CN1150588A

CN1150588A - Method for preparing N-(4-phenelyl)-2-hydroxybenzamide drug composition and its use

Info

Publication number: CN1150588A
Application number: CN96102256A
Authority: CN
Inventors: 刘百里; 张晓友; 张东增
Original assignee: DAQING OIL FIELD GENERAL HOSPITAL; Shenyang Pharmaceutical University
Current assignee: DAQING OIL FIELD GENERAL HOSPITAL; Shenyang Pharmaceutical University
Priority date: 1996-06-17
Filing date: 1996-06-17
Publication date: 1997-05-28

Abstract

The present invention relates to a new method for preparing N-(4-phenelyl)-2-hydroxybenzamide (BBA) and its application in preparation of medicine for curing allergic disease as active component. Said invention uses no solvent, and can directly prepare BBA by means of ammonolysis reaction of salicylate and p-ethoxy-phenylamine, and its yield is high. According to said invention the BBA can be used for curing the diseases of cutaneous pruritus, urticaria, neurodermatitis, prurigo, solar dermatitis and mosquito bite, etc..

Description

Preparation method, pharmaceutical composition and the purposes of N-(4-phenelyl)-2-hydroxybenzamide

The present invention relates to the preparation method of N-(4-phenelyl)-2-hydroxybenzamide (BBA), contain pharmaceutical composition and its medical applications of described compound.

N-(4-phenelyl)-2-hydroxybenzamide is a kind of known compound.Present inventor and colleague thereof had found many medicinal uses of BBA in recent years.People such as Zou Bentian are at " Chinese journal of dermatology " 1985 (6); 1 (19): it is remarkable to disclose BBA preparation for treating acne effect in 33.But N-(4-the phenelyl)-validity of 2-hydroxyformamide in other medical fields still requires study.Along with the discovery of increasing biological activity of BBA and medical applications, its industrial production is also more and more important.(Acta Pharmaceutica Sinica, 1987 such as Liu Baili; 22 (4): 312-3) described and a kind ofly prepared the method for BBA again through hydrolysis by the reaction of acetyl bigcatkin willow acyl chlorides and p-ethoxyaniline, this method yield lower (52%), and need to use multiple solvent, comprising deleterious pyridine.Liu Baili etc. are at " Shenyang Pharmacy College's journal " (1988; 5 (1); 43) described the method for Whitfield's ointment and the direct condensation prepared BBA of p-ethoxyaniline in, its yield (42.6%) is also lower.Need the little BBA preparation method of a kind of yield height and environmental pollution in this area always.

One of the object of the invention provides a kind of yield height, does not use the preparation method of preparation N-(4-the phenelyl)-2-hydroxybenzamide of any solvent.

Another object of the present invention provides the new medicinal use of a kind of N-(4-phenelyl)-2-Oxybenzamides.

Another object of the present invention provides the pharmaceutical composition that be used for above-mentioned new medicine use of a kind of N-of containing (4-phenelyl)-2-Oxybenzamides as activeconstituents.

The present invention relates to the preparation method of N-(4-phenelyl)-2-hydroxybenzamide, it is characterized in that the salicylate of following formula and p-ethoxyaniline in 120-210 ℃ of following reacting by heating,

Wherein R is C _1-6Alkyl, phenyl or quilt are selected from halogen, nitro or C _1-6The phenyl that one or more substituting groups of alkyl replace.

" C described herein _1-6Alkyl " refer to contain the straight or branched alkyl of 1-6 carbon atom, comprise methyl, ethyl, propyl group, butyl, amyl group, hexyl and their branched chain isomer, as sec.-propyl, isobutyl-etc." C _1-6Alkyl " be preferably methyl or ethyl.

" halogen " speech refers to fluorine, chlorine, bromine or iodine.

