DD254937A5 - PROCESS FOR THE PREPARATION OF NEW ARYL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel aryl derivatives, which are effective inhibitors of lipoxygenase or cyclo-oxygenase and can be used to treat various asthmatic and inflammatory conditions. In addition, these compounds are also useful for preventing the early wilting of cut or picked plants.

Description

wherein R ^{1 is} independently selected from

Hydrogen, C 1-4 -alkyl, groups as defined above for Ar and groups of the formula -COR ³ , wherein R ^{3 is} selected from C 1-4 alkyl (optionally substituted by a carboxy or C 1-4 alkoxycarbonyl group) and groups of the formula -N (R ⁴ ) R ⁵ , wherein R ^{4 is} hydrogen or d ^ alkyl and R ^{5 is} hydrogen, Ci ^ alkyl or phenyl, optionally independently by one or more substituents selected from those defined as possible substituents in the definition (i) of Ar are substituted, and R ² is selected from hydrogen, C ^ -alkyl, amino, C ^ AIkylamino, di-Ci_4Alkylamino, C5_ ₇ cycloalkylamino, (^ cycloalkyl, (C ^ AIkyllAmino, anilino, NC ₁ ^ -Alkylanilino and groups as defined above for Ar, with the proviso that:

when q is O, kO, or 1 and ρ 1, Ar is phenyl or naphthyl, one optionally substituted by one or more substituents as defined in definition (i) of Ar, and X is oxygen or sulfur, ( in the case when k1 is HstYC ^ o alkylene and Q is a non-cyclic radical as previously defined in which one of R ¹ and R ^{2 is} hydrogen or C 1-4 alkyl, then the other radical of R ¹ and R ^{2 is} neither Hydrogen still ^^ alkyl.

The unexpected advantages found of the compounds of formula (I) and their salts are the following, namely:

surprisingly high activity, surprising oral effectiveness, surprising effectiveness in inhalation and surprisingly long duration of action.

Compounds of formula (I) and their salts, processes for their preparation, compositions containing these compounds and their use are not claimed unless they are novel with respect to the following references:

a) Patents: EP0161939A

GB 1226344 GB 1427 114

GB 1278739 GB 1437 783

GB 1315830 GB 1444492

GB 1382 996 GB 2 047 234 A

GB 1396726

U.S. 3,600,437, U.S. 3,972,934

US3821289 US3978116

US 3,890,377

JP57035543 JP57062239

b) References: Tetrahedron 1970 26 (23) 5653-64

Fur. J. Med. Chem. Chimica. Therapeutica 197510 (2) 125-128

Fur. J. Med. Chem. Chimica. Therapeutica 197013 (2) 211-13

J. Chem. Eng. Data 1985 30 237-9

Chem. Biol. Hydroxamic Acids [Proc. Int. Symp.] 1981, 51-62

Pharm. Research. 197828 (11) 2087-92

For example, European Patent 0161 939 A describes a genus of compounds which are said to be antiallergic and antiasthmatic inhibitors of delta-5 lipoxigenase. This species includes compounds of formula (I) as defined above which are inter alia excluded by the proviso that when Q is the non-cyclic radical as previously defined, and

when R ¹ is hydrogen or C ^ -alkyl and R ² is phenyl, optionally substituted by a single substituent selected from C ^ -alkyl, C ^ ₁ jAIkOXy and phenyl, optionally substituted by one or more substituents independently selected from those when possible substituents in the definition (i) of Ar are given, then at least one of k and ρ must be 1 and in the case when k0 and ρ is 1, YC must be ^^ alkenylene. U.S. Patent 3,600,437 describes a genus of compounds which are said to be anti-inflammatory, analgesic and anti-pyretic agents.

The above-mentioned U.S. Patent 3,600,437 describes inter alia, the single compound 2- (3-phenoxyphenyl) propionohydroxamic acid. Throughout this specification, unless otherwise stated, alkyl and alkyl-containing radicals (such as alkylene and alkoxy) may be straight or branched. An alkyl of 1-4C atoms, either alone or as part of another group, includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and t-butyl.

For medical use, the salts of the compound of formula (I) are those salts which are physiologically acceptable. However, non-physiologically acceptable salts are also present within the scope of the present invention, which are used either in non-medical applications, as described below, or in the preparation of the compounds of formula (I) and their physiologically acceptable salts.

When Ar is an optionally substituted naphthyl, it may mean naphth-1-yl or naphth-2-yl, although the latter is generally preferable.

When Ar is an optionally substituted tetrahydronaphthyl, 5,6,7,8-tetrahydronaphth-i-and-2-yl is preferred, especially -2-yl.

When Ar is an optionally substituted pyridyl, pyrid-2-yl and pyrid-4-yl are preferred.

When q is and Ar 'is optionally substituted phenylene, L- and - (X) k- are preferably meta or para substituted in the phenyl ring relative to each other.

When q is and Ar 'is optionally substituted thienylene, -L- and - (X) k- are preferably attached in the 1- and 5-positions of the phenyl ring.

A preferred subclass of the compounds of formula (I) are the compounds wherein q is O and p1;

Ar is naphthyl, optionally substituted by one or more substituents independently selected from those defined in definition (i) of Ar;

X (in the case when k is 1) is oxygen; and

Q is the non-cyclic radical as defined above and R ^{2 is} C ₁ -alkyl; and the salts thereof.

A particularly preferred group of compounds and salts within the last defined subclass are those wherein R ^{1 is} hydrogen and R ^{2 is} methyl. This group includes compounds and salts wherein Ar is unsubstituted.

q and ρ are 1 and k is 0;

another preferred subclass of the compounds of formula (I) includes those compounds wherein Ar is optionally substituted by one or more substituents independently selected from those listed in definition (ii) of Ar;

LO or -CH ₂ O-;

Ar 'phenylene, if necessary by one or more substituents independently selected from those as defined in definition (i) of Ar;

and Q is the non-cyclic radical as previously defined;

A particularly preferred group of the compounds and salts within the last defined subclass are those wherein Ar and / or Ar 'are substituted by one or two fluorine atoms or both are unsubstituted and R ^{2 is} Ci_4alkyl, especially methyl. Of this group, the meta-or para-relative substitution of L and - (X) i <- in Ar 'is preferable. The general class of compounds of formula (I) and their salts includes the following, which are claimed separately, namely those in which:

(i) k is 1 and X is oxygen;

(ii) k is 1 and X is sulfur;

(iii) qO is;

(iv) q is 1;

(v) q1 is and -L is selected from -O-, -CH ₂ O-, -CH ₂ S-, -NHCO- and -CO-;

(vi) Ar 'is optionally substituted by phenylene;

(vii) Ar 'is optionally substituted by thienylene;

(viii) Ar is optionally substituted by naphthyl;

(ix) Ar is optionally substituted by tetrahydronaphthyl;

(x) Ar is optionally substituted by pyridyl;

(xi) k is O;

(xii) ρ is O;

(xiii) 'ρ is 1 and YCi_ ₁₀ alkylene;

(xiv) p1 is ₀ istundYCi_i alkenylene;

(xv) any two or more of (i) to (xv) taken together in combination, provided that the combination is compatible with the provisos contained in formula (I) as defined above.

Preferred compounds of the formula (I) include

N-iso-phenoxycinnamylacetohydroxamic acid, N- (4-benzyloxybenzyl) acetohydroxamic acid, N- [2- (5,6,7,8-tetrahydro-2-naphthyloxy) ethyl] acetohydroxamic acid and N- (5,6,7,8- tetrahydro-2-naphthylallyl) acetohydroxamic acid. Salts of the latter compounds are also preferred.

