Derivatives of 4-aminophenol or n-alkyl or salt derivatives exhibiting anti-inflammatory activity


(57) Abstract:

Usage: in medicine as substances possessing anti-inflammatory activity. The inventive product is a derivative of 4-aminophenol f-ly I, where R1group-C(O)YZ, where Y is a simple bond, O, -NR7or; Z IS H, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted " HE, lower alkoxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8phenyl(lower)alkoxy, phenyl, halogen, cyano or NR10R12, R2, R3, R6and R5lower alkyl or alkenyl, lower alkoxy or halogen; R4and R7or lower alkyl; X is 4,5-dihydropyrazolo or pyrazolyl, which may be substituted C3-C6cycloalkyl or phenyl which can be substituted by trihalomethyl; R8, R9, R10and R11-H, lower alkyl or benzyloxycarbonyl, or N-acyl derivative or salt. 5 C. p. F.-ly. The structure of f-crystals, 1:

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/Z;

Y represents Soboh what alogena, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl, or a salt, derivative, exhibiting anti-inflammatory activity.

The compounds of formula I produced by methods that include:

a) interaction of the compounds of formula II

X L1where L1is the deleted group, and X has the meanings given above, with a compound of formula III

XNROR1where R1, R2, R3, R4 where X, R2, R3, R4, R5, R6have the above meanings, with a compound of formula V: R1L2where L2is the deleted group, and R1has the specified values.

C) obtaining the compounds of formula I by oxidation of the corresponding compounds of formula VI

XcNROR1where Xwithrepresents the corresponding heterocycle, more intense than X, and

R1, R2, R3, R4, R5and R6have the meanings given above.

d) obtaining the compounds of formula I, which carries one or more alkyl substituents containing at least two carbon atoms, with the recovery of the corresponding compounds of formula I, in which the appropriate Deputy// contains one or more double or triple carbon-carbon bonds.

e) obtaining the compounds of formula I, where X is substituted by cyclohexyl, by restoring the corresponding compounds of formula I, where X is substituted by phenyl,

f) obtaining the compounds of formula I substituted by one or more of HE, with other10or COOH, which includes removing the protective group from the corresponding compounds of formula I bearing a protected HE NR10
h) obtaining the compounds of formula I, which is N-alkyl salt through reaction of the corresponding compounds of formula I in which X represents a nitrogen-containing heterocycle, with an alkylating agent,

and if desirable or necessary, converting the resulting compounds of formula I in a pharmaceutically acceptable N-alkyl or salt derivative, or Vice versa.

In process (a) remove groups that can represent l1include, for example, halogen, e.g. chlorine or bromine; arylsulfonyl; hydroxy and esters; alkoxy, for example methoxy or ethoxy; dialogfactory, for example, dichloro - or dibromophenyl; and-NRaRb, where Ra and Rb each can independently represent hydrogen or alkyl WITH1-C6.

The reaction can be carried out using a solvent or without him. When the reaction is carried out using a solvent, the solvent is preferably inert to the reaction conditions, and may be, for example, a polar solvent, such as 1,4-dioxane, Writely, for example, toluene. The reaction preferably is carried out at a temperature of from about 25 to 200aboutC.

In method (b) delete group, which can be L2include 0-acyl (i.e., the compound Y is an acid anhydride), toilet, mesilate, imidazole, bromide or, preferably, chloride. The reaction may be carried out by mixing the reagents in anhydrous conditions in the presence of an inert solvent, such as dichloromethane. When the reagent of formula V is galoyanized acid, the reaction is preferably carried out in the presence of a base such as triethylamine and/or dimethylaminopyridine.

In some cases, for example, and when R2and R6are bulky groups, such as tertiary butyl, especially good results have conditions Schotten's-Bauman, in which the reaction is carried out using a base strong enough for removal of a proton from the phenol of formula IV. A particularly suitable base, which may be mentioned is tert-butyl potassium.

Oxidizing agents that can be used in process (C) for the oxidation of heterocycles XC, include metal catalysts, organice include palladium on charcoal in the presence or in the absence of air. Preferred inorganic oxidizing agents include manganese dioxide and chromium trioxide. Suitable organic oxidizing agents include, nagkalat, for example, 3-chlormadinone acid, and easily restored acceptors of hydrogen, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and organic hypohalite, such as tertiary butylhypochlorite. The oxidation may be carried out in a solvent which is inert to the reaction conditions. The choice of solvent depends on the connection subjected to oxidation and oxidizing agent. However, suitable solvents include halogenated hydrocarbons such as dichloromethane, alcohols, such as ethanol and aromatic hydrocarbons, e.g. toluene. The reaction may be carried out at a temperature of about 0-150aboutC.

