CA2241093C - Tri-substituted phenyl derivatives useful as pde iv inhibitors - Google Patents

Abstract

Compounds of general formula (1) are described, wherein W, L, R3, R4, R5, R6 and R7 have the meanings as defined in the description, according to which at least one of R4 or R5 is a -(CH2)t ArN(R b)CX1N(R b)L2(Alk)m Ar group. The compounds are 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

TRI-SUBSTITUTED PHENYL DERIVATIVES USEFUL AS
PDE IV INHIBITORS
This invention relates to a novel series of triarylethanes, 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 adenyl 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 adenyl 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 I-VII) the distribution of which varies from tissue to tissue. This 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 & Reifsnyder {1990) TIPS, 11: 150-155 and Nicholson et al (1991) TIPS, 12: 19-27].
There is clear evidence that elevation of cAMP in inflammatory leukocytes leads to inhibition of their activation. Furthermore, elevation of cAMP in airway smooth muscle has a spasmolytic effect. In these tissues, PDE IV
plays a major role in the hydrolysis of cAMP. It can be expected, t rcfnraa~that gglg~tiyca iniiihit~r~ of PII~ I\/ wny;ld hays thrrratng~,~tin he. ~..>
effects in inflammatory diseases such as asthma, by achieving both anti-inflammatory and bronchodilator effects.
In our International Patent Specification No. W094/14742 we describe a series of triarylethanes which are potent inhibitors of the PDE IV
isoenzyme at concentrations at which they have little or no inhibitory action on other PDE isoenzymes. The compounds are of use in medicine, especially in the prophylaxis and treatment of asthma. An enantioselective process for the preparation of these compounds is described in our International Patent Specification No. W095/17386.
We have now found a particular series of triarylethanes which are potent and selective PDE IV inhibitors and which also have other advantageous pharmacological properties, including especially good oral availability and improved metabolic stability.
Thus according to one aspect of the invention, we provide a compound of formula (1 ) L
/ ~ Rs R~
W

R4 (1) wherein =W- is (1 ) =C(Y)- where Y is a halogen atom, or an alkyl or -XRa group where X is -O-, -S(O)p- [where p is zero or an integer of value 1 or 2], or -N(Rb)- [ where Rb is a hydrogen atom or an optionally substituted alkyl group] and Ra is a hydrogen atom or an optionally substituted alkyl group or, (2) =N-;
L is a -XR, [where R is an optionally substituted alkyl, alkenyt, cycloalkyl or cyloalkenyl groupj, -C(Rjj)=C(R~)(R2) or [-CH(R1~)]~CH(Rj)(R2) group where Ri ~ is a hydrogen or a fluorine atom or a methyl group, and R~ and R2, which may be the same or different, is each a hydrogen or fluorine atom or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, -C02R8, [where R8 is a hydrogen atom or an optionally substituted alkyl, aralkyl, or aryl group], -CONRsRio [where R9 and R'~o, which may be the same or different is each as defined for R$], -CSNR9R'~~, -CN or -N02 group, or R1 and R2 together with the C atom to which they are attached are linked to form an optionally substituted cycloalkyl or cycloalkenyl group and n is zero or the integer 1;
R3 is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or a hydroxyl group;

WO 97!23461 PCTJGB96/03196 R4 is a hydrogen atom or group -(CH2)tAr [where t is zero or an integer 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group, optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms] or a group -(CH2)t-Ar-(L1 )~-Ar' [where Lt is a divalent linking group n is zero or an integer 1 and Ar' is -Ar, -CO(Alk)n,Ar, [where Alk is an optionally substituted straight or branched C1 _s atkylene, C2_6 alkenylene or C2_6 atkynylene chain optionally interrupted by one, two or three -O- or -S- atoms or -S(O)q- (where q is an integer 1 or 2) or -N(Rb)- groups and m is zero or an integer 1 ], -S02(Aik)~Ar, -S02NH(Alk)mAr, -S02N(Alki){Alk)~Ar [where Alki is as defined for Alk] -S02N[(Alk)n.,Ar]2, -CONH(Alk)mAr, -CON(Alki )(Alk),~,~,Ar, -CON[(Alk)mAr]2, -N(Alk~ )SOZ(Alk)mAr, -NHS02(Alk)mAr, -N[S02(Alk)mAr]2, -NHS02NH(Alk)mAr, -N(AIk1 )S02NH(Alk)r,.,Ar, -NHS02N(AIk1)(Atk),nAr, -N(AIk1)S02N(Alki)(Alk)~,Ar, -NHS02N[(Atk)mAr]2, -N(AIk1 )S02N[(Alk)mAr]2, -NHC(O)(Alk),nAr, -N(Atk~)C(O)(Atk)mAr, -N[C(O)(Alk)mAr]2, - NHC(O)NH(Alk)~Ar, -N(AIk1)C(O)NH(Alk),r,Ar, -NHC(O)N(Alky)(Alk)n,Ar, .
-N(Alk~)C(O)N(Alk~)(Alk)mAr, -NHC(O)O(A1k)mAr, -N(Alk'~)C(O)O(Alk),~.~Ar, -C(S)NH(Alk)mAr, -C(S)N(Alk~)(Alk)mAr, -C(S)N(Alk~)(Alk),~,~,Ar, -C(S)N[(Alk)r,.~Ar]2, -NHC(S)(Alk)~-,Ar, -N(Atk~ )C(S)(Alk)mAr, -N[C(S)(Alk),~,~,Ar]2, -NHC(S)NH(Alk)mAr, -N(Alk~ )C(S)NH(Alk)mAr, -NHC(S)N{AIk1)(Alk),~,~,Ar, -N(AIk1)C(S)N(Alki)(Alk)~,Ar, -S02(Alk)mNHet [where -NHet is an optionally substituted C~_~ heterocyclic amino group optionally containing one or more other -O- or -S- atoms or -N(Rb)-, -C{O)-or -C(S)- groups], -CO(Atk}r,~,NHet, -CS(Alk)r,.,NHet, -NHS02(Alk)=,~,NHet, -NHC(O)(Alk)r,.,NHet, -NHC(S)(Alk)mNHet, -S02NH((Alk)mHet') [where Het' is an optionally substituted C~_~monocyclic carbocyclic group optionally containing one or more -O- or -S- atoms or -N(R~)- groups], -CC_~I~jHIIA~kI H~t'1 -~~,itl~llAlk) HAt') -NI-tSn~NN'(Atk)~,uot~)~
v iiil~ i~ w Wt r -NHC{O)NH(Alk)~,.,(Het') or -NHC(S)NH(Alk),~,.,(Het') group] or R4 is a -(CH2)tArN(R~)CX1 N{Rb)L2(Alk)mAr group where X is an oxygen or sulphur atom and L2 is a divalent linking group;
R~ is a -(CH2)tAr, -(CH2)t-Ar-(L~ )n-Ar' o r -(CH2)tArN(Rb)CX'~ N(Rb)L2(Alk),nAr group, provided that at least one of R4 or R5 is a -(CH2)tArN(Rb)CX1 N(Rb)L2{Alk)mAr group;

