JPH03287536A - Antipruritic agent and zinc picolinate analogue compound - Google Patents

Abstract

PURPOSE:To obtain a fast acting antipruritic agent containing zinc picolinate analogue as a main ingredient and free from side effect and capable of directly acting on itchy place. CONSTITUTION:The aimed compound containing a compound expressed by the formula (R is O, OH, NO2, Cl, COOH, alkoxy or alkyl) as a main ingredient at an amount of 0.1-10.0wt.%, preferably 0.5-3.0wt.%. An agent containing 0.5-10.0wt.% compound expressed by the formula, 10.0-50.0wt.% glycerin, 5.0-40wt.% ethyl alcohol, 5.0-20wt.% glycol and 10-40wt.% water and having pH controlled to 4.0-8.0, especially 5.0-7.0 is preferably used as the above mentioned antipruritic agent. The compound expressed by the formula is preferably administered at an amount of 3-10mg/kg when used as oral medicine and at an amount of 1-3mg/kg when used as injection.

Description

[Detailed description of the invention] Related compounds.

[Industrial Application Field] The present invention relates to an antipruritic agent and a zinc picolinate analog, particularly a novel antipruritic agent containing zinc as an active ingredient, and compounds used therein.

[Prior Art] The skin has the function of protecting the living body from various stimuli from the external environment, but when the body maintenance function loses its balance, skin symptoms such as rough skin and eczema appear.

Most of these skin symptoms have itching, and this itching causes skin pruritus, which can often worsen the symptoms.

The itching caused by such pruritic skin diseases and skin pruritus varies from person to person and ranges from extremely mild to extremely severe. Furthermore, in the case of elderly people, sebum deficiency is observed to varying degrees, and this causes skin pruritus, so urea ointment, zinc chloride ointment, etc., which have a moisturizing effect, are sometimes used.

Furthermore, steroid preparations, antihistamines, crotamiton preparations, and the like have conventionally been widely used as antipruritic agents.

[Problems to be solved by the invention] However, in the medical field, these antipruritic agents are used to treat itching caused by liver diseases, renal failure, malignant tumors, metabolic disorders, etc., and skin conditions such as senile pruritus, for which ring-stopping effects cannot be obtained with these antipruritic agents. Pruritus,
Pruritic skin diseases such as atopic dermatitis, eczema, and measles have become major problems.

These symptoms are often accompanied by strong itching, and the itching can make the symptoms worse if the skin is scratched.
There has been a desire for an antipruritic agent that can provide a sufficient ring-locking effect. Furthermore, steroid preparations, antihistamine preparations, and the like may sometimes cause side effects.

The present invention has been made in view of the problems of the prior art, and its purpose is to provide an antipruritic agent that has no side effects and has immediate effects by directly acting on the itch itself, and a new compound that is an active ingredient thereof.

[Means for Solving the Problem] As a result of intensive research by the present inventors to achieve the above object, they discovered that a unique zinc compound has excellent antipruritic properties and is also excellent in usability. The present invention has now been completed.

In other words, itch receptors exist between the epidermis and dermis of the skin (Modern Medicine J, Vol. 16, No. 11, 46).
~Page 47 (1987, Asahi Shimbun), the skin has a high zinc content, about 20% of the total, and it is especially abundant in the epidermis (
“Zinc and Clinical Practice” Breakfast Bookstore, pages 20-21, 123
Page 1984), it was reported that there is a deep relationship between the skin and zinc metabolism. In addition, hereditary enteric dermatitis (Acrodermatitis), which is mainly caused by zinc deficiency.
is enteropathica) or high-calorie infusions (parenteral nutrition), and it has been reported that these skin rashes can be improved by supplementing with zinc (Zinc and Clinical Research). Breakfast Bookstore, pages 77-97, 1984).

Therefore, the present inventors conducted research focusing on the relationship between zinc and itching. Research on the metabolism of zinc has shown that zinc is absorbed from the duodenum after oral administration, and its chemical form during absorption is chelated zinc, zinc dipicolinate (
Zinc bis[2-pyridinecarboxylate N102
] Nitrin Yon Review Vol. 38 Pages 137-141 19
1980), zinc picolinate and its related compounds were adopted as a form of supplying zinc to living organisms.

That is, the antipruritic agent according to claim 1 of the present application has as a main component a compound represented by the following general formula 1 (in the above formula, R is 10 groups, -OH group, -No2 group, -CI group, - Co○I
4 groups, an alkoxy group, or an alkyl group. ) Further, the antipruritic agent according to claim 2 is characterized in that zinc is retained as a chelate.The antipruritic agent according to claim 3 contains zinc picrate as the chelated zinc, and zinc picolinate is 0.5% zinc picolinate. 5-10.0% by weight, glycerin 5.
0-80% by weight, ethyl alcohol 3.0-50% by weight
, 0.5 to 30% by weight of glycol, 5.0 to 50% by weight of water, and the pH is adjusted to 4.0 to 8.0. It is a zinc picolinate analog compound represented by formula 2.

The invention according to claim 7 is a zinc picolinate analog compound represented by the following structural formula 5.

The invention according to claim 8 is a zinc picolinate analog compound represented by the following structural formula 6.

The invention according to claim 5 is a zinc picolinate analog compound represented by the following structural formula 3.

The invention according to claim 9 is a zinc picolinate analog compound represented by the following structural formula 7.

The invention according to claim 6 is a zinc picolinate analog compound represented by the following structural formula 4.

The invention according to claim 10 is a zinc picolinate analog compound represented by the following structural formula 8.

The invention according to claim 11 is a zinc picolinate analog compound represented by the following structural formula 9.

The invention according to claim 15 is a zinc picolinate analog compound represented by the following structural formula 13.

The invention according to claim 12 is a zinc picolinate analog compound represented by the following structural formula 10.

The invention according to claim 16 is a zinc picolinate analog compound represented by the following structural formula 14.

The invention according to claim 13 is a zinc picolinate analog compound represented by the following structural formula 11.

The invention according to claim 17 is a zinc picolinate analog compound represented by the following structural formula 15.

The fourteenth aspect of the invention is a zinc picolinate analog compound represented by the following structural formula 12.

The invention according to claim 18 is a zinc picolinate analog compound represented by the following structural formula 16.

The invention according to claim 19 is a zinc picolinate analog compound represented by the following structural formula 17.

The invention according to claim 20 is a zinc picolinate analog compound represented by the following structural formula 18.

Hereinafter, the configuration of the present invention will be explained in detail.

Zinc picolinate is a known substance that is formed when zinc is absorbed in living organisms, and a method for synthesizing the hydrate represented by the following formula has been reported (Journal of Thermal Analysis Vol. 30, 353-363). page 19
1985).

The invention according to claim 21 is a zinc picolinate analog compound represented by the following structural formula 19.

The invention according to claim 22 is a zinc picolinate analog compound represented by the following structural formula 20.

Further, in the antipruritic agent of the present invention, the amount of zinc picolinate or its related compounds is generally 0.001 to 10.0% by weight, preferably 0.5 to 3.0% by weight.

If the amount of zinc picrate etc. is too small, it is easy to formulate, but the antipruritic effect is poor, so it is not preferable.If it is too large, it is necessary to use a large amount of glycerin or ethyl alcohol to dissolve the zinc picolinate. This is not preferable because it impairs pharmaceutical stability and usability.

When the amount of zinc picrate or the like is 0.5% by weight or less, it is soluble in water and can be used as an external preparation or an injectable drug by directly dissolving in water.

However, if zinc picrate or the like exceeds 0.5% by weight, it cannot be dissolved in water as it is, so it is necessary to dissolve it together with glycerin, ethyl alcohol, glycol, water, etc.

Here, when blending glycerin, the blending amount is generally 5.0 to 80% by weight, preferably 10.0 to 50.0% by weight.

If the amount of glycerin blended is too small, zinc picolinate etc. cannot be dissolved, which is undesirable. On the other hand, if it is too large, usability is significantly impaired, which is not preferable.

Instead of glycerin, polyglycerin such as diglycerin can be used alone or in combination with glycerin to dissolve zinc picolinate and the like.

The amount of ethyl alcohol blended in the present invention is 3.0
-50% by weight, preferably 5.0-40% by weight.

If the amount of ethyl alcohol blended is too small, zinc picolinate and the like cannot be dissolved, which is undesirable.On the other hand, if it is too large, skin irritation increases, which is not preferable.

Zinc picolinate can also be dissolved using isopropyl alcohol, acetone, etc. instead of ethyl alcohol. However, from the viewpoint of solubility, ethyl alcohol is preferable.

Glycols that can be used in the present invention include propylene glycol, dipropylene glycol, 13-butylene glycol, hexylene glycol, polyethylene glycol, and the like. These glycols are blended as a solubilizing agent for zinc picolinate, etc., and have a concentration of 0.5 to 30
% by weight, preferably from 5.0 to 20% by weight.

If the amount of glycol is too small, a large amount of glycerin or ethyl alcohol will be added to dissolve zinc picolinate, etc., which is undesirable as it impairs usability and increases skin irritation.On the other hand, if it is too large, picolinate This is not preferable because zinc etc. cannot be dissolved.

In addition, the water added to the antipruritic agent according to the present invention is generally 5%
．． It is 0 to 50% by weight, preferably 10 to 40% by weight.

Zinc picolinate is a biologically derived component contained in breast milk, etc., and exists in the form of a complex, and its solubility is extremely specific.
Stability is greatly influenced by

The long-term stability of the formulation of the present invention is maintained by adjusting the pH to 4.0 to 8.0, preferably 5.0 to 7.0.

In order to prepare a preparation containing zinc picolinate, etc. according to the present invention, in addition to the above-mentioned essential ingredients, antioxidants, preservatives, buffers, polar oils, surfactants, water-soluble polymers, and other drugs are added. It can be blended as desired.

As mentioned above, in order to dissolve more than 0.5% by weight of zinc picolinate, glycerin, ethyl alcohol, glycol, and water are essential ingredients.
When the amount of zinc picolinate is 0.5% by weight or less, the combination of the above components is not necessarily required.

In addition, the present invention also provides pharmaceuticals as external preparations, injection drugs, and internal medicines.
It can be applied not only to quasi-drugs but also to cosmetics and the like.

When the antipruritic agent according to the present invention is used in an antipruritic external skin composition, the amount of zinc picolinate is generally 0.
．． 01 to 10.0% by weight, preferably 0.5 to 3.0% by weight.

In addition, when the external composition according to the present invention is used as a skin external preparation, it contains the usual ingredients that are included in general skin external preparations, such as oil, water, surfactant, humectant, lower alcohol, and alcohol. Adhesives, chelating agents, pigments, preservatives, fragrances, etc. can be added as appropriate.

Furthermore, the term "external skin preparations" as used herein broadly refers to those used on the skin, and includes external medicines such as ointments, facial cosmetics such as lotions, milky lotions, creams, and the like.

Furthermore, the external composition according to the present invention can be used on the head, and can be applied, for example, to hair tonics, scalp emulsions, hair liquids, hair shampoos, hair shampoos, hair creams, hair sprays, etc. can.

When used as an external composition for the head, for example, oily components, ultraviolet absorbers, preservatives, humectants, surfactants, fragrances, water, alcohol, thickeners, colorants, drugs, etc. are added. be able to.

In addition, when using the antipruritic agent of the present invention as an internal medicine,
The dosage of zinc picolinate etc. is preferably 3 to 10a+g/kg live weight.

On the other hand, when the antipruritic agent according to the present invention is used as an injection, the preferred dose is 1 to 3+ng/kg live weight.

