CA2135479C - Styryl derivatives, their preparation and use as pde-iv inhibitors - Google Patents

Abstract

Compounds of general formula (1) are described (see formula 1) wherein Y is a halogen atom or a group -OR1, wherein R1 is C1-13 alkyl group which is either unsubstituted or substituted with one or more halogen atoms; X is -O-, -S-, or -N(R6), wherein R6 is a hydrogen atom or C1-6 alkyl group; R2 is C3-8 cycloalkyl or C3-8 cycloalkenyl group either unsubstituted or substituted with up to three substituents of specific types; R3 and R4, which may be the same or different, is each a hydrogen atom or C1-6 alkyl (optionally substituted with substituents of specific types), -CN, -CH2CN, -CO2R7, -CONR8R9 or CSNR8R9 (wherein R7, R8 and R9 represent groups of a specific type); Z is -(CH2)n- where n is zero or an integer 1, 2 or 3; R5 is a C6-12 monocyclic or bicyclic aryl group or a C1-9 monocyclic or bicyclic heteroaryl group containing up to four heteroatoms, the aryl group being either unsubstituted or substituted with up to four substituents of specific types; or a salt, solvate, hydrate, or N-oxide thereof.
Compounds according to the invention are potent and selective phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of diseases such as asthma where an unwanted inflammatory response or muscular spasm is present.

Description

'.CVO 94/20455 '~ ~ PCT/GB94/00452 STYRYL DERIVATIVES, THEIR PREPARATION AND USE AS PDE-IV INHIBITORS
This invention relates to a novel series of styryl derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of adenosine 3', 5'-cyclic monophosphate ;cAMP). The cellular levels of CAMP are regulated by mechanisms which control synthesis and breakdown. The synthesis of cAMP is controlled by adenyiyl cyciase which may be directly activated by agents such as forskolin or indirectly activated by the binding of specific agonists to cell surface receptors which are coupled to adenylyl cyciase. The breakdown of cAMP is controlled by a family of phosphodiesterase (PDE) isoenzymes, which also control the breakdown of guanosine 3',5'-cyclic monophosphate (cGMP). To date, seven members of the family have been described (PDE 1-VII) the distribution of which varies from tissue to ~0 tissue. T his suggests that specific inhibitors of PDE isoenzymes could achieve differential elevation of cAMP in different tissues, (for reviews of PDE distribution, structure, function and regulation, see Beavo &
~eifsnyder ( 1990) TIPS, i 1: 15G- i 55 and Nicholson et al ( 1991 ) TIPS, 12:
9_27).
There is clear evioence that elevation of cAMP in inflammatory leukocytes leads to inhibition of their activation. urthermore, elevation of cAMP in airway smooth muscle has a spasmoiytic effect. In these tissues, PDE IV
plays a major role m the hydrolysis of CAMP. it can be expected, ~0 herefore, that selective inhibitors or PDE iV would have therapeutic effects in inflammatory diseases sucn as asthma, by achieving both anti-inflammatory and broncnodilator effects.
T he design of PDE 1V inhibitors has met with limited success to date, in 35 :hat many of the potential PDE iV inhibitors which have been synthesised nave lacked potency and/or nave been caa7able of inhibiting more than one l~ 2 f-ype of PDE isoenzyme in a non-selective manner. Lack of a selective action has been a particular problem given the widespread role of cAMP in_ viv and what is needed are potent selective PDE IV inhibitors with an inhibitory action against PDE IV and little or no action against other PDE
isoenzymes.
We have now found a novel series of styryl derivatives, members of which, compared to known structurally similar compounds, are potent inhibitors of PDE 1V at concentrations at which they have little or no inhibitory action on other PDE isoenzymes. These compounds inhibit human recombinant PDE IV enzyme and also elevate cAMP in isolated leukocytes. Certain compounds prevent inflammation in the lungs induced by carrageenan, platelet-activating factor (PAF), interleukin-5 (IL-5) or antigen challenge.
These compounds also suppress the hyperresponsiveness of airway smooth muscle seen in inflamed lungs. Advantageously, compounds according to the invention nave good oral activity and at orally effective doses exhibit little or none of the side-effects associated with known PDE
IV inhibitors, such as rolipram. The compounds of the invention are therefore of use in medicine, especially in the prophylaxis and treatment of asthma.
Thus according to one aspect of the invention, we provide a compound of formula (1 ) I/
~~v(R3)=C(R'')ZR' (1 ) wherein Y is a halogen atom or a group -ORS ~ where R~ is an optionally substituted alkyl group;
~0 X is -O-, -S-, or -N(R6)-, where R6 is a hydrogen atom or an optionally substituted alkyl group;
R2 is an optionally sunstituted cycloaikyl or cycloalkenyl group;

R3 and R4, which may be the same or different, is each a hydrogen atom or an optionally substituted alkyl, -C02R~ (where R~ is a hydrogen atom, or an optionally substituted alkyl, aralkyl or aryl group), -CONR8R9 (where R8 and R9 which may be the same or different is as described for R~), -CSNR8R9, -CN or -CH2CN group;
Z is -(CH2)n- where n is zero or an integer ~ , 2 or 3;
R5 is an optionally substituted monocyciic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;
and the salts, solvates, hydrates, prodrugs and N-oxides thereof.
The compounds of formula (1 ) exist as geometrical isomers, and the invention extends to all such individual isomers and mixtures thereof.
Formula {1) and the formulae hereinafter should be understood to include all individual isomers and mixtures thereof. ~niess stated otherwise, and even though only one isomer may be depicted.
In the compounds of formula (1 ), vvnen Y is a halogen atom it may be for example a fluorine, chlorine. bromine or iodine atom.
'Nhen Y in the compounas of formula (1) is a group -ORS. R~ may be, for example, an optionally substituted straight or branched C1_3alkyi group, such as a methyl, athyl, n-propyi, or i-propyl groups. Optional substitutents which may be present on R~ groups include one or more halogen atoms, 2.g. fluorine. or chlorine atoms.
When X in compounds of formula ( ~ ) is a -V(R6)- group it may be a -NH-group or a group -N{Rb!- where R6 vs an optionally substitued C1_6 alkyl group such as a methyl or ethyl group.
~Nhen R2 in the compounds of formula ( 1 ) is an optionally substituted cycloalkyi or cycioaikenyi group ii may be for example a C3_8cycloalkyl group such as a cyclodutyl, cyctopentyi or cyclohexyi group or a C3_8 cycioalkenyl group containing for example one or two double bonds such ;,5 as a 2-cycfobuten-1-vl, 2-cyciooenten-?-yl, 3-cyclopenten-1-yl, 2,4-~yciopentadien-i-yl, ~-cyclohexen-1-vl, 3-cvciohexen-?-yl, 2,4-WO 94120455 ~ PCTlGB94/00452 cyclohexadien-1-yl or 3,5-cyclohexadien-1-yl group, each cycloalkyl or cycloalkenyl group being optionally substituted by one, two or three substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, siraight or branched C1_6alkyl e.g. C1_3alkyl such as methyl or ethyl, hydroxyl or C1_salkoxy e.g. Cy_3alkoxy such as methoxy or ethoxy groups.
Alkyl groups represented by R3 and R4 in compounds of formula (1 ) include optionally substituted straight or branched C1_6 alkyl groups for example Cy_3 alkyl groups, such as methyl, ethyl n-propyl or i-propyl groups. Optional substituents which may be present on R3 or R4 include one or more halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl or C1_s alkoxy e.g. Cy_3 alkoxy such as methoxy or ethoxy groups, or thiof or Ci _6 alkylthio e.g. C1 _3 alkythio such as methylthio or ethylthio groups. Particular examples of R3 or R4 alkyl groups include -CH3, -CH2CH3, -CH20H, -CH2C1, -CH2F, -CHC12, -CHF2 and -CH20CH3 groups.
When R3 and/or R4 is a -C02R~, -CONR8R9 or -CSNR8R9 group it may be for example a -C02H, -CONH2, or -CSNH2 group, or a group -C02R~, -CONR8R9, -CSNR8R9, -CONHR9, or -CSNHR9 wherein R~, R8 and R9 where present is a C~_3 alkyl group such as a methyl or ethyl group, a C6-~ 2 aryl group, for example an optionally substituted phenyl, or a 1- or 2-naphthyl group, or a C6_i 2 arylC~ _3 alkyl group such as an optionally substituted benzyl or phenethyi group. Optional substituents which may be present on these groups include R» substituents discussed below in relation to the group R5.
In the compounds of formula (1) Z may represent a bond connecting the group Rs to the rest of the molecule, or represents a group -CH2-, -(CH2)2- or -(CH2)3-.
lllonocyclic or bicyclic aryl groups represented by the group R5 in compounds of formula i11 include for example Cs-~2 optionally substituted aryl groups, for example optionally substituted phenyl, 1-or 2-naphthyl, indent' or is~indeny groups.

WO 94/20455 213 5 4 ~' 9 PCT/GB94/00452 When the monocyciic or bicyclic aryl group contains one or more heteroatoms it may be a C~-9 for example a C3_9, optionally substituted heteroaryi group containing ror example one, two, three or more 5 heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, heteroaryl groups may be for example monocyclic or bicyciic heteroaryi groups. Monocycfic heteroaryl groups include for example five-or six-membered heteroaryl groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Examples of heteroaryl groups represented by R5 include pyrroiyl, furyl, thienyl, imidazolyl, N-methylimidazoiyl, N-ethyiimidazoiyl, oxazofyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazoiyl, ~ ,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazoiyl, 1,2,5-oxadiazoiyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyi, pyridazinyl, pyrazinyi, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2.3-triazinyl, benzofuryl, isotienzofuryi, benzothienyi, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazoiyl, quinazoiinyl, r~aphthyridinyl, pyrido[3,4-b]pyridyi, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyi, quinofinyl, isoquinolinyl, tetrazoiyl, 5,6,7,8-tetra-hydroquinoiinyl and 5,6,7,8-tetrahyaroisoquinoiinyl.
The heteroaryi group represented by R5 may be attached to the remainder of the molecule of formula (1) through any ring carbon or heteroatom as appropriate. Thus. for example, wnen the heteroaryl group is a pyridyl group it may be a 2-pyridyl, 3-pyridyl or 4-pyridyl group. When it is a ;hienyi group it may be a 2-thienyl or 3-thienyl group, and, similarly, when it is a Turyl group ii may be a 2-furyl or 3-furyl group. '~Illhen it is a pyridazinyi group ii may be a 3- or ~- oyridazinyi group, and when it is an imidazoiyi group it may oe a 1-, 2-. .+- or 5- imidazoiyi group.
When in compounds of formula (1; the heteroaryi group is a nitrogen-containing neterocycle ~t may de possible to form quaternary salts, for example N-alkyl quaternary salts and the invention is to be understood to extend to such salts. Thus for cxampfe when the heteroaryl group is a pyridyl group, pyridinium salts may be ~ormed, nor example N-aikyfpyridinium salts such as N-methyipyridinium.

WO 94I204SS PCTlGB94100452 '~~ ~'~ ~J 6 The aryl or heteroaryi groups represented by R5 in compounds of formula (1) may each optionally be substituted by one, two, three or more substituents [R~°]. The substituent R» may be selected from an atom or group R> > or -Alk~ (R' ~ )m wnerein R> > is a halogen atom, or an amino (-NH2), substituted amino, nitro, cyano, hydroxyl (-OH), substituted hydroxyl, cycioalkoxy, formy~ [HC(O)-], carboxyl (-C02H), esterified carboxyl, thiol (-SH), substituted thioi, -C(O)R~a [where Rya is as defined above for R~], -S03H, -S02R~a, -j02N[R~aR~], (where R~ is as defined for Rya and may be the same as or different to Rya), -CON[R~aR8a], -NHS02R~a, -N[S02R~a]2, -NHS02N[R~aR8a], -NHC(O)R~a, or -NHC(O)OR~a group; AIk1 is a straight or branched C1-salkylene, C2_ salkenylene, or C2_salkynyiene chain optionally interrupted by one, two, or three -O-, or -S- atoms or -S(O)p-, [where p is an integer 1 or 2] or -N(R6)-groups; and m is zero or an integer 1, 2 or 3.
When in the group -Alk~(R~~)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R> > may be present on any suitable carbon atom in -Alk~ . Where more than one R~ ~ substitutent is present these may be the same or different and may be present on the same or different carbon atom in Alk~ . Clearly, when m is zero and no substituent R~ i is present the alkyfene, alkenylene or alkynylene chain represented by Alk~ necomes an alkyl, alkenyl or alkynyl group.
'Nhen R> > is a substituted amino group it may be a group -NH[Alk~ (R~2)ml [where Alki and m are as defined above and R~2 is as defined above for R~1 but is not a substituted amino, a substituted hydroxyl or a substituted thiol group] or a group -N[Alk~ (R~2?m]2 wherein each -Alk~ (R12)m group is the same or different.
When R> > is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R1 i is a cvcioalkoxy group it may be for example a C5_~cycloaikoxy group such as a cvciopentyloxy or cyciohexyloxy group.

t When R> > is a substituted hydroxyl or substituted thiol group it may be a group -OAIk~(R~2)m or -SAIk~(R~2)m respectively, where Alk~, Ri2 and m are as just defined.
Esterified carboxyl groups represented by the group R~ ~ include groups of formula -C02AIk2 wherein AIk2 is a straight or branched, optionally substituted C~_8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6_~2arylC~-8alkyl group such as an optionally substituted benzyf, phenyiethyl, phenylpropyl, 1-naphthyimethyl or 2-naphthyimethyl group; a C6_l2aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a Ca.~2 aryioxyC~_8aikyi group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, ~ -naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted Cy _$alkanoyioxyC~ _8alkyl group, such as a pivaloyloxymethyl, propionyioxyethyi or propionyioxypropyi group; or a C6_~2aroyloxyCy_8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyi group. Optional substituents present on the AIk2 group include Rio substituents describeo above.
When Alk~ is present in or as a substituent R~ c it may be for examale a rnethyiene, ethylene, n-propylene, i-propylene, n-butyiene, i-butylene, s-bmylene, t-butyiene, ethenyiene, 2-propenyiene, 2-butenylene, 3-butenyiene, ethynyiene. 2-propynyiene, 2-buiynyiene or 3-butynyiene chain. optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O)-, -S(O)2- or -N(R6)- groups.
°articulariy useful atoms or groups represented by R» include fluorine, chlorine, bromine or iodine atoms, or C1_saikyl, e.g. methyl or ethyl, C1_ 3C salkylamino. e.g. methylamino or ethylamino. C1_6 hydroxyafkyl, e.g.
~ydroxymethyi or hydroxyethyl, C1_6alkyithioi e.g. methyithioi or ethyithiol, C~_6aikoxy, e.g. methoxy or ethoxy, Cs_;cycioaikoxy, e.g. cyclopentyloxy, naioCi_6aikyf, e.g. trifluoromethyl, C1_6alkviamino, e.g. methyfamino or 3thvlamino. amino i-NH2), aminoC~_6alkyl, e.g. aminomethyl or aminoethyl, C~_6dialkyiamino, e.g. dimethylamino or diethylamino, vitro, cyano, hyaroxyi (-OH), ;ormyi jHC(O)-], -CO?H, -C02AIk2jwhere AIk2 is as defined above], Ci_6 alkanoyi e.g. acetyl, thiol (-SH), thioCl_salkyl, e.g. thiomethyl or thioethyl, sulphonyl (-S03H), C~_6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (-S02NH?), C~_6alkylaminosuiphonyl, e.g. methylamino-sulphonyi or ethyiaminosumhonyl, C~_sdialkylaminosulphonyf, e.g.
dimethylaminosuiphonyl or diethyiaminosulphonyl, arylaminosulphonyl, e.g.
optionally substituted phenyiammosulphonyl, araikylaminosulphonyl, e.g.
optionally substituted benzyiaminosuiphonyl, carboxamido (-CONH2), C~_ 6alkylaminocarbonyl, e.g. methyiaminocarbonyi or ethylaminocarbonyl, C~_ sdialkylaminocarbonyl, e.g. dimethyl-aminocarbonyl or diethylamino-carbonyl, sulphonylamino (-NHS02H), Ci_6alkylsulphonyiamino, e.g.
methylsulphonyiamino or ethyisulphonyl-amino, Cy~dialkyisuiphonylamino, e.g. dimethylsuiphonyiamino or diethyl-sulphonylamino, aminosulphonyl-amino (-NHS02NH2), C1_6alkytaminosutphonylamino, e.g. methylamino-sulphonylamino or ethyiammosuiphonyiamino, C~_sdialkylaminosulphonyl-amino, e.g. dimethylaminosuiphonylamino or diethylaminosulphonyiamino, C1_6alkanoylamino, e.g. acetylamino, C1_6alkanoyfamino C~_6alkyl, e.g.
acetylaminomethyl or Ci_6alkoxycarbonylamino, e.g. methoxycarbonyl-amino, ethoxycarbonylamino or t-butoxycarbonylamino groups.
Where desired, two R» substituents may be finked together to form a cyclic group such as a cyclic ether. e.g. a C2_6alkylenedioxy group such as ethyienedioxy.
It will be appreciated that where two or more R» substituents are present, these need not necessarily be the same atoms and/or groups. The R~
substituents may be present at any ring carbon atom away from that attached to the rest of the molecule of formula (1 ). Thus, for example, in phenyl groups represented by R5 any substituent may be present at the 2-, 3-, 4-, 5- or 6- positions relative to the ring carrion atom attached to the remainder of the molecule.
in the compounds of formula (1 ), when an ester group is present, for example a group -C02AIk2 this may advantageously be a metabolically labile ester.
~5 v The presence or certain substituents in the compounds of formula (1 ) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids. and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besyfates or ~ 0 napsylates, phosphates. sulphates. hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maieates, fumarates, maionates.
succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts 15 such as sodium or potassium salts. alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethyiamine salts.
Particularly useful salts of compounds according to the invention include 20 pharmaceutically acceptable salts. especially acid addition pharmaceutically acce~tabte salts.
Prodrugs or compounds or formula ( 1 ) include those compounds for example esters. aiconots or amines. which are convertible, i. n vivo, by ?5 metabolic means, e.g. by hydrolysis. reduction, oxidation or transesterification, to compounds of formula (1 ).
in general in compounds or formula (1 ), the group a5 and the phenyl ring to which the group C(R3)=C(R4)ZR5 is attached are in a "trans" position 30 relative to one another.
in the compounds of formula (1 ), the group '! is preferably an -4R~ group, aspecrally where R~ is an optionally surJStituted C~_3alkvi group, particularly an ethyl group or, =specially, a methyl group. especially useful 35 substituents which may be present on R~ groups include one, two or three fluorine or chlorine atoms.