WO 97/23461 1'CT/GB96/03196 Rs is a hydrogen or a fluorine atom, or an optionally substituted alkyl group;
R~ is a hydrogen or a fluorine atom, an optionally substituted straight or branched alley! group or an ORS group where R~ is a hydrogen atom or an optionally substituted alkyl or alkeny! group, or an alkoxyalkyf, alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts, solvates, hydrates, prodrugs and N-oxides thereof.
it will be appreciated that certain compounds of formula (i ) may have one or more chiral centres, depending on the nature of the groups L, R'~ , R2, R3, R4, R5, R6 and R~. Where one or more chirat centres is present, enantiomers or diastereomers may exist, and the invention is to be understood to extend to al! such enantiomers, diastereomers and mixtures thereof, including racemates.
Compounds of formula (1 ) wherein L is a -C(R1 i }=C(Ri){R2) group may exist as geometric isomers depending on the nature of the groups R1, R2, and R1 ~ and the invention is to be understood to extend to all such isomers and mixtures thereof.
In the compounds of formula (1), when =W- is =C(Y}- and Y is a halogen atom Y may be for example a fluorine, chlorine, bromine or iodine atom.
When W in the compounds of formula (1 ) is a group =C(Y)- and Y is -XRa, Ra may be, for example, a hydrogen atom or an optionally substituted straight or branched alkyl group, for example, an optionally substituted Ci _ salkyl group, such as a methyl, ethyl, n-propyl or i-propyl group. Optional substituents which may be present on Ra groups include one or more halogen atoms, e.g. fluorine, or chlorine atoms. Particular Ra groups include for example -CH2F, -CH2CI, -CHF2, -CHCI2, -CF3 or -CCI3 groups.
When =W- in the compounds of formula (1) is a group =C(Y}- where -Y is -N(Rb), =W- may be a =C(NH2)-, =C(NHCH3)- or =C(NHC2H5)- group.

In compounds of formula (1 ), X may be an oxygen or a sulphur atom, or a group -S(O)-, -S(O)2-, -NH- or C~_s alkylamino, for example a Cy_3 alkylamino, e.g. methylamino [-N(CH3)-] or ethylamino [-N(C2H5)-] group.

5 Alkyl groups represented by Y, R, R1, R2, or Rb in the compounds of formula (1) include optionally substituted straight or branched Ci_s alkyl groups optionally interrupted by one or more X atoms or groups.
Particular examples include C~_3 alkyl groups such as methyl or ethyl groups. t~ptiona~ substituents on these groups include one, two or three substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl or C1_s alkoxy e.g. Ci_3 alkoxy such as methoxy or ethoxy or -C02R8, -CONR9R», -CSNR9R~o or -CN groups.
Alkenyl groups represented by R, R1 or R2 in the compounds of formula (1) include optionally substituted straight or branched C2_salkenyl groups optionally interrupted by one or more X atoms or groups. Particular examples include ethenyl, propen-1-yl and 2-methyipropen-1-yl groups.
Optional substituents include those described above in relation to alkyl groups represented by the groups Rj or R2.
Alkynyl groups represented by Ry or R2 in compounds of formula (1 ) include optionally substituted straight or branched C2_salkynyl groups optionally interrupted by one or more X atoms or groups. Particular examples include ethynyl and propyn-1-yl groups. Optional substituents include those described above in relation to alkyl groups represented by the groups R1 or R2.
When R~ or R2 in compounds of formula (1 ) is an alkoxy or alkylthio group it may be for example an optionally substituted straight or branched CI-s alkoxy or Cy_salkylthio group optionally interrupted by one or more X
atoms or groups. Particular examples include C1 _3alkoxy, e.g. methoxy or ethoxy, or C~ _3alkylthio e.g. methylthio or ethylthio groups. Optional substituents include those described above i_n relation to alkyl groups represented by the groups R1 or R2.

When RI and R2 together with the carbon atom to which they are attached in the compounds of formula (1 ) are linked to form a cycloalkyl or cyclo-alkenyl group, the group may be for example a C3_8cycloalkyl group such as a cyclobutyl, cyclopentyl or cyclohexyl group or a C3_$ cycloalkenyl group containing for example one or two double bonds such as a 2-cyclo-buten-1-yl, 2-cyclopenten-1-yl, 3-cyciopenten-1-yl, 2,4-cyclopentadien-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-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, straight or branched C~_salkyl e.g. C1-3atkyl such as methyl or ethyl, hydroxyl or C1_6alkoxy e.g. C~_3alkoxy such as methoxy or ethoxy groups.
When R in the compounds of formula (1) is an optionally substituted cyctoalkyl or cycloalkenyt group it may be for example a C3_$cycloalky!
group such as a cyclobutyl, cyclopentyl or cyclohexyl group or a C3-8cyctoalkenyl group containing for example one or two double bonds such as a 2-cyclobuten-1-yl, 2-cyclopenten-1-y1, 3-cyclopenten-1-yl, 2,4-~yclopentadien-1-yl, 2-cyclohexen-1-yt, 3-cyclohexen-1-yl, 2,4-cyclohexadien-i-yl or 3,5-cyclohexadien-1-yi group, each cycloalkyf or cycloalkenyl group being optionally substituted by one, two or three substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, straight or branched C~_safkyl e.g. C1_3alkyl such as methyl or ethyl, hydroxyl or C1 _salkoxy e.g. C1 _3alkoxy such as methoxy or ethoxy groups.
When the group R7 in compounds of formula (i) is an ORS group it may be for example a hydroxyl group; or a group -ORS where R~ is an optionally substituted straight or branched C~ _salkyl group, e.g. a C1 _3alkyl group such as a methyl or ethyl group, a C2_satkenyl group such as an ethenyl or 2-propen-1-yl group, a Cy _3alkoxyCy _3alkyl group such as a methoxymethyl, ethoxymethyl or ethoxyethyl group, a C~_~alkanoyl, e.g.
C~ _3alkanoyl group such as an acetyl group, or a formyl [HC(O)-j, carboxamido (COI~1R~2R'~2a) or thiocarboxamido (CSNR~2R12a) group, where Ri2 and R'~2a in each instance may be the same or different and is each a hydrogen atom or an optionally substituted straight or branched C1 _ 6alkyl, e.g. Cj_3aikyl group such as methyl or ethyl group. Optional substituents which may be present on such R~, R12 or Rl2a groups include those described below in relation to the alkyl groups R6 or R~.
w 5 Alkyl groups represented by R3, R6 or R7 in compounds of formula (1 ) include optionally substituted straight or branched C~_6 alkyl groups, e.g.
C1_3 alkyl groups such as methyl, ethyl, n-propyl or i-propyl groups.
Optional substituents which may be present on these groups include one or more halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl or C1 _salkoxy e.g. C j _3atkoxy such as methoxy or ethoxy groups.
When the group Rs in compounds of formula (1 ) is a halogen atom it may be for example a fluorine, chlorine, bromine or iodine atom.
75 When R1 or R2 is a -C02R8, -CONR9R» or CSNR9R'~c group or these groups appear as substituents, the groups may be for example a -C02H, -CONH2 or -CSNH2 group or a group -C02R8, -CONR9R~o, -CSNR9R», -CONHR~a, or -CSNHR» where R8, R9 and R'~c where present is a C~_ 3alkyl group such as methyl or ethyl group, a Cs_y2aryl group, for example an optionally substituted phenyl, or a 1- or 2- naphthyt group, or a C6_ ~2aryl C~-3alkyl group such as an optionally substituted benzyl or phenethyl group. Optional substituents which may be present on these aryl groups include R'~3 substituents discussed below in relation to the group Ar.
In the compounds of formula (7 ), the groups -{CH2)tAr and -(CH2)~Ar(L1 )~Ar' when present may be -Ar, -CH2Ar, -(CH2)2Ar, -{CH2)3Ar-, -Ar-Ar', -Ar-L1-Ar', -CH2ArAr', -CH2ArL~Ar', -(CH2)2ArAr', -(CH2)2ArL~Ar', -(CHz)3ArAr' or -(CH2)3ArL~ Ar' groups.
Monocyclic~or bicyclic aryl groups represented by the group Ar or Ar' in compounds of formula (1) include for example C6_~2 optionally substituted aryl groups, for example optionally substituted phenyl, 1-or 2-naphthyl, indenyl or isoindenyl groups.

