JPS6143198A - Novel n6-substituted adenosine derivative, preparation thereof and hypotensitve agent containing same as active constituent - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {X is NR [R is 1-10C alkyl, OH-monosubstituted 1-4C alkyl, 3-6C alkenyl or (halogen, halogenated lower alkyl, lower acyl or lower alkylenedioxy)-substituted benzene derivative], S, SO, SO2 or CH2; Y is CH2or CO; n is an integer 0-4} and a sugar part adduct thereof. EXAMPLE:N<6>-(N'-Trifluoromethylphenylpiperazino)adenosine. USE:A hypotensive agent. PRAPARATION:A compound expressed by formula II (A is halogen), e.g. 6- chloroinosine, is reacted with a compound expressed by formula III, e.g. 1- methylpiperazine, in an amount of 1-2 times that of the compound expressed by formula II in a polar high-boiling solvent, e.g. dimethylformamide (DMF), at room temperature or the boiling temperature of the solvent.

Description

[Detailed description of the invention]

The present invention relates to a novel Nb-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 is based on the following general formula (■
]; (wherein, X is:>N-R1-5-1-SO, -2 or -CH2-, Y is -CH2-1 or)C=O, and n is an integer from 0 to 4 (However, R has 1 carbon number
~10 linear or branched alkyl groups, alkyl groups having 1 to 4 carbon atoms and monosubstituted with hydroxyl groups, alkenyl groups having 3 to 6 carbon atoms, halogens, halogenated lower alkyl groups, lower (Indicates a benzene derivative group substituted with an acyl group or lower alkylenedioxy group)]
The present invention provides a novel Nb-substituted adenosine derivative represented by the above formula, and its sugar adducts such as triacetyl sugar, tribenzoyl sugar, and isopropylidene sugar. 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), Nb
, revealed that the 8-position derivative of Nb-dimethyladenosine has an extremely excellent analgesic effect, and subsequently, the present inventors synthesized various new Nb-substituted derivatives having the same basic adenosine structure. However, as a result of conducting pharmacological tests on each of them, it has become clear that such Nb-substituted 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 purpose of the present invention is to provide novel Nb-substituted adenosine derivatives and glycoadducts thereof shown in 1), and by using such compounds as active ingredients,
This enabled us to provide an antihypertensive drug that can exhibit excellent antihypertensive effects. 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),
-R, -3 or -CH2-, Y is -CH2-, and n is an integer of θ to 4 (However, R follows the above definition. The same applies hereinafter) The compound has the following general formula [ ■]; Δ [In the formula, A is a halogen atom such as chlorine, bromine, or iodine. 6-halogenoinosine represented by (the same applies hereinafter),
The following general formula [■]; carbon dioxide (in the formula, X is >N-R, -3- or -CH, Y is -CHt-, and n is an integer from O to 4); It can be advantageously synthesized by reacting with the alicyclic secondary amine shown. The reaction between 6-halogenoinosine (U) and alicyclic secondary amine (CDI) uses a polar high-boiling solvent such as dimethylformamide or methyl cellosolve as a reaction solvent, and in the presence of such a reaction solvent, , which can proceed using triethylamine or the like as a catalyst,
At this time, the reaction is allowed to proceed at room temperature when dimethylformamide is used as the reaction solvent, or under heated conditions where the reaction solvent is boiled when methyl cellosolve is used. In addition, in this reaction, the amount of the compound of the general formula CIII) to be used relative to the compound of the general formula (II) is:
Usually, it is selected within the range of about equimolar to about 2 times molar. Furthermore, the reaction time depends on the raw material compounds, solvent, reaction temperature, etc. used, and will be set appropriately to obtain the best results in each case, but is generally about 1 to 10 hours. reaction time is adopted. 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) is added and stirred at room temperature.Then, the ion exchange resin is filtered off, the filtrate is evaporated to dryness, and the residue is recrystallized or silica gel. A method of purification by column chromatography is preferably employed. Examples of target compounds obtained in this way include N'
-(N'-methylpiperazino)adenosine, N'-(N
'-ethylpiperazino)adenosif, N'-(N'-hydroxyethylpiperazino)adenosine, N'-(N
