The present invention relates to novel compounds, to methods o* preparing such compounds, compositions containing them and to their use in medicine and in other applications.

Certain agents such as are described in European patent specification no. FP 0 055 418 are dual inhibitors of the lipoxygenase and cyclo-oxygenase enzymes of the mammalian arachidonic acid metabolism and have been found to exhibit anti-in'lammatory and related activities. Other compounds which have been described as lipoxygenase and/or cyclo-oxygenase inhibitors include certain naphthyloxy derivatives (eg as described in US patent speci ^f ication 3 740 437 or in Proc. Ann. Symp. Inst. Basic Med. Sci, Royal College o* Surgeons o* England, October 1982, pp 263-274. Compounds described in the latter re ^f erence include the compound known as na'azatrom. It has also been demonstrated previously that certain hydroxamates have cyclo-oxygenase and/or lipoxygenase inhibitory activity. Surprisingly, we have now *ound that the compounds a* *ormula (I) as de'ined hereinbelow, are potent dual inhibitors o* the lipoxygenase and/or cyclo-oxygenase enzymes and have use ^f ul anti-inflammatory and other properties.

In 'ormula (I)

. OR

Ar - (X ) , - Y - (CO ) N n (I)

(CO) R m

is 0 or 1;

one of m and n is 0 and the other is 1;

Ar represents a phenyl or a naphthyl group, both of which optionally may be substituted by one or more substituents selected from , _ alkyl (which may itself optionally be substituted by one or more halogen atoms), C, * alkoxy, halo, nitro, amino, carboxy, C-, ^aikoxycarbonyl and hydroxy;

X represents oxygen or sulphur;

Y is Cι_ό alkylene; and

R and R are independently selected 'rom hydrogen and C-^ alkyl; and salts thereo*;

provided that:-

(i) when Ar represents phenyl optionally substituted by the substituents de ^f ined above, then n is 0 and m is 1;

(ϋ) when Ar represents unsubstituted phenyl, n is 0 and m is 1, R 2 and R are both hydrogen, k is 1 and X represents oxygen, or when k is 0, then Y does not represent -(C )--;

(iii) when Ar represents unsubstituted phenyl, n is 0 and m is 1, and k is 0,

then when R 1 is hydrogen and R 2 is methyl, Y does not represent a straight alkylene chain having 'rom 2-4 carbon atoms,

and when R 1 is methyl, and R 2 is hydrogen and Y contains 3 carbon atoms, then Y represents -(ChL) -;

(iv) when Ar represents phenyl, n is 0 and m is 1, k is 0, R 1 and R 2 are both hydrogen and Y represents -(CH )--, then the phenyl ring is not substituted by a single 4-nitro or 4-chloro substituent;

(v) when Ar represents naphthyl to which the side chain is attached in the 2-position but bears no other substituents, n is 1 and m is 0, k is 1 and X represents oxygen,

then when Y has from 1 to 4 carbon atoms, then R 1 and R 2 are not simultaneously methyl;

(vi) when Ar represents naphthyl to which the side chain is attached in the 2-position, n is 1 and m is 0, k is 1, X represents oxygen and

1 2

R and R are both hydrogen,

then when the naphthyl ring system is substituted by a single 1-bromo or 1-chloro substituent and Y has 2 carbon atoms, then Y represents -(C -j

and when the naphthyl ring system is substituted by a single 1-bromo, 1- methyl or 1-nitro substituent, then Y does not represent methylene;

(vii) when Ar represents naphthyl to which the side chain is attached in the 1-position, n is 1 and m is 0, k is 1, X represents oxygen and R 1 and R 2 are both hydrogen,

then Y does not represent methylene,

and when Y has 2 carbon atoms, Y represents -(.C i - or when Y has 4 carbon atoms, Y represents -(Ch )^- _'

Throughout this speci ^f ication, unless indicated to the contrary, alkyi and alkyl- containing moieties (such as alkylene and alkoxy) can be either straight or branched. For use in medicine, the salts o* the compounds of *ormula (I) are those salts which are physiologically acceptable. However, non-physiologically acceptable salts are included within the ambit o* the present invention, either for use in non-medical applications such as ^f urt er described hereinbelow, or as may be used in the preparation o* compounds of formula (I) and their physiologically acceptable salts. Also included within the scope of the present invention are pro-drugs o* the above de ^f ined compounds, that is to say compounds which are metabolised in vivo to produce the compounds o* formula (I) and their physiologically acceptable salts.

