dimethylformamide) and stirred at room temperature for 20 minutes. Then, 1.15 g of the compound obtained in Reference Example 1 and 20 ml of dry DMF were added, and the mixture was further stirred for 1 hour. Next, 3.06 g of 4'-bromomethyl-2- (triphenylmethyltetrazol-5-yl) biphenyl was dissolved in 20 ml of dry DMF and added dropwise to this reaction solution, and the mixture was stirred at room temperature for 60 hours. After completion of the reaction, the reaction solution was 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, 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 the system n-hexane: ethyl acetate (3: 2) to obtain 1.26 g of the title compound as an amorphous substance.

Yield: 35% Melting point: 55-57 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.6Hz), 1.35 (3H, t, J =
7.6Hz), 2.77 (2H, q, J = 7.6Hz), 2.86 (2H, q, J = 7.5Hz), 4.15
(2H, s), 5.36 (2H, s), 6.88-6.94 (5H, m), 7.07 (4H, s), 7.18-
7.31 (10H, m), 7.36-7.53 (4H, m), 7.90-7.94 (1H, m), 8.48-
8.50 (1H, m) IR (KBr) cm ^-1 : 1575,1415,1345,750 MS (FAB) m / z 720 (M + 1)

Example 2: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = ethyl group,
R ² = ethyl group, X = O, Het = 2-pyridyl group, A
= Tetrazolyl group, m = 1, n = 1,2,6-diethyl-5- (2-pyridylmethyl) -4- (2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl)
Methoxypyrimidine was prepared.

1.23 g of the compound obtained in Example 1 was dissolved in 50 ml of methanol, a few drops of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours.
Stirred for hours. Then, 4.0 ml of 2N NaOH was added and the reaction mixture was concentrated under reduced pressure. 30 ml of water was added to the obtained residue and the insoluble matter was filtered off. The obtained aqueous solution is neutralized with 1N hydrochloric acid,
The precipitated crystals were collected by filtration and white powder of the title compound 0.73
got g.

Yield: 89%. Melting point: 82-84 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.12 (3H, t, J = 7.4Hz), 1.25 (3H, t,
J = 7.4Hz), 2.74 (2H, q, J = 7.6Hz), 2.75 (2H, q, J = 7.6Hz), 4.1
0 (2H, s), 5.39 (2H, s), 7.03-7.22 (6H, m), 7.50-7.69 (5H,
m), 8.25-8.42 (1H, m) IR (KBr) cm ^-1 : 1580,1415,1350,760 MS (FAB) m / z 478 (M + 1)

Example 3: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = methyl group,
R ² = methyl group, X = O, Het = 2-pyridyl group, A
= Tetrazolyl group, m = 1, n = 1, 2,6-dimethyl-5- (2-pyridylmethyl) -4- [2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methoxypyrimidine was prepared.

The corresponding compound (Ie) of the present invention was synthesized by using the compound of Reference Example 2 according to the method of Example 1, and using this, the title compound was synthesized according to the method of Example 2.

Yield: 6% Melting point: 96-98 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 2.40 (3H, s), 2.47 (3H, s), 4.09 (2
H, s), 5.38 (2H, s), 7.04-7.22 (6H, m), 7.51-7.69 (5H, m), 8.
40 (1H, d, J = 4.6Hz) IR (KBr) cm ^-1 : 3600-3300,1580,1435,1345 MS (FAB) m / z: 460 (M + 1)

Example 4 Synthesis of Compound (Ib) of the Present Invention by Reaction (e) As one example of compound (Ib) of the present invention, R ¹ = ethyl group,
R ² = methyl group, X = O, Het = 2-pyridyl group, A
= Tetrazolyl group, 2-ethyl-in which m = 1 and n = 1
6-methyl-5- (2-pyridylmethyl) -4- [2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Il] methoxypyrimidine was prepared.

