DD291756A5 - PROCESS FOR PRODUCING NEW ARYL COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of novel aryl derivatives of the formula * in which Ar is 4-halophenyl, Ar is 1,3- or 1,4-phenylene, Y (E) is CHCH and R 1 and R 2 are independent of hydrogen and C 1-4 -alkyl be selected, and their base salts and physiologically active derivatives. The new compounds are suitable for pharmaceutical preparations. Formula (I) {production; Method; aryl derivatives; pharmaceutical preparations}

Description

as defined above means reacting with a suitable agent or agents and under such reaction conditions that conversion of the N-hydrogen to an N-CONH ₂ group is achieved, and the compound of formula (I) thus formed is converted into a corresponding Base salt or a physiologically active derivative, characterized in that it is mixed or dissolved with / for the preparation of a pharmaceutical preparation with the product of step (a) and optionally one or more other pharmacologically active ingredients with / in a pharmaceutically acceptable carrier or vehicle / is suspended.

8. Use according to claim 7, characterized in that in the compound of formula (I) Ar 4-fluorophenyl and / or

Ar '1,3-phenylene and / or R ¹ and R ^{2 is} hydrogen.

9. Use according to claim 8, characterized in that the compound of formula (I) '{(E) -N-1-methyl-3- [3- (4-fluorophenoxy) -phenyl) -prop-2-ene 1-yl} -N-hydroxyurea in the enantiomeric (R) or (S) -form or their mixture in any ratio.

10. Use according to Anspi jch 7 to 9, characterized in that the compound of formula (II) is optically active and the compound of formula (I) is obtained in its enantiomeric (R) -form and is substantially free of (S) Isomer.

11. Use according to claim 7 to 9, characterized in that the compound of formula (II) is optically active and the compound of formula (I) is obtained in its enantiomeric (S) -form and is substantially free of (R) - Isomer is.

12. Use according to claim 7 to 9, characterized in that the compound of formula (II) is optically inactive and the compound of formula (I) is recovered as a catalysis.

13. Use according to claim 7 to 12, characterized in that the step (b) mixing or dissolving / suspending one or more other pharmacologically active ingredients (s) such as an antibiotic, antimycotic, antiviral, antihistaminic and nonsteroidal anti-inflammatory with / in the Carrier or vehicle.

Use according to claims 7-13, characterized in that step (b) comprises mixing or dissolving / suspending one or more non-steroidal anti-inflammatory / anti-inflammatory drugs with / in the carrier or vehicle.

15. Use according to claim 7 to 14, characterized in that the product of step (b) by an additional step (c) is brought into a suitable form for oral, topical, pulmonary or intra-articular application form.

Field of application of the invention

The invention relates to a process for the preparation of novel arylhydroxyurea compounds having an antiinflammatory effect.

Characteristic of the known state of the art

A class of compounds defined in EP-0055418 is described there as an inhibitor of both the 5-lipoxygenase and the cyclooxygenase enzymes of the mammalian arachidonic acid metabolism, and has been found to exhibit anti-inflammatory and similar effects. Other compounds described as 5-lipoxygenase and / or cyclooxygenase inhibitors include certain naphthyloxy derivatives, e.g. For example, U.S. Patent 3,740,437 or Proc. Ann. Symp. Inst. Basic Med. Sei., Royal College of Surgeons of England (October 1982, p.26? ·? 74). Among the compounds described in the latter reference also known as Nafazatrom compound.

EP-PS 0196184 describes a class of hydroxamic acid derivatives which are inhibitors of the enzyme 5-lipoxygenase. EP-PS 0299761 describes an omission of the α-alkylated N-alkanoyl hydroxamic acids, which belong to the scope of the class of hydroxamic acid derivatives described in EP-PS 0196184; the compounds of this subclass have particularly desirable pharmacological properties with respect to their ability to inhibit 5-lipoxygenase.

Explanation of the essence of the invention

Within the class of compounds described in EP-PS 0196184 now another subclass has been found, which is characterized as α-methylated N-hydroxyureas and has particularly advantageous pharmacological and physical properties, for example, with respect to their 5-lipoxygenase-inhibiting and Antioxydanseigenschaften and the long duration of action that their two enantiomers show

 According to the present invention, therefore, a compound of formula (I)

Ar-O-Ar'-YCN ' , ₉ (D.

CH ₃ ^N CONR ¹ Fr

in the

Ar 4-halophenyl,

Ar '1,3- or 1,4-phenylene,

Y (E) -CH = CH and

R ¹ and R ^{2 are} independently selected from hydrogen and C 1-4 -alkyl,

and their bases salts and physiologically active derivatives are provided.

It is believed that the compounds of formula (I) and their base salts can exist in the enantiomeric (R) or (S) form. The scope of this invention therefore includes each individual (R) and (S) enantiomer of the compounds of formula (I) and their base salts which are substantially free of the other enantiomer, i. H.

less than 5% thereof, as well as mixtures of these enantiomers in any ratio including racemates containing substantially equal amounts of the two enantiomers.

Preferred compounds of the invention include compounds in which Ar, 4-fluorophenyl and / or

Ar '1,3-phenylene and / or

R ¹ and R ^{2 are} hydrogen,

and their base salts and physiologically active derivatives.

A particularly preferred compound of formula (I) having exceptionally advantageous 5-lipoxygenase inhibiting and antioxidant properties, especially in terms of their duration of action, is (E) -N- (I-methyl-3- [3- (4-fluorophenoxy) phenyl] prop-2-en-1-yl} -N-hydroxyurea, preferably in the form of a racemate of the two enantiomers.

Base salts of the compounds of formula (I) which are suitable for use in medicine are those in which the cation is physiologically acceptable. However, base salts having physiologically unacceptable cations are within the scope of this invention, either for non-medical purposes or as intermediates in the preparation of compounds of formula (I) and their physiologically acceptable salts and physiologically active derivatives.

Salts of the invention include ammonium salts, salts of alkali metals such as sodium and potassium salts, salts of alkaline earth metals such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine and salts with amino acids such as arginine and lysine.

The o.g. Compounds of formula (I) and their physiologically acceptable base salts and physiologically active derivatives are hereinafter referred to as "compounds of the invention" in relation to the therapeutic and pharmaceutical aspects of the invention discussed below.

According to further aspects of the invention, the following are provided:

(a) Fiction-free compounds for use in therapy

(b) pharmaceutical preparations containing a compound of the invention, at least one pharmaceutical carrier or vehicle, and optionally one or more therapeutically active ingredients,

(c) the use of a compound of the invention in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition in which a 5-lipoxygenase inhibitor or antioxidant is indicated,

(d) the use of a compound of the invention in the preparation of a medicament for prophylaxis or treatment

(I) a spasmogenic condition,

(II) an allergic condition,

(III) a tumor image,

(IV) a condition with thrombo-glutination,

(V) an inflammatory condition or

(VI) of atherosclerosis,

(e) a method for the prophylaxis or treatment of a clinical condition in a mammal such as a human, in which a 5-lipoxydase inhibitor or antioxidant is indicated, which includes administering to said subject a therapeutically effective amount of a compound of the invention, and

(f) A method for the prophylaxis or treatment of a clinical condition in a mammal such as a human having one of the following conditions

(I) spasmogenic condition,

(II) allergic condition,

(III) tumor formation,

(IV) condition with thrombo-glutination,

(V) inflammatory condition or

(VI) atherosclerosis,

involving the administration of a therapeutically effective amount of a compound of the invention to said subject,

(g) Process for the preparation of the compounds according to the invention.

Because of their 5-L.ipoxygenase H3mmungseigenschaften the compounds of the invention are used in the prophylaxis or treatment of clinical conditions in which an inhibitor of the lipoxygenase-mediated arachidonic acid metabolism is indicated, in particular at

(I) spasmogenic states,

(II) allergic conditions,

(III) tumor formation,

(IV) conditions with thrombo-glutination and

(V) inflammatory conditions

 These are discussed in turn.

Examples of spasmogenic conditions include smooth muscle tissue conditions, in particular airway smooth muscle constriction such as endogenous asthma (including idiopathic bronchial asthma and cardiac asthma), bronchitis, and smooth muscle constriction of arteries such as coronary spasm (including those associated with myocardial infarction) Left insufficiency may lead to subsequent cardiac asthma) and brain-related spasm or stroke.

