KR910000480B1 - Process for preparing azacycloalkane derivatives - Google Patents

Abstract

General formula

Wherein A is -CH _2- , B is O, R 'is a hydrogen element, an alkyl group, an alkyloxycarbonyl group having 1 to 4 carbon atoms, and m represents an integer of 1 to 3

Wherein R is -SR ", -OR" (R "means alkyl group, alkylthioalkyl group, alkyloxyalkyl group), n means an integer of 2-10. React, general formula

A method for producing an azacycloalkane derivative represented by [wherein A, B, R, R ', m and n are the same as described above].

Description

[Name of invention]

Method for preparing azacyclo alkan derivatives

Detailed description of the invention

[Background of invention]

[Field of Invention]

The present invention relates to a method for producing azacycloalkane derivatives that increase the permeability and permeability of drugs and is hypoallergenic and low systemic toxicity to biological membranes. In addition, the compound of the present invention (azacycloalkane derivative) is useful as a drug for promoting drug delivery, as well as pharmaceuticals, pesticides, cosmetics, and insecticides.

[Private Technology]

So far known absorption accelerators include organic solvents such as dimethyl sulfoxide, dimethylacetamide and pyrrolidone, and 1-n-dodecylazacycloheptan-2-one (Azone) disclosed in Japanese Patent Application Laid-open No. 52-1035. And compounds such as N- (2-hydroxyethyl) pyrrolidone disclosed in Japanese Patent Application Laid-Open Nos. 60-13711 and 60-36423 are known.

In addition, although 1- (2-propylthioethyl) azacyclopentan-2-one is reported in "Z hur. Obshchei Khim. 30, 410 (1960)", the absorption promoting effect exerted by the compound of the present invention No announcement or suggestion was made.

[Problems to Be Solved by the Invention]

In recent years, the interest in the development of preparations for the purpose of transdermal absorption has become increasingly high. The reason is that when a drug is expected to have a local or systemic pharmacological action percutaneously, the drug can maintain its efficacy, easily control the rate of absorption of the drug, and prevent side effects caused by overdose of the drug. It is possible to prevent it, and because it is first passed through the liver as in the case of oral administration, it is possible to use the medicine effectively because of the low metabolic effects and the use of the drug, although it may cause hepatic disorders when used. Because there is. Since normal body skin naturally protects against irritation from the outside, it is considered to be very difficult to absorb and penetrate medicine through the skin. Thus, even if the drug is administered in the form of an ointment, cream, gel, lotion or plaster, it is currently difficult to readily absorb the amount necessary to achieve the desired effect sufficiently.

Although drugs are administered transdermally, orally, rectally, orally, nose or under the tongue, many drugs are difficult to penetrate or penetrate through the biofilm. Therefore, these drugs have low bioavailability.

Therefore, it is possible to sufficiently increase permeability, permeability and absorption through biological membranes such as skin, exhibit satisfactory pharmacological efficacy when used at practical temperatures, and have their own high locality and systemic toxicity, and high availability and stability. I've been trying to find it.

Known absorption promoters are still not satisfactory enough to improve the bioavailability of drugs that are poorly penetrated and penetrated through the biofilm, and some of them are irritating and severely discolored to the skin when administered repeatedly. Let's do it. Therefore, they are generally limited in how they are applied and used and do not solve the problem of practicality.

The present inventors have diligently studied to develop compounds having better absorption promoting action and higher safety at practical concentrations than those of dimethylsulfoxide and azacycloalkane derivatives known to date, and thus, one or two ether bonds, thioethers, Alternatively, certain compounds have been found in which the amino bonds are azacycloalkane derivatives substituted at the N-position, or azacycloalkane derivatives in which one methylene chain is substituted with an oxygen atom or a sulfur atom.

These predetermined compounds are completely suitable for the purpose of the present invention, and are also compounds obtained by the production method of the present invention.

[Summary of invention]

The present invention relates to a method for producing an azacycloalkane derivative represented by the following general formula (I).