The corresponding compound (Ie) of the present invention was synthesized according to the method of Example 1 using the compound of Reference Example 3, and the title compound was synthesized according to the method of Example 2 using the compound.

Yield: 12% Melting point: 95-97 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (3H, t, J = 7.6Hz), 2.40 (3H,
s), 2.73 (2H, q, J = 7.6Hz), 4.08 (2H, s), 5.39 (2H, s), 7.03-
7.23 (6H, m), 7.50-7.69 (5H, m), 8.25-8.42 (1H, m) IR (KBr) cm ^-1 : 1575,1435,1415,1345 MS (FAB) m / z 464 (M +1)

Example 5: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = methyl group,
R ² = ethyl group, X = O, Het = 2-pyridyl group, A
= 6-ethyl- in which tetrazolyl group, m = 1 and n = 1
2-Methyl-5- (2-pyridylmethyl) -4- [2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Il] methoxypyrimidine was prepared.

The corresponding compound (Ie) of the present invention was synthesized according to the method of Example 1 using the compound of Reference Example 4, and the title compound was synthesized according to the method of Example 2 using the compound.

Yield: 12% Melting point: 96-98 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.6Hz), 2.48 (3H,
s), 2.72 (2H, q, J = 7.5Hz), 4.09 (2H, s), 5.37 (2H, s), 7.03-
7.21 (6H, m), 7.51-7.69 (5H, m), 8.39-8.41 (1H, m) IR (KBr) cm ^-1 : 1575,1420,1345,760 MS (FAB) m / z 464 (M +1)

Example 6: Synthesis of compound (Ib) of the present invention by reaction (e) As an example of compound (Ib) of the present invention, R ¹ = propyl group, R ² = methyl group, X = O, Het = 2 6-methyl-2-propyl-5- (2-pyridylmethyl) -4 in which pyridyl group, A = tetrazolyl group, m = 1 and n = 1
-[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methoxypyrimidine was prepared.

Using the compound of Reference Example 5 above, the corresponding compound (Ie) of the present invention was synthesized according to the method of Example 1 above, and using this, the title compound was synthesized according to the method of Example 2.

Yield: 20% Melting point: 143-145 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (3H, t, J = 7.3Hz), 1.67-1.78
(2H, m), 2.40 (3H, s), 2.68 (2H, t, J = 7.4Hz), 4.08 (2H, s), 5.
39 (2H, s), 7.03-7.22 (6H, m), 7.50-7.69 (6H, m) IR (KBr) cm ^-1 : 2960,1570,1430,1345 MS (FAB) m / z 478 (M +1)

Example 7: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = propyl group, R ² = methyl group, X = O, Het = 3 6-methyl-2-propyl-5- (3-pyridylmethyl) -4, wherein pyridyl group, A = tetrazolyl group, m = 1 and n = 1
-[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methoxypyrimidine was prepared.

The corresponding compound (Ie) of the present invention was synthesized according to the method of Example 1 using the compound of Reference Example 6, and was used to synthesize the title compound according to the method of Example 2.

Yield: 9% Melting point: 168 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (3H, t, J = 7.4Hz), 1.68-1.81
(2H, m), 2.39 (3H, s), 2.69 (2H, t, J = 7.5Hz), 3.96 (2H, s), 5.
42 (2H, s), 7.05-7.08 (2H, m), 7.23-7.27 (3H, m), 7.45-7.59
(3H, m), 7.64-7.70 (2H, m), 8.37-8.38 (2H, m) IR (KBr) cm ^-1 : 3600-3300,2960,1575,1420,1345 MS (FAB) m / z: 478 (M + 1)

Example 8: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = propyl group, R ² = methyl group, X = O, Het = 4 -Pyridyl group, A = tetrazolyl group, 6-methyl-2-propyl-5- (4-pyridylmethyl) -4 in which m = 1 and n = 1
-[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methoxypyrimidine was prepared.

