JPH0525195A - Adenosine derivative - Google Patents

Abstract

PURPOSE:To provide the subject novel derivative having an alkinyl group at the 2-position, having high selectivity to A2 receptors, not exhibiting adverse actions such as a cardioinhibitory action and a central inhibitory action, and useful for treating or preventing hypertension, ischemic heart diseases, ischemic cerebral diseases, etc. CONSTITUTION:2-Iodoadenosine is suspended in acetone, reacted with 70% perchloric acid under chilling and stirring to produce 2-iodo-2',3'-O-isopropylidene adenosine of formula I (X is halogen; Z is one or two protecting groups). The compound is oxidized with potassium periodate in acetone, etc., and the produced corresponding 4'-carboxylic acid derivative is reacted with methanol to produce a 4'-carboxylic acid methyl ester derivative. The compound is allowed to react with an alkine compound of formula II (R<2> is alkyl, etc.) (e.g. 1-hexine) and subsequently subjected to a protecting group-removing reaction to produce the objective derivative of formula III (R<1> is ester, azide, etc.) [e.g. 2-(1-hexinyl) adenosine-4'-carboxylic acid methyl ester].

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Conventionally, adenosine has been known to have a strong antihypertensive action and a platelet aggregation inhibitory action. However, it also has an inhibitory effect on the heart and an inhibitory effect on the central nervous system, and when adenosine is used as a therapeutic drug for diseases such as hypertension and angina, these effects are considered to act as side effects.

A large number of adenosine derivatives have been synthesized in order to solve these drawbacks of adenosine. Among such compounds, 2-alkynyl adenosine having an alkynyl group at the 2-position of adenosine (Japanese Patent Publication No.
Japanese Patent Publication No. 77; Japanese Patent Publication No. 2-17526). Further, as a 5'-position carboxamide of adenosine, adenosine-5'-carboxamide (JP-A-47-
25193 gazette; Physiological and Regulatory Fun
ctions of Adenosine and Adenine Nucleotides, pp.183-
187, Raven Press, 1979) and 5'-N-ethylcarboxamide adenosine (NECA) (Archs. Pharmacody.
n., 230 , 140-149 (1977)), 5'-chloro-5'-deoxyadenosine, 5'-bromo-5'-deoxyadenosine and the like (Br. J.Pharmac., 50 (1), 25-33 (1974); J.Pharm.Sc
i., 67 (1), 121-123 (1978), etc.) are known. However, these compounds have problems that their main actions are not satisfactory and that side effects are not sufficiently improved.

In recent years, an antihypertensive effect, an inhibitory effect on platelet aggregation and the like are expressed through adenosine A ₂ receptor (hereinafter referred to as A ₂ receptor), while an inhibitory effect on the heart and a central inhibitory effect are exerted on adenosine A ₁ receptor. (Hereafter, A ₁
It is reported to be expressed via the receptor). The NECA compound is known to have a high affinity for the A ₂ receptor and has already been used as a ligand for a binding assay (Mol. Pharma.
col. 29 , 331-346 (1986)). However, since it also has a high affinity for the A ₁ receptor, the above-mentioned side effects are likely to occur, and thus it has not been 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 associated with hypertension, ischemic heart disease, It may be useful as a drug for treating or preventing ischemic brain disease. An object of the present invention, selectivity for A ₂ receptor (A ₂ receptors A ₁ affinity ratio for the receptor) is high, providing cardiac inhibitory effect, a few side effects adenosine derivatives such as central depressant action To do.

[0006]

In the process of developing new adenosine derivatives and investigating various pharmacological activities thereof, the present inventors have found that certain adenosine derivatives
Show high affinity for _receptor, A ₁ indicates a low affinity for the receptor, thus, found that selectivity for A ₂ receptor is a compound having high, further they circulation improving agent The present invention has been completed by confirming that it is useful as

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

[Chemical 2] R ² represents an alkyl group or a hydroxyalkyl group,
R ³ is ^{-NR 6 R} 6 ^'or Other indicates _{^{-SO 2 -R 10, R 6,}} R 6 ' is hydrogen atom,
Represents an alkyl group or a cycloalkyl group, R ⁷ represents a hydrogen atom or an alkyl group, R ⁸ represents an oxygen atom or a sulfur atom, R ⁹ represents a hydrogen atom, an alkyl group, an amino group or an alkylamino group, R ¹⁰ represents an alkyl group or an aryl group] and salts thereof.

[0008] Examples of R ^{6 ′} include a hydrogen atom, a linear or branched alkyl group having about 1 to 10 carbon atoms or a cycloalkyl group having about 3 to 10 carbon atoms, and R ⁷ is a hydrogen atom or 1 carbon atom. A linear or branched alkyl group having about 10 to 10 is exemplified. Typical examples of such R ¹ include carbamoyl, methylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclohexylcarbamoyl, carboxyl, methoxycarbonyl, ethoxycarbonyl and the like.

In the general formula [I], R ¹ is --CH ₂ --NHR.
If it is ⁵ , specifically —CH ₂ —NH—SO ₂ —R ¹⁰ is included, wherein R ⁸ is an oxygen atom or a sulfur atom, and R ⁹ is a hydrogen atom, a straight-chain or branched-chain having about 1 to 10 carbon atoms. Examples thereof include an alkyl group, an amino group, and an alkylamino group having a linear or branched alkyl group having about 1 to 10 carbon atoms, and R ¹⁰ is an alkyl group having about 1 to 10 carbon atoms or an unsubstituted or substituted group. As carbon number 1-3
Illustrative are aryl groups such as phenyl having a degree of alkyl. N'-methyl ureido, N'-methyl thioureido, etc. are illustrated. Typical methanesulfonylamino Examples of -NH-SO ₂ -R ¹⁰ moiety, benzenesulfonylamino, p- toluenesulfonyl amino and the like.

The alkyl group or hydroxyalkyl group represented by R ² is specifically a straight chain, branched or cyclic group having 1 to 16 carbon atoms, preferably 1 to 7 carbon atoms.
The straight-chain alkyl group of, or a hydroxyalkyl group having 1 to 2 hydroxyl groups at arbitrary positions of these alkyl groups is exemplified.

Typical examples of the adenosine derivative represented by the general formula [I] (hereinafter sometimes referred to as the compound of the present invention) are shown below. 2- (1-propynyl) adenosine-4'-carboxamide 2- (1-butynyl) adenosine-4'-carboxamide 2- (1-pentynyl) adenosine-4'-carboxamide 2- (1-hexynyl) adenosine-4 ' -Carboxamide 2- (1-heptynyl) adenosine-4'-carboxamide 2- (1-octynyl) adenosine-4'-carboxamide 2- (1-nonynyl) adenosine-4'-carboxamide 2- (3-hydroxy-1- Propynyl) adenosine-
4'-carboxamide 2- (8-hydroxy-1-octynyl) adenosine-
4'-carboxamide 2- (1-propynyl) adenosine-4'-ethylcarboxamide 2- (1-butynyl) adenosine-4'-ethylcarboxamide 2- (1-pentynyl) adenosine-4'-ethylcarboxamide 2- (1 -Hexynyl) adenosine-4'-ethylcarboxamide 2- (1-heptinyl) adenosine-4'-ethylcarboxamide 2- (1-octynyl) adenosine-4'-ethylcarboxamide 2- (1-nonynyl) adenosine-4'- Ethylcarboxamide 2- (3-hydroxy-1-propynyl) adenosine-
4'-ethylcarboxamide 2- (8-hydroxy-1-octynyl) adenosine-
4'-Ethylcarboxamide 2- (1-hexynyl) adenosine-4'-methylcarboxamide (mp: 187-189 ° C) 2- (1-octynyl) adenosine-4'-methylcarboxamide 2- (1-hexynyl) adenosine- 4'-Propylcarboxamide (mp: 142-144 ° C) 2- (1-hexynyl) adenosine-4'-butylcarboxamide (mp: 130-133 ° C) 2- (1-propynyl) adenosine-4'-cyclopropylcarboxamide 2- (1-butynyl) adenosine-4'-cyclopropylcarboxamide 2- (1-pentynyl) adenosine-4'-cyclopropylcarboxamide 2- (1-hexynyl) adenosine-4'-cyclopropylcarboxamide 2- (1- Heptinyl) adenosine-4'-cyclopropylca Bokisamido 2- (1-octynyl) adenosine-4'-cyclopropyl carboxamide 2- (1-nonynyl) adenosine-4'-cyclopropyl carboxamide 2- (3-hydroxy-1-propynyl) adenosine -
4'-Cyclopropylcarboxamide 2- (8-hydroxy-1-octynyl) adenosine-
4'-Cyclopropylcarboxamide 2- (1-hexynyl) adenosine-4'-cyclohexylcarboxamide 2- (1-octynyl) adenosine-4'-cyclohexylcarboxamide 2- (3-hydroxy-1-propynyl) adenosine-
4'-cyclohexylcarboxamide 2-[(1-hydroxycyclohexyl) ethynyl] adenosine-4'-carboxamide (mp: 119-122)
℃)

[0012] 2- (1-hexynyl) adenosine-4'-carboxylic acid 2- (1-octynyl) adenosine-4'-carboxylic acid 2- (3-hydroxy-1-propynyl) adenosine-
4 -'- carboxylic acid 2- (1-hexynyl) adenosine-4'-carboxylic acid methyl 2- (1-octynyl) adenosine-4'-carboxylic acid methyl 2- (3-hydroxy-1-propynyl) adenosine-
Methyl 4'-carboxylate 2- (1-octynyl) adenosine-4'-carboxylate

[3] Those in which R ¹ is -CH ₂ -R ⁴ : 5'-azido-5'-deoxy-2- (1-hexynyl) adenosine 5'-azido-5'-deoxy-2- ( 1-octynyl) adenosine 5'-azido-5'-deoxy-2- (3-hydroxy-1-propynyl) adenosine

[4] R ¹ is -CH ₂ -NH ₂ 5'-amino-5'-deoxy-2- (1-hexynyl) adenosine 5'-amino-5'-deoxy-2- ( 1-octynyl) adenosine 5'-amino-5'-deoxy-2- (3-hydroxy-1-propynyl) adenosine

