JP3053908B2 - 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 (19
85); JP-B 1-33377; JP-B 2-175
No. 26). 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 the emergence of compounds with enhanced features is expected. ing.

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 a 2-alkynyladenosine derivative represented by the following formula (I) (hereinafter sometimes referred to as “the compound of the present invention”) and a salt thereof.

Embedded image Wherein R represents any of formulas (A) to (F):

Embedded image (Wherein R ¹ and R ² may be the same or different and represent a hydrogen atom or an alkyl group;
Represents 0 or an integer of 1 to 10, and R ³ represents an alkenyl group, an alkynyl group, an aryl group, an azide group or a cyano group. )

[0008] 1. The Compound of the Present Invention The compound of the present invention is represented by the formula (I) wherein R is represented by any one of the above formulas (A) to (F). In the formulas (A) to (E), examples of the alkyl group represented by R ¹ and R ² include a linear or branched one having about 1 to 10 carbon atoms. In equation (F),
Examples of the aryl group represented by R ³ include phenyl, tolyl, and naphthyl. Examples of the alkenyl group and alkynyl group represented by R ³ include those having about 1 to 10 carbon atoms. The alkyl group represented by R ¹ and R ² and the alkenyl group, alkynyl group and aryl group represented by R ³ may be substituted at any position by a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a carbonyl group, an alkoxycarbonyl group, or the like. It may have one or more groups.

Representative examples of the 2-alkynyl adenosine derivative represented by the general formula (I) are shown below.

(1) 2- (3-hydroxy-3-methyl-1-butynyl) adenosine (formula (A): R ¹ = R ² =
CH ₃ ) (Compound 1) (2) 2- (3,5-dimethyl-3-hydroxy-1-)
Hexinyl) adenosine (3) 2- (3-hydroxy-1-octynyl) adenosine (Formula (A): R ¹ = (CH ₂ ) ₄ CH ₃ , R ² =
H) (Compound 3) (4) 2- (3-Methoxy-1-propynyl) adenosine (Formula (B): R ¹ ＣＨCH ₃ , n = 1) (Compound 4) (5) 2- (3-n -Butoxy-1-propynyl) adenosine (Formula (B): R ¹ = (CH ₂ ) ₃ CH ₃ , n =
1) (Compound 5) (6) 2- (4-n-propoxy-1-butynyl) adenosine (Formula (B): R ¹ = (CH ₂ ) ₂ CH ₃ , n =
2) (Compound 6) (7) 2- (5-ethoxy-1-pentynyl) adenosine (Formula (B): R ¹ = CH ₂ CH ₃ , n = 3) (Compound 7) (8) 2- (4 -N-octoxy-1-butynyl) adenosine (Formula (B): R ¹ = (CH ₂ ) ₇ CH ₃ , n =
2) (Compound 8) (9) 2- (6-Hydroxy-1-hexynyl) adenosine (Formula (B): R ¹ = H, n = 4) (Compound 9) (10) 2- (3-dimethylamino) -1-propynyl) adenosine (Formula (C): R ¹ ＲR ² ＣＨCH ₃ , n = 1)
(Compound 10) (11) 2- (6-amino-1-hexynyl) adenosine (Formula (C): R ¹ = R ² = H, n = 4) (Compound 11) (12) 2- (7-carboxy) -1-Heptynyl) adenosine (Formula (D): R ¹ = H, n = 5) (Compound 12) (13) 2- (5-carboxy-1-pentynyl) adenosine (Formula (D): R ¹ = H , N = 3) (Compound 13) (14) 2- (4-ethoxycarbonyl-1-butynyl)
Adenosine (Formula (D): R ¹ = CH ₂ CH ₃ , n = 2)
(Compound 14) (15) 2- (3-oxo-1-octynyl) adenosine (Formula (E): R ¹ = (CH ₂ ) ₄ CH ₃ ) (Compound 1)
5) (16) 2- (6-phenyl-1-hexynyl) adenosine (Formula (F): R ³ = phenyl, n = 4) (Compound 1)
6) (17) 2- (6- (4-ethoxycarbonyl) phenyl-1-hexynyl) adenosine (Formula (F): R ³ = 4-
(Ethoxycarbonylphenyl, n = 4) (compound 17) (18) 2- (4-phenyl-1-butynyl) adenosine (Formula (F): R ³ = phenyl, n = 2) (compound 18) (19) 2 -(6-azido-1-hexynyl) adenosine (formula (F): R ³ = azide, n = 4) (compound 19) (20) 2- (5-cyano-1-pentynyl) adenosine (formula (F) : R ³ = cyano, n = 3) (compound 20) (21) 2- (4- (p-tolyl) -1-butynyl) adenosine (Formula (F): R ³ = p-tolyl, n = 2) (Compound 21) (22) 2- (4- (o-chlorophenyl) -1-butynyl) adenosine (Formula (F): R ³ = o-chlorophenyl, n = 2) (Compound 22) (23) 2- ( 4-(p-methoxyphenyl) -1-butynyl) adenosine (formula ^(F): R 3 = p- methemoglobin Shifeniru, n = 2) (Compound 23) (24) 2- (1,7-Dekajiiniru) adenosine (formula _{^{(F): R 3 = CH}} 3 CH 2 three C, n = 4) (Compound 2
4) (25) 2- (Braninyl) adenosine (Formula (F): R ³
ＣＨCH ₂ ＣＨCH, n = 0) (compound 25)

