Agents that have anti-allergic and anti-inflammatory activity in skin lesions nemikrobnoy genesis

 

(57) Abstract:

The compound of formula I:

< / BR>
where X is oxygen, sulfur or - CH2; Y is chlorine or bromine, and Z is the remains of SO2H, NO2or C1- C4is alkyl and r is 0 to 3; o is 0 to 3; p is 0 or I; m is the number 1 or 2 and n is the number 0 or 1, have the overwhelming lipoxygenase and prostaglandin - H - synthesis effect. They can be applied in the form of emulsions, ointments, gels, aerosols, powders, etc. locally or inhalation with inflammatory, allergic skin lesions nemikrobnoy Genesis. 2 C. p. F. - ly, 2 tab.

The invention relates to compositions with the overwhelming lipoxygenase - and prostaglandin-H-synthesis of biologically active substances, preferably for topical application in veterinary medicine and medicine. They possess anti-allergic and anti-inflammatory activity in skin lesions nemikrobnoy Genesis, as for example, psoriasis, skin erythema, fibroproliferative diseases, allergic diseases.

To create compositions with valuable pharmacological, in particular, anti-inflammatory, antipsoriaticescoe regulating proliferation of cells, anti-allergic, inflammatory, gastrotoxicity and antiene especially on the suppression of reactions oxygenlive, associated with arachidonic acid metabolism and for local use does not show any side effects.

Known 2-hydroxy-diphenyl ether, 2-hydroxy-diphenylmethane and 2-hydroxy-diphenylthiophene General formula I

ZX where X is oxygen, sulfur or-CH2-; Y is chlorine or bromine and Z SO2H, NO2or C1-C4alkyl, and r=0-3; o=0-3, p=0 or 1; m=1 or 2 and n= 0 or 1, have pronounced anti-inflammatory, anti-allergic and anti-asthma action will be confirmed in vitro hepatocellular and in vitro and in vivo experimental animal studies.

Need to emphasize the compounds of formula I

ZX where X is oxygen, sulfur, and-CH2-; Y is chlorine or bromine and Z SO2H, NO2or1-C4-alkyl, and r=0-3; o=0-3, p=0 or 1; m=0 or 1 and n= 0 or 1, the compounds of formula (I) where X denotes oxygen, sulfur or-CH2and Y denotes chlorine or bromine and m=0, n=0 or 1, o=1 or 2, r=1 or 2, and p=0.

Mostly interesting compounds of formula (I), where X is oxygen and Y is chlorine and m=0, n=0, o=1, r=2 and p=0.

Compounds of General formula I according to the lower dose induced arachidonic acid reduction of the isolated strip parenchyma lung and isolated spiral tratoria based on the influence associated with arachidonic acid metabolism in the lung tissue.

Owing to the above compounds of formula I reduced specific allergic compression of bronchi in sensitised ovalbumin under anesthesia and artificial respiration Guinea pigs (example 2).

In in vivo asthma model intratracheal istallyatsii arachidonic acid in the case of Guinea pigs decreases the compression of the bronchi due to these compounds (example 3).

The compounds of formula I in low concentrations inhibit purified erythroid 15-lipoxygenase rabbits (example 4), and prostaglandin-H synthase from sheep seminal vesicles (example 5).

Eicosanoids, which are formed by lipoxygenase or prostaglandin-H - synthesis from arachidonic acid in mammalian cells, play a key role in the pathogenesis of bronchial asthma induced by ultraviolet light dermatitis and many allergic pathogens.

The compounds of formula I according to the invention directly as an integral part of galenical compositions together with one or more pharmaceutical applicable media effective for allergic diseases, fibroproliferative diseases psoriasis, skin eritem and other inflammatory Zab is particularly important to understand the form of the introduction of local (topical) and inhalation treatment as emulsions, ointments, jellies, powders, preparations for inhalation, etc. of Compounds of formula I can also be contained in liposomes or used together with conventional carriers and/or penetration accelerators, as for example, urea, propylene glycol, oleic acid and other in amounts of 0.001 to 15, preferably 0.1 to 4 wt. from all of the mixture.

