f°,~! 1 Z
i ~_ rj '. ,J
TRI-SUBSTITUTED PHENYL DERIVATIVES USEFUL AS PDE IV TNHIBITORS
This invention relates to a novel series of tri-substituted phenyl 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 adenyl cyclase 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 cyclase. 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-VIt) 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-i55 and Nicholson et al (1991) TIPS, ~: 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 affect. In these tissues, PDE IV
plays a major role in the hydrolysis of CAMP. It can be expected, therefore, that selective inhibitors of PDE IV would have therapeutic effects in inflammatory diseases such as asthma, by achieving both anti-inflammatory and bronchodilator effects.
The design of PDE IV inhibitors has met with limited success to date, in that many of the potential PDE IV inhibitors which have been synthesised have tacked potency and/or have been capable of inhibiting more than one type of PDE isoenzyme in a non-selective manner. Lack of a selective W O 95135281 PCTfGB95/01~59 Ifr a_ v ~ .~
action has been a particular problem given the widespread role of cAMP in vivo 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 tri-substituted phenyl derivatives, members of which are potent inhibitors of PDE IV at concentrations at which they have little or no inhibitory action on other PDE isoenzymes.
These compounds inhibit the human recombinant PDE IV enzyme and 1Q also elevate cAMP in isolated teukocytes. The compounds of the invention are Therefore of use in medicine, especially fn the prophylaxis and treatment of asthma.
Thus according to one aspect of the invention, we provide a compound of formula (1) L
i~
W1~ Z
(1) wherein =W- is (1 ) =C(Y)- where Y is a halogen atom, ar an alkyl or -XR~ group where X is -O-, -S(O)m- [where m is zero or an integer of value i or 2], or -N(Rb)- ( where R5 is a hydrogen atom or an optionally substituted alkyl group] and R8 is a hydrogen atom or an optionally substituted alkyl group or, (2) =N-;
L is a -XR, [where R is an optionally substituted alkyl, alkenyl, cyciaalkyl or cyloalkenyl group], -C(Rii)=C(R~)(R2) or [-CH(Rjj)]nCH(R1)(R2) group where R~ ~ 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, alkenyi, alkynyl, alkoxy, alkylthio, -COZR8, [where R$ is a hydrogen atom or an optionally substituted alkyl, aralkyl, or aryl group], -CONR9Rzo [where R9 and Rio, which may be the same or different are as defined for R~], -CSNR9Rlo, -CN or -N02 group, or R~ and R~ together with the C atom to which they are attached are w0 95135281 ~ ~ ~~ ~ ~ a~ ~ PCTJGB95IQ1459 linked to form an optionally substituted cycloalkyl or cycloalkenyl group and n is zero or the integer 1;
Z is a group (A), or (B):
R3 R7 Ra Rs Rs ~ /I~w R4 R5 "7 R5 (A}, or (B), wherein R3 is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or a hydroxyl group;
R4 is a hydrogen atom or group -(CHZ}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 -(GH2)t-Ar-(Ll )~-Ar' [where Lt is a divalent linking group and Ar' is Ar, -COAr, -SOZAr, -S02NHAr, -SOpN(Alkl)Ar [where Alkl is a straight or branched Cl-6 alkylene, C2-6 alkenylene or C2~ alkynylene chain optionally interrupted by one, two or three -O-or -S- atoms or -S(O}p- (where p is an integer i ar 2) or -N(Rb)- groups], -S02N[Ar]2, -CONHAr, -CON(Alkt)Ar, -CON[Ar]z, -NAlkl SOpAr, -NHS02Ar, -N[S02Ar]2, -NHSO2NNAr, -NAIkISOpNHAr, -NHS02N(Alkl)Ar, -NAIk1S02NAIkIAr, -NHS02N[Ar]2, -NAlkl S02N[Ar]2, -NHC(O)Ar, -NAIkIC(O)Ar, -N[C(O)Ar]2, -NHC(O)NHAr, -NAIkIC(O)NHAr, -NHC(O)N(Alkl)Ar, -NAIkIC(O)N(Alkt)Ar, -NHC(O)OAr, -NAlkIC(O)OAr, -C(S}NHAr, -C(S)NAIkIAr, -C(S}NAIkIAr, -C(S)N[Ar]2, -NHC(S)Ar, -NAIkIC(S)Ar, -N[C(S}Ar]p, -NHC(S)NHAr, -NAIkIC(S)NHAr, -NHC(S)NAIkIAr, -NAIktC(S)NaIklAr, -S02NHet [where -NHet is an optionally substituted Cs_~ heterocyclic amino group optionally containing one or more other -O- or -S- atoms or -N(Rb)-, -C(O)-or -C(S)- groups], -CONHet, -CSNHet, -NHS02NHet, -NHC(O)NHet, -NHC(S)NHet, -SOpNH(Het') [where Het' is an optionally substituted C5_~monocyclic carbocyclic group optionally containing one or more -O-or -S- atoms or ' -N(Rb)- groups], -CONH(Het'), -CSNH(Het'), -NHS02NH(Het'), -NHC(O)NHHet' or -NHC(S)NHHet'];
WO 95135281 ,, ~ -7 f r , PCTlGB95I01-059 ~ I :,:.;~~~J
R5 is a -(CH2jtAr or -(CH2)~-Ar-(Lt )~-Ar' group, provided that when R5 is a -(CH2)tAr group, =W- is =C(Y)- and L is -XR, then R4 is a group -(CH2jr Ar-(Ly )~Ar ; , Rs is a hydrogen or a fluorine atom, or an optionally substituted alkyl group; _ R~ is a hydrogen or a fluorine atom, an optionally substftuted straight or branched alkyl group or an ORS group where R~ is a hydrogen atom or an optionally substituted alkyl or alkenyl group, or an alkoxyalkyl, 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 (1 ) may have one or more chiral centres, depending on the nature of the groups L, R~, R2, Rs, R4, R5, R~ and R~. Where one or more chiral centres is present, enantiomers or diastereomers may exist, and the invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates.
Compounds of formula (1j wherein L is a-C(Rj~)=C{R~)(Rz) group andlor Z is the group (B), may exist as geometric isomers depending on the nature of the groups R3, R2, R4, R5, Rg 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(Yj- and Y is -XRa, Rg may be, for example, a hydrogen atom or an optionally substituted straight or branched alkyl group, for example, an optionally substituted Ct.
salkyl group, such as a methyl, ethyl, n-propyi 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(NH2j-, =C(NNCH3)- or =C(NHC2HSj- group.
WO 95/35281 ~ ~ (1 ~i ~~ ?' f PCT/GB95101459 a ~ ~. _'t =~ :) In compounds of formula (1 ), X may be an oxygen or a sulphur atom, or a group -S(O)-, -S(O)2-, -NH- or Ci_6 alkylamino, for example a Ct-3 alkylamino, e.g. methylamino [-N(CH3)-] or ethylamino [-N(C2H5)-] group.
Alkyl groups represented by Y, R, R~, R2, or Rb in the compounds of formula (1) include optionally substituted straight or branched Cs.s alkyl groups optionally interrupted by one or more X atoms or groups.
Particular examples include C1.3 alkyl groups such as methyl or ethyl groups. Optional 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 Cl.s alkoxy e.g. C~_3 alkoxy such as methoxy or ethoxy or -C02R8, -CONR9Rlo, -CSNR9RIO or -CN groups.
Alkenyl groups represented by R, Rt or R2 in the compounds of formula (1) include optionally substituted straight or branched CZ_safkenyl groups optionally interrupted by one or more X atoms or groups. Particular examples include ethenyl, propen-1-yl and 2-methylpropen-1-yl groups.
Optional substituents include those described above in relation to alkyl groups represented by the groups Rt or R2.
Alkynyl groups represented by Rl or R2 in compounds of formula (1) include optionally substituted straight or branched Cp-6alkynyl 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 Rt or R2.
When Rt or R2 in compounds of fom~ula (1 ) is an alkoxy or alkylthio group it may be for example an optionally substituted straight or branched Cl.s alkoxy or Ct-salkylthio group optionally interrupted by one or more X
atoms or groups. Particular examples include Gl.3alkoxy, e.g. methoxy or ethoxy, or Cl-3alkylthio e.g. methylthio or ethylthia groups. Optional substituents include those described above in relation to alkyl groups represented by the groups Rt or R2.
W 0 9'35281 ~ 1 '~ ~ .A 7 PCTIGB95I01~159 ~. ( ~~..t;~+J
When R3 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 Gs-8cycloalkyl grcup such , as a cyciobutyl, cyclopentyl or cyclohexyl group or a Ca-$ 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-cyciopentadien-1-yl, 2-cyclohexen-1-yl, 3-oyclohexen-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 Cy~alkyl e.g. C1_3alkyf such as methyl or ethyl, hydroxyl or Ct~alkoxy e.g. Cl.salkoxy such as methoxy or ethoxy groups.
When R in the compounds of formula (1) is an optionally substituted cycloalkyi or cycloalkenyl group ft may be for example a G3.acycloalkyl group such as a cyclobutyl, cyclopentyl or cyclohexyl group or a Gs-$cycloalkenyl group containing for example one or two double bonds such as a 2-cyclobuten-1-yl, 2-cyciopenten-1-yl, 3-oyolopenten-1-y(, 2,4-cyclopentadfen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl or 3,5-cyclohexadien-1-yt group, each cycloalkyl or cycloaikenyl 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 Gl.aalkyl e.g. Ci_3atkyi such as methyl or ethyl, hydroxyl or C~_salkoxy e.g. Cl.3alkoxy such as methoxy or ethoxy groups.
When the group R~ in compounds of formula (1) 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 Cl.fialkyl group, e.g. a C~.3alkyl group such as a methyl or ethyl group, a Ca~alkenyl group such as an ethenyl or 2-propen-1-yi group, a G~_3aikoxyC~_3alkyl group such as a methoxymethyl, ethoxymethyl or ethoxyethyl group, a C~.salkanoyl, e.g.
Cl-3alkanoyl group such as an acetyl group; or a farmyl [HG(O)-], carboxamido ~GONR~2Rt2a) or thiocarboxamido (CSNRr2Rl~) group, where R12 and Rl2g in each instance may be thd same or different and is each a hydrogen atom or an optionally substituted straight or branched C~ _ WO 95/35281 ~ i PCTIGB95101459 ~ ~, ~ ~, ,,~
salkyi, e.g. C~-3aikyl group such as methyl or ethyl group. Optional substituents which may be present on such R~, Rt 2 or R~ 2a groups include those described below in relation to the alkyl groups R6 or R~.
Alkyl groups represented by R3, Rs or R~ in compounds of formula (1) include optionally substituted straight or branched Cy.s alkyl groups, e.g.
C~_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 Cj~alkoxy e.g. Cy-3alkoxy 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.
When R~ or R2 is a -C02R8, -CONR9R» or CSNR9RZ~ group it may be for example a -COpH, -CONHp or -CSNHp group or a group -C02Rs, -CONR9R~o, -CSNR9RYO, -CONHRto, or -CSNHRio where R8, R9 and Ryo where present is a C~_3afkyl group such as methyl or ethyl group, a C6_~2aryl group, for example an optionally substituted phenyl, or a 1- or 2-naphthyl group, or a Gr,_~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 (1), the groups -(CH2)~Ar and -(CH2)tAr(Ly )~Ar' when present may be -Ar, -CH2Ar, -(CH2)2Ar, -(CH2)3Ar-, -Ar-Ar', -Ar-L1-Ar', -CH2ArAr', -CH2ArLtAr', -(CHZ)2ArAr', -(CH2)2ArL~Ar', -(CH2)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 Cs_~2 optionally substituted aryl groups, for example optionally substituted phenyl, 1-or 2-naphthyl, indenyl or isoindenyl groups.