When the antipruritic agent according to the present invention is used as an oral preparation or an injection, it may contain ingredients commonly used in general oral preparations or injections, such as excipients such as corn starch, lactose, glucose, and crystalline cellulose, and starch. , binders such as gelatin and gum arabic, disintegrants such as agar, sodium carboxymethyl cellulose, and sodium hydrogen carbonate; lubricants such as magnesium stearate and talc; tonicity agents such as sodium chloride; phosphates and boric acid. Buffers such as, soothing agents such as benzyl alcohol, other additives, solubilizing agents, stabilizers, preservatives, etc. may be appropriately blended as necessary.

In addition to medicines, examples of oral preparations include powders, fine granules, granules, pills, tablets, capsules, liquids for internal use, drinks, etc. for health foods and beverages.

[Effects of the Invention] As explained above, since the antipruritic agent using the compound according to the present invention contains zinc picolinate or its related compounds as an antipruritic ingredient, conventional antipruritic agents are not sufficient to provide sufficient antipruritic effects. It can exhibit excellent antipruritic properties for itching that has not been effective.

The test was carried out by suspending it in water.

The results are shown in Table 1 below.

Table 1 [Examples] Hereinafter, preferred embodiments of the present invention will be described. Note that the present invention is not limited to this example. Further, as for zinc picolinate, unless otherwise specified, tetrahydrate is used, and the blending amount is shown in weight %.

Motoki Kamesho First, the toxicity of the antipruritic agent according to the present invention was investigated.

Healthy 5-6 week old rats (Sprague Dowr
Acute toxicity tests were conducted using males and females of the Y strain.

For oral administration, zinc picolinate is suspended in 20% carboxymethyl cellulose, and for subcutaneous administration, zinc picolinate is suspended in 10% carboxymethyl cellulose.As is clear from Table 1 above, when compared with inorganic zinc compounds for both oral and subcutaneous administration, the LD50 It is understood that the value is high and the safety is also high.

, 1. Next, the safety of the antipruritic agent according to the present invention on the skin was investigated.

(1) Skin irritation test A test method according to the FDA method (US Food and Drug Administration Law) was conducted. The test method and evaluation method are as follows.

Eight rabbits weighing 2.3 to 3 kg were used, and their backs were shaved with electric clippers. They were divided into two groups of four, and one group remained intact (Futat 5 with intact skin).
In the other group, an abrasion is made at the test site (paid skin Adraded 5kin) and fixed in a fixator.

0.3 ml of the test substance is applied to the skin using an animal test bandage with a lint cloth 25 mm in diameter. After 24 hours, the bandage is removed, and the degree of erythema and edema is recorded according to the skin reaction criteria. Judgment is made again after another 72 hours.

Evaluation method ■Formation of erythema and derma ・No erythema at all ・Slight erythema ・Clear erythema ・Strong erythema ・Strong erythema with slight moderation ■ Edema formation/No edema O: Very slight edema 1: Slight edema 2: Approximately 1 mm of edema 3: Edema of 1 mm or more 4 intact skin, 2 for 4 paid skin
4. The average value of the evaluation of the formation of erythema and edema after 72 hours is added, and this is divided by the number of animal specimens (4), and the average value is used to indicate the skin irritation score.

The criteria for the skin safety score (average value) are as follows.

Rating less than 2 Slight irritation or almost no irritation Rating 2~
5 Moderate irritation Rating 5 or higher Strong irritation Results are shown in Table 2 below.

It is understood from Table 2 above that the antipruritic agent according to the present invention has extremely low skin irritation.

Next, the antipruritic effect of the antipruritic agent according to the present invention will be explained.

It is thought that histamine is the main cause of itching, but many cases of itching cannot be suppressed with antihistamines, which is a major problem in the medical field.

Therefore, by subcutaneously administering bradykinin or kallikrein to guinea pigs, we created an animal model of pruritus that cannot be suppressed by antihistamines, and confirmed the antipruritic effect of the antipruritic agent according to the present invention.

(1) Model of pruritus caused by bradykinin Using healthy male Hartley guinea pigs, bradykinin, an pruritic substance, was subtly administered to the flank to produce pruritic animals.

The itching behavior was then scored according to the following criteria and expressed as itching activity.

Evaluation method Score ■ Irritated behavior due to itching 1 When the following behavior that is not seen under normal conditions occurs: Scratching the face, ears, etc. with the front paws.

- Move your body.

-Bites the floor or hands.

・Stand on the hind legs.

■Scratch the itchy area on the flank with your mouth or hind legs 2 ■Previous ■
For each group, the above behavior was observed for 20 minutes by three or more people at the same time, and the itching activity (score) was calculated as the average Shinshi standard deviation of the score.
The antipruritic effect is determined by a significant difference test with the vehicle control group using 5student's T test.

■Comparison of antipruritic effects with antihistamine preparations (pre-pruritic administration)
Preventive test) Four healthy male guinea pigs (1 ton, 450 to 600 g) whose hair on the right ventral side was shaved with electric clippers the day before were placed in each group.
They were divided into groups, and one group received only external application solvent (solvent control, Ve
In the other groups, 0.1 ml of each concentration of zinc picolinate preparation and 1% diphenhydramine (antihistamine preparation) were applied externally to the right ventral region.

Immediately after that, apply bradykinin 10 μg 10°1 to the same application site.
ml was administered sarcastically, and the itching activity score (
The average Shinshi standard deviation) was compared and examined.

The results are shown in Table 3 below.

Healthy male guinea pigs (weighing 450~eoo g) whose right ventral region was shaved the day before with electric clippers were divided into 3 groups of 6 animals each.Bradykinin 50 μg 10 was placed on the right ventral region.
．． 05ml was administered sarcastically, and 5 minutes later, one group received only external application solvent (vehicle control);
For the other groups, 0.1 ml each of 1% zinc picolinate preparation and diphenhydramine (antihistamine preparation) was applied topically to the site of bradykinin administration, and the itching activity scores (average Shinshi standard deviation) based on itching behavior were compared. did.

The results are shown in Table 4 below.

*P<0.01 (VS control group) ■Comparison of antipruritic effect with antihistamine preparations (administered after onset of pruritus)
Treatment test) * p < 0.01 (VS control group) ■ Comparison of antipruritic effect with crotamiton preparation Same as in ■
The antipruritic effects of the zinc picolinate preparation and the crotamiton preparation at 1% concentration were compared with respect to the control solvent group using the test method described above.

The results are shown in Table 5 below.

Table 5 0.1011 of each of the preparations of the % zinc sulfate alone group and the 3.17 wt % zinc pyrithione group corresponding to the amount of zinc was applied externally to the right abdominal region. Immediately thereafter, 10 μg of bradykinin (70.1 ml) was subtly administered to the same application site, and the itching activity scores based on itching behavior were compared and examined.

The results are shown in Table 6 below.

Table 6 * P < 0.001 (VS control group) ■ Comparison of antipruritic effect with zinc pyrithione Similar to the previous ■, healthy male guinea pigs (weighing 450 to 600 g) whose right ventral region was shaved with electric clippers the day before. ) were divided into 4 groups of 4 animals each, and one group received only external application solvent (solvent control, Vehicleco
ntrol), the other groups are a mixture group of picric acid amount of 3 wt. % zinc picolinate, 124 wt. % picolinic acid corresponding to the zinc amount and 2.88 wt. % zinc sulfate, and 2 and 88 Weight *1・P<0.01 (VS control group) *2...1.24 wt% picolinic acid + 2.88 wt%
The zinc sulfate mixture group corresponds to the amount of picric acid and zinc contained in 3% by weight of zinc picolinate.

*3...288% by weight zinc sulfate group corresponds to the amount of zinc contained in 3% by weight of zinc picolinate.

*4...3.17% by weight zinc pyrithione group corresponds to the amount of zinc contained in 3% by weight of zinc picolinate.

The above results revealed that zinc picolinate also significantly suppresses bradykinin-induced itching, which cannot be suppressed with the conventional antipruritic agent crotamiton, antihistamines, or zinc pyrithione, which prevents dandruff and itching.

Therefore, it was confirmed that it can be used as a new antipruritic agent that is effective against itching that cannot be suppressed by antihistamines, zinc pyrithione, or the like.

(2) Kallikrein-induced pruritus model Kallikrein is also known as a biological substance that causes pruritus that cannot be suppressed by antihistamines (International Journal of Dermatology Vol. 14, 45)
6-484, 1975) Therefore, we created a model of pruritus that cannot be suppressed by antihistamines by subcutaneously administering kallikrein to guinea pigs, and confirmed the antipruritic effect of the antipruritic agent according to the present invention.

The evaluation method is as described above.

■Antipruritic effect The pruritic model was created using a healthy male guinea pig (weighing 450 to
00g) were divided into 3 groups of 6 animals each.

Then, 10.05 ml of 25 units of Kallikrein (Boehringer Mannheim) was administered subcutaneously to the right ventral region, and 5 minutes later, 1
Group is only topical application solvent (vehicle co
In the other groups, 0.1 ml of each of 001 and 10% by weight zinc picolinate preparations were applied topically to the site of administration of kallikrein, and the itching activity scores (average above standard deviation) based on itching behavior were compared and examined. .

The results are shown in Table 7 below.

Table 8 * P < 0.01 (VS control group) ** P < 0.001 (VS control group) ■Comparison of antipruritic effects with antihistamine preparations and crotamiton preparations Six animals each using the same test method as in ■ Divide into 4 groups.

One group received only topical solvent (vehicle control).

(vehicle control), 3% by weight each for other groups
Diphenhydramine (antihistamine), crotamiton (commercially available antipruritic agent), and zinc picolinate were each applied topically to the site of kallikrein administration (0.1 ml), and the itching activity score (average above standard deviation) was determined based on the itching behavior. A comparative study was conducted.

The results are shown in Table 8 below.

The above results revealed that zinc picolinate also significantly suppresses kallikrein itching, which cannot be suppressed by conventional commercially available antipruritic agents such as crotamiton and antihistamines.

Therefore, it is more clearly suggested that the antipruritic agent according to the present invention is a novel antipruritic agent that is effective against itching that cannot be suppressed by crotamiton, antihistamines, or the like.

(3) Antipruritic effect when used as an internal or injectable preparation Next, the antipruritic effect when the antipruritic agent according to the present invention is used as an internal or injectable preparation will be explained.

Histamine is thought to be the main cause of itching, but many cases of itching cannot be controlled with antihistamines, making it a major problem.

Therefore, by raising young guinea pigs on a zinc-deficient diet for a long period of time, we created an animal model that exhibits frequent itching behavior that cannot be suppressed by antihistamines, and confirmed the antipruritic effect of the antipruritic agent of the present invention. .

Healthy young male Hartley guinea pigs (-group 5
2 to 3 mice) with zinc-deficient diet (Oriental yeast)
Exhibiting animals were obtained by breeding for a week.

The itching behavior was then scored according to the criteria described above and expressed as itching activity.

In the case of oral administration, the drug was administered in solution using a gastric probe. In the case of injection, a catheter was previously implanted chronically in the femoral vein and administered through a catheter inlet filled with anticoagulant heparin sodium solution, which was guided through a subcutaneous tunnel to the back of the neck. Administration was performed once a day for 6 consecutive days, and the test was conducted 1 hour after the final administration.

The results are shown in Table 9 below.

**P<0.01 (vs. control group) From the above results, animals exhibiting this effect were obtained by being fed a zinc-deficient diet, and diphenhydramine hydrochloride, an antihistamine, had no antipruritic effect on these animals, whereas zinc picolinate did not have an antipruritic effect on these animals. is understood to exhibit excellent antipruritic effects.

Next, the anti-plasmin activity effect when the antipruritic agent according to the present invention is used as an external composition will be explained.

The anti-plasmin activity was determined from the inhibition rate of fibrinolytic ability by plasmin using the fibrin plate method.
Sample amount required for % inhibition (Ice.

mg/ml).

