KR100646829B1 - Novel adenosine derivative and its salt, process for preparation, pharmaceutical composition comprising the same and use thereof - Google Patents

Abstract

A novel adenosine derivative and its salt, a process for preparation thereof, a pharmaceutical composition comprising the same compound and use thereof are provided to increase production of actinorhodin in Actinomyces including Streptomyces coelicolor present around plants, so that insects around plants are controlled. The adenosine derivative represented by the formula(1) and its salt are provided. The process for preparing the adenosine derivative represented by the formula(1) and its salt comprises the steps of: (1) preparing compounds of the formula(2); (2) preparing compounds of the formula(3); (3) removing a protecting group of nucleoside to prepare compounds of the formula(4); and (4) acetylating the compounds of the formula(4). The pharmaceutical composition comprises the adenosine derivative represented by the formula(1) and its salt as effective ingredients.

Description

Novel adenosine derivative and its salt, process for preparation, pharmaceutical composition comprising the same and use according to novel adenosine derivatives and salts thereof, methods for their preparation, pharmaceutical compositions for antibiotics using them as active ingredients

1 shows a proton nuclear magnetic resonance spectrum of an adenosine derivative having the structure of Formula 1 of the present invention;

Figure 2 is a photograph showing the antibacterial effect of the adenosine derivative of the present invention to increase the production of actinolodine in actinomycetes.

Left: when the adenosine derivative is added;

Right: When the adenosine derivative is not added

The present invention relates to novel adenosine derivatives having the structure of Formula 1 and pharmaceutically acceptable salts thereof, methods for their preparation, pharmaceutical compositions for antibiotics using them as active ingredients, and their use as biological pesticides.

[Formula 1]

It is well known that humanity's food shortages are inevitable because the population grows exponentially and food grows arithmetically. One of the food problems is that pests and humans share food, and without pesticides, food production is reduced by about a quarter. Therefore, the use of pesticides is essential to control pests.

However, most pesticides are chemical pesticides, and most of them are used to control pests directly. In addition, since consumers have a feeling of rejection of chemical pesticides, there are many situations in which it is difficult to actually use chemical pesticides, although the use of pesticides is necessary. Therefore, there is a need for pest control measures by methods other than such chemical pesticides. Specifically, a new control method called biological pesticides will emerge, including pest control by indirect methods not included in existing chemical pesticides, including the case of using the organism itself as a pesticide. Examples include vegetable attractants, plant growth regulators, pheromones, attractants, and repellents.

Actinomycetes, on the other hand, have been reported for decades to produce various kinds of antibiotics as secondary metabolites. In fact, antibiotics such as streptomycin have been found using actinomycetes and have been widely used. Since streptomycin was first discovered in 1944, tetracycline and erythromycin have been found sequentially from actinomycetes.

Streptomyces coelicolor A3 (2) produces two antibiotics, blue actinorhodin and red tripyrrole undecylprodigiosin. For example, the actinodine, the former, changes color depending on its acidity, similar to litmus. That is, it is red in acid and blue in basic. Such actinolodine is reported to have an antimicrobial effect.

The metabolic circuits in which actinolodine is produced in actinomycetes are not known in full, but until now, a series of proteins such as AfsK and AsfR have been known to be involved in the production of actinolodine. Among them, AfsK protein is a kind of kinase composed of 799 amino acids and has an ATP binding domain at its N-terminal region to perform autophosphorylation. This AfsK protein phosphorylates the serine and threonine of the AfsR protein. As a result, the AsfR protein acts as a transcriptional activator of the afsR gene, which is involved in the production of actinorodin. Activate the ORF4 site. Since actinorodin is produced through this series of processes, the overexpression of AfsK protein acting early in the process affects the production of actinolodine. Indeed, it has been reported in the paper that AfsK proteins are overexpressed by signal transduction agents, thereby increasing the production of actinolodine ( J. Bacteriology , 185: 592-600, 2003).