When the monocyclic or bicyciic aryl group Ar or Ar' contains one or more heteroatoms, Ar or Ar' may be for example a Cf_9 optionally substituted heteroaryl group containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, Ar or Ar' heteroaryl groups may be for example monocyclic or bicyclic heteroaryl groups. Monocyctic 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. Bicyclic heteroaryl groups include for example nine- or ten- membered heteroaryl groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Examples of heteroaryl groups represented by Ar or Ar' include pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyi, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyt, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyt, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetra-hydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl. Example of bicycfic heteroaryl groups include quinolinyf or isoquinolinyl groups.
The heteroaryl group represented by Ar or Ar' may be attached to the remainder of the molecule of formula (1 ) through any ring carbon or heteroatom as appropriate. Thus, for example, when the group Ar or Ar' is a pyridyl group it may be a 2-pyridyl, 3-pyridyl or 4-pyridyl group. When it is a thienyl group it may be a 2-thienyl or 3-thienyl group, and, similarly, when it is a furyl group it may be a 2-furyl or 3-furyl group. in another example, when the group Ar or Ar' is a quinolinyl group it may be a 2-, 3-, 4-, 5-, 6-, 7- or 8- quinolinyi and when it is an isoquinolinyl, it may be a 1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolinyl group.
When in compounds of formula (1 ) the Ar or Ar' group is a nitrogen-containing heterocycle it may be 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 example when the group Ar or Ar' is a pyridyl group, pyridinium salts may be formed, for example N-alkyfpyridinium salts such as N-methylpyridinium.
The aryl or heteroaryl groups represented by Ar or Ar' in compounds of formula (1 ) may each optionally be substituted by one, two, three or more substituents [R13]. The substituent R~3 may be selected from an atom or group R14 or -AIk2(R_ 14},r, wherein R~4 is a halogen atom, or an amino (-NH2), substituted amino, vitro, cyano, hydroxyl (-OH), substituted hydroxyl, cycloalkoxy, formyl [HC(O)-], carboxyl (-C02H), esterified carboxyl, thiol {-SH), substituted thiol, -C(O)AIk2, -S03H, -S02AIk2, -S02NH2, -S02NHAIk2, -S02N[AIk2]2, -CONH2, -CONHAIk2 , CON[AIk2]2, -NHS02H, -NAIk2S02H, -NHS02AIk2, -NAIk2S02A1k2, -N[S02AIk2]2, -NHS02NH2, -NAIk2S02NH2, -NHS02NHAIk2, -NAIk2S02NHAlk2, -NHS02N[Alk2] 2 , -NAIk2S02N[AIk2]2, -NHC(O)H, -NHC(O)Aik2, -NAIk2C(O)H, -NAIk2C(O)AIk2, -N[Cl0)Alk2]2, -NHC{O)OH, -NHC(O)OAtk2, -NAIk2C{O)OH, -NAIk2C(O)OAIk2, -NHCONH2, -NHCONHAlk2, -NHCON[AIk2]2, -NAIk2CON[AIk2]2, -NAIk~CONH[AIk2], -NAIk2CONH2, - C(S)H, -C{S)AIk2, -CSNH2, -CSNHAIk2, -CSN[AIk2]2, -NHC(S)H, -NHCSAlk2, -NAIk2C(S}H, -NAIk2C(S)AIk2, -N[C(S)AIk2]2, -N[C(O}AIk2]S02H, -NHCSNH2, -NHCSNHAlk2, -NHCSN[Alk2]2r -NAIk2CSN[Aik2]2, - N A I k2CSNHAlk2, - N A I k2CSNH2, o r -N[C(O)AIk2]S02AIk2 group, AIk2 is a straight or branched Ci_6 alkylene, C2_6alkenylene, or C2_salkynyfene 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(R8)- groups; and m is zero or an integer 1, 2 or 3 .
When in the group -AIk2(R»),~ m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R14 may be present on any suitable carbon atom in -Alk2. Where more than one R~4 substituent is present these may be the same or different and may be present on the same or different carbon atom in AIk2. Clearly, when m is zero and no substituent R14 is present or when AIk2 forms part of a group such as -S02AIk2 the alkylene, alkenylene or alkynylene chain represented by AIk2 becomes an alkyl, alkenyl or alkynyl group.

When R14 is a substituted amino group it may be a group -NH[AIk2(Rl4a}mj [where Alk2 and m ace as defined above and Rla.a is as defined above for .
R14 but is not a substituted amino, a substituted hydroxyl or a substituted 5 thiol group] or a group -N[AIk2(Rl4a}mj2 wherein each -AIk2(Rl4a)m group , is the same or different.
When R14 is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R14 is a cycloalkoxy group it may be for example a C5_~cycloalkoxy group such as a cyclopentytoxy or cyclohexyloxy group.
When R14 is a substituted hydroxyl or substituted thiol group it may be a i5 group -OAIk2(Rla.a}m or -SAIk2(Rl4a}m respectively, where AIk2, Rl4a and m are as just defined.
Esterified carboxyl groups represented by the group R14 include groups of formula -C02Aik3 wherein Alk3 is a straight or branched, optionally substituted C1_$alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6_l2aryIC1_8alkyl group such as an optionally substituted benzyl, phenylethyi, phenyipropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6_l2aryB group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6_l2aryloxyCl_8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1_$alkanoyloxyCl_$alkyl group, such as a pivaloyloxymethyl, propionyioxyethyl or propionyloxypropyl group; or a Cs_l2aroytoxyCl _$alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxy-propyi group. Optional substituents present on the AIk3 group include R13 substituents described above.
It will be appreciated that the group Ar or Ar' may be attached to the remainder of the molecule of formula (1) through either a ring carbon atom or heteroatom.