Wherein A is -CH _2- , B is 0, R is -SR ", -OR" (R "means alkyl group, alkylthioalkyl group, alkyloxyalkyl group), R 'is hydrogen atom, alkyl group , An alkyloxycarbonyl group having 1 to 4 carbon atoms, m means an integer of 1 to 3, n means an integer of 2 to 10.

When explaining the symbols R, R 'and R "of the general formula (I) in detail, the alkyl groups of R include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, Linear or branched alkyl groups having 1 to 20 carbon atoms, such as dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or icosyl groups.

As an alkyl group of R ', it means said C1-C4 lower alkyl group.

In addition, as an alkyl group of R ", the alkyl group of said C1-C20 alkyl group, the alkylthio alkyl group, and the alkyloxyalkyl group means an alkyl group of said C1-C20.

The compound obtained by the manufacturing method of this invention can be manufactured efficiently by the method described below.

Hereinafter, the manufacturing method of the compound of this invention is demonstrated.

[Manufacturing method]

[Wherein A is -CH _2- , B is -0-, R is -SR "or -OR" (wherein R means an alkyl group, an alkylthioalkyl group or an alkyloxyalkyl group), and R 'is A hydrogen atom, an alkyl group, m is an integer of 1 to 3, n is an integer of 2 to 10.] That is, this production method reacts the cyclic compound [II] and the amine compound [III] represented by the above general formula. This is a method of obtaining the target compound [I].

For example, a method of directly heating a cyclic compound of formula (II) and an amine compound of formula (III) in a solvent-free dehydration method, or in the presence of a dehydrating agent under normal pressure or pressure in a solvent not involved in the reaction or The method of heat-dehydrating in absence is mentioned. The above two production methods will be described in detail again. The dehydration of direct heating by using a solvent is performed at 300 ° C. or lower in an atmosphere of an inert gas (for example, nitrogen gas, helium gas, or the like) or in the absence of it. The reaction proceeds by reacting at a temperature, preferably at a temperature of 100 ° C. to 250 ° C. for 1 to 50 hours, preferably 2 to 30 hours, whereby the desired compound of the present invention can be efficiently obtained.

In particular, the present reaction is improved when the reaction is carried out in a reaction vessel equipped with a dehydration reactor. The dehydration reaction in the solvent is in an organic solvent which is not involved in the reaction in the presence or absence of a dehydrating agent (e.g. p-toluenesulfonic acid, dicyclohexylcarbodiimide, phosphorus pentaoxide, polyphosphoric acid, phosphorus oxychloride, etc.). (For example, tetrahydrofuran, carbon tetrachloride, benzene, toluene, xylene, dioxane, dimethylformamide, dimethyl sulfoxide, N, N-dimethylaniline, N, N-diethylaniline, tetramine, etc.) 1 to 50 hours (preferably 10 to 35 hours) at an atmosphere of an inert gas (for example, nitrogen gas, helium gas, etc.) or at a temperature of 300 ° C. or lower (preferably 50 to 250 ° C.) in the absence. By the reaction, the target compound of the present invention can be efficiently obtained.

In particular, at normal pressure, it is possible to advance the reaction in a shorter time by removing the water generated during the reaction out of the system using a reaction vessel equipped with a dehydration reactor. This method is therefore an effective method for obtaining the target compound.

Example 1

8.6 g of r-butyrolactone and 21.7 g of 4- (n-octylthio) butylamine are heated to 170 to 190 ° C. under a nitrogen atmosphere, and reacted for 20 hours while removing water from a Dean / stark water separator. After completion of the reaction, the reactants are dissolved in ether and washed with 5% hydrochloric acid and then water. The ether layer is dried after distilling off the solvent, followed by distillation under reduced pressure to obtain 21.4 g of colorless 1- [4- (n-octylthio) butyl] azacyclopentan-2-one.

The shape, column temperature and elemental analysis of this material are as follows.