Thus, if the actinomycetes present in the periphery of the plant provide a signaling material to overexpress the AfsK protein, even if the actinorodin is not directly provided, the production of the actinodine is increased to indirectly control the pests around the plant. . In addition, if the signaling material provided at this time is harmless to humans, the toxicity problem of general chemical pesticides can be solved at the same time. Furthermore, if only actinomycetes provide signaling materials, the production of actinolodine can increase the activity of these signaling processes.

The present inventors had studied a bar Streptomyces nose elementary colors (Streptomyces coelicolor) strain as a kind of such Actinomycetes. The actinomycetes are known as microorganisms found around the roots where plants grow, and for the first time, the actinomycetes have been identified.

Therefore, the present inventors have continued to develop biological pesticides, and as a result, investigates that adenosine derivatives can increase the production of antimicrobial substances in microorganisms acting around plants as harmless signaling substances. The adenosine derivatives were synthesized and treated with actinomycetes Streptomyces coelicolor strains to confirm that they increase the production of actinolodine with antimicrobial activity.These adenosine derivatives and their pharmaceutically acceptable salts and these are effective. The present invention has been successfully completed by providing pharmaceutical compositions for antibiotics and their use as biological pesticides.

It is an object of the present invention to provide a novel adenosine derivative having a structure represented by the following formula (1), a pharmaceutically acceptable salt thereof, a method for preparing the same, a pharmaceutical composition for antibiotics having them as an active ingredient, and a use thereof as a biological pesticide.

In order to achieve the above object, the present invention is an adenosine derivative represented by the following formula (1), namely 4-((5- (6-acetoamido-9H-purin-9-yl) -3,4-diacetoxytetra Hydrofuran-2-yl) methylthiobutanoic acid and pharmaceutically acceptable salts thereof.

[Formula 1]

In addition, the present invention is the same process as in Scheme 1 below:

(1) obtaining intermediate compound 2;

(2) obtaining intermediate compound 3;

(3) obtaining the intermediate compound 4 by removing the nucleoside masking group;

(4) provides a method for preparing an adenosine derivative of Chemical Formula 1 comprising acetylating the intermediate compound 4.

Scheme 1

In addition, the present invention provides a pharmaceutical composition for antibiotics using the adenosine derivative and its pharmaceutically acceptable salts as an active ingredient.

The present invention also provides a use of the pharmaceutical composition for antibiotic use as a biological pesticide.

Hereinafter, the present invention will be described in detail.

The present inventors have developed a new compound 4-((5- (6-acetoami) having a structure of Formula 1, which can increase the production of actinolodine from actinomycetes Streptomyce scoelicolor strains to develop biological pesticides. Fig. 9H-Purin-9-yl) -3,4-diacetoxytetrahydrofuran-2-yl) methylthiobutanoic acid was prepared to investigate the signaling effect of this compound, and this material was actinodidine. It has been confirmed that it has the property to increase the production of.

The present invention provides adenosine derivatives of the general formula (1) and pharmaceutically acceptable salts thereof.

[Formula 1]

Preferably, the adenosine derivative of the present invention is 4-((5- (6-acetoamido-9H-purin-9-yl) -3,4-diacetoxytetrahydrofuran- having the structure of Formula 1 2-yl) methylthiobutanoic acid and pharmaceutically acceptable salts thereof.

At this time, examples of the pharmaceutically acceptable salts include inorganic salts such as hydrochloric acid, sulfuric acid and phosphoric acid; Organic salts such as hydroxyl, fumaric acid, maleic acid, neumumic acid, citric acid, tartaric acid and glutamic acid; And acid addition salts.

In addition, the present invention provides a method for preparing the adenosine derivative by the same process as in Scheme 1 below.

Scheme 1

Specifically, the present invention prepares the adenosine derivative of the present invention having the structure of Formula 1 according to the following process as shown in Scheme 1.