The example of substituted-phenyl includes but not limited to: adjacent, or p-methylphenyl, 2,3-, 2,4-, 2,5-or 2,6-xylyl, 3,4-xylyl, 3,6-xylyl, 3,4,5-trimethylphenyl; Adjacent, or rubigan, 2,3-, 2,4-, 2,5-or 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4,5-trichlorophenyl; Adjacent, or p-nitrophenyl, 2,3-, 2,4-, 2,5-or 2,6-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitrophenyl; Adjacent, or to bromophenyl, 2,3-, 2,4-, 2,5-or 2,6-dibromo phenyl; Halogen and alkyl substituted benzene; Halogen and nitro substituted benzene.

In the ester of above-mentioned general formula, R is preferably methyl, ethyl or phenyl.

Initiator salicylate in the inventive method is that known compound maybe can be by method preparation known in the art.

Used salicylate is preferably with following method preparation in the inventive method.This method comprise following formula fat or aromatic alcohol in the presence of condensing agent with the Whitfield's ointment reacting by heating,

ROH

Wherein R as defined above.Used condensing agent for example can be phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride (POCl in the reaction ₃) etc.Used alcohol or phenol such as methyl alcohol in this reaction, ethanol, Virahol, phenol, 2,2, 4-dinitrophenol, 2,5-xylenol, 2,6-chlorophenesic acid etc. all has commercially available.Heating temperature is according to different alcohol and difference, for phenols for example the temperature of reacting by heating be 90-130 ℃.Except that reactant itself, this reaction system can not add any other solvent.

Another reactant p-ethoxyaniline (or p-phenetidine) in the inventive method has the wide range of commercial supply.

In the inventive method, the temperature of reacting by heating is generally between 120-210 ℃, preferably between 150-200 ℃.For using different esters to carry out the optimum temps of the inventive method, those skilled in the art can obtain by the minority repeated experiments.

Do not have strict restriction for the reaction times, it will change along with starting raw material, Heating temperature.But reaction was generally finished in 1-6 hour.

Do not use any solvent in the inventive method, with salicylate and the condensation of p-ethoxyaniline direct heating.

In the inventive method, the yield of BBA is generally 60-90%, preferred 75-85%.

Obviously, the inventive method does not compared with prior art use any solvent and yield to improve.

The present inventor has carried out extensive studies to the pharmacological action of N-(4-phenelyl)-2-hydroxybenzamide (BBA), found that this compound has the anti-allergic activity, more making us is that its anti-allergic is active comparable with steroid hormone class medicine uncannily, does not pay effect but there is steroid hormone class medicine inherent.

The present inventor by following experiment confirm the anti-allergic activity of N-(4-phenelyl)-2-hydroxybenzamide: BBA to the sensitized guinea pig influence that ileum smooth muscle shrinks of exsomatizing; BBA gastric infusion (i.g.) discharges the influence of histamine to the rat abdominal cavity mastocyte to the influence of rat Arthus reaction: BBA (i.g.); BBA ointment is induced the influence of cavy DCHR to DNCB.The concrete operation method of these experiments is seen experiment I-V.

Based on this discovery, the present invention relates to N-(4-phenelyl)-2-hydroxybenzamide and be used for the treatment of purposes in the medicine of allergic disorder in preparation.

" transformation reactions " comprises I, II, III and IV allergic reaction type herein.

" allergic disorder " refers to the transformation reactions to be people or other mammalian diseases of feature herein, comprises that skin pruritus, nettle are examined, neurodermatitis, pruigo, sunburn, dermatitis and mosquito bite.

The present invention also provides a kind of pharmaceutical composition that is used for the treatment of allergic disorder, and it comprises N-(4-phenelyl)-2-hydroxybenzamide and suitable pharmaceutically acceptable carrier as activeconstituents.

The active constituents of medicine that also can contain other in the pharmaceutical composition of the present invention, for example dapsone.BBA and dapsone share, and the preferred oral administration has synergistic therapeutic action to skin pruritus, urticaria etc.

