JPH0637463B2 - 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, 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, an azacycloalkane derivative obtained by substituting an unsubstituted or substituted phenoxyalkyl group or an unsubstituted or substituted benzoyloxyalkyl group at the N-position, The present invention has been completed by finding that it can sufficiently meet the purpose.

(D) Means for Solving Problems The present invention provides the following general formula (I) (In the formula, R ¹ and R ² are each a hydrogen atom, a lower alkoxy group, a hydroxyl group, a carboxyl group or a carbon number of C ₁ to
Means an alkoxycarbonyl group having C ₈ [wherein R
¹ and R ² are not both hydrogen atoms, and m is 3-5.
, N is an integer of 4 to 10, and p is an integer of 0 or 1).

The R ¹ and R ² of the general formula (I) will be described more specifically. The lower alkoxy group is methoxy, ethoxy,
Propoxy, butoxy and the like, an alkoxycarbonyl group having a carbon number of C _{1 to} C ₈ is a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl group, It is meant. Further, R ¹ and R ² also mean a hydrogen atom, a hydroxyl group and a carboxyl group, respectively, but both R ¹ and R ² are not hydrogen atoms.

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 and M'are alkali metal ions, X is a halogen atom or a mesyl group or a tosyl group, and m, n, p and R ¹ and R ² have the same meanings as described above.) Azacycloalkane-2 -One and an alkali catalyst, such as sodium alcoholate or sodium hydride,
Alternatively, in the presence of a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate, etc., in a solvent that does not participate in the reaction (eg, benzene, toluene, tetrahydrofuran, methanol, ethanol, dimethylformamide, dimethylsulfoxide, etc.), 0 to 300 ° C., preferably 0 ~ 1
(II) is produced by treating at 00 ° C. for about 0.5 to 20 hours in a nitrogen atmosphere or in the absence thereof, and an excess molar amount of dihalogenoalkyl is added to this to synthesize (III). Further obtained (III) and (IV) alkali salts, for example sodium salt or potassium salt without solvent or benzene, toluene, tetrahydrofuran, methanol,
In a solvent such as ethanol, dimethylformamide, or dimethyl sulfoxide, 0 to 300 ° C., preferably 80
The target compound (I) can be obtained by reacting at -100 ° C for about 5 to 25 hours in a nitrogen atmosphere or in the absence thereof.

Manufacturing method 2 (In the formula, M and M'are alkali metal ions, X is a halogen atom, a mesyl group or a tosyl group, and m, n, p and R ¹ and R ² have the same meanings as described above). When it is, it can also be manufactured by the following method.

Manufacturing method 3 (In the formula, M is an alkali metal ion, X is a halogen atom, a mesyl group or a tosyl group, m, n and R ¹ , R ²
Has the same meaning as above) Production Method 4 (In the formula, m, n, p and R ¹ and R ² have the same meanings as described above.) (E) Action The compound azacycloalkane derivative of the present invention can be incorporated into a drug in an appropriate amount so that the drug can be permeated. Alternatively, it has the effect of significantly increasing the permeability.

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.

(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 1.06 g 50% sodium hydride and 20 dry toluene
2.26 g azacycloheptan-2-one in 0 ml mixture
Of toluene solution was added dropwise. After the dropwise addition was completed, the mixture was heated under reflux for 1 hour, 17.3 g of 1,4-dibromobutane was added, and the mixture was refluxed for 17 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 to obtain a pale yellow substance. Further, this substance was added to a mixture of 3.50 g of sodium o-anisate and 100 ml of dimethylformamide to add 80 to 10
Heated at 0 ° C. for 8 hours. The mixture was extracted with ethyl acetate, washed with water and dried, and the solvent was distilled off under reduced pressure. Colorless 1- [4 by distillation
4.15 g of-(2-methoxybenzoyloxy) butyl] azacycloheptan-2-one was obtained.

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

Shape clear colorless oil boiling point 193~197 ℃ / 0.1mmHg Elemental analysis C ₁₈ H ₂₅ NO ₄ theory C: 66.65 H: 7.94 N: 4.32 Found C: 66.72 H: 7.84 N: 4.36 Example 2 50% hydrogen To a toluene solution of 1.06 g of sodium iodide, 3.04 g of methyl salicylate and 18.4 g of dibromopentane were added, heated at 100 ° C. for 3 hours, washed with water and dried, and the solvent was distilled off under reduced pressure. Further, the oil obtained by distillation and 2.7 g of sodium salt of azacycloheptan-2-one were heated in a toluene solvent at 100 ° C. for 5 hours, washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was distilled to obtain 4.90 g of colorless 1- [5- (2-methoxycarbonylphenoxy) pentyl] azacycloheptan-2-one.

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

Form Colorless transparent oil Boiling point 192-198 ° C / 0.2mmHg Elemental analysis value C ₁₉ H ₂₇ NO ₄ Theoretical value C: 68.44 H: 8.16 N: 4.20 Actual value C: 68.30 H: 8.19 N: 4.21 Example 3 50% hydrogen Sodium iodide 1.06 g and dry toluene 2
Azacyclopentan-2-one 1.96 in 00 ml of the mixture
After adding g of a toluene solution dropwise, the mixture was refluxed for 1 hour. Then, 22.4 g of 1,6-dibromohexane was added, and the mixture was further 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. This material was further added to a mixture of 3.82 g of ethyl salicylate, 1.21 g of 50% sodium hydride and 100 ml of dimethylformamide, and 8
Heated at 0-100 ° C for 15 hours. Then, the mixture was extracted with ethyl acetate, washed with water and dried, and the solvent was distilled off under reduced pressure. Colorless 1- [6- (2-ethoxycarbonylphenoxy) hexyl] azacyclopentan-2-one by distillation 3.29 g
Got

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

Form Colorless transparent oil Boiling point 181 to 186 ° C / 0.2mmHg Elemental analysis value C ₁₉ H ₂₇ NO ₄ Theoretical value C: 68.44 H: 8.16 N: 4.20 Actual value C: 68.52 H: 8.20 N: 4.09 Examples 4 to 23 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.
This compound has a significant enhancing effect on the permeability and permeability of the drug through biological membranes, and has a local irritation to biological membranes,
It has very low systemic toxicity and high 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.

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 833-1 Tadai Daikancho, Tosu City, Saga Prefecture (72) Inventor Akira Nakagawa 970, Fujikicho, Tosu City, Saga Prefecture (56) References 46-3824 (JP, A) JP-A-53-98816 (JP, A)

Claims (1)

[Claims] 1. A general formula (I) (In the formula, R ¹ and R ² are each a hydrogen atom, a lower alkoxy group, a hydroxyl group, a carboxyl group or a carbon number of C ₁ to
Means an alkoxycarbonyl group having C ₈ [wherein R
¹ and R ² are not both hydrogen atoms, and m is 3-5.
, N is an integer of 4 to 10, and p is an integer of 0 or 1.).