Other examples include intestinal disorders caused by abnormal colonic muscle contraction, e.g. Conditions known as irritable bowel syndrome, irritable bowel syndrome, and mucous membrane colitis.

Examples of allergic conditions are exogenous asthma, allergic dermatoses of complete or partial allergic origin such as eczema, allergic bowel disorders (including celiac disease), allergic ocular manifestations such as hay fever (which may additionally or alternatively attack the upper airways) and allergic conjunctivitis.

Examples of tumors include skin neoplasms, mastocytoma, and other forms of cell proliferation that can be benign and malignant. It should be noted that the efficacy of the compounds of the invention in the prophylaxis and treatment of tumors may result from properties which, in addition to inhibiting 5-lipoxygenase, cause inhibition of cell proliferation.

Examples of conditions with thrombo-glutination are conditions resulting from thrombosis including apoplexies of complete or partial thrombotic origin, coronary thrombosis, phlebitis and venous thrombosis (the latter two conditions may also be associated with inflammation).

Examples of inflammatory conditions are inflammatory conditions of (a) the lung, (b) the joints, (c) the eyes, (d) the intestine, (e) the skin, and (f) the heart, especially those associated with leukocyte infiltration are connected to the inflamed tissue.

Examples of such inflammatory conditions are:

(a) Inflammatory conditions of the lung include asthma, bronchitis and cystic fibrosis (which, in addition or alternatively, may affect the gut or other tissue).

(b) Inflammatory conditions of the joints include rheumatoid arthritis, Marie-Stümpell disease, osteoarthritis, gouty arthritis and other arthritic conditions.

(c) Inflammatory conditions of the eyes include uveitis, (including iritis) and conjunctivitis.

(d) Inflammatory conditions of the gut include Crohn's disease, ulcerative colitis, and distal proctitis.

(e) Inflammatory skin diseases include those associated with cell proliferation such as psoriasis, eczema and dermatitis (with or without allergic origin).

(f) The inflammatory conditions of the heart include coronary artery damage.

Other inflammatory conditions are e.g. B. tissue necrosis in chronic inflammation and tissue rejection after transplantation.

Because of their antioxidant properties erfindungsyemäßen compounds are also in the prophylaxis or treatment of clinical conditions such. Atherosclerosis and arthritis, in which a cell protecting agent having such properties is indicated.

In view of their unique properties, the compounds of the invention may also be used in the prophylaxis or treatment of bacterial and fungal infections, dysmenorrhoea, multiple sclerosis, and clinical conditions where an immunosuppressant, anticonvulsant, or analgesic is indicated. The compounds of the invention may also exhibit hypocholesterolemic activity.

The amount of the compound of the invention (hereinafter referred to as the active ingredient) required for a therapeutic effect will of course vary with respect to the particular compound, the route of administration, the subject to be treated and the particular disorder or disease. The appropriate dose for a mammal suffering or likely to suffer from any of the clinical conditions described above is in the range 0.1 μg to 500 mg compound / kg body mass. In the case of systemic administration, the typical dose is in the range 0.5 to 500 mg compound / kg body mass, with the am

most preferred dosage is 0.5 to 50 mg / kg of body mass, for example 5 to 25 mg / kg in two or three times daily administration. In the case of topical administration, ie external application to the skin or eye, the appropriate dose is in the range of 0.1 ng to 100 mg base / kg and the typical dose is about 0.1 mg / kg. For oral administration for the prophylaxis or treatment of constriction of the airway smooth muscle, for example in asthma or bronchitis, the appropriate dose of the compound of the invention may be in the range described in the preceding paragraph; however, it is preferable to have a dose of 1 to 10 mg base / kg body mass, and the most preferred dosage is 1 to 5 mg / kg body mass, for example 1 to 2 mg / kg. In the case of pulmonary administration, the typical dose is in the range from 2 μg to 100 mg / kg, for example in the range from 20 μg to 0.5 mg / kg, in particular from 0.1 to 0.5 mg / kg.

While it is possible to administer the active ingredient alone, it is preferable to present it as a pharmaceutical preparation containing a compound of the invention in association with a pharmaceutically acceptable carrier or vehicle and, as desired, one or more therapeutically active ingredients. The carrier or vehicle must, of course, be compatible with the other ingredients of the preparation and must not harm the recipient. The active ingredient can make up from 0.1% to 99.9% of the preparation. Typical unit doses of a preparation according to the invention contain from 0.1 mg to 1 g of active ingredient. For topical administration, the active ingredient preferably constitutes 1 to 2 parts by weight in% of the preparation, but the active ingredient may also constitute 10 parts by weight in% (w / w). For nasal or buccal administration suitable formulations usually contain 0.1 to 20 parts by weight in% (w / w), z. B. 2 parts by mass in% (w / w) of active ingredient. The preparations according to the invention include preparations in a form suitable for oral, pulmonary, ophthalmological, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular, topical or intranasal / buccal administration.

The preparations of the invention may conveniently be presented in unit form and prepared by any method known in the pharmaceutical art. All of these methods include the step of bringing the active ingredient into association with a carrier which is one or more accessory ingredients. In general, the preparations are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the required form. The compositions according to the invention which are suitable for peroral administration may take the form of discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of active ingredient, the form of a powder or granules, the form of a solution or a suspension in one aqueous or non-aqueous liquid or in the form of an oil-in-water or water-in-oil emulsion. The active ingredient may also be in the form of a bolus, electuary or paste. A tablet may be prepared by pressing or compressing the active ingredient, optionally with one or more accessory ingredients. Compressed tablets can be made by mixing the active ingredient in free-flowing form, e.g. as a powder or granules, optionally in admixture with a binder, lubricants, inert diluents and / or a surface-active agent or dispersant, pressed in a suitable machine. Molded tablets may be prepared in a suitable machine from a mixture of the powdered active and a suitable carrier moistened with an inert liquid diluent.

Preparations for rectal administration may take the form of a suppository containing the active ingredient and a carrier such as cocoa butter or the form of an enema.

Preparations suitable for parenteral administration are usually a sterile aqueous preparation of the active ingredient which is preferably isotonic with the recipient blood.

Preparations suitable for intraarticular administration may be in the form of a sterile aqueous preparation of the active ingredient, e.g. As an aqueous microcrystalline suspension, when the active ingredient is in microcrystalline form. Liposome preparations and biodegradable polymer systems can also be used to provide the active ingredient for both intra-articular and ophthalmic applications.

Suitable external preparations are liquid and semi-liquid preparations such as liniments, lotions and oil-in-water and water-in-oil emulsions such as creams, ointments and pastes as well as solutions and suspensions such as drops ophthalmic use in the form of aqueous eye drops, ζ. B. be presented as 0.1 to 1.07oige (w / v) solution.

Suitable formulations for inhalation use are fine dusts or mists which can be produced by means of various dosing pressure atomizer doses, nebulizers or powder atomizers.

For pulmonary administration per os, the particle size of the powder or droplets is usually in the range of 0.5 to 10μηΊ, preferably 1 to 5pm, to ensure entry into the bronchial tree. For intranasal administration, a particle size in the range of 10 to 500 μm is preferred to ensure retention in the nasal cavity. Dosing inhalers are aerosol dispensers, which usually contain a suspension or solution of the active ingredient in a liquefied propellant. In use, these devices deliver the preparation through a valve set to a measured volume, typically 10 to 150μΙ, producing an aerosol spray containing the active ingredient. Suitable propellants are certain chlorofluorocarbons, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and their mixtures. The preparation may additionally contain one or more cosolvents, e.g. As ethanol, surfactants, eg. As oleic acid or sorbitan trioleate, antioxidants and suitable flavorings.

Nebulizers are commercially available devices that deliver drug solutions or suspensions into a therapeutically effective aerosol mist, either by accelerating a compressed gas, usually air or oxygen, through a narrow venturi, or by ultrasonic agitation. Suitable formulations for use in nebulizers consist of the active ingredient in a liquid carrier and contain up to 40 parts by weight in% (w / w) of the preparation, preferably less than 20 parts by weight in% (w / w). The carrier is usually water or a dilute aqueous alcoholic solution, which can be added by adding e.g. of sodium chloride has been rendered isotonic with the body fluids. Free choice additives are preservatives if the preparation is not made sterile, eg. Methyl hydroxybenzoate, antioxidants, flavorants, volatile oils, buffering agents and surfactants.

