JPH0751574B2 - Cyclic sulfoxide derivative and percutaneous absorption enhancer - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel cyclic sulfoxide derivative and its use as a percutaneous absorption enhancer for promoting permeation and absorption of a drug through the skin.

[Prior art]

The cyclic sulfoxide derivative of the present invention is a compound not described in the literature, and it has not been known at all that the cyclic sulfoxide is useful as a percutaneous absorption enhancer.

Drug delivery systems (DDS) are being actively researched for the purpose of more efficiently reaching the target site and suppressing side effects. Among these, in recent years, a percutaneous absorption system in which the skin is the application site of the drug has attracted attention. The advantages of this system are that it avoids the first-pass effect in the liver, the skin permeation rate of the drug is controlled, the blood concentration can be maintained continuously and constantly, the administration is not affected by food and vomiting, the administration is not regulated. Easy,
The point is that it can be administered near the target site. But,
At present, there are disadvantages such that the dose is limited to a relatively small amount of drug, the drug that can be used is limited, the deterioration of the stratum corneum and the skin allergic reaction may be promoted, and immediate effect cannot be expected. Therefore, in order to improve these points, the combined use of a percutaneous absorption enhancer is being studied.

So far, dimethyl sulfoxide, 1-dodecyl-2
-Pyrrolidone, 1-dodecylazacycloheptane-2-
The use of ON, urea, etc. has been proposed (supervised by Isao Kaetsu, Drag Delivery System, pages 213-237, CMC).

[Problems to be solved by the invention]

However, the accelerating effect of these is not always satisfactory, and the accelerating effect may be drastically reduced depending on the type of drug medium, and a more effective accelerating agent has been desired.

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, have found that a cyclic sulfoxide derivative having a specific substituent has an extremely excellent transdermal absorption promoting action and completed the present invention. It was

[Means for solving problems]

That is, the present invention has the general formula And a percutaneous absorption enhancer of a drug comprising the cyclic sulfoxide derivative represented by the formula (wherein R ¹ is a hydrogen atom,
An alkyl group or a lower alkenyl group, R ² is a branched or linear hydrocarbon group having 8 or more carbon atoms, and n is an integer of 1 to 4).

In the formula, the hydrocarbon group having 8 or more carbon atoms represented by R ² is a saturated group represented by C _m H _{2m + 1} , C _m H _2m-1 , C _m H _2m-3 , and C _m H _2m-5. Or an unsaturated branched or straight chain hydrocarbon group, m
Can be exemplified by 8 to 20. Of these, those having 10 or more carbon atoms, particularly those having 12 or more carbon atoms, are preferable because of their large promoting effect.

The cyclic sulfoxide derivative in the present invention has, for example, a general formula (Wherein R ¹ and n are the same as above), in the presence of a base, a general formula R ² X- (III) (wherein R ² is the same as above, X is Halogen atom,
It represents a tosyloxy group, a mesyloxy group, or a trifluoromethanesulfonyloxy group. It can be easily produced by reacting an alkylating agent represented by

Examples of the cyclic sulfoxide represented by the general formula (II) include tetramethylene sulfoxide, α-methyltetramethylene sulfoxide, α-ethyltetramethylene sulfoxide, α-n-propyltetramethylene sulfoxide, α.
Examples thereof include -i-butyl tetramethylene sulfoxide, trimethylene sulfoxide, pentamethylene sulfoxide, α-ethylpentamethylene sulfoxide, hexamethylene sulfoxide and α-n-pentylhexamethylene sulfoxide. Some of these compounds are commercially available and can be easily synthesized by alkylation of cyclic sulfoxide.

As the base, sodium hydride, potassium hydride, n
-Butyllithium, s-butyllithium, t-butyllithium, phenyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, phenylmagnesium bromide and the like can be mentioned, and they are usually equivalent to the cyclic sulfoxide of the general formula (II). To use 1.5 equivalents.

As the alkylating agent represented by the general formula (III), chloride, bromide, iodide, tosylate, mesylate, triflate and the like of the corresponding hydrocarbon group (R ² ) can be used, but in view of reactivity, bromide The following are preferable, and an amount according to the amount of base is usually used.

The reaction is preferably carried out in a solvent, and any solvent may be used as long as it does not participate in the reaction, and examples thereof include terahydrofuran, dimethoxyethane, dioxane, benzene, toluene and the like. The reaction temperature may be -100 ° C to 50 ° C, preferably -80 ° C to 30 ° C.

