JPH0632782A - Pyrazole derivative and method for producing the same and medicine containing the same - Google Patents

Abstract

(57) [Summary] [Structure] The following general formula (I): (In the formula, A is an oxygen atom when it is bonded to the carbon of the pyrazol ring by a double bond, and is an -OR ₄ group when it is bonded to the carbon of the pyrazol ring by a single bond. R ₁ Is a hydroxycarbonyl group or a tetrazole group, R ₂ is a hydrogen atom,
A methyl, n-butyl or propionyl group, R ₃ represents a hydrogen atom, a methyl or phenyl group, and R ₄ represents a hydrogen atom, a methyl or propionyl group. ) Or a pharmaceutically usable salt thereof and a method for producing the same. [Effect] A novel pyrazol derivative having angiotensin II receptor antagonistic activity, which is excellent as a therapeutic agent for hypertension and congestive heart failure and an intraocular pressure-lowering agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrazole derivative, a method for producing the same, and a therapeutic agent for hypertension and congestive heart failure containing the same.

[0002]

2. Description of the Related Art Various drugs have been developed as therapeutic agents for hypertension or congestive heart failure or agents for lowering intraocular pressure. By the way, in the renin-angiotensin system, the plasma protein angiotensinogen becomes angiotensin I by the enzyme renin, and angiotensin I becomes the final product angiotensin II by the angiotensin converting enzyme. This angiotensin II is a substance having a strong vasoconstrictor action that exerts its action by interacting with a specific receptor existing on the cell membrane as the final product of the renin-angiotensin system. It is previously known that the development of hypertension and congestive heart failure are associated with this angiotensin II. A method using an angiotensin II receptor antagonist is known as part of the development of a therapeutic agent for hypertension or congestive heart failure or an intraocular pressure-lowering agent.

However, it is known that some peptide derivatives block their hormonal effects by antagonizing the receptor. However, all of these peptide derivatives lack oral activity and their clinical application is limited. In recent years, non-peptide compounds have been attracting attention as a supplement to these drawbacks. And recently, some non-peptide compounds have been reported as angiotensin II receptor antagonists.
For example, regarding imidazole derivatives, JP-A 1-1
It is reported in Japanese Patent No. 17876 and Japanese Patent Laid-Open No. 3-2169. Regarding the pyrimidine derivative, JP-A-3-
19744, JP-A-3-44377, and JP-A-3-133964, and regarding pyrazole derivatives, JP-A-1-287071 and JP-A-3-21.
8371.

Further, regarding such a compound, JP-A-3-5480, JP-A-3-5464,
"Journal of Medicinal Chemistry" 3
3, 1312 (1990), "Journal of Medicinal Chemistry" 33, 1330 (1990),
"Journal of Medicinal Chemistry" 3
4, 1514 (1991), "Journal of Medicinal Chemistry" 34, 2525 (1991) and the like.

[0005]

DISCLOSURE OF THE INVENTION The present invention finds a novel pyrazol derivative having angiotensin II receptor antagonistic activity, and provides a therapeutic agent for hypertension and congestive heart failure or an intraocular pressure-lowering agent, that is, hypertension. And a novel pyrazole derivative useful as a therapeutic agent for congestive heart failure or an intraocular pressure-lowering agent.

[0006]

The present invention has the general formula (I)

[0007]

[Chemical 5]

(In the formula, A is a ═O group when it is bonded to the carbon of the pyrazole ring by a double bond, and is an —OR ₄ group when it is bonded to the carbon of the pyrazole ring by a single bond. R ₁ is a hydroxycarbonyl or tetrazole group, R ₂ is a hydrogen atom, methyl, n-butyl or propionyl group, R ₃
Is a hydrogen atom, a methyl or phenyl group, R ₄ is a hydrogen atom,
Represents a methyl or propionyl group. ) Is a compound or a pharmaceutically usable salt thereof. The novel pyrazole derivative of the present invention represented by the general formula (I) has a high blood pressure,
It is an angiotensin II receptor antagonist useful as a therapeutic agent for congestive heart failure and decreased intraocular pressure.

