JPH059197A - 2-alkynyladenosine derivative - Google Patents

Abstract

PURPOSE:To provide the subject new derivative having alkynyl group at 2-site, exhibiting excellent pharmacological action to improve circulation such as hypotensive action, having high selectivity to A2-receptor and low side-effect such as cardioinhibitory action and useful for the treatment of hypertension, stenocardia, etc. CONSTITUTION:The objective 2-alkynyladenosine derivative (salt) [e.g. 2-(3- hydroxy-3-methyl-1-butynyl)adenosine] of formula I [R is group of formula II (R<1> and R<2> are H or alkyl), formula III ((n) is integer of 0-10), etc.] can be produced by dissolving 2-iodoadenosine in a solvent such as dimethylformamide, adding bis(triphenylphosphine)palladium dichloride, cuprous iodide, triethylamine and an acetylene compound to the solution, reacting the components by heating at 70-120 deg.C, concentrating the reaction mixture under reduced pressure, dissolving the residue in methanol, introducing hydrogen sulfide gas into the solution for 1min, removing the precipitate by filtration, concentrating the filtrate under reduced pressure and purifying the residue by silica gel chromatography.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 2-alkynyl adenosine derivative.

[0002]

2. Description of the Related Art Conventionally, adenosine is known to have a strong hypotensive action and an inhibitory action on platelet aggregation, but these actions are not persistent and, on the other hand, they have an effect on the heart. It also has side effects such as inhibitory effect (heart rate lowering effect) and central inhibitory effect. Therefore, when adenosine or its derivative is used as a therapeutic drug for diseases such as hypertension and angina, it is necessary to solve these problems. To solve these problems, various 2-substituted adenosine derivatives have been synthesized (Chem. Pharm. Bull., 23 (4),
759-774 (1975); Japanese Patent Laid-Open No. 1-265100), these derivatives have not sufficiently solved the above-mentioned problems and have not yet been put into practical use as pharmaceuticals.

The present inventors have previously 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. Bul.
l., 33 (4), 1766-1769 (1985)), and found that these compounds have a remarkable and persistent antihypertensive effect and have little effect on heart rate (eg, Nuclei
c Acids Research, Symposium SeriesNo.16, 97-100 (19
85); Japanese Patent Publication No. 1-33477; Japanese Patent Publication No. 2-175.
No. 26). 2- having such a linear carbon chain
Alkynyladenosine has a stronger and longer-lasting pharmacological effect on the circulatory organs and weaker side effects in comparison with other conventional adenosine derivatives, but there is a long-awaited appearance of compounds with further enhanced these characteristics. ing.

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

That is, the object of the present invention is to have potent and long-lasting pharmacological actions such as antihypertensive action, coronary vasodilator action, peripheral vasodilator action, cerebral circulation improving action, peripheral circulation improving action, and platelet aggregation inhibiting action. It is intended to provide a novel 2-alkynyladenosine derivative which has a high affinity for the A ₂ receptor and, on the other hand, has few side effects such as cardiac inhibitory action and central inhibitory action.

[0006]

[Means for Solving the Problems]
In the process of developing alkynyl adenosine derivatives and investigating their pharmacological activities,
Alkynyl adenosine derivatives exhibit high affinity for A ₂ receptors, while exhibiting low affinity for A ₁ receptors, that is, compounds having high selectivity for A ₂ receptors. The inventors have completed the present invention by finding the findings and confirming that they are useful as drugs for cardiovascular diseases.

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.

[Chemical 3] In the formula, R represents any one of formulas (A) to (F):

[Chemical 4] (In the formula, R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group;
Represents an integer of 0 or 1 to 10, and R ³ represents an alkenyl group, an alkynyl group, an aryl group, an azido group or a cyano group. )

1. The Compound of the Present Invention The compound of the present invention is one in which R in the above formula (I) is represented by any one of the above formulas (A) to (F). In formulas (A) to (E), examples of the alkyl group represented by R ¹ and R ² include linear or branched ones having about 1 to 10 carbon atoms. In formula (F),
Examples of the aryl group represented by R ³ include phenyl, tolyl, naphthyl and the like. 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 are substituted at any position with 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.

Typical examples of the 2-alkynyladenosine 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-
Hexynyl) 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 = CH 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 = R ² = CH 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-Heptinyl) 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- (Branynyl) adenosine (Formula (F): R ³
= CH ₂ = CH, n = 0) (Compound 25)

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

2. Method for Producing the Compound of the Present Invention

[Chemical 5] (Wherein, X represents iodine or bromine, Y represents a hydrogen atom or a hydroxyl-protecting group), and the 2-halogenoadenosine compound is represented by the formula (III) RC in the presence of a palladium catalyst and a copper compound. Three CH 3 (III) (wherein R is as defined above) is reacted (cross-coupling reaction) with an acetylene compound and, if necessary, the protective group for the hydroxyl group represented by Y is removed. be able to.