The recovery process (d) may be carried out using hydrogen and an appropriate metal catalyst, for example, 10% palladium or rhodium on an inert carrier, such as charcoal. The reaction may be carried out in an inert solvent, for example ethanol, at a pressure of from 1 to 10 atmospheres of hydrogen.

The recovery process (a) may be exercised in conditions in basically is it the nature of the protective groups, but usually can be well-established techniques, including methods using acids, bases, electrolytic, photolytic and especially gidrojenergeticheskie methods. Protective groups that may be mentioned include benzyl (Bzl), benzyloxycarbonyl (CBZ) or butoxycarbonyl (Boc). Benzyl protective group Bzl and BZ can be removed by hydrogenolysis, for example, through reaction with hydrogen in a suitable solvent, such as alcohol, in the presence of a catalyst based on a transition metal, such as palladium on coal. The BOC-protective group may be removed by treatment with acid, for example, triperoxonane acid.

In process (g) substitution of the halogen may be carried out in a solvent which is inert to the reaction conditions. We are particularly preferred polar aprotic solvent, such as acetonitrile, dimethylformamide or dimethylsulfoxide. The reaction may be carried out at a temperature of from about 0 to 100aboutC.

The alkylation according to process (h) may be carried out using an excess of the alkylating agent as a solvent or using a solvent which is inert to the conditions of the reactions is ethylsulfonyl. The reaction may be carried out at a temperature of from about 0 to 100aboutC. Suitable alkylating agents include alkylhalogenide, for example, methyliodide, and alkylsulfate.

The compounds of formula II can be obtained from the corresponding 4-aminophenol according to the method of process (b). Such 4-aminophenols are either known or can be prepared from known compounds using conventional methods.

Some of the compounds of formula IV are known or from EP-A-154259 or from EP-A-178035. Some of the intermediates of formula IV are novel, for example, the compounds of formula IV

XaOTHER1where Ha represents 1H-pyrazole-3-yl, substituted 1-phenyl or 1-cryptomaterial, R2a and R6and that may be the same or different, selected from lower alkyl, halogen or lower alkoxy, and both of R3a and R5and represent hydrogen.

New phenols of the formula IV can be obtained according to the methods specified in European applications referred to above, or by methods described here.

The compounds of formula VI may be obtained by methods similar to the methods described in processes (a), (b), (d), (e), (f), (g) or (h).

Seedit techniques, known in themselves.

Acid additive salts of compounds of formula I can be obtained with the cooperation of the free base with the appropriate acid. Acid additive salts can be transformed into the corresponding free base by the action of a stronger Foundation.

The processes described above can give compounds of formula I or derivatives thereof.

Pharmaceutically acceptable derivatives of compounds of formula I include pharmaceutically acceptable acid salt additive. Suitable salts include salts of mineral acids, for example, galoidvodorodnykh acids, for example hydrochloric acid or Hydrobromic acid, or organic acids, for example formic, acetic or lactic acid. The acid may be polybasic, sulfuric, fumaric or citric acid.

When the compound of formula I contains carbonation group, it may form pharmaceutically acceptable salt, ester or amide derivative. Suitable salts include ammonium salts, alkali metal salt (e.g. sodium, potassium or lithium) salt and alkaline-earth metal (e.g. calcium or magnesium, and salts with suitable organizes substituted lower alkylamines followed, for example, replacement bonds alkylamines, such as Tris (hydroxymethyl)methylamine or triethanolamine, with simple monocyclic nitrogen-containing heterocyclic compounds, for example, pyridine or morpholine, with the amino acid, e.g. lysine, ornithine, arginine or N-alkyl, especially N-methyl derivative of any of them, or amino sugar, for example, glucamine, N-methylglucamine or glucosamine.

Preferred compounds of formula I are compounds in which R2and R6both represent lower alkyl, or R3and R5both represent hydrogen; or where X pyrazolyl substituted by phenyl.

Preferred are the compounds of formula I, represents 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenylacetate or its pharmaceutically acceptable salt; 4-(4,5-dihydro-1-phenyl-1H-pyrazole-3-yl)amino-2,6-dimethylphenylacetate; 4-(4,5-dihydro-1-(3-triptoreline)-1H-pyrazole-3-yl-amino-2,6 - dimethylphenylacetate; 4-(1-phenyl-1H-pyrazole - 3-yl)-amino-2,6-di(prop-2-enyl)-phenylace - tat; 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminophenylalanine, 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)-AMINOPHENYL-2,2-dimethylpropanoate; 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)-aminophenylalanine - whitesky acceptable derivatives are useful because they possess pharmacological activity in animals. In particular the compounds are useful as anti-inflammatory agents of broad-spectrum, as shown in one or more of the following systems analysis.

