JP3025541B2 - 2-Substituted adenosine derivatives and drugs for cardiovascular diseases - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 2-substituted adenosine derivative and a drug for cardiovascular diseases containing the compound as an active ingredient.

[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);
No. 5100), these derivatives do not sufficiently solve the above problems, and have not yet been put to practical use as pharmaceuticals.

The present inventors have previously succeeded in synthesizing a compound having a specific alkynyl group introduced at the 2-position of adenosine (see, for example, Chem. Pharm. Bull., 33 (4), 1766-1769 (1)
985)), among these compounds, compounds having a straight-chain carbon chain as an alkynyl group are particularly remarkable, show a sustained blood pressure lowering effect, and have a small effect on heart rate (for example, Nucleic Acids Resear
ch, SymposiumSeries No. 16, 97-100 (1985);
-33477; JP-B-2-17526).

[0005] Compared with other conventional adenosine derivatives, 2-alkynyladenosine having such a linear carbon chain has a strong and long-lasting pharmacological action on circulatory organs and has weak side effects. Further, the appearance of a compound having these enhanced properties has been expected.

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 inhibitory action on the heart, central inhibitory action, etc. are exhibited 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.

[0007] Thus, if adenosine derivatives with high affinity for the A ₂ receptor while having low affinity for the A ₁ receptor are developed, they may be associated with hypertension, ischemic heart disease, It would be useful as a medicament for treating or preventing cardiovascular diseases such as ischemic brain disease.

That is, an object of the present invention is to exert strong pharmacological actions such as blood pressure lowering action, coronary vasodilator action, peripheral vasodilator action, cerebral circulation improvement action, peripheral circulation improvement action, platelet aggregation inhibitory action, and anti-atherosclerosis action. Another object of the present invention is to provide a 2-substituted adenosine derivative which is long-lasting and has high selectivity for A ₂ receptor, while having few side effects such as a cardiac inhibitory action and a central inhibitory action.

[0009]

The present inventors have SUMMARY OF THE INVENTION The development of novel adenosine derivatives, as well as in the process of various studies of their pharmacological activity, high affinity certain adenosine derivatives against A ₂ receptor On the other hand, it has been found that the compound exhibits low affinity for the A ₁ receptor, that is, a compound having high selectivity for the A ₂ receptor,
Furthermore, they have confirmed that they are useful as drugs for cardiovascular diseases, and have completed the present invention.

That is, the present invention provides the following general formula [I]

Embedded image In the formula, R represents a hydrogen atom or a hydroxyl group, m represents an integer of 2 to 7,
n represents 0 or an integer of 1 to 3, and R ¹ , R ² and R
³ represents a hydrogen atom, a protecting group for a hydroxyl group or a phosphoric acid residue, and R ¹ , R ² and R ³ may be the same or different from each other (hereinafter, abbreviated as “the compound of the present invention”) In some cases) and its salts.

The present invention also provides a drug for cardiovascular diseases, comprising a 2-substituted adenosine derivative represented by the above general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient. Is what you do.

In the general formula [I], when R ¹ , R ² and / or R ³ are hydroxyl-protecting groups, these are substituents commonly used as hydroxyl-protecting groups of nucleosides. They are the same or different. 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,
acyl groups such as p-anisoyl, 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-
Aralkyl groups such as naphthylmethyl and α-naphthyldiphenylmethyl; trimethylsilyl, triethylsilyl,
Silyl groups such as dimethylisopropylsilyl, isopropyldimethylsilyl, methyldi-t-butylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl and tetraisopropyldisiloxanyl; alkoxymethyl such as methoxymethyl and ethoxymethyl Groups: Acetal-type or ketal-type protecting groups such as isopropylidene, ethylidene, propylidene, benzylidene, and methoxymethylidene.

When R ¹ , R ² and / or R ^{3 are} phosphoric acid residues, they are represented by the formula [A] or [B]

Embedded image It is represented by M in the formula [A] or [B] represents one or more cations having a positive charge corresponding to the negative charge of the phosphate residue, and specifically includes hydrogen ion, sodium ion, potassium ion, calcium ion , Barium ion, magnesium ion, ammonium ion and the like. The phosphate residue of the formula [A] is represented by the general formula [I]
Forms a phosphate ester with one hydroxyl group of the ribose skeleton in formula (B), and the phosphate residue of formula [B] forms a cyclic phosphate ester with two hydroxyl groups of the ribose skeleton in formula [I].

Among the 2-substituted adenosine derivatives represented by the general formula [I], compounds in which R ¹ , R ² and R ³ are hydrogen atoms are exemplified in the following Tables (A) and (B).

[0015]

[Table 1]

[0016]

[Table 2]

Examples of the adenosine derivative represented by the general formula [I] in which R ¹ , R ² and R ³ are substituents other than a hydrogen atom are shown in Tables 1 (A) and 1 (B). A 2 ', 3', 5'-tri-O-acyl form of the compound,
5'-O-acyl compound, 5'-O-aralkyl compound, 3'-
O-aralkyl, 5'-phosphate, 3 ',
A 5'-cyclic phosphate is exemplified.

The adenosine derivative represented by the general formula [I] can exist as a free form or a salt form. Examples of the salt type 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; sodium salt, potassium Alkali metal salts such as salts; alkaline earth metal salts such as calcium salts, barium salts, and magnesium salts; and ammonium salts. Of these, hydrochloride, oxalate,
Pharmaceutically acceptable salts such as citrate, malate and sodium salt are preferred.

Hereinafter, an example of a method for synthesizing the compound of the present invention will be described. [Synthesis Method 1] The compound of the present invention has the general formula [II]

Embedded image [In the formula, R ^{1 ′ to} R ^{3 ′} are a hydrogen atom, a protecting group for a hydroxyl group (the same protecting group as that exemplified as the above R ^{1 to} R ³ ) or a phosphoric acid residue (the above R ^{1 to} R ³ And X represents iodine or bromine.] 2-halogenoadenosines (hereinafter, referred to as the following).
Abbreviated as "raw material compound") in a solvent in the presence of a palladium catalyst and a copper compound of the general formula [III]

Embedded image [Wherein m, n and R are the same as defined above], by reacting (cross-coupling reaction) with the acetylene compound represented by the formula (1), and if necessary, removing the protecting group of the sugar moiety hydroxyl group or protecting the sugar moiety hydroxyl group. It can be synthesized by a method of introducing a group or a phosphoric acid residue. The cross-coupling reaction is performed by a known synthesis method of 2-alkynyl adenosine (Japanese Patent Publication No.
33477 and JP-B-2-17526).