Included within the general class o' the compounds of -Ormula (I) and their salts are those wherein:-

(i) Ar represents phenyl optionally substituted by one or more substituents selected from C-, _. alkyl (which may itself optionally be substituted by one or more halogen atoms), , . alkoxy, halo, nitro, amino, carboxy, C, alkoxycarbonyi and hydroxy;

(ii) Ar represents naphthyl optionally substituted by one or more substituents selected from C-, A alkyi (which may itself optionally be substituted by one or more halogen atoms), C, _. alkoxy, halo, nitro, amino, carboxy, C, _ . alkoxycarbonyi and hydroxy;

(iii) X represents oxygen;

(iv) X represents sulphur;

(v) m is 0 and n is 1; and

(vi) m is 1 and n is 0;

and combinations thereof.

Examples of compounds a* formula (I) include the following and salts thereo*:

J-methyl-3-(2-naphthyloxy) propanohydrαxamic acid N-_2-(2-naphthyloxy)ethyl]acetohydroxamic acid ^-methyl-2-(l-naphthyloxy)acetohydroxarnic.acid ^-(2-naphthyloxymethyl)acεtohydroxamic acid ^-_3-(2-naphthyloxypropyl3acεtohydroxamic acid N-[4-(2-naphthyloxy)butyl]acetohydroxamic acid N-_2-(2-naphthylthio)ethyl3acetohydroxamic acid N- -(2-naphthyl)propyl3acetohydroxamic acid 3-(2-naphthyloxy)propanohydroxarτuc acid J^-[2-(2-naphthy_oxy)ethyl3formohydroχarmc acid

J.-[(2-methyl-l-naphthyloxy)methyl3acetohydroxamic acid N-[(2-nitro-l-naphthyoxy)methyl3acetohydroxamic acid N-(2-(3-carboxy-2-Naphthyloxy)ethyl3acetohydroxamic acid

£-methyl- J-[2-naphthyloχy)ethyl3acetohydroχamic acid J-[2-(2-naphthyloxy)ethyl3butanohydroxamic acid l-[l-(2-naphthyloxymethyl)ethyl3acetohydroxamic acid N-[2-(6-bromo-2-naphthyloxy)ethyl_ ace o hydroxamic acid N-[2-(6-hydro ^χ y-2-naphthyioxy)ethyl] aceto hydroxamic acid NI-.2-(6-mek oxy-2-naphthyloxy}ethyl) ace to hydroxamic acid N-(l-naphthyloxymethyl) ace to hydroxamic ac id N-(4-rnethoxy-l-naphthyloxyrnethyl)aceto hydroxamic acid

In another aspect, the present invention provides the compounds of formula (I') as defined hereinbeiow and their physiologically acceptable salts for use in a method o* treatment o' the human or animal body by therapy, or o diagnosis.

In "Ormula (D

OR

Ar - (X) _k - - - (C0) _n N _(r)

(CO ) ²

St k is 0 or 1;

one o* m and n is 0 and the other is 1;

Ar represents a phenyl or a naphthyl group, both o* which optionally may be substituted by one or more substituents selected *rom C, _Λ alkyl (which may itsel* optionally be substituted by one or more halogen atoms), C,_. alkoxy, halo, nitro, amino, carboxy, C-, _^ alkoxycarbonyi and hydroxy;

X represents oxygen or sulphur;

Y is C- , alkylene; and

R 1 and R 2 are independently selected *rom hydrogen and C. _. alkyl; and salts thereo*.

Subject to any limitations expressed or implied herein, the present invention also provides any compound of formula (I) (as hereinbefore defined) or physiologically acceptable salt thereof for use as an inhibitor of the lipoxygenase and/or cyclo-oxygenase enzymes of the mammalian arachidonic acid metabolism, to methods of inhibition of such enzyme(s) by administration to a mammal of a lipoxygenase and/or cyclo-oxygenase (as appropriate) inhibiting amount of any such compound or salt, and to use of any such compound or salt in the manufacture of lipoxygenase and/or cyclo-oxygenase inhibitor (as appropriate) agents.

Further, and also subject to any limitations expressed or implied herein, the present invention also provides any compound of formula (D (as hereinbefore defined) or physiologically acceptable salt thereof, for use as a medical therapeutic and/or prophylactic agent, to methods of medical therapeutic and/or prophylactic treatment by administration to a mammal of a medically therapeutic and/or prophylactic (as appropriate) effective amount of any such compound or salt, and to use of any such compound or salt in the manufacture a* medical therapeutic and/or prophylactic (as appropriate) agents. The kinds

By virtue of their enzyme inhibitory effects, the compounds o formula (D and salts thereof are also useful for controlling the processes of growth and decay in plants. Thus the present invention also provides the compounds of formula (I') and their salts for use in a method of regulating the growth of, or delaying senescence in vegetable matter by application to said matter of an effective amount of a compound of formula (D or a salt thereof.