The fibrin plate was prepared according to the method of Warren et al. (Hemostasis Vol. 4, p. 110, 1975), and 100 mg of agarose was prepared with 0.15 M salt. After heating and dissolving in 5 ml of OIM phosphate buffer, the mixture was cooled to 50°C.

10 mg of plasminogen-removed fibrinogen (Daiichi Kagaku Yakuhin) was dissolved in this. Add thrombin solution (100 units/ml, Kawasaki Pharmaceutical Co., Ltd.) to this solution. in+1
Immediately after dropping the
The mixture was poured into water and allowed to cool and solidify. A plasminogen-removed fibrin plate was prepared by making a hole with a diameter of 6 mm in the center.

Measurement of activity inhibition was performed by Ambrus et al.
Volume 32, page 10, 1963), add 0.1 ml of sample solutions of various concentrations to 0.1 ml of the plasmin solution prepared above (0.2 units/ml, Sigma), and shake at 37°C for 30 minutes. After incubation, 20 μm of the fibrin plate was inserted into the holes of the fibrin plate prepared above, and after being left at 37°C for 18 minutes, the lysis area of the fibrin plate was compared with the lysis area of the fibrin plate to which no sample was added, and 50% of the plasmin activity was found. The sample amount (ICs.+mg/ml) required for inhibition was determined.

The results are shown in Table 10 below.

As is clear from Cloth-10, the anti-plasmin activity of zinc picolinate was extremely high compared to tranexamic acid, and no effect was observed on diphenhydramine hydrochloride, an antihistamine.

Thus, it is understood from this experiment that zinc picolinate has excellent antiplasmin activity.

Add it gradually and stir to make a preparation. This antipruritic agent is -5
Stable even after long-term storage at ~40°C. Furthermore, the antipruritic effect is extremely high as shown in the antipruritic test.

Next, more specific examples will be given and explained.

(1) Zinc picolinate 0.5% (2)
Glycerin 20.0% (3) Propylene glycol 10.0% (4) Ethyl alcohol 5.0% (5) Hydroxypropylcellulose 1.0% (6) Methylvarachen
0.05% (7) Purified water remainder
Production method> Components (1) and (6) are added to components (2) and (4), heated to 40 to 50°C, and stirred and dissolved. On the other hand, after pre-wetting component (5) with component (3) and adding component (7) and dissolving it with stirring, the previously dissolved composition 2
Country (1) Zinc picolinate 1.0% (2
) Isopropyl alcohol 25.0% (3) Polyethylene glycol 30020.0% (4) Glycerin 20.0% (5) Phosphate buffer
Appropriate amount (6) Purified water
Residue production method> Component (1) is added to components (2) and (4) and 40 to 5
After heating to 0° C. and stirring to dissolve, component (3) is added and mixed by stirring.

Component (5) is dissolved in component (6) under stirring, and the mixture is added to the previously prepared solution and stirred to obtain a stable preparation of P)(=5.6).

3 (1) Zinc picolinate 3.0% (2)
Glycerin 40.0% (3) Ethyl alcohol 25.0% (4) 1.3-butylene glycol 10.0% (5) Isopropyl adipate 1.0% (6) Hydroxymethylcellulose 0.3% (7) Purified water Residual Production method> Add component (1) to components (2) and (3), and add 40~
After heating to 50° C. and dissolving with stirring, components (4) and (5) are sequentially added and mixed with stirring. On the other hand, component (6) is replaced by component (7
), the previously prepared components were gradually added and stirred sufficiently to obtain a stable formulation with a pH of 5.50.

(1) Zinc picolinate (2) Glycerin (3) Ethyl alcohol 5.0% 45.0% 30.0% (4) Dipropylene glycol 10.0% (5)
Diethyl adipate 1.0% (6) Purified water Residual manufacturing method> Add component (1) to components (2) and (3) and add 40 to 5
After heating to 0°C and stirring and dissolving, components (4), (5),
(6) was sequentially added and stirred to obtain a stable formulation with a pH of 5.2.

(1) (2) (3) (4) (5) (6) (7) (8) (9) (11) 5 days stop cream cetanol stearate hydrogenated oil silicone KF96A-6 squalane (POE) a. Stearyl ester, glyceryl monosterate, glycerin, zinc picolinate, antioxidant and 2,0% 5,0 5.0 5.0 10,0 2,0 3,0 10.0 5 Preservatives, fragrances Appropriate amount (12) Purified Water Residual Production Method> (1) to (7) and (10) are heated and dissolved at 70°C to prepare an oil phase.

On the other hand, (9) is added to (8) and (11), heated and stirred to dissolve, and then the oil phase is gradually added, treated with a homomixer, and then cooled.

Daizo Ero L Nireni (1) Setanol (2) Hydrogenated oil (3) Stearic acid (4) Squalane (5) Polyoxyethylene (20 mol) Solhytan monolaurate (6) Lyceryl monostearate (7) ) Ethylparaben (8) Fragrance (9) Glycerin (10) Chiffyl glycol 0,5% 1,0 0 3.0 1.0 0 0,15 0.2 10,0 5,0 (11 ) Zinc picolinate 1.0 (1
2) Calfoxyvinyl polymer -1050,3
(13) Triethanolamine 1.0 (1
4) Purified water, residual production method> Dissolve (1) to (8) with stirring at 70°C to prepare an oil phase.

(11) is dissolved in a portion of (9), (10) and (14) to prepare a zinc picolinate phase. On the other hand, (13)
Add and dissolve in most of (14), heat to 70°C to prepare aqueous phase, and gradually add oil phase to this to emulsify (12).
After adding a solution of (14) to a portion of (14), a zinc picolinate phase was added, homomixer treatment was performed, and the mixture was stirred and cooled to obtain a milky lotion.

Kankiwajiji 2 UJL (1) Glycerin (2) Modified ethyl alcohol (3) Polyoxyethylene (60 mol) Hydrogenated castor oil d
eriv 5.0% 15.0 1.0 (4) Zinc picrate 0.3 (5) Fragrance appropriate amount (6) Methylparaben 0.2 (7) Allantoin
0.1 (8) Purified water
Remaining Production Method> At room temperature, stir and dissolve (1), (2), (3), (4), (5), and (6) to prepare an alcohol phase.

After dissolving (7) in (8), the alcohol phase was gradually added while stirring to obtain a homogeneous solution, thereby obtaining a lotion having a skin conditioning effect.

8 Sunscreen (1) Zinc picolinate (2) Glycerin (3) Polyethylene glycol (PEG-400)
) (4) Polyethylene Recall (PEG-600
0) (5) Hydrogenated oil (6) Stearic acid (7) Isobrobyl balmitate 2,5% 35, O 25, O 0 20 0 0 (8) Lyceryl monosterate
3.0(9) Methylparaben
0.2(10) Potassium hydroxide
0.1 (11) Purified water 1
3.2 Manufacturing method> Parts of (1) to (4) and (11) are added and dissolved with stirring at 70°C to prepare a zinc picolinate phase. On the other hand (5
) to (9) were heated to 70°C to adjust the oil phase, and (lO)
was gradually added to (11) and dissolved by heating, and the previously prepared zinc picolinate phase was added, homogenized with a homomixer, stirred and cooled to obtain a sunscreen ointment.

I9 missing (1) diglycerin isostearate (2) water-swellable clay mineral (heku)rai)” (3)
Methylstearylammonium chloride (4) Dimethylborin Roquinsan (5) Liquid paraffin (6) Microcrystalline wax 2, 0% 5 0, 5 0 18, 8 0 (7) Ethylparaben 092 (8) Ion Exchange water 10.0 (9) Glycerin 48.0 (10) Propylene glycol 10.0 (11) Zinc picolinate
2.0 Manufacturing method> After sufficiently swelling the water-swellable clay mineral (2) in ion-exchanged water (8), add the ingredients (9) and <10) in advance.
, (11) was dispersed in a heated solution to form an aqueous phase.

Meanwhile, oil-soluble components (1) and (3) to (7) were heated at about 70°C.
The mixture was mixed and dissolved to form an oil phase.

Then, while stirring the oil phase with a disper, the aqueous phase was gradually added to obtain an emulsified dispersion system, which was then cooled to room temperature to obtain the desired emulsified ointment.

Note that the water-swellable clay mineral (*1) used in this example
is a type of colloidal hydrated aluminum silicate with a three-layer structure, and is generally expressed by the general formula % below. It consists of the montmorillonite group (substituted with (OH) group or fluorine).

LQ (1) Polyoxyalkylene-modified organopolysiloxane (2) Water-swellable clay mineral (smectite) (3)
Stearylsomethylammonium chloribidium (4)
Production method of methylborine (6C3) (5) liquid paraffin (6) ethylparaben (7) ion-exchanged water (8) glycerin (9) zinc picolinate The method was as per Example 9.

The water-swellable clay mineral (*l) is the same as in Example 0% 05255, and the polyoxyalkylene-modified organopolysiloxane (*2) has the structural formulas [A] to [D] on the next page. ].

(Left below) 11 (1) Polyoxyalkylene-modified organopolysiloxane 12 (2) Water-swellable clay mineral 1 (3) Stearylcyclomethylammonium chloride (4) Octatecyltetracyclosiloxane (
5) Dimethylpolysiloxane (6CS) (6) Ethylparaben (7) Glycerin (8) Zinc picolinate Production method> According to Example 9.

In addition, water-swellable clay mineral (*1) Alkylene modified organosiloxane Pursuant to Damage Examples 9 and 10.

, Polyoxy (*2) is 2.0% 1゜10゜15゜67゜3゜12 Hair tonic (1) Denatured ethyl alcohol (2) Propylene glycol (3) Glycerin 65.0% 0 5.0 (4 ) Zinc picrate 0.5 (5) Flavor appropriate amount (6) Polyoxyethylene (60 mol) Hydrogenated castor oil deriv,
1.0(7) Hinokitiol 0.
01(8) Vitamin E Acetate 0.1(9
) Purified water residual production method> After heating and dissolving component (4) in components (1), (2), and (3), components (5), (6), and (7) are added.
, (8) was added and dissolved with stirring, and then component (9) was gradually added while stirring to obtain a hair tonic.

Implementation <- Tablets 100 mg of lactose, 30 mg of corn starch, 80 mg of talc, and 2 mg of magnesium stearate were added to 100 mg of zinc picrate, mixed, and tableted.

In the case of enteric-coated tablets, the tablets were coated with an enteric coating of hydroxypropyl methylcellulose phthalate to produce enteric-coated tablets.

14 Kacellu 50mg of zinc picolinate and 100mg of corn starch.

Add 150 mg of lactose and 1 mg of light anhydrous silicic acid and mix.
It was filled into No. 2 gelatin hard capsules. In the case of enteric-coated capsules, the capsules were provided with an enteric coating of hydroxylpropyl methyl cellulose phthalate to produce enteric-coated capsules.

Add 10 mg of zinc picolinate to 10 m of Japanese Pharmacopoeia physiological saline.
The mixture was dissolved at a ratio of 1:1 and aseptically filtered through a membrane filter. The filtrate was dispensed into sterilized ampoule bottles and sealed.

Next, related compounds that exhibit the same antipruritic effect as zinc picolinate explained above will be explained.

The antipruritic activity was determined as follows.

Two healthy male guinea pigs (weighing 450 to 600 g), each with hair on the right ventral side shaved the day before using electric clippers, were placed in each group.
Divide into groups. Bradykinin 50 μg 10.0 on the right ventral region
After 5 minutes, one group received topical application vehicle only (vehicle control), and the other group received bradykinin (0.1 ml) containing 1% by weight of each compound according to the present invention. It is applied externally to the administration site, and the average score of itching activity based on itching behavior is determined based on the evaluation method described above.

The antipruritic activity was expressed as a percentage of the score relative to the vehicle control group (a smaller value indicates a higher antipruritic effect).