As the acetylene compound [III], a compound having m number, n number and R according to the kind of the intended compound of the present invention is selected.

As a reaction solvent, triethylamine, tributylamine, N, N-diisopropylethylamine, trioctylamine, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine, dimethylaniline, diethylaniline, A basic solvent such as pyridine alone, or acetonitrile, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),
A mixed solvent of an aprotic polar solvent such as N, N-dimethylacetamide, tetrahydrofuran (THF), and 1,4-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 may be about 0.001 to 0.1 times the mol of the starting compound represented by the formula [II], that is, the so-called catalyst amount.

In addition to the palladium catalyst, a copper compound is added to the reaction solution to promote the cross coupling reaction. For example, a copper halide compound such as cuprous iodide or cuprous bromide may be added to the reaction solution in an amount of about 0.06 mole per mole of the compound of the formula [II].

The reaction between the starting compound and the acetylene compound is carried out in the presence of the starting compound 1 in the presence of a palladium catalyst and a copper compound.
Using 1 to 2 moles of the acetylene compound with respect to the mole,
The reaction can be carried out at a reaction temperature of 10 to 90 ° C. for 1 to 100 hours.

After the completion of the cross-coupling reaction, the resulting 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, when removing the protecting group of the hydroxyl group,
It can be performed 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, sulfuric acid,
The protecting group can be removed by hydrolysis using an acid such as hydrochloric acid. When the protecting group is a silyl group, a suitable solvent (THF, DMSO, acetonitrile,
1,4-dioxane), trifluoroacetic acid, trichloroacetic acid, tosylic acid, sulfuric acid, acids such as hydrochloric acid, tetrabutylammonium fluoride, hydrogen fluoride pyridine salt,
The protecting group can be removed using ammonium fluoride or the like. When the protecting group is an acyl group, methanolic ammonia, concentrated aqueous ammonia, sodium methoxide,
The protecting group can be removed by hydrolysis using sodium ethoxide, sodium hydroxide, potassium hydroxide, or the like. Thus, R ¹ to R ^{1 of} the general formula [I]
From the compounds in which R ³ is a protecting group, compounds in which these are hydrogen atoms can be obtained.

When the target compound is a compound in which R ^{1 to} R ³ of the general formula [I] is a protecting group or a phosphoric acid residue, R ^{1 ′ to} R ³ ′ of the general formula [II] is the starting compound. If a compound that is a protecting group or a phosphoric acid residue corresponding to R ^{1 to} R ³ is selected, the target compound can be synthesized by subjecting the compound to the above cross-coupling reaction.

Further, after previously synthesizing a compound of the general formula [I] wherein R ^{1 to} R ³ are hydrogen atoms, 2 ′, 3 ′ and / or
Alternatively, it is also possible to introduce a protecting group at the 5'-position by a conventional method. For example, a reactive derivative of a protecting group to be introduced (an aralkyl group, a silyl group, a halide thereof (bromide, chloride, iodide), etc.), and an acyl group, a corresponding carboxylic acid anhydride, Ester or halide (bromide, chloride, iodide, etc.)
With a suitable reaction solvent (pyridine, dioxane, THF,
R ¹ of the general formula [I] in acetonitrile, chloroform, dichloromethane, methanol, ethanol, water, etc.).
A protective group can be introduced by reacting with a compound in which -R ³ is a hydrogen atom. When an aralkyl group is introduced using a halogenated aralkyl, sodium hydride (sodium hydride) or the like is used. When a silyl group is introduced using a silyl halide, imidazole or the like is used. When an acyl group is introduced using an anhydride, a tertiary amine such as triethylamine, an organic base such as pyridine, picoline, and dimethylaminopyridine, an alkali metal hydroxide, and an alkali metal carbonate are respectively present in the reaction system. This can accelerate the reaction.

After previously synthesizing a compound of the formula [I] wherein R ^{1 to} R ³ are hydrogen atoms, a phosphoric acid residue can be introduced into the 2 ′, 3 ′ and / or 5 ′ position by a conventional method. . In this case, a protecting group is previously introduced at a site other than the site where a phosphate residue is to be introduced, in the sugar moiety of the compound of the general formula [I],
Thereafter, a phosphorylating agent (for example, phosphorus oxychloride or the like) is allowed to act to introduce a phosphoric acid residue into a target site.

When the general formula [I] is 2 ', 3', 5'-tri-
The outline of typical synthetic methods for compounds which are O-acyl, 5'-O-acyl, 5'-O-aralkyl, 3'-O-aralkyl or 5'-phosphate is as follows. It is shown below.

2 ′, 3 ′, 5′-tri-O-acyl compound (1)

Embedded image Wherein m, n, R and X are as defined above,
^A , R ^B and R ^C represent the case where R ^{1 to} R ³ or R ^{1 ′ to} R ^{3 ′ in the} general formula [I] or [II] is an acyl group. ]

(2)

Embedded image [Wherein, m, n, R, R ^A , R ^B and R ^C are as defined above. ]

5′-O-acyl compound (1)

Embedded image [Wherein, m, n, R, R ^C and X are as defined above. ]

(2)

Embedded image [Wherein, m, n, R and R ^C are as defined above. ]

5′-O-aralkyl body (1)

Embedded image Wherein m, n, R and X are as defined above,
^D is R ³ or R ^{3 ′ in the} general formula [I] or [II].
Is an aralkyl group. ]

(2)

Embedded image [Wherein, m, n, R ¹ , R ² and R ^D are as defined above. ]

3′-O-aralkyl body (1)

Embedded image Wherein m, n, R and X are as defined above,
^E represents R ² or R ^{2 ′ in the} general formula [I] or [II].
Is an aralkyl group. ]

(2)

Embedded image [Wherein, m, n, R, R ¹ , R ² and R ^E are as defined above. ]

5′-phosphate ester

Embedded image Wherein m, n, R and X are as defined above,
¹ and R ² represent a hydrogen atom or a hydroxyl-protecting group;
R ^{1 ′} and R ^{2 ′} represent the same hydroxyl-protecting group as R ¹ and R ² , respectively, and P in ○ represents the above formula [A]. ]

[Synthesis Method 2] The compound of the present invention represented by the general formula [I] can also be synthesized by a method different from the above. For example, the following synthesis method previously developed by the present inventors (see WO 90/15812) can be employed.