(a) Inhibition lipoxygenase, such as 5, 12 and 15 lipoxygenase in the presence of exogenous arachidonic acid and measurement of enzyme activity with or modification of the method of C. A. Jahshik and other Biochemal and Biophysical Communications Rescarch 95(1), 103, (1980) using obetovannoi LC (liquid chromatography high resolution or high pressure) for qualitative determination of products or modifications to method F. F. Sun and other Prostaglandins, 21 (2), 333 (1981) using UV absorption for the quantitative analysis of product education.

(b) Inhibition of prostaglandin synthetase, using seminal vesicle microsomes bull by the method Etap etc. Biochemistry 17, 2230 (1978) using or radiolucency arachidonic acid as substrate and separation of the product by thin-layer chromatography and quantification by using scintillation counting, or unlabeled arachidonic acid as a substrate and a specific set of radioimmunotherapy in intact human neutrophils, stimulated iodoform A and with the addition of exogenous arachidonic acid by the method of R. Borglat and B. Sanmelsson. Proccedings New York Academy of Scilna, 70, 2147 (1979) using back-phase HPLC to measure products.

(d) Inhibition of formation of metabolites of arachidonic acid using peritoneally macrophages of mice with the introduction of in vitro immune complexes by the method of Blackman and others J. Pharm. Pharmac, 37, 787 (1985).

(e) Inhibition of education RSU2and cellular infiltration model sponge with carageenan method Higgs and other EIG. J. Pharmac - 66 - 81 (1980).

(f) Inhibition of inflammation, eposredstvennoe immune complex in perianalnoe cavity of mice according to the method of Blackman and others J. Pharmac. Methods 15, 77 (1985).

(g) Inhibition of kareninova oedema in rats according to the method of Winter and other Proc. Soc. Exp. Biol. III, 544 (1962).

(h) Inhibition of bronchial anaphylaxis in Guinea pigs according to the method of Anderson, Br. J. Pharmac. 77, 301 (1982).

(i) Inhibition of oedema and the production of eicosanoids on the ears of mice treated with arachidonic acid by the methods Joung and other J. Invest. Deun. 82, 367 (1984) and Oas etc. I. Invest Deun. 84, 253 (1985).

The connection is shown for use in the treatment or prophylaxis of inflammatory conditions in micommunity spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis, burns, including sunburn, ulcers, wounds, acne and other inflammatory skin conditions such as sunburn, inflammatory condition of the eye including conjunctivitis and uveitis, pulmonary disorders, in which there is inflammation, for example, bronchitis, disease Golubyatnikov (deducing new breed of pigeons), and exogenous allergic alveolitis; painful conditions of the ears, including external otitis; diseases of the gastrointestinal tract, including aphthous ulcers (expressing mucosa), gingivitis, Crohn's disease (granulomatous disease), a disease of the small and sometimes large intestine), atrophic gastritis and gastritis varioliform (pox), disease of the stomach, ulcerative colitis (a disease of the colon, and sometimes the small intestine), colic (a disease of the small intestines), regional REIT (regional inflammation of the terminal ileum) and mucous colitis or irritable bowel syndrome; paresis, pain, and other conditions associated with inflammation, especially of the state, a factor which is lipoxygenase and cyclooxygenase products.

With the R:

to ensure, in particular, colitis, Crohn's disease and psoriasis; with steroids, especially those steroids that appear predestine, salazopyrine, keratolytic agents such as salicylic acid or purified fractions of liquid products of the distillation of coal tar, dithranol, vitamins, such as vitamins a, d, or E, antifungal agents, such as besultanova acid, hexetidine, enilconazole or other azole antifungal agents, natamycin, polyoxin, povidon-iodine, griseofulvin and 2,4,6-tribromsalan;

for the treatment of eczema compounds can be combined with steroids or antipruritic agents such as crotamiton;

for the treatment of acne connections may be combined with benzoyl peroxide or tretonin;

for the treatment of seborrheic dermatitis of the compounds may be combined with selenium sulphide, fractions of coal tar, sincerities, sulfur, salicylic acid or steroids;

for the treatment of red acne connection may be merged or combined with sulfur, especially in the form of ointment.