'-Hydroxypropylpiperazino)adenosine, N
'-(N'-orthochlorophenylpiperazino)adenosine, N'-(N'-metachlorophenylpiperazino)
Adenosine, N'-(N'-parachlorophenylpiperazino)adenosine, N'-(N'-metafluorophenylpiperazino)adenosine, N'-(N'-trifluoromethylphenylpiperazino)adenosine, N'-(N'-
paraacetophenone piperazino) adenosine, N'-(
Examples include N'-piveroylpiperazino)adenosine, N'-thiacyridinoadenosine, N'-thiomorpholinoadenosine, and N'-heptamethyleneiminoadenosine. Next, in the general formula (1), X is -802-
A compound in which 1Y is -CH and -1n is 0 or 2 can be synthesized as follows. That is, N'-thiacyridinoadenosine or N' obtained by reacting 6-valogenoinosine represented by the above general formula (II) with the alicyclic secondary amine represented by the above general formula CIII). - Thiomorpholinoadenosine is reacted with 6 to 10 times the molar amount of acetic anhydride or benzoic anhydride in dry pyridine at room temperature by a conventional method to form the following general formula [■];
(In the formula, Yl is -CH2-, m is 0 or 1, and B is an acetyl group or a benzoyl group as a protecting group), which is a sugar whose hydroxyl group is protected with a protective MW of 14. The partial adduct is synthesized, then dissolved in 50% acetic acid, and 2 to 2.5 times the molar amount of potassium permanganate is added thereto, followed by reaction (oxidation) at room temperature for 10 to 30 minutes. be. 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 further drying this with magnesium sulfate or calcium chloride, chloroform is distilled off, and the resulting residue is purified by silica gel column chromatography to obtain the following general formula [V]; , Y, , B, and m each have the same meanings as above) to obtain an N6-substituted adenosine derivative. Next, this compound (V) was hydrolyzed in a methanol-ammonium solution (containing 5 to 10 times the molar amount of ammonia) at around 0°C,
Thereafter, the solvent is distilled off and the residue is recrystallized with an appropriate solvent to form a compound represented by the following general formula [■]; (wherein, Y and m each have the same meanings as above). The desired N6-substituted adenosine derivative is obtained. Moreover, such a compound (Vl) can also be synthesized as follows. That is, by reacting the above N6-thiasilidinoadenosine or N6-thiomorpholinoadenosine with a 70% perchloric acid solution or paratoluenesulfonic acid in acetone by a conventional method, the following general formula [■]; × (In the formula, Yl and m each have the same meaning as above), a 2',3'-0-isopropylidene compound in which the hydroxyl group of the sugar moiety is protected with an isopropyritine group is synthesized, and this is oxidized with potassium permanganate as described above to obtain a compound represented by the following general formula [■]; [■]
is hydrolyzed in 70% formic acid or acetic acid at room temperature, then the solvent is distilled off and the residue is recrystallized with an appropriate solvent to obtain the compound of general formula (VI). be. Examples of the target compound obtained in this manner include N6-(thiacilisino-3,3-dioxo)adenosine and N6(thiomorpholino-4,4-dioxo)adenosine. Next, in the general formula (1), X is -CH2-1Y
A compound in which C-0 and n is 3 or 4 can be synthesized as follows. That is, a compound known in the literature: 6-(1-hexahydroazepinyl)adenosine

[(Annalen (^nnale)
n)] + pages 745 to 760 (1976)], or N6-hebutamethyleneiminoadenosine obtained by reacting the above compound (n) with the above compound [■], in dry pyridine by a conventional method. By reacting with 6 to 10 times the molar amount of acetic anhydride or benzoic anhydride at room temperature, the following general formula [■]; (wherein, X2 is -CH2- and B is an acetyl group or a benzoyl group and p is 3 or 4), and then this compound (IX) was heated to 50