Example 2

11.4 g of 6-hexanonlactone and 20.1 g of 6- (n-hexyloxy) hexylamine are heated at 180 ° C. for 30 hours under a nitrogen atmosphere. After completion of the reaction, the reaction product was subjected to the same treatment as in Example 1 to obtain 9.0 g of 1- [6- (n-hexyloxy) hexyl] azacycloheptan-2-one.

The shape, column temperature and elemental analysis of this material are as follows.

Example 3

8.6 g of r-butyrolactone and 18.7 g of 2- (n-nonyloxy) ethylamine are dissolved in 30 ml of dimethyl sulfoxide and heated at 180 to 200 ° C for 30 hours. After completion of the reaction, water was added to the reaction solution, the insolubles were extracted with ether, and washed with 5% hydrochloric acid followed by water. The ether layer is dried after distilling off the solvent, followed by distillation under reduced pressure to obtain 18.2 g of colorless 1- [2- (n-nonyloxy) ethyl] azacyclopentan-2-one.

The shape, column temperature and elemental analysis of this material are as follows.

Example 4

Dissolve 8.6 g of r-butyrolactone and 18.7 g of 4- (2-methylhexyloxy) butylamine in 50 ml of xylene, add 0.2 g of p-toluenesulfonic acid, and reflux for 15 hours while removing water with a Dean / stank separator. After completion of the reaction, the operation is carried out according to the method of Example 3. 17.0 g of colorless 1- [4- (2-methylhexyloxy) ethyl] azacyclopentan-2-one are obtained.

The shape, column temperature and elemental analysis of this material are as follows.

Example 5

10.0 g of r-valerolactone and 20.3 g of 4- (n-heptylthio) butylamine were operated according to the method of Example 2 to obtain colorless 5-methyl-1- [4- (n-heptylthio) butyl] 21.6 g of azacyclopentan-2-one is obtained.

The shape, column temperature and elemental analysis of this material are as follows.

[Examples 6 to 86]

The target compound of the present invention represented by formula (I) is synthesized in Examples 1 to 5 and similar methods. Table 1 shows the symbols and column temperatures used in the formulas of the compounds.

[Table 1]

The compound obtained by the production method of the present invention is used by using together with the following drugs in order to have the absorption promoting action of the drug. That is, the drug used in the present invention is a drug whose biomembrane permeability or permeability is low enough to require an enhancer, for example, antibiotics, chemotherapeutic agents, bacteriostatics, bactericidal agents, antiseptics, antifungal agents, nonsteroidal anti-inflammatory agents, steroid anti-inflammatory agents. Anticancer drugs, antipsychotics, local anesthetics, antiperkinson drugs, sex hormones, antiperspirants, sunscreens, antiallergic drugs, antiarrhythmics, antihypertensives, vasodilators, vascular adjuvant, skeletal muscle relaxants, antiemetics Emollients, emollients, prostaglandins, fat-soluble vitamins, enzymes, peptide hormones, diabetes treatments, insect repellents, insecticides and pesticides.

Specific examples of these drugs are as follows.

1. Antibiotics

Examples of the agent include penicillin-type antibiotics such as penicillin G, penicillin V, methicillin, oxacillin, clocksacillin, ampicillin, hetacillin, cyclacillin, amoxicillin, carbenicillin and sulfenicillin; Cerarosine-type antibiotics such as cephaloridine, cephalotin, cefazoline, cepharoglycine and ceparexin; Aminoglycoside antibiotics such as streptomycin, kanamycin, dibecacin, gentamicin and furadimycin; Tetracycline antibiotics such as oxytetracycline, tetracycline, dimethyl chlortetracycline, doxycycline and minocycline; Macrolide antibiotics such as erythromycin, leucomycin and irradiated mycin; Lincomycin-type antibiotics such as lincomycin and clindamycin; Chloramphenicol, Mycamycin, Gramicidine, Gramicidine S, Capreomycin, Cycloserine, Enbiomycin, Rapamycin, Nystatin, Trichomycin, Amphotericin B, Griseofulvin, Variotin, Pyrronitrin, Sikkanin, nitrofurantoin, 5-iodine-2-deoxyuridine, sefazingin, fosfomycin or N-formimidoyl enamycin-1 hydrate and the like can be listed.

