JPS6330465A - Cyclic compound - Google Patents

Abstract

NEW MATERIAL:A cyclic compound expressed by formula I (R is substituted amino; m is 2-7; n is 1-15). EXAMPLE:1-(4-Heptylaminobutyl)azacycloheptan-2-one. USE:Useful as an absorption promoter, having remarkable enhancing action on penetrability and permeability of chemicals through biomembranes as well as extremely weak local irritation to biomembranes, systemic toxicity, etc., exhibiting high safety, individually showing antimicrobial action and further utilizable as a drug for promoting drug transmission in not only medicines but also cosmetics which are quasi-drugs, agricultural chemicals, insecticides, etc. PREPARATION:For example, as shown in the reaction formulas, an azacycloalkan-2-one is reacted in the presence of a catalyst and the resultant compound is reacted with a dihalogenoalkyl. The reaction product is then reacted with an amine in the presence of a dehalogenating agent to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (a) Industrial 1 ＼ The present invention is a novel highly safe cyclic compound that increases the permeability and permeability of drugs, and has low stimulatory effects on biological membranes and low systemic toxicity. This invention relates to an azacycloalkane derivative consisting of the following.

In detail, drugs applied to biological membranes such as skin and mucous membranes,
That is, the objective is to develop an absorption enhancer that increases the permeability or permeability of drugs during transdermal and transmucosal administration such as rectal, nasal cavity, and vaginal administration.

Furthermore, the compound of the present invention can be used not only as a drug for promoting drug delivery, but also for cosmetics such as quasi-drugs, agricultural chemicals, insecticides, and the like.

Furthermore, another object of the present invention relates to an azacycloalkane derivative which has an effect of enhancing the absorption of drugs from biological membranes and also has an antibacterial effect itself.

(II+) Conventional technology Regarding azacycloalkane derivatives, there have been
Publication No. 2-1035, Japanese Unexamined Patent Publication No. 56-49316,
JP-A-57-142918, JP-A-58-210
It has been reported in JP-A No. 026, JP-A No. 58-210066, and the like. However, these known compounds having an absorption promoting effect are only related to derivatives having an alkyl group, a phenyl-substituted alkyl group, and a substituted or unsubstituted phenyl group as a substituent on the N-position. There is no disclosure at all, nor is there any statement that suggests it.

(c) Problems to be Solved by the Invention In recent years, interest in the development of formulations for transdermal absorption has been gradually increasing. The reason for this is that when a drug with expected pharmacological effects is administered transdermally locally or systemically, the persistence of the drug can be maintained, the absorption rate of the drug can be easily adjusted, and side effects due to overdosing can be prevented. The drug can be used effectively, with less metabolic influence due to the first-pass effect by the liver that occurs with oral administration, etc., and even drugs that cause liver damage can be administered in relatively safe doses. This is because it has the following advantages. However, since normal skin naturally has a protective effect against external stimuli, drug absorption and permeation are relatively difficult. Therefore, even if drugs are administered in the form of ointments, creams, gels, lotions, or patches, it is currently difficult to absorb the amount of drug required to fully exhibit the desired medicinal effect.

In addition, absorption routes from biological membranes other than the cortical layer, such as oral,
Even with administration methods such as rectal, oral, nasal, and sublingual administration, some drugs have difficulty permeating or permeating the relevant biological membranes, and many drugs have low bioavailability. Therefore, it has high permeability, permeability, and absorption through the skin and other biological membranes, exhibits sufficient pharmacological effects at practically used concentrations, and has low local toxicity and systemic toxicity, and is highly useful and safe for absorption. Accelerators are desired.

However, currently known absorption enhancers are not yet sufficient to increase the bioavailability of drugs that have low permeability and permeability through biological membranes, and may also cause skin irritation, tissue discoloration due to continuous administration, and serious side effects. However, there are still problems with its practicality, such as restrictions on general adaptation and usage.

Therefore, the present inventors have discovered that the present inventors have an absorption-promoting activity that is even superior to that of conventionally known dimethyl sulfoxide and azacycloalkane derivatives at practical concentrations.
As a result of extensive research in order to develop highly safe compounds, we discovered that azacycloalkane derivatives in which an alkyl group with an amine bond was substituted at the N-position were fully suitable for this purpose. It is a completed invention.

The present invention is based on the following general formula (1) (wherein, R is a substituted amino group, m is an integer of 2 to 7, and n is 1
(meaning an integer of 15 to 15).

To explain more specifically the substituted amino group of R in the general formula (I), the substituted amino group is (i)-Nl(-
R' (wherein R1 is an alkyl group having 1 to 20 carbon atoms (eg, methyl, ethyl, propyl, butyl).