Further, among the cyclic sulphoxides of general formula (I) obtained by the above method, the raw materials that R ¹ is a hydrogen atom, the general formula ^{R 1 'X - (IV)} ( In the formula, R ^1' Is a lower alkyl group or a lower alkenyl group, and X is the same as the above.), And the R of the cyclic sulfoxide of the general formula (I) ^It is also possible to obtain one in which ¹ is a lower alkyl group or a lower alkenyl group.

The transdermal absorption enhancer comprising the cyclic sulfoxide derivative of the present invention is a tincture dissolved in a solvent such as water or alcohol together with the drug to be administered, or an ointment, an ointment mixed in a cream base, a cream, and It can be used in any form such as a tape preparation mixed in a polymer film or an adhesive.

The content of the absorption enhancer of the present invention varies depending on its use form, but is generally 0.1% by weight to 50% by weight, preferably 1% by weight to 20% by weight. In many cases, side effects such as skin irritation become significant and the drug release may be suppressed.

The drug used in the present invention may be any drug for humans or animals. For example, as an anti-inflammatory analgesic, acetaminophen, aspirin, methyl salicylate, choline salicylate, glycol salicylate, l-
Menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, fempfen, flurbiprofen, indoprofen, fentiazac, tolmetin, suprofen , Penzadac, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofezone, pentazocine, mepyrizole; as steroidal anti-inflammatory agents,
Hydrocorzotin, prednisolone, dexamethasone,
Triamcinolone acetonide, fluocinolone acetonide, fludrocortisone acetate, etc .; chlorpheniramine as an antihistamine or antiallergic agent,
Glycyrrhizic acid, diphenhydramine, periactin, etc .; local anesthetics include benzocaine, procaine,
Dibucaine, lidocaine, etc .; Antibacterial agents, etc., include tetracyclines such as chlortetracycline, penicillins such as ampicillin, cephalosporins such as cephalothin, aminoglycosides such as kanamycin, macrolides such as erythromycin, chloramphenicol, Iodo compounds, nitrofurantoin, nystatin, amphotericin, fradiomycin, sulfonamides, pyrrolenitrin, clotrimazole,
Nitrofurazone etc .; Clonidine as an antihypertensive agent,
α-methyldova, reserpine, syrosingopine, resinamine, cinnarizine, hydrazine, brazosin, etc .;
Antihypertensive diuretics include theophylline, trichloromethiazide, furosemide, tripamide, meticlotiazide, penfluzide, hydrothiazide, spironolactone,
Metrazone, etc .; cardiotonics, digitalis, ubidecarenone, dopamine, etc .; coronary vasodilators, nitroglycerin, isosorbitol-dinitrate, erythritol-tetranitrate, pentaerythritol tetranitrate, dipyridamole, dilazeb, trapidil, trimetazidine, etc. Vasoconstrictors such as dihydroergotamine, dihydroergotoxin; β-blockers or antiarrhythmic agents such as pindol and propranolol hydrochloride; calcium antagonists such as diltiazem, nifedipine, nicardipine, verapamil, bencyclane, dilazeb; antiepileptic agents Examples include nitrazepam, mefrobamate, phenytoin;
Anti-vertigo agents such as isoprenaline, betahistine, scopolamine; tranquilizers such as diazepam, lorazepam, flunitrazepam, fluphenazine, etc .; hypnotics such as phenobarbital, amobarbital, cyclobarbital; and muscle relaxants triperizone, baclofen. , Tantrolene sodium, cyclobenzaprine, etc .; atropine, levodova, etc. as agents for autonomic nerves; codeine, ephedrine, isoproterenol, dextromethorphan, orciprenaline, ipratropium bromide, as agents for respiratory organs
Cromoglycic acid etc .; Hormonal agents or antihormonal agents include corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol, salivary hormone, thyroid hormone, adrenal hormone,
Kallikrein, insulin, oxendron, etc .; as vitamins, vitamins A, B, C, D, E, K and their derivatives, calchepherols, mecobalamin, etc .; as antitumor agents, 5-fluoroolacil (5-FU) and Derivatives thereof, adriamycin, krestin, picibanil, ancitabine, cytarabine, etc .; enzymes such as urokinase; herbal medicines or herbal extracts such as licorice, aloe, purple root; antiulcer agents such as allantoin, aldioxa, alcloxa; and other prostaglandins Examples thereof include gins and antidiabetic agents.

If necessary, two or more of these drugs may be used in combination.

The drug preparation containing the percutaneous absorption enhancer of the present invention can be applied by applying a necessary amount to the skin and mucous membranes (oral cavity, nasal cavity, rectum, vagina) of various parts of the human body according to the purpose. For example, for local treatment of trauma, skin ulcer, myalgia, arthritis, etc., directly to the affected area or its vicinity, and for systemic treatment of internal organs, etc. (Example: Area where keratin is not developed)
It is preferable to apply to When used as a cosmetic, the above-mentioned preparations as they are or those containing known cosmetic ingredients selected from the above-mentioned drugs are used for the purpose of cleaning the skin, packing, measures against sunburn and rough skin, and moisturizing. Can be used.