% acetic acid, add 2 to 2.5 times the molar amount of potassium permanganate, and react at room temperature for 10 to 30 minutes. The target compound obtained by this reaction is separated by adding 35% hydrogen peroxide solution to the reaction solution, decolorizing it, extracting it with chloroform, washing the chloroform solution with saturated sodium bicarbonate solution, and then After drying with magnesium sulfate or calcium chloride, chloroform was distilled off, and the resulting residue was further purified by silica gel column chromatography to form the following general formula [X]; (wherein, Xz, 'B and p are each (having the same meaning as above), further hydrolyzing this compound (Xl) in a methanol-ammonia solution (using a solution containing 5 to 10 times the molar amount of ammonia) at around 0°C, Thereafter, the solvent is distilled off and the residue is purified by silica gel column chromatography to obtain a compound represented by the following general formula (Xl); (wherein x2 and p each have the same meaning as above). The above compound (XI) can also be obtained by the following method. That is, the above-mentioned 6-(1-hexahydroazepinyl)adenosine or N&-hebutamethyleneimino By reacting adenosine with a 70% perchloric acid solution or para-toluenesulfonic acid in acetone by a conventional method, the following general formula (XI [); ) is synthesized, and this compound (
XII) is oxidized with potassium permanganate as described above to obtain a compound represented by the following general formula (Xll+); Compound (X I
II) in 70% formic acid or acetic acid at room temperature, then the solvent is distilled off and the residue is purified by silica gel column chromatography to obtain the desired compound of general formula [XI]. is obtained. Examples of target compounds obtained in this way include N'
-(1-hexahydroazepinyl-2-one)adenosine, Nh-(1-hebutamethyleneiminol-2-one)
There are azo-7nosine, etc. As mentioned above, the compound according to the present invention, that is, the N6-substituted adenosine derivative represented by the general formula (1) and its sugar moiety adduct, has been described in detail by the present inventors. As a result of pharmacological tests, it was revealed that it has an extremely superior force-control effect. The compound according to the present invention can be used as an antihypertensive drug or an antihypertensive agent in oral preparations, and if desired, can be formulated into parenteral preparations such as injections and crude drugs. In addition, when used as an oral preparation, it is formulated using conventional stabilizers and excipients, and
The dose will be in the range of mg to 2 g/person, preferably 5 Qmg to Ig/person. Examples of stabilizers and excipients used in such formulations include known ones such as starch, colloidal silicon dioxide, and magnesium stearate. 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 a) 1 g of 6-chloroinosine, 0.4 g of 1-methylpiperazine and further 1 mβ of triethylamine in 100 rrt of methylcellosolve as reaction medium (solvent)
p and d were added, and the reaction was carried out under reflux for 1.5 hours at a bath temperature of 130-1.1.0°C. 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 (OH type) was added, and the mixture was stirred at room temperature for 30 minutes. Further, this ion exchange resin was filtered out, the ion exchange resin was washed, the filtrate and the washing liquid were combined, the solvent was removed, and the residue was subjected to silica gel column chromatography [developing solvent, chloroform: methanol = 93 nia (volume ratio)]. )] and the second eluted portion was collected. After removing the solvent from the eluate, the resulting residue was crystallized from hot methyl acetate and further recrystallized from a mixed solvent of ethyl acetate and methanol to produce a colorless prism product, melting point = 186. ~188℃
, yield: 1.08 g (yield: 88%). b) 1 g of 6-chloroinosine, 0.4 g of 1-methylpiperazine, and 1 mj2 of triethylamine were added to 50 ml of anhydrous dimethylformamide as a reaction solvent, and reacted with stirring at room temperature for 16 hours. Then, in order to remove the solvent (dimethylformamide) and triethylamine in the obtained reaction solution, it was concentrated to dryness under reduced pressure using an evaporator. The residue was then heated to 80%
% ethanol, ion exchange resin (OH type)
was added and stirred at room temperature for 30 minutes. The ion exchange resin is filtered from this ethanol solution, the resulting filtrate is combined with the washing solution obtained by washing the ion exchange resin, the solvent is removed, and the residue is subjected to silica gel column chromatography [developing solvent, chloroform: methanol = 93 = 7 (volume ratio)], and the second eluted portion was collected. After removing the solvent in the eluate, the residue was crystallized from hot ethyl acetate, and further recrystallized from a mixed solvent of ethyl acetate and methanol.
Colorless prism crystals, melting point: 186-188°C, yield: 1.
05g (yield: 86%) was obtained. In addition, this obtained crystal is the same as the N′ obtained in the above section a).
