JP3025557B2 - 2-alkynyl adenosine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2-alkynyl adenosine derivative.

[0002]

2. Description of the Related Art Adenosine has been known to have a strong blood pressure lowering action and a platelet aggregation inhibitory action. However, these actions are not persistent and, on the other hand, have an effect on the heart. It also has side effects such as inhibitory action (heart rate lowering action) and central inhibitory action. Therefore, it is necessary to solve these problems when adenosine or its derivative is used as a therapeutic drug for diseases such as hypertension and angina. In order to solve such problems, various 2-substituted adenosine derivatives have been synthesized (Chem. Pharm. Bull., 23 (4),
759-774 (1975); JP-A-1-265100), these derivatives have not sufficiently solved the above-mentioned problems, and have not yet been put to practical use as pharmaceuticals.

The present inventors have succeeded in synthesizing a compound in which a specific alkynyl group having a linear carbon chain is introduced at the 2-position of adenosine (for example, Chem. Pharm.
l., 33 (4), 1766-1769 (1985)) and found that these compounds exhibited a pronounced and sustained blood pressure lowering effect and had little effect on heart rate (for example, Nuclei).
c Acids Research, Symposium Series No. 16, 97-100 (1
985); Japanese Patent Publication No. 1-333477;
No. 526). 2 having such a linear carbon chain
-Alkynyl adenosine has a strong and long-lasting pharmacological action on the circulatory organs and weak side effects in comparison with other conventional adenosine derivatives, but it is expected that a compound with further enhanced these characteristics will appear. Have been.

In recent years, blood pressure lowering action, platelet aggregation inhibitory action, etc. are expressed via adenosine A ₂ receptor (hereinafter, referred to as A ₂ receptor), while cardiac inhibitory action, central inhibitory action, etc. are caused by adenosine A ₁ receptor. body (hereinafter, referred to as a ₁ receptor) it has been reported to express through. For example, 5'-N-ethylcarboxamide adenosine (N
ECA) (Archs. Pharmacodyn., 230 , 140-149 (1977))
Is known as a compound having a high affinity for A ₂ receptor have already been used as a ligand binding assay (Mol. Pharmacol., 29, 331-346 (198
6)). However, since it has a high affinity for A ₁ receptors, side effects easily expressed as described above,
Therefore, it is not used as a therapeutic drug. Therefore, it has a high affinity for A ₂ receptor, while for A ₁ receptor if low adenosine derivatives having affinity are developed, they hypertension, ischemic heart disease, ischemic brain It is considered to be useful as a medicament for use in treating or preventing cardiovascular diseases such as diseases.

That is, an object of the present invention is to provide a strong and sustained pharmacological action such as a blood pressure lowering action, coronary vasodilator action, peripheral vasodilator action, cerebral circulation improving action, peripheral circulation improving action, and platelet aggregation inhibitory action. a ₂ is high affinity for the receptor, to provide a little side effects novel 2 alkynyl adenosine derivatives such as cardiac depression action, central inhibitory effects at one.

[0006]

Means for Solving the Problems The present inventors have proposed a novel 2-
In the process of developing alkynyl adenosine derivatives and examining their pharmacological activities in various ways,
Alkynyl adenosine derivatives exhibit high affinity for A ₂ receptor, whereas by showing a low affinity for A ₁ receptors, i.e., the selectivity for A ₂ receptor has a high compound The present invention has been completed, and furthermore, they have been confirmed to be useful as drugs for cardiovascular diseases, thereby completing the present invention.

That is, the present invention provides the following formula (I)

Embedded image Wherein R represents the formula (A) or (B):

Embedded image (In the formula, R ¹ represents an alkyl group, an aryl group, an aralkyl group or a halogenated alkyl group, and n represents an integer of 0 to 10.)

Embedded image (Wherein R ² represents a hydrogen atom, an alkyl group, an alkoxy group or a halogen atom, and n has the same meaning as described above)] (hereinafter, a 2-alkynyl adenosine derivative)
"May also be referred to as" the compound of the present invention ") and salts thereof.