Pharmaceutical composition of the present invention can pass through epidermis, oral, and parenteral administration.The parenteral approach comprises intramuscular, intravenously, subcutaneous, intradermal, intraperitoneal etc.

The preparation that is used for the epidermis administration includes but not limited to ointment, creme, emulsion, solution, suspension or sprays.The pharmaceutically acceptable carrier that is suitable for these preparations for example is stearic acid, stearyl alcohol, ethylene glycol, glycerine, Vaseline, lanolin etc., also can contain sodium lauryl sulphate, tell wet-80, skin permeation promoter and sanitas etc.The content of BBA is about the 1-10% of total formulation weight in these preparations.

The preparation that is used for oral administration can be tablet, pill, pulvis, capsule or granula etc.Being suitable for the carrier of oral Preparation and the example of additive has: sucrose, starch, Mierocrystalline cellulose, lubricant, sweeting agent, tinting material and stablizer etc.The dosage of oral administration is generally 0.1-30mg/kg/ day, is preferably 1-10mg/kg/ day.

Below by specific embodiment the present invention is further described, but the scope of the invention is not constituted any restriction.

Embodiment 1

The preparation of salol

With the mixture heating up to 120 of 17.00g (0.2132mol) Whitfield's ointment and 12.00g (0.1277mol) phenol ℃, stir and in this mixture, drip about 3ml POCl down ₃, drip off in about 40 minutes.Continued reacting by heating then 2 hours.Mixture is cooled to 60 ℃, with warm water (60 ℃) washing.Add an amount of warm water dissolving, use 5%Na ₂CO ₃Be neutralized to PH7.Allow the cooling of this solution, separate out crystallization, filter the 24.80g crude product.Crude product is recrystallization in ethanol, gets 21.35g salol white crystals, and m.p.41-42 ℃, yield 91.2%.

The preparation of N-(4-phenelyl)-2-hydroxybenzamide

21.4g (0.1mol) salol and 15.80g (0.1152mol) p-ethoxyaniline are mixed, be heated to 200 ℃ of reactions 2 hours.With an amount of washing with alcohol reaction mixture, get crude product 24.1g.With the proper amount of active carbon decolouring, recrystallization in ethanol gets N-(4-phenelyl)-2-hydroxybenzamide white crystalline powder 22.03g, and mp.141-143 ℃, yield is 85.6%.In Whitfield's ointment, two step total recoverys are 78.07%.

Embodiment 2

5.22g (0.1mol) wintergreen oil and 15.80g (0.1152mol) p-ethoxyaniline mixes, and heats 170 ℃ of reactions 5 hours, reclaims methyl alcohol in reaction process.An amount of ethyl alcohol recrystallization of solid that reaction generates must N-(4-phenelyl)-2-hydroxybenzamide white crystalline powder 18.61g, mp141～143 ℃, yield 72.36%.

Embodiment 3

30.42g (0.1mol) Whitfield's ointment-2,4-dinitrobenzene phenyl ester and 15.80g (0.1152mol) p-ethoxyaniline mixes, and heats 180 ℃ of reactions 1 hour, with an amount of washing with alcohol reaction mixture.The proper amount of active carbon decolouring, recrystallization in the ethanol gets N-(4-phenelyl)-2-hydroxybenzamide white crystals 22.10g.Yield 86.32%.

Embodiment 4

24.20g (0.1mol) Whitfield's ointment-2,5-diformazan phenyl ester and 15.80g (0.1152mol) p-ethoxyaniline mixes, and heats 150 ℃ of reactions 6 hours, uses proper amount of active carbon, recrystallization in the ethanol gets N-(4-phenelyl)-2-hydroxybenzamide white crystals 21.68g.Yield 84.25%.

Embodiment 5

28.32g (0.1mol) Whitfield's ointment-2,6-Dichlorfop and 15.80g (0.1152mol) p-ethoxyaniline mixes, and heats 130 ℃ of reactions 5 hours, the proper amount of active carbon decolouring, ethyl alcohol recrystallization gets N-(4-phenelyl)-2-hydroxybenzamide white crystals 21.51g.Yield 83.61%.