[0015] 5'-formylamino-5'-deoxy-2- (1-
Hexynyl) adenosine 5'-formylamino-5'-deoxy-2- (1-octynyl) adenosine 5'-formylamino-5'-deoxy-2- (3-hydroxy-1-propynyl) adenosine 5'-acetylamino -5'-deoxy-2- (1-hexynyl) adenosine 5'-acetylamino-5'-deoxy-2- (1-octynyl) adenosine 5'-acetylamino-5'-deoxy-2- (3-hydroxy -1-Propinyl) adenosine 5 '-(N'-methylureido) -5'-deoxy-2
-(1-hexynyl) adenosine 5 '-(N'-methylureido) -5'-deoxy-2
-(1-Octynyl) adenosine 5 '-(N'-methylureido) -5'-deoxy-2
-(3-Hydroxy-1-propynyl) adenosine 5 '-(N'-methylthioureido) -5'-deoxy-2- (1-hexynyl) adenosine 5'-(N'-methylthioureido) -5'-deoxy -2- (1-octynyl) adenosine 5 '-(N'-methylthioureido) -5'-deoxy-2- (3-hydroxy-1-propynyl) adenosine

[6] R ¹ is —CH ₂ —NH—SO ₂ —
What is R ¹⁰ : 5′-methanesulfonylamino-5′-deoxy-2-
(1-hexynyl) adenosine 5'-methanesulfonylamino-5'-deoxy-2-
(1-octynyl) adenosine 5'-methanesulfonylamino-5'-deoxy-2-
(3-Hydroxy-1-propynyl) adenosine 5'-p-toluenesulfonylamino-5'deoxy-
2- (1-hexynyl) adenosine 5'-p-toluenesulfonylamino-5'deoxy-
2- (1-octynyl) adenosine 5'-p-toluenesulfonylamino-5'deoxy-
2- (3-hydroxy-1-propynyl) adenosine

The adenosine derivative represented by the general formula [I] can exist in a free form or a salt form. Examples of the salt form include inorganic acid salts such as hydrochlorides, sulfates and hydrobromides, or acid addition salts such as organic acid salts such as oxalates, citrates and malates; sodium salts, potassium salts. Examples thereof include alkali metal salts such as salts; alkaline earth metal salts such as calcium salts and barium salts; ammonium salts.

An example of the synthetic method of the compound of the present invention will be described below.
Explain.Raw material compound  As a starting compound for synthesizing the compound of the present invention,
Formula [A]

[Chemical 3] A 2-halogenoadenosine derivative represented by the formula [wherein X represents a halogen atom and Z represents one or two protecting groups] can be used. Here, the halogen atom represented by X is exemplified by iodine or bromine.
The protecting group represented by Z may be any protecting group commonly used in sugar chemistry and capable of protecting cisdiol. Such protecting groups include alkylidene groups (isopropylidene, ethylidene, etc.), alkoxyalkylene groups (methoxymethylene, ethoxymethylene, ethoxyethylene, etc.), aralkylidene groups (benzylidene,
One that can protect two hydroxyl groups with one protecting group such as p-dimethylaminobenzylidene, one that can protect one hydroxyl group with one protecting group such as an acyl group (acetyl, benzoyl, etc.), etc. It is illustrated.

Synthesis Method I It can be synthesized by combining the steps. Step I-1 (oxidation at 5'position) : Chemical conversion is a method known per se (for example, “Nucleic Acid Organic Chemistry”, p. 56, October 1, 1979, published by Kagaku Doujin Co., Ltd .;
JP-A-50-96595, etc.). That is, a known oxidizing agent (eg, potassium periodate, sodium periodate, potassium permanganate, chromic acid, pyridinium dichromate, etc.) can be used to oxidize the sugar moiety 5 ′ position. It may be oxidized by air oxidation with a platinum catalyst or enzymatic oxidation with a nucleoside oxidase. Specifically, for example, when a compound of the general formula [A] is oxidized using potassium periodate as an oxidant, 1 is added to the starting compound in a suitable solvent (acetonitrile, chloroform, water, etc.).
The reaction may be carried out at room temperature using an oxidizing agent of about 3 equivalents (see Scheme I-1). The reaction can be promoted by adding a catalytic amount of ruthenium dioxide to the reaction solution.

(Scheme I-1)

[Chemical 4]

Step I-2 (modification of carboxyl group) : Modification of the carboxyl group at the 5′-position of the sugar moiety can be carried out by an ordinary method in synthetic organic chemistry using an appropriate reagent depending on the target compound. (A) Esterification Type compound), R ⁷ is an alkyl group (R ^{7 ′} )
The compound represented by the formula ( ¹⁾ is esterified by reacting the compound (general formula [B]) in which R ¹ is a carboxyl group obtained in the step I-1 with an alcohol represented by R ^{7 ′} —OH to give I-3 described below. It can be synthesized by introducing an alkynyl group at the 2-position of the adenine ring by the process. For example, the esterification reaction is carried out by a conventional method (JP-A-48-34196).
JP-A-49-70994 and JP-A-50-9659.
No. 5, JP-A No. 62-111996, etc.)
Generally, a halogenating agent such as thionyl halide (thionyl chloride, thionyl bromide, etc.) or phosphorus oxyhalide (phosphorus oxychloride, etc.) is added to the carboxyl group of the starting compound (general formula [B]). It is made to act as an acid halide, and at the same time, alcohol (R
⁷ '-OH) is carried out by the action of (see Scheme I-2-A). Usually, the starting compound may be suspended or dissolved in alcohol (R ^{7 ′} —OH), thionyl halide may be added thereto in an amount of about 1 to 5 equivalents, and the reaction may be performed at about 0 ° C. to room temperature. The esterification reaction may be carried out after removing the protecting group (Z) at the 2 ', 3'positions of the compound of the general formula [B], and the 2nd position of the adenine ring can be obtained by the step I-3 described later. It may be carried out after introducing an alkynyl group into.

(Scheme I-2-A)

[Chemical 5]

(B) Amidation The compound of the type [1] is a compound (general formula [C]) obtained in the esterification step or I-
An amine represented by NHR ⁶ R ^{6 ′} is allowed to act on a compound (general formula [E]) in which an alkynyl group is introduced at the 2-position of the adenine ring, and then the 2-position of the adenine ring is a halogen atom. The compound can be synthesized by further introducing an alkynyl group at the 2-position according to the step I-3 described later. The amidation reaction is carried out by a conventional method (JP-A 47-2879, JP-A 47-25193, JP-A 49-13200, JP-A 50-12100, JP-A 61-286398, JP-A 61-286398, 62-111996
No. 63-201196, 63-258.
892) and, for example, amines (NHR ⁶ R ^{6 ′} ) corresponding to the desired amide compound in the compound of the general formula [C] or [E], for example, ammonia, ethylamine, methylamine, It is carried out by reacting cyclopropylamine, cyclohexylamine and the like (Schemes I-2-B and I-2).
-C). Usually, the starting compound (general formula [C] or [E]) and an excess amount of amines may be sealed in a suitable solvent (ethanol, methanol, etc.) and reacted at room temperature to reflux conditions. In this case, the starting compound and the amines may be reacted without using a solvent, but it is advantageous to use a large excess of amines. As a raw material compound for the amidation reaction, a reactive derivative of a carboxylic acid such as the general formula [B] or a carboxylic acid such as an acid halide thereof (such as an acid chloride) is used and reacted with an amine. You may. Further, the protecting group (Z) at the 2 ', 3'position of the general formula [C] or [E] may be removed and then reacted with an amine.

(Scheme I-2-B)

[Chemical 6]

(Scheme I-2-C)

[Chemical 7]

Step I-3 (induction of alkynyl group to 2-position)
Input ; cross-coupling reaction) : R at the 2-position of the adenine ring
^The step of introducing an alkynyl group represented by ^2- C3C- is a method known per se (for example, JP-B-1-33477).
No. 2-17526). That is, the compound of general formula [B] obtained in step I-1 or the compound of general formula [C] or [D] obtained in step I-2 is reacted with an alkyne represented by R ² -C 3 CH. As a result, an alkynyl group can be introduced at the 2-position of the adenine ring. This reaction can be basically carried out by a method of reacting a raw material compound and an alkyne in the presence of a palladium catalyst (see Schemes I-3-A, I-3-B and I-3-C).

As the reaction solvent, triethylamine, tributylamine, N, N-diisopropylethylamine, trioctylamine, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine, dimethylaniline, diethylaniline, Basic solvent such as pyridine alone, or a mixture of aprotic polar solvent such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane with the above basic solvent A 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 dichloride or palladium diacetate and triphenylphosphine to the reaction solution may be used as they are.
The amount of palladium catalyst used is 0.00 based on the starting compound
A so-called catalytic amount of about 1 to 0.1 equivalent is sufficient. In addition to the palladium catalyst, a copper compound may be added to the reaction solution in order to accelerate the cross-coupling reaction. Therefore, a very small amount of about 0.001 to 0.02 equivalent may be added to the reaction solution.

The reaction between the raw material compound and the alkyne is carried out by reacting 1 to 2 equivalents of the alkyne with respect to the raw material compound in the presence of a palladium catalyst or a palladium catalyst and a copper compound, at a reaction temperature of 10 to 90 ° C. for 1 to 100 hours. Can be carried out. In addition, this cross-coupling reaction is carried out by 2'of the general formula [B], [C] or [D],
It may be performed after removing the protecting group (Z) at the 3'position.

(Scheme I-3-A)

[Chemical 8]

(Scheme I-3-B)

[Chemical 9]

(Scheme I-3-C)

[Chemical 10]

Step I-4 (deprotection) : Steps I-1 to I-3 are appropriately combined depending on the purpose, the carboxyl group at the 5 ′ position is modified, and an alkynyl group is introduced at the 2 position. When the compound is a compound having a protecting group (Z) at the 2 ', 3'positions, it is subjected to a deprotection reaction commonly used for removing the protecting group of cisdiol (for example, "Chemical Synthesis of Nucleic Acid-Biochemistry Experimental Method"). X- ", pp. 34-39, published by Kyoritsu Shuppan Co., Ltd. on July 25, 1968. For example, a compound having a hydroxyl group at the 2'and 3'positions can be obtained by subjecting a compound of the general formula [E] or [F] to a deprotection reaction (Scheme I-4-A,
See I-4-B). For example, when the protecting group is an alkylidene group, an alkoxyalkylene group or an aralkylidene group, trifluoroacetic acid, trichloroacetic acid, acetic acid,
It may be hydrolyzed using an acid such as formic acid, sulfuric acid or hydrochloric acid. The reaction is to dissolve the starting compound in the above acid solution,
It may be carried out at room temperature to about 80 ° C.

