JPS62215553A - Glycerol derivative and pharmaceutical preparation containing same - Google Patents

Abstract

NEW MATERIAL:A glycerol derivative of formula I (R1 is 8-18C alkyl or <=4C acyl; R2 is <=4C alkyl or <=4C acyl; R3 and R4 are <=18C alkyl). EXAMPLE:N-(2-methoxy-3-dodecyloxypropyl)-N-methylacetamide. USE:A compound effective in promoting the absorption of a drug-active component in living body. PREPARATION:The glycerol derivative of formula I can be produced by reacting a glycidyl ether compound of formula II with a primary amine of formula III, reacting the resultant secondary amine derivative of formula IV with an acylating agent of formula V to form a compound of formula VI and reacting the compound with an alkylating agent or acylating agent of formula VII.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel glycerin derivative, and more particularly to a glycerin derivative that has an effect of promoting the absorption of medicinal ingredients into living bodies, and a pharmaceutical preparation containing the same.

[Conventional technology]

In recent years, various studies have been conducted on substances that have the effect of promoting the permeability of drugs with low permeability to biological membranes.

Substances that promote the permeation of drugs into biological membranes include organic solvents that increase the solubility of drugs, such as zomethylnurfoxide, dimethylacetamide, and propylene glycol; Esters; amides such as N,N-diethyl-m-)lamide and 2-gyrolidone; lactams; surfactants such as sodium lauryl sulfate and polyoxyethylene sorbitan fatty acid ester, and the like are known.

Furthermore, recently, N-dodecyl-derolactam has been reported as a substance that has an effect of promoting drug permeation through biological membranes better than these conventionally known substances.

[Problem that the invention seeks to solve]

However, these substances have drawbacks and problems, such as insufficient effects and skin necrosis when applied to the skin. Therefore, it has been desired to develop a substance that has sufficient effects and is less irritating to the skin and the like.

[Means for solving problems]

As a result of intensive research in view of the current situation, the present inventors found that a novel glycerin derivative represented by the following general formula (I1) exhibits an excellent effect of promoting drug permeation into biological membranes, and is non-irritating to the skin, etc. He discovered something small and completed the present invention.

That is, the present invention relates to the following general formula (I1 (wherein R1 is an alkyl group having 8 to 18 carbon atoms or an acyl group having 4 or less carbon atoms, R7 is an alkyl group or acyl group having 4 or less carbon atoms, and The present invention provides a glycerin derivative represented by the following formula ( 几 represents an alkyl group having 18 or less carbon atoms) and a pharmaceutical preparation containing the same.

The glycerin derivative of the present invention represented by general formula (I) (
I) can be prepared, for example, according to the following reactions (a) and (b).

Reaction (I): (■) 1 (厘)
I(.

(In the formula, 几 and ~■4 are the same as above) Glycisol ethers (I) and -class amines (reacted to obtain a secondary amine conductor (M), which was then used as an acylating agent 6) to obtain compound (vI), which is further reacted with an alkylating agent or an acylating agent (■) to produce the glycerin derivative (I) of the present invention.

Here, glycysol ethers (l is octylglycisol ether, decylglycisol ether, dodecylglycisol ether, millinutylglycisol ether, cetylglycisol ether, stearylglycisol X-thyl, 2-ethyl) xyl glycysol ether,
Examples include methyl branched isostearyl glycysol ethyl, 2-hebutyl undecyl glycysol ether, and the like.

Primary amines (+++l include methylamine, ethylamine, n-propylamine, isozolopylamine,
n-butylamine, 1lee-butylamine, t・rl
-butylamine, n-pentylamine, 5ee-pentylamine, n-hexylamine, n-octylamine, n-decylamine, n-dodecylamine, n-
Examples include tetradecylamine, n-hexadecylamine, n-octadecylamine, and the like.

Acylating agents (■ include acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride; acetyl chloride, propionyl chloride, butanoyl chloride, hexanoyl chloride, octanoyl chloride, decanoyl chloride, dobnoyl chloride, tetra Examples include acid chlorides such as decanoyl chloride, hexadecanoyl chloride, and octadecanoyl chloride.

