JPS6160695A - Novel n6-substituted adenosine derivative, its preparation and hypotensor comprising it as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [X is 1-4C alkyl- substituted)cyclohexylene; Y is -CH2-, or carbonyl; n is 0 or 1] and its adduct at the saccharide part. EXAMPLE:N-(Adenosin-6-yl)-1,3,3-rimethyl-6-azabicyclo[3,2,1]oct-an-7-one. USE:A hypotensor. PREPARATION:A 6-halogenoinosine shown by the formula II (A is halogen) is reacted with an alicyclic secondary amine (e.g., 3-azabicyclo[3,2,2]nonane, etc.) shown by the formula III (Y is -CH2-) preferably in a polar high-boiling solvent such as methyl Cellosolve, etc. by the use of triethylamine, etc. as a catalyst, and, if necessary, the prepared reaction product is converted into an adduct at the saccharide part.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel N6-substituted adenosine derivative, a method for producing the same, and an antihypertensive drug containing the same as an active ingredient. More specifically, the present invention provides the following general formula (I
〕 ; stomach? 'through-I/ (wherein, X is a cyclohexylene group or has 1 to 4 carbon atoms
is a cyclohexylene group substituted with an alkyl group,
A novel N6-substituted adenosine derivative represented by -CH,- or '; C-O, and n is O or l), as well as its sugar moiety triacetyl form, sugar moiety tribenzoyl form, sugar moiety 4) provides sugar moiety adducts such as isopropylidene derivatives.

By the way, the applicant of this application previously filed Japanese Patent Application No. 56-3175.
No. 8 (Japanese Unexamined Patent Publication No. 57-145898), N6
, it was revealed that the 8-position derivative of Nh-dimethyladenosine has an extremely excellent analgesic effect, and later on, the present inventors discovered a novel N6-position F! derivative having a similar basic adenosine structure. As a result of synthesizing various A derivatives and conducting pharmacological tests on each, we found that such Nh-'fl
It has become clear that certain adenosine derivatives have an extremely excellent blood pressure lowering effect, in other words, a blood pressure lowering effect.

That is, the present invention was completed based on this knowledge, and its gist is that the general formula (
The object of the present invention is to provide a novel N6-substituted adenosine derivative as shown in 1) and a sugar moiety adduct thereof, and also, among such compounds, Y is carbonyl! (:;C
-0) as an active ingredient, it was possible to provide an antihypertensive drug that can exhibit an excellent antihypertensive effect.

Furthermore, such compounds according to the present invention can be synthesized by various methods as detailed below.

That is, first, in the general formula (1), X is a cyclo-xylene group or a cyclohexylene group substituted with an alkyl group having 1 to 4 carbon atoms, and Y is -01(2
- and n is O or 1 is a compound represented by the following general formula [■]; Logenoinosine and the following general formula [■]; (wherein, X is a cyclohexylene group or has 1 to 4 carbon atoms
is a cyclohexylene group substituted with an alkyl group,
Y is -ct-tz- and n is O or l)
It can be advantageously synthesized by reacting with an alicyclic secondary amine represented by:

The reaction between 6-halogen inosine (II) and alicyclic secondary amine (III) can be carried out using dimethylformamide,
A polar high-boiling solvent such as methyl cellosolve is used as a reaction solvent, and the reaction can proceed in the presence of such a reaction solvent using triethylamine or the like as a catalyst. The reaction is allowed to proceed at room temperature or, if methyl cellosolve is used, under heating to boiling conditions.

In addition, in such a reaction, the amount of the compound of the general formula (DI) to be used relative to the compound of the general formula (If) is usually selected within the range of approximately equimolar to 2 times the molar range. Furthermore, the reaction time is based on the raw material compound used,
Depending on the solvent, reaction temperature, etc., the reaction time will be set appropriately to obtain the best results in each case, but generally a reaction time of about 1 to 10 hours is employed.

