JPH06329676A - Pyrazolo(1,5-a)pyrimidin-7(4h)-one derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound, having antagonistic action on angiotensin II receptors and useful for treating, etc., hypertension, congestive heart failure, etc. CONSTITUTION:The compound is expressed by formula I [R<1> and R<2> are H, (substituted)alkyl, cycloalkyl or alkoxy; R<3> and R<4> are H, alkyl, (substituted) alkoxycarbonyl, carboxyl, tetrazolyl, etc.; X is carboxyl, tetrazolyl, etc.], e.g. ethyl 6-n-butyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrazolo[1,5- a]pyrimidin-7(4H)-one-3-carboxylate. Furthermore, this compound expressed by formula I is obtained by reacting, e.g. a compound expressed by formula II (X' is protected carboxyl, etc.) with a compound expressed by formula III and then deprotecting the resultant compound expressed by formula IV.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is an angiotensin II receptor antagonist, which is induced by angiotensin II,
Or a novel pyrazolo [1,5-a] useful in the control of aggravating hypertension and the treatment of congestive heart failure
It relates to a pyrimidin-7 (4H) -one derivative. Furthermore, the present invention relates to antihypertensive agents containing the above compounds.

[0002]

BACKGROUND OF THE INVENTION Angiotensin II is a renin-angiotensin system active substance that regulates blood pressure, body fluid volume, electrolyte balance and the like in the body. Angiotensin
II contracts blood vessels via the angiotensin receptor on the cell membrane to raise blood pressure. Therefore, angiotensin II is considered to be a causative agent that causes hypertension in various mammals. An angiotensin II converting enzyme inhibitor (ACE inhibitor) that produces angiotensin II has already been put to practical use.

Angiotensin II receptor antagonists are also ACE
Like the inhibitor, it is useful as a therapeutic agent for hypertension caused by angiotensin II, that is, an antihypertensive agent, has a strong action, and does not have side effects such as dry cough which is a problem with ACE inhibitors. Peptidic angiotensin II analogs such as salaracin have been studied so far, and it has been reported that these have a potent angiotensin II receptor antagonistic action. However, due to its antagonistic properties, salaracin generally exhibits a pressor effect when hypertension is not due to angiotensin II. Furthermore, it has been reported that such a peptidic antagonist has a short duration of action in parenteral administration and is ineffective in oral administration [MA On.
detti and DW Cushman, Annual Reports in Medicin
al Chemistry, 13 , 82-91 (1978)].

In order to solve the problems of these peptidic angiotensin II receptor antagonists, studies on non-peptidic angiotensin II receptor antagonists have been conducted.
As the non-peptide angiotensin II receptor antagonist, there are disclosed in JP-A-56-71073 and JP-A-56-7107.
4, European Patent Application Publication Nos. 0324377, 505954, and 04031.
No. 59 discloses an imidazole derivative. International Publication No. WO9207834 and European Patent Application Publication No. 245637 disclose imidazolone derivatives, and International Publication No. WO9117148 discloses triazole derivatives. European Patent Application Publication No. 0
In 475206, a pyridine derivative is described in
Japanese Patent No. 0974 discloses imidazopyridine derivatives. Further, JP-A-4-364171 discloses a benzimidazole derivative.

Although all of these compounds have been confirmed to be effective as angiotensin II receptor antagonists, further development of novel non-peptide angiotensin II receptor antagonists is desired.

[0006]

OBJECT OF THE INVENTION The object of the present invention is an angiotensin II receptor antagonist, which is induced by angiotensin II,
Or a novel pyrazolo [1,5-a] useful in the control of aggravating hypertension and the treatment of congestive heart failure
It is intended to provide a pyrimidin-7 (4H) -one derivative. Still another object of the present invention is to provide antihypertensive agents containing these compounds.

[0007]

DETAILED DESCRIPTION OF THE INVENTION The meanings of the abbreviations in the present specification are as follows: Ac: acetyl Bu: butyl DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide Et: ethyl Me: methyl THF: tetrahydrofuran.

The pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative of the present invention is represented by the following general formula (I):

[0009]

[Chemical 2]

(In the formula, R ¹ and R ² are each independently a group selected from the group consisting of hydrogen, an optionally substituted alkyl group, a cycloalkyl group, and an alkoxy group, and R ³ and R 2 ⁴ are each independently hydrogen, an alkyl group, an optionally substituted alkoxycarbonyl group,
A carboxyl group or a salt thereof, and a group selected from the group consisting of a tetrazolyl group or a salt thereof, and X is a group selected from the group consisting of a carboxyl group or a salt thereof, and a tetrazolyl group or a salt thereof).

The alkyl groups of R ¹ and R ² each have 1 to 6 carbon atoms, and examples of such an alkyl group include methyl, ethyl, n-propyl, iso-propyl, n-butyl and iso-. Butyl, t-butyl, sec
-Butyl, pentyl, hexyl and the like. Examples of the substituent of the optionally substituted alkyl group include an alkoxyalkyl group such as methoxymethyl and ethoxymethyl. The cycloalkyl group of R ¹ and R ^{2 has} a carbon number of 3 to 6, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The alkoxy groups of R ¹ and R ² each have 1 to 4 carbon atoms and include methoxy, ethoxy, propyloxy, butoxy and the like.

The alkyl groups of R ³ and R ⁴ are the same as those of R ¹
And any of the alkyl groups listed for R ² . Examples of the alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl. Examples of the substituent of the optionally substituted alkoxycarbonyl group include an alkylcarbonyloxy group such as pivaloyloxy and cyclohexyloxycarbonyloxy, a cycloalkyloxycarbonyloxy group, and the like. Examples of the salt of the carboxyl group and the tetrazolyl group include sodium salt and potassium salt.

The salt of the carboxyl group and the tetrazolyl group of X may be the same as the salt of the carboxyl group and the tetrazolyl group of R ³ and R ⁴ .

In a preferred embodiment, R ¹ is an alkyl group, R ² is hydrogen, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen and X is a tetrazolyl group.

In a preferred embodiment, R ¹ is an alkoxy group, R ² is hydrogen, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen and X is a tetrazolyl group.

In a preferred embodiment, R ¹ is an alkyl group, R ² is hydrogen, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is an alkyl group, and X is a tetrazolyl group.

In a preferred embodiment, R ¹ is a cycloalkyl group, R ² is hydrogen, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen and X is a tetrazolyl group.

In a preferred embodiment, R ¹ is an alkyl group, R ² is hydrogen, R ³ is hydrogen, R ⁴ is an alkoxycarbonyl or carboxyl group, and X is a tetrazolyl group.

In a preferred embodiment R ¹ is hydrogen,
R ² is an alkyl group, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen, and X is a tetrazolyl group.

Preferred examples of the pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (I) of the present invention include compounds represented by the following formulas (Ib) and (Ih).

[0021]

[Chemical 3]

The pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative of the present invention can be obtained, for example, by the following method.

[0023]

[Chemical 4]

Wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined in formula (I), R ⁵ is lower alkyl and the like. X ′ is a cyano group, a protected carboxyl group or the like, and is a group which can be converted to X by an arbitrary reaction. Y is a protective group having an acyl group, for example,
Trifluoromethylcarbonyl and tert-butoxycarbonyl. Z is halogen such as chlorine, bromine, or iodine, or paratoluenesulfonyloxy (tosyloxy), methanesulfonyloxy (mesyloxy), or the like.