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.

[0012] 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 hydroxyl-protecting group represented by Y may be any of those commonly used as hydroxyl-protecting groups for nucleosides, 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 formula (II) and the compound of 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 the 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, and bis (triphenylphosphine) palladium diacetate. 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 in the presence of a palladium catalyst and a copper compound 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. 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.

[0020]

The present invention will be described more specifically with reference to the following examples. Examples 1-21 786 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 passed through the solution for 1 minute. Then, 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 21 kinds of target compounds, respectively.

(1) 2- (3-hydroxy-3-methyl-
1-butynyl) adenosine (compound 1) m. p. : 142 to 147 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (6H,
s, CH ₃ × 2), 3.40-3.69 (1H, m, H
-5 '), 3.94 (1H, m, H-4'), 4.12
(2H, dd, H-3 '), 4.48 (1H, dd, H
-2 '), 5.1-5.2 (2H, m, OH x 2),
5.4 (1H, d, OH), 5.5 (1H, s, C3C
COH), 5.87 (1H, d, H-1 ', J = 6.3)
_{5Hz), 7.4 (2H, s} , NH 2), 8.41 (1
H, s, H-8)

(2) 2- (3,5-dimethyl-3-hydro
(Xy-1-hexynyl) adenosine (compound 2) ¹ H-NMR (CDCl ₃ -DMSO-d ₆ ) δ: 0.
98 (6H, d, J = 6 Hz, (CH ₃ ) ₂ ), 1.5
0 (3H, s, CH ₃ ), 1.62 (2H, bs, CH
₂ ), 1.70-2.05 (1H, m, CH), 3.6
6-4.06 (3H, m, H-5 ', H-4');
66 (1H, m, H-3 '), 4.95-5.32 (1
H, m, H-2 '), 5.85 (1H, d, J = 6H)
z, H-1 '), 6.04 (1H, br, OH), 7.
_{10-7.80 (2H, br, NH 2} ), 7.97 (1
H, s, H-8)

(3) 2- (3-hydroxy-1-octini)
A) adenosine (compound 3) m. p. : 177-179 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (3H,
t, CH ₃ ), 1.69 (8H, m, (CH ₂ ) ×
4) 3.56-3.72 (2H, m, H-5 ');
3.98 (1H, m, H-4 '), 4.16 (1H, d
d, H-3 '), 4.40 (1H, dd, CHC3C), 4.51 (1H, dd, H-2'), 5.1,
5.2, 5.4, 5.5 (4H, brs (each), OH
× 4), 5.89 (1H, d, H-1 ′, J = 5.86)
_{Hz), 7.38 (2H, s} , NH 2), 8.39 (1
H, s, H-8)