Then, the target compound is extracted from the reaction mixture obtained by such a reaction by an appropriate separation method, but here, for example, the reaction mixture is first concentrated to dryness, and the residue is 80% After removing the ethanol, an anion exchange resin (OH type) was added and stirred at room temperature.Then, the ion exchange resin was filtered off, the filtrate was evaporated to dryness, and the residue was recrystallized or purified on a silica gel column. By chromatography, tr'? A method of manufacturing is preferably adopted.

Examples of target compounds obtained in this way include N-
(Adenosin-6-yl)-3-azabicyclo[3.2
．． 2] Nonane, N-(adenosine-6-yl)-1,3
, 3-)dimethyl-6-azabicyclo[3.2.1]octane.

Further, in the general formula (1), X is a cyclohexylene group or a cyclohexylene group substituted with an alkyl group having 1 to 4 carbon atoms, Y is 〉C=0, and n
A compound having 0 or 1 can be synthesized as follows.

That is, N6- obtained by reacting the 6-halogenoinosine represented by the above-mentioned ImeQ formula (II) with the alicyclic secondary amine represented by the above-mentioned -FJQ formula (III).
By using bicycloaminoadenosine and reacting it with 6 to 10 times the molar amount of acetic anhydride or benzoic anhydride in dry pyridine at room temperature by a conventional method, the following general formula [■]; X is a cyclohexylene group or a cyclohexylene group substituted with an alkyl group having 1 to 4 carbon atoms, Y is -G Hz-, and n
is 0 or 1, and B is an acetyl group or benzoyl group as a protecting group), a 3-part adduct in which the 11h-part hydroxyl group is protected by a =υ group was synthesized, and then this was added to 50 Dissolved in % acetic acid and further added 2-2.5% to it.
After adding twice the molar amount of potassium permanganate, the mixture is allowed to react (oxidize) for 10 to 30 minutes at room temperature.

The target compound obtained by this reaction can be separated by adding 35% hydrogen peroxide solution to the reaction solution to decolorize it, and then extracting it with chloroform. After washing and drying with magnesium sulfate or calcium chloride, chloroform was distilled off, and the resulting residue was purified by silica gel column chromatography using JR'J
By J, the following general formula [■];

(In the formula, X and n each have the same meaning as above)
The N61-substituted adenosine derivative shown in is obtained. Next, this compound (V) was hydrolyzed in a methanol-ammonia solution (containing 5 to 10 times the molar amount of ammonia) at around 0°C, and then the solvent was distilled off to remove the residue. By recrystallizing with an appropriate solvent, the following general formula [■]; (wherein, each Xsn has the same meaning as above)
The desired N611m1i adenosine derivative shown in is obtained.

Moreover, such a compound (Vl) can also be synthesized as follows.

That is, the above N6-bicycloaminoadenosine,
By reacting with a 70% perchloric acid solution or para-toluenesulfonic acid in acetone by a conventional method, the following general formula [■] ; ), in which the hydroxyl group of the sugar moiety is protected with an isopropylidene group, is synthesized, and this is oxidized with potassium permanganate as described above to form the following general formula. A compound represented by the formula [■]; The compound of general formula (VI) can be obtained by hydrolysis, then distilling off the solvent, and recrystallizing the residue from an appropriate solvent.

An example of the target compound obtained in this way is N-(adenosin-6-yl)-3-azabicyclo[
3.2.2] Nonan-2-one, N-(adenosine-6
-yl)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-7-one.

And such a compound according to the present invention, that is, N6-substituted adenosine ER represented by the general formula (Vl)
4 and its sugar adducts (general formulas [■], [■]), as mentioned above, have been shown to have extremely excellent antihypertensive effects as a result of detailed pharmacological tests conducted by the present inventors. It became.