In this method, the amino group of the 3-aminopyrazole derivative (II) is protected with a protecting group Y, and the obtained compound is added to the 4-methylbiphenyl derivative (III).
Is reacted at about 0 ° C. to room temperature in the presence of a base such as NaH using DMF as a solvent to introduce a biphenyl group. Furthermore, the amino group is deprotected. The β-ketoester (V) is added to the obtained compound (IV) and cyclized by refluxing in acetic acid or acetic acid-ethanol to obtain the compound (I ′). By converting the substituent X ′ located at the 2′-position of the biphenyl group of the compound (I ′) into the desired substituent X by an arbitrary reaction, the pyrazolo [1,5-a] pyrimidine of the present invention- 7 (4H) -one derivative (I) is obtained. For example, when X ′ is a protected carboxyl group, the protecting group can be removed by hydrolysis or the like to give a free carboxylic acid. X '
When is a cyano group, it can be reacted with an azide compound to introduce a tetrazolyl group.
The compound pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (I) of the present invention in which R ³ and / or R ⁴ is a substituted alkoxycarbonyl group can be prepared by previously preparing R ³ and / or R ⁴ After synthesizing the compound of the present invention in which is a carboxyl group, the above-mentioned carboxyl group is reacted with an alkyl halide having a desired substituent, etc., and an alkoxycarbonyl group substituted with the desired substituent is converted into R ³
And / or it is also possible to synthesize by introducing into R ⁴ . In this reaction, other reactive groups in the molecule are protected with optional protecting groups, if necessary.

Further, the pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative of the present invention in which R ² is H (I-1) can be obtained by the following method, for example.

[0027]

[Chemical 5]

Where R ¹ , R ³ , R ⁴ and X are as defined in formula (I), R ⁶ , R ⁷ and R
⁸ is lower alkyl and the like. M is an alkali metal such as potassium or sodium. X ′ and Z are the same as defined in Scheme 1 above.

In this method, ester (VI) is condensed with formic acid ester in the presence of alkoxide to obtain ester (VII) having an enol moiety. This ester (VII) and the 3-aminopyrazole derivative (II) are cyclized by refluxing in acetic acid or acetic acid-ethanol to give an intermediate pyrazolo [1,5-a] pyrimidine-7 (4H ) -One derivative (VIII) is obtained. 4-methylbiphenyl derivative (III) is added to this compound (VIII),
Using DMF or the like as a solvent and reacting at about 0 ° C. to room temperature in the presence of a base such as NaH, a compound (I′-1) having a biphenyl group introduced is obtained. By converting the substituent X ′ located at the 2′-position of the biphenyl group of the compound (I′-1) into the desired substituent X by an arbitrary reaction in the same manner as in the scheme 1, R ² A pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (I-1) of the present invention wherein H is H is obtained. The compound pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (I) of the present invention in which R ³ and / or R ⁴ is a substituted alkoxycarbonyl group can be prepared by previously preparing R ³ and / or R ⁴ After synthesizing the compound of the present invention in which is a carboxyl group, the above-mentioned carboxyl group is reacted with an alkyl halide having a desired substituent or the like to form an alkoxycarbonyl group substituted with the desired substituent with R ³ and / or It is also possible to synthesize it by introducing it into R ⁴ . In this reaction, other reactive groups in the molecule are protected with optional protecting groups, if necessary.

The pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (I) of the present invention is angiotensin.
It may be used as an II receptor antagonist, especially as an antihypertensive agent, and is useful in the control of angiotensin II-induced or exacerbated hypertension, and in the treatment of congestive heart failure and the like.

The pharmaceutical composition containing the compound (I) of the present invention is administered orally or parenterally. Examples of parenteral administration include intravenous injection, intramuscular injection, intraperitoneal injection, and drip infusion. The pharmaceutical composition may be administered as a prodrug. The pharmaceutical composition of the pharmaceutical composition may be powder, granules,
Examples include tablets, capsules, injections, solutions, suspensions, emulsions and suppositories. In addition to the compound (I) of the present invention, the above-mentioned preparations include, in addition to the pharmaceutically and pharmacologically acceptable excipients, auxiliaries, stabilizers, wetting agents, emulsifiers, other Known compounds such as additives can be arbitrarily selected and used.

The dose varies depending on the disease, condition, subject to be administered, administration method, etc., but when administered as a therapeutic agent for adult essential hypertension, the daily dose is 1 to 50 by oral administration.
In the case of intravenous injection, the daily dose of 1 to 30 mg is preferably administered once or in 2 to 3 divided doses.