The following physical constants matched those of -(N'-methylpiperazino)adenosine, and as a result of the mixing test, no decrease in the melting point was observed. Physical constant a) Nuclear magnetic resonance spectrum (dimethyl sulfoxide-d
6) δppm; 2.20 (3H, singlet, -N N-CJlfl), 2.43 (4H,
Blow H1 Broad Singlet, 5'-Old, 4.03
(IH, chlortent, 4'-suke, 4.25 (5H1 broad singlet, 3'-H + singlet 2'-H
After adding 1 heavy water, it changes to triplet), 5.20 (IH
, broad singlet, −〇 river, disappeared after adding heavy water)
, 5.44 (2■1, broad singlet, 2x −
OH1 disappeared after addition of heavy water), 5.98 (IH, doublet, J=611z, 1'-old, 8.26 (IH, singlet, 2-old, 8.41 (IH, singlet, 8-
H). Mouth) Elemental analysis value Elemental analysis value: C+ s Hz 2N b Oa, theoretical value - C: 5], 42, H: 6.33, N: 2
3.99 Actual value---C: 51.33, H: 6.23, N: 2
3.84 Instead of 1-methylpiperazine in the above examples, other substituents, i.e. straight-chain or branched alkyl groups having 1 to 10 carbon atoms, alkenyl groups having 3 to 6 carbon atoms, or halogen , using a piperazine derivative having a benzene derivative group substituted with a trinololomethyl group, etc., and reacting in exactly the same manner as above, and the corresponding N6-(N'
-substituted) adenosine was obtained. The physical properties of each are shown below.
Shown in the table. However, R in Table 1 is R in the following general formula. tilJ LJ11 Example 2 1 g of 6-chloroinosine and 0.33 g of thiazolidine
And more triethylamine 1m7! were added to 100 ml of solvent: methyl cellosolve, bath ijl: 130-14
The reaction was carried out at 0° C. for 2.5 hours under reflux. Then, in order to remove the solvent (methyl cellosolve) and triethylamine in the obtained reaction solution, it was concentrated to dryness under reduced pressure using an evaporator. Next, the residue was dissolved in 80% ethanol, an ion exchange resin (OH type) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The ion exchange resin was filtered from this ethanol solution, and the washing solution obtained by washing the ion exchange resin was combined with the filtrate. After removing the solvent, a small amount of methanol was added to the residue to precipitate. The crystals were collected by filtration and recrystallized from a mixed solvent of water and methanol to give colorless prism crystals, melting point: 140-143°C (semi-molten), 147-14
8°C (dissolution), yield: 0.9g (yield near 6%). The elemental analysis values of this obtained compound were as follows. Elemental analysis value: Cl5HI7NS Os S, theoretical value... c: 4s, o group, H: 5.05, NIo, 6
4 Actual measurement value...C: 46.23, H: 5.23, NlO,
33 Furthermore, the results of nuclear magnetic resonance spectroscopy of this compound were as follows. δppm in dimethyl sulfoxide-d6; 3.15-4
．． 00 (2H, multiplet, 5'-H), 4.08
(IH, quartet, 4"H), 4.20 (LH, quartet, 3'-H), 5°04~5.32 (5
H, multiplet, 2'-blend, -0H1 disappeared after addition of heavy water), 5.50-5.78 (2H, multiplet, 2X-OH. disappeared after addition of heavy water), 5.96 (IH, doublet, J =
6Hz, 1'-H), 8.27 (IH, singlet, 2-H), 8.42 (IH, singlet, 8-H). In addition, thiomorpholine was used instead of thiazolidine in the above example, and the reaction was carried out in the same manner as above, and N6
-Thiomorpholinoadenosine (melting point: 179.5-18
0'c) was obtained. Example 3 1 g of 6-chloroinosine and 0.0 g of heptamethyleneimine.