Suitable preparations for intranasal administration include fine powders supplied by means of a powder pulverizer or drawn into the nasal cavity like snuff. In the powder atomizer, the powder is contained in capsules or cartridges, usually made of gelatin or plastic, which are perforated or opened in situ, and the powder is passed through the air drawn through the device during inhalation or by means of a hand-operated pump fed. The powder used in the powder atomizer consists either only of active substance or of a powder mixture which contains the electrolyte, a suitable powdery diluent such as lactose and a surface-active agent left to the free choice. The active ingredient content of the preparation is usually from 0.1 to 100 parts by weight in% (w / w).

In addition to the above ingredients, the formulations of the present invention may contain one or more additional ingredients such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives, e.g. Methyl hydroxybenzoate, antioxidants and emulsifiers. The compounds of the present invention may suitably be used in association with one or more therapeutically active ingredients such as an antibiotic (e.g., a bactericidal agent), an antifungal agent, an antiviral agent, an antihistamine (especially a peripherally acting antihistamine), or a non-steroidal antiinflammatory drug (non steroidal anti-inflammatory drug).

The compounds of these combinations may be administered simultaneously, for example in the same preparation, or in separate preparations, or sequentially in a sufficiently short period of time to achieve the desired combined therapeutic effect. When the compounds are used in the same preparation, a preparation according to the present invention containing, in addition to a compound of the invention, the further constituent (s) may be used.

The combination with an antihistamine is particularly advantageous in asthma prophylaxis and therapy. A suitable antihistamine may be selected from the compounds described in European Patent Nos. 0859959 and 0117302. The amount and dosage of such an antihistamine may be selected as described in these two documents. Particularly preferred are the antihistamines (E) -3- (6- (3-pyrrolidin-1- (4-tolyl) prop-1 E-enyl- (2-pyridylacrylic acid and (E) -3- (6- (3- Pyrrolidine-1- (4-tolyl) -prop-1E-enyl- (2-pyridyl) -propionic acid Another preferred antihistamine is (E) -1- (4-methylphenyl) -1- (2-pyridyl) -3 pyrrolidine-prop-1-ene, also known as triprolidine.

The combination with a non-steroidal anti-inflammatory drug is particularly advantageous in the prophylaxis and treatment of inflammatory conditions of the joints similar to those referred to above apply. It has been found that the use of such combinations in the treatment of inflammatory conditions of the joints has a therapeutic effect superior to that of single use of the drugs. In particular, the decrease in joint swelling and the decrease in thickness of the synovial lining of the joint are significantly improved when the combination therapy is used. In addition, there is a decrease in proteoglycan loss from articular cartilage and decreased infiltration of polymorphonuclear and other leukocytes into the synovium; these effects are not observed when both medicines are used separately.

Non-steroidal anti-inflammatory drugs are known to be the cause of gastric ulcers, especially in high doses. In addition to the improved therapeutic effect observed with the combined use of a non-steroidal anti-inflammatory drug and a compound of the invention, the antioxidant properties of the latter compound protect the cells against the ulcerative effect of the non-steroidal anti-inflammatory drug, so that higher doses of the non-steroidal anti-inflammatory drug can be administered with a lower ulcer risk.

Thus, the present invention further provides a pharmaceutical composition suitable for oral administration or intra-articular injection containing a compound of the invention (as defined above) and at least one non-steroidal anti-inflammatory drug. Suitable non-steroidal anti-inflammatory drugs include acemetacin, alminoprofen, sodium amfenac, aminoprofen, antitrazafan, antrafenine, auranofin, bendazac-lysinate, benzydamine, beprozin, broperamol, bufezolac, carprofen, cinmetacin, ciproquazone, clidanac, cloximate, diazidamine, deboxamet, delmetacin, Detomidine, Dexindoprofen, Diacerein, Diclofenac, Difisalamin, Difenpyramid, Emorfozon, Enfenamic acid, Enolicam, Epirizol, Eatsalat, Etodolac, Etofenamat, Fanetizolmesilat, Fenclofenac, Fenclorac, Fendosal, Feniflumizol, Fentiazac, Feprazone, Floctafenin, Flunixin, Flunoxaprofen, Fluproquazone, Flurbiprofen, Fopirtolin, Fosfosal, Furcloprofen, Furofenac, Glucametacin, Guaimesal, Ibuprofen, Ibuproxam, Indomethacin, Isofezolate. sonixim, isoprofen, isoxepac, isoxicam, ketoprofen, lefetamine HCI, leflunomide, lofemizole, lonazolac, calcium, lotifazole, loxoprofen, lysine clonixinate, meclofenamate sodium, meseclazone, miroprofen, nabumetone, naproxen, nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin, Perisoxalcitrate, Pimeprofen, Pimetacin, Piproxen, Pimzolac, Pirfenidone, Piroxicam, Pirprofen, Pranoprofen, Proglumetacin Maleate, Proquazone, Pyridoxiprofen, Sudoxicam, Suprofen, Talmetacin, Talniflumat, Tcnoxicam, Thiazolinobutazone, Thielavin B, Tiaprofenic Acid, Tiaramid HCI, Tiflamizole, Timegadine, Tioxaprofen, Tolfenamic acid, Tolpadol, Tryptamide, Ufenamate and Zidometacin.

Preferred non-steroidal anti-inflammatory drugs are naproxen, flurbiprofen, ketoprofen, aminoprofen, carprofen, clidanac, dexindoprofen, diclofenac, enfenamic acid, fenclofenac, flunoxaprofen, ibuprfen, indomethacin, isoprofen, loxoprofen, meclofenamate sodium, miroprofen, piroxicam, pirprofen, pranoprofen, suproons, Tiaprofenic acid, Tioxaprofen and Zidometacin.

Particularly preferred non-steroidal anti-inflammatory drugs for use in accordance with this aspect of the invention are clidanac, diclofenac, ibuprofen, indomethacin, suprofen, naproxen, piroxicam, flurbiprofen, ketoprofen and tiaprofenoic acid. Also used may be the following non-steroidal anti-inflammatory drugs designated by the Company Key Number (see Chemical Abstracts Index Guide, 1989): 480156S, AA861, AD1491, AD1590, AFP802, AFP860, AHR6293, A177B, AP504, AU8001, BAY08276, BPPC, BW540C. BW775C, CHINOIN127, CN100, CO893XX, CPP, D10242, DKA9, DV17, EB382, EGYT2829, EL508, F1044, FZ, GP53633, GP650, GV3658, HG / 3, ITC1, ITF, ITF182, KB1043, KC8973, KCNTE16090, KME4, LA2851, LT696, LU20884, M7074, MED15, MG18311, MR714, MR897, MY309, NO164, ONO3144, PR823, PV102, PV108, QZ16, R830, RS2131, RU16029, RU26559, RUB265, SCR152, SH440, SIR133, SIR136, SIR92, SPAS510, SQ27239, ST281, SX1032, SY6001, SaH46798, TA60, TAI901, TEI615, TVX2706, TVX960, TZI615, U60257, UR2310, WY23205, WY41770, YMO9561, YM3162, YS1033 and ZK31945.

The non-steroidal anti-inflammatory drugs also include the salicylates, namely aspirin, and the phenylbutazone and their pharmaceutically acceptable salts.,

Usually, a preparation according to this aspect of the invention contains a non-toxic cell-protective amount of a compound according to the invention and an effective nontoxic (without the compound according to the invention but possibly ulcerogenic) amount of non-steroidal antiphlogistic.

The amount of non-steroidal anti-inflammatory agent in the preparation will depend on the intended effect and will be determined by the physician according to the age, body mass, general health, etc. of the patient. The amount of the compound of the invention provided as part of the composition is selected to be compatible with the amount of non-steroidal anti-inflammatory drug and to provide sufficient anti-cellulite activity to reduce or eliminate the gastric ulcer-forming effect of the non-steroidal anti-inflammatory drug , The typical amounts of the compounds of the invention for use in conjunction with a non-steroidal anti-inflammatory drug in oral or intra-articular preparations are as previously indicated.