The effect of the pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative of the present invention as an angiotensin II receptor antagonist can be evaluated by, for example, the following method. First, the membrane components prepared from rat liver and ¹²⁵
The compound of the present invention is added to the mixture with I-labeled angiotensin II at various concentrations and incubated. From the radioactivity of ¹²⁵ I-labeled angiotensin II bound to the membrane component, the concentration of the compound of the present invention that inhibits the specific binding of ¹²⁵ I-labeled angiotensin II to the membrane component by 50% (IC ₅₀ ) was obtained. , Inhibition constant (Ki) is determined.

[0034]

[Equation 1]

Where C is ¹²⁵ I-labeled angiotensin I
I concentration and Kd are dissociation constants of angiotensin II.

As is apparent from the examples described below, the pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative of the present invention exhibits an excellent angiotensin II receptor antagonistic action.

[0037]

EXAMPLES The present invention will be described below based on Examples and Reference Examples. Reference Example 1 Ethyl 6-n-butyl-pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate (intermediate)
Production of (VIIIa)

[0038]

[Chemical 6]

Potassium t-butoxide (2.50 g, 22.3mmo
l) in THF (20 mL) at room temperature with ethyl hexanoate (1.44 g, 10.0 mmol) and ethyl formate (1.60 g, 21.6 mm).
ol) in THF (5 mL) is added dropwise. After stirring for 3 hours, the reaction solution is concentrated under reduced pressure. Partition the residue between ice water (20 mL) and ether (20 mL). Then the aqueous layer is hydrochloric acid (2 mL)
Acidify with. The resulting oil was washed with ether (20 mL) 2
Extract twice. After drying the extract over anhydrous magnesium sulfate,
Evaporation of the solvent gives 1.19 g of oil. Dissolve this in ethanol (5 mL), add 3-amino-4-ethoxycarbonylpyrazole (700 mg, 4.51 mmol) and acetic acid (1 mL), and reflux for 12 hours. After cooling, the product was collected by filtration and washed several times with ethyl acetate to give 900 mg (yield 76
%) Of the title compound. Recrystallization of this product from ethanol gives colorless crystals with a melting point of 293 ° C (decomposition).

Elemental analysis: Calculated as C ₁₃ H ₁₇ N ₃ O ₃ (%): C, 59.30; H, 6.51; N, 15.96 Measured value (%): C, 59.40; H, 6.53; N, 16.01 NMR (CDCl ₃ -CD ₃ OD) δ: 0.95 (3H, t, J = 7Hz), 1.39 (3H,
t, J = 7Hz), 1.32-1.65 (4H, m), 2.55 (2H, t, J = 7Hz), 4.3
6 (2H, q, J = 7Hz), 7.53 (1H, s), 8.18 (1H, s).

Reference Example 2 Pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (intermediate) (VIIIb) to (VIII
Production of g) According to Scheme 2 above and according to Reference Example 1 below Table 1
To obtain compounds (VIIIb) to (VIIIg). The physical properties of the obtained compound are shown in Tables 1 and 2 below.

[0042]

[Chemical 7]

[0043]

[Table 1]

[0044]

[Table 2]

Reference Example 3 Ethyl 6-n-butyl-4-[(2 '
-Cyanobiphenyl-4-yl) methyl] -pyrazolo [1,5-
a] Preparation of pyrimidine-7 (4H) -one-3-carboxylate (intermediate) (I'-1a)

[0046]

[Chemical 8]

DMF (20 mg of ethyl 6-n-butyl-pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate (520 mg 1.97 mmol) (VIIIa) obtained in Reference Example 1 m
L) The suspension is heated at 60 ° C for 15 minutes. Allow the solution to come to room temperature and add sodium hydride (90 mg, 60% mineral oil). Next, 4-bromomethyl-2'-cyanobiphenyl (700 mg, 2.57 mmol) is added and the mixture is stirred for 4 hours. Then, the reaction solution is added to ice water and extracted three times with ethyl acetate. The organic layer is washed 3 times with water, washed with saturated saline and then dried. Ethyl acetate is distilled off and the resulting residue is purified by silica gel column chromatography. Fractions eluting with ethyl acetate-n-hexane (1: 1, v / v) were concentrated and crystallized with n-hexane to give 660 mg (yield: 73.5%) of the title compound. This product is recrystallized from ethyl acetate-n-hexane to give colorless crystals with a melting point of 135-136 ° C.