(4)2- (3-methoxy-1-propini
A) Adenosine (compound 4) m. p. : 118-123 ° C¹ H-NMR (DMSO-d₆) Δ: 3.35 (3H,
t, CH₃), 3.54-3.70 (2H, m, H-
5 '), 3.96 (1H, m, H-4'), 4.13
(1H, dd, H-3 '), 4.32 (2H, s, CH
₂C3C), 4.55 (1H, dd, H-2 '), 5.
2,5.5 (3H, s (each), OH × 3), 5.87
(1H, d, H-1 ', J = 5.93 Hz), 7.5
(2H, s, NH₂), 8.43 (1H, s, H-
8 ')

(5) 2- (3-n-butoxy-1-propyl)
Nyl) adenosine (compound 5) m. p. : 105 to 110 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H,
t, CH ₃ ), 1.34, 1.52 (4H, m (each), CH ₂ × 2), 3.51 (2H, t, CH
₂ O), 3.62 (2H, m, H-5 '), 3.95
(1H, m, H-4 '), 4.13 (1H, dd, H-
3 '), 4.35 (2H, s, OCH 2 C three C), 4.
54 (1H, dd, H-2 '), 5.2 (2H, br
s, OH × 2), 5.5 (1H, brs, OH), 5.
86 (1H, d, H-1 ', J = 5.93 Hz);
43 (1H, s, H-8)

(6) 2- (4-n-propoxy-1-butyl)
Nyl) adenosine (compound 6) ¹ H-NMR (DMSO-d ₆ ) δ: 0.87 (3H,
_{t, CH 3), 1.53 (} 2H, m, MeC H 2),
_{2.65 (2H, t, CH 2} C three C), 3.38-3.
_{69 (6H, m, H-} 5 ', C H 2 OC H 2), 3.9
5 (1H, m, H-4 '), 4.12 (1H, dd, H
-3 '), 4.52 (1H, dd, H-2'), 5.1
7-5.23 (2H, m, OH × 2), 5.46 (1
H, d, OH), 5.86 (1H, d, H-1 ', J =
_{6.27Hz), 7.4 (2H, s} , NH 2), 8.4
2 (1H, s, H-8)

(7)2- (5-ethoxy-1-pentini)
A) Adenosine (compound 7) ¹ H-NMR (DMSO-d₆) Δ: 1.12 (3H,
t, CH₃), 1.76 (2H, t, OCH₂C
H₂), 2.44 (2H, t, CH₂C3C), 3.4
2-3.70 (6H, m, H-5 ', CH ₂ OC
H ₂ ), 3.95 (1H, m, H-4 '), 4.13
(1H, brs, H-3 '), 4.54 (1H, br
s, H-2 '), 5.2, 5.25 (2H, brs (each
Each), OH × 2), 5.5 (1H, brs, OH),
5.85 (1H, d, H-1 ', J = 6.27 Hz),
7.4 (2H, s, NH₂), 8.39 (1H, s, H
-8)

(8) 2- (4-n-octoxy-1-butyric )
Nyl) adenosine (compound 8) ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (3H,
_{t, CH 3), 1.23-1.47 (} 12H, m, (C
_{H 2) × 6), 2.63} (2H, t, CH 2 C three C),
_{3.42 (2H, t, OC H} 2 CH 2 C three C), 3.5
3-3.69 (4H, m, H- 5 ', CH 2 O), 3.
96 (1H, m, H-4 '), 4.14 (1H, dd,
H-3 '), 4.52 (1H, dd, H-2'), 5.
1, 5.2 (2H, brs (each), OH × 2);
4 (1H, d, OH), 5.87 (1H, d, H-
1 ′, J = 5.86 Hz), 7.4 (2H, s, N)
_{H 2), 8.39 (1H,} s, H-8)

