CN1139402C - Usage of benzoisothiazole ketone compound being used as percutaneous medicine-feeding osmotic promoting agent and preparation process thereof - Google Patents
Usage of benzoisothiazole ketone compound being used as percutaneous medicine-feeding osmotic promoting agent and preparation process thereof Download PDFInfo
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- CN1139402C CN1139402C CNB001244043A CN00124404A CN1139402C CN 1139402 C CN1139402 C CN 1139402C CN B001244043 A CNB001244043 A CN B001244043A CN 00124404 A CN00124404 A CN 00124404A CN 1139402 C CN1139402 C CN 1139402C
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Abstract
The present invention relates to a novel percutaneous administration penetration promoting agent which is a benzoisothiazole ketone compound with a structure represented by the formula I, wherein R represents the alkyl group of C<1-7>, and R is preferably a propyl group. The present invention also relates to a new method for synthesizing the compound represented by formula I. The method is characterized in that a benzoic sulfimide sodium salt is used as a raw material, and the raw material reacts with corresponding halogenated hydrocarbon under the existence of anhydrous carbonate, dioxane and polyethyleneglycol so as to obtain the compound represented by formula I.
Description
The present invention relates to a kind of percutaneous dosing penetration enhancer, particularly, the present invention relates to the purposes of benzisothia sulfinpyrazone compound as the percutaneous dosing penetration enhancer.
Medicine administration by percutaneous absorption system is emerging field in the pharmaceutics, and other common drug preparations that transdermal delivery system compares have following characteristics and advantage:
(1) keeping blood level to be stabilized in the treatment valid density scope, is the pharmaceutical preparation with better efficiency;
(2) improve medicine predictability in vivo, owing to avoided the first-pass effect of gastrointestinal tract and liver, percutaneous dosing more stably directly enters blood than oral administration;
(3) improve patient's adaptability, needn't frequent drug administration, particularly therapeutic regimen is unfamiliar with or is remembered inaccurate elderly patients, particular importance seems;
(4) improve safety,, easily patch is removed, reduce the danger of oral or drug administration by injection if any side effect.
Because percutaneous dosing has plurality of advantages, the research of percutaneous dosing penetration enhancer is more and more paid attention to by people, as far back as 1970, Crown Zellerbach and Foster Miburn successfully use dimethyl sulfoxide and the dimethyl caproamide promotes the steroid drugs topical and obtained patent; U.S. Nelson company developed azone (Azone) from a series of N-alkyl azacyclo-ketone compounds in 1976, and patented in the U.S., and the patent No. is: US3989816, US4301481 and US4316893; Ministry of Health of China was named the ketone into Laurel nitrogen , and is listed Chinese Pharmacopoeia in class pharmaceutic adjuvant approval production azone in 1987.Penetration enhancer plays an important role in percutaneous drug administration preparation.Because skin is to be difficult to the barrier that permeates together to most drug, after many drug transdermal administrations, infiltration rate does not reach the treatment requirement.
The invention provides a kind of novel percutaneous dosing penetration enhancer, they are benzisothia sulfinpyrazone compounds, have formula I structure:
Wherein: R is C
1-7Alkyl, propyl group preferably.
Another object of the present invention has provided a kind of method of new synthetic compound of formula i, this method is to be raw material with the saccharin sodium salt, in the presence of anhydrous carbonate, dioxane and Polyethylene Glycol, obtain formula I chemical compound with corresponding halogenated hydrocarbon reaction.
The inventor finds, although some chemical compounds in the formula I chemical compound are known compounds, can use used as pesticides and antibacterial as having described formula I chemical compound of the present invention among the Japan special permission JP48010228B4, having described formula I chemical compound of the present invention among the open JP57210077A2 of Japan's special permission can be as the carrier of fiber dyeing agent.But, can be as any report of percutaneous dosing promoter in the prior art about formula I chemical compound of the present invention.And the inventor is surprised to find, and formula I chemical compound of the present invention has the ability that good promotion medicine percutaneous absorbs, can be as the penetration enhancer pharmaceutic adjuvant of percutaneous dosing.