Hereinafter, the present invention will be described in more detail with reference to Examples, Use Examples, and Comparative Examples.

Examples 1-3 Sodium hydride 0.48g and tetramethylene sulfoxide
1.8 g was reacted in tetrahydrofuran at the boiling point of reflux for 30 minutes. After cooling, the amount of alkyl bromide shown in Table 1 was added, and the mixture was refluxed at the boiling point for 2.5 hours. The insoluble material was filtered and then purified by silica gel column chromatography to obtain the corresponding 2-alkyltetramethylene sulfoxide as a colorless oil. The results are shown in Table 1.

Example 4 0.54 g of 2-dodecyltetramethylene sulfoxide synthesized in Example 2 was dissolved in tetrahydrofuran, and 1.3 ml of a 15% hexane solution of n-butyllithium was added dropwise at -78 ° C. After stirring at 0 ° C. for 1 hour and at room temperature for 30 minutes, 0.2 ml of ethyl iodide was added at 0 ° C. and reacted overnight at room temperature. After treatment by a conventional method, the product was purified by silica gel column chromatography to obtain the desired product as a colorless oil. The results are shown in Table 2.

Example 5 0.41 g of pentamethylene sulfide and 0.94 g of sodium metaperiodate were reacted in methanol at room temperature for 5 minutes to synthesize pentamethylene sulfoxide (yield 0.40.
g). This sulfoxide was dissolved in tetrahydrofuran, 10 ml of a 1.3 M cyclohexane solution of s-butyllithium was added at -78 ° C, and the mixture was reacted for 1.5 hours. 2.6 ml of dodecyl bromide was added to this solution, and the mixture was reacted at room temperature for 1.5 hours. After treatment by a conventional method, purification was carried out by silica gel column chromatography to obtain 1.70 g of 2-dotecilpentamethylene sulfoxide as a colorless oily substance. ¹ H-NMR spectrum (chloroform-d ₁ ) 0.83 (t, 3H), 1.0 to 1.8 (m, 22H), 2.00 (m, 4H), 2.56
(M, 3H), 3.23 (m, 2H). Use Examples 1 to 4 Rabbit abdominal exfoliation skin is sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and anti-inflammatory agent indomethacin (1%) is added to the donor portion, the cyclic sulfoxide derivative of the present invention (transdermal absorption enhancer). 2 ml of a 60% aqueous solution of ethyl alcohol (2%) was added, 2 ml of a phosphate buffer was added to the receptor portion, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were sampled from the receptor portion 6 hours after stirring and 12 hours after stirring, and the permeated indomethacin was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 3. Further, Comparative Example 1 shows the case where no transdermal absorption enhancer was added.

Use Examples 5 to 7 Rabbit abdominal peeling skin is sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), anti-inflammatory agent indomethacin (1%) and donor percutaneous absorption enhancer of the present invention (2%) in the donor part. 2 ml of the ethyl alcohol solution described above was added, 2 ml of the phosphate buffer was added to the receptor portion, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were sampled from the receptor portion 6 hours after stirring and 12 hours after stirring, and the permeated indomethacin was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 4. Comparative Example 2 shows the case where no transdermal absorption enhancer was added.

Use Example 8 A rabbit abdominal peeling skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and β-blocker propranolol hydrochloride (1%) and the transdermal absorption enhancer (2%) of the present invention were used as donors. 2 ml of 60% ethyl alcohol aqueous solution, 2 ml of phosphate buffer solution in the receptor part, and the whole cell at 37 ℃
It was immersed in a constant temperature bath. Both chambers were sampled from the receptor portion 6 hours after stirring and 12 hours after stirring, and the amount of permeated propranolol hydrochloride was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 5.
Comparative Example 3 shows the case where no transdermal absorption enhancer was added.

Claims (2)

[Claims] 1. A general formula (Wherein R ¹ is a hydrogen atom, a lower alkyl group or a lower alkenyl group, R ² is a branched or straight-chain hydrocarbon group having 8 or more carbon atoms, and n
Is an integer of 1 to 4. ). 2. General formula A percutaneous absorption enhancer of a drug comprising a cyclic sulfoxide derivative represented by the formula (wherein R ¹ is a hydrogen atom, a lower alkyl group or a lower alkenyl group, and R ² is a branched or straight-chain carbon atom having 8 or more carbon atoms. It is a hydrogen group, and n is an integer of 1 to 4.).