The corresponding compound (Ie) of the present invention was synthesized according to the method of Example 1 using the compound of Reference Example 7, and was used to synthesize the title compound according to the method of Example 2.

Yield: 10% Melting point: Oily substance ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.3Hz), 1.65-1.68
(2H, m), 2.43 (3H, m), 2.70 (2H, t, J = 7.2Hz), 3.95 (2H, s), 5.
40 (2H, s), 7.05-7.69 (12H, m) IR (KBr) cm ^-1 : 2960,2925,1260,1100 MS (FAB) m / z 478 (M + 1)

Example 9: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = butyl group,
R ² = methyl group, X = O, Het = 2-pyridyl group, A
= Tetrazolyl group, 2-butyl-where m = 1 and n = 1
6-methyl-5- (2-pyridylmethyl) -4- [2 '
-(1H-tetrazol-5-yl) biphenyl-4-
Il] methoxypyrimidine was prepared.

The corresponding compound (Ie) of the present invention was synthesized according to the method of Example 1 using the compound of Reference Example 8 and the title compound was synthesized according to the method of Example 2 using the compound.

Yield: 18% Melting point: 70-72 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7.3Hz), 1.29-1.37
(2H, m), 1.65-1.76 (2H, m), 2.39 (3H, s), 2.70 (2H, t, J = 7.3H
z), 4.08 (2H, s), 5.39 (2H, s), 7.03-7.22 (6H, m), 7.50-7.69
(5H, m), 8.40-8.41 (1H, m) IR (KBr) cm ^-1 : 2960,1575,1420,1345 MS (FAB) m / z 492 (M + 1)

Example 10: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = ethyl group,
R ² = methyl group, X = O, Het = 2-thienyl group, A
= Tetrazolyl group, 2-ethyl-in which m = 1 and n = 1
6-methyl-4- [2 '-(1H-tetrazole-5-
Il) biphenyl-4-yl] methoxy-5- (2-thienylmethyl) pyrimidine was prepared.

Yield: 20% Melting point: 90-92 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 7.6Hz), 2.46 (3H,
s), 2.79 (2H, q, J = 7.6Hz), 4.12 (2H, s), 5.49 (2H, s), 6.80-
6.81 (1H, m), 6.88-6.91 (1H, m), 7.10 (2H, d, J = 8.1Hz), 7.26
(1H, dd, J = 5.1Hz, 1.0Hz), 7.33 (2H, d, J = 8.1Hz), 7.51-7.59
(2H, m), 7.64-7.69 (2H, m) IR (KBr) cm ^-1 : 3600-3300,1575,1421,1345 MS (FAB) m / z 469 (M + 1)

Example 11: Synthesis of compound (Ib) of the present invention by reaction (e) As one example of compound (Ib) of the present invention, R ¹ = propyl group, R ² = methyl group, X = O, Het = 2 -Thienyl group, A = tetrazolyl group, m = 1, n = 1 6-methyl-2-propyl-4- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methoxy-5 −
(2-thienylmethyl) pyrimidine was prepared.

Yield: 13% Melting point: 97 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H, t, J = 7.4Hz), 1.67-1.78
(2H, m), 2.40 (3H, s), 2.68 (2H, t, J = 7.4Hz), 4.10 (2H, s), 5.
44 (2H, s), 6.79 (1H, dd, J = 3.4Hz, 1.2Hz), 6.89 (1H, dd, J = 5.
1Hz, 3.4Hz), 7.09 (2H, d, J = 8.1Hz), 7.24 (1H, dd, J = 5.1Hz,
1.2Hz), 7.32 (2H, d, J = 8.1Hz), 7.51-7.66 (4H, m) IR (KBr) cm ^-1 : 3600-3300,1575,1420,1340 MS (FAB) m / z: 483 (M + 1)

Example 12: Angiotensin II (AII)
Receptor binding test Angiotensin II (AII) receptor binding test was carried out on the example compounds and control compounds prepared in Examples 2-11. The results are shown below.

