CA2141214A1 - Hydroxamic acid derivatives and their use as anti-inflammatory compounds - Google Patents

Abstract

The present invention is concerned with novel hydroxamic acid derivatives of formula (I) and their use in medical therapy particularly in the treatment of a clinical condition for which an inhibitor of the lipoxygenase or cyclooxygenase mediated ara-chadonic acid metabolic pathway is indicated. The invention also relates to pharmaceutical formulations and processes for the preparation of compounds according to the invention.

Description

~. , 21412i~

HYDROXAMIC ACID DERIVATIVES AND THEIR USE AS ANTI-INFLAMMATORY COMPOUNDS

The present invention is concerned with novel hydroxamic acid derivatives havinganti-infl~mm~tory activity, with processes for their prepala~ion, with pharm~ce~ltical formulations cont~ining said derivatives and with their use in medicine.

European Patent Specification 0196184 describes hydro~ll~ic acid derivatives having anti-infl~mm~tory activity by virtue of their ability to inhibit the enzymes 5-lipoxygenase and cyclooxygenase in the m~mm~ n arachidonic acid cascade. The compounds in question include those of formula OH
Ar-O-Ar'-Y-~
COR
wherein:
Ar is phenyl;
Ar ' is phenylene;
Y is C2 10 alkenylene;
R1 is C 1 4 alkyl, amino, C 1-4 alkylamino, or di-C 1 4 alkylamino;
and Ar and Ar' are optionally substituted by one or more substit~ltent~ independently selected from C1 4 alkyl (which may itself be optionally substituted by one or more halogen atoms), C 1-4 alkoxy, halo, nitro, amino, carboxy, C 1-4 alkoxycarbonyl and hydroxy.

EP 0299761 discloses phenoxyphenyl hydlo~ ic acid derivatives having lipoxygenase inhibiting activity.

International patent application WO 90/12008 describes urea based lipoxygenase inhibiting compounds inc~ lriing those of formula /OH
Rl-X-N~

AMEI\ DE~:) SHEET
IPEA/EP

wherein:

R1 is phenyl substituted by carbocyclic aryloxy optionally substituted by one, two, or three groups independently selected from halo, nitro, cyano, alkyl, alkoxy, and halosubstituted alkyl;

X is C2 6 alkenylene; and R ~ and R3 are independently selected from hvdrogèn, C 1-6 alkyl, and carbocyclic aryl.

International patent application W092/10469 describes hydroxamic acid derivatives, inr~ ing those of formuia /\ ,OH
B~ A~r C(O)R
wherein:

B is aryl or aryl substituted with one or more substituents selected from a group in~ t~in~ halo, cyano, aminoccuuollyl, Cl 6 alkylaminocarbonyl, di Cl 6 al~l~llinocarbonyl, and C 1-6 alkylsulphonyl;

A is alkynylene; and R1 is hydrogen, Cl~ alkyl, or -NR2R3 (wherein R2 and R3 are independently sPIected from hydrogen and C14 alkyl).

International patent application W092/01682 desclil,es acetylene derivatives, in~ ing those of formula OH
A-C_C-B-N-C(O)-R
wllt;~

A is phenyl optionally substituted by phenoxy (optionally s~hstit~tPd by Cl 6 alkyl, C 1~ haloalkyl, C 1-6 alkoxy, hyLo~y or halogen);

WO94/02448 2~14I2I4 PCI/GB93/01585 B is a bond or a straight or branched divalent C l 12 alkylene group; and Rl is hydrogen, Cl l2 alkyl, C3 8 cycloalkyl, or -NR2R3 (wherein R~and R3 are independently selectel from hydrogen and C 1 -6 alkyl) .

A group of compounds, related to those described in EP 0196184, WO 92110469, WO 92/01682, and WO 90/12008 has now been discovered which have use in the prophylaxis and tre~tem~nt of clinical conditions for which an inhibitor of the lipoxygenase or cyclooxygenase medi~ted arachadonic acid metabolic pathway is intiiC~t~

Therefore, according to the present invention, there is provided a group of compounds of forrnula (I) coD (I) wherein:

One/both of rings A and B is/are s~ ed by one or more groups independently s~lected from halo, cyano, -CONRlR2 (wherein Rl and R2 are independently selec~ed from hydrogen and C1~ alkyl), and -S(o)nR3 (wl~e~ n is an integer offrom 0 to 2, and R3 is Cl~ alkyl, C6 10 aryl, or Cg 12 aralkyl);

Y is -HC=CH- ((E) or (Z)), or -C_C-;

D is C1 4 alkyl or -NR4R5 (wherein R4 and R5 are independently selected from hydrogen and C 1-4 alkyl); and R is hydrogen or C I ,~ alkyl;

with the proviso that (i) at least one of the sllbstit~l~ntc on rings A and/or B is other than halo; and (ii) the compound of formula (I) is not N-hydluky-N-(i-methyl-3-{3-[4-(,l.t;LllylLl~io)ph~ o~y]phenyl}-2-p'ol~y~'yl)-urea;

WO 94/02448 7 4 PCr/GB93/015~

or a salt, solvate or physiologically functional derivative thereo It will be a,ople~,ated that some compounds of formula (I) and their salts may exist in (R) or (S) enantiomeric forms. The present invention therefore incluci~s within its scope each of the individual (R) and (S) enantiorners of the compounds of formula (I) and their salts substantially free, ie associ~ated with less than 5%, of the other enantiomer and mixtures of such enantiomers In any proportions in~ Aing racemic mixtures cont~ining substantially equal amwnts of the two enantiomers.

By the term halo is meant fluoro, chloro, bromo, or iodo; most preferably fluoro.

Ring A may be unsubstituted or s~lbstitllted by I to 5 groups independently selected from those listed in the definition of formula (I); pr~re,~bly, ring A is unsubstituted or is substituted by one group selected from halo, cyano, and -S02CH3.

Ring B may be unsubstituted or s~lbsl;luled by I to 4 groups indep~n-lently selected from those listed in the definition of formula (I); preferably, ring B is ul~sllb..liLIlted or is substituted by a cyano group.

Group Y may be ~tt~rlled to ring B at the 2-, 3-, or 4- position; preferably, the 3-position; relative to the -O- bridging group.

R is preferably methyl.

D is preferably methyl or amino; most plef~-~bly methyl.

According to a further aspect, the present invention provides col..~ounds of formula (Ia) A' ~ ~¢~--¦~ ~ COD' WO 94/02448 214121~ PCI/GB93/01585 wherein:

A' and B' are independently selectecl from hydrogen, halo, cyano, -CONRlaR2a (where Rla and R2a are independently selected from hydrogen and Cl 4 alkyl), and -S(o)mR3a (where m is an integer of from 0 to 2 and R3a is Cl 4 alkyl, C6 10 aryl, or C~ 12 aralkyl); and D' is Cl 4 alkyl or -NR4aR5a ~where R4a and RSa are independently selected from hydrogen and C 1-4 alkyl~; and R' is C 1_4 alkyl;

with the proviso that at least one of A' and B' is other than hydrogen or halogen;

or a salt, solvate, or a physiologically functional derivative thereof.

In a further aspect, the present invention provides compounds of formula (I) wherein is Cl 4 alkyl;

or a salt, solvate, or physiologically functional derivative thereof.

In a yet a further aspect, the present invention provides compounds of formula (I) wherein Y is -CH=CH-, preferably in the (E) configuration;

or a salt, solvate, or physiologically functional derivative thereo In a yet a further aspect, the present invention provides compounds of formula (I) wherein Y is -CH-CH-, and at least one of the sllbstitllPntc on ring A is other than halogen;

or a salt, solvate, or physiologically functional derivative thereo ,~
felled compounds of formula (I) include those wL~ u~:

214121~

One/both of rings A and B is/are substituted by one group selected from halo, cyano, and -SO~CH3;

Y is ~ rhed to ring B at the 3-position relative to the -O- bridging group;

R is methyl; and D is methyl or amino;

or a salt, solvate. or physiologically fi~nctional derivative thereof.

Particularly ~l~fel~ed compounds offormula (I) include:

(E)- I - ~ 3 -[3 -(4-cyanophenoxy)phenyl]- 1 -methylprop-2-enyl } - I -hydroxvurea;

(E)- 1- { 3 -[3 -(4-cyanophenoxy)phenyl]- 1 (R)-methylprop-2-enyl } - I -hydroxvurea;

(E)-1-{3-[3-(4-cyanophenoxy)phenyl]-l(S)-methylprop-2-enyl}-1-hydroxvurea;

(E)- I - { 3 -~4-Cyano-3 -phenoxyphenyl]- I -methylprop-2-enyl } -1 -hydroxyurea;

(E)- I - { 3 -[2-Cyano-5-phenoxyphenyl]- I -m~Lyl~l op-2-enyl } - I -hydroxyurea;

(E)-1-{3-[2-Cyano-3-phel,oAyl~henyl]-l-mc;L}-ylprop-2-enyl}-1-hydroxyurea;

(E)- I - { 3 -[3 -(4-Cyanophenoxy)phenyl]prop-2-enyl } - I -hy~ll oAyllrea;

(E)-1-{3-[5-(4-C~oph~n~,Ay)-2-cyanophenyl]-1-mel},yll"op-2-enyl}-1-hydroAyurea;

(E)-1-{3-[2-Cyano-5-(4-fluorophenoxy)phenyl]-1-1nel}lyllJIul)-2-enyl}-l-llydluAy~lrea;

(E)- 1- { 3 -~2-Cyano-3 -(4-fluo- uphenuAy)phenyl]- 1 -ll~ Lyl~l up-2-enyl } - I -hydl Oxyul ~a;

(E)-1-{3-~2-Cyano-3-(4-~;y~-ophelluAy3phenyl]-1-n.~,.l.rl~,op-2-enyl}-1-hy~lloAyurea:

WO 94/02448 7 21 4 I ? I ~ PCI /GB93/01585 ., .

(E)- 1- { 3 -[3 -(4-Cyanophenoxy)-2-cyanophenyl] -1 (R)-methylprop-2-enyl ~ -1-hydroxyurea;

(E)- 1- { 3 -[4-Cyano-3 -(4-fluorophenoxy)phenyl] -1 -methylprop-2-enyl } -1 -hydroxyurea;

(E)- 1-{ 3 -[3 -(4-mesylphenoxy)phenyl]- 1 -methylprop-2-enyl } - I -hydroxyurea;

(E)-N-{3-~3-(4-cyanophenoxy)phenyl]-l(S)-methylprop-2-enyl}acetohy-llùxamic acid;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-l(R)-methylprop-2-enyl}acetoh~dlox~lllic acid;

(E)-N-{ 3-[3-(4-cyanophenoxy)phenyl]- 1 -methylprop-2-enyl } acetohydroxamic acid;

N-{3-[3-(4-cyanophenoxy)phenyl]-1(S)-meLllyl~lop-2-ynyl}acetohydlox~llic acid;

or a salt, solvate, or physiologically functional derivative thereof.

Salts of compounds of formula (I) which are suitable for use in me~iirine are those wl,erei" the counterion is pharm~ce~-tic~lly acceyLable. However, salts having non-pharm~celltically acceptable cou,lLelions are within the arnbit of the present invention, either for use in non-medical applications or as il"~ ellia~c in the prepa,~Lion of culllpou,lds of formula (I) and their pharm~cel-tic~lly accept~ble salts and physiologically functional derivatives.

Salts according to the invention include ~u~onium salts, alkali metal salts such as those of sodium and pot~cil~m~ ~lk~line earth metal salts such as those of s~irillm and salts with organic bases such as dicycloh~,Ayla~ ,e and N-methyl-D-~hlc~mine, and salts with amino acids, such as arginine and Iysine. Examples of pharm~cel-tir~lly acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, pho~lho.ic, ~e~ ho~ho~;c, nitric, and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycollic, glllconir" sucrinic and mPth~ne~llphonic and arylsulphonic, for example ~-toln~ P,,. ~ h~ acids.
.

WO 94/02448 8 PCr/GB93/015~
2l4~21~

By the terrn phvsiologically functional derivatives is meant çhemic~l derivatives of compounds of formula (I) which have the same physiological function as the free compound of formula (I), for eY~mpl~ by being convertible in the body thereto.
According to the present invention, examples of physiologically functional derivatives include compounds of formula (I) in which the hydroxyl of the h~d,oxa"lic acid functional group has been converted to a pharm~ce~ 'ly acceptable salt, a urethane or an ester.

As mentioned hereinbefore. compounds of ~ormula (I) and salts, solvates, and physiologically functional derivatives thereof have use in the prophylaxis and tre~tm~nt of clinical conditions for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway is in-lic~te~, as deulons~,~ted hereinafter in the S-lipoxygenase and cyclooxygenase inhibition assays in which representative compounds of the present invention have been shown to be active. For example, the ability of compounds of formula (I) to inhibit the lipoxygenase and cyclooxygenase m~ ted arachadonic acid metabolic pathways, renders them useful for the prophylaxis and tre~tment of spasmogenic conditions, allergic conditions, tumour formation, conditions involving blood platelet ag~ lion, and infl~,.""~lu~y conditions.
Examples of spasmogenic conditions are those involving smooth muscle tissue, especially airway smooth muscle constriction such as asthma (in~ ing idiopathic bluricllial asthma), bronchitis and arterial smooth muscle constriction such as coron~y spasm (inrl--(iing that associated with myocardial infarction, which may or may not lead to left ventricular failure reY-lting in cardiac asthma), i~rl-f .,.;~-in~ ce~ myocardial injury, and cerebral spasm or 'stroke' (which may lead to central nervous pathophysiology). Other examples include bowel disease caused by abnormal colonic mlle~ r contraction such as the con~litions known as 'ill;l~le bowel syndlolllc', 'spastic colon' and 'ml-colle colitis'.
Examples of allergic conditions are extrinsic asthma, allergic skin ~licf~e~e having a total or partial allergic origin, such as e~.7~nn~, allergic bowel ~ e~c~e (in~ in~
coeliac disease), allergic eye co~dilions~ such as hayfever (which may additionally or alttl-l~lively affect the upper l~spil~Lo,y tract), allergic rhinitis, and allergic conjunctiv~tis.

WO 94/02448 , 21 ~ 1 ? 1 11 PCI ~GB93/01585 Examples of tumours are skin neoplasms, mastocytoma and other forms of cellular proliferation, both benign and m~ nAnt It is to be noted that the effectiveness of the present compounds in the prophylaxis and tr~tment of tumours may arise from properties in addition to 5-lipoxygenase inhibition which also inhibit cell proliferation.
Examples of conditions involving blood platelet aggregation are those res~lting from thrombosis, inr~ ling istrokes' having a total or partial thrombotic origin, co,~na,y thrombosis, phlebitis and phlébothrombosis (the latter two conditions also possibly being associated with inflAmnnAf~on) Examples of inflAmmAtory conditions are those of the lungs, joints, eyes, bowel, skin, and heart; particularly those associated with the infiltration of leucocytes into infl,.me(l tissue. Tnfl,.mmAtory lung conditions include ~cthmA, adult respiratory distresssyndrome, bronchitis and cystic fibrosis (which may additionally or alternatively involve the bowel or other tissue(s)). Tnfl,.mmAtory joint conditions include rl~e--mAtoid arthritis, rhe~-mAtoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions. TnflAmmAtory eye conditions include uveitis (inr~ in~ iritis) and conjunctivitis. Tl~n~,.,...,.lory bowel conditions include Crohn's disease, ulcerative colitis and distal proctitis. Tnfl~"."~AIo~y skin ~iceAces include those associated with cell proliferation, such as pso~ias;s, eczema and dermatitis (whether or not of allergic origin). TnflA.. I~to,y conditions of the heart include coronary infarct damage. Other inflA.~.,A~oly conditions include tissue necrosis in chronic infl,mmAtion, endotoxin shoclc, smooth muscle proliferation disorders (for example, restenosis followingangioplasty), and tissue rejection following tr~ncplAnt surgery.
In view of their unique properties the compounds of the invention may also be employed in the prophylaxis or Lle~ l.l of bone disorders (for ex~mrle, o~leopo-osis), bacterial and fungal infections, dysmenorrhoea, multiple sclerosis and clinical co~itions for which an immllnos~.~,pre~ll, anti-convulsant, or ~nAig~cic is in-lir.Ated The compounds of the invention also exhibit hypor~lol~ct~rolaemic activity.

Acco~ ly, the present invention provides a method for the prophylaxis or Lle~
of a clinical condition in a IIIAIIII~IAI, such as a human, for which an i.~iLor of the lil)o~ygenase or cycloo~ygellase mPriiAted arachadonic acid metabolic pathway, for e-A~ )lP, a 5-lipo~ygellase or cyclooxygenase inhibitor, is in~ir~te-l which Col~ lises ~1",;,~ ~ion of a lLe~ tically effective amount of a compo4nd of formula (I), or a WO 94/02448 . 10 PCI/GB93/015~
21~121~

pharm~selltic~lly acceptable salt, solvate, or physiologically functional derivative thereof. The present invention further provides a method for the prophylaxis or tr~tment of a clinical condition in a m~mm~l such as a human, which clinical condition is a spasmogenic condition, an allergic condition, tumour formation, acondition involving blood platelet aggregation, or an infl~ ory condition; whichco,n~,ises ~ c~ldlion of a therapeutically effective amount of a compound of formula (I)t or a pharm~ceutically acceptable sa4 s~vate, or physiologically functional derivative thereof.

In the alternative, there is also provided a compound of formula (I), or a pharm~c~eutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy; particularly, for use in the prophylaxis or tre~tmf~nt of a clinical condition in a m~mm~.l such as a human, for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway, for example, a 5-lipoxygenase or cyclooxygenase inhibitor, is inrlic~ted; for example a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet agglt:gdlion, or an infl~mm~tory condition.

The amount of a compound of formula (I), or a pharm~ceutic~lly acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of lion~ the subject under ll e<'~ 7 and the particular disorder or disease being treated. A suitable daily dose for a m~mm~l suffering from, or likely to suffer from, any of the clinical conditions described her~ e~ole is in the range O.l!lg- SOOmg of compound/kilogram bodyweight. In the case of systemic ~ l, dlion7 the daily doseis typically in the range 0.05 - 500mg of compound/kilogram bodyweight, the most~lc;r~ d dosage being from 0.05 to 50mg/kg bodyweight, for example, from 0.1 to lOmglkg, ~minict~red as two or three sub-doses daily. In the case of topical ?~minictration7 e.g. to the skin or eye, a suitable dose is in the range O.lng- 100~1g of base per kilogram, typically about 0.1 ~Lg/kg.

In the case of oral dosing for the prophylaxis or lle~ l of airway smooth muscleconstriction, for example, in asthma or bron.,hilis, a suitable dose of the compound of the invention may be as specified in the yl~ce~ paragraph, but preferably is from 0 1mg to 10mg of compound/kilogram bodyweight, the most ~ler~ d dosage being ~W094/02448 11 2l~l2l ~ PCI/GB93/01585 from 0. lmg to 5mg/kg bodyweight. In the case of pulmonary ~-1 " ~ lion, the dose is typically in the range 2~g - lOOmg/kg, preferably, from 5~g to 5m~/kg, for example from 0.01 to 1 mg/kg.

The present invention also provides the use of a compound of formula (I), or a pharrn,.ce~ltically acceptabie salt, solvate, or physiologically functional derivative thereof in the m~nnf~rtllre of a men'if".mfnt for the prophylaxis or tre~tm~nt of a clinical condition for which an ir~hibitor of the lipoxygenase or cyclooxygenasemer~i~tf cj arachadonic acid metabolic pathway, for example, a 5-lipoxygenase orcyclooxygenase inhibitor, is indicated; for example a spasmogenic condition, an allergic condition, tumour formation, a condition involving blood platelet aggregation, or an infl~mm~tory condition.

While it is possible for the compound of formula (I), or a salt, solvate, or physiologically functional derivative thereof to be a~mini~tered alone, it is preferable to present it as a pharm~-e~ltical formulation. Accordingly, the present invention further provides a pharm~cel~tical formulation comprising a compound of formula (I) or apharm,.cel1ti-,.lly acceptable salt, solvate, or physiologically functional derivative thereof, and a pharrn~ce~lti~.~lly acceptable carrier or excipiçnt, and optionally one or more other therapeutic ingredients.

He~ein~ler, the term "active ingredient" means a compound of formula (I), or a ph~rm~cel-tif,~lly acceptable salt, solvate, or physiologically functional derivative thereof.

The carrier or excipient must, of course, be col"palible with the other ingredients in the formulation and must not be del~ ,nlal to the recirient The active h1~fediell~
may colll,ulise from 0.1% to 99.9% by weight of the formulation. Typical unit doses of a formulation accoldi.1g to the invention contain from 0.01mg to lg of the active ingredient. For topical ~fl..,;i..~ ion, the active ingredient plt;~l~bly con~titlltes from 1% to 2% by weight of the forrn~ ti- n, but the active ingredient may con~tihlte as much as 10% w/w. Formulations suitable for nasal or buccal ~ lion, typically contain from 0.1 to 20% w/w, for example, 2% w/w of the active in~diellL.

WO 94/0244~ 12 PCI/GB93/01585t ~,~4i2~

Forrnulations according to the invention include those in a form suitable for oral, pulmonary, ophth,.imic, rectal, pal~-lL~-~I (incl~l~inP subc~lt~nloous, intr~m--sc ll~r and intravenous), intra-articular, topical, or nasal/buccal ~iminictration.

The forrnulations of the invention may conveniently se presented in unit dosage form and may be p.epa-~d by any method well know~ m the art of pharmacy. All such methods include the step of bringing the aG~iv.~ ingredient into association with a carrier which constit~lt~ps one or more ~cessory ingredients. In general, the formulations are prepa.t;d by uniformly and imim~tPIy bringing the active ingredient imo ~csori~tion with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product into the required forrn.

Formulations according to the present invention which are suitable for oral ~minietration may be in the form of discre~e units such as c~rs~lPc~ c~rhP~t~ tablets, or 1O7Pnge~7 each con~ g 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 or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. The active ingredient may also be in the form of a bolus, electuary, or paste.

A tablet may be made by co-..~,rt;.,.,illg or moulding the active ingredient, optionally with one or more accessory ing.edie..ls. Co---~le~,sed tablets may be prepared by co.ll~ies~,ill~" in a suitable m,.rhin~ the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, and/or surface active or di~,pe-~ g agent. Moulded tablets may be made by moulding, in a suitable m~rhinP, a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.

Formulations for rectal ~ ion 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.

Forrn~ tion~ suitable for p&ellLe,al ~ Lion typically co~ ,l;se a sterile ~q~leo~ls pr~p~Lion of the active i.l~ dielll which is ple~l~bly isotonic with the blood of the re~irirnt ¦~ W0 94/02448 21 4 1 2 I 4 PCI/GB93/01585 Formulations suitable for intra-articular ~minictration may be in the form of a sterile aqueous plep~dLion of the active ingredient, which latter may be in microcrystalline form, for example, an aqueous microcrystalline suspension. Liposomal forrnulations and biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic a~ministration.
.
Formulations suitable for topical a~ministration include liquid and semi-liquid pr~ Lions such as li,,;,,~ C. Iqtions and applications; oil-in-water and water-in-oil emulsions such as creams, ointm~ntC and pastes; and solutions and suspensions such as drops. For example, for ophthalmic ~rlminictration, the active ingredient may bepresented as ac~ueous eye drops, for example, in the form of a 0.1 - 1.0% w/v solution.

Suitable formulations for a~l",;~ Lion by inhalation include fine particle dusts or mists which may be generated by means of various types of ~l~cLelcd dose pressurised aerosols, nebulisers, or inc~ tors.

For pulmonary ~lminictration via the mouth, the particle size of the powder or droplets is typically in the range 0.5 - IO!lm, preferably I - 5~1m, to ensure delivery into the bronchial tree. For nasal ~I",;..;~ Lion, a particle size in the range 10 - 500~1m is prercll cd to ensure retention in the nasal cavity.

Metered dose inhalers are pressurised aerosol dispensers, typically co,~ ;";"g asuspension or solution form-ll~fion of the active ingredient in a liquefied propellant.
During use, these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150~11, to produce a fine particle spray co.~ the active ingredient. Suitable propellants include certain chlorofluorocarbon cG".~)oullds, for eY~mplP., dichlorodifluoro..,. Ih~l-P., trichlorofiuor~ e~ e, dichloruteLId~ oroethane and mixtures thereo The formnl~tion may additionally contain one or more co-solvents, for Py~mpl~, ethanol, surf~ct~ntc, such as oleic acid or SOI~ trioleate, anti-oxidants and s ~it~hle flavouring agents.

Nebulisers are comme~cially available devices that "~l..r~ solutions or sUsppncions of the active ingredient into a Lllc.~,ue~ltic aerosol mist either by means of acceleration of a collll)r~ssed gas through a narrow venturi orifice, typically air or oxygen, or by ~ ~12 i 14 PCr/GB93/01~

means of ultrasonic agitation. Suitable forrnulations for use in nPblllicPrs consist of the active ingredient in a liquid carrier and comprising up to 40% w/w of the forrnulation, preferably less than 20% w/w. The carrier is typically water or a dilute a~ueousalcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not ple~aled sterile, for example, methyl hydroxy-bPn7o~rP anti-oxidants, flavouring agents, volatile oils, buffering agents and ~ ct~ntc Suitable formulations for ~iminictration by in.cllffl~ion include finely co.~ ted powders which may be delivered by means of an inc~ tor or taken into the nasal cavity in the manner of a snu In the incllffl~tQr, the powder is contained in c~ps~lles or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air dtawn through the device upon inh~l~tion or by means of a m~n~ ly-operated pump. The powder employed in the incllffl~tQr consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w ofthe formulation.

In addition to the afolel-le--Lioned ingredients, formulations according to the invention may include one or more additional ingredients such as dilllPntc buffers, flavouring agents, binders, co.llp-es~.ion aids, dis;ll~evl~l~ surface active agents, thickeners, lubricants, preservatives, for example, methyl hydroxyben7O~te, anti-oxidants and emulsifying agents. The compounds of the invention may adv~nt~eollcly be employed in collll,in~ion with one or more other therapeutic ingredients sel~ted from an antibiotic (for example, an anti-bacterial), anti-fungal, or anti-viral agent, an anti-e (particularly a peripherally-acting anti-l-;cli,.,...-e), or a non-steroidal anti-infl~mm~tory drug (NSAID).

The compounds of these culll~;llaLions may be ~rlminictPred ~ ously~ for example, in the same forrnulation or in separate form~ tinns, or sequentially within a snffi~i~ntly short time interval to achieve the desired cou.b;ned therapeutic effect.
When the compounds are employed in the same formulation, a ro.ll-ulalion accoltlin~
to the invention may contain, in addition to a compound of the invention, the further in~edient(s).

~ WO94/02448 15 214121~ Pcr~.~93/0ls8s Acco,ding to a further aspect of the invention, there is provided a process for ~repa,ing the compounds of formula (I), or salts, solvates, or physiologically functional derivatives thereof, which comprises reacting a compound of formula (II) 1~1~ o,~ ~ (II) wherein Y, R, and the substitu~ntc on rings A and B are as defined for the compound of forrnula (I), or a salt thereof, with a suitable agent or agents to effect conversion of the N-hydrogen to an N-COD group, where D is (a) Cl~ alkyl, or (b) NR4RS
(wherein R4 and R5 are as defined for formula (I));

and optionally converting the compound of the formula (I) so formed to a corresponding salt, solvate, or physiologically functional derivative thereof.

Conversion (a) is typically carried out by Ll~;~Ling ofthe compound offormula (II) with an acylating agent, for exarnple, an a~,oy,iaLe anhydride or activated acid, such as an acid halide, for example, acetyl chloride. This reàction is suitably ~.ffe~e~ in an inert solvent, such as a halohydrocarbon, for example, dichloromethane, at a temperature in the range -10C to 150C, for exarnple 0-25C.

Conversion (b) is typically carried out by Ll~Ling the compound of formula (II), or a salt thereof, (i) where R4 and R5 are to be hydrogen with a Group I cyanate, for eA~l,l)le, pot~cci-lm cyanate, in a non-polar solvent, such as t~Ll~,~dlo~LIran (THF), in the s~;,.ce of acid, such as a rnineral acid, for example, dilute ~q~eollc HC1, at atelllp~.aL~lre in the range -10C tolS0, for example 0-25C;

(ii) where R4 is to be Cl~ alkyl and RS is to be hydrogen, w~th the co,.t;s~,onding iso?anate R4NCo, in a suitable solvent, such as a halohydrocarbon, for WO 94/02448 ` 16 PCI/GB93/01~8~
2~4~214 example, dichlororneth~ne at a temperature in the range of -10C tolS0, for example 20-100C;

(iii) where R4 and RS are each to be C l 4 alkyl, with the co~ ,.,onding carbamoyl halide, for example R4R5NCOCI, in an inert solvent, such as a halohydrocarbon, for example, dichlo~ .le~ ne/ in the ~esence of base, such as an organic base, for example, pyridine, at a tem~erature in the range -10C to 150C, for example, 20-100C.

Compounds of formula (II), and salts thereof, may be yle~red by acid or base hydrolysis of the corresponding N,O- or O- blocked compound, for example, the -N(CO2Me)OCO2Me, or -N(Boc)OBoc or -N(Boc)OH compound where Boc is t-butoxycarbonyl. For example, where the -N(Boc)OBoc or -N(Boc)OH compound is used, the compound of formula (II), or a salt thereof, may be ,~ ed by ~ .1-P..lwith an acid, such as an arylsulphonic acid, for example, p-tolllen~s..lrhonic acid; in a non-polar solvent for example, toluene; at a moderate te~ elalllre~ suitably in the range 10-100C, for example, 50-60C. The reslllting salt of the compound of formula (II) may then optionally be treated to release the free base, for example, by ~l"o"laLography on silica. The N,O- or O- blocked compound may be obtained by reaction of the corresponding compound of formula (m) H-Y-CHR-N(P)OP (m) wherein Y and R are as defined for formula (I) and P is a plOle~,lillg group, such as -C02Me or -butoxycarbonyl, with a compound of formula (IV) ~ ~ L (~

wherein rings A and B are optionally substituted as described for forrnula (I) and L is a suitable leaving group, for PY~mrl~, a halogen, (typically bromo or iodo) or trifluo,o~ ne~ fonate; typically at elevated ten~l~el~L~re ,in the ylesellce of a WO 94/02448 17 21 4 1 2 I 4 Pcr/GB93/ol585 catalyst, such as p~ m (II) acetate, tri(o-tolyl)phosphine, and a suitable base, for example, triethylamine.

Compounds of formula (m) may be obtained by one or more of the methods describedin EP 0384594.

Compounds of formula (IV) may be obtained commercially or prepared, for example,by coupling a compound of formula (V) ~ L' ¦¦ A ¦ (V) ~O

wherein L' is a leaving group, such as a halogen, for example, fluorine, and ring A is substi~lted as defined for a compound of formula (I), or a suitably protected form thereof, with a compound of formula (VI) HO ~ L
~ , (~) wherein L is as defined above for formula (IV). This coupling may be eff~cted byreaction in the plc;sence of an ;nOl~;aniC base, for ~Y~mple, potassium c~l,ollale, in an aprotic sohent, for example DMF; at an elevated temperature, for example, 50-200C.

AlL~;llla~ y~ compounds of formula (II) may be prel)~ued by oxim~tion of the Collt;:~Ondill~, ketone, for example, using h-y~llu~yl~lllne in a polar solvent, such as ",e~ oi followed by reduction of the re~-lting oxime, for ~,A~ullylc, using sodium cyanoborohydride/oxalic acid.

WO 94/02448 18 PCl[/GB93/015~
2~4~2~4 The individual enantiomers of the compound of the invention may be obtained by separation of the components of the racemic mixture, for example, by means of a chiral cl~olllatography column or by ple~-ng and sep~lhlg suitable diastereoisomers, orby direct synthesis from the corresponding chiral compound of formula (II) by the method described above.

Optional conversion of a compound of fornu~a (I) to a corresponding salt may conveniently be effected by reaction with th~ applopliate acid or base. Optionalconversion of a compound of formula (I) to `a corresponding solvate or physiologically functional derivative may be effected by methods kno~vn to those skilled in the art.

Accolding to a further aspect, the present invention provides compounds of formula (II) as defined above, or a salt thereof; particularly a compound selected from:
(E)-N-~3-[3-(4-cyanophenoxy)phenylJ-1 -methylprop-2-enyl}-h~.llo~y~ll.l,onium p-tolu~nesnlrhonate;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-l(R)-Ill~lhylplop-2-enyl}-hydroxyammonium p-toh~nes~.lrhonate;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-l(S)-,IleLllylprop-2-enyl}-hydrox~alll.llol~ium p-toll~çn~slliphonate;

(E)-N-{3-~3-(4-cyanophenoxy)phenyl]-1 (S)-mt;lhylpl op-2-enyl~-hydroxylamine; and (E)-N-{3-~3-(4-cyanophenoxy)phenyl]-l(S)-,ll~Lllylpl-,p-2-ynyl}-lly~lr~"~ylamine.

For a better undela~ l;llo of the invention, the following Examples are given by way of illustration.

2~9121~ ; ~
.. ..

SY~I l ~ l lC EXAMPLES

Synthetic Exarnple I

Plel~alalion of (E)-1-{3-r3-(4-cvanophenoxv)phenvll-1-"lelllyl~iop-2-enyl}-1-hydroxyurea ~.
(a) 4-(3-Bromophenoxy)bel~0~ l ile Anhydrous potassium carbonate (13.9 g) was added in one portion to a stirred solution of 4-fluorobell,ollillile (12.1g, Aldrich) and 3-bromophenol (17.3g, Aldrich) in DMF (75ml). The mixture was refluxed for 6 hours, then stirred overnight at room temperature and filtered. The filtrate was evaporated in vacuoand the l~ g gum partitioned between ethyl acetate (~OOml) and water (300ml). The organic phase was separated, washed with lN aqu. NaOH, 0.5N
aqu. HCI and saturated brine, dried over anhydrous sodium sulphate and evaporated in vacuo to give a tan oil. This was ch~vn~aLographed (Merck 9385 silica, 9:1 hexane:ethyl acetate eluant) to give the desired product as a white solid (24.5g), mp 70-72C.

(b) (E)-N-t-Buto~ycal bonvl-N- ~ 3 -~3 -(4-cyanophenoxy)phenyl~- 1 -methvl-prop-2-envl ~ hvdroxvlamine Triethylarnine (12.7g, Aldrich) was added to a stirred solution of the product from Example 1(a) (17.2g), N,O-_(t-buto~yc~l~onyl)-N-[but-3-en-2-yl]hydlv~ylamine (19.8g, obtained from but-3-yn-2-ol by the method described in EPS 0384594, Synthetic FY~ rles 2 and 3) and _(tri-o-tolylphosphine)p~ m(II) chloride (2.5g, Aldrich) in DMF (200 ml). The Ul~, was heated at 100-110C for 8 hours, then stirred overnight at room tellll)Gl~Lule, evaporated in vacuo and the residue partitioned between ethyl acetate (1OOOml) and water (800rnl). The organic phase was se~aLed and washed with 0.5N aqu. HCl and saLulaLed brine, dned over a~ly-lluus sodium slllrh~te and e~a~)o.~led in vacuo to give an orange gum. This was chrolll~Lographed (Merck 9385 silica, 9:1 -> 7:3 h~oY~ne ethyl acetate graded eluant) to give the desired product (16.5g).

~=

WO 94/02448 ; . 20 PCr/GB93/015~
2~4121~ .

(c) (E)-N-{3-r3-(4-cvanophenoxy)phenyl~-1-methylprop-2-enyl}-hvdroxvammonium p-toluenesulphonate p-Tol~l~n~slllrhonic acid monohydrate (9.lg? A~drich) was added in one portion to a stirred solution of the product fro-~ Example l(b) (16.5g) in toluene (lOOml). The mixture was heated at 50-60C for 2 hours, then stirred overnight at room t~ ,e,~ re and the desired product (11.Og) filtered o (d) fE)- 1 - ~ 3 -~3 -(4-Cyanophenoxy)phenvll - I -methvlprop-2-enyl ~ - I - hvdroxvurea Potassium cyanate (14.4g, Aldrich) was added in one portion to a stirred solution ofthe product from Example l(c) (26.8g) in THF (200ml)/water (lOml) at 0C followed by the dropwise addition of IN aqu. HCl (118ml) over 30 min~lt~S The mixture was stirred at room temperature for 2 hours, then poured into a mixture of ethyl acetate (IOOOml) and water (500ml). The organic phase was separated and washed with 0.5N aqu. HCl, water, saturated aqu. sodium bicarbonate and saturated brine, dried over anhydrous sodium sulphate and e~,a~o,aLed in vacuo to give a pale tan foam. This was cl~umàlographed on silica, using 5% to 10% meth~nol/dichlolu...~ e graded eluant and the res Itinsg solid (17.4g) le~ly~ ed from ethyl acetate/hexane to give the desired product as a white solid (12.3g), m.p. 138-140C.

lH NMR (200MHz, DMSO-d6) ~: 1.35 (3H, d, -CHCH3), 4.85 (IH, m, -CHCH3), 6.32 (2H, s, -NH2), 6.35 (lH, dd, -CH-), 6.50 (lH, d, -CH-), 7.0-7.85 (8H, m, aromatics), 9.02 (lH, s, -00 +

FAB MS: m/e 324 (MH ) Microanalysis: ClgH17N303 found (c~lc ll~te~ ) %
C 66.56 (66.86)7 H 5.35 (5.30), N 12.78 (13.00) Synthetic Example 2 Preparation of (E)- 1 - { 3 -r3 -(4-cyanophenoxy)phenyl] - I (R)-methylprop-2-enyl } - I -hvdroxyurea (a) (E)-N-t-Butoxycarbonyf-~{ 3 -r3-(4-cyanophenoxy)phenyll- 1 (R)-methyl-prop-2-enyl } hydroxylamine To a solution of the product from Example l(a) (1.Og) in DMF (lOml) was added N,O-bis (t-butoxycarbonyl)-N-[but-3-en-2(R)-yl]hydroxylamine (1.06g, obtained from but-3-yn-2(S)-ol by the method described in EP 0384594), followed by triethylamine (0.822g), and bis(tri-o-tolylphosphine)p~ di-lm(II) chloride (140mg). The reaction was heated at 100-110C for 2 hours, then stirred at room temperature overnight, and then heated for a further 3-4 hours at 100-110C. On cooling, ethyl acetate was added and the mixture was filtered through Hyflo (Trademark). The filtrate was washed twice with 10% citric acid, twice with brine, and then dried on anhydrous sodium sulphate, filtered, and thesolvent was removed in vacuo. Purification of the residue by flash c~o~ ography on silica, eluting with ethyl acetate/hexane (20:80) afforded the title product.

(b) (E)-N- { 3 -r3 -(4-cyanophenoxy)phenyl~ - I (R)-methylprop-2-enyl } -hydr~yammonium p-toluenesulphonate p-Tolu~n~sulrhonic acid monohydrate (260mg) was added .to a solution of the product from Example 2(a) in toluene (8ml). The mixture was heated at 50C
for 2-3 hours, then stirred at room tell~pelaLIlre for 24 hours. The reaction was then dried in vacuo, the residue taken up in toluene and the title product was ~IC~ ed by addition of diethyl ether and collected.

(c) (E)-1-{3-~3-(4-Cyanophenoxy)phenyl~-l(R)----~Lhyl~ p-2-enyl~-1- hydroxyurea Pot~cillm cyanate (357mg) was added to a stirred solution of the product from Example 2(b) in TH~ (20ml), with cooling in an ice bath. lN aqueous HCI
(2eq) was then added dropwise, and the reaction was stirred for 1-2 hours until WO 94/02448 22 PCI/CB93/01589~
21, 4~2~

reaction was complete. The organic phase was separated and then washed sucessively with lN HCI, saturated sodium bicarbonate, then brine, before being dried over anhydrous sodium sulphate, filtered, and the solvent was removed in vacuo. Purification of the residue by flash chlu.l-aLography on silica, eluting with methanolldichlorometh~nt~ (3 :97) afforded the title product as a white solid, mp 62-64C.

Microanalysis: ClgH17N3O~ . 0.2S H~O
C 65.92 (65.94), H 5.33 (5.38), N 12.64 (12.81) Optical Rotation (c=l,methanol,2'): [a]Hg = +46 14, [a]Na = +30 76 Synthetic Example 3 Plepa.~Lion of (E)-1-~3-r3-(4-cvanophenoxy)phenyl1-1(S)-".~;Ll~yl,~,lop-2-enyl}-1-hydroxyurea (a) (E)-N-~3-[3-(4-cyanophenoxy)phenyll-l(S)-methylprop-2-enyl}-hydro~y~ l"onium p-tol~ç~es~llphonate The title product was obtained from 4-(3-bromophenoxy)bel~oniLt:L.;le and N,O-bis (_-lulu~yc~bG..yl)-N-[but-3-en-2(S)-yl]l.yd-o"ylamine (obtained from but-3-yn-2(R)-ol by the method described in EP 0384594), by the method of EY~mples 1 and 2.

(b) (E)-1-{3-~3-(4-Cyanophenoxy)phenyl~-l(Sh"~ vl,o-up-2-enyl}-1- hyd,u~yulea The title product was obtained by reaction of the product from Example 3(a) with potassium cyanate under the co~ ;ons desclil,ed in Example 2(c). The product was isolated as a white solid, mp 58-60C.

Micr~ alysis: C18H17N3O3 0-22 H2O
C 66.35 (66.05), H 5.63 (5.37), N 12.54 (12.84) Optical Rotation (c=l,.~ -ol ~7): [a]Hg = -48.06, [aJNa = -32.21 WO 94/02448 21 412 ¦ J ~ PCr/G~93/01585 Synthetic Examples 4 - 14 The following compounds of formula (I) were prepared in a manner analogous to the method of Synthetic Examples 1 - 3. The NMR, FAB, Mass Spec., and microanalysis of each compound were consistent with the proposed structure.

4) (E)- 1-{ 3 -{4-Cyano-3-phenoxyphenyl]- 1 -methylprop-2-enyl } - I -hydroxyurea, mp 155-156C;

S) (E)-1-{3-[2-Cyano-S-phenoxyphenyl]-1-methylprop-2-enyl}-1-hydroxyurea, mp 141-142C;

6) (E)-1-{3-[2-Cyano-3-phenoxyphenyl]-1-methylprop-2-enyl}-1-hydroxyurea, 0.4 hydrate, mp 140-141C;

7) (E)-1-{3-[3-(4-Cyanophenoxy)phenyl]prop-2-enyl}-1-hydroxyurea, Microanalysis: C17H15N303 C 65.94 (66.01), H 4.96 (4.89), N 13.30 (13.58);

8) (E)-1-{3-[5-(4-Cyanophenoxy)-2-cyanophenyl]-1-methylprop-2-enyl}-1-hydroxyurea, Microanalysis: ClgH16N4O3 Ø5 C4HgO2 C 64.06 (64,27), H4.67 (5.13), N 14.50 (14.27);
9) (E)-1-{3-~2-Cyano-5-(4-fluo,upheno~y)phenyl]-1--,1t;Lllylp,up-2-enyl}-l-Lydl u~yurea7 Microanalysis: ClgH16FN3O3 Ø33 H20 C 62.17 (62.25), H4.35 (4.83), N 11.61 (12.09);

10) (E)- 1-~ 3-~2-Cyano-3 -(4-fluol ù?her o~y)phenyl]- 1 -I--elhylpl op-2-enyl } -1-I.yd.u~yurea, 0.22 hydrate, mp 160-162C;

1 1) (E)-1-~3-~2-Cyano-3-(4-uy~ûphe-loxy)phenyl]-1-,-,ell,ylp,up-2-enyl}-1-h-ydl u~yu~
Miwoallalysis: ClgH16N403 Ø5 H20 C 63.84 (63.87), H 4.76 (4.76), N 15.2,8 (15.69);

WO 94/02448 24 PCI/GB93/015~
2~2~

12) (E)-1-{3-(4-Cyanophenoxy)-2-cyanophenyl]-l(R)-methylprop-2-enyl}-1-hydroxyurea, 0.40 hydrate, mpl74-175C;

13) (E)- 1 - { 3 -[4-Cyano-3-(4-fluoropheno~phenyl]- 1 -methylprop-2-enyl } - I -hydroxyurea, mp 151-153C, 14) 85%(E)- 1 - { 3 -~3 -(4-mesylphenoxy)phenyl]- 1 -methylprop-2-enyl ~ - I -hydroxyurea 15% 1 - ~ 3 -[3 -(4-mesylphenoxy)phenyl]- 1 -methylpropyl } - I -hydroxyurea1 Microanalysis:15% C18H22N25,S- 85% ClgH20N20sS, 0.4CH30H
.C 56.71 (56.78), H 5.48 (5.59), N-7.19 (7.19);

Synthetic Example 15 P-eyar~lion of (E)-N-~3-~3-(4-cyanophenoxy)phenyl]-1(S)-methylprop-2-enyl~-acetohydlux~l..ic acid (a) (E)-N-t-Butoxycarbonyl-N- { 3 -~3 -(4-cyanophenoxy)phenyll - 1 (R)-methyl-prop-2-enyl~hvdroxylamine and (E)-N~O-bis(t-Buto~y~,a,l)onyl-N-{3-r3-(4-c~callo,~he.loxy)phenyll-l(R)-methyl-prop-2-enyl}hydroxylamine The title products were pret)altd by reaction of the product from Exarnple l(a) and N,O-bis(-buto~y~,~bG"y~ N-rbut-3-en-2($)-yl]hydroxylamine (see Example 3(a)) by the method of F.Y~mrle 2(a). The products were purified by colurnn clllulllatography on silica, eluting with ethyl acetate/hexane (1:9).

(b) (E)-N-{3-~3-(4-cyanophenoxy)phenyl~-l(s)-lll~lllyl~lo~l)-2-enyl}llydlu?~lamine The products from Exarnple lS(a) were deprotected by heating in dry tûluene with p-toluen~llrhonic acid (1.OSeq), under N2, at 50C for 2 hours, and then stirring at room t~ re overnight. The crude products were collll)i-,ed, and the solvent removed in vacuo. The residue was purified by flash cL~ alography on silica, eluting with meth~nol/dichloro~ ;h~l~e (2:98) to afford the title product.

WO 94/02448 ~ 1 4121 4 PCr/GB93/01585 (c) O-Acetyl-(E)-N-{ 3 -r3-(4-cyanophenoxy)phenyl]- 1 (S)-methvl-prop-2-enyl acetohydl ox~.nic acid To a stirred solution of the product from Example 15(b) (0.84g) in dichlorometh~ne (20ml), was added pyridine (2eq), under N2 and with cooling in an ice-bath. Acetyl chloride (2eq, Aldrich), in dichlolo...e~ ne (lOml) was then added dropwise and thé reaction was stirred at room temperature overnight. The reslllting mixture was dried in vacuo, and the residue was partitioned between ethyl acetate and lN HCl. The organic phase was separated, washed s~-cceccively with water, saturated sodium bicarbonate (x2), water, then brine; dried over sodium sulphate, filtered and then the solvent wasremoved in vacuo. Purification of the residue by flash ch~ a~ography on silica, eluting with ethyl acetatelhexane (1: 1) gave the title product.

(d) E-N-{3-r3-(4-Cyanophenoxy)phenvl]-l(S)-methylprop-2-envl}
acetohydro~lllic acid To a stirred solution of the product from Example 15(c) (0.56g) in meth~nol (lOml), was added anhydrous potassium c~l.ollale (0.424g) under N2, with cooling in an ice-bath. The reaction was stirred for ~ /2 hours until complete, then the solvent was removed in vacuo. The residue was partitioned between diethyl ether and lM HCl. The organic phase was separated, washed s ~ccPc~ively with saturated sodium bic~bonate, water, and brine, then dried over sodium sulphate, filtered and dried in vacuo. Purification of the residue by flash ~hlo...~L~graphy on silica, eluting with ethyl acetate, afforded the titleproduct as a white solid.

Microanalysis: ClgHlgN2O3 . 0.36 H2O
C 69.27 (69.39), H 5.52 (5.74), N 8.30 (8.51) Optical Rotation (C=l~mp~th~nr)l~??o): [a]Hg = -148.95, [a]Na = -117.20 WO 94/02448 . 26 PCI/GB93/015~
2l4~2~

Synthetic Example 16 Pl epa, ~Lion of (E)-N- ~ 3 -~3 -(4-cyanophenoxv)phenyl~ - I (S)-methvlprop-2-enyl ~
acetoh~d,ox~",;c acid. sodium salt: and (E)-N-{3-r3-(4-cyanophe,lu~) phenyl~-l(S)-methylprop-2-enyl} acetohvdlo~",;c acid~ca~ci~m salt:

(a) (E)-N-{ 3 -r3-(4-cyanophenoxy)p~enyll- 1 (S)-methylprop-2-enyl }
acetoh~d,ù~"-;c acid~ sodium salt To a solution ofthe product from Example 15 (204mg) in meth~n~l (30ml) was added sodium hydride (25.32mg) in meth~nol (6ml) under nitrogen. The reaction was stirred at room te",~e,~ re then dned in vacuo to form the title compound.

(b) (E)-N-{ 3-r3-(4-cvanophenoxv)phenyl~- 1 (S)-methylprop-2-envl }
acetol,ydro~a",ic acid. calcium salt To a solution of the product from Example 16(a) in water was added calcium chloride dihydrate (93mg) in water and the reaction was stirred at room te~ )e.~ re until the crude product pre~ipit~ted The ple~ te was collected by filtration then washed with water, then diethyl ether. The product was dried at 40C under high vacuum mp 135C (shrinks 100C).

lH N~ (d6-DMSO 353K) ~: 7.8 (d 2X Ar-H) 7.5-6.9 (m, 6H ArH), 6.5 (s,2X-CH=CH-) 4.7 (br.s lH CH) 2.0 (S,3X C(O)CH3~, 1.3 (d, 3H, CH3).

Microanalysis: (C1gHIgN2O3)2 Ca 1 6 H2O
C 64.19 (64.14) H 4.99 (5.04), N 7.82 (7.87).

Svnthetic Exarnple 17 ,~alion of (E)-N-{3-r3-(4-cvanophenoxy)phenyl~-1(R)-"Ietl,yl~ o~)-2-enyl~
acetol,yd,o~l,ic acid .

WO 94/02448 27 2 1 4 1 2 1 ~ PCI /GB93/01585 (a) (E)-N-{ 3-~3-(4-cvanophenoxy)phenvll- 1 (R)-methvlprop-2-enyl acetohyd.~,~cd,,,;c acid. acetate ester The title produc~ was obtained from the product of Example l(a) and N,O-bis(t-butoxycarbonyl)-N Ebut-3-en-2(R)-yl]hydroxylamine acco-di..g to the method of Example 15.

(b) (E)-N- ~ 3 -{3 -(4-cvanophenoxy)phenvl~- 1 (R)-methvlprop-2-enyl }
acetohvd~oxa..l;c acid The title product was obtained from the product of Exarnple 17(a) according to the melhod of Example 15(b).

Microanalysis: ClgHlgN~7O3 . 0.40 H20 C 69.55 (69.24), H 5.84 (5.75), N 8.52 (8.50) Optical Rotation (c=l meth~nol,22): [a]Hg = +117.67, [a~Na = +142.04 Synthetic Example 18 P I ~ al dlion of (E)-N- { 3 -r3 -(4-cyanophenoxy)phenyll - I -methvlprop -2 -envl }
acetohyd..,~n;c acid The title compound was prepared from the product of Exarnple l(a) and N,O-_(t-buLo~ycall~onyl)-N-[but-3-en-2-yl]hydroxylamine by the method of Example 15.

MicroanalysiS: C l9H1 8N23 C 70.83 (70.79), H 5.67 (5.63), N 8.54 (8.69) Synthetic Example 19 P~el~dlion of N-{3-r3-(4-~ dnophenoxy)phenyl]-1(S)-m~Ll-ylplup-2-ynvl}
acetol,ydro~"ic acid WO 94/02448 , 28 PCI/GB93/015~

2l~l2i~

(a) 4-(3-lodophenoxv)be,l~o,l;~l ile 4-Fluorobenzo"n,;le (5.0g, Aldrich), 3-iodophenol (9.09g, Aldrich) and potassium carbonate (5.78g) were dissolved in DMF (35ml) and heated at 150 C for 3 hours. The reaction was then poured into water (lOOml) and extracted three times with ethyl acetate. The combined organic extracts were washed sllcce~.cively with IM sodium h~ide, water (x2), and brine before being dried over Na~S04, filtered, ~ d the solvent was removed in vacuo. The title product was obtained by re~yst~ in~ the residue from hexane.

