2024年3月27日发(作者：尹棠华)
Bioorganic&MedicinalChemistryLetters20(2010)346–349
ContentslistsavailableatScienceDirect
Bioorganic&MedicinalChemistryLetters
journalhomepage:/locate/bmcl
2-ArylbenzoxazolesasCETPinhibitors:Substitutionofthebenzoxazolemoiety
a,
*
,AmjadAli
a
,LiyaChen
a
,d
a
,on
b
,YingChen
b
,
d
b
,QiuGuo
b
,
b
,
b
,w
b
,
b
,ir
a
a
b
DepartmentofMedicinalChemistry,MerckResearchLaboratories,RahwayNJ07065,UnitedStates
DepartmentofCardiovascularDiseases,MerckResearchLaboratories,RahwayNJ07065,UnitedStates
articleinfo
abstract
Aseriesof2-arylbenzoxazoleinhibitorsofthecholesterolestertransferprotein(CETP)isdescribed.
Structure–activitystu-
tionatthe5-and7-positionsofthebenzoxazolemoietywasfoundtobebeneficialforCETPinhibition.
Compound47wasfoundtobethemostpotentinhibitorinthisseriesandinhibitedCETPwithanIC
50
of
28nM.
Óhtsreserved.
Articlehistory:
Received26June2009
Revised23October2009
Accepted26October2009
Availableonline29October2009
Keywords:
Cholesterylestertransferprotein
CETP
Highdensitylipoprotein
HDL
Benzoxazole
Coronaryheartdisease(CHD)isnowtheleadingcauseofdeath
edlevelsoflow-density
lipoprotein-cholesterol(LDL-C)hasbeenidentifiedasamajorrisk
elopmentofthestatinshassignificantly
helpedtoreduceLDL-ClevelsinpatientsatriskforCHD.
1,2
There
isnowagrowingbodyofepidemiologicalevidencelinkingin-
creasedlevelsofhighdensitylipoprotein-cholesterol(HDL-C)with
decreasedriskofdevelopmentofCHD.
3–6
Somecholesterollower-
ingdrugs,includingniacin,fibratesandstatins,haveamodestef-
fectonincreasingHDL-Clevels.
7–10
Regardless,niacinremainsthe
frontlinetherapyforraisingHDL-Clevelsdespiteitsmodesteffi-
cacy($20%increase).Consequentlythereisaneedforbetterther-
apiestoaddressthisproblem.
Thebeneficialeffectsofhighdensitylipoprotein(HDL)are
thoughttoarisefromitsparticipationinreversecholesteroltrans-
port(RCT)aswellasitsanti-inflammatoryandanti-oxidantprop-
erties.
11,12
Cholesterylestertransferprotein(CETP)mediatesthe
exchangeofcholesterylester(CE)fromHDLwithtriglyceridespri-
marilyfromverylow-densitylipoprotein(VLDL).
11,12
Inhibitionof
CETPwouldthereforebeexpectedtoincreaseserumHDL-Clevels.
ClinicalstudiesinhumanswiththeCETPinhibitors,dalcetrapib
(JTT-705),
13,14
torcetrapib,
15–19
andanacetrapib
20–22
established
thatpharmacologicalinhibitionofCETPleadstosignificantin-
ethisobservation,imaging
OO
O
NHS
O
F
3
C
O
O
F
3
CCF
3
N
dalcetrapib (JTT-705)
OF
torcetrapib
F
3
C
O
N
O
CF
3
F
3
C
anacetrapib
*.:+;fax:+.
E-mailaddress:cameron_smith@().
0960-894X/$-seefrontmatterÓhtsreserved.
doi:10.1016/.2009.10.099
studieswithtorcetrapibshowedthecompoundhadnoeffecton
theprogressionofatherosclerosis.
23–25
Additionally,thetorcetra-
pibphaseIIItrialwasprematurelyhaltedaftertheobservationof
tal./.20(2010)346–349
347
increasedmortalityinpatientsreceivingtorcetrapibandatorva-
statinrelativetotheatorvastatin-onlygroup.
19
Thisadverseeffect
mayhavebeenrelatedtotheobservationofanincreaseinmean
scur-
rentlysignificantdebateoverwhethertheadverseeffectsobserved
withtorcetrapibwerecausedbymechanismbasedfactorsoroff-
targetactivities.
26–28
Despitetheuncertaintyregardingtheviabil-
ityofCETPinhibitors,thereiscontinuedinterestinthedevelop-
communicationdetailstheidentificationandoptimizationofaser-
iesof2-arylbenzoxazolebasedCETPinhibitors.
InhibitionofCETPmediatedCEtransferwascharacterized
invitrousingafluorescencetransferassay.
29
Theassayusessyn-
theticHDLdonorparticlesthatcontainself-quenchingBODIPYla-
beledCEalongwithanadditionalfl
BODIPYlabeledCEistransferredfromthedonorparticletoan
acceptorlipoproteinbyCETP,fluorescenceisobservedandquanti-
fitionofCETPmediatedCEtransferwascharacterizedby
adecreaseinlevelsoffluorescenceobservedrelativetocontrol.