The evaluation of products therefrom among the embodiment 1-5

Ultimate analysis

C ₁₅H ₁₅NO ₃Calculated value (%) C70.02 H5.88 N5.44

Experimental value (%) C69.88 H5.80 N5.53

There is maximum absorption at UV:290 ± 1nm wavelength place, and there is minimal absorption at 249 ± 1nm wavelength place.

IR (KBr sheet, cm ^-1): 3330 (NH), 3200 (OH), 1625 (acid amides band I absorptions), 1570 (acid amides band II absorptions), 1610 (C=C phenyl ring), 1510 (C-C phenyl ring), 1245 (=C-O), 1050 (C-O), 825 (CH, phenyl ring), 745 (CH, phenyl ring).

¹The H-NMR data see Table 1

Table 1 proton nmr spectra data and parsing tabulation

Solvent C D ₃COCD ₃

Interior mark TMS chemical shift of proton splits branch coupling constant sequence number δ (ppm) proton number J (Hz)

a????????1.39??????t??????3H???????8.5

B 3.20 (variation) s 1H-

c????????4.15??????q??????2H???????8.5

d????????7.07??????m??????1H???J ₁＝7J ₂＝1.5

e????????7.09??????d??????2H???????9.5

f????????7.13??????q??????1H???J ₁＝7J ₂＝1.5

g????????7.62??????m??????1H???J ₁＝7J ₂＝1.5

h????????7.85??????d??????2H???????9.5

i????8.20?????q????1H????8.5

j????10.00????s????1H?????-

¹³The C-NMR data see Table 2

Table 2 carbon-13 nmr spectra data and parsing tabulation

Solvent C D ₃COCD ₃

Interior mark TMS

The carbon atom sequence	a??????b??????c??????d??????e??????f??????g??????h??????i??????j??????k??????l??????m
The carbon atom sequence		Chemical shift (δ ppm) carbonatoms	13.7???63.2???113.???115.???116.???117.???122.???126.???129.???133.???155.???160.???167. 4??????8??????9??????6??????8??????8??????1??????4??????7??????1??????2??????1??????2 1C?????1C?????2C?????1C?????1C?????1C?????2C?????1C?????1C?????1C?????1C?????1C?????1C

MS：C ₁₅H ₁₅N0 ₃??MW：257.29m/e：257，137，121，108，109，93，80，81，65，64，54，55.

By EXAMPLE l-5 as seen, the inventive method is separated with salicylate and the direct ammonia of p-ethoxyaniline, does not add any solvent, non-environmental-pollution, but yield improves.

Be pharmacology and toxicological test method and the result of BBA below.

Test I

The influence that BBA shrinks the sensitized guinea pig isolated smooth muscle

Every each intramuscular injection 5% Protalbinic acid solution 0.4ml of cavy two back legs, abdominal injection Protalbinic acid solution 1ml sensitization simultaneously.External use antigen is attacked after 3～5 weeks, and measures its ileum contraction with the isolated organ experiment instrument.After the ileum sample was put and stablized in the isolated organ instrument, (final concentration was 10 μ molL to add histamine earlier ^-1), after record shrank height, flush away histamine, (final concentration was respectively 1,5,10,50,100 μ molL to add the BBA suspension of different concns respectively ^-1) contact 10 minutes with sample, (final concentration is 1mgml with Protalbinic acid ^-1) attack, record shrinks height.Capacity solvents such as control group adding, and attack with antigen.Experimental result sees Table 1.