5g and more triethylamine 1m7! were added to 100 ml of methyl cellosolve as a solvent, and in a nitrogen stream,
The reaction was carried out at a bath temperature of 130 to 140°C for 1 hour under reflux. Then, in order to remove the solvent (methylcellosolve) and triethylamine in the obtained reaction solution, it was concentrated to dryness under reduced pressure using an evaporator. The obtained residue was
Dissolve in 0% ethanol and add ion exchange resin (
OH type) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The ion exchange resin is filtered out from this ethanol solution, the washing liquid obtained by washing the ion exchange resin and the filtrate are combined, the solvent is removed, and the remaining crystals are recrystallized from isopropyl alcohol. Please,
Colorless needle crystals, melting point: 173-174°C, yield: 1.2g
(yield: 95%). The elemental analysis values of this obtained compound were as follows. Elemental analysis value: CI 7 Hzs N s O4, theoretical value...C: 56.19, H: 6.93, N: 1
9.21 Actual measurement value...C: 55.96, H: 7.22, N: 1
8.79 Furthermore, the results of nuclear magnetic resonance spectrum analysis of the obtained compound were as follows. Dimethyl sulfoxide-d, medium δppm; 1.4 B (1,84(
4H, broad singlet, 5'-H), 4.6
4 (IH, scrubber, 2'-H), 3.80
~4.40 (6H, multiplex (IH, doublet,
J=5Hz, 1'-H), 8.21 (IH, singlet, 2-H), 8.33 (IH, singlet,
8-H). Example 4 a) 1 g of N6-thiasilidinoadenosine obtained in Example 2 was mixed with 20 ml of acetic anhydride! , and anhydrous pyridine 20
The mixture was added to a mixed solution of ml, and 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 acetic anhydride and pyridine. The remaining syrup was subjected to silica gel column chromatography [developing solvent, chloroform:methanol=981 (volume ratio)], and the second eluate was collected. After removing the solvent in the elution area, the remaining 2', 3', 5'-triacetyl-N6-thiasilidinoadenosine syrup was mixed with 50 mj of 50% acetic acid.
! 1.2 g of potassium permanganate was added thereto, and the mixture was stirred and reacted at room temperature for 30 minutes. A 35% hydrogen peroxide solution was added to the reaction mixture thus obtained to decolorize it and obtain a transparent solution. The solution was then extracted with chloroform and the resulting organic layer was washed with saturated sodium bicarbonate solution and dried over MgSO4. Then, 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 eluted portion was collected. Then, the 2', 3', 5'-〇-)lyacetyl-N6-
(Thiacilisino 3,3-dioxo) adenosine cilosop, 50mj! The mixture was dissolved in an ammonia-methanol solution, and the mixture was left sealed overnight at -10°C. After distilling off the solvent from this solution, the remaining crystals were recrystallized from water to form colorless needle-shaped crystals, melting point: 162-164.
°C, yield: 0.6 g (yield: 55%). b) 1 g of N6-thiasilidinoadenosine obtained in Example 2 was suspended in 100 m6 of acetone, and 1 g of 70% perchloric acid solution was added dropwise thereto over 30 minutes. After that, 3
After stirring at room temperature for 0 minutes, 2.5 g of sodium hydrogen carbonate was added to the resulting solution, and the mixture was further stirred for 30 minutes. Insoluble matter was filtered off, the resulting filtrate was concentrated to dryness, and the residue was subjected to silica gel column chromatography [developing solvent, chloroform:methanol-93:VC volume ratio], and the second elution part was collected. After removing the solvent in the eluate, the remaining syrup of 2',3'-O-isopropylidene-N6-thiasilidinoadenosine was dissolved in 50% acetic acid (50 mj+), and then dissolved in permanganic acid on a water bath. 1.2 g of potassium was added, and the mixture was stirred and reacted for 10 minutes. A 35% hydrogen peroxide solution was added to the reaction mixture thus obtained to decolorize it to obtain a transparent solution. This solution was extracted with chloroform, and the organic layer was extracted with MgSO.
It was dried at step 4. After the solvent was distilled off, 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 resulting syrup of 2',3'-〇-isopropylidene-N6-(thiacilisino-3,3-dioxo)adenosine was dissolved in 50 mj2 of 70% formic acid, and the mixture was dissolved at room temperature. The container was sealed and left overnight. After evaporating the solvent, methanol is added to the residue to obtain a suspension. This suspension was added with ammonia in a water bath.
A clear solution was obtained by adding approximately 30 mA of methanol solution. Next, when this solution was stirred for 40 minutes, crystals precipitated and were collected by filtration. Next, the crystals were recrystallized from water to form colorless needle crystals, melting point: 16.