As alkylating agents, methyl iodide, ethyl iodide,
Examples include zorogyl iodide, 1-propyl bromide, 2-zorogyl bromide, 1-butyl bromide, and 2-butyl bromide.

Examples of the acylating agent (■) include acid anhydrides such as acetic anhydride, propionic anhydride, and butyric anhydride; acid chlorides such as acetyl chloride, propionyl chloride, butanoyl chloride, and the like.

The reaction between glycysol ethers +11 and primary amines group C is carried out by a conventional method, for example, without solvent or in a polar solvent such as alcohol, dioxane, tetrahydrofuran, dimethylformamide, etc. at -5 to 100°C for 10 minutes to 10 hours. This is easily done by stirring. The reaction between the secondary amine conductor (IT) and the acylating agent (■) is carried out by a conventional acylation reaction, for example, in the presence of a condensing agent such as an amine or an alkali hydroxide.
) with an alkylating agent is a normal alkylation reaction,
For example, metallic sodium, metallic lithium, sodium hydride, lithium hydride, n-butyllithium, II@C-
The reaction is carried out in the presence of a base such as butyllithium, lobethyllithium, sodium amide, etc., in an inert solvent such as ethers. Also compound (yl)
The reaction between the compound and the acylating agent (■) is carried out by the usual acylation reaction as described above.

Reaction (b): (Vl) (wherein IL and ~R4 are the same as above) Glycisol ethers C) and amides (■) are reacted in the presence of a base to obtain a compound (vl), Next, the glycerin derivative (
I) is produced.

Amides (■) include N-ethylacetamide, N
-ethylacetamide, N-butylacetamide, N-
Examples include methylzolopionamide, N-ethylzolopionamide, N-butylpropionic acid amide, and the like.

Examples of the base used in the reaction include metallic sodium, metallic lithium, sodium hydride, lithium hydride, a-butyllithium, 5et-butyllithium, Lark-butyllithium, sodium amide, etc.
Particularly preferred are lithium bases.

The reaction between glycysol ethers (I) and amides (■) is carried out in the presence of the above base in an inert solvent such as an ether or a hydrocarbon at a temperature of -5 to 150°C for 1 to 10 hours. It is often done. The reaction between compound (n) and the alkylating agent or acylating agent (■) is the same as in the reaction (a) above.

By blending the glycerin derivative (I) thus obtained with a medicinal ingredient, an excellent pharmaceutical preparation can be obtained.

The medicinal ingredients used in the present invention include steroidal anti-inflammatory agents such as prednisolone and dexamethacin, nonsteroidal anti-inflammatory agents such as indomethacin, flufenamic acid, and mefenamic acid, repernamine, incibencil,
Antihistamines such as ralpheniramine, cyphenhydramine, promethacin, sulfa such as sulfamonomethoxine and sulfamethizole ¥14. penicillin,
Cephalothrin, erythromycin, tetracycline, chloramphenicol, streptomycin antibiotics, naphthiomate, clotrimazole antifungal agents, 5-fluoro-racil, cyclophosphamide,
Anti-malignant drugs such as busulfan and actinomycin, morphine, codin, naalfin, pentazocine,
Analgesics such as aspirin, acetanilide, and aminovirine, prostaglancin preparations, hypnotics and sedatives such as barbital and thiobental, antipsychotics such as chlorzolomacin, reserpine, and chlorzoazeboxide, anti-8 birds, disease drugs, Anti-9-dialysis drugs such as chlorzolomasin, 1f-do, and Q; inotropes such as zochitoxin and digoxin; antiarrhythmic drugs such as procytoinamide hydrochloride and prosilanol hydrochloride; Cardiac drugs, anti-hyperpressure agents such as reserpine and guanethidine sulfate, ultraviolet inhibitors such as /♀laminopenzoate s ``tirunato'', melanin production inhibitors such as hydroquinone, vitamin C esters, and hydroxycinnamate. , 8-methoxypsoralen and other psoriatic PUs
VA treatment drugs, vitamins such as vitamin A, vitamin E, and vitamin C, insulin, estradiol, etc.