When the monocyclic or bicyclic aryl.group Ar or Ar' contains, one or more heteroatams, Ar or Ar' may be for example a C~_9 optionally substituted WO )5!35281 v ': ~? ! :~ 'T PCTlGB95n11d59 G s ~ r= C:; '~t .) heteroaryl group containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, Ar or Ar' hetsroaryl groups may be for example monocyclic or bicyclic , heteroaryi groups. Monocyclic hsteroaryl groups include for example fivs-or six-membsrsd hsteroaryl groups containing one, two, three or four heteroatoms selected from oxygen, sulphur ar nitrogen atoms. Bicyclic hsteroaryl groups include for example nine- or ten- membered heteroaryi groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
F~camplss of h$teroaryl groups represented by Ar or Ar' include pyrrolyl, fury!, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazofyf, oxazolyl, isoxazolyl, thiazoiyl, isothiazolyi, pyrazofyi, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazoiyt, 1,2,4-oxadiazolyl, 1,2,5-oxadiazofyl, 1,3,4-oxadiazolyl, pyridyt, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryi, isobenzofuryl, benzothienyl, isobenzothienyf, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, rtaphthyridlnyl, pyrido[3,4-b)pyridyl, pyrido[3,2-bjpyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetra-hydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyi. Example of bicyclic heteroaryl groups include quinolinyl 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-thisnyi group, and, similarly, when it is a fury) group it may be a 2-fury! or 3-fury) group. In another example, when the group Ar or Ar' is a quinalinyl group it may be a 2-, 3-, 4-, 5-, 6-, 7- a>' 8- quinolinyl and when it is an isoquinolinyi, it may be a 1-, 3-, 4-, 5-, 6-, 1--or 8- isoquinolinyl group.
When in compounds of formula {i) the Ar or Ar' group is a nitrogen-containing heterocycle it may be possible to foim 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 W0 9513528I ~ ~ ~ ~ a , ,~ PC'fIGB95101459 ~ , l t. ~~ ~E .~
s pyridyl group, pyridinium salts may be formed, for example N-alkylpyridinium salts such as N-methyipyridinium.
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 mare substituents (RI3]. The substituent R13 may be selected from an atom or group R14 or-AIk2(R~4}m wherein Rt4 is a halogen atom, or an amino (-NH2), substituted amino, nitro, cyano, hydroxyl (-OH), substituted hydroxyl, cycloalkoxy, formyl (HC(O)-], carboxyl (-C02H), esterified carboxyl, thiol (-SH), substituted thiol, -C(O)AIk2, -S03H, -S02AIk2, -SOpNHp, -SOpNHAlk2, -SOpN[AIk2]2, -CONHp, -CONHAlk2 , CON[AIk2]p, -NHS02H, -NAIk2S02H, -NHS02AIk2, -NAIk2S02A1k2, -N[S02AIk2]2, -NHS02NH2, -NAIk2SOpNH2, -NHS02NHAIk2, -NAIk2S02NHAlk2, -NHS02N[AIk2]p , -NAIk2S02N[AIk2]2, -NHC(O)H, -NHG(O)AIk2, -NAIk2C(O)H, -NAIk2C(O}AIk2, -N[C(O)AIk2]2, -NHC(O)OH, -NHC{O)OAIk2, -NAIk2C{O)OH, -NAIk2C(O)OAlk2, -NHCONHp, -NHCONHAIk~, -NHCON[AIk2]2, -NAIk2CON[AIk2]2, -NAIk2CONH[AIk2], -NAIk2CONH2, - G(S)H, -C(S)AIk2, -CSNH2, -CSNHAIkz, -CSN[AIk2]2, -NHC(5)H, -NHCSAIk2, -NAIk2C(S)H, -NAIk2C(S)AIk2, -N[G(S)AIk2]2, -N[C(O)AIk2]S02H, -NHCSNHp, -NHCSNHAik2, -NHCSN[AIk2]2, -NAIkzCSN[AIk2]2, -N A I k2CSNHAlk2, - N A I k2CSNH2, o r -N[C{O)Alk2]S02AIk2 group, AIk2 is a straight or branched C~_6 alkylene, C2~alkenylene, or C2-salkynylene chain optionally ihterrupted by one, two, or three -O-, or -S- atoms or -S(O}p-, [where p is an integer 1 or 2] or -N(Rs)- groups; and m is zero or an integer 1, 2 or 3 .
When in the group -AIk2{R~4)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents RI4 may be present on any suitable carbon atom in -AIk2. Where more than one R14 substituent is present these may be the same or different and may be present on the same or different carbon atom in Afk2. Clearly, when m is zero and no substituent RI4 is present or when AIk2 forms part of a group such as -S02AIk2 the alkylene, alkenylene or alkynylene chain represented by Alk2 becomes an alkyl, alkenyl or alkynyl group.
W0 95135281 ~ t1 '°t i it -r PCTIGB95101459 f r~ ~'ys-'t.) When R14 is a substituted amino group it may be a group -NH[A(k~(Rt~)m]
[where AIk2 and m are as defined above and Rl~a is as defined above for R14 but is not a substituted amino, a subs#ituted hydroxyl or a substituted thiol group] or a group -N[AIk2(Rt~)~,]2 wherein each -Aik2(R1'~)m group 5 is the same or different.
When R1~ is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
10 When R14 is a ~ycloalkoxy group it may be for example a C5_~cycloalkoxy group such as a cyciopentyloxy or cyclohexyloxy group.
When R14 is a substituted hydroxyl or substituted thiol group it may be a group-OAIk2(RY'~)r" or-SAIk2(Rt~)m respectively, where AIk2, Rlaa and m are as just defined.
Esterified carboxyl groups represented by the group R14 include groups of formula -CO2Alks wherein Alks is a straight or branched, optionally substituted C1_gaikyi group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a Cs.~parylCl_8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphfhylmethyl or,2-naphthylmethyl group; a Cs_~2aryl group such as an optionally substituted phenyl, 1-naphthyi or 2-naphthyi group; a C&l2aryloxyCl_$alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-~alkanoyloxyCi_8alkyt group, such as a pivaloyloxymethyl, propionyloxyettiyl or propionytoxypropyl group; or a Cs_y2aroyloxyCl$alkyl group such as an optionally substituted benzoyloxyethyl or benzcyloxy propyl group. Optional substituents present on the AIk3 group include R1s substituents described above.
It wi8 be appr~ciated that the group Ar or Ar' may be attached to the remainder of tha molecule of formula (1) through either a ring carbon atom or heteroatom.
W095l35281 . ° ~ (') ;. ' " PCTlGB95101459 J !~ ~.,' ! f J
Particular examples of the chain AIk2 when present include methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 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 R13 include fluorine, chlorine, bromine or iodine atoms, or Ct.salkyl, e.g. methyl or ethyl, Ct-salkylamino, e.g. methylamino or ethylamino, C~_6 hydraxyalkyl, e.g.
hydroxymethyl or hydroxyethyl, C~.salkylthiol e.g. methylthiol or ethylthiol, Cl~alkoxy, e.g. methoxy or ethoxy, C5-7cycloaikoxy, e.g. cyclopentyloxy, haloCy.salkyl, e.g. trifluoromethyl, Cl-salkylamino, e.g. methylamino or ethylamino, amino (-NH2), aminoCt.aalkyl, e.g. aminomethyl or aminoethyl, C~_sdialkylamino, e.g. dimethylamino or diethylamino, nitra, cyano, hydroxyl (-OH}, formyl [NC(O)-], carboxyl (-C02H), -C02AIk3 [where AIk3 is as defined above], Cy~ alkanoyi e.g. acetyl, thiol (-SH), thioCi_6alkyl, e.g.
thiomethyl or thioethyl, sulphonyl (-SOsH), Cy_salkylsulphonyl, e.g.
methylsulphonyl, aminosulphonyl (-SO2NH2), C1_salkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C~_6dialkylamino-sulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, carboxamido (-CONH2), Ci_salkylaminocarbonyl, e.g. methylamino-carbonyl or ethylaminocarbonyl, G~_sdialkylaminocarbonyl, e.g. dimethyl-aminocarbonyl or diethylaminocarbonyl, sulphonylamino (-NHS02H), Cj_salkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonyl-amino, Ct~dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethyl-sulphonylamino, aminosulphonylamino (-NHSO2NH2), Ct~alkylamino-sulphonylamino, e.g. methylaminosulphonylamino or ethylamino-sulphonylamino, Gt-edialkylaminosulphonylamino, e.g. dimethylamino-sulphonylamino or diethylaminosulphonylamino, Ci_salkanoylamino, e.g.
acetylamino, Cl-saikanoylaminoCy_salkyl, e.g. acetylaminomethyl or C~_6 alkoxycarbonylamino, e.g. methoxycarbonylamino, ethaxycarbonylamino or t-butoxycarbonylamino thiocarboxamido (-CSNH2), Ci_6 alkylamino-thiocarbonyf, e.g. methylaminothiocarbanyl or ethylaminothiocarbonyl, C~_sdialkylaminathiocarbonyt, e.g. dimethylaminothiocarbonyl or diethyl-aminothiocarbonyl, aminocarbonylamino, Ci_salkylaminocarbonylamino, W095l35281 ~ ~ ~ e) ~,!"~. ~ PCTIGD9510i499 e.g. methylamiriocarbonyiamino or ethylaminocarbonylamino, Cl.sdialkyla-minocarbonylamino, e.g. dimethylaminocarbonylamino or diethylamino-carbonylamino, aminothiocarbonylamina, Cl.6alkylaminnthiocarbonyl- , amino, e.g. methylaminofhioearbonyiamino or ethylaminothiocarbonyl-amino, Cj_s dialkylaminothiocarbonylamfno, e.g. dimethylaminothio- , carbonylamino, ordiethylaminothiocarbonylamino, aminocarbonyiCl~alkyl-amino, e.g. aminocarbonylmethylamino or aminocarbonylethylamino, amfnnthiocarbonylCl.salkylamino e.g. aminothincarbonyimethyiaminn or aminothiocarbonylethylamino, formylaminoCl_g alkylsulphonylamino, e.g.
formyiaminomethylsulphonylamino or formyl-aminoethylsulphonylamino, thioformylaminoCl.salkylsulphonylamino, e.g. thioformylaminomethyl-sulphonylamino orthiofonnylethylsulphonylamino, ~1$acylaminosulphonyi-amino, e.g. acetylaminosuiphonylamino, Cl.sthio-acylaminnsulphonyl-amino, e.g. thioacetylaminosulphonylamino groups.
Where desired, two R1s substituents may be finked together to form a cyclic group such as a cyclic ether, e.g. a C2.salkylenedioxy group such as ethylenedioxy.
it will be appreciated that where two or mare Rr3 substituents are present, these need not necessarily be the same atoms andlor groups. The R~3 substituents may be present at any ring carbon atom away from that attached to the rest of the molecule of formula {i ). Thus, for example, in phenyl groups represented by Ar or Ar' any substituent may be present at the 2-, 3-, 4-, 5- or 6- positions relative to the ring carbon atom attached to the remainder of the molecule.
In the compounds of formula (1), when the group -(CH2)tAr(L1)~Ar' is present in R4 andtor R5, the linker group L1 may be any divalent Linking group. Particular examples of L1 groups which may be present in compounds of the invention include groups of foimula -(Alk~)r{Xa)g(AIk5}r-where A1kø and AIkS is each an optionally substituted straight or branched Cl.eaikylene, C2.salkenylene or C2$alkynylene chain optionally interrupted by one or mare, e.g. nne, 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 i , t is zero or the integer 1 and s is W095l35281 ~ ~ e:? ~l ~ ~ ~ PCTIGB95101459 ,.
E
zerc 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 Alk4 or AIkS chains include for example -0- or -S- atoms. Carbocyclic grcups 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 Alks include oxygen-, sulphur- or nitrogen-containing groups such as -S(O)-, -S(0)2-, -N(Rb)-, -C(O)-, -C(S)-, -C(NRb)-, -GON(Rb)-, -CSN{Rb)-, -N(Rb)CO-, -N(Rb)GS-, -SON(Rb)-, -S02N(Rb)-, -N(Rb)SO-. -N(Rb)S02-, -N{Rb)S02N(Rb)-, -N(Rb)SON(Rb)-. or -N(Rb)CON(Rb)- groups. It will be appreciated that when the chains AIk4 or Alk$ are interrupted by two or more heteraatoms, carbocyclic or heteroatom-containing groups, such atoms or groups may be adjacent to i5 one another, for example to form a group -N(Rb)-C(NRb)-N(Rb)- or -O-CONH-.