The inhibiting rate that influences group markups given figure concentration ileum shrinkage amplitude that table 1 BBA shrinks the sensitized guinea pig isolated smooth muscle

(n) (μ molL ^-1) (%) the solvent contrast 7-10.4 ± 6.37 13.67 ± 5.88 of average relative value (%)

6????????1??????????86.13±19.24 ^*???29.33±14.28

6????????5??????????78.20±4.66 ^**???48.51±18.96???BBA???????7????????10?????????64.74±25.63 ^**??65.02±31.64

6????????50?????????36.68±33.63 ^**??95.49±4.81

7 100 4.73 ± 5.09 ^*X ± SD ^*P＜0.05 ^*Compare with control group P＜0.01, adopts rank test

Test IIBBA is to the influence of the passive Arthus reaction of rat

Rat is divided into the solvent control group, various dose BBA (100,200,400mg, kg ^-1) group and dexamethasone (25mgkg ^-1) group, in attacking preceding 24,12,1 hours gastric infusions respectively, the right sufficient plantar aponeurosis of rat is injected serum 0.1ml/ of Arthus reaction control rats down, intravenous injection horse serum-physiological saline (1: 5) is attacked immediately, attack the back and detected the claw volume with the volume determination instrument respectively in 1,2,4,6 and 24 hour, the results are shown in Table 2.

Table 2. BBA (ig) is to the influence grouping dosage claw volume (ml) of the passive Arthus reaction of rat

(mg/kg) contrast of 1h 2h 4h 6h 24h solvent-0.47 ± 0.14 0.46 ± 0.07 0.43 ± 0.09 0.37 ± 0.11 0.17 ± 0.08

100??????0.39±0.07????0.42±0.09??????0.28±0.10 ^*??0.19±0.11 ^**??0.09±0.06??BBA???????200??????0.34±0.11????0.26±0.10 ^**???0.27±0.09 ^**?0.10±0.05 ^**??0.09±0.06

400 0.38 ± 0.11 0.31 ± 0.16 ^*0.09 ± 0.06 ^*0.07 ± 0.05 ^*0.06 ± 0.04 ^*Dexamethasone 25 0.21 ± 0.09 ^*0.14 ± 0.10 ^*0.07 ± 0.06 ^*0.01 ± 0.01 ^*0.01 ± 0.02 ^*

X ± SD n=7 ^*P＜0.05 ^*Compare with the solvent control group P＜0.01

Test III BBA is to the influence of DNFB inducing mouse DTH reaction

Mouse is pressed table 3 grouping, and in preceding 1 day to the 6th day difference of sensitization gastric infusion, the mouse web portion cropping evenly is coated with 1%DNFB acetone-sesame oil (1: 1) solution 25 μ l sensitization, every day 1 time, continuous two days.Last was strengthened after the sensitization the 4th day, and the DNFB 10 μ l that are coated with same concentration in every mouse auris dextra attack, and the cervical vertebra dislocation is put to death after 24 hours.Cut left and right sides auricular concha, the auricle of each cut-off footpath 8mm is weighed, and as swelling degree (Δ mg), the results are shown in Table 3 with the difference of left and right sides auricle weight.

Table 3 BBA (ig) is to influence grouping number of animals (n) dosage (mg/kg * d) ear swelling degree (Δ mg) inhibiting rate (%) solvent contrast 8-* 7 12.15 ± 6.65 of DNFB inducing mouse DTH reaction

10??????????100×7???????7.4±4.59????????40.8

BBA???????9???????????200×7???????6.4±4.75 ^*??????48.8

11 400 * 7 2.5 ± 1.87 ^*80.0 dexamethasone 7 25 * 7 2.3 ± 1.0 ^*81.6

X ± SD ^*P＜0.05 ^*Compare with the solvent control group p＜0.01

Test IV BBA discharges the influence of histamine to the rat abdominal cavity mastocyte

Rat is divided into the solvent control group, BBA various dose group (100,200,400mgkg ^-1) and prednisone (50mgkg ^-1) group, 6 every group.Rat muscle injection Protalbinic acid normal saline solution 10mgkg ^-1, while abdominal injection 2 * 10 ¹⁰After the unit bordetella pertussis vaccine sensitization sensitization 10～14 days, press table 4 gastric infusion respectively, after 2 hours, abdominal injection 5ml 0.5% Protalbinic acid normal saline solution is attacked, massage belly 10 minutes, the sacrificed by exsanguination animal, quantitative sucking-off peritoneal fluid 4ml, the centrifuging and taking supernatant liquor is measured the histamine that has discharged; Sedimentary mastocyte is added quantitative physiological saline 4ml, boil 10 minutes after, separate again, the histamine in the gained supernatant liquor is represented remaining histamine.The results are shown in Table 4.