Hormone drugs such as methyldestosterone, diagnostic drugs 1. Q
Examples include, but are not limited to, allergens for testing.

Forms of the pharmaceutical preparation of the present invention include ointments, creams,
Examples include external preparations such as lozenges, tinctures, and a-johns; suppositories; oral preparations such as powders, granules, tablets, troches, and troches; and injections, among which external preparations are preferred.

The amount of glycerin derivative m to be added to a pharmaceutical preparation varies depending on the medicinal ingredient, form, etc., but for example, when adding it as an auxiliary agent to promote percutaneous absorption in an external preparation, the amount of glycerin derivative m added to the external preparation is 0.01 to 0.01. It is appropriate to add 5% by weight.

Furthermore, when used as a base for promoting transdermal absorption, it can be added in an amount of 10% by weight or more based on the total amount.

〔Effect of the invention〕

The glycerin derivative (I) of the present invention has an excellent effect of promoting drug permeation through biological membranes and is less irritating to the skin, etc., so pharmaceutical preparations containing it have improved absorption of the medicinal ingredients contained therein. , 4-f is effective and safe.

〔Example〕

Next, the present invention will be explained with reference to Examples.

Example 1 (+l N-(2-Hydroxy-3-dobushimixigumipyr)-N-methylacetamide: dodecylglycisol ether 24.29 (0.10 mol) p-dioxane 500- and methylamine aqueous solution (approx. 40%) 500
When the mixture was stirred at 15 to 20°C for about 5 hours, it changed from a cloudy state to an almost colorless and transparent homogeneous solution. The reaction mixture was repeatedly extracted with ether and the solvent was distilled off to obtain 25.49 g of pale white crude crystals. Subsequently, 1.2 g (o, tomol) of acetic anhydride was added to this under cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, acetic acid was distilled off from the reaction mixture to obtain a pale yellow oil. By purifying this with silica gel medium pressure column chromatography, N-(2
-human axy-3-dobushimixipropyl)-N-methylacetamide 26. Of'fr: Obtained.

Yield 82%.

(ii) N-(2-methoxy-3-dobushimixigumipyr)-N-methylacetamide: N! Into a 3001R14 Turow flask equipped with an inlet tube, reflux condenser, dropping funnel, and thermometer, add (+)T and 7'cN-(
2-Hydroxy-3-dobushimixigumipyr)-N-methylacetamide 15.8f (0,050 mol), TI
(F150Tnl was added, and NaH2,09 was added there. CH, I 7.8 y (0
, 055 mol) was added dropwise, and the reaction proceeded promptly. 150 ml of ether was added to the reaction mixture, and the mixture was washed several times with saturated brine. After drying the organic layer over anhydrous sodium sulfate, the desired N-(2-
16.39% of methoxy-3-totisyloxyzolovir)-N-methylacetamide was obtained. Yield 99%.

Example 2 N-(2-acetoxy-3-totisiloxyzorobyl)-
N-Methylacetamide: Example 1 (
I) 9N-(Z-hydroxy-3-1'7'siloxide avir)-N-methylacetamide 15.89(0
,050 mol), acetic anhydride 25.5 g (0.25 mol)
and triethylamine 0.51 g (0,005 mol)
was added and stirred at 80°C. After the reaction was completed, the reaction mixture was repeatedly extracted with ether, and the organic layer was concentrated under reduced pressure to obtain a pale yellow oil. By purifying this using a Rishikaguru short column, #1 was obtained as a colorless and transparent oil.
Totisyloxyzolovir)-N-methylacetamide 16
．． I got 69. Yield 93%.

Example 3 (i) N-(2-hydroxy-3-dobusyloxy 7”a
Methylacetamide 13.29 (0,1
8 mol) and 250 tR1 of p-dioxane were added, and the mixture was cooled in a water bath. n-Butyllithium/hexane solution (I
79. sg (o, equivalent to 18 moles) about 3
It was slowly added dropwise over 0 minutes.

After the dropwise addition was completed, the reaction mixture was gradually heated to 70°C.
36.3 g (0.15 mol) of -dodecyl glycisol ether was quickly added dropwise.