Particular examples of the chain AIk2 when present include methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-- butylene, ethenyiene, 2-propenylene, 2-butenytene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O}-, -S(O)2- or -N{Rb)- groups.
Particularly useful atoms or groups represented by R1 s include fluorine, chlorine, bromine or iodine atoms, or C1_salkyl, e.g.
methyl or ethyl, i0 C1_salkylamino, e.g. methylamino or ethylamino, C1_s hydroxyalkyl, e.g.

hydroxymethyt or hydroxyethyl, C1_6alkylthiol e.g. methylthiol or ethylthiol, C1 _salkoxy, e.g. methoxy or ethoxy, C5_7cycloalkoxy, e.g. cyctopentyloxy, haloCl _6alkyl, e.g. triffuoromethyl, C1 _salkylamino, e.g. methytamino or ethyiamino, amino (-NH2), aminoCl~alkyl, e.g. aminomethyl or aminoethyl, C1_sdialkylamino, e.g. dimethylamino or diethytamino, nitro, cyano, hydroxyl (-OH), formyl [HC(O)-], carboxyl (-C02H), -C02AIk3 [where Alk3 is as defined above], C1_s alkanoyl e.g. acetyl, thiol (-SH), thioCl_6alkyl, e.g.

thiomethyl or thioethyl, sulphonyl (-S03H), C1_salkylsulphonyi, e.g:

methytsulphonyi, aminosuiphonyl (-S02NH2), C1_salkylaminosutphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1_sdialkylamino-sulphonyl, e.g. dimethylaminosulphonyl or diethylaminosufphonyl, carboxamido (-CONH2), C1_safkylaminocarbonyi, e.g. methylamino-carbonyl or ethyfaminocarbonyl, C1_sdialkytaminocarbonyi, e.g. dimethyl-aminocarbonyl or diethylaminocarbonyl, sulphonyfamino (-NHS02H), G1_satkyisulphonylamino, e.g. methylsulphonylamino or ethylsulphonyi-amino, C1_sdialkylsulphonylamino, e.g. dimethytsulphonylamino or diethyl-sulphonylamino, aminosulphonylamino {-NHS02NH2), C1_salkyiamino-sulphonylamino, e.g. methylaminosulphonylamino or ethylamino-sulphonytamino, C1_sdialkylaminosulphonylamino, e.g. dimethylamino-sulphonylamino or diethylaminosuiphonylamino, C1_~alkanoylamino, e.g.

acetyfamino, C1 _6alkanoylaminoCl _6alkyl, e.g. acetylaminomethyl or C1 _6 alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino thiocarboxamido (-CSNH2), C1_6 alkylamino-thiocarbonyl, e.g. methylaminothiocarbonyl or ethylaminothiocarbonyl, C1_sdialkylaminothiocarbonyl, e.g. dimethylaminothiocarbonyt or diethyl-aminothiocarbonyl, aminocarbonyiamino, C1_salkylaminocarbonylamino, '12 e.g. methylaminocarbonylamino or ethytaminocarbonylamino, C~-sdialkyla-minocarbonylamino, e.g. dimethylaminocarbonylamino or diethylamino-carbonylamino, aminothiocarbonylamino, C1_salkylaminothiocarbonyl-amino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonyt-amino, C~_s dtalkylaminothiocarbonylamino, e.g. dimethyfaminothio-carbonylamino, or dtethylaminothiocarbonylamino, aminocarbonylCl _salkyl-amino, e.g. aminocarbonylmethylamino or aminocarbonylethytamino, amtnothiocarbonylCl _satkyiamino e.g. aminothiocarbonylmethylamino or aminothiocarbonylethylamino, formylaminoCi_6 alkylsulphonylamino, e.g.
formylaminomethytsutphonylamino or formyl-aminoethylsulphonylamino, thioformylaminoC~_6alkylsulphonylamino, e.g. thtoformytaminomethyl-sulphonylamino or thioformylethylsulphonylamino, C1_gacylaminosulphonyt-amino, e.g. acetylaminosulphonytamino, C1_6thio-acylaminosulphonyl-amino, e.g. thioacetylaminosulphonylamino groups.
Where desired, two R'~ 3 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C2_salkylenedioxy group such as ethylenedioxy.
It wilt be appreciated that where two or more R~3 substituents are present, these need not necessarily be the same atoms and/or groups. The R~ 3 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 Ar or Ar' any substituent may be present at the 2-, 3-, 4-, 5- or 6- positions relative to the ring carbon atom attached to the remainder of the molecule.
In the compounds of formula (1 ), when the group -(CH2)tAr(L1 )nAr' is present in R4 and/or R5, the linker group L1 may be any divalent linking group. Particular examples of L~ groups which may be present in compounds of the invention include groups of formula -(AIk4)r(Xa)S(Alk~)~-where Alk4 and AIkS is each an optionally substituted straight or branched C~_~alkylene, C2_salkenylene or C2_6aikynylene chain optionally interrupted by one or more, e.g. one, two or three heteroatoms or carbocyclic or ' heteroatom-containing groups, Xa is an -O- or -S- atom or a -S(O)-, -S(O)2-or -N(Rb)- group, r is zero or the integer 1, t is zero or the integer 1 and s is zero or the integer 1, provided that when one of r, s, or t is zero at least one of the remainder is the integer 1.
The heteroatoms which may interrupt the AIk4 or AIkS chains include for example -O- or -S- atoms. Carbocyclic groups include for example cycloalkyl, e.g. cyclopentyl or cyclohexyl, or cycloalkenyl e.g. cyclopentenyl or cyclohexenyl, groups. Particular heteroatom-containing groups which may interrupt AIk4 or Alk5 include oxygen-, sulphur- or nitrogen-containing groups such as -S(O)-, -S(O)2-, -N(Rb)-, -C(O)-, -C(S)-, -C(NRb)-, -CON(Rb)-, -CSN(Rb)-, -N(R~)CO-, -N{Rb)CS-, -SON{R~)-, -S02N(Rb)-, -N(Rb)SO-, -N(Rb)S02-, -N{Rb)S02N(Rb)-, -N{Rb)SON(R~)-, or -N(Rb)CON(Rb)- groups. It will be appreciated that when the chains AEk4 or AIkS are interrupted by two or more heteroatoms, carbocyclic or heteroatom-containing groups, such atoms or groups may be adjacent to one another, for example to form a group -N(Rb)-C{NRb)-N(R~)- or -O-CONH-.
Optional substituents which may be present on AIk4 or AIk5 chains include those described above in relation to the group R1 when it is an alkyl group.
The group -(L1 )~,Ar' may be attached to the group Ar through any available carbon or heteroatoms present in the two groups. Thus, for example, when Ar is a phenyl group, -(L1 )~Ar' may be attached through a carbon or heteroatom in -(L1 )~Ar' to a carbon atom in Ar at the 2-, 3-, 4-, 5-, or 6-position relative to the Ar carbon atom attached to the remainder of the molecule.
In the group {L1 )~Ar' particular examples of Alk4 or AIkS include optionally substituted methylene, ethylene, propylene, butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chains, optionally interrupted by one, two or three heteroatoms, carbocyclic or heteroatom-containing groups as described above.
Particular examples of the group -(L1 )~Ar' include the groups -AIk4Ar', -XAr', -AIk4XAr' and -XAlkSAr', especially for example -CH2Ar', -(CH2)2Ar', -(CH2)3Ar', -CH20CH~Ar', -CH2SCH2Ar', -CH2N(Rb)CH2Ar', -CH=CHAr', -CH2CH=CHAr', -OAr', -SAr', -N(R~)Ar', -CH20Ar', -CH2SAr', -CH2N(Rb)Ar', -CH20CH20Ar', -OCH2Ar', -O(CH2)2Ar', -SCH2Ar', -S(CH2)2Ar', -N(Rb)CH2Ar' and -N(Rb)(CH2)2Ar'. In these particular groups, Ar' may be as generally described herein and as particularly described below.
In general, and in the particular groups just mentioned, Alk in A~' may be an optionally substituted ~methylene, ethylene, n-propylene, i-propylene, n-butylene, s-butytene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propenylene, 2-butynylene, or 3-butynylene chain optionally interrupted by one, two or three -O- or -S- atoms or -S(O)-, -S(O)2- or -N(Rb)- groups. Optional substttuents which may be present include one or more halogen atoms, e.g. #luortne, chlorine, bromine or iodine atoms, or hydroxyl or Ci~alkoxy e.g. Cj_3alkOXy such as methoxy or ethoxy groups. The group Alki when present in Ar' may also be as just described #or Alk, but will clearly be an alkyl, alkenyl or alkynyl group, rather than a corresponding alkylene, afkenytene or alkynylene chain.
Particular examples of the group Ar' include optionally substituted Cs_~2aryl or C~_9heteroaryl groups, especiaEly optionally substituted phenyl or pyridyl groups, or, in particular, -CO(Alk),~,~Ph ( where Ph is an optionally substituted phenyl group), -SONH(Alk),~,~,Ph, -S02N(AIk1)(Alk)n,Ph, -S02N[(Alk),~,~Ph]2, -CONH(Alk),~,~Ph, -CON(Alk~)(Atk),rPh, -CON[(Alk}mPh]2, -NAIk1S02(Alk}mPh, -NHS02N(Alk~)(Alk),~,~Ph, -NAIk~ SOzAIk~ (Alk),~,iPh, -NHS02Nj(Alk)~,Ph]2, - NAlki S02N[(Alk)~,Ph]2, -NHC(O)(Alk)~,.~Ph, -NAIkrtCO{Alk)mPh, -NC(O)N[(Alk)mPh]2, -NHC(O)NH(Alk}mPh, -NAIkyC(O}NH{Alk)mPh, -NHC(O)N(Alk~)(Alk),~.~Ph, -NAIkIG(O)N(Alki)(Alk)~Ph, -NHC(O)O(Alk)~.,Ph, -NAIkIC(O)O(Alk)r,~,Ph, -C{S)NH(Alk),~Ph, -C(S)N(Alk~)(Alk)mPh, -N(S)N[(Alk),~,~,Ph]2, -NHC(S}(Alk)~,~,Ph, -N(Atki}C(S)(Alk)mPh, -NjC(S)(Alk)mPh]2, -NHC(S)NH(Aik)~,Ph, -NAIkIC(S)NH{Atk),r,Ph, -NHC(S)N{Alk'~){Alk)mPh, or -N(Aik1)C(S)N(Alk~)(Alk)mPh groups. In these groups, the groups Atk and Alk~ may in particular each be a methylene or ethylene, and a methyl or ethyl group respectively and m may be zero or in particular 1.