The term senescence refers to the process whereby plant matter decays, especially after being picked, cut or otherwise removed *rom its normal growing environment. Vegetable matter includes trees, shrubs, flowers and edible vegetables and other food crops.

The above method is particularly applicable to flowers intended for decorative or display purposes such as carnations, crysanthemums, daisies, begonias, etc. These include perennial annual and biannual flowers, for example those that grow from bulbs (eg dahlias) or from seed (eg marigolds). The method is also especially suited to use with decorative shrubs and trees, for example those which are displayed when cut, such as Christmas trees.

The compound of formula (I ¹ ) and their salts may also be used for the preservation of picked fruits.

For medical use, the amount required o* a compound of formula (I ¹ ) (hereina ^f ter referred to as the active ingredient) to achieve a therapeutic effect will, o ^* f course, vary both with the particular compound, the route of administration and the mammal under treatment and the particular disorder or disease concerned. A suitable dose o* a compound of formula (I ¹ ) for a mammal su ^f fering from an inflammatory, painful or pyretic condition as defined hereinbefore is 0.1 yg- 500mg of base per kilogram bodyweight. In the case of systemic administration, the dose may be in the range 0.5 to 500 mg of base per kilogram bodyweight, the most preferred dosage being 0.5 to 50 mg/kg of mammal bodyweight for example 5 to 25 mg/kg; administered two or three times daily. In the case o* topical administration, eg. to the skin or eye, a suitable dose may be in the range O.lng - lOOyg of base per kilogram, typically about 0.1 yg/ g.

o* medical therapy and prophylaxis pertinent to the *oregoing and therefore in that sense comprising part o* the present invention, are elaborated by way o* example in the following paragraphs which are not intended to be construed as in any way limiting the scope of these aspects of said invention.

By virtue o* their lipoxygenase inhibitory properties, said compounds and salts find application in the treatment and/or prophylaxis o* any condition where a lipoxygenase inhibitor is indicated, especially spasmogenic and allergic conditions and tumours.

By virtue of their cyclo-oxygenase inhibitory properties, said compounds and salts find application in the treatment and/or prophylaxis of any condition where a cyclo-oxygenase inhibitor is indicated, especially pyresis and pain.

By virtue of both their lipoxygenase and cyclo-oxygenase inhibitory properties, said compounds and salts find application in the treatment and/or prophylaxis of any condition where a dual lipoxygenase/cycio-oxygenase inhibitor is indicated, especially any condition involving blood platelet aggregation or inflammation. In the case of inflammation, the compounds and salts are particularly suited to the treatment and/or prophylaxis of conditions associated with infiltration of leucocytes into inflamed tissue.

In determining when a lipoxygenase, cyclo-oxygenase or dual lipoxygenase/cyclo-oxygenase inhibitor is indicated, of course inter alia, the particular condition in question and its severity must be taken into consideration and this determination is ultimately at the discretion of the attendant physician.

Fxamples of the aforesaid spasmogenic conditions are those involving smooth muscle tissue, especially airway smooth muscle constriction such as intrinsic asthma (including intrinsic or idiopathic bronchial asthma and cardiac asthma), bronchitis and arterial smooth muscle constriction such as coronary spasm (including that associated with myocardiai infarction, which may or may not lead to left ventricular failure resulting in cardiac asthma) and cerebral :asm or 'stroke'. Other examples include bowel disease caused by abnormal colonic muscular contraction such as may be termed rritable bowel syndrome', 'spastic colon' or 'mucous colitis'.

Fxamples of the aforesaid allergic conditions are extrinsic asthma (from which it will be appreciated that said compounds and salts are particularly favourable as anti-asthmatic agents), ailergic skin diseases such 83 eczema having a total or partial allergic origin, allergic bowel disease (including coeiiac disease) and

allergic eye conditions such as hay*ever (which may additionally or alternatively affect the upper respiratory tract) and allergic conjunctivitis. Fxamples of the a ^f oresaid tumours are skin neoplasms, both benign and malignant.

Fxamples of the aforesaid pyretic and painful conditions include fever associated with infections, trauma and injury, malignant disease, and diseases affecting the immune system (including anto-immune diseases).

Fxamples of the aforesaid conditions involving blood platelet aggregation are those resulting from thrombosis, including 'stroke' having a total or partial thrombotic origin, coronary thrombosis, phlebitis and phlebothrombosis (the latter two conditions also possibly being associated with Inflammation).

Fxamples of the aforesaid conditions involving Inflammation are inflammatory conditions of the lung, joints, eye, bowel, skin and heart.

Inflammatory lung conditions which may be so treated and/or prevented include asthma and bronchitis (vide supra) and cystic flbrosis (which may also or alternatively involve the bowel or other tissue).