(Scheme I-4-A)

[Chemical 11]

(Scheme I-4-B)

[Chemical 12]

[0036]Synthetic methodII R in the general formula [I]¹Is -CH_Two-R^FourIs a compound
Basically, a product can be synthesized by combining the following steps.
it can.II-1 step (5'-substituted-5'-deoxyadenosine induction
Conductor composition) :Azide  The hydroxyl group at the 5'-position of the sugar moiety is determined by a method known per se (for example, rice
In accordance with national patent No. 3,575,959).
By substituting a zido group, 5'-azido-5'-de
Oxyadenosine derivatives can be synthesized. Tato
For example, the general method obtained by the method of step II-2 described below.
By reacting a compound of formula [L] with an azidating agent,
To obtain a compound of the general formula [M] (ski
See II-1). This azidation reaction is
Phosphine compound in a suitable solvent such as orchid (THF)
(Such as triphenylphosphine) and azodicarboxylic
Presence of acid diesters (eg diethyl azodicarboxylate)
Below, using diphenylphosphoric acid azide as azidating agent
Can be done by In addition, the 5'-position hydroxyl group is sulfonic acid
After esterification (tosylation, mesylation, etc.), azidation
Acts with azidating agents such as sodium and lithium azide.
Then, the compound of the general formula [M] may be synthesized. General formula
The protecting group (Z) at the 2'and 3'positions of the compound [M] is the above-mentioned I
It can be removed in the same manner as in the step-4, the general formula
R in (I)¹Is -CH_Two-N_ThreeTo obtain a compound that is
You can

(Scheme II-1)

[Chemical 13]

Step II-2 (Derivation of alkynyl group to 2-position
(Introduction and deprotection) : Using the compound of the general formula [A] as a raw material,
The compound of the general formula [L] can be synthesized by introducing an alkynyl group at the 2-position of the adenine ring in the same manner as in the step I-3 (see Scheme II-2). It can be used as a raw material for the reaction of step -1.

(Scheme II-2)

[Chemical 14]

[0040]Synthetic method III  R in the general formula [I]¹Is -CH_Two-NHR⁵Is
The compounds can be synthesized by the following steps.
it can.III-1 step (reduction of azido group) : Azide at 5'position of sugar
Having an amino group at the 5'position by reducing the group
You can get a compound. For example, in the general formula [M]
Compound or [M] 2 ', 3'position protecting groups were deprotected
Methods for determining the azido group of a compound are known per se (for example, Chem.
Lett., 601, (1976); "Synthetic Reagents", 215, 198.
Published by Kodansha Ltd. on June 1, 0; U.S. Pat. No. 3,57
No. 5,959), each raw material
R corresponding to the compound¹Is -CH_Two-NH_TwoIs a compound
The product can be obtained (see Scheme III-1). Concrete
For example, a phosphine compound (triphenylphosphine
Fins, etc.), tris (trimethylsilyl) phosphite
And reducing agents such as lithium aluminum hydride
Can be adopted. Phos as a reducing agent
When using fin compounds, react pyridine and water
Adopt a method of coexisting in the system and preferably reacting at low temperature
can do.

(Scheme III-1)

[Chemical 15]

Step III-2 (of carbonylamide compound
(Synthesis) : The compound having an amino group at the 5'-position obtained in the step III-1 is added to the target compound. React with a derivative (an acid anhydride, etc.) and remove the protecting groups at the 2'and 3'positions if necessary. In this case, a compound in which R ⁹ is a hydrogen atom or an alkyl group) can be obtained. For example, the compound of the general formula [O] and the general formula [P] [Wherein R ⁹ and R ^{9 ′} are hydrogen atoms or the same or different alkyl groups] By doing so, the compound of the general formula [Q] can be obtained (see Scheme III-2). The reaction is promoted when a small amount of pyridine is present in the reaction solution. The above reaction can be carried out by a method known per se (eg, US Pat. No. 3,573).
No. 5,959).

(Scheme III-2)

[Chemical 16]

Step III-3 (ureide compound or thiol
Synthesis of ureide compound) : 5 ′ obtained in step III-1
In the compound having an amino group at the position, an isocyanate (R ¹¹ -N = C = O; R ¹¹ is a hydrogen atom or an alkyl group) or an isothiocyanate (R ¹¹ -N) corresponding to the target ureido compound or thioureido compound is obtained. = C =
S; R ¹¹ is a hydrogen atom or an alkyl group) or a salt thereof is reacted to obtain R ¹ corresponding to the starting compound. You can get things. For example, the compound of general formula [S] can be obtained by reacting the compound of general formula [O] with the above isocyanate or isothiocyanate (see Scheme III-3). The above reaction can be carried out by a method known per se (for example, US Pat. No. 3,575,959).
No. specification).

(Scheme III-3)

[Chemical 17]

Step III-4 (of the sulfonylamino compound
Synthesis): III to a compound having the obtained 5 'position to the amino group at -1 step, such as a reactive derivative (chloride acid sulfonic acid corresponding to the sulfonylamino compound of interest (R ¹⁰ -SO 3 _H) Sulfonic acid halide etc.)
By reacting R ¹ with —CH ₂ —NH—SO
It is possible to obtain compounds which are _2- R ¹⁰ . For example,
Compound of the general formula [O] and halogen of sulfonic acid of the general formula [T] R ¹⁰ -SO ₃ X [T] [in the formula, R ¹⁰ represents an alkyl group or an aryl group, and X represents a halogen atom] A compound of the general formula [U] can be obtained by reacting a compound (see Scheme III-4). The reaction can be promoted by removing the hydrogen halide produced by the presence of bases such as amines (such as triethylamine) and organic bases (such as pyridine and picoline) in the reaction solution.

(Scheme III-4)

[Chemical 18]

Step III-5 (deprotection) : III-1 to III
A compound having a protecting group (Z) at the 2 ′ and 3 ′ positions (general formula [O], general formula [Q], general formula [S], general formula [U]) In some cases, a compound having a hydroxyl group at the 2'- and 3'-positions can be obtained by subjecting it to a deprotection reaction in the same manner as in the above-mentioned step I-4.

[0049]Isolation and purification  The compound obtained in each step of the above synthetic method is a nucleoside
Conventional means for isolation and purification (eg adsorption or ionic
Various chromatography such as exchange, solvent extraction, crystallization
Isolation and purification using a method that utilizes the difference in solubility etc.)
You can

[Effects of the Invention] The compound of the present invention has a high affinity for the A ₂ receptor and a low affinity for the A ₁ receptor, and therefore has selectivity for the A ₂ receptor. Is an extremely high compound. 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 circulation improving agent for treating or preventing hypertension, ischemic diseases and the like.

Hereinafter, in vitro (in v) of the compound of the present invention will be described.
The above-described effects of the compound of the present invention will be specifically described by itro) and in vivo pharmacological activity tests. Test Example 1 (Affinity for Adenosine Receptor) Affinity for adenosine receptor was determined by RFBruns et al., Mo.
l.Pharmacol. 29 , 331-346, (1986); RFBruns et al., Pro
c.Natl.Acad.Sci., USA, 77 , 5547, (1980);
It was measured according to a method substantially similar to the method described in 3-201196 and JP-A-62-111996. That is, the affinity for the A ₁ receptor was measured using a Wistar rat brain membrane preparation and was found to be 2.5.
nM [ ³ H] -N ⁶ -Cyclohexyladenosine ( ³ H
The affinity constant (Ki) was calculated from the concentration of the test compound that displaces 50% of the specific binding of -CHA) to the membrane preparation. The affinity for the A ₂ receptor was measured using a linear membrane preparation of Wistar rat and was 5 nM [ ³
[H] -5′-N-ethylcarboxamide adenosine ( ³
The affinity constant (Ki) was calculated from the concentration of the test compound that displaces 50% of the specific binding of (H-NECA) to the membrane preparation. Specifically, the results of the saturation binding experiment of the radioligand ( ³ H-CHA or ³ H-NECA) to each of the above membrane preparations were calculated using the least squares method using a computer program, and Scatchard analysis was performed. It was determined (linear data conversion) to go with dissociation constant (K _D) and the maximum number of binding sites (Bmax). Further, a substitution curve was drawn from the results of incubation by adding various concentrations of the test compound, and the concentration of the test compound (IC ₅₀ ) at which the specific binding of the radioligand of the above concentration was displaced by 50% was determined. From these results, Cheng and Prusoff's formula (Biochem. Pharmac
ol., 22 , 3099 (1973)), and calculated the affinity constant (Ki) (“Neurotransmitter and receptor binding”, No. 83).
Pp. 119, September 15, 1987, published by Seiwa Shoten Co., Ltd.). Further, the selectivity for A ₁ receptor and A ₂ receptor was calculated from the ratio (A ₂ / A ₁ ) of the above Ki values.
The results are shown in Table 1.

Test Example 2 (Effect of SHR on blood pressure and heart rate) Male spontaneously hypertensive rats (SHR) were treated with urethane and α-.
Anesthesia was performed using chloralose. Blood pressure and heart rate
It was measured using a pressure transducer via a cannula inserted into the carotid artery. The test compound is administered from the femoral vein at a dose of 0.03 to 100 μg / kg and a public ratio of 3 at 5 minute intervals. After administration of each dose, blood pressure and heart rate are measured for 5 minutes, and the maximum value is determined. I asked. The dose of the test compound that lowered the blood pressure by 30% before administration of each SHR was determined as ED _30, and the dose of the test compound that reduced the heart rate by 10% before administration was determined as ED ₁₀ . The effects of each test compound on blood pressure and heart rate were compared using ED ₃₀ and ED ₁₀ as indexes. The results are also shown in Table 1.