The proposed invention in the pharmaceutical composition in addition to the compounds of formula I can also contain other pharmaceutical biological active substances, for example, anti-inflammatory, antipsoriatics regulating cell proliferation, anti-allergic, inflammatory, gastronomiche and anti-asthma biologically active substances.

P R I m e R 1. Action 2,4,4-trichloro-2-hydroxy-diphenyl ether (Triclosan) and 2,2-deoxy-5,5'-dichloro-diphenylsulfide-Yes (Fenticlor) induced arachidonic acid reduction of isolated preparations of the trachea and parenchyma lung.

Test Triclosan and Fenticlor on anti-asthma effects in vitro were carried out on isolated tracheal spirals and bands parenchyma easy adult Guinea pigs (250-500 g) of both sexes. Special importance is attached to the complete destruction of the surrounding fibrous tissue and the Henseleit (pH= 7,4) of the following composition (m moll-1), NaCl=134,8, KCl=5,9, Tris=10,02, CaCl2= 1,82, MgCl2=1,145, glucose=1,11. The gasification is carried out using air. Temperature strips parenchyma light is 37aboutAnd for spirals trachea 35aboutC. air Conditioning preparations carried out repeatedly using 5 10-4M acetylcholine to obtain normalization (standard) values with subsequent rinsing of the substance.

In all studies, the reduction induced due to supplementation of arachidonic acid in the bath for organ in increasing concentrations and cumulative measured. All measurements carried out in the presence of 5 mm Indomethacin.

Arachidonic acid in both preparation causes dependent on the concentration of the reducing value of E50an average of 10-4M for pulmonary strips and 5 10-5M spiral tracheae.

Triclosan at a concentration of 10-6M leads to the complete suppression induced arachidonic acid reduction (10-7-10-3M) in isolated strips parenchyma lung.

Compared to this Ketotifen at a concentration of 10-M on the same spooling causes only 25% inhibition and 5 10-5M nordihydroguaiaretic acid and 5 10-5Ei equal experience pronounced, dose-dependent, relaxation in isolated strips parenchyma easy. In the presence of 5 to 10-6or 5 10-5M Triclosan concentration of arachidonic acid, which causes premaxillary relaxation is LD50=3 10-6M. the Corresponding value in the case of the spirals of the trachea is LC50=10-6M

Fenticlor isolated strip parenchyma easy: LD50=5 10-6M isolated spiral tracheae LD50=1 10-5M

P R I m m e R 2. Action Fenticlor not ovalbumin-induced compression of the bronchi in sensitized by ovalbumin Guinea pigs.

Guinea pigs sencibilisiruet according to the method of Anderson with 10 μg of ovalbumin and 100 mg of aluminum hydroxide in 0.5 ml of isotonic solution of sodium chloride, administered intraperitoneally. After 14 days perform inhalation processing awake animals by tumaniana 0.1% solution of ovalbumin. Only animals with a positive response are used for comparison with the 4 days after treatment. Guinea pigs weighing 450-550 g narcoticyou administered intraperitoneally using 1.3 g/kg of ethylurethane. Then insert a cannula into the trachea. Animals relax with the help of 0.2 mg/kg pancuronium is installed outside of the tracheal cannula. The volume of breath Vtmeasured pneumotachographs. For the emergence of spasm instilliruut intratrahealno 1 mg/kg of ovalbumin in 300 μl of water.

Thanks to the pre-processing using Fenticlor significantly reduced allergic reaction compared to control. Maximum spasm of the bronchi is suppressed to 0% and after 25 min going back up to the original volume.

P R I m e R 3. Action Fenticlor not induced arachidonic acid compression of the bronchi in Guinea pigs.