Histamine is measured and is adopted spectrophotofluorimetry, and calculates release rate.

Table 4 BBA (ig) discharges the influence of histamine to the rat abdominal cavity mastocyte

Grouping number of animals dosage release rate

(n)????(mg·kg ^-1)??????(％)

Solvent contrast 6-91.67 ± 5.72

6????????100???????80.12±9.10 ^*

BBA???????6????????200???????74.63±6.01 ^**

6????????400???????70.68±13.33 ^**

Prednisone 6 50 66.11 ± 9.73 ^*

X ± SD ^*P＜0.05 ^*Compare with the solvent control group p＜0.01

Test V BBA ointment is induced the influence of cavy DCHR to DNCB

48 of cavys are divided into 6 groups, 8 every group by sex.Hair is shaved at the back, and every mouse is dripped 50%DNCB acetone soln 2 μ l (diameter 4.0mm) sensitization in shaving a mao portion.Shaved hair a 3 * 3cm after the sensitization on the 13rd in each cavy stomach wall place ²Every mouse is coated with respectively in three positions with 2.0%, 0.5% and each 20 μ l of 0.15%DNCB acetone soln shaving on the fur skin, attacks.Attacking first three day each mouse attacks the position in desire and shaves a mao coating, continuous 5 days.Three groups are coated with the BBA ointment with 1%, 5% and 10% respectively, and one group is coated with ointment base, and one group is coated with fluocinonide ointment, and dosage is 1.0g/ time.Remaining one group of coating not.Attack back 48 hours observationss.The judgement of skin reaction branch rank sees Table 5.The results are shown in Table 6.

Table 5 skin reaction classification levels skin reaction 0 reactionless 0.5 has skin change or fash 1.0 color changes obvious 2.0 to have to have fallen slightly or oedema 3.0 rednesses have downright bad 4.0 downright bad incrustations slightly

Table 6 BBA ointment influences drug dose (g) number of animals (only) skin reaction level P to the cavy DCHR

(X ± SD) blank is organized-8 2.50 ± 0.76 fluocinonide ointments 1.0 8 0.31 ± 0.45＜0.01 matrix 1.0 8 2.62 ± 0.92＞0.051%BBA ointment 1.0 8 2.25 ± 0.46＞0.055%BBA ointment 1.0 8 1.19 ± 0.53＜0.0110%BBA ointment 1.0 8 0.76 ± 0.37＜0.01

The P value is to compare with the blank group.

The toxicity test of test VI BBA

Mouse oral (op) LD ₅₀＞8000mgkg ^-1, abdominal injection (ip) LD ₅₀＞5500mgkg ^-1Long term toxicity by 500,200,50mgkg ^-1Three dosage groups, the oral BBA of rat morning every day 1 time, successive administration 183 days; Dog by 100,10mgkg ^-1Two dosage groups; Oral 1 time of morning every day, successive administration 180 days.Each body weight, food ration, water uptake and blank group of organizing rat, dog compares basic no change.It is no abnormal that each organizes the general signs such as behavior, appetite, mobility, hair of rat, dog.But digestive tract hemorrhage appears in high dose group dog 2 examples, behind 10 days symptomatic treatments, the termination of having blood in stool of two dogs, appetite is normal, after change administration behind the feeding in morning into, above-mentioned symptom does not appear again.Each organize the hematological examination of rat, dog, just, routine urinalysis, liver power checking, there is no unusual.Rat chest gland weight, spleen weight all reduce, and suprarenal gland weight increases, and this may be relevant with the immunosuppressive activity of BBA.The dog tissue slice is checked, high dosage 1 routine severe liver cell oedema and steatosis.Salmonella reversion test, micronucleus test, cell chromosome aberration test all are negative, to the various observed results of rat embryo growth and the young abnormal rate of tire, no teratogenesis.The acute toxicity and chronic toxicity that this shows BBA is all very low, and does not have teratogenesis.