Pentyl 2hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl.

Straight chain and branched alkyl groups such as tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, etc.], (rJ)l means an alkyl group. ], or (c) pyrrolidino group, piperidino group 1 morpholino group, piperazino group or -
In the NN-R3C formula, R3 is a lower alkyl group.

Lower alkyl group substituted with hydroxyl group, benzyl group.

Substituted benzyl group (for example, lower alkyl group, lower alkoxy group, hydroxyl group, halogen atom, trifluoromethyl group, nitro group, amino group as a substituent).

A cyclic amino group such as a carboxyl group or its ester, or (d)-NH-R' In the formula, R4 is a phenyl group, a substituted phenyl group (e.g., a lower alkyl group, a lower alkoxy group, as a substituent) hydroxyl group, halogen atom,
Trifluoromethyl group, nitro group.

amino groups) or heterocyclic groups (e.g. pyridyl).

Thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, pyrimidine, pyrazole, pyrazine, pyran, pyrrole.

pyridazine, etc.). ] means a substituted amino group consisting of.

The compound of the present invention can also be produced with good yield by the method described below or other known methods.

The method for producing the compound of the present invention will be exemplified below.

Production method 1 (In the formula, M represents an alkali metal ion, X represents a halogen atom, mesyl group, or tosyl group, and R'-m and n have the same meanings as above) Azacycloalkan-2-one and an alkali catalyst , such as sodium flucorate 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 (such as benzene, toluene, tetrahydrofuran, methanol,
ethanol, dimethylformamide, dimethyl sulfoxide, etc.) 0 to 300°C, preferably 0 to 100°C
(II) is produced by treatment for about 0.5 to 20 hours in a nitrogen atmosphere or in the absence of nitrogen, and an excess molar amount of dihalogenoalkyl is added thereto to synthesize (I[I). Furthermore, the obtained (I[I) and amines were treated with a commonly known dehalogenating agent (for example, 1,5-diazabicyclo(4,
3,0)nene-5 (DBN), 1,8-diazabicyclo(5,4,O)undecene-7 (DBU), etc.) in an inert solvent that does not participate in the reaction (e.g. benzene,
toluene, tetrahydrofuran, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, etc.) 0 to 300°C, preferably 0 to 100°C
The target compound (1) can be obtained by treating for about 0.5 to 3 days in a nitrogen atmosphere or in the absence of nitrogen.

Production method 2 Dehalogenating agent amines X (CHz) nX
□ (where M is an alkali metal ion, X is a halogen atom, mesyl group or tosyl group,
RSm %n has the same meaning as above) Dehalogenating agent, molar excess of dihalogenoalkyl and a solvent that does not participate in the reaction (e.g. benzene, toluene,
(2) is synthesized by adding amines to a mixture of (tetrahydrofuran, dimethylformamide, dimethylsulfoxide, etc.) at full moon and reacting at 0 to 100°C for about 0.5 to 3 days. Furthermore, azacycloalkane-2
The target compound (I) can be obtained by reacting the metal salt of -one and (r'/) at 0 to 300°C, preferably 0 to 150°C for about 2 to 24 hours in a solvent that does not participate in the reaction. .

(f) Effect The compound azacycloalkane derivative of the present invention has the effect of significantly increasing the permeability or permeability of a drug when incorporated in an appropriate amount with a drug.

Furthermore, the compounds of the present invention have extremely low local irritation and have extremely low toxicity in acute toxicity tests.

Furthermore, the compound of the present invention itself has antibacterial activity.

K) Refreshing Examples The present invention will be specifically explained below using examples, but of course the present invention is not limited only to these examples.

Example 1 A toluene solution of 2.26 g of azacyclohebutan-2-one was added dropwise to a mixture of 0.88 g of 60% sodium hydride and 200 ml of dry toluene.

After the full moon was over, the mixture was heated under reflux for 1 hour, 17.3 g of 1,4-dibromobutane was added, and the mixture was refluxed for 18 hours. Next, insoluble materials were removed by filtration, the filtrate was washed with water and dried, and then the solvent was distilled off. 3.92 g and n of oil obtained by distillation
A benzene solution of 2.64 g of 1,8-diazabicyclo(5,4,0)undecene-7 (DBU) was added dropwise to a mixture of 1.82 g of -hebutylamine and 50 ml of benzene, followed by stirring at room temperature for one day. The reaction-completed solution was then washed with water and dried, and the solvent was distilled off under reduced pressure. Colorless 1-
(4-hebutylaminobutyl)azacyclohebutane-2
-one 3.16 g was obtained.