[0008] 1. Compound of the Present Invention In the compound of the present invention, in the above formula (I), R is represented by the formula (A) or (B). In the formula (A), examples of the alkyl group represented by R ¹ include a linear or branched alkyl group having 1 to 20 carbon atoms. Phenyl as the aryl group,
Alternatively, a substituted phenyl group having a substituent such as halogen, alkyl, or alkoxy is exemplified. Examples of the aralkyl group include those in which a terminal hydrogen atom of the above-mentioned alkyl group is substituted with the above-mentioned aryl group. Examples of the halogenated alkyl group include an alkyl group in which a terminal hydrogen atom is substituted with a halogen atom. In the formula (B), R ²
Examples of the alkyl group and alkoxy group represented by are those having 1 to 3 carbon atoms. Incidentally, the substitution position of R ² is not intended to be identified.

Representative examples of the 2-alkynyl adenosine derivative represented by the general formula (I) are shown below. (1) 2- (3-N-acetylamino-1-propynyl) adenosine (Formula (A): R ¹ = methyl, n = 1)
(Compound 1) (2) 2- (3-N-trifluoroacetylamino-1
-Propynyl) adenosine (Formula (A): R ¹ = trifluoromethyl, n = 1) (Compound 2) (3) 2- (3-N-Heptanoylamino-1-propynyl) adenosine (Formula (A): R ¹ = (CH ₂ ) ₅ CH
₃ , n = 1) (Compound 3) (4) 2- (3-N-stearoylamino-1-propynyl) adenosine (Formula (A): R ¹ = (CH ₂ ) ₁₆ CH
₃ , n = 1) (compound 4) (5) 2- (6-N-benzoylamino-1-hexynyl) adenosine (Formula (A): R ¹ = phenyl, n = 4)
(Compound 5) (6) 2- (3-N- (p-toluoyl) amino-1-
Propinyl) adenosine (Formula (A): R ¹ = p-tolyl, n = 1) (Compound 6) (7) 2- (3-N-benzoylamino-1-propynyl) adenosine (Formula (A): R ¹ = Phenyl, n = 1)
(Compound 7) (8) 2- (3-N- (p-chlorobenzoyl) amino-1-propynyl) adenosine (Formula (A): R ¹ = p-
Chlorophenyl, n = 1) (Compound 8) (9) 2- (3-N- (o-methoxybenzoyl) amino-1-propynyl) adenosine (Formula (A): R ¹ = o
-Methoxyphenyl, n = 1) (compound 9) (10) 2- (3-N-phenylacetylamino-1-propynyl) adenosine (Formula (A): R ¹ = benzyl, n
= 1) (Compound 10) (11) 2- (3-phthalimidyl-1-propynyl) adenosine (Formula (B): R ² = hydrogen atom, n = 1) (Compound 11) (12) 2- (6- Phthalimidyl-1-hexynyl) adenosine (Formula (B): R ² = hydrogen atom, n = 4) (Compound 12) (13) 2- (3- (3-Chlorophthalimidyl) -1-
Propynyl) adenosine (Formula (B): R ² = chlorine, n =
1) (Compound 13) (14) 2- (3- (4-methylphthalimidyl) -1-
Propynyl) adenosine (Formula (B): R ² = methyl, n
= 1) (compound 14) (15) 2- (3- (3-methoxyphthalimidyl) -1
-Propynyl) adenosine (Formula (B): R ² = methoxy, n = 1) (Compound 15)

The compounds of the present invention can exist in free or salt form. Examples of the salt form include acid addition salts such as inorganic acid salts such as hydrochloride, sulfate and hydrobromide, or organic acid salts such as oxalate, citrate and malate;
Alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, barium salt and magnesium salt; ammonium salt and the like. Among these, pharmaceutically acceptable salts such as hydrochloride, oxalate, citrate, malate and sodium salt are preferred.

[0011] 2. Process for Preparing the Compound of the Present Invention

Embedded image (Wherein X represents iodine or bromine, and Y represents a hydrogen atom or a protecting group for a hydroxyl group) in a solvent in the presence of a palladium catalyst and a copper compound. It is prepared by reacting (cross-coupling reaction) with an acetylene compound represented by tri-CH (III) (wherein R is as defined above) and, if necessary, removing a hydroxyl-protecting group represented by Y. be able to.