(1) Preparation of thionucleoside

As shown in Scheme 1, the thionucleoside represented by Intermediate Compound 2 is dissolved in triphenylphosphine in anhydrous tetrahydrofuran and cooled again, and then added by diisopropyl azodicarboxylate, followed by stirring. After adding and stirring propylidine adenosine, the suspension obtained therefrom is added thioacetic acid dissolved in anhydrous tetrahydrofuran. After the reaction, the solvent is removed and the residue is purified by silica gel column chromatography.

(2) Preparation of methoxycarbonylpropylthionucleoside

As shown in Scheme 1, methoxycarbonylpropylthionucleoside represented by Intermediate Compound 3 was dissolved in the thionucleoside obtained above with methyl-4-brominated butyrate in anhydrous methanol, and then stirred at room temperature with methoxy sodium. Let's do it. After completion of the reaction, the residue was separated by adding dichloromethane and water, the water layer was extracted with dichloromethane, the organic layer was washed with brine, filtered, distilled under reduced pressure, and purified by silica gel column chromatography. At this time the methoxycarbonylpropylthionucleoside is obtained in the form of a free-form foam.

(3) Removal reaction of nucleoside masking group

As shown in Scheme 1, the nucleoside represented by Intermediate Compound 4 is prepared through a reaction to remove nucleoside masking groups. The methoxycarbonylpropylthionucleoside is mixed with the cooled ammonia water, stirred and the solvent is removed by distillation under reduced pressure. The resulting residue is used directly in the next reaction without purification.

Then, the nucleoside compound obtained above was treated with a 1: 1 mixture of formic acid and water, stirred, distilled under reduced pressure to remove the solvent, and then distilled several times by adding anhydrous ethanol to the residue, and from pure Reaction Formula 1, Compound 4 Obtained nucleoside compounds denoted by.

(4) acetylation of nucleosides

As shown in Scheme 1, in the adenosine derivative of the present invention, the nucleoside represented by Intermediate Compound 4 obtained above was dissolved in anhydrous pyridine, stirred with addition of acetic anhydride, and distilled under reduced pressure to remove the solvent. Prepared by purifying water by silica gel column chromatography.

According to the present invention, adenosine derivatives having the structure of Formula 1 are analyzed by proton nuclear magnetic resonance spectra. As a result, a novel substance having the structure of Chemical Formula 1 represented by the chemical molecular formula of 495.5 and C ₂₀ H ₂₅ N ₅ O ₈ S is represented. Confirming that the specific physical properties are investigated as described in the following experimental example.

In addition, the present invention provides a pharmaceutical composition for antibiotics using the adenosine derivative of Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for antibiotics, characterized in that the antibacterial agent to increase the production of actinolodine in actinomycetes.

In addition, the present invention provides a pharmaceutical composition for antibiotics that affects a signaling substance involved in the production of actinolodine.

The present invention also provides, among Streptomyces antibiotic pharmaceutical composition for increasing the production of liquid Martino Rodin of Streptomyces nose elementary colors (Streptomyces coelicolor) strain.

The present invention also provides the use of a novel adenosine derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for antibiotics using the same as a biological pesticide.

The novel adenosine derivatives of the present invention and pharmaceutically acceptable salts thereof and antibiotic compositions containing them as active ingredients can be used independently or as pharmaceutical additives or administered together with pharmaceutically acceptable carriers or excipients according to the application. It may be used in all other forms suitable for the following. Carriers that can be used herein can include extenders, high fiber additives, encapsulating agents, lipids, and the like, examples of which are well known in the art.

In addition, the biological pesticide preparation of the present invention is in the form of a variety of preparations, including adenosine derivatives of Formula 1, pharmaceutically acceptable salts thereof, and antibiotic compositions containing them as active ingredients, that is, liquids, hydrates, powders, granules. , Emulsions and the like. The method of preparation is according to the general methods known in the art.

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are merely to illustrate the present invention, the contents of the present invention is not limited to the following examples.