Optional substituents which may be present on AIk4 or Alks chains include those described above in relation to the group Rl when it is an alkyl group.
The group -(L1)nAr' 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, -(Ll)~Ar' may be attached through a carbon or heteroatom in -(Ll )~,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 AIk4 or AIkS include optionally substituted methylene, ethylene, propylene, butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynyfene 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 -(Ll)~Ar' include the groups -AIk4Ar', -XAr', -AIk4XAr' and -XAIkSAr', especially for example -CH2Ar', -(CH2)2Ar', W095I352g1 'f 1 ~y ~ r ,~ PCTlOB95f01459 l_ ; J ;.. eri ev -{CH2)3Ar', -CHpOCH2Ar', -CH2SCH2Ar', -CHIN{R~)CH~Ar', -GH=CHAr', -CH~CH=CHAr', -OAr', -SAr', -N(R~)Ar', -CH20Ar', -CH~SAr', -CH2N(R5)Ar', -CH20CH20Ar', -OCH2Ar', -O(CH~)2Ar', -SCH2Ar', -S(CH2}2Ar', -N(Rb)CH2Ar' and -N(R~)(GH~2Ar'.
in these particular groups, Ar' may be as described herein, and may be especially an optionally substituted Cs_~2aryl or O~_9heteroaryl group, in particular an szptionally substituted phenyl or pyridyl group or a -COPh {where Ph is an optionally substituted phenyl group), -S02Ph, -SONHPh, -S02N(Alk~}Ph, -SO2N[Ph]2, -CONHPh, -CON{Alk~)Ph, -CON[Ph]2, -NAtk~SOpPh, -NHS02N(AIk1)Ph, -NAtk~S02Aik~Ph, -NHS02N[Ph]2, -NAIktSO~NjPh]2, -NHC(O}Ph, -NAlkl COPh, -NC(O)N[Ph]~, -NHC(O)NHPh, -NAIkIC(O)NHPh, -NHC(O)N{Alkt)Ph, -f.IAlkaC(O)N(Aik~}Ph, -NHC(O)OPh, -NAIk~C(O)OPh, -C(S)NHPh, -G(S)NAIk~Ph, -N(S)N[Ph]2, -NHC(S)Ph, -NAIkjG{S)Ph, -N[C{S)Ph]~, -NHC(S)NHPh, -NAlky C(S)NHPh, -NHC(S)NAIk~ Ph, or -NAfk~C{S)NAIk~ Ph group. In these groups, the group Alk~ may in particular be a methyl or ethyl group.
When in R4 andlor RS a -NHet group is present this may be for example a pyrrolidinyl, pyazolidinyl, piperidinyi, morphalinyl, piperazinyl or thiomor-pholinyi group: Optional substituents that may be present in such groups include R~ 3 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, pyrazolidinyi, piperidinyi, morphotinyt, piperazinyl, thio-morpholinyl, cyctopentyl, or cydohexyl group. Optional substituents that may be present on such groups include R~3 substituents described above.
In the compounds of formula (i), when an ester group is present, for example a group COpR$ or -C02A1k3 this may advantageously be a metabolically labile ester.
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 WO95/35281 ,~ i ~~ 1 ,, ~ .~ PCTlGB951Q1459 i l.. U t J
firom inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, 5 alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, mafonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal 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 v'v by metabolic means, e.g. by hydrolysis, reduction, oxidation or trans-esterification, to compounds of formula (i).
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. fn 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 optionally substituted methyl group. Especially useful substituents which may be present on Re 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 cycloalkyl group, particularly an optionally substituted cyciopentyl group, and is, especially a cyclopentyl group.
W0 95135281 PC't'1GB951Ot459 ~~ ~~i:~~~~
is In another group of compounds of formula (1) L is preferably a -CH=C{R~)(R2) group. tn compounds of this type Rt and R2 are preferably linked together with the C atom to which they are attached to form an optionally substituted cycloaikyl or cycloalkenyl group, especially a substituted cyclopentyl ar cyclohexyl or, especially, a cyclopentyl or cyclohexyl grope.
The groups R4 and Rs in compounds of formula (1 ) is each, independently, preferably a -{GH2}rAr or -{CH2)tAr-(L1 )~-Ar' group , particularly a GH2Ar or -CH2Ar{Lt)~Ar' group or especially an -Ar, Ar=Ar' or ArLtAr' group.
Particularly useful R4 or RS groups of this type include those groups in which Ar or Ac' 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, iwo, three or more R1~
substituents. In these compounds, when the group represented by Ar or Ar' is a heteroaryl group ft is preferably a nitrogen-containing monocycGc heteroaryl group, especially a six-membered nitrogen-containing heteroaryl group. Thus, tn one preferred example, the groups R4 and R$
may each contain a six-membered nitrogen-containing heteroaryl Ar or Ar' group. In another preferred example R~ may contain a monocyclic aryl group or a monocyclic or bicycllc heteroaryl group Ar or Ar' containing one or more oxygeh, sulphur or nitrogen atoms and RS may contain a six-membered nitrogen-containing heteroaryl group Ar or Ar'. In these examples, the six-membersd nitrogen-containing heteroaryl group may bs an optionally substituted pyridyt, pyridazinyl, pyrlmidinyl, pyrazinyl or imidazolyl group. Particular examples include optionally substituted 2-pyridyl, 3-pyridyl, 5-imidazolyl, or, especially, 4-pyridyi, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyi, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl or 3-pyrazinyl. The monocyclic aryl group may be a phenyl group or a subst'ttuted phenyl group, and the monocyciie or bicyclic heteroaryl group containing one or more oxygen, sulphur or nitrogen atom may be an optionally substituted 2-furyl, 3-furyi, 2-thienyl, 3-thienyl, 2-thiazolyl, 2-benzo{b)thiophenyl, 2-benzo(b)furyl or 4-isoquinolinyl group.
WO 95135281 ~ ; ~~~~ r PCTIGB95101459 ~!. I i f_ li In another preference relating to R4 groups of the just mentioned particular types, Ar' is a -NHC(O)NHPh (where Ph is as just described, -NHCH3C(O)NHPh, -NHC(0)NCH3Ph, -NCH3C(O)NCH3Ph, -COPh, -NHS02NHPh, -NCH3SOpNNPh, -NC H3S02NCH3Ph, -NHCOPh, -NCH3COPh or-NHSOpPh group, particularly in those instances where L1 is a -CH2- group.
In general in compounds of formula (1) when R4 andlor R5 contains a substituted phenyl group it may be for example a mono-, di- 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 R~3 which may be present an Ar groups in R4 and R5, especially on phenyl groups, include halogen atoms or alkyl, haloalkyl, amino, substituted amino, vitro, -NHS02NH2, -NHS02NHCH3, -NHS02N(CH3)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 and/or R5 contains a substituted pyridyl group it may be for example a mono-or disubstituted pyridyl group, such as a mono- or disubstituted 2-pyridyl, 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.
WO 95135281 ~ ~f ~ ~) 't A particularly useful group of compounds of formula {1 ) has the formula {2):
L
GH3~ Z
/ (2) whore -L is a OR, where R is an optionally sutisfituted cycloalkyl group, -CH=C(Ry)(R2) or -CH2CH(Rt)(R2) group where R~ and R2 are linked together with the carbon atom to which they are attached to form a cycioalkyi group; Z is as defined for formula (1); and the salts, solvates, hydrates, prodrugs and N-oxides thereof.
In the compounds of formulae (1) or (2) where Z is the group {A), 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 R~ and RS are as defined for formula (1 ). In compounds of this type R~
and R7 is each especially a hydrogen atom.
In general in compounds of formulae (1 ) or (2) the group Z is preferably a group of type (A). In compounds of this type R3, R6 and R~ is each especially s hydrogen atom, R5 is in particular an optionally substituted pyridyi group, especially a 4-pyridyi group and R~ is in particular a -(GN~)t-Ar-(L~)n-Ar' group, especially a -Ar-(L1)n-Ar" group. Particular examples of -Ar-(Lt)n-Ar' groups include -Ar-Ar, -Ar-O-Ar, -Ar-CH2-Ar, -Ar-(CH2)2Ar, -Ar-NHC(O)NHAr, -Ar-CH2NHC(O)NHAr, -Ar-GOAr, -Ar-CHpCOAr, -Ar-NHS02NHAr, -Ar-CH2NHS02NHAr, -Ar-NHSO~Ar, -Ar-CH2NHSOzAr, -Ar-NCH3C(O)NHAr, -Ar-GH2NCH3C(O)NHAr, -pr-NGHsSO2NHAr or -Ar-GH2NCH3S02NHAr groups. In these groups Ar may in particular be an optionally substituted phenylgroup. Optional substituents include for example, halogen atoms, e.g. chlorine or fluorine atoms, alkyl, e.g. methyl, 3g haloalkyi, e.g. trifluoromethnyl, amino, substituted amino, e.g.
methyiamino, ethylamino, dimethylamino, vitro, -NHS02NH2, -NHS02NHCH3, -NHSOaN(CHs)2, -NHCOCH3, -NHC(0)NH2, -NCH3C(O)NH2, -NHC{O)NHGH3, -NHC{O)NHCH2CH3, or WO 95/35281 ~ ~ ~~ / ~ ~J ~ ~ PCTJGB95101459 -NHC(O)N(CH3)2 groups, each of said atoms or groups being optionally separated from the remainder of the phenyl group by a -CH2- group.
In the above examples, when Ar is a phenyl group, the -(L~)~Ar group or any other optional substituent may be attached to any available ring carbon atom away from that attached to the remainder of the compound of formula (1).
Particularly useful compounds according to the invention are:
(~}-4-{2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-[4-(4-trifluoromethyl-phenyl) phenylethyl]}pyridine;
(t)-4-[2-{4-Benzyloxyphenyl)-2-(3-cyclopentyfoxy-4-methoxyphenyl)ethyl]
pyridine;
(~)-4-{2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-[4-(4-nitrophenyioxy)-phenyl]ethyl}pyridine;
(E) and (Z) isomers of 4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)ethenyl]-3-(phenylethyl)pyridine);
(~)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl}ethyl]-3-(phenylethyl)pyridine;
(~)-4-{2-[4-{4-Aminophenyioxy}phenyl]-2-(3-cyclopentyioxy-4-methoxy-phenyl)ethyl}pyridine;
(~)-4-{2-[4-{4-Acetamidophenyioxy)phenyl]-2-(3-cyclopentyloxy-4-methoxyphenyi)ethyl]pyridine;
(~)-4-{2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-[4-(4-N',N'-dimethylamino-sulphonylaminophenyl)phenyloxy]ethyl}pyridine;
(~)-4-{2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-{4-(4-methylsulphonyl-aminophenyl)phenyloxy]ethyl}pyridine;
(~}-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl}-2-(4'-methyl-4-biphenyl)-ethyl]pyridine;
(_+}-N-{3-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl-methyl}-N'phenylurea;
or each isomer or the resolved enantianers, and the salts, solvates, hydrates, prodrugs and N-oxides thereof.
Compounds according to the invention are selective and potent 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.
WO 95!35281 ~ '3 !'~ ~ ~ ~ YI PCT1GB95f01~59 Particular uses to which the compounds of the invention may be put include the prophyiaxfs and treatment of asthma, especially inflamed lung associated with asthma, cystic fibrosis, or in the treatment of inflammatory 5 airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis and other benign and malignant proifferative skin diseases, endotoxic shock, septic shock, uicerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atapic dermatitis, urticaria, adult respiratory distress syndrome, diabetes 10 insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis and artheroscterosis.
Compounds of the invention may also suppress neurogenic inflammation through elevation of cAMP in sensory neurones. They are, therefore, 15 analgesic, anti-tussive and anti-hyperalgesic in inflammatory diseases associated with irritation and pain.
Compcunds according to the invention may also elevate cAMP in lymphocytes and thereby suppress unwanted lymphocyte activation in 20 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 (ThIF) are key mediators. Also compounds of the invention may suppress inflammation and pyrexia dus to cytokines and ors, therefore, useful in the treatment of inflammation and cytokine-mediated chronic tissue degeneration which occurs in diseases such as rheumatoid or osteo arthritis.
! 1~) C~ is ~ i 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 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.
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 diluents.
