JPH0629252B2 - Azacycloalkane derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention provides a novel highly safe azacyclo compound that increases drug permeability and permeability, and has low irritation and systemic toxicity to biological membranes. It relates to alkane derivatives.

Specifically, drugs applied to biological membranes such as skin and mucous membranes,
That is, it is intended to develop an absorption enhancer that enhances drug permeability or permeability in transdermal and transmucosal administration such as rectum, nose, oral cavity, vagina.

Further, the compound of the present invention can be used not only as a drug as a drug for enhancing permeation etc., but also as a cosmetic such as a quasi drug and an agricultural chemical or an insecticide.

Still another object of the present invention relates to an azacycloalkane derivative which has an action of enhancing absorption of a drug from a biological membrane and has an antibacterial action itself.

(B) Conventional Technology Regarding the azacycloalkane derivative, there is a conventional technique described in Japanese Patent Application Laid-Open No.
2-1035, JP-A-56-49316,
JP-A-57-142918, JP-A-58-210
No. 026 and Japanese Patent Laid-Open No. 58-210066. However, these known compounds having an absorption promoting action are only related to derivatives having an alkyl group, a phenyl-substituted alkyl group and a substituted or unsubstituted phenyl group as a substituent for the N-position, and the compounds of the present invention are not , There is no disclosure or suggestion.

(C) Problems to be Solved by the Invention In recent years, interest in the development of preparations for percutaneous absorption has been gradually increasing. The reason for this is that when a drug that is expected to exert its pharmacological effect locally or systemically is administered transdermally, the drug can be maintained for a long time, and the absorption rate of the drug can be easily controlled, and side effects due to excessive administration can be prevented. Is possible, there is little effect of metabolism due to the first-pass effect by the liver as seen in oral administration, the effective action of the drug is possible, and it is possible to relatively safely administer a drug with liver damage etc. This is because it has an advantage. However, since normal skin naturally has a protective effect against external stimuli, absorption and permeation of drugs are relatively difficult. Therefore, even if the drug is administered in the form of an ointment, cream, gel, lotion or patch, the amount of drug required to sufficiently develop the desired drug effect is not easily absorbed at present. .

In addition, absorption routes from biological membranes other than skin, such as oral,
Even in the rectal, buccal, nasal, sublingual administration methods, depending on the drug, it is difficult to penetrate or permeate the relevant biological membrane, and many drugs with low bioavailability are found. Therefore, there is a demand for a highly safe absorption enhancer that sufficiently enhances the bioavailability of a drug having low penetration and penetration into a biological membrane and does not cause irritation, tissue necrosis, or systemic toxicity.

Therefore, the present inventors have a compound having a higher safety than the absorption promoting action of conventionally known dimethyl sulfoxide and azacycloalkane derivatives, and a highly safe compound,
Moreover, as a result of intensive studies to develop a compound having an antibacterial action, it was found that an azacycloalkane derivative obtained by substituting an alkyl group having a sulfide bond at the N position can sufficiently meet the purpose. The present invention has been completed.

(D) Means for Solving the Problem The present invention has the following general formula (I). (In the formula, R is an alkyl group, m is an integer of 5 to 7, and n is 3 to
(Meaning an integer of 15).

More specifically, R in the general formula (I) is an alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, It means a straight chain or branched alkyl group such as hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl.

The compounds of the present invention are all novel compounds that have not been published in the literature, and can be produced in good yield by the methods described below or other known methods.

Manufacturing method 1 (In the formula, M is an alkali metal ion, X is a halogen atom or a mesyl group or a tosyl group, and R, m and n have the same meanings as described above.) Azacycloalkane-2-one and an alkali catalyst such as sodium Alcoholate or sodium hydride,
Or in the presence of a phase transfer catalyst, such as tetrabutylammonium sulfate, in a solution that does not participate in the reaction (for example, benzene, toluene, tetrahydrofuran, methanol,
Ethanol, dimethylformamide, dimethylsulfoxide, etc.) 0 to 300 ° C., preferably 0 to 100 ° C.
(II) is formed by treating the product in a nitrogen atmosphere or in the absence thereof for about 0.5 to 20 hours, and an excess molar amount of dihalogenoalkyls is added thereto to synthesize (III). Further obtained (III) and halogenoalkyls in the presence of a phase transfer catalyst (for example, cetyl tributyl phosphonium bromide, cetyl trimethyl ammonium chloride, cetyl trimethyl ammonium bromide, etc.) in an alkaline aqueous solution of sodium sulfide at 0 to 300 ° C., Preferably, the target compound (I) can be obtained by reacting at 0 to 100 ° C. for about 2 to 10 hours under a nitrogen atmosphere.

