JPH07157485A - Condensed pyrimidinone derivative and angiotensin ii antagonist containing the same - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a medicine for various diseases of circulatory organs such as hypertension, heart diseases, cerebral apoplexy or arteriosclerosis, having angiotensin II antagonism. CONSTITUTION:A compound of formula I (R<1> is H, a lower alkyl, a lower alkenyl, a lower alkynyl, etc.; R<2> is tetrazolyl; X, Y and Z are each N, CR<3>; R<3> is H, a lower alkyl, a lower alkenyl, a lower alkoxy, etc.) such as 5- butyl-4-[2'-(N-triphenylmethyl-1-H-tetrazol-5-yl)biphenyl-4-yl]methyl- sym-triazolo[ 1,5-a]-pyrimidin-7-one. This compound of formula I is obtained by reacting a compound of formula II with a compound of formula III (A is a halogen, an alkylsulfonyloxy or an arylsulfonyloxy) in the presence of a base (e.g. NaOH) in a solvent (e.g. DMF) at -20 to 200 deg.C for 1-48 hours.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fused pyrimidinone derivative and an angiotensin II antagonist containing the fused pyrimidinone derivative as an active ingredient. Since the novel fused pyrimidinone derivative according to the present invention has angiotensin II antagonistic activity, various cardiovascular diseases,
For example, it is useful for 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 by the kidney
Specifically acts on the renin substrate (angiotensinogen) produced in the liver to produce angiotensin I (AI).
To produce. This AI is angiotensin II (A) produced by angiotensin converting enzyme (ACE) produced in the lung.
II), and this AII is considered to exhibit strong pressor activity. Therefore, AII antagonists can be used to treat 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 antagonism, but these peptidic AII antagonists have a short action time and have a drawback that they are not effective in oral administration. It was As a non-peptidic AII antagonist, imidazole derivatives are disclosed in many patent publications. For example, JP-A-56-7
1074, JP-A-57-98270, JP-A-58-157768, and JP-A-63-23868.
JP-A No. 1-287071 and the like, and a pyrimidine derivative is also disclosed in EP-0407342.
No. 3, JP-A-3-133964, JP-A-3-197.
No. 466, No. 4-120072, No. 4-230370, No. 4-261156, No. 4-330073, and EP-04458.
No. 11 is disclosed.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that
As a result of intensive studies to obtain a non-peptide AII antagonist having an II-antagonistic action and being orally administrable and highly safe, it has a chemical structure different from that of each of the above-mentioned conventionally known pyrimidine derivatives, It was found that a group of novel fused pyrimidinone derivatives having an oxo group has a strong AII antagonistic action. The present invention is based on these findings.

[0005]

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

[Chemical 2] [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group or a lower alkylthio group, and R ² represents an optionally protected tetrazolyl group, and X, Y and Z are the same or different and are or -N- or be -CR ³ - indicates, R ³ is a hydrogen atom, a lower alkyl group, lower alkenyl group, lower alkynyl group, a lower alkoxy group, lower alkoxycarbonyl group, a carboxyl group or a And a fused pyrimidinone derivative [hereinafter sometimes referred to as the compound (I) of the present invention] or a salt thereof. Furthermore, the present invention also relates to a cardiovascular agent containing the fused pyrimidinone derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the lower alkyl group means, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, such as 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 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.

As the lower alkoxycarbonyl group, for example, a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms (particularly 2 to 4), such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, iso Examples thereof include a propoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group.

The lower alkylthio group is, for example, a linear or branched alkylthio group 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 protecting group for the optionally protected tetrazolyl group include a trityl group, a p-nitrobenzyl group, a 1-ethoxyethyl group and a t-butoxycarbonyl group.

The salts of the compound (I) of the present invention, especially the pharmacologically acceptable salts include inorganic salts such as hydrochlorides, sulfates and nitrates, acetates, oxalates, tartrates and citrates.
Organic acid salts such as maleates, 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 , 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. It

The compound (I) of the present invention can be prepared, for example, by the following method. That is, the general formula (II)

[Chemical 3] (In the formula, R ¹ , X, Y and Z have the same meanings as described above.)
And a compound represented by the general formula (III)

[Chemical 4] (Wherein R ² has the same meaning as described above and A represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group) in the presence of a base to give a compound of the present invention. (I) is obtained.