However, the distillation was carried out using a glass tube oven GTO-25OR rotary type manufactured by Shibata Kagaku Kikai Kogyo. (Hereinafter, it will be referred to as column temperature.) The shape, column temperature, and elemental analysis values of this substance were as follows.

Shape Colorless transparent oil column Temperature 129-133℃ 10.2mmHg Elemental analysis value C+43JzO Theoretical value C near 2.29 H: 12.13 N: 9.9
2 actual measurement value C near 2.18) 1:12.10 N:9
．． 85 Example 2 A toluene solution of 1.70 g of azacyclohebutan-2-one was added dropwise to a mixture of 0.88 g of 60% sodium hydride and 200 ml of dry toluene, and the mixture was heated under reflux for 1 hour. Then 19.5 g of 1,6-dipromohexane
was added, and the mixture was further heated under reflux for 15 hours.

The reaction product was then washed with water and dried, and the solvent was distilled off under reduced pressure.

1,8-Diazabicyclo(5,4,0)undecene-
A solution of 2.54 g of 7-(DBU) in benzene was added dropwise, followed by stirring at room temperature for one day. The mixture was then washed with water and dried, and the solvent was distilled off under reduced pressure. Distillation produces colorless 1-(6(2-methylpropylamino)hexyl)azacyclopenkune-2.
2.06 g of -one was obtained.

The shape, column temperature, and elemental analysis values of this substance were as follows.

Shape Colorless transparent oil column temperature 117-121°C 10.2mdg Elemental analysis value C+sHtmNzO Theoretical value C: 69.95 H: 11.74 N: 11.
65 actual measurement value C: 69.98 H: 11.62 N: 1
1.64 Example 1 Example 3 l-(6-bromohexyl)azacyclopentane-2-
1,8-cyazabicyclo(5,4,O)undecene-7 (DBU) 3,
34 g of benzene solution was added dropwise and then stirred at room temperature for 1 day. The reaction-completed solution was then washed with water and dried, and the solvent was distilled off under reduced pressure. 2.62 g of 1-(6-dinithylaminohexyl)azacyclopenkun-2-one, colorless by distillation
I got it.

The shape, column temperature, and elemental analysis values of this substance were as follows.

Shape Colorless transparent oil column Temperature 108-113℃ 10.2mmHg Elemental analysis value C+JzaJO Theoretical value C: 69.95 H: 11.74 N: 11.
65 actual measurement value C: 69.89 H: 11.71 N: 1
1.63 Examples 4 to 12 The following compounds were synthesized according to the methods of Examples 1 to 3.

The azacycloalkane derivative of the present invention is a compound having a novel structure synthesized for the first time by the present inventors.

This compound has a remarkable effect of enhancing the permeability and permeability of drugs through biological membranes, and has local irritation to biological membranes.
It has extremely low systemic toxicity and is highly safe.

In addition, the composition containing the compound of the present invention together with a drug can be used as a topical drug expected to have a pharmacological effect at the local site of administration, such as the skin, nose, oral cavity, rectum, or vagina, or as a systemic drug expected to have a systemic effect. It is very useful for both medicines.

In addition, drugs that can be used with the compound of the present invention include:
Steroidal or nonsteroidal anti-inflammatory agents, bactericidal agents, anticancer agents, antibiotics, antifungal agents, antidiabetic agents, antihistamines, antiasthmatic agents, diuretics, local anesthetics, sex hormones, sleeping pills, muscle relaxants , antispasmodic agents, sedatives, antiarrhythmic agents, antihypertensive agents, vascular enhancers, angina treatment agents, tranquilizers, prostaglandins, vitamins, enzymes, peptides and hormones, etc.

In addition, the formulations include ointments, gels, creams, aerosols, liniments, herbal medicines, eye drops, plasters, poultices, and oral preparations.

Furthermore, it can be added to insecticides, agricultural chemicals, cosmetics, etc.

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

Patent applicant Hisamitsu Pharmaceutical Co., Ltd. Representative Hirotaka Nakatomi Procedural amendment 0. Eh, October 15, 1988 Patent Application No. 175346, 1988 4. Date of amendment order Voluntary action 5. Subject of amendment (1) No. 7 in column ``3. Detailed description of the invention'' in the specification In the second line from the top, correct the word "wait" to read i or j.

(2) In the same book, page 12, 4th line from the top, rl, 4-J
I did not correct the statement as '1.4-'.

(3) In the same book, the phrase ``azacyclohebutan-2-one'' in lines 8 to 9 from directly above No. 13 is corrected to ``azacyclopentan-2-one j.

(4) In the same book, page 13, line 10 from the top, rl, 6-
Correct the text "J" to '1.6-J.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R is a substituted amino group, m is an integer from ¥2 to ¥7, n
means an integer of 1 to 15).