JPS6163617A - Anti-inflammatory drug - Google Patents

Abstract

PURPOSE:An anti-inflammatory drug having extremely low toxicity, containing a dioxaphosphorane derivative as an active ingredient. CONSTITUTION:An anti-inflammatory drug containing a compound (e.g., compound shown by the formula II, etc.) shown by the formula I (R<1> is 1-25C straight-chain or branched alkyl; R<2> is 1-6C straight-chain or branched alkyl; A is 1-6C alkylene) as an active ingredient. Oral administration, injection, external preparation, suppository, etc. may be used as administration method. A dose is 0.1-1,000mg/kg/day in the case of oral administration, and preferably 0.01-1,000mg/kg/day in the case of injection. In the case of external preparation, a proper amount of external preparation containing 0.01-10wt% compound shown by the formula I is locally applied to the affected part. In the case of suppository, addition of another anti-inflammatory drug, various natural extracts, etc., to suppository can raise anti-inflammatory effects, and usable further as a remedy for hemorrhoids.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to anti-inflammatory agents.

[Conventional technology]

Anti-inflammatory agents can be broadly classified into three categories: steroids, non-steroids, and anti-inflammatory enzyme agents, and the present invention belongs to non-steroids.

Conventionally, aspirin, phenylbutacin, indomethacin, flufenamic acid, mefenamic acid, ibufenac, aminopurine, etc. are known as main non-steroidal drugs.

[Problem that the invention seeks to solve]

However, these conventional non-steroidal drugs are ineffective against infectious inflammation, have extremely low effects when used externally, are relatively toxic, and have a strong gastric irritating effect, so they have drawbacks such as being prone to gastric ulcers. had.

[Means for solving problems]

The present inventor focused on dioxaphosphorane derivatives under such circumstances, and while intensively searching for their pharmacological activity, found that a specific dioxaphosphorane derivative, which has a completely different basic structure from conventional non-steroidal drugs, was found to have anti-inflammatory properties. The present invention was completed based on the discovery that it has an inflammatory effect and has extremely low toxicity.

That is, the present invention provides general formula (I) R20-CH.

(In the formula, R1 represents a straight chain or branched alkyl group having 1 to 25 carbon atoms, R2 represents a straight chain or branched alkyl group having 1 to 6 carbon atoms, and A represents an alkylene group having 1 to 6 carbon atoms.) R1 in formula I) is, for example, methyl, ethyl, n-propyl, inpropyl, butyl, -butyl,
Pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl,
Examples thereof include tocosyl, tricosyl, tetradecyl, bentacosyl, etc. Among them, an alkyl group having 7 or more carbon atoms is preferred.

As A in formula (I), for example, ethylene, propylene, and butylene groups are particularly suitable.

Note that the dioxaphosphorane derivative represented by the general formula (I) includes all optical isomers based on asymmetric carbon atoms in the molecule.

Dioxaphosphorane derivatives represented by general formula (I) include He1v, Chln, Acta, 65, 1
059 (I982), by a known method disclosed in JP-A-59-67295. Specific production examples of these substances are described in the [Example] section as reference examples.

The anti-inflammatory agent of the present invention can be administered by oral administration, injection (intravenously, subcutaneously, intramuscularly), externally, suppositories, and other methods, and can be used in various forms depending on the administration method.

In the case of oral administration, the anti-inflammatory agent of the present invention can be used in either a solid preparation or a liquid preparation. Examples of solid preparations include tablets, granules, powders, capsules, and sugar-coated preparations. These solid preparations can contain additives such as excipients such as sugars and celluloses, binders such as starch paste and methylcellulose, and fillers and disintegrants that are commonly used in preparations. Oral liquid preparations can be in the form of internal solutions, suspensions, emulsions, syrups, and the like. In the case of oral administration, the dose may be adjusted depending on the symptoms, age, dosage form, etc., but it is preferably in the range of 0.1 to 10 o OrvlCf per day for adults.