(A) Preparation of AII receptor preparation 5-week-old male Wistar rats (Charles River Japan)
The liver was removed more. A 9-fold volume of the following homogenizing buffer was added to this and homogenized to prepare a 10% homogenate. The homogenate was centrifuged at 3000 × G for 15 minutes and the supernatant was collected. The collected supernatant was centrifuged at 50,000 x G for 30 minutes to obtain a precipitate. A homogenizing buffer (20 ml) was added to the resulting precipitate and resuspended to prepare an AII receptor preparation. It was stored frozen at −80 ° C. until use.

Homogenizing buffer 10 mM HEPES ^* (pH7.4) 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

(B) AII Receptor Binding Test In a test tube, [3H] -AII at a final concentration of 0.5 nM and a test compound diluted with several steps (Example compound or control compound)
Was dispensed. For the compound-free control, the same amount of assay buffer was dispensed instead of the compound solution. For the measurement of non-specific binding, a final concentration of 10 ^-5 M unlabeled AII was further added.
Was added. The receptor preparation obtained in (a) above was thawed in advance and diluted with assay buffer so that the total protein content was 250 μg / ml, and this was added to each test tube to start the reaction. (The reaction amount per test tube was about 1
ml). After incubating at 25 ° C. for 1 hour, the reaction mixture was suction-filtered through a glass fiber filter (Whatman GF / B filter) to remove unreacted [ ³ H] -AII to stop the reaction. Wash the filter with washing buffer (10 mM HE
After rinsing with PES, pH 7.4), the radiation dose (receptor binding part) adsorbed on the filter was measured using a liquid scintillation counter (Beckman). IC _{50 by} the method described above
The value was calculated. The results are shown in Table 1.

Assay buffer 10 mM HEPES (pH7.4) 0.2% Bovine serum albumin 10 mM Magnesium chloride

[0111]

[Table 1]

Example 13: Toxicity test The toxicity test of the example compounds prepared in Examples 2, 4 and 5 was carried out. The compound of Example was intraperitoneally administered to 4 to 5 week-old ICR male mice at 300 mg / kg. 10 mice were used for each compound and observed for 2 weeks. As a result, no deaths were observed in any of the treatment groups.

Example 14: Formulation example [0113] The example compounds prepared in Examples 2 to 5 are used below, and angiotensin containing them as an active ingredient.
Examples of II antagonists are shown.

Formulation Example 1 Compound of Example 2 20 g Lactose 100 g Corn starch 36 g Microcrystalline cellulose 30 g Carboxymethyl cellulose calcium 10 g Magnesium stearate 4 g The components of the above composition were uniformly mixed to prepare 1 of the present compound.
A tablet containing 200 mg per tablet was prepared.

Formulation Example 2 Compound of Example 4 20 g Lactose 315 g Corn starch 125 g Microcrystalline cellulose 25 g The components of the above composition were uniformly mixed and granulated to give a granule.

Formulation Example 3 Compound of Example 5 20 g Lactose 100 g Microcrystalline cellulose 70 g Magnesium stearate 10 g The components of the above composition were uniformly mixed and then granulated. This was filled into a gelatin capsule so as to contain 200 mg of the compound of the present invention per capsule to obtain a capsule.

Formulation Example 4 Sodium salt of the compound of Example 10 5 g Glucose 50 g Benzyl alcohol 10 g The components of the above composition were dissolved in distilled water for injection to a total volume of 1000 ml. Each 1 ml of this was sealed in an ampoule to give an injection containing 5 mg of a salt of the compound per ampoule.