According to a further aspect of the invention, a process for the preparation of a compound according to the invention is provided which comprises the reaction of a compound of the formula (II)

R ³ NHOH, (II)

in the R ^{3 is} a group of the formula

^H Ar-O-Ar'-Y-Ij: -

CH ₃

as defined for a compound of formula (I), with a suitable agent or agents and under such reaction conditions that the conversion of the N-hydrogen to an N-CONHj group is achieved, and optionally the conversion of so comprising the compound of the invention formed in its corresponding salt. The reaction is usually carried out by treating the compound of formula (II) with a cyanate of main group I of the periodic table, for example sodium cyanate, in a non-polar solvent such as tetrahydrofuran (THF) in the presence of an acid.

The compounds of formula (II) may be prepared by oximation of the corresponding ketone using e.g. For example, hydroxylamine in a suitable polar solvent such as methanol, followed by in situ reduction of the oxime using z. As sodium cyanoboranate / oxalic acid are produced. The appropriate ketone can be purchased or by reaction of the corresponding aldehyde with z. For example, aqueous sodium hydroxide (NaOH) / acetone or Dimethylacetylmethylphosphonat / anhydrous potassium carbonate in a suitable solvent such as THF are obtained. The suitable aldehyde can be purchased or z. B. by lithiation of the corresponding bromine compound and subsequent treatment with dimethylformamide (DMF) are obtained. The Brorr connection can be purchased or z. B. by reaction of a compound of formula ArLS in which Ar and L have the abovementioned meaning and S is a metal of the main group I, with a compound of the formula Ar'Br, in which Ar 'has the abovementioned meaning, in a suitable Solvent such as 1-methyl-2-pyrrolidinone be recovered. The lithiation is usually carried out with butyllithium at a lower temperature, e.g. B. at -60 ⁰ C in a non-polar solvent such as THF. The aldehyde can also be recovered by treating the corresponding dibromomethyl compound with disodium ethylenediaminetetraacetate (EDTA.2 Na) / calcium carbonate in a polar solvent system such as ethanol / water. The dibromomethyl compound can also be purchased or z. Example, by irradiation of a compound of the formula ArLAr'CH ₃ , in which Ar, L and Ar 'have the abovementioned meaning, in a non-polar solvent such as CCt ₄ in the presence of N-bromosuccinimide (NBS) / azoisobutyronitrile (AIBN).

The individual enantiomers of the compound of the present invention may be obtained by separation of the racemate components, for example by means of a chiral chromatography column or by preparation and separation of the appropriate diastereoisomers or by direct synthesis from the corresponding chiral compound of formula (II) by the method described above.

Chiralc compounds of formula (II) can conveniently be obtained by acidic or alkaline hydrolysis of the corresponding di-blocked chiral compound, for example the NICOiMeJ-OCC ^ Me compound or the -N (BOC) OBOC compound in which BOC is tert. -Butoxycarbonyl means. The latter compound may be prepared by treating the appropriate chiral alcohol A with HN (BOC) OBOC in the presence of triphenylphosphine / diethyl azodicarboxylate (DEAD) at low temperature in a non-polar solvent such as toluene or by reaction of the corresponding chiral compound of formula (III) ₍

H OR ⁴

H ₉ C = CH-CN ^ _ς <>">

^L W^N R⁵

where W has the meaning described above and R ⁴ and R ^{5 are} tert-butoxycarbonyl groups, with a compound of the formula (IV)

Ar-L-Ar'-T, (IV)

wherein Ar, L and Ar 'have the meaning described for the compound according to the invention and T is a suitable leaving group such as bromine, usually at elevated temperature in the presence of palladium D-acetate, tri (otolyl) phosphine and a suitable base such. For example, tributylamine can be obtained.

Chiral precursors of formula (III) can conveniently be prepared by treatment of the appropriate chiral alcohol B with HN (BOC) OBOC in the presence of triulylphenol / DEAD or by partial reduction of the corresponding chiral alkyne by e.g. B. quantitative hydrogenation of a suitable catalyst such as palladium on barium sulfate in a basic solvent such as pyridine win. The chiral AlkIn can be obtained by treating the corresponding chialic alcohol C with HN (BOC) OBOC in the presence of triphenylphosphine / DEAD. The suitable chiral alcohols A, B and C can be purchased or prepared from the corresponding ketones using suitable chiralor reducing agents (J. Amer., Ed Soc. 109 (1987) 7925). They may also be obtained from derivatives of the racemic alcohols by derivatization and selective hydrolysis (JCS Chom, Comni. (1988) 598) or by separation of the appropriate diastereoisomers (J. Med., Chom., 31 [1988] 156.) Compounds of the formula (IV ) are commercially available or can be represented by literature methods.

The released? Conversion of the compound of the invention into a corresponding base salt can be conveniently achieved by reaction with the appropriate base

 For a better understanding of the invention, the following examples are given by way of illustration.

Exemplary embodiments Synthesis examples

Synthesis Report 1

Preparation of (E) -N- {3- [3- (4-fluorophenoxy) phenyl] -1 (R, S) -methylprop-2-en-1-yl) -N-hydroxyurea

(a) 3- (4-fluorophenoxy) toluene

A solution of 4-fluorophenol (112g, Aldrich) in anisole (250ml) was added dropwise with stirring to a suspension of NaH (26.4g) in anisole (250ml) over 1h. After completion of the addition, the mixture was stirred at room temperature for 16 h. Thereafter, 3-bromotoluene (188.1 g, Aldrich), copper (I) chloride (50.0 g) and TDA-1 (Tris / 2- (2-methoxyethoxyl-ethyl / amine, 158 ml) were added successively in 30 min. After complete addition, the mixture was refluxed for 22 hours, then cooled to room temperature and ether (2000 ml) was added, the mixture filtered through hyflo, the filtrate washed with 2M aqueous HCl, 1M aqueous NaOH and water, dried and The residual oil was distilled to give the target product of bp 129-134 ° C / 9mm Hg.

(b) 1-Dibromomethyl-3- (4-fluorophenoxy) benzene

A solution of the product of step (a) (101.9g) and NBS (206.7g) in CCI ₄ (500ml) was refluxed. AIBN (100 mg) was added and the mixture was irradiated with a medium pressure lamp at 254 nm while refluxing for 7 h. Additional AIBN portions (100 mg) were added after 0.5, 1, 2, 4 and 6 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated in vacuo to give the title product, an orange oil (195.3g).

(c) 3- (4-fluorophenoxy) benzaldehyde

A mixture of the product of step (b) (181.8g), CaCO ₃ (151.7g) and EDTA. 2Na. 2H ₂ O (37.7g) in ethanol / water (1140ml / 248ml) was refluxed for 20 hours cooked. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated in vacuo. The residual oil was taken up in ether (500ml), washed with 2M aqueous HCl, saturated NaHCO _3, water, dried and evaporated in vacuo to leave a viscous orange oil, which was washed twice using ether / petroleum ether (40%). 60) (1: 9) was chromatographed through silica gel to obtain the target product (69.6 g).

(d) 1- [3- (4-fluorophenoxy) phenyl] buM-en-3-one

A mixture of the product of step (c) (69.6g), dimethyl acetylmethylphosphonate (56.2g) and anhydrous K ₂ CO ₃ (88.9g) in THF (500ml) was refluxed for 24 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated in vacuo. The residual oil was taken up in ether (500 ml), washed with water, saturated NaHCO ₃ solution and water, dried and evaporated in vacuo to give the desired target product (83.4 g).

(e) N- (1- [3- (fluorophenoxy) phenyl] but-2-en-3-yl} hydroxylamine

Pyridine (63.6 g) was added dropwise in 1 h of stirring to a solution of the product from step (d) (82.5 g) and hydroxylammonium chloride (33.6 g) in methanol (1000 ml). After complete addition, the mixture was stirred for 1.5 h, then cooled in ice / water and treated with anhydrous oxalic acid (289.8 g). Additional methanol (750 mL) was added and to the mixture was added sodium cyanoboranate (101.2 g) over 3.5 h with continued stirring. After complete addition, the mixture was stirred for ² h at 0-5 ⁰ C and then for 20 h at room temperature. The mixture was filtered, the filtrate was evaporated in vacuo and the residual oil was taken up in ether (1000 ml), washed with water and cooled in ice / water. The pH of the mixture was adjusted to about 9 by the addition of 10m aqueous NaOH and the organic phase was separated. The aqueous phase was extracted with ether and the organic phase and extract were combined, washed with water, dried and evaporated in vacuo to give the title product as a tan oil (92.7 g) which crystallized on standing.