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 insuffiation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with phamlaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone 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 fauryl 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 W0 95135281 . PCTlGB95tOl.~i9 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 admipistratlon the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formulae {l) and {2) may he formulated for parepteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage farm, 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.
Alternativety, ttie 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 {l) 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 inventiop 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. dichlorodifluoramethans, trichlorofluoromethane, dichlorotetrafiuoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositfor~s may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms captaining the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
WO 95/35281 ~ ~ f j ~ li ~ .i PCT/GB95l01459 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 100nglkg to 100mg/kg, e.g. around 0.01mg/kg to 40mglkg body weight for oral or buccal administration, from around l0nglkg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g.
around 0.5mg 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. The symbols W, L, Z, X, R~, R2, R3, R4, R5, R6, R~
and R~~ when used in the formulae below are to be understood to represent those groups described above in relation to formula (1 ) unless otherwise indicated. In the reactions described below it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio, 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 practice [see, for example, Green, T. W. in °Protective Groups in Organic Synthesis" Jahn Wiley and Sons, 1981].
Thus, according to a further aspect of the invention, compounds of general formula (1) where L is a-G(R~j}=C(Rt)(R2) group, R» is a hydrogen atom or a methyl group and R3 when present is a hydrogen atom, may be prepared by coupling a compound of formula (3}
C(O)R~~
W
Z
(3) where R» is as described above with an olefination agent.
W 0 95!3528 L - ~ a ~ PCTIGB95/01459 l ~$ ~ (~t :~
Particular examples of olefination agents include phosphonium salts such as compounds {R~ )(R~)CHP(D)3Hal where Hal is a halogen atom, such as a bromine atom, and D is an optionally substituted alkyl, e.g. methyl, or aryC, especially phenyl, group; phosphoranes (Rt)(R2)C=P(D)3;
phosphonates (DO)2P{O)CH(R~)(R2); or silane derivatives, for example compounds of formula {D)3SiG{R~)(R2), e.g. trialkylsiianes such as (CH3)3SiC{R~ )(R2).
Bases for use in the above reaction include organometallic bases, for example, an organotithium compound such as an alkyllithium e.g. n-butyllithium, a hydride, such as sodium or potassium hydride or an alkoxide, such as a sodium alkoxide, e.g. sodium methoxide.
The reaction may be performed in a suitable solvent, for example a polar aprotic solvent, such as an alkyl sulphoxide, e.g. methyl sulphoxide, an amide such as N,N-dimethyiformamide or hexamethylphosphorous triamide; a non-polar solvent, such as an ether, e.g. tetrahydrofuran or diethyC ether or an aromatic solvent such as benzene, toluene or xyiene; or a polar erotic solvent, such as an alcohol, for example ethanol. Preferably the reaction i~ carried out at a low temperatur~, tar example from around -7BaC to around room temperature.
The olefination agents a sed in this reaction are either known compounds or may be prepared from known starting materials using reagents and conditions similar to those used to prepare the known compounds. For example, a ptTOSphorane may be prepared in situ by reaction of a phosphonium salt with a base of the type described above. in another example, a phosphonate may be prepared by reacting a halide (Rt){R2)GHHai with a phosphite (DO)3P, as described in the Arbuzov reaction. Shane derivatives may be prepared by reaction of a halosilane (D)3SiHal wfth a base, such as lithium diisopropylamide, in a sohrent, such as an ether, for example a cyclic ether, e.g. tetrahydrofuran, at low temperature, e:g. around -10~C.
According to a further aspect of the invention compounds of formula (l) where L is a group -C(R11)=CH(R1) and R1 is an optionally substituted W095I35281 ,. ~_~,-? .r ~ -Y PCTIGB95/01459 'I' i U' 't .~
alkyl, alkenyl or alkyny! group may also be prepared by reaction of an intermediate of formula (3) with an organometallic reagent, followed by dehydration of the corresponding alcohol.
5 Examples of organometallic reagents include organolithium R~Li or organomagnesium RiMgHal reagents. The reaction with the organo-metallic reagent may be performed in a solvent such as an ether, such as diethyl ether or for example a cyclic ether such as tetrahydrofuran, at a tow temperature for example -10~C to room temperature. The dehydration 10 may be performed using an acid, far example an organic acid such as p-toluene sulphonic acid or trifluoroacetic acid, in the presence of a base, such as an amine, e.g. triethylamine.
Intermediates of formula (3) where R~ ~ is a methyl group, may be 15 prepared by reacting an intermediate of formula (3) where R~ ~ is a hydrogen atom with an organometaitic reagent, such as methyllithium or CH3MgHaf, using the conditions just described followed by oxidation of the resulting alcohol, using an oxidising agent, e.g. manganese dioxide.
20 Intermediates of formula (3) where R> > is a hydrogen atom may be prepared by deprotecting a protected aldehyde of formula (4) P
Z (4) 25 where P is a protected aldehyde group, e.g. a dioxanyl group, using acid hydrolysis e.g. by reaction with trffluoroacetic acid or p-toluene sulphonic acid, in the presence of a solvent, e.g. acetone, or a mixture of solvents, e.g. chloroform and water.
Intermediates of formula (4) where Z is a group (A} in which R3 is a hydroxyl group may be prepared by reacting a ketone of formula (5) WO 95/~52Fti PCTlGB95f01459 f ~~ ~~ii,y~
P
W
~C(O)R4 5 () with a reagent R~CHRBR~ using a base, such as an organometallic base, for example an organolithium reagent e.g. n-butyllithium, in a solvent, such as an ether, e.g. tetrahydrofuran, at around -70~C to room temperature.
Intermediates of formula (5) may be prepared by oxidation of an alcohol of formula (6) F
w CH(OH)(R4) (8) using an oxidising agent, such as manganese (15i) oxide, in a solvent, such as dichloromethane, at room temperature.
Intermediates of formula (6) may be prepared by reacting a halide of formula (8) described below wi#h an aIdehyde R4CH0, in the presence of abase, such as n-butyllithium, In a solvent, e.g. tetrahydrofuran, at a temperature from around -70~C to room temperature.
Intermediates of formula (4) where Z is a group (A) in which R3 is a hydrogen atom may be prepared by hydrogenation of an intermediate of formula (4) where Z is a group (B) using the reagents and conditions described hereinafter for the hydrogenation of a qompound of formula (l) where L is a -C(Rtt)=C(R~)(R~) group to give a compound of formula (1) where L is a -CH(R»)-CN(R~ )(R2) group.
Intermediates ~f formula (4) where Z is the group (B) may be prepared by dehydrating ary intermediate of formula (4) where Z is the group (A) and R3 is a hydroxyl group, by using an acid, e.g. trifluoroacetic acid, in the W095I35281 ~ ~ °y~ ~' ~ ~1 ~~ PCTlGB951U1459 presence of a base, such as an amine, e.g. triethylamine, in a solvent, such as dichloromethane, at a low temperature, e.g. around -10~C.
intermediates of formula (4) where Z is a group (B) may be prepared by condensing an intermediate of formula (7) P
Wi '' ~ wa (~) where (a) Wa is a -C(O)Rd group, with a compound R5CH2R6; or where (b) Wa is a -CH2R4 group with an aldehyde or ketone R5COR6; or where (c) Wa is a -C(O)R4 group with a silane derivative (Alka)sSICH(Rs}(R6}, where Alka is an alkyl group; in each instance 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; organic bases, for example amines such as piperidine; and organolithium bases, such as alkyllithium, e.g. n-butyllithium bases. Suitable solvents include alcohols such as ethanol, or ethers such as tetrahydrofuran. Acids for use in the reactions include organic acids, e.g. carboxylic acids such as acetic acid.
The reactions may be performed at any suitable temperature, for example from around -78~C to ambient temperature or to the reflex 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 of the starting materials, from a range of known alternatives for reactions of this type.
In silane derivatives of #ormula (Alka}3SICH(R5)(R6), Alka may be for example a Ci-salkyl group such as a methyl group. Derivatives of this T ~~ .~ r ~ y pCTIGB95l(11459 type may be prepared for example by reacting a compound R~-CH2-Ra with a silane derivative, such as a chlorotriafkylsilane, e.g. chlorotrimethyl-siiane in the presence of a base, e.g. lithium diisopropylamide, in a solvent, e.g. tstrahydrofuran, at a low temperature, e.g. around -lOnC, The starting materials R~COR~ and R$ CH2R6 are either knowr compounds or may be prepared from known starting materials by methods analogous to those us9d for the preparation of the known compounds.
Intermediates of formula (7) where -Wa is a -C{O)R4 group may be prepared by reacting an aldehyde of formula (7) where -Wa is a -CHO
group with an organometallic reagent in a solvent, e.g. tetrahydrofuran, at low temperature, e.g. around 10~C, followed by pxidation of the resulting alcohol with aii'oxidising agent, such as manganese dioxide, in a solvent, e.g. dichloromefhane.
Intermediates of formula (7) where -Wa is -CHO may be prepared by reacting a compound of formula (8) P
~ Ha3 {~;
where Haf is a halogen atom, e.g. a bromine atom, with an organometatlic reagent, such as n-hutyllfthium, in a solvent, such as an amide, e.g. dimethytformamide, at a low temperature, e.g. below -60~C.
Intermediates of formula (8) may be prepared by protecting an aldehyde or ketone of formula {9) wo ssrsszay' g ';~ ' i~.; 4~ S~ rcrrcsssroiass 2s C(O)R
W
Hal (9) where Hal is a halogen atom, e.g. a bromine atom with an aldehyde or ketone protecting group, using for example a suitable diol, e.g. 1,3-propanediol, in the presence of an acid catalyst, e.g. 4 toluenesulphonic acid, in a solvent, such as an aromatic solvent, e.g.
toluene, at art elevated temperature such as the reflux temperature.
fn general, this reaction may be used when it is desired to protect an aldehyde in any intermediate described herein.
Intermediates of formula (9) are either known compounds or may be prepared in a similar manner to the known compounds.
In another process according to the invention, compounds of formula (1) where Z is a group (B) may be prepared by reacting a compound of formula (10) L
W .i C(O)R°
(1Q) with a phosphonate ester (R'O)(OR")P(O)CH(R5)(Rs) [where R' and R", which may be the same or different is an alkyl, or aralkyl group] in the presence of a base in a suitable solvent.
Suitable bases include organometallic bases such as organolithium, e.g.
n-butyllithium, alkoxides, for example alkali metal alkoxides such as sodium ethoxide or sodium methoxide and a hydride such as potassium hydride or sodium hydride. Solvents include ethers, e.g. diethylether or cyclic ethers such as tetrahydrofuran and alcohol, e.g. methanol or ethanol.
Wf195i352$1 ~-y , ;_~ ') ! ,.~ ' PCTlGB95ItiId59 l ~.. 1J 't .'7 The phosphonate derivatives used in this reaction are either known compounds or may be prepared by reacting a phosphate P(OR')2{OR") with a compourid RSCHRbHaI jwhere Hal is a halogen atom, for example a 5 bromine atom] using conventions! methods.
Intermediates of formula {10} where R4 is as described for compounds of formula (1 ) but is not a hydrogen atom may be prepared by reaction of the corresponding compound where R4 is a hydrogen atom with an 10 organometallic reagent, followed by oxidation, as described previously for the preparation of ~termediates of forrrtuta (7) where Wa is a -C(O)R4 group.
Intermediates of formula (10) where R4 is a hydrogen atom may be 15 prepared by reacting a halide of formula {11 }
L
W~
{ii) Ha1 where Hai is a halogen atom, e.g. a bromine or chlorine atom with an 20 organometallic reagent using the same reagents arid conditions described above for the preparation of intermediates of formula (7) where W~ is -CHO from intermediates of formula {8).
intermediates of formula (11 ) where L is a -C(Rt t)=C(R~)(R2} group may 25 be prepared by coupling a compound of formula {9) with a phosphonium salt (Rl){R2}CHP(D)3Hai as described above for the preparation o1 compounds of fomlula {i } from intermediate of formula (3).