Examples of other compounds of the formula (I) and their salts are the following compounds and their salts:

N- [1- (4-biphenylyl) ethyl] acetohydroxamic acid

N- [2- (2-fluoro-4-biphenylyl) propyl] acetohydroxamic acid

N- [2- (4-biphenylyloxy) ethyl] acetohydroxamic acid

N- [2- (4-biphenylyloxy) -ethyl] isobutyrohydroxamsäure

N- [3- (4-biphenylyloxy) propyl] acetohydroxamic acid

N- [3- (5,6,7,8-tetrahydro-1- (or 2-) naphthoxy) propyl] acethoydroxamsäure

N- [6- (5,6,7,8-tetrahydro-1- (or 2-) naphthoxy) hexyl] acetohydroxamic acid

N- [2- (5,6,7,8-Tetrahydro-1- (or 2-naphthoxy) ethyl] isobutyrohydroxamic acid N- [3- (5,6,7,8-Tetrahydro-1- (or 2-) naphthyl ) propyl] acetohydroxamic

N- [5- (5,6,7,8-tetrahydro-1- (or 2-) naphthyl) pentyl] acetohydroxamic acid

N- [3- (5,6,7,8-Tetrahydro-1- (or 2-) naphthyl) propyl] isobutyrohydroxamic acid N- [2- (2-Naphthyloxy) ethyl] benzohydroxamic acid

N- [1- (4-benzyloxy-2-hydroxyphenyl) ethyl] -acetohydroxamsäure

N- (2-Benzyloxybenzyl) acetohydroxamic acid, viscous oil

| \ | - [(1-Naphthyimethoxy) benzl 4] a.cetahydroxamsäure

N- (3-phenoxybenzyl) acetohydroxamic acid

N- (3-Benzyloxybenzyl) acetohydroxamic acid N- [1- (4-biphenylyl) ethyl] acetohydroxamic acid N- (4-biphenylylmethyl) acetohydroxamic acid N- [4- (2-naphthylmethoxy) benzyl] acetohydroxamic acid N- (4-phenoxybenzyl) acetohydroxamic acid N- (4-Benzyloxybenzyl) pivalohydroxamic acid N- (4-Benzyloxybenzyl) -2-methyl-1-prochanohydroxamic acid N- (4-phenylcarbamoylbenzylacetohydroxamic acid N - [(2 ', 4'-difluoro-4-biphenylyl) methyl] acetohydroxamic acid N- [1- (2 ', 4'-Difluoro-4-biphenylyl) ethyl] 2,2-dimethylpropanohydroxamic acid N- [4- (4-biphenylylmethoxy) benzyl] acetohydroxamic acid N- [4- (2,4-difluorobenzyloxy) benzyl] acetohydroxamic acid N ^: [4- (2,4-difluorobenzyloxy) benzyl] pivalohydroxamic acid N- [5,6,7,8-tetrahydro-2-naphthyl) methyl] acetohydroxamic acid N- [2- (5,6,7, 8-tetrahydro-2-naphthyloxy) ethyl] -pivalohydroxamic acid N- (5,6,7,8-tetrahydro-2-naphthylallyl) pivalohydroxamic acid N- (5,6,7,8-tetrahydro-2-naphthylmethyl) pivalohydroxamic acid [2- (2 ', 4'-Difluoro-4-biphenylyl) ethylacetohydroxamic acid N- (4-isobutylbenzyl) acetohydroxam N- [1- (4-biphenyl) ethyl] pivalohydroxamic acid N [(4-biphenyl) methyl] pivalohydroxamic acid 1-Hydroxy-1- [2- (2-naphthyloxy) ethyl] -3-phenylurea N- (4-Benzyloxybenzyl ) -N-hydroxy-N-methylurea N- (4-benzyloxybenzyl) -0-methylcarbamoylacetohydroxamic acid N- [2- (2-naphthylthio) ethyl] -N- (phenylcarbamoyloxy) acetamide N- [4- (benzyloxybenzyl) -O- (methylcarbamoyl) pivalohydroxamic acid N- (4-Benzyloxybenzyl) -O- (2,2-dimethylethyl) carbamoylacetohydroxamic acid N- (4-Benzyloxybenzyl) -N- (t-butylcarbonyloxy) acetamide 3- [N- (4-Benzyloxybenzyl) acetamidooxycarbonyl] propanoic acid N- [3- (4-benzyloxyphenyl) prop-2-enyl] acetohydroxamic acid N- (3-phenoxycinnamyl) acetohydroxamic acid N- [2- (4-biphenylyloxy) ethyl] acetohydroxamic acid N- [3- (4-benzyloxyphenyl) prop -2-enyl] acetohydroxamic acid N- [4- (2-pyridyl) benzyl] acetohydroxamic acid N- [4- (2,4-difluorophenoxymethyl) benzyl] acetohydroxamic acid N- [4- (2-pyridyloxy) benzyl] acetohydroxamic acid N- 5-phenoxymethyl-2-thienylmethyl) acetohydroxamic acid N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-e nyl] acetohydroxamic acid N- [4- (benzylthio) benzyl] acetohydroxamic acid N- [3- (2-pyridyloxy) benzyl] acetohydroxamic acid N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl] -N- hydroxy-N'-methyl urea N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl] -N-hydroxy-N'-t-butylurea N- [3- (4-fluoro-3 -phenoxyphenyl) prop-2-enyl] -N-hydroxy-N'-cyclohexy! urea N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl] -N-hydroxy-N'-phenylurea N - (Biphenyl-4-ylmethyl) -N-hydroxy-N'-methylurea N- (Biphenyl-4-ylmethyl) -N-hydroxy-N'-butylurea N-f-biphenyl-1-methyl-N-hydroxy-N ' -cyclohexylurea N- (biphenyl-4-ylmethyl) -N-hydroxy-N'-phenyl, urea-N-hydroxy-N'-methyl-N- [3- (2-pyridyloxy) benzyl] urea N- ( 2- [4- (2-Pyridylmethoxy) phenoxy] ethyl) acetohydroxamic acid N- (2- [3- (2-Pyridylmethoxy) phenoxy] ethyl) acetohydroxamic acid N- (2- [4- (Benzyloxy) phenoxy] ethyl) acetohydroxamic acid N - [4-fluoro-2-phenoxyphenyl) methyl] -N-hydroxy-N'-methylurea N- [4-fluoro-3-phenoxyphenyl) methyl] -N-hydroxy-N'-phenylurea N- [3- (biphenyl 4-yl I) prop-2-enyl] -N-hydroxy-N'-methylurea N- [3- (biphenyl-4-yl) prop-2-enyl] -N-hydroxy-N'-phenylurea N - [( 4-benzyloxyphenyl) methyl] -N-hydroxyurea N - [(4-BenzyloxyphenyI) methyl] -N-hydroxy-N'-methylurea N- [4- (4-hydroxybenzyloxy) benzyl] acetohydroxamic acid N- [ 4- (4-pyridylmethoxy) methyl] acetohydroxamic acid

Further examples of the compounds of formula (I) include any and all specific compounds which are listed below:

N- [3- (Ar) -2-propenyl] acetohydroxamsäureund

N- [3- (Ar) -2-propenyl] isobutyrohydroxamsäure

where Ar means

(i) 1 (or 2) -naphthyl

(ii) 4-isobutylphenyl

(iii) 4-biphenylyi

(iv) 2 (or 3 or 4) benzyloxyphenyl

(v) phenyl or

(vi) 4-methylphenyl

It will be understood that any of the compounds in the above list may be claimed alone or with one or more of the others forming a preferred aspect of the present invention. Subject to any limitation noted, the present invention also provides any compound of formula (I) (as defined above) or its physiologically acceptable salt for use as an inhibitor of lipoxygenase and / or cyclo-oxygenase enzymes of arachidonic acid metabolism in mammals, methods for inhibiting these enzymes by administering an amount of any of these compounds or salts which inhibit lipoxygenase and / or cyclo-oxygenase (as required) and the use of any of these compounds or salts for the production of lipoxygenase and / or cyclo-oxygenase inhibitors as appropriate; to disposal.

Furthermore, and also subject to any limitation herein, the present invention contemplates the use of any compound of formula (I) (as hereinbefore defined) or physiologically acceptable salt as a medicinal therapeutic and / or prophylactic treatment by administration of a medicinal therapeutic and / or or prophylactically effective (as appropriate) amount of any of these compounds or a salt and the use of any of these compounds or the salt in the preparation of medico-therapeutic and / or prophylactic (as required) agents. The types of medical therapy and prophylaxis which are relevant to the above and therefore constitute part of the present invention in this sense are further illustrated by the examples in the following paragraphs, which, however, should not be construed as limiting the scope of the various aspects limit the invention.

Because of their lipoxygenase inhibiting properties, the compounds and salts are used in the treatment and / or prophylaxis in conditions where the use of a lypoxygenase inhibitor is indicated, especially in spasmogenic and allergic conditions as well as in tumors.

Because of their cyclo-oxygenase inhibiting properties, these compounds and their salts find use in the treatment and / or prophylaxis of any condition where the use of a cyclo-oxygenase inhibitor is indicated, especially in fever states and pain conditions.

Due to both their lipoxygenase and cyclo-oxygenase inhibiting properties, these compounds and the salts find use in the treatment and / or prophylaxis of any condition, wherein the use of a double, i.e.. H. a lipoxygenase / cyclo-oxygenase inhibitor, especially in any condition where platelet aggregation or inflammatory conditions are involved. In the case of inflammation, the compounds and salts are particularly suitable for the treatment and / or prophylaxis of the conditions associated with the infiltration of leukocytes into the inflamed tissue.