(f) (E) -N- {3- [3- (4-Fluorophenoxyphenyll-1 (R, S) -methylprop-2-en-1-yl} -N-hydroxa-urea

2m aqueous HCl (645ml) was added at 0 ° C in 1.5h with stirring to a solution of the product from step (e) (88.0g) and potassium cyanate (79.2g) in THF (750ml). After complete addition, the mixture was stirred for 2 h at 0 ° C and then allowed to stand for separation. The organic phase was separated, the aqueous phase was extracted with ether and the organic phase and extracts were combined, washed with saturated NaHCO ₃ solution and water, dried and evaporated in vacuo to give a sticky solid. This was triturated with ether / petroleum ether (40-60) (3: 2) and then ethyl acetate / petroleum ether (40-60) (2: 1) to give a colorless solid (67.8g), mp 133.5 -135 ° C (decomp.)

recrystallized. The 200 MHz ¹ H NMR and IR spectra were consistent with the target product. Analysis: C 64.81% (64.54%); H 5.4% (5.42%); N 8.52% (8.86%). >

Synthesis Example 2 Preparation of (E) -N- (3- [3- (4-fluorophenoxy) phenyl] -1 (R) -methylprop-2-en-1-yl} -N-hydroxyharnstoH

(a) But-3-ln-2 (S) -ol

But-3-yn-2 (S) -ol was obtained by cleavage of (±) -but-3-yn-2-ol (Aldrich) according to the method described in J. Mod. Chem. 31 (1988) 156.

(b) N, α-bis (tert-butoxycarbonyl) -N- [but-3-ln-2 (R) -yl] -hydroxylamine

DEAD (180,9g) was dissolved in 1 h at -78 ⁰ C under stirring to a solution of but-3-in-2 (S) -ol from step (a) (55,0g), triphenylphosphine (258,0g) and N, O-bis (tert -butoxycarboxyl (hydroxylamine (183.0 g, Fluka) in toluene (1 500 ml) was added dropwise.) After complete addition, the mixture was allowed to warm to room temperature and then stirred for 2 hrs Petroleum ether (40-60 ) (1500ml) was added, the mixture was filtered through hyflo and the filtrate was evaporated in vacuo to give the target product as an oil (200.0g) which crystallized on standing.

(c) N.O. BlsUr.-butoxycarboxyD-Ntbut-S-an-ZtRI-yU-hydroxylamine

A mixture of the product from step (b) (200.0g) and 6 wt % (w / w) Pd / BaSO 2 (8.8g) in pyridine (1000ml) was hydrogenated with stirring at atmospheric pressure until the end of the water uptake , The mixture was filtered through hyflox, the filtrate evaporated in vacuo and the residual oil taken up in ether (1000 ml), washed with 20% (w / v) aqueous citric acid and water, dried and evaporated in vacuo to give the final product (192.0g) incurred.

(d) 1-Bromo-3- (4-fluorophenoxy) benzene

An aqueous solution of KOH (49.0g in 100ml water) was added with stirring to a solution of 4-fluorophenol (84.0g, Aldrich) in methanol (250ml). Upon complete addition, the mixture was evaporated in vacuo and the remaining Solid was powdered and taken up in 1-methyl-2-pyrrolidinone (300 ml). 3-Fluorobromobenzene (131.3 g, Aldrich) was added, the mixture was refluxed for 24 h, then cooled to room temperature, poured into water (IbOOmI) and extracted with ether. The combined extracts were washed with 2M aqueous NaOH, 2M aqueous HCl and water, dried and evaporated in vacuo. The remaining oil was distilled to give the target product of bp. 85-100 ° C / 0.2mg Hg.

(e) (E) - N - {3- [3- (4-Fluorophenoxy) phenyl] -1 (R) -methylprop-2-en-1-yl} -hydroxylamine

A mixture of the product ve η stage (c) (100.7g), the product of stage (d) (103.0g), tri (o-toly!) Phosphine (10.0g) and palladium (II) acetate (4.0g) in tributylamine (300ml) was stirred at 115 ° C for 3h. The mixture was cooled to about 9O ⁰ C, evaporated in vacuo and the residue was taken up in ether (1000ml), with 33% (w / v) aqueous citric acid and filtered through Hyflo washed. The filtrate was washed with 10% (w / v) aqueous citric acid and water, dried and evaporated in vacuo to give a viscous tan oil. This was dissolved in methanol (1000 ml) and conc. HCl (100 ml) and the mixture was refluxed for 1 h, then cooled to room temperature and evaporated in vacuo. The residue was taken up in water (1000ml) and 10m aqueous NaOH (125ml), extracted with ether and the combined extracts were washed with water, dried and evaporated in vacuo. The remaining yellow-brown oil was chromatographed using ether / petroleum ether (40-60) (9: 1) and then ether by silica gel chromatography to give the title product as a yellow oil (21.9g).

(f) (E) -N- {3- [3- (4-Fluorophenoxy) phenyl] -1 (R) -methylprop-2-en-1-yl) -N-hydroxyurea

2M aqueous HCl (160ml) was added dropwise in 1h at 0 ° C with stirring to a solution of the product from step (e) (21.9g) and potassium cyanate (19.7g) in THF (190ml). After complete addition, the mixture was stirred for 1.5 h at 0 ° C, filtered with saturated NaCl solution, and the organic phase was separated. The aqueous phase was extracted with ether, and the organic phase and extracts were combined, washed with 2M aqueous HCl, saturated NaHCOa solution, water and saturated NaCl solution, dried and evaporated in vacuo to give a cream solid which was obtained from ethyl acetate / petroleum ether (40-60) (2: 1) to give colorless plates (17.7 g), mp 133-135 ⁰ C (dec.) was urnkristallisiert.. The 200 MHz 'H NMR and IR spectra were consistent with the target product. Analysis: C 64.10%, (64.54%); H 5.47% (5.42%); N 8.78% (8.86%). / a / g ³ : + 40.81 ° (c = 1.0, EtOH).

Synthesis Example 3 Preparation of (E) -N- (3- [3- (4-fluoro-phenoxy) -phenyl] -1 (S) -methyl-prop-2-en-1-yl} -N-hydroxyurea

(a) But-3-ln-2 (R) -ol

But-3-yn-2 (R) -ol was obtained by cleavage of (±) -but-3-yn-2-ol (Aldrich) according to the method described in J. Mod. Chem. 31 (1988) 156.

(b) N, O-Bls (tert-butoxycarbonyl) -N- [but-3-yn-2 (S) -yl] hydroxylamine

DEAD (81,8g) was dissolved in 1 h at -7O ⁰ C to a stirred solution of but-3-in-2 (R) -ol from step (a) (25.0 g), triphenylphosphine (117,0g) and N, O-bis (tert-butoxycarbonyl) hydroxylamine (83.2g, Fluka) in toluene (760ml). After complete addition, the mixture was allowed to warm to room temperature, filtered, and the filtrate was evaporated in vacuo. The residual oil was flash chromatographed through silica gel using DCM or ether / petroleum ether (40-60) (1: 4) to give the target product as a pale yellow oil (98.6g).

(c) N, O-Bls (tert-bJtoxycerbonyl-N; but-3-en-2 (S) -yl] -hydroxylamine

A mixture of the product of step (b) (98.6g) and 10 wt.% (W / w) Pd / BaSO ₄ (2.2g) in pyridine (500ml) was hydrogenated with stirring at atmospheric pressure until the hydrogen uptake ceased , The mixture was filtered through hyflo, the filtrate evaporated in vacuo and the residual oil taken up in ether (500ml), washed with 20% (w / v) aqueous citric acid and water, dried and evaporated in vacuo to give the title product as a pale orange Oil (90.0g) accrued.

(d) 1-bromo-3- (4- (luorophenoxy) benzene

1-Bromo-3- (4-fluorophenoxy) benzene was prepared by the method described in step (d) of Synthesis Example 2.