For these purposes the use of prescribed doses, of course, will vary depending on the compounds, method of appointment and require the Oh (daily) dose of about 0.1-60 mg per kg animal body weight, preferably provided in the form of separate doses 1-4 times a day, or in the form of a delayed release of the drug. For a human, the total daily dose is in the range of 7.0 to 4.2 g and form of dosage units suitable for oral assignments include a 2.0 to 4.2 g of compound mixed with solid or liquid pharmaceutical carrier or diluent.

The compounds of formula I and their pharmaceutically acceptable derivatives may be used by themselves or in the form of relevant medical preparations for enteral, including topical, or parenteral destination. Thus, the new compounds can compoundrelated with inorganic or organic pharmaceutical acceptable auxil - Chairman agents, diluents or carriers. Examples of such auxiliary agents or adjuvants, diluents and carriers are: for tablets and coated tablets: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose; for injectable solutions, include water, alcohols, glycerol, vegetable oils; for suppositories or medical candles: natural or hardened oils or waxes.

Composition in a form suitable for oral (i.e., water or navodnitcky, which may be mentioned include pre-formulation with enterococci coating, metered distributed designed for chewing, and a formulation intended for sublingual or buccal absorption.

Composition in a form suitable for appointment to the lungs include preparative forms inhalers, sprayers or spray guns, aerosol inhalers or insufflator (poroshkovaya) in the form of aerosols, especially aerosols under pressure.

Compositions for rectal products include suppositories or enemas, compositions for parenteral distribution by injection (intravenous, subcutaneous, intramuscular) include solutions with a co-solvent, suspension, emulsion, oil for parenterale allocation.

Composition in a form suitable for topical purposes in relation to the skin include ointments, creams, emulsions oil in water or water in oil, water or organic gels (for example, cellulose or carboxyquinolone).

Composition in a form suitable or topic destination in the eyes or the nose, include solutions, suspensions, semi-solid gels, ointments and emulsions.

We predpochitayuschih acceptable derivative.

The compound of formula I and its pharmaceutically acceptable derivatives have the advantage that they are less toxic, more effective, have a long action; have a broader spectrum of activity, are more powerful, fewer side effects, more selective, are more easily absorbed, more stable, or have other useful pharmacological properties, in comparison with compounds of similar structure.

The invention is illustrated by the following examples.

A. the production of intermediate compounds.

P R I m e R A. 4-Amino-2,6-dimethylphenylacetate.

To 2,6-dimethyl-4-NITROPHENOL (10 g) and triethylamine (21 ml) in dry dichloromethane (100 ml) at 0aboutSlowly add acetylchloride (5.6 ml). After 16 h the mixture was washed with water, dried and evaporated, getting acetate (9.4 g) so pl. 109-110aboutC. Acetate (9.4 g) hydronaut in ethanol at atmospheric pressure over platinum oxide for 4 hours Filtration, evaporation and crystallization (ethyl acetate-hexane) of the residue gives the target acetate (5.6 g) so pl. 82-83aboutC.

P R I m e R C. 4-Amino-3,6-dimethoxy-2-METHYLPHENOL.

Sulfanilic acid (10.8 g) diasterous, as described in Toru 3,6-dimethoxy-2-METHYLPHENOL (8,1 g) and sodium hydroxide (10.8 g) in water (100 ml). After one hour, the mixture is heated to 45-50aboutWith and portions add hydrosulfite sodium (22,2 g). When the red color disappears, the mixture is cooled, receiving a yellow precipitate bisulfite salt (10 g) of the target phenol.

P R I m e R C. using the method of the example described above, will receive the following phenols through their bisulfite salt:

a) 4-amino-2,6-dimethylphenol;

b) 4-amino-2,3,4,5-tetramethylene,


P R I m e R D. 2,6-Dimethyl-4-(4-phenyl-1H-pyrazole-3-yl)aminophenol.

2,6-Dimethyl-4-aminophenol (15 g) and 4,5-dihydro-1-phenyl-1H-pyrazole-3-amine (17.6 g) is heated with n-toluensulfonate acid (0.2 g) at 160aboutC for 1 h in nitrogen atmosphere. The mixture is cooled, add in dichloromethane and washed with diluted Hcl and water. Evaporation and chromatography of the residue (silica, dichloromethane) in ethyl acetate (9:1)) to give 4-(4,5-dihydro-1 - phenyl-1H-pyrazole-3-yl)-amino-2,6-dimethyl - phenol (14.2 g), so pl. 154-158aboutC. This substance is heated under reflux in toluene (40 ml) using 10% palladium on charcoal (10 g) for 3 hours the Mixture is filtered and evaporated, getting after crystallization from a mixture of cyclohexane/ethyl acetate target compound (8 g), so pl. ">

a) 2,3,5,6-tetramethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminophenol, so pl. 160-162aboutC;

b) 3,6-dimethoxy-2-methyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenol, so pl. 107-108aboutWITH,

(C) 2,6-bis(1,1-dimethylethyl)-3-(1-phenyl-1H-pyrazole-3-yl) aminophenol, so pl. 114-115aboutWITH,

d) 2,6-dichloro-4-(1-phenyl-1H-pyrazole-3-yl)aminophenol, so pl. 144-146aboutC.