Elemental analysis: Calculated as C ₂₇ H ₂₆ N ₄ O ₃ (%): C, 71.35; H, 5.57; N, 12.33 Measured value (%): C, 71.44; H, 5.85; N, 12.01 NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.4Hz), 1.35 (3H, t, J =
7.2Hz), 1.24-1.68 (4H, m), 4.29 (2H, q, J = 7.2Hz), 6.0
2 (2H, s), 7.24-7.80 (9H, m), 8.32 (1H, s).

Reference Example 4 Pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (intermediate) (I'-1b) to (I '
Preparation of -1 g) According to Scheme 2 above and according to Reference Example 2 below Table 3
Compounds (I'-1b) to (I'-1g) shown in are obtained. Physical properties of the obtained compound are shown in Tables 3 and 4 below.

[0050]

[Chemical 9]

[0051]

[Table 3]

[0052]

[Table 4]

Example 1 Ethyl 6-n-butyl-4-[[2 '
Preparation of-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate (Ia)

[0054]

[Chemical 10]

Ethyl 6-n-butyl-4-obtained in Reference Example 3
[(2'-Cyanobiphenyl-4-yl) methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate (I'-1a) (560 mg, 1.23 mmol) A suspension of trimethyltin azide (510 mg, 2.48 mmol) in xylene (10 mL) is heated under reflux at 110 ° C for 24 hours. After cooling, the precipitate is collected by filtration, washed with xylene, and then suspended in ethanol (10 mL). Add 1N hydrochloric acid (4 mL) to this and stir at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is partitioned between dichloromethane and water. The pH of the aqueous layer is adjusted to 3-4 and the dichloromethane layer is extracted. Extract twice with dichloromethane and dry the organic layer. The solvent is distilled off, and the resulting residue is purified by silica gel column chromatography. The fraction eluted with chloroform-methanol (20: 3, v / v) was concentrated and crystallized with ether to yield 420 mg (yield: 68.5
%) Of the title compound. Recrystallization of this product from ethanol-ethyl acetate gives colorless crystals with a melting point of 223-225 ° C.
This is the compound of the invention, the pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (Ia).

Elemental analysis: Calculated as C ₂₇ H ₂₇ N ₇ O ₃ (%): C, 65.18; H, 5.47;
N, 19.71 Found (%): C, 65.17; H, 5.55; N, 19.60 NMR (CDCl 3) δ: 0.88 (3H, t, J = 7.4Hz), 1.32 (3H, t, J = 7
Hz), 1.20-1.62 (4H, m), 2.49 (2H, t, J = 7.8Hz), 4.25
(2H, q, J = 7.4Hz), 5.90 (2H, s), 7.00 and 7.O5 (2H ×
2, ABq, J = 9Hz), 7.33-7.58 (4H, m), 7.87-7.92 (1H, m),
8.17 (1H, s).

(Example 2) 6-n-butyl-4-[[(2'-1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl]-
Production of pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylic acid (Ib)

[0058]

[Chemical 11]

Ethyl 6-n-butyl-4-obtained in Example 1
[[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-a] pyrimidine-7 (4H)-
On-3-carboxylate (Ia) (370 mg, 0.74 mmo
l) To the ethanol suspension, add 4N NaOH (2.5 mL),
Reflux for 1 hour. After cooling, the reaction solution is concentrated under reduced pressure. Dissolve the obtained residue in water, wash once with ethyl acetate, and acidify the aqueous layer with 1N hydrochloric acid (12 mL). The precipitated crystals are collected by filtration, washed several times with water, and then dried under reduced pressure at 70 ° C.
290 mg (yield: 83%) of the title compound are obtained. Recrystallization of this product from methanol gives colorless crystals with a melting point of 252-254 ° C. This is the compound of the invention, the pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (Ib).

