KR0173436B1 - Silkworm bioactivity regulator - Google Patents

Abstract

The present invention provides a novel 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadienyl] imidazole compound, and a process for preparing the same, Provided are a physiological activity regulating composition of silkworms containing and a method of controlling physiological activity of silkworms.

Unlike the conventional compounds, the compounds of the present invention do not need to be separated from each other because the (E) and (Z) forms all have a physiological activity that can induce tricotylation of silkworms. It is simple and furthermore has higher physiological activity as compared with the conventional compound.

Description

[Name of invention]

Silkworm bioactive modulator

Detailed description of the invention

The present invention relates to a novel compound that changes the physiological activity of silkworms to induce premature transformation and trilates (3 (化), a preparation method thereof, and a method of trimodating silkworms by premature transformation using the same.

Silkworms usually have four sides, but treatment with anti-glaze hormone actives that prematurely ages larvae induces premature metamorphosis, resulting in tricotylation. Then, they dig up the cocoons on the seventh and eighth days of the fourth year.

Although the thickness of cocoon thread produced by the common silkworm (4 면) is about 3 denier (d), high-quality fine silk thread is produced from cocoons produced by treating anti-glaze hormone active material (about 2d or less). ) Can be obtained.

Conventional compounds used to induce tricotton of silkworms are E. Kuwano, R. Takeya and Mo. 1-benzyl-5 [(E) -2,6-dimethyl-1,5-heptadiethyl)] imidazole (KK-42) developed by Eto, which has a high antiglaze effect against silkworms. It is also active in other insects and is expected to be used in the future.

However, although the compound can induce 100% tri-cotton, the minimum concentration required to induce tri-cotton is 20 µg, the yield remains 20% in synthesis, and only geometric isomers (E) have bioactivity. Because of this complex separation process and production costs are very expensive.

The present inventors can induce silkworm tricotyl in lesser amounts than known compounds (ie, have high bioactivity) and are very demanding because both geometric isomers (E) and (Z) are active. Extensive research has been conducted with the aim of providing a novel tri-cotton inducer for silkworms that can omit complex isomer separation processes.

As a result, 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadiee in imidazol compounds having antiglaze hormone activity It has been found that the above object can be achieved for nil] imidazole and the present invention has been completed.

That is, an object of the present invention is to provide a novel imidazole compound represented by the following general formulas (1A) and (1B).

Another object of the present invention is to react a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (5), followed by compound of formula (5) 1- (4-fluorobenzyl)-in the form of a mixture of the compound (E-form) of the following general formula (1A) and the compound (Z-form) of the following general formula (1B) by reacting with the compound of (2) 1- (4-fluorobenzyl) 5-[(E) or (Z) -2,6- characterized by obtaining 5- [2,6-dimethyl-1,5-heptadienyl] imidazole Dimethyl-1,5-heptadienyl] imidazole is provided.

The present invention also provides a method of effectively prematurely transforming silkworms by using the compound (1A), (1B) or a mixture of (1A) and (1B) to trilate the silkworm.

Other objects, features, and applications of the present invention will become apparent to those skilled in the art from the following detailed description.

Hereinafter, the present invention will be described in more detail.

Treatment of silkworms using 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadienyl] imidazole provided according to the invention It can induce almost 100% 3 cotton, and can mass produce fine fine cocoon thread of average 1.75d.

The ratio of the (Z) (formula 1A compound) and (E) (formula 1B compound) obtained by the method of the present invention is in the range of 100: about 85-90. Since all of these geometric isomers have biological activity, there is no need to separate them, and thus, there is an advantage that a complicated separation process can be omitted, and all of them have a higher biological activity than known compounds.

1- (4-Fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadienyl] imidazole of the present invention can be used orally to induce tricotization of silkworms. Alternatively, the silkworm may be administered to the silkworm by various methods such as transdermal administration, but is preferably administered orally.

In addition, it may be formulated and used in the form of a hydrating agent for the purpose of oral administration, and the concentration of the compound of the present invention in the preparation may be about 20% by weight. The types and amounts of other excipients included in the formulation are known in the art and can be readily determined by one skilled in the art.

On the other hand, oral (feeding) treatment method of the hydrating agent of formulated 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadienyl] imidazole Although not particularly limited, it is preferable to spray 2 liters of 500 times 2 liters of silkworms per three-month-long silkworm box, and then spray it on 7 kg of pure mulberry, and then dry it a little and divide it at the time of giving the mulberry three times a day. This eliminates the period corresponding to the latter part of the 5th age, which requires the most labor for breeding labor, which reduces about 50% of the labor force and reduces the mulberry leaf requirements by 40%, thus allowing 1.8 times the amount of sleep in the mulberry field of the same area. The income of farmers can be increased, and the produced cocoon is 1.75d fineness, which can enhance the added value of silk products and can be applied to the production of hybrid silk. The international competitiveness of the silk industry is expected to be strengthened.