The novel pyrazole derivative of the present invention is exemplified below. (1) 3-n-butyl-4- [2 '-(hydroxycarbonyl) -biphenyl-4-yl] -methyl-pyrazol-5-one (Compound 1) (2) 3-n-butyl-4 -[2 '-(tetrazole-
5-yl) -biphenyl-4-yl] -methyl-pyrazol-5-one (Compound 2) (3) 1-methyl-n-butyl-4- [2 '-(hydroxycarbonyl) -biphenyl-4 -Yl] -methyl-pyrazol-5-one (Compound 3) (4) 1-methyl-n-butyl-4- [2 '-(tetrazol-5-yl) -biphenyl-4-yl] -Methyl-pyrazol-5-one (Compound 4) (5) 1-phenyl-3-n-butyl-4- [2'-
(Hydroxycarbonyl) -biphenyl-4-yl]
-Methyl-pyrazol-5-one (Compound 5)

(6) 1-phenyl-3-n-butyl-4
-[2 '-(Tetrazol-5-yl) -biphenyl-
4-yl] -methyl-pyrazol-5-one (Compound 6) (7) 2-methyl-3-n-butyl-4- [2 '-(tetrazol-5-yl) -biphenyl-4 -Yl] -methyl-5-hydroxy-pyrazole (Compound 7) (8) 2-methyl-3-n-butyl-4- [2 '-(tetrazol-5-yl) -biphenyl-4- Iyl] -methyl-5-methoxy-pyrazol (Compound 8) (9) 2-n-butyl-3-n-butyl-4- [2'-
(Tetrazol-5-yl) -biphenyl-4-yl]
-Methyl-5-hydroxy-pyrazole (Compound 9) (10) 2-propionyl-3-n-butyl-4-
[2 '-(tetrazol-5-yl) -biphenyl-4
-Yl] -methyl-5-propionyloxy-pyrazo-
Le (compound 10)

The compounds of formula (I) according to the invention are AOFitto
n, RK Smalley, `` Practical Heterocyclic Chemistry; A
“Cadmic” (1968, P24), KRHenery-Logan and others “J. Heter
ocycl.Chem. ”(1970, 7,923.) and H. Don et al.“ Heterocyc
l.Compd. (Engl.Transl.) "(1980, 16, 1). The method for producing the novel pyrazole compound of the present invention will be described in detail below. The novel pyrazole compound of the present invention has the following general formula (II)

[0012]

[Chemical 6]

(Wherein R ₅ represents a methoxycarbonyl group or a trityltetrazole group and R ₆ represents a lower alkyl group) and a β-ketoester represented by the general formula H ₂ N-NH.
-R ₃ (wherein R ₃ represents a hydrogen atom, a methyl or a phenyl group) is reacted with hydrazine to give a compound represented by the following general formula (III):

[0014]

[Chemical 7]

(In the formula, A is an ═O group when it is bonded to the carbon of the pyrazol ring by a double bond, and is an —OR ₄ group when it is bonded to the carbon of the pyrazol ring by a single bond. R ₅ is a methoxycarbonyl group or a trityltetrazole group, R 5
₂ represents a hydrogen atom, a methyl, n-butyl or propionyl group, R ₃ represents a hydrogen atom, a methyl or phenyl group, and R ₄ represents a hydrogen atom, a methyl or propionyl group. ), And then hydrolyzing it to form a methoxycarbonyl group or a trityltetrazole group into a hydroxycarbonyl or tetrazole group.

That is, the novel pyrazol compound of the present invention is obtained by reacting a β-ketoester having an R ₅ group with a hydrazine having an R ₃ group to give a 1-substituted pyrazole-5.
-Produce and produce on. For example, in the case of synthesizing compound 1 to compound 6, as shown in the following chemical formula 8, β-keto ester (1) is reacted with hydrazine to synthesize tautomer (2) or (3). When R ₅ is trityl tetrazole and R ₃ is hydrogen, methyl or phenyl, or when R ₅ is methoxycarbonyl and R ₃ is hydrogen, the pyrazole compound of formula (2) is obtained. When R ₅ is methoxycarbonyl and R ₃ is a methyl group or a phenyl group, the pyrazole compound of the formula (3) is obtained. In these cases,
As the solvent, methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide or the like is used, and the reaction temperature can be from room temperature to reflux.