(e) (E) -N- {3- [3- (4-Fluorophenoxy) phenyl] -1 (S) -methylprop-2-en-1-yl) -hydroxylamine

A mixture of the product of step (c) (57.4g), the product of step (d) (58.7g), trl (o-tolyl) phosphine (5.0g) and palladium D-acetate (2.0g) inTributylamin (150ml) was stirred at 110-12O ⁰ C 3.5h. The mixture was cooled to room temperature, evaporated in vacuo, and the residue was taken up in ether (500ml) and filtered through hyflo. The filtrate was washed with 10% (w / v) aqueous citric acid and water, dried and evaporated in vacuo to give a yellow-brown oil. This was dissolved in methanol (500 ml) and conc. HCI (50 ml) and the mixture was refluxed for 1 h, then cooled to room temperature and evaporated in vacuo. The residue v. in water (500ml) and 10m NaOH solution (60ml), extracted with ether and the combined extracts were washed with water until neutral, dried and evaporated in vacuo. The residue was flash chromatographed on silica gel using ether / petroleum ether (40-60) (1: 1) (discarded) then (9: 1) to give the target product as a viscous pale yellow oil (32.5 g).

(f) (E) -N- (3- [3- (4-Fluorophenoxy) phenyl] -1 (S) -methylprop-2-en-1-yl) -N-hydroxyurea

2M aqueous HCl (71.4 ml) was added dropwise in 45 min at ⁰ ° C. with stirring to a solution of the product from step (e) (32.5 g) and potassium cyanate (29.3 g) in THF (282 ml). After complete addition, the mixture was stirred for 45 min at 0 ° C, treated with saturated NaCl solution, and the organic phase was separated. The aqueous phase was extracted with ether, and the organic phase and extract were combined, washed with 2M aqueous HCl and water, dried and evaporated in vacuo to give a V.lebrige solid which was extracted from ethyl acetate to give colorless platelets. 25.8 g) of the mp 131-132.5 ° C (dec.) Umkri Jtallisiert. The 200 MHz ¹ H NMR and IR spectra were consistent with the target product. Analysis: C P '., 37% (64.54%); H 5.42% (5.42%); N 8.79% (8.86%). / a / l ³ : -41.61 ° (c = 1.0, EtOH).

Synthesis Example 4

Preparation of (E) -N- (3- [3- (4-chlorophenoxy) phenyl] -1 (R, S) -methylprop-2-en-1-yl} -N-hydroxyharnstoH

(a) (E) -1- [3- (4-Chlorophenoxy) phenyl] butene-3-one

10N NaOH solution (2 ml) was added to a solution of 3- (4-chlorophenoxy) benzaldehyde (23.3 g, Aldrich) in acetone (150 ml) and stirred vigorously. After a few minutes stirring, the temperature rose to 32 ⁰ C. The mixture was allowed to stand for 5 min, then at 2m aqueous HCl (600ml) and extracted with ether / petroleum ether (1: 1,400ml) extracted. The extract was washed with water and saturated NaCl solution, dried over MgSO ₄ and stripped to give the aldol product. This was taken up in toluene (300 ml), p-toluenesulfonic acid (1 g) was added and the mixture was heated for 1 h. Thereafter, the mixture was cooled, washed with saturated NaHCO 3 solution and saturated NaCl solution, dried over MgSO ₄ and stripped off. The residue was eluted using methylene chloride / petroleum ether (40-60) (1: 1, then 3: 1) and the eluate was stripped to give the target product (19.0g).

(b) (E) -1 - [3- (4-chlorophenoxy) phenyl] butene-3-one oxime

The product from step (a) (19.0g) and hydroxylammonium chloride (6.9g) were taken up in methanol (100ml), pyridine (20ml) was added and the mixture was stirred for 1h. The mixture was then removed by evaporation, redissolved in ether (200 ml), washed with 2M aqueous HCl and saturated NaCl solution, dried over MgSO ₄ and stripped to give the target product (20.3 g).

(c) (E) -N- {1-Methyl-3- [3- (4-chlorophenoxy (phonyl) prop-2-enyl} -hydroxylamine

The product from step (b) (20g) was taken up in methanol (100ml) and oxalic acid (31.3g) added. The mixture was cooled in an ice-bath and Sodium cyanoboranate (22 g) was added in portions under Nj for 3 h. The mixture was stirred for a further 1.5 h after which additional sodium cyanoboranate (2 g) was added and stirred for a further half hour. The mixture was stripped off and the residue was separated with ethyl acetate (300 ml) and water (300 ml). The organic layer was separated, washed with saturated NaHCO ₃ solution and saturated NaCl solution and stripped to give the crude hydroxylamine.

(d) (E) -N- (1-Methyl-3- [3- (4-chlorophenoxy) phonyl] prop-2-en-1-yl} -N-hydroxyurea

A portion of the product from step (c) (6.0g) was taken up in THF (60ml) and potassium cyanate (4.9g) was added at 0 ° C. After 15 minutes, Om aqueous HCl (20 ml) was added dropwise and the mixture was stirred for 10 minutes. Saturated NaCl solution (100ml) and ether (100ml) were added and the organic layer separated, washed with 2m aqueous HCI (100ml) and saturated NaCl solution (100ml), dried over MgSO ₄ and stripped to give the target product, which was recrystallized from ethyl acetate / petroleum ether

Yield 4.4 g, mp. 132-135 ⁰ C.

Synthesis Example 5 Preparation of (Ε) · Ν · (3 · [3 · (4 · 0ΙιΙθΓρΗβηοχν) ρΗθηνΙ] · 1 (8) · ηΐθΐΗνΙ · ρΓθ · 2 · βη · 1 · νΙ · · · ΗναΓθχνίιβΓη5ΐοίί

(a) (E) -1- [3- (4-Chlorophenoxy) phenyl] but-1-en-3-one

A mixture of 3- (4-chlorophenoxy) benzaldehyde (50.0g, Aldrlch), dimethyl acetylmethylphosphonate (35.7g, Lancaster) and anhydrous K ₂ CO ₃ (59.4g) in THF (300ml) was added under N _{2 for} 20h at 50-55 ⁰ C stirred. The cooled mixture was filtered, the residue washed with THF and the combined filtrates evaporated in vacuo to give an orange oil which was purified using ether / petroleum ether (40-60) (1: 1, v / v) as eluent was flash chromatographed through a silica gel column to obtain the target product as a viscous pale yellow oil (52.8 g).

(b) (E) -1 (R) -methyl-3- [3- (4-chlorophenoxy) phenyl] prop-2-en-1-ol

BH ₃ THF (1.0m, 96ml) and a solution of the product from step (a) (52.7g) in THF (total volume 96ml) were added simultaneously under N ₂ and with stirring to a solution of (S) -3, 3-Diphenylpyrrole (1,2-c] (1,3,2-oxazaborolidine in THF (0.3m, 33ml, prepared according to the procedure described in JOC 53 [1988] 2861). After complete addition, the mixture was allowed to react for 15 min Stirred at room temperature, then poured into ice / 2m aqueous HCl (300g / 300ml), stirred for 30min and extracted with ether (3x 300ml) The combined extracts were washed with 2m aqueous HCl (200ml), saturated NaHCOa solution (200ml). and water (200ml), dried over Na ₂ SO ₄ and evaporated in vacuo to give the target product as a viscous yellow oil (55.3g) partially from ether / petroleum ether (40-60) (1: 1, v / The mother liquor was decanted and flash chromatographed through a silica gel column to give the target product as a pale yellow oil (25.7 g) / α / ξ ³ ' ⁶ + 8, 7 "(c = 3.0, EtOH). The 200 MHz ¹ H NMR and IR spectra were consistent with the assumed structure.

(c) (E) -N, O-Bls (tert-butoxycarbonyl) -N- {1 (S) -methyl-3- [3- (4-chlorophenoxy) phenyl] prop-2-en-1-yl } hydroxylamln

A solution of OEAD (24.5 g) in toluene (50 ml) was added with stirring to a mixture of the product of step (b) (25.7 g), N, O-bis (tert-butoxycarbonyl) hydroxylamine (22 , 9g, Fluka) and triphenylphosphine (36.8g) in toluene (375ml) at -65 to -70 ° C. After complete addition the mixture was stirred until -7O ⁰ C for 4 h at -65, followed by further triphenylphosphine (5.0g) and thereafter further DEAD (3.3g) were added and the mixture stirred for another hour at -65 to -7O ⁰ C has been. The heated mixture was evaporated in vacuo to give a brown oil which was flash chromatographed through two silica gel columns using DCM and DCM / petroleum ether (40-60) (3: 6: 0.25), respectively, as eluent to obtain the target product as a viscous yellow oil (20.3 g).