Using this procedure the experiment as in example 2 desensibilisation Guinea pigs by intratracheal instillation of 2 mg/kg of solution arachidonate sodium phosphate buffer with pH=7,4 cause a spasm of the bronchi.

Thanks to the pre-processing using Fenticlor, starting with 5 minutes, significantly suppressed induced arachidonic acid reaction compression of the bronchi. Maximum bronchospasm suppressed by 16.5% and after 25 min is achieved refund up to the original volume.

P R I m e R 4. Suppression of the activity of 15-lipoxygenase from rabbit reticulocytes.

Lipoxygenase from rabbit reticulocytes get described in the literature, the way in or>aboutUsing amperometric measurement of oxygen consumption using the Clark electrode in the following system: 0.1 M potassium phosphate, pH to 7.4 with 0.2% of cholate sodium and 0.53 mm linoleic acid. The concentration of the enzyme is measured in a mixture of 25 nm. Subjects substances are added dissolved in methylglycol (fresh). Dilution of the compounds are selected so that the final concentration of methylglycol in a pre-incubated mixture did not exceed 2% under these conditions will not occur none worth mentioning suppression in the control mixtures, the enzyme reaction is initiated due to the additives of cholate sodium and linoleic acid. By varying the concentration of biologically active substances is based titration curve suppress and from it determine the required concentration for 50% inhibition.

The results are presented in table. 1.

P R I m e R 5. Suppression of the activity of prostaglandin-H synthase from sheep seminal vesicles.

Prostaglandin-H synthase from sheep seminal vesicles get described in the literature method.

Determination of enzyme activity is carried out at 25aboutWith by polarographic measurement of oxygen consumption with POM,1 M Tris-HCl-buffer pH=8,0, 5 mm tryptophan, 1 mm Haemin and 0,124 mm arachidonic acid. Subjects substances dissolved in methylglycol and within 10 minutes at 25aboutWith incubated with the enzyme in the absence of arachidonic acid. The enzymatic reaction is initiated by arachidonic acid.

By varying the concentration of biologically active substances is based titration curve for suppression and from it determine the required concentration for 50% inhibition.

The results are presented in table. 2.

Sample preparation 1: ointment containing 0.05% 2,4,4'-trichloro-2'-hydroxy-diphenyl ether can be prepared as follows:

The composition, the Biologically active substance 0.05 Vaseline 45,0 Paraffin oil 19,6 Cetyl alcohol 5.0 Propolis 5.0 Sorbitan-sesquioleate 5,0 ester p-oksibenzoynoy acid 0.2 Demineralized water until the total number 100,0

Fats and emulsifiers are melted together and the melt is dissolved biologically active substance. The preservative is dissolved in water and the solution emuleret to melt fat at an elevated temperature and cooled with stirring.

Example of preparation 2: cream containing 0.5% of 2,4,4'-trichloro-2'-hydroxy-diphenyl ether, can gotovi silicone oil 100 0.5 Servicemonitor 3.0 Polysorbate 60 3,5 1,2-propylene glycol PH 20,0 Polyacrylic acid 0.5 Triethanolamine 0,7 Demineralized water, to the total number 100,0

Polyacrylic acid is suspended in a mixture of demineralised water with 1,2-propylene glycol. With stirring, then add the triethanolamine, allowing it turns out mucus. The mixture of isopropylpalmitate, cetylpalmitate, silicone oil, servicemonitoring and Polysorbate heated to approximately 75aboutWith and in it dissolve the biologically active substance. This fatty phase with stirring, introducing also heated to approximately 75aboutWith slime and with stirring, cool.