Intermediates bf formula {11} where L is an -XR group may be prepared 30 by aikyiation of a corresponding compound where L is -XH using a compound RHaI (where Hal is a halogen atom) ih the presence of a base in a solvent such as dimethyfformamide at ambient temperature or above, e.g. around 40~C to 50~C. intermediates of formula (11) where L is -XH
W095135281 ~ ~ ~% rT} (vi ~ ~ PCTlGB95101459 are either known compounds or may be prepared from known starting materials using conventional procedures, for example when X is -O- from the corresponding aldehyde by oxidation.
In yet another process according to the invention, a compound of formula (1 ) where one or both of R4 and R5 is a -(CH2)tAr(Ly )~Ar' group may be prepared by coupling a compound of formula (12), L
wr t (12) [where Z' is as defined for Z in formula (1 ) except that one or both of R4 and RS is a group -(CH2)tArE where E is a boronic acid -B(OH)2 or a tin reagent Sn(R~5)3, where R15 is an alkyl group, for example a methyl group], with a reagent Ar'(L~)nL2 where L2 is a leaving group, in the presence of a complex metal catalyst.
Particular leaving groups LZ include for example halogen atoms, e.g.
bromine, iodine or chlorine atoms and an alkyl sulphonate, such as trifluoromethanesulphonate. Particular tin reagents include those compounds for example where R~~ in the formula Sn(R15)3 is a methyl group.
Suitable catalysts include heavy metal catalysts, for example palladium catalysts, such as tetrakis (triphenylphosphine)palladium. The reaction may be performed in an inert solvent, for example an aromatic hydrocarbon such as toluene or benzene, or an ether, such as dimethoxyethane or dioxane, if necessary in the presence of a base, e.g.
an alkali carbonate such as sodium carbonate, at an elevated temperature, e.g. the reflux temperature. In general, the metal catalyst and reaction conditions may be selected, depending on the nature of the compound of formula (12) and/or the compound of Ar'(Ll )~L2 from a range of known alternatives for reactions of this type [see for example Miyaura, N ~#~!, Synth. Comm. (1981), 11, 513; Thompson, W. J. and Gaudino, J., WO 95!35281 PC'i'I(:$95101459 J. Org. Chem, (1984), 4~, 5237 and Sharp, N1. J. ,fit, Tetrahedron Lett.
(1987}, 2$,, 5093].
Intermediates Ai''(L1)~L2 are either known compounds or may be prepared from known starting materials by methods analogous to (hose used for the preparation of fihe known compounds. Thus, for example, where it is desired to obtain a compound Ar'(L1 )nL2 where L~ is a halogen atom such as bromine or chlorine atom and this compound is not readily available, such a compound may be prepared by diazotisation of the corresponding amine using for example a nitrite such as sodium nitrite in an aqueous acid at a low temperature foAowed by reaction with an appropriate copper (I) halide in an aqueous acid.
Intermediates of formula (12) may be prepared by halogen-metal exchange with a base such as n-butyl or t-butyllithium followed by reaction with a borate such as trilsopropylborate or a tin reagent (R~5)sSnHal, where R is as described above and Hal is a halogen atom, such as chlorine atom, optionally at a low temperature e.g. around -70~C, in a solvent such as tetrahydrofuran.
In another example of a process according to the invention, a compound of,formula (1).where one or both of R4 and Rs is a group -(CH2~ArLjAr' where Lt is -X~(Atks)t- may be prepared by reacting a compound of formula (i2) where Z' is as defined for Z in formula (1}, except that one or both of Rø and R5 is a group -(CHa}tArXBH with a reagent Ar'(Rlk$}tL2, where L2 is a leaving group, as described above.
The reaction n;ay be performed in the presence of a base, for example triethylamine or potassium tart-butoxide, in a solvent such as dichloro-methane or tetrahydrofuran, at a suitable temperature, e.g. room temperature.
According to a further aspect of the inven#ion, compounds of formula (1 }
where L is a group -CH(R1)(R~) where R2 is a -C02R8 or -CONR9Rto group may be prepared by reacting a compound of formula (13) W095/35281 ~ ~ ~f ~ v:r~, ~ PCTIGB95101459 G(O)Hal W
a (13) where Hal is a halogen atom, such as a chlorine or a bromine atom, with a diazoalkane CH(R~)N2 fiollowed by reaction with R80H or R9R»NH in the presence of silver oxide or a silver salt optionally in the presence of a base.
intermediates of formula (13) may be prepared by oxidation of an intermediate of formula (3) where R1 y is a hydrogen atom, using an oxidising agent, such as permanganate or chromic acid, to give the corresponding carboxylic acid which is then reacted with a halide reagent, such as thionylchloride, phosphorous pentachloride or phosphorous pentabromide.
According to another aspect of the invention, a compound of formula (1) where L is a group -XR, R3 is a hydroxyl group and R7 is a hydrogen atom may be prepared by reaction of an intermediate of formula (10) with an organometallic reagent RSR6CHM, where M is a metal atom.
Metal atoms represented by M include, for example, a lithium atom.
The reaction may be performed in a solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, at a low temperature, e.g. around -70aC to ambient temperature. This reaction is particularly suitable for the preparation of compounds of formula (1) wherein R5 is an electron deficient group such as a 2- or 4-pyridyi group.
In another process according to the invention compounds ofi formula (1) wherein W is =N- and R~ is a hydroxyl group may be prepared by reacting a compound of formula (14}
~i'0 95135281 PCTfGB95101~t59 ( ~7 ri ~!._~, ~
N L
CHpR4 (14) or its N-oxide ' with a reagent R5C(O)Rs using the conditions described herein for the preparation of a compound of formula (1) from an intermediate of formula ( 10).
N-oxides of compounds of formula (14) may be prepared by reacting a compound of formula (14) with a hydrogen peroxide or a peroxyacid, e.g.
peracetic acid, peroxymonophthalic acid, krifiuoroacetkc acid or metachloroperbenzoic acid in carboxyUc acid solution, e.g. acetic acid, a halogenated solvent, e.g. dichloromethane or an ether such as tetrahydrofuran. It is to be understood that in this case the compound of formula (1) wauid be obtained as kts fV-oxide.
Reagents R5G(O)RB are known compounds or may be prepared in a manner similar to the preparation of the known compounds.
Intermediates of formula (14) may be prepared by reacting a halide of formula (15) N Hal CH~R4 (15) where Hal is a halogen atom, e.g. a bromine, chlorine or iodine atom with a compound RXH, where X is -O-, -S- or -NH- in the presence of a base.
Bases used in this reaction include hydrides, such as sodium hydride, or an organometallic base, such as butyilithium in a soluent, such as an WO 95135281 ~ ~ w ~ ~ ~ a ~ PCTIGB95101459 amide, for example dimethylformamide at a temperature from room temperature to above, e.g. 80~C.
Intermediates of formula (15) may be prepared by reacting the 5 commercially available amine of formula (16) ~N NHz CH2R4 (16}
with nitrous acid (made in situ by reacting sodium nitrite with an acid, for 10 example sulphuric acid or hydrobromic acid) to produce the diazonium salt. This in turn may be reacted with a haloacid, e.g. hydrobromic, hydrochloride or hydriodic acid if necessary in the presence of the corresponding copper (I) halide (CuBr or Cu I) or halogen e.g. Br2, CI2 or 12.
i5 Compounds of formula (1) may be prepared by interconversion of another compound of formula (1). For example, a compound of formula (i) where L is a -CH2-CH(Rt}(R2} group may be prepared by hydrogenation of a compound of formula (1) where L is a -CH=C(Rt}(R2) group. The 20 hydrogenation may be performed using for example hydrogen in the presence of a cataylst. Suitable catalysts include metals such as platinum or palladium optionally supported on an inert carrier such as carbon or calcium carbonate; nickel, e.g. Raney nickel, or rhodium. The reaction may be performed in a suitable solvent, for example an alcohol such as 25 methanol or ethancl, an ether such as tetrahydrofuran or diaxane, or an ester such as ethyl acetate, optionally in the presence of a base, for example a tertiary organic base such as triethylamine, at for example ambient temperature.
30 Alternatively, the reaction may be accomplished by transfer hydrogenation using an organic hydrogen donor and a transfer agent. Suitable hydrogen donors include for example acids, such as formic acid, .formates, e.g.
R'05~5/35281 '"~ ~ ( '"~ ~' < PCTlGB95lO1d59 G. t~ 4 .a ammonium formats, alcohois, such as benzyi. afcohof or ethylene glycol, hydrazine, and cycloalkenes such as cyciohexene or cyclohexadiene. The transfer agent may be for example a transition metal, far example palladium or platinum, optionally supported on an inert carrier as discussed above, nickel, e.g. Raney nickel, ruthenium, e.g. tris (triphenylphosphine) ruthenium chloride or copper. The reaction may generally be performed at an ambient or elevated temperature, optionally in the presence of a solvent, for example an alcohol such as ethanol or an acid such as acetic acid.
The same hydrogenation or transfer hydrogenation reagents and conditions may be used to also interconvert (a) compounds of formula (1) where L is a -XR group and Z is a group (13) to compounds of formula (1) where L is a -XR group and Z is a group (A) where R3 and R~ is each a hydrogen atom; and (b) compounds of formula (1). where a NO~ group is present as a substituent on an Ar or Ar' group to compounds of formula (1 ) where a Nli2 group is present as a substituent on an Ar or Ar' group.
In another example of an interconversion process, compounds of formula (1) where Z is a group (A) in which R~ is an ORS group where R~ is an alkyl ar alkenyl group, may be prepared by reacting a compound of formula (1) where Z is a group (A) in which R7 is a -ON group, with a reagent R~-OH, in the presence of an acid, such as sulphuric acid.
In yet another example of an interconversion process, compounds of formula (i ) where Z is a group (A) in which R~ is an ORS group where R~
is a carboxamido or thiocarboxamido group may be prepared by reaction of a compound of formula (1) where Z is a group (A) in which R~ is a -ON
group, with an isocyanate RAN=C=O or an isothiocyanate R~N~=S in the presence of a base, such as sodium hydride, in a solvent, such as tetrahydrofurah. Compounds RAN=C=O and RAN=C=S are known compounds or may be prepared using the reagents and conditions used for the preparation of the known compounds. UVhen RAN=C=S is not available, a compound of formula (1) where R~ is a thiocarboxamido group may be prepared by interconverting a compound of formula (1) where R~
is a carboxamido group using a thiation reagent, such as Lawesson's wo vsr~szai rc~rtcavsro~asv r3 ~~ /
!~
i i.. I~..O 'Y J
reagent [2,4-bis(4-methoxyphenyl)-1,3,2_,4-dithiadiphosphetane-..2,4-di-sulphide], in an aromatic solvent, such as xylene or toluene.
In a still further example of an interconversion process, a compound of formula (1) where Z is a group (A) in which R3 is a fluorine atom may be prepared by reacting a compound of formula (1) where Z is a group (A) in which R3 is a hydroxyl group, with a fluorinating reagent, such as diethylaminosulphur trifluoride (DAST), in a solvent, for example a chlorinated solvent, e.g. dichloromethane, at a low temperature, e.g.
around OoC.
In a still further example of an interconversion process, a compound of formula (1) where Z is a group (A) in which R3 is an alkyl group, may be prepared by alkylation of a compound of formula (1 ) where Z is a group (A), and R3 is a hydrogen atom, with a reagent R3L~ using a base, for example n-butyllithium or lithium diisopropylamide. In this process, Ra in the starting material is preferably an electron withdrawing group.
A compound of formula (1) where L is a group -CH(R~)(R2) may also be prepared by interconversion of a compound of formula (1) where L is a -CH(R1)COpH group. For example, a compound of formula {1) where L is a group -CH(R~)CONR9R~e, may be prepared by reacting a compound of formula (1) where L is a group -CH{R~}CO2H (or an active derivative thereof, such as a -CH(R~ )C(O)Hal group) with an amine R9R~oNH using standard conditions.
In another example of an interconversion process, a compound of formula (i) where L is a group -CH(Rt)(R2) where R2 is a nitrite group may be prepared (a) by dehydrogenating the corresponding compound of formula { 1 ) where L is a group -GH(R~ )CH2NH2 using for example nickel peroxide;
or (b) by reacting the corresponding aldehyde [obtained by reduction of a compound of formula (i) where L is a group -CH{R~)C02H] using (i) Li in MeNH2 or NH3 followed by pyridinium chlorochromate; or (ii) borane-Me2S
followed by pyridinium chlarochramate, with hydroxylamine hydrochloride, in a solvent, such as an amine, for example an aromatic amine, e.g.
wo 9sr~szs~ rcTrcs~srows~
7~~;r,.2<,n~
t... 1 I f.. C.. T
s pyridine, followed by treatment with an acid, such as formic acid or hydrochloric acid.