The compound according to the present invention can be used as an antihypertensive drug or an antihypertensive agent in the form of an oral preparation or, if desired, in the form of a parenteral preparation, such as an injection drug or a crude drug. In addition, when used as an oral preparation, it is formulated using conventional stabilizers and excipients, and
mg"2 g/person, preferably in the range of 50 mg to Ig/person. Examples of stabilizers and excipients used in such preparations include starch, colloidal silicon dioxide, Known materials such as magnesium stearate can be mentioned.

Hereinafter, examples of the present invention will be shown and more specifically explained, but it goes without saying that the present invention is not limited in any way by the description of these examples.

Example 1 1 g of 6-chloroinosine and 3-azabicyclo[3.2
．． 2] 0.44 g of nonane and 3 m of triethylamine
1 was added to 100 ml of purified methyl cellosolve as a reaction medium (solvent), and reacted under reflux at a bath temperature of 130 to 140°C for 45 minutes. Then, in order to remove the solvent and triethylamine in the reaction solution, the reaction solution was concentrated to dryness under reduced pressure using an evaporator. Then, the residue was reduced to 80%
It was dissolved in ethanol (as an aqueous solution; the same applies hereinafter), an anion exchange resin (O14 type) was added, and the mixture was stirred at room temperature for 30 minutes.

Further, the ion exchange resin was filtered out, the ion exchange resin was washed, the filtrate and the washing solution were combined, and the solvent was removed. Methanol =
9:l (volume ratio)] and the second eluted portion was collected.

After removing the solvent from the eluate, the resulting residual syrup was crystallized from hot methanol:water (1:3) to form colorless scaly crystals, melting point = 178-179°C.
1 Yield: 1.27 g (yield: 96%) was obtained.

The elemental analysis values of this compound were as follows.

Elemental analysis value: C+5lhsNsOn・1ノ3)1zO
As, the theoretical value...C: 56.6B, H: 6.78,
N: 18.36 Actual value...C: 56.65, H: 6. -74, N:
18.47 Furthermore, the results of nuclear magnetic resonance spectrum analysis of this product were as follows.

Dimethyl sulfoxide-d, medium δppm+ 0.64
2.16<28, broad singlet, 5'-H),
4.01 (IH, multiplet, 4″-H),
4.20 (I H, multiplet, 3'-H)
, 4.43 (4H, multiplet, 2'-H)
, 5.95 (LH, doublet, J-6H2,1''
-H), 8.22 (IH, single L/7t, 2-
H), 8.36 (I H, singlet, 8-H
).

Example 2 a) N-(adenosine-6-yl) obtained in Example 1 above
1 g of -3-azabicyclo[3.2.2]nonane was added to a mixture of 20 m2 of acetic anhydride, anhydride, and 20 mβ of lysine, and the mixture was stirred and reacted at room temperature for 12 hours. The solvent was removed under reduced pressure using an evaporator, and the mixture was subjected to azeotropic distillation with toluene to remove remaining anhydride acid and pyridine.

The remaining syrup was purified by silica gel column chromatography [developing solvent: chloroform dimethanol-97:3 (
volume ratio)] and the second eluted portion was collected. and,
After removing the solvent from the elution area, the remaining 2', 3'
, 5'-o-triacetyl-N-(adenosin-6-yl)-3-azabicyclo[3.2.2]nonane syrup was dissolved in 50% acetic acid 5 Qme and 162 g of potassium permanganate was added. The mixture was stirred and reacted at room temperature for 15 minutes.