The group X in compounds of formula (1 ) is preferably -O-.
A particularly useful croup of compounds of formula (1 ) has the formula 5 (2):

CH30~~
I
C(R3) L(R'~)ZRs (2) where R2 is an optionally substituted cycloalkyl group; R3 ,R4, R5 and Z
10 are as defined for formula (1 ); and the salts, solvates, hydrates and N
oxides thereof.
In the compounds of formulae (1) and (2) R2 is preferably an optionally substituted cyciopentyl group. in particular, R2 is a cyclopentyl group.
The group R3 in compounds of formulae (1 ) or (2) is preferably a -CH3 group, or especially a hydrogen atom.
In compounds of formulae (1 ) or (2) the group R4 is preferably a hydrogen atom, a -CN or a -CH3 group.
Z in the compounas of formulae (1 ) or (2) is preferably -(CH2)~- where n is zero. 1 or 2. In particular. however, Z is especially -(CH2)~- where n is zero.
R5 in the compounds of formulae (1 ) or (2) is preferably an optionally substituted phenyl group, particularly a phenyl group optionally substituted by one, two or more R~ ~ groups, and is especially a 2-, 3- or 4-monosubstituted or 2,6-disubstituted phenyl group. Particular substituents incnde halogen atoms, especially fluorine or chlorine atoms and nitro, amino, aikoxy, ;laioalkyl, hydroxy, -NHCOR7a, -NHCONHR~a and -NHS02R~a groups.

Particular R5 groups include 2-nitrophenyl, 2-haloalkyiphenyl, e.g. 2-trifluoroalkylphenyl, 2-halophenyi, e.g. 2-fluorophenyi, 2-chlorophenyl, or 2-bromophenyl, 3-halophenyl, e.g. 3-fluorophenyl, 4-hydroxyphenyl, 2,6-di-halophenyl, e.g. 2,6-difluorophenyl, or 2,6-dichlorophenyl and 2,6-dialkoxyphenyl, e.g. 2, 6-dimethoxyphenyl.
Other particularly useful R5 groups in compounds of formulae (1) and (2) include 2-,3- and 4-pyridinyl, thienyi e.g. 2-thienyl, pyridazinyl, e.g. 3- or pyridazinyl, and imidazolyl e.g. 1-, 2-, 4- or 5- imidazolyl groups, optionally substituted by one, two or more R~~ groups, especially halogen atoms.
e.g. fluorine or chlorine atoms, e.g. 3,5-dichloro-4-pyridinyi, nitro, amino, alkoxy, hafoaikyl, hydroxy, -NHCOR~a, -NHCONHR~a or -NHS02R7a groups.
Particularly useful groups of compounds of formulae (1) or (2) are those ~Nherein R3 is a hydrogen atom, R4 is a hydrogen atom, or a -CH3 or -CN
group and Z is a group (CH2)~ where n is zero, and the salts, solvents, hydrates and N-oxides thereof. specially useful compounds in groups of these types are those wherein R5 is an optionally substituted phenyl or pyridinyi group.
Particularly useful compounds according to the invention are Z)-3-(3-Cyclopentyfoxy-~-methoxyphenyl)-2-(4-hydroxyphenyl) propenenitrile;
(E)-4-f2-(3-Cyciopentyloxy-~-methoxyphenyf)ethenyi]pyridine;
Z)-4-[2-(3-Cyciopentyloxy-4-methoxypnenyi)ethenyl]pyridine;
~Z)-3-(3-Cyclopentyloxy-~-methoxypnenyi)-2-i_2-nitrophenyl)propenenitrile;
(Z)-3-(3-Cyciopentyloxy-4-methoxyphenyi)-2-(4,5-dichioro-1-imidazolyl) propenenitrile :;Z)-3-f3-Cycfopentyioxy-~t-methoxyphenyi )-2-(4-pyridyl)propenenitrile;
e;E)-~-(2-[1-(3-Cyciopentyloxy-~+-methoxy)phenyl]-1-propenyl}pyridine;
aZ)-3-(3-Cyciopentyloxy-4-methoxyphenvi)-2-(2-thienyi) propenenitrile;
Z)-3-(3-Cyclopentyioxv-~-methoxyphenyi)-2-(2,6-difluoropnenyl) arooenenitrile;

WO 94/20455 ~ PCT/GB94100452 ~13'~ 12 (E)-4-[2-(3-Cyclopenryioxy-4-methoxyphenyl)ethenyl]-3,5-dichloropyridine;
(Z)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)-propenenitrile;
N-{4-[2-(3--Cyclopentyioxy-4-methoxyphenyl)ethenyl]-3-pyridyl}
phenyisufphonamide;
(E)-4-[2-(3-Cyciopentyfoxy-4-methoxyphenyl)ethenyl]-3-nitropyridine;
(E)-2-[2-(3-Cyclopentyloxy-4-methoxyphenyl)ethanyl]pyridine;
(E)-4-[2-{3-Cyclopentyloxy-4-methoxyphenyl)ethenyl]pyrimidine; or (E)-4-[2-(3-Cyclopentyioxy-4-methoxyphenyl)ethenyl]pyridazine;
and the salts, solvates, hydrates and N-oxides thereof.
Compounds according to the invention are selective and potent orally active inhibitors of PDE IV. The ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of human or animal diseases where an unwanted inflammatory response or muscular spasm (for example bladder or alimentary smooth muscle spasm) is present and where the elevation of cAMP levels may be expected to prevent or alleviate the inflammation and relax muscle.
Particular uses to which the compounds of the invention may be put include the prophylaxis and treatment of asthma, especially inflamed lung associated with asthma, cystic fibrosis, or in the treatment of inflammatory airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis and other benign and malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis. Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticana. adult respiratory distress syndrome, diabetes insipidus, allergic rhinitis. allergic contunctivitis, vernal conjunctivitis, arterial restenosis and artherosclerosis.
Compounas of the invention a~so suppress neurogenic inflammation ~hrougn elevation of cAMP in sensory neurones. They are, therefore, Wo ~4/2°4~5 2 ~ 3 5 4 7 9 analgesic, anti-tussive and anti-hyperalgesic in inflammatory diseases associated with irritation and pain.
Compounds according to the. invention may also elevate cAMP in lymphocytes and thereby suppress unwanted ly~n~hoc te~,ayptivation. in immune-based diseases such as rheumatoid arthritis; w~nkyiosing spondyiitis, transplant rejection and graft versus host disease.
Compounds according to the invention have also been found to reduce gastric acid secretion and therefore can be used to treat conditions associated with hypersecretion.
Compounds of the invention suppress cytokine synthesis by inflammatory cells in response to immune or infectious stimulation. They are, therefore, useful in the treatment of bacterial, fungal or viral induced sepsis and septic shock in which cytokines such as tumour necrosis factor (TNF) are key mediators. Also compounas of the invention suppress inflammation and pyrexia due to cytokines and are, therefore, useful in the treatment of inflammation and cytokine-mediated chronic tissue degeneration which occurs in diseases sucr~ as rheumatoid or osteo-arthritis.
Over-production of cytokines such as TNF in bacterial, fungal or viral infections or in diseases such as cancer, leads to. cachexia and muscle wasting. Compounds of the invention ameliorate these symptoms with a conseauent enhancement or auaiity of life.
Compounds or the invention also elevate cAMP in certain areas of the brain and thereby counteract aeoression and memory impairment.
Compounds of the invention suppress cell proliferation in certain tumour cells ana can be used. therefore. to prevent tumour growth and invasion of normal tissues For the prophyiaxis or treatment or disease the compounds according to the invention may be administerea as pharmaceutical compositions, and according to a further aspect or the invention we provide a pharmaceutical c~'t~ ~,~ ~ 14 composition which comprises a compound of formula (1 ) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccai. parenteral or nasal administration, or a form suitable for administration by inhalation or insufflation. Forms suitable for oral administration are particularly useful.
For oral administration, the pharmaceutical compositions may take the form of, for example. tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregeiatinised maize starch, poiyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated for adult or pediatric use and/or to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion.
Formulations for injection may be presented in unit dosage form. The compositions for injection may Lake such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising andjor dispersing agents.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
5 In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection. For transdermal administration, the compounds according to the invention may be formulated in delivery vehicles such as patches, For nasal administration or administration by inhalation, the compounds fog use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the ?0 active ingredient. The pack or dispense device may be accompanied by instructions for administration. .
The quantity of a compound of the invention required for the prophyiaxis or treatment of a particular inflammatory condition will vary depending on the compound chosen, and the condition of the patient to be treated. fn general, however, daily dosages may range from around 100ng/kg to 1 OOmg/kg, e.g. around 0.01 mgikg to ~Omg/kg body weight for oral or buccai administration. trom around l0ngikg to 50mg/kg body weight for parenteral administration, and around 0.05mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
The compounds according to the invention may be prepared by the following processes. T he symbols Y. 1~2. A3, R4. R5, X and Z, when used .n tr;e formulae below are to be understood to represent those groups described above in relation to formula (1 ) unless otherwise indicated.

WO 94120455 ~ PCT/GB94/00452 1s Thus according to a further aspect of the invention, a compound of formula (1) may be prepared by reacting a compound of formula (3):
x-R2 I
W (3) where (a) W is a -C(O)R3 group wherein R3 is as defined for formula (1 ) but is not a -CN or -CH2CN group, with a compound R5ZCH2R4; or where (b) W is a -CH2R3 group with an aldehyde or ketone R5ZCOR4, where R4 is as just defined for R3; or where (c) W is a -CO(R)3 groin with a silane derivative AIk3SiCH(R4){R5), where Alk is an alkyl group; in the presence of a base or an acid in a suitable solvent.
Bases for use in these reactions include inorganic bases, for example alkali and alkaline earth metal bases, e.g. hydroxides, such as sodium or potassium hydroxide; alkoxides, for example sodium ethoxide, and organic bases, for example amines such as piperidine; or an organolithium, such as an alkyllithium, e.g. n-butyllithium. Suitable solvents include alcohols such as ethanol, or ethers such as tetrahydrofuran. Acids for use in the reaction include organic acids, e.g. carboxylic acids such as acetic acid.
The reaction may be performed at any suitable temperature, for example from around -78°C to ambient temperature to the reflux temperature depending on the nature of the starting materials.
In general, the base. acid, solvent and reaction conditions may be selected depending on the nature or the starting materials, from a range of known alternatives for reactions of this type.

in silane derivatives of formula Alk SiCH(R4)(R5), Alk may be for example a C1_6alkyl group such as a methyl group. Derivatives of this type may be prepared for example by reacting a compound R5-CH2-R4 with a silane 213 ~ 4 7 9 pCT~GB94/00452 derivative, such as chlorotrimethylsilane, in the presence of a base, e.g.
Lithium diisopropylamide, in a solvent, e.g. tetrahydrofuran, at a low temperature e.g. around -10~C.
The starting materials R5ZCH2R4, RSZCOR4, and R5CH2R4 are either known compounds or may be prepared from known starting materials by methods analogous to those used for the preparation of the known compounds.
Intermediates of formula (3) where W is a -C(OlR3 group where R3 is an alkyl group, such as a methyl group, may be prepared by reacting an aldehyde of formula (3) where W is a -CHO group with an organometallic reagent, such as methyimagnesiumbromide, in a solvent, e.g.
tetrahydrofuran, at low temperature, e.g. around 10~C, followed by oxidation with an oxidising agent, such as manganese dioxide, in a solvent, e.g. dichforomethane.
Alternatively, intermediates of formula (3) may be prepared by alkylation of a corresponding compound of formula (4) X-H
~r j (4) using a compound R2Hal (where Hal is a halogen atom such as a bromine or chlorine atom] where necessary m the presence of a base such as caesium or potassium carnonate or an alkoxide such as potassium t-butoxide, in a dipo~ar aprotic solvent such as an amide, e.g. a substituted amide such as dimethyiformamide at ambient temperature or above e.g.
around 40oC to 50oC.
Intermediates of formula (41 are either known compounds or may be prepared from known starting materials by methods analogous to those used for the preparation of the known compounds.

In another aspect of the invention, a compound of formula (1) may be prepared by alkylation of a compound of formula (5) XH
Y I
C(R3)=C(R4)ZR~
(5) with a halide R2Hal, or with an aiconol R20H.
The alkylation with the halide R2Hai may be performed using the reagents and conditions described above for the preparation of compounds of formula (4). Alkylation using an alcohol R20H may be performed in the presence of a phosphine, such as triphenylphosphine, and an activator, for example diethyl azodicarboxylate, in the presence of an organic base such as triethyfamine in a solvent such as tetrahydrofuran at an elevated temperature, e.g. the reflux temperature [see for example Mitsunobu, O., ,5 n h i , 1981, 1].
Intermediates of formula (5) may be prepared by reaction of an aldehyde or ketone of formula {4) with a compound R5ZCH2R4 as described above for the preparation of compounds of formula (1) from compounds of formula (3). In this reaction the group X-H may need to be in a protected state. Conventional hydroxy. amino or thiol protecting groups may be used in accordance with standard practice [see, for example,. Green T.W., in "Protective Groups in Organic Synthesis" John Wiley and Sons, 1981].
According to a further aspect of the invention a compound of formula (1 ) may be arepared by aehydration of an alcohol of formula (6) I/
i~
~C(R~)(OH)CH(R'~)(ZRs) (6) ,9 using an acid at an elevated temperature.
Suitable acids include for example phosphoric or sulphonic acids, e.g. 4-toiuenesulphonic acid. The reaction may be performed in an inert organic solvent, for example a hydrocarnon such as toluene, at an elevated temperature, for example the reflux temperature.
Intermediate alcohols of formula (6) may be prepared by reaction of a ketone of formula (3) with an organometallic reagent R4R5ZCHM [where N
is a metal atom, for example a lithium atom] in a solvent such as an ether, e.g. a cyclic ether such as tetranydrofuran, at a low temperature e.g.
around -70oC to ambient temperature.
Reagents R4R5ZCHM are either Known compounds or may be preparea.
preTerably in i during the above process, by reaction of a compound AIkCH2M or (Alk]2NM [where Alk is an alkyl group such as a n-propyl or i-propyi group] with a compound R4R5ZCH2 using the just mentioned reaction conditions.
According to a still furtner aspect of the invention, a compound of formula (1 ) may be prepared by reaction or a phosphonium salt R13P+Ar3Haf-where R~3 is a group of formula X_R 2 j') ~. ~i v \CHR' s ;fir is an aryl group such as a phenyl group and Hal is a halogen atom such as a chlorine, bromine or iodine atom. with a compound RSZCOR4 in the presence of a base in a suitable solvent.
3G 3ases for use in this reaction incnde alkoxides. .or example alkali metal aikoxides sucn as soaium ethoxide or organometailic bases such as phenyilithium. ~uitabie solvents include aicohois, such as ethanol, and a ethers, e.g. cyclic ethers such as tetrahydrofuran. The reaction may generally be performed at ambient temperature.
Intermediate phosphonium salts of formula R~3P+Ar3Hal- may be ;, prepared by reaction of a halide of formula (7) x-RZ
Y
CH(R'')(Hal) (7) with a phosphine Ar3P.
Intermediate halides of formula (7) may be prepared by reaction of an alcohol of formula (8) ,f ~1 CH(R3)(OH) (8) with a hydrogen halide in a solvent such as an ether.
Intermediate alcohois of formula (8) may be prepared by alkylation of a compound of formula (9) x-H
w i~
CH(R3)(OH) (9) with a halide R2Hal as described above for the preparation of compounds of formula (1 ) from intermediates of formula (5).