In determining when a lipoxygenase, cyclo-oxygenase or a double, i. Of course, inter alia, lipoxygenase / cyclo-oxygenase inhibitor is considered to include the particular condition as well as its severity in the consideration, and this decision ultimately remains at the discretion of the attending physician.

Examples of the spasmogenic states referred to above are those involving smooth muscle tissue, in particular the narrowing of airway smooth muscle, for example congenital asthma (including congenital or idiopathic bronchial asthma and cardiac asthma), bronchitis, and narrowing of arterial smooth muscle, for example Coronary spasms (including those associated with myocardial infarction that can result in failure or even left ventricle leading to cardiac asthma) and brain spasm or "stroke." Other examples include visceral pain caused by abnormal contraction of the intestinal musculature, for example which are termed "nervous bowel syndrome", "spastic colon" or "mucous colitis". Examples of the allergic conditions referred to above are external asthma (from which it can be concluded that these compounds and the salts are particularly advantageous anti-asthmatic agents) allergic skin diseases, for example eczema of partial or exclusively allergic origin, allergic bowel disease (including the disease Coeliacus) and allergic conditions of the eye, for example hay fever (which additionally or alternatively may affect the upper respiratory tract) and allergic conjunctivitis. Examples of the aforementioned tumors are both benign and malignant neoplasms of the skin. Examples of the inflammatory and pain conditions referred to above are fever conditions associated with infections, trauma and injuries, malignancies and diseases affecting the immune system (including autoimmune diseases).

Examples of the above-mentioned conditions in which blood cell aggregation is involved are those arising from a thrombosis, including stroke, having a total or partial thrombotic origin, coronary thrombosis, phlebitis, and phlebothrombosis (the latter two states including inflammation can be connected).

Examples of the above-mentioned conditions in which inflammation is involved are inflammatory conditions of the lung, joints, eye, intestine, skin and heart.

Inflammatory conditions of the lung that may be treated and / or prevented in this manner include asthma and bronchitis (vide supra) and cystic fibrosis (which may also or alternatively involve the gut or other tissues).

Inflammatory conditions of the joints that may be treated or prevented in this manner include rheumatoid arthritis, rheumatoid spondilitis, osteoarthritis, gouty arthritis, and other arthritic conditions.

Inflammatory conditions of the eye that may be treated and / or treated for prevention include uveitis (including iritis) and conjunctivitis (vide supra).

Inflammatory conditions of the viscera that may be treated and / or treated for prevention include Crohn's disease and ulcerative colitis.

Skin inflammatory diseases that can be treated and / or treated for prevention include those associated with cell proliferation, such as psoriasis and eczema (vide supra) and dermatitis (regardless of an allergic cause).

Inflammatory conditions of the heart that may be treated and / or prevented in this manner include coronary artery damage.

Other inflammatory conditions that may be treated and / or treated for prevention include tissue necrosis of chronic inflammation and tissue rejection due to a transplantation treatment.

It is also known that the compounds of the formula (I) according to the invention and their physiologically tolerated salts are active agents in the prophylaxis and / or treatment of bacterial and fungal infections. This likewise forms a broad aspect of the present invention.

It is known in the literature that some compounds which are cyclo-oxygenase and / or oxygenase and / or lypoxygenase inhibitors may retard the aging of cut plants. Therefore, it can be considered that the compounds of formula (I) and their salts, because of their enzyme-inhibitory activity, are useful for controlling the growth and aging processes in plants. Therefore, the present invention also provides the compounds of formula (I) and their salts for use in a method of regulating the growth or aging of plants by applying to plants an effective amount of a compound of formula (I) or a salt thereof available.

The term "aging" refers to the process whereby the plants decay, in particular after they have been picked, cut or otherwise removed from the normal growth area.The term plants includes trees, shrubs, shrubs, flowers and edible plants and plants other food fruits.

The method described above is particularly applicable to plants intended for decorative or demonstration purposes, such as carnations, chrysanthemums, daisies, begonias, etc. These include perennial and semi-annual plants, for example those growing from onions (e.g., dahlias ) or grow from seeds

(eg marigolds). The method is also particularly suitable for use on decorative shrubs and trees, for example those that are shown when cut, for example Christmas trees.

The compounds of formula (I) and their salts can also be used for the freshness of picked fruits.

For medical use, of course, the required amount of a compound of the formula (I) or the physiologically acceptable salt thereof (hereinafter referred to as the active ingredient) for obtaining a therapeutic effect depending on the individual compound, the route of administration and the treated mammal and the affected specific disorder or illness vary. A suitable dose of a compound of formula (I) or physiologically acceptable salt thereof for a mammal suffering from a disease or similarly suffering from any of the conditions described above is from 0.1 μg to 500 mg of the base per kilogram of body weight. In the case of systemic administration, the dose may range from 0.5 to 500 mg of base per kilogram of body weight, with the most preferred dose being 0.5 to 50 mg / kg of mammalian body weight, e.g. 5 to 25 mg / kg; administered two or three times a day. In the case of topical administration, e.g. To the skin or the eye may be a suitable dose in the range 0.1 ng-100jU.g of base per kilogram, typically about 0.1 // g / kg.

In the case of oral administration for the treatment or prophylaxis of airway narrow muscle contraction, or in asthma or bronchitis in general, corresponding to each course, a suitable dose of the compound of formula (I) or a physiologically acceptable salt thereof is as in the preceding paragraph most preferably from 1 mg to 10 mg of the base per kilogram, with the most preferred dose range of 1 mg to 5 mg / kg of the body weight of the mammal, e.g. B. from 1 to 2 mg / kg. In the case of pulmonary administration for the last-mentioned conditions, the dose may be in the range of 2, ag to 100 mg, for example from 20 / ng to 0.5 mg, especially from 0.1 to 0.5 mg / kg.

Although it is possible to administer an active ingredient alone, it is preferable to administer the active ingredients in the form of a pharmaceutical formulation containing a compound of the formula (I) or a pharmacologically acceptable acid addition salt thereof and a physiologically acceptable carrier material. Such formulations form a further aspect of the present invention. Usually, the active ingredient comprises from 0.1% to 99.9% by weight of the formulation. Typically, a single dose of formulation will contain between 0.1 mg and 1 g of the active ingredient. For topical administration, the active ingredient comprises from 1 to 2% by weight of the formulation, however, the active ingredient may comprise up to 10% w / w. Formulations suitable for nasal or buccal administration, e.g. The self-atomizing powder formulations as described below can be 0.1 to 20% w / w, e.g. 2% w / w of the active ingredient.

Both the veterinary and human medical formulations of the present invention contain an active ingredient in association with a pharmaceutically acceptable carrier material and optionally other therapeutic ingredients. The carrier materials must be "compatible" in the sense that they are compatible with the other ingredients of the formulations and have no adverse effects on the recipient of the formulations.

The formulations include those forms which are suitable for oral, pulmonary, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular, topical, nasal or buccal administration.

The formulations may conveniently be in the form of a single dose and may be prepared by any of the methods known in the pharmaceutical arts. All methods include the step of contacting the active ingredient with the carrier material which constitutes one or more additional ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into contact with a liquid carrier material or a finely divided solid carrier material or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the invention suitable for oral administration may be in the form of particular units, for example capsules, cachets, tablets or lozenges, each containing a certain amount of the active ingredient; in the form of a powder or granule; in the form of a solution or suspension in an aqueous or non-aqueous liquid or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be in the form of a bolus, syrup or paste.

A tablet may be prepared by compression or molding of the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by pressing in a suitable machine, the active ingredient being in free-flowing form, for example as a powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, surfactants or dispersing agents. Shaped tablets may be prepared by casting, in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier, moistened with an inert liquid diluent material. The formulations for rectal administration may be in the form of a suppository containing the active ingredient and a carrier material such as cocoa butter or in the form of an enema.

Formulations suitable for parenteral administration conveniently contain a sterile aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.

Formulations suitable for intraarticular administration may be in the form of a sterile aqueous preparation of the active ingredient, which may be in microcrystalline form, for example in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to prepare the active ingredient for both intraarticular and ophthalmic administration. Formulations suitable for topical administration include liquid or semi-liquid preparations, e.g. B. liniments, lotions, compositions; Oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions, such as. B. drops. For example, the active ingredient for ophthalmic administration may be in the form of aqueous eye drops, for example in the form of a 0.1-1% solution. Formulations suitable for administration to the nasal or buccal cavity include powders, self-atomizing and spray formulations such as For example, aerosols and atomizers The formulations, when dispersed, preferably have a particle size in the range of 0.1 to 200μ.ιη.

A particularly valuable form of a pharmaceutical composition according to the present invention for use in prophylaxis or treatment in the narrowing of the airway smooth muscle, or asthma or bronchitis, generally due to any cause, is those responsible for pulmonary administration over the Cheek cavity is suitable. Preferably, the composition is such that the particles have a diameter of 0.5 to 7μηι , most preferably 1-6 / xm and the active ingredient to be delivered to the lungs of a patient. Such compositions are conveniently in the form of dry powders for administration from a powder inhaler or automatic powder atomizing container, e.g. B. as a self-atomizing aerosol composition in a sealed container before; Preferably, the powders contain particles containing the active ingredient, at least 98% by weight of the particles having a diameter greater than 0.5μΓη and at least 95% by number having a diameter of less than 7μνη . It is particularly desirable that at least 95% by weight of the particles have a diameter greater than 1 μm and at least 90%, by number, of the particles have a diameter of less than 6 μm.

The compositions in the form of dry powders preferably consist of a solid, finely ground powder as a diluent, such as sugar, and are conveniently present in a pierceable capsule, such as a gelatin capsule.

The self-dispensing compositions of the present invention may be either powder-dispensing compositions or compositions that deliver the active ingredient in the form of drops or a solution or suspension. The self-acting powder-dispensing compositions comprise a liquid propellant having a boiling point below 65 ° F at atmospheric pressure. In general, the blowing agent may constitute from 50 to 99.9% w / w of the composition while the active ingredient is from 0.1% to 20% w / w, for example, about 2% w / w of the composition. The carrier material in such compositions may include other ingredients, particularly a liquid nonionic or solid anionic surfactant, or a solid diluent, preferably having a particle size of about the same order of magnitude as the particles of the active ingredient, or both. The surfactant may account for 0.01 to 20% w / w, although it is preferably less than 1% w / w of the composition.

The self-sustained-release compositions in which the active ingredient is in solution contain an active ingredient, a propellant and an auxiliary solvent, and advantageously an anti-oxidant stabilizer. The additional solvent may account for 5 to 40% w / w of the composition, although preferably it is less than 20% w / w of the composition.

The compositions of the invention may also be in the form of an aqueous or dilute alcoholic solution, optionally a sterile solution of the active ingredient for use in a mist former or atomizer. The compositions of the invention may also be used in the form of an aqueous or dilute alcoholic solution, optionally a sterile solution of the active ingredient for use in a nebulizer or atomizer in which an accelerated air stream is used to produce a fine mist containing small droplets of the solution. Such formulations usually contain a flavoring such. Sodium saccharin and a volatile oil. Such formulations may also contain a buffering agent and a surfactant. Also, a preservative, such as. B. be included in methyl hydroxybenzoate.

Other formulations suitable for nasal administration include a coarse powder having a particle size of 20 to 500 / xm which is administered in the same manner as snuff, i. by rapid inhalation through the nasal passage from a vessel containing the powder, which is kept immediately under the nose.

In addition to the ingredients listed above, the formulations of the invention may contain one or more additional ingredients, such as. Diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives, e.g. Methyl hydroxybenzoate (including antioxidants), emulsifiers and the like. Any other therapeutic ingredients may include one or more of the following: antibiotics (e.g., antibacterial agents), antifungal and antiviral agents, antihistamine agents, in particular, peripherally acting antihistamines). However, if such other agents are also present, the compounds of formula (I) or the physiologically acceptable salts thereof and the other agents according to another aspect of the present invention need not necessarily be in the form of a pharmaceutical formulation as defined above, but only in combination or intimate mixing, d. H. if necessary, a pharmaceutically acceptable carrier material need not be present.

The combination with antihistamines is particularly advantageous for anti-asthmatic use. Such an antihistamine can be selected from any compound described in European Patent Applications EP-A-0859959A and EP-A-0117302A. The amount and dosage range for such an antihistamine can be selected from any of the two European patent applications just cited. Especially preferred are the anti-histamines (E) -3- (6- (3-pyrrolidino-1- (4-tolyl) prop-1E-enyl (-2-pyridyl) acrylic acid and (E) -3- (6- (3-Pyrrolidino-1- (4-tolyl) prop-1E-enyl (-2-pyridyl) propionic acid.) Another preferred anti-histamine is (E) -1- (4-methylphenyl) -1- (2-pyridyl 3-pyrrolodinoprop-1-ene, also known as tripolidine, in order to retard the aging process of cut or picked plants or to control plant growth, the compounds of formula (I) and their salts are preferably in a suitable composition, optionally containing one or more other agents to enhance the freshness of the plants Such compositions contain solutions and suspensions of the compound in a suitable agent, such as an aqueous medium The compositions may be obtained by partial immersion (e.g. of the cut end) or immersion of the whole plant or by spraying the plants before or after cutting or the like picking or by application to the root structure before or after picking. The compounds may likewise be used by spraying on the soil before cutting or picking and transferring to the plant root by rainwater or by other irrigation operations. When the application is in the form of an aqueous solution, the compounds are in a concentration of 1 μ, ΜοΙ to 1 mole, for example 10ΟμΜοΙ-1 OOmMol before. A typical concentration may be about 1 mmol.

The compounds of the formula (I) and their salts can be prepared by the following process, which (subject to any limitation cited) forms a further part of the present invention:

a) for the preparation of the compounds of the formula (I) in which U is the non-cyclic radical (as defined above) in which R ^{1 is} hydrogen, a compound of the formula (II)

R ⁶ NHOH (II)

with a compound of the formula (III)

R ⁷ -R ⁸ _t (III)

(wherein R ^{7 is} a group R ² as previously defined, and R ^{6 is} a group of the formula Ar- (L-Ar ') q- (X) _k - (Y) p- as previously defined and R ⁸

is a group capable of reacting with the NH group in the compound of the formula (II) to give the corresponding hydroxamic acid or a derivative thereof);

b) for the preparation of the compounds of the formula (I) in which Q is the non-cyclic radical (as defined above), in which R ^{1 is} hydrogen, a compound of the formula (V) is employed

¹ R ⁹ N (OZ ¹ IH, (V)

(wherein R ^{9 is} a group of the formula Ar- (L-Ar ') _q - (X) _k - (Y) _p - as previously defined, as appropriate and Z ^{1 is} hydrogen or a suitable protecting group) with a suitable acylating agent and wherein Z ^{1 is} a protecting group, subjecting the reaction product to such conditions and / or reacting it with one or more agents as appropriate to effect removal of the protecting group; or

and, if desired, one or more of the following transformations, in any desired order, are performed by:

(i) when in the compound of formula (I) which is formed such that any of R ¹ , R ² and (in the definition of R ¹ ) R ⁴ and R ^{5 are} hydrogen atoms, this compound is converted into a corresponding compound of the formula (I) wherein any of the hydrogen atoms can be converted as desired into C 1-4 alkyl groups; (ii) converting the compound of formula (I) into an appropriate salt; (iii) when in the compound of the formula (I) thus formed, R ^{1 is} hydrogen, the compound is converted to

corresponding compound of the formula (I), wherein R ^{1 is} a group of the formula -COR ³ , as defined above, (iv) when in a compound of the formula (I), R ^{1 is} a group of the formula -COR ³ , in which R ³ is a Ci_4 alkyl group substituted by carboxy, this compound is converted into a corresponding compound wherein R ³ is a substituted C ₁ ^ alkoxycarbonyl C ₁ ^ ₄ alkyl group.

In the process of option (a) above, the compound of formula (II) may be used in the form of the salt, and the compound of formula (III), for example a suitably mixed anhydride or activated acid, e.g. An acid halide (eg the chloride). Preferably, the reaction is carried out in a suitable solvent and when the compound of formula (II) is in the form of the salt, in the presence of a base, for example a suitable amine, to release the free hydroxylamine compound in situ.

In the process of choice (b) where the group Z ¹ in the compound of formula (V) is a protecting group, this may for example be acetyl, benzyl, O-benzyl, trityl, tetrahydropyranyl, O-tetrahydropyranyl, ot-butyl and benzoyl , to be selected. The protecting group may be removed by treatment with an acid or base or by hydrogenation as known to those skilled in the art. In general, suitable protecting groups and methods for their removal are found in TWGreene, Protective Groups in Organic Synthesis, Wiley, New York, 1981. Individual examples of removal of such protecting groups include removal of an O-benzyl group by hydrogenolysis over 5% palladium on charcoal at room temperature or removing O-tetrahydropyranyl with pyridine para-toluene sulphate in methanol at reflux.

When the process of choice (b) is used to prepare a compound of formula (I) wherein Q is the non-cyclic radical (as previously defined), R ^{2 is} an amino group or a monoamine derivative and Z is a protecting group Acylating agent is an isocyanate of the formula (VII).

Q ¹ NCO ₁ (VII)

(where Q ^{1 is} the group R ² minus the -NH moiety). The reaction is carried out in a suitable solvent such. As toluene, optionally at a temperature above room temperature, performed.

When the process of option (b) is to produce a compound of formula (I) wherein Q is the non-cyclic radical (as previously defined and R ^{2 is} different from what was specified in the previous paragraph, whether Z is hydrogen or a protecting group For example, the acylating agent may be a suitable mixed anhydride or an activated acid, such as

z. Example, an acid halide (for example, chloride).

The possible conversion (i) can be carried out, for example, by reaction with a suitable alkyl halide or sulfate in the presence of a mild base. In the case where one or more but not all hydrogens are to be selectively alkylated, the transformation may require one or more steps of protection and then removal of the protection.

The possible conversion (ii) may conveniently be carried out by reaction with a suitable organic or mineral acid or with a base.

The possible conversion (iii), if used for the preparation of the compounds wherein R ^{3 represents} a group of formula -N (R ⁴ ) R ⁵ , can be achieved by reacting the compound of formula (I) with a suitable isocyanate, in one corresponding solvents, such as. For example, tetrahydrofuran or toluene, optionally in the presence of a catalyst such. For example, 1,8-diazabicyclo [5.4.0] undec-7-ene.

The possible conversion (iii), if used for the preparation of the compounds wherein R ^{3 is} an alkyl group optionally substituted by a carboxy group or a C 1-4 alkoxycarbonyl group, may be carried out in the reaction of the compound of formula (I) with a corresponding acylating agent, such as z. A mixed anhydride or a suitable activated acid, e.g. B.

an acid halide, such as. B. chloride exist. Preferably, the reaction is carried out in a solvent, such as. B.

Methylene dichloride or tetrahydrofuran, suitably at a temperature around ⁰ ° C. to room temperature.

The possible conversion (iv) can be carried out by reaction with a suitable alcohol in the presence of a suitable mineral acid, for example sulfuric acid.

Salts derived from acids include the acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanopropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, Hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

Salts with bases include the ammonium salts, alkali metal salts, such as. For example, sodium and potassium salts, alkaline earth metal salts, such as

z. For example, calcium and magnesium salts, salts with organic bases such. B. dicyclohexylamine salts, N-methyl-D-glucamine and salts with amino acids, such as. Arginine and lysine.

Quaternary ammonium salts, if a nitrogen-containing group is present, for. By reaction with lower alkyl halides, for example methyl, ethyl, propyl and butyl chlorides, bromides and iodides; Dialkyl sulfates, long chain halides, e.g. Decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethylbromides.

Therefore, in accordance with the requirements of novelty and inventive level in the present invention, the following inter alia claims:

(a) a compound of the forms MO of an acid addition salt thereof;

(b) a process for the preparation of a compound of formula (I) of a pharmacologically acceptable acid addition salt thereof;

(c) a pharmaceutical formulation comprising a compound of formula (I) or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier therefor;

(d) process for preparing such formulations;

(e) A method for inhibiting the lipoxigenase and / or cyclo-oxygenase pathways in arachidonic acid metabolism by using a non-toxic, effective inhibitor-amount compound of the formula (I) or a physiologically acceptable salt thereof;

(f) A method for the prophylaxis or treatment of a disease in a mammal, including a human, comprising administering to the mammal a non-toxic, therapeutically or prophylactically effective amount of a compound of formula (I) or a physiologically acceptable salt thereof;

(g) A method for the prophylaxis or treatment of any condition as described herein in a mammal, including a human, comprising administering a non-toxic, therapeutic or prophylactically effective amount of a compound of formula (I) or a physiologically acceptable salt thereof The mammal;

(h) A method for the prophylaxis or treatment of asthma in a mammal, including a human, comprising administering a non-toxic, effective, antiasthmatic amount of a compound of formula (I) or a physiologically acceptable salt thereof;

(i) A compound of the formula (I) or a physiologically acceptable salt thereof for use in medicine, in particular

as defined in (f) to (h) above; (j) Use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of

medical, therapeutic agents, in particular those for use as defined in (f) to (h) above; (k) A method for regulating the growth or retarding the aging process in plants by applying a

effective amount of a compound of the formula (I) or a salt thereof on the plants; or (I) any new feature described herein.

The following examples further illustrate the present invention, but are not to be construed as limiting the same. All temperatures are in degrees Celsius.

embodiments example 1

Preparation of N- (4-benzyloxybenzyl) acetohydroxamic acid

Sodium cyanoborohydride (21.3 g) was added portionwise to a solution of 4-benzyloxybenzaldehyde oxime (51 g) in acetic acid (250 ml) at ca. 50 ° (cooling). After complete reduction, acetic anhydride (22.5 ml) was added in one portion and the reaction mixture was stirred for one hour. The mixture was then poured into water and the neutral product was isolated with ethyl acetate. The residue was treated with sodium carbonate (2g), methanol (400ml) to hydrolyze the O-acetyl material, then the solvent was evaporated . Addition of a 20% citric acid solution (400 ml) and isolation with ethyl acetate gave N- (4-benzyloxybenzyl) acetohydroxamic acid (32 g), Sp. 119-120 ⁰ C (from ethyl acetate-petroleum ether, bp. 60-80 ⁰ C) ,

Example 2

Preparation of N- [4- (2-pyridyloxy) benzyl] acetohydroxamic acid

2-Bromopyridine (4.74g) was added to the sodium salt of 4-methylphenol (from 50% sodium hydride [1.58g] and the phenol [3.65g]) in dimethylsulphoxide and the mixture stirred at 150 ^° C for 20 hours. Addition of water and isolation of the non-phenolic material with ether gave the pyridiloxy compound (4.81 g). Without purification, this compound (4.74g) in carbon tetrachloride (125ml) was refluxed with N-bromosuccinimide (5.02g) and azo-bis-isobutyronitrile starter (50ml). After one hour (additional starter was added after 15 and 30 minutes), the filtered solution was evaporated in vacuo. The crude product (6.76 g) was immediately stirred with O- (tetrahydropyran-2-yl) hydroxylamine (8> 99 g) in N, N-dimethylformamide (65 ml) for 65 hours at room temperature. Addition of water and isolation with ether gave the protected hydroxylamine as a viscous oil. Acetylation of the crude, protected hydroxylamine (3.84g) in methylenedichloride (30ml) was performed with acetic anhydride (1.44g) for 2 hours at room temperature. Evaporation of the solvent and isolation of the non-acidic material with ether yielded the O-protected hydroxamic acid, which was purified by silica gel chromatography (elution with 1: 1 ethyl acetate / petroleum ether [K.p.60-80 ° C]) ( 2.61 g). A mixture of O-tetrahydroxpyranylhydroxamic acid, (2.6g) and pyridinium p -toluenesulphonate (191mg) in methanol (25ml) was heated at reflux for 9 hours, then evaporated in vacuo. By isolation with ethyl acetate to give N- [4- (2-pyridyloxy) benzyl] acetohydroxamic acid (1.42g), Fp97-99 ° C after consultation crystallization from ethyl acetate-petroleum ether (K. p. 60-80 ⁰ C).

Examples 3 to 41

The following compounds were prepared in a manner generally analogous to the procedures of Examples 1 and 2:

3) N- [2- (2-Naphthyloxy) ethyl] benzohydroxamic acid, m.p.163-165 ° C

4) N- [2- (5,6,7,8-Tetrahydro-2-naphthyloxy) ethyl] acetohydroxamic acid, m.p. 73-74 ° C

5) N- [1- (4-biphenylyl) ethyl] acetohydroxamicacid, m.pt. 143-153T, inaccurate F.p.

6) N- [1- (4-Benzyloxy-2-hydroxyphenyl) ethyl] acetohydroxamic acid, mp 149-15O ⁰ C

7) N- (2-Benzyloxybenzyl) acetohydroxamic acid, oil

8) N- 3-benzyloxybenzyl) acetohydroxamic acid, (C ⁰ Fp95-98

9) N- (3-phenoxylbenzyl) acetohydroxamic acid, m.p. 81-82 ° C

10) N- (4-biphenylylmethyl) acetohydroxamic acid, m.p. 152-155 ° C

11) N- [4- (1-Naphthylmethoxy) benzyl] acetohydroxamic acid, mp 127-13O ⁰ C

12) N- [4- (2-naphthylmethoxy) benzyl] acetohydroxamic acid, m.p. 161-14 ° C

13) N- (4-phenoxybenzyl) acetohydroxamic acid, m.p.116-119 ° C

14) N- (4-benzyloxybenzyl) pivalohydroxamsäure, mp 143-144 ⁰ C.

15) N- (4-benzyloxybenzyl) -2-methylpropanohydroxamsäure, Fp113-115 ⁰ C

16) N- (4-Phenylcarbamoylbenzyl) acetohydroxamic acid, mp 194-196 ⁰ C.

17) N - [(2 ', 4'-Difluoro-4-biphenylyl) methyl] acetohydroxamic acid, m.p. 134-135 ° C

18) N- [1- (2 ', 4'-Difluoro-4-biphenylyl) ethyl] -2,2-dimethylpropanohydroxamic acid, m.p. 152-153 ° C

19) N- [4- (4-biphenylylmethoxy) benzyl] acetohydroxamic acid, mp inaccurate, softening at 165 ° C, melts at 175 ⁰ C.

20) N- [4- (2,4-Difluorobenzyloxy) benzyl] acetohydroxamic acid, m.p. 113-115 ° C

21) N- [4- (2,4-Difluorobenzyloxy) benzyl] pivalohydroxamic acid, m.p.134-136 ° C

22) N- [5,6,7,8-tetrahydro-2-naphthyl) methyl] acetohydroxamic acid, m.p.79-81 ° C

23) N- [2- (5,6,7,8-tetrohydro-2-naphthyloxy) ethyl] pivalohydroxamic acid, m.p. 85-87 ° C

24) N-fö ^^ S-Tetraliydro ^ -naphthylallyDacetohydroxamic acid, softening at 95 ° C, melts at 106-107 ⁰ C.

25) N- (5,6,7,8-tetrahydro-2-naphthylallyl) pivalohydroxamic acid, m.p. 144-145 ⁰ C

26) N- (5,6,7,8-tetrahydro-2-naphthylmethyl) pivalohydroxamic acid, m.p. 103-105 ° C

27) N- [2- (2 ', 4'-Difluoro-4-biphenylyl) ethylacetohydroxamic acid, m.p. 122-123 ° C

28) N- (4-isobutylbenzyl) acetohydroxamic acid, m.p. 89-90 ° C

29) N- [1- (4-biphenyl) ethyl] pivalohydroxamic acid, m.p. 170-171 ° C

30) N - [(4-biphenylyl) methyl] pivalohydroxamic acid, m.p. 164-165T

31) N-O-phenoxycinnamic acetohydroxamic acid, light brown oil

32) N- [2- (4-biphenylyloxy) ethyl] acetohydroxamic acid, mp 125-127 ⁰ C.

33) N- [3- (4-benzyloxyphenyl) prop-2-enyl] acetohydroxamic acid, mp 148-149 ⁰ C.

34) N- [4- (2-pyridyl) benzyl] acetohydroxamic acid, m.p. 134-135 ° C (softened at approx. 125 ° C)

35) N- [4- (2,4-Difluorophenoxymethyl) benzyl] acetohydroxamic acid, m.p. 112-113 ° C

36) N- [4- (2-pyridyloxy) benzyl] acetohydroxamic acid, m.p. 97-99 ° C

37) N-IB-phenoxymethyl ^ -thienylmethyDacetohydroxamsäure, mp 103-104 ⁰ C.

38) N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl) acetohydroxamic acid, m.p.

39) N- [4- (benzylthio) benzyl] acetohydroxamic acid

40) N- [3- (2-pyridyloxy) benzyl] acetohydroxamic acid

Example 41

Preparation of 1-hydroxy-1- [2- (2-naphthyloxy) ethyl] -3-phenyl-urea

A mixture of 2-naphthyloxyacetaldehyde hydrate (9.85g), benzyloxyamine (5.94g) and ethanol (100ml) was added overnight under nitrogen to precipitate 11.21g of the protected oxime having a melting point of 68-69.5 ° C. touched. The oxime (10.1 g) in acetic acid (100ml) was reduced with sodium cyanoborohydride, then the isolated O-benzylhydroxylamine was used without purification with phenyl isocyanate (1 equivalent) in toluene for 4 hours at 11O ⁰ C. The product had a melting point of 75-77 ⁰ C after silica gel chromatography (elution with methylene chloride) and recrystallization from SVM. Hydrogenation of the latter compound O-Benzylhydroxyurea over 5% palladium on charcoal in ethanol containing a few drops of acetic acid gave 1-hydroxy-1- [2- (2-naphthyloxy) ethyl] -3-phenylurea, mp 165-167 ° C ( from ethanol).

Example 42

Preparation of N- (4-benzyloxybenzyl) -N-hydroxy-N-methylurea

Sodium cyanoborohydride (1.94 g) was added to 4-benzyloxybenzaldoxime (3.5 g) in acetic acid (30 ml) under N ₂ and the mixture stirred overnight at room temperature. The solvent was evaporated and the product (4g) was isolated with ether. Methyl isocyanate (0.88g) in ether (10ml) was added dropwise to a solution of the crude hydroxylamine in toluene (100ml) at ⁰ ° C and the mixture was stirred at room temperature for 3 hours to give N- (4-benzyloxybenzyl ) -N-hydroxy-N-methylurea (2.2 g), mp 152-154 ⁰ C after recrystallization from ethyl acetate-petroleum ether (Kp60

Examples 43-51

The following examples were prepared by a procedure generally analogous to the procedures described in Examples 41 and 42:

43) N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl] -N-hydroxy-N'-methyl-urea

44) N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl] -N-hydroxy-N'-t-butyl-urea

45) N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl] -N-hydroxy-N'-cyclohexylurea

46) N- [3- (4-fluoro-3-phenoxyphenyl) prop-2-enyl] -N-hydroxy-N'-phenylurea

47) N- (biphenyl-4-ylmethyl) -N-hydroxy-N'-methylurea

48) N- (biphenyl-4-ylmethyl) -N-hydroxy-N'-t-butylurea

49) N-i-biphenyl-1-methyl-N-hydroxy-N'-cyclohexylurea

50) N- (biphenyl-4-ylmethyl) -N-hydroxy-N'-phenylurea

51) N-hydroxy-N'-methyl-N- [3- (2-pyridyloxy) benzyl] urea

Example 52

Preparation of N- (4-benzyloxybenzyl) -0-methylcarbamoylacetohydroxamic acid A mixture of N- (4-benzyloxybenzyl) acetohydroxamic acid (1.35g), methyl isocyanate (0.65g) and 1,8-diazabicyclo [5.4.0] undec-7 The catalyst (1 drop) in tetrahydrofuran (10 ml) was stirred for 3 hours and allowed to stand overnight to give N- (4-benzyloxybenzyl) -0-methylcarbamoylacetohydroxamic acid (1.35 g). Mp 101-102 ° C (from ethyl acetate-petroleum ether [pp 60-80 ⁰ C]).

Examples 53-55

The following compounds were prepared by a procedure generally analogous to that described in Example 52:

53) N- [2- (2-Naphthylthio) ethyl] -N- (phenylcarbamoyloxy) acetamide, m.p. 96-98 ° C

54) N- [4- (Benzyloxybenzyl) -O- (methylcarbamoyl) pivalohydroxamic acid, m.p. 135-136 ° C

55) N- (4-benzyloxybenzyl) -O- (2,2-dimethylethyl) carbamoylacetohydroxamsäure, Fp82-83 ⁰ C

Example 56

Preparation of N- (4-benzyloxybenzyl) -N- (t-butylcarbonyloxy (acetamide

Pivaloyl chloride (1.36 ml) was added dropwise to a solution of N- (4-benzyloxybenzyl) -acetohydroxamic acid (2.71 g) and triethylamine (1.7 ml) in methylene dichloride (15 ml) and dimethylaminopyridine (100 ml). The mixture was stirred for 2 hours at room temperature, then the neutral material was isolated with ether. The product N- (4-benzyloxybenzyl) -N- (t-butylcarbonyloxy) acetamide was a colorless oil.

Example 57

S-IN-K-Benzyloxybenzylacetamidooxycarbonylpropanoic acid, m.p. 102-105 ° C, was prepared by an analogous procedure generally described in Example 56.

Example 58

Fresh keeping of cut flowers

The compound of Example 1 was prepared in the form of a 1 mM solution and the cut stem ends of carnations were immersed in the resulting solution to prolong their freshness.

Pharmaceutical formulations

In the following formulation examples, the "Active Ingredient" may be any compound of Formula (I) or a physiologically acceptable salt thereof, e.g., the compound of the Example

Example A: Tablet

IneinerTablette

Active ingredient 5.0 mg

Lactose 82.0 mg

Starch 10.0 mg

Povidone 2.0 mg

Magnesium stearate 1.0 mg

The active ingredient is mixed with lactose and starch. Using a solution of povidone in purified water, the powder is granulated. The granules are dried, magnesium stearate added and compressed to make tablets, 100 mg per tablet.

Example B: ointment

Active ingredient 1.0 g

White, soft paraffin up to 100.0 g

The active ingredient is dispersed in a small volume of the vehicle. This is gradually transferred into the bulk for the production of a spreadable, homogeneous product. The material is filled into compressible metal tubes.

Examples: Cream for topical use

Active ingredient 1.0 g

PolawaxGP200 20.0 g

Water-free lanolin 2.0 g

White beeswax 2.5 g

Methyl hydroxybenzoate 0.1 g Distilled water to 100.0 g

Heating the Polawax, beeswax and lanolin together at 60 ⁰ C. To this is added a solution of methyl hydroxybenzoate. The mixture is then homogenized using a high speed stirrer. The temperature is allowed to drop to 50 ^° C. and the active ingredient which is dispersed is added. The mixture is allowed to cool with slow stirring.

Example D: Lotion for topical use

Active ingredient 1.0 g

Sorbitan monolaurate 0.6 g

Polysorbate20 0.6 g

Cetostearyl alcohol 1.2 g

Glycerol 6.0 g

Methyl hydroxybenzoate 0.2 g purified water B.P. up to 100.00 ml

Dissolve the methyl hydroxybenzoate and glycerol in 70 ml of water at 75 ° C. The sorbitan monolaurate, polysorbate 20 and cetostearyl alcohol are melted together at 75 ° C. and added to the aqueous solution. The resulting emulsion is homogenized, allowed to cool with continuous stirring, and the active ingredient is added in the form of a suspension in the remaining water. The entire solution is stirred until homogeneous.

Example E: Eye drops

active ingredient 0.5 g

Methyl hydroxybenzoate 0.01 g

Propyl hydroxybenzoate 0.04 g

purified water B.P. up to 100.00 ml

The methyl and propyl hydroxybenzoate are dissolved in 70 ml of purified water at 75 ° C. and the resulting solution is then allowed to cool. Then add the active ingredient and make up to 100ml with purified water. The solution is sterilized by filtration through a membrane filter having a pore size of 0.22 / nm and aseptically filling the mixture into suitable, sterile containers.

Example F: Injection solution

Active ingredient 10.0 mg

Water for injection B.P. to 1.0 ml

Dissolve the active ingredient in half of the water suitable for injection and then replenish with the remaining water. The solution is sterilized by filtration. The resulting solution is dispensed into ampoules under aseptic conditions.

Pulmonary formulations

In the subsequent formulations G and H, the "active ingredient" may be any compound of formula (I) or a physiologically acceptable salt thereof.

Example G: Powder capsules for inhalation

Active ingredient (0.5-7.0 μ, ηη powder 4 mg

Lactose (30-90 Aim powder) 46.0 mg

The powders are mixed to homogeneity and filled into hard gelatin capsules of suitable size, 50 mg of the mixture per capsule.

Example H: Aerosol for inhalation

Active ingredient (0.5-7.0 μνη powder) 200mg

Sorbitan trioleate 100 mg

Sodium saccharin (0.5-7.0 μνη powder) 5 mg

Methanol 2 mg

Trichlorofluoromethane 4.2 g

Dichlorodifluoromethane to 10.0 ml

Dissolve the sorbitan trioleate and menthol in trichlorofluoromethane. The sodium saccharin and the active ingredient are dispersed in the mixture, which is then transferred to a suitable aerosol container and the dichlorofluoromethane is introduced through a tube system. This composition gives 2 mg of the active ingredient per 100μ.Ι dose.

In Vitro Inhibition of 5-Lipoxygenase (LO) and Cyclooxygenase (CO)

Blood from aspirin-free volunteers was centrifuged to remove the leukocytes from red blood cells and platelets. The leukocytes were homogenized and 5μ.ΜοΙ arachidonic acid added, followed by incubation at 37 ° C for 5 minutes. The reaction was stopped by boiling. A radioimmunoassay was performed to determine leukotriene B ₄ (an LO product) and thromboxane B ₄ (a CO product). The results are calculated as IC ₅₀ aiMoI activity against each enzyme.

Claims (14)