It below is the example of pharmaceutical composition of the present invention.

Formulation example 1

Ointment

Every 100g ointment contains BBA 5g stearic acid 5g stearyl alcohol 4g glyceryl monostearate 3g sodium lauryl sulphate 2g glycerine 14g ethyl p-hydroxybenzoate 0.1g adding distil water to 100g

BBA and oil phase are heated 90～120 ℃, and water heating 70～80 along under the same direction high degree of agitation, is added to aqueous phase with oil phase, when being stirred to 40～50 ℃, stops to stir, and places room temperature promptly.

Be used for the treatment of allergic skin disease, 2 times on the 1st, each 0.5～1.0g ointment or take the circumstances into consideration consumption is smeared the affected part.

Formulation example 2

Tablet

Every contains BBA 300mgNa ₂HPO ₄Every 470mg of 100mg starch 50mg talcum powder 7mg Magnesium Stearate 5mg carboxymethyl cellulose 15mg

With each component uniform mixing, preparation method's allotment, compressing tablet by general tablet carry out enteric coating film dressing in case of necessity.

Formulation example 3

Capsule

Every capsules contains BBA 400mg lactose 150mg starch 40mg talcum powder 40mg Magnesium Stearate 1mg

Above formulation example 2, the 3 oral allergic disorders that are used for the treatment of, 3 times on the 1st, each 1 or 1.

With each component uniform mixing or make slow-releasing granules, be filled in the hard capsule promptly.

Formulation example 4

A. label BBA 300mg dapsone 50mgNa ₂HPO ₄100mg starch 50mg Magnesium Stearate 3mg water is made 1 label in right amount

B. dressing acrylic resin IV 10mg talcum powder 4mg titanium dioxide 4mg tween-80 2mg propylene glycol 2mg95% ethanol 24mg

With each component uniform mixing among the A, by preparation method's allotment, the compressing tablet of common tablet, each component is made the enteric film coating tablet among the adding B.Make the coating tablet of every 520mg.

Be used for the treatment of skin pruritus, urticaria.Every day 3 times, 1 time 1.

Claims

1. the preparation method of N-(4-phenelyl)-2-hydroxybenzamide is characterized in that the salicylate of following formula and p-ethoxyaniline in 120-210 ℃ of following reacting by heating,

2. according to the process of claim 1 wherein that R is a methyl.

3. according to the process of claim 1 wherein that R is an ethyl.

4. according to the process of claim 1 wherein that R is a phenyl

5. N-(4-phenelyl)-2-hydroxybenzamide is used for the treatment of application in the medicine of allergic disorder in preparation.

6. according to the purposes of claim 5, wherein said allergic disorder is selected from skin pruritus, urticaria, neurodermatitis, pruigo, sunburn, dermatitis and mosquito bite.

7. a pharmaceutical composition that is used for the treatment of allergic disorder wherein contains N-(4-phenelyl)-2-hydroxybenzamide and the pharmaceutically acceptable carrier as activeconstituents.

8. according to the composition of claim 7, it is ointment, creme, emulsion, solution, suspension or the sprays that is suitable for the epidermis administration.

9. according to the composition of claim 7, it is tablet, pill, pulvis, capsule or the granula that is suitable for oral administration.

10. according to the composition of claim 7, wherein also contain dapsone.

11. according to the composition of claim 10, it is an oral administered dosage form.