WO ~~5 Intermediates of formula (9) are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds.
In yet another aspect of the invention, a compound of formula (1) may be prepared by reaction of a phosphonate ester of formula (10) x-RZ
W
CH?R~4 ( 10) [wherein R» is a -P(O)(OR»)(OR~6) group, where R~5 and Ris, which may be the same or different is each an alkyl, e.g. ethyl, aryl, e.g. phenyl or araikyl e.g. benzyi group] with a compound RSZCOR4 in the presence of a base in a suitable solvent.
Suitable bases include hydrides such as sodium hydride and alkoxides, for example alkali metal alkoxides such as sodium ethoxide. Solvents include .hers, for example cyclic ethers such as tetrahydrofuran.
Phosphonate esters of formula (10) may be prepared by a Michaelis Arbuzov reaction of a halide of formula (8) with a phosphite °(OR~S)20R~6.
Compounds of formula (1 ) may also be prepared by interconversion of other compounds of formma (.1 ). i hus, .or example, a substituted monocyclic or bicyclic aryl group R5 in compounds of formula (1 ) may generally be obtained by an appropriate sunstitution reaction using the corresponding unsubstituted compound of formula (1) and a Rio containing nucleoahile or eiectrophile. Similarly, where it is desired to obtain a compound or formula (1 ) where R3 and/or R4 is other than a hydrogen atom. an appropriate nucieophile aria reagents and/or reaction conditions savouring nucleophilic addition. may be used with the corresponding compound of formula (1 ) where R3 and R4 is a hydrogen atom. Alternatively. a group R3 and/or R4 in formula (1 ) may be WO 94/20455 ~"~~ PCT/GB9410C452 manipulated using conventional chemical procedures to yield other groups R3 andlor R4.
Thus, in one example of an interconversion process a compound of formula (1 ) wherein R5 contains a -CH2NH2 substituent may be prepared by reduction of a corresponding compound wherein R5 contains a nitrite group, using for example a complex metal hydride such as lithium aluminium hydride in a solvent such as an ether e.g. diethylether.
In a further example, a compouna of formula (1 ) wherein R5 contains -NHCOR~a, -NHCONHR~a, -NHCON(R~a)2, -NHCSR~a or aikanoyiamino-alkyl substituent may be prepared by acylation or thiolation of a corresponding compo~~nd wnerein R5 contains a -NH2 or alkylamino group by reaction with an acyl halide e.g. an acyl chloride, an acyl alkyl or aryl isocyanate or a thioi halide in the presence of a base, such as a tertiary amine e.g. triethylamine or pyridine, optionally in a solvent such as dichloromethane.
in a still further example, a compound of formula (1) wherein R5 contains an alkoxy substituent may be prepared by alkylation of a corresponding compound wherein R5 contains a hydroxyl group by reaction with a compound AIkHaI [where Alk is a Ci_6 alkyl group such as a methyl or ethyl group and Hal is a halogen atom such as an iodine atom] in the presence of a base such as caesium or potassium carbonate in a Bipolar aprotic solvent such as an amide, e.g. dimethylformamide at ambient temperature or above.
In another example, a compound of formula (1 ) wherein R3 and/or R4 is a -CN or -CH2CN group may be prepared by dehydration of a corresponding amide where R3 and/or R4 is -CONH2 or -CH~CONH2 using for example trifluoroacetic anhydride in the presence of a base such a pyridine in a solvent such as tetrahydrofuran.
N-oxides of compounds of formula (1 ) may be prepared by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen WO 94120455 213 ~ 4 7 9 PCT/GB94/00452 peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70oC to 80oC.
Salts of compounds of formula (1) may be prepared by reaction of a compound of form ula ( 1 ) with an appropriate acid or base in a suitable solvent using conventional procedures.
The following examples illustrate the invention.

The following abbreviations are used:

DMF dimethyiformamide THF tetrahydrofuran DME dimethoxyethane ', 5 EtOAcethyl acetate Et20 diethylether RT room temperature LDA lithium diisopropyiamide INTERMEDIATE '1 a) 3-Cycionentyloxy-~-methoxvdenzaldehlrde Caesium carbonate (214g, 0.66mo1) was added to a mixture of 3-hydroxy-4-methoxybenzaidehyde (100g, 0.66mo1) and cyclopentyl bromide (98g, 0.66mo1) in anhydrous DMF (50mi). T he reaction mixture was stirred at RT for 16h then treated with a further portion of cyciopenty) bromide (98g, 0.66mo1) and caesmm carnonate (214g, 0.66mo1). after a further 6h at RT, the mixture was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (300mi) and washed with sodium hydroxide solution (10%; 2x150m1). The organic layer was dried (MgS04), concentrated in vacuo, and distilled (150oC, 10-2mbar) to afford the ti~gl compound (130g) as a viscous colourless oil. (Found: C, 70.38; H, 7.48.
~~t3H~s03 requires C. 70.89: H. 7.32%); bH (CDC13) 1.5-2.0 (8H, br m, C~)4), 3.87 (3H, s. 0l~/le), 4.80 (1 H, br m. OCHCH2), 6.90 (1 H, d, ~

3.7Hz. ArH ortho to OMe), -.3G-7.45 (2H, m. 2xArH mesa to OMe), and 9.77 ( 1 H, s, ArCHO).

b) 3-CXcio~entlriox;r-4-methoxybenzlrlaicohol From 3-hydroxy-4-methoxybenzyl alcoho~ (50g, 0.324mo1), cycfopentyloxy-bromide (70m1, 0.648mo1), caesium carbonate {72.83g, 0.222mo1) and sodium iodide (5.63g, 0.037mo1). Chromatography (Si02; EtOAc-C6H~4.
1:3) to yield the title compound (25.782g). {Found C, 69.92; H, 8.18.
C13H~803 requires C, 70.25; H, 8.16).

3, 5-Dichloro-4-methyf~~yridine 3,5-Dichioropyridine (2.04g, 13.5mmol) in THF (5ml) was added dropwise to a solution of LDA [prepared from diisopropylamine (l.9ml, 13.5mmol) and n-butyllithium (1.6M, 8.4m1, 13.5mmol)] in THF (25m1) at -70oC. After stirring at this temperaturE for 5 min, iodomethane (0.85m1, 13.5 mmol) was added and the reaction mixture stirred for a further 1.5h at -70oC.
Saturated sodium hydrogen carbonate solution (20m1) and dichloromethane (20m1) was added and the organic phase separated, dried (MgS04), and concentrated in vacuo. The residue was subjected to chromatography (Si02; Et20-hexane, 1:3) to afford the title com op and (1.16g) as a pale yellow solid; 8H (CDC13) 2.46 (3H, s, m.e), and 8.36 (2H, s, pyridine H2, Hue).

aj 4-[~~3-Cyciopentyloxlr-4-methoxyr~henyl)~2-hyrdroxvethvll-3.5-dichloro~yridine Intermediate 2 (2.22g, 13 mmol) in THF (40m1) was added dropwise to a solution of LDA _[prepared from diisopropyiamine (2.4m1, l7mmol) and n-butyllithium (1.6M, 10.2m1. l6mmol)] in THF (50m1) at -70oC and the mixture stirred at this temperature for 0.25h. A solution of Intermediate 1 (3.32g, l5mmol) in THF (50m1) was then added at -70oC and the reaction mixture allowed to warm to RT overnight. Saturated ammonium chloride solution (50 ml) and dichloromethane (50m1) was added and the organic phase separated, dried (MgS04), and concentrated in vacuo. The r esiduai yellow solid was triturated with hot Et20 to afford the t, i I~
compound (2.65gj as a white solid m.p. 139-140oC (Found: C, 59.49; H, 5.68: N, 3.57. Ci9i-i21C12N03 reqmres C, 59.69; H, 5.53; N, 3.66%); 8H
;CDC13) 1.5-2.1 (9H, br m. CH2)4 + OH), 3.2-3.5 (2H, m, CH2Ar), 3.81 (3H, s, O~.e), 4.7 (1 H, br m, OCHCH2), 5.01 (1 H, dd ~. 5.8, 8.4Hz, CHOH), 6.75-6.9 (3H, m, ArH ortho to OMe + 2xArH meta to OMe), and 8.36 (2H, s, pyridine H2, H6); ml_z 383 (10%), 381 (17), 221 (46), 163 (49), 161 (74), 153 (100); 152 (24), 151 (17), 125 (27), 93 (48), 65 (25), and 41 (34).

The following intermediates were prepared in a manner similar to Intermediate 3a:
10 b) 2~(3-Cycioiaent,~rloxy-4-methoxvoheny~y-2-~2-hvdroxvethvll ri From 2-methyfpyridine (1.02g, llmmol), LDA (1.0 equiv), and intermediate 1 (2.458, 11 mmol). The crude product was subjected to chromatography (Si0?; Et20) to afford the title comb o~ and (2.67g) as a 15 yellow solid m.p. 94-96oC (Found: C. 72.89; H, 7.43; N, 4.58.
C~9H23N03 requires C, 72.82: H, 7.40; N, 4.47%); 8H {CDC13) 1.5-2.1 (9H, br m, (CHz)4 + OH) ,3.09 (2H, d, ~ 6.1 Hz, C_H,2Ar), 3.80 (3H, s, Ofl~le), 4.74 (1 H, br, d. OCHCH2), 5.06 (1 H, t, J_ 6.1 Hz, CHOH), 6.8-7.2 (5H, m, ArH ortho to OMe + 2xArH mesa to OMe + pyridine _H,3, ,~4), 7.56 20 (1 H, m, pyridine H5), and 8.47 (1 H, dm, J 4.5Hz, pyridine I~); Ln/~ 313 (M+, 5%), 153 (16), 152 (90), 151 (53), 93 (100), 80 (17), and 41 (14).
c) 4-~2-(3-Cvciopenivioxy-4-meihoxypnenyi)-2-hydroxyethvll 25 gyrrimidine From 4-methylpyr~midine (2.15g, 23.6mmoi'i, ! DA (1.0 equiv), and intermediate 1 (5.128, 23.Ommoi). The crude product was subjected to chromatography.{Si0?; Et20) to afford the title com o~nd (3.83g) as an amber oil. (HCi salt m.p. 211-213oC) (HCI sait Found: C, 62.24; H, 6.68;
N, 8.06. C18iH23~~203 requires C, 01.44: H, 8.87; N, ?.96%); 8H (CDC13) .5-2.1 (8H, br m. (CH2)4), 3.10 (2H, a, J 6.5 Hz. C_H2Ar), 3.80 (3H, s, O(Vle), 4.15 (1 H. br, s OH), 4.74 {1 H, br, m. OCHCH2), 5.10 (1 H, t, J_ 5.5Hz, CHOH), 6.75-fi.9 (3H, m. ArH ortho to OMe + 2xArH meta to OMe), 7.09 (1 H. dd, J_ 4.9Hz, pyrimidine H~), 8.53 (1 H. ci, J_ 4.9Hz, pyrimidine H6), and 9.07 (1H. d. ~ 4.OHz. pyrimidine H2); m~z 314 (M+. 16%), 296 (19), 28 (23), 227 (75). ; 66 (18), ' S3 (22), ~ 52 (20), 151 (16), 94 (100), and 41 d) 4-~2-[1-,~3-Cycio~entyl_oxlr-4-methoxyr hu envl)~-1-hvdroxvloronvl~
ri i a From 4-ethylpyridine (2.50g, 2.65m1, 23.33mmol), LDA and Intermediate 1 (5.14g, 23.33mmol). Recrystallisation (CHCI3/hexane) afforded the ill com oE~ and (0.582g) as colourless fiufify needles. m.p. 131.5-132.3~C.
(Found: C, 72.38; H, 7.74; N, 4.22. C2~H25NO2~14H2O requires C, 72.44; H, 7.56; N, 4.10°,'0).

a) 4-[2-(~-Cyciol~n_tyiox~r-4-methoxy~henyl)~2-hvdroxvethvll ~yrridazine n-Butyllithium (1.6M in hexanes) (9.5m1, 6.Ommol) was added dropwise to a solution of methyipyridazine (0.47g, 5.0mmol) in THF (25m1) at -70oC.
The reaction mixture was allowed to stir at this temperature for 0.5h then a solution of Intermediate 1 (1.1g, 5.Ommol) in THF (20m1) was added. The mixture was allowed to warm to RT then partitioned between dichloromethane (25m1) and saturated sodium hydrogen carbonate solution (25m1). The organic phase was separated, dried (MgS04), and concentrated in vacuo to afford the title com op and which was used in the next step [Example 7a] without any further purification.
The following Intermediates were prepared in a manner similar to Intermediate 4 a.
b) 4-f2-y3-Cyclo~pent5rtoxy-d-methoxl! h~e~ll-2-hyrdroxyethvll ~,rridine =rom 4-methylpyridine (3.OOg, 32.1 mmol), n-butyllithium (32.1 mmol), and Intermediate 1 (6.82g, 3l.Ommol}. The crude product was subject to chromatography [Si02; EtOAc-hexane. 3:2 (500m1} to 4:1 (1000m1) then EtOAc-methanol 9:1 (1500m1)] to afford the title com op and (9.68g) as fine white needles m.p. 97-101 oC (from toluene) 8H (CDC13) 1.5-2.0 (8H, br m, ~CH2)4, 2.45(1H, br, s. CHOH), 2.96 (2H, d, J 6.5 Hz, CH2 pyridine), 3.80 3- -3H. s, OMe), 4.70 (1 H. br, m, OCHCH2), 4.81 (1 H, t, J 6.5Hz, CHOH), . PCT/GB94/00452 6.76(3H, s, ArH artho to OMe + 2xArH meta to OMe), 7.00 (2H, dm, J_ 4.5Hz, pyridine _H3, HSj, and 8.33 (2H, dm, ~ 4.5Hz, pyridine ~, ~).
c) 2-f2-l3-Cyclof en~~x~r-4-methoxyl~henyri)~-2 ~yrdroxvethvll l~~,rrazine From methyipyrazine (0.94g, llmmoi), n_-butyllithium (1.6.p1~.; 6.9m1, 1 ? mmol), and intermediate 1 (2.2g, 1 Ommol) to afford the title comp o~ and which was used in the next step [Example 7c)] without any further purification.

~3-Cvcionentlr~y-4-methoxyrl henylj-3-hvdroxy-2-~(hhenyrimet r,]~ ropane-1-nitrilg 3-Phenylpropionitrile (2.62g, 20mmol) was added dropwise to a solution of LDA [prepared from n-BuLi (1.6 /I solution in hexanes) (l4ml, 22mmol) ana N ~I-diisopropylamine (3.5m1, 25mmol)] in T.-IF (100m1) at -70oC. A
solution of intermediate 1 (4.4g) in THF (25m1) was then added and the reaction mixture was allowed to warm to RT then poured into NaHC03 solution (50mf) and extracted with CH2C12 (2x50m1). The extract was dried (Na~S04), concentrated in vacuo, and the residue subjected to chromatography (Si02; Et20-hexane, ~ :1 ) to afford the title compound (4.34g) as a pale yellow oil; m/~ 351 (M+, 10%), 221 (22), 153 (100), 152 (19), 151 (15), 125 (15), 93 f25), 92 (25), 65 (14) and 41 (16).

l -_,3 ~yrcio~enty oxlr-4-methox~rjl~henyi methvi ketone To a solution of methyfmagnesiumbromide (5.44mi) in THF (150m1) at O~C was added intermediate 1. The reaction mixture was left to stir at RT for 5-6hr, then NHaCI and Et~O (100m1) were added and the solution stirred for another 90 min (the solution went from nazy io clear). The ayers were separated. the aaueous layer was extracted with Et20 (50m1) the combined organic layer was extracted with a saturated bicarbonate solution (100mi) then trine i.100mi). Evaporation ~n vacuo afforded 1 ~,~,~ ~~ g mei9idxy-2-cyciopentyloxy-4-(1-hydroxyethyl)benzene which was disolved in dichloromethane (300m1) before adding Mn02 (l0eq). The reaction mixture was stirred for 120h, then the Mn02 was filtered off and the solvent evaporation in vacuo. Purification by column chromatography (Si02; dichloromethane-hexane. 350-150 to dichloromethane) afforded the 4 [2 [3-Cvcic~entyrloxy_4-methox_yrohenyl)r-2-methyl-2-hvdroxvethvll ~yrridine To a cold (-78°C) solution of 4-picoiine (0.80mi) in THF was added n-BuLi (5.6m1), the solution stirred for 30min then transferred to a cold suspension of cerium chloride anhydrous (2.Og) at -78°C. The reaction mixture was stirred for 1 h before adding Intermediate 6 in THF then left to warm to RT
overnight. 10% NH4C1 solution and EtOAc were added, the solution was filtered through Celite, washed with EtOAC {150m1) and the organic layer was separated, washed with brine (100m1) then dried (Na2S04). The solvents were evaporated in vacuo to afford the title com op and (2.367g) as pale off-white crystals m.p. 99-101°C. Found C, 73.21; H, 7.63; N, 4.20. C2oH25N03 requires C 73.37; H, 7.70; N, 4.28%). ~~ (EI) 327 (M+, 3%), 235 (18), 166 (38), 151 (100), and 93 (54).

3-CYcioRentvlo~cy-4-methoxlrbenzvi alcohol Intermediate 1 b (0.6g, 2.7mmol) was dissolved in ethereal HCI, the solution stirred at RT and followed by thin layer chromatography until complete disappearance of the starting material. The solution was washed with saturatea sodium bicarbonate solution. The organic layer extracted and dried (Na2S04). Concentration in vacuo afforded the come o~ and (0.395g).

3-Cyclo~entyrloxv-4-methoxybenzyltriphenyri~hosohoni~rm chloride A mixture of Intermediate 8 (10.~g. =~3.2mmol) and triphenylphosphine (11.5g, 43.8mmol) in toluene (100m1) was heated to reflux for 18h. The WO 94120455 213 ~ ~ 7 ~ PCT/GB94/0045Z

reaction mixture was concentrated in vacuo and the residue triturated with acetone (250m1) to afford the title compound (19.5g) as a white solid.