Elemental analysis: Calculated as C ₂₅ H ₂₃ N ₇ O ₃ (%): C, 63.96; H, 4.94; N, 20.88 Measured value (%): C, 63.75; H, 5.14; N, 20.76 NMR (DMSO-d ₆ ) δ: 0.89 (3H, t, J = 7Hz), 1.20-1.62 (4H,
m), 2.44 (2H, t, J = 7.4Hz), 5.99 (2H, s), 7.06 and
7.12 (2H × 2, ABq, J = 8.6Hz), 7.50-7.68 (4H, m), 8.05
(1H, s), 8.24 (1H, s).

Example 3 Preparation of Pyrazolo [1,5-a] pyrimidin-7 (4H) -one Derivatives (Ic) to (Ip) According to Scheme 2 above and according to Examples 1 and 2, the following table is obtained. Compounds (Ic) to (Ip) shown in 5 are obtained. Physical properties of the obtained compound are shown in Tables 5 and 6 below.

[0062]

[Chemical 12]

[0063]

[Table 5]

[0064]

[Table 6]

[0065]

[Table 7]

[0066]

[Table 8]

The names of the compounds shown in Tables 5 to 8 are shown below: Ic: ethyl 6-ethyl-4-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-
a] Pyrimidin-7 (4H) -one-3-carboxylate Id: 6-ethyl-4-[[2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylic acid Ie: ethyl 6-ethoxy-4-[[2 '-(1H-tetrazole
-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5
-a] pyrimidin-7 (4H) -one-3-carboxylate If: 6-ethoxy-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1 , 5-a]
Pyrimidin-7 (4H) -one-3-carboxylic acid Ig: ethyl 6-n-propyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1 , 5-a] Pyrimidin-7 (4H) -one-3-carboxylate Ih: 6-n-propyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -Pyrazolo 〔1,5-a〕
Pyrimidin-7 (4H) -one-3-carboxylic acid Ii: ethyl 2-ethyl-6-n-propyl-4-[[2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl]-
Pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate Ij: 2-ethyl-6-n-propyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl -4-yl] methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylic acid Ik: ethyl 6-n-pentyl-4-[[2 '-(1H-tetrazole- 5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate Il: 6-n-pentyl-4-[[2 '-( 1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-a]
Pyrimidin-7 (4H) -one-3-carboxylic acid Im: ethyl 6-cyclopropyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1, 5-a] pyrimidin-7 (4H) -one-3-carboxylate In: 6-cyclopropyl-4-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-
a] Pyrimidin-7 (4H) -one-3-carboxylic acid Io: ethyl 6-n-propyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-a] Pyrimidin-7 (4H) -one-2-carboxylate Ip: 6-n-propyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] Methyl] -pyrazolo [1,5-a]
Pyrimidin-7 (4H) -one-2-carboxylic acid.

(Example 4) 6-n-propyl-4-[[2 '-(N-
Triphenylmethyltetrazol-5-yl) biphenyl-
4-yl] methyl] -pyrazolo [1,5-a] pyrimidine-
Production of 7 (4H) -one-3-carboxylic acid

[0069]

[Chemical 13]

6-n-propyl-4-obtained in Example 3
[[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylic acid (Ih) (1.05 g , 2.30 mmol) is suspended in dichloromethane (25 mL). Then trityl chloride (0.
77 mg, 2.76 mmol), triethylamine (0.28 g, 2.76 mm
ol) is added and the mixture is stirred at room temperature for 2 hours. The reaction solution is washed with water and dried. The solvent is distilled off and the residue is purified by silica gel column chromatography. Fractions eluting with ethyl acetate-methanol (4: 1, v / v) were concentrated and treated with n-hexane to give 1.05 g (65%) of the title compound as a powder.

NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.2Hz), 1.
45-1.65 (2H, m), 2.42 (2H, t, J = 7.4Hz), 5.80 (2H, s),
6.85-6.95 (8H, m), 7.05-7.55 (15H, m), 7.87-7.95 (1
H, m), 8.34 (1H, s).

Example 5 1- (Cyclohexyloxycarbonyloxy) ethyl 6-n-propyl-4-[[2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl]-
Preparation of pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylate (Iq)

[0073]

[Chemical 14]

6-n-propyl-4-obtained in Example 4
[[2 '-(N-triphenylmethyltetrazol-5-yl)
Biphenyl-4-yl] methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-carboxylic acid (350 mg, 0.50 mmol)
In DMF (3.5 mL) solution of potassium carbonate (85 mg, 0.60 mmol)
And stir at room temperature for 20 minutes. Then, sodium iodide (76 mg, 0.50 mmol) and 1-chloroethyl cyclohexyl carbonate (160 mg, 0.77 mmol) were added, and the mixture was stirred at 50 ° C for 22 hr. Water is added to the reaction solution, extracted with ethyl acetate, washed with water and dried. The solvent is distilled off, and the resulting residue is purified by silica gel column chromatography. Concentrate the fractions eluting with n-hexane-ethyl acetate (1: 1, v / v) to give 400 mg of oil. Add this to methanol (10 m
Dissolve L) in dichloromethane (5 mL), add 1N hydrochloric acid (2 mL), and stir for 2 hours. The reaction mixture is concentrated, water is added, the mixture is extracted with dichloromethane, washed with water, and dried. The solvent is distilled off and the residue is purified by silica gel column chromatography. 170 mg when the fractions eluting with chloroform-methanol (20: 3, v / v) were concentrated and crystallized from ethanol.
(54%) of the title compound is obtained. Recrystallization of this product from ethanol gives colorless crystals with a melting point of 222-224 ℃. This is the compound of the present invention, a pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative (Iq).

Elemental analysis: Calculated value as C ₃₃ H ₃₅ N ₇ O ₆ (%): C, 63.35; H, 5.64; N, 15.67 Measured value (%): C, 63.30; H, 5.71; N, 15.65 NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.4Hz), 1.15-1.90 (15
H, m), 2.52 (2H, t, J = 7.8Hz), 4.42-4.60 (1H, m), 5.73
and 6.00 (2H, ABq, J = 16.4Hz), 6.86 (1H, q, J = 5Hz), 7.0
4 and 7.13 (2H × 2, ABq, J = 6.4Hz), 7.35-7.60 (4H, m),
7.59-7.99 (1H, m), 8.21 (1H, s).

Example 6 Preparation of Pyrazolo [1,5-a] pyrimidin-7 (4H) -one Derivatives (Ir) and (Is) According to Scheme 2 above and according to Examples 4 and 5, the following table is obtained. The compounds (Ir) and (Is) shown in 9 are obtained.

Example 7 Preparation of Pyrazolo [1,5-a] pyrimidin-7 (4H) -one Derivatives (It) and (Iu) According to Scheme 1 above, the compounds (I
t) and (Iu) are obtained.

[0078]

[Chemical 15]

[0079]

[Table 9]

The names of the compounds in Table 9 are shown below: Ir: pivaloyloxymethyl 6-n-butyl-4-[[2'-
(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5-a] pyrimidin-7 (4H) -one-3-
Carboxylate Is: 1- (cyclohexyloxycarbonyloxy) ethyl 6-n-butyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1,5- a)
Pyrimidin-7 (4H) -one-3-carboxylate It: Ethyl 5-n-propyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrazolo [1 , 5-a] Pyrimidin-7 (4H) -one-3-carboxylate Iu: 5-n-propyl-4-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -Pyrazolo [1,5-a]
Pyrimidin-7 (4H) -one-3-carboxylic acid (Iu).