As the base that can be used in the reaction,
Alkali metal compounds such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, Triethylamine, diisopropylethylamine, pyridine, N, N
-Organic amines such as dimethylaminopyridine. 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 200 ° C., preferably 0
The temperature is in the range of -100 ° C, and the reaction is usually completed in 1 to 48 hours.

The compound (I) of the present invention having an unprotected tetrazolyl group as a substituent can also be produced by deprotecting the compound (I) of the present invention having a corresponding protected tetrazolyl group. Also, it can be produced by reacting the corresponding cyano compound with various azides.

The compound (I) of the present invention having a carboxyl group as a substituent can also be produced by hydrolyzing the compound (I) of the present invention having a corresponding lower alkoxycarbonyl group in the presence of an acid or a base. . Examples of the acid used in this reaction include hydrochloric acid and sulfuric acid, and examples of the base include sodium hydroxide and potassium hydroxide. As the solvent, a mixed solvent of water and alcohol (for example, methanol, ethanol, etc.) is preferable, and it is usually completed in 10 minutes to 10 hours in the temperature range of room temperature to reflux.

The compound (I) of the present invention having a lower alkoxycarbonyl group as a substituent can also be produced by esterifying the compound (I) of the present invention having a corresponding carboxyl group in the presence of an acid. Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid, arylsulfonic acid and the like. The reaction is usually an alcohol,
For example, methanol, ethanol, propanol, butanol or the like is used as a solvent, and the reaction is completed within 1 to 24 hours within a temperature range from room temperature to reflux.

The compounds represented by the above general formulas (II) and (III), which are the raw material compounds, are known per se or can be produced by a method known per se. For example, the compound of general formula (II) is described in Chem. Pharm. B
all. , 10, 612 (1962). The compound of general formula (III) can be synthesized according to the method described in WO-89 / 06233.

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 of the present invention containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is orally or parenterally (for example, intramuscularly, intravenously or subcutaneously). Injection, rectal 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. Examples of pharmaceutically acceptable adjuvants include excipients, binders, disintegrants, lubricants,
Examples thereof include buffering agents, preservatives, solubilizing agents, preservatives, flavoring agents, soothing agents, stabilizers, coloring agents, and the like, which 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 carboxymethylcellulose 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 general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient in an amount effective for angiotensin II antagonistic activity, for example, It is contained in an amount of 5 to 100% by weight, preferably 25 to 100% by weight. The dosage is age,
Although it varies depending on the body weight, sex, symptoms, administration method, administration period, therapeutic effect, etc., 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 divided into 1 to 3 times. To administer.

[0023]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. Example 1: 5-Butyl-4- [2 '-(N-triphenyl
Lumethyl-1H-tetrazol-5-yl) biphenyl
-4-yl] methyl-sym-triazolo [1,5-
a] -Pyrimidin- 7-one preparation A suspension of sodium hydride (132 mg ) in dry dimethylformamide (DMF) (10 ml) was stirred under ice-cooling under stirring.
Butyl-sym-triazolo [1,5-a] pyrimidin-7-one (577 mg) was added, and the mixture was stirred for 30 minutes, then,
4'-Bromomethyl-2- (N-triphenylmethyl-
1H-tetrazol-5-yl) biphenyl 1.67 g
Was added and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated, water was added to the residue, the precipitated crystals were collected by filtration, the obtained crystals were purified by silica gel column chromatography (chloroform), and recrystallized from ethyl acetate-hexane. Thus, 510 mg of the title compound was obtained as colorless crystals.
Yield 25%. Melting point: 184 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.79 (3H,
t, J = 7.3 Hz), 1.18-1.31 (2H,
m), 1.42-1.53 (2H, m), 2.54 (2
H, t, J = 7.6 Hz), 5.50 (2H, s),
5.92 (1H, s), 6.86-6.91 (6H,
m), 7.07 (4H, s), 7.26-7.41 (1
0H, m), 7.49-7.61 (2H, m), 7.7
7-7.81 (1H, m), 8.15 (1H, s) MS (FAB) m / z: 669 (M + 1)