Diethvl3-Cy~l~enty~~y-4-methoxvt~enzlrji~honate A mixture of Intermediate 8 (52.7g, 0.22moi) and sodium iodide (32.9g, 0.22mo1) in triethyl phosphate (76.48, 0.46moi) was heated at 100°C for 24h. The reaction mixture was partitioned between EtOAc (200m1) and water (200m1) and the organic layer was separated. The extract Was washed (brine; 50mi), dried (MgS04), and concentrated in vacuo to give a pale yellow oil (70g). A portion (40g) of the oil was distilled (190-210°C, 10-2 mbar) to afford the title compound (20,3g, 27"/0) as a colourless oil.

a) (Z)r3-~(3-Cycio entvioxv-~-methoxyrph~,~Yyi)-2-~2-thienvl) gro~enenitrile 2-Thiopheneacetonitrile (l.lml, l0mmol) and Intermediate 1 (2.29g, l0mmol) was dissolved in ethanol (l0ml) and added to a solution of sodium hydroxide (0.51 g, 12.8mmol) in water (5ml). The reaction mixture was allowed to stir at RT for 2h then partitioned between dichloromethane (20m1) and saturated sodium hydrogen carbonate solution (l5ml). The organic layer was separated, dried (MgS04), and concentrated inin vacuo to give a yellow gum which was recrystailised from ethanol to afford the ,~i~g com op and (3.35g) as yellow crystals m.p. 100-101oC. (Found: C, 69.47;
H, 5.80; N, 4.18. Cy9Hi9v02S requires C. '0.13; H, 5.80; N, 4.18%); 8H
(CDC13) 1.5-2.1 (8H. br m, (C~)4), 3.87 (3H. s, OMe), 4.85 (1H, br m, OCHCH2), 6.83 (1 H, d, ~ 8.5Hz. ArH or h to OMe), 7.00 (1 H, dd, ,~ 4.5, 3.5Hz, thiophene L-14), ; .15-7.3 (4H, m, ,arl-~ ara to cyclopentyloxy +
CH=CCN+thiophene H3, H 5), and 7.60 ( 1 H, d, ~ 2.2Hz, ArH ortho to cyclopentyloxy); m/~ 326 (M+ -~- 1. 23°,'°), 325 (M+. 87), 259 (34), 258 (85), 257 (100), 224 (24), 214 (27), 197 (21), 196 (93) and 41 (29).
s he following compounds were prepared in a manner similar to the compound of Example 1 a.

b) ~1~~3-Cyciopentyloxy-4-methoxyr~hen,lrll-2-ohenvl-prQ~~nenitrile From phenylacetonitrife (0.52g, 4.4mmol) and Intermediate 1 (0.95g, 5 4.3mmol). Chromatography (Si02; EtOAc-hexane) gave the ~itlg corr~oound (0.81 g) as a yellow solid m.p. 84-86% (Found: C, 78.83; H, 6.60; N, 4.38. C21 H2y N02 requires C, 78.97; H, 6.63; N, 4.39%); SH
(CDCI3) 1.5-2.1 (8H, m, {CI~)4), 3.86 (3H, s, O V~le), 4.82 (1 H, br m, OCHCH2), 6.85 (1H, d, J_ 8.8Hz, ArH ortho to OMe), 7.15-7.7 (7H, m, ArH_ 10 para _ -to cyciopentyfoxy + CH=CCN + C Hue), and 7.67 (1 H, d, ,~ 2.3Hz, ArH
9rtho to cyclopentyloxy); m/z_ 319 (M+, 33%), 252 (49), 251 (100), 218 {15), 208 (32), 190 {48), 180 (15), 152 (15) and 41 (20).
15 c) ~Z~3-~~-Cyci~~entyiox~r-4-methoxlrphenyi)-2-l2-uvridvl)-proihenenitrile From 2-pyridylacetonitriie (llmmol) and Intermediate 1 (2.20g, l0mmol).
Trituration of the crude product with ethanol gave the title compound (2.40g) as a yellow solid m.p. 82.5-83oC (Feund: C, 74.87; H, 6.27; N, 20 8.46. C2oH2oN202 requires C, 74.98; H, 6.29; N, 8.74%); 8H (CDC13) 1.5-2.1 (8H, br m, (CHz)4), 3.824(3H, s, OMe), 4.80 (1 H, br m, OCHCH2), 6.84 (1 H, d, ,~ 8.6Hz, ArH ortho to OMe), 7.05-7.25 (1 H, m, pyridine H_5), {1 H, dd, ,~ 8.6, 1.95Hz, ArH ~ to OMe ), 7.6-7.75 (3H, m ArH ortho to cyclopentyloxy+ pyridine H3,H4), 8.29 (1 H. s, CH=CCN) and 8.52 (1 H, 25 ca_.a, J 4.6 Hz, pyridine N6); m/z 320 (M+, 15%), 252 (38), 251 (100), 237 (5), 236 ( 10), 209 (5), 179 (5), and 41 (8).
d) ~ )-~ 3-l,3-Cyclooentyloxy-4-methoxyr~phenyrl)-2-i(3-ovridvl)-30 pro~penenitrile From 3-pyridylacetonitrile (2.35m1, 22mmol) and Intermediate 1 (4.408, 20mmol). Chromatography (Si02; EtOAc) gave the title com o~ (5.31 g) as a pale yellow solid m.p. 86.5-87.5oC (Found: C, 74.80; H, 6.26; N, 8.74. C2oH2oN2O? re4uires C, 74.98: H. 6.29; N, 8.74%); 8H (CDC13) 1.5-2.1 (8H; br m, (CH,2)4). 3.87 (3H, s. OMe), 4.82 (1 H, br m, OCHCH2), 6.86 (1 H, d, J 8.6Hz. ArH ortho to OMe), 7.2-7.4 (2H, m, ArH ~ to OMe +

WO 94120455 ~ ~ ~ PCT/GB94/00452 pyridine ice), 7.42 (1 H, s, CH=CCN), 7.70 (1 H, d, ,~ 2.OHz, ArH ortho to cyclopentyioxy), 7.87 (1 H, dm, ~, 7.6Hz, pyridine .~), 8.53 (1 H, dd, ,~ 4.8, 1.3Hz, pyridine ~) and 8.84 (1 H, d, ~ 2.4Hz, pyridine ~); r~/~ 320 (M+, 20%), 252 (100), 251 (67), 234 (20), 223 (27), 205 (27), 151 (50), 69 (22), and 41 (31 ).
e) (Z~3-(3-Clrclopentyloxyr-4-methoxyly~(~ycrirJvl)-)~roi2enenitrile From 4-pyridylacetonitrile (1.7g, llmmol) and Intermediate 1 (2.20g, 20mmol). Trituration of the crude product with ethanol gave the com op and (2.75g) as an orange solid m.p. 125-127oC. (Found: C, 74.84;
H, 6.29; N, 8.33. C2oH2oN2O2 requires C, 74.98; H, 6.29; N, 8.74%); 8H
(CDCI3) 1.5-2.1 (8H, br m, (CI-~)4), 3.84 (3H, s, Ol~le), 4.83 (1 H, br m, OCHCH2), 6.83 (1 H, d, ~ 8.2Hz, ArH crtho to OMe), 7.26 (1 H, dd, ~ 8.2, 2.2Hz, Arl~- ~ to OMe ), 7.44 (2H, dd, J_ 4.7, 1.7Hz pyridine H3,~i ), 7.53 (1 H, s, CSI=CCN) 7.69 ( 1 H, d, ,~ 2.2Hz, Arl~ ortho to cyciopentyloxy), 8.56 (2H, dd, ~, 4.7,1.5 Hz, pyridine H2, H6); ~~ 320 (M+, 28), 253 (19), 252 ( 100), 251 (59), 224 ( 15), 223 (38), 209 ( 10), and 41 (23).
') ~(Z~-3-,~3-~ycio~,Pentyioxy-~-methoxY~phenvi-2-{1-naphthvl) Rr_,openenitrile From i-naphthyiacetomtrile (1.67g, ~Ommoll and Intermediate 1 (2.2g, l0mmol). The reaction mixture was extracted with dichloromethane then she extract dried (MgS04) and concentrated in vacuo to afford the i IP
compound (2.56g) as a yellow solid.p. 161-163oC (Found: C, 81.22: H. 6.29: N. 3.77. C25H2sN02 requires C, 81.27; H, 6.27; N, 3.79%); 8H (CDC13) i.5-2. 1 (8ti, br m, (CH,2).~), 3.89 (3H, s, OMe), 4.85 ~1 H, br m. OCHCH2), 6.87 (? H. d, ~ 8.1 Hz, ArH ortho to OMe), and 7.15-8.1 (10H, m, 2xArH orrho to OMe + CH=CCN + C~oh~); mi_z 320 (M++ 1, 9%), 369 (M+, 30), 302 (28), 301 (100), 268 (10), 240 (17), 202 (5), and 41 (5).
g~ (Z)-3-(3-Cvcionentvloxv-a-methox~rphen~)-2-(2-naphthvl) nronenenitriie From ~r~apnthyiacetonitrile (1.67g, l0mmol) and Intermediate 1 (2.2g, l0mmol). The crude product was recrystallised from ethanol to afford the title com o~~ and (3.14g) as a pale yellow solid. m.p. 147-148oC {Found: C, 81.15; H, 6.24; N, 3.56. C25H2sN02 requires C, 81.27; H, 6.27; N, 3.79%); 8H {CDC13) 1.5-2.1 (8H, br m, (C_Hz)4), 3.88 (3H, s, OMe), 4.87 (1 H, br m, OCHCH2), 6.86 (1 H, d, J_ 8.3Hz, ArH meta to OMe), and 7.2-8.1 (10H, m, 2xArH mesa to OMe + CH=CCN + C~oH~); r~(_z 370 (M+ + 1, 10%), 369 (M+, 40), 302 (23), 301 (100), 240 (20), 167 (12), 124 (38), and 41 (10).
h) 1Z1~3-y3-Cycio~n_tyioxyr-a-snethoxyphen)L)v-2-r(3-thienvl) propenenitrile From 3-thienylacetonitrile (l.2ml, 10.5mmol) and Intermediate 1 (2.21g, 1 Ommol). The crude product was recrystallised from ethanol to afford the tile corm o~ and (2.50g) as a yellow solid m.p. 83-84oC (Found: C, 69.86;
H, 5.85; N, 4.18. C~9Hi9N02S requires C, 70.13; H, 5.89; N, 4.30%); 8H
(CDC13) 1.5-2.1 (8H, br, m, (C I~)4), 3.86 (3H, s, Oi~le), 4.85 (1 H, br m, OCL-ICH2), 6.84 (1 H, d, J_ 8.OHz, ArH ortho to CMe) 7.15-7.5 (5H, m, ,tiara to cyclopentyloxy + CH=CCN) + thiophene H2, H4, ,I~) and 7.62 (1 H, d, ,~
2.2Hz, ArH ortho to cyclopentyloxy); ~~ 325 (M+, 34%), 258 (23), 257 (100), 256 (10), 226 (11 ), 214 (19), 197 (12), and 196 (30).
i) ~~~ -~-Cycio en ioxyr-4-methoxvuhenyl)f-2-i(2-fluoro tin env_Il_ ~laenenitrile From 2-fluorophenyiacetonitrile (1.35g, l0mmol) and Intermediate 1 (2.20g, l0mmoi). Chromatography (Si02; Et~O-hexane) gave the ~g comQound (0.51 g) as a yellow solid m.p. 70-73oC (Found: C, 74.58; H, 6.08; N, 4.03. C2i H2oNO2 requires C, 74.76; H, 5.97; N, 4.15%); 8H
(CDC13) 1.5-2.1 (8H, br, m, (C_Hz)4), 3.88 (3H, s, OMe), 4.83 (1 H, br m, OCHCH2), 6.85 (1H, d, J_ 8.6Hz, ArH o ho to OMe), 6.9-7.6 (5H, m, ArH
to cyclopentyloxy + C6H4F),7.40 (1 H, s, CH=CCN), and 7.69 (1 H, d, J_ 2.2Hz, ArH ortho to cyciopentyloxy); nl _z 337 (M+, 5%), 269 (55), 220 (13), 153 (25), 152 (100), 151 (96), 69 (17), 67 (13), and 41 (51).
;) {Z)-3-~3-Cyciopentyloxy-4-methoxyphenyi?-2-(3-fluoroohenvl) propenenitrile WO 94/20455 ~ I ~ 5 4 7 9 PCT/GB94/00452 From 3-fluorophenylacetonitrile (1.2g, l0mmol) and Intermediate 1 (2.20g, l0mmol). The crude product was recrystallised from ethanol to afford the ~itle coml ound (2.77g) as yellow crystals m.p. 1 i 4-1 l6oC (Found: C, 74.79; H, 5.96; N, 4.07. C2yH2or=NO2 requires C, 74.76; H, 5.97; N, 4.15%); 8H (CDC13) 1.5-2.1 (8H, br, m, (CI~)~), 3.88 (3H, s, OMe), 4.85 (1 H, br m, OCHCH2), 6.86 (1 H, d, ,~ 8.4Hz, Arl-~ ortho to OMe), 7.0-7.45 (6H, m, ArH to OMe + CH_=CCN + C~4F), and 7.68 (1 H, d, ,~ 1.BHz, Ar,~l ortho to cyclopentyloxy); J~ 337 (M+, 10%), 270 (23), 269 (100), 208 (30), 149 (13), 55 (14) and 41 (17).
I<) ~(~)~3-(3-Clrc~ci i~~tvioxv-4-methoxvohenvil-2-(4-f From 4-fluorophenyiacetonitrile (1.3g, l0mmol) and Intermediate 1 (2.41g, llmmol). The reaction mixture was filtered to afiford the title com op and (3.34g) as colourless crystals m.p. 139-141oC (Found: C, 74.80; H, 5.95;
N. 4.05. C2~H2pFN02 requires C, 74.76; H, 5.97; N, 4.15%); SH (CDC13) 1.5-2.1 (8H, br, m, (CI~)4), 3.87 (3H, s. O VL1 e), 4.82 (1 H, br m, OCI~-.CH2), 6.85 (1 H, d, ,~ 8.6Hz, ArH ortho to OMe), 6.95-7.2 (3H, m, Ark ~ to cyciopentyloxy + 2xArH ortho to F), 7.30 (1 H, s, CH=CCN), 7.45 '.7 (3H, m, ArH ortho to OCp + 2xAr~i meta to F); mj_z 337 (M+, 11%), 271 (21 ), 269 ( 100), 226 ( 13), 208 (25), and 41 ( 19).
i) {~)~-~~3-Chior henyriJ~-3 {3 cvcionentvioxv 4-metho»r henvl) pro~laenenitrile From 3-chlorophenyiacetonitrile (1.53g, l0mmol) and Intermediate 1 (2.21 g, 1 Ommoi). The crude product was recrystallised from ethanol to afford the title com ound (3.01 g) as yellow crystals m.p. 98-100.5oC
(Found: C, 71.40; H, 5.70; N, 4.03. C21 H2oCIN0? requires C, 71.28; H, 5.70; N, 3.96%); aH (CDC13) 1.5-2.1 (8H, br m. (CH,2)4), 3.87 (3H, s, Oll~le), x.82 (1 H, br m. OCHCH2), 6.85 (1 H, d. ~. 8.4Hz, ArH orthc to OMej, and 7.2-7.7 (7H, m. 2xArH meta to OMe + C6H4C1 + CH=CCN);
m/_z 353 (M+, 26%), 288 (18), 2F37 (85), 286 (56), 285 (100),224 (37), 207 (22) and 41 (45).
m) ~Z~-2-(3-Bromonhenyri)-3-{3-cycio~~centvioxy-~i-methoxyy h~ env_I,) ~ropenenitrile ~4 From 3-bromophenyiacetonitrile (1.97g, l0mmol) and Intermediate 1 (2.24g, l0mmol). The crude product was recrystallised from ethanol to afford the title com o~ and (2.94g) as yellow crystals m.p. 90-91.5oC
(Found: C, 63.38; H, 5.01; N, 3.48. C21 H2oBrN02 requires C, 63.33 H, 5.06; N, 3.52%1; aH (CDC13) i.5-2.1 (8H, br m, (CH2)4), 3.88 (3H, s, OMe), 4.85 (1 H, br m, OCH_CH2), 6.85 (1 H, d, ~ 8.5Hz, ArH o_rtno to OMe), and 7.15-7.75 (7H, m, 2xArH_ meta to OMe + C6b.4Br + CH_=CCN) ;
r~/~ 399 (8%), 397 (8), 332 (21), 331 (100), 330 (23), 329 (100), 235 (15), 217 (16), 207 (26), 190 (14), 178 (12), and 41 (38).
n) ~~(3 Clrciooentyloxy-4-methox~eny~l -2-~~~6-difluoro ho envi)_ Rr_~enenitrile From 2,6-difluorophenylacetonitrile (1.86g, l0mmol) and Intermediate 1 (2.19g, l0mmol). Chromatography (Si02; Et20-hexane, 1:4) followed by recrystallisation from ethanol gave the title com~ op and (0.3g) as yellow crystals m.p. 111-~ l3oC. (Found: C, 70.78; H, 5.37; N, 3.85.
C2~H~9F2N02 requires C, 70.97 H, 5.39; N, 3.94%); 8H (CDC13) 1.4-1.8 (8H, br s, (C_Hz)4), 3.80 (3H, s, OMe), 4.22 (1 H, br s, OCHCH2), 6.52 (1 H, br s, ArH ortho to OMe), and 6.7-7.5 (6H, m, 2xArH meta to OMe +
Chi 4F2) ; m/z 355 (M+~ 21%), 288 (19), 287 (100), 244 (11), 152 (48), 151 (31 ), and 41 (22).
o) ~Z~3-(3-Cyciooentyioxy-4-methox~rphenyrl)i-2-x(2.6-dichloronhenvll a~rQJ~enenitrile From 2,6-dichiorophenyiacetonitriie (1.88g, l0mmol) and Intermediate 1 (2.21 g, l0mmol). The cr ude product was recrystallised from ethanol to afford the title compound ( 1.95g) as a white solid m.p. 164-166oC.
(Found: C, 64.88; H, 4.93; N, 3.60. C21H~9C12N02 requires C, 64.96; H, 4.93; N, 3.61%); aH (CDC13) 1.5-2.1 (8H, br m, (CHz)4), 3.88 (3H, s, OMe). 4.85 (1 H, br m, OCHCH2), 6.94 (1 H, d, ,~ 8.4Hz, ArH ortho to OMe), 6.86 (1 H. s, CH=CCN), 7.1-7.45 (4H, m, ArH to cyclopentyloxy - C6H3C12), and 7.75(1 H, d. .~ 1.BHz, ArH ortho to cyclopentyloxy); ~z_ 389 (18%), 388 (7), 387 (29), 323 (19), 322 (19), 321 (87), 320 (29), 319 (100), 284 (18), 252 (19), 249 (24), 241 (25), 177 (14), and 41 (33).