According to a further fnterconversion process, a compound of formula (1 ) where Z is the group (B) may be prepared by dehydration of a corresponding compound of formula (1) where Z is a group (A) where R3 or R~ is a hydroxyl group using an acid- or base-catalysed elimination.
Suitable acids )nclude for example phosphoric or sulphonic acids, e.g. 4-toluenesulphonfc acid. The reaction may be performed in an inert organic solvent, for example a hydrocarbon such as toluene, at an elevated temperature, for example the refiux temperature. Base-catalysed elimination may be performed using for example trffluoroacetic anhydride in the presence of an organic base such as trfethylamine at a law 75 temperature, e.g. from around OflG to ambient temperature, in a solvent such as dichtoromethane or tetrahydrofuran.
In yet another example of an interconversion process, a compound of formula (1) where Ar or Ar' is substituted by an amIdo, e.g. aeetamido, or alkyl amfnosulphonylamino e.g. dimethyiamlnosulphonyiamina group may be prepared by reacting a compound of formula (l) wherein Ar or Ar' is substituted by an amino group using an anhydride. e.g. acetic anhydride, or a sulphamoyt halide, e.g. dimethyisulphamoyl chloride, in a solvent e.g.
an amine such as pyridine, at room tempera#ure.
In a still further example of an interconversicn process, a compound of formula (1) where Ar or Ar' is substituted by an alkylsulphonylamino, e.g.
methyfsulphonytamino group, may be prepared by reacting a compound of formula (1) where Ar or Ar' is substituted by an amino group with an alkylsulphonylhalide, e.g. methanesulphonylchlorfde, in the presence of a base, e.g a tertiary amine such as triethylamine or N-methylmorpholine, in a solvent, e.g. a halogenated solvent such as dichloromethane.
N-oxides of compounds of formula (l ) may be prepared for example by oxidation of th~ corresponding nitrogen bass using an oxidising agent such as hydrogen peroxide fn the presence of an acid such as acetic acid, WO 95135281 ~ PCTIGB95101d59 rl,,~,,~~
~~w~~~~
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.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) 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.
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.
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 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 Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
The following Examples illustrate the invention. In the Examples, the following abbreviations are used:DME - ethylene glycol dimethyl ether;
THF - tetrahydrofuran; CH2GI2 _ dichloromethane; Et20 - diethyl ether;
EtOH - ethanol; RT - room temperature; DMF - N, N-dimethyl-formamide; EtOAc - ethyl acetate; DMPU - 1,3-dimethyl-3,4,5,6-tetrahydro-2(i H)pyrimidinone; BuLi - butyllithium.
WO 95/35281 ~ ~ , r ~ ~ PCTIGB95101459 ~ 1 :~E_a.:4.~
INTERMEDIATE l 5-Bromo-2-methoxvohenol The title com a~ was prepared as described in International Patent 5 Specification No. WO 93/10118.
4-Bromo-2-cyclo er rio~ranisots The title com~und was prepared as described in International Patent 10 Specification No. WO 94/i0118.
j4-Bromo~n~r[~,(, cvcioa en ricer-4-methoxvahenvl)ketone The title compynd was prepared as described in International Patent 15 Specification No. WO 94/14742.
4-[2=(4-Bromo~ i~(3-cyc~J~rJ,g,~v-4-methoxyhhenvi)-2-hv dr roxyeth~jpyridine 20 The title compound was prepared as described in International Patent Specification No. WO 94/14742.
(E) and lZl isomers of 4d2-f r opheny~ 2 f3 cyctooentyloxy-4-25 metha3nyahsrtvitethenvij~yridine The title com o~un~d was prepared as described in International Patent Specification No. WO 94/14742.
30 Acvi Sultam (l W 4 95/35281 , ~ ,~ ,. , q .~ PCTIGB95I01459 ~~ ~ ~" ~~ i~ Lt ~
The sultam was synthesised as described in our International Patent Application No. PCT/GB 94102799.
tNTERMED1ATE 7 (1R.55rN-((3Ry.~4-Benryloxy!~ h~ enviL3~3-cvclopent,~ox,L
methoxvohenvll-2-f4-oyridvl]~ropanoyi]_10.10-dimethvi-3-thia-4-azatricvloj5.2.i .0~]decane-3.3-dioxide OMe ~O /
N
O / O N
OzS
A solution of 4-bromobenzyloxybenzene (22.3g, 84.9mmol, 2.2 equiv) in THF (100m1) was addad to magnesium turnings (2.448, 101.9mmol, 2.6 equiv) in THF (10m1) containing 1,2-dibromaethane (2 drops) and the mixture heated to reflux for 0.5h. The cooled solution was added dropwise at -40~C to a solution of Intermediate 6 (20.688, 38.6mmol) in THF-Et20 (1:5; 600m1) and the mixture allowed to warm to -10~C over 4h.
Ammonium chloride solution (10°!°; 150m1) and EtOAc (300m1) were W 0 95!3528 i ! ~ ! t . ~ ~ F~ PC1'lGB95l01459 ,~ f. 4,.Y .~
added and the organic layer was separated and combined with further EtOAC portions (3xi00ml). The extract was dried (MgS04) and concentrated ~n vacuo and the yellow residue recrystallised from EtOH to afford the title compound {17.93g) as a pale yellow solid. 8H (CDC13}
0.69 (3H, s, ~jeCMe), 0.87 (3H, s, MeCN~e), 7.15-1.35 (2H, br m), 1.4-1.5 (1 H, br m), 1:5-2.0 (12H, br m), 3.31 (1 H, d, ,~ 13.8Hz, C~S02), 3.44 (1 H, d, ,) 13.8Hz, C,f/fi02), 3.65-3.75 (1H, m, NC,~), 4.57 (1H, d, ,j 11.5Hz, C~[CHO), 4.58 (1 H, br m, OCJj), 4.95-5.1 {3H, m, OCj~ + CHC~,CO), 8.55-6.fi5 (3H; m, Cue), 6.86 {2H, fig,' d, ,) 8.7Hz, 2xArf-~ ortho to benzyloxy), 7.25-7.45 {9H, m, C~5+ pyridine j~, ,(js + 2xArl~- meta to benzytoxy), and 8.37 {2H, dd, ~, 4.5, l.5Hz, pyridine H_2, J~).
(R)-4-.L2-f3-CyS~gpentyi~-4-methoovohenVi) 2 f4 hydroxv! nvl ethyilpyrridine A mixture of the compound of Example 3 (9.35g, 19.5mmol), cyclohexadiene (25m1, i95mmol}, and 10°k PdlC (1.0g) in EtOH {300m1) was heated to reflux for 2h. The reaction mixture was filtered through Celite~ and the filtrate and washings concentrated in vacuo to afford the title compound {7.6g) as a white foam; 8~ (CDCI3) i.4-1.9 (1H, br m, {CH2)4}, 3.2-3.35 (2H, m, CHC -~I ), 3.79 (3H, s, O,p~s), 4.05 {1 H, ~. t, I
~ 7.8Hz CjjCH2), 4.65 (i H, br m, OCR, 6.6-6.8 {5H, m, C H~ + 2xArH
ortho to OH), 6.9 - 7.0 {4H, m, pyridine ~t , Hs + 2xAri"j, to OH) and 8.36 (2H, ~, d, ~"g~ 4.5Hz pyridine _H2, ~).
4-Methvl-&Byridinecarbo~irje~yrdg n-BuLi (1.6M in hexanes) {2.2mmol, 1.37m() was added dropwise to a stirred solution of N,N,N'-trimethylethylenediamine (2.4mmol, 0.245g) in THF at -78~C. A solution of 3-pyridinecarboxatiiehyde {2mmol, 0.214g) in THF was added and the mixture stirred for i 5min before adding a further portion of n-Butt (i.6M in hexanes) (4mmol, 2.5mt). After stirring for 2h of -70~C, iodomethane was added, the mixture stirred at RT for 30min, then poured into aqueous NaCt solution, extracted twice with Et20, dried WO 95135281 ~ ~ ~j ~i ~ ~~ ,~ , PCTIGB95l01459 r (MgS04), filtered and concentrated in vacuo. The residue was subjected to chromatography (Si02; Et2O) to afford the title com op and as an oil.
(4-Methvl-3-phen le~)ri~ridine Benzyltriphenylphosphonium bromide (mixture with sodium amide) (99mmol, 4.96g) was dissolved in THF at RT and stirred for 30min. A red solution was obtained. Intermediate 9 (8.3mmol, 1g) in solution in THF
was added, the reaction mixture stirred for 16h then poured into aqueous i0 NaHC03 solution, extracted twice with CHpCl2, dried (MgS04), filtered and concentrated in vacuo. The residue was subjected to chromatography (Si02;Et20) to afford the title com oya and (1.5g) as an oily compound.
(4-Methyl-3-~gpygthlr~g idine A stirred solution of Intermediate 10 (1.8g) in EtOH was hydrogenated using H2-Pd/C for 16h. The title com odd was obtained as an oil.
3-Cvclopentyloxv-4-methoxv6enzaldehvde_ The title com ound was prepared as described in International Patent Specification No. WO 94/20455.
2-Bromo-4-methvl~yridine To an aqueous solution of 48°~ HBr (56.55m1, 520.64mmol) was slowly added 2-amino-4-methyipyridine (i0g, 92.47mmol) at below -5~C.
Bromine (14m!, 274mmol) was then added dropwise whilst maintaining the temperature below OQC, followed by careful addition of a solution of sodium nitrite (17.5g, 254mmoi) in water (20m1) to keep the temperature below 5~C. After stirring for ihr, a solution of NaOH (37g, 940mmol) in H20 (50m1) was added at a temperature below 25~C. The reaction mixture was extracted with Et20 (3x75m1), the combined layer was washed (brine), dried (MgS04) then evaporated to dryness to give a crude oil. Flash chromatography (Si02;hexanelEt20, 50:50) afforded the l la W09~I35281 ' t ~ ""~~ '~ i'~, ~' ' PCT/GB9'SIOid59 f cam o~und (10.2g) as a yellow ail. 8H (CDC13) 2.45 (3H, s, ArClda), 7.00 (1H, d, pyridine ijs), 7.25 (1H, s, pyridine ~), and 8.15 {iH, d, pyridine Ns). m/g 172 M + 1 ), 174 (M + 1 ).
2-Cycio n toxlr-4-methy~yridin~
To a cold (OaC) suspension of sodium hydride (2g, 50mmol) in DMF
(20m1) was added dropwise cyclopentanol (4.99mi, 55mmai) and the solution allowed to warm to RT and stirred for 1 hr. Intermediate 13 (8.fig, 49.67mmol) was added dropwise and the reaction mixture heated at 80~C
for 2hr. After coating, Hp0 {100mi) was added, the mixture extracted into Et20 (3x100mi), washed {brine), dried (MgSO4) then evaporated to dryness to give an orange oil. Chromatography (SiO2; hexanelEt2O, 50:50) afforded the title com op and (7.5g) as an orange oil. m/~ 179 (M +
1 ). &H (CDCl3} 1.5-2.0 (8H, m, (CH2)4), 2.25 (3H, s, C_H3), 5.35 (1 H, m, OCi~- ), 6.45 (1 N, s, pyridine )~), 6.65 (1 H, d, pyridine )~), and 7.96 (1 H, d, PYridine ,fig).
EXAMPt.E 1 a) ~j~ and )isomers of 4-~'[2-f3-C3~lopentvloxy-4-methaxv-phenyt)-2-r4-l4-trifltlorom~thy henvi'G ha envllethenvf~mrridine A mixture of Intermediate 5 (500mg, l.immol) and tetrakis (triphenyi-phosphine) palladium in DME (20m1} was allowed to stir at RT far 0.5h.