In formula (II), the protecting group for the hydroxyl group represented by Y may be any of those commonly used as a protecting group for the hydroxyl group of a nucleoside, and is not particularly limited. Specifically, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, methoxyacetyl, propionyl, n-butyryl, (E) -2-methylbutenoyl, isobutyryl, pentanoyl, benzoyl, o- (dibromomethyl) benzoyl, o- (Methoxycarbonyl) benzoyl, p-phenylbenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl,
acyl groups such as p-chlorobenzoyl, p-nitrobenzoyl and α-naphthoyl; benzyl, phenethyl, 3-
Phenylpropyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, p-halobenzyl, p
-Cyanobenzyl, diphenylmethyl, triphenylmethyl (trityl), α or β-naphthylmethyl, α
Aralkyl groups such as -naphthyldiphenylmethyl; trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, isopropyldimethylsilyl, methyldi-t
Silyl groups such as -butylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl and tetraisopropyldisiloxanyl; alkoxymethyl groups such as methoxymethyl and ethoxymethyl; isopropylidene, ethylidene, propylidene, benzylidene, Acetal-type or ketal-type protecting groups such as methoxymethylidene can be exemplified. In addition,
The introduction of such a protecting group may be performed according to a conventional method.

As the R of the acetylene compound represented by the formula (III), a compound corresponding to the R of the compound of the formula (I) to be synthesized is selected and used. Such an acetylene compound is commercially available or can be easily prepared by appropriately applying a general organic compound synthesis method.

The cross-coupling reaction between the compound of the formula (II) and the compound of the formula (III) may be carried out according to a known method for synthesizing 2-alkynyl adenosine (Japanese Patent Publication No. 1-334).
No. 77, Japanese Patent Publication No. 17526/1990).

As a reaction solvent, triethylamine, tributylamine, N, N-diisopropylethylamine, trioctylamine, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine, N, N-dimethylaniline , N, N-diethylaniline, pyridine or other basic solvent alone, or acetonitrile, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N, N-dimethylacetamide, tetrahydrofuran (THF), 1,4 -A mixed solvent of an aprotic polar solvent such as dioxane and the above basic solvent can be used.

Examples of the palladium catalyst include bis (acetonitrile) palladium dichloride, bis (triphenylphosphine) palladium dichloride, bis (benzonitrile) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium diacetate and the like. Can be used. Among the above palladium catalysts, bis (triphenylphosphine) palladium dichloride, bis (triphenylphosphine) palladium diacetate,
Those produced by separately adding palladium chloride or palladium diacetate and triphenylphosphine to the reaction solution may be used as they are. The amount of the palladium catalyst used is the amount of the compound 1 represented by the formula (II).
A so-called catalyst amount of about 0.001 to 0.1 times the mole may be used. In addition to the palladium catalyst, a copper compound is added to the reaction solution to promote a cross coupling reaction. For example, a copper halide compound such as cuprous iodide or cuprous bromide is used in an amount of 0.06 per mole of the compound of formula (II).
It may be added to the reaction solution in a molar amount of about twice.

The cross-coupling reaction is carried out at a reaction temperature of 10 to 130 ° C. for 1 to 100 hours using 1 to 3 moles of an acetylene compound per 1 mole of a 2-halogenoadenosine compound in the presence of a palladium catalyst and a copper compound. It can be carried out by reacting. After the completion of the cross-coupling reaction, the obtained compound can be isolated and purified by a conventional means for isolating and purifying nucleosides (adsorption chromatography, recrystallization, etc.). Further, a copper compound can be separated from the reaction solution by appropriately combining a hydrogen sulfide treatment or an extraction / partition treatment with an organic solvent-water as required.

Next, the removal of the hydroxyl-protecting group may be carried out according to a conventional method. For example, when the protecting group is an acetal-type or ketal-type protecting group, trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid,
The protecting group may be removed by hydrolysis using an acid such as sulfuric acid or hydrochloric acid. When the protecting group is a silyl group, an acid such as trifluoroacetic acid, trichloroacetic acid, tosylic acid, sulfuric acid, and hydrochloric acid in a suitable solvent (THF, DMSO, acetonitrile, 1,4-dioxane, etc.),
The protecting group can be removed using tetrabutylammonium fluoride, pyridine hydrogen fluoride, ammonium fluoride, or the like. Furthermore, when the protecting group is an acyl group, the protecting group is removed by hydrolysis using methanolic ammonia, concentrated aqueous ammonia, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, or the like. can do.