Inflammatory joint conditions which may be so treated and/or prevented include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions.

Inflammatory eye conditions which may be so treated and/or prevented include uveitis (including iritis) and conjunctivitis (vide supra).

In ^f lammatory bowel conditions which may be so treated and/or prevented include Crohn's disease and ulcerative colitis.

Inflammatory skin diseases which may be so treated and/or prevented include those associated with ceil proli ^f eration, such as psoriasis and eczema (vide supra) and dermatitis (whether or not of allergic origin).

Inflammatory conditions of the heart which may be so treated and/or prevented include coronary Infarct damage.

Other inflammatory conditions which may be so treated and/or prevented include tissue necrosis o chronic in ^f lammation and tissue rejection following transplant surgery.

It is ai«Λ believed that the compound o Ormula (I) and their physiologically acceptable salts are ef ^f ective agents in the prophylaxis and/or treatment o* bacterial and fungal infections, this forming a further aspect o* the present

In the case o* the treatment or prophylaxis o* in ^f lammatory airway conditions, a suitable anti-asthmatic dose o* a compound o* *ormula (?) is 1 mg to 10 mg o* base per kilogram, the most pre ^f erred dosage being 1 mg to 5 mg/kg of mammal bodyweight, Or example *rom 1 to 2 mg/kg.

While it is possible for an active ingredient to be administered alone, it is pre ^f erable to present it as a pharmaceutical formulation comprising a compound of formula (I') or a pharmacologically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier there*or. Such *ormulations consitute a *urther feature o* the present invention. Conveniently, the active ingredient comprises from 0.1% to 99.9% by weight of the formulation. Conveniently, unit doses of a 'ormulation contain between 0,1 mg and 1 g of the active ingredient. For topical administration, the active ingredient pre ^f erably comprises from 1% to 2% by weight o* the ^f ormulation but the active ingredient may comprise as much as 10% w/w. Formulations suitable for nasal or buccal administration, (such as sel^-propelling powder dispensing ^f ormulations described hereina ^f ter), may comprise 0.1 to 20% w/w, for example 2% w/w of active ingredient.

The formulations, both for veterinary and for human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier there*or and optionally other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense o* being compatible with the other ingredients o' the formulations and not deleterious to the recipient thereof.

The *ormulations include those in a *orm suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra- articular, topical, nasal or buccal administration.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Ail methods include the step o bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uni'ormly and intimately bringing the active ingredient into association with a liquid carrier or a *inely divided solid carrier or both, and then, i* necessary, shaping the product into the desired *ormulation.

Formulations o* the present invention suitable *or oral administration may be in the *orm of discrete units such as capsules, cachets, tablets or lozenges, each

containing a predetermined amount of the active ingredient; in the 'orm o' a powder or granules; in the form o* a solution or a suspension in an aqueous liquid 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 o* a bolus, electuary or paste.

A tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing *orm such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, sur ^f ace active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form o* a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the *orm o ^x an enema.

Formulations suitable or parenteral administration conveniently comprise a sterile aqueous preparation o the active ingredient which is preferably isotonic with the blood o* the recipient.

Formulations suitable for intra- articular administration may be in the form o* a sterile aqueous preparation o the active ingredient which may be in microcrystalline form, ^or example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient 'or both intra -articular and ophthalmic administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applications; oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. For example, *or ophthalmic administration, the active ingredient may be presented in the form of aqueous eye drops as, for example, a 0.1 - 1.0% solution.

Formulations suitable for administration to the nose or buccal cavity include powder, sel*- ropelling and spray *ormulations such as aerosols and atomizers. The formulations, when dispersed, pre ^f erably have a particle size in the range o* 10 to 200y.

Formulations o* the present invention may also be in the *orm o ^x an aqueous or dilute alcoholic solution, optionally a sterile solution, o* the active ingredient for use in a nebuϋser or atomiser, wherein an accelerated air steam is used to produce a *ine mist consisting o* small droplets o ^f the solution. Such formulations usually contain a ^f lavouring agent such as saccharin sodium and a volatile oil. A bu ^f fering agent and a sur ^f ace active agent may also be included in such a *ormulation which should also contain a preservative such as methylhydroxybenzoate.

Other *ormulations suitable *or nasal administration include a coarse powder having a particle size o* 20 to 500 microns which is administered in the manner in which snu** is taken i.e. by rapid inhalation through the nasal passage from a container o* the powder held close up to the nose.

In addition to the a ^f orementioned ingredients, the ^f ormulations o* this invention may include one or more additional ingredients such as diluents, bu ^y ers, ^f lavouring agents, binders, sur ^f ace active agents, thickeners, lubricants, preservatives eg. methylhydroxybenzoate (including anti-oxidants), emulsi ^f ying agents and the like. Any other therapeutic ingredient may comprise one or more o* the following: antibiotic, anti-*ungal and anti-viral agents.