Example 2: 5-Butyl-4- [2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methyl-sym-triazolo [1,5-a] -pyrimidi
Preparation of N-7-one 201 mg of the compound of Example 1 was dissolved in 15 ml of methanol, a few drops of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated and the residue was recrystallized from ethanol-diisopropyl ether to obtain 94 mg of the title compound as colorless crystals. Yield 74%. Melting point: 242 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (3H,
t, J = 7.2 Hz), 1.26-1.39 (2H,
m), 1.46-1.57 (2H, m), 2.63 (2
H, t, J = 7.7 Hz), 5.54 (2H, s),
5.94 (1H, s), 7.07-7.17 (4H,
m), 7.47-7.57 (2H, m), 7.62-
7.67 (2H, m), 8.16 (1H, s) MS (FAB) m / z: 427 (M + 1)

Example 3: 5-Methyl-4- [2 '-(N
-Triphenylmethyl-1H-tetrazol-5-i
Ru) biphenyl-4-yl] methyl-sym-triazo
Preparation of bolo [1,5-a] -pyrimidin-7-one According to the method of Example 1, 5-methyl-sym-triazolo [1,5-a] pyrimidin-7-one was used as a starting material. , The title compound was obtained. Yield 31%. Melting point: 196 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H,
s), 5.40 (2H, s), 5.86 (1H, s),
6.88-6.95 (8H, m), 7.12-7.15
(2H, m), 7.21-7.37 (10H, m),
7.43-7.51 (2H, m), 7.94-7.98
(1H, m), 8.04 (1H, s) MS (FAB) m / z: 627 (M + 1)

Example 4: 5-Methyl-4- [2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methyl-sym-triazolo [1,5-a] -pyrimidi
Preparation of N-7-one According to the method of Example 2, the title compound was obtained from the compound of Example 3. Yield 53%. Melting point: 265 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.36 (3 H,
s), 5.53 (2H, s), 6.01 (1H, s),
7.08-7.11 (2H, m), 7.17-7.21
(2H, m), 7.49-7.58 (2H, m), 7.
62-7.68 (2H, m), 8.18 (1H, s) MS (FAB) m / z: 385 (M + 1)

Example 5: 5-Ethyl-4- [2 '-(N
-Triphenylmethyl-1H-tetrazol-5-i
Ru) biphenyl-4-yl] methyl-sym-triazo
Preparation of Boro [1,5-a] -pyrimidin-7-one According to the method of Example 1, 5-ethyl-sym-triazolo [1,5-a] pyrimidin-7-one was used as a starting material. , The title compound was obtained. Yield 24%. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3 H, t,
J = 7.3 Hz), 2.52 (2H, q, J = 7.3H)
z), 5.43 (2H, s), 5.93 (1H, s),
6.89-6.94 (8H, m), 7.12-7.15
(2H, m), 7.22-7.37 (10H, m),
7.43-7.53 (2H, m), 7.93-7.98
(1H, m), 8.04 (1H, s) MS (FAB) m / z: 641 (M + 1)

Example 6: 5-Ethyl-4- [2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methyl-sym-triazolo [1,5-a] -pyrimidi
Preparation of N-7-one According to the method of Example 2, the title compound was obtained from the compound of Example 5. Yield 76%. Melting point: 108 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3H,
t, J = 7.3 Hz), 2.66 (2H, q, J = 7.
3Hz), 5.55 (2H, s), 5.97 (1H,
s), 7.05-7.09 (2H, m), 7.15-
7.18 (2H, m), 7.51-7.59 (2H,
m), 7.64-7.70 (2H, m), 8.23 (1
H, s) MS (FAB) m / z: 399 (M + 1)