In addition, no inflammation was observed due to external application of each compound.

In addition, each compound could be used to form preparations as shown in the Examples above, and each preparation showed excellent antipruritic effects.

Alkoxypicolinic acid Zinc 3-hydroxypicolinate Antipruritic activity: 58.0 Production method: See Figure 1 Dissolve 3.00 g of 3-hydroxypicolinic acid (commercial product decolorized with activated carbon) in water and heat at 60°C. While stirring, a solution of 2.37 g of zinc acetate dihydrate in 6 liters of water was added dropwise. The mixture was stirred at the same temperature for 30 minutes and left in the refrigerator overnight. The precipitated solid was collected by filtration and recrystallized with aqueous ethanol to obtain 3.30 g of crystals.

(Yield 81.1%) m, p,: 2B4-292°C (decomposition)
IR(KBr): 3300,1650.1
570cm-' Elemental analysis: CztHaN*0
Calculated value as @Zn・2H10 C3B, 17 H3
,2O N 7.42 Analysis value C3B, 1682.95 N 7.23 ■Zinc 3-propoxypicolinate Antipruritic activity: 41.2 Production method: See Figure 2 a. Synthesis of 3-propoxypicolinate propyl ester 3-hydroxypicolinic acid 2.8 g (0.02 mo
l) 3.7 g (0.02 mol) of propyl iodide was dissolved in 30 ml of dimethylformamide, 28 g (0.02 rnol) of anhydrous potassium carbonate was added, and the mixture was heated at 60°C.
The mixture was further heated and stirred at 100° C. for 1 hour. After cooling,
120ml of ice water was added and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was separated using a silica gel column chromatograph (ethyl acetate:hexane=3.7) to obtain 1.00 g of a colorless oily substance. (Yield 22.3%) GC-MS
, M◆223” H-NMR (400MHz); δ1.047(
dt, 6H), δ1.83(m, 4d) (CDCIs
-ds) δ4.10(t, 2H), 64.32(t
, 2H,).

δ7.31 (dd, IH), δ7.35 (dd, LH
) δ8.24 (tid, IH) b, Synthesis of 3-propoxypicolinic acid Dissolve 1.8 g of 3-propoxypicolinic acid propyl ester in 20 ml of methanol, and add 20 ml of 5% sodium hydroxide solution.
1 was added and refluxed for 45 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in 10 ml of water. The pH was adjusted to about 2 with 6N hydrochloric acid, and the mixture was thoroughly extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off and recrystallized from ethyl acetate to obtain a 0.9
2 g of crystals were obtained. (yield 63.0%) m, p,
;117.5-119℃GC-MS
;137 (M”-COx)IR(KBr)
;1850.1700.1575cm""H-NMR
(400MHz); δ0.97 (t, 3H), δ1
．． 72 (m, 2H).

(CDCIs-dt) δ4.03(t, 2H),
67.45 (dd, IHj=4.4, 8.3), 67.
58 (d, LH, J=8.8).

68.13 (d 1) 1. J=4.9) Synthesis of C23-propoxypicolinate zinc 3-propoxypicolinate 0
．． Dissolve 85g (4.7n+mol) in 35ml of water and add 0.52g (2.3n+mol) of zinc acetate dihydrate while stirring.
A solution of 2 ml of water (mmol) dissolved in 2 ml of water was added dropwise. After dropping, the mixture was stirred at room temperature for 60 minutes. The mixture was allowed to stand overnight in the refrigerator, but since no crystals were obtained, it was concentrated under reduced pressure. The precipitated solid was recrystallized with ethanol to obtain 0.50 g of crystals. (Yield 47.6%) m, p, : 186-191.5°C IR (KB
r) ;3425,1650,1620.1560
．． 1360cm-' Elemental analysis: CzsH*oN20
Calculated value as @Zn・2H20 C4B, 72 H5,
00N 6.31 analysis value C48,63H4,94N
6.31 ■ Antipruritic activity of zinc 3-hexyloxypicolinate 5.7 Production method: See Figure 3 a. Synthesis of 3-hexyloxypicolinate hexyl ester 3-hydroxypicolinic acid (commercially available) 2. 80g (20
mmol) and n-hexyl bromide 4.13g (25mm
ol) was mixed with 30 ml of N,N-dimethylformamide, 2.8 g (0.02 mol) of anhydrous potassium carbonate was added, and the mixture was heated and stirred at 100° C. for 4.5 hours. After cooling 6
011[11] was added with ice water and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate:hexane=3 nia) to obtain 2.60 g of a colorless oil. (Yield 40.5%) IR (film); 1735, 1580.11
90cm-'”H-NMR (60Mt(z): 64
．． 03(t, 21(), δ4.37(t, 314)(
CDCLB-d,) δ7.28 (d, 2H, J=
3) 68.20 (t-1ike, IH) b, Synthesis of 3-hexyloxypicolinic acid 2.50 g of 3-hexyloxypicolinic acid hexyl ester
(8.1 mmol) was dissolved in 10 ml of methanol, and 1
10 ml of 0% potassium hydroxide solution was added and the mixture was refluxed for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 30 ml of water. The pH was adjusted to about 2 with 6N hydrochloric acid, and the mixture was thoroughly extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 2.01 g of oil. Since it could not be recrystallized from any solvent, repeated washing with hexane was performed.
0.80 g of oil was obtained. This was used as it was in the next reaction.

IR (film); 3500, 1900.1
720.1575 cm-'c, Synthesis of zinc 3-hexyloxypicolinate 0.57 g of 3-hexyloxypicolinate (2,6 m
Dissolve mol) in 20ml of ethanol and add zinc acetate.
A solution of 0.28 g (1.3 mmol) of hydrate dissolved in 2 ml of water was added dropwise. After dropping, the mixture was stirred at room temperature for 2 hours. Since no crystals were obtained, it was concentrated under reduced pressure.

The precipitated solid was recrystallized from an ethyl acetate-ethanol mixture to obtain 0.04 g of crystals. (Yield 604%) m, p, ; 223-224°C IR (KBr)
;3400.1660.16351600157
0an-' elemental analysis; C1JsaN206Zn4/
2LO Calculated value C55,5686,41N 5.40 Analysis value C55,8286,46N 5.29■ 5-propoxy zinc picolinate antipruritic activity...81.5 Production method>; see Figure 4a, 5-propoxy -Synthesis of α-picoline 5-hydroxy-2-methylpyridine (commercially available) 16.5g (0
, 15 mol), n-propyl bromide 188 g (0,1
5 mol) and anhydrous potassium carbonate8. OOg (0,06
mol) was mixed with 100 ml of acetone and refluxed for 24 hours. The solvent was removed, 100 ml of water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.

k silica gel column chromatography (ethyl acetate:hexane = 1
: After separation in 4), 963 g of oil was obtained. (Yield 42.1%) GC-MS -M+151'H-NMR (400MH,) ・δ1.04(t,
3H), δ1.81 (m, 2H) (CDC1a-d→
δ3.94 (t, 2H), δ7.07 (d, IHJ=
8.1), δ7.14 (dd, IHJ=2.98.8)
, δ8.19 (d, IHJ=2.9) b, Synthesis of 5-propoxypicolinic acid 8.02 g (53 mmol) of 5-propoxy-α-picolinic acid was added to 1
Stir at 40-150℃, selenium dioxide 9.01g
(79 mmol) was added little by little and kept at that temperature for 45 minutes. The reaction product was dissolved in ethyl acetate and extracted with sodium bicarbonate Uranami.

The mixture was adjusted to p)1=2 with hydrochloric acid, extracted with ethyl acetate, and concentrated under reduced pressure to precipitate a solid. Recrystallize from ethyl acetate 1.
32 g of crystals were obtained. (Yield 137%) p GC-MS IR (KBr) 124-125°C 137 (M-CO2) 2450188017301690158055cm- δ0.99 (t, 311), δ1,77 (m, 2H) 6
4.09 (t 2H), 67.49 (dd, IH'J
=2.93.8.79), 68.01(d IH,J
='H-NMR (400MH,) (DMSO-δ6) 8.79), 68.35 (d, IH, J = 2.93) c
, Synthesis of zinc 5-propoxypicolinate 1.20g (6.6mmol) of 5-propoxypicolinate was added to 7g of water.
0.73 g of zinc acetate dihydrate dissolved in 2.5 ml of water (3.3 m (equity))
1) was added and stirred for 1 hour. The obtained white precipitate was collected by filtration and recrystallized from water to obtain 1.38 g of colorless crystals.

(Yield 89.9%) m, p, ; 143.5-144℃ Summer R (KB
r): 3225, 1650, 1590, 157
0.1365cm-'■ Zinc 5-butoxypicolinate Antipruritic activity: 66.2 Production method: See Figure 5a, Synthesis of 5-butoxy-α-picolin 5-hydroxy-2-methylpyridine (commercially available) 11 .0g (0
, 10 mol), n-butyl bromide 13.8 g (01
0 mol) and anhydrous potassium carbonate 6.0 gg (0,04
w+ol) was mixed with 100 ml of acetone and refluxed for 24 hours.

The solvent was removed, 100 ml of water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Silica gel column chromatography (
When separated with ethyl acetate:hexane 1:4), 8.00
g of oil was obtained. (Yield 47.9%) GC-MS; M"165" H-NMR (400MH2); δ0.97 (t, 3
H), 61.49 (m, 2H).

(CDCIs-dt) δ1.7? (m, 2H),
δ2.49 (S, 3H).

δ3.98 (t, 2H), 67.05 (d, IH, J=
8.4), 67.11 (dd, IH, J=2.7,8
．． 6) 68.18 (d, IH, J = 2.9) bl, Synthesis of 5-butoxypicolinic acid Stir 5-butoxy-α-picolinic acid at 140-155°C, add selenium dioxide little by little, and stir. Hold at temperature for 50 minutes. The reaction was dissolved in ethyl acetate and extracted with sodium bicarbonate solution.

When the pH was adjusted to 2 with hydrochloric acid, a solid precipitated out. After decolorizing with activated carbon, it was recrystallized from ethanol to obtain 1.39 g of crystals. (Yield 11.8%) m, p, :9
3. O~94.5℃GC-MS;151 (
M-Cot)IR(KBr) ;3450,25
25.1900.1680.1585°1570cm-
''' H-NMR (400MH!) ; δ0.94 (t
, 3H), δ1.45(m,2)1).

(DMSO-ds) δ1.74 (m, 2H),
64.13(t, 2H) δ7,49(dd, IH, J=
2.69, 8.55).

68.01 (d, IH, J=8.79), δ8.35
d, IH, J = 2.93) c, Synthesis of zinc 5-butoxypicolinate 1.20 g (6.2 mmol) of 5-butoxypicolinate was added to 2 ml of water.
0.68 g of zinc acetate dihydrate dissolved in 2.5 rnl of water (3.1 mr
1101) and stirred for 1 hour. The obtained white precipitate was collected by filtration and recrystallized from water to obtain 0.82 g of colorless crystals. (Yield 54.0%) m, p, : 140.5-144.5°C IR (
KBr) ;3250,1650,1620,15
90.156513.70cm-' Elemental analysis: Calculated value as C2oHsaN*O*Zn・2Hz C49,04H5,76N 5.72 Analysis value C49,285,81N 5.60■ 5-(2-
Zinc ethylhexyloxy) picolinate Antipruritic activity: 60,3 <Production method>: See Figure 6a, 5-(2-ethylhexyloxy)-α-picoline synthesis 5-hydroxy-α-picolin (commercially available) 7. 63g
(70 mmol) and 2-ethylhexyl bromide 13.5 g
(70 mmol) in N,N-dimethylformamide 10
Dissolved in 0ml of anhydrous potassium carbonate 9.66g (7
0 mmol) and stirred at 85 to 95°C for 6 hours. 300 ml of ice water was poured into the mixture, followed by extraction with ethyl acetate, and the resulting oily extract was separated using silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 10.5g of an oily substance. (Yield 67%) IR (KBr);
1560,1260cm-"b, Synthesis of 5-(2-ethylhexyloxy)picolinic acid 5-(2-ethylhexyloxy)-α-picolinic 9,
8 g (44 mmol) was stirred at 140 to 155°C, 7.30 g (66 mmol) of selenium dioxide was added little by little, and the mixture was maintained at that temperature for 1 hour. The reaction product was dissolved in ethyl acetate and concentrated under reduced pressure. After decolorizing with activated carbon, it was dissolved in hexane while heating and cooled to obtain 1.27 g of oil.