(9) 2- (6-hydroxy-1-hexini)
A) adenosine (compound 9) m. p. : 103 to 107 ° C ¹ H-NMR (CDCl ₃ -DMSO-d ₆ ) δ: 1.
_{50-1.83 (4H, m, -CH 2} CH 2 -), 2.
_{23-2.50 (2H, m, CH 2} ), 3.53-3.
93 (4H, m, H-5 ', OH × 2), 4.07-
4.43 (3H, m, H-4 ', H-3'), 4.80
−5.08 (1H, br, H-2 ′), 5.28 (1
H, bs, OH), 5.82 (1H, d, J = 6 Hz,
H-1 '), 6.30-6.52 (1H, m, OH),
_{6.97 (2H, bs, NH 2} ), 7.92 (1H,
s, H-8)

(10) 2- (3-dimethylamino-1-pro
Pinyl) adenosine (Compound 10) m. p. : 199 to 200 ° C (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ: 2.25 (6H,
_{s, CH 3 × 2),} 3.45 (2H, s, CH 2 C three C), 3.54-3.68 (2H, m , H-5 '),
3.95 (1H, m, H-4 '), 4.13 (1H,
m, H-3 '), 4.54 (1H, dd, H-2'),
5.2, 5.5 (3H, brs (each), OH × 3),
5.89 (1H, d, H-1 ', J = 5.86 Hz),
_{7.5 (2H, s, NH 2} ), 8.40 (1H, s, H
-8)

(11) 2- (6-amino-1-hexynyl)
Data for adenosine (compound 11) as 2 ', 3', 5'-tri-O-acetate is shown. ¹ H-NMR (CDCl ₃ ) δ: 8.02 (1H, s,
H-8), 7.71-7.51 (1H, m, 6 "-N
H), 6.29 (1H, d, H-1 ', J1', 2 '=
5.9 Hz), 5.89 (2H, brs, 6-N
_{H 2), 5.85-5.80 (1H,} m, H-2 '),
5.72-5.60 (1H, m, H-3 '), 4.51
-4.43 (3H, m, H-4 ', H-5'a, H-
5'b), 3.64-3.60 (2H, m, H-
6 "), 2.58-2.41 (2H, m, H-3"),
2.15 (6H, s, acetyl × 2), 2.05 (3
H, s, acetyl), 1.70-1.50 (4H, m,
H-4 ", H-5")

(12) 2- (7-carboxy-1-heptini
A) Adenosine (compound 12) ¹ H-NMR (DMSO-d ₆ ) δ: 1.39-1.5
5 (6H, m, methylene), 2.13 (2H, t, methylene), 2.39 (2H, t, methylene), 3.52-
3.68 (2H, m, H-5 '), 3.94 (2H, d
d, H-4 '), 4.13 (1H, t, H-3'),
4.54 (1H, t, H-2 '), 5.85 (1H,
d, H-1 '), 8.38 (1H, s, H-8)

(13) 2- (5-carboxy-1-pentini)
A) Adenosine (compound 13) ¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.8
0 (2H, m, methylene), 2.34 (2H, t, methylene), 2.45 (2H, t, methylene), 3.57-
3.70 (2H, m, H-5 '), 3.96 (2H, d
d, H-4 '), 4.14 (1H, t, H-3'),
4.54 (1H, dd, H-2 '), 5.23 (1H,
d, OH), 5.26 (1H, t, OH), 5.49
(1H, d, OH), 5.85 (1H, d, H-
1 ′), 7.41 (2H, bs, NH ₂ ), 8.40
(1H, s, H-8)

(14) 2- (4-ethoxycarbonyl-1-
Butynyl) adenosine (compound 14) m. p. : 103 to 106 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t,
J = 7 Hz, CH ₃ ), 2.04 (3H, bs, OH ×
_{2), 2.52 (4H, s} , -CH 2 CH 2 -), 3.
62-3.94 (2H, m, H-5 '), 4.30 (2
H, bs, H-4 ', H-3'), 4.17 (2H,
q, J = 7 Hz, CH ₂ ), 5.10-5.40 (1
H, m, H-2 '), 5.88 (1H, d, J = 5H)
z, H-1 '), 7.79 (1H, s, H-8)