Chemical compound of the present invention just has the short necessary functional group of effect of oozing on the structure, it contains a polar head and a long hydrocarbon chain, and its structure has also determined it all to have the good short effect of oozing for the medicine of hydrophilic and lipophilic compound behind compatibility.The short mechanism of oozing with differential scanning calorimetry and Fourier transform infrared spectroscopy research The compounds of this invention, think that chemical compound of the present invention has special dissolution to the cuticular lipid of skin, it can destroy the formed film of lipoid, it can make the cellular lipids bilayer exist with liquid crystal state, increase the flowability of bilayer, reduced phase transition temperature, thereby improved the infiltration rate of medicine, and interact with the iuntercellular lipid, making it arrange order descends, form the duct, reduce the diffusional resistance of medicine.
It has following characteristics to chemical compound of the present invention as a kind of novel penetration enhancer: safe, nontoxic, colourless, tasteless, do not have smell, nonirritant, ametaboly reaction, with skin good intermiscibility is arranged, its physicochemical property is stable, storage life was above 7 years.It all has the good short effect of oozing to hydrophilic and lipophilic compound, compare with domestic and international widely used osmosis promoter azone (AZONE), littler with putting in poison property of isoconcentration, osmosis is stronger, The compounds of this invention is carried out the designer of transdermal administration for increasing drug transdermal speed, dwindle the area of percutaneous plaster, make medicine in transdermal administration, reach the clinical treatment level, new varieties are provided, increased a newcomer in the penetration enhancer family in its discovery administrable adjuvant, because its special performance makes The compounds of this invention not only can be used for the different dosage form of medical percutaneous dosing, ointment, unguentum, rubber-emplastrum, cream, colloid, suppository, aerosol, membrane and cosmetic industry, also can be used for agricultural as insecticide, herbicide, the synergist of growth regulator makes the use of pesticide more trend towards saving pesticide dosage, reduces the medication number of times, improve the pesticide utilization rate, avoid waste, reduce the dispenser integrated cost significantly, more low toxic and environment-friendly.The different field such as efficient dyeing auxiliaries that can also be used for dyeing synthetic fibers, the linen fabrics and leather coloring, valuable aspect Application and Development.
We use
3H labeled drug berberine is done the embodiment of the invention 1 chemical compound and the isocyatic short contrast test of oozing of azone 4% equivalent under surface area conditions such as mice animal body surface, and respectively at 0.5,1,2,4,6,12,24 hour measurement blood drug level, the result who obtains is 3.95 times of the bioavailability of the azone berberine that can improve transdermal administration, the embodiment of the invention 1 chemical compound can improve 12.13 times of this bioavailability, and it is 3.07 times of azone with the short intensity of oozing that the embodiment of the invention 1 chemical compound short oozed effect.
Experimental result is seen accompanying drawing 1 and table 1, and except as otherwise noted, percentage ratio of the present invention is percentage by weight.
Accompanying drawing 1 is measured in different time under surface area equivalent isoconcentration conditions such as mice body surface for contrast liquid, azone and the embodiment of the invention 1 chemical compound
3Area is S below the H berberine plasma concentration curve, curve, the size reflection drug bioavailability of its value.In the accompanying drawing:
1 is that contrast liquid is promptly prepared with 75% ethanol
3H berberine standard solution plasma concentration curve;
2 4% azones that contain for preparing with the standard solution in 1
3H berberine plasma concentration curve;
3 contain 4% embodiment of the invention, 1 chemical compound for what prepare with the standard solution in 1
3H berberine plasma concentration curve.
Table 1: the short effect of oozing of different penetrating agents
| Sample | Contrast liquid | 4% azone | 4% embodiment, 1 chemical compound |
| S/(GB9.L -1.h -1) | 9.278 | 36.655 | 112.526 |
| The S/S contrast | 1.00 | 3.95 | 12.13 |
| S/S (azone) | - | 1.00 | 3.07 |
In guinea pig skin, guinea pig skin is the show speckle not, part and systemic anaphylaxises such as edema with the embodiment of the invention 1 compound administration; Smeared for rabbit skin 7 days, damaged skin and intact skin there is no the stimulation phenomenon as a result; Smear for rabbit skin, as a result damaged skin and intact skin there is no ulcer, ooze out, part and general toxic reaction such as redness.
The The compounds of this invention long term toxicity test:
The embodiment of the invention 1 chemical compound was through rabbit percutaneous drug delivery 0.1g/kg (being equivalent to 50 times of people's consumptions) successive administration 1 month, the hematology, blood biochemical learns every index inspection and matched group compares, basic there was no significant difference, but blood glucose administration group and vehicle group are a little more than normal value after the drug withdrawal, but in normal range, organ coefficient inspection and histopathologic examination and matched group are not seen obvious change.In sum, the embodiment of the invention 1 chemical compound skin long term toxicity test is seen toxic reaction.