(Yield 11.4%) m, p, ; Oil GC-MS +207 M-CO*IR (fi
lm) ;2500,1880.16901580
゜1565cm"""H-NMR(400M)lZ"); δ0.8
7(t, 3H), δ0.90(t, 3) 1) (DMSO
-de) δ1.39 (m, 8H), δ1.7
1<mjH).

δ4.13 (d, 2H), 67.51 (dd, IHJ=
2.93.8.30), δ8.01 (d, IH, J=8
゜79), 68.35 (d, II (, J = 2.93) 5
-Synthesis of zinc (2-ethylhexyloxy)picolinate 5-(2-ethylhexyloxy)picolinate 1.27
g (5.1 mrnol) in 10 ml of ethanol and 0.55 g of zinc acetate dihydrate dissolved in 3 ml of water.
(2.5 mmol) was added and stirred for 1 hour. Since no crystals were obtained, it was concentrated under reduced pressure. The obtained white precipitate was collected by filtration and recrystallized from a water-ethanol mixture to give 1.48
g of solid was obtained. (Yield 981%) m, p, ; 66.0-68.0°C IR (KB
r) +3380.1610,1585,1560
an-' elemental analysis: C25H4ONtOsZn・2
Calculated value as HzO C55,86H7,37N 4.6
5 Analysis value C55,71H7,18N 4.640 ■ Zinc 6-butoxypicolinate Antipruritic activity Near 1.8 Production method: See Figure 7 a Synthesis of 6-butoxy-α-picoline 6-hydroxy 2-methylpyridine (Commercially available) 18.7g (0,17
mol) and n-butyl bromide24. Og (017mol
) was dissolved in 100 ml of N,N-dimethylformamide, 23.0 g (0.17 mol) of potassium carbonate was added, and the mixture was stirred at 90 to 110°C for 8 hours. Ice water 300m
1 and extracted with ethyl acetate, and the obtained oily extract was chromatographed on silica gel column (ethyl acetate; hexane =
7:93) to give 198 g of oil. (Yield 699%) IR (filrn); 1590
．． 1570.1300 cm-'b, Synthesis of 6-butoxy-α-picoline N-oxide 6-Butoxy-α-picoline 19. Og (0,12m
.

1) 23.8 g (0.14 mol) of m-chloroperbenzoic acid was dissolved in 250 ml of diethyl ether and cooled with water.
was added little by little. After being left for 1 hour under water cooling, it was further left to stand at room temperature for several days. After thoroughly extracting the reaction solution with water,
Sodium carbonate was added to pH=11. After extraction with chloroform, the mixture was concentrated under reduced pressure to obtain 11.2 g of the target product.

IR(film) ;1610,1560.150
0.1315cm-”'H-NMR (400M)lz)
;δ0.99(t,3)1),δ1.55(m,2
H) (DMSO-da) δ1.91 (tn, 2
N), δ2,54 (s, 3H) δ4.22(t
, 2) 1), 66.75 (d, LH, J = 830) 66
．． 89 (d, IH, J = 6.35) δ7.10 (t, I
H, J = 8.60) c, 2-acetoxymethyl-
Synthesis of 6-butoxypyridine 60ml of acetic anhydride was stirred at about 120°C, and 6-butoxypyridine was added to it.
A solution of 111 g of butoxy-α-picoline N-oxide in 25 ml of glacial acetic acid was added dropwise over about 1 hour. 13 after dripping
The mixture was stirred at 5°C for 4.5 hours.

Acetic acid and acetic anhydride were removed by vacuum concentration.

The reaction solution was dissolved in ether, and the remaining acetic acid was neutralized with sodium hydrogen carbonate solution. After extraction with ether and concentration under reduced pressure, separation was performed using silica gel column chromatography (ethyl acetate:hexane = 8:92) to obtain 4.89 g of the target product. (
Yield 35.9%) d, Synthesis of 6-butoxy-2hydroxymethylpyridine 2-acetoxymethyl-6-ptoxypyridine 4.89
g (21.9 mmol) was dissolved in 20 ml of ethanol, 20 ml of 8% sodium hydroxide solution was added thereto, and the mixture was refluxed for 1 hour. After removing ethanol under reduced pressure, the residue was extracted with ether and separated using silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 4.29 g of the target product. (yield 100%). Synthesis of 6-butoxypicolinic acid 6
-Ptoxy 2-hydroxymethylpyridine 4.29g
(24 mmol) and 0.2 g of tetra n-butylammonium bromide were dissolved in 25 ml of benzene, and 4.99 g of potassium permanganate (3
A solution of 1 mmol) dissolved in 100 ml of water was added dropwise. After dropping, the mixture was stirred at room temperature for 2 hours.

The filtrate was concentrated to half volume and made alkaline by adding sodium bicarbonate solution. After removing impurities by shaking with chloroform, the pH was adjusted to 2 with concentrated hydrochloric acid. The resulting white precipitate was collected by filtration and recrystallized from hexane to obtain 2.60 g of colorless crystals.

(Yield 56.3%) m, p, : 65.5-66.5°C IR (K
Br) :2575,1680,1585,14
35ctf'' H-NMR (400MHZ');
δ0.93(t, 3H), δ1.43(m, 2H)(
DMSO-di) 61.71 (m, 2H), δ
4.32 (t, 2H).

δ7.01 (d, IHJ=8JO), δ7.64 (d.

IH, J = 7.33), 67.84 (t, IH, J =
8.30, 7.32), 612.9(s, 0.5)1
f, Synthesis of zinc 6-butoxypicolinate Dissolve 1.35 g (6.9 mmol) of 6-butoxypicolinate in 10 ml of ethanol and 0.77 g (3.5 n+mol) of zinc acetate dihydrate dissolved in 2 ml of water. was added and stirred for 90 minutes. Since no crystals were obtained, it was concentrated under reduced pressure. The obtained white precipitate was recrystallized from water to give 0.9
3 g of crystals were obtained. (yield 522%) m, p,
:83.5~85.0℃IR(KBr) ;3
400, 1650, 1630j580, 1375cm-
'Elemental analysis: Calculated value as C*oH2aNzO@Zn・3JO C47, 30H5, 95N 5.52 Analysis value C47, 11H546N 5.48 ■ Zinc 6-hexyloxypicolinate antipruritic activity Near 4. g <Production method>: See Figure 8a, Synthesis of 6-hexyloxy-α-picoline 6-hydroxy-2-methylpyridine (commercially available) 12.0
g (0.11 mol) and n-hexyl bromide 18.2 g
(0.11 mol) with N,N-dimethylformamide 1
15.2 g of potassium carbonate (0,1
1 mol) was added and stirred at 80-90"C for 8 hours. 300 ml of ice water was poured and extracted with ethyl acetate. The obtained oily extract was purified by silica gel column chromatography (ethyl acetate:hexane 1:9). Separation gave 12Ig of oily substance (yield 570%)'H-NMR (400MH
1): 60.90 (t, 3H), δ1.34 (m,
48) (CDCII-di) 61.45 (m, 2
B), 61.76 (m, 2H) 62.43 (s, 3H)
, δ4.25 (t, 2H) 66.50 (d, IH, J
=8.30), 6668(d, IH1J=7.32),
67.43 (t, IHJ = 7.32, 8.06) b, Synthesis of 6-hexyloxy-α-picoline N-oxide 6-hexyloxy-α-picoline 8.60 g (44 m
mol) in 43 ml of acetic acid, and 64 ml of hydrogen peroxide.
m1 was added. The mixture was stirred at 70 to 80°C for 3 hours, 4 ml of hydrogen peroxide was added, and the mixture was stirred at the same temperature for 3 hours. After concentrating to half the volume under reduced pressure, water was added and the mixture was concentrated under reduced pressure (repeated 3 times). 550 g of crude was obtained.

c, Synthesis of 2-acetoxymethyl-6hexyloxydipyridine Acetic anhydride 40! Ill was stirred at about 115°C, and 6-hexyloxy-α-picoline N-oxide 5.
A solution of 50 g of glacial acetic acid in 20 ml was added dropwise over about 1 hour. After dropping, the mixture was stirred at 130°C for 5 hours. Acetic acid and acetic anhydride were removed by vacuum concentration. The reaction solution was dissolved in ether, and the remaining acetic acid was neutralized with sodium hydrogen carbonate solution. After extraction with ether and concentration under reduced pressure, separation was performed using silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 685 g of the target product. (, yield 100%) d,
Synthesis of 6-hexyloxy-2-hydroxymethylpyridine 2-acetoxymethyl-6-hexyloxypyridine 6
．． 85 g (27 mrnol) was dissolved in 20 ml of ethanol, 20 ml of 8% sodium hydroxide solution was added thereto, and the mixture was refluxed for 1 hour. After removing ethanol under reduced pressure, the residue was extracted with ether and separated using silica gel column chromatography (ethyl acetate:hexane=1+3) to obtain 5.13 g of the target product. (
Yield 899%)e, Synthesis of 6-hexyloxypicolinic acid 5.13 g (24 rnmol) of 6-hexyloxy-2-hydroxymethylpyridine and 02 g of tetra-n-butylammonium bromide were dissolved in 25 ml of benzene, and 5-10 While stirring at °C, a solution of 5.20 g (33 mmol) of potassium permanganate dissolved in 100 tnl of water was added dropwise. After dropping, the mixture was stirred at room temperature for 2 hours. The filtrate was concentrated to half volume and made alkaline by adding sodium bicarbonate solution. After removing impurities by shaking with chloroform, the pH was adjusted to 2 with concentrated hydrochloric acid. The resulting white precipitate was collected by filtration and recrystallized from a hexane-ethyl acetate mixture to obtain 2.24 g of colorless needle crystals.

(Yield 40.9%) m, p, +87.0~88.0°C IR (K
Br) ;2575,1680,1590.14
35cm-””H-NMR (400MH,): 0th degree
87 (t, 3H), δ1.36 (rn, 6H) (DMS
O-do) δ1.72 (m, 2H), 4th degree 31st
(t, 2H).

7th ° 01 (d IHj = 8.30) 6763 (d, l
H, J = 7.32), 67.84 (t, 1HJ = 7.
817.33) f, Synthesis of zinc 6-hexyloxypicolinate 1.37 g (6,1 m
Zinc acetate dihydrate 0.68 (3.1 mmol) was dissolved in 20 tnl of ethanol and 2 ml of water.
1) was added and stirred for 90 minutes. Since no crystals were obtained, the mixture was condensed under reduced pressure 2a. The obtained white precipitate was recrystallized from a water-ethanol mixture to obtain 142 g of crystals. (Yield 840%) m, p, ; 77.0-790°C IR (KBr
) ;3400,1645,1635,1580.
1375cm-'Elemental analysis; C24Hs2N206
Calculated value as Zn'2HJ C52,80) 16.65
N 5.13 Analysis value C53,54H6,52N 5.1
5 Alkylpicoline 1 ■ Zinc 3-methylbicolinate Antipruritic activity +65.9 Production method: See Figure 9 a. Synthesis of 2-cyano-3-methylpyridine 3-
Methylpyridine N-oxide 10.9g (OlmoL
) and dimethyl sulfate (12.6 g (0.1 mol)) was heated and stirred at 70-75°C for 2 hours.
A solution prepared by dissolving 1) in 40 ml of water was added dropwise while stirring. After stirring at the same temperature for 1 hour and further at room temperature for 1 hour, 150 ml of water was added and extracted with dichloromethane. After drying with anhydrous sodium sulfate, it was concentrated and subjected to silica gel column chromatography (ethyl acetate:hexane-2, 8-3 nia,
The second time, it was separated at a ratio of 2:8) and recrystallized from hexane to give 2
20 g of colorless solid was obtained. (yield 18.6%) m, p
, :82.5~835℃IR(KBr)
;2210.1560cm-''H-NMR(6
0MHz): 2nd degree 6 (s, 3H), 7th degree 4 (dd
, IH, J=(CDC1a-c!+) 8.5)
, 67.7 (dd, IH, J=8.5) 68.5 (dc
l, IH, J = 5.1)b, Synthesis of 8-methylpicolinic acid 2-cyano-3-methylpyridine 2.0Og (19■
(2) was dissolved in 90% sulfuric acid, heated and stirred at 120°C for 2 hours, and then cooled to 20°C. A solution of 4.00 g of sodium sulfite in 8 ml of water was added dropwise at 20 to 25°C, and at the same temperature
．． The mixture was heated for 5 hours and further heated at 75-85°C for 1.5 hours. After cooling, the pH was adjusted to about 3 by adding sodium carbonate, and the mixture was thoroughly extracted with chloroform. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, 1.38 g of solid was obtained. It was recrystallized from a mixture of ethyl acetate and hexane. (Yield 54.
0%) ■, p, : 115.5-116.5℃
IR(KBr) ;3350,1650.159
0cm-”1, J(-NMR (400MH,); δ2
．． 46 (s, 3H), δ7,47 (dd, IH.

(DMSO-da) J=4.4, 7.8), 67
．． 77 (d, IH, J = 7.8), δ8.46 (d, 1
B, J=4.9) c, Synthesis of zinc 3-methylpicolinate 0.90 g (7 mmol) of 3-methylpicolinate
was dissolved in 10 ml of water, and a solution of 080 g (3.5 mmol) of zinc acetate dihydrate dissolved in 2.5 ml of water was added dropwise while stirring. After dropping, the mixture was stirred at room temperature for 1 hour.

The solid obtained by standing in a refrigerator overnight was collected by filtration and recrystallized from water to obtain 0.68 g of crystals. (Yield 52.2%) Theory/p/IR (KBr) Elemental analysis 1320℃ or higher Unknown: 3000, 1640.1570 mark -1: C*aHs*
Calculated value C47,28H3 as N*OaZn-HgO,
97N 7.88 Analysis value C46, 97H3, 95N 7
．． 72 ■ Synthesis of zinc 3-undecyl picolinate Antipruritic activity Near 0.1 Production method: See Figure 10 a. Synthesis of 3-undecanoylpyridine 3.60 g of magnesium for Grignard reaction in anhydrous ether
was added, and 365 g of 1-bromodecane was added dropwise while stirring. After the magnesium was completely dissolved, a solution of 15.6 g (0.15 mol) of 3-cyanopyridine in diethyl ether was added dropwise, and the mixture was refluxed for 4 hours. After cooling, a saturated ammonium chloride solution was added to separate the diethyl ether layer, and the aqueous layer was further extracted with diethyl ether. The ether layers were combined, washed with water, and then dried over anhydrous sodium sulfate. After vacuum concentration,
Silica gel column chromatography (ethyl acetate:hexane=1
: The product was separated and purified in step 4) to obtain 12.2 g of the target product.

(Yield 32.9%) IR (KBr); 1675, 1580 cm-'
b, Synthesis of 3-n-undecylpyridine 3-n-undecanoylpyridine 12.2g (49@mol), hydrazine monohydrate 7.60g (0.15m).

1), potassium hydroxide 5.60g (0.10mol)
and 50 ml of triethylene glycol at 110 ~
Heat at 125℃ for 1 hour, then heat at 180-185℃ for 6#
It was heated for a while. After cooling, 200 ml of water was added and extracted with diethyl ether, washed with water, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the product was purified by distillation under reduced pressure to obtain 11.0 g of the target product. (Yield/rate 95.6%) bp; 135-136°C IR (film
); 1570cn+-"c, Synthesis of 3-n-undecylpyridine N-oxide 3-n-undecylpyridine 11,0 g (47mm
ol) and 8 ml of 35% hydrogen peroxide solution were dissolved in 30 ml of glacial acetic acid and heated at 70 to 80°C for 3 hours, then 3 ml of hydrogen peroxide was added and heated at the same temperature for 9 hours.

After cooling, the mixture was concentrated under reduced pressure to about half its volume, 50 ml of water was added, and the mixture was similarly concentrated to half its volume (repeated twice). Extracted with diethyl ether and washed with sodium bicarbonate solution. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. Silica gel column chromatography (ethyl acetate-methanol: ethyl acetate = 1
5:85) to obtain 10.2 g of the target product.

(Yield 86.8%) IR (film); 1270 cm-'d,
Synthesis of 2-cyano-3-n-undecylpyridine 3-n-undecylpyridine N-oxide 10.0g
(40rnmol) and triethylamine 8.10g (
Dissolve 80 mmol) in 40 ml of acetonitrile and add 158 g of trimethylsilylalinide while stirring at room temperature.
was dripped. After dropping, the mixture was refluxed for 66 hours and concentrated under reduced pressure, followed by silica gel column chromatography (ethyl acetate:hexane=15:
85), two types A (4,40g) B (4,1
0g) of solid was obtained. From the NMR data, A was determined to be 2-cyano-5-n-undecylpyridine, and B was determined to be the desired 2-cyano-3-n-undecylpyridine. (Yield 388%) m, p, : 59.0-60.0°C IR (K
Br) :2220.1560cm-”1)1-
NMR (60MH,); 60.87 (t, 3) 1)
, 61.1-2.0 (m.

(CDCIs-ds) 18H), δ2.85(t,
2) 1) , δ7.38(ddll(, J=4.8)
, 67.65 (dd, IH, J=28), 68.48 (
dd, IHj = 2.4)e, Synthesis of 3-n-undecylpicolinic acid 380 g (15 tnmol) of 2-cyano-3-n-undecylpyridine was dissolved in 90% sulfuric acid and stirred at 115-125°C for 4 hours. I hung out. 500ml of water
was added, the pH was adjusted to about 3 with sodium carbonate, and the precipitate was filtered and dried. After treatment with activated carbon, 320 g of crystals were obtained by recrystallization from hexane. (Yield 78.4%) ,, p, ;so, o ~ 51.0 °C IR (K
Br)';1655,1595cm-''H-
NMR (400MHz): 60.85 (t, 3H)
, δ1.26 (m, 16).

(DMSO-da) δ1.54(m, 2[(),
62.79 (t, 2H) 67.46 (dd, IH, J=
4.4, 7.8).

67.77 (dd IHJ=1.5, 7.8) 68.4
5 (dd, IH, J = 1.5, 4.4) f, Synthesis of zinc 3-n-undecyl picolinate 2.50 g (9,0 m
mol) in 40n+1 ethanol at 40-50°C, and dissolve 0.99g of zinc acetate dihydrate (4.5mrno
A solution prepared by dissolving 1) in 4 ml of water was added dropwise. After dropping, the mixture was stirred at the same temperature for 2 hours. After adding 40 ml of water and leaving it in the refrigerator, it solidified. This solid was collected by filtration and recrystallized from a water-ethanol mixture to obtain 2.74 g of crystals. (Yield 9
5.5%)! 11.1), :184-186℃ (decomposition)
IR (KBr: 1650, 1575 cm-' Elemental analysis: Calculated value as C3aHsJsO4zn-IH*o C64, 1988, 56N 4.40 Analysis value C64
,28) 18.70 N 4.43■ Zinc 4-methylbicolinate Antipruritic activity Near 4.1 <Production method>: See Figure 11a, Synthesis of 2-cyano-4-methylpyridine 4-
Methylpyridine N-oxide 10.9g (0,1mo
1) and 12.6 g (0.1 mol) of dimethyl sulfate was heated and stirred at 70 to 75°C for 2 hours, and then 126 g (0.2 mol) of potassium cyanide was added to this solution at 10°C or lower.
A solution prepared by dissolving 1) in 40 ml of water was added dropwise while stirring. After stirring at the same temperature for 1 hour and further at room temperature for 1 hour, 150 ml of water was added and extracted with dichloromethane. After drying with anhydrous sodium sulfate, it was concentrated and subjected to silica gel column chromatography (the first time was ethyl acetate:hexane=2.8-3.7.
The 200th fraction was separated at a ratio of 2:8) and recrystallized from hexane to obtain 080 g of a colorless solid.

(Yield 6.78%) m, p, : 84.5-855°C IR (KB
r) ;2240,1595cm-''H-NM
R (400MHz): 62.43 (s, 3H), 67
．． 33 (d, IH (CDC11-d,) J=5)
, 67.50 (s IH), δ8,53 (d, 1) 1j
=5) b, Synthesis of 4-methylbicolinate 2-cyano-4
-0.80 g (68 mmol) of methylpyridine was dissolved in 10.0 g of 90% sulfuric acid, heated and stirred at 120°C for 2 hours, and then cooled to 20°C. Sodium sulfite at 20-25°C4. Add 8 ml of OOg solution dropwise and stir at the same temperature for 1
．． It was heated for 5 hours and then at 75-85°C for 1.5 hours.

After cooling, add sodium carbonate to adjust the pH to about 3.
It was thoroughly extracted with chloroform. After drying over anhydrous sodium sulfate, the residue was concentrated under reduced pressure and recrystallized from a mixture of ethyl acetate and hexane to obtain 0.50 g of crystals.

(Yield 53.8%) m, p,; 127-128°C IR (KB
r) ;3400,3150,2600,215
0,1590°1515an-'” H-NMR (400MHz): δ2.40(S,
3H), δ7.45 (d, IH.

(DMSO-da) J=4,9), 67.8
8 (s, 1B).

δ8.46 (d, IH, J=4.9) Synthesis of zinc 9,4-methylpicolinate 4-methylpicolinate 0.49g (3.6mmol)
was dissolved in 2.5 ml of water, and a solution of 0.40 g (1.8 mmol) of zinc acetate dihydrate dissolved in 1.5 ml of water was added dropwise while stirring. After dropping, the mixture was stirred at room temperature for 1 hour. Since the solid did not precipitate, it was dried under reduced pressure and washed with acetone under heat to obtain 0.50 g of the target zinc compound. Neither water nor ethanol could be recrystallized.

(Yield 79.1%) m, p, : Unknown IR (KBr) above 290°C
:3400,1650,1585.1555cm
-"Elemental analysis: Cs 481 *N104Zn・1
Calculated value C4B as /2H10, 5183.78 N
8.08 Analysis value C49, 18H3, 65N 8.12■
Zinc 4-t-butylpicolinate Antipruritic activity: 63.3 Production method: See Figure 12a, Synthesis of 4-t-butylpyridine N-oxide 4-t-butylpyridine 15.1g (0.0mol)
was dissolved in 200ml of diethyl ether and m-
16.9 g (0.12 mol) of chloroperbenzoic acid were added portionwise. Leave it in the refrigerator for 8 days and at room temperature for 2 days.
Extracted with water. The aqueous solution was made alkaline with sodium carbonate, thoroughly extracted with chloroform, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from isopropyl ether to obtain 900 g of crystals.

(Yield 53.3%) Town, 1)/; 103-104℃ IR (KB
r) ;1484,1240.1185cm-”
'H-NMR (60MH,), 61.33(s, 9H
), δ7.23 (d, 2H, J = (CDC1, -dl)
? ), 68.10 (d, 2H1J=7)b,
Synthesis of 2-cyano-4-t-butylpyridine 4-t-butylpyridine N-oxide 800g (5
3 mmol) and dimethyl sulfate 6.7 g (53 mmol)
) were mixed and stirred at 70-80°C for 3 hours. After cooling,
It was dissolved in 60 ml of ethanol-water mixture. While stirring at a temperature below 10°C, add 6.9 g of potassium cyanide (0,1
1 mol) of water was added dropwise, and further 1 mol of water was added at the same temperature.
The mixture was stirred at room temperature for 1.5 hours.

After adding 200 ml of water and thoroughly extracting with chloroform, drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure.

Separation was performed using silica gel column chromatography (ethyl acetate:hexane = 1:4 for the first time, 1:9 for the second time) to obtain 200 g of an oily substance. (Yield 23.6%) JR (film)
;2240,1590.1540cm-”'H-
NMR (60MH2); δ7.4B (dd, IH, J
= 2.6), 6766 (CDCII-dl) (d
, IN, J=2), δ8.58(d, IH, J=6)c
, Synthesis of 4-t-butylpicolinic acid 170 g (llm
Dissolve mol) in 15g of 90% sulfuric acid at 115-125℃.
The mixture was stirred for 2 hours. Thereafter, 300 g of sodium nitrite and 6 ml of water were added dropwise at 20 to 25°C, and at the same temperature 1.
The mixture was heated and stirred for 5 hours and then at 70 to 80°C for 1.5 hours. After cooling, 50 g of ice water was added, and the pH was adjusted to about 2 with sodium carbonate. The mixture was thoroughly extracted with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Hexane was added to solidify, and the mixture was collected by filtration. Recrystallization from a hexane-isopropyl ether mixture gave 1.30 g of colorless crystals. (Yield 684%) m, p, ; 134-135°C IR (KBr
) :1720.1600cm-'”H-NMR
(60MH,): 67.56 (dd, IH, J=2.
6), 68.30(I)MSO-d6) (d,
IH, J=6), δ8.69 (d, 1) 1. J=6)d
, Synthesis of zinc 4-t-butylpicolinate 4-t-
Butyl picolinic acid 1. Dissolve OOg (5.6 mmol) in 15 ml of water and add zinc acetate while stirring at room temperature.
A solution of 0.61 g (2.8 mmol) of dihydrate dissolved in 2 ml of water was added dropwise. After dropping, heat at 50-60℃ for 30 minutes.
Stir for a minute. After cooling, the obtained solid was collected by filtration and recrystallized from a water-ethanol mixture to obtain 1.13 g of crystals.

(Yield 88.8%) m, p, ; 263°C IR (KBr): 3200, 163516001
545cm-1 elemental analysis: CxoH*4N20aZ
Calculated value C52,4786,16N as n・2H20
6.12 Analysis value C52,47H6,16N 6.07■
Zinc 4-undecylpicolinate antipruritic activity: 64.4 Production method: see Figure 13 a. Synthesis of 4-undecanoylpyridine 1 1 of magnesium for Grignard reaction in 50 ml of anhydrous ether
．． Add 22g of 1-bromodecane and add 11.0g of 1-bromodecane while stirring.
g was added dropwise. After the magnesium was completely dissolved, a solution of 5.20 g (50 mmol) of 3-cyanopyridine in diethyl ether was added dropwise, and the mixture was refluxed for 4 hours.

After cooling, a saturated ammonium chloride solution was added to separate the diethyl ether layer, and the aqueous layer was further extracted with diethyl ether. The ether layers were combined, washed with water, and then dried over anhydrous sodium sulfate. After concentrating under reduced pressure, it was separated and purified using silica gel column chromatography (ethyl acetate:hexane = 1 + 4) to obtain 720%
g target product was obtained. (Yield 583%) m, p, : 51.0-520°C IR (KBr
): 1680.1545cm-'b, 4-n-
Synthesis of undecylpyridine 4-n-undecanoylpyridine 8.50g (34mmol), hydrazine 1
A mixture of 5.55 g of hydrate (0,11+TK)1), 4.14 g (74 mmol) of potassium hydroxide, and 30 ml of triethylene glycol was heated at 110 to 125°C for 1 hour, and further heated to 180 to 185°C. It was heated for 4 hours.

After cooling, 50 ml of water was added and extracted with diethyl ether, washed with water, and dried over anhydrous potassium carbonate. After vacuum concentration,
Purification was performed by vacuum distillation to obtain 640 g of the desired product. (Yield 798%) bp2; 140°C IR (film) 1595cm-'c, 4-n
-Undecylpyridine Synthesis of N-oxide 4-n-Undecylpyridine 6.00g (26mmol
l) and 2.4 ml of 35% hydrogen peroxide solution in 15 ml of glacial acetic acid.
After heating at 70 to 80°C for 2 hours, 2rnl of hydrogen peroxide was further added and heated at the same temperature for 9 hours. After cooling, the mixture was concentrated under reduced pressure to about half its volume, 50 ml of water was added, and the mixture was similarly concentrated to half its volume (repeated twice).

Extracted with diethyl ether and washed with sodium bicarbonate. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure.

The obtained solid was recrystallized from benzene-hexane alpha wave to obtain 600 g of solid.

(Yield 936%) m, p, :50. (1-51,0'CIR(
KBr) ;1230cm-'d 2-cyano-
Synthesis of 4-n-undecylpyridine 4-n-undecylpyridine N-oxide 5.00g
(20 mmol) and triethylamine 4.04 g (4
Dissolve 0 mmol) in 20 ml of acetonitrile and add 7.92 g of trimethylsilylalinide while stirring at room temperature.
was dripped. After dropping, the mixture was refluxed for 22 hours, concentrated under reduced pressure, dissolved in diethyl ether, and washed with saturated sodium bicarbonate solution. After drying with anhydrous sodium sulfate and concentration under reduced pressure, silica gel column chromatography (ethyl acetate:hexane = 1.
9) to obtain 3.95 g of the target product (solidified).

(Yield 76.2%) IR (lcBr); 222G, 1595cm-
Synthesis of e,4-n-undecylpicolinic acid 3°50g of 2-cyano-4-n-undecylpyridine (14nu
Nol) in 40ml of 90% sulfuric acid, 115~12
The mixture was stirred at 5°C for 2 hours. 400 ml of water was added and the pH was adjusted to about 3 with sodium carbonate, and the precipitate was filtered and dried. After activated carbon treatment, recrystallize from ethanol to give 2.90g
crystals were obtained.

(Yield 77.2%) m, p, ; 94.0-94.5°C IR (K
Br) :2400,1900.1700.16
00an-””H-NMR (400MH,); δ0.
85 (t, 3H), δ1.25 (t16H) (DMS
O-ds) δ1.60 (m, 2H), δ2.68
(t, 2H).

67.46 (d, IH, J = 4.9), 67.88 (
s, IH), 6111.56(d, II(, J=
4.9) Synthesis of f,4-n-undecylpicolinate zinc 4-n-undecylpicolinate 2.50g (9,00
Dissolve 1 mol) of zinc acetate dihydrate in 40 ml of ethanol at 40-50°C and add 0.99 g of zinc acetate dihydrate (4,5a+mo
A solution prepared by dissolving 1) in 4 liters of water was added dropwise. After dropping, the mixture was stirred at the same temperature for 2 hours. After adding 40 ml of water and leaving it in the refrigerator, it solidified. This solid was collected by filtration and recrystallized from a water-ethanol mixture to obtain 2.69 g of crystals. (Yield 9
5.1%) m, p, : 129-132℃ (decomposition) IR (
KBr) ;330G, 1650.1600cm-
”Elemental analysis: C3aHs*N*04Zn・1/2H
*Calculated value as 0 C65, 11H8, 52N 4.47
Analysis value C64,86H8,58N 4.60■ Zinc 5-butylpicolinate Antipruritic activity Near 4.6 Production method: See Figure 14 5-n-butylpicolinate 1.70g (9.5mmol)
Dissolve l) in 5 ml of ethanol and add 1.04 g of zinc acetate dihydrate (4.7 m
mol) was dissolved in 5 ml of water, and the solution was added dropwise. After dropping, the mixture was stirred at the same temperature for 30 minutes. Since no crystals were obtained, the mixture was concentrated under reduced pressure, 15 ml of water was added, and the mixture was heated at 70°C to solidify. This solid was collected by filtration and crystallized again with a water-ethanol mixture to obtain crystals of 2.03. (Yield 936
%) m-p・IR (KBr) Original 41 analysis 1142°C; 3500, 1620, 1600, 1570an-':
Calculated value C5 as C*oH*aN*04Zn・2H*O
2,47H6,16N 6.12 Analysis value C52,41H
5,94N 6.07■ Zinc 6-unzosylpicolinate Antipruritic activity: 65.0 Production method: See Figure 15 a. Synthesis of 2-undecanoylpicillin Add 3 parts of magnesium for Grignard reaction to 100 ml of anhydrous ether.
Add 60g of 1-bromodecane and add 36.5g of 1-bromodecane while stirring.
was dripped. After the magnesium was completely dissolved, a solution of 15.6 g (0.15 mol) of 2-cyanopyridine in diethyl ether was added dropwise, and the mixture was refluxed for 7 hours. After cooling, add saturated ammonium chloride solution and separate the diethyl ether layer.
The aqueous layer was further extracted with diethyl ether. The ether layers were combined, washed with water, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was separated and purified using silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 21.6 g of the desired product.

(Yield 583%) IR (film); 1695.1580 cm-'
Synthesis of 1p,2-n-undecylpyridine 21.5g (87mmol) of 2-n-undecanoylpyridine,
Hydrazine monohydrate 13.7g (0,27□□□1
), a mixture of 10.1 g (0.18 mol) of potassium hydroxide and 50 ml of triethylene glycol was added to 110-1
It was heated at 25°C for 1 hour, and further heated at 180-185°C for 7 hours. After cooling, 400 ml of water was added and extracted with diethyl ether, washed with water and dried over anhydrous potassium carbonate.

After concentration under reduced pressure, silica gel column chromatography (ethyl acetate:
Hexane (1:9) was used to separate the product, and the product was further purified by distillation under reduced pressure to obtain 119 g of the desired product. (yield 58.7%)b
p2; 128°C IR (film); 1590cm”c, 2-
n-Undecylpyridine Synthesis of N-oxide 2-n-Undecylpyridine 11.0 g (47 mmo
1) and 8 ml of 35% hydrogen peroxide solution were dissolved in 30 ml of glacial acetic acid and heated at 70 to 80°C for 3 hours, then 3 ml of hydrogen peroxide was added and heated at the same temperature for 9 hours.

After cooling, the mixture was concentrated under reduced pressure to about half its volume, 50 ml of water was added, and the mixture was similarly concentrated to half its volume (repeated twice).

Extracted with diethyl ether and washed with sodium bicarbonate solution. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure.

Silica gel column chromatography (ethyl acetate-methanol:
Separate and purify with ethyl acetate = 15:85) to give 10.7
g target product was obtained.

(Yield 91.0%) m, p, : 45.0-46.0°C IR (KB
r) ;1250cm-'d, 2-cyano-
Synthesis of 6-n-undecylpyridine 2-n-undecylpyridine N-oxide 10.0g
(40 mmol) and triethylamine 8.10 g (8
Dissolve 0 mmo 1 ) in 40 n+1 acetonitrile and dissolve trimethylsilylalinide 15 while stirring at room temperature.
．． 8 g was added dropwise. After dropping, the mixture was refluxed for 67 hours and concentrated under reduced pressure, followed by silica gel column chromatography (ethyl acetate:hexane=
1:9) to obtain 5.40 g of oil. (Yield 521%) IR (film); 2220, 1590 cm-”
'H-NMR (400MH2); 60.9 (t, 3
H), 61.1-2.0 (m, 18 (DMSO-ds)
H), δ2.8 (t, 2B), 67.3 (dd,
IHJ=1.8), 67.6(dd, IH,J=1.5
) 67.7 (t-1ike, LH) Synthesis of e,6-n-undecylpicolinic acid 2-cyano-
6-n-undecylpyridine 400g (15mmol
) was dissolved in 50 g of 90% sulfuric acid and heated at 115-125℃ for 4 hours.
I stirred for hours. 500 ml of water was added, the pH was adjusted to about 3 with sodium carbonate, and the precipitate was filtered and dried. After treatment with activated carbon, it was recrystallized from hexane to obtain 10 g of 3' crystals. (Yield 722%) rn, p, ; 71.5-725°C IR (K
Br) ;1940,1680.1580cm-
'11(-NMR(400MHz):60.85(t
, 38) , 61.24 (m, 16H) (DMSO-
d s ) δ1.67 (m, 2H), δ2.78
(t, 2H), δ7.47(dd, 18.J=2.6.
4) 67.85 (rn, 2H) f, Synthesis of 6-n-undecyl picolinate zinc 6-n-undecyl picolinate 2.50 g (9,0 m
m01) in 40 ml of ethanol at 40-50°C, 0.99 g (4.5 mmol) of zinc acetate dihydrate
A solution prepared by dissolving this in 4rnl of water was added dropwise. After dropping, the mixture was stirred at the same temperature for 2 hours. After adding 40 ml of water and leaving it in the refrigerator, it solidified. This solid was collected by filtration and recrystallized from a water-ethanol mixture to obtain 1.89 g of crystals. (yield 67
．． 8%) m, p, : 198-200℃ IR (KBr)
:3400.1655.1575cm-'Elemental analysis: Calculated value as C3JsJz04Zn-OH20 C66,06) 18.48 N 4.53 Analysis value C66
, 19H8,67N 4.65 Picolinic acid N-oxide Zinc antipruritic activity: 87.1 Manufacturing method> See Figure 16 Picric acid N-oxide 4.50 g (32 mtn
ol) in 120 ml of water was heated, and a solution of 15.0 g (68 mrnol) of zinc acetate dihydrate dissolved in 50 ml of water was added dropwise.

After dropping, the mixture was stirred at 50 to 60°C for 2 hours. 3 in the refrigerator
The solid obtained by standing for 1 day was collected by filtration and recrystallized from water.
．． 30 g of crystals were obtained. (Yield 70.4%) 11, p
, ;223-225℃IR (KBr)
;3260,1615.1590cm-”Elemental analysis: Calculated value as CxJsNtOsZn・2H10 C38,17H3,20N 7.42 Analysis value C38,1
283,15N 7.13 ■ Zinc 4-nitropicolinate Antipruritic activity: 58.3 Manufacturing method: See Figure 17. Synthesis of 2-cyano-4-nitroviridine 4-nitropyridine N-oxide 20.0 g (0,14mo
1) and 18.0 g (0.14 mol) of dimethyl sulfate were mixed, stirred at 65 to 70°C for 2 hours, and solidified when left overnight in a refrigerator. Dissolve in 50ml of water, -7~
14.6 g (0.3 rnof) of sodium cyanide in 100 g of water with vigorous stirring under a nitrogen atmosphere at -8°C.
The m1 solution was added dropwise, and the mixture was further stirred at the same temperature for 7 hours. After standing overnight at room temperature, the precipitate was collected by filtration, washed with water, dried, and recrystallized from isopropyl ether to obtain 4.90 g of yellow crystals. (Yield 230%) Town, p, ;'7o, o ~ 71.0℃ IR (
KBr) :2240,1600.1575cm
-”'H-NMR (60MHz): δ8.23 (dd
,1)1. J=2.6), 6838 (CDCI, -d
i) (d, IH, J=2), 69.03 (d, IH
, J=6) b, Synthesis of 4-nitropicolinic acid 2-cyano-4-nitropyridine 5.00 g (34 m
Mo1) was dissolved in 50 g of 90% sulfuric acid and stirred at 120"C for 2 hours. Thereafter, a solution of 5.60 g of sodium nitrite in 10 ml of water was added dropwise at 20-25°C, and the solution was stirred at the same temperature for 1 hour and then at 80°C. Heat and stir for 1 hour.After cooling, add ice water 1
00g was added and the pH was adjusted to about 2 with sodium carbonate. When left in the refrigerator, a solid precipitated. This solid was collected by filtration and recrystallized from a water-acetone mixture to obtain 3.50 g of pale yellow crystals. (Yield 62.1%) m, p, ; 157-158°C (decomposition) I
R (KBr); 1710, 1600, 1585
．． 1535cm-”'H-NMR (60MH: δ8
．． 33 (dd, IH, J=2.5), 68.50 (D
MSO-d@) (d, IH, J=2), 69.0
7(d, IH, J=5)c, Synthesis of zinc 4-nitropicolinate 2.0*g (12
mmol) in 5 ml of ethanol at 70°C, and 1.30 g (5.9 mmol) of zinc acetate dihydrate was dissolved in 5 ml of water.
ml solution was added dropwise. After dropping, the mixture was stirred at the same temperature for 1 hour. The solid obtained by standing in a refrigerator for 3 days was collected by filtration and recrystallized from water to obtain 205 g of pale yellow crystals. (Yield 792%) m, p, ; 258-269°C IR (KBr)
;3250,1665,1580,1525.1
350cm-1 elemental analysis: C,, H, N, O, Zn
・2) Calculated value C33,09H2,31N as 1.0
12.86 Analysis value C33, 11H2, 27N 12.6
5. Zinc 4-chloropicolinate antipruritic activity: 18.5 Production method: See Figure 18a.
ol) and acetyl chloride 25.0g (0.32m
ol) was stirred at 25° C., the temperature was gradually raised, and the mixture was heated under reflux for 1 hour and 20 minutes (until the generation of No. ceased).

After cooling, the mixture was placed in 200 g of ice, made alkaline by adding sodium carbonate, extracted with chloroform, and dried over anhydrous potassium carbonate.

After concentration under reduced pressure, the obtained solid was recrystallized from acetone to give 4
．． 20 g of solid was obtained.

IR (KBr); 1470.1240cm-”
'H-NMR (60MH; δ7.23(d, IH,
J=7), δ8.1O (CDC1*-dt)
(d, 2H, J = 7) b, Synthesis of 2-cyano-4-chloropyridine 4-chloropyridine N-oxide IO, Og (77 mmol) and dimethyl sulfate 9,80
g (78+++a+ol) was dissolved in 25 ml of anhydrous benzene, and the reaction was carried out at 50 to 60°C for 1 hour. After standing overnight at room temperature, dissolve in 100ml of ethanol-water mixture and add 1
Potassium cyanide 9.80g (0,14
A solution of 20 ml of water (mol) was added dropwise. After the dropwise addition, the mixture was separated for 30 minutes at room temperature, extracted with chloroform, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, silica gel column chromatography (ethyl acetate:chloroform = 1 = 9
．． The second time, the mixture was separated using ethyl acetate:hexane=15+85) and recrystallized from hexane to obtain 4.20 g of solid.

(Yield 39.3%) m, p, :82. (1~83.0℃IR(
KBr) ;2240,1565.1545cm
-'”H-NMR (60MH2); δ7.50 (dd
, IH, J=2.6), 6766 (CDCIs-dx)
(d, 1) 1. J=2), δ8.59(d, LH
”, J=6) Synthesis of C94-chloropicolinic acid 4.00 g of 2-cyano-4-chloropyridine was dissolved in 40 g of 90% sulfuric acid, heated and stirred at 120°C for 2 hours, and then
Cooled to ℃. Sodium sulfite 400 at 20-25℃
A solution of 10g of water in 10ml of
The mixture was heated and stirred at 0°C for 1 hour. After cooling, 100 g of ice water was added, and the pH was adjusted to about 2 with sodium carbonate. The obtained solid was collected by filtration and recrystallized from water to obtain 2.50 g of crystals.

(Yield 54.9%) rr+, p: 184-185°C (decomposition)
IR(KBr) ;1740,1595.157
5cm-'1)! -NMR (60MH2): 67.6
6 (dd, IH, J=2.5), δ803 (DMSO
-ds) (d, IH, J=2) , 68.66(
d, IH, J=5) d, Synthesis of zinc 4-chloropicolinate 1.00 g (6 mmo
1) was dissolved in 115 ml of water at 75°C, and a solution of 070 g (3 mrnol) of zinc acetate dihydrate dissolved in 3 ml of water was added dropwise. After dropping, the mixture was stirred at the same temperature for 30 minutes. The solid obtained by standing in a refrigerator overnight was collected by filtration and recrystallized from water to obtain 114 g of crystals. (Yield 86.4%) m, p IR (KBr) Elemental analysis 238-249°C 3300.1655.15801550cm-”C12
Calculated value C34 as H6N204C12Zn・2H20
,77H2,43N 6.76 analysis value C34,81H2
,25N 6.87 ■ Synthesis of zinc 4-carboxypicolinate m, p IR (KBr) Elemental analysis 300℃ or more unknown; 3340.1690.164016101560cm
-”: Calculated value C as CtaHJzOsZn・2H20
38,78H2,79N 6.46 Analysis value C38,64
H2,49N 6.31

[Brief explanation of drawings]

FIGS. 1 to 19 are explanatory diagrams showing the manufacturing process of zinc picolinate analogues according to the present invention. Antipruritic activity: 66.3 Manufacturability; see Figure 19

Claims (22)

[Claims] (1) An antipruritic agent containing a compound represented by the following general formula 1 as a main component. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...1 (In the above formula, R is -O group, -OH group, -NO_2 group, -C
It is any one of l group, -COOH group, alkoxy group, and alkyl group. ) (2) The antipruritic agent according to claim 1, wherein zinc is retained as a chelate. (3) In the antipruritic agent according to claim 1, zinc picolinate 0.5-10.0% by weight, glycerin 5.0-80% by weight, ethyl alcohol 3.0-50% by weight, glycol 0.5-30% by weight. % by weight, containing 5.0-50% by weight of water, P
An antipruritic agent characterized in that H is adjusted to 4.0 to 8.0. (4) A zinc picolinate analog compound represented by the following structural formula 2. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...2 (5) A zinc picolinate analog compound represented by the following structural formula 3. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...3 (6) A zinc picolinate analog compound represented by the following structural formula 4. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...4 (7) A zinc picolinate analog compound represented by the following structural formula 5. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...5 (8) A zinc picolinate analog compound represented by the following structural formula 6. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...6 (9) A zinc picolinate analog compound represented by the following structural formula 7. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...7 (10) A zinc picolinate analog compound represented by the following structural formula 8. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...8 (11) A zinc picolinate analog compound represented by the following structural formula 9. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...9 (12) A zinc picolinate analog compound represented by the following structural formula 10. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...10 (13) A zinc picolinate analog compound represented by the following structural formula 11. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...11 (14) A zinc picolinate analog compound represented by the following structural formula 12. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...12 (15) A zinc picolinate analog compound represented by the following structural formula 13. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...13 (16) A zinc picolinate analog compound represented by the following structural formula 14. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...14 (17) A zinc picolinate analog compound represented by the following structural formula 15. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...15 (18) A zinc picolinate analog compound represented by the following structural formula 16. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...16 (19) A zinc picolinate analog compound represented by the following structural formula 17. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...17 (20) A zinc picolinate analog compound represented by the following structural formula 18. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...18 (21) A zinc picolinate analog compound represented by the following structural formula 19. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...19 (22) A zinc picolinate analog compound represented by the following structural formula 20. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...20