A 35% hydrogen peroxide solution was added to the reaction mixture thus obtained to decolorize it and obtain a transparent solution. This solution was then extracted with chloroform, and the resulting organic layer was diluted with saturated hydrogen carbonate)
Washed with IJum solution and dried with MF:SO4. Thereafter, the solvent was distilled off, and the remaining syrup was subjected to silica gel column chromatography [developing solvent: chloroform:methanol - 95:5 (volume ratio)], and the second eluate was collected. 2', 3', 5' -0- obtained by removing the 7 volumes of the discharge part
The residual syrup of triacetyl-N-'(adenosin-6-yl)3-azabicyclo[3.2.2]nonan-2-one was dissolved in 5 Gml of ammonia-methanol? To 8 liquid?
The mixture was dissolved and left overnight at -10°C with a tightly stoppered cap. After distilling off the solvent from this solution, the remaining syrup was subjected to silica gel column chromatography [Development medium chloroform:methanol-4:1 (volume ratio)] and the second eluate was collected. After removing the solvent in the eluate, the remaining syrup was crystallized from ether; petroleum ether to yield a colorless amorphous powder.
．． Obtained in an amount of 25 g (yield: 23%).

b) N-(adenosine-6-yl) obtained in Example 1 above
-3-Azabicyclo[3.2,21 1 g of nonane was dissolved in 100 mL of acetone for 7 gJ, and 1 g of a 70% perchloric acid solution was added dropwise thereto over 30 minutes. Thereafter, the mixture was stirred at room temperature for 30 minutes, 2.5 g of sodium hydrogen carbonate was added to the resulting solution, and the mixture was further stirred for 30 minutes. 4G of insoluble matter
The resulting filtrate was concentrated to dryness, and the residue was subjected to silica gel column chromatography [developing solvent, chloroform:methanol = 95:5 (volume ratio)].
The eluted portion was collected. After removing the solvent in the elution area, the remaining 2',3''-〇-isopropyriden-N
-(adenosine-6-yl)-3-azabicyclo [3.
2゜2] Nonane syrup was dissolved in 50 ml of 50% acetic acid, 1.2 g of potassium permanganate was added on a water bath, and the mixture was reacted for 20 minutes.

The reaction mixture obtained was extracted with chloroform, and the organic layer was dried with MgS Oa. After distilling off the solvent, the remaining syrup was purified by silica gel column chromatography [developing solvent, chloroform:methanol = 95%]. :
5 (volume ratio)] and the second eluted portion was collected. After removing the solvent in the elution area, the obtained 2',
3'-〇-isopropylidene-N-(adenosine-6-
The residual syrup of azabicyclo[3.2.2]nonan-2-one was dissolved in 50 ml of 70% formic acid, and the solution was sealed and left overnight at room temperature.

After distilling off the solvent, the remaining syrup was crystallized from petroleum ether to obtain a colorless amorphous powder in a yield of 0.25<yield: 18%).

This obtained crystal is the N-(adenosin-6-yl)-3-azapink l:l [3.2
．． 2] Nonane-2-one and the following physical constants were defeated.

Ultraviolet absorption spectrum UVλ'nm (a); 274 (1170
0) Nuclear magnetic resonance spectrum (chloroform-d.

middle) δppm; 1.62 to 2.48 (9H, multiple broad single left, 5'-H), 4.15 (I
H, Broad Singlet, 4”-H), 4.32(I
H, broad singlet, 3'-H), 4.74
(IH, multiplet, 2'-H), 5.91
(IH, doublet, J-6Hz sl'-H)
, 8.30 (1)1. Singlet, 2-H),
8.74 (I H, singlet, 8-H).

C) Elemental analysis value: C+allzJsOs ・3/2
As uzo, theoretical value...C: 51.89, H: 5
．． 71N:16.11 Actual value...C:51.92, H:5.99N:16.
82' Example 3 1 g of 6-chloroinosine and 1,3.3-trimethyl-
6-azabicyclo[3.2.1]octane 0.7. and,
Furthermore, in addition to 3 mff1 of triethylamine and 100 mJ of purified methyl cellosolve as a solvent, bath temperature: 130-140
The reaction was allowed to take place at 30 minutes under reflux. Then, in order to remove the solvent 78 (methylcellolph) and triethylamine in the obtained reaction solution, it was concentrated to dryness under reduced pressure using an evaporator.Then, the obtained residue was dissolved in 80% ethanol and ion-exchanged with it. Add resin (OH type),
The mixture was stirred at room temperature for 30 minutes.