For delaying senesence o* cut or picked plant matter, or *or controlling plant growth, the compounds o* formula (I') and their salts are preferably presented in a suitable compostion, optionally containing one or more other agents for enhancing the freshness of the plants. Such compositions include solutions and suspensions o* the compound in a suitable medium such as an aqueous medium.

The compositions may be applied by immersing part (eg the cut end) or whole of the plant or by spraying the plants be*ore ar a^ter cutting or picking, or by application to the root structure before or after picking. The compounds may also be applied by being spread on the soil prior to cutting or picking and conveyed to the plant roots by rainwater, or by other watering means.

When applied in aqueous solution, the compounds may be presented in a concentration o' 'rom lyM to 1M, *or example lOOyM to lOOmM. A typical concentration might be about ImM.

The compounds a' 'ormula (I) and their salts may be prepared by the allowing process which constitutes a 'urther aspect o* the present ⁱ nvent ⁱ on:-

- .-

a) for the preparation o* compounds of *ormula (I) wherein R represents hydrogen, reaction o* a compound o ^£ 'ormula (II)

R ⁴ R ³ CON OZ (II)

(wherein one of R and R is a group of formula Ar-(X)>,-Y-; Ar, X, Y and k being as defined in ^ormula (I), and the other is a group of formula R 2 as de ^f ined in formula (I), and Z is an appropriate protecting group) with an agent or agents serving to e"ect removal o* the protecting group Z;

b) for the preparation o' a compounds of formula (I) wherein R^ represents hydrogen, reaction o* a compound o* 'ormula (III)

R ³ NHOH (III)

with a compound α* ^f ormula (IV)

R ⁴ COX (IV)

3 4 wherein R and R are as hereinbe ^f ore de ^f ined and X represents an appropriate leaving group); or

c) for the preparation of compounds o formula (I) wherein n is 1, m is 0 and R represents hydrogen, reaction of a compound of formula (V)

R ⁵ CHO (V)

(wherein R represents a group of formula Ar-(X). -Y-; Ar, X, Y and k being as defined in ^f ormula (I)) with Piloty's acid, ie. the compound o* formula PhS0 ₂ NHOH;

and optionally if desired, e ^j ecting one or more o* the *ollowing inter- conversions in any desired order:-

(i) converting a compound α* *orrnuia (I) wherein R represents hydrogen to a corresponding compound wherein R represents a C, _^ alkyl group;

(ii) converting the compound o* 'ormula (I) to a corresponding salt thεreo*.

In process (a), pre ^f erred protecting groups include benzoyl, acetyl, benzyl, trityl and tetrahydropyranyl. The protecting group may be removed by treatment with acid or base or by hydrogenation,as appropriate.

In process (b), the leaving group may *or example be a halogen (eg chlorine, bromine or iodine), alkoxy or alkoxycarbonyloxy.

Process (c) is desirably e ^j ected in the presence o* a base such as an alkali metal hydroxide or alkoxide, eg sodium hydroxide or sodium methoxide.

Optional conversion (i) may *or example be ef ^f ected by reaction with an appropriate alkyl halide or sulphate in the presence o* a mild base.

Optional conversion (ii) conveniently may be e*fected by reaction with an appropriate organic or mineral acid, or with a base.

Salts derived *rom acids include the acetate, adipate, alginate, aspartate, beπzoate, benzenesulphonate, bisulphate, butyrate, citrate, camphorate, camphorsulphonate, cyclopentanepropionate, digluconate, dodecylsulphate, ethanesulphonate, fumarate, glucoheptanoate, glycerophos-phate, hemisulphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulphonate, lactate, maleate, methanesulphonate, 2- naphthaienesulphonate, nicotinate, oxalate, palmoate, pectinate, persulphate, 3-phenyl-proprionate, picrate, pivalate, proprionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include ammonium salts, alkali metal salt3 such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.

Quaternary ammonium salts can be 'ormed where a nitrogen-containing group is present, 'or example by reaction with lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulphates, long chain

- -

haiides such as decyl, lauryl, myristyi and stearyl chlorides, bromides and iodides, aralkyl haiides like benzyl and phenethyl bromides.