In the case of injection, the anti-inflammatory agent of the present invention is used in the form of an aqueous solution, a suspension, an oily liquid or aqueous emulsion, among others,
It is preferable to use it by dissolving it in an aqueous liquid medium such as sterile water or physiological saline. Furthermore, if necessary, solubilizers, stabilizers, preservatives, tonicity agents, etc. commonly used in injection solutions can be added. Injectable solutions are administered by intravenous injection, intramuscular injection, subcutaneous injection, or the like. The dosage may be adjusted depending on symptoms, age, dosage form, administration method, etc.
For example, when injecting into adults, 0.01 to 1000η per day
/Ky range is preferable.

For external use, the anti-inflammatory agent of the present invention can be used in various forms, such as lotion, milk, cream,
Preferably, the composition is in the form of an ointment, a stick, a disinfectant made by adding ffi M to an organic solvent, a pack, a gel, or the like. These external preparations may contain oily substances, moisturizers, thickeners, preservatives, emulsifiers, medicinal ingredients, fragrances, emulsion stabilizers, and the like during formulation. Furthermore, by incorporating other anti-inflammatory agents, various plant extracts, etc., the anti-inflammatory effect can be improved. For the external preparation, for example, in the case of adults, a preparation containing 0.01 to 10% by weight of the compound (I) of the present invention may be applied to the relevant area by topical VC in an appropriate amount at appropriate times.

In the case of suppositories, the anti-inflammatory agent of the present invention includes, in addition to the suppository base,
As optional ingredients, oily substances, emulsifiers, medicinal ingredients, emulsion stabilizers, etc. can be used in combination. In addition, the anti-inflammatory effect can be improved by adding other anti-inflammatory agents, natural product extracts, etc., and it can also be used as a therapeutic agent for hemorrhoids.

[Effect]

Next, the results of testing the pharmacological action of dioxaphosphorane derivative (I) are shown.

(I) Acutely toxic dioxaphosphorane derivative rl) was found to have 2 f/Kg orally administered to ICR mice as a result of an acute toxicity test.
No deaths were observed even at the maximum dose (maximum dose that can be administered), indicating extremely low toxicity.

(I1) Effect on suppressing edema The effect of carrageenan on rat paw edema was tested by the following method. The results are shown in Table 1.

(Test Method) The following experiment was conducted using 6-week-old male Wistar rats with a body weight of 120 to 1,502 kg per group (8 rats).

After orally administering the drugs shown in Table 1 (20 cm/kg), the hindlimb stepping volume was measured. After 1 hour, carrageenin (I
%, 0.1 me) was subcutaneously injected into the kick to give an inflammatory stimulus, and changes in the kick volume were measured 6 hours later. The edema rate and edema suppression rate were calculated using the following formulas.

As is clear from Table 1, dioxaphosphorane derivatives have anti-inflammatory effects.

〔Effect of the invention〕

As mentioned above, the anti-inflammatory agent of the present invention can be administered orally, by injection, by application on the skin, by suppository, etc., to achieve anti-inflammatory,
It exhibits antipyretic and analgesic effects), is extremely safe, and has little irritating effect.

〔Example〕

The present invention will be explained with reference to the following reference examples and examples.

Reference Example 1 CH2OCH2 (Ita) 1-o-octadecyl-3-o-methylglycerol While stirring 35.8P of phosphorus (Ita), 100mj of benzene, and 12.IP of triethylamine at room temperature, 2-chloro-2-okino was added. 1,3,2-dioxaphosphorane (
I) A 14.3 F benzene 100 solution is added dropwise over 0.5 hours. After the addition was completed, the mixture was stirred at room temperature for 6 hours, and then triethylamine hydrochloride was filtered off and the solvent was distilled off. 100 ml of n-hexane is added to the residue to perform recrystallization. The obtained crystals are dissolved in 100% n-hexane and washed with 200 ml of saturated saline. After separating the n-hexane layer and drying, the n-hexane is distilled off to obtain the desired product (I) as colorless crystals.
a) (mp, 50-50.5°C) 30. Of is obtained (yield 65%).