(b) N.O-bis(t^butoxvcarbonyl)-N-~ 3-r3-(4-cyanophenoxy)phenvl3- 1 (S)-methvlprop-2-vnvl ~ hvdrox,vlamine To a mixture of the product from Example 19(a) (3.21g), N,O-bis (~-butoxycarbonyl)-N-[but-3-yn-2(S)-yl~hydroxylamine (2.85g) (prepared as describçd in Example 3 of EP 0384594) and copper (I) iodide (38mg) in triethylamine (40ml) was added bis(triphenylphosphinyl)p~ m dichloride (140mg) with the exclusion of moisture. The reaction was stirred at room temperature for 21/2 hours, then diluted with ethyl acetate and water. The organic phase was sepalated7 washed s~ccessively twice with 5% citric acid, water, and brine, then dried over Na2SO47 filtered, and the solvent was removed in vacuo. Purification of the residue by flash chlullla~ography on silica, eluting with ethyl acetate/hexane (12.5:87:5) afforded the title product.

(c) N-~ 3-~3-(4-cvanophenoxv)phenyl~- 1 (S)-methvlprop-2-vnyl~hydroxvlamine To a solution of the product from Example l9(b) (4.5g) in toluene (SOml), was added p-tolll~nes~llphonic acid (1.90g). The reaction was heated at 50-60C
for 2 hours under N2 then stirred at room te~ aLLIre until reaction was complete. The mixture was then diluted with diethyl ether, filtered, and the ple~ e washed with diethyl ether to give the p-tolu~nr~ .h~.. .A~ e salt of the title compound.
The p-toluenes Irhonate salt (2.2g) was stirred with a solution of potassiu carbonate (2g) in water (SOml), then extracted 3 times with ethyl acetate. The collll.h~ed organic phases were washed with water, then semi-saturated brine, 1-- WO 94/02448 2 1 4 1 21 ~ PCI /GB93/01585 before being dried over Na~SO47 filtered, and the solvent was removed in vacuo.

(d) O-Acetyl-N- 1-~ 3-r3-(4-cyanophenoxv)phenyl~- 1 (S)-methylprop-~-yllyl } acetohvdl o~-,-ic acid;

To a stirred solution of the product from Exampie 1 9(c) ( 1.3 Sg) in dichloromethane (25ml), was added pyridine (0.77g)followed by acetyl chloride (0.77g) in dichloromethane (lOml), cooling with an ice-bath under N~. The reaction was stirred at room temperature overnight under N2 before removing the solvent in vacuo. The residue was partitioned between ethyl acetate and lM HCI and the separated organic layer was washed with lMCI, twice with NaHC03, then with brine, before being dried over Na~S04, filtered, and the solvent was removed in vacuo. Purification of the residue by flash chrc..~ ography using ethyl acetate/hexane ( 1:1) afforded the title compound.

(e) N-1-{3-~3-(4-cyanophenoxv)phenyl~-1(S)-methylprop-2-ynyl}acetohvdroxamic acid To a stirred solution of the product from Example l9(d) (1.39g) in meth~nol (20rnl) was added potassium carbonate (1.06g), cooling with an ice-bath under N2. The reaction was stirred at room temperature for 1-2 hours, then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and lM HCl. The separated organic phase was washed with water, saturated NaHC03, water, then with brine, before being dried over Na2S04, filtered, and the solvent was removed in vacuo. Purification of the residue by flash chr~lllatography on silica, eluting with ethyl ~cet~te, afforded the titleproduct.

- lH NMR (d6 DMSO) o: 9.8 (s, lH, N-OH), 7.9-7.1 (m, 8H, ArH), 5.5 (q,lH,CH), 2.0 (s, 3H, C(O)CH3~, 1.4 (d, 3H, CH3).

Microanalysis: C 19H16N23 C 70.97 (71.24), H 5.29 (5.03), N 8.46 (8.74) WO 94/02448 30 PCr/GB93/015~
2l4~2~

PHARMACEUTICAL FORMULATION EXAMPLES

The "active ingredient" in the following formulations is as defined above; preferably one of the compounds of Synthetic Examples I to 18 Example A: Oral Tablet (i) Per tablet Active Ingredient 50.0 mg T ~r.tose 61.0 mg Sodium Starch Glycollate 10 0 mg Povidone 3.0 mg Magnesium Stearate 1.0 mg Mix together the active ingredient. Iactose and starch. Granulate the powders using a solution of povidone in purified water. Dry the granules~ add the m~gn~cillm stearate and COlllyl ess to produce tablets.

ExampleB. Oi~Ll~ n~

Active Ingredient 1.0 g White Soft Paraffin 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 I3ee~x 2.5 g Methylllydlor.yl,e,,o~re0.1 g Distilled Water to 100.0 g 21 4121 ~

Heat the Polawax, beeswax and lanolin together at 60C. Add a solution of methylhydroxybenzoate. Homogenise using high speed stirring. Allow the temperature to fall to 50C. Add and disperse the active ingredient. Allow to cool with slow speed stirring. .~
. .
Example D: ~otion for topical use Active Ingredient 1.0 g Sorbitan Monolaurate 0.6 g Polysorbate '0 0.6 g Cetostearyl Alcohol 1.~ g Glycerin 6.0 g Methyl Hydroxvbenzoate 0.2 g Purified Water B.P. to 100 ml The methyl hydroxybenzoate and glycerin were dissolved in 70ml of the water at 75C.
The sorbitan monolaurate, Polysorbate ~0 and cetostearyl alcohol were melted together at 75C and added to the aqueous solution. The res-llting emulsion was homogenised, allowed to cool with continuous stirring and the active ingredient added as a suspension in the le~ il-F water. The whole was stirred until homogeneous.

Example E: Oral Tablet (ii) Per tablet Active Ingredient 10.0 mg T ~ctose 80.0 mg Microcrystalline Cellulose40.0 mg Povidone 4.0 mg Sodium Starch Glycollate15.0 mg ~r~gnrcillm Stearate 1.0 mg Mix together the active ingredient and microcrystalline cullolose before blending with lactose, povidone and sodium starch glycollate. Lubricate with m~nrcillm stearate and compress to produce tablets ( 1 50mg per tablet).

WO 94/02448 32 PCI/GB93/015~

Example F: Oral capsule Active Ingredient 25.0 mg Starch 1500 100.0 mg Sodium Starch Glycollate 14.0 mg ~gne~ m Stearate 1.0mg Mix together the active ingredient, Starc~ 1500 and sodium starch glycollate before blending with m~gneSillm stearate. Fill power into Size 3 capsule shells (140 mg per capsule).

Example G: Powder capsules for inhalation Active Ingredient (0.5-7.0!1m powder) 1.0 mg Lactose (30-90~m powder) 49.0 mg The powders were mixed until homogeneous and filled into suitably sized hard gelatin capsules (50mg per capsule).

Example H: Inhalation aerosol Active Ingredient (0.5-7.0~Lm powder) 50.0 mg Sorbitan Trioleate 100.0 mg Saccharin Sodium ~0.5-7.0!1m powder) 5.0 mg Methanol 2.0 mg Trichlorofluoro-.,elh~ne 4.2 g Dichlorodifluolo.. ~P~ nf to 10.0 ml The sorbitan trioleate and menthol were dissolved in the trichloro-fluo.u..lelh~ne. The saccharin sodium and active ingredient were dispersed in the mixture which was then L,~1srt:l~ed to a suitable aerosol canister and the dichlorofluolu,~ ne injectedthrough the valve system. This composition provides 0.5mg of active ingredient in each 100,ul dose.

~ WO 94/02448 33 PCI/GB93/01585 21~12I~

BTOLOGICAL DATA

Ex vivo inhibition of 5-lipoxy~enase Pr~limin~ry studies in rabbits in~ ted that the compound of the Synthetic Examples effectively inhibited the stim~ ted svnthesis of leukotriene B4 (LTB4), a compound formed from arachidonic acid via the S-lipoxygenase pathway.
r The test compound was atlmini~tered both intravenously. (1/4 DMSO/3/4 PEG 200) and orally. (0.25% celacol). The concentration of LTB4 in the plasma was measured periodically and expressed as a percentage of the mean control value. The procedure used is described in Br. J. Pharrnacol. 94, 528 (1988) and may be summarised as follows.

Within 2 mimltes of collection, duplicate samples (0.Sml) of blood were equilibrated at 37C for 5 mimltes and then stimnl~ted with the calcium ionophore A23187 (10~
final concentration 1511glml~ for a fi~rther 30 min~ltes at 37C. When incubation was complete, the sarnples were centrifuged (10,OOOrpm for 2 min~tes at 0C) and the cell-free plasma removed. The plasma concentration of LTB4 was dt:Le~ ed by specific radioimml-no~s~y.