[0017]

[Chemical 8]

(Wherein R ₃ is a hydrogen atom, a methyl or phenyl group, R ₅ is —COOCH ₃ or a trityltetrazole group, and R ₆ is a lower alkyl group.) Next, as shown in the following formula 9. In addition, R ₅ of the pyrazole compound (2) or (3) is changed to a desired group. That is, when R ₅ is methyl ester (a), it is converted to hydroxycarbonyl by hydrolysis with 10% aqueous hydrochloric acid to obtain the compound (Ia) of the present invention. When R ₅ is trityl tetrazole (b), it is converted to tetrazole by hydrolysis with 75% acetic acid water and the compound of the present invention (I
b) is obtained.

[0019]

[Chemical 9]

(In the formula, R ₅ is —COOCH ₃ or a trityltetrazole group, and R ₃ is a hydrogen atom, a methyl or a phenyl group.) In the pyrazole compound of the present invention, a substituent at the 2-position or the 5-position. The compound having: can be obtained by reaction with a suitable halide. The following chemical formula 10 is a 2-substituted pyrazo-
1 shows the synthetic route of 2- or 5-position substituted pyrazol [compound 7 to compound 10]. That is, the pyrazole compound (4) is treated with an appropriate halide (lower alkyl halide or acyl halide) and then decomposed with a silica gel column. A 2-position substitution product (5) and 2-position and 5-position (carbonyl) substitution product (6) are obtained. As the reaction solvent, chloroform, methylene chloride, tetrahydrofuran, dimethylformamide or the like is used. As the base, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine and the like are used. The pyrazole compound (5) or (6) was hydrolyzed with 75% acetic acid to obtain the pyrazole compound (Ic) or (Id) of the present invention.

[0021]

[Chemical 10]

(Wherein X is a chlorine or bromine atom, R ₂ is a methyl, n-butyl or --COC ₂ H ₅ group, and R ₄ is a hydrogen atom, methyl, n-butyl or --COC ₂ H ₅ group. The β-keto ester (1), which is the starting material compound of the present invention, is produced by the following formula. That is, the halogenomethylbiphenyl derivative (7) and ethyl-3-oxaheptanoe-
(8) and (8) can be obtained by treating with sodium hydride in tetrahydrofuran (THF).

[0023]

[Chemical 11]

(In the formula, R ₅ is —COOCH ₃ or a trityltetrazole group, and R ₆ is a lower alkyl group.) Next, a method for producing the above halogenomethylbiphenyl compound (7) will be described. The halogenomethylbiphenyl compound (7) is first prepared by the method of Meyer, AI et al. [J. Am .. Chem. Soc., 97, 7383 (1975)] shown in Chemical formula 12 below.
An oxazoline compound (9) is reacted with a Grignard reagent to produce a methylbiphenyl compound (10), and this methylbiphenyl compound (10) is used as a raw material for production.
The above oxazoline compound (9) has the following formula
Meyer, AI, etc. [J.Org.Chem.39,2787 (1974)]
It can be obtained from the acid chloride (11) by the method (1).

[0025]

[Chemical 12]

[0026]

[Chemical 13]

The following formula 14 shows a process of synthesizing the halogenomethylbiphenyl compound (7) from the above-mentioned methylbiphenyl compound (10) as a raw material.

[0028]

[Chemical 14]

That is, the methylbiphenyl compound (1
0) is hydrolyzed to form a carboxylic acid compound (12),
This is esterified to obtain a methyl ester compound (13), and then halogenated to obtain a halogenomethyl biphenyl derivative (7a). Alternatively, the carboxylic acid compound (12) is converted to the acid amide (14) and then dehydrated with SOCl ₂ , or by using Dordor, IM, etc. (Tetra Let. 24, 1437).
(1983)) and methylbiphenyl compound (1
0) is treated with POCl ₃ to give a nitrile compound (15), which is heated in tributyltin azide (Bu ₃ SnN ₃ ) and toluene to give tributyltin tetrazole (16). ) And NaOH
Debutyltin, followed by trityl chloride (Ph
Tritylation is carried out with ( ₃ CCl) to give trityltetrazole (17), which is then halogenated to obtain a halogenomethylbiphenyl derivative (7b).