The mixture was then refluxed at 70-80°C for about 4 hours. After the reaction was completed, the reaction mixture was cooled and neutralized with 6N-hydrochloric acid.
Extracted with ether 300@7 and saturated brine 150ml, and the organic layer was further extracted with saturated brine 150ml! , and washed with 200 m of purified water. The aqueous layer was re-extracted with 100% ether, then combined with the organic layer and dried over anhydrous sodium sulfate. Purification using flash column chromatography (solvent: ethyl acetate) yields N-(
36.9f of 2-hydroxy-3-dodecyloxide-N-methylacetamide (#1) was obtained as a colorless and transparent oil. Yield 78%.

(ii) N-(2-hydroxy- obtained in (il)
N-(2-methoxy-3-dodecyloxide 0 pyl) was prepared in the same manner as in Example 1(ii) or Example 2 using 3-totisyloxyzorobyl)-N-methylacetamide.
-N-methylacetamide or N-(2-acetoxy-3-dodecymixypropyl)-N-methylacetamide was obtained.

Example 4 In the same manner as in Examples 1 to 3, glycerin visiting conductors shown in Table 1 were obtained. In addition, the compounds obtained in Examples 1 to 3 are also listed in Table 1.

The clues below *: “-’+**: δcoct.

neat Example 5 3 tons of N-(2-hydroxy-3-dodecyloxyfavir)-N-methylacetamide was mixed with 97 g of a commercially available gel-like external preparation Inchipan ointment (manufactured by Sumitomo Chemical Co., Ltd.) containing 1% of indomethacin. , an ointment (product 1 of the present invention) was obtained.

Example 6 3 g of N-(2-methoxy-3-dobusyloxyzorovir)-N-methylacetamide was mixed with 97 g of a commercially available gel-like external preparation Inchipan ointment (manufactured by Sumitomo Chemical ■) containing 1% by weight of indomethacin. An ointment (invention product 2) was obtained.

Example 7 N-(2
-acetoxy-3-hexadecyloxyzolovir)-N-
Ointment prepared by mixing methylacetamide 39 (invention product 3)
I got it.

Example 8 The transdermal absorbability of the indomethacin-containing external preparations obtained in Examples 5 to 7 was tested. The results are shown in Table 2. Comparative products 1 to 3 shown in Table 2 are as follows.

Comparative Product 1 Commercially available Inchipan ointment (manufactured by Sumitomo Chemical Co., Ltd.), a glue-like external preparation containing 1% by weight of indomethacin.

Comparative product 2 A liquid external preparation prepared by adding purified water to a mixture of indomethacin if, N, N-zoethyl-methatolamide 14f1 and ethanol 451 to make 100 g.

Comparative product 3 Indomethacin If, zomethyl sulfoxide 149,
A liquid external preparation made by adding purified water to a mixture of 45f of ethanol to make 100f.

〔Test method〕

Indomethacin percutaneous absorption test: Seven Japanese white female domestic rabbits weighing 3 Ky were used as 111 tons, and the normal depilated abdominal skin of each group of rabbits (I0cItX1
4α), the external preparation of the present invention and the comparative product were applied in an amount equivalent to indomethacin 2011LI, and 4 hours later,
After 10 and 20 hours, samples were taken from the ear vein, and the concentration of indomethacin in the plum was measured.

〔result〕

As is clear from the above results in Table 1, VC1 products 1 to 3 of the present invention all exhibited significantly higher percutaneous absorption of indomethacin than the comparative product.

that's all

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R_1 is an alkyl group having 8 to 18 carbon atoms or an acyl group having 4 or less carbon atoms, R_2 represents an alkyl or acyl group having 4 or less carbon atoms, and R_3 and R_4 represent an alkyl group having 18 or less carbon atoms. 2. General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is an alkyl group with 8 to 18 carbon atoms or an acyl group with 4 or less carbon atoms, and R_2 is an acyl group with 4 or less carbon atoms. R_3 and R_4 represent an alkyl group having 18 or less carbon atoms.