Example 1: Streptomyces coelicolor Cultivation of Strains

In the present invention, the Streptomyces coelicolor strains were shaken for 3-4 days at 160 rpm at 28 ° C using Luria broth. The strain so cultured was again 0.25 g of potassium sulfate (K ₂ SO ₄ ) per liter; MgCl ₂ .6H ₂ O, 10.12 g; Glucose, 10 g; L-proline, 3 g; Casamino acid, 0.1 g; Trace element solution, 2 ml; Yeast extract, 1 g; TES, 5.73 g; And R4YE agar plate containing CaCl ₂ · 2H ₂ O, 4 g, and cultured, and the acidity of the medium was adjusted to pH 7.2. In addition, the adenosine derivative used in the present invention was adjusted to a concentration of 100 mM, was added when the medium temperature is 50 ~ 60 ℃. Then the Streptomyces strain nose elementary colors on the plate of the produced R4YE agar medium inoculated as described above and incubated at 28 ℃ for 4 days. After the culture, the strain medium is bluish. At this time, the blue part is scraped together with the medium and dissolved in Tris-HCl (pH 7.5) buffer solution, and the cell suspension is sonicated in ice for about 2 minutes. Crushed. Again, sodium hydroxide was added to the cell disruption solution to adjust the acidity to pH 12. The cell lysate was centrifuged at 15,000 rpm for 30 minutes to obtain a clear cell supernatant, and the UV absorbance was measured at 640 nm using this cell supernatant.

As is already known from previous studies, the amount of activinin increased by adding esadenosyl methionine and the absorbance of the control group without adding anything were measured, and the results were measured to determine the solution of the adenosine derivative of the present invention. The antimicrobial effect was determined by calculating the degree of increase of tinorodin activity.

Example 2 Preparation of Adenosine Derivatives of the Invention

The present invention was carried out the following process as shown in Scheme 1 to prepare the adenosine derivative of the present invention having a structure of formula (1).

(1) Preparation of thionucleoside

To prepare a thionucleoside represented by Intermediate Compound 2 in Scheme 1, triphenylphosphine (5.7 g, 21.6 mmol) was dissolved in anhydrous tetrahydrofuran (THF) and cooled to 0 ° C. Diisopropyl azodicarboxylate (4.2 mL, 21.6 mmol) was slowly added dropwise to this solution, stirred for about 30 minutes, and then to 2, 3-isopropylidine adenosine (1, 3.0 g, 9.8 mmol) in the mixture. To the mixture was further stirred for about 10 minutes, and thioacetic acid (1.6 mL, 21.6 mmol) dissolved in anhydrous THF (5 mL) was added dropwise to a yellow suspension, which was stirred at 0 ° C for 1 hour. During this reaction, the yellow suspension is cleared and converted into an orange solution. After this reaction, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography [i.e., CHCl ₃ / THF ( 4: 1 v / v) and intermediate compound 2, which is a thionucleoside covered with CHCl ₃ / CH ₃ OH (9: 1 v / v), is obtained in the form of a pale yellow foam.

(3.5 g, 9.5 mmol, 97%): 1 H NMR (CDCl ₃ , 400 MHz) d 8.37 (s, 1H), 7.90 (s, 1H), 6.07 (d, J = 2.1 Hz, 1H), 5.72 (br s, 2H), 5.52 (dd, J = 6.4, 2.1 Hz, 1H), 4.98 (dd, J = 6.4, 3.1 Hz, 1H), 4.35 (dt, J = 3.1, 6.9 Hz, 1H), 3.30 (dd , J = 13.8, 7.2 Hz, 1H), 3.19 (dd, J = 13.8, 6.6 Hz, 1H), 2.35 (s, 3H), 1.60 (s, 3H), 1.39 (s, 3H); 13 C NMR (CDCl 3, 100 MHz) d 194.51, 155.57, 155.52, 153.24, 149.29, 140.05, 120.41, 114.56, 90.96, 86.16, 84.23, 83.76, 31.32, 30.57, 27.11, 25.39.