The pyrazol derivative of the present invention acts as an angiotensin II receptor antagonist and is useful as a therapeutic agent for hypertension or congestive heart failure or an intraocular pressure-lowering agent. The pharmacological test for angiotensin II receptor antagonism is shown below. This pharmacological test is based on Wong, PC, etc. (Hyp
ertension 15,823,1990), using the thoracic aorta of rabbits, the antagonistic action against contraction by angiotensin II was examined, and from the dose-effect curve, the method of Schild (Br.J.Pharmacol.14,48,1959) Then, PA ₂ was obtained. The results are shown in Table 1.

[0031]

[Table 1]

[0032]

EXAMPLES The present invention will be described in more detail with reference to Examples. Example 1. 3-n-butyl-4- [2 '-(hydroxycarbonyl) -biphenyl-4-yl] methyl-pyrazole-5
-Example of production of one (Compound 1). (A) Production of ethyl-2- (2'-methoxycarbonyl-biphenylmethyl) -3-oxoheptanoate. NaH (60% in mineral oil, 225 mg, 5.63 mmol) was added to anhydrous TH under an argon atmosphere.
Ethyl-3-oxaheptanoe dissolved in 20 ml of F
Solution (969 mg, 5.63 mmol) was added in small portions. After the addition was complete the mixture was stirred for 30 minutes then 4-bromomethyl-dissolved in anhydrous THF (10 ml).
2'-methoxycarbonyl-biphenyl (1.717
g, 5.63 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under vacuum. 50 ml of water was added and the mixture was extracted with 70 ml of ethyl acetate. The organic layer was washed with 50 ml of water and then with 20 ml of saturated saline, dehydrated (Na ₂ SO ₄ ), evaporated under reduced pressure, and the residue was subjected to silica gel chromatography [hexane: ethyl acetate (10:
1)] to obtain 1.57 g of the target compound as a colorless oil.

IR cm ~ ¹ : 2944, 1719, 144
6, 1368, 1245, 1194, 1155, 108
9, 1044, 762, MS (M / Z): 396, 311 (M +), 279, 2
33, 193, 165, 85, 57 (BP), NMR δ (CDCl ₃ ) ppm: 0.86 (t-lik
_{e, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.1~1.7
_{(M, 4H, CH 3 CH} 2 CH 2 CH 2 -), 1.21
(T, 3H, J = 8, COOCH ₂ CH ₃ ), 2.46
(Q, 2H, J = 8 , CH 3 CH 2 CH 2 CH 2 -), 3.
18 (d, 2H, J = 7, CH 2 -Ph), 3.60
(S, 3H, COO CH ₃ ), 3.80 (t, 2H, J
= 7, CO CH CO), 4.15 (q, 2H, J = 8,
_{COO CH 2 CH 3), 7.0~7.89} (m, 8H, A
r)

(B) Preparation of 3-n-butyl-4- [2 '-(methoxycarbonyl) -biphenyl-4-yl] -methyl-pyrazol-5-one. The compound (396 mg, 1 mmol) obtained in (a) was dissolved in 10 ml of anhydrous ethanol, hydrazine hydrate (102 mg, 2 mmol) was added, and the mixture was heated and stirred for 3 hours. After cooling, the solvent was distilled off under reduced pressure, 20 ml of water was added, and the mixture was extracted with 70 ml of ethyl acetate. After washing with 50 ml of water and then with 20 ml of saturated saline, dehydration (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform; methanol (20: 1)) to obtain the target compound. 238 mg was obtained as a pale yellow oil. IR cm ~ ¹ : 2994, 1725, 1605, 157
5,1446,1431,1284,1260,124
5 MS (M / Z): 364 (M +), 332, 303, 2
75,225 (BP), 193,153,111 NMRδ ( CDCl 3) ppm: 0.86 (t-lik
_{e, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.1~1.8
_{(Bm, 4H, CH 3 CH} 2 CH 2 CH 2 -), 2.49
(T-like, 2H, CH 3 CH 2 CH 2 CH 2 -),
3.62 (s, 3H, COO CH 3), 3.75 (s,
_{2H, CH 2 -Ph), 7.1~7.9} (m, 8H, A
r)