According to the present invention there are there ^f ore provided: -

(a) a novel compound o* formula (I) or an acid addition salt thereo*;

(b) a method for preparing a compound of formula (I) or a pharmacologically acceptable acid addition salt thereo*;

(c) a pharmaceutical formulation comprising a non- toxic, e ^f fective arachidonic acid oxygenation inhibitory amount o* a compound of formula (I') or a pharmacologically acceptable acid addition salt thereo* and a pharmaceutically acceptable carrier therefor;

(d) a method for preparing such formulations;

(e) a method for the inhibition o the lipoxygenase and cyclooxygenase pathways of arachidonic acid metabolism comprising the administration o* a non-toxic, e ^l ective, inhibitory amount of a compound of formula (P) or a pharmacologically acceptable acid addition salt thereof; and

(*) a method *or the prophylaxis or treatment o* inflammation in a mammal, including man, comprising the administration to said mammal of a ^' non-toxic, ef ^f ective anti-inflammatory amount of a compound o* formula (P) or a pharmacologically acceptable acid addition salt thereo*;

(g) a method for the prophylaxis or treatment o* pain in a mammal, including man, comprising the administration to said mammal of a non-toxic e ^f fective analgesic amount o* a compound o* ^f ormula (P) or a pharmacologically acid addition salt thereof;

(h) a method for the prophylaxis or treatment o* pyresis in a mammal, including man, comprising the administration to said mammal of a non-toxic, effective anti-pyretic amount of a compound of formula (P) or a pharmacologically acceptable acid addition salt thereof;

(i) a method for the prophylaxis or treatment of asthma in a mammal, including man, comprising administration to said mammal of a non-toxic, effective, anti-asthmatic amount of a compound of formula (P) or a pharmacologically acceptable acid addition salt thereof;

(j) a compound of formula (P) or a pharmacologically acceptable acid addition salt thereof for use in medicine in the inhibition of the lipoxygenase and cyclooxygenase pathways o* arachidonic acid metabolism; and

(k) a method of regulating the growth of, or delaying senescence in vegetable matter by application to said matter of an ef ^f ective amount of a compound of formula (P) or a salt thereof.

The *αllowing Fxamples are provided by way of an illustration o* the present invention and should in no way be construed as a limitation thereo*. Ail temperatures indicated are in degrees Celsius.

Fxample 1

Preparation o* N-methyl-3-(2-naphthyloxy)propanohydroxamic acid

Triethylamine (2.8 ml) was added to a solution o* 3-(2-naphthyloxy)propanoic acid (4.32g) in dry tetrahydro*uran (25 ml) at 0°, under nitrogen. The mixture was stirred and ethyl chioro*αrmate (2 ml) was added dropwise over 10 mins., the temperature then being maintained at 0° *or a further 15 mins. The reaction mixture was treated with a mixture containing N-methylhydroxylarnine hydrochloride (5.1g), triethylamine (8.4 ml), tetrahydro*uran (15 ml) and water (10 ml) which had previously been cooled to 0°. Stirring was continued at 0° for 15 mins. and then at ambient temperature for 20 hours. The reaction mixture was evaporated to one third volume and then water (50 ml) was added. The crude product was isolated by extraction with ethyl acetate followed by washing with 2N1 hydrochloric acid and water, drying over anhydrous sodium sulphate and evaporation. Recrystailisation *rom ethyl acetate - light petroleum (60-80 ) a*forded N-methyl-3-(2-naphthyloxy)propanohydroxamic acid (3.02g), m.p. 127-129°.

Fxample 2

Preparation o* N-.2-(2-naphthyloχy)ethyl3acetohydroxamic acid

a) Preparation o* Q-benzyl N-.2-(2-naphthyloxy)ethy_3acetohydroxarnate

A stirred mixture o* O-benzyl acetohydroxamate (2g),2-(2- bromoethoxy)naphthalene (3.04g), finely powdered, anhydrous potassium carbonate (1.92g) and acetone (100 ml) was heated under re*lux for 5 days, with the exclusion of moisture. The reaction mixture was allowed to cool to ambient temperature and then filtered. Fvaporation of the filtrate followed by isolation with ether yielded crude O-benzyl j -[2-(2-naphthyloxy)ethyl3acetohydroxamate (4.22g) as an oil

b) Preparation o* N-.2-(2-naphthyloxy)ethyl3acetohydroχamic acid

A mixture of crude O-benzyl N-[2-(2-naphthyloxy)ethyi3acetohydroxamate (4.22g), 10% palladium on charcoal catalyst (0.5g), glacial acetic acid (12 drops) and absolute ethanol (150 ml) was hydrogenated at ambient temperature and pressure until hydrogen uptake had ceased. The mixture was *iltered and the filtrate evaporated to obtain the crude product as an oil. Purification by flash chromatography over silica gel (elution with chloroform-methanol, 99:1) and rεcrystallisation from ethyl acetate - light petroleum (60-80°) afforded N-[2-(2- naphthyloxy)ethyI3acetohydroxamic acid (O.Slg), m.p. 101-103°.