(2) Preparation of methoxycarbonylpropylthionucleoside

To prepare the methoxycarbonylpropylthionucleoside represented by Intermediate Compound 3 in Scheme 1, the thionucleoside (2, 267 mg, 0.73 mmol) obtained above was added to methyl-4-brominated butyrate (199 mg, 1.02 mmol) in anhydrous methanol (15 mL) and then NaOMe (87 mg, 1.61 mmol) was added. The clear solution was stirred at room temperature for about 12 hours, and then the solvent was removed by distillation under reduced pressure. To the resulting residue was added dichloromethane and water to separate the layers, and the water layer was extracted three times (3 × 50 mL) with dichloromethane. The combined organic layers were washed once with brine, and then the remaining water was removed with sodium sulfate, and again filtered and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography [CH ₂ Cl ₂ / CH ₃ OH (9: 1 v / v)] from which intermediate compound 3 (201) which is the methoxycarbonylpropylthionucleoside. Mg, 0.47 mmol, 65%) was obtained in the form of a glass foam.

1 H NMR (CD ₃ OD, 400 MHz) d 8.26 (s, 1H), 8.23 (s, 1H), 6.17 (d, J = 2.3 Hz, 1H), 5.53 (dd, J = 6.4, 2.3 Hz, 1H) , 5.05 (dd, J = 6.3, 3.0 Hz, 1H), 4.33 (td, J = 6.9, 3.0 Hz, 1H), 3.62 (s, 3H), 2.78 (dd, J = 7.2, 3.1 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.3 Hz, 2H), 1.75 (quintet, J = 7.3 Hz, 2H), 1.58 (s, 3H), 1.37 (s, 3H); 13C NMR (CD3OD, 100 MHz) d 175.63, 157.85, 154.47, 150.67, 142.34, 121.06, 115.87, 92.18, 88.72, 85.63, 52.51, 35.38, 33.80, 32.94, 27.83, 26.21, 25.98.

(3) Removal reaction of nucleoside masking group

To prepare a nucleoside represented by Intermediate Compound 4 in Scheme 1, a nucleoside masking reaction was performed as follows. The mixture of nucleoside 3 (161 mg, 0.38 mmol) and cooled aqueous ammonia (3 mL, 33%) was stirred at 0 ° C. for 2 hours and at room temperature for about 12 hours, then the solvent was removed via reduced pressure distillation. It was. The resulting residue was used directly for the next reaction without purification.

1 H NMR (acetone-d6, 400 MHz) d 8.24 (s, 1H), 8.21 (s, 1H), 6.65 (br s, 2H), 6.19 (d, J = 1.9 Hz, 1H), 5.61 (dd, J = 6.2, 1.9 Hz, 1H), 5.12 (dd, J = 6.1, 2.7 Hz, 1H), 4.35-4.31 (m, 1H), 2.90-2.74 (m, 2H), 2.55 (t, J = 7.4 Hz, 2H), 2.23 (t, J = 7.3 Hz, 2H), 1.79 (quintet, J = 7.2 Hz, 2H), 1.56 (s, 3H), 1.37 (s, 3H); C NMR (acetone-d6, 100 MHz) d 174.33, 157.32, 153.80, 150.18, 141.21, 125.78, 114.45, 91.33, 87.80, 84.95, 84.79, 34.71, 34.60, 32.37, 27.42, 26.18, 25.54.

The nucleoside (100 mg, 0.24 mmol) obtained above was then treated with a 1: 1 mixture of formic acid and water, and the resulting mixture was stirred at room temperature for about 19 hours. After distilling off the solvent under reduced pressure, the obtained residue was distilled with anhydrous ethanol about three times to prepare Intermediate Compound 4 (90 mg, 0.24 mmol, 100%) as a pure nucleoside.

1 H NMR (CD ₃ OD, 400 MHz) d 8.35 (s, 1H), 8.24 (s, 1H), 6.03 (d, J = 5.0 Hz, 1H), 4.81 (t, J = 5.1 Hz, 1H), 4.36 (t, J = 5.0 Hz, 1H), 4.23 (q, J = 5.3 Hz, 1H), 3.01 (dd, J = 14.1, 5.5 Hz, 1H), 2.93 (dd, J = 14.1, 6.1 Hz, 1H) , 2.62 (t, J = 7.1 Hz, 2H), 2.30 (t, J = 7.2 Hz, 2H), 1.88 (quintet, J = 7.3 Hz, 2H); 13 C NMR (CD ₃ OD, 100 MHz) d 178.76, 157.72, 154.26, 151.12, 141.85, 129.88, 90.51, 86.16, 75.38, 74.43, 35.62, 34.46, 33.65, 27.13.