'15 When in R4 andlor R5 a -NHet group is present this may be for example a pyrrolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomor-pholinyl group. Optional substituents that may be present in such groups include R13 substituents described above in relation to Ar or Ar' groups.
When in R4 and/or R5 a Het' group is present this may be for example a pyrrolidinyl, pyrazolidinyt, pipertdinyl, morpholinyl, piperazinyl, thio-morpholinyl, cycfopentyl, or cyclohexyt group. Optional substituents that may be present on such groups include R13 substituents described above.
In the compounds of formula (1 ), when an ester group is present, for example a group C02R8 or -C02A1k3 this may advantageously be a metabolically labile ester.
In the -(CH2)tArN(Rb)CXy N{R~)L2(Alk),~,~,Ar group present as R4 and/or R5 in compounds of formula (1) the divalent linking group represented by L?
may be for example a -S(O)-, -S(O}N{Rb)-, -S(O)2-, -S(O)2N(Rb)-, -C(O)-, -C(O)N(Rb)-, -C(S)- or -C(S)N(R)- group. All the other groups represented by -{CH2)t, Ar, Rb X1, and (Alk),~,~, may be as generally and particularly discussed above.
Particular examples of R4 and/or R5 groups of these types include -ArN{Rb}CONHS02(Alk}"~ Ar and -ArN(Rb)CONHS02N(R2)(Alk)r,-,Ar groups, especially where Ar is an optionally substitued phenyl group.
The presence of 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, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trif(uoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metat salts 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 diethylamine salts.
Prodrugs of compounds of formula (1 ) include those compounds, for example esters, alcohols or aminos, which are convertible in vivo by metabolic means, e.g. by hydrolysis, reduction, oxidation or trans-esterification, to compounds of formula (l ).
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
in the compounds of formula (1 ) the group =W- is preferably a =C(Y)-group. In compounds of this type Y is preferably a -XRa group where X ~is -O- and Ra is an optionally substituted ethyl group or, especially, an optionaEly substituted methyl group. Especially useful substituents which may be present on Ra groups include one, two or three fluorine or chlorine atoms.
One particularly useful group of compounds of the invention has the formula (1 ) where L is a group -XR. In compounds of this type X is preferably -O-. The group R in these compounds is preferably an optionally substituted cycloalky! group, particularly an optionally substituted cyclopentyl group, and is, especially a cyclopentyl group.
In another group of compounds of formula (1 ) L is preferably a -CH=C(R1 )(R2) group. In compounds of this type R1 and R2 are preferably linked together with the C atom to which they are attached to form an optionally substituted cycloalkyl or cycloalkenyl group, especially a substituted cyclopentyl or ' cyclohexyl or, especially, a cyclopentyl or cyciohexyl group.

'! 7 The groups R4 and R5 in compounds of formula (1 ) is each, independently, preferably a CH2Ar, -CH2Ar(L~ )nAr' or -CH2ArN(Rb)CX1 N(Rb)L2(Alk),I,Ar group or especially an -Ar, Ar-Ar', ArL1 Ar' or -ArN(Rb)CXi N(R5)L2(Atk),~.~Ar group, with the proviso mentioned in connection with formula (1 ). In one preference the group R4 is especially a -ArN(Rb)CX1 N(Rb)L2{Alk)mAr group and R~ is an -Ar group. Particularly useful R4 or R5 groups of these types include those groups in which Ar or Ar' is a monocyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur, or, in particular, nitrogen atoms, and optionally substituted by one, two, three or more R~3 substituents. In these compounds, when the group represented by Ar or Ar' is a heteroaryl group it is preferably a nitrogen-containing monocyclic heteroaryl group, especially a six-membered nitrogen-containing heteroaryl group. Thus, in one preferred example, the groups R4 and R5 may each contain a six-membered nitrogen-containing heteroaryl Ar or Ar' group. In another preferred example R4 may contain a monocyclic aryl group or a monocyclic or bicyclic heteroaryl group Ar or Ar' containing one or more oxygen, sulphur or nitrogen atoms and R5 rnay contain a six-membered nitrogen-containing heteroaryt group Ar or Ar'. In these examples, the six-membered nitrogen-containing heteroaryl group may be an optionally substituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or imidazolyl group. Particular examples include optionally substituted 2-pyridyl, 3-pyridyl, 5-imidazolyt, or, especially, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyt or 3-pyrazinyl. The monocyclic aryl group may be a phenyl group or a substituted phenyl group, and the monocyctic or bicyclic heteroaryl group containing one or more oxygen, sulphur or nitrogen atom may be an optionally substituted 2-fury!, 3-fury!, 2-thienyl, 3-thienyl, 2-thiazolyl, 2-benzo(b)thiophenyl, 2-benzo(b)furyl or 4-isoquinolinyl group.
In another preference relating to R4 groups of the just mentioned particular types, Ar' is a -NHC(O}NH(Alk)mPh (where Ph is as just described, -NHCH3C{O)NH(Alk},~,~Ph, -NHC(O)N(CH3)(Afk)~Ph, -N{CH3)C{O)N(CHg)(Alk)mPh, -CO(Alk}mPh, -NHS02NH(Alk)mPh, -N{CHg)S02NH{Alk},~,~,Ph, -N(CH3)S02N(CH3)(Alk)mPh, -NHCO(Atk),~,~,Ph, -N(CH3)CO(Alk),~,~,Ph or -NHS02(Alk)mPh group.