Manufacturing method 2 (In the formula, X represents a halogen atom, a mesyl group or a tosyl group, and R, m and n have the same meanings as described above.) The synthetic intermediate (III) synthesized by the production method 1 and mercaptans are generally known. Dehalogenating agent (for example, 1,5-
In the presence of diazabicyclo [4.3.0] nene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBC), etc.) in an inert solvent that does not participate in the reaction (eg, benzene, toluene, tetrahydrofuran). , Methanol, ethanol,
Dimethylformamide or dimethylsulfoxide, etc.) 0 to 300 ° C., preferably 0 to 100 ° C. and 0.5 to 2
The target compound (I) is obtained by treating for about 0 hours in a nitrogen atmosphere or in the absence thereof.

Other manufacturing methods include the method shown below.

Manufacturing method 3 (In the formula, X represents a halogen atom, a mesyl group, or a tosyl group, and R, m, and n have the same meanings as described above.) In addition, this production method is performed in a good yield according to the method of alkylation for the N-position which is usually performed. The target compound (I) can be obtained.

Manufacturing method 4 (In the formula, M is an alkali metal ion, X is a halogen atom, a mesyl group, or a tosyl group, and R, m, and n have the same meanings as described above.) In this production method, alkyl for a mercapto group is usually used. The target compound (I) can be obtained in good yield according to the compounding method.

(E) Action The compound azacycloalkane derivative of the present invention has an action of remarkably increasing the drug permeability or permeability when compounded in an appropriate amount.

Further, the compounds having the action of the present invention are extremely weak in local irritation and have extremely low toxicity in an acute toxicity test.

Further, the compound of the present invention has an antibacterial action itself.

Hereinafter, the action and usefulness of the compound of the present invention will be described with reference to pharmacological examples.

Pharmacological experiment 1 Percutaneous absorption promoting action against Pindolol 1 group of Wistar male rats (body weight: 200 to 250 g)
It was used as 4 animals. With electric hair clipper and electric razor
Propylene with 4% Pindolol on the shaved back
Recall / Ethanol = 1: 1 solution 150μ / 2.5
× 2.5cm²It was applied in a sealed manner. Blood is collected 3 hours after application and in blood
Of Pindolol concentration in
It was Known compounds used as test compounds and comparative drugs
Azone, an absorption enhancer (1-n-dodecyl azashik
Roheptan-2-one) and DMSO (dimethyl sulfoxide)
Sid) was comparatively examined at a concentration of 3%.

The results obtained are shown in Table 1.

The compound of the present invention shows a remarkable pindolol concentration as compared with the control group.
Increased absorption was observed. Further, the compound of the present application is a known DMSO.
Both compounds show absorption promoting effect compared to
e It was confirmed that it showed a good absorption promoting effect even when compared with
To be

In addition, in this experiment, no abnormality such as erythema or edema was observed on the skin at the administration site when the compound of the present invention was used.

Pharmacological Experiment 2 Absorption-Promoting Effect on Phenol Red The effect of Phenol red, which is a poorly absorbable compound in vitro, on skin permeability was examined using the back skin of hairless mice (weight: 27 to 30 g).

That is, put the skin on the diffusion cell and put Phenol on the donor side.
0.5 ml of a physiological saline solution containing red 2 mM and physiological saline was placed on the receptor side, and the time-dependent permeation amount of Phenol red to the receptor side was measured with an absorptiometer (0D 559 nm).

The obtained results are shown in Table 2.