That is, the general formula [IV]

Embedded image [Wherein, R ^{1 ′ to} R ^{3 ′} and X are the same as those described above, and Y is a leaving group (having low reactivity with an acetylene compound, and is easily replaced with an amino group by reacting with an aminating agent. Functional groups that can be used; specifically, arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, mesitylenesulfonyloxy, and 2,4,6-triisopropylbenzenesulfonyloxy;
A chlorine atom) is reacted with an acetylene compound represented by the general formula [III] (cross-coupling reaction) in a reaction solvent in the presence of the same palladium catalyst as described above to obtain a compound represented by the general formula [V]

Embedded image Wherein m, n, R, R ^{1 ′} , R ^{2 ′} , R ^{3 ′} and Y have the same meanings as described above.

This cross-coupling reaction can be carried out basically in the same manner and under the same conditions as the above-mentioned cross-coupling reaction, but it is not always necessary to allow a copper compound to be present in the reaction solution. When a copper compound is used, the amount of the compound represented by the general formula [IV] is 0.001 to
A very small amount of about 0.02 mole may be added to the reaction solution.

After completion of the reaction, the resulting synthetic intermediate [V]
If necessary, conventional means for isolating and purifying nucleosides (adsorption chromatography, recrystallization, etc.) and, when a copper compound is added to the reaction solution, an organic solvent-
After subjecting to a treatment for removing copper compounds such as extraction and distribution with water, the mixture is subjected to the next amination reaction step for preparing the compound of the present invention.

Next, the compound of the present invention represented by the general formula [I] can be synthesized by reacting the synthetic intermediate [V] with an aminating agent and, if necessary, removing the protecting group. Examples of the aminating agent used in this reaction include liquid ammonia, alcoholic ammonia (methanolic ammonia, ethanolic ammonia, etc.), and organic solvents (acetonitrile, 1,2-dimethoxyethane, 1,4-dioxane, THF, etc.). A mixture of aqueous ammonia and the like can be given. The reaction can be carried out by reacting the above synthetic intermediate and the above aminating agent at room temperature to 100 ° C for 2 hours to 2 weeks. After the reaction, the compound of the present invention can be obtained by deprotecting, if necessary, and isolation and purification by a conventional method.

When an acyl group is used as a protecting group, the acyl group is removed and deprotected simultaneously with the reaction of the synthetic intermediate [V] with the aminating agent. Without protection, R ¹ to R ^{1 of the} general formula [I]
A compound in which R ³ is a hydrogen atom can be obtained.

In the synthesis method 2, R of the general formula [I]
When synthesizing a compound in which ^{1 to} R ³ are a protecting group or a phosphoric acid residue, a compound in which R ^{1 to} R ³ of the general formula [I] is a hydrogen atom is synthesized by the above-described method, and then 2 ′, A preferred method is to introduce a desired protecting group or phosphate residue at the 3 'and / or 5' position.

A drug containing the compound of the present invention or a pharmaceutically acceptable salt thereof (hereinafter, referred to as “the compound of the present invention” including the salts thereof in the description of pharmaceutical preparations) as an active ingredient includes mammals including humans. It is used as a medicament for treating or preventing cardiovascular diseases such as hypertension and ischemic diseases (ischemic heart disease, ischemic brain disease, etc.) in animals. The compound of the present invention can be orally or parenterally administered together with a pharmaceutically acceptable carrier to treat or prevent the above-mentioned cardiovascular disease.

[0049] Oral preparations are usually powders, granules,
Solid preparations such as capsules and tablets or liquid preparations such as syrups and elixirs are used. In addition, as parenteral administration agents, injections, rectal administration agents, external preparations for skin, and inhalants are usually used. These preparations are produced according to a conventional method by adding a pharmaceutically acceptable adjuvant to the compound of the present invention. Furthermore, it is also possible to prepare a sustained-release preparation by a known technique.

To prepare a solid preparation for oral administration, the compound of the present invention and excipients (lactose, starch, crystalline cellulose,
Powdered mixture with calcium lactate, calcium hydrogen phosphate, magnesium metasilicate aluminate, silicic anhydride, etc., or, if necessary, a binder (sucrose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), a disintegrant (Carboxymethylcellulose, calcium carboxymethylcellulose, etc.) and wet or dry granulation to give granules. In order to produce tablets, these powders and granules may be compressed as they are or by adding a lubricant (eg, magnesium stearate, talc, etc.). In addition, these granules or tablets are coated with an enteric base (hydroxypropylmethylcellulose phthalate, methyl methacrylate copolymer, etc.) to form an enteric preparation, or coated with ethylcellulose, carnauba wax, hydrogenated oil, etc. to form a sustained release preparation. You can also. Further, in order to produce capsules, powders or granules are filled in hard capsules, or the compound of the present invention is dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form soft capsules. You can also.

To prepare a liquid preparation for oral administration, the compound of the present invention and a sweetener (sucrose, sorbitol, glycerin, etc.) are dissolved in water to give a clear syrup, or essential oil, ethanol, etc. In addition, elixirs or emulsions or suspensions by adding gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose and the like. If desired, flavoring agents, coloring agents, preservatives, and the like may be added to these liquid preparations.

To prepare an injection, the compound of the present invention may be optionally adjusted with a pH adjuster (eg, hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, sodium monohydrogen phosphate, sodium dihydrogen phosphate), isotonic Agent (sodium chloride,
Dissolved in distilled water for injection together with glucose, etc.), sterile filtered and filled into ampoules, or lyophilized under vacuum after adding mannitol, dextrin, cyclodextrin, gelatin, etc. Good. Further, an emulsifier (lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.) may be added to the compound of the present invention to emulsify in water to obtain an emulsion for injection.

In order to produce a rectal preparation, the compound of the present invention is heated and melted together with a suppository base (eg, tri-, di- or monoglyceride of cocoa fatty acid, polyethylene glycol), poured into a mold and cooled. The compound of the present invention may be dissolved in polyethylene glycol, soybean oil or the like, and then coated with a gelatin film.

To prepare an external preparation for skin, the compound of the present invention is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol and the like, and if necessary, heated and kneaded to form an ointment or an adhesive ( Rosin, acrylic acid alkyl ester polymer, etc.) and then spread on a non-woven fabric such as polyethylene to form a tape.

To produce an inhalant, the compound of the present invention is dissolved or dispersed in a propellant (such as Freon gas) and filled into a pressure-resistant container to form an aerosol. The dose of the compound of the present invention varies depending on the age, body weight and disease state of the patient, but is usually about 0.1 mg to 100 mg per individual per day, and it is desirable to administer the compound once or several times.