[0019]

The present invention will now be described more specifically with reference to examples and test examples. Examples 1-8 786 mg (2 mmol) of 2-iodoadenosine was added to DMF10
Then, 70 mg of bis (triphenylphosphine) palladium dichloride, 38 mg of cuprous iodide, 1.4 ml of triethylamine and various acetylene compounds (compounds of formula (III)) (2 to 5 mmoles) were added, and the mixture was added at 70 to 120 ° C.
Was reacted. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, and hydrogen sulfide was bubbled through the solution for 1 minute. Next, the deposited precipitate was removed by filtration, and the obtained filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain eight kinds of target compounds, respectively.

[0020] 2- (3-N-acetylamino-1-
Propinyl) adenosine (compound 1) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
_{1.87 (3H, s, CH 3} ), 3.55-3.70
(2H, m, H-5 '), 3.97 (1H, brs, H
-4 '), 4.09 (2H, d, CH 2 C three C), 4.
14 (1H, dd, H-3 '), 4.50 (1H, d
d, H-2 '), 5.14 (1H, brs, OH),
5.18 (1H, t, OH), 5.45 (1H, d, O
H), 5.88 (1H, d, H-1 ', J = 5.86H)
_{z), 7.4 (2H, brs} , NH 2), 8.42 (2
H, brs, H-8 and CONH)

2- (3-N-trifluoroacetyl
Amino-1-propynyl) adenosine (compound 2) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.56-3.71 (2H, m, H-5 '), 3.97
(1H, m, H-4 '), 4.15 (1H, dd, H-
3 '), 4.26 (2H, d, CH 2 C three C), 4.5
0 (1H, dd, H-2 '), 5.14 (1H, d, O
H), 5.20 (1H, t, OH), 5.45 (1H,
d, OH), 5.89 (1H, d, H-1 ', J = 5.
_{86Hz), 7.45 (2H, s} , NH 2), 8.42
(1H, s, H-8)

2- (3-N-heptanoylamino-
1-propynyl) adenosine (compound 3) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
_{0.86 (3H, t, CH 3} ), 1.26 (6H, m,
(CH ₂ ) × 3), 1.51 (2H, m, CH ₂ ),
_{2.12 (2H, t, C H} 2 CONH), 3.55-
3.73 (2H, m, H-5 '), 3.97 (1H,
m, H-4 '), 4.09 (2H, d, CH 2 C three C), 4.14 (1H, dd , H-3'), 4.50
(1H, dd, H-2 '), 5.13 (1H, d, O
H), 5.19 (1H, t, OH), 5.44 (1H,
d, OH), 5.89 (1H, d, H-1 ', J = 5.
86Hz), 7.43 (2H, brs , NH 2), 8.
34 (1H, t, CONH), 8.40 (1H, s, H
-8)

[0023] 2- (3-N-stearoylamino-
1-propynyl) adenosine (compound 4) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
_{0.86 (3H, t, CH 3} ), 1.23 (28H, b
rs, (CH ₂ ) × 14), 1.51 (2H, m, CH
_{2), 2.11 (2H, t} , C H 2 CONH), 3.5
4-3.73 (2H, m, H-5 '), 3.97 (1
H, dd, H-4 ' ), 4.09 (2H, d, CH 2 C
3C), 4.15 (1H, dd, H-3 '), 4.50
(1H, dd, H-2 '), 5.13 (1H, d, O
H), 5.20 (1H, t, OH), 5.45 (1H,
d, OH), 5.88 (1H, d, H-1 ', J = 5.
38Hz), 7.41 (2H, brs , NH 2), 8.
34 (1H, t, CONH), 8.40 (1H, s, H
-8)