(C) Preparation of 3-n-butyl-4- [2 '-(hydroxycarbonyl) -biphenyl-4-yl] methyl-pyrazol-5-one (Compound 1). Compound obtained in (b) (238 mg, 0.645 mmo
l) was dissolved in 5 ml of dioxane, then 5 ml of 6N-hydrochloric acid was added, and the mixture was heated with stirring for 3 days. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography [chloroform: methanol (5: 1)] to obtain the target compound 15
7 mg was obtained as a white powder. mp. 171-173 ° C IRcm ~ ¹ : 3106, 2744, 1677, 160
8, 1575, 1254 MS (M / Z): 351 (M +
+1), 333, 305, 276, 212 (BP), 1
94, 180, 154, 112 NMR δ (CD3OD) ppm: 0.89 (t-lik)
_{e, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.1~1.7
_{(M, 4H, CH 3 CH} 2 CH 2 CH 2 -), 2.56 (t
_{-Like, 2H, CH 3 CH 2} CH 2 CH 2 -), 3.8
3 (s, 2H, CH ₂ -Ph), 7.1 to 7.9 (m,
8H, Ar)

Example 2. 3-n-butyl-4- [2 '-(tetrazol-5-yl) -biphenyl-4-yl] -methyl-pyrazol-
Production Example of 5-one (Compound 2). (A) Ethyl 2- (2'-trityltetrazole-5-
Il-biphenylmethyl) -3-oxoheptanoate (A) and ethyl 2- (2'-tetrazol-5-yl-
Biphenylmethyl) -3-oxoheptanoate (B)
Manufacturing of. NaH (60% in mineral oil, 76 mg, 2.29
mmol), ethyl-3-oxaheptanoate (39
5 mg, 2.29 mmol), 4-bromomethyl-2 '
Reaction was carried out in the same manner as in (a) of Example 1 using-(trityltetrazol-5-yl) -biphenyl (1.06 g, 1.91 mmol). Purification by silica gel chromatography [hexane / ethyl acetate (10: 1)] gave 723 mg of compound (A) and 257 of compound (B).
mg was obtained as a colorless oil.

Compound (A) IRcm ~ ¹ : 2950, 1710, 1476, 144
5,1371,1242,1155,1110,109
5,1062,1005,852,825,756,
MS (M / Z): 592 (M + -55), 520, 42.
0,243 (BP), 165 NMR δ (CDCl ₃ ) ppm 0.83 (t-lik
_{e, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.1~1.6
_{(M, 4H, CH 3 CH} 2 CH 2 CH 2 -) 1.19 (t, 3H, J = 8, COOCH 2 CH 3),
_{2.20 (q-like, CH 3} CH 2 CH 2 CH 2 -),
3.04 (d, 2H, J = 8, CH 2 -Ph), 3.6
6 (t, 1H, J = 8, CO CH CO), 4.11
(Q, 2H, J = 8, COO CH ₂ CH ₃ ), 6.8-
7.9 (m, 23H, Ar).

Compound (B) IRcm ~ ¹ : 2950, 1710, 1476, 144
5,1371,1242,1155,1110,109
5,1062,1005,852,825,756,
MS (M / Z): 406 (M +), 321 NMR δ (CDCl ₃ ) ppm: 0.7 to 1.0 (t-
_{like, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.0~
_{1.7 (m, 4H, CH 3} CH 2 CH 2 CH 2 -), 1.2
0 (t3H, J = 7, COOCH 2 CH 3), 2.25~
_{2.65 (q-like, CH 3} CH 2 CH 2 CH 2 -),
3.09 (d, 2H, J = 7, CH 2 -Ph), 3.5
5 to 3.90 (m, 1H, CO CH CO), 4.12
(Q, 2H, J = 7, COO CH ₂ CH ₃ ), 6.8-
7.9 (m, 8H, Ar)

