JPH0629253B2 - Azacycloalkane derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention provides a highly safe novel 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, the purpose is to develop an absorption enhancer that enhances drug permeability or permeability in transdermal and transmucosal administrations such as rectum, nasal cavity, oral cavity, and 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, it has hitherto been disclosed in Japanese Patent 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 description suggesting it.

(C) Problems to be Solved by the Invention In recent years, interest in the development of formulations 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, effective use of the drug is possible, and it is possible to relatively safely administer drugs with liver disorders 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,
Some administration methods such as rectal, buccal, nasal, and sublingual are difficult for some drugs to penetrate or permeate the relevant biomembrane,
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 research to develop a compound having an antibacterial action, it was found that an azacycloalkane derivative obtained by substituting an alkyl group having an ether bond at the N-position can sufficiently meet the purpose. The present invention has been completed.

(D) Means for Solving the Problems 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 of the general formula (I) will be described.
Alkyl groups are linear and branched such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl. It means a branched alkyl group.

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, etc.
Or in the presence of a phase transfer catalyst, such as tetrabutylammonium sulfate, in a solvent 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.
For about 0.5 to 20 hours under a nitrogen atmosphere or in the absence thereof to produce (II), to which an excess molar amount of dihalogenoalkyls is added to synthesize (III). Further, the obtained (III) and alcohols are treated in the presence of an alkali catalyst such as sodium alcoholate, sodium hydride or potassium hydroxide in an alcohol solvent or a solvent that does not participate in the reaction (for example, benzene, toluene, dimethylformamide, or Dimethyl sulfoxide, etc.) 2 at 0 to 300 ° C, preferably 0 to 100 ° C
The target compound (I) can be obtained by reacting for 10 hours.

Manufacturing method 2 (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.) Alcohol and an alkali catalyst such as sodium hydride or potassium hydroxide. In a solvent that does not participate in the reaction (for example, benzene, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, etc.) at 0 to 150 ° C. for 0.5 to 20 hours to produce (IV), which is excessive. (V) is synthesized by adding moles of dihalogenoalkyls. Furthermore, the alkali metal salt of lactam and (V) are used in a solvent that does not participate in the reaction.
The target compound (I) can be obtained by reacting at ˜300 ° C., preferably 0˜150 ° C. for 2˜24 hours.

Other manufacturing methods include the method shown below.

Manufacturing method 3 (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.) (E) Action The compound azacycloalkane derivative of the present invention is When it is mixed with an appropriate amount of a drug, it has the effect of significantly increasing the permeability or permeability of the drug.

Furthermore, the compound of the present invention has extremely weak local irritation and has 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 experiments.

Pharmacological Experiment 1 Percutaneous absorption accelerating action on Pindolol Male Wistar rats (body weight: about 200 to 250 g) were used as 4 animals per group. Propylene glycol containing 4% pindolol on the back shaved with electric clippers and razors /
The ethanol = 1: 1 solution was applied to 150 μ / 2.5 × 2.5 cm ² in a hermetically sealed manner. Blood was collected 3 hours after application, and Pindolo in the blood
The concentration was quantified by liquid chromatography. In addition,
Azone (1-n-dodecylazacycloheptane-), which is a known absorption enhancer used as a test compound and a comparative drug
2-on) and DMSO (dimethyl sulfoxide) were both comparatively examined at a 3% concentration.

The obtained results are shown in Table 1.

With the compound of the present invention, a remarkable increase in Pindolol absorption was observed as compared with the control group. In addition, the compounds of the present invention show an absorption promoting action in comparison with DMSO which is a known compound.
It is recognized that a good promoting action is exhibited even when compared with e.

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 Using the back skin of hairless mice (weight: 27 to 30 g), the effect of Phenol red, which is a poorly absorbable compound, on skin permeability was examined in vitro. That is, the back cell was attached to the diffusion cell, 0.5 m of physiological saline solution containing Phenol red 2 mM was added to the donor side, and physiological saline was added to the receptor side, and the amount of permeation of Phenol red to the receptor side was measured with an absorptiometer. It was measured at (OD559 nm).

The obtained results are shown in Table 2.

The amount of Phenol red permeated through the skin was extremely small in the control group, but the addition of 3% of the compound of the present invention exhibited a markedly increasing effect of about 35 times. Moreover, this effect was more remarkable than that of Azone used as a comparative compound.

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

That is, a patch test adhesive bandage was prepared by dropping 100 μl 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 to 3.0 kg) whose backs were shaved on the previous day 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 method of Draize.

The results obtained are shown in Table 3.

0-2 points-Mild 2-6 points-Medium 6-8 points-Strength Similar to the control group, the compound of the present invention showed almost no skin irritation. However, Az used as a comparison compound
A moderate stimulatory effect was continuously observed in one until 48 hours later.

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 conducted in rats by oral and subcutaneous administration.

That is, male wistar 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.

With the compound of the present invention, no abnormal symptoms or deaths were observed in both oral and subcutaneous routes of administration. In addition, in the case of oral administration, the stomach, intestine, and mucous membranes were administered subcutaneously, and in the case of subcutaneous administration, abnormalities in the dorsal skin and subcutaneous tissue were autopsied after 1 week of the test, but no abnormal findings were observed.