IR spectrum (liquid film): 2920.2850.1455.1285.1105.
1020.925.840 cm-' PMR spectrum (CDCt,) δ: 0.86 (3H, t, 5.0 Hz), 1.27
(32H), 3.35 (3H, S), 3.3-44 (I
1H, m) Elemental analysis value (Cz+H4*OsP) Calculated value C62,06Hlo, 63 Actual value C62,35Hlo, 59 Reference Examples 2 to 3 In the same manner as Reference Example 1, expressed by the above formulas (Ib) and (Ic) A dioxaphosphorane derivative was synthesized.

Example 1 Compound (Ia)s□η obtained in Reference Example 1 was thoroughly mixed with crystalline cellulose 630rn9 and carboxymethyl cellulose sodium salt, and the mixture was compressed to make tablets.

Example 2 10μ of Compound (Ia) obtained in Reference Example 1 was dissolved in 1 ml of physiological saline, made into a 1% solution by aseptic operation, filtered,
Example 3 (Composition) ■ Dioxaphosphorane derivative (lb) 1.0
Weight%■ Prednisolone O, OS■
Set up
0.1 ■ Egg yolk lecithin
5.0■ Ethyl aminobenzoate
1.00■ Incacao (Hanadamaishi@C Co., Ltd., suppository base) balance meter 100 ■~■ were heated at 60°C and mixed well, then 1.5
Formulate the product using a 1-sized manufacturing mold.

Example 4 (Composition) ■ Dioxaphosphorane derivative ([,) 1.00
Heavy tS■ Hydrocortisone 0.05■
dt-tocopherol acetate 1.00■ Allantoin 1.00■ Ethyl aminobenzoate 1.50■ Incacao (same as Example 3) Balance meter 100 Heat ■～■ at 60℃, mix well, and then transfer to 12 Formulate using a suppository manufacturing mold.

Example 5 (Composition) ■Vaseline 10.0% by weight■
Lanolin 4.5■ Inpropyl myristate 5.0■ Stearyl alcohol 5.0■ Liquid paraffin
4.5■ Benzoic acid propyl ester 0.1
■ Rubitan monostearate 260 ■ Glycerol monostearate 2.0% by weight ■ Polyoxyethylene rubitan monostearate 1.5 ■ Benzoic acid methyl ester 0.1 ■ Dioxaphosphorane derivative (Io) 1.00 Purification water
Balance meter 100 ■Heat O at 70°C, and while stirring gently, gradually add ■ to ■0, which were also heated to <70°C, and emulsify. This is then cooled to form a hemorrhoid ointment.

Example 6 (Composition) ■ Dioxaphosphorane derivative (Ia) 1. o Weight % ■ Silicone 25. O■ Jojoba oil 25.0■ Squalene balance■■ Warm to 50℃,
After adding (2) and sufficiently dissolving it, add (2) and mix well. The product of the present invention is filled into a spray bottle and used in the following method.

That is, after a person with hemorrhoid disease has defecated, the product of the present invention can be used to finish wiping the area after defecation, and the product of the present invention can be used to clean the area around the anus. Use methods such as wiping.

Example 7 (Composition) Glycerin 40% by weight dioxaphosphorane derivative (Ib) t.

Polyoxyethylene hydrogenated castor oil 1.5 Ethanol 10.0 pid Sodium IJtoncarboxylate 2.0 Fragrance
Trace purified water 10 remaining
0.0 Example 8 W10 cream type anti-inflammatory agent: (Composition).