Sodium carbonate solution (2~ 1.5m1, 3.Ommo1) and 4-trifiuoromethyiphenylboronic acid (190mg, l.Ommat) Was added and the reaction mixture heated to refiux for 18h. The mixture was cooled, partitioned between water (10m1} and EtOAc (20mi), and the organic layer separated and combined with further EtOAc portions {2x10mI). The extract was washed with brine (l5mi), dried (MgSO4}, and concentrated in vacuo to give a pals brown oil. The residue was subjected to chromatography (SiO2; EtOAc-hexane, 1:1 ) to afford the tifle com ound {410mg) as a colourless oil. EH (CDCI3) 1.5-2.0 (8H, br m, (C_Nz)a). 3.86 and 3.89 {3H, s, O)~],e), 4.57 and 4.70 (iH, br m; OCJ~, 6.ii-7.8 (14H, m, 2xCeH_4 + C6H_3 +pyridine ,~, ~+ C=Cjj), and 8.3-8.45 (2H, m, pyridine H_2, I-~s).
W0951352$I , f , PCT/GB95/01459 I~ .'~ ~l "'~ .
The following compound was prepared in a similar manner to the compound of Example 1a}.
b) (~ and Qj~ isomers of 4-I2-t3-f~rclo .2en~t rl~-4-methoxy-5 phenvll-2-f4'-methvl-4-biohenvl)ethenvi~rridine From tntermediate 5 (0.408, 0.89mmol), tetrakis (triphenylphosphine) palladium (0.05ig, 0.045mmoi) in DME (20m1), sodium carbonate solution (2~,, 1.49m1, 2.7mmo1) and 4-methylbenzeneboronic acid (0.1151g, 0.846mmo1). Chromatography (Si02; EtOAc-hexane, 1:1 ) afforded the 10 title compound (0.311g). 8H (CDGI3) 1.25 (1H, t), 1.5-1.75 (6H, m), 1.85 (2H, s), 2.4 (3H, s), 3.95 (3H, s}, 6.4-6.9 (5H, m), 7.2-7.3 (3H, m), 7.5 (iH, m), 7.55-7.6 (3H, m), and 8.4 (2H, m).
15 a) (t -4-f~2-(3-Cy~loy en rloxy-4-methoxyoheny~-2-[4-(4-trifluoro methyl ~hepyltoheny I~ ethyliiovridinium farmate A mixture of the compound of Example 1 (380mg) and 10°f°
Pd/C (50mg}
in fomlic acid (5m1} and EtOH (35m1} was heated to reflux for 3h. The reaction mixture was filtered through Celite~ and concentrated in vacuo to 20 give a yellow oil which was subjected to chromatography (Si02; EtOAc-hexane, 1:1} to afford the title compound, (190mg) as a pale yellow solid.
8H (GDCi3) i.5-1.95 (8H, br m, (Cji_z)4), 3.57 (2H, d, ~ 7.9Hz, CHCj~), 3.80 (3H, s, O,~te), 4.24 (1 H, t, ,~ 7.9Hz, CFiCHp), 4.68 (1 H, br m, OCR), 6.65-6.75 (2H, m, 2xArjj to OMe), 6.78 (1 H, d, ,j, 8.1 Hz, ArH ortho to 25 OMe), 7.29 (2H, d, ,~ 8.2Hz, 2xArfj meta to GF3), 7.41 (2H, d, ,( 5.6Hz, pyridine ,~,j~), 7.53 (2H, d, 2xArjj ortho to CF3), 7.63 (2H, d, ,~ 8.8Hz, 2xArH of C6H4CF3}, 7.67 (2H, d, ,~ 8.8Hz, 2xAr~ of C6H4CF3), and 8.62 (2H, br d, ,),~ 5Hz, pyridine j~, H6}; ~~ (El) 517 (M+, 8%), 426 (15), 425 (48), 358 (20}, 357 (100), 296 (22), and 69 (28}.
The following compound was prepared in a manner similar to the compound of Example 2a).
b) t~ji-4-(2-r(3-Cy~~yioxy-4-methoxvuheny~-2-t4'-meth b heny~ethytleyridine WO 95!35281 PCTIGB95101459 i"f...ti~r._ 4&
From the compound of F~cample 1b) {0.311g, 0.673mmot) in 10°!° formic acid in EtOH (35mi) and 10°l° Pd/C. Purification by HPLC (60-80°!°
acetonitrile-water) afforded the title com odd (023g). &H (MeOH) 1.5-1.75 (9H, m), 2.3 (3H, s), 3.3 (2H, dd), 3.5 (2H, d), 3.65 (3H, s), 4.3 (1H, t), 6.8 {3H, d}, 7.2 (2H, d), 7.3 {2H, d), 7.35 (2H, d), 7.45 (2H, d), and 8.5 (2H, m). py~ (ES+) 464.2 {M+H~).
F~CAMPLE 3 (~1~4 [~f4-Benzyloxylohenvll 2d3 ~vclo~n yloxv 4-methoxv hp envil-ethyl]~~ rlr dine ~-BuLi (1.6~ solution in hexane} (27m1, 43.Ommol, 1.5 equiv) was added dropwise to a solution of ethanethiol {10.6m1, 14.3mmol, 5 equiv) in THF
(300m1) at ~ -10~C. After 0.5h, a solution of Intermediate 7 (20.6g, 28.7mmoi) in THF (204m1) was added dropwise and the reaction mixture allowed to stir at RT for 12.5h. Water {!0m!) was added and the solvent removed ~n vacuo. The residual fioam was dissolved in EtOH (100m1) and aqueous sodium hydroxide (2A~1; 200m1) and the mixture heated to reftux for 1h. The reaction mixture was cooled to ~ 50~C and treated with concentrated hydrochloric acid (37mi) to pH 5 then heated to reflux for 0.75h. The organic solvents were removed in vacuo and the residue partitioned between aqueous NaOH solution (1.0~,; 400m1) and EtzO
(~OOmI). The organic layer was separated, combined with further Et20 volumes (3x100m1), and the extract washed with aqueous NaOH solution (1.0M 2x100m1), then dried {MgS04), and concentrated in vacuo. The residual pale yellow gum was subjected to -chromatography (Si02;
hexane-Et20, 7:3 to 100°I° Et20} to afford the title com ound {9.35g) as a white solid {Found: C, 79.76; H, 6.98; N, 2.62. C32H33N03. requires C, 79.63; H, 7.i1; N, 3.00°~); 8H (CDCI3) 1.5.2.1 {8H, br m, {CH2)4), 3.27 (2H, d, ,). 7.8 Hz, CHC,~}, 3.79 {3H, s, OMe}, 4.09 (1H, t, ,~ 7.8Hz, C,)=[CH2), 4.63 {1 H, br m, OCj~, 5.02 (2H, s, OG~), 6.64 (l H, d, ,~ 2.OHz, ArH_ ortho to cyclopentytoxy}, 6.67 (iH, dd, ~ 8.2, 2.OHz, Ar~to cyclopentyloxy), 6.74 (1 H, d, ,~ 8.2Hz, Arjj ~g to OMe), 6.87 (2H, ca. d, ,~ ~ 8.6Hz, 2xAr~ ortho to benzyloxy), 8.91 (2H, ~ d, ,~ ~ 4.5Hz, pyridine j~, Lie}, 7.08 (2H, ~,, d ,,~,~ 8.8Hz, 2xArH meta to benzyloxy), 7.3-7.5 (5H, m, CsljS}, and 8.38 (2H, dd, ~ 4.5, 1.SHz, pyridine F~, J~).
1 1'j ~ r.., ~ ~i 4 ~ e.. ;.l r ...' (R1-4-t2-(3-Cvclonenhrloxy-4-methoxvPhenyl)-2 [4 f4 nitraphenvio~cv) Ahenvl]ethylJ;~,yridine Potassium ~.-butoxide (258mg, 2.19mmol) was added to a solution of Intermediate 8 (710mg, 1.83mmol) in DMF (25m1) and DMPU (lOml) and the mixture stirred at RT. After 0.5h, 4-bromanitrobenzene (553mg, 2.74mmol) was added and the solution stirred overnight at RT. Water (100m1) and aqueous sodium hydroxide solution (2M 20m1) was added and the mixture extracted with Et2O (3x150m1). The extract was washed with aqueous sodium hydroxide solution (1M 2x30m1), water (2x100m1j, and brine (i00mI), then dried (MgS04), and concentrated in vacuo. The yellow residue was subjected to chromatography (Si02; Et20) to afford the title com ound (729mg) as a pale yellow solid; 8~ (CDCI3) 1.5-1.9 (8H, br m, (Cjj2)4), 3.32 (2H, d, ,) 7.9 Hz, CHCHz), 3.81 (3H, s, OMe), 4.18 (1 H, t, ~ 7.9Hz, CHCH2), 4.67 (iH, br m, OCj~,}, 6.66 (1H, d, I 2.OHz, ArH ortho to cyclopentyloxy), 6.71 (1 H, dd, ,~ 8.2, 2.OHz, ArH g~ to cyclopentyloxy), 6.77 (1 H, d, ,~ 8.2Hz, Arjj ortho to OMe), 6.9-7.05 (tiH, m, CHCs,~i4 f pyridine 1-~, )~, 7.2-7.3 (2H, m, Arl-~ meta to N02), 8.15-8.25 (2H, m, Arjj ortho to N02), and 8.42 (2H, dd, ,~ 4.5, l.6Hz, pyridine H_2, _H~).
(E) and Zt isomers of 4 !2 (3 Cvcmnantvloxv-4-methoxlq henvt)-ethenvl]-3-(phenylethyl)y rir dine A catalytic amount of tosic acid was added to a solution of compound of Example 10a) (1.8g, 4.32mmol) in toluene (150mI) and the mixture heated to reflux in a Dean Starfc equipment for 8h. The reaction was cooled, poured into aqueous NaHC03 solution and extracted twice with CH2Cl2.
The combined organic phase was dried (MgS04), filtered then concentrated in vacuo. The residue was subjected to chromatography to give the title comb a nd (1.3g) as a yellow solid. m.p. 78-80~C. (Found C, 81.44; H, 7.35; N, 3.62. C27H29N02 requires C, 81.17; H, 7.32; N, 3.51 °1°). 8H (CDCI3) 1.6-2.0 (8H, br m, (CH_2)4), 2.9-3.1 (4H, m, Ar(C~)2), 3.81 (3H, s, OC/~), 4.85 (1H, s, OCJ~, 6.9-7.4 (9H, m, ArH
and CH=Cue, 7.37 (1 H, d, ,) 8Hz, ArH), 8.37 (1 H, s, _H2 pyridine) and 8.42 (1 H, d, ~j 5Hz, ,~ pyridine).
WO 95!35281 ,~ -~ r ~ PCT/GB95f0145g j 1~ tJ ~r EXAMPLE B
4-f -f - y~loixentvloxv-4-metho~rt~henylj~ethyi]-3-(nhenvlethvl) ri in The compound of Example 5 (SOOm,g, 2mmol) was hydrogenated using the reagents and conditions described for obtaining Intermediate 11 from Intermediate 10. Purification by chromatography (Si20; Et20) gave the title compound {605mg) as a colourless gum. (Found C, 80.82; H, 7.77;
N, 3.54. C27N3tNO2 requires C, 80.76; H, 7.78; N, 3.49°~). 8H
{CDCI3}
1.5-1.9 (8H, m, (C,f~)4), 3.27-3.29 (8H, m, alkyl H}, 3.81 (3H, s, OCR), 4.67 (1 H, m, OCI~-,), 6.59 {l H, br s, ArH), 6.66 {1 H, d, ,)r 7Hz, ArH}, 6.78 (1 H, d, ,j. 7Hz, ArH), 7.03 (1 H, d, ~, SHz, _H5 pyridine}, 7.1-7.4 (5H, m, Cue), and 8.3-8.4 {2H, m, H2, I-~ pyridine).
i5 ~[2-(S1-r4-f4-Aminol~henyri~)hhenvll-2-f3-cvciopentytoxv-4-methoxvnhenyl)ethy[j~yrridine dihyrdrochforfde A stirred solution of the compound of Example 4 (800mg, 1.46mmol) in EtOH (100m1) was hydrogenated with 10°k Pd/C (100mg) under a hydrogen atmosphere for 24h at RT. The reaction mixture was filtered through Cefrts~ and the filtrate concentrated err vacuo to afford a yellow brown glass which was partitioned between aqueous 1 M NaOH and EtOAc. The combined organic phase was dried (Na2S0~) then concentrated in vacuo to give an oily solid. Chromatography (Si02;
EtOAc-Et2O, 1:1) afforded the title compgund free base (384.9mg) as a near white solid. iiH (C~Cl3) 1.50-1.90 (8H, br m), 3.27 (2H, d, ,~ 7.9Hz), 3.79 (3H, s), 4.10 {1 H, t, ,) 7.9Hz), 4.65 {1 H, br m), 6.63-6.69 (4M, m), 6.75 (1 H, d, ,~ 8.2tiz), 6.80-6.85 (4H, m), 6.93 (2H, dd, ,} 4.5, l.SHz), 7.09 (2H, dd, ~. 6.5, 2.OHz), and 8.38 (2H, dd, ,~ 7.4, 1.SHz).