2- (6-N-benzoylamino-1
-Hexynyl ) adenosine (compound 5) ¹ H-NMR (270 MHz, DMSO-d ₆ ) δ:
8.49 (1H, t, 6 ″ -NH), 8.39 (1H,
s, H-8), 7.86-7.42 (5H, m, _{phenyl), 7.48 (2H, brs,} 6-NH 2), 5.8
4 (1H, d, H-1 ', J1', 2 '= 6.0H
z), 5.44 (1H, d, 2'-OH, J2'OH,
2 '= 6.0 Hz), 5.22 (1H, t, 5'-O
H, J5'OH, 5 '= 5.8 Hz), 5.16 (1
H, d, 3'-OH, J3'OH, 3 '= 4.4H
z), 4.53 (1H, ddd, H-2 ', J2',
1 '= 6.0 Hz, J2', 2'OH = 6.0 Hz, J
2 ', 3' = 4.4 Hz), 4.12 (1H, ddd,
H-3 ', J3', 2 '= 4.4 Hz, J3', 3'O
H = 4.4 Hz, J3 ', 4' = 5.0 Hz), 3.9
4 (1H, ddd, H-4 ', J4', 3 '= 5.0H
z, J4 ', 5'a = 4.8 Hz, J4', 5'b =
4.8 Hz), 3.66 (1H, ddd, H-5'a,
J5'a, 4 '= 4.8 Hz, J5'a, 5'b = 1
2.1 Hz, J5'a, 5'OH = 5.5 Hz);
46 (1H, ddd, H-5'b, J5'b, 4 '=
4.8 Hz, J5'b, 5'a = 12.1 Hz, J5 '
b, 5'OH = 5.5 Hz), 3.32 (2H, t, H
−6 ″), 2.46−2.43 (2H, m, H−
3 "), 1.67-1.59 (4H, m, H-4", H
-5 ")

2- (3-N- (p-toluoyl) a
Mino-1-propynyl) adenosine (compound 6) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
_{2.37 (3H, s, CH 3} ), 3.55-3.70
(2H, m, H-5 '), 3.97 (1H, m, H-
4 '), 4.15 (1H, m, H-3'), 4.30
(2H, d, CH ₂ C three C), 4.50 (1H, dd ,
H-2 '), 5.14 (1H, d, OH), 5.21
(1H, dd, OH), 5.46 (1H, d, OH),
5.88 (1H, d, H-1 ', J = 5.38 Hz),
_{7.40 (2H, brs, NH 2} ), 7.27,7.8
1 (2H (each), d (each), aromatic ring), 8.40
(1H, s, H-8)

2- (3-phthalimidyl-1-pro
Pinyl) adenosine (compound 11) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.47-3.67 (2H, m, H-5 '), 3.95
(1H, m, H-4 '), 4.12 (1H, dd, H-
3 '), 4.48 (1H, dd, H-2'), 4.63
(2H, s, CH ₂ C three C), 5.12 (1H, d , O
H), 5.17 (1H, t, OH), 5.44 (1H,
d, OH), 5.87 (1H, d, H-1 ', J = 5.
_{86Hz), 7.44 (2H, s} , NH 2), 7.87
-7.95 (4H, m, aromatic ring), 8.40 (1H,
s, H-8)

2- (6-phthalimidyl-1-hexyl )
(Synyl) adenosine (compound 12) ¹ H-NMR (270 MHz, DMSO-d ₆ ) δ:
8.39 (1H, s, H-8), 7.64-7.22
(4H, m, phthalimidyl), 7.44 (2H, br
_{s, 6-NH 2),} 5.85 (1H, d, H-1 ', J
1 ′, 2 ′ = 6.1 Hz), 5.46 (1H, d, 2 ′)
−OH, J2′OH, 2 ′ = 6.0 Hz), 5.23
(1H, t, 5'-OH, J5'OH, 5 '= 5.8H
z), 5.17 (1H, d, 3'-OH, J3'OH,
3 '= 5.0 Hz), 4.52 (1H, ddd, H-
2 ', J2', 1 '= 6.1 Hz, J2', 2'OH =
6.0 Hz, J2 ', 3' = 4.5 Hz), 4.12
(1H, ddd, H-3 ', J3', 2 '= 4.5H
z, J3 ', 3'OH = 5.0 Hz, J3', 4 '=
3.3 Hz), 3.95-3.94 (1H, m, H-
4 '), 3.69-3.63 (1H, m, H-5'
a) 3.57-3.47 (1H, m, H-5'b);
3.25-3.23 (2H, m, H-6 "), 2.48
-2.43 (2H, m, H-3 "), 1.70-1.6
0 (4H, m, H-4 ", H-5")