In general in compounds of formula (1 ) when R4 and/or R5 contains a substituted phenyl group it may be for example a mono-, dl- or trisubstituted phenyl group in which the substituent is an atom or group R13 as defined above. When the R4 andlor R5 group contains a monosubstituted phenyl group the substituent may be in the 2-, or preferably 3-, or especially 4-position relative to the ring carbon atom attached to the remainder of the molecule. When the R4 andlor R5 group contains a disubstituted phenyl group, the substituents may be in the 2,6 position relative to the ring carbon atom attached to the remainder of the molecule.
Particularly useful substituents R13 Which may be present on Ar groups in R4 and R5, especially on phenyl groups, include halogen atoms or alkyl, haloafkyl, amino, substituted amino, vitro, -NHS02NH2, -NHS02NHCH3, -NHS02N(CHg)2, -NHCOCH3, -NHC(O)NH2, -NCH3C(O)NH2, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, or -NHC(O)N(CH3)2 groups, each of said atoms or groups being optinally separated from the remainder of the Ar group by a group AIk2 as defined above.
When in compounds of formula (1 ) R4 andlor R~ contains a substituted pyridyl group it may be for example a mono-or disubstituted pyridyl group, such as a mono- or disubstituted 2-pyridyi, 3-pyridyl or especially 4-pyridyl group substituted by one or two atoms or groups R13 as defined above, in particular one or two halogen atoms such as fluorine or chlorine atoms, or methyl, methoxy, hydroxyl or vitro groups. Particularly useful pyridyl groups of these types are 3-monosubstituted-4-pyridyl or 3,5-disubstituted-4-pyridyl, or 2- or 4-monosubstituted-3-pyridyl or 2,4-disubstituted-3-pyridyl groups.
A particularly useful group of compounds of formula (1 ) has the formula (2):

WO 97/23461 PCTlGB96103196 L
Ra ~ ~ R3 R~
Rs Rs Ra {2) where -L is a OR, where R is an optionally substituted cycloalkyl group, -CH=C{R1){R2) or -CH2CH(Ri){R2) group where R1 and R2 are linked together with the carbon atom to which they are attached to form a cycloalkyl group; Ra is an optionally substituted alkyl group and R3, R4, R5, R6 and R~ are as defined for formula (1 ); and the salts, solvates, hydrates, prodrugs and N-oxides thereof.
In the compounds of formutae {1 ) or (2) one preferred group of compounds are those where the group R3 is a hydrogen atom; the group R6 is a methyl group, or especially a hydrogen atom; the group R~ is a methyl group, or especially a hydrogen atom; and R4 and R5 are as defined for formula (1 ). In compounds of this type R6 and R7 is each especially a hydrogen atom.
In general in compounds of formulae {1) or (2) R3, R6 and R~ is each especially a hydrogen atom, R5 is in particular a -(CH2)tAr group, especially an optionally substituted pyridyl group, especially a 4-pyridyl group. The group R4 in compounds of these types is preferably an -ArN(Rb)CX1 N(Rb)L2(Alk)~,Ar group, particularly where each Ar group is a monocyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or, especially, nitrogen atoms. Particularly useful R4 groups are those of formula -ArN(Rb)CXi N(Rb)S(O}2(Alk}r,-,Ar or -ArN{Rb)CXi N{R~)S(O)2N{Rb)(Alk)r"Ar, especially where each Ar group is an optionally substituted phenyl group. Particular examples of such groups include -ArNHCONHS(O)2Ar, -ArNHCSNHS(O)2Ar, -ArNHCONHS(O)2NHAr and -ArNHCSNHS(O)2NHAr, especially where in each instance Ar is an optionally substituted phenyl group as defined herein. in general in these compounds, when Ar is a phenyl group the -N(R6)CXi N{Rb}L2{Alk)mAr group is preferably attached to this group at WO 97/23461 1'CT/GB96/03196 the 3- or 4-position of the phenyl ring relative to the point of attachment of the ring to the remainder of the molecule of formula (1 ).
In one particular group of compounds of formulae (1 ) or (2} R4 is 5 preferably a -ArNHCONHS(O)2Ar" group wherein Ar is a phenyl group and Ar" is an optionally substituted phenyl group. In these compounds the -NHCONHS(O)2Ar" group is preferably attached to the Ar group at the 3 or 4-position of the phenyl ring as explained above. In this particular group of compounds the other groups W, L, R3, R5, R6 and R~ may be as 10 generally or particularly defined above.
Particularly useful compounds according to the invention are:
($)-,~I-[4-{i -(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl}phenyl]-,[y,'-(phenylsulphonyl) urea;
15 (~)-.~.-[4-{i-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl}phenyl]-]~'-(methyiphenylsulphonyl) urea; and ($)-,C-[4-{'! -(3-cyclopentytoxy-4-methoxyphenyl}-2-{4-pyridyl}ethyl}phenyl]-~'-{4-chlorophenyfsulphonyt) urea;
and the salts, solvates, hydrates, prodrugs and N-oxides thereof.
Compounds according to the invention are selective and potent inhibitors of PDE IV and advantageously have improved metabolic stability. The ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.
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, eosinophitic 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, urticaria, adult respiratory distress syndrome, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis and artherosclerosis.

Compounds of the invention may also suppress neurogenic inflammation through elevation of cAMP in sensory neurones. They are, therefore, 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 lymphocyte activation in immune-based diseases such as rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease.
Compounds according to the invention may also reduce gastric acid secretion and therefore can be used to treat conditions associated with hypersecretion.
Compounds of the invention may 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 compounds of the invention may 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 such as rheumatoid or osteo-arthritis.
Over-production of cytoktnes 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 may ameliorate these symptoms with a consequent enhancement of quality of life.
Compounds of the invention may also elevate cAMP in certain areas of the brain and thereby counteract depression and memory impairment.
Compounds of the invention may suppress cell proliferation in certain tumour cells and can be used, therefore, to prevent tumour growth and invasion of normal tissues.