AhighthroughputscreenofcompoundsintheMerckcollection
at2
l
Musingtheaboveassaywasconductedandhitswerecon-
firmedbytitration.2-Arylbenzoxazole1wasidentifiedasascreen-
adclasswasalsoindependentlyidentifiedby
researchersatBristol–MyersSquibbandpublishedsubsequentto
ourstudies.
30
Theirworkshowedtheimportanceofsubstitution
workdescribedinthispublicationisconsistentwiththatdescribed
byBMS,butalsoshowsthatfurthersubstitutionofthebenzoxaz-
olemoietyatthe7-positionleadstocompoundswithadditional
enhancementofCETPinhibition.
O
O
O
NH
Cl
N
1
Thedevelopmentofleadcompound1beganwiththeinvestiga-
tionoftheeffectofvariationofthesubstitutionofthebenzoxazole
OO
a
O
O
HOCl
34
OO
b
O
NH
HO
2
O
O
c
O
R
NH
NH
OH
6
d
R
O
O
O
or 2
e
NH
N
7
tsandconditions:(a)(COCl)
2
,,CH
2
Cl
2
,room
temperature,1h,quant.;(b)4-aminobenzoicacid,i-Pr
3
NEt,CH
2
Cl
2
,roomtemper-
ature,30min,87%;(c)(i)(COCl)
2
,,CH
2
Cl
2
,roomtemperature,2h;(ii)2-
aminophenolderivative,1,4-dioxane,reflux,2h;(d)PPTS,xylene,
refluxunderDean–Stark,16h,10–53%;(e)2-aminophenolderivative,boricacid,
xylene,reflux,24h,7–37%,ormicrowaveirradiation,270°C,1h,7–33%.
carboxylicacid2wassynthesizedfromphenoxyaceticacid3by
firsttreatingwithoxalylchloridetoformthecorrespondingacid
ngwith4-aminobenzoicacidaffordedcarboxylic
azoleswerethensynthesizedbyoneofthreemeth-
ods.
31
Activationof2asthecorrespondingacidchlorideusingoxa-
lylchloridefollowedbycouplingwitharangeofsubstituted2-
-
tionofamides6inxylenewasheatedatrefluxinaDean–Stark
apparatuswitheitherp-tolenesulfonicacidorpyridiniump-tolu-
enesulfonicacid,toafford2-arylbenzoxazolesofgeneralstructure
atively,asolutionofcarboxylicacid2,a2-aminophenol
andboricacidinxylenecouldbeheatedatrefluxorsubjectedto
microwaveirradiationat270°Ctoaffordthecorresponding2-aryl-
benzoxazole.2-Aminophenolswereeithercommerciallyavailable
orobtainedbyreductionofthecorresponding2-nitrophenolusing
eitherheterogeneouspalladiumorplatinumoxidecatalyzed
hydrogenationortreatmentwithtin(II)chloride(Scheme2).Some
2-nitrophenolswereobtainedbynitrationofthecorresponding
phenols.
TheCETPinhibitiondataforaseriesofcompoundsofdifferent
benzoxazolephenylringsubstitutionisshowninTable1anditcan
beseenthatsubstitutionofthisringappreciablyaltersCETPinhib-
ubstitutedbenzoxazole(8)was10-foldless
yofaseriesofbenzoxazole
substituents(compounds9–22)showedaclearpreferenceforsub-
icularthe5-nitroand5-cyano
OHOH
R
a
R
b, c, d or e
OH
R
NO
2
NH
2
tsandconditions:(a)90%HNO
3
,AcOH,40°Ctoroomtemper-
ature,1h,16–70%;(b)H
2
,10%Pd/C,EtOH,roomtemperature,5–15h,97–99%;(c)
HCO
2
NH
4
,10%Pd/C,MeOH,roomtemperature,15h,quant.;(d)H
2
,PtO
2
,EtOH,
roomtemperature,2–15h,99%;(e)SnCl
2
Á2H
2
O,concdHCl,MeOH,roomtemper-
ature,15h,38–97%.
Table1
SARof2-arylbenzoxazoles
R
4
R
3
6
7
O
NH
R
2
5
4
N
R
1
OO
CompdR
1
R
2
R
3
R
4
CE
a
IC
50
a
(
l
M)%Max
8HHHH1379
1HClHH1.194
9HHClHn.d.
b
32
10HHHCl2171
11MeHHH2362
12HMeHH2.089
13HHMeHn.d.
b
34
14NO
2
HHHn.d.
b
42
15HNO
2
HH0.9479
16HHNO
2
H3.271
17HFHH1.991
18HHFH7.550
19HHHFn.d.
b
36
20HCNHH0.1390
21HHCNH0.4197
22HHHCN5.289
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
b
IC
50
notdeterminedif%maxinhibitionwas<50%.
tal./.20(2010)346–349
derivatives15and20werefoundtobethemostpotentCETP
inhibitorswithIC
50
sof0.94and0.13
l
M,nds
23–29(Table2)representaseriesofsubstitutionsthataretoler-
atedatthe5-positionwithonlymethoxy(compound24)showing
5-substituentssuch
aslargeralkyl,trifluoromethyl,methylester,carboxylicacid,
amides,carbamates,sulfonamides,sulfones,hydroxyl,anilino,
amidine,tetrazoleandsubstitutedphenylwerefoundtohavelittle
ornoinhibitoryactivity(datanotshown).Thebest5-substituted
derivativefoundwastherefore5-cyanoderivative20andthisrep-
sconsistentwith
theworkpublishedbyresearchersatBristol–MyersSquibb.