The ion exchange resin was separated from this ethanol solution,
Then, the washing liquid obtained by washing the ion exchange resin and the filtrate are combined, and after removing the solvent, the remaining syrup is subjected to silica gel column chromatography [Developing solvent, chloroform:methanol - 9:1 (volume ratio)] The second eluted portion was collected. Then, by removing the solvent of the eluate obtained by
g (yield: 93%) of a syrupy compound was obtained.

Moreover, the elemental analysis values of this compound were as follows.

Elemental analysis value: C2゜H□N, 04・1/2CHCl, ・2/3
Theoretical value for H and O: C: 51.82, To 1:6
．． 5/, N: 14.74 Actual value...C: 51.74, H: 6.25, N: 14
．． 74 Furthermore, the results of nuclear magnetic resonance spectroscopy of this compound were as follows.

dimethyl sulfoxide-d, medium δ1) pHl io,
84.0.96 (3H13H, each singlet, 3.5
6-3.75 (IH, LH, double left, maH, double left-double left, 5'-H), 4.26 (IH,
Broad singlet, 4-H), 4.38 (I
H, doublet-doublet, 3'-H), 4.82
(IH, multi-bullet, 2”-H), 5.28
(I H, multi-bullet, J=7Hz, 1'
-H), 8.05 (IH, doublet, 2-1()
, 8.20 (IH, singlet, 8-H).

Example 4 a) N-(adenosine-6-yl) obtained in Example 3 above
-1,3,3-)rifthyl-6-azabicyclo [3.
2.1] Add 1 g of octane to a mixture of anhydrous vinegar 6I20 m II and anhydrous pyridine 20 mf, and at room temperature,
After stirring and reacting for 1.2 hours, acetic anhydride and pyridine as solvents were removed under reduced pressure using an evaporator, and in order to further remove remaining acetic anhydride and pyridine, the mixture was subjected to azeotropic distillation with toluene. The remaining syrup was subjected to silica gel column chromatography [developing solvent: chloroform:methanol - 95:5 (volume ratio)], and the second eluate was collected. After removing the solvent in the elution area, the remaining 2',3',s-0-triacetyl-N-(adenosine-6-yl)-1,3,3-trimethyl-6-azabicyclo[3 .2.1] Octane syrup was dissolved in 50% acetic acid, 1.2 g of potassium permanganate was added thereto, and the mixture was stirred and reacted at room temperature for 20 minutes.

Next, 35% hydrogen peroxide solution was added to the resulting reaction mixture to decolorize it and form a transparent solution.The solution was further extracted with chloroform, and the organic layer was washed with saturated sodium bicarbonate solution. After that, it was dried with MgSO4. Next, after distilling off the solvent from this dried organic layer,
The remaining syrup was subjected to silica gel column chromatography (developing solvent, chloroborm: methanol-95 = 5
(volume, volume ratio)] and the second eluted portion was collected. Then, 2',3',5''-〇-triacetyl-N-(adenosine-6-yl)-1,3,3-trimethyl-6-azabicyclo[3 , 2,11 octan-7-one syrup was temporarily dissolved in 50 ml of ammonia-7 volumes of methanol, and the mixture was sealed and left overnight at a temperature of -10°C.Then, the solvent was distilled off. , the remaining syrup was subjected to silica gel column chromatography (developing solvent, chloroform:methanol - 9:1 (volume ratio))]
The second eluted portion was collected. Then, by removing the t-solvent from the elution area, 0.46 g (yield: 50%) of syrup was obtained.