In formula (II), the protective group for the hydroxyl group represented by Y may be any group commonly used as a protective group for the hydroxyl group of 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, 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
-Butylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, tetraisopropyldisiloxanyl and other silyl groups; methoxymethyl, ethoxymethyl and other alkoxymethyl groups; isopropylidene, ethylidene, propylidene, benzylidene, Examples thereof include acetal-type or ketal-type protecting groups such as methoxymethylidene. In addition,
Introduction of such a protecting group may be carried out according to a conventional method.

As R of the acetylene compound represented by the formula (III), one corresponding to 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 method for synthesizing an organic compound.

The cross-coupling reaction between the compound of formula (II) and the compound of formula (III) may be carried out in accordance with a known synthetic method of 2-alkynyladenosine (Japanese Patent Publication No. 1-334).
77, Japanese Patent Publication No. 2-17526).

The reaction solvent used is triethylamine, tributylamine, N, N-diisopropylethylamine, trioctylamine, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine, N, N-dimethylaniline. , N, N-diethylaniline, basic solvent such as pyridine 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, etc.
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 compound 1 represented by the formula (II).
The so-called catalytic amount may be about 0.001 to 0.1 times the molar amount. In addition to the palladium catalyst, a copper compound is added to the reaction solution to accelerate the cross coupling reaction. For example, a copper halide compound such as cuprous iodide or cuprous bromide is added in an amount of 0.06 per mol of the compound of the 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 using 1 to 3 moles of the acetylene compound to 1 mole of the 2-halogenoadenosine compound at a reaction temperature of 10 to 130 ° C. for 1 to 100 hours. It can be carried out by reacting. After completion of the cross-coupling reaction, isolation and purification of the obtained compound can be carried out by using a usual nucleoside isolation and purification means (adsorption chromatography treatment, recrystallization method, etc.). Further, if necessary, hydrogen sulfide treatment or extraction / distribution treatment with an organic solvent-water may be appropriately combined and applied to separate the copper compound from the reaction solution.

Then, the removal of the hydroxyl-protecting group may be carried out by 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 with 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 or hydrochloric acid in a suitable solvent (THF, DMSO, acetonitrile, 1,4-dioxane, etc.),
The protecting group can be removed using tetrabutylammonium fluoride, hydrogen fluoride pyridine salt, ammonium fluoride or the like. Furthermore, when the protecting group is an acyl group, the protecting group is removed by hydrolysis with methanolic ammonia, concentrated aqueous ammonia, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide or the like. can do.

[0020]

EXAMPLES The present invention will be described in more detail below with reference to examples. Examples 1-21 786 mg (2 mmole) of 2-iodoadenosine was added to DMF10
70 ml of bis (triphenylphosphine) palladium dichloride, 38 mg of cuprous iodide, 1.4 ml of triethylamine and various acetylene compounds (compounds of formula (III)) (2-5 mmole) were added to the solution, and the mixture was dissolved at 70-120 ° C.
It was made to react with.

After the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, and hydrogen sulfide was bubbled through this for 1 minute. Then, the deposited precipitate was filtered off, 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. : 142-147 ° 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, C 3C
COH), 5.87 (1H, d, H-1 ', J = 6.3)
5 Hz), 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 = 6Hz, (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'), 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 to 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 to 123 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 3.35 (3H,
_{t, CH 3), 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
₂ C 3 C), 4.55 (1H, dd, H-2 '), 5.
2,5.5 (3H, s (each), OH × 3), 5.87
(1H, d, H-1 ', J = 5.93Hz), 7.5
_{(2H, s, NH 2)} , 8.43 (1H, s, H-
8 ')

(5) 2- (3-n-butoxy-1-propynyl)
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 = 5.93Hz), 8.
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 x 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-pentynyl)
A) Adenosine (Compound 7) ¹ H-NMR (DMSO-d ₆ ) δ: 1.12 (3H,
t, CH ₃ ), 1.76 (2H, t, OCH ₂ C
_{H 2), 2.44 (2H,} t, CH 2 C three C), 3.4
2-3.70 (6H, m, H- 5 ', C H 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), OH × 2), 5.5 (1H, brs, OH),
5.85 (1H, d, H-1 ', J = 6.27Hz),
7.4 (2H, s, NH ₂ ), 8.39 (1H, s, H
-8)

(8) 2- (4-n-octoxy-1-butyrate)
Nil) adenosine (Compound 8) ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (3H,
t, CH ₃ ), 1.23 to 1.47 (12H, m, (C
H ₂ ) × 6), 2.63 (2H, t, CH ₂ C 3C),
_{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), 5.
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. : 103-107 ° 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 x 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 = 6Hz,
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 3C), 3.54 to 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 = 5.86Hz),
7.5 (2H, s, NH ₂ ), 8.40 (1H, s, H
-8)

(11) 2- (6-amino-1-hexynyl)
Data for adenosine (compound 11) 2 ', 3', 5'-tri-O-acetate form are shown. ¹ H-NMR (CDCl ₃ ) δ: 8.02 (1 H, 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 x 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-pentynyl
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 (3 H, t,
_{J = 7Hz, 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 = 7Hz, 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 to 1.37 (4H, m, CH ₂
X2), 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
Le) adenosine (compound 16) m. p. : 201 to 203 ° C. ¹ H-NMR (CDCl ₃ -DMSO-d ₆ ) δ: 1.
_{50-1.93 (4H, m, -CH 2} CH 2 -), 2.
_{27-2.75 (4H, m, CH 2} × 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 = 6Hz, H
_{-1 '), 6.56 (2H,} bs, NH 2), 7.19
(5H, s, phenyl), 8.05 (1H, s, 8-
H)

(17) 2- (6- (4-ethoxycarbonyl )
Lu) phenyl-1-hexynyl) adenosine (compound 1
7) m. p. : 93-96 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, t,
_{J = 8Hz, CH 3),} 1.20-1.86 (4H,
_{m, -CH 2 CH 2 -)} , 1.90-2.40 (2H,
m, CH ₂ ), 2.66 (2H, t, J = 6Hz, Ph
_{CH 2 -), 3.55-3.86 (3H} , m, H-
5 ', H-4'), 4.27 (4H, m, H-3 ', O
H × 3), 4.33 (2H, q, J = 8Hz, C
_{H 2), 5.18 (1H,} br, H-2 '), 5.73
(1H, d, J = 6Hz, H-1 '), 6.80-7.
50 (2H, br, NH ₂ ), 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. : 115-120 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 2.71 (2H,
t, CH ₂ C 3C), 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 = 5.86Hz),
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 (1 H, 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 '= 5.5Hz, 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), 3.
56 (1H, ddd, H-5'b, J5'b, 4 '=
3.9Hz, J5'b, 5'a = 12.1Hz, 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. : 113-115 ° 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 = 6.35Hz), 7.
_{41 (2H, s, NH 2} ), 8.37 (1H, s, H-
8)

(21) 2- (1,7-decadiynyl) adeno
Syn (Compound 24) m. p. : 90-94 ° 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]

INDUSTRIAL APPLICABILITY The compound of the present invention has a high affinity for the A ₂ receptor, while having a low affinity for the A ₁ receptor. That is, it is a compound having extremely high selectivity for the A ₂ receptor. Further, the compound of the present invention exhibits a remarkable hypotensive action, but has a low inhibitory action on the heart. Therefore, these compounds can be expected to be used as a cardiovascular drug for treating or preventing hypertension, ischemic diseases (ischemic heart disease, ischemic brain disease, etc.).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor 14th sentence Yamaguchi 1-7-7 Sanada-cho, Hachioji-shi, Tokyo 403 Hime Nishihachioji 403 (72) Inventor Takanori Miyashita 1 Suehiro-cho, Choshi-shi, Chiba No. 12 (72) Inventor Kuro Hitoichi 508-1 Okura, Sawara, Chiba Prefecture (72) Inventor Yoko Watanabe 28 (25) Kasugacho, Choshi City, Chiba 28 (72) Inventor Takao Goto Fukushima Prefecture 1 Tanaka, Yuno, Iisaka-cho, Fukushima City, Toa Eyo Co., Ltd. (72) Inventor, Kentaro Kojo, Fukushima City, 1 Yuno, Izaka-cho, Fukushima City, Toa, Eyo Co., Ltd. (72) Inventor, Senichi Narita, Fukushima Prefecture 1 Tanaka, Yuno, Iizaka-cho, Tochi, Japan

Claims (1)

1. A 2-alkynyl adenosine derivative represented by the formula (I) and a salt thereof. [Chemical 1] In the formula, R represents any one of formulas (A) to (F): (In the formula, R ¹ and R ² may be the same or different and each represents 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 azido group or a cyano group. )