2-164°C, yield: 0.65g (yield: 60%). This obtained crystal is the N6- (
The following physical constants matched those of thiasilicino (3,3-dioxo)adenosine, and as a result of the mixing test, no decrease in the melting point was observed. Physical constant a) Ultraviolet absorption spectrum UVλ, Px'nm (g); 273 (25500
), 266 (25000), 257 (23600
), 250 (18000). ) Nuclear magnetic resonance spectrum (dimethyl sulfoxide)
d6) δppm; 3.39-3.60 (2H1 multiplet, 5'-H), 4.11 (IH. broad singlet, 4'-H), 4.23-
4.32 (LH, multiplet, 3'-H), 4.4
4-4.76 (3H, multiplet, 2'HO, J=6Hz, 1'-H), 8.33 (
IH, singlet, 2-H), 8.37 (L
H, singlet, 8-H). +X) Elemental analysis value: C+sH+? Ns Oh S
As, the theoretical value...C: 42.05, I(: 4.61
, N: 18.86 Actual value...C: 42.21, H: 4.79, N: 18
．． 95 N6-thiomorpholino-4,4-dioxo)adenosine [192-194
°C (melting), 200-202 °C (solidification), 214-2
15°C (dissolution)]. Example 5 a) 1 g of N''-hebutamethyleneiminoadenosine obtained in Example 3 was added to a mixed solution of 20 mff of acetic anhydride and 20 mff of anhydrous pyridine, and the mixture was stirred and reacted at room temperature for 1.5 hours. Next, pyridine on acetic anhydride as a solvent was 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 - 94:6 (volume ratio)], and the first eluate was collected. After removing the solvent in the elution area, the remaining syrup of 2', 3', 5' = 〇-triacetyl-N6-hebutamethyleneiminoadenosine was dissolved in 50% acetic acid, and 1.2 g of it was dissolved in 50% acetic acid. of potassium permanganate was added thereto, and the mixture was stirred and reacted at room temperature for 10 minutes. Next, 35% hydrogen peroxide solution was added to the obtained reaction mixture to decolorize it to obtain a transparent solution.The solution was further extracted with chloroform, and the organic layer 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, chloroform:methanol-95:5
(volume ratio), and the second eluted portion was collected. And, obtained by removing the solvent of such elution part,
2', 3', 5'-0-triacetyl-N'-(1-
A syrup of adenosine (hebutamethyleneiminol-2-one) was dissolved in 50 ml of ammonia-methanol solution, and the solution was sealed and left overnight at -15°C. Then, after distilling off the solvent, the remaining syrup was subjected to silica gel thin layer chromatography [developing solvent, chloroform:methanol = 9:1 (volume ratio)],
The corresponding bands were extracted. After distilling off the solvent, the syrup that gives off a whirlpool is crystallized from hot methanol to give colorless needle-shaped crystals.
Melting point: 135-136°C, yield: 0.15g (yield: 1
2%). Mouth) 1 g of N6-hebutamethyleneiminoadenosine obtained in Example 3 was mixed with 10 mj of acetone! After adding 1 g of 70% perchloric acid solution dropwise over 30 minutes, the solution was stirred at room temperature for 30 minutes.
．． 5 g of sodium hydrogen carbonate was added and stirring was continued for an additional 30 minutes. Next, insoluble matter was filtered from the obtained reaction solution, the filtrate was concentrated to dryness, and the residue was subjected to silica gel column chromatography [developing solvent, chloroform:methanol-93 nia (volume ratio)]. The second eluate was collected. After removing the solvent in the elution area, the remaining 2',3'-0-isopropylidene-N
6-50 hebutamethyleneiminoadenosine syrup
% acetic acid 50rrl! Further, 1.2 g of potassium permanganate was added thereto, and the mixture was stirred and reacted for 20 minutes. Next, 35% hydrogen peroxide solution was added to this reaction mixture,
After decolorization to obtain a clear solution, the solution was extracted with chloroform and dried with MgSO. 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. Then, 2',3'-〇-isopropylidene-N'-(1-hebutamethyleneiminol-2-one)adenosine obtained by removing the solvent in the elution area was dissolved in 50 m# of 70% formic acid. Then, the mixture was left sealed at room temperature overnight. Then add 30% of the solvent
℃ or below, methanol was added to the residue, and further about 2
0 ml of ammonia-methanol solution was added, and the mixture was stirred for 1 hour under water cooling. After distilling off the solvent, the remaining syrup was subjected to silica gel thin layer chromatography [developing solvent,
Chloroborum:methanol-9:1 (volume ratio)] and the corresponding band was extracted. After distilling off the solvent, the remaining cilosop was crystallized from hot methanol to give colorless needle crystals, melting point 135-136°C, yield: 0.2 g (yield: 2
0%) was obtained. The obtained crystals had the following physical constants that matched those of N6-(l-hebutamethyleneiminon-2-one) adenosine obtained by method a) above, and no drop in melting point was observed as a result of the mixing test. . Physical constants a) Ultraviolet absorption spectrum UVλ', R, Qnm (ε); 277 (10700
), 212 (16000). ) Nuclear magnetic resonance spectrum (in chloroform-d3) δppm; 1.40-2.06 (8H, multiplet, 5'-H), 4.14 (3H, multi-H, multiplet, 3'-H) , 4.71
(LH, triplet, 2'-H), 5.98
(I H, doublet, J=6Hz, 1'-H)
, 8.42 (IH, singlet, 2-H), 8.