The amount of Phenol red that penetrates the skin is extremely small in the target group.
No, but remarkable by about 42.7 times by adding 3% of the compound of the present invention
Showed an increasing effect. In addition, the effects of the compounds of the present invention are compared.
Azone used as a compound Was significantly more pronounced.

Pharmacological Experiment 3 Primary Skin Irritation Effect As part of local toxicity of the compound of the present invention, primary skin irritation experiment in rabbits was carried out.

That is, a patch test adhesive bandage was prepared by dropping 100 µ of polyethylene glycol 300 solution containing 3% of the compound of the present invention on the backs of three Japanese domestic rabbits (body weight 2.5-3.0g) whose backs were shaved the day before, and sealed for 24 hours. I attached it. The skin reaction 0, 24, and 48 hours after the removal of the adhesive bandage was evaluated according to the Draize method.

The results obtained are shown in Table 3.

0-2 points-Mild 2-6 points-Medium 6-8 points-StrengthSimilar to the control group, the compound of the present application has almost no skin irritating effect.
I was not able to admit. But relatively used as a compound
Azone Has a moderate stimulant effect for up to 48 hours
Was recognized.

From the results of this experiment, it was found that the skin stimulating action of the compound of the present invention is extremely weak.

Pharmacological Experiment 4 Acute Toxicity Test As part of the systemic toxicity of the compound of the present invention, an acute toxicity test was carried out by oral and subcutaneous administration in rats.

That is, Wistar male rats (body weight 100-120
g) was 4 animals per group, 5 g / kg was administered orally, and 3 g / kg was administered subcutaneously, and the general symptoms, weight change, and the presence of death were observed for 1 week after administration.

The results obtained are shown in Table 4.

As shown in Table 4, it is clear that the compound of the present invention has extremely high safety, with no abnormal symptoms or mortality observed in both oral and subcutaneous routes of administration. In addition, no abnormalities that were of particular concern were found in the autopsy findings after the observation for one week.

From the above results, it was found that the compound of the present invention has extremely high safety.

As is clear from the results of the above pharmacological experiments,
DM of known compounds for permeation and permeation of drugs through biological membranes
SO and Azone It has a stronger potentiating effect.

Further, it was revealed that the compound of the present invention has extremely low local irritation and systemic toxicity (acute toxicity), and has high safety.

(F) Examples Hereinafter, the present invention will be specifically described with reference to Examples, but of course the present invention is not limited to these Examples.

Example 1 1.32 g of 60% sodium hydride and dry toluene 1
3.39 g of azacycloheptan-2-one in a mixture of 00 ml
Of toluene solution was added dropwise. After completion of the dropwise addition, the mixture was refluxed for 1 hour, 19.4 g of 1,4-dibromobutane was added, and the mixture was refluxed for 12 hours. Then, the insoluble matter is filtered, and the filtrate is washed with water and dried,
The solvent was distilled off under reduced pressure to obtain a pale yellow substance. Further, this substance was added to a mixture of 3.69 g of n-propyl bromide, 0.608 g of cetyl tributyl phosphonium bromide and 30 ml of 1M sodium sulfide aqueous solution (containing alkali), and added 40-
The mixture was heated and stirred at 60 ° C for 5 hours. It was extracted with diethyl ether, washed with water and dried, and the solvent was distilled off under reduced pressure. Distillation gave 1.79 g (yield 24.6%) of colorless 1- (4-propylthiobutyl) azacycloheptan-2-one. However, the distillation is done by the glass tube oven GT of Shibata Chemical Industry Co., Ltd.
O-250R) rotary method.

The shape, boiling point and elemental analysis value of this substance were as follows.

Form Colorless transparent oil Boiling point 122-126 ℃ / 0.3mmHg Elemental analysis value C ₁₃ H ₂₅ NOS theoretical value C: 64.15 H: 10.35 N: 5.75 Actual value C: 64.02 H: 10.39 N: 5.50 Example 2 n -Butyl mercaptan 2.70 g, 1,5-dibromopentane 20.7 g, triethylamine 3.03 g and benzene 20
The mixture was refluxed for 3 hours, washed with water and dried, and the solvent was distilled off under reduced pressure. Further, the oil obtained by distillation and 4.05 g of the sodium salt of azacycloheptan-2-one were heated in a toluene solvent at 100 ° C. for 5 hours, washed with water and dried,
The solvent was distilled off under reduced pressure. The residue was distilled to obtain 2.05 g (yield 25.2%) of colorless 1- (5-butylthiopentyl) azacycloheptan-2-one.