[0118]

INDUSTRIAL APPLICABILITY As described above, the compound (I) of the present invention and a pharmaceutically acceptable salt thereof have a safe and excellent angiotensin II (AII) antagonistic action. Therefore, the AII antagonist of the present invention containing these as active ingredients is useful as a therapeutic agent for diseases caused by AII, for example, cardiovascular diseases such as hypertension, heart disease, stroke and arteriosclerosis.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] March 13, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0016

[Correction method] Change

[Correction content]

The lower alkynyl group means a straight or branched alkynyl group having 2 to 6 carbon atoms (preferably 2 to 4). It is as its example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl group, 2-butynyl, 3-butynyl, 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.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction content]

The lower alkylthio group has 1 to 6 carbon atoms.
(Preferably 1 to 4) It means a linear or branched alkylthio group. Examples thereof include 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.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0019

[Correction method] Change

[Correction content]

[0019] The halogen atom means a typical elements belonging to Group 7 of the periodic table, for example, fluorine, chlorine, bromine, iodine.

[Procedure amendment 4]

[Document name to be amended] Statement

[Name of item to be corrected] 0027

[Correction method] Change

[Correction content]

[0027]

Embedded image

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0028

[Correction method] Change

[Correction content]

[0028]

[Chemical 4]

[Procedure correction 6]

[Document name to be amended] Statement

[Name of item to be corrected] 0037

[Correction method] Change

[Correction content]

[0037] Reaction (c), the general formula compound group A is a cyano group among the compounds of (I) a (Ia), in an organic solvent, by reacting the cyano group with various A disilazide compound It is converted to the tetrazole form (Ib). In this reaction, azide compounds 1 to 3 are used with respect to 1 mol of the compound (Ia).
It is usually used in a solvent using a molar amount. Examples of the azide compound used in this reaction include trialkyltin azide or triphenyltin azide and hydrazoic acid. Examples of the solvent used include N, N-dimethylformamide, dimethylacetamide, toluene, benzene and the like. When the organotin azide compound is used, the reaction is carried out in toluene or benzene while heating under reflux for about 10 to 30 hours. Further, when the hydrazoic acid is reacted, sodium azide and ammonium chloride are used in an amount about 2 times the mole of the compound (Ia), and the reaction is carried out in dimethylformamide at about 100 to 130 ° C. for about 1 to 3 days. During this period, it is preferable to accelerate the reaction by adding appropriate amounts of sodium azide and ammonium chloride.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 401/06 239 403/14 405/14 239 409/06 239 409/14 239 413/14 239 417 / 14 239 // (C07D 401/14 213: 06 239: 26 257: 04) (C07D 409/14 239: 26 257: 04 333: 10) (72) Inventor Hirosuke Sato 1-chome Marunouchi, Chiyoda-ku, Tokyo No. 1-2 Nihon Steel Pipe Co., Ltd. (72) Inventor Katsumasa Iijima 1-2-1, Marunouchi, Chiyoda-ku, Tokyo No. 1-2 Nihon Steel Pipe Co., Ltd. (72) Takemi Uehara 1-1-Chome, Marunouchi, Chiyoda-ku, Tokyo No. 2 Nihon Steel Pipe Co., Ltd. (72) Inventor Tadashi Mizuta 1-1-2 Marunouchi, Chiyoda-ku, Tokyo Nihon Steel Pipe Co., Ltd.

Claims (2)

[Claims] 1. A pyrimidine derivative having a heteroarylalkyl group represented by the following general formula (I) and a pharmaceutically acceptable salt thereof. Embedded image However, in the formula (I), R ¹ , R ² , Het, X,
A, m and n represent the following, respectively. R ¹ and R ² : may be the same or different, each independently being 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 or an optionally substituted phenyl group is shown. Het: represents a heteroaryl group which may be substituted. X: O, NH or S (O) _p (wherein p represents an integer of 0 to 2) is shown. A: represents a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a tetrazolyl group or a protected tetrazolyl group. m and n: each represents an integer of 1 to 2. 2. An angiotensin II antagonist containing as an active ingredient a pyrimidine derivative represented by the general formula (I) according to claim 1 and a pharmaceutically acceptable salt thereof.