(d) (E) -N- {1 (S) -methyl-3- [3- (4-chlorophenoxy) phenyl] prop-2-en-1-yl} -hydroxylamine

Trifluoroacetic acid (28ml) was added under N ₂ at ⁰ ° C with stirring to a solution of the product from step (c) (20.3g) in DCM (112ml). After complete addition, the mixture was stirred for 3 h at room temperature, to which ether (100 ml) and water (100 ml) were added. To the vigorously stirred mixture was added O ⁰ C 10 η NaOH solution (32 mL). The mixture was basified with excess saturated NaHCO ₃ solution and extracted with ether (200 mL), and the extract was washed with saturated NaHCO ₃ solution (100 mL) and water (2 times 100 mL), dried over Na ₂ SO ₄ , and concentrated Vacuum to give a viscous yellow oil, which was flash-chromatographed through a silica gel column using ether / petroleum ether (4: 1) to obtain the target product. . Mp 83-84 ⁰ C, / a / J ^6: -31.1 ° (c = 1.2, CHCI _3).

(e) (E) -N- (1 (S) -methyl-3- [3- (4-chlorophenoxy) phenyl] prop-2-en-1-vl) -N-hydroxyharnstoH

A portion of the product from step (d) (0.29g) was taken up in THF (10ml) and potassium cyanate (0.25g) added at 0 "C. After 15min, 2m aqueous HCl (2ml) was added dropwise and the mixture was stirred for 2h Then, saturated NaCl solution (50 ml) and ether were added and the organic layer separated, washed with saturated NaCl solution (50 ml _), dried over MgSO ₄ and stripped to give the target product, which was recrystallized from ethyl acetate / petroleum ether. Yield 0.26 g, mp 119-12O ⁰ C, / a / g ³ : -40.0 ° (c = 1.0, EtOH).

Synthesis Example β Preparation of (E) -N- {3- [3- (4-fluorophenoxy) phenyl] -1 (R, S) -methylprop-2-en-1-yl} -N-hydroxyurea, sodium salt The compound according to Synthesis Example 1 (1.0 g) was dissolved in a mixture of NaOH solution (0.11 g in 25 ml of water) and Dissolved methanol (30ml). The methanol was evaporated in vacuo and the remaining solution was freeze-dried, so

that the target product was obtained as a cream-colored solid.

200MHz ¹ H-NMR (DMSO-d ,, ppm): 1.10-1.21 (3 H, d, -CH _3), 4.75 to 4.92 ^ IH, m, / CH-),

5.27-6.14 (2H, br, -NH ₂ ), 6.22-6.51 (2H, s, -HC-CH-) and 6.69-7.37 (9H, m , aromatic); no -OH signal.

Examples of pharmaceutical preparations The active ingredient in the following preparations is any compound of the invention (as defined above,

for example one of the compounds according to Synthesis Examples 1 to 5).

Example A: Tablet per tablet Active ingredient 5.0 mg

Lactose 82.0 mg

Thickness 10.0mg

Povidone 2.0 mg

Magnesium stearate 1.0 mg Mix active ingredient, lactose and starch. Granulate powder using povidone in purified water. granules

dry, add magnesium stearate and tablet (100mg per tablet).

Example B: ointment

Active ingredient * 1.0 g

White soft paraffin residue to 100.0 g

Disperse drug in a small amount of the vehicle. Work this into the bulk, gradually, producing a homogeneous product. Filling in collapsible metal tubes.

Example C: Cream for external use

Active ingredient 1.0 g

PolawaxGP200 20.0 g

Anhydrous lanolin 2.0 g

White beeswax 2.5 g

Methyl hydroxybenzoate 0.1 g

Distilled water balance to 100.0g

Polawax, beeswax and lanolin together at 60 ⁰ C warm. Add a solution of methyl hydroxybenzoate. Homogenize by churning. Allow the temperature to drop to 50 ° C. Add active ingredient and disperse. Allow to cool with slow stirring.

Example D: Lotion for external use

Active ingredient 1.0 g

Sorbitan monolaurate 0.6 g

Polysorbate20 0.6 g

Ketostearyl alcohol 1.2 g

Glycerol 6.0g

Methyl hydroxybenzoate 0.2 g

Purified water B.P. balance to 100 ml

Methyl hydroxybenzoate and glycerol were dissolved at 75 ⁰ C in 70 ml of water. Sorbitan monnlaurat, Polysorbate 20 and cetostearyl alcohol were melted together at 75 ⁰ C and added to the aqueous solution. The resulting emulsion was homogenized, left to cool with constant stirring, and the active ingredient was added as a suspension in the remaining water. The whole was homogenized by stirring.

Example E: Eye drops

Active ingredient 0.5 g

Methyl hydroxybenzoate 0.01 g

Propyl hydroxybenzoate 0.04 g

Purified water B.P. rest to 100ml

Methyl and Propylhydroxybenzoat were dissolved at 75 ⁰ C in 70 ml of purified water and the resulting solution allowed to cool. Then the active ingredient was added and the solution made up to 100 ml with purified water.

The solution was sterilized by filtering through a membrane filter (pore size 0.22 pm) and aseptically filled into suitable sterile containers.

Example F: Injection solution

Active substance 10.0 mg

Water for injections B. P. Remainder to 1.0ml

The active ingredient was dissolved in half of the water for injections, made up to the intended volume and sterilized by filtration. The resulting solution was removed under aseptic conditions on ampoules.

Example G: Powder capsules for inhalation

Active ingredient (0.5-7.0pm powder) 4.0mg

Lactose (30-90 pm powder) 46.0 mg

The powders were homogenized by mixing and filled into capsules of suitable size (50 mg per capsule).

Example H: inhalation aerosol

Active ingredient (0.5-7.0 pm powder) 200 mg

Sorbitan trioleate 100mg

Saccharin sodium (0.5-7.0 pm powder) 5 mg

Methanol 2 mg

Trichlorofluoromethane 4.2 g

Dichlorodifluoromethane residue to 10.0ml

Sorbitan trioleate and methanol were dissolved in trichlorofluoromethane. Saccharin sodium and drug were dispersed in the mixture, which was then transferred to a suitable aerosol canister, and the dichlorodifluoromethane was injected through the valve system. Each 100-pl dose of this composition contains 2 mg of active ingredient.

Biological data

Ex vivo inhibition of B-lipoxygenase

Preliminary studies in rats and rabbits showed that the razemmate according to Synthesis Example 1 and the corresponding enantiomers according to Examples 2 and 3 effectively inhibited the stimulated synthesis of leukotriene B ₄ (LTB ₄ ), a compound derived from arachidonic acid via the 5-lipoxygenase growth product ,

After application of the compound to be tested, the LTB ₄ concentration in the plasma was measured periodically and expressed in% of the average control value. The method used is described in Br. J. Pharmacol. 94 (1988) 528 and can be summarized as follows.

In two samples, double blood samples (0.5 ml) were stimulated with calcium ionophore A23187 (final concentration 15 μg / ml) for 30 min at 37 ° C. At the end of the incubation, the samples were centrifuged (12,000 g, 2 min) and the cell-free plasma was removed. The plasma concentration of LTB ₄ was then determined after a specific radioimmunoassay. The compounds according to Synthesis Examples 1 to 3 after their application inhibited the stimulated ex vivo synthesis of LTB ₄ for several hours. For example, the compound of Synthesis Example 1 inhibited the LTB ₄ synthesis by more than 50% for more than 16 hours when orally administered to rabbits at a dose of 2 mg / kg. The same compound inhibited LTB ₄ synthesis by more than 50% for more than 10 hours when orally administered to rats at a dose of 10 mg / kg. The enantiomers according to Synthesis Examples 2 and 3 showed similar results.

In-vltro inhibition of 5-Llpoxygenase Blood from normal aspirin-free subjects was centrifuged to separate leukocytes from erythrocytes and platelets. A Solution of the compound to be tested in DMSO (10μΙ, final concentration between 0.01 and 100pmol) was added to the Cell homogenate (470μΙ) was added, and the mixture was incubated at 37 ⁰ C for 5 min. Methanolic arachidonic acid solution

(250pmol, 10μΙ, final concentration δμιηο!) And aqueous calcium chloride solution (100mmol, ΙΟμΙ, final concentration 2mmol) were added simultaneously and the mixture was incubated at 37 ° C for a further 5min. The fraction was stopped by boiling. The radioimmunoassay was performed on leukotriene B ₄ .