Dioxaphosphorane derivative (LC) to heavy duty cetanol 0.5 vase
6.0 Rubitan Sesquiolate 2.0 Cholesterol
0.6 Liquid Lanolin 4.
0 Isopropyl palmitate 8.0 Squalane 10.0 Solid paraffin 4.0 Butyl paraben
0.1 methylparaben
0.1 glycerin
3.0 Fragrance 0.2 Purified water Nokurance Example 9 Q/W cream-type anti-inflammatory agent: (Composition) Stearic acid 2.0% by weight Dioxaphosphorane derivative (Ia) 1.0 Cetanol 4.0 Vaseline
5.0 Squalane
8.0 Hydrogenated palm oil 4
．． 0 Polyoxyethylene rubitan monostearate (20E, O) 1.4 Lipophilic glycerin monostearate 2.4 Butyl paraben
0.1 methylparaben
0.1 Glycerin 3
．． 0 dipropylene glyco-tb 3.
QL-arginine 10.0 Potassium hydroxide 0.2 Purified water
Balance Example 10 Ointment-type anti-inflammatory agent: (Composition) Dioxaphosphorane derivative (Ib) 1.0! i
i% White Petrolatum 99.0 Example 11 Liquid anti-inflammatory agent: (Composition) Dioxaphosphorane derivative (Ic) 1.0% by weight Ethanol 99.0 Example 12 Cream shampoo c Pearl-like): (Composition) Di Oxaphosphorane derivative (I,) 1% by weight
Alkyl sulfate triethanolamine salt (As-TEA)
15 coconut fatty acid monoethanolamide 5 ethylene glycol monostearate 2 protection! Island agent, pigment, fragrance, trace amount of water
Nokurance Example 13 Anti-dandruff shampoo: (Composition) Dioxaphosphorane derivative (Ib) 1% by weight alkyl sulfur rfjR triethanolamine salt (As-TEA)
15 Lauric acid diethanolamide 3 Polyacrylic acid triethanolamine salt 0.5zpt
1 dye,
Fragrance trace water
Hair lance Example 14 Cream rinse: (Composition) Dioxaphosphorane derivative (Ic) 1.0 weight stearyldimethylbenzyl ammonium chloride 1
．． 4 Stearyl alcohol 0.6 Glyceryl monostearate 1.5 Salt 0.2 Water
Balance Example 15 Oil rinse: (Composition) Dioxaphosphorane derivative (Ia) 1.0it
% stearyltrimethylammonium chloride 2
．． 0 polyoxyethylene cetyl ether 10~
1.5 polyoxyethylene lanolin ether
3.0 Propylene glycol 5.0 Citric acid 0.1 Citric and sodium 0.15 Butyl paraoxybenzoate 0.05 Paraoquin benzomethyl 0.1 Fragrance
0.2 water
Noirance Example 16 Condesyonin rinse: (Composition) Dioxaphosphorane derivative (Ib) i, o wt% modified starch 2.0 Phorioxyethylene cholesterol 1.0 Glyceryl monostearate 2.0 Silicone
0.2 fragrance
appropriate amount of water
Nozurance Example 17 Hair lotion: (Composition) Dioxaphosphorane derivative (IC) 1.0 weight t
S ethanol (95°), 79.5 Purified water 16,6 L-Menthol 0.4 Capsicum tincture
1゜0 resorcinol
0.5 Glycerin 0.
5 Mixed fragrance for hair lotion 1.5 Ethanol-soluble pigment Appropriate amount Example 18 Hair tonic: (Composition) Dioxaphosphorane derivative (I1)) 1.00% by weight Ethanol (95°) 80.65 Purified water 16.9OL- Menthol 0.40 Capsicum tincture
1.00 resorcinol
0.50 salicylic acid
0.30 Quinine Hydrochloride 0.05 Diethylstilbestrol o, ooi Glycerin 0.50 Camphor
0.10 Mixed fragrance for Yatonic
1.50% ethanol-soluble pigment Example 19 Toothpaste: (A) Dioxaphosphorane derivative (Ia) 1.0% dibasic calcium phosphate dihydrate 50.0% io.

Glycerin 10.0 Indium lariur sulfate 2.0 Carboquine methylcellulose 1°Fragrance
i.

Ginger oleoresin 0.2 Sodium monofluorophosphate 0.3 Ethanol
2゜0 Satukarin
0.1 Mutanase 0.
1 water balance meter 100 or more

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is a linear or branched alkyl group having 1 to 25 carbon atoms, R^ 2 represents a linear or branched alkyl group having 1 to 6 carbon atoms, and A represents an alkylene group having 1 to 6 carbon atoms.