66 (IH, singlet, 8-H). c) Elemental analysis value: C+tHz3Ns Os ・1
/ 4 CHCβ3 ・1/4H, O, theoretical value...C: 50.32, H: 5.81, N: 1
7.01 Actual measurement value...C: 50.03, H: 6.01, N: 16
．． 92 Example 6 Using spontaneously hypertensive rats, the compound of the present invention: N6-
The antihypertensive effect of Jl-converted adenosine derivatives was tested. The results of the blood pressure lowering effect obtained are shown in Table 2 below. The test consisted of one group of 5 people with a blood pressure of 19011 IHg.
Place the animal in a preheated box at 60°C for 3 to 4 days.
After heating for minutes, blood pressure was measured non-invasively using a 7) foot artery pressure and pulse measuring device (Natsume Seisaku Shiki). In addition, blood pressure was measured before administration and 1 hour after administration.
A significance test was conducted for each control group. Furthermore, the blood pressure value 1 hour after administration of the sample was 180 ++n
An all-independent reaction (all
or none response), the effectiveness rate was determined. The sample has a dosage of 0.1 ml/1
Distilled water for injection or 0°2 to 00g (body weight)
% CM C-Na and administered intraperitoneally. .

Claims (25)

[Claims] (1) General formula below; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is >NR, -S-, -SO_2-, or -CH_2-, and Y is -CH_2-, or >C=
O, and n is an integer of 0 to 4 (however, R is a linear or branched alkyl group having 1 to 10 carbon atoms, and a monosubstituted hydroxyl group having 1 to 4 carbon atoms. an alkyl group, an alkenyl group having 3 to 6 carbon atoms, or a benzene derivative group substituted with a halogen, a halogenated lower alkyl group, a lower acyl group, or a lower alkylene dioxy group)], the 6-position amino group Adenosine derivatives substituted with an alicyclic amino group and sugar moiety adducts thereof. (2) X in the general formula is >N-R, and Y is -CH
_2-, and n is 1 (however, R has 1 to 1 carbon atoms
0 linear or branched alkyl groups, 1 carbon number
2. The compound according to claim 1, wherein the alicyclic amino group is a piperazine derivative group (representing an alkyl group monosubstituted with a hydroxyl group or an alkenyl group having 3 to 6 carbon atoms). (3) The piperazine derivative group, as R, is a methyl group, ethyl group, n-propyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, hydroxy The compound according to claim 2, which has an ethyl group, a hydroxypropyl group, an n-allyl group, or an isopentenyl group. (4) X in the general formula is >N-R, and Y is -CH
_2-, and n is 1 (wherein R represents a benzene derivative group substituted with a halogen, a halogenated lower alkyl group, a lower acyl group, or a lower alkylene dioxy group); The compound according to claim 1, having the formula amino group. (5) In the piperazine derivative group, R is an orthochlorophenyl group, a metachlorophenyl group, a parachlorophenyl group, a metafluorophenyl group, a metatrifluoromethylphenyl group, a 3,4-methylenedioxyphenyl group,
or Claim 4 having an acetylphenyl group
Compounds described in Section. (6) The compound according to claim 1, wherein X in the general formula is -S- or -SO_2-, Y is -CH_2=, and n is 0 or 1. (7) The compound according to claim 6, wherein the alicyclic amino group has a thiazolidine, thiomorpholine, dioxothiazolidine, or dioxothiomorpholine skeleton. (8) X in the general formula is -CH_2-, and Y is -
The compound according to claim 1, which is CH_2- and n is 3 or 4. (9) The compound according to claim 8, wherein the alicyclic amino group has a hexahydroazepine or heptamethyleneimine skeleton. (10) The compound according to claim 1, wherein X in the general formula is -CH_2-, Y is >C=O, and n is 3 or 4. (11) The compound according to claim 10, wherein the alicyclic amino group has a hexahydroazepin-2-one or heptamethyleneimin-2-one skeleton. (12) The compound according to any one of claims 1 to 11, wherein the sugar adduct is a triacetyl sugar, tribenzoyl sugar, or isopropylidene sugar. (13) 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. ▼ (In the formula, X_1 is >NR, -S-, or -CH_2