Fxample 3

Preparation o* N-methyl-2-(l-naphthyloxy)acetohydroχamic acid

Triethylamine (2.8 ml) was added to a solution of 2-(l-naphthyloxy)acetic acid (4.04 g) in dry tetrahydro*uran (25 ml) at 0°, under nitrogen. The mixture was stirred and ethyl chloroformate (2 ml) was added dropwise over 10 mins., the temperature then being maintained at 0° for a further 15 mins. The reaction mixture was treated with a mixture containing N-methylhydroxylamine hydrochloride (5.1g), triethylamine (8.4 ml), tetrahydrofuran (15 ml) and water (10 ml) which had previously been cooled to 0°. Stirring was continued at 0° ^f or 15 mins. and then at ambient temperature for 30 mins. The reaction mixture was evaporated to one third volume and then water (50 ml) was added. The crude product was isolated by extraction with ethyl acetate followed by washing with 2M hydrochloric acid and water, drying over anhydrous sodium sulphate and evaporation. Recrystallisation from 95% ethanol a**orded N- methyl-2-(l-naphthyloxy)acetohydroxamic acid (1.2g), m.p. 155-157°.

Exampl e 4

Preparation of N- [ 2- (2-Naphthylthio) ethyl] acetohydroxamic acid

(A) Preparation of 2-(2-naphthylthio) acetaldehyde

Bromoacetal (4.925g) was added over 5 min to a solution of 2-thionaρhthol (4.4g) and potassium t _^ -butoxide (3.22g) in dimethyl sulphoxide (25ml) at room temperature under nitrogen. The mixture was stirred for 2 h, then left overnight. Addition of water, and isolation with ether afforded the acetal (6.5g) as an oil. Without pu ification, the acetal was stirred and heated under reflux for 4 h with acetone (70ml) and 2M hydrochloric acid (20ml) under nitrogen. Evaporation, and isolation with ether furnished 2- (2-naphthylthio) acetaldehyde (c_a 4.75g) as a yellow oil.

(B) Preparation of N- [2- (2-naρhthylthio) ethyl]- acetohydroxamic acid

A suspension of crude 2- (2-naphthylthio) acetaldehyde (4.75g) , sodium acetate (1.93g) and hydroxyla ine hydrochloride (1.64g) in ethanol (40ml) was stirred for 4 h at room temperature, then evaporated in vacuo. Addition of water and isolation with chloroform provided the oxime as an orange oil which slowly solidified (Rf 0.59 on silica gel; elution with 10:1 chloroform : methanol) .

Sodium cyanborohydride (1.63g) was added over 15 min to a solution of the last-mentioned crude oxime (5,lg) in acetic acid (40ml) and acetic anhydride (4.4ml) under nitrogen, and the mixture was then stirred for 4 h. Addition of water and isolation with ether gave crude O-acetyl-N- [2- (2-naρhthylthio) ethyl] acetohydroxamic acid (5g) as a yellow oil.

This 0, N-diacetyl compound was stirred in

methanol (100ml) with potassium carbonate (2.5g) for 10 min at room temperature. Evaporation, addition of water, and isolation with ether afforded N-[2- (2-naphthylthio) ethyl] acetohydroxamic acid (2.49g) , .pt 94-96°C after recrystallization from ethyl acetate.

Example 5

Preparation of N- [3-(2-Naphthyl) propyl] acetohydroxamic

Acid

(A) Preparation of O-benzyl-N-[3- (2-naphthyl)propyl] - acetohydroxamic acid

A mixture of 3-(2-naphthyl) ropyl bromide (2.89g) , benzyl acetohydroxamate(1.98g) and potassium carbonate (1.843g) in acetone (100ml) was heated under reflux for 5 days, then filtered. Evaporation of the filtrate afforded the O-benzyl derivative, which was purified by chromotography over silica gel and elution with 1 1::11 eetthhyyll aacceettaattee:: lliigghhtt ppeettrroolleeuumm ((bb..ppt 60-80°) The pure product (2.25g) was a yellow-brown oil.

( ^B ) Preparation of N-[3- (2-naρhthyl)propyl] - acetohydroxamic acid

A mixture of the O-benzylhydroxamic acid above (ca 2.2g), methylene chloride (15ml), dimethyl sulphide (10ml) and boron trifluoride etherate (5ml) was stirred overnight at room temperature, then evaporated under nitrogen. Addition of sodium bicarbonate solution and isolation with ether furnished N- [3- (2-naρhthyl) propyl] acetohydroxamic acid (0.6g), m.pt. 146-148° (from ethyl acetate) .

Exa ples 6 to 15

The following compounds were prepared by the methods of Examples 4 and 5:

Example Compound M.pt( C)

No.

6 N- (2-phenoxyethyl) acetohydroxamic acid 85 - 87

7 N- (3-phenoxypropyl) acetohydroxamic acid 122 - 123

8 N- (4-phenoxybutyl) acetohydroxamic acid 112 - 114

9 N-{1- [4- (2-methylpropyl) henyl] ethyl}aceto- hydroxamic acid 93 - 95

10 N- (1-naphthyloxymethyl) acetohydroxamic acid 121 - 122

11 N- (2-naphthyloxymethyl) acetohydroxamic acid 112 - 114

12 N- [2-(2-naphthyloxy)ethyl]-2-methylρropano- hydroxamic acid 136 - 138

13 N-[4- (2-methylpropyl)phenylmethyl]-2,2- dimethylpropanohydroxamic acid 108 - 109

14 N-(phenylmethyl) acetohydroxamic acid 121 - 123

15 N- [4-(2-methylpropyl)phenylmethyl] acetohydroxamic acid 89 - 90

Fxamplelβ Preservation o* Cut Flowers

The compound o* Fxample 1 was made up as a 1 mM solution and the cut stem ends of cut carnations were immersed in the resultant solution in order to prolong their freshness.

Pharmaceutical Formulations

In the following formulation Fxamples, the "Active Ingredient" may be any compound of formula (I ¹ ) or a physiologically acceptable salt thereo ^f .

Fxample A: Tablet:

In one tablet

Active Ingredient 5.0 mg

Lactose 82.0 mg

Starch 10.0 mg

Povidone 2.0 mg

Magnesium Stearate 1.0 mg

Mix together the active ingredient, lactose and starch. Granulate the powders using a solution of povidone in purified water. Dry the granules, add the magnesium stearate and compress to produce tablets, lOOmg per tablet.

Fxample B: Ointment

Active Ingredient 1.0 g

White So*t Paraf*in to 100.0 g

Disperse the active ingredient in a small volume of the vehicle. Gradually incorporate this into the bulk to produce a smooth, homogeneous product. Fill into collapsible metal tubes.

Fxample C: Cream *or Topical Use

Active Ingredient 1.0 g

Polawax GP 200 20.0 g

Lanolin Anhydrous 2.0 g

White Beeswax 2.5 g

Methyl Hydroxybenzoate 0.1 g

Distilled Water to 100.0 g

Heat the Polawax, beeswax and lanolin together at 60°C. Add a solution of methyl hydroxybenzoate. Homogenise using high speed stirring. Allow the temperature to fall to 50°. Add and disperse the active ingredient. Allow to cool with slow speed stirring.

Fxample D: Lotion *or Topical Use

Active Ingredient 1.0 g

Sorbitan Monolaurate 0.6 g

Polysorbate 20 0.6 g

Cetostearyl Alcohol 1.2 g

Glycerin 6.0 g

Methyl Hydroxybenzoate 0.2 g

Puri ^f ied Water B.P. to 100.00 ml

The methyl hydroxybenzoate and glycerin were dissolved in 70mi of the water at 75 C. The sorbitan monolaurate, Polysorbate 20 and cetostearyl alcohol were melted together at 75 C and added to the aqueous solution. The resulting emulsion was homogenised, alowed to cool with continuous stirring and the active ingredient added as a suspension in the remaining water. The whole was

Fxample F: Fye Drops

Active Ingredient 0>5 g

Methyl Hydroxybenzoate 0.01 g

Propyl Hydroxybenzoate 0-0 _

Purified Water B.P. to 100.00 ml

The methyl and propyl hydroxybenzoates were dissolved in 70ml purified water at 75° and the resulting solution then allowed to cool. The active ingredient was added next and the solution made up to 100ml with purified water. The solution was sterilised by filtration through a membrane filter 0.22 y pore size and packed aseptically into suitable sterile containers.

Fxample F: Injection Solution

Active Ingredient 10.0 mg

Water for Injections B.P. to 1.0 ml

The active ingredient was dissolved in hal* of the Water *or Injections and then made up to volume and sterilised by filtration. The resulting solution was distributed into ampoules under asceptic conditions.

In vitro inhibition o* 5-lipoxyqenase (LO) and Cyclooxygenase (CO)

Blood from normal aspirin-free volunteers was centrifuged to separate leukocytes from red cells and platelets. The leukocytes were homogenised and 5 JvJ arachidonic acid added, followed by incubation at 37° for 5 minutes. The reaction was stopped by boiling. Radϊoimmunassay was conducted for leukotriene B^ (an LO product) and thromboxane B^ (a CO product). Results were calculated as IC--yM activity against each enzyme and as listed below.

Compound Activity (yM)

Fxample No. CO LO

1 >10 0.6

2 >10 1.0

3 >10 2.0