(Example 8) ¹²⁵ I-labeled angiotensin I
Evaluation of Inhibitory Effect of Pyrazolo [1,5-a] pyrimidin-7 (4H) -one Derivatives on Receptor Binding of I. A membrane component was prepared from rat liver and the compound of the present invention was added to 10 ^−6.
100 pM with or without addition in the range of M to ^{10 -10} M
Incubated with ¹²⁵ I-labeled angiotensin II at 25 ° C. for 1 hour. After the reaction was completed, ¹²⁵ I-labeled angiotensin II bound to the membrane component was separated by a glass fiber filter paper,
Radioactivity was measured with a gamma counter. The specific binding of ¹²⁵ I-labeled angiotensin II to the membrane component was determined by subtracting the nonspecific binding obtained under the condition containing 10 ⁻⁶ M of non-radioactive angiotensin II from the total binding. Concentration (IC ₅₀ ) of the compound of the present invention which inhibits the specific binding of ¹²⁵ I-labeled angiotensin II to membrane components by 50%
The inhibition constant (Ki) was calculated from the following equation (Table 1)
0).

[0082]

[Equation 2]

[0083]

[Table 10]

Where C is ¹²⁵ I-labeled angiotensin I
I concentration (100 pM) and Kd are dissociation constants of angiotensin II (1.3 nM).

As described above, the pyrazolo [1,5-
It is understood that the a] pyrimidin-7 (4H) -one derivative has a strong inhibitory action and can effectively bind to the angiotensin II receptor.

Claims (11)

[Claims] 1. A pyrazolo [1,5-
a] Pyrimidin-7 (4H) -one derivative: (In the formula, R ¹ and R ² are each independently a group selected from the group consisting of hydrogen, an optionally substituted alkyl group, a cycloalkyl group, and an alkoxy group, and R ³
And R ⁴ are each independently a group selected from the group consisting of hydrogen, an alkyl group, an optionally substituted alkoxycarbonyl group, a carboxyl group or a salt thereof, and a tetrazolyl group or a salt thereof, and X is a carboxyl group. Or a salt thereof, and a group selected from the group consisting of a tetrazolyl group or a salt thereof). 2. R ¹ is an alkyl group, R ² is hydrogen, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen,
The pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative according to claim 1, wherein X is a tetrazolyl group. 3. The compound according to claim 2, wherein R ¹ is butyl. 4. The compound according to claim 2, wherein R ¹ is propyl. 5. The pyrazolo [1,5-a] according to claim 1, wherein R ¹ is an alkoxy group, R ² is hydrogen, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen and X is a tetrazolyl group. Pyrimidin-7 (4H) -one derivative. 6. The pyrazolo [1,5-a] according to claim 1, wherein R ¹ is an alkyl group, R ² is hydrogen, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is an alkyl group, and X is a tetrazolyl group. ] Pyrimidin-7 (4H) -one derivative. 7. R ¹ is a cycloalkyl group, R ² is hydrogen, R ³
Is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen, and X is a tetrazolyl group. The pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative according to claim 1. 8. The pyrazolo [1,5-a] according to claim 1, wherein R ¹ is an alkyl group, R ² is hydrogen, R ³ is hydrogen, R ⁴ is an alkoxycarbonyl or carboxyl group, and X is a tetrazolyl group. Pyrimidin-7 (4H) -one derivative. 9. R ¹ is hydrogen, R ² is an alkyl group, R ³ is an alkoxycarbonyl or carboxyl group, R ⁴ is hydrogen,
The pyrazolo [1,5-a] pyrimidin-7 (4H) -one derivative according to claim 1, wherein X is a tetrazolyl group. 10. The pyrazolo [1,5-as claimed in claim 1.
a] An angiotensin II receptor antagonist containing a pyrimidine-7 (4H) -one derivative. 11. The pyrazolo [1,5-as claimed in claim 1.
a] An antihypertensive agent containing a pyrimidin-7 (4H) -one derivative.