The free base {384.9mg, 0.801mmol) in Ef20 (50m1) was treated with 1.0M HCI in Ei20 (1.76m1) at RT. The resulting oily precipitate was dissolved by the addition of EtOH and the solvent removed in vacuo. The residue was suspended in Et20 and the solvent removed irt vacuo to give a very pale::buff solid. Recrystallisation (THF-EtOH) afforded the '~I , compound as a very pale buff highly hygrascopic solid. 8H (CD3ODj 1.5-1.9 {8H, m), 3.72 (2H, m (overlap)), 3.76 (3H, s), 4.46 (iH, t, ,~ 8.2Hz}, W0 95J3528t PCTJGB95J01459 "t f'~ '7 ~', '~ ~' ,1 _. . : r.. ~~
4.75 (1 H, m), 6.81 (1 H, s), 6.84 (1 H, s), 6.85 (1 H, s), 6.97 (2H, dd, ,~
6.6, 2.OHz), 7.06 (2H, dd, ~ 6.75, 2.3Hz), 7.30-7.40 (4H, m), 7.87 (2H, d, I
6.6Hz) and 8.634 (2H, d, ,) 6.45Hz). Lp/~ (EI+) 480 (M+).
EXAMPLE $
a) 4-f2-lS)-f4-l4-Acetamidouheny~,xy])~~-2-(3_cvctooentvl wzaL-4-methoxyt~henyl]~y~,j~yri ine hydrochloride A solution of the free base of compound of Example 7 (322mg, 0.67mmo1}
in pyridine (l0mi) was heated with acetic anhydride (1261) and the mixture stirred at RT far 24h. The solvent was removed in vacuo, the residue azeotroped twice with toluene and partitioned between aqueous NaOH (pH 13) and EtOAc. The aqueous layer was further extracted with EtOAc and the combined organic layer dried (Na2S04) then concentrated in vacuo to give an off-white glass. Chromatography (Si02; EtOAc) afforded the title compound free base (303.6mg} as an off-white glass.
Treatment of the free base (303.6mg) in EtOH-Et20 {30m1; 1:2) with 1.0M
HCI in Et20 (0.62m1) as described for the compound of Example 7 followed by the recrystallisation (THF-Et20} afforded the title compound as an off-white amorphous solid (highly hygroscopic). 8H (CD30D) 1.50-1.90 {8H, br m), 2.11 (3H, s), 3.67 (2H, d, ,~ 8.3Hz), 3.76 (3H, s), 4.40 (1 H, t, ,~
8.3Hz), 4.73 (1 H, br m), 6.79 (1 H, s), 6.83 (1 H, s), 6.84 (1 H, s), 6.85-6.95 {4H, m}, 7.28 (2H, d, (fine split), ,~ 8.5Hz), 7.50 (2H, dd, ,f 6.9, 2.3Hz), 7.80 (2H, d, ,j 6.4Hz), and 8.60 (2H, d, ,~ 5.9Hz).
The following compound was prepared in a manner similar to compound of Example 8a).
b) 4-f2-(Sl-l3-Cvcio ert -4-m~thoxvphenyi -2-(~4-N' N' ~iimethvlaminosuinhonvtamino henr~jphenvioxylethvijRvridvi hydrochloride From the compound of Example 7 (250mg, 0.52mmol) in pyridine (15m1) and dimethylsulphamoyl chloride (112p1, 1.04mmol}. Chromatography {Si02; EtOAc-EtpO, 1:2) afforded the title com ound free base (188.1mg) as an off-white glass. 8H {CDGI3) 1.50-1.90 (8H, br m), 2.84 {6H, s), 3.29 (2H, t, ,) 7.9Hz), 3.80 (3H, s}, 4.13 (1H, t, ~ 7.9Hz), 4.66 (1H, br m), 6.68 W095135281 , a .~ PCTICB951014.59 ;.
(1 H, dd, 1 8.2, 2.OHz), 6.76 {1 H, d, ,~ 8.2Hz), 6.80-6.95 (6H, m), 7.14 (2H, d, ,~ 8.6Hz), 7.16 {2H, d, ,~ 8.9Hz), and 8.40 (2H, d, ,) 6.0Hz).
Treatment of the free base {259.img, 0.44mmol) in EtOH-Et2O(40m1, 1:1) with aqueous 1.0M HC1 in Et20 (0.5m1) followed by recrystallisation {1'HF-Et20) afforded the title comQound as an highly hygroscopic off-white solid, tI1li {ES+) M#+H 558. &H (CD3OD) 1.50-1.90 {8H, br m), 2.77 (6H, s), 3.38 {2H, d, ,~ 8.1 Hz), 3.76 {3H, s), 4.26 (1 H, t, ,) 8.1 Hz), 4.70 (1 H, m), 6.74 (1 H, d, ,~ 1.9Hz), 6.75-6.89 (6H, m), 7.10-7.30 (6H, m), and 8.29 (2H, dd, ,~
6, l.SHz).
aminoflhen~rli]bhenvtoxvjethy~~iavridine hvdrachivride A solution of the free base of compound of Example 7 (0.36678, 0.6mmoi) and N-methylmorpholine {284p1, 0.24mmol) in anhydrous GH2CI2 (15m1) was heated with met~,:,vsulphonylchioride (93p1, l.2mmol) and the mixture stirred at RT for 24h. The crude mixture was partitioned between water and EtOAc and the aqueous layer further extracted with EtOAc. The combined organic layer was washed with aqueous 0.5M NaOH and brine, dried (Na2S04) then concentrated in vacuv to give a pale brown glass.
Chromatography (SiOp; E#OAc-Et20, 2:1) afforded the title comaound free base {230m8) as an off-white glassy solid. ~ (CDCl3) 1.50-1.90 (8H, br m), 2.98 {3H, s), 3.29 (2H, d, ,~ 7.9Hz), 3.80 {3H, s), 4.14 (1 H, t, ,~
7.9Hz), 4.68 {1H, m), 6.65 (1H, d,,) 2.0Hz), 6.68 (1H, dd, J 8.2, 2.OHz), 6.77 (1H, d, ,~ 8.2Hz), 6.8-7.0 {6H, m), 7.15 {2H, d, ,~ 8.6Hz), 7.20 (2H, d, ,~ 8.9Hz), and 8.40 (2H, ~d, ,~ 4.5, l.SHz).
The salt was obtained using the procedure described for the compound of Example 7. From a solution of the free bass {224.8m8, 0.4024mmoi) in Et20-EtOH (40mi, 3:1) and aqueous 1.0M HCI in Et20 (0.44m1).
Chromatography {Si02; CHZCI2 -5~ MsOH) afforded a colourless glass which was recrystallised (THF-Et20) to give the Title com! o~ and as a very hygroscopic off-white solid . mid (E1+) 550 (M+).
EXAMPLE iQ
1V0 95!35281 PCTIGB95)OIa59 .~ 1 f~~ "~ ~' ' . ,v~ 1y w c. ; ~ r_ a) 1+14-[2 (8 Cvclooe~t~ioxv-4-mett,o~phenvll 2 hvdroxveth n-BuLi (1.6M in hexanes) (8.03mmol, 5.02m1) was added dropwise to a solution of Intermediate 11 (1.458, 7.3mmol) in THF and the mixture stirred for 30min before adding a solution of Intermediate 12 (1.77g, 8.03mmol) in THF. The mixture was stirred for 30min at -78QC, allowed to warm to RT, poured into aqueous NaHCO3 solution, extracted twice with GH2CI2, dried (MgS04), filtered and concentrated in vacuo. The residue was subjected to chromatography (Si02;EtOAc) to give the title com o~und (2.3g) as an off-white solid.
The following compound was prepared in a manner similar to compound of Example 10 a).
b) IZ-!3-Gvcionentyrio~r-~Srrid-4-y~J~pvrid-4-vl1 ethanol From Intermediate 14 (ig, 5.61mmol) in THF (!0m!) under N2, n-BuLi (i.6M) (3.5m1) pyridine-4-carboxaldehyde (534u1, 5.61mmol). Chroma-tography (Si02; Et20) afforded the title comb aund (550mg) as a yellow oil.
8H (CDCI3) 1.5-2.0 (8H, m, (CH2)4), 2.9 (2H, m, CH_z-CHOH), 4.93 (1 H, t, CjjOH), 5.37 (1 H, m, OCR, 6.51 (1 H, s, pyridine jj'3), 6.65 (1 H, d, pyridine ,bf5), 7.24 (2H, d, pyridine )js, ~), 8.2 (1 H, d, pyridine H'S), and 8.51 (2H, d, pyridine j~, ,~).
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-farmyi-met-leu-phe.
1. Isolated Enzyme The potency and selectivity of the compounds of the invention was determined using distinct PDE isoenzymes as follows:
l. PDE t, rabbit heart ii. PDE il, rabbit heart iii. PDE III, rabbit heart, Jurkat cells iv,. PDE IV, HL60 cells, rabbit brain, rabbit kidney and human recombinant PDE IV
W0 95/35281 PCTlGB95141459 v. PDE V, rabbit sung, guinea pig Lung A gene encoding human PDE IV has been cloned from human monocytes (lavi, at al., 9990, Mofeoular acrd Cellular Biology, ~Q, 2ti7f3]. 1lsing 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 (Beaux and Reifsnyder, 1990, TIPS, ~; 95~. These recombinant enzymes, particularly the human eosinophil recombinant PDE IV, have been used as the basis of a screen fdr potent, selective PDE IV inhibitors.
i5 The enzymes were purified to isoenzyme homogeneity using standard chromatographic techniques.
Phosphodiesterase activity was assayed as follows. The reaction was conducted in 150u1 of standard mixture containing (final conoentrationsj: 50mM 2-[[tris(hydroxymethyljmethyl]amino]-1-ethanesutphonic acid (TESj -NaOH buffer (pH 7.5], iOmM MgCiz, 0.1 pM [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.12~o trifluoroacetic acid containing ["4C]-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 {pHBj. The [3H]-5'-AMP product was eluted with 2mi 2M NaOH into a scintillation via( containing l0ml of scintillation coelctail. Recovery of [3H]-5'AMP was determiried using the [14C]-5'AMP and all assays were conducted in the linear range of tfle reaction.
Compounds according to the invention such as compounds of the Examples herein cause a concentration-dependent inhibition of W4 95135281 ~ ;') '~; ~ ~ ~ PCTIGB95101459 recombinant PDE IV at 0.1 - 1000nM with little or no activity against PDE I, II, III or V at concentrations up to 100p.M.
2. The Elevation of cAMP in Le~lkocvte~
The affect 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.lnM to lp,M.
3., '~naression of Leukocyte Fenction Compounds of the invention were investigated for their effects on superoxide generation, chemotaxis and adhesion of neutrophifs and eosinophils. Isolated leukocytes were incubated with dihydrocyto chalasin B for superoxide generation only and test compound prior to stimulation with FMLP. The mast potent compounds of the Examples caused a concentration-dependent inhibition of superoxide generation, chemotaxis and adhesion at concentrations of 0.1 nM to luM.
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 O.OInM to lOpM.
4. Adverse Effects W09~135E81 °~ ~ f.~'~ !. i ~ QCTlGB9i10145') r_.. f_. ~_i ~r .7 5a In general, in our tests, compounds of the invention have had no observed toxic effects when administered to animals at pharmacoiogicaity effect doses.
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