(4) acetylation of nucleosides

To prepare the adenosine derivative of the present invention, the nucleoside (50 mg, 0.14 mmol) represented by Intermediate Compound 4 in Scheme 1 obtained above was dissolved in anhydrous pyridine (10 mL), followed by acetic anhydride (0.06 mL, 0.61 mmol). ) Was added at 0 ° C. Again the reaction mixture was stirred at room temperature for about 12 hours and distilled under reduced pressure to remove solvent therefrom. The resulting residue was purified by silica gel column chromatography [CH ₂ Cl ₂ / CH ₃ OH (15: 1 v / v)] to give the adenosine derivative having the structure of Formula 1 of the present invention (37 mg, 0.08 mmol, 55%).

As a result of the analysis of the proton nuclear magnetic resonance spectrum, the separated material was confirmed to be a new material having a structure of Chemical Formula 1 represented by a chemical molecular formula of 495.5 and C ₂₀ H ₂₅ N ₅ O ₈ S. Specific physical properties were examined as in the following experimental example.

Experimental Example 1: Physical property test

(1) solubility test

The adenosine derivatives of the present invention were well dissolved in methanol, ethanol, dimethyl sulfoxide, isopropanol, methylene chloride, ethyl acetate and tetrahydrofuran.

(2) nuclear magnetic resonance spectrum

In order to investigate the nuclear magnetic resonance spectrum of the adenosine derivative of the present invention, it was measured using an Avance 400 (9.4 T) spectrometer of Bruker (Germany), and deuterium methyl alcohol was used as a solvent. As a result, the proton nuclear magnetic resonance spectrum is as shown in Figure 1 summarized as follows.

H-NMR (400 MHz) δ: 8.63-8.61 (br s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 6.16 (d, J = 5.7 Hz, 1H), 6.07 (br s, 1H ), 5.96 (t, J = 5.7 Hz, 1H), 5.61 (dd, J = 5.9, 4.6 Hz, 1H), 4.39 (dd, J = 10.1, 5.6 Hz, 1H), 3.02 (dd, J = 9.0, 5.0 Hz, 1H), 2.97 (dd, J = 14.0, 5.8 Hz, 1H), 2.61 (t, J = 7.3 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.17 (s, 3H) , 2.14 (s, 3H), 2.06 (s, 3H), 1.90 (quintet, J = 7.1, 2H).

Where m, s, and d represent the coupling states as multiplets, singlets, and doublets, respectively, and the numbers in parentheses indicate the coupling constants.

(3) overall structure of the adenosine derivative of formula (1)

All nuclear magnetic resonance spectroscopy used a Bruker Avance 400 spectrometer system (Karlsruhe, Germany) with the temperature set at 298 K. The experiment was carried out by hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR), and deuterium methanol (MeOH-d ₄ ) was used as a solvent. 16 scans were performed at 1 second intervals and 32 K data points were used. The 90 degree pulse was recorded at 9.7 seconds and the spectrum width was set at 3906 Hz. First, hydrogen peak magnetic resonance spectroscopy showed that the two peaks near 8 ppm showed that the compound of the present invention had an adenine ring (8.34 ppm: H8, 8.04 ppm: H2). The chemical shifts of hydrogen corresponding to the 1 ', 2', 3 ', and 4' positions of the ribose ring are found between 4 and 6 ppm, in particular the chemical shifts of the 2 'and 3' positions (6.07, 5.96 ppm, respectively) Compared with this reactant, it could be seen that about 0.5 to 1 ppm was shifted to the left, thus demonstrating that acetylation was performed at the 2 'and 3' sites. In particular, three singlets found near 2 ppm mean that three different acetyl groups have been added and their positions include the N7 nitrogen atoms of the adenine ring in addition to the 2 'and 3' of the ribose identified above. As a result, the adenosine derivative (ADMB) of the present invention has a chemical structure of 4-((5- (6-acetoamido-9H-purin-9-yl) -3,4-diacetoxytetra of Formula 1 above. It was found to be hydrofuran-2-ylmethylthiobutanoic acid.