P R I m e R f 2,6-Dimethyl-4-(N-methyl-N-(1-phenyl-1H - pyrazole-3-yl) aminophenol.

To 2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminophenol (8 g), acetic acid (2.8 ml) and water 40% increase formaldehyde (3.3 ml) in acetonitrile (40 ml) add cyanoborohydride sodium (5,4 g). After 2 h, the mixture was quenched with water and extracted with dichloromethane. The organic phase is washed with aqueous sodium bicarbonate solution, then with water, dried, evaporated and chromatographic (silica, dichloromethane) to give the target product (3 g), so pl. 139-140aboutC (from ethanol).

P R I m e R G. the Following intermediate products are obtained according to the method of example F.

(a) 2,6-bis(1,1-dimethylethyl)-4-[N-methyl-N-(1-phenyl-1H - pyrazole-8-yl)amino] phenol, I. pl. 117-118aboutC.

C. Obtaining compounds of formula I.

The following compounds of formula I are obtained from intermediate products described above or known connected is-yl) amino-2,6-dimethylphenylacetate.

4,5-Dihydro-1-phenyl-1H-pyrazole-3-amine (0.16 g), 4-amino-2,6-dimethylphenylacetate (0.2 g) and toluene-4-sulfonic acid (0.02 g) is heated under reflux in toluene in a nitrogen atmosphere for 8 hours Evaporation and chromatography (silica, dichloromethane-ethyl acetate (95:5)) remainder give the desired product (0.15 g) as a solid.

P R I m m e R 2. Using the method of example 1 get the following connection.

a) 4-(4,5-dihydro-1-(3-triptoreline)-1H-pyrazole-3-yl)amino-2,6-dimethylphenylacetate, so pl. 190-191aboutC.

P R I m e R 3. 4-(1-Phenyl-1H-pyrazole-3-yl)amino-2,6-di(prop-2-enyl) phenylacetate.

(a) 4-(1-Phenyl-1H-pyrazole-3-yl)amino-2-(prop-2-enyl) phenol.

4-(1-Phenyl-1H-pyrazole-3-yl)aminophe-Nol (19 g) is added to sodium hydride (4.0 g of a 50% suspension of chilled oil) in dry dimethylformamide (150 ml). After 0.5 h, add allylbromide (7.2 ml) and the mixture stirred for 16 h, poured into water, and extracted with ethyl acetate. Evaporation of solvent and chromatography (silica) dichloromethane/ give 1-phenyl-N-(4-[L-prop-2-enyl] oxyphenyl)-1H-pyrazole-3-amine (21,9 g), so pl. 80-81aboutC. This solid (2.9 g) is heated under 200aboutC in nitrogen atmosphere for 5 hours Chromatograms (DMCO): 8,7 (1H, C. MO), AND 8.4 (1H, s), 6,0 (1H, m,- CH=), 5,1 (2H, DD.CH2) at 3.25 (2H, D. och2).

(b) 4-(1-Phenyl-1H-pyrazole-3-yl)amino-2,6-di(prop-2-enyl)phenol.

Pricelevel product from step (a) (10,5 g) make using processes similar to (a) 1-phenyl-N-(3-[prop-2-enyl]-4-[prop-2-enyl] oxyphenyl)-1H - pyrazole-3-amine (7.6 g, oil), and then in pricelevel phenol (5.5 g), so pl. 87-88aboutC.

(C) 4-(1-Phenyl-1H-pyrazole-3-yl) amino-2,6-di(prop-2-enyl)-phenylacetate.

To the product from stage (b) (5.0 g) in dichloromethane (100 ml) containing 4-dimethylaminopyridine (10 mg) and triethylamine (2.1 ml) slowly with stirring, add acetylchloride (1.1 ml). After 6 h, water is added and the residue after evaporation of the organic phase chromatographic (silicon dioxide) dichloromethane), and then the crystal from cyclohexane, obtaining the target product (4.5 g), so pl. 110-111aboutC.

P R I m e R 4. The following connections receive according to the method of example 3 from the corresponding phenol and the corresponding carbonyl - or sulfonyl-chloride.