The shape, boiling point and elemental analysis value of this substance were as follows.

Form Colorless transparent oil Boiling point 133-138 ℃ / 0.3mmHg Elemental analysis value C ₁₅ H ₂₉ NOS theoretical value C: 66.37 H: 10.77 N: 5.16 Actual value C: 66.35 H: 10.88 N: 5.03 Example 3 60 % Sodium hydride 1.32 g and dry toluene 10
A toluene solution of 3.39 g of azacycloheptan-2-one was added dropwise to 0 ml of the mixture, and the mixture was heated under reflux for 1 hour. afterwards
22.0 g of 1,6-dibromohexane was added, and the mixture was refluxed for 12 hours. Then, the reaction product was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain a pale yellow substance. Further, this substance was added with 6.24 g of n-pentyl mercaptan and 1,8-diazabicyclo [5.
4.0] 5.47 g of undecene-7 and 100 ml of benzene
Was heated to 40-60 ° C for 5 hours. Then, the mixture was extracted with ethyl acetate, washed with water and dried, and the solvent was distilled off under reduced pressure. By distillation, colorless 1- (6-pentylthiohexyl) azacycloheptan-2-one 6.69 g (yield 74.6
%) Was obtained.

The shape, boiling point and elemental analysis value of this substance were as follows.

Form Colorless transparent oil Boiling point 146-150 ℃ / 0.5mmHg Elemental analysis value C ₁₇ H ₃₃ NOS theoretical value C: 68.17 H: 11.10 N: 4.68 Actual value C: 68.20 H: 11.29 N: 4.75 Example 4〜 27 The following compounds were synthesized according to the methods of Examples 1 to 3.

(G) Effect of the Invention The azacycloalkane derivative of the present invention is a compound having a novel structure, which was first synthesized by the present inventors.
As is clear from the above-mentioned pharmacological experimental examples, this compound has a remarkable enhancing effect on the permeability and permeability of the drug into the biological membrane, and has extremely weak local irritation to the biological membrane, systemic toxicity, etc. It has safety.

In addition, a composition containing the compound of the present invention together with a drug is a local drug expected to have a pharmacological action at a local site where skin, nose, oral cavity, rectum, vagina or the like is administered, or a systemic agent expected to have a systemic action. It is very useful as a drug.

The drugs that can be used with the compound of the present invention include
Steroidal or non-steroidal anti-inflammatory agent, bactericidal agent, anticancer agent, antibiotic, antifungal agent, antidiabetic agent, antihistamine agent, antiasthmatic agent, diuretic agent, local anesthetic agent, sex hormone agent, sleeping agent, muscle relaxant , Anticonvulsants, sedatives, antiarrhythmic agents, antihypertensive agents, antihypertensive agents, vasodilators, antianginal agents, tranquilizers, prostaglandins, vitamins, enzymes, peptides, hormones and the like. In addition, as the formulation form,
It can be used as each preparation such as ointment, gel, cream, aerosol, liniment, suppository, eye drop, plaster, pap and oral cavity.

Further, it can be incorporated into insecticides, agricultural chemicals, cosmetics and the like.

As described above in detail, the compound of the present invention has excellent characteristics such as efficacy of absorption promoting action, usefulness, and safety, and is extremely useful as an absorption promoter in the pharmaceutical industry.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical indication location A61K 47/22 E 7433-4C C07D 223/10 225/02 (A61K 31/395 31:40) 9360 −4C (A61K 31/55 31:40) 9360−4C Examiner Naoko Tsukanaka

Claims (1)

[Claims] 1. A general formula (I) (In the formula, R is an alkyl group, m is an integer of 5 to 7, and n is 3 to
An azacycloalkane derivative represented by (meaning an integer of 15).