[0053]

[Table 1]

As shown in Table 1, when the compounds of the present invention and the reference compound are compared with respect to the affinity (Ki) for the A ₁ receptor and the A ₂ receptor, A of the compound of the present invention is compared.
_{The 2} / A ₁ value is lower than that of the control compound. That is, it is shown that the selectivity for the A ₂ receptor was increased by modifying the 5′-position of the control compound having an alkynyl group at the 2-position of the adenine ring. Also, SH
The ratio (ED ₁₀ / E) of the dose that reduces the heart rate of R by 10% (ED ₁₀ ) and the dose that reduces blood pressure by 30% (ED ₃₀ ).
When D ₃₀ ) is compared between the compound of the present invention and the control compound, the value of the compound of the present invention tends to be high.
That is, it was shown that the compound of the present invention has an effect of sufficiently lowering blood pressure even at a dose having a small effect on heart rate. As described above, the compound of the present invention can enhance the selectivity for the A ₂ receptor as compared with the known 2-alkynyladenosine, and exhibits an excellent circulatory improving action without significantly affecting the heart rate.

[0055]

EXAMPLES The present invention will be described in more detail below with reference to examples.
RevealExample 1  1-1:2-iodo-2 ', 3'-O-isopropylide
Adenosine(Two) 2-iodoadenosine (1) (5 g, 12.7 mmol)
Suspend in acetone (150 ml) and cool with ice to 70% perchloric acid.
(2 ml) was added, and the mixture was stirred at room temperature for 4 hours. Ammonia water
Was added until the solution became neutral, and then the solvent was distilled off under reduced pressure.
Silica gel column chromatography.
ー (φ5.0 × 9cm, 4% EtOH / CHCl_Three)
Purified, crystallized from ethanol, compoundTwo(6.0
2 g) was obtained as colorless needle crystals. MS (m / z): 433 (M⁺); UV (in MeOH) λ max nm: 265 (neutral), 267 (acidic), 267 (basic); mp: 178-181 ° C;¹ H-NMR (100MHz, CDCl₃) Δppm: 7.
74 (1H, s, H-8), 6.10 (2H, bs, 6
-NH₂), 5.80 (1H, d, H-1 ', J_{1 ', 2'}
= 4.4 Hz), 5.30-5.10 (3H, m, H-
2 ', H-3', 5'-OH), 4.45 (1H, b
s, H-4 '), 4.10-3.71 (2H, m, H-
5'a, 5'b)

1-2: 2-iodo-2 ', 3'-O-a
Sopropylidene adenosine-4'-carboxylic acid ( 3 ) Compound 2 (4.33 g, 10 mmol) was dissolved in acetonitrile (60 ml), chloroform (60 ml), water (90 ml) and potassium periodate (3.45 g, 15
mmol) was added. Ruthenium dioxide (200
mg) was added and the mixture was stirred at room temperature for 5 hours, potassium periodate (3.45 g, 15 mmol) was further added, and the mixture was stirred at room temperature for 2 hours. After adding isopropanol and stirring, the reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure.
2N Hydrochloric acid was added under ice-cooling until the pH of the obtained residue became 2-3, and the precipitated crystals were collected by filtration and washed with ether to give crude compound 3 (3.04 g, yield 67.9). %) Was obtained as a precipitate. MS (m / z): 433 (M + + H-CH 3); UV ( in MeOH) .lambda.max nm: 266 (neutral), 266 (acidic), 266 ^{(basic); 1 H-NMR (100MHz} , DMSO -D ₆ ) δppm: 8.16 (1H, s, H-8), 7.70 (2
_{H, bs, 6-NH 2} ), 6.27 (1H, s, H-
1 '), 5.49 (1H, dd, H-3', J3 _{', 2'} =
5.9Hz, J _{3 ', 4'} = 1.7Hz), 5.39 (1H,
d, H-2 ', J2 _{', 3 '} = 5.9 Hz), 4.68 (1
H, d, H-4 ', J4 _{', 3 '} = 1.7 Hz), 1.52
_{(3H, s, C-CH} 3), 1.36 (3H, s, C-
CH ₃ )

1-3:2-iodo-2 ', 3'-O-i
Sopropylidene adenosine-4'-carboxylic acid methyl ester
(Four) CompoundThree(40 mg, 0.09 mmol) in methanol (5 m
l). Thionyl chloride under an ice-cold argon atmosphere
Lido (13 μl, 0.18 mmol) was added and the mixture was kept at room temperature for 2 hours.
After stirring, the solvent was distilled off under reduced pressure. Saturated carbonated water in the residue
After adding an aqueous solution of sodium, extracted with chloroform,
The organic layer was saturated aqueous sodium hydrogen carbonate solution and saturated brine.
Washed in. After drying over anhydrous sodium sulfate, dissolve under reduced pressure
The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography.
Graphography (φ2.2 × 5cm, 4% MeOH / CHCl)
_Three), The compoundFour(32 mg, yield 77.6
%) As a foam. MS (m / z): 461 (M⁺), 261 (purine base
⁺), 201 (sugar⁺); UV (in MeOH) λ max nm: 267 (neutral), 267 (acidic), 266 (basic);¹ H-NMR (100MHz, CDCl₃) Δppm: 7.
82 (1H, s, H-8), 6.13 (1H, s, H-)
1 '), 5.90 (2H, bs, 6-NH₂) 5.6
8 (1H, dd, H-3 ', J_{3 ', 2'}= 5.9Hz, J
_{3 ', 4'}= 1.7 Hz), 5.41 (1H, d, H-2 ',
J_{2 ', 3'}= 5.9 Hz), 4.83 (1H, d, H-
4 ', J_{4 ', 3'}= 1.7 Hz), 3.65 (3H, s,-
O-CH_Three), 1.60 (3H, s, C-CH_Three),
1.44 (3H, s, C-CH_Three)

1-4:2-iodo-2 ', 3'-O-i
Sopropylidene adenosine-4'-carboxamide
(5) CompoundFour(100 mg, 0.21 mmol) was added to methanolic acid
Dissolve in mmonia (saturated at 0 ° C, 10 ml) and steel
The mixture was stirred in a sealed tube at 80 ° C for 5 hours. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography (φ2.7
× 5 cm, 8% MeOH / CHCl_Three) Purified by
Compound5(80 mg, yield 82.7%) as a colorless solid
Obtained. MS (m / z): 446 (M⁺), 261 (purine base
⁺), 186 (sugar⁺); UV (in MeOH) λ max nm: 266 (neutral), 265 (acidic), 265 (basic);¹ H-NMR (100MHz, CDCl₃) Δppm: 7.
27 (1H, s, H-8), 7.30 (1H, bs,
5'-NHa), 6.22 (2H, bs, 6-N
H₂), 6.15 (1H, bs, 5'-NHb), 6.
00 (1H, d, H-1 ', J_{1 ', 2'}= 2.93Hz),
5.40-5.20 (2H, m, H-3 ', H-
2 '), 4.71 (1H, d, H-4', J_{4 ', 3'}=
1.95Hz), 1.63 (3H, s, C-CH_Three),
1.39 (3H, s, C-CH_Three)

1-5: 2- (1-hexynyl) -2 ',
3'-O-isopropylidene adenosine-4'-carbo
Kisamido (6) Compound 5 (70 mg, 0.16 mmol) was dissolved in DMF (5 ml), bis (triphenylphosphine) palladium dichloride _{(Pd (PPh 3) 2 Cl} 2) (11mg, 10
mol%), 1-hexyne (38 μl, 0.32 mmol),
Cuprous iodide (10 mg), and triethylamine (27
μl, 0.19 mmol) was added, and at 70 ° C. under an argon atmosphere.
And stirred for 20 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in chloroform, hydrogen sulfide and nitrogen were passed through, the reaction solution was filtered through Celite, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (φ2.2 × 5 cm,
4% EtOH / CHCl ₃ ) to give compound 6 (7
6 mg) was obtained as a foam. MS (m / z): 400 (M ⁺ ); UV (in MeOH) λ max nm: 269 (neutral), 272 (acidic), 268 (basic); ¹ H-NMR (100 MHz, CDCl ₃ ) δppm: 8.
10 (1H, bs, 5'-NHa), 7.84 (1H,
s, H-8), 6.16 (2H, bs, 6-NH ₂ ),
6.03 (1H, d, H-1 ', J1 _{', 2 '} = 3.0H
z), 5.92 (1H, bs, 5'-NHb), 5.2
9-5.27 (2H, m, H-3 ', H-2'), 4.
71 (1H, d, H-4 ', J4 _{', 3 '} = 1.5Hz),
2.50-2.30 (2H, m, H-3 ″), 1.64
_{(3H, s, C-CH} 3), 1.60-1.40 (4
H, m, H-4 ", H-5"), 1.39 (3H, s,
_{C-CH 3), 1.00-0.88 (} 3H, m, H-
6 ″)

1-6: 2- (1-hexynyl) adenosine
Compound 4'-carboxamide ( 7 ) Compound 6 (60 mg, 0.15 mmol) was dissolved in 90% trifluoroacetic acid (5 ml) and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure and azeotropically distilling with ethanol, the obtained residue was subjected to silica gel column chromatography (φ2.2 ×).
8 cm, purified by 10% EtOH / CHCl ₃ ) and crystallized from ethanol to give compound 7 (51.8 mg, yield 9)
5.9%) as colorless needles. MS (m / z): 360 (M ⁺ ); UV (in MeOH) λmax nm: 269 (neutral), 271 (acidic), 267 (basic); IR (nujol) νmax cm ^-1 : 2240; mp 176-178 ° C .; ¹ H-NMR (270 MHz, DMSO-d ₆ ) δppm: 8.46 (1 H, s, H-8), 8.27 (1
H, bs, 5'-NHa), 7.53 (1H, bs,
5'-NHb), 7.49 (2H, bs, 6-N
_{H 2), 5.95 (1H,} d, H-1 ', J 1', 2 '=
7.7 Hz), 5.70 (1H, bs, 2'-OH),
5.56 (1H, bs, 3'-OH), 4.54 (1
H, bs, H-2 '), 4.28 (1H, d, H-
4 ', J4 _{', 3 '} = 1.7Hz), 4.15-4.14 (1
H, m, H-3 ′), 2.42 (2H, t, H-3 ″ a,
b, J _{3 ", 4"} = 7.1 Hz), 1.59-1.48 (2
H, m, H-4 ″ a, b), 1.46−1.35 (2H,
m, H-5 ″ a, b), 0.91 (3H, t, H-6 ″ a, b,
c, J _{6 ", 5"} = 7.1 Hz); ¹ H-NMR (270 MHz, DMSO-d ₆ + D ₂ O)
δppm: 4.52 (1H, dd, H-2 ', J2 _{', 1 '} =
7.7Hz, J _{2 ', 3'} = 4.4Hz), 4.28 (1H,
d, H-4 ', J4 _{', 3 '} = 1.7 Hz), 4.14 (1
H, dd, H-3 ', J3 _{', 2 '} = 4.4Hz, J3 _{', 4 '} =
1.7 Hz); Elemental analysis _{[C 16 H 20 N 6 O 4} · 1/3 H 2 O ]: Calculated: C, 52.45; H, 5.69 ; N, 22.9
4 Found: C, 52.45; H, 5.98; N, 23.1.
Four