(a) 2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminophenylalanine, so pl. 138-140aboutWith; (b) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)AMINOPHENYL 2,2-dimethylpropanoate, so pl. 139-140aboutWith; (C) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminopheaboutWith; (e) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenylacetate, so pl. 117-118aboutWith; (f) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL 2-methylpropanoate, so pl. 127-128aboutWith; (g) 2,6-dimethyl-4-(1-phenyl-1H - pyrazole-3-yl)aminophenylacetylene, so pl. 105-106aboutWith; (h) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL-4-methoxybenzoate, so pl. 185-187aboutWith; (i) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL methoxyacetate, so pl. 149-150aboutS; j) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL the CHLOROACETATE, so pl. 141-142aboutS; k) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)AMINOPHENYL (1,1-dimethylethyl) carbonate, so pl. 122-123aboutC; l) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL-4-nitrobenzoate, so pl. 210-211aboutC; m) of 2,6-dimethyl-4-(1 - phenyl-1H-pyrazole-3-yl)aminopenicillanic, so pl. 72-73aboutS; n) of 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL-3-pyridinecarboxylic, so pl. 158-160aboutWith; o) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL-4-chlorobenzoate, so pl. 166-167aboutS; R) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)AMINOPHENYL-3 - methoxypropanol, so pl. 125-126aboutS; q) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminopenicillanic, so pl. 171-173aboutS; r) 2,6-dimethyl-4-(1 - phenyl-1H-pyrazole-3-yl) AMINOPHENYL-4-dimethylamino-4-oxobutanoate, so pl. 210-211aboutWITH,

s) of 2,6-dimethyl-yl) AMINOPHENYL propandiol, so pl. 112-113aboutS; u) methyl 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)AMINOPHENYL 1,5-pentadien, so pl. 108-109aboutS; v) methyl 2,6-dimethyl-4-(1-phenyl-1H - pyrazole-3-yl) AMINOPHENYL 1,4-butandiol, so pl. 90-91aboutC; w) 3,6-dimethoxy-2-methyl-4-(1 - phenyl-1H-pyrazole-3-yl) aminophenylacetate, so pl. 132-134aboutS; x) 2,6-dimethyl - 4-(1-methyl-N-(1-phenyl-1H-pyrazole-3-yl// aminophenylalanine, so pl. 111-112aboutC; y) 2,3,5,6-tetramethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenylacetate, so pl. 179-180aboutC; z) 2,6-dichloro-4-(1-phenyl-1H-pyrazole-3-yl) aminophenylacetate, so pl. 169-170aboutC; AA) of 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminobenzylpenicillin, so pl. 101-101,5aboutC; AB (2,5-dimethoxy-4-(1-phenyl-1H-pyrazole-3-yl)aminophenylacetate, so pl. 149-150aboutC; AC) Benzene-1,4-dicarboxylic acid mono-(2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL) ester, mono-fenilmetilovy ester, so pl. 169-171aboutC.

P R I m e R 5. 2,6-bis(1,1-Dimethylethyl)-4-(N-methyl-N-[1-phenyl-1H-pyrazole-3-yl] amino) phenyl acetate.

To 2,6-bis(1,1-Dimethylethyl)-4-(N-methyl-N- [1-phenyl-1H-pyrazole-3-yl]amino) phenol (0.6 g) in dry tetrahydrofuran (15 ml) at -78aboutC in nitrogen atmosphere add utility (1,29 ml) 1.4 M hexane solution). After 10 min add acetylchloride (0.2 ml). The reaction mixture ostable the'étang/hexane (1:1)) of the residue followed by recrystallization from hexane at -20aboutC give the target compound (0.35 g), so pl. 102-103aboutC.

P R I m e R 6. Using the appropriate acylchlorides and phenols receive the following compounds according to the method of example 5:

(a) 2,6-bis (1,1-dimethylethyl)-4-(N-methyl-N- [1-phenyl-1H-pyrazole-3-yl] amino)phenyl methoxyacetate, so pl. 102-103aboutWith; (b) 2,6-bis (1,1-dimethylethyl)-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL acetate, so PL 186-187aboutWith the position of the acetyl confirmed range OYE differences.

P R I m e R 7. 1,4-Batandjieva acid, mono (2,6-dimethyl-4-[1-phenyl-1H-pyrazole-3-yl]-aminophenoxy) ether.