Example 7: 5-Propyl-4- [2'-
(N-triphenylmethyl-1H-tetrazole-5-
Il) biphenyl-4-yl] methyl-sym-tria
Preparation of zolo [1,5-a] -pyrimidin-7-one According to the method of Example 1, 5-propyl-sym-triazolo [1,5-a] pyrimidin-7-one was used as starting material. , The title compound was obtained. Yield 19%. Melting point: 93 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 0.94 (3 H, t,
J = 7.3 Hz), 1.54 to 1.68 (2H, m),
2.49 (2H, t, J = 7.7Hz), 5.43 (2
H, s), 5.92 (1 H, s), 6.90-6.94.
(8H, m), 7.12-7.15 (2H, m), 7.
22-7.37 (10H, m), 7.42-7.52
(2H, m), 7.92-7.95 (1H, m), 8.
02 (1H, s) MS (FAB) m / z: 651 (M + 1)

Example 8: 5-Propyl-4- [2'-
(1H-tetrazol-5-yl) biphenyl-4-i
]] Methyl-sym-triazolo [1,5-a] -pyri
Preparation of Midin-7-one According to the method of Example 2, the title compound was obtained from the compound of Example 7. Yield 73%. Melting point: 230 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H,
t, J = 7.3 Hz), 1.48-1.62 (2H,
m), 2.62 (2H, t, J = 7.6Hz), 5.5
5 (2H, s), 5.96 (1H, s), 7.07-
7.10 (2H, m), 7.15-7.18 (2H,
m), 7.49-7.58 (2H, m), 7.63-
7.69 (2H, m), 8.18 (1H, s) MS (FAB) m / z: 413 (M + 1)

Example 9: 5-Pentyl-4- [2'-
(N-triphenylmethyl-1H-tetrazole-5-
Il) biphenyl-4-yl] methyl-sym-tria
Preparation of zolo [1,5-a] -pyrimidin-7-one According to the method of Example 1, 5-pentyl-sym-triazolo [1,5-a] pyrimidin-7-one was used as starting material. , The title compound was obtained. Yield 11%. Melting point: 167 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 0.87 (3 H, t,
J = 7.1 Hz), 1.22-1.38 (4H, m),
1.52-1.63 (2H, m), 2.50 (2H, m)
t, J = 7.7 Hz), 5.43 (2H, s), 5.9
3 (1H, s), 6.90-6.93 (8H, m),
7.12-7.15 (2H, m), 7.22-7.36
(10H, m), 7.43-7.49 (2H, m),
7.92-7.95 (1H, m), 8.02 (1H,
s) MS (FAB) m / z: 683 (M + 1)

Example 10: 5-Pentyl-4- [2'-
(1H-tetrazol-5-yl) biphenyl-4-i
]] Methyl-sym-triazolo [1,5-a] -pyri
Preparation of Midin-7-one According to the method of Example 2, the title compound was obtained from the compound of Example 9. Yield 75%. Melting point: 232 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.83 (3H,
t, J = 7.1 Hz), 1.17-1.33 (4H,
m), 1.47-1.58 (2H, m), 2.63 (2
H, t, J = 7.7 Hz), 5.54 (2H, s),
5.96 (1H, s), 7.07-7.17 (4H,
m), 7.48-7.68 (4H, m), 8.19 (1
H, s) MS (FAB) m / z: 441 (M + 1)

Example 11: 5-Ethyl-3-methylthio
-4- [2 '-(N-triphenylmethyl-1H-teto
Razol-5-yl) biphenyl-4-yl] methyl-
sym-triazolo [1,5-a] -pyrimidine-7-
Preparation of One According to the method of Example 1, 5-ethyl-3-methylthio-sym-triazolo [1,5-a] pyrimidine-7
Using the -one as the starting material, the title compound was obtained. Yield 23%. Melting point: 189 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3 H, t,
J = 7.4 Hz), 2.48 (2H, q, J = 7.4H)
z), 2.68 (3H, s), 5.37 (2H, s),
5.89 (1H, s), 6.89-6.93 (8H,
m), 7.11-7.14 (2H, m), 7.22-
7.37 (10H, m), 7.43-7.53 (2H,
m), 7.94-7.97 (1H, m) MS (FAB) m / z: 687 (M + 1).

