JPH0637462B2 - Azacycloalkane derivative and absorption promoter containing the derivative as an absorption promoting active ingredient - 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. The present invention relates to an alkane derivative and an absorption enhancer containing the derivative as an absorption enhancing active ingredient.

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, 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 studies 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 Problem The present invention has the following general formula (I) (In the formula, R is an alkyl group, m is an integer of 2 to 4, and n is 4 to
(Meaning an integer of 15). The present invention also relates to an absorption enhancer containing at least one compound selected from the azacycloalkane derivatives represented by the above general formula (I) as the absorption enhancer active ingredient.

More specifically, R of 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 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.
(II) is produced 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 alcohols in the presence of an alkali catalyst, such as sodium alcoholate, sodium hydride, potassium hydroxide, etc., in an alcohol solvent or a solvent that does not participate in the reaction (for example, benzene, toluene, dimethylformamide, or Dimethyl sulfoxide, etc.)
The target compound (I) can be obtained by reacting at 0 to 300 ° C, preferably 0 to 100 ° C for 2 to 10 hours.

Manufacturing method 2 (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.) Alcohol and alkali catalyst, for example, sodium hydroxide or potassium hydroxide And the like in a solvent that does not participate in the reaction (for example, benzene, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, etc.) at 0 to 150 ° C. for about 0.5 to 20 hours to produce (IV). An excess mole of dihalogenoalkyls is added to synthesize (V). 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 The compound has an action of remarkably increasing the permeability or permeability of the drug when blended in an appropriate amount with 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-Promoting Action for Pindolol Male Wistar rats (body weight: about 200 to 250 g) were used as one group consisting of 4 rats. 150 μl / 2.5 × propylene glycol / ethanol = 1: 1 solution containing 4% Pindolol on the back shaved with an electric clipper and an electric razor
2.5 cm ² was applied by sealing. Blood was collected 3 hours after application
Pindolol concentration was quantified by liquid chromatography. The test compound and Azone (1-n-dodecylazacycloheptan-2-one) and DMSO (dimethyl sulfoxide), which are known absorption enhancers used as comparative drugs, were compared and examined at a concentration of 3%.

The results obtained are shown in Table 1.

Magnification = blood concentration of test compound / blood concentration of control group The compound of the present invention shows a remarkable pindolol content as compared with the control group.
Increased absorption was observed. Further, the compound of the present application is a known DMSO.
In comparison with Azone And ratio
It is recognized that a good absorption promoting action is exhibited even by comparison.

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.

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

Example 1 1.43 g of 60% sodium hydride and dry toluene 1
Azacyclopentan-2-one 2.76 in a mixture of 00 ml
g toluene solution was added dropwise. After completion of the dropwise addition, the mixture was refluxed for 1 hour, 21.1 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,
A colorless transparent substance was obtained by distilling off the solvent under reduced pressure and distilling. Further, 5.95 g of this substance was added to a mixture of 1.57 g of n-heptyl alcohol, 3.02 g of powdered potassium hydroxide and 30 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 1 day. Extract with dichloromethane, wash with water, dry,
The solvent was distilled off under reduced pressure. Colorless 1- (4-heptyloxybutyl) azacyclopentan-2-one by distillation 2.69
g was obtained.

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

Form Colorless transparent oil Boiling point 108-112 ℃ / 0.2mmHg Elemental analysis value C ₁₅ H ₂₉ NO ₂ Theoretical value C: 70.54 H: 11.44 N: 5.48 Actual value C: 70.62 H: 11.37 N: 5.53 Example 2 60% hydrogen Sodium iodide 1.54g and dry toluene 1
Azacyclopentan-2-one 2.98 in 00 ml of the mixture
g toluene solution was added dropwise. After completion of the dropwise addition, the mixture was refluxed for 1 hour, 25.6 g of 1,6-dibromohexane 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 and transparent substance. Further, 6.82 g of this substance was added to a mixture of 1.21 g of n-pentyl alcohol, 0.55 g of 60% sodium hydride and 150 ml 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- (6 by distillation
-Pentyloxyhexyl) azacyclopentane-2-
Obtained 2.83 g of on.

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

Form Colorless transparent oil Boiling point 111-115 ° C / 0.2mmHg Elemental analysis value C ₁₅ H ₂₉ NO ₂ Theoretical value C: 70.54 H: 11.44 N: 5.48 Actual value C: 70.57 H: 11.49 N: 5.66 Examples 3 to 7 Examples The following compounds were synthesized according to the methods 1 and 2.

(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. In addition, the composition containing the compound of the present invention with safety, a topical drug expected to have a pharmacological action at the administered local site such as skin, nose, oral cavity, rectum, vagina, or It is very useful for any systemic drug that is expected to have a systemic effect.

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.

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 (72) Inventor Yuji Shimozono 1 of 833 Tashiro Daikanmachi, Tosu City, Saga Prefecture (72) Inventor Masumi Katsuki 711 Iida, Zenjiji Town, Kurume City, Fukuoka Prefecture (72) Sakai Michijun 1412-13 Naratsu, Narazu, Kijima-cho, Mihama-gun, Fukuoka (56) Reference JP-A-53-98816 (JP, A)

Claims (2)

[Claims] 1. A general formula (I) (In the formula, R is an alkyl group, m is an integer of 2 to 4, and n is 4 to
An azacycloalkane derivative represented by the formula: 2. General formula (I) (In the formula, R is an alkyl group, m is an integer of 2 to 4, and n is 4 to
An absorption promoter having at least one compound selected from the azacycloalkane derivatives represented by the formula (1) as an absorption-promoting active ingredient.