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-mentioned pharmacological experiments, the compound of the present invention is a DM compound of known compound for permeation / permeation of a drug through a biological membrane.
It has a stronger potentiating effect than SO and Azone.

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 described in detail with reference to Examples, but of course the present invention is not limited to these Examples.

Example 1 0.93 g of 60% sodium hydride and dry toluene 1
To a 00 m mixture was added dropwise a solution of 3.00 g of n-octyl alcohol in toluene. Reflux for 1 hour after the addition is complete, 1.
14.1 g of 3-dibromopropane was added and the mixture was refluxed for 12 hours.
Then, the insoluble matter was filtered, the filtrate was washed with water and dried, the solvent was distilled off, and a colorless transparent substance was obtained by distillation. Furthermore, 4.59 g of this substance was added to 2.07 g of azacycloheptan-2-one, 0.80 g of 60% sodium hydride and 15% of dry toluene.
The mixture was added to 0 m of the mixture and refluxed for 12 hours. The reaction solution was filtered to remove insoluble materials, the filtrate was washed with water and dried, and the solvent was distilled off under reduced pressure. Distillation gave 3.60 g of colorless 1- (3-octyloxypropyl) azacycloheptan-2-one.

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

Form Colorless transparent oil Boiling point 121-124 ℃ / 0.3mmHg Elemental analysis value C ₁₇ H ₃₃ NO ₂ Theoretical value C: 72.04 H: 11.73 N: 4.94 Measured value C: 71.92 H: 11.85 N: 4.91 Example 2 60% hydrogen Sodium iodide 1.32g and dry toluene 1
Azacycloheptan-2-one 3.39 in a mixture of 00m
g 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 was filtered off, the filtrate was washed with water and dried, and then the solvent was distilled off under reduced pressure and distilled to obtain a colorless transparent substance. Further, 5.65 g of this substance was added to a mixture of 2.64 g of n-heptyl alcohol, 1.00 g of 60% sodium hydride and 150 m of dry toluene and refluxed for 12 hours. The reaction solution was filtered to remove insoluble materials, the filtrate was washed with water and dried, and the solvent was distilled off under reduced pressure. Colorless 1- (4 by distillation
4.53 g of -heptyloxybutyl) azacycloheptan-2-one were obtained.

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

Form Colorless transparent oil Boiling point 117-122 ° C / 0.2mmHg Elemental analysis value C ₁₇ H ₃₃ NO ₂ Theoretical value C: 72.04 H: 11.73 N: 4.94 Actual value C: 71.96 H: 12.01 N: 4.92 Example 3 60% hydrogen Sodium iodide 1.32g and dry toluene 1
Azacycloheptan-2-one 3.39 in a mixture of 00m
g toluene solution was added dropwise. After completion of the dropwise addition, the mixture was refluxed for 1 hour, 20.7 g of 1,5-dibromopentane was added, and the mixture was refluxed for 12 hours. Then, the insoluble matter was filtered off, the filtrate was washed with water and dried, and then the solvent was distilled off under reduced pressure and distilled to obtain a colorless transparent substance. Further, 6.48 g of this substance was added to a mixture of 2.52 g of n-hexyl alcohol, 2.77 g of powdered potassium hydroxide and 30 m of dimethyl sulfoxide, and stirred at room temperature for 1 day. It was extracted with dichloromethane, washed with water and dried, and the solvent was distilled off under reduced pressure. Colorless 1- (5-
Hexyloxypentyl) azacycloheptan-2-one (4.16 g) was obtained.

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

Form Colorless transparent oil Boiling point 119-122 ° C / 0.2mmHg Elemental analysis value C ₁₇ H ₃₃ NO ₂ Theoretical value C: 72.04 H: 11.73 N: 4.94 Measured value C: 71.82 H: 11.63 N: 4.94 Examples 4-12 Examples The following compounds were synthesized according to the methods of 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.

Further, 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, nasal cavity, 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 nonsteroidal anti-inflammatory agent, bactericidal agent, carcinostatic agent, antibiotic, antifungal agent, antidiabetic agent, antihistamine, antiasthmatic agent, diuretic, local anesthetic, sex hormone, sleeping agent, muscle relaxant , Anticonvulsants, sedatives, antiarrhythmic agents, antihypertensive agents, blood vessel enhancers, anginal therapeutic agents, tranquilizers, prostaglandins, vitamins, enzymes, peptides, hormones and the like.

Further, as a formulation form, each formulation such as ointment, gel, cream, aerosol, liniment, suppository, eye drop, plaster, pap and oral cavity can be used.

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

As described in detail above, the compound of the present invention is characterized by being excellent in potency such as absorption promoting action, usefulness and safety, and is extremely useful in the pharmaceutical industry as an absorption promoting agent.

─────────────────────────────────────────────────── ─── 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 (72) Inventor Michijun Sakai 1412-13 Naratsu, Narazu, Kijima-cho, Mitsui-gun, Fukuoka Prefecture Naoko Tsukanaka, Examiner

Claims (1)

[Claims] 1. A general formula (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).