Example 12: 5-Ethyl-3-methylthio
-4- [2 '-(1H-tetrazol-5-yl) bif
Phenyl-4-yl] methyl-sym-triazolo [1,
Preparation of 5-a] -pyrimidin-7-one According to the method of Example 2, the title compound was obtained from the compound of Example 11. Yield 77%. Melting point: 151 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.13 (3H,
t, J = 7.3 Hz), 2.59 (3H, s), 2.6
2 (2H, q, J = 7.3 Hz), 5.49 (2H,
s), 5.91 (1H, s), 7.07-7.10 (2
H, m), 7.15-7.18 (2H, m), 7.49.
-7.68 (4H, m) MS (FAB) m / z: 445 (M + 1)

Example 13: 5-Butyl-4- [2'-
(N-triphenylmethyl-1H-tetrazole-5-
Il) biphenyl-4-yl] methylpyrazolo [2,3
Preparation of -a] -pyrimidin-7- one According to the method of Example 1, 5-butylpyrazolo [2,2]
3-a] pyrimidin-7-one was used as the starting material,
The title compound was obtained. Yield 15%. Melting point: 189 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 0.89 (3 H, t,
J = 7.2 Hz), 1.23-1.41 (2H, m),
1.52-1.63 (2H, m), 2.48 (2H,
t, J = 7.7 Hz), 5.06 (2H, s), 5.6
8 (1H, d, J = 2.0Hz), 5.80 (1H,
s), 6.80-6.83 (2H, m), 6.89-
6.93 (6H, m), 7.12-7.15 (2H,
m), 7.21-7.26 (6H, m), 7.31-
7.36 (4H, m), 7.42-7.53 (2H,
m), 7.67 (1H, d, J = 2.0 Hz), 7.9
3-7.96 (1H, m) MS (FAB) m / z: 668 (M + 1)

Example 14: 5-Butyl-4- [2'-
(1H-tetrazol-5-yl) biphenyl-4-i
]] Methylpyrazolo [2,3-a] -pyrimidine-7-
Preparation of On According to the method of Example 2, the title compound was obtained from the compound of Example 13. Yield 66%. Melting point: 218 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 0.86 (3H,
t, J = 7.2 Hz), 1.28-1.41 (2H,
m), 1.49-1.60 (2H, m), 2.63 (2
H, t, J = 7.7 Hz), 5.36 (2H, s),
5.74 (1H, s), 6.25 (1H, d, J = 2.
0 Hz), 7.10-7.13 (4H, m), 7.47
-7.67 (4H, m), 7.81 (1H, d, J =
2.0 Hz) MS (FAB) m / z: 426 (M + 1)

Example 15: 5-Ethyl-2-methyl-4
-[2 '-(N-triphenylmethyl-1H-tetrazo
Rol-5-yl) biphenyl-4-yl] methylpyrazo
Preparation of b [2,3-a] -pyrimidin-7- one According to the method of Example 1, 5-ethyl-2-methylpyrazolo [2,3-a] pyrimidin-7-one was used as the starting material. , The title compound was obtained. Yield 23%. Melting point: 180 ° C. (decomposition) ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3 H, t,
J = 7.4 Hz), 2.24 (3H, s), 2.44
(2H, q, J = 7.4Hz), 4.99 (2H,
s), 5.54 (1H, s), 5.78 (1H, s),
6.79-6.91 (8H, m), 7.16-7.36
(12H, m), 7.44-7.52 (2H, m),
7.94-7.97 (1H, m) MS (FAB) m / z: 654 (M + 1)

Example 16: 5-Ethyl-2-methyl-4
-[2 '-(1H-tetrazol-5-yl) biphenyl
Lu-4-yl] methylpyrazolo [2,3-a] -pyrimy
Preparation of Zin-7-one According to the method of Example 2, the title compound was obtained from the compound of Example 15. Yield 44%. Melting point: 202 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3 H,
t, J = 7.3 Hz), 2.50 (3H, s), 2.6
3 (2H, q, J = 7.3Hz), 5.30 (2H,
s), 5.68 (1H, s), 6.07 (1H, s),
7.09-7.12 (4H, m), 7.48-7.68
(4H, m) MS (FAB) m / z: 412 (M + 1)

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 6-week-old male Wistar rat (Charles River Japan) and homogenized in a homogenizing buffer (see Table 1 below) to prepare a 10% homogenate. . The homogenate was centrifuged at 3000 xg for 15 minutes and the supernatant was collected. 50,000 collected supernatant
Centrifugation at xg for 30 minutes gave a pellet. To the obtained pellet, 20 ml of homogenizing buffer was added and resuspended to prepare an angiotensin II receptor sample,
It was stored frozen at ℃.