At 2mg/kg oral dosing, the compounds of Synthetic Examples 1 and 15 inhibited exvivo LTB4 production by more than 80% for over 12 hours. Under the same conditions, the compounds of Synthetic Examples 2, 3, 11, and 18 gave 80% inhibition for at least one hour. Compounds of the other Synthetic Exarnples were either untested or gave less than 80% inhibition.

In vitro inhibition of 5-lipoxy~enase Leulcocytes were isolated from blood donated by normal aspirin-free volunteers by washing and centrifugation. A solution of the test compound in DMSO (10~1, finalconc~lL,~ion 0.01 - lOO!lM) was added to the washed cell s~Spencion (480~1l) and the mixture in~lh~ted at room temperature for 5 min-ltes The tubes were placed on ice for 5 minlltes and then stimnl~ted with the c~ m ionophore A23157 (10,ul, finalconc~.lLl~ion 2.0~LM) for 5 ,.,;,~ ~les at 37C. The reaction was tel ".;l., ~eri by boiling WO 94/02448 34 PCr/GB93/015~
2~121~ ' and the plasma concellL~tion of LTB4 deterrnined by S~intill~tion Ploxi~ y Assay (SPA).

Each of the compounds of Synthetic Examples 1-19, when tested in this screen, was found to have an average ICso of less~han I~LM, with the exception of Synthetic Examples 8 (2.49~1M), 1'7 (2.79~1M~ Z~h~ 14 (1.48~LM).

In Vitro inhibition of cyclooxv~enase Washed platelet suspensions from healthy human donors were prepared according tothe method of Radomski et al (Thromb. Res., 30, 383-393, 1983). Tubes cont~ininaaliquots (0.5ml) of platelet suspension (107 cells/ml) were in~lb~t~d with test drug or vehicle for S minues at room tenl~el~L.lre before being placed on an ice bath for a further 5 mimltec The calcium ionophore A-23187 was added (final concentration 211M) and the tubes were inc~lhated for S minlltes at 37C. The reaction was terrnin~te~ by boiling for ~ minutes and the cellular pl ecip;~le removed for centrifugation. The thromboxane B~ content of the supelllaLan~ was determined by radio-immllno~c~y, The compounds of Synthetic Exarnples 6, 10, 15, and 19, when tested in this screen, were found to have an ICso f less than 10~

Bronchoconstriction Assav in the Guinea Pig The animals were pre-sPn~iti~ed to antigen (ovalbumin) 2 to 3 weeks prior to testing in the bronrhosp~.~nl model. Compounds were given to the animals orally, 1-6 hours before antigen ~h~ n~e at a dose of lOmg/kg. Control animals were dosed only with vehicle. The time of dosing before ch~llenae was noted. Indometh~rin and l"e~y,~lline were also given 10 minutes before çh~llpn~;p~

A me~ult;d ch~llPnge of nP~blllised antigen was given to ~n~esthPticed animals to pro,llo~e an allerg,ic asthma-like res,uol~se~ and the change in pullllol1~uy infl~tion pressure (PIP) measured. PIP was measured continuollcly from before the challenge for 11 ,..;.~ s WO 94/02448 21~ PCI/GB93/01585 The compound of Synthetic Example 1, when given I hour before challenge gave 64%7 inhibition of response. The compound of Synthetic Example 15 gave 66% inhibition of response when given 6 hours before ch~llenge~

Toxicit,v ~

The compounds of Synthetic Examples 1, 1 1, and 15 were tested in female Wistar rats at 10, 100, and 500 mg/kglday over 14 days. No serious toxic effects were observed.

! ~

Claims (15)

Claims

1. Compounds of formula (I) (I) wherein:

One/both of rings A and B is/are substituted by one or more groups independently selected from halo, cyano, -CONR1R2 (wherein R1 and R2 are independently selected from hydrogen and C1-4 alkyl), and -S(O)nR3 (wherein n is an integer of from 0 to 2, and R3 is C1-4 alkyl, C6-10 aryl, or C8-12 aralkyl);
Y is -HC=CH- ((E) or (Z));

D is C1-4 alkyl or -NR4R5 (wherein R4 and R5 are independently selected from hydrogen and C1-4 alkyl); and R is hydrogen or C1-4 alkyl;

with the proviso that at least one of the substituents on rings A and/or B is other than halo;
or a salt, solvate or physiologically functional derivative thereof.

2. Compounds of formula (Ia) according to claim 1 (Ia) wherein:

A' and B' are independently selected from hydrogen, halo, cyano, -CONR1aR2a (where R1a and R2a are independently selected from hydrogen and C1-4 alkyl), and -S(O)mR3a (where m is an integer of from 0 to 2 and R3a is C1-4 alkyl, C6-10 aryl, or C8-12 aralkyl); and D' is C1-4 alkyl or -NR4aR5a (where R4a and R5a are independently selected from hydrogen and C1-4 alkyl); and R' is C1-4 alkyl;

with the proviso that at least one of A' and B' is other than hydrogen or halogen;
or a salt, solvate, or a physiologically functional derivative thereof.

3. Compounds of formula (I) according to claim 1 wherein:

One/both of rings A and B is/are substituted by one group selected from halo, cyano, and -SO2CH3;
Y is attached to ring B at the 3-position relative to the -O- bridging group;
R is methyl; and D is methyl or amino;
or a salt, solvate, or physiologically functional derivative thereof.

4. A compound of formula (I) according to claim 1 selected from (E)-1-{3-[3-(4-cyanophenoxy)phenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[3-(4-cyanophenoxy)phenyl]-1(R)-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[3-(4-cyanophenoxy)phenyl]-1(S)-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[4-Cyano-3-phenoxyphenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[2-Cyano-5-phenoxyphenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[2-Cyano-3-phenoxyphenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[3-(4-Cyanophenoxy)phenyl]prop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[5-(4-Cyanophenoxy)-2-cyanophenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[2-Cyano-5-(4-fluorophenoxy)phenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[2-Cyano-3-(4-fluorophenoxy)phenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[2-Cyano-3-(4-cyanophenoxy)phenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[3-(4-Cyanophenoxy)-2-cyanophenyl]-1(R)-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[4-Cyano-3-(4-fluorophenoxy)phenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-1-{3-[3-(4-mesylphenoxy)phenyl]-1-methylprop-2-enyl}-1-hydroxyurea;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1(S)-methylprop-2-enyl}-acetohydroxamic acid;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1(R)-methylprop-2-enyl}-acetohydroxamic acid;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1-methylprop-2-enyl}acetohydroxamic acid;

or a salt, solvate, or physiologically functional derivative thereof

5. (E)-1-{3-[3-(4-cyanophenoxy)phenyl]-1-methylprop-2-enyl}-1-hydroxyurea or a salt, solvate, or physiologically functional derivative thereof.

6. (E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1(S)-methylprop-2-enyl}-acetohydroxamic acid or a salt, solvate, or physiologically functional derivative thereof.

7. A salt according to Claims 1 - 6 which is the calcium salt.

8. A method for the prophylaxis or treatment of a clinical condition in a mammal for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway is indicated which comprises administration of a therapeutically effective amount of a compound of formula (I) according to claims 1 - 7, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

9. A method according to claim 8 wherein the clinical condition is asthma.

10. A compound of formula (I) according to claims 1 - 7, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, for use in medical therapy.

11. Use of a compound of formula (I), according to claims 1 - 7, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an inhibitor of the lipoxygenase or cyclooxygenase mediated arachadonic acid metabolic pathway is indicated.

12. A pharmaceutical formulation comprising a compound of formula (I) accordingto claims 1 - 7, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.

13. A process for preparing the compounds of formula (I), according to claims 1 -7, or salts, solvates, or physiologically functional derivatives thereof which comprises reacting a compound of formula (II) (II) wherein Y, R, and the substituents on rings A and B are as defined for the compound of formula (I), according to claims 1 - 7, or a salt thereof, with a suitable agent or agents to effect conversion of the N-hydrogen to an N-COD
group, where D is C1-4 alkyl, or -NR4R5 (wherein R4 and R5 are independently selected from hydrogen and C1-4 alkyl); followed by optional conversion to a salt, solvate, or physiologically functional derivative thereof.

14. Compounds of formula (II) (II) wherein Y, R, and the substituents on rings A and B are as defined for compounds of formula (I), according to claims 1 - 7, or a salt thereof.

15. A compound of formula (II), or a salt thereof, according to claim 14 selected from (E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1-methylprop-2-enyl}-hydroxyammonium p-toluenesulphonate;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1(R)-methylprop-2-enyl}-hydroxyammonium p-toluenesulphonate;

(E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1(S)-methylprop-2-enyl}-hydroxyammonium p-toluenesulphonate; and (E)-N-{3-[3-(4-cyanophenoxy)phenyl]-1(S)-methylprop-2-enyl}-hydroxylamine.