b) N-(adenosine-6-yl) obtained in Example 3 above
-1,3,3-trimethyl-6-azabicyclo [3.2
．． 1] 1 g of octane, 5 Qm of acetone! 1 g of 70% perchloric acid solution was added dropwise to this over 30 minutes, and the resulting solution was stirred at room temperature for 30 minutes;
Add 2.5g of sodium hydrogen carbonate to the container and add 3.
Stirring was performed for 0 minutes. Then, this obtained reaction)6
Insoluble materials were separated from the solution, the filtrate was dried with Concentration 11, and the residue was subjected to silica gel column chromatography [Developing solvent, chloroform:methanol = 95:5 (volume ratio)]
], and the first eluate was collected. After removing the solvent from the elution area, the remaining 2',3'-0-isopropylidene-N-(adenosine-6-yl)-1゜3.3-trimethyl-6-azabicyclo[3゜2 .1]
The octane syrup was dissolved in 50 ml of 50% acetic acid, and 1.2 g of potassium permanganate was added thereto on a water bath, followed by reaction for 20 minutes.

The reaction mixture was then extracted with chloroform, and the organic layer was dried with M g SOa. After distilling off the solvent from this dry solution, the remaining syrup was subjected to silica gel column chromatography [developing solvent: chloroform:methanol-95:'5 (volume ratio)], and the second eluate was collected.

2゛,3'-〇-isopropylidene-N-(adenosine-6-yl)-1,3゜3-trimethyl-6-azapicic LI[3, 2.1] Octan-7-one syrup was dissolved in 50 ml of 70% acid, and the solution was sealed and left overnight at room temperature. Then, the solvent was distilled off,
The remaining syrup was subjected to silica gel column chromatography [Developing solvent: chloroform; methanol-9:1 (
volume ratio)] and the second eluted portion was collected. and,
By removing the solvent from the eluate thus obtained, 0.3 g (yield: 33%) of syrup was obtained.

The resulting syrup was prepared by combining N-(adenosin-6-yl)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-7-one obtained by method a) above with the following physical The constants matched.

lyutanku b) Ultraviolet absorption spectrum UVλH shiso nm (ε); 291 (sh) (15100), 282 (20000).

) Nuclear magnetic resonance spectrum (chloroborum-d.

Medium) δppm; 0.66. 0.75 (3H
22:1, ), 2.07-2.52 (2H, multiplet, 5′-H), 4.22 (I H
, broad singlet, 4-H), 4.44 (L
H, Doublet-sama, 3゛-1 season, 4.76-5.00 (
2H.

5.98 (IH, double left, J-GHz, I'-H
), 8.34 (I H, singlet, 2-H
), 8.52, 8.59 (IH, 2: 1, each singlet, 8-H).

C) Elemental analysis value: CzoHzvNs Os ・1/6 CHC7! a
Theoretical value...C: 55.38, H: 6.26, N: 1
6.01 Actual measurement value... c: ss, si, H: 6.23, N: 15
．． 63 Example 5 N-(adenosine-6-yl)-1,3,3-trimethyl-6-azabicyclo[3,2.1]octane- obtained in Example 4 using spontaneously hypertensive rats. 7-
A test was conducted on the antihypertensive effect of On. The results of the hypotensive effect obtained are shown in Table 1 below, comparing the case of no administration (control) and the case of administration of lAM hydralazine as a control.

In addition, in the test, animals with a blood pressure of 190 inHg were placed in a preheated box at 60°C in a group of 5 animals for 3 to 4 days.
After heating for minutes, blood pressure was measured non-invasively using a rat tail artery pressure and pulse rate measuring device (Natsume Seisaku Shiki). In addition, blood pressure was measured before administration and 1 hour after administration.
A significance test was performed for each control group.

Furthermore, a blood pressure value of less than 180 mmHg 1 hour after administration of the sample is considered to have a hypotensive effect (all or n).
The effectiveness rate was calculated based on the one response. The specimen was distilled water for injection or 0.2% CM C-N so that the dose was 0.1 ml/100 g (body weight).
It was prepared as above and administered intraperitoneally.