(15) 2- (3-oxo-1-octynyl)
Adenosine (compound 15) ¹ H-NMR (DMSO-d ₆ ) δ: 0.88 (3H,
_{t, CH 3), 1.23-1.37 (} 4H, m, CH 2
× 2), 3.57-3.75 (2H, m, H-5 '), 3.95
-3.97 (1H, m, H-4 '), 4.14 (1H,
dd, H-3 '), 4.52 (1H, dd, H-
2 '), 5.12 (1H, t, OH), 5.19 (1
H, d, OH), 5.48 (1H, d, OH), 5.8
9 (1H, d, H-1 '), 7.68 (2H, bs, N
_{H 2), 8.52 (1H,} s, H-8)

(16)2- (6-phenyl-1-hexini
A) Adenosine (compound 16) m. p. : 201-203 ° C¹ H-NMR (CDCl₃-DMSO-d₆) Δ: 1.
50-1.93 (4H, m, -CH₂CH₂-), 2.
27-2.75 (4H, m, CH₂× 2), 3.60-
3.87 (2H, m, H-5 '), 4.06-4.95
(4H, m, H-4 ′, H-3 ′, OH × 2), 5.1
1 (1H, bd, H-2 '), 5.56-5.79 (1
H, m, OH), 5.88 (1H, d, J = 6 Hz, H
-1 '), 6.56 (2H, bs, NH₂), 7.19
(5H, s, phenyl), 8.05 (1H, s, 8-
H)

(17)2- (6--4-ethoxycarboni
L) phenyl-1-hexynyl) adenosine (compound 1
7) m. p. : 93-96 ° C¹ H-NMR (CDCl₃) Δ: 1.36 (3H, t,
J = 8Hz, CH₃), 1.20-1.86 (4H,
m, -CH₂CH₂−), 1.90-2.40 (2H,
m, CH₂), 2.66 (2H, t, J = 6 Hz, Ph)
CH₂−), 3.55−3.86 (3H, m, H−
5 ', H-4'), 4.27 (4H, m, H-3 ', O
H × 3), 4.33 (2H, q, J = 8 Hz, C
H₂), 5.18 (1H, br, H-2 '), 5.73
(1H, d, J = 6 Hz, H-1 '), 6.80-7.
50 (2H, br, NH₂), 7.18, 7.88 (4
H, dd, J = 9 Hz, phenyl), 7.66 (1H,
s, H-8)

(18) 2- (4-phenyl-1-butynyl)
Adenosine (compound 18) m. p. : 115 to 120 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.71 (2H,
t, CH ₂ C three C), 2.87 (2H, t , phC
_{H 2), 3.54-3.67 (2H,} m, H-5 '),
3.95 (1H, m, H-4 '), 4.13 (1H, d
d, H-3 '), 4.54 (1H, dd, H-2'),
5.85 (1H, d, H-1 ', J = 5.86 Hz),
7.20-7.33 (5H, m, phenyl), 7.42
_{(2H, brs, NH 2)} , 8.40 (1H, s, H-
8)

(19) 2- (6-azido-1-hexynyl)
Adenosine (compound 19) ¹ H-NMR (CDCl ₃ ) δ: 8.38 (1H, s,
H-8), 7.36 (2H , brs, 6-NH 2),
5.85 (1H, d, H-1 ', J1', 2 '= 6.6
Hz), 5.38 (1H, d, 2'-OH, J2'O
H, 2 '= 6.0 Hz), 5.17 (1H, dd, 5')
−OH, J5′OH, 5 ′ = 6.6 Hz), 5.10
(1H, d, 3'-OH, J3'OH, 3 '= 4.9H
z), 4.53 (1H, ddd, H-2 ', J2',
1 '= 6.6 Hz, J2', 2'OH = 6.0 Hz, J
2 ', 3' = 5.5 Hz), 4.13 (1H, ddd,
H-3 ', J3', 2 '= 5.5 Hz, J3', 3'O
H = 4.9 Hz, J3 ', 4' = 3.3 Hz) 3.9
5 (1H, ddd, H-4 ', J4', 3 '= 3.3H
z, J4 ', 5'a = 3.9 Hz, J4', 5'b =
3.9 Hz), 3.67 (1H, ddd, H-5'a,
J5'a, 4 '= 3.9 Hz, J5'a, 5'b = 1
2.1 Hz, J5'a, 5'OH = 6.6 Hz);
56 (1H, ddd, H-5'b, J5'b, 4 '=
3.9 Hz, J5'b, 5'a = 12.1 Hz, J5 '
b, 5'OH = 6.6 Hz), 3.40 (2H, t, H
-6 "), 2.44 (2H, t, H-3"), 1.76
-1.57 (4H, m, H-4 ", H-5")

(20) 2- (5-cyano-1-pentynyl)
Adenosine (compound 20) m. p. : 113 to 115 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.88 (2H,
m, CH ₂ ), 2.51-2.66 (4H, m, CH ₂₎
C three _{C, NCCH 2), 3.63 (} 2H, m, H-
5 '), 3.99 (1H, m, H-4'), 4.15
(1H, dd, H-3 '), 4.55 (1H, dd, H
-2 '), 5.14 (1H, d, OH), 5.34 (1
H, dd, OH), 5.42 (1H, d, OH), 5.
87 (1H, d, H-1 ', J = 6.35 Hz);
_{41 (2H, s, NH 2} ), 8.37 (1H, s, H-
8)

(21) 2- (1,7-decadinyl) adeno
Syn (Compound 24) m. p. : 90 to 94 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, t,
_{J = 8Hz, CH 3),} 1.30-1.80 (4H,
_{m, CH 2 CH 2),} 1.80-2.40 (6H,
m, CH ₂ C three C), 3.37 (1H, brs , O
H) 3.50-4.05 (2H, m, H-5 '),
4.05-4.40 (2H, m, H-3 ', H-
4 '), 5.20 (1H, m, H-2'), 5.75
(2H, m, H-1 ', OH), 6.95-7.95
_{(3H, NH 2, OH)} , 7.72 (1H, s, H-
8)

[0043]

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).

Continued on the front page (72) Inventor Takanori Miyashita 12-1, Suehirocho, Choshi City, Chiba Prefecture (72) Inventor Kazuto Hiru Hiru 508-1, Okura 1, Sahara City, Chiba Prefecture (72) Inventor Yoko Watanabe Takao Goto, Inventor Takao Goto, Iinosaka-cho, Fukushima-shi, Fukushima, 1st Tanaka, To A-Ayo Co., Ltd. (72) Inventor Kentaro Furushiro Yuno, Iiza-cho, Fukushima-shi, Fukushima (1) Tanaka 1 To A Ayo Corporation Research Institute (72) Inventor Senichi Narita Yuno Iimachi, Fukushima City, Fukushima Prefecture Yuno 1 Ta Ta To A Ayo Corporation Research Institute (56) References Chemical & Pharmaceutical Bulletin, Vol. 33, No. 4, p. 1766-1769 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07H 19/167 A61K 31/7076 A61P 7 / 02,9 / 12 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A 2-alkynyl adenosine derivative represented by the following formula (I) and a salt thereof: In the formula, R represents any one of the following formulas (A) to (F); (Wherein R ¹ and R ² may be the same or different and represent a hydrogen atom or an alkyl group;
Represents an integer of 0 to 10, and R ³ represents an alkenyl group, an alkynyl group, an aryl group, an azide group or a cyano group.
Here, R is a phenyl group, _-CH 2 OH group, _-CH 2 C
H ₂ OH group, except when it is -CH (OH) CH ₃ group. )