[0061]Example 2  2-1:2- (3-hydroxy-1-propynyl)-
2 ', 3'-O-isopropylidene adenosine-4'-
Methyl carboxylate(8) CompoundFour(250 mg, 0.54 mmol) in DMF (4 ml)
Dissolved in Pd (PPh_Three)_TwoCl_Two(38mg, 10mo
l%), propargyl alcohol (64 μl, 1.08 mm
ol), cuprous iodide (10 mg), and triethylamine
(90 μl, 0.65 mmol) was added, and under argon atmosphere
The mixture was stirred at 70 ° C for 2 hours. The solvent was distilled off under reduced pressure and the residue
Was dissolved in chloroform and hydrogen sulfide and nitrogen were passed through
After that, the reaction solution was filtered through Celite, and the filtrate was saturated with sodium hydrogen carbonate.
It was washed with a thorium aqueous solution and saturated saline. Anhydrous sulfuric acid
After drying over sodium, the solvent was distilled off under reduced pressure, and the obtained residue
The residue is subjected to silica gel column chromatography (φ2.2 ×
7 cm, 8% MeOH / CHCl_Three) And then combine
object8(288.7 mg) was obtained as a foam. MS (m / z): 389 (M⁺); UV (in MeOH) λ max nm: 267 (neutral), 271 (acidic), 264 (basic);¹ H-NMR (100MHz, CDCl₃) Δppm: 8.
01 (1H, s, H-8), 6.40 (2H, bs, 6)
-NH₂), 6.20 (1H, s, H-1 ′), 5.7.
1 (1H, dd, H-3 ', J_{3 ', 2'}= 6.1 Hz, J
_{3 ', 4'}= 1.7 Hz), 5.38 (1H, d, H-2 ',
J_{2 ', 3'}= 6.1 Hz), 4.83 (1H, d, H-
4 ', J_{4 ', 3'}= 1.7 Hz), 4.53 (2H, bs,
H-3 ″ a, 3 ″ -OH), 4.34 (1H, s, H-
3 "b), 3.59 (3H, s, -O-CH_Three), 1.
61 (3H, s, C-CH_Three), 1.44 (3H, s,
C-CH_Three)

2-2: 2- (3-hydroxy-1-pro
Pinyl) -2 ', 3'-O-isopropylidene adenosine
4′-carboxamide ( 9 ) Compound 8 (250 mg, 0.64 mmol) was dissolved in methanolic ammonia (saturated at 0 ° C., 20 ml) and stirred in a steel sealed tube at 80 ° C. for 5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (φ2.7 ×).
Purification by 7 cm, 10% MeOH / CHCl ₃ ) gave compound 9 (130 mg, 54.0% yield) as a colorless solid. MS (m / z): 374 (M ⁺ ); UV (in MeOH) λ max nm: 267 (neutral), 271 (acidic), 264 (basic); ¹ H-NMR (100 MHz, DMSO-d ₆ ). δppm: 8.35 (1H, s, H-8), 7.60-
7.20 (4H, m, 5'- NH 2, 6-NH 2),
6.22 (1H, d, H-1 ', J1 _{', 2 '} = 2.0H
z), 5.40-5.20 (3H, m, H-2 ', H-
3 ', 3 "-OH), 4.52 (1H, d, H-4', J
_{4 ', 3'} = 1.7 Hz), 4.29 (2H, d, H-3 ",
J _{3 "a, 3" b} = 5.9Hz), 1.56 (3H, s, C-C
_{H 3), 1.35 (3H,} s, C-CH 3)

2-3: 2- (3-hydroxy-1-pro
Pinyl) adenosine-4'-carboxamide ( 10 ) Compound 9 (100 mg, 0.27 mmol) was dissolved in 90% trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 4 hours.
After distilling off the solvent under reduced pressure and azeotropically distilling with ethanol, the resulting residue was subjected to silica gel column chromatography (φ2.
2 × 8 cm, purified by 10% MeOH / CHCl ₃ ) and crystallized from methanol to give compound 10 (103.7).
mg) was obtained as colorless needle crystals. MS (m / z): 334 (M ⁺ ); UV (in MeOH) λ max nm: 268 (neutral), 271 (acidic), 264 (basic); mp: 180-181 ° C; ¹ H-NMR ( 270 MHz, DMSO-d ₆ ) δppm: 8.47 (1H, s, H-8), 8.44 (1
H, bs, 5'-NHa), 7.54 (3H, bs,
_{5'-HNb, 6-NH 2} ), 5.94 (1H, d, H
-1 ', J _{1', 2 '} = 7.1 Hz), 5.71 (1H, d,
2'-OH, _{J2'OH, 2 '} = 4.4 Hz), 5.58 (1
H, d, 3'-OH, _{J3'OH, 3 '} = 6.6 Hz), 5.3
6 (1H, t, 3 "-OH, J3 _{" OH, 3 "} = 6.1Hz),
4.53 (1H, ddd, H-2 ', J2 _{', 1 '} = 7.1
Hz, J _{2 ', 2'OH} = 4.4 Hz, J _{2' , 3 '} = 4.9 Hz),
4.30 (2H, m, H-3 ″), 4.28 (1H,
d, H-4 ', J4 _{', 3 '} = 2.7 Hz), 4.15 (1
H, ddd, H-3 ', _J3'2' = 4.9Hz, J3 _{', 3'OH}
= 6.6 Hz, J _{3 ′, 4 ′} = 2.7 Hz); Elemental analysis [C ₁₃ H ₁₄ N ₆ O ₅ · 6/5 H ₂ O]: Calculated value: C, 43.87; H, 4. 64; N, 23.6.
1 Found: C, 44.17; H, 4.58; N, 23.3.
Two

[0064]Example 3  3-1:2- (1-hexynyl) -2 ', 3'-O-i
Sopropylidene adenosine-4'-carboxylic acid methyl ester
(11) CompoundFour(269.3 mg, 0.58 mmol) was added to DMF (1
Dissolve in Pd (PPh_Three)_TwoCl_Two(41 mg,
10mol%, 1-hexyne (137μl, 1.16mm
ol), cuprous iodide (40 mg), and triethylamine
(97 μl, 0.70 mmol) was added and under argon atmosphere 7
The mixture was stirred at 0 ° C for 2 hours. The solution is distilled off under reduced pressure and the residue is removed.
After dissolving in loroform and passing hydrogen sulfide and nitrogen,
The reaction solution was filtered through Celite, and the filtrate was washed with saturated sodium hydrogen carbonate.
It was washed with aqueous sodium chloride solution and saturated saline. Anhydrous sodium sulfate
After drying over sodium chloride, the solvent was distilled off under reduced pressure, and the resulting residue was filtered.
Rica gel column chromatography (φ1.8 × 7cm,
4% EtOH / CHCl_Three), The compound11
(239 mg, yield 98.5%) was obtained as a foam-like substance.
It was MS (m / z): 415 (M⁺); UV (in MeOH) λmax nm: 269 (neutral), 271 (acidic), 267 (basic); IR (nujol) νmax cm^-1: 2240;¹ H-NMR (100MHz, CDCl₃) Δppm: 7.
91 (1H, s, H-8), 6.17 (1H, s, H-)
1 '), 5.79-5.65 (3H, m, 6-NH₂，
H-3 '), 5.43 (1H, d, H-2', J_{2 ', 3'}
= 6.1 Hz), 4.81 (1H, s, H-4 '), 3.
56 (3H, s, O-CH_Three), 2.52-2.38
(2H, m, H-3 ″), 1.70-1.37 (4H,
m, H-4 ", H-5"), 1.60 (3H, s, C-
CH_Three), 1.43 (3H, s, C-CH_Three), 1.0
3-0.88 (3H, m, H-6 ″)

3-2: 2- (1-hexynyl) -2 ',
3'-O-isopropylidene adenosine-4'-ethyl
Carboxamide ( 12 ) Compound 11 (100 mg, 0.24 mmol) was dissolved in methanol (2 ml), 70% ethylamine solution (1 ml) was added, and the mixture was stirred in a steel sealed tube at 80 ° C for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (φ2.2 × 6 cm, n-hexane: acetic acid ethyl ester = 1: 4) to give compound 12 (73 mg, yield 70.8%). Obtained as a colorless solid. MS (m / z): 429 (M ⁺ + H); UV (in MeOH) λ max nm: 269 (neutral), 271 (acidic), 267 (basic); ¹ H-NMR (100 MHz, CDCl ₃ ) δppm. : 7.
83 (1H, s, H-8), 7.44 (1H, bs,
5'-NH), 6.00 (1H, d, H-1 ', J
_{1 ', 2'} = 3.7 Hz), 5.67 (2H, bs, 6-NH
₂ ) 5.35-5.15 (2H, m, H-2 ', H-
3 '), 4.69 (1H, d, H-4', J4 _{', 3'} =
1.7 Hz), 3.49-3.22 (2H, m, H-1 ''
'), 2.51-2.37 (2H, m, H-3 "),
_{1.62 (3H, s, C-} CH 3), 1.86-1.2
6 (4H, m, H-4 ", H-5"), 1.38 (3
_{H, s, C-CH 3} ), 1.04-0.87 (6H,
m, H-2 '", H-6")