(B) Preparation of 3-n-butyl-4- [2 '-(trityltetrazol-5-yl) -biphenyl-4-yl] methyl-pyrazol-5-one. Compound (A) obtained in (a) (3.16 g, 4.88 mm)
ol), hydrazine hydrate (293 mg, 9.7)
(6 mmol) and in the same manner as in (b) of Example 1 to obtain 1.81 g of the target compound as a colorless oil. IR cm ~ ¹ : 3412, 2920, 1602, 152
7, 1494, 1446, 744, 696 MS (M / Z): 616 (M +), 331, 289, 2
43, 211, 192 (BP), 153, 111

(C) Preparation of 3-n-butyl-4- [2 '-(tetrazol-5-yl) -biphenyl-4-yl] methyl-pyrazol-5-one (Compound 2). Compound obtained in (b) (181 mg, 0.294 mm
ol) dissolved in 10 ml of dioxane, 20% of 75% acetic acid
1 was added and the mixture was stirred at room temperature for 6 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography [chloroforum; methanol (20: 1)] to obtain 70 mg of the desired compound as a white solid. mp. 118-120 ° C IRcm- ¹ : 3406, 2920, 1740, 171.
3, 1446, 1194, 1155, 747, 699 MS (M / Z): 311 (M + -61), 279, 20.
5,149,88 (BP), 58 NMR δ (CDCl3) ppm: 0.83 (t-lik)
_{e, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.0~1.7
_{(M4H, CH 3 CH 2 CH} 2 CH 2 -), 2.40 (t-
_{like, 2H, CH 3 CH 2} CH 2 CH 2 -), 3.63
(S, 2H, CH ₂ Ph), 6.85 to 7.7 (m, 8
H, Ar)

Examples 3-4. In the same manner as in Example 1, 1
-Methyl-n-butyl-4- [2 '-(hydroxycarbonyl) -biphenyl-4-yl] -methyl-pyrazol-5-one (Compound 3: mp. 139-140 ° C)
And 1-phenyl-3-n-butyl-4- [2 '-(hydroxycarbonyl) -biphenyl-4-yl] -methyl-pyrazol-5-one (Compound 5: mp.212.
C) was obtained.

Examples 5-6. In the same manner as in Example 2, 1
-Methyl-n-butyl-4- [2 '-(tetrazole-
5-yl) -biphenyl-4-yl] -methyl-pyrazol-5-one (Compound 4: mp. 141-143 ° C)
And 1-phenyl-3-n-butyl-4- [2 '-(tetrazol-5-yl) -biphenyl-4-yl] -methyl-pyrazol-5-one (Compound 6: mp.122.
˜124 ° C.) was obtained.

Examples 7-8.2 2-Methyl-3-n-butyl-4- [2 '-(tetrazol-5-yl) -biphenyl-4-yl] methyl-5-hydroxy-pyrazo-
(Compound 7) and 2-methyl-3-n-butyl-4-
[2 '-(tetrazol-5-yl) -biphenyl-4
-Yl] methyl-5-methoxy-pyrazole (Compound 8) Production Example.

(A) 2-Methyl-3-n-butyl-4-
[2 '-(Trityltetrazol-5-yl) -biphenyl-4-yl] methyl-5-hydroxy-pyrazo-
(A) and 2-methyl-3-n-butyl-4- [2 '
-(Trityltetrazol-5-yl) -biphenyl-
Preparation of 4-yl] methyl-5-methoxy-pyrazole (B). The compound obtained in (b) of Example 2 (500 mg, 0.
813 mmol) was dissolved in 20 ml of dimethylformamide and potassium carbonate (247 mg, 1.79 mmol) was added.
And CH ₃ I (241 mg, 1.62 mmol) were added, and the mixture was stirred at room temperature for 2 days. 100 ml of ethyl acetate
Was added, and the mixture was washed with 100 ml of water and then with 20 ml of saturated saline, dehydrated (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography [hexane: ether (1: 2)]. Purification yielded 126 mg of compound (A) and 376 mg of compound (B) as colorless oils.