[0056]

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 is, it is a compound having extremely high selectivity for the A ₂ receptor. 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).

The compound of the present invention will now be described in vitro.
The above-mentioned effects of the compounds of the present invention will be specifically described by pharmacological activity tests in vitro and in vivo.

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, the affinity for the A ₁ receptor was measured using a membrane preparation of the Wistar rat brain, and was determined to be 2.5 nM [ ³
H] -N ⁶ -cyclohexyladenosine ([ ³ H] -C
The affinity constant (Ki) was calculated from the concentration of the test compound that caused 50% displacement of the specific binding of HA) 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-ethyl carboxamide adenosine ^([3 H]
-NECA) was used to calculate the affinity constant (Ki) from the concentration of the test compound that caused 50% displacement of the specific binding to the membrane preparation. Specifically, from the results of the saturation binding experiment of the radioligand ([ ³ H] -CHA or [ ³ H] -NECA) to each of the above membrane preparations, calculation was performed using the least square method using a computer program. and to determine the Scatchard analysis dissociation constants performed (linear data transformation) (K _D) and the maximum number of binding sites (Bmax). Furthermore, a displacement curve was drawn from the results of incubation with various concentrations of the test compound, and the concentration (IC ₅₀ ) of the test compound that caused 50% displacement of the specific binding of the radioligand at the above concentration was determined. From these results, the Cheng and Prusoff formulas (Biochem. Phar
macol., 22 , 3099 (1973)) according to the affinity constant (Ki).
Was calculated (“Neurotransmitter-receptor binding”, No. 8).
(See pages 3-119, September 15, 1987, published by Seiwa Shoten Co., Ltd.) The selectivity for the A ₁ receptor and the A ₂ receptor was calculated from the ratio (A ₁ / A ₂ ) of the above Ki values. The results are shown in Table 2.

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 administration of the test compound is from 0.03 to the femoral vein.
The test was performed at a dose of 100 μg / kg at a common ratio of 3 at intervals of 5 minutes. After administration of each dose, the blood pressure and heart rate were measured for 5 minutes and the maximum values were determined. From these results, the dose (E) of the test compound that reduced the blood pressure of each SHR before administration of the test compound by 30% was reduced.
D ₃₀ ) and the dose (ED ₁₀ ) of the test compound that reduces the heart rate before administration by 10% were determined. The effect of each test compound on blood pressure and heart rate was determined by ED ₃₀ and ED ₁₀ , respectively.
Were used as indices. The results are also shown in Table 2.

[0060]

[Table 3]

As shown in Table ₂ , the compounds of the present invention were compared with the control compound with respect to the affinity (Ki) for the A ₁ receptor and the A ₂ receptor.
_{The 1} / A ₂ value is higher than that of the control compound. That is, by substituting the alkynyl group of the control compound having a linear carbon chain alkynyl group at the 2-position of the adenine ring with the alkynyl group having a cycloalkyl group of the present invention, the selectivity for the A ₂ receptor is increased. Is shown. In addition, the ratio (ED ₁₀ / ED ₃₀ ) of the dose (ED ₁₀ ) for lowering the heart rate of SHR by 10% and the dose (ED ₃₀ ) for lowering the blood pressure by 30% was compared between the compound of the present invention and the control compound. For compounds, their values tend to be high. That is, it was shown that the compound of the present invention has a sufficient blood pressure lowering effect at a dose that has little effect on heart rate.

As described above, the compounds of the present invention are known
Compared with alkynyl adenosine can increase selectivity for A ₂ receptors, show excellent circulation improving action without significantly affecting the heart rate (blood pressure lowering effects).

[0063]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples.
explain.Example 1 2- (cyclohexylethynyl) adenosine (compound N
o.25): 1.95 g (5 mmol) of 2-iodoadenosine was added to N, N
-Dissolve in 20 ml of dimethylformamide (DMF)
Liphenylphosphine) palladium dichloride 0.18 g,
Cuprous iodide 0.1g, triethylamine 2.8ml and cycle
Add 0.8 ml of rohexyl acetylene and stir at 90 ° C for 2 hours.
Stirred. After allowing the reaction solution to cool, the residue obtained by concentration to dryness was removed.
Dissolve in chloroform and pass hydrogen sulfide gas vigorously for 1 minute
I did The residue after drying under reduced pressure is subjected to silica gel column chromatography.
Purified by luffy, crystallized from ethanol-water and 2-
1.11 g of (cyclohexylethynyl) adenosine crystals
(2.97 mmol, yield 59%) was obtained.

Melting point [mp]: 135-141 ° C. (recrystallized EtOH-
H ₂ O) Infrared absorption spectrum [IR] (KBr, cm ^-1 ): 2220 (acetylene) Nuclear magnetic resonance spectrum [ ¹ H-NMR] (400 MHz, DMSO-d ₆ ) δppm: 1.29-1.84 (10H, m, Cyclohexyl), 2.61 (1
H, m, CH-C3C-), 3.54-3.68 (2H, m, H-5 '),
3.95 (1H, m, H-4 '), 4.12 (1H, dd, H-3'), 4.52 (1H, d
d, H-2 '), 5.86 (1H, d, H-1', J = 5.86Hz), 7.43 (2H, b
_{rs, NH 2), 8.39 (} 1H, s, H-8)

UV absorption spectrum [UV] [nm (ε)] H ₂ O: λmax 285 (sh), 270 (14,700) λmin 247 (7,100) 50 mM HCl: λmax 294 (12,000), 271 (15,800) λmin 283 ( 11,400), 247 (6,800) 50mM NaOH: λmax 285 (sh), 270 (14,700) λmin 247 (7,400)

Elemental analysis (as C ₁₈ H ₂₃ N ₅ O ₄ .H ₂ O) Calculated value (%): C, 55.23; H, 6.44; N, 17.89 Actual value (%): C, 55.30; H, 6 , 46; N, 17.72

Example 22 2-[(1-hydroxycyclohexane-1-yl) d
[Thinyl] adenosine (Compound No. 29): In the method of Example 1, 1.14 g of 2-iodoadenosine (2.9 m
mol) and replace 1 with cyclohexylacetylene.
Reaction using -ethynyl-1-cyclohexanol
Purification was carried out in the same manner as in Example 1 except that the reaction was carried out at 100 ° C. for 1 hour, and crystallized from ethanol-water to give 2-[(1-
There was obtained 0.91 g (2.3 mmol, 79% yield) of crystals of [hydroxycyclohexane-1-yl) ethynyl] adenosine.