The experiment was repeated with ionophore-stimulated human whole blood. For the compounds according to Synthesis Examples 1 to 5, the following results were obtained:

IC ₆₀ (μπιοΙ) Synthesis Example homogenate whole blood

1 0.20 0.15

2 0,20 0,08

3 0.20 0.08

Oxidation-inhibiting effect

As a measure of the antioxidant activity, the ability of the compounds of the invention to scavenge peroxyl radicals was determined by evaluating the ability of each compound to inhibit the peroxidation of linoleic acid according to the method described in Biochem. Pharm. 38 (1989) 1465.

The compound according to Synthesis Example 1 had an apparent rate constant of 0.408 for the scavenging of peroxyl radicals.

Effect when combined with a non-sterol anti-inflammatory drug

Male white "New Zealand" rabbits (2.5 to 3kg) were immunized by intracutaneous injections of 4mg ovalbumin in 1 ml of Freund's complete adjuvant and were immunized 14 days later in the same manner five days after the second immunization Injection in front of 1 ml of sterile ovalbumin solution (5 mg / ml) into the articular cavity in the right knee joint induces arthritis.

Joint diameters were measured (randomly) with circles at close intervals after antigen challenge.

The animals were killed after 14 days and the joint space was washed with 1 ml saline. The resulting fluid was used for total and differential counts of leukocytes.

The sensitized animals were randomly assigned to groups of 5 to 8 animals. The compound according to Synthesis Example 1, (E) -N- {1-Methyl-3-I3- (4-fluorophenoxy) phenylprop-2-en-1-yl} -N-hydroxyurea (Compound A), was after 18h milling in the ball mill suspended in 0.25% Celacol suspended as a vehikulum. The non-steroidal anti-inflammatory indomethacin was dissolved in a small volume in Tris buffer of pH 8 and then made up to 0.25% Celacol.

The Kontiolltiere received 0.25% celacol. Each animal received an oral dose (about 5 ml) of the vehicle or drug three times every 24 hours. The doses were administered at 8:00, 16:00 and 24:00 for 16 to 17 days starting 1 hour prior to daytime antigen challenge. All doses were delivered orally through the gastric tube. These were the following groups:

1-7: Control animals (5ml, 0.25% Celacol, 3x in 24h)

8-14: I mg / kg indomethacin dissolved in 0.25% celacol 3x in 24h 15-21: 2mg / kg compound A suspended in 0.25% Celacol 3x in 24h

 22-28: 2mg / kg Compound A suspended in 0.25% celacol plus 1 mg / kg indomethacin dissolved in 0.25% Celacol

joint swelling

In the control animals, antigen challenge caused an increase in joint diameter of 6-7 mm with peak 2 days after challenge. Joint swelling was maintained in the control group during the experimental period (14 days), and by the time the animals were sacrificed, the diameters of the arthritic joints were about 5 mm larger than those of the contralateral joints. No drug treatment reduced joint swelling in the first two days after exposure, but by day 3, compound A reduced swelling by up to 23% and indomethacin by up to 53% compared to the vehicle treated control animals. The strongest and most persistent decreases in swelling (up to 72%) were in the group receiving the combination of compound A and indomethacin. Table 1 contains the results.

ν indomethacin Verb. A + -14- 291 756 Table 1 Compound A indomethacin Joint swelling (mm) 4.3 3.9 Duration of 4.6 4.5 4.2 control arthritis 5.2 3.5 3.1 1 4.6 2.6 1.6 5.6 2 3.5 2.0 1.2 6.0 3 3.2 5.7 8th 4.3 , 14 4.3

Studies of synovial fluidity The synovial lining tissue was removed from the joint, fixed, treated, cut and microscopic Dye colored. Histological sections were used to determine the total mass of the inflamed Synovial lining, lymphocyte infiltration and levels of polymorphic leukocytes. The slides were after

a random selection evaluated.

The synovial fluid of the arthritic joints of the control animals contained about 10 ^s leukocytes, of which about 80%

were polymorphic. Compound A or indomethacin individually set the average leukocyte infiltration into

Synovial fluid slightly decreased, but the greatest decrease was seen using Compound A plus indomethacin. Table 2 contains the results. Table 2 Leucocytes (number of cells, X 10 ')

Compound A

indomethacin

Comp. A + indomethacin

Kontrollle

7.3

7.9

Red blood glucose content in cartilage

The articular cartilage was cut off from the ends of the femurs and before measuring the concentration of the

sulfated glycosaminoglycans (GAG) digested with papain. The proteoglycan content was measured in Mg GAG / mg wet weight of the

Cartilage expressed and compared with the values obtained for the cartilage from the contralateral control joint

were.

The articular cartilage that separates from the arthritic joints of the vehicle treated animals 14 days after Antigen exposure was 43% less proteoglycan than the cartilage from the contralateral joints

the same animals.

Compound A or indomethacin individually decreased proteoglycan loss from the cartilage, but the large one resulted Decrease in the group receiving compound A plus indomethacin. Table 3 contains the results.

Table 3 Proteoglycan Loss (%)

Compound A indomethacin

Comp. A + indonethacin

control

38

43

Histological assessment of the synovial lining Both the lymphocyte count and the total number of cells in the synovial lining were in the group, the Compound A plus indomethacin was significantly decreased. Table 4 contains the results.

Table 4 Total lymphocyte cells Compound A indomethacin Comp. A + indomethacin control 59,367 51 365 36,255 68 435

The above results illustrate the anti-tarnishing effect of compound A in arthritis, especially in the presence of the nichi-steroidal anti-inflammatory drug indomethacin.

toxicity

The compound according to Synthesis Example 1 was orally administered to mice in doses of up to 300 mg / kg and intraperitoneally in doses of

administered up to 100mg / kg. Deaths or serious injuries were not observed.

Claims (7)

claims: 1. A process for the preparation of a compound of formula (I) _f ^ OH Γ-γ-γγ'-Y-C-N '(I) CH ₃ CONR R in the Ar 4-halophenyl, Ar '1,3- or 1,4-phenylene, Y (E) -CH = CH and R ¹ and R ^{2 are} independently selected from hydrogen and C 1-4 -alkyl, characterized in that a compound of the formula (II) ₍ R ³ NHOH '(II) in the R ^{3 is} a group of the formula Ar-O-Ar'-YC-CH ₃ as defined above means reacting with a suitable agent or agents and under such reaction conditions that conversion of the N-hydrogen to an N-CONH ₂ group is achieved, and the compound of formula (I) thus formed, optionally in a corresponding Base salt or a physiologically active derivative is transferred. 2. The method according to claim 1 for the preparation of a compound of formula (I) according to claim 1, characterized in that Ar 4-fluorophenyl and / or Ar '1,3-phenylene and / or R ¹ and R ^{2 are} hydrogen. 3. The method according to claim 2, characterized in that (E) -N- {1-methyl-3- [3- (4-fluorophenoxy) phenyl) -prop-2-en-1-yl} -N-hydroxyurea finder enantiomers ( R) or (S) -form or as their mixture is prepared in any ratio. 4. The method according to claim 1 to 3, characterized in that the compound of formula (II) is optically active and the compound of formula (I) is obtained in its enantiomeric (R) -form and substantially free of the (S) -isomer is. 5. The method according to claim 1 to 3, characterized in that the compound of formula (II) is optically active and the compound of formula (I) is obtained in its enantiomeric (S) -form and substantially free of the (R) -isomer is. 6. The method according to claim 1 to 3, characterized in that the compound of formula (II) is optically inactive and the compound of formula (I) is obtained as a racemate. 7. Use of a compound of the formula (I) Ar-O-Ar'-Y-C ~ 12 in the Ar 4-halophenyl,
Ar '1,3 or 1,4-phenylene,
Y (E) -CH == CH are and ^CH 3 R ¹ and R ^{2 are} independently selected from hydrogen and C 1-4 -alkyl and obtained by reacting a compound of formula (II) R ³ NHOH (II) in the R ^{3 is} a group of the formula Ar-O-Ar'-YC-CH ₃