3-3: 2- (1-hexynyl) adenosine
4'- Ethylcarboxamide ( 13 ) Compound 12 (69 mg, 0.161 mmol) was dissolved in 80% trifluoroacetic acid (7 ml), and the mixture was stirred at room temperature for 2 hours.
After distilling off the solvent under reduced pressure and azeotropically distilling with ethanol, the resulting residue was subjected to silica gel column chromatography (φ2.
2 × 4 cm, 8% EtOH / CHCl ₃ ) and
Crystallization from ethanol gave Compound 13 (54.2 mg, yield 86.7%) as colorless needle crystals. MS (m / z): 389 (M ⁺ + H); UV (in MeOH) λ max nm: 269 (neutral), 271 (acidic), 267 (basic); mp: 147-150 ° C; ¹ H-NMR. _{(270MHz, DMSO-d 6)} δppm: 8.79 (1H, t, 5'-NH), 8.41
(1H, s, H-8), 7.55 (2H, bs, 6-N
_{H 2), 5.92 (1H,} d, H-1 ', J 1', 2 '=
7.7 Hz), 5.77 (1H, d, 3'-OH, J
_{3'OH, 3 '} = 4.0 Hz), 5.56 (1H, d, 2'-O
H, J _{2'OH, 2 '} = _{6.6 Hz} ), 4.57 (1H, dd
d, H-2 ', J2 _{', 1 '} = 7.7 Hz, J2 _{', 2'OH} = 6.
6Hz, J _{2 ', 3'} = 4.8Hz), 4.30 (1H, d, H
-4 ', J4 _{', 3 '} = 1.1Hz), 4.11 (1H, dd
d, H-3 ', J3 _{', 2 '} = 4.8 Hz, J3 _{', 3'OH} = 4.
0 Hz, J _{3 ', 4'} = 1.1 Hz), 3.36-3.25 (2
H, m, H-1 '''), 2.41 (2H, t, H-
3 "), 1.56-1.35 (4H, m, H-4", H
-5 "), 1.08 (3H, t, H-2 '"), 0.9
1 (3H, t, H-6 ″); Elemental analysis [C ₁₈ H ₂₄ N ₆ O ₄ .1H ₂ O]: Calculated value: C, 53.19; H, 6.45; N, 20.6
8 Found: C, 53.04; H, 6.30; N, 20.6.
5

[0067]Example 4  4-1:2- (1-hexynyl) -2 ', 3'-O-i
Sopropylidene adenosine-4'-cyclopropylcal
Voxamide(14) Compound11(100 mg, 0.24 mmol) in methanol
Dissolve it in (2 ml) and use 98% cyclopropylamine (1 m
l) was added and the mixture was stirred in a steel sealed tube at 80 ° C. for 6 hours.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
For graphography (φ1.8 × 7cm, ethyl acetate)
More purified, compound14(116 mg) as a colorless solid
I got it. MS (m / z): 441 (M⁺+ H); UV (in MeOH) λ max nm: 267 (neutral), 270 (acidic), 267 (basic);¹ H-NMR (100MHz, CDCl₃) Δppm: 7.
80 (1H, s, H-8), 6.82-6.78 (1
H, m, 5'-NH), 6.03 (1H, d, H-
1 ', J_{1 ', 2'}= 2.4 Hz), 5.64 (2H, bs,
6-NH₂) 5.42-5.33 (2H, m, H-
2 ', H-3'), 4.64 (1H, d, H-4 ', J
_{4 ', 3'}= 1.7 Hz), 2.66-2.38 (3H, m,
H-3 ", H-1 '"), 1.61 (3H, s, C-C
H_Three), 1.38 (3H, s, C-CH_Three) 1.70
-1.26 (4H, m, H-4 ", H-5"), 1.0
1-0.82 (3H, m, H-6 "), 0.77-0.
60 (2H, m, H-2 '' '), 0.46-0.34
(2H, m, H-3 '' ')

4-2: 2- (1-hexynyl) adenosine
-4'-Cyclopropylcarboxamide ( 15 ) Compound 14 (100 mg, 0.227 mmol) was dissolved in 80% trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After distilling off the solvent under reduced pressure and azeotroping with ethanol, the obtained residue was subjected to silica gel column chromatography (φ
Purified by 1.8 × 6 cm, 4% EtOH / CHCl ₃ ) and crystallized from ethanol to give compound 15 (66.7 m
g, yield 73.4%) was obtained as colorless needle crystals. MS (m / z): 400 (M ⁺ ); UV (in MeOH) λ max nm: 267 (neutral), 270 (acidic), 267 (basic); mp: 133-138 ° C; ¹ H-NMR ( 270 MHz, DMSO-d ₆ ) δppm: 8.52 (1H, s, H-8), 8.25 (1
H, d, 5'-NH, _{J5'NH, 1} '''= 3.9 Hz), 7.
46 (2H, bs, 6- NH 2), 5.94 (1H,
d, H-1 ', J1 _{', 2 '} = 6.6 Hz), 5.66 (1
H, d, 3'-OH, J3'OH _{, 3 '} = 5.0 Hz), 5.5
9 (1H, d, 2'-OH, _{J2'OH, 2 '} = 6.0Hz),
4.61 (1H, ddd, H-2 ', J2 _{', 1 '} = 6.6
Hz, J _{2 ', 2'OH} = 6.0 Hz, J _{2' , 3 '} = 4.4 Hz),
4.27 (1H, d, H-4 ', J4 _{', 3 '} = 2.2H
z), 4.17 (1H, ddd, H-3 ', J3 _{', 2 '} =
4.4Hz, J _{3 ', 3'OH} = 5.0Hz, J _{3', 4 '} = 2.2H
z), 2.72-2.65 (1H, m, H-1 '''),
2.41 (2H, t, H-3 ″), 1.58-1.36
(4H, m, H-4 ", H-5"), 0.91 (3H,
t, H-6 ″), 0.69-0.61 (2H, m, H-
2 "'), 0.50-0.43 (2H, m, H-3'"
); Elemental analysis [C ₁₉ H ₂₄ N ₆ O ₄ .4 / 3H ₂ O]: Calculated value: C, 53.76; H, 6.33; N, 19.8
0 Found: C, 53.96; H, 6.40; N, 19.6.
1

[0069]Example 5  5-1:5'-azido-5'-deoxy-2 ', 3'-
O-isopropylidene-2- (1-hexynyl) adeno
Shin(17) Compound obtained in Example 1-1TwoAs in Example 1-5
2- (1-hexynyl) -2 ', 3' obtained by reacting with
-O-isopropylidene adenosine (16) (1.00
g, 2.58 mmol) and triphenylphosphine
(1.02 g, 3.87 mmol) in tetrahydrofuran
It was dissolved in (30 ml). Diphenylphosphoric acid azide under ice cooling
(0.83 ml, 3.87 mmol) and azodicarboxylic acid di
Tetrahydrofuran in ethyl (0.62 ml, 3.87 mmol)
The run solution (20 ml) was added dropwise over 10 minutes. At room temperature
After stirring for 4 hours, the reaction solution is evaporated under reduced pressure to remove the solvent.
The resulting residue is subjected to silica gel column chromatography (φ
3.3 x 11 cm, 4% MeOH / CHCl₃) By the
Made and compound17(0.882 g, yield 82.8%)
Obtained as a foam. MS (m / z): 412 (M⁺); UV (in MeOH) λ max nm: 270 (neutral), 273 (acidic), 269 (basic);¹ H-NMR (100MHz, CDCl_Three) Δppm: 7.91 (1H, s, H-8), 6.12 (1
H, d, H-1 ', J_{1 ', 2'}= 2.2 Hz), 5.88
(2H, bs, 6-NH₂), 5.35 (1H, dd,
H-2 ', J_{2 ', 1'}= 2.2Hz, J_{2 ', 3'}= 6.4H
z), 5.09 (1H, dd, H-3 ', J_{3 ', 2'}=
6.4Hz, J_{3 ', 4'}= 3.4 Hz), 4.43-4.28
(1H, m, H-4 '), 3.67-3.61 (2H,
m, H-5'a, 5'b), 2.46 (2H, t, H-
3 "), 1.62 (3H, s, C-CH₃), 1.40
(3H, s, C-CH₃), 1.89-1.25 (4
H, m, H-4 ", H-5"), 0.95 (3H, t,
H-6 ")

5-2: 5'-azido-5'-deoxy-
2- (1-hexynyl) adenosine ( 18 ) Compound 17 was reacted in the same manner as in Example 1-6 and then purified to obtain Compound 18 .

[0071]Example 6  6-1:5'-amino-5'-deoxy-2 ', 3'-
O-isopropylidene-2- (1-hexynyl) adeno
Shin(19) Compound17(200 mg, 0.485 mmol) in pyridine
It was dissolved in (10 ml). Triphenylphosphine under ice cooling
(190 mg, 0.724 mmol), water (2 ml) and pyridinium
Solution (5 ml) was added dropwise over 25 minutes. Under ice cooling
After stirring for 1 hour, the reaction mixture is evaporated under reduced pressure to remove the solvent.
After azeotroping with ruene, the resulting residue is purified by a silica gel column.
Chromatography (φ2.2 × 9 cm, 8% MeOH /
CHCl₃), The compound19(102.6m
g, yield 54.8%) was obtained as a colorless solid. MS (m / z): 387 (M⁺+ H); UV (in MeOH) λ max nm: 270 (neutral), 273 (acidic), 269 (basic);¹ 1 H-NMR (100 MHz, DMSO-d₆) Δppm: 8.41 (1H, s, H-8), 7.42 (2
H, bs, 6-NH₂), 6.04 (1H, d, H-
1 ', J_{1 ', 2'}= 3.2 Hz), 5.36 (1H, dd,
H-2 ', J_{2 ', 1'}= 3.2Hz, J_{2 ', 3'}= 6.1H
z), 4.98 (1H, dd, H-3 ', J_{3 ', 2'}=
6.1Hz, J_{3 ', 4'}= 2.7 Hz), 4.20-4.00
(1H, m, H-4 '), 3.00 (2H, bs, 5'
-NH₂) 2.80-2.60 (2H, m, H-5 '
a, H-5'b), 2.42 (2H, t, H-3 "),
1.54 (3H, s, C-CH₃), 1.34 (3H,
s, C-CH₃), 1.60-1.20 (4H, m, H
-4 ", H-5"), 0.99 (3H, t, H-6 ")

6-2: 5'-amino-5'-deoxy-
2- (1-hexynyl) adenosine ( 20 ) Compound 19 was reacted in the same manner as in Example 1-6 and then purified to obtain Compound 20 .

[0073]Example 7  7-1:5'-formylamino-5'-deoxy-
2 ', 3'-O-isopropylidene-2- (1-hexyl
Nil) adenosine(21) Compound19(250 mg, 0.67 mmol) was added to pyridine (1
0 ml). Formic acid and acetic acid under ice-cold argon atmosphere
Add the mixed acid anhydride (85 μl, 1.34 mmol) of
After stirring at room temperature for 1.5 hours, the solvent was distilled off under reduced pressure, and
It was azeotropic with En. Saturated aqueous sodium hydrogencarbonate solution in the residue
After extraction with chloroform, extract the organic layer with saturated carbonated water.
It was washed with an aqueous solution of sodium and saturated saline. anhydrous
After drying over sodium sulfate, the solvent was distilled off under reduced pressure.
The resulting residue was subjected to silica gel column chromatography (φ1.
8 × 6 cm, 4% EtOH / CHCl₃),
Compound21(205 mg, 76.5% yield)
Got as. MS (m / z): 414 (M⁺); UV (in MeOH) λ max nm: 269 (neutral), 271 (acidic), 269 (basic);¹ H-NMR (100MHz, CDCl_Three) Δppm: 9.01-8.90 (1H, m, 5'-N
H), 8.60 (1H, s, formyl), 7.84 (1
H, s, H-8), 5.92 (2H, bs, 6-N
H₂), 5.78 (1H, d, H-1 ', J_{1 ', 2'}=
4.9 Hz), 5.24 (1H, dd, H-2 ', J
_{2 ', 1'}= 4.9Hz, J_{2 ', 3'}= 6.1 Hz), 4.83
(1H, dd, H-3 ', J_{3 ', 2'}= 6.1 Hz, J
_{3 ', 4'}= 2.2 Hz), 4.55-4.53 (1H, m,
H-4 '), 4.45-4.20 (1H, m, H-5'
a) 3.30-3.15 (1H, m, H-5'b),
2.50-2.40 (2H, m, H-3 ″), 1.63
(3H, s, C-CH₃), 1.35 (3H, s, C-
CH₃) 1.80-1.30 (4H, m, H-4 ",
H-5 "), 0.95 (3H, t, H-6")

7-2: 5'-formylamino-5'-de
Oxy-2- (1-hexynyl) adenosine ( 22 ) Compound 21 (272 mg, 0.67 mmol) was dissolved in 80% trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 1 hr. After distilling off the solvent under reduced pressure and azeotroping with ethanol, the obtained residue was subjected to silica gel column chromatography (φ
2.8 × 4 cm, 8% MeOH / CHCl ₃ ) and crystallized from ethanol to give compound 22 (226 mg,
Yield 92.1%) was obtained as colorless needle crystals. MS (m / z): 373 (M ⁺ ); UV (in MeOH) λ max nm: 270 (neutral), 272 (acidic), 270 (basic); mp: 135-137 ° C; ¹ H-NMR ( _{270MHz, DMSO-d 6) δppm} : 8.52 (1H, bs, 5'-NH), 8.3
9 (1H, s, H- 8), 8.15 (1H, s, formyl), 7.47 (2H, bs, 6-NH 2), 5.84
(1H, d, H-1 ', J1 _{', 2 '} = 6.6Hz), 5.5
-5.4 (1H, bs, 2'-OH), 5.4-5.2
(1H, bs, 3'-OH), 4.62 (1H, m, H
-2 '), 4.00 (2H, m, H-3', H-
4 '), 3.60-3.30 (2H, m, H-5'a,
H-5'b), 2.41 (2H, t, H-3 "), 1.
60-1.35 (4H, m, H-4 ", H-5"),
0.91 (3H, t, H- 6 "); Elemental analysis _{[C 17 H 21 N 6 O 4} · 2/3 H 2 O ]: Calculated: C, 52.98; H, 5.84 ; N , 21.8
1 Found: C, 53.00; H, 6.00; N, 21.8.
5

[0075]Example 8  8-1:5'-acetylamino-5'-deoxy-
2 ', 3'-O-isopropylidene-2- (1-hexyl
Nil) adenosine(23) Compound19(62.7 mg, 0.162 mmol) in pyridine
It was dissolved in (5 ml). Acetic anhydride under ice-cold argon atmosphere
(31 μl, 0.324 mmol) was added and the mixture was stirred at room temperature for 2 hours.
After stirring, the solvent was distilled off under reduced pressure, and the residue was azeotropically distilled with toluene.
After adding saturated aqueous sodium hydrogen carbonate solution to the residue, chloro
Extract with organic form and extract the organic layer with saturated aqueous sodium hydrogen carbonate.
It was washed with liquid and saturated saline. With anhydrous sodium sulfate
After drying, the solvent was distilled off under reduced pressure, and the resulting residue was treated with silica gel.
Column chromatography (φ1.8 × 3cm, 8% M
eOH / CHCl₃), The compound23(59
mg, yield 84.9%) was obtained as a foam. MS (m / z): 428 (M⁺); UV (in MeOH) λ max nm: 269 (neutral), 271 (acidic), 269 (basic);¹ H-NMR (100MHz, CDCl₃) Δppm: 7.
82 (1H, s, H-8), 7.78 (1H, d, 5′-NH, J_{5'NH, 5 '}= 8.5Hz),
5.83 (2H, bs, 6-NH₂), 5.80 (1
H, d, H-1 ', J_{1 ', 2'}= 4.6 Hz), 5.16
(1H, dd, H-2 ', J_{2 ', 1'}= 4.6Hz, J
_{2 ', 3'}= 6.1 Hz), 4.83 (1H, dd, H-
3 ', J_{3 ', 2'}= 6.1 Hz, J_{3 ', 4'}= 2.7 Hz),
4.46 (1H, dd, H-4 ', J_{4 ', 3'}= 2.7H
z, J_{4 ', 5'}= 5.4 Hz), 4.15 (1H, ddd, H
-5'a, J_{5'a, 5'NH}= 8.5Hz, J_{5'a, 5'b}= 14.
7Hz, J_{5'a, 4 '}= 5.4 Hz), 3.40-3.23 (1
H, m, H-5'b), 2.42 (2H, t, H-
3 ″), 2.19 (3H, s, acetyl), 1.62
(3H, s, C-CH₃), 1.36 (3H, s, C-
CH₃), 1.60-1.20 (4H, m, H-4 ″,
H-5 "), 0.94 (3H, t, H-6")

8-2: 5'-acetylamino-5'-de
Oxy-2- (1-hexynyl) adenosine ( 24 ) Compound 23 (152 mg, 0.354 mmol) was dissolved in 80% trifluoroacetic acid (10 ml), and the mixture was stirred under ice cooling for 4 hours. After distilling off the solvent under reduced pressure and azeotropically distilling with ethanol,
The obtained residue was purified by silica gel column chromatography (φ1.8 × 6 cm, 8% MeOH / CHCl ₃ ) and crystallized from ethanol to give compound 24 (123
mg, yield 89.2%) was obtained as colorless needle crystals. MS (m / z): 388 (M ⁺ ); UV (in MeOH) λ max nm: 269 (neutral), 272 (acidic), 270 (basic); mp: 198-203 ° C; ¹ H-NMR ( 270 MHz, DMSO-d ₆ ) δppm: 8.38 (1H, s, H-8), 8.13 (1
H, t, 5'-NH), 7.43 (2H, bs, 6-N)
_{H 2), 5.82 (1H,} d, H-1 ', J 1', 2 '=
6.1 Hz), 5.46 (1H, d, 2'-OH, J
_{2'OH, 2 '} = 5.0Hz), 5.26 (1H, bs, 3'-
OH), 4.56 (1H, bs, H-2 '), 4.02
(1H, bs, H-3 '), 3.93 (1H, bs, H
-4 '), 3.46-3.37 (2H, m, H-5'
a, H-5'b), 2.41 (2H, t, H-3 "),
1.87 (3H, s, acetyl), 1.58-1.38
(4H, m, H-4 ", H-5"), 0.91 (3H,
t, H-6 ″); Elemental analysis [C ₁₈ H ₂₄ N ₆ O ₄ 1/2 H ₂ O]: Calculated value: C, 54.40; H, 6.34; N, 21.1
5 Found: C, 54.55; H, 6.19; N, 20.8.
5

[0077]Example 9  9-1:5'-methanesulfonylamino-5'-deoxy
Ci-2 ', 3'-O-isopropylidene-2- (1-f
Xynyl) adenosine(25) Compound19(300 mg, 0.776 mmol) was added to dichlorometh
Dissolved in tongue (10 ml). Birds under an ice-cold argon atmosphere
Ethylamine (0.18 ml, 1.319 mmol) and chloride
Add methanesulfonic acid (90 μl, 1.164 mmol)
After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure.
After adding saturated aqueous sodium hydrogen carbonate solution to the residue, chloro
Extracted with form and the organic layer was saturated aqueous sodium hydrogen carbonate solution.
And washed with saturated saline. Dry with anhydrous sodium sulfate
After drying, the solvent was distilled off under reduced pressure, and the resulting residue was silica gel.
Column chromatography (φ2.2 × 8cm, 2% Et
OH / CHCl₃) Purified by25(154
mg, yield 42.7%) was obtained as a foam-like substance. MS (m / z): 464 (M⁺); UV (in MeOH) λ max nm: 269 (neutral), 271 (acidic), 269 (basic);¹ H-NMR (100MHz, CDCl₃) Δppm: 7.80 (1H, s, H-8), 7.52 (1
H, m, 5'-NH), 5.78 (1H, d, H-
1 ', J_{1 ', 2'}= 3.4 Hz), 5.70 (2H, bs,
6-NH₂), 5.27 (1H, m, H-2 '), 5.
06 (1H, dd, H-3 ', J_{3 ', 2'}= 5.8Hz, J
_{3 ', 4'}= 2.0 Hz), 4.53 (1H, bs, H-
4 '), 3.80-3.40 (2H, m, H-5'a,
H-5'b), 3.01 (3H, s, mesyl), 2.4
6 (2H, t, H-3 ″), 1.80-1.20 (4
H, m, H-4 ", H-5"), 1.62 (3H, s,
C-CH₃), 1.38 (3H, s, C-CH₃),
0.96 (3H, t, H-6 ″)