To 4-(1-Phenyl-1H-pyrazole-3-yl) amino-2,6-dimethylphenol (1.8 g) in dry dichloromethane (30 ml) and triethylamine (2.25 ml) at 0aboutC in an atmosphere of nitrogen added succinic anhydride (0.84 g). The mixture is stirred at room temperature for 16 h, then poured into water. The organic phase is dried and evaporated. The resulting oil chromatographic (silica, 2% methanol/dichloromethane) to give the desired product (1.5 g), so pl. 160-161aboutAfter crystallization from a mixture of hexane and ethyl acetate.

P R I m e R 8. The following connection receive according to the method of example 7:

f) 1,5-pentanedionate acid, mono(2,6-dimethyl - 4-(1-phenyl-1H-pyrazole-3-yl) aminoborane.

1,1-Carbonyldiimidazole (4.9 g) is added in portions to pyruvic acid (2.6 g) in dichloromethane (100 ml) and after 0.5 h add 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminophenol (2.8 g). The mixture is left for 16 h, then evaporated, and the residue chromatographic/silica, dichloromethane) to give after crystallization (hexane:ethyl acetate) of the target product (1.0 g), so pl. 123-125aboutC.

P R I m e R 10. The following connections receive according to the method of example 9.

(a) 2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL-N-/(phenylmethoxy) carbonyl) glycinate, so pl. 142-143aboutC; C) 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL-4-dimethylaminobutyric, so pl. 83-85aboutC.

P R I m e R 11. 2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenylacetate.

The product of example 1 is heated under reflux in toluene with 5% palladium on charcoal (0.15 g) for 4 h Filtration, evaporation and chromatography (silica, dichloromethane) in ethyl acetate (96:5) balance give the target compound (0.07 g), so pl. 114-116aboutWith cyclohexane/ advanced polymorph, so pl. 134aboutC.

Found, 71,2; N 6,1; N 12,85.

WITH19H19N3O2< / BR>
Calculated C For 70.9; H 5,9; N 12,5.

P R I m e R 12. Mark Neal)-1H-pyrazole-3-yl/ aminophenylacetate, so pl. 142-143aboutC.

P R I m e p 13. 4-(1-phenyl-1H-pyrazole-3-yl)-amino-2,6-dipropylacetate.

4-(1-Phenyl-1H-pyrazole-3-yl) amino-2,6-di(prop-2-enyl)-phenyl acetate from example 3 (3.5 g) in ethanol (150 ml) hydronaut at atmospheric pressure over 10% palladium on charcoal, giving after crystallization from cyclohexane target product (1.8 g) so pl. 71-74aboutC.

P R I m e R 14. Using the method Primera of these predecessors obtain the following compounds.

(a) 2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenylacetate, so pl. 155-157aboutC; C) 4-(1-Cyclohexyl-1H-pyrazole-3-yl)amino-2,6 - dimetilfenil hydroxyacetate, so pl. 160-164aboutWith; (a) and (b) derived from 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)-aminophenylacetate by hydrogenation at 5 atmospheres for 6 days, and separating the resulting mixture of compounds using chromatography (silica, dichloromethane-ethyl acetate) (9:1)); (C) 2,6-Dimethyl-4- (1-phenyl-1H-pyrazole-3-yl) aminophenylacetate hydrochloride is obtained from the product of example 10A with the subsequent processing of ethereal hydrogen chloride, so pl. 230-231aboutWith; (d) benzene-1,4-dicarboxylic acid mono-(2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenoxy/ether poluchautsa-3-yl/ aminophenylacetate.

2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenylacetate. The product of example 4j (1 g) and sodium cyanide (0.5 g), stirred in dimethyl sulfoxide for 16 h to give after dilution of the salt solution, extraction with ethyl acetate and subsequent evaporation of the target compound (0.3 g) so pl. 116-117aboutC (from ethyl acetate/hexane).

P R I m e R 16. 3-(2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) aminophenoxyethanol)-1-methylpyridinium.

2,6-Dimethyl-4-(1-phenyl-1H-pyrazole-3-yl) AMINOPHENYL 3-pyridinecarboxylic example 4n (0.5 g) is heated under reflux in methyliodide (100 ml) for 4 days, unreacted methyliodide removed by evaporation, and the target product is obtained by trituration of the resulting oil with ether, so pl. 150aboutC (decomp.).