2. Chemotherapy

Examples of the drug include external sulfamides such as maphenide acetate, sulfadiazine, sulfadiazineone, sulfamethoxazole sodium, sulfisomidine, sulfisomidine sodium or nalidic acid.

3. Germ growth suppression, sterilization or disinfectant

The agent may include iodine, povidone iodine, diiodohydroxypropane, benzalkonium chloride, benzetonium chloride, methyllosaniline, hexachlorophene, chlorohexacydine or benzoyl peroxide tolnaphate.

4. Antifungal Agents

These drugs include naphthiomate, clotrimazole, glyofulvin, saccanin, trichomycin, nystatin, pyrronitrin, exalamide, coloconazole hydrochloride, isoconazole nitrate, econazole nitrate, and oxyconate nitrate. Examples include sol, sulconazole nitrate, myconazole, thioconazole, tolcate, bariotin, haloprozin phenyl 11-iodine-10-undecinoate, biponazole, naphthypine, ketoconazole or cyclorilox olamine can do.

5. Nonsteroidal anti-inflammatory

These drugs include salicylic acid, aspirin, acetaminophen, aminopyrin, antipyrine, oxyphenbutazone, sulfirin, indomethacin, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, etofenamate, salicyamide, triethanol Amine salicylate, flufenamic acid, meclofenamic acid, colchicine, bufexa film, allopurinol, oxyfurinol, ibufenac, fenbufen, dipulunisal, alclofenac, phenylbutazone, mefenamic acid, phenophene Nopropene, bendazac, pyroxicam or flurbiprofen.

6. Steroid Anti-inflammatory

This drug includes amcinonide, valeric acid prednisolone, valeric acid dipullucortolone, valeric acid betamethasone, betamethasone, dexamethasone acetate, dipropionate betamethasone, dexamethasone, triamcinolone acetonide, hydrocortisone, pivalate plumethasone , Pulluloxinide, pulluloxinone acetonide, pullulolometholone, pulluloxycortide, prednisolone, propionic acid clobetasol, propionic acid beclomethasone, bethiamethasone, methyl propynsolone, methyl acetate prednisolone or butyric acid Hydrocortisone.

7. Anticancer

This drug includes 5-Pluurouracil, 6-mercaptopurine, methotrexate, bleomycin, mitomycin C, adriamycin, carbocone, actinomycin C, daunorobibion, neocarcinostatin, chromomycin A, L-asparaquinase, fishvanyl, vinblastine and vincristine.

8. Psychotropic Agents

The agent includes chlorpromazine, chlordiazepoxide, reserpin, etizolam, oxazolam, mexazolam or haloxazolam.

9. Local Anesthetic

The agent may include benzocaine, procaine, propoxycaine, dibucaine, lidocaine, mepivacaine, bupivacaine or tetracaine.

10. Antiperkins Hands

The agent may include L-dopa or chloroxazone.

11. Sex hormones

The agent may include estrogen, androgen, estradiol, testosterone or progesterone.

12. Antiperspirant

The agent may include propanerin bromide, scopolamine or acyloxymethylammonium salts.

13. Sunscreen

The drug includes P-aminobenzoic acid or P-dimethylaminobenzoic acid.

14. Antiallergic agents

The agent includes sodium chromoglycate or ketotifen.

15. Antiarrhythmics

Examples of the agent include acebutolol, alprenolol, indenolol, cateol, bucumolol, bufetolol, bufranolol, propranolol or pindolol.

16. Blood pressure lowering agent

Reagents include reserpin, resinnimin, lauwalpia alkaloids, clonidine, prazosin, mesylic acid dihydro ergotoxine, meticrane, methyldopa, guanetidine or betanidine.

17. Vasodilators

These drugs include epoloxate etaphenone, oxyphedrine, carbochromen, dilazem, diltiazem, trimetazidine, pentaerythritol tetrapyridine, dipyridamole, isosorbide dinitrate, trapidyl, Nitroglycerin, nifedipine, prenylamine, molecidomin, trolnitrate, hexanicotinic acid inositol, isoxsuphrine, nilidrin nicamethate cyclate, cinnarizine, nicotinyl alcohol or hepronicate.

18. vascular adjuvant

Routine is mentioned as this medicine.

19. Skeletal Muscle Relaxant

The agent includes diazepam.

20. Antje

The drug includes chlorpromazine.

21. Psoriasis treatment

The drug includes methoxalene.

22. Emollients or emollients

Examples of this agent include hydroquinone, urea, heparin or chondroitin sulfate.

23. Prostaglandins

This drug is prostaglandin F _2, prostacyclin, prostaglandin E _1, prostaglandin E _2, 7- thiazol prostaglandin _{E 1, 16, 17, 18} , 19, 20- 15-cyclohexyl-pentanol -7-thiaprostaglandin E ₁ , 16, 17, 18, 19, 20-pentanol-15-cyclopentyl-7-thiaprostaglandin E ₁ , 16, 16-dimethyl-7-thiaprost glandin E ₁ , 17, 20-dimethyl-7-thiazol prostaglandin _{E 1, 16, 17, 18} , 19, 20- 15-cyclohexyl-pentanol - △ ^{2-thiazol-7-prostaglandin} E _1, 16, 16- dimethyl - △ ² - prostaglandin E ₁ , 7-Pluoroprostacyclin, 5-Pluoroprostacyclin, 16, 17, 18, 19, 20-pentanol-15-cyclohexylprostacyclin or 16, 17, 18, 19, 20 -Pentanol-15-cyclopentylprostacyclin can be enumerated.

24. Fat-soluble vitamins and water-soluble vitamins

The water-soluble vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , nicotinic acid, nicotinamide, pantothenic acid, biotin, vitamin B ₁₂ , vitamin C, lipoic acid, and inositol.

Fat-soluble vitamins include vitamin A, vitamin D, vitamin D ₂ , vitamin D ₃ , vitamin E, vitamin K ₁ , vitamin K ₂ , ubiquinone, vitamin F, 1α, 25-dihydroxycholecalciferol, 1, 25-dihydroxy vitamin D ₃ , 1α-hydroxy vitamin D ₃ , 1, 24-dihydroxy vitamin D ₃ , 24, 25-dihydroxy vitamin, 1α, 25-dihydroxy vitamin D ₃ , -26 , 23-lactone and 25-hydroxy vitamin D ₃ -26, 23-lactone.

25. Enzyme Preparation

Examples of the agent include trypsin, paraine, protease, lysozyme, streptokinase, plasmin, urokinase, hyaluronidase, α-chymotrypsin, seraopeptidase, bromelain or semi-alkalipeptidase.

26. Peptide Hormones

These drugs include insulin, angiotensin, vasopressin felipressin, protyreline, gonadotropin hormone, corticotropin, prolactin, somatropin, tyrotropin, progesterone, calcitonin, kallikrein, glucagon, oxytocin, Gastrin or secretin.

27. Diabetes Medications

The agent includes cleebenclamide or glyclazide.

28. Other

Cardiac medicine, cough medicine, expectorant medicine, interferon and interleukin.

The compound of the present invention for use as an absorption accelerator can be added to the drug described above in a desired amount, but as a safe and effective amount, 0.001 to 25% of the total composition is preferable, and 0.01 to 20% is more preferable.

Absorption accelerators and medicaments of the present invention are intended for use as external preparations for skin, hair, nails, and the like, or other biofilms, for example, oral, suppository, oral, vaginal, and nasal administrations. For use as preparations or eye drops, it may be mixed and molded into suppositories, plastics, tapes, cataplasms, pastes, ointments, gels, creams, lotions, lining agents, dry syrups, aerosols, tablets, granules or films. Can be. Prior to molding, the mixture or composition may be mixed with other components depending on the form of drug obtained.

For example, when the composition is molded into an ointment, it may be added in advance to beeswax, vegetable oil, lanolin, boric acid, white waseline (waceline) and the like. When the composition is used as a creaming agent, it can be added with fats and oils, wax, higher fatty acids, higher alcohols and the like. In the case of the lotion material, the composition can be mixed with ethanol, glycerin, butylene glycol and the like. When preparing a solution, a composition can be mixed with ethanol, purified water, glycol, etc. normally. When preparing a suspending agent, the composition can be mixed with tragant, gum arabic, sodium alginate, gelatin, methylcellulose, CMC and the like. In the case of suppositories, the composition can be mixed with cacao butter, rock oil, coconut oil and the like. In the case of tablets and sebaceous agents, the composition can be mixed with substrates commonly used such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl, methyl cellulose, crystalline cellulose, and starch. In the case of a film agent, a composition can be mixed with hydroxypropyl cellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, etc.

The composition thus mixed containing the substrate for the preparation, the absorption accelerator and the medicine of the present invention can be produced by a known method commonly used.

Example 83

Prepare the following ointment.

Example 84

The following solution prescription is prepared.

The effect of ketoprofen on the transdermal absorption of dorsal skin of female hairless mice (9 years old) is examined by the diffusion gel method. That is, 0.5 ml of the preparation is added to the donor side, and the amount of ketoprofen penetrating the receptor layer is measured by high performance liquid chromatography (HPLL). The obtained results are shown in Table 2.

[Table 2]

As shown in Table 2, remarkable absorption promoting action is recognized by the addition of the compound obtained by the production method of the present invention.

Example 85

The following spray spray is prepared.

Example 86

Prepare the following hydrophilic ointment.

As an evaluation method of the percutaneous absorption promoting action of the compound obtained by the production method of the present invention, it is tested in a diffusion gel using the embryonic skin of female hairless mice (9 weeks old). That is, 0.5 g of indomethacin ointment is added to the donor side, and the amount of indomethacin permeating through the phosphate layer is measured by HPLC over time. The results obtained are shown in Table 3.

[Table 3]

As shown in Table 3, remarkable absorption promoting action of indomethacin is recognized by the addition of the compound obtained by the production method of the present invention.

Example 87

The following gel ointment is prepared.

It evaluated using the diffusion gel similarly to Example 86. The obtained results are shown in Table 4.

[Table 4]

As shown in Table 4, remarkable absorption promoting action is recognized by the addition of the compound obtained by the production method of the present invention.

Example 88

Prepare the following cream prescription.

Example 89

Prepare the following macro bone ointment.

Example 90

The following solution prescription is prepared.

Wistor male rats (200-250 g in weight) are used as 1 group of 4 rats. A pindolol-containing detergent (composition) is sealed with 150 μl / 2.5 × 2.5 cm 2 on the dorsal skin shaved with an electric razor. Blood is collected 3 hours after application and the pindolol concentration of the blood is quantified by HPLC. The obtained results are shown in Table 5.

As shown in Table 5, the compound obtained by the production method of the present invention showed a significant increase in the percutaneous absorption of pindolol compared to the control group, and also showed a good absorption promoting effect compared with the comparative compound. In the present Example, when the compound obtained by the manufacturing method of this invention used the skin of the administration part, abnormality, such as erythema and edema, was not recognized.

Example 91

The following solution prescription is prepared.

The dorsal skin of female hairless mice (9 weeks old) is used to detect the effect on the percutaneous absorption of pindolol using diffusion gels. That is, 0.5 ml of pindolol tablets (the composition) are added to the donor side, and the amount of pindolol permeating to the receptor layer is measured by HPLC. Table 6 shows the results to be obtained.

[Table 6]

As shown in Table 6, the compound obtained by the preparation method of the present invention is recognized to have a remarkable absorption-promoting action as compared to the control. Moreover, it is also good compared with a comparative compound.

Example 92

The following acryl tape prescription was produced.

The dorsal skin of female hairless mice (9 weeks old) is used to detect the effect on the percutaneous absorption of pindolol by the diffusion gel method. That is, 0.785 cm 2 of tape tablet (containing 0.8 mg of pindolol) was attached to the donor side, and the amount of pindolol diffused to the receiving side through the skin was measured by HPLC. The results are shown in Table 7.

[Table 7]

As shown in Table 7, the compound obtained by the production method of the present invention exhibits remarkable absorption promoting action.

Example 93

Prepare the following solution prescription.

[Table 8]

Wiston male rats (body weight about 200-250 g) fasted for 24 hours are used as one group of four. Glibenclamide was sealed with 175 ml / 2.5 × 2.5 cm 2 on the dorsal skin shaved with an electric razor and electric scissors, and 1.5 ml of 20% glucose was subcutaneously injected after 3 hours. 2 hours after glucose treatment, blood was collected and blood glucose level was measured. In addition, as a normal group, fasting only forms a formulation containing no drug as control A, and a group containing no test compound as control B, respectively. The obtained results are shown in Table 9.

[Table 9]

As shown in Table 9, in the control group B (glybenclide only), no hypoglycemic action was recognized as compared to the control A, but the compound obtained by the production method of the present invention has a remarkable absorption promoting action, and the gleebenkle Meade is percutaneously absorbed and hypoglycemic action is recognized. This absorption promoting action was stronger than that of Azone used as a comparative compound.

Example 94

Prepare the following suspension prescriptions.

Example 95

The following solution prescription is prepared.

The effect of 5-fluorouracil on the percutaneous absorption of 5-fluorouracil using female hairless mouse (9 week old) dorsal skin is examined using a diffusion gel. That is, 0.5 solution is added to the donor side, and the amount of 5-fluorouracil permeating through the receptor layer is measured by HPLC. The results obtained are shown in Table 10.

[Table 10]

As shown in Table 10, the compound obtained by the production method of the present invention was recognized as a significant absorption promoting action compared to the control, but the activity of the comparative compound was hardly recognized.

Example 96

The following solution prescription is prepared.

The effect on the permeation of phenol red, a compound that is hardly absorbed by the dorsal skin of female hairless mice (9 weeks old), is detected using a diffusion gel. That is, 0.5 ml of physiological saline solution containing 2 mM of phenol red was added to the dorsal skin and the donor was added to the donor gel, and then the amount of phenol red permeated to the receptor layer was measured with an absorbance meter (0D559 nm). The obtained results are shown in Table 11.

[Table 11]

As shown in Table 11, the compounds obtained by the production method of the present invention as compared to the control is recognized a significant absorption promoting action. In addition, even when compared with the comparative compound, good absorption promoting action is recognized.

Example 97

Prepare the following lotion prescription.

Example 98

The following solution prescription is prepared.

The effect on the transdermal absorption of various drugs using the dorsal skin of female hairless mice (9 weeks old) is examined using a diffusion gel. That is, 0.5 ml of the agent (the composition) containing the drug is added to the donor side, and the amount of drug permeating through the receptor layer is measured.

[Table 12]

As shown in Table 12, the compound obtained by the production method of the present invention exhibits significant absorption promoting action for various drugs.

Example 99

The following suppository prescription is prepared.

[Table 13]

Using 5 male rabbits (2.5-3.5 kg) in one group, 0.3 kg of suppositories are inserted into the rectum, and blood is collected from the vein over time, and the blood glucose level is measured by the glucose oxidase method. Results are expressed as changes in blood glucose levels prior to administration.

[Table 14]

As shown in Table 14, the control group (insulin only) as compared to the normal group is not affected by the blood glucose level at all, but significant hypoglycemic action is recognized by the addition of the compound obtained by the production method of the present invention. In addition, no mucosal irritation was recognized at the administration site.

Example 100

Prepare the following antibiotic suppository prescription.

[Table 15]

A male rabbit (2.5-3.5 kg) fasted for 24 hours is used as 5 per group. 0.3 g / kg of suppository is inserted into the rectum, and blood is collected from the ear vein over time, and the concentration of antibiotics in serum is measured by HPLC. The results of each drug are shown in Table 16.

[Table 16]

As shown in Table 16, remarkable absorption promoting action is recognized by the addition of the compound obtained by the production method of the present invention together with the antibiotic preparation of anpicillin and seralotene.

Example 101

Suppositories containing the following drugs are prepared.

A male rabbit (2.5-3.5kg) fasted for 24 hours was used in groups of 3 to 4, and 0.3 g / kg of suppository was inserted into the rectum. Over time, blood was collected from the vein and the concentration of the drug in the serum was analyzed by HPLC. Measure The results are shown in Table 17.

[Table 17]

As shown in Table 17, the compound obtained by the production method of the present invention exhibits significant absorption promoting action.

Example 102

The following suppository prescription is prepared.

Example 103

The following purification prescriptions are prepared.

Example 104

As part of the local toxicity of the compounds obtained by the preparation method of the present invention, the primary stimulation test in the rabbit skin is tested. That is, 100 microliters of 300 glycol solution of polyethyleneglycol 3% containing the compound of this invention are dripped at the 3 Japanese rabbits (2.5-3.5 kg) which cut the back hair on the day before. A bandage for batch testing of the cornea is sealed for 24 hours. The skin reactions of 24, 48 and 72 hours after banding were assessed according to the Draize method. The obtained results are shown in Table 18.

Total evaluation = (evaluation at 0 hours + evaluation at 48 hours) / 2

0 to 2 weak points

About 2 to 6 points

6 to 8 strong

[Table 18]

As shown in Table 18, almost no skin irritation was recognized in the compound obtained by the production method of the present invention as in the control. However, in the Azone used for comparison, moderate stimuli persisted for more than 48 hours.

As a result of this experiment, it was found that the skin irritation action of the compound obtained by the production method of the present invention is very weak.

Example 105

As part of the systemic toxicity of the compound obtained by the method of the present invention, an acute toxicity test is performed in oral and subcutaneous administration in rabbits. That is, Wistar male rabbits (200-120 g) are used in 1 group of 4-5 mice, and the test compound is administered at a rate of 0.5 ml / 100 g. The general condition, weight change, and death are observed for one week after administration.

The results are shown in Table 19 as LD50.

As shown in Table 19, the compound obtained by the production method of the present invention was not recognized abnormal conditions or death in oral and subcutaneous nursing.

From the above results, it was found that the compound obtained by the production method of the present invention has very high stability.

As is clear from the results of the above examples, the compound obtained by the production method of the present invention has a stronger sensitizing effect than the known compound against the penetration and permeation of drugs in biological membranes, particularly in the mucosal mucosa of the skin and rectum, nose, mouth, vagina and the like. It has a wide range of drug or pharmacological effects, and is widely applicable to the base and the formulation used.

In addition, the local toxicity and systemic toxicity of the compound obtained by the production method of the present invention was found to be very weak and have high stability.

[Effects of the Invention]

The azacycloalkane derivative obtained by the production method of the present invention is a compound having a novel structure synthesized by the present inventors. As is apparent from the above examples, this compound shows a marked enhancement in the permeability and permeability of the biofilm of the drug, and the local toxicity and systemic toxicity to the biofilm are very strong and have high stability.

In addition, the composition comprising the compound obtained by the production method of the present invention with a drug is a topical drug that expects pharmacological action at the site of administration such as skin, nose, mouth, rectum, vagina or as a systemic drug that expects systemic action. Anything is very useful.

Claims (1)

General formula Wherein A is -CH _2- , B is O, R 'is a hydrogen atom, an alkyl group, an alkyloxycarbonyl group having 1 to 4 carbon atoms, and m is an integer of 1 to 3 Wherein R is -SR ", -OR" (R "means alkyl group, alkylthioalkyl group, alkyloxyalkyl group), n means an integer of 2-10. React, general formula A method for producing an azacycloalkane derivative represented by [wherein A, B, R, R ', m and n are the same as described above].