[0040]

[Table 1] (*) 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.
The assay buffer was adjusted to g / ml (Table 2 below).
After dilution with 0.5 nM [ ³⁾ as a final concentration.
[H] -angiotensin II and various concentrations of test compounds were added and incubated at 25 ° C. for 1 hour. Add the reaction mixture to a glass fiber filter (Whatman GF / B
The reaction is stopped by suction filtration through a filter, and [ ³ H] -angiotensin II bound to the receptor and free [ ³ H] -angiotensin II are bound.
Separated. Wash the filter with a washing buffer (10 mM
After rinsing with HEPES, pH 7.4), the radiation dose adsorbed on the filter was measured using a liquid scintillation counter (Beckman). Non-specific binding was measured by adding 10 ^-6 M unlabeled angiotensin II and reacting.

[0042]

[Table 2]

(3) Calculation of IC ₅₀ value Relational expression Y = T-SxD / (D + K) (RFBruns, et.al., Molecular Pharmacology, 29: 331-3)
46, 1986) was used to calculate IC ₅₀ values. 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, D is the concentration of the test compound, and K is the test. The IC ₅₀ value of the compound is shown. The test results are shown in Table 3.

[0044]

[Table 3]

Pharmacological Test Example 2: Vasoconstriction Inhibitory Activity The usefulness of the compound of the present invention was confirmed by its inhibitory effect on angiotensin II-induced contraction of rat aorta. (1) Measurement of contraction using vascular Magnus device Wistar male rats (Nihon Charles River) having a body weight of 150 to 250 g were beaten to death by exsanguination, and the thoracic aorta was extracted. After removing the attached connective tissue, the endothelial cells were peeled off by rubbing the blood vessel lumen with a thread, and a ring-shaped specimen was prepared. Specimens were taken by Krebs-Henselei
t solution (unit: mM; NaCl = 118, KCl = 4.7, CaCl ₂ = 2.55, M
gSO ₄ = 1.18, KH ₂ PO ₄ = 1.18, NaHCO ₃ = 24.88, glucose = 1
1.1) and 37% under 95% O ₂ -5% CO ₂ aeration
It was suspended in an organ bath with a volume of 5 ml kept at room temperature. An initial tension of 1.5 g was applied and the measurement started after 60 minutes of pre-incubation. The test compound was administered at various concentrations, and 15 minutes later, angiotensin II was cumulatively administered. The inhibitory effect on angiotensin II-induced contraction creates a Child plot, pA ₂
Was evaluated for. Specimen contraction is isometric
transducer (UL-10GR: Minebea)
And isometrically measured using an amplifier (6M92: NEC Sanei), and a rectifier (RECTI-HORIZ-8).
K: NEC Sanei).

Example 4 Toxicity Test Example 2 was carried out on 4 to 5 week-old male ICR mice.
When the compounds 8, 10, and 14 were intraperitoneally administered in an amount of 200 mg / kg, no deaths were observed in any of the administration groups.

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 give tablets of 200 mg each.

Formulation Example 2 Compound of Example 8 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 10 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 to give a capsule having a content of 200 mg per capsule. did.

Formulation Example 4 Sodium salt of the compound of Example 8 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, and enclosed in an ampoule to prepare 1 ampoule and 1 ml of an injection. did.

[0051]

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 front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 31/505 ABX AEQ 9454-4C (72) Inventor Hirosuke Sato 1-2-1, Marunouchi, Chiyoda-ku, Tokyo Nippon 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): [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group or a lower alkylthio group, and R ² represents an optionally protected tetrazolyl group, and X, Y and Z are the same or different and are or -N- or be -CR ³ - indicates, R ³ is a hydrogen atom, a lower alkyl group, lower alkenyl group, lower alkynyl group, a lower alkoxy group, lower alkoxycarbonyl group, a carboxyl group or a A lower alkylthio group] or a fused pyrimidinone derivative represented by the formula: 2. An angiotensin II antagonist comprising the fused pyrimidinone derivative represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.