P R I m e R 17. Song.

a) for topical application on the skin

Gel cosolvent type for topical application, the Active ingredient of 0.5 Hydroxypropylcellulose 1.0 Ethanol 90,0 Water To 100

C) Ophthalmic application, the Active ingredient (micronized) 2.0 Carbopol R 1.0 sodium Hydroxide to pH 7 Chloride benzalconi of 0.01 sodium Chloride 0,9 Water To 100.0

C) Enema for rectal R>
d) oil Subcutaneous injection, the Active ingredient 3.0 Miglyol 812N to 100.0

a) Nasal suspension, the Active ingredient (micronized) 1.0 Polysorbate 80 0,5 Chloride benzalconi 0.01 Glycerol 2.4 Avicel 2,0 Water Up to 200,0

The claimed compounds have low toxicity.

The data below refers to 2,6-dimethyl-4-(1-phenyl - 1H-pyrazole-3-yl) aminophenylacetate

In oral introduction: Rodents maximum



>4000 mg/kg intravenously Rodents maximum




100 mg/kg

Data on toxicity indicate that the specified connection has a relatively low acute toxicity and does not present any significant danger to humans.

Inhibition derivative of 4-aminophenol and 5-lipoxygenase in human neutrophils.


The products of 5-lipoxygenase (5-L) is well known as the mediators of inflammation in many conditions such as psoriasis. The symptoms of inflammation can occur as a result of products 5-L, derived from arachidonic acid, and indeed, in psoriatic skin, as izvesti to inhibit 5-L and therefore, the biosynthesis eicosanoid products, can offer a useful therapeutic approach to the treatment of inflammatory conditions.

Derivatives of 4-aminophenol in this application was tested for inhibition of 5-L from intact human neutrophils. Inhibition of 5-L was measured as a function of the reduction product of the oxidation of arachidonic acid 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-NET). The activity of the compounds was compared with clinically effective antipsoriatics means Lopazalen (1).


Human neutrophils were obtained by the method Blackham and other (2) content of neutrophils over 95% of the total cells. Test 5-L activity was carried out at 37aboutWith full yrodes (final volume 0.5 ml) containing 1x107cells, 50 M arachidonic acid and 1 M ionophore A. The test compound in ethanol (final concentration 1%) pre-incubated with cells for 4 min before activation of the cells by arachidonic acid and iodoform. The reaction was stopped after 2 min by ice-cold methanol (0.5 ml). After 45 min exposure in ice, the suspension was centrifuged for 10 min at 1800 g of the upper layer UDA is a radio connection, required to obtain 50% inhibition of 5-L), which are listed in the table below.

The results show that all the tested derivatives of 4-aminophenol are inhibitors of 5-lipoxygenase.

In each case, these connections are stronger inhibitors of 5-lipoxygenase, clinically effective than antipsoriatics agent Lopazalen.

1. Derivatives of 4-aminophenol of the General formula

< / BR>
where R1group C(O)YZ, where Y is single bond, O, NR7or;

Z is hydrogen, pyridyl, phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower alkoxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl (lower)alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6the same or different, is hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7the same or different, hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3WITH6-cycloalkyl or phenyl which may be substituted TRIG is ronil,

or their N-alkyl or salt derivatives exhibiting anti-inflammatory activity.

2. Derivatives under item 1, where R2and R6both lower alkyl.

3. Derivatives PP. 1 and 2, where R3and R5both hydrogen.

4. Derivatives PP. 1 3, where X pyrazolyl substituted by phenyl.

5. Derived under item 1, which is 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)-aminophenylacetate or its pharmaceutically acceptable salt.

6. Derived under item 1, which is 4-(4,5-dihydro-1-phenyl-1H-pyrazole-3-yl) amino-2,6-dimethylphenylacetate, 4-(4,5-dihydro-1-)3-triptoreline(-1H-pyrazole-3-yl)amino-2,6-dimethylphenylacetate, 4-(1-phenyl-1H-pyrazole-3-yl)-amino-2,6-di(prop-2-enyl)phenylacetate, 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminophenylalanine, 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)AMINOPHENYL-2,2-dimethylpropanoate, 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminobenzylpenicillin, 2,6-dimethyl-4-(1-phenyl-1H-pyrazole-3-yl)aminophenylarsonic.

Priority signs:

20.05.89 when Y is a single bond, Z is methyl or hydrogen, R3and R5hydrogen, R2and R6methyl or chlorine, R4hydrogen, X pyrazolyl substituted by phenyl.

10.02.90 when Y is O or-NR7, UB>WITH6-alkoxy, R7hydrogen or C1WITH6-alkyl.


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R5azetidinone, pyrolidine, hexamethyleneimino or heptamethylnonane or piperidino group in which the methylene group in the fourth position may be substituted with oxygen, sulfenyl, sulfinil or sulfonylureas or aminogroups, which can be substituted for R3, R4CO4, alkylsulfonyl - or aryl is

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FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex