WO1987004152A1

WO1987004152A1 - New aryl derivatives

Info

Publication number: WO1987004152A1
Application number: PCT/GB1986/000791
Authority: WO
Inventors: Geoffrey Kneen; William Paul Jackson; Peter John Islip
Original assignee: The Wellcome Foundation Ltd.
Priority date: 1985-12-30
Filing date: 1986-12-23
Publication date: 1987-07-16
Also published as: EP0250530A1; JPS63502179A; GB8531838D0

Abstract

Compounds of formula (I) where k 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 C1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C1-4 alkoxy, halo, nitro, amino, carboxy, C1-4 alkoxycarbonyl and hydroxy; X represents oxygen or sulphur; Y is C1-6 alkylene; and R1 and R2 are independently selected from hydrogen and C1-4 alkyl; and salts thereof for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body have lipoxygenase and cyclooxygenase inhibiting properties.

Description

NEW ARYL DFRIVATIVFS

The present invention relates to novel compounds, to methods of 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-inflammatory 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 fication 3 740 437 or in Proc. Ann. Symp. Inst. Basic Med. Sci, Royal College of Surgeons of England, October 1982, pp 263-274. Compounds described in the latter reference include the compound known as nafazatrom. It has also been demonstrated previously that certain hydroxamates have cyclo-oxygenase and/or lipoxygenase inhibitory activity. Surprisingly, we have now found that the compounds af formula (I) as defined hereinbelow, are potent dual inhibitors of the lipoxygenase and/or cyclo-oxygenase enzymes and have useful anti-inflammatory and other properties.

In formula (I)

k 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 C _1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C₁ alkoxy, halo, nitro, amino, carboxy, C_1-4alkoxycarbonyl and hydroxy;

X represents oxygen or sulphur;

Y is C_1-6 alkylene; and R¹ and R² are independently selected from hydrogen and C _1-4 alkyl; and salts thereof ;

provided that:-

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

(ii) when Ar represents unsubstituted phenyl, n is 0 and m is 1, R¹ and R ² are both hydrogen, k is 1 and X represents oxygen, or when k is 0, then Y does not represent -(CH₂)₂-;

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

then when R¹ is hydrogen and R² is methyl, Y does not represent a straight alkylene chain having from 2-4 carbon atoms,

and when R¹ is methyl, and R² is hydrogen and Y contains 3 carbon atoms, then Y represents -(CH₂)₃-;

(iv) when Ar represents phenyl, n is 0 and m is 1, k is 0, R₁ and R₂ are both hydrogen and Y represents -(CH₂)₂-, 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 R¹ and R² 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

R¹ and R² 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 -(CH₂)₂-, 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 R¹ and R² are both hydrogen,

then Y does not represent methylene,

and when Y has 2 carbon atoms, Y represents -(CH₂)₂- or when Y has 4 carbon atoms, Y represents -(CH₂)₄-.

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

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

(i) Ar represents phenyl optionally substituted by one or more substituents selected from C_1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C_1-4 alkoxy, halo, nitro, amino, carboxy, C_1-4 alkoxycarbonyl and hydroxy;

(ii) Ar represents naphthyl optionally substituted by one or more substituents selected from C_{1- 4} alkyl (which may itself optionally be substituted by one or more halogen atoms), C_1-4 alkoxy, halo, nitro, amino, carboxy, C_1-4 alkoxycarbonyl 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 of formula (I) include the following and salts thereof :

N-methyl-3-(2-naphthyloxy) propanohydroxamic acid N-[2-(2-naphthyloxy)ethyl]acetohydroxamic acid N-methyl-2-(1-naphthyloxy)acetohydroxamic acid N-(2-naphthyloxymethyl)acetohydroxamic acid N-[3-(2-naphthyloxypropyl]acetohydroxamic acid N-[4-(2-naphthyloxy)butyl]acetohydroxamic acid N-[2-(2-naphthylthio)ethyl]acetohydroxamic acid N-[3-(2-naphthyl)propyl]acetohydroxamic acid 3-(2-naphthyloxy)propanohydroxamic acid N-[2-(2-naphthyloxy)ethyl]formohydroxamic acid N-[(2-methyl-1-naphthyloxy)methyl]acetohydroxamic acid N-[(2-nitro-1-naphthyoxy)methyl]acetohydroxamic acid N-(2-(3-carboxy-2-Naphthyloxy)ethyl]acetohydroxamic acid O-methyl-N-[2-naphthyloxy)ethyl]acetohydroxamic acid N-[2-(2-naphthyloxy)ethyl]butanohydroxamic acid N-[1-(2-naphthyloxymethyl)ethyl]acetohydroxamic acid N-[2-(6-bromo-2-naphthyloxy)ethyl] aceto hydroxamic acid N-[2-(6-hydroXy-2-naphthyloxy)ethyl] aceto hydroxamic acid N-[2-(6-methoxy-2-naphthyloxy}ethyl) aceto hydroxamic acid N-(1-naphthyloxymethyl) aceto hydroxamic ac id N-(4-methoxy-1-naphthyloxymethyl) 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 of treatment of the human or animal body by therapy, or of diagnosis. In formula (I')

k 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 C_{1 -4} alkyl (which may itself optionally be substituted by one or more halogen atoms), C _1-4 lkoxy, halo, nitro, amino, carboxy, C _1-4 alkoxycarbonyi and hydroxy;

X represents oxygen or sulphur;

Y is C_{1 -6} alkylene; and

R¹ and R² are independently selected from hydrogen and C_{1 -4} alkyl; and salts thereof.

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 of medical therapeutic and/or prophylactic (as appropriate) agents. The kinds By virtue of their enzyme inhibitory effects, the compounds of formula (I') 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 (I' ) or a salt thereof.

The term senescence refers to the process whereby plant matter decays, especially after being picked, cut or otherwise removed from 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') and their salts may also be used for the preservation of picked fruits.

For medical use, the amount required of a compound of formula (I') (hereinafter referred to as the active ingredient) to achieve a therapeutic effect will, of 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 of a compound of formula (I') for a mammal suffering from an inflammatory, painful or pyretic condition as defined hereinbefore is 0.1 μg500mg 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 of topical administration, eg. to the skin or eye, a suitable dose may be in the range 0.lng - 100μg of base per kilogram, typically about 0.1 μg/Kg. of medical therapy and prophylaxis pertinent to the foregoing and there fore in that sense comprising part of the present invention, are elaborated by way of 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.

virtue of their lipoxygenase inhibitory properties, said compounds and salts fi nd application in the treatment and/or prophylaxis of 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 spasm or 'stroke'. Other examples include bowel disease caused by abnormal colonic muscular contraction such as may be termed 'irritable bowel syndrome', 'spastic colon' or 'mucous colitis'.

Examples 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 hayfever (which may additionally or alternatively affect the upper respiratory tract) and allergic conjunctivitis. Examples of the aforesaid tumours are skin neoplasms, both benign and malignant.

Examples 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).

Examples 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).

Examples 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 fibrosis (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).

Inflammatory 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 cell proliferation, 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 of chronic inflammation and tissue rejection following transplant surgery.

It is also believed that the compound of formula (I) and their physiologically acceptable salts are effective agents in the prophylaxis and/or treatment of bacterial and fungal infections, this forming a further aspect of the present In the case of the treatment or prophylaxis of inflammatory airway conditions, a suitable anti-asthmatic dose of a compound of formula (I') is 1 mg to 10 mg of base per kilogram, the most preferred dosage being 1 mg to 5 mg/kg of mammal bodyweight, for example from 1 to 2 mg/kg.

While it is possible for an active ingredient to be administered alone, it is preferable 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 therefor. Such formulations consitute a further feature of the present invention. Conveniently, the active ingredient comprises from 0.1% to 99.9% by weight of the formulation. Conveniently, unit doses of a formulation contain between 0,1 mg and 1 g of the active ingredient. For topical administration, the active ingredient preferably comprises from 1% to 2% by weight of the formulation but the active ingredient may comprise as much as 10% w/w. Formulations suitable for nasal or buccal administration, (such as self-propelling powder dispensing formulations described hereinafter), 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 therefor and optionally other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.

The formulations include those in a form 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. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of 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 of 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 form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface 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 of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

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

Formulations suitable for intra-articular 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 may also be used to present the active ingredient for 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, for 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, self-propelling and spray formulations such as aerosols and atomizers. The formulations, when dispersed, preferably have a particle size in the range of 10 to 200μ. Formulations of the present 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 nebuliser or atomiser, wherein an accelerated air steam is used to produce a fine mist consisting of small droplets of the solution. Such formulations usually contain a flavouring agent such as saccharin sodium and a volatile oil. A buffering agent and a surface active agent may also be included in such a formulation which should also contain a preservative such as methylhydroxybenzoate.

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

In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives eg. methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like. Any other therapeutic ingredient may comprise one or more of the following: antibiotic, anti-fungal and anti-viral agents.

For delaying senesence of cut or picked plant matter, or for controlling plant growth, the compounds of 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 of 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 before ar after 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 of from 1μM to 1M, for example 100μM to 100mM. A typical concentration might be about 1mM.

The compounds of formula (I) and their salts may be prepared by the allowing process which constitutes a further aspect of the present invention:- a) for the preparation of compounds of formula (I) wherein R¹ represents hydrogen, reaction of a compound of formula (II)

(wherein one of R³ and R⁴ is a group of formula Ar-(X)_k-Y-; Ar, X, Y and k being as defined in formula (I), and the other is a group of formula R² as defined in formula (I), and Z is an appropriate protecting group) with an agent or agents serving to effect removal of the protecting group Z;

b) for the preparation of a compounds of formula (I) wherein R¹ represents hydrogen, reaction of a compound of formula (III)

R³NHOH (III)

with a compound of formula (IV)

R⁴COX (IV)

wherein R³ and R⁴ are as hereinbefore defined and X represents an appropriate leaving group); or

c) for the preparation of compounds of formula (I) wherein n is 1, m is O and R¹ represents hydrogen, reaction of a compound of formula (V)

R⁵CHO (V)

(wherein R⁵ represents a group of formula Ar-(X)_k -Y-; Ar, X, Y and k being as defined in formula (I)) with Piloty's acid, ie. the compound of formula PhSO₂NHOH;

and optionally if desired, effecting one or more of the following interconversions in any desired order:- (i) converting a compound αf forrnuia (I) wherein R¹ represents hydrogen to a corresponding compound wherein R¹ represents a C_{1 -4} alkyl group;

(ii) converting the compound of formula (I) to a corresponding salt thereof.

In process (a), preferred 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 for example be a halogen (eg chlorine, bromine or iodine), alkoxy or alkoxycarbonyloxy.

Process (c) is desirably ejected in the presence of a base such as an alkali metal hydroxide or alkoxide, eg sodium hydroxide or sodium methoxide.

Optional conversion (i) may for example be effected by reaction with an appropriate alkyl halide or sulphate in the presence of a mild base.

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

Salts derived from acids include the acetate, adipate, alginate, aspartate, benzoate, 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 salts 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 formed where a nitrogen-containing group is present, for 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 therefore provided:-

(a) a novel compound of formula (I) or an acid addition salt thereof;

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

(c) a pharmaceutical formulation comprising a non-toxic, effective arachidonic acid oxygenation inhibitory amount of a compound of formula (I') or a pharmacologically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier therefor;

(d) a method for preparing such formulations;

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

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

(g) a method for the prophylaxis or treatment of pain in a mammal, including man, comprising the administration to said mammal of a non-toxic effective analgesic amount of a compound of formula (I') or a pharmacologically acid addition salt thereof;

(h) a method for the prophylaxis or treatment of 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 (I') 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 (I') or a pharmacologically acceptable acid addition salt thereof;

(j) a compound of formula (I') or a pharmacologically acceptable acid addition salt thereof for use in medicine in the inhibition of the lipoxygenase and cyclooxygenase pathways of 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 effective amount of a compound of formula (I') or a salt thereof. The following Examples are provided by way of an illustration of the present invention and should in no way be construed as a limitation thereof. All temperatures indicated are in degrees Celsius.

Example 1

Preparation of N-methyl-3-(2-naphthyloxy)propanohydroxamic acid

Triethylamine (2.8 ml) was added to a solution of 3-(2-naphthyloxy)propanoic acid (4.32g) in dry tetrahydrofuran (25 ml) at 0°, under nitrogen. The mixture was stirred and ethyl chioroformate (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-methylhydroxylarnine 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° 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 2M hydrochloric acid and water, drying over anhydrous sodium sulphate and evaporation. Recrystallisation from ethyl acetate - light petroleum (60-80 ) afforded N-methyl-3-(2-naphthyloxy)propanohydroxamic acid (3.02g), m.p. 127-129°.

Example 2

Preparation of N-[2-(2-naphthyloxy)ethyl]acetohydroxam ic acid

a) Preparation of O-benzyl N-[2-(2-naphthyloxy)ethy_]acetohydroxarnate

A stirred mixture of O-benzyl acetohydroxamate (2g),2-(2-bromoethoxy)naphthalene (3.04g), finely powdered, anhydrous potassium carbonate (1.92g) and acetone (100 ml) was heated under reflux for 5 days, with the exclusion of moisture. The reaction mixture was allowed to cool to ambient temperature and then filtered. Evaporation of the filtrate followed by isolation with ether yielded crude O-benzyl N-[2-(2-naphthyloxy)ethyl]acetohydroxamate (4.22g) as an oil b) Preparation of N-[2-(2-naphthyloxy)ethyl]acetohydroxamic acid

A mixture of crude O-benzyl N-[2-(2-naphthyloxy)ethyl]acetohydroxamate (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 filtered 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 recrystallisation from ethyl acetate - light petroleum (60-80°) afforded N-[2-(2-naphthyloxy)ethyI]acetohydroxamic acid (0.81g), m.p. 101-103°.

Example 3

Preparation of N-methyl-2-(1-naphthyloxy)acetohydroxamic acid

Triethylamine (2.8 ml) was added to a solution of 2-(1-naphthyloxy)acetic acid (4.04 g) in dry tetrahydrofuran (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° for 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 afforded N-methyl-2-(1-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 purification, 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 (ca 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 hydroxylamine 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 (5,1g) 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 O, 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), m.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) propyl 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 ethyl acetate: light petroleum (b.pt 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). Examples 6 to 15

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

Example Compound M.pt(ºC)

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)phenyl]ethyl}acetohydroxamic 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-methylpropano- 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 Example16 Preservation of Cut Flowers

The compound of Example 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') or a physiologically acceptable salt thereof.

Example 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, 100mg per tablet.

Fxamp le B : Ointment

Active Ingredient 1.0 g

White Soft Paraf fin 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. Example C: Cream for 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.

Example D: Lotion for 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

Purified Water B.P. to 100.00 ml

The methyl hydroxybenzoate and glycerin were dissolved in 70mi of the water at 75ºC. The sorbitan monolaurate, Polysorbate 20 and cetostearyl alcohol were melted together at 75ºC 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 Example E: Eye Drops

Active Ingredient 0.5 g

Methyl Hydroxybenzoate 0.01 g

Propyl Hydroxybenzoate 0.04 g

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 μ pore size and packed aseptically into suitable sterile containers.

Example F: Injection Solution

Active Ingredient 10.0 mg

Water for Injections B.P. to 1.0 ml

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

In vitro inhibition of 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 5μM arachidonic acid added, followed by incubation at 37° for 5 minutes. The reaction was stopped by boiling. Radϊoimmunassay was conducted for leukotriene B₄ (an LO product) and thromboxane B₄ (a CO product). Results were calculated as IC₅₀μM activity against each enzyme and as listed below. Compound Activity (μM)

Fxample No. CO LO

1 >10 0.6

2 >10 1.0

3 >10 2.0

Claims

1. A compound of formula (I):

k 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 C_1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C_1-4 alkoxy, halo, nitro, amino, carboxy, C_1-4 alkoxycarbonyl and hydroxy;

X represents oxygen or sulphur;

Y is C_1-6 alkylene; and

R ¹ and R² are independently selected from hydrogen and

C_1-4 alkyl; and salts thereof;

provided that:-

(ii) when Ar represents unsubstituted phenyl, n is 0 and m is 1, R¹ and R² are both hydrogen, k is 1 and X represents oxygen, or when k is 0, then Y does not represent -(CH₂)₂-; (iii) when Ar represents unsubstituted phenyl, n is 0 and m is 1, and k is 0,

then when R ¹ is hydrogen and R² is methyl, Y does not represent a straight alkylene chain having from

2-4 carbon atoms,

and when R ¹ is methyl, and R² is hydrogen and Y contains 3 carbon atoms, then Y represents -(CH₂)₃-;

(iv) when Ar represents phenyl, n is 0 and m is 1, k is 0, R ¹ and R² are both hydrogen and Y represents

-(CH₂)₂-, 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 R¹ 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 R¹ and R² 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 -(CH₂)₂-,

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 R² are both hydrogen,

then Y does not represent methylene,

2. A compound according to claim 1 wherein m is 1 and n is 0.

3. A compound according to claim 1 or claim 2 wherein Ar represents naphthyl optionally substituted by one or more substituents selected from C_1-4 alkyl (which may itself optionally be substituted by one or more halogen atoms), C_1-4 alkoxy, halo, nitro, amino, carboxy, C_1-4 alkoxycarbonyl and hydroxy.

4. A compound according to any one of claims 1 to 3 wherein k is 0.

5. A compound according to any one of claims 1 to 3 wherein k is 1 and X is oxygen.

6. A compound according to any one of claims 1 to 4 wherein Y is methylene or dimethylene.

7. A compound selected from

3-(2-naphthyloxy)propanohydroxamic acid N-[2-(2-naphthyloxy)ethyl]formohydroxamic acid

N-[3-(2-naphthyloxypropyl]acetohydroxamic acid

N-[(2-methyl-1-naphthyloxy)methyl]acetohydroxamic acid

N-[(2-nitro-1-naphthyoxy)methyl]acetohydroxamic acid N-[2-(3-carboxy-2-N-phthyloxy)ethyl]acetohydroxamic acid N-[4-(2-naphthyloxy)butyl]acetohydroxamic acid O-methyl-N-[2-naphthyloxy)ethyl]acetohydroxamic acid

N-[2-(2-naphthyloxy)ethyl]butanohydroxamic acid N-[1-(2-naphthyloxymethyl)ethyl]acetohydroxamic acid N-[2-(6-bromo-2-naphthyloxy)ethyl]aceto hydroxamic acid N-[2-(6-hydroxy-2-naphthyloxy)ethyl]aceto hydroxamic acid N-[2-(6-methoxy-2-naphthyloxy)ethyl] aceto hydroxamic acid N-(1-naphthyioxymethyl) aceto hydroxamic acid N-(4-methoxy-1-naphthyloχymethyl)aceto hydroxamic acid

N-methyl-3-(2-naphthyloxy)propanohydroxamic acid

N-[2-(2-naphthyloxy)ethyl]acetohydroxamic acid

N-methyl-2-(1-naphthyloxy) acetohydroxamic acid

N-[2-(2-naphthylthio)ethyl]acetohydroxamic acid

N-[3-(2-naphthyl)propyl]acetohydroxamic acid

N-(2-phenoxyethyl)acetohydroxamic acid

N-(3-phenoxypropyl)acetohydroxamic acid

N-(4-phenoxybutyl)acetohydroxamic acid

N-{1-[4-(2-methylpropyl)phenyl]ethyl]acetohydroxamic acid

N-(1-naphthyloxymethyl)acetohydroxainic acid

N-(2-naphthyloxymethyl)acetohydroxamic acid

N-[2-(2-naphthyloxy)ethyl]-2-methylpcopanohydroxamic acid

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

N-(phenylmethyl)acetohydroxamic acid and

N-[4-(2-methylpropyl)phenylmethyl]acetohydroxamic acid.

8. A compound of formula (I')

k is 0 or 1;

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

X represents oxygen or sulphur;

Y is C_1-6 alkylene; and

R ¹ and R² are independently selected from hydrogen and

C_{1 -4} alkyl; and salts thereof for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body.

9. A process for producing a compound of formula (I):

k is 0 or 1 ;

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

X represents oxygen or sulphur;

is C_1-6 alkylene; and

R ¹ and R² are independently selected from hydrogen and

C_1-4 alkyl; and salts thereof;

provided that:-

(ii) when Ar represents unsubstituted phenyl, n is 0 and m is 1, R ¹ and R² are both hydrogen, k is 1 and X represents oxygen, or when k is 0, then Y does not represent -(CH₂)₂-;

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

2-4 carbon atoms, and when R¹ is methyl, and R² is hydrogen and Y contains 3 carbon atoms, then Y represents -(CH₂)₃-;

(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 R ¹ and R² are both hydrogen,

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, XX represents oxygen and R ¹ and R² are both hydrogen, then Y does not represent methylene,

and when Y has 2 carbon atoms, Y represents - (CH₂) ₂ - or when Y has 4 carbon atoms, Y represents -(CH₂)₄-.

comprising

a) for the preparation of compounds of formula (I) wherein R¹ represents hydrogen, reaction of a compound of formula (II)

(wherein one of R ³ and R⁴ is a group of formula Ar-(X)_k-Y;

Ar, X, Y and k being as defined in formula (I), and the other is a group of formula R² as defined in formula (I), and Z is an appropriate protecting group) with an agent or agents serving to effect removal of the protecting group

Z;

b) for the preparation of a compound of formula (I) wherein R¹ represents hydrogen, reaction of a compound of formula (III)

R³NHOH (III)

with a compound of formula (IV)

R⁴COX (IV)

wherein R³ and R⁴ are as hereinbefore defined and X represents an appropriate leaving group); or c) for the preparation of compounds of formula (I) wherein n is 1, m is 0 and R¹ represents hydrogen, reaction of a compound of formula (V)

R⁵CHO (V)

(wherein R⁵ represents a group of formula Ar-(X)_k-Y; Ar, X, Y and k being as defined in formula (I)) with Piloty's acid, i.e. the compound of formula PhSO₂NHOH;

and optionally if desired, effecting one or more of the following inter-conversions in any desired order:-

(i) converting a compound of formula (I) wherein R¹ represents hydrogen to a corresponding compound wherein R¹ represents a C_1-4 group;

(ii) converting the compound of formula (I) to a corresponding salt thereof.

10. A process according to claim 9(a) wherein the protecting groups are selected from benzoyl, acetyl, benzyl, trityl and tetrahydropyranyl.

11. A process according to claim 9(b) wherein the leaving group is selected from chlorine, bromine, iodine, alkoxy and alkoxycarbonyloxy.

12. A process according to claim 9(c) effected in the presence of a base such as an alkali metal hydroxide or alkoxide.

13. A pharmaceutical formulation comprising a non-toxic effective amount of a compound of formula (I') as defined in claim 8 or a pharmacologically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier therefor.

14. A formulation according to claim 13 in unit dosage form.

15. A method for inhibiting the lipoxygenase and cycloxygenase pathways of arachidonic acid metabolism in a mammal comprising the administration to said mammal of a non-toxic effective inhibitory amount of a compound of formula (I') as defined in claim 8 or a pharmacologically acceptable acid addition salt thereof.

16. A method according to claim 15 for prophylaxis or treatment of inflammation, pain, pyresis or asthma in said mammal.