Sample preparation 3: cream containing 0.05% 2,4,4'-trichloro-2'-hydroxy-diphenyl ether can be prepared as follows:

The composition, the Biologically active substance 0.05 Cetylpalmitate PH 2.00 Cetyl alcohol PH 2,00 Triglyceride mixture of saturated medium length chain fatty acids of 5.00 Stearic acid 3.00 Glitzenstein PH 4.00 Cetomacrogol 1000 1,00 Microcrystalline cellulose and 0.50 1,2-propylene glycol, distilled 20,00 Demineralized water until the total number of 100.00

Cetyl alcohol, cetylpalmitate, triglyceride mixture, stearic acid and glitzenstein melted together and the melt is dissolved biologically active substance. Microcode same blended with propylene glycol, as well as mucus. The fat phase is then under stirring injected into the aqueous phase and all cooled under stirring.

Sample preparation 4: transparent hydrogel containing 0.5% of 2,4,4'-trichloro-2'-hydroxy-diphenyl ether is prepared as follows:

The composition, the Biologically active substance is 0.5 Propylene glycol 10.0 To 20.0 Isopropanol 20.0 Oksipropil - methylcellulose 2,0 Water To 100.00

Oksipropil-methylcellulose lead to swelling in water. Biologically active substance dissolved in a mixture of propylene glycol. Then a solution of the biologically active substance is mixed with the swollen derivative of cellulose, and if desired, mixed with fragrant substances (0,1%).

Sample preparation 5: transparent hydrogel containing 0.005% 2,4,4'-trichloro-2'-hydroxy-diphenyl ether is prepared as follows:

The composition, the Biologically active substance of 0.005 Propylene glycol Isopropanol 20.0 20,0 Polyacrylic acid 2.0 Triethanolamine 3,0 Water To 100.00

Polyacrylic acid and water is dispersed and neutralized with triethanolamine. Biologically active substance dissolved in a mixture of isopropanol and propylene glycol. Then a solution of the biologically active substance is mixed with the gel, and, if desirable, can be added-diphenyl ether can be prepared as follows:

The composition, the Biologically active substance is 0.01 Cetyl alcohol PH 1,70 Paraffin oil is thick 1.00 Isopropylmyristate 2.00 Cetomacrogol 1000 2,40 Servicemonitor 1,50 1,2-propylene glycol PH 5.00 Methylparaben 0.18 propyl paraben 0.02 Themodern 314 0,10 Demineralized water Up to 100.00

Cetyl alcohol, paraffin oil, isopropylmyristate, cetomacrogol and servicestart melted together and the melt is dissolved biologically active substance. Methyl-and propylparaben are dissolved in the propylene glycol and add to hot water. The melt and the solution then mixed. After cooling, add Themodern and add water to the final weight.

Filling:

20 ml of the mixture is filled in an aluminum container. Carton supply valve and pressure put working gas.

Example of preparation 7: Main ointment containing 1% of 2,4,4'-trichloro-2'-hydroxy-diphenyl ether can be prepared as follows:

The composition, the Biologically active substance 1 Thick paraffin oil 10 Anhydrous lanolin 10 White petrolatum 79

__________

100

Integral part of the melt and sterile filtered.

Example of preparation 8: Suitable for injection (insufflate) containing 0.025 g of 2,4,4'-trichogyne active substance 25,00 Milled lactose 25,00

Biologically active substance and very finely milled lactose mix well with each other. The resulting powder was sieved and portions of 0.05 g each contribute in gelatin capsules.

1. The use of compounds of General formula I

< / BR>
where X is O, S or-CH2-;

Y is Cl or Br;

Z SO2H, NO2or C1C4-alkyl;

o r 0 3;

m, n, p is 0 or 1,

as a means possessing anti-allergic and anti-inflammatory activity in skin lesions nemikrobnoy Genesis by local and/or inhalation.

2. Application under item 1 of compounds of General formula I where X is O,S or-CH2-, Y is Cl or Br, Z SO2H, NO2or C1- C4-alkyl, p, m 0, n is 0 or 1, o,r is 1 or 2.

3. Application under item 1 of compounds of General formula I where X is O, Y is Cl, m, n, p 0, o 1, r 2.

 

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