213 5 4 7 9 ~,~.~GB94/00452 p) ~~(3-~yrclooenrirloxv-4-methoxvnhenvll-2-l3 4-dichloronh Fromng 3,4-dichlorophenylacetonitrile (1.88g, l0mmol) and Intermediate 1 (2.23g, l0mmol). The crude product was recrystallised from ethanol to 5 afford the title com_IZu~ (3.56g, 90%) as a yellow solid m.p. 151.5-154oC (Found: C. 64.89; H, 4.93; N, 3.61. C2~H~9CI2N02 requires C, 64.96; H, 4.93; N, 3.61 %); 8H (CDC13) 1.5-2.1 (8H, br m, (C.~)4), 3.88 {3H, s, O~e), 4.82(1 H, br m, OCHCH2), 6.86 (1 H, d, ,1 8.4Hz, ArH ortho to OMe), and 7.2-7.7 (6H, m, 2xArH meta to OMe + CH_=CCN+ C6H_3C12);
10 r~r/~ 389 (13%), 388 (5), 387 (20), 323 (12), 322 (12), 321 (69), 320 (19), 319 (100), and 41 (21 ).
q) fZ)-3-l3-Cyrciol!~entlrloxy-4-methoxy~epa,ri~~,2 4-dichlorol~heny~
~rooenenitrile 5 From 2,4-dichlorophenylacetonitrile (1.90g, 1 Ommol) and Intermediate 1 (2.21 g, l0mmol). The crude product was recrystallised from ethanol to afford the title com oD Und (2.25g) as a white solid m.p. 105-107oC (Found:
C, 64.93; H, 4.92: N, 3.64. C2yHi9C12N02 requires C, 64.96; H, 4.93; N, 3.61%); bH (CDC13) 1.5-2.1 {8H, br m. (C_H2)4), 3.88 (3H, s, Ol~le), 4.86 20 (1 H, br m, OCHCH2), 6.85 {1 H, d, ,~ 8.6Hz, ArH .ortho to OMe), 7.05-7.45 (5H, m, ArH , ara to cyciopentyoxy + CH=CCN+ C6H3C12); and 7.70 (1 H, d. ~ l.9Hz, Ar_H ortho to cyclopentyloxy); rn/_z 389 {12%), 387 (28), 319 ( 100), 284 (23), 252 (24), 249 (31 ), and 41 (49) 25 ; p fZ1-3-f3-Cvcio~en tyrioxy-4-methoxy ~n~en~ry-2-i(2-trifluoromethyl-Qhenyrly r~openenitrille From 2-trifiuoromethyiphenyiacetonitrile ( 1.8g, 1 Ommoi) ano Intermediate 1 (2.27g, l0mmoi). Chromatography (Si02; Et20-hexane, 1:2) followed oy recrystallisation from ethanol gave the title com ound (0.82g) as a 30 white solid m.p. 96-98oC (Found: C. 07.93; H, 5.21; N, 3.53.
C22H2oF3N02 requires C, 08.21; H. 5.20: N. 3.62%); ~H (CDC13) 1.5-2.1 (8H, br m, (C_H2)4), 3.88 (3H, s. OMe), :x.83 ( 1 H, br m. OCHCH2), 6.85 1 H, d, ~ 8.4Hz. ,4rH .Qrtho to OMe), 0.98 (1 H.s,CH=CCN), 7.18 (1 H, dd, ~
8.4, 2.2Hz. ArH onho to cyctooentyloxyj, 7.25-7.8 (4H. m. C6H,4CF3)), and :,5 '.67 c 1 H, d, J 2.2Hz. ArH or h to cyciopentyloxy; mid 387 (M+, 17%), WO 94/20455 ~~ ~'~ ~ PCT/GB94/00452 320 (53), 319 (100), 276 (14), 256 (19), 248 (18), 208 (9), 207 (9), and 41 (34).
s) ;'~(3-C~ctopentyi_oxy-d-methoxyphenvl)-2-t3-trifluoromethvl-oheny~, oropenenitrile From 3-trifluoromethyiphenytacetonitrile (1.56g, l0mmol) and Intermediate 1 (2.34g, 10.6mmol). Chromatography (Si02; Et20-hexane, 1:1 ) gave the title compound (2.62) as a yellow solid m.p. 70-73oC (Found: C, 68.14; H, 5.18; N, 3.55. C22H2oFsN02 requires C, 68.21; H, 5.20; N, 3.62%); 8H
(CDCI3) 1.5-2.1 (8H, br m, (CH2)4), 3.88 (3H, s, Ol~lle), 4.85 (1 H, br m, OCHCH2), 6.87 (1 H, d, J_ 8.2Hz, ArH ortho to OMe), 7.29 (1 H, dd, ,~ 8.2, 2.1 Hz, ArH ~ to OMe), 7.42 (1 H, s, CH=CCN), 7.45-7.85 (4H, m, C61~4CF3), and 7.68 (1 H, d, J 2.1 Hz, ArH ortho to cyciopentyloxy;) ~z_ 387 (M+, 11 %), 320 (23), 319 ( 100), 276 (7), 258 (9), 67 (6), and 41 (21 ).
t) ,~Z~3-l3-Cvciopent~oxy-4-methoxya~henyi)~-2-~(4-triffuoromethvl-~en~rll r~ooenenitrile From 4-trifluoromethyiphenyfacetonitrile (1.85g, l0mmol) and Intermediate 1 (2.36g, 10.7mmol). Chromatography (Si02; Et20-hexane, 2:1 ) gave the title comBound (3.77g) as a yellow solid m.p. 96-99oC (Found: C, 68.32;
H, 5.26; N, 3.38. C22H2oF3N02 requires C, 68.21; H, 5.20; N, 3.62%); 8H
(CDC13) 1.5-2.1 (8H, br m, (CH_2)4), 3.89 (3H, s, Ol~e), 4.85 (1 H, br m, OCHCH2), 6.87 (1 H, d, J 8.1 Hz, ArH ortho to OMe) and 7.2-7.75 (7H, m, 2xArH meta to OMe + C6H_4CF3 + CH=CCN); ~z_ 387 (M+, 14%), 320 (26), 319 (100), 276 (12), 258 (15), and 41 (10).
u) ~ ~Z 3-l3-C,yrciopentlrloxlr-4-methoxyphenyrl)-2-i(3-methoxvuhenvll propenenitrile From 3-methoxyphenyiacetonitril2 (1.48g, l0mmol) and intermediate 1 (2.23g, 1 Ommol). Chromatography (Si02; Et20-hexane, 1:1 ) gave the i'~
com~Qound (1.97gj as a yellow solid m.p. 83-85oC (Found: C, 75.80; H, 6.62; N, 4.13. C22H2sN03 requires C, 75.62; H, 6.63; N, 4.00%); 8H
(CDC13) 1.5-2.1 (8H, br m, (C.H~)4), 3.83 (3H, s, OMe), 3.87 (3H, s, OMe). 4.84 (1H, br m, OCHCH2j, 6.8-6.95 (3H, m + d (86.85, J_ 7.9Hz), 3 x ArH ortho to OMe), 7.1-7.4 (4H, m, ArH Sara to OMe + Arty ~ to cyclopentyioxv _+ ArH meta to OMe and olefin + CH=CCN) and 7.66 (1 H, 213 5 ~ '~ g PCT/GB94/00452 d, ~ l.9Hz, ArH ortho to cyciopentyloxy); m/~ 349 (M+, 27%) 282 (28), 281 (100), 248 (7), 220 (13), and 41 (22).
v) (Z)-3-(3-C~ en Ayr-4-methoxyi~henyil-2-(3 4-dimethox~a~heQyi)oropenenitrile From 3,4-dimethoxyphenyiacetonitriie (1.95g, 11 mmol) and Intermediate 1 (2.20g, l0mmol). Chromatography (Si02; Et20-hexane, 1:1 ) gave the com ound (2.41g) as a yellow solid m.p. 101-103oC. (Found: C, 72.68;
H, 6.46; N, 3.49. C23H2sNO3 reqmres C, 72.80; H, 6.64; N, 3.69%); 8H
(CDC13) 1.5-2.1 (8H, br m, (Chi2)4), 3.87 {3H, s, OI~V e), 3.89 (3H, s, O Ile), 3.92 (3H, s, OMe), 4.84 (1 H, br m, OCHCH2), 6.85 (2H, d, ~ 8.1 Hz ArH mA to cyclopentyloxy +ArH ortho to OMej, 7.0-7.35 (4H, m, ArH
~ to cyclopentyloxy + C_H=CCN + ArH ortho and ArH para to OMe), and 7.64 (1 H, d, ,~ 2.OHz, ArH ortho to cyciopentyloxy); ~~ 380 (M+ + 1. 5%), 379 (M+, 27), 312 (20), 311 (100), 295 (12), 278 (5), 250 (8), and 41 (8).
w) ~)~~3-C~rcio~enivioxy-4-methoxy '~nenyl)-2-l2 3 4 5 6 t~entafluoro~ahenyl)nroeenenitrile From 2, 3, 4, 5, 6-pentafluorophenylacetonitrile (2.07g, l0mmol) and Intermediate 1 (2.208, ~ Ommoi). The crude product was recrystallised from ethanol to afford the titl~c~m o~ and (1.1 g) as orange crystals m.p.94.5-96oC. (Found: C. 01.64; H. 3.94; N, 3.26. C2~ HlsF5N03 requires C, 61.62: H, 3.94: N. 3.42%); aH (CDC13) 1.5-2.1 (8H, br m, {C_Hz)4), 3.89 (3H, s. OMe), 4.85 (1 H, br m. OCHCH2), 6.85 (1 H, d, J_ 8.4Hz. ArH_ ortho to OMe); 7. ~ 5 (1 H, slightly broadened s, CH=CCN) and 7.23 (1 H, dd, J_ 8.4, 2. 7 Hz. ArH g~ to cyciopentyioxy); ~~ 409 (M+, 12%), 367 (8), 342 (21),341 (100). 298 (20). 27(10), 250 (10), and 41 (21).

a) ;Z)~-2-,14-Amino henvi~-3-(3-cyciopentyioxy-4-methoxyphen~) orooenenitriie WO 94/20455 C~ PCTIGB94100452 A mixture ofi intermediate ~ (2.24g, l0mmol), 4-aminophenylacetonitrile (1.37g, l0mmol), and ptperidine (10 drops) in ethanol (8ml) was heated to reflux for 6h. The reaction mixture was partitioned between dichloromethane (20mf) and brine (l0ml). The organic layer was separated, dried (MgS04), and concentrated in vacuo. The residue was subjected to chromatography (Si02; Et20-hexane, 2:1 ) to afford the t~
com op and (1.15g) as a yellow solid m.p. 82-84oC (Found: C, 75.22; H, 6.68; N, 7.86. C2~ H22N202 requires C, 75.42; H, 6.63; N, 8.38%); 8H
(CDCI3) 1.5-2.1 (8H, br m, (CH2)4), 3.72 (2H, s, ArN~) 3.88 (3H, s, Of~U e), 4.85 (1 _H, br m, OCHCH2), 6.87 (1 H, d, J_ 8.3Hz, ArH ortho to OMe), 7.05-7.4 (5H, m ArH ~ to cyclopentyloxy + C6H_4NH2), 7.52 (1 H, d, ~ 1.BHz, ArH Qrtho to cyciopentyioxy) and 8.26 (1 H, s, CH=CCN); ~z_ 314 (M+, 79%), 268 ( i3), 267 (98). 266 (100), 265 (100), 250 (19), 143 (14), 116 (34), 89 (21 ) and 41 (33).
The following compounds were prepared in a manner similar to the compound of Example 2 a.
b) ~Z~2-~~,2-Chlorol~i~eny~,)-3-y3-cyrciopentvloxk-4-methoxyphenvl) ~ropenenitrile From 2-chlorophenytacetonitrile (1.53g, l0mmol) and intermediate 1 (2.23g, l0mmol). Chromatography (Si02; Et20-hexane, 3:2) gave the t~
com ound (1.85g) as pale yellow crystals m.p. 94-95oC (Found: C, 71.25; H, 5.72; N, 3.84. C21 H2oCIN02 requires C, 71.28; H, 5.70; N, 3.96%); 8H (CDC13) i .5-2.1 (8H. br m, (CI~)4), 3.88 (3H, s, OMe), 4.85 (1 H, br m, OCH_CH2), 6.85 (1 H, d, ,~ 8.3Hz, ArH Qrtno to OMe), 7.11 (1 H, s, CH=CCN), 7.15-7.5 (5H, m, ArH_ ~ to cyciopentyloxy + C6~4CI), and 7.72 (1 H, d, J_ 2.2Hz, ArH ortho to cyclopentyloxy); m/z 353 (M+, 17%), 287 (43), 286 (23), 285 ( 100), 250 (64), 218 (75), 207 (28), 206 (25), 190 (38), and 41 (52).
c) ~Z~2-~2-Bromopheny_il-3-~~3-~ciol~entyloxr-4-methoxy~henvl) oro~enenitrile prom 2-bromophenyacetonitrile (1.OOg, 5.1 mmol) and Intermediate 1 1.13g, 5.1 mmoil. The crude product was recrystallised from ethanol to afford the title com ound (0.48g) as a white solid m.p. 100-103oC
(Found: C, 63.36; H, 5.07; N, 3.51. C2~ H2oi3rN02 requires C, 63.33 H, 5..06; N, 3.52%); 8H (CDC13) 1.5-2.1 (8H, br m, (CH_2)4), 3.88 (3H, s, OMe), 4.86 (1 H, br rn, OCHCH2), 6.85 (1 H, d, ,~ 8.4Hz, Ar -~I ortho to OMe), 7.06 (1H, s, CH=CCN), 7.15-7.4 (45H, m, ArH ara to cycfopentyloxy + 2xArH meta to Br + ArH ara to Br), 7.5-7.65 (1 H, m, ArH
onho to Br), and 7.72 (1 H, d, J 1.9Hz, ArH ortho to cyciopentyloxy); m/~
399 (47°Jo), 397 (47)" 331 (94), 329 (89), 250 (57), 219 (24), 218 (100), 207 (25), 190 (48), and 41 (36).
d) (Z~3-(3-Cvciopentyloxy-4-methoxya~henyi)-~4-nitroi~i~enyl) prc,~penenitrile prom 4-nitrophenylaceionitrile (1.66,g l0mmol) and Intermediate 1 (2.20g, l0mmol). Chromatography (Si02; Et20-hexane, 1:1 ) followed by recrystallisation from methanol-ethanol gave the title compound (1.76g) as ;.yellow crystals m.p. 185.5-187oC (Found: C, 69.29; H, 5.40; N, 7.67.
C2~ H2oN204 requires C, 69.22; H, 5.53; N, 7.69%); dH (CDC13) 1.5-2.1 (8H. br m, (CH2)4), 3.90 13H, s. OMe), 4.85 (1 H, br m, OCHCH2), 6.88 ( 1 H, d, J_ 8.5Hz, ArH ortho to OMe), 7.3 ( 1 H, dd, J_ 8.5, 1.9Hz, ArH foam to OMe), 7.52 (1H, s. CH=CCN), 7.73 (1H, d, J l.9Hz, ArH ortho to cycfopentyloxy), 7.75 (2H, ca.d, ~ 8,7Hz, 2xArH ortho to N02); m/z 364 (M+. 7%), 297 (28), 296 (100), 266 (29), 207 (13), 206 (10), 190 (10), and 41 (28).
a~ fZ)-2-(2-Aminoonenyi)-3-(3-cyciopentyioxy a-methoxvohenvll ,oropenenitrile from 2-aminophenyiacetonitriie (1.3g, l0mmol) and Intermediate 1 (2.20g, ' Ommol). Filtration of the reaction mixture gave the title compound (1.75g) as a white solid m.p. 81-82.5oC (Found: C, 74.86; H, 6.63; N, 8.32. C2i H22N202 reamres C. '5.42; H, 6.63: N, 8.38%); 8H (CDC13) 1.5 2.1 (8H, br m, (CH2)4), 2.14 (2H, s, NH2), 3.89 (3H, s. OMe) 4.85 (1 H, br m. OCHCH2), 6.88 (1 H. d, J_ 8.4Hz. ArH o ho to OMej, 7.0-7.5 (4H, m, ~~6H4NH?), 7.30 ( 1 H. dd, J 8.4, 1.9Hz, ArH ~ to cyclopentyloxy), 7 .55 ;1 H, d, ~ 1.9Hz, ArH artho to cvciopentyloxyj and 8.28 (1 H, s, CH_=CCN);