Meanwhile, the process for preparing compounds (1A) and (1B) according to the method of the present invention is as follows: First, tosylmethyl isocyanide (TOSMIC) is prepared, and the compound ( 1A) and 1B are prepared.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1

[Production of tosylmethyl isocyanide (TOSMIC) (2)]

Reagents required for TOSMIC synthesis are sodium paratoluate, formic acid, formic acid amide and POCl ₃ , and TOSMIC obtained in this example is a series of reactions using citral, parafluorobenzylamine and t-butylamine, as in Example 2 below. It is used in, and a single step reaction gives a mixture having a ratio of (1A) and (1B) of 100: 87. The yield at this time is 81%, there is a big advantage that does not need to separate the positional isomers.

p-TsNa (26.7g, 0.15mol), 75ml distilled water, 35% formaldehyde (35ml, 0.44mol), formamide (60ml, 1.5ml), formic acid (24g, 0.53mol) heated at 90 ° C for 2 hours do.

Cool it, stir in an ice bath and leave at -20 ° C overnight. The white solid is washed several times with water to give a white solid (mp 106-110 ° C., 45%, 14 g). The resulting tosylmethylformamide (10.7 g, 0.05 mol), 25 mL DME, 10 mL ether, 35 mL triethylamineol was cooled down at 90 DEG C and POCI (5 mL, 8.4 g, 55 mmol) was added to 6 mL of ethylene glycol dimethyl ether. The dissolved solution is slowly added dropwise over 30 minutes and then 15 ml of ice water is added to give a solid. The wet solid is dissolved in 40 ml of benzene at 40 ° C., the water layer is removed, the benzene layer is dried, stirred for 5 minutes at 60 ° C. with activated carbon, and the solid is filtered to obtain 7.5 g (80%) of TOSMIC.

Example 2

[Synthesis of 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadienyl] imidazole]

Place a cooling tube in a 250 ml two-necked flask, add citral (6.02 g, 39.6 mmol), anhydrous methylene chloride, 30 ml of anhydrous magnesium sulfate and 4.76 g of anhydrous magnesium sulfate under a nitrogen atmosphere, and then use a syringe with 4-flow benzylamine (4.70 ml, 41.2 mmol) is dissolved in anhydrous methylene chloride and slowly added dropwise to reflux for about 2 hours. After confirming the reaction by thin layer chromatography, anhydrous magnesium sulfate was filtered off and the solvent was removed under reduced pressure to obtain the above imine compound as a mixture (E), (Z). (8.92g, 34.6mmol, 87%)

Place a cooling tube in a 100 ml two-necked flask, dissolve the imine compound (8.92 g, 34.6 mmol) in 40 ml MeOH, add TOSMIC (10.13 g, 51.9 mmol), and add t-butyl amine (10.9 ml, 103.8 mmol) under a nitrogen atmosphere. ) Is slowly added to the dropping funnel and refluxed for about 3 hours to obtain 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadienyl] imide. Obtains a dazole compound. MeOH was extracted, extracted with ether, washed with brine, ether was removed under reduced pressure, and column separated with ethyl acetate (EA) to obtain (E), (Z) -compound (8.35g, 28.0mmol, 82.4%).

The above compounds do not separate as positional site isomers.

(Z) :( E) = 100: 87

Example 3

In the same manner as in Example 2, except that 4-chlorobenzylamine, 4-methoxybenzylamine or 4-trichlorozmethylbenzyl is used instead of the 4-fluorobenzylamine of Example 2. 16), (19) and (20) were prepared.

Rf of each compound obtained by chromatography with ethyl acetate: ether (1: 2) is as follows;

(11) 0.46

(12) 0.35

(13) 0.33

(14) 0.22

(15) 0.37

(16) 0.27

(19) 0.40

(20) 0.30

Experimental Example 1

KK-42 was percutaneously treated with silkworms of four worms as 13 compounds synthesized in each of the above examples and a control compound. That is, 5 µg of each compound was melted per silkworm and spread on the silkworm chest area with a microsyringe. Twenty animals were reported for one compound, and then spiked 30 minutes after treatment, and then spiked three times a day to observe the breeding progress and to investigate the activity of the three-dive dive. The results are shown in Table 1.

As can be seen from the results of Table 1, the control group and the acetone-only treatment group all entered 4 sides and became 5-year-old silkworms, and the silkworms triangulated by kk-42 showed the highest activity as 75%. . Also, among the compounds synthesized in each example, (15) was 70% and the activity was comparable to kk-42. On the other hand, (1A) and (1B) each exhibited 3% cotton 3%.