Experimental Example 2 Investigation of Increased Production of Actinolodine by Adenosine Derivatives of the Present Invention

In the present invention, adenosyl methionine was used as a comparative compound to investigate the degree of increase in the production of actinolodine by a new adenosine derivative. The reason is that adenosyl methionine is already streptomyces Coelicolor This is because the strain is reported to increase the production of actinolodine. The culture solution of the Streptomyces coelicolor strain without addition of the existing adenosyl methionine or the adenosine derivative ADMB of the present invention had a low UV absorbance of 0.041, whereas the streptomyces with 2 μM of the adenosylmethionine was added. Coelicolor The culture medium of the strain had an absorbance of 0.089, and the culture solution to which 2 μM of the adenosine derivative of the present invention was added was measured to have an absorbance of 0.095, respectively. This result indicates that the addition of adenosine methionine produces 2.17 times more actinordine, and the addition of the adenosine derivative of the present invention produces 2.32 times more actinordine.

In addition, as shown in Figure 2, when the adenosine derivative of the present invention is not added, the growth state of the Streptomyces coelicolor is more than the blue color in the case of adding it, compared to only part of the blue color in the flat medium I could see the worse. This difference seemed to distinguish UV absorbance. In conclusion, the adenosine derivatives of the present invention, namely 4-((5- (6-acetoamido-9H-purin-9-yl) -3,4-diacetoxytetrahydrofuran-2-ylmethylthiobutano Iksan was confirmed to increase the production of actinolodine in microorganisms, particularly Streptomyces sp .

As described above, the present invention is directed to a novel adenosine derivative having a structure represented by the following formula (1) and a pharmaceutically acceptable salt thereof, a method for preparing the same, a pharmaceutical composition for antibiotics using them as an active ingredient, and their use as a biological pesticide. relates, pharmaceutical compositions containing the adenosine derivative, and it is while the antimicrobial effect of increasing the production of liquid Martino Rodin (actinorhodin) in actinomycetes, including Streptomyces nose elementary colors (Streptomyces coelicolor) strains acting on the surrounding vegetation excellent It is completely harmless to human body and can be widely used as biological pesticide.

Claims (7)

Adenosine derivatives represented by the following formula (1) and pharmaceutically acceptable salts thereof. [Formula 1]

The method of claim 1, Preferably 4-((5- (6-acetoamido-9H-purin-9-yl) -3,4-diacetoxytetrahydrofuran-2-yl) methylthiobutanoic acid Adenosine derivatives and pharmaceutically acceptable salts thereof. In the same manner as in Scheme 1 below: (1) obtaining intermediate compound 2; (2) obtaining intermediate compound 3; (3) obtaining intermediate compound 4 by removing the nucleoside masking group; (4) A method for producing the adenosine derivative according to claim 1, which comprises the step of acetylating the intermediate compound 4. Scheme 1

A pharmaceutical composition for antibiotics comprising the adenosine derivative of claim 1 and a pharmaceutically acceptable salt thereof. The method of claim 4, wherein Pharmaceutical composition for antibiotics, characterized in that the antimicrobial agent to increase the production of actinorhodin (actinorhodin) in actinomycetes. The method of claim 5, Actinomycetes are Streptomyces Eli nose color (Streptomyces coelicolor ) pharmaceutical composition for antibiotics, characterized in that the strain. Biological pesticide preparation comprising the adenosine derivative of claim 1, the pharmaceutical composition of claim 4 or the adenosine derivative of claim 1 and the pharmaceutical composition of claim 4.

Images