WO 94/20455 ~ PCT/GB94/00452 °~~ ~~ ' 40 m/z 334 {M+, 32%), 266 (41 ), 265 (97), 252 (12), 251 (65), 250 (26), 249 (100), 69 (11 ), and 41 (32).
f) ~Z)-3 ~3-Cyclopentyloxlr-4-methoxvphenvi)-2-(2-nitroohenvil pro~penenitrile From 2-nitrophenylacetronitrile (1.62g, l0mmol) and Intermediate 1 (2.20g, 1 Ommol). Chromatography (Si02; Et~O-hexane, 1:1 ) gave the title compound (2.60g) as a yellow solid m.p. 95.5-97oC (Found: C, 69.14;
H, 5.43; N, 7.70. C2~ H2oN2O4 requires C, 69.22; H, 5.53; N, 46.69%); 8H
(CDC13) 1.5-2.1 (8H, br m, (CH2)4), 3.88 (3H, s, OMe), 4.86 (1 H, br m, OCHCH2), 6.8-7.7 (7H, m, 2xArH meta to OMe + ArH ortho to OMe +
CH=CCN + 2xArH meta toN02 + ArH para toN02), and 7.95-8.1 (1 H, m, ArH ortho to N02); m/z 364 (M+. 9%), 332 (19), 296 (33), 265 (20), 264 (100), 250 (12), 249 (35), 225 (10), 221 (17), 152 (60), 151 (26), 69 (16), and 41 (30).

a) ~Z 3-(3-Cycioeentyioxv-4-methoxy~phenvl)-2-(4-hvdroxyphen~)ipropenenitrile Sodium ethoxide jprepared from sodium (0.35g, l5mmol) in ethanol (l0ml)] was added dropwise to a mixture of Intermediate 1 (1.09g, 4.95mmol) and 4-hydroxyphenyiacetonitrile (0.67g, 5.03mmol) in ethanol (l0ml). The reaction mixture was heated to refiux for 3h then partitioned between dichloromethane (25m1) and saturated sodium hydrogen carbonate solution (l5ml). The organic layer was separated, dried (MgS04), and concentrated in vacuo. The residue was subjected to chromatogrpahy (Si0?; Et20-hexane, 2:3) to afford the title compound (1.57g) as a yellow solid m.p. 138-140oC. (Found: C, 75.16; H, 6.35; N, 4. 11. C21 H21 N03 requires C, 75.20; H, 6.31; N, 4.18%); 8H (CDC13) 1.5-2.0 (8H, -br m, (CH,2)4), 3.86 (3H, s, OMe), 4.85 (1 H, br m, OCHCH2), 5.57 f 1 H, br s. OH), 6.84 13H. ca. d. J ca. 8.6Hz, ArH ortho to OMe + 2xArH
ortho to OH), 7.22 {1 H. dd, J 8.4, 1.9Hz, ArH para to OCp), 7.26 (1 H, s, CH=CCN), 7.47 (2H, ca. d. J ca. 8.7Hz, 2x ArH meta to OH) and 7.62 (1 H, d, ,~ 8.7Hz, ArH ortho to OCp); r~(~ 335 (M+, 58%), 267 (100), 154 (28), 129 (41 ), 70 (25), 57 (33), and 41 (40).
The following compounds were prepared in a manner similar to the compound of Example 3 a.
b) ~(~~-3-( 3-Clrcionentvloxv-4-methoxvohenvll-?=(~ - eth From 2-methoxyphenylacetonitrile (1.52g, l0mmol) and Intermediate 1 i 0 (2.21 g, 10mmol). The crude product was recrystallised from ethanol to afford the title com o~und (1.26g) as white crystals m.p. 85-87.5oC
(Found: C, 75.67; H, 6.63; N, 3.95. C~H23N03 requires C, 75.62; H, 6.63; N, 4.01 %); 8H (CDC13) 1.5-2.1 (8H, br m, (C -~-21 )4), 3.87 (3H, s, OMe), 3.88 (3H, s, OMe), 4.83 (1 H, br m. OC~-ICH2), 6.83 (1 H, d, ~ 8.4Hz, ArH ortho to OMe), 8.8-7.4 (5H, m, ArH ,~~ra to cyciopentyloxy +
C61~-40Me), 7.25 (1 H, s, CH=CCN), and 7.70 (1 H, d, ,~ 2.1 Hz, ArH ortho to cyciopentyloxy); m/z_ 350 (M+ + 1, 14%), 349 (M+, 57) 282 (20) 281 (100), 150 (12), 129 (37), 71 (11), 70 (11), 67 (13), 57 (16), and 41 (22).
c) (Z)~-2~4-Chtoronhen~ril-3-(3-cyciooentvio~~r-~t-metho~yrohenvi) nroa~enenitriie From 4-chlorophenylacetronitrile (1.65g, 8.7mmol) and Intermediate 1 (2.00g, 9.1 mmoi). The crude product was recrystallised from ethanol to 2~ afford the title compound (2.74x) as page yellow crystals m.p. 129-137oC
(Found: C. 71.18; H, 5.69; N, 3.82. C2~ i-l2oCINO2 requires C, 71.28; H, 5.70: N. 3.96%); 8H (CDCIs) 1.5-2.1 (8H, br m. (CHz)4), 3.88 (3H, s, OMe), 4.85 (1H, br m, OCH_CH2), 6.85 (1H, d, ,~ 8.4Hz, ArH ortho to OMe), 7.2-7.6 (6H, m. ArH ara to cyciopentyloxy + CH=CCN + C6H4C1), and 7.67 (1 H. d, J_ 2.1 Hz. ArH onho to cyciopentyloxy); ~z_ 353 (M+ +
10%), 288 (6), 287 (35), 286 (18), 285 (100), 224 (7), and 207 (10).
d) fZ)-2-~,4-promo ~n~envi~3-~3-clrciopentvioxy-~-methoxY~her)yi) v5 pro~penenitriie WO 94120455 ~ PCT/GB94100452 a2 From 4-bromophenylacetonitrile (2.15g, l0mmol) and Intermediate 1 (2.OOg, 9.1 mmol). The crude product was recrystallised from ethanol to afford the Title comQound (3.27g) as yellow crystals m.p. 116-119oC
(Found: C, 63.17; H, 5.03; N, 3.35. C2i H2oBrN02 requires C, 63.33; H, 5.06; N, 3.52%); cSH (CDC13) 1.5-2.1 (8H. br m, (C_Hz)4), 3.88 (3H, s, OMe), 4.84 (1 H, br m, OC~iCH2), 6.85 (1 H, d, J_ 8.5Hz, ArH ortho to OMe), 7.15-7.35 (1 H, m, ArH ~.r~. to cyclopentyloxy), 7.35 (1 H, s, CH=CCN), 7.48 (4H, s, C6H4CBr), and 7.67 (1 H, d, ~. 2.1 Hz, ArH ~rtho to cyclopentyloxyj; ~_z 399 (16%), 397 (17), 332 (19), 331 (100), 329 (19), 328 (100), 235 (8), 207 (15), and 41 (17).
e) ~~~3 C),rclooentyioxy-4-methoxypheny!)-2-~(2 6-dichloroohenvl) prohenenitrile From 2,6-dichlorophenylacetonitrile (8.OOg, 43mmol) and Intermediate 1 (9.46g, 43mmol). The crude product was recrystallised from ethanol to afford the it~lp comr~ound (12.35g) as a white solid (see Example 1 0) for spectral data).
f) ~7,~~3-Cy~io_henfi~rloxy-4-methoxyrphenvl)~2-(2.6-dimethoxv-phenxl_1 oroi~enitrile From 2,6-dimethoxyphenylacetonitrile and Intermediate 1. The crude product was recrystallised from ethanol to afford the title comQound as white crystals m.p. 120.5-122oC (Found: C, 72-88; H, 6.33; N, 3.13.
C2sH2sN04 requires C, 77.80; H, 6.64; N, 3.69%); 8H (CDCI3) 1.45-2.1 (8H, br m, (CH2)4), 3.84 (6H, s, C6H3 (OMe)2), 3.89 {3H, s, OMe ortho to cyciopentyloxy), 4.87 ( 1 H, br m, OCH ), 6.60 (2H, d, J_ 8.4 Hz, C6H3 (O~JIe)2), 6.87 (1 H, d, J 8.4 Hz, ArH meta to OCp), 7.00 (1 H, s, CH=CCN), 7.2 (1 H, dd, J_ 8.4, 2.1 Hz, ArH para to OCp), 7.29 (1 H, d, ~ 8.4Hz, ArH
meta to 2 xOMe), and 7.79 {1 H, d, ~ 2.1 Hz, ArH ortho to OCp); m z 379 (M'f', 20%), 312 (21 ), 311 (100), 280 (11 ), 152 (43), 151 (72), 150 (33), 137 (18), 91 (16), 85 (15). 83 (23), 43 (10), and 41 (19).
~'' S
~Xt~MPLE 4 (Z)~-(3-Cyrclol~entyl~-4-methoxyrphen,y~~-2-~,4-methoxyr~vl)-pr_~aenenitrlle .a mixture of the phenol of Example 3 (600mg, 1.79mmol), caesium carbonate (580mg, 1.79mmol), and methyl iodide (0.24mg, 3.8mmol) in :, DMF (l0ml) was allowed to stir at ambient temperature for 18h. The reaction mixture was partitioned between dichloromethane (20m1) and saturated sodium hydrogen carbonate solution (l0ml). The organic layer was separated, dried (MgS04), and concentrated in vacuo. The residue was recrystallised from ethanol to afford the title com op and (490mg) as yellow crystals m.p. 102-105oC. (Found: C, 75.43; H, 6.60; N, 3.98.
C22H2sN03 requires C, 75.62; H, 6.63; N, 4.01 %); SH (CDC13) 1.5-2.1 (8H, br m, (CH2)4), 3.82 (3H, s, OI~V e), 3.87 (3H, s, O /le), 4.82 (1 H, br m, OCHCH2), 6.84 (1 H, d, ,~ c~.. 8.6Hz, Ar_H meta to cyclopentyloxy), 6.89 (2H, c~.d, ,~ 8.8Hz, 2x ArH ortho to OMe), 7.23 (1 H, dd, ,~ 8.6, 2.5Hz, Arl~
~ to OMe), 7.27 (1 H, s, CH=CCN), 7.53 (2H, c~.d, ~ 8.8Hz, 2x ArH
meta to OMe) and 7.64 (1 H, d, ,~ 2.OHz, ArH ortho to cyclopentyloxyj; m/~
349 (M+, 32%), 282 (36), 281 (100), 266 (19), 238 (14), 220 (8), and 41 (11 ).

lE~-412-~(3-Cvciopent,lrloxy-4-methox~rnhen~i)e~ then_yrll-3-nitroRyridirte A mixture of Intermediate 1 (2.13g, 9.68mmol), 4-methyl-3-nitropyridine (2.47g, l7mmol), and ammonium acetate (1.19g, l5mmol) in acetic acid (20m1) was heated to reflux for 3h. T he reaction mixture was cooled and partitioned between dichlorometnane (20m1) and saturated sodium hydrogen carbonate solution (2 x l0ml). i he organic layer was separated, dried (MgS04), and concentrated in nacuo. i he residue was subjected to ~~hromatography (Si02; Et20-hexane. 1:1 ) to afford the title com ound ( 1.83g) as an orange solid m.p. 114-116oC. (Found: C, 66.94; H. 5.94; N, 8.01. Ci9H2oN203 reAUires C, 67.05; H. 5.92; N, 8.23%); 8H (CDC13) 1.5-2.1 (8H, br m, (C.H~)4), 3.86 (3H, s, OMe), 4.75 (1H, br m, OCt!-CH2), 6.84 (1 H, d, J_ 8.5Hz. .4rH o ho to OMe), 7.0-7.2 (2H, m, 2x ArH_ meta to OMe) 7 .30 (1 H, s, CH=CH), 7.38 (1 H. s, CH=CH), 7.61 (1 H, d, ~ 5.4 Hz, pyridine ~s), 8.73. (1 H, d . ~ 5.4 Hz. pyridine H~), and 9.09 (1 H, s, pyridine _H2);
mJ_z 340 (M+, 15%) 308 (25), 240 (69), 226 (20), 225 (34), 152 (100), 151 (31 ), 149 (29), ~ 21 (29), 68 (26), 67 (66), and 57 (22).

~~ t~ 44 EXAMPLE fi a) ~F~[2-~(3-Clrcio~~Qent~,rioxy-4-methoxy~henyl)~ethenvll-3.5-dichloro~yrridine Intermediate 3a) (2.65g, 6.92mmol) was dissolved in toluene (60m1) containing p-toluenesulphonic acid (0.2g) and the mixture heated to reflux for 2.5h in a Dean-Stark apparatus. The reaction mixture was concentrated in vacuo and the residue subjected to chromatography (Si02; Et20-hexane, 1:2) to afford the title compound (1.55g) as yellow crystals m.p. 99-101oC. (Found: C, 62.68; H, 5.22; N, 3.70.
C19H~9C12N02 requires C, 62.65; H, 5.26; N, 3.85%); 8H (CDC13) 1.5-2.7 (8H, br m, (C_Hz)4), 3.86 (3H, s, OMe), 4.82 (1 H, br m, OCHCH2), 6.83 (1 H, d, ~. 8.9Hz, ArH o ho to OMe), 6.90 (1 H, d, ~ 16.6 Hz,CH=CH) 7.0 7.2 (2H, m, 2x ArH meta to OMe), 7.40 (1 H, d, ,L 16.6 Hz,CH=CH), and 8.42(2H, s, pyridine H2, Hs); mlz 365 (15%), 363 (20), 297 (67), 296 (28), 295 ( 100), 262 (28), 260 (79), 245 (36), 230 (22), 228 (27), 216 (23), and 152 (24).
The following compounds were prepared in a manner similar to the compound of Example 6 a.
b) fE)-2-(2-(,3-Cvcio~en.~loxv-4-methoxyr~henyl)~ethenyllpvridine From Intermediate 3b). The crude product was subjected to chromatography (Si02; Et20-hexane, 2:1 ) to afford the title com op and (1.58g) as a pale yellow solid m.p. 76-77.5oC. (Found: C, 77.20; H, 7.20;
N, 4.63. C19H2iN02 requires C, 77.26; H, 7.17; N, 4.74%); 8H (CDC13) 1.5-2.1 (8H, br m, (CHz)4), 3.84 (3H, s, OMe), 4.80 (1 H, br m, OCR, 6.80 (1 H, d, J_ 8.5Hz, ArH ro tho to OMe); 6.95 (1 H, d, J_ 15.6 Hz,CH=CH), 6.95-7.7 (5H, m, 2x ArH meta to OMe + pyridine H3, H~, H5), 7.51 (1 H, d, J_ 15.6 Hz,CH--CH), and 8.53(1 H, dm, J_ 4.9 Hz, pyridine Hb); m/~ 295 (M+, 23%), 294 (11 ), 227 (21 ), 226 (100), 211 (18), 184 (10), and 154 (13).
3~
V
c. fE)-4-f~-(3-Cyciopentyioxy-4-methoxyphenvilethenvllwrimidine From Intermediate 3 c). The crude product was subjected to chromatography (Si02; EtOAc) then recrystallised from Et20-hexane to afford the title com o~ ( i .64g) as a pale yellow amorphous solid m.p.
83-84.5oC. (Found: C, 72.58: H. 6.81; N, 9.40. C~ 8H2oN202 requires C, 5 72.95; H, 6.80; N, 9.45%); aH (300MHz; CDC13) 1.6-1.7 (2H, br m, cyciopentyl H's), 1.8-2.1 (6H, br m, cyclopentyl la's), 3.90 (3H, s, ON~e), 4.84 (1 H, br m, OCt!- CH2), 6.91 (1 H, d, ,~ l6Hz, C.d.=CH), 6.92 (1 H, d, ,~
8.3 Hz, Art- ortho to OMe), 7.1-7.2 (2H, m, 2x Ari-1 meta to OMe), 7.31 (1 H, dd, ,~ 5.3, 1.3 Hz, pyridine ,~I ), 7.81 (1 H, d, ~, 16 Hz,CH=CH), 8.65 10 (1 H, d, ,~ 5.3 Hz, pyridine Hs), and 9.14 (1 H, d, ,~ l.3Hz, pyridine F~);
r y 296 (M+, 18%), 228 (26), 227 (100), 213 (6), 212 (7), and 41 (9).

a) (E;~j2 ~(3 Cycio e~ntyloxv-4-methoxy~j en~lethenyi~l~yrridazine 15 Intermediate 4a) was dissolved in toluene (50m1) containing 4-toluenesulphonic acid (0.1g) and the mixture heated to reflux in a Dean-Staric apparatus for 2h. The cooled reaction mixture was poured into saturated sodium hydrogen carbonate solution (25m1) and extracted with dichloromethane (1x50m1, ix25ml). The organic extract was dried 20 (MgSC4), concentrated in vacuo and the residue subjected to chromatography (Si02; Et20-hexane, i :1 ) to afford the title com ound (370mg). (Found: C, 72.75; H, 6.78: N. 9.23. Ci 8H2oN202 requires C, 72.95; H, 6.80; N, 9.45%); dH (CDC13) 1.5-2.1 (8H, br m, (C~)4), 3.85 (3H, s, 011/le), 4.82 (1H, br m. OCH_), 6.75-7.7 (7H, br m, ArH ortno to OMe 25 + 2x ArH meta to OMe + CH=CH_ + pyridazine H3, H5), 8.95 (1 H, dd, ,~ 4.3, 1.4 Hz, pyridazine H6);