Experimental Example 2

Using the formulation shown in Table 2 below, after formulating various concentrations of KK-42 and the compound of the present invention, it was determined that the minimum concentration at which farming and triangulation was achieved 100%.

As a result, KK-42 achieved 100% tri-cotton at a concentration of about 20 μg, while the compound of the present invention achieved 100% tri-cotton at a concentration of about 10 μg.

Accordingly, the compounds of the present invention can be used in amounts of 10-30% by weight per total weight of the composition.

Example 3

The same prescription as in Experimental Example 2 was used, but the preparations were prepared by using 10 μg of each compound shown in Table 3 below, and then orally administered to the 4th-stage silkworm.

Three cotton ratio, the weight of the entire dog, the weight and fineness of the shoulders were measured and the results are shown in Table 3 below.

Among the test compounds, 1A + 1B is a mixture obtained without separating the isomers as obtained in Example 2, and when used as a mixture of 1A + 1B from the results of Table 3, the three-cotton ratio is much higher than the conventional compound KK-42 It is high and also excellent in fineness.

Experimental Example 4

The same formulation as in Experimental Example 2 was used, except that the compound shown in Table 4 below was contained 5 ㎍, and then administered to the three-year-old silkworm by oral and transdermal methods, and the three-masking rate was measured.

The results are shown in Table 4 below.

From the results in Table 4, it can be seen that it is more effective to administer in the form of a mixture of 1A + 1B than orally administered 1A or 1B compound alone, and oral administration than transdermal. Therefore, it is not necessary to separate each of these isomers after obtaining these compounds in the form of a mixture as in Example 2, which is advantageous in terms of cost and manufacturing process and further has excellent advantages in terms of activity.

Experimental Example 5

The same prescription as in Experimental Example 2 was used, except that 3 μg of a mixture of 1A + 1B was administered to the silkworms of 2nd, 3rd, or 4th year by transdermal method, and the percentage of three cotton, the total weight of the dog, Weight and the ratio of the shoulder layer were measured. The results are shown in Table 5 below.

Experimental Example 6

[Formulation of Compound of the Present Invention and Farm Processing Sesumido Kochi Mass Production]

Content of 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1,5-heptadienyl] imidazole using the same prescription as in Experimental Example 2 above Was prepared in an amount of 20% by weight. As shown in Table 2, nearly 100% of the three cottons were induced in the spring season, and the number of days was 19-20 days, which was shortened by more than 5 days. In addition, the production of cocoons (10 boxes), which had an average hardness of about 1.75d (1.12g), was very successful at 223.3kg in spring and 206kg in autumn.

On the other hand, the results of comparing 1A, 1B or 1A + 1B mixtures to silkworms of artificial feed meat and mulberry leaf meat were compared with that of mulberry leaf meat than artificial feed meat and 1A + 1B mixture rather than 1A and 1B alone. The activity of 3 cotton rate was high.

To summarize the above results, in the case of mulberry leaf meat when spraying the mulberry leaf three times a day after spraying the aqueous solution diluted 10-20 ㎍ of the compound of the present invention per silkworm on the 3rd 1-2 days It is expected to be able to produce cocoons of about 2.0d in thickness. In addition, the activity of the trivalent cotton with respect to the compound of the present invention was higher in the autumn than in the spring. In addition, when the time of administering the compound of the present invention is delayed from 3 to 4, high fine thread can be obtained.

Claims (4)

The compound of formula (3) is reacted with the compound of formula (4) to obtain a compound of formula (5), and the compound of formula (5) is then reacted with the compound of formula (2) 1- (4-fluorobenzyl) -5-[-2, in the form of a mixture of a compound of formula (1A) (E-form) and a compound of formula (1B) (Z-form) 1- (4-fluorobenzyl) -5-[(E) or (Z) -2,6-dimethyl-1, characterized in that 6-dimethyl-1,5-heptadienyl] imidazole is obtained. Method for preparing 5-heptadienyl] imidazole. 1- (4-fluorobenzyl) -5-[(E) -2,6-dimethyl-1,5-heptadienyl] imidazole (1A) and 1- (4-fluorobenzyl) -5- [ (Z) -2,6-dimethyl-1,5-heptadienyl] imidazole (1B) containing a mixture of the active ingredient, a bioactive regulator composition for triangulating silkworms. The composition according to claim 2, wherein the mixture of (1A) and (1B) is contained in an amount of 10 to 20% by weight. A method of inducing tricot by premature transformation of silkworms, characterized by orally administering the composition of claim 2 to 3 or 4 silkworms.