WO 97/23461 PCT/GB96/03~96 For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1 ) together with one or more pharmaceutically acceptable carriers, excipients or dlluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
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. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers {e.g. lactose, microcrystaliine 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 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 formulae (1 ) and (2) may be formulated for parentera!
administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or 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.
In addition to the formulations described above, the compounds of formulae (1 ) and (2) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for 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 active ingredient. .The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular inflammatory condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100ng/kg to 100mglkg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around l0ng/kg to 50mglkg body weight for parenteral administration and around 0.05mg to around 1000mg e.g.
around 0.5mg to around 1 OOOmg for nasal administration or administratino by inhalation or insufflation.
The compounds according to the invention may be prepared by the following processes. In the reactions described below it may be necessary to protect reactive functional groups, for example hydroxy, amino, thin, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with standard 5 practice [see, for example, Green, T.W. in "Protective Groups in Organic Synthesis" John Wiley and Sons, 1981 J.
Thus according to a further aspect of the invention a compound of formula (1 ) may be prepared by reaction of a corresponding intermediate 10 compound of formula (1 ) wherein R4 and/or R~ is a -(CH2)tArNHRb group with an isocyanate Ar(Alk)mL2N=C=O or isothiocyanate Ar(Alk)mL2N=C=S. The reaction may be performed in a solvent, for example an organic solvent such as a halogenated hydrocarbon, e.g.
dichloromethane, at around -O~C to around ambient temperature.
In a variation of this process the starting intermediate amine of formula (1) may first be treated with phosgene in the presence of a base, e.g. an organic amine such as triethylamine, and subsequently reacted with an amine Ar(Alk)mL2NHRb to yield the desired compound of formula (1) 20 wherein R4 and/or R5 contains a urea group. The reaction may be carried out in an organic solvent such as a halogenated hydrocarbon, e.g dichloromethane, at from around O~C to ambient temperature. .
The intermediate amines of formula (1 ) for use as starting materials in these reactions are either described in International Patent Spec'~'tcation Nos. W094114742 and W095/17386 or may be obtained using the processes described therein from known starting materials. The intermediate isocyanates, isothiocyanates and amines also for use in these processes are readily 30 available known compounds or may be prepared from known starting materials using methods analogous to those used for the preparation of the known compounds.
N-oxides of compounds of formula (1 ) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, WO 97/23461 PCTlGB96/03196 at an elevated temperature, for example around 70oC to 80oC, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
5 Salts of compounds of formula (1 ) may be prepared by reaction of a compound of formuta (i ) with an appropriate acid or base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g.
diethylether, or an alcohol, e.g. ethanol using conventional procedures.
10 Where it is desired to obtain a particular enantiomer of a compound of formula (1 ) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
15 Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1 ) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral acid or base. Suitable chiral acids include, for example, tartaric acid and other tartrates such as dibenzoyl tartrates and ditoluoyl tartrates, sulphonates such as camphor 20 sulphonates, mandelic acid and other mandelates and phosphates such as 1,1'-binaphthalene-2,2'-diyl hydrogen phosphate. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid or base in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1 ) may be separated using chiral High Perfomlance Liquid Chromatography.
Alternatively, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
Chiral intermediates may be obtained in particular by use of the enantioselective process described in International Patent Specification No. W095/1738fi.
The following Examples illustrate the invention, and describe the preparation of the following compounds:

WO 9'7123461 PCT/GB96/03196 OCp R
NHCONHS(O)2Ar where Cp is cyclopentyl, R5 is 4-pyridyl and Ar is:

Example 1:
hydrochloride salt Example 2:
l ~ cH3 , hydrochloride salt Example 3:
C~ , hydrochloride salt i 5 EXAMPLE 1 ~$)~ N f4 ~1 (3~'yrctoAentyrloxy-4 methoxxphen~L)~ 2 (4 ~,rridy~eth~CLt hoe yrtl-N'-( hens Ii sutphonvt) urea, hyrdrochloride Benzenesulphonyltsocyanate (205p,1) was added dropwise to a solution of 4-ji -(R)-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline (500mg prepared as described in lntemational Patent specification No.
W095/17386) in dichloromethane (10m1) under nitrogen at room temperature. The mixture was stirred or 30min at this temperature and the solvent then removed in va~uo to yield a yellow gum. Trituration with ether furnished a pate yellow solid (the free base of the title corn op sand which was disolved in dichloromethane (5m1) and treated with ethereal HCI to afford a yellow solid. Subsequent recrystallisation of the solid from methanol yielded the title compound (450mg) as an off white solid 8H
{CD30D) 1.40-1.90 (8H, br m), 3.64 {2H, d, ,~ 9Hz), 3.72 {3H, s), 4.34 (1 H, t, ~ 9Hz), 4.72 (1 H, m}, 6.75 (3H, d+d+s), 7.20 {4H, d+d}, 7.50-7.75 (3H, m), 7.72 (2H, d, J_ SHz), 8.00 (2H, d, ~ 8Hz), and 8.55 (2H, d, J_ 8Hz).
The following compounds were prepared in a similar manner to the compound of Example 1:

~Rl-N-[4-.(1-i(3- 'yctopentyrloxy-4-methoxyrphenyrl~-~4-plrridyl)~ethyrl~-phen~ll-N'-~(methylahenyrtsulphonlrl) urea hyrdrochloride From the starting aniline (1.0g) used in Example 1 and p-toluenesulphonylisocyanate (507mg) in dichloromethane (20m#) at 0-5~C
to yield the free base of the title compound (1.29g) as a white solid (CDCl3} i 49-1.95 (8H, m), 2.4 (3H, s), 3.28 (2H, d, ~ 7.9Hz), 3.6-3.9 (1 H, br s), 3.78 (3H, s), 4.11 {1 H, t, ~ 6.OHz), 4.65 (1 H, m), 6.62-6.78 (3H, m), 6.95 (2H, d, ~ 6.06Hz), 7.1 {2H, d, J_ 8.57Hz), 7.26 (4H, m), 7.79 (2H, d,.~
8.37Hz}, and 8.40 (3H, m). r~/~ (ESI} (MH+586, 100%).
The solid on treatment with ethereal HCI gave the title compound as an off white solid. (Found: C, 62.04; H, 5.90; N, 6.39. C33H35N3o5s~ HCI.
H20 requires C, 61.91; H, 5.98, N, 6.56%) 8H {CD30D) 1.45-1.85 (8H, m), 2.38 (3H, s), 3.6 (2H, d, ~ 6.OHz}, 3.7 (3H, s), 4.3 (1 H, m), 4.68 (1 H, br s), 6.68-6.8 (3H, m), 7.1-7.45 {6H, m), 7.7-7.9 (4H, m) and 8.52 {2H, br s).