-, Y_1 is -CH_2-, and n is an integer of 0 to 4 (However, R is a linear or branched alkyl group having 1 to 10 carbon atoms, and represents an alkyl group monosubstituted with a hydroxyl group, an alkenyl group having 3 to 6 carbon atoms, or a benzene derivative group substituted with a halogen, a halogenated lower alkyl group, a lower acyl group, or a lower alkylenedioxy group)] 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 represented by the formula (wherein X_1, Y_1 and n each have the same meanings as above) or a sugar moiety adduct thereof. (14) using the alicyclic secondary amine in an equimolar to twice molar amount relative to the 6-halogeninoinosine;
14. The production method according to claim 13, wherein the reaction is carried out at room temperature or at the boiling temperature of the solvent in the presence of a polar high-boiling solvent such as dimethylformamide or methyl cellosolve. (15) 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. ▼ (In the formula, Y_1 is -CH_2- and m is 0 or 1) is reacted with an alicyclic secondary amine to form the following general formula; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Y_1 and m each have the same meaning as above) is produced, and then this N^6-substituted adenosine derivative is protected with a protecting group for the hydroxyl group of the sugar moiety. The following general formula consists of reacting with potassium permanganate under the same conditions, followed by acid or alkali treatment as necessary; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, m has the same meaning as above) A method for producing a N^6-substituted adenosine derivative or a sugar moiety adduct thereof. (16) The production method according to claim 15, 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. (17) 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, 17. The production method according to claim 15 or 16, 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. (18) 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. ▼ (In the formula, X_2 is -CH_2-, Y_2 is -CH
_2-, and p is 3 or 4) is reacted with an alicyclic secondary amine represented by the following general formula: ▲Mathematical formula, chemical formula, table, etc.▼ p has the same meaning as above) is produced, and then this N^6-substituted adenosine derivative is subjected to peroxidation in a state in which the hydroxyl group of the sugar moiety is protected with a protecting group. React with potassium manganate, and then,
The following general formula, which consists of acid or alkali treatment as necessary; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, X_2 and p each have the same meaning as above) N^6 - A method for producing a substituted adenosine derivative or a sugar moiety adduct thereof. (19) The production method according to claim 18, 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. (20) Using 2 to 3 times the mole of the potassium permanganate relative to the hydroxyl group of the sugar moiety of the N^6-substituted adenosine derivative, and in the presence of 50% acetic acid as a solvent, 20. The production method according to claim 18 or 19, 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. (21) The following general formula; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is >NR, -S-, -SO_2- or -
CH_2-, Y is -CH_2- or >C=O, and n is an integer from 0 to 4 (however, R is a carbon number of 1
~10 linear or branched alkyl groups, alkyl groups having 1 to 4 carbon atoms and monosubstituted with a hydroxyl group, alkenyl groups having 3 to 6 carbon atoms, or halogen, halogenated lower alkyl groups, (represents a benzene derivative group substituted with a lower acyl group or lower alkylenedioxy group)
An antihypertensive drug containing as an active ingredient an N^6-substituted adenosine derivative or a sugar adduct thereof, in which the 6-position amino group is substituted with an alicyclic amino group. (22) The N^6-substituted adenosine derivative has N^6
The antihypertensive drug according to claim 21, which is -(thiomorpholino-4,4-dioxo)adenosine. (23) The N^6-substituted adenosine derivative has N^6
The antihypertensive drug according to claim 21, which is -(N^6-trifluoromethylphenylpiperazino)adenosine. (24) The N^6-substituted adenosine derivative has N^6
The antihypertensive drug according to claim 21, which is -(N'-paraacetophenone piperazino)adenosine. (25) 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 any one of claims 21 to 24, which is a 3'-O-isopropylidene compound.