9-2:5'-methanesulfonylamino-
5'-deoxy-2- (1-hexynyl) adenosine
(26) Compound25(150 mg, 0.323 mmol) was added to 80% tri
Dissolve in fluoroacetic acid (10 ml) and stir under ice cooling for 4 hours
It was After distilling off the solvent under reduced pressure and azeotroping with ethanol,
The resulting residue is subjected to silica gel column chromatography (φ
2.2 × 6 cm, 8% EtOH / CHCl₃) Purified by
And crystallized from ethanol to give the compound26(126 mg,
Yield 91.9%) was obtained as colorless needle crystals. MS (m / z): 424 (M⁺); UV (in MeOH) λ max nm: 269 (neutral), 272 (acidic), 270 (basic); mp: 122-126 ° C;¹ 1 H-NMR (270 MHz, DMSO-d₆) Δppm: 8.39 (1H, s, H-8), 7.41 (2
H, bs, 6-NH₂), 7.32 (1H, t, 5'-
NH), 5.85 (1H, d, H-1 ', J_{1 ', 2'}=
6.6 Hz), 5.51 (1H, d, 2'-OH, J
_{2'OH, 2 '}= 6.0 Hz), 5.30 (1H, d, 3'-O
H, J_{3'OH, 3 '}= 4.4 Hz), 4.62 (1 H, m, H
-2 '), 4.12 (1H, bs, H-3'), 3.9
8 (1H, m, H-4 '), 3.36-3.16 (2
H, m, H-5'a, H-5'b), 2.91 (3H,
s, mesyl), 2.41 (2H, t, H-3 ″), 1.
60-1.35 (4H, m, H-4 ", H-5"),
0.91 (3H, t, H-6 ″); Elemental analysis [C₁₇H_{twenty four}N₆O_FiveS₁・ 1H₂O]: Calculated: C, 46.10; H, 5.88; N, 18.9.
8 Found: C, 46.40; H, 5.60; N, 18.6.
9

[0079]Example 10  10-1:5 '-(N'-methylureido) -5'-de
Oxy-2 ', 3'-O-isopropylidene-2- (1
-Hexynyl) adenosine(27) Compound19(254 mg, 0.659 mmol) in pyridine
It was dissolved in (10 ml). Under ice-cold argon atmosphere
Add socyanate (78 μl, 1.317 mmol) to the chamber
After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure and toluene was added.
Azeotropically. The obtained residue is subjected to silica gel column chromatography.
Graphography (φ2.8 x 6 cm, 8% MeOH / CHCl
₃), The compound27(252 mg, yield 86.
4%) as a foam. MS (m / z): 444 (M⁺); UV (in MeOH) λ max nm: 269 (neutral), 271 (acidic), 269 (basic);¹ H-NMR (100MHz, CDCl_Three) Δppm: 7.82 (1H, s, H-8), 7.07 (1
H, m, 5'-NH), 5.97 (2H, bs, 6-N
H₂), 5.72 (1H, d, H-1 ', J_{1 ', 2'}=
5.4 Hz), 5.40-5.28 (1H, m, NH),
5.15 (1H, dd, H-2 ', J_{2 ', 1'}= 5.4H
z, J_{2 ', 3'}= 5.9 Hz), 4.86 (1H, dd, H
-3 ', J_{3 ', 2'}= 5.9Hz, J_{3 ', 4'}= 1.5Hz),
4.48 (1H, bs, H-4 '), 4.18 (1H,
ddd, H-5'a, J_{5'a, 4 '}= 2.1Hz, J_{5'a, 5'b}
= 14.7Hz, J_{5'a, 5'NH}= 9.9 Hz), 3.27-
3.13 (1H, m, H-5'b), 2.84 (3H,
d, CH₃), 2.45 (2H, t, H-3 ″), 1.
62 (3H, s, C-CH₃), 1.35 (3H, s,
C-CH₃) 1.73-1.23 (4H, m, H-
4 ", H-5"), 0.94 (3H, t, H-6 ")

10-2: 5 '-(N'-methylurei
De) -5'-deoxy-2- (1-hexynyl) adeno
Shin (28) Compound 27 (240 mg, 0.54 mmol), was dissolved in 80% trifluoroacetic acid was cooled to -20 ° C. (10 ml),
The mixture was stirred at -20 ° C for 3 hours. After distilling off the solvent under reduced pressure and azeotroping with ethanol, the obtained residue was subjected to silica gel column chromatography (φ2.2 × 5 cm, 10% EtOH).
/ CHCl ₃ ) and crystallized from ethanol to obtain Compound 28 (180 mg, yield 82.4%) as colorless needle crystals. MS (m / z): 403 (M ⁺ ); UV (in MeOH) λ max nm: 270 (neutral), 272 (acidic), 270 (basic); mp: 146-148 ° C; ¹ H-NMR ( 270 MHz, DMSO-d ₆ ) δppm: 8.39 (1H, s, H-8), 7.44 (2
_{H, bs, 6-NH 2} ), 6.17 (1H, bs, 5 '
-NH), 5.83 (1H, d, H-1 ', J1 _{', 2 '} =
6.6 Hz), 5.74 (1H, bs, 6-NH), 5.
60-5.00 (2H, m, 2'-OH, 3'-O
H), 4.55 (1H, m, H-2 '), 4.02 (1
H, m, H-3 '), 3.90 (1H, m, H-
4 '), 3,80-3.50 (1H, m, H-5'
a) 3.40-3.25 (1H, m, H-5'b),
2.56 (3H, s, CH ₃ ) 2.41 (2H, t,
H-3 "), 1.60-1.35 (4H, m, H-
4 ", H-5") , 0.91 (3H, t, H-6 "); the _{D 2 O: J 2 ',} 3' = 5.0Hz, J 3 ', 4' = 3.3H
z; Elemental analysis _{[C 18 H 25 N 7 O 4} · 1H 2 O ]: Calculated: C, 51.30; H, 6.46 ; N, 23.2
6 Found: C, 51.11; H, 6.16; N, 23.1.
5

[0081]Example 11  11-1:5 '-(N'-methylthioureido) -5'
-Deoxy-2 ', 3'-O-isopropylidene-2-
(1-hexynyl) adenosine (29) Compound19(100 mg, 0.259 mmol) in pyridine
It was dissolved in (5 ml). Methyl iso under an ice-cold argon atmosphere
Add thiocyanate (22 μl, 0.31 mmol) to the chamber
After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure and toluene was added.
Azeotropically. The obtained residue is subjected to silica gel column chromatography.
Graphography (φ1.8 × 6cm, 4% EtOH / CHCl
₃), The compound29(105 mg, yield 88.
0%) was obtained as a foam. MS (m / z): 459 (M⁺); UV (in MeOH) λ max nm: 269 (neutral), 271 (acidic), 269 (basic);¹ H-NMR (270 MHz, CDCl₃) Δppm: 8.
24 (1H, bs, 5'-NH), 7.82 (1H,
s, H-8), 6.68-6.66 (1H, m, N
H), 5.92 (2H, bs, 6-NH₂), 5.74
(1H, d, H-1 ', J_{1 ', 2'}= 5.5 Hz), 5.1
1 (1H, dd, H-2 ', J_{2 ', 1'}= 5.5Hz, J
_{2 ', 3'}= 1.7 Hz), 5.02-4.98 (1H, m,
H-3 '), 4.94-4.90 (1H, m, H-5'
a), 4.55-4.54 (1H, m, H-4 '),
3.52-3.47 (1H, m, H-5'b), 2.44 (2H, t, H-3 ″), 1.62 (3H,
s, C-CH₃), 1.35 (3H, s, CC)
H₃) 1.80-1.26 (4H, m, H-4 ", H
-5 "), 0.94 (3H, t, H-6")

11-2: 5 '-(N'-methylthiouree
Id) -5'-deoxy-2- (1-hexynyl) ade
Nosin ( 30 ) Compound 29 (200 mg, 0.435 mmol) was dissolved in 80% trifluoroacetic acid (10 ml) cooled to -20 ° C,
The mixture was stirred at -20 ° C for 6 hours. After distilling off the solvent under reduced pressure and azeotroping with ethanol, the obtained residue was subjected to silica gel column chromatography (φ1.8 × 6 cm, 8% MeOH /
CHCl ₃ ) and crystallized from ethanol,
Compound 30 (96 mg, yield 52.6%) was obtained as colorless needle crystals. MS (m / z): 419 (M ⁺ ); UV (in MeOH) λ max nm: 269 (neutral), 272 (acidic), 269 (basic); mp: 131-135 ° C; ¹ H-NMR ( 270 MHz, DMSO-d ₆ ) δppm: 8.39 (1H, s, H-8), 7.61 (1
H, bs, 5'-NH), 7.41 (3H, bs, 6-
_{NH 2, NH), 5.83 (} 1H, d, H-1 ', J
_{1 ', 2'} = 6.6Hz), 5.47 (1H, bs, 2'-O
H), 5.28 (1H, bs, 3'-OH), 4.59
(1H, bs, H-2 '), 4.15-4.00 (2
H, m, H-3 ', H-4'), 3.90-3.60.
(2H, m, H-5'a, H-5'b), 2.81 (3
_{H, bs, CH 3),} 2.41 (2H, t, H-
3 "), 1.60-1.36 (4H, m, H-4", H
-5 "), 0.91 (3H, t, H-6"); Elemental analysis _{[C 18 H 25 N 7 O 3} S 1 · 1H 2 O ]: Calculated: C, 49.41; H, 6 .22; N, 22.4.
1 Found: C, 49.12; H, 6.50; N, 22.7.
1

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoko Watanabe, 25, Kasuga-cho, Choshi-shi, Chiba 28 (72) Inventor Takanori Miyashita, 12, Suehiro-cho, Choshi-shi, Chiba

Claims (1)

Claims: [Claim 1] General formula [I] R ² represents an alkyl group or a hydroxyalkyl group,
R ³ is ^{-NR 6 R} 6 ^'or Other indicates _{^{-SO 2 -R 10, R 6,}} R 6 ' is hydrogen atom,
Represents an alkyl group or a cycloalkyl group, R ⁷ represents a hydrogen atom or an alkyl group, R ⁸ represents an oxygen atom or a sulfur atom, R ⁹ represents a hydrogen atom, an alkyl group, an amino group or an alkylamino group, R ¹⁰ represents an alkyl group or an aryl group], and a salt thereof.