1. Process for the preparation of a novel compound of the formula (I) Ar- (L-Ar ') _q - (X) k- (Y) pQ, (I) k, ρ and q are independently 0 or 1 with the proviso that if k is 1 then ρ must also be 1 and where Ar means: (i) naphthyl, tetrahydronaphthyl or pyridyl, each of which is optionally substituted by one or more substituents independently selected from C 1-4 alkyl (which itself may optionally be substituted by one or more halogen atoms), C 1-4 alkoxy, halogen, nitro, amino, Carboxy, C ₁ ^, alkoxycarbonyl and hydroxy substituted, or (ii) phenyl, optionally substituted by one or more substituents independently selected from phenyl (optionally independently substituted by one or more substituents selected from the group defined as possible substituents in (i) above) and the described possible substituents in (i) above, substituted; L is selected from - (CH ₂ ),., (Wherein r is 1-4), -O-, -CH ₂ O-, -CH ₂ S-, -OCH ₂ -, -CONH-, -NHCO-, -CO- and -CH ₂ NH-, Ar 'is phenylene or thienylene, each may optionally be substituted by one or more substituents independently selected from those listed as possible substituents in the definition (i) of Ar are substituted; X represents oxygen, sulfur or carbonyl, provided that at least one atom separates the carbonyl group from any carbonyl group in Q as defined above; Y is C _n _ ₁₀ alkylene or alkenylene CI_ _10; Q is a non-cyclic radical selected from the groups of the formula -N C0R ^X wherein R ^{1 is} independently selected from ^ Is hydrogen, C ₁ alkyl, groups as Ar defined above and groups of formula -COR ³ wherein R ³ is selected from C ₁ ^ alkyl (optionally by a carboxy or C | _4 alkoxycarbonyl group) and groups of the formula -N (R ⁴ ) R ⁵ in which R ^{4 is} hydrogen or C ₁ -alkyl and R ^{5 is} hydrogen, C 1-4 -alkyl or phenyl, optionally substituted by one or more substituents independently selected from those which may be used as possible substituents in the definition ( i) are defined by Ar is substituted, and R ² is selected from hydrogen, C1-4 alkyl, amino, C ₁ ^ ₁ alkylamino, di-C ₁ ^ ₁ alkylamino, C ^ ₇ cycloalkylamino, C ^ ₇ cycloalkyl, ( C ₁ ^ alkyl) amino, anilino, NC ₁ _ ₄ defined alkylanilino and groups as Aroben; and physiologically acceptable salts thereof, with the proviso that: when q is O, k is O or 1 and ρ is 1, Ar is phenyl or naphthyl, one of the radicals optionally being substituted by one or more substituents as specified in definition (i) of Ar, and X is oxygen or sulfur (in the case when k is 1) Y is C ₁ ^ ₀ is AIkylen and Q represents the non-cyclic moiety as defined before, wherein one of R ¹ and R ² is hydrogen or CI_ ₄ is alkyl; then the other radical of R ¹ and R ^{2 is} neither hydrogen nor C ₁ ^ Al kyl; characterized in that: a) for the preparation of the compounds of the formula (I) in which Q denotes the non-cyclic radical (as defined above) in which R ^{1 is} hydrogen, a compound of the formula (II) R ⁶ NHOH (II) with a compound of formula (III), R ⁷ -R ⁸ (III) (wherein R ^{7 is} a group R ² as defined above, and the group R ^{6 is} a group of the formula Ar- (1-Ar ') q- (X) k- (Y) p- as previously defined, and R ^{8 is} a group capable of reacting with the NH group in the compound of the formula (II) to give the corresponding hydroxamic acid or a derivative thereof); b) for the preparation of the compounds of the formula (I) in which Q denotes the non-cyclic radical (as defined above) in which R ^{1 is} hydrogen, a compound of the formula (V) R ⁹ N (OZ ¹ ) H, (V) (where R ^{9 is} a Group of the formula Ar- (L-Ar ') _q - (X) _k - (Y) _P as previously defined as required and Z ^{1 is} hydrogen or a suitable protecting group) is reacted with a suitable acylating agent wherein Z is ¹ is a protecting group and subjecting the reaction product to such conditions and / or reacting with one or more agents as necessary to deprotect it; and optionally, if desired, one or more of the following transformations in any desired order: (i) when in the compound of formula (I) formed so that any of R ¹ , R ² and (in the definition of R ¹ ) R ⁴ and R ^{5 are} hydrogen atoms, converting this compound into a corresponding compound of Formula (I) wherein any of the hydrogen atoms, such as desired, can be converted into C ₁ ^ alkyl groups; (ii) converting the compound of formula (I) into an appropriate salt; (iii) when in the compound of formula (I) thus formed, R ^{1 is} hydrogen, the compound is converted to the corresponding compound of formula (I), wherein R ^{1 is} a group of Formula -COR ³ as previously defined;
(iv) when in a compound of formula (I), R ^{1 is} a group of formula COR ³ wherein R ^{3 is} a C _1-1 alkyl group substituted by carboxy, this compound is converted to a corresponding compound wherein R ³ is Ci_4 alkoxycarbonyl substituted Ci_4 alkyl group. 2. The method according to item 1, section (a), characterized in that the compound of formula (II) is in the form of a salt and the compound of formula (III) is a suitable, mixed anhydride or an activated acid and the reaction in a suitable solvent in the presence of a base, such as. A suitable amine, to liberate the free hydroxylamine compound in situ. 3. The method according to item 1, section (b), characterized in that the group Z ¹ in the compound of formula (V) is a protective group, and is selected from acetyl, benzyl, O-benzyl, trityl, tetrahydropyranyl, O- Tetrahydropyranyl, ot-butyl and benzoyl. 4. The method according to item 1, section (b), characterized in that in the compound of formula (I) Q is the non-cyclic radical (as defined in point 1), wherein R ^{2 is} an amino group or a mono-amine derivative and Z ^{1 is} a protective group and the acylating agent is an isocyanate of the formula (VII), Q ¹ NCO (VII) , (where Q ^{1 is} the group R ² minus the -NH moiety). 5. Method according to item 1, section (b), characterized in that in the compound of formula (I) Q represents the non-cyclic radical (as defined in point 1) and R ² defines a group other than in point 4, means (whether Z is hydrogen or a protecting group) and the acylating agent is a suitable mixed anhydride or an activated acid, such. As an acid halide, is. 6. The method according to item 1, characterized in that one uses the optional conversion of (iii) for the preparation of the compounds wherein R ^{3 is} an alkyl group, optionally substituted by a carboxy group or a C ^ alkoxycarbonyl group, by reacting a compound of Formula (I) with a suitable acylating agent, such as. B. a mixed anhydride or a suitable activated acid. 7. A process according to items 1 to 6 for the preparation of a compound of formula (I) or a salt thereof, characterized in that when Q represents the non-cyclic radical as defined in point 1 and when R ^{1 is} hydrogen or carbonyl ^ Is alkyl and R ^{2 is} phenyl optionally substituted by a single substituent selected from C 1-4 alkyl, C 1-4 alkoxy and phenyl optionally substituted by one or more substituents independently selected from those described as possible substituents in of definition (i) of Ar, is substituted, then at least one of k and ρ must be 1, and in the case when k is 0 and ρ is 1, YC ₁ -T ₀ must be alkenylene. 8. A process according to items 1 to 7 for the preparation of a compound of formula (I) or a salt thereof, characterized in that Ar is optionally selected from one or more substituents independently selected from those defined in (ii) for Ar, substituted phenyl; LO or -CH ₂ O-; Ar 'is phenylene optionally substituted with one or more substituents independently selected from those as defined in (i) for Ar; and Q is the non-cyclic radical as defined in item 1. 9. The method according to item 1, for the preparation of a compound of formula (I), characterized in that the compound is selected from: N- [2- (5,6,7,8-tetrahydro-2-naphthyloxy) ethylacetohydroxamic acid and N- (5,6,7,8-tetrahydro-2-naphthylallyl) acetohydroxamic acid and its salts. 10. The method according to item 1, for the preparation of a compound of formula (I), characterized in that the compound is selected from N- (3-Phenoxycinnamyl) acetohydroxamic acid and salts thereof. 11. The method according to item 1, for the preparation of a compound of formula (I), characterized in that the compound is selected from N- (4-benzyloxybenzyl) acetohydroxamic acid and salts thereof. 12. A process according to items 1 to 11 for the preparation of a compound of formula (I) or salts thereof, characterized in that q is 0 and ρ is 1; Ar naphthyl optionally substituted by one or more substituents independently selected from those as defined in definition (i) for Ar; X (in the case when k1 is) is oxygen; and Q represents the non-cyclic moiety as defined in item 1, is wherein nO, m1 and R ² _is C ₁ ^ ₁ is alkyl. 13. A method according to item 1 to 12, for preparing a compound of formula (I) or a salt thereof, characterized in that Ar is optionally substituted by one or more substituents independently selected from those as defined in (ii) for Ar, substituted phenyl; LO or -CH ₂ O-; Ar 'is phenylene optionally substituted with one or more substituents independently selected from those as defined in (i) for Ar; and Q is the non-cyclic radical as defined in item 1, provided that when L-CH ₂ O- and y is C _1- alkenylene then m is ₁ and n is O. 14. The method according to item 1, for the preparation of a compound of formula (I), characterized in that the compound is selected from: 3-phenoxy-N-methylcinnamohydroxamsäure
N- (3-phenoxycinnamyl) acetohydroxamic acid
N- (4-benzyloxybenzyl) acetohydroxamic acid and N- [2- (5,6,7,8-tetrahydro-2-naphthyloxy) ethyl] acetohydroxamic acid and N- (5,6,7,8-tetrahydro-2-naphthylallyl) acetohydroxamic acid and their salts. Field of application of the invention The invention relates to a process for the preparation of novel aryl derivatives which are useful in medicine and other fields. Characteristic of the known technical solutions One class of agents described in European Patent EP 0055418 are referred to as dual inhibitors of lipoxigenase and cyclooxygenase of the mammalian arachidonic acid metabolite. These compounds were found to have anti-inflammatory and similar activities. Other compounds described as lipoxygenase and / or cyclooxygenase inhibitors include certain naphthyloxy derivatives (e.g., as disclosed in U.S. Patent 3,740,437 or Proc. Ann. Symp. Inst. Basic Med. Sei, Royal College of Surgeons of England, October 1982, pages 263-274). Compounds described in the last document include the compounds known as Nafazatrom. Object of the invention It was an object and purpose of this invention to provide processes for the preparation of novel aryl derivatives which are useful in medicine and in other fields as inhibitors of cyclooxygenase and lipoxygenase, respectively. Explanation of the essence of the invention It has now surprisingly been found that, depending on the subsequently stated provisos (explicit and implicit), the compounds of formula (I), as subsequently defined, are in particular advantageous inhibitors of lipoxygenase and / or cyclooxygenase enzymes and are useful medically possess prophylactic and therapeutic properties as well as certain non-medical applicabilities.
The definition of the formula (I) Ar- (L-Ar ') _q - (X) k- (Y) _P -a (I) is therefore: k, ρ and q are independently 0 or 1, with the proviso that if k1, then ρ must also be 1; Ar means either:
(i) naphthyl, tetrahydronaphthyl or pyridyl, each of them is, if necessary, by one or more substituents independently selected from C · ^ alkyl (which if desired may itself be substituted by one or more halogen atoms) ^, C ₁ alkoxy, halo, Nitro, amino, carboxy, _C1 ^ substituted or ₁ alkoxycarbonyl and hydroxy (ii) phenyl optionally substituted by one or more substituents independently selected from phenyl (optionally substituted independently by one or more substituents selected from the group as a possible Substituents in (i) have been defined) and the listed possible substituents defined in (i) above; L is selected from - (CH ₂ ) _r , (wherein r is 1-4), -O-, -CH ₂ O-, -CH ₂ S-, -OCH ₂ -, -CONH-, -NHCO-, - CO- and -CH ₂ NH-, and Ar 'means phenylene or thienylene, each may optionally be independently substituted by one or more substituents selected from those given as possible substituents in the definition (i) of Ar ; X represents oxygen, sulfur or carbonyl, provided that at least one atom separates the carbonyl group from any carbonyl group in Q as defined above; Y is C ₁ -C ₃ alkylene or Ci_i ₀ alkenylene;
Q is a non-cyclic radical of the formula .-OR ¹ COR *