Mp: 142-147 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2230 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.25-1.87 (10H , m, cyclohexyl), 3.56-
3.71 (2H, m, H-5 '), 3.97 (1H, m, H-4'), 4.15 (1H, dd, H
-3 '), 4.50 (1H, dd, H-2'), 5.1 (1H, d, OH), 5.2 (1H, t,
OH), 5.4 (1H, d, OH), 5.5 (1H, s, -C3C-C-O
H), 5.89 (1H, d, H-1 ', J = 5.86Hz), 7.4 (2H, s, NH
₂ ), 8.39 (1H, s, H-8)

UV [nm (ε)] H ₂ O: λmax 287 (sh), 270 (14,400) λmin 246 (7,100) 50 mM HCl: λmax 294 (10,800), 271 (15,600) λmin 284 (10,300), 247 ( 7,300) 50 mM NaOH: λmax 287 (sh), 270 (14,000) λmin 247 (7,400)

Elemental analysis (as C ₁₈ H ₂₃ N ₅ O ₅ .H ₂ O) Calculated value (%): C, 53.06; H, 6.18; N, 17.19 Actual value (%): C, 53.22; H, 6 , 23; N, 17.01

Example 3 2- (3-cyclopentyl-1-propynyl) adenosine
(Compound No. 18): The procedure of Example 1 was repeated except that 1.56 g (3.98 mmol) of 2-iodoadenosine was used as a raw material and 3-cyclopentylpropyne was used instead of cyclohexylacetylene. Purified by the same reaction, crystallized from ethanol-water to give 1.05 g of 2- (3-cyclopentyl-1-propynyl) adenosine as crystals.
(2.8 mmol, 70.3% yield).

Mp: 125-127 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2230 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.29-1.84, 2.10 (9H, m, cyclopentyl) 2.40 (2H, d, CH 2 C three C), 3.55-3.71 (2H, m , H-5 '),
3.98 (1H, m, H-4 '), 4.15 (1H, dd, H-3'), 4.53 (1H, dd,
H-2 '), 5.12 (1H, d, OH), 5.25 (1H, dd, OH), 5.41 (1H, d, OH
OH), 5.88 (1H, d, H-1 ', J = 5.86Hz), 7.36 (2H, s, N
_{H 2), 8.39 (1H,} s, H-8)

UV [nm (ε)] H ₂ O: λmax 286 (sh), 271 (14,900) λmin 246 (6,800) 50 mM HCl: λmax 293 (12,000), 272 (16,700) λmin 284 (11,600), 248 ( 6,600) 50mM NaOH: λmax 286 (sh), 271 (14,900) λmin 247 (7,200)

[0074] Elemental analysis _{(C 18 H 23 N 5 O} 4 · 2 / 3H 2
(As O) Calculated value (%): C, 56.09; H, 6.36; N, 18.17 Actual value (%): C, 56.30; H, 6.29; N, 17.90

Example 4 2-[(1-hydroxycyclopentan-1-yl) e
[Thinyl] adenosine (Compound No. 21): 9- ( 2,3,3)
5-tri-O-acetyl-β-D-ribofuranosyl)-
6-chloro-2-iodopurine 4.0 g (7.4 mmol), bis (triphenylphosphine) palladium dichloride 190
mg (0.27 mmol) and cuprous iodide 28 mg (0.15 mmol)
Is suspended in 30 ml of 1,4-dioxane, and triethylamine is suspended.
2.0 ml, 1-ethynyl-1-cyclopentanol 0.98 g
(8.9 mmol) was added, and the mixture was stirred and reacted at room temperature for 10 hours. After the reaction, the reaction solution was concentrated, and 200 ml of chloroform was added to the obtained residue to dissolve it. The solution was distributed and washed several times with an aqueous solution of EDTA (ethylenediaminetetraacetic acid) · 2Na, and then with saturated saline to remove copper ions. After removing the organic layer, the organic layer was concentrated and subjected to silica gel column chromatography, and 9- (2,3,5-tri-O-acetyl-β-) was extracted from the elution portion with an elution solvent (chloroform: ethyl acetate = 2: 1). D-ribofuranosyl) -6-chloro-2-[(1
-Hydroxycyclopentan-1-yl) ethynyl] purine (2.5 g, yield 64.6%) was obtained as a candy-like substance.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.28 (1 H, s, H-8), 6.22 (1 H, d, H-1 ′), 5.90 (1
H, t, H-2 '), 5.73-5.71 (1H, m, H-3'), 4.51-4.43 (3H,
m, H-4 ', H-5'), 2.85 (1H, s, OH), 2.18 (3H, s, acetyl), 2.1
3 (3H, s, acetyl), 2.09 (3H, s, acetyl), 1.93-1.67 (8H, m, cyclopentyl)

9- (2,3,5-tri-O-acetyl-
β-D-ribofuranosyl) -6-chloro-2-[(1-
Hydroxycyclopentan-1-yl) ethynyl] purine (2.5 g, 4.8 mmol) in dioxane-concentrated aqueous ammonia (2:
(V / v) (90 ml) was added, the tube was sealed, and heated at 70 ° C. for 20 hours to remove the acetyl group simultaneously with the amination. After the reaction, the reaction solution was concentrated and subjected to silica gel column chromatography, and the fraction eluted with an elution solvent (chloroform: methanol = 7: 1) was added to 2-[(1-hydroxycyclopentan-1-yl) ethynyl] adenosine. And ethanol-
Recrystallized from water to obtain 0.93 g of the desired compound as crystals (51.7% yield)
) Got.

Mp: 138-144 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2232 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.41 (1H, s) , H-8), 7.43 ( 2H, s, NH 2), 5.87
(1H, d, H-1 '), 5.46 (1H, d, OH), 5.41 (1H, s, -C3C
−C-OH), 5.18-5.15 (2H, m, OH × 2), 4.48 (1H, d
d, H-2 '), 4.11 (1H, dd, H-3'), 3.95 (1H, dd, H-4 '), 3.6
9-3.53 (2H, m, H-5 '), 1.93-1.66 (8H, m, cyclopentyl)

UV [nm (ε)] H ₂ O: λmax 270 (14,900) λmin 248 (8,800) 50 mM HCl: λmax 271 (16,300) λmin 248 (8,600) 50 mM NaOH: λmax 270 (15,000) λmin 247 (8,400)

Elemental analysis (as C ₁₇ H ₂₁ N ₅ O ₅ .H ₂ O) Calculated value (%): C, 51.90; H, 5.89; N, 17.80 Actual value (%): C, 52.00; H, 5.83 ; N, 17.54

Example 5 5'-O-benzyl-2-[(1-hydroxycyclo
Xan-1-yl) ethynyl] adenosine (Compound No. 2
5′-O-benzyl form of 1) : (1) 5′-O-benzyl-2-iodo-2 ′, 3′-
Synthesis of O-isopropylidene adenosine: 2-iodo-
433 mg of 2 ', 3'-O-isopropylideneadenosine (1.
(0 mmol) was dissolved in 20 ml of THF, 150 mg (3.8 mmol) of 60% sodium hydride was added at room temperature, and the mixture was stirred for 30 minutes. Next, 190 mg (1.1 mmol) of benzyl bromide was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with chloroform, and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to obtain 120 m of the desired compound.
g (33.5% yield) was obtained as a foam.

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 7.86 (1 H, s, H-8), 7.33-7.25 (5 H, m, H-φ),
6.10 (1H, d, H- 1 '), 6.01 (2H, s, NH 2), 5.24 (1H, dd,
H-2 '), 5.00 (1H, dd, H-3'), 4.56-4.46 (3H, m, φ-CH
₂ , H-4 '), 3.73-3.63 (2H, m, H-5'), 1.61 (3H, s, methyl),
1.39 (3H, s, methyl)

(2) 5′-O-benzyl-2-[(1-
Hydroxycyclohexane-1-yl) ethynyl]-
Synthesis of 2 ', 3'-O-isopropylideneadenosine:
230 mg (0.44 mmol) of 5'-O-benzyl-2-iodo-2 ', 3'-O-isopropylideneadenosine was added to DMF.
Dissolved in 10 ml, bis (triphenylphosphine) palladium dichloride 30 mg (10 mol%), 1-ethynyl-1-cyclohexanol 70 mg (0.56 mmol), cuprous iodide 8 mg (10 mol
1%) and 0.5 ml of triethylamine, and the mixture was stirred at 70 ° C. for 20 hours under an argon atmosphere. The solvent was distilled off under reduced pressure, and the mixture was partitioned using chloroform and an aqueous solution of EDTA · 2Na, and the chloroform layer was washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. From the fraction eluted with the elution solvent (chloroform: methanol = 50: 1), 190 mg of the desired compound (yield) 82.6%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 8.03 (1 H, s, H-8), 7.31-7.22 (5 H, m, H-φ),
6.20 (1H, d, H- 1 '), 5.63 (2H, brs, NH 2), 5.24 (1H, d
d, H-2 '), 5.01 (1H, dd, H-3'), 4.55-4.46 (3H, m, φ-C
_{H 2, H-4 ')} , 3.70-3.64 (2H, m, H-5'), 1.62 (3H, s, methyl), 1.39 (3H, s, methyl), 2.04-1.39 (10H, m, cyclohexyl )

(3) 5′-O-benzyl-2-[(1-
Synthesis of hydroxycyclohexane-1-yl) ethynyl] adenosine: 5′-O-benzyl-2-[(1-hydroxycyclohexane-1-yl) ethynyl] -2 ′,
3′-O-isopropylidene adenosine 190 mg (0.37 mmo
l) was dissolved in 2 ml of trifluoroacetic acid, and 0.5 ml of water was added.
Stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to elute the solvent (chloroform:
The compound was eluted with methanol (10: 1) and crystallized from ether to obtain 46 mg of the desired compound (yield: 26.3%).

Mp: 179-180 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2220 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.28 (1H, s) , H-8), 7.43 ( 2H, s, NH 2), 7.37-
7.29 (5H, m, H-φ), 5.89 (1H, d, H-1 '), 5.56 (1H, s,
-C3C-C-OH), 5.55 (1H, d, OH), 5.31 (1H, d,
OH), 4.54-4.52 (3H, m , φ-CH 2, H-2 '), 4.16 (1H, d
d, H-3 '), 4.08 (1H, dd, H-4'), 3.75-3.64 (2H, m, H-5 '),
1.81-1.26 (10H, m, cyclohexyl)

Elemental analysis (as C ₂₅ H ₂₉ N ₅ O ₅ ) Calculated value (%): C, 62.61; H, 6.10; N, 14.60 Actual value (%): C, 62.56; H, 6, 11; N , 14.48

Example 6 Synthesis of Compound of General Formula [I] (Compounds Nos. 17, 19, 2)
6, 27, 28, 37, 45) : (1) Synthesis of synthetic intermediate [V]: 9- (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -6-chloro-2 -Iodopurine (general formula [IV]), bis (triphenylphosphine) palladium dichloride (catalyst)
(0.05 equivalent) and cuprous iodide (copper compound)
(0.05 equivalent) was suspended in 1,4-dioxane (solvent), and triethylamine and an acetylene compound having a cycloalkylalkynyl chain corresponding to the target compound (general formula [III]) were added, followed by stirring at room temperature for 12 hours. Reacted.

After the reaction, the reaction solution was concentrated, and the obtained residue was dissolved by adding 200 ml of ethyl acetate.
a) Aqueous solution and then saturated saline were used to distribute and wash several times to remove copper ions. The organic layer was concentrated, subjected to silica gel column chromatography, and subjected to elution with an elution solvent (chloroform: ethyl acetate). 9- (2,
3,5-Tri-O-acetyl-β-D-ribofuranosyl) -6-chloro-2-cycloalkylalkynylpurine (general formula [V]) was obtained as an oil. Table 3 shows the types and amounts of starting compounds used in the above reaction, the amounts of reagents used, the types and yields of the target synthetic intermediates (yields), and the compositions of elution solvents for silica gel column chromatography.

[0090]Table 3 Type Raw material compound Target synthesis reagent (amount used) Elution solvent    Intermediate body   Composition of Formula [IV] Formula [III]_Mark Formula [V] Catalyst Copper-coupling Solvent Trie (Chloroform nmR Used amount Used amount Yield (g) Compound Film: acetic acid (g) (g)_issue Amine chill)(M mol) (Yield (%)) (mg) (mg) (ml) (ml) 0 4 H 5.38 1.1 (a) 4.8 350 95 50 2.1 2: 1 (10) (95) 24 H 4.00 1.2 (b) 3.3 260 70 40 1.6 2: 1 (7.4) (84) 15 H 5.38 1.5 ( C) 5.6 350 95 50 2.1 2: 1 (10) (100) 25 H 5.38 1.7 (d) 5.5 350 95 50 2.1 2: 1 (10) (100) 35 H 5.38 1.8 (e) 2.7 350 95 50 2.1 3: 1 (10) (48) 0 6 OH 4.00 1.3 (F) 3.9 260 70 40 1.6 2: 1 to 1: 1 (7.4) (71) 0 7 OH 5.38 1.7 (G) 5.5 350 95 50 2.1 2 : 1 to 1: 1(10) (98)

The identification data of the target synthetic intermediate [ ¹ H
-NMR (400 MHz, CDCl ₃ ) data] are shown below. Synthetic intermediate (a) δ ppm: 1.24 to 1.84 (8H, m, cyclopentyl), 2.08 (3H, s, acetyl), 2.16 (3
H, s, acetyl), 2.17 (3H, s, acetyl), 2.88~2.92 (1H, m, -C three C-C H
<), 4.41 (2H, d, H-5 '), 4.46 (1
H, dd, H-4 '), 5.58 (1H, dd, H-
3 '), 5.81 (1H, t, H-2'), 6.32.
(1H, d, H-1 '), 8.30 (1H, s, H-
8)

Synthetic intermediate (b) δ ppm: 1.10 to 1.97 (11H, m, C ₅ H ₉ C
_{H 2), 2.08 (3H,} s, acetyl), 2.16
(3H, s, acetyl), 2.17 (3H, s, acetyl), 4.41 (2H, d, H-5 '), 4.46 (1
H, dd, H-4 '), 5.57 (1H, dd, H-
3 '), 5.81 (1H, t, H-2'), 6.32.
(1H, d, H-1 '), 8.31 (1H, s, H-
8)

Synthetic intermediate (c) δ ppm: 1.05 to 1.92 (11H, m, cyclohexyl), 2.08 (3H, s, acetyl), 2.16
(3H, s, acetyl), 2.17 (3H, s, acetyl), 2.38 (2H, d, -C three C-C H ₂ -),
4.41 (2H, d, H-5 '), 4.47 (1H, d
d, H-4 '), 5.58 (1H, dd, H-3'),
5.81 (1H, t, H-2 '), 6.31 (1H,
d, H-1 '), 8.30 (1H, s, H-8)

Synthetic intermediate (d) δ ppm: 0.88 to 1.77 (13H, m, C ₆ H ₁₁ C
H ₂ −), 2.08 (3H, s, acetyl), 2.16
(3H, s, acetyl), 2.17 (3H, s, acetyl), 2.49 (2H, t, -C three C-C H ₂ -),
4.41 (2H, d, H-5 '), 4.46 (1H, d
d, H-4 '), 5.57 (1H, dd, H-3'),
5.80 (1H, t, H-2 '), 6.32 (1H,
d, H-1 '), 8.31 (1H, s, H-8)

[0095]Synthetic intermediate (e) δ ppm: 0.84 to 1.72 (15H, m, C₆H₁₁C
H_TwoCH_Two), 2.08 (3H, s, acetyl), 2.
16 (3H, s, acetyl), 2.17 (3H, s, acetyl)
Cetyl), 2.46 (2H, t, -C3C-CH
_Two −), 4.41 (2H, d, H-5 ′), 4.47
(1H, dd, H-4 '), 5.57 (1H, dd, H
-3 '), 5.80 (1H, t, H-2'), 6.32
(1H, d, H-1 '), 8.31 (1H, s, H-
8)

Synthetic intermediate (f) δ ppm: 1.63 to 2.04 (12H, m, cycloheptyl), 2.10 (3H, s, acetyl), 2.12
(3H, s, acetyl), 2.17 (3H, s, acetyl), 2.82 (1H, s, -C3CC-OH),
4.44 to 4.52 (3H, m, H-5 ', H-
4 '), 5.75 (1H, dd, H-3'), 5.90
(1H, t, H-2 '), 6.21 (1H, d, H-
1 '), 8.27 (1H, s, H-8)

Synthetic intermediate ( g ) δ ppm: 1.51 to 2.14 (14H, m, cyclooctyl), 2.10 (3H, s, acetyl), 2.12
(3H, s, acetyl), 2.17 (3H, s, acetyl), 2.65 (1H, s, -C3CC-OH),
4.42 to 4.51 (3H, m, H-4 ', H-
5 '), 5.75 (1H, dd, H-3'), 5.89
(1H, t, H-2 '), 6.20 (1H, d, H-
1 '), 8.27 (1H, s, H-8)

(2) Synthesis of compound of general formula [I]: 9-
120 ml of (2,3,5-tri-O-acetyl-β-D-ribofuranosyl) -6-chloro-2-cycloalkylalkynylpurine (general formula [V]) in 1,4-dioxane
And concentrated ammonia water (60 ml) was added.
For 18 hours to remove the acetyl group simultaneously with the amination. After the reaction, the reaction solution is concentrated, and the obtained residue is subjected to silica gel column chromatography. From the fraction eluted with an elution solvent (chloroform: methanol), 2-cycloalkylalkynyladenosine (general formula [ I]) was obtained.

Table 4 shows the types and amounts of the starting compounds (synthetic intermediates of the above (1)), the types and yields (yields) of the target compounds, and the compositions of the elution solvents for silica gel column chromatography in the above reaction. .

Table 4 Type Raw material compound Target compound Compound of elution solvent (synthesis intermediate) nmR formula [V] Chemical formula [I] (chloroform used amount (g) combined yield (g): methanol) (Yield (%)) No. 0 4 H 4.8 17 2.3 10: 1 (67) 24 H 2.8 19 1.7 10: 1 (85) 15 H 5.6 26 2.6 10: 1 (67) 25 H 5.5 27 2.8 10: 1 (70) 3 5 H 2.7 28 1.1 10: 1 (55) 06 OH 3.4 37 1.6 5: 1 (65) 07 OH 5.5 45 2.3 5: 1 (56)

The identification data of the target compound is shown below. Compound No. 17 mp: 127-133 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2232 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.56- 1.99 (8H, m, cyclopentyl), 2.84 (1H, m, -C three C-C H <), 3 .
55 to 3.65 (2H, m, H-5 '), 3.95 (1
H, d, H-4 '), 4.12 (1H, dd, H-
3 '), 4.51 (1H, dd, H-2'), 5.18
(1H, d, OH), 5.22 (1H, dd, HO)
H), 5.45 (1H, d, OH), 5.85 (1H,
d, H-1 '), 7.41 (2H, brs, NH 2),
8.38 (s, 1H, H-8)

Elemental analysis (as C ₁₇ H ₂₁ N ₅ O ₄ .1H ₂ O) Calculated value (%): C, 54.10; H, 6.14; N, 1
8.56 actual value (%): C, 54.15; H, 6.15; N, 1
8.64

Compound No. 19 mp: 108-114 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2236 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1 _{.09~1.95 (11H, m, C 5} H 9 C
_{H 2), 2.40 (2H,} t, -C three _{C-C H} 2 -),
3.53-3.68 (2H, m, H-5 '), 3.95
(1H, dd, H-4 '), 4.12 (1H, dd, H
-3 '), 4.53 (1H, dd, H-2'), 5.1
6 (1H, d, OH), 5.21 (1H, t, OH),
5.44 (1H, d, OH), 5.85 (1H, d, H
-1 '), 7.41 (1H, brs, NH 2), 8.3
8 (1H, s, H-8)

Compound No. 26 mp: 97-103 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2236 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1 .03~1.83 (11H, m, cyclohexyl), 2.31 (2H, d, -C three C-C H ₂ -),
3.53-3.68 (2H, m, H-5 '), 3.95
(1H, dd, H-4 '), 4.12 (1H, dd, H
-3 '), 4.53 (1H, dd, H-2'), 5.1
8 (1H, d, OH), 5.23 (1H, dd, O
H), 5.45 (1H, d, OH), 5.85 (1H,
d, H-1 '), 7.41 (2H, brs, NH 2),
8.38 (1H, s, H-8)

Compound No. 27 mp: 104-111 ° C. (recrystallized EtOH—H ₂ O) IR (KBr, cm ⁻¹ ): 2240 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0 _{.87~1.76 (13H, m, C 6} H 11 C
_{H 2), 2.41 (2H,} t, -C three C-C H ₂ -),
3.57-3.68 (2H, m, H-5 '), 3.95
(1H, dd, H-4 '), 4.12 (1H, d, H-
3 '), 4.53 (1H, dd, H-2'), 5.16
(1H, d, OH), 5.22 (1H, brs, O
H), 5.44 (1H, d, OH), 5.85 (1H,
d, H-1 '), 7.41 (2H, brs, NH 2),
8.38 (1H, s, H-8)

[0106] Elemental analysis _{(C 20 H 27 N 5 O} 4 · 2/3 H 2 O
Calculated) (%): C, 58.09; H, 6.91; N, 1
6.94 Found (%): C, 58.09; H, 6.80; N, 1
7.06

Compound No. 28 mp: 117-127 ° C. (recrystallized EtOH-H ₂ O) IR (KBr, cm ⁻¹ ): 2232 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0 _{.86~1.71 (15H, m, C 6} H 11 C
_{H 2 CH 2), 2.38 (} 2H, t, -C three C-C H ₂
−), 3.55 to 3.68 (2H, m, H-5 ′),
3.95 (1H, d, H-4 '), 4.12 (1H, d
d, H-3 '), 4.54 (1H, dd, H-2'),
5.18 (1H, d, OH), 5.24 (1H, dd,
OH), 5.85 (1H, d, OH), 7.42 (2
_{H, brs, NH 2),} 8.39 (1H, s, H-8)

Elemental analysis (as C ₂₁ H ₂₉ N ₅ O ₄ .1H ₂ O) Calculated value (%): C, 58.18; H, 7.21; N, 1
6.15 found (%): C, 58.27; H, 7.15; N, 1
6.17

Compound No. 37 mp: 128-140 ° C. (foam) IR (KBr, cm ⁻¹ ): 2228 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.49-2.00 (12H, m, cycloheptyl), 3.53-3.69 (2H, m, H-5 '),
3.95 (1H, dd, H-4 '), 4.11 (1H,
dd, H-3 '), 4.50 (1H, dd, H-
2 ′), 5.14 to 5.17 (2H, m, OH × 2)
5.41 (1H, s, -C3C-C-OH), 5.45
(1H, d, OH), 5.87 (1H, d, H-
1 '), 7.44 (2H, brs, NH 2), 8.42
(1H, s, H-8)

Compound No. 45 mp: 132-142 ° C. (foam) IR (KBr, cm ⁻¹ ): 2232 (acetylene) ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.45 to 1.93 (14H, m, cyclooctyl), 3.54 to 3.68 (2H, m, H-5 '),
3.95 (1H, dd, H-4 '), 4.12 (1H,
dd, H-3 '), 4.50 (1H, t, H-2'),
5.87 (1H, d, H-1 '), 7.45 (2H, b
_{rs, NH 2), 8.41 (} 1H, s, H-8)

Elemental analysis (C ₂₀ H ₂₇ N ₅ O ₅ .1.5H ₂
Calculated value (%): C, 54.04; H, 6.80; N, 1
5.76 found (%): C, 54.23; H, 6.80; N, 1
5.49

Formulation Example 1 The above components were uniformly mixed and filled into hard capsules at 200 mg each.

Formulation Example 2 2-[(1-hydroxycyclohexane-1-yl) ethynyl] adenosine, lactose, potato starch, microcrystalline cellulose and light anhydrous silicic acid are mixed, and a 10% methanol solution of hydroxypropylcellulose is added and kneaded and granulated, The granules were extruded with a screen having a diameter of 0.8 mm to prepare granules, and after drying, magnesium stearate was added and compression-molded to give tablets of 200 mg.

Formulation Example 3 2- (cyclohexylethynyl) adenosine (compound No. 25) 25 mg propylene glycol Total amount 10 ml 2- (cyclohexylethynyl) adenosine was dissolved in propylene glycol, sterile-filtered, and added to an ampoule.
Each 2 ml was filled.

Formulation Example 4 The above components were heated and melted at 60 ° C., mixed uniformly, poured into a plastic mold and cooled to obtain 1 g of a suppository.

Continuation of the front page (51) Int.Cl. ⁷ identification symbol FI C07H 19/20 C07H 19/20 Examiner Aki Nakagi (58) Investigated field (Int.Cl. ⁷ , DB name) C07H 19/16-19 / 20 A61K 31/7076 CAPLUS (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (I) (Wherein, R represents a hydrogen atom or a hydroxyl group, and m represents 2 to 7
And n represents an integer of 0 or 1 to 3,
R ¹ , R ² and R ³ each represent a hydrogen atom, a hydroxyl-protecting group or a phosphate residue, and R ¹ , R ² and R ³ may be the same or different. -Substituted adenosine derivatives and salts thereof. 2. A blood pressure lowering agent comprising the 2-substituted adenosine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.