Claims (12)

[Claims] (1) The following general formula; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X is a cyclohexylene group or has 1 to 4 carbon atoms.
is a cyclohexylene group substituted with an alkyl group,
Y is -CH_2- or >C=0, n is 0 or 1), and an adenosine derivative in which the amino group at the 6-position is substituted with an alicyclic amino group and a sugar adduct thereof. (2) The alicyclic amino group is 3-azabicyclo [3.
2.2] Nonane skeleton or 3-azabicyclo [3.2.
2] Claim 1 having a nonan-2-one skeleton
Compounds described in Section. (3) The alicyclic amino group is 6-azabicyclo [3.
2.1] Octane skeleton or 6-azabicyclo [3.2
．． 1] A compound according to claim 1 having an octan-7-one skeleton. (4) The compound according to any one of claims 1 to 3, wherein the sugar adduct is a triacetyl sugar, tribenzoyl sugar, or isopropylidene sugar. (5) The following general formula; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 6-halogeninoinosine represented by (in the formula, A is a halogen atom) and the following general formula; ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein, X is a cyclohexylene group or has 1 to 4 carbon atoms
is a cyclohexylene group substituted with an alkyl group,
Y_1 is -CH_2- and n is 0 or 1)
The following general formula is characterized by reacting with an alicyclic secondary amine represented by and, if necessary, converting the product into a sugar adduct; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for producing a novel N^6-substituted adenosine derivative or a sugar moiety adduct thereof represented by the formula (wherein X, Y_1 and n each have the same meanings as above). (6) using the alicyclic secondary amine in an equimolar to twice the molar amount relative to the 6-halogenoinosine, and in the presence of a polar high-boiling solvent such as dimethylformamide or methyl cellosolve; 6. The manufacturing method according to claim 5, wherein the reaction is carried out at room temperature or at the boiling temperature of the solvent. (7) The following general formula; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 6-halogenoinosine represented by (in the formula, A is a halogen atom) and the following general formula; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein, X is a cyclohexylene group or has 1 to 4 carbon atoms
is a cyclohexylene group substituted with an alkyl group,
Y_1 is -CH_2- and n is 0 or 1) is reacted with an alicyclic secondary amine represented by the following general formula; , Y_1 and n have the same meanings as above), and then this N^6-substituted adenosine derivative was treated with the hydroxyl group of the sugar moiety protected with a protecting group. In,
The following general formula consists of reacting with potassium permanganate and then performing acid or alkali treatment as necessary; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, have the same meaning)
A method for producing an N^6-substituted adenosine derivative or a sugar moiety adduct thereof. (8) The production method according to claim 7, wherein the protecting group for the hydroxyl group on the sugar moiety of the N^6-substituted adenosine derivative is an acetyl group, a benzoyl group, or an isopropylidene group. (9) The potassium permanganate is used in a molar amount 2 to 3 times that of the N^6-substituted adenosine derivative with the sugar moiety hydroxyl group protected, and in the presence of 50% acetic acid as a solvent, 9. The production method according to claim 7 or 8, wherein the reaction is carried out at room temperature and, if necessary, the protecting group is removed with methanol-ammonia, formic acid or acetic acid. (10) The following general formula; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X is a cyclohexylene group or has 1 to 4 carbon atoms
is a cyclohexylene group substituted with an alkyl group,
An antihypertensive drug containing, as an active ingredient, an N^6-substituted adenosine derivative or a sugar moiety adduct thereof, in which the 6-position amino group is substituted with an alicyclic amino group, represented by (n is 0 or 1). (11) The N^6-substituted adenosine derivative has N-(
Adenosin-6-yl)-1,3,3-trimethyl-6
The antihypertensive drug according to claim 10, which is -azabicyclo[3.2.1]octan-7-one. (12) The sugar moiety adduct is a 2',3',5'-O-triacetyl derivative of the N^6-substituted adenosine derivative, 2
',3',5'-O-tribenzoyl body or 2',
The antihypertensive drug according to claim 10 or 11, which is a 3'-O-isopropylidene compound.