The following compounds were prepared in a manner similar to the compound of Example 7a.
b) fE)-4-f2-t3-Cvciooentvl~xy-~-methoxvohenvilethenvilovridine From Intermediate 4b). The cr ude product was subjected to chromatography (Si02; EtOAc) to affora the title com ound (7.47g) as pale yellow needles m.p. 108-108.5oC (from Et201-hexane). (Found: C, 76.92; H, 7.12; N, 4.88. ClgH2~N02 requires C. 77.26; H, 7.17; N, 4.74%); 8H (CDCl3) 1.5-2.1 (8H. br m. (CH2)4), 3.84 (3H, s, OMe), 4.81 (1 H, br m, OCHCH2), 6.77 f 1 H, d, J 15.8 Hz, CH=CH), 6.81 (1 H, d, J_ ~.
9 Hz, ArH ortho to OMe), 6.95-7.1 (3H, m, ArH meta to OMe + CH=CH), ?.28 (2H, dd, J_ 4.7, 1.6 Hz, pyridine H3, H5), and 8.49 (2H, dd , ,~ 4.7, 1.6 Hz, pyridine ~, H6); m/z 295 (M+, 35%), 228 (20), 227 (100), 226 (86), 198 (34), 184 (23), 167 (12), 166 (16), 154 (10), and 41 (20).
c) ,~E~-2~2-r(3-Cvclopentlrloxlr-4-methoxvphenyrllethenvllovrazine From Intermediate 4c). i he crude product was subjected to chromatography (Si02; Et20-hexane, 1:1 ) to afford the title com op and (0.80g) as a pate brown solid m.p. 81-83oC. (Found: C, 72.94; H, 6.78; N, 9.23. C~$H2pN202 requires C, 72.94; H, 6.80; N, 9.45%); 8H (CDC13) 1.5-2.0 {8H, br m, (CH2)4), 3.84 (3H, s, 011 e), 4.80 (1 H, br m, OCR, 6.81 (1 H, d, ,~ 8.8 Hz, ArN ortho to OMe), 6.93 (1 H, d, J_ 15.9 Hz, CH=CH), 7.0-7.15 (2H, m, 2xArH meta to OMe), 7.63 (1 H, d, J_ 15.9 Hz, CH=CH), and 8.25-8.60 (3H, m, pyrazine _Hs, Hs, H6).
d) ~E -4-~2-~3-Clrclopent,yrioxy-4-methoxy~henyl~l- r~O ep nvll ii From Intermediate 7 (1g) using 10% NaOH solution (25m1).
Chromatography (Si02; dichloromethane) followed by recrystallisation (hexane) afforded a mixture of (Z)- title compound, 4-{2-[1-l,3-Cycio-pentyfoxy-4-methoxyphenyl)propenylJpyridine, and the title coml o~ and {247mg) as white needles m.p. 78-79~C. Found C, 77.64; H, 7.58; N, 4.41 C2oH23NO2 requires C, 77.63; H, 7.49; N, 4.52%). 8H (80 MHz;
CDC13) 1.6-2.0 (8H, br m, (C_H2)4), 2.26 (3H, d, ~ 1.3Hz, CH3), 3.85 (3H, s, OMe), 4.75-4.85 (1 H, m, OCHCH2), 6.60-7.21 (6H, m, ArH + PyH3, H5 +
C=CH), and 8.52 {2H, br d, PyH2, H6). mlz (EI) 309 (M+, 30%), 241 (100), 222 (21 ), and 212 (29).
s) ~E)-4-~2-f1-~3-CyciolaentyloxY 4-methoxyrphenyl)~-1- r~ol e~ nvll pyridine hyrdrochloride From Intermediate 3d (0.408, 1.22mmol). Purification by column chromatography (Si02; EtOAc) afforded the title compound free base ~ruhich was dissolved in Et20 and treated with ethanolic HCI to give the title com op and as a fine yellow precipitate. m.p. 197.1 - 200.6°C. (Found:
C, 69.12; H. 6.92: N, 3.96 C2oH23N0 HCI requires C, 69.45; H, 6.99; N, ~~ ~~4 ~9 4.05%). 8H (80 MHz; CDC13) 1.6-2.0 {8H, br m, (CFi,2)4), 2.39 (3H, d, ~
1.OHz, CH3), 3.87 (3H, s, OCH3), 4.73-4.83 (1 H, m, OCHCH2), 6.93-7.0 (3H, m, ArH), 7.25 (1 H, s, HC=C), 7.90 (2H, br d, PyH3, H,s), and 8.65 (2H.
br d, PyH2, Hs). m/z (El) 309 (M~-HCI), 241 and 212.
EXAMPLE $
~-4-f2-(3-Cvciooentyrloxv-4-methoxyphenyyethenlrliplrridine A solution of sodium ethoxide [prepared from sodium (0.10g, 4.50mmoi)]
in ethanol (50m1) was added over 5 min to a stirred mixture of 4-pyridine carboxaidehyde (0.44g, 4.10mmo!) and (3-cyciopentyloxy-4-methoxyphenyl)-methyltriphenyiphosphonium chloride (2.OOg, 4.08g) in ethanol (30m1). After 2h, the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (75m1) and brine (50m1). The organic layer was separated, then dried (MgS04) and concentrated in v o. A ~ H n.m.r. spectrum indicated that the mixture consisted of a 3:2 mixture of (Z) : (E) title compound (and triphenylphosphine oxide). A
portion (0.6g) of the mixture was subjected to chromatography (Si02;
hexane to EtOAc) to afford pure lZ)-title compound (0.14g) as a pale yelow solid m.p. (Found: C, 77.18; H. 7.16; N, 4.63. C1 gH2~ N02 requires C, 77.26; H, 7.17; N, 4.74%); 8H (300MHz; CDC13) 1.5-1.55 (2H, br m, cyclopentyl H's), 1.65-1.9 (6H, br m. cyciopentyl H's), 3.83 (3H, s, OMe), 4.44 {1 H, br m, OCHCHZ), 6.40 (1 H. d. J 12.2 Hz. CH=CH), 6.65-6.80 (4H, m. ArH ortho to OMe + 2xArH meta to OMe + CH=CH), 7.15 (2H, ca.
d, J_ 6.0 Hz, pyridine ~, !-isj; m/z 295 (M+, 22°/a), 228 (15), 227 (100), 226 (94), 198 (35), 184 (15), 166 (12), 43 (19), and 41 (29).
~XAMPLE 9 (Z)-3-l3-Cyciopenxyioxy..~-methox~rQnenvi)-2-~phenyimeth~
oropenenitrile ;~ solution of Intermediate 5 (l.lgj in toluene (100m1) containing 4-tolu~nesu~phonic acid (0.05g) was heated to reflux for 3h. The reaction mixture was partitioned between saturated sodium hydrogen carbonate solution (50m1) and dichforomethane (50m1). The organic phase was separated then dried (MgSOa) and concentrateC in vacuo. The residue ~Nas subjected to chromatography (SiO~; ~t20-hexane, 1:1 ) to afford the title compound (0.90g) as an off-white solid m.p. 111-112oC. (Found: C, ~~9.12; H, 7.00; N. 4.13. C22H2sN02 requires C, 79.25; H, 6.95, N, 4.20%); SH (CDC13) 1.5-2.1 (8H, br m, (CHz)4), 3.64 (2H, d, ~0.9Hz, phCH~), 3.83 (3H, s, OMe), 4.85 (1 H, br m, OCHCH2), 6.78 (1 H, d, ~ 8.3 Hz, ArH ortho to OMe), 6.82 (1 H, d, J_ 0.9Hz, CH=CCN), 7.07 (1 H, dd, ,~
8.6, 2.OHz, ArH bra to cyciopentyloxy), 7.2-7.3 (5H, ~. s, Cst~), and 7.50 (1 H, d, .~ 1.BHz, ArH or h to cyclopentyloxy); ~~ 333 (M+, 16%), 266 (19), 265 (100), 264 (25), 222 (11), 137 (11), 115 (14), and 41 (13).

~E) and ~(~) isomers of 3-(3-Cycio~~~entyf oxy-~-methoxvohenvl~2-(4.5-dichloro-1-imidazoiyrl)~ propenenitrile 4,5-dichloroimidazol-1-yl acetonitrile (purified by dissolution in CH2C12, containing florisil and Si02) (2.998, 0.016mo1) in THF (5ml) was added to a solution of LDA [made from diisopropyiamine (190m1, 0.0135mo1) and n-butyllithium (10.60m1)] in THF at 0°C. The reaction mixture was stirred at 0°C. for ~ 30min, filtered and concentrated to dryness. Purification by column chromatography (Si02; EtOAc-hexane, 1:3) gave {1 ) ~Zl title compound (0.218g) after trituration in hexane as a yellow solid m.p. 87.8-88.8 (Found: C, 57.05; H, 4.48; N, 10.96 Ci8H1~02N3C12 requires C, 57.16; H, 4.53; N, 11.11 %). 8H (80MHz; CDC13) 1.5-2.0 (8H, br m, (CHz)4), 3.84 (3H, s, OC~13), 4.3-4.4 (1 H, m, OCHCH2), 6.00 (1 H, s, ArH), 6.77 (2H, br s, ArH), 7.33 (1 H, s, HC=C or imid Cue, and 7.42 {1 H, s, HC=C or imid CH). m/z_ (EI) 379 (M+, 3%), 377 (5), 308 {10), 276 (11), 275 (13), 274 (41 ), 273 (28), 247 (11 ), 242 (100), 230 (22), and 214 (10).
(2) ~,El title comlcound (0.189g) as pale yellow crystals m.p. 129.3-131.9 (from EtOH). (Found: C, 57.08; H. 4.48; N, 10.92 C~gH~702N3C12 requires C. 57.16; H, 4.53; N, 11,11 %) 8H (80 MHz; CDC13) 1.6-2.0 (8H, br m, (CHz)4), 3.91 (3H. s, OCH3), 4.78-4.86(1 H, m, OCHCH2), 6.88 (1 H, d, ~ 8.5Hz, ArHS), 7.15-7.3 (2H, m, ArH), 7.51 (1 H, s, imid CH), and 7.60 (1 H, d, J_ 2.OHz, HC=C). m/z_ (EI) 379 (M+, 63%), 377 (88), 311 (27), 310 ( 12), 309 (39), 276 (33), 275 (27), 274 (96), 273 (35), and 242 (100).
~XAMPLE 11 xv-4-To a solution of LDA [made from butyllithium (6.70m1, 0.010mo1) and diisopropylamine (1.80m1, 0.012mo1); in THF at -10~C was added 2,6-difluorophenyiacetonitrile (1.20mi, 9.70rnmoi). The solution became yellow. Left to stir at -10~ C for ca 30min before adding chlorotrimethylsiiane (1.30m1, 0.010moi). The solution became colourless.
Left to stir at -10~C for ca 20min before cooling to -78°c and adding butyllithium (6mi; 9.6mmol)). The solution became light orange. Left to stir ca 15 min before adding intermediate 1 (2.13g, 9.68mmol). The reaction mixture was left to warm to RT overnight, washed with saturated sodium bicarbonate solution, extracted with dichloromethane, dried (MgS04) and concentrated in vacuo. Chromatography (Si02; Et20-hexane, 1:4) afforded the title com ound (0.301 g) as white crystals. m.p.
79.1-81 ~C (Found C, 70.80; H, 5.39; N, 3.93. C2y Hy9F2N02 requires C, 70.97; H, 5.39; N, 3.94%). 8H (80MHz; CDC13) 1.5-2.0 (8H, br m, (Ct-~)4), 3.88 (3H, s, OCH_3), 4.18-4.9 (1 H, m, OCH_CH2), 6.78-7.4 (6H, m, ArH + HC=C), and 7.74 (1 H. d, ,~ 2.1 Hz, Ark. ~~ (EI) 355 (11~-, 15%), 287 (100), 244 (15) and 84 (25).
~XAMP~E 72 Ethyl cis-(3-Cvc~ntyloxv-4-methoxvohenyik~~ (,4-gyri rl) ep noate A mixture of Intermediate 1 (26.628; 0.12mo1), athyl-4-pyridylacetate ( 19.928; 0.12mo~; 1 eq) ana ammonium acetate ( 18.638; 0.248; 2eq) in glacial acetic acid (200m1) was stirreo at 120~C under N2 for 20 hours.
The solution was cooled to room temperature and the acid removed in ~acuo to give an orangey/brown residue. This residue was taken up in a saturated bicarbonate solution (to pH=8.5) and extracted several times with ethyl acetate. The combined organic layer was washed with brine, dried (MgS04) and evaporated to dryness to give a yellow solid.
Recrystallisation from tolueneihexane c:1 st crop) then toluene (2nd crop) ~oilowed by column chromatography (Si02; hexane-EtOAc/hexane: 7/3) gave the title com ound m.p. 109-11 1 ~C as a white crystalline solid. SH
(CDC13) 1.27 (3H, t, J_ 7.1 Hz, CH2C~), i .45-1.8 (8H, br m, cyclopentyl I-I's), 3.81 (3H, s. OMe), 4.16 (1 H. br m, OCH), 4.25 (2H, q, J_ 7.1 Hz, H CH3), 6.43 (? H, d, ~ 2.OHz, ArH ortho to cyclopentylolxy), 6.73 (1 H, d, J_ 8.4 Hz, ArH ortho to OMe), 6.80 (1 H, dd, ~ 2.0, 8.4 Hz, ArH para to cyclopentyloxy), 7.22 (2H, dd, J 1.6, 4.5 Hz, pyridine .H~, H5), 7.83 (1 H, s, HC = C) and 8.64 (2H, dd, J_ 1.6, 4.5 Hz, pyridine H_2, H_s).
5 An alternative procedure is as follows:
To a stirred solution of Intermediate 1 (22g; 100mmol) and ethyl-4-pyridyl-acetate (16.5g; 100mmol) in dry toluene (150m1) at room temperature was added glacial acetic acid (2.4m1) followed by piperidine (O.8ml). The solution was heated to refiux and the water produced removed as an 10 azeotrope, collected by a Dean Stark Apparatus. After 16 hrs, the solution was allowed to cool to room temperature, charcoal and Florisil added, stirred for 5 minutes and then filtered. The solvent was removed by evaporation in vacuo. The crystalline solid obtained was dissolved in dichloromethane, washed with a saturated sodium bicarbonate solution, 15 dried (MgS04), filtered and the solvent removed by evaporation in vacuo.
The product was recrystallised (diisopropyl ether) to give the ~ii~
som~ound as a white crystalline solid, with melting point and NMR
consistent with the above values.

i E)-1-(3-CKclopentyloxy-4-methoxyphenyrl)~-2-(3-~vridvllethene Potassium ert.-butoxide (197mg, 1.75mmol, l.2eq) was added to a solution of Intermediate 10(500mg, 1.46mmol) in THF at 0°C. The mixture was stirred for 5 min then a solution of 3-pyridinecarboxaldehyde (156mg, 25 1.46mmol) in THF (5ml) was added dropwise. After stirring at RT for 16h the reaction mixture was concentrated in vacuo. The residue was partitioned between chloroform (l0ml) and water (5ml), and the organic phase was separated, dried (MgS04), and concentrated in vacuo. The residue was subjected to chromatography (Si02; EtOAc-hexane, 1:1 ) to 30 afford the title corn op and (196mg) as a pale yellow oil; SH (80MHz;
CDCI3) 1.5-2.1 (8H, br m, (CH2)4), 3.82 (3H, s, OMe), 4.80 (1 H, br m, OCR, 6.7-7 .3 (6H, m. C6H3 + H C=CH + pyridine H4), 7.73 (1 H, m, pyridine F_i,5), 8.40 ( i H, dd, J 4.5, 2.OHz, pyridine H6), and 8.64 (1 H, d, J_ 2.OHZ, pyridine H2).