Mutagenicity test:
Do not detect the embodiment of the invention 1 chemical compound through Salmonella reversion test and in the 5-500ug/ml scope, have mutagenic action.In the 500-2000mg/kg dosage range, the mouse marrow cell micro nuclear test result is negative.
The test of animal body internal dynamics:
Intravenously administrable, the K of the embodiment of the invention 1 chemical compound
10Be worth greatlyyer, be about 0.6g, this shows that it removes comparatively fast in vivo, remove to the half-life only be about 10 hours.Oral administration, result of study are removed soon in vivo, and bioavailability is low, and is distributed more widely, and do not have specific accumulation phenomenon.Therefore, the use of The compounds of this invention is safe.
The preparation method embodiment 1:2-propyl group-1 of The compounds of this invention, 2-benzisothiazole-3 (2H)-ketone 1, the preparation of 1-dioxide
In the 100ml there-necked flask, reflux condensing tube is installed, thermometer and agitator, and add saccharin sodium salt 3.7g (0.025mol), Anhydrous potassium carbonate 4.1g (0.03mol), Polyethylene Glycol (PEG-400) 1.5g (0.00375mol), 1-N-Propyl Bromide 6.2g (0.05mol), dioxane 30ml, under agitation heating and keeping reaction temperature is 69 ℃ of reactions 4 hours, again reaction temperature is increased to 90-98 ℃ and continues reaction 4 hours, the solids of separating out to be cooled.Transfer to then and remove excessive 1-N-Propyl Bromide and solvent on the rotary evaporator, the solid of separating out in solids and the former reaction bulb is merged, the cooling back adds the sodium hydrate aqueous solution of 20ml 5% and removes unreacted saccharin sodium salt, suction strainer, add 100ml water and make the inorganic salt dissolving, separate out three after drying of product reuse low amounts of water washing, get The compounds of this invention 5.5g (yield 90%), product can be used the dehydrated alcohol recrystallization.
Product C
10H
11NO
3The S elementary analysis:
C% H% N% O% S% measured value: 53.62 4.77 6.10 21.12 14.38 value of calculation: 53.32 4.92 6.22 21.31 14.23
The inventor has used Polyethylene Glycol phase transfer catalyst and dioxane organic solvent in the method for preparing formula I chemical compound of the present invention, make synthetic reaction fully and effectively carry out, and has not only shortened the response time, and has improved productive rate significantly.
Claims (4)
1. the benzisothia sulfinpyrazone compound of a formula I is used as the purposes of percutaneous dosing penetration enhancer:
Wherein: R is C
1-7Alkyl.
2. according to the benzisothia sulfinpyrazone compound of the formula I of claim 1 purposes as the percutaneous dosing penetration enhancer, its Chinese style I chemical compound is:
2-propyl group-1,2-benzisothiazole-3 (2H)-ketone 1,1-dioxide.
3. the preparation method of the benzisothia sulfinpyrazone compound of formula I as claimed in claim 1, this method is a raw material with the saccharin sodium salt, in the presence of anhydrous carbonate, dioxane and Polyethylene Glycol, obtain formula I chemical compound with corresponding halogenated hydrocarbon reaction.
4. according to the preparation method of claim 3, the formula I chemical compound that wherein obtains is:
2-propyl group-1,2-benzisothiazole-3 (2H)-ketone 1,1-dioxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001244043A CN1139402C (en) | 2000-09-05 | 2000-09-05 | Usage of benzoisothiazole ketone compound being used as percutaneous medicine-feeding osmotic promoting agent and preparation process thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001244043A CN1139402C (en) | 2000-09-05 | 2000-09-05 | Usage of benzoisothiazole ketone compound being used as percutaneous medicine-feeding osmotic promoting agent and preparation process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1285224A CN1285224A (en) | 2001-02-28 |
| CN1139402C true CN1139402C (en) | 2004-02-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001244043A Expired - Fee Related CN1139402C (en) | 2000-09-05 | 2000-09-05 | Usage of benzoisothiazole ketone compound being used as percutaneous medicine-feeding osmotic promoting agent and preparation process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1323791A (en) * | 2001-04-19 | 2001-11-28 | 容军 | Prepn. of N-butyl benzoyl-2-sulfonyl inner imine |
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