Compound (A) IRcm- ¹ : 3220, 2926, 1509, 146
7, 1446, 1413, 1218, 750, 696 MS (M / Z): 574 (M + -56), 407, 32.
9,243,167 (BP), 125,111 NMRδ ( CDCl 3) ppm: 0.7~0.95
_{(M, 3H, CH 3 CH} 2 CH 2 CH 2 -), 1.1~1.
_{7 (m, 4H, CH 3} CH 2 CH 2 CH 2 -), 2.2~
_{2.5 (m, 2H, CH 3} CH 2 CH 2 CH 2 -), 3.5
_{9 (s, 2H, CH 2} -Ph), 3.86 (s, 3H,
_{N- CH 3), 7.75~8.9 (m} , 23H, Ar)

Compound (B) IRcm ~ ¹ : 2944, 1512, 1449, 141
3,1218,750,696 MS (M / Z): 588 (M + -56), 420, 34.
3,181 (BP), 165, 139, 126 NMR δ (CDCl ₃ ) ppm: 0.7 to 1.09
_{(M, 3H, CH 3 CH} 2 CH 2 CH 2 -), 1.1~1.
_{7 (m, 4H, CH 2} CH 2 CH 2 -), 2.2~2.4
_{3 (m, 2H, CH 3} CH 2 CH 2 CH 2 -), 3.55
_{(S, 2H, CH 2 -Ph} ), 3.59 (s, 3H, O
_{- CH 3), 3.85 (s} , 3H, N- CH 3), 6.7
~ 7.9 (m, 23H, Ar)

(B) Compound (A) obtained in the above (a)
And (B) are detritylated in the same manner as in Example 2 to give compound 7 (mp. 75 to 77 ° C) and compound 8 (m
p. 50-51 ° C) was obtained.

Example 9. In the same manner as in Example 7, 2-n
-Butyl-3-butyl-4- [2 '-(tetrazole-
5-yl) -Biphenyl-4-yl] -methyl-5-hydroxy-pyrazyl (Compound 9) was obtained as a white solid. mp. 164-165 ° C

Example 10. 2-Propyronyl-3-n-butyl-4- (2 '-(tetrazol-5-yl) -biphenyl-4-yl) -methyl-5-propionyloxy-pyrazole (Compound 1
0) Production example. (A) 2-propionyl-3-n-butyl-4- [2 '
-(Trityltetrazol-5-yl) -biphenyl-
Preparation of 4-yl] -methyl-5-propionyloxy-pyrazole. The compound (30) obtained in (b) of Example 2
0 mg, 0.488 mmol) in 30 m of dichloromethane
It dissolves in 1 and potassium carbonate (224mg, 1.62mm
ol) was added and propionyl chloride (150 mg, 1.62 mmol) was added dropwise with vigorous stirring under ice cooling. After 1 hour, 20 ml of water was added to obtain a dichloromethane layer,
It was washed with 20 ml of saturated saline. Dehydration (Na ₂ SO ₄ )
The post-solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography [hexane: ethyl acetate (5: 1)] to obtain 274 mg of the target compound as a colorless oil.

IR cm ~ ¹ : 2944, 1785, 173
1, 1449, 1374, 1107, 753, 696 MS (M / Z): 672 (M + -55), 616, 56.
0,402,331,243 (BP), 165,11
2,57 NMR δ (CDCl ₃ ) ppm: 0.83 (t-lik
_{e, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.0~1.6
_{(M, 4H, CH 3 CH} 2 CH 2 CH 2 -), 1.16
(T, 6H, J = 7, COOCH ₂ CH ₃ , COCH ₂ C
H ₃ ), 2.34 (t-like, 2H, CH ₃ CH ₂ C
H ₂ CH ₂ −), 2.53 (q, 2H, J = 7, CO CH
₂ CH ₃ ), 3.06 (q, 2H, J = 7, COO CH _{2
CH 3), 3.53 (s,} 2H, CH 2 -Ph), 6.8
0 to 7.90 (m, 23H, Ar)