Test Example 1 (Affinity for Adenosine Receptor) The affinity for adenosine receptor was determined by RF Bruns et al., Mol. Pharmacol.,
29 , 331-346, (1986); RF Bruns et al., Proc. Natl. Ac.
ad. Sci., USA, 77 , 5547, (1980);
The measurement was performed according to a method substantially similar to the method described in JP-A No. 01196 and JP-A-62-111996. That is, affinity for A ₁ receptors was determined using membrane preparations of brain Wistar rats, 2.5 nM
[ ³ H] -N ⁶ -cyclohexyladenosine ([ ³ H]
The affinity constant (Ki) was calculated from the concentration of the test compound that caused 50% displacement of the specific binding of -CHA) to the membrane preparation. Moreover, affinity for A ₂ receptor was measured using the membrane preparation of the linear body Wistar rats, 5 nM ^[3
H] -5'-N-ethylcarboxamide adenosine ([[
³ H] -NECA) specific binding to membranes preparation 50%
The affinity constant (Ki) was calculated from the concentration of the test compound to be replaced. Specifically, the radioligand ([ ³ H] -C
The above results of saturation binding experiments for each film preparation of HA or ^[3 H] -NECA), was determined dissociation constant _{(K D)} and the maximum number of binding sites (Bmax). Furthermore, a displacement curve was drawn from the results of incubation with the addition of various concentrations of the test compound, and the specific binding of the radioligand at the above concentration was determined.
The concentration (IC ₅₀ ) of the test compound to be replaced by% was determined. From these results, the Cheng and Prusoff formulas (Bioche
m. Pharmacol., 22 , 3099 (1973)), the affinity constant (Ki) was calculated ("Binding of neurotransmitter and receptor", pp. 83-119, September 15, 1987,
(See Seiwa Publishing Co., Ltd.). Moreover, selectivity for _{A 2} receptors was expressed as the ratio of the respective Ki values _(A 1 / A _2). The results are shown in Table 1.

Test Example 2 (Effect of SHR on Blood Pressure and Heart Rate) Male spontaneously hypertensive rats (SHR) were anesthetized with urethane and α-chloralose. Blood pressure and heart rate were measured using a pressure transducer via a cannula inserted into the carotid artery. The test compound was administered at 0.0
The administration was performed at a dose of 3 to 100 μg / kg at a common ratio of 3 at intervals of 5 minutes. After administration of each dose, blood pressure and heart rate were measured for 5 minutes and the maximum values were determined. From these results, the dose of the test compound (ED ₃₀ ) that reduces the blood pressure of each SHR before administration of the test compound by 30% and the dose of the test compound (ED ₁₀ ) that reduces the heart rate before administration by 10% were respectively determined. I asked. The effect of each test compound on blood pressure and heart rate was determined by ED ₃₀ and E
Comparing D ₁₀ as an indicator. The results are also shown in Table 1.

[0030]

[Table 1]

[0031]

The present invention compounds according to the present invention, while having a high affinity for A ₂ receptor, having a low affinity for A ₁ receptors. That selectivity for A ₂ receptor is very high compound. In addition, the compound of the present invention shows a remarkable blood pressure lowering effect, but has a low inhibitory effect on the heart. Therefore, these compounds can be expected to be used as drugs for cardiovascular diseases for treating or preventing hypertension, ischemic diseases (such as ischemic heart diseases and ischemic brain diseases).

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07H 19/167 A61K 31/7076 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the formula (I) [Wherein R represents the formula (A) or (B): (Wherein, R ¹ represents an alkyl group, an aryl group, an aralkyl group or a halogenated alkyl group, and n represents an integer of 0 to 10). (Wherein, R ² represents a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom, and n represents an integer of 0 to 10)], and a salt thereof.