,(R)~-N-I[4-~'f -i(3-Cyctopentlrloxyr-4-methoxyrphenyl}~-2-i(4-pyrridyi)iethvlJ~-phenyl]-N'-(4-chlorophenyrlsulphonyrl} urea. hydrochloride From the starting aniline (1.0g} used in Example 1 and 4-chlorobenzenesulphonylisocyanate (0.384m1) in dichloromethane (20m1) at 0-5~C to yield the free base of the title cam ound (1.49g) as a white solid, 8H {CDco3) 1.43-1.9 (8H, m), 3.3 (2H, d, ~ 7.82Hz), 3.77 (3H, s), 4.09 (1 H, t, ,~ 7.75Hz, ,~' 7.96Hz), 4.69 (1 H, m), 5.59 (1 H, br s), 6.62-6.8 {3H, m), 6.95-7.1 (4H, m), 7.15-7.4 (4H, m), 7.88 (2H, d, ,~ 7.1 Hz), 8.36 (2H, d, ~
6.OHz) and 8.50 (1 H, s); rr z_ (ESI) (MHO- 505 100%) The solid on treatment with ethereal HCI gave the title compound as a light yellow solid (Found: C, 58.33, H, 5.17, N, 6.12. C32H32CIN3O5S. HCt.
0.75H20 requires C, 58.58, H, 5.30, N, 6.41 %) SH (CD30D) 1.42-1.8 (8H, m), 3.i2 (2H. d, ~ 6.OHz), 3.68 (3H, s), 4.3 (1 H, m), 4.67 (1 H, m), 6.72 (3H, m), 7.1-7.25 (4H, m), 7.45-7.55 (2H, m), 7.77 (2H, d, ~j 3.OHz), 7.94 (2H, d, ~ 8.7Hz) and 8.55 (2H, d, ~ 3.OHz); ~n/~ (ESI) (MH+ 606 100%.
The advantageous pharmacological properties of the compounds according to the invention may be demonstrated in the following inin tritro and inin vivo tests:
1. isolated Recombinant ~luman PDE IVA Enzyrme A gene encoding human PDE iV has been cloned from human monocytes (Livi, et al., y990, Molecular and Cellular Biology, ~Q, 267. Using similar procedures we have ctoned human PDE 1V 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, 1990, TIPS, ~, 150). These recombinant enzymes, particularly the human eosinophil recombinant PDE IVA, 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 150,1 of standard mixture containing (final concentrations):
50mM 2-[[tris(hydroxymethyl)methyl]amino]-1-ethanesulphonic acid (TES) -NaOH buffer (pH 7.5), lOmM MgCl2, 0.1 p.M [3H]-cAMP and vehicle or various concentrations of the test compounds. The reaction was initiated by addition of enzyme and conducted at 30oC for between 5 to 30 min.
The reaction was terminated by addition of 50p,1 2% trifluoroacetic acid containing [14C]-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 10m1 0.1 TES-NaOH buffer (pH8). The [3H]-5'-AMP
product was eluted with 2m1 2M NaOH into a scintillation viat containing 10m1 of scintillation cocktail. Recovery of [3H]-5'AMP was determined using the [14C]-5'AMP and all assays were conducted in the linear range of the reaction. Results were expressed as ICSa values.
Using this procedure, the compounds according to the invention had ICSo values of 4nM (compound of Example 1 ), 13.9nM (compound of Example 2) and l7.finM (compound of Example 3).
The compounds of the Examples had little or no activity against other isolated PDE isoenzymes (specifically PDE l, 11, III or V - see WO
94/14742 for experimental details) at concentrations up to 100wM, thus illustrating the selectivity of their action against PDE IV.
2. at Hepatocyrte Metabolism The improved metabolic stability of the compounds according to the invention was demonstrated in a conventional rat hepatocyte model in which rat hepatocytes were cultured in the presence of test compound.
The quantity of compound remaining after a fixed period of time was then detem~ined using mass spectroscopy.
Thus in one such test the compound of Example 1 was compared with a reiated compound particularly described in International Patent Specification No. W094/14742 in which the phenylsulphonyl group in the compound of Example 1 is replaced by a hydrogen atom. After 3h the percentage of each compound remaining was:
Compound of Example 1 - 56%
' WO 94/14732 comparison compound - 3%.
The W094/14742 compound had been extensively metabolised whereas over 50% of the compound of the invention remained after 3h, illustrating the advantageous in vitro metabolic stability of the compound.

The same two compounds were also administered orally to squirrel monkeys at l0mg/kg p.o,. and the plasma levels of each determined.
After 1 h the W094/14732 compound was present at 1 p.glml whereas after 5 30min the compound of Example 1 was present at 341ug/ml, thus , illustrating the good oral availability of the compound.
r

Claims (12)

Claims

1. A compound of formula (1) wherein:
=W- is either (1) a =C(Y)- group in which Y is a halogen atom, a C1-6 alkyl group or an -XR a group where X is -O-, -S(O)p- [where p is zero or an integer of value 1 or 2]
or -N(R b)- [where R b is a hydrogen atom or a C1-6 alkyl group], and R a is a hydrogen atom or a C1-6 alkyl group optionally substituted by up to three chlorine or fluorine atoms, or (2) =N-;
L is -XR where X is as defined above and R is a C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl or C3-8 cycloalkenyl group;
R3 is a hydrogen atom;
R9 is a group -ArN(R b)CX1N(R b)L2(Alk)m Ar where:
Ar 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, R b is as defined above, X1 is an oxygen or sulphur atom, L2 is an -S(O)-, -S(O)N(R b)-, -S(O)2-, -S(O)2N(R b)-, -C(O)-, -C(O)N(R b)-, -C(S)- or C(S)N(R b)- group where R b is as defined above, and Alk is a straight or branched C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain optionally interrupted by up to three of -O-, -S(O)p- [where p is as defined above] or -N(R b)- [where R b is as defined above], and m is zero or the integer 1;
R5 is an Ar group as defined above;
R6 is a hydrogen atom; and R7 is a hydrogen atom;
and the salts, solvates, hydrates, prodrugs and N-oxides thereof.

2. A compound according to claim 1 wherein L2 is an -S(O)2- or -S(O)2NH- group.

3. A compound according to claim 2 wherein R4 is an -ArNHCONHS(O)2Ar, -ArNHCSNHS(O)2Ar, -ArNHCONHS(O)2NHAr or -ArNHCSNHS(O)2NHAr group wherein the Ar groups are phenyl groups.

4. A compound according to any one of claims 1 to 3 wherein =W- is a =C(Y)- group.

5. A compound according to claim 4 wherein Y is an -OR a group in which R a is a C1-6 alkyl group.

6. A compound according to claim 4 wherein R a is a methyl group optionally substituted by up to three fluorine or chlorine atoms.

7. A compound according to any one of claims 1 to 6 wherein L is an -OR group in which R is a C3-8 cycloalkyl group.

8. A compound according to claim 7 wherein R is a cyclopentyl group.

9. A compound according to any one of claims 1 to 8 wherein R5 is a pyridyl group.

10. A compound according to claim 9 wherein R5 is a 4-pyridyl group.

11. A compound according to claim 1 selected from (R)-N-[4-{1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl}-phenyl]-N'-(phenylsulphonyl)urea;
(R)-N-[4-{1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl}-phenyl]-N'-(methylphenylsulphonyl)urea;
(R)-N-[4-{1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl)-phenyl]-N-'-(4-chlorophenylsulphonyl)urea;
and salts, solvates, hydrates, prodrugs and N-oxides thereof.

12. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 11 together with one or more pharmaceutically acceptable carriers, excipients or diluents.