(B) 2-propionyl-3-n-butyl-4- (2 '-(tetrazol-5-yl) -biphenyl-4-yl) methyl-5-propionyloxy-pyrazole (compound Manufacturing of 10). The target compound was obtained as a white solid in the same manner as in (c) of Example 2. mp. 109-110 ° C IRcm ~ ¹ : 2926, 1782, 1731, 137
4,1110,750 MS (M / Z): 458 (M + -28), 402 (B
P), 359, 330, 288, 263, 180, 15
_{3,111,57 NMRδ (CDCl 3) ppm:} 0.88 (t-lik
_{e, 3H, CH 3 CH 2} CH 2 CH 2 -), 1.1~1.7
_{(M, 4H, CH 3 CH} 2 CH 2 CH 2 -), 1.16
(T, 6H, J = 7, COOCH ₂ CH ₃ COCH ₂ C
H ₃ ), 2.34 (t-like, 2H, CH ₃ CH ₂ C
H ₂ CH ₂ −), 2.59 (q, 2H, J = 7, CO CH
₂ CH ₃ ), 3.03 (q, 2H, J = 7, COO CH _{2
CH 3), 3.65 (s,} 2H, CH 2 -Ph), 7.0
~ 8.1 (m, 8H, Ar)

[0052]

INDUSTRIAL APPLICABILITY The pyrazol derivative of the present invention is a novel compound, has angiotensin II receptor antagonistic activity, and has excellent effects as a therapeutic agent for hypertension and congestive heart failure and an agent for lowering intraocular pressure.

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Claims (5)

[Claims] 1. The following general formula (I): (In the formula, A is a = O group when it is bonded to the carbon of the pyrazole ring by a double bond, and is an -O-R ₄ group when it is bonded to the carbon of the pyrazole ring by a single bond. R ₁ is a hydroxycarbonyl group or a tetrazole group, R ₂ is a hydrogen atom,
Methyl, n-butyl or propionyl group, R ₃ represents a hydrogen atom, methyl or phenyl group, R ₄ represents a hydrogen atom, methyl or propionyl group. ) Is a compound or a pharmaceutically usable salt thereof. 2. A β-ketoester represented by the following general formula (II): (In the formula, R ₅ represents a methoxycarbonyl group or a trityltetrazole group, and R ₆ represents a lower alkyl group) and the general formula H
₂ N-NH-R ₃ (wherein R ₃ represents a hydrogen atom, a methyl or a phenyl group) is reacted with a hydrazine represented by the general formula (III): (In the formula, A is a = O group when it is bonded to the carbon of the pyrazole ring by a double bond, and is an -O-R ₄ group when it is bonded to the carbon of the pyrazole ring by a single bond. R ₅ is a methoxycarbonyl group or a trityl tetrazole group, R ₂ is a hydrogen atom, methyl, n-butyl or propionyl group, R ₃ is a hydrogen atom, methyl or phenyl group, R ₄ is a hydrogen atom, methyl or propionyl group. A general formula (I) embedded image characterized in that a pyrazol compound represented by (In the formula, A is a = O group when it is bonded to the carbon of the pyrazole ring by a double bond, and is an -O-R ₄ group when it is bonded to the carbon of the pyrazole ring by a single bond. R ₁ represents a hydroxycarbonyl or tetrazole group, R ₂ represents a hydrogen atom, methyl, n-butyl or propionyl group, R ₃ represents a hydrogen atom, methyl or phenyl group, R ₄ represents a hydrogen atom, methyl or propionyl group. )) Or a pharmaceutically usable salt thereof. 3. A therapeutic agent for hypertension or the like containing a compound represented by the general formula (I) or a pharmaceutically usable salt thereof. 4. A therapeutic agent for congestive heart failure containing a compound represented by the general formula (I) or a pharmaceutically usable salt thereof. 5. An intraocular pressure-lowering agent containing a compound represented by the general formula (I) or a pharmaceutically usable salt thereof.