30
Holdingthecyanogroupconstant,theSARofadditionalbenz-
oxazolesubstitutionwasthenexplored(Table3).Thethreepossi-
bleregioisomericmethylderivatives31,33and35wereprepared
viapalladiumcatalyzedcyanationofthecorrespondingarylha-
lides30,32and34,Pinhibitiondataclearly
showsthatincorporationofamethylgroupispreferredatthe7-
positionandaffordsatwofoldincreaseinpotency(compare35
to20and34to23).Compound35hasaCETPIC
50
-
pounds36–41showthatanumberofothersubstituentsaretoler-
atedatthe7-positionincombinationwitheither5-cyanoor5-halo
themostpotentbeing5-cyano-7-fluoroderivative39withaCETP
IC
50
of62nM.
Thesubstitutionofthe7-positionwasfurtherinvestigatedby
thesynthesisofaseriesofalcohols(compounds44–57,Table4).
Thesecompoundsweresynthesizedfromacetophenone40as
entofketone40withsodiumborohy-
drideoraGrignardreagentaffordedsecondaryortertiaryalcohols
ompoundswerethen
transformedintonitrilesofgeneralstructure43viapalladiumcat-
arge,potencyofCETPinhibitionisinver-
selyproportionaltothesizeofthealkylgroupaddedto
acetophenone40,thebestcompoundbeingmethylderivative47
withaCETPIC
50
ementofthe5-cyanogroupof
47withahydrogentogivecompound57resultsina10-foldloss
inpotencyofCETPinhibitionconfirmingtheimportanceofsubsti-
tutionatboththe5-and7-positions.
Compounds20,35and47wereevaluatedinapharmacody-
namicmodelinmiceexpressingcynomolgusmonkeyCETPand
Table2
SARof5-substituted-2-arylbenzoxazoles
6
7
O
NH
R
1
5
4
N
OO
CompdR
1
CE
a
IC
50
a
(
l
M)
8H13
20CN0.13
23Br1.3
24OMe0.84
25SMe2.9
26COMe1.3
27
b
CH(OH)Me3.4
28
c
Vinyl2.8
29
d
Ethynyl2.0
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
b
Synthesizedbyreductionof26;NaBH
4
,MeOH,roomtemperature,1h,quant.
c
Synthesizedfrom23byStillecoupling;vinyltributyltin.(Ph
3
P)
4
Pd,DMF,80°C,
12h,13%.
d
Synthesizedfrom23bySonagashiracoupling;(i)TMSacetylene,Pd(PPh
3
)
2
Cl
2
,
CuI,Ph
3
P,Et
2
NH,DMF,microwaveirradiation,120°C,75min,(ii)aqNaOH,THF,
roomtemperature,1h,32%.
Table3
SARofdisubstituted-2-arylbenzoxazoles
R
4
R
3
6
7
O
NH
R
2
5
4
N
R
1
OO
CompdR
1
R
2
R
3
R
4
CE
a
IC
50
(
l
M)
30MeBrHH>100
31MeCNHH38
32HClMeH>100
33HCNMeH1.9
34HBrHMe0.51
35HCNHMe0.060
36HCNHCN0.27
37HClHNO
2
0.57
38HBrHF0.91
39HCNHF0.062
40HBrHCOMe0.38
41HCNHCOMe0.086
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
Table4
SARof5,7-disubstituted-2-arylbenzoxazoles
R
2
R
3
OH
6
7
O
NH
R
1
5
4
N
OO
CompdR
1
R
2
R
3
CE
a
IC
50
(
l
M)
44
b
BrHMe0.059
45CNHMe0.046
46BrMeMe0.044
47CNMeMe0.028
48BrMeEt0.11
49CNMeEt0.031
50BrMen-Pr0.20
51CNMen-Pr0.058
52BrMei-Pr0.21
53CNMei-Pr0.080
54BrMeEthynyl0.094
55BrMe1-Propynyl0.21
56CNMe1-Propynyl0.16
57
c
HMeMe0.44
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
b
Synthesizedbyreductionof40;NaBH
4
,MeOH,roomtemperature,1h,quant.
c
Synthesizedfrom46;LiAlH
4
,THF,roomtemperature,1.5h,14%.
ybeattributed
tothelackoforalbioavailabilityobservedwiththesecompounds
inmousePKstudies.
Insummary,afterhighthroughputscreeningoftheMerckcom-
poundcollectionidentified2-arylbenzoxazole1asalead,itwas
developedintocompounds35and47usingamodularsynthetic
approachthatshowedtheimportanceofsubstitutionatthe7-po