WO 94/20455 ~ 9 PCT/GB94/00452 The title compound (185mg) was dissolved in ethanol (5ml) and treated with Et20-HCI. The mixture was concentrated in u~;uo and the residue recrystallised form chloroform-hexane to afford the title coml oc and hydrochloride (173mg) as pale yellow crystals m.p. 177-181~C (300MHz;
CDC13) 1.65-2.1 (8H, br m, (C~)4), 3.91 (3H, s, Ome), 4.87 (1 H, br, m, OCR.), 6.91 (1 H, d, ,~ 8.0 Hz, Ark ortho to OMe), 6.93 (1 H, d, ,~ 16.2Hz, C~=CH), 7.05-7.15 (2H, m, 2 x ArH meta to OMe), 7.2-7.3 (1 H, m, pyridine b,4), 7.73 (1 H, d, ,~ 16.2Hz, CH=Cue, 7.85 (1 H, dd, ,~ 7.5, 5.OHz, pyridine Ij~), 8.41 (1 H, d, ~ 7.5Hz, pyridine ,ds), 8.55 (1 H, d,,L 5.OHz, pyridine ~), and 8.87 (1 H, br s, NH); ,~ry~ (EI) 295 (~I+-HCI, 49%), 228 (20), 227 (100), 226 (92), 207 (28), 198 (25), 180 (39), 41 (34), 38 (27), and 36 (85).
FORMULATION EXAMPLES
The compounds of the invention may be formulated for pharmaceutical use in a number of forms using any suitable excipients. Thus, for example, for oral use the compounds of the invention such as the compounds of the Examples may be formulated as a solid dosage form, by mixing an appropriate weight of compound (for example 50mg) with maize starch (50-99%w/wj, anhydrous colloidal silica (0-10%w/w) and organic or inorganic acid (up to 1 %w/w), to fill capsules of an appropriate size, e.g. white opaque hard gelatine capsules size 3. If desired the same mixture may be compressed into tablets.
The activity and selectivity of compounds according to the invention was demonstrated in the following tests. In these tests the abbreviation FMLP
represents the peptide N-formyl-met-leu-phe.
Isolated Enzvme The potency and selectivity of the compounds of the invention was determined using distinct PDE isoenzymes as follows:
i. PDE l, rabbit heart ii. PDE II, rabbit heart iii. PDE III, rabbit heart, Jurkat cells iv. PDE IV, HL60 cells, rabbit brain. rabbit kidney and human recombinant PDE IV
v. PDE V. rabbit lung, guinea pig lung A gene encoding human PDE IV has been cloned from human monocytes (Livi, dal., 1990, Molecular and Cellular Biology, ~, 2678). Using similar procedures we have cloned human PDE IV genes from a number of sources including eosinophils, neutrophils, lymphocytes, monocytes, brain and neuronal tissues. These genes have been transfected into yeast using an inducible vector and various recombinant proteins have been expressed which have the biochemical characteristics of PDE IV (Beavo and Reifsnyder, 7990, TI,°S, r 1, 150). These recombinant enzymes, particularly the human eosinophil recombinant PDE IV, have been used as the basis of a screen for potent, selective PDE IV inhibitors.
The enzymes were purified to isoenzyme homogeneity using standard chromatographic techniques.
Phosphodiesterase activity was assayed as follows. The reaction was conducted in 1501 of standard mixture containing (final concentrations):
50mM 2-[[tris(hydroxymethyl)methyl]amino]-1-ethane-sulphonic acid (TES) -NaOH buffer (pH 7.5), 1 OmM MgCl2, 0.1 uM [3H]-cAMP and vehicle or various concentrations of the test compounds. The reaction was initiated by addition of enzyme ana conducted at 30oC for between 5 to 30 min.
The reaction was terminatea by addition of 50p1 2% trifluoroacetic acid containing (~4C1-5'AMP for determining recovery of the product. An aliquot of the sample was then applied to a column of neutral alumina and the [3H]-cAMP eluted with l0ml 0.1 TES-NaOH buffer (pH8). The (3H]-5'-AMP
product was eluted with 2ml 2M NaOH into a scintillation vial containing l0ml or scintillation cocktail. Recovery of [3H]-5'AMP was determined using the ('4C]-5'AMP and all assays were conducted in the linear range of the reaction.
Compounds according to the invention such as compounds of the Examples herein cause a concentration-dependent inhibition of WO 94120455 ~ ~ ~ PCT/GB94/00452 recombinant PDE IV at 0.1 - 1000nM with little or no activity against PDE I, II, III or V at concentrations up to 100~.M.
2. The Elevation of cAMP in Leukocy es The effect of compounds of the invention on intracellular cAMP was investigated using human neutrophils or guinea pig eosinophils.
Human neutrophils were separated from peripheral blood, incubated with dihydrocytochalasin B and the test compound for 10 min and then stimulated with FMLP. Guinea pig eosinophils were harvested by peritoneal lavage of animals previously treated with intra-peritoneal injections of human serum. Eosinophils were separated from the peritoneal exudate and incubated with isoprenaline and test compound. With both cell types, suspensions were centrifuged at the end of the incubation, the cell pellets were resuspended in buffer and boiled for 10 min prior to measurement of cAMP by specific radioimmunoassay (DuPont).
The most potent compounds according to the Examples induced a concentration -dependent elevation of CAMP in neutrophils and/or eosinophils at concentrations of 0.1 nM to 1 pM.
3. Su~hression of Leukocyte Function Compounds of the invention were investigated for their effects on superoxide generation, chemotaxis and adhesidn of neutrophils and eosinophils. Isolated leukocytes were incubated with dihydrocyto chalasin B for superoxide generation only and test compound prior to stimulation with FMLP. The most potent compounds of the Examples caused a concentration-dependent inhibition of superoxide generation, chemotaxis and adhesion at concentrations of 0.1 nM to 1 p.M.
Lipopolysaccharide (LPS)-induced synthesis of tumour necrosis factor (TNF) by human peripheral blood monocytes (PBM) is inhibited by compounds of the Examples at concentrations of 0.01 nM to 1 O~,M.

WO 94/20455 ~ PCTIGB94100452 a. 9efaxation of Constricted Airway Smooth Muscle in vitro The effects of compounds of the invention on guinea-pig isolated tracheal smooth muscle were investigated. Isolated tracheal rings were suspended in organ baths and immersed in oxygenated Krebs' solution. The smooth muscle was contracted with sub-maximal concentrations of histamine or carbachol prior to the addition of increasing concentrations of test compound to the organ baths. The most potent compounds of the Examples caused a concentration-dependent reversal of both histamine and carbachol-induced contractions at concentrations of 1 nM to 1 OO~,M. The compounds were generally more potent in reversing histamine-induced tone than carbachol-induced tone.
;,. Effects on Cardiac Muscle in vitro Compounds of the invention have been tested for their effects on isolated cardiac muscle. Right atrial and papillary muscles were dissected out from the hearts of guinea pigs and suspended in organ baths for measuring the rate (chronotropic) of spontaneously beating atria and force (inotropic) of the electrically stimulated papillary muscle. In these preparations, selective PDE IV inhibitors such as rolipram do not have any direct effects whereas selective PDE 111 inhibitors such as milrinone have positive chronotropic and inotropic effects. The non-specific PDE inhibitor theophylline, which is used in asthma as a bronchodilator, also causes significant cardiovascular changes such as tachycardia. Selective PDE IV inhibitors have advantage over theophylline, therefore, through reduced cardiovascular side effects. The most potent and selective compounds of the Examples had no direct effects on the atrial and papillary muscles in vitro at concentrations up to lOp.M but in 3C combination with PDE III inhibitors, These inhibitors showed an enhancement oz chronotropic and inotropic activity, typical cf selective type IV inhibitors.
5. 4nti-inflammatory Activity in vivo Interieukin-5 !IL-5)-induced pleural eosinophilia in the rat (Lisle, gel, 1993. Br.J. Pharmacol. 708, 230p) is inhibited by compounds of the WO 94120455 ~ ~ 9 PCT/GB94/00452 Examples given orally at doses of 0.0001 to lO.Omg/kg. The most potent compounds cause a dose-dependent reduction in migrating aosinophils with EDSOS of 0.003 to 0.03mg/kg p.o.
5 Compounds of the invention also reduce the inflammatory responses induced in rats by platelet activating factor (PAF).
7. Anti-allergic Activitlr in vivo 10 Compounds of the invention have been tested for effects on an IgE-mediated allergic pulmonary inflammation induced by inhalation of antigen by sensitised guinea pigs. Guinea pigs were initially sensitised to ovalbumin under mild cyclophosphamide-induced immunosuppression, by intraperitoneal injection of antigen in 15 combinations with aluminium hydroxide and pertussis vaccine.
Booster doses of antigen were given two and four weeks later and at six weeks, animals were challenged with aerosolised ovalbumin whilst under cover of an intraperitoneally administered anti-histamine agent (mepyramine). After a further 48h, bronchial alveolar lavages 20 (BAL) were performed and the numbers of eosinophils and other leukocytes in the BAL fluids were counted. The lungs were also removed for histological examination for inflammatory damage.
Administration of compounds of the Examples (0.001-l0mg/kg i.p. or p.o.), up to three times during the 48h following antigen challenge, 25 lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes. There was also less inflammatory damage in the lungs of animals treated with compounds of the Examples.
30 8. Effects on Pulmonaryr Dynamics Compounds of the invention (0.001-1 Omg/kg by oral or other route of aministration~ reduce the allergic bronchoconstruction caused by antigen in sensitized guinea pigs.
35 Compounds of the invention have been tested for their effects on ozone-induced hyperreactivity of the airways of guinea pigs.
Following the inhalation of ozone, guinea pigs become very much WO 94120455 ~ PCT/GB94100452 more sensitive to the bronchoconstrictor effects of inhaled histamine than naive animals ( Yeadon a al 1992, Pulmonary Pharm., ~, 39).
There is a pronounced shift to the left (10-30 fold) of the dose response curve to histamine and a highly significant increase in the maximum increase in pulmonary resistance. Compounds of the Examples administered 1h prior to ozone by the intraperitoneal or oral (0.001-l0mg/kg) route caused a dose-dependent inhibition of ozone-induced hyperreactivity.
9. Adverse Effects in general, in our tests above, compounds of the invention have had no observed toxic effects when administered to animals at the doses shown.

Claims

571. A compound of formula (1) wherein:
Y is a halogen atom or a group -OR1, wherein R1 is a C1-3 alkyl group which is either unsubstituted or substituted by one or more halogen atoms;
X is -O-, -S- or -N(R6)-, wherein R6 is a hydrogen atom or a C1-6 alkyl group;
R2 is a a C3-8 cycloalkyl or C3-8 cycloalkenyl group which is either unsubstituted or substituted by up to three substituents selected from halogen atoms and C1-6 alkyl, hydroxyl and C1-6 alkoxy groups;
R3 and R4, which may be the same or different, are each selected from hydrogen atoms, C1-6 alkyl groups [which may either be unsubstituted or carry halogen, hydroxyl, C1-6 alkoxy, thiol or C1-6 alkylthio substituents] , -CN, -CH2CN, -CO2R7, -CONR8R9 and -CSNR8R9 groups [wherein R7, R8 and R9 each independently represent hydrogen atoms or C1-3 alkyl , C6-12 aryl or C6-12 aryl-C1-3 alkyl groups which are either unsubstituted or substituted by R10 substituents selected from fluorine, chlorine, bromine and iodine atoms and C1-6 alkyl, C1-6 alkyl amino, C1-6 hydroxyalkyl , C1-6 alkylthiol , C1-6 alkoxy, C5-7 cycloalkoxy, C1-6 haloalkyl, amino, C1-6 aminoalkyl, C1-6 dialkylamino, nitro, cyano, hydroxy, formyl, carboxyl, -CO2Alk2 (where Alk2 is an unsubstituted or R10-substituted C1-8 alkyl, C6-12 aryl-C1-8 alkyl, C6-12 aryl, C6-12 aryloxy-C1-8 alkyl, C1-8 alkanoyloxy-C1-8 alkyl or C6-12 aroyloxy-C1-8 alkyl group), C1-6 alkanoyl, thiol, C1-6 thioalkyl, sulphonyl, C1-6 alkylsulphonyl, aminosulphonyl , C1-6 alkylaminosulphonyl , C1-6 dialkylaminosulphonyl , C6-12 arylaminosulphonyl, C6-12 aryl-C1-3 alkylaminosulphonyl, carboxamido, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, sulphonylamino, aminosulphonylamino, C1-6 alkylaminosulphonylamino, C1-6 dialkylaminosulphonyl-amino, C1-6 alkanoylamino-C1-6 alkyl, C1-6 alkoxycarbonylamino, -NHCOR7, -NHCONHR7 and -NHSO2R7 groups (where R7 is as defined above), or wherein two R10 substituents together form a C1-6 alkylenedioxy group];
Z is - (CH2)n- where n is zero or an integer 1, 2 or 3;
R5 is a C6-12 monocyclic or bicyclic aryl group or a C1-9 monocyclic or bicyclic heteroaryl group containing up to four heteroatoms selected from oxygen, sulphur and nitrogen, said aryl group being either unsubstituted or substituted by up to four substituents R10 as defined above;
or a salt, solvate, hydrate or N-oxide thereof;
with the proviso that said compound of formula (1) is not methyl 3-{2-[3-(cyclopentyloxy)-4-methoxyphenyl]-ethenyl}benzoate or 3-{2-[3'-(cyclopentyloxy)-4-methoxy-phenyl]ethenyl}benzoic acid.
2. A compound according to claim 1 wherein Y is an -OR1 group.
3. A compound according to claim 2 wherein R1 is a methyl group.
4. A compound according to any one of claims 1 to 3 wherein X is -O-.
5. A compound according to any one of claims 1 to 4 wherein R2 is a cyclopentyl group.
6. A compound according to any one of claims 1 to 5 wherein Z is a -(CH2)n- group wherein n is zero or an integer 1 or 2.
7. A compound according to claim 6 wherein n is zero.
8. A compound according to any one of claims 1 to 7 wherein R3 is a hydrogen atom or a methyl group.
9. A compound according to claim 8 wherein R3 is a hydrogen atom.
10. A compound according to any one of claims 1 to 9 wherein R9 is a hydrogen atom, a -CN group or a C1-6 alkyl group which is either unsubstituted or carries one or more halogen, hydroxyl, C1-6 alkoxy, thiol or C1-6 alkylthio substituents.
11. A compound according to claim 10 wherein R9 is a hydrogen atom or a -CN group.
12. A compound according to any one of claim 1 to 11 wherein R5 is a phenyl, pyridyl, thienyl, imidazolyl, pyridazinyl or pyrimidinyl group which is either unsubstituted or substituted by up to four R10 substituents.
13. A compound according to claim 12 wherein R5 is a phenyl or pyridyl group which is either unsubstituted or substituted by up to four R10 substituents.
14. A compound according to claim 13 wherein R5 is an unsubstituted, 2- or 3-mono-R10-substituted or 2,6-di-R10-substituted phenyl group.
15. A compound according to claim 13 wherein R5 is an unsubstituted 2-, 3- or 4-pyridyl group or a 3,5-di-R10-substituted 4-pyridyl group.

16. A compound according to any one of claims 12 to 15 wherein the aryl or heteroaryl group of R5 is substituted by one or two R10 substituents selected from halogen atoms and nitro, amino, C1-6 alkoxy, C1-6 haloalkyl, hydroxy, -NHCOR7, -NHCONHR7 and -NHSO2R7 groups [where R7 is as defined in claim 1].
17. A compound according to claim 1 which is:
(Z)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-hydroxyphenyl)propenenitrile;
(E)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethenyl]-pyridine;
(Z)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethenyl]-pyridine;
(Z)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2-nitrophenyl)propenenitrile;
(Z)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4,5-dichloro-1-imidazolyl)propenenitrile;
(Z)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)propenenitrile;
(Z)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2-thienyl)propenenitrile;
(Z)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-difluorophenyl)propenenitrile;
(E) -4-{2-[1-(3-cyclopentyloxy-4-methoxy)phenyl]-1-propenyl}pyridine;
(E) -4-[2-(3-cyclopentyloxy-4-methoxy)ethenyl]-3,5-dichloropyridine;
(Z)-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)propenenitrile;
N-f4-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethenyl]-3-pyridyl}phenylsulphonamide;
(E)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethenyl]-3-nitropyridine;
(E)-2-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethenyl]-pyridine;
(E) -4-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethenyl]-pyrimidine;
(E)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethenyl]-pyridazine;
or a salt, solvate, hydrate or N-oxide thereof.
18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 together with one or more pharmaceutically acceptable carriers, excipients or diluents.
19. A composition according to claim 18 in a form suitable for oral administration.
20. A composition according to claim 19 where the form for oral administration is a tablet, lozenge or capsule.
21. A process for the preparation of a compound of formula (1) as defined in claim 1, or a salt, solvate, hydrate or N-oxide thereof, which comprises:
i) reacting a compound of formula (3) [where Y, X and R2 are as defined in claim 1 and W is a -C(O)R3 group in which R3 is as defined in claim 1 but is not a -CN or -CH2CN group] with a compound R5ZCH2R4 [where R4, Z and R5 are as defined in claim 1] in the presence of a base or an acid;
ii) reacting a compound of the above formula (3) [where Y, X, and R2 are as defined in claim 1 and W is a -CH2R3 group in which R3 is as defined in claim 1] with an aldehyde or ketone R52COR4 [where R4, Z and R5 are as defined in claim 1 except that R9 is not a -CN or -CH2CN
group] in the presence of a base or an acid;
iii) reacting a compound of the above formula (3) [where Y, X and R2 are as defined in claim 1 and W is a -C (O) R3 group in which R3 is as defined in claim 1] with a silane derivative Alk3SiCH (R4) (R5) [where R4 and R5 are as defined in claim 1 and Alk is a C1-6 alkyl group] in the presence of a base or an acid;
iv) alkylating a compound of formula (5) [wherein Y, X, R3, R4, Z and R5 are as defined in claim 1] with a halide R2Hal or an alcohol R2OH [wherein R2 is as defined in claim 1 and Hal is a halogen atom];
v) dehydrating an alcohol of formula (6) [wherein Y, X, R2, R3, R9, Z and R5 are as defined in

claim 1] using an acid at elevated temperature;
vi) reacting a phosphonium salt of formula [wherein Y, X, R2 and R3 are as defined in claim 1, Ar is an aryl group and Hal is a halogen atom] with a compound R5ZCOR4 [where R4, Z and R5 are as defined in claim 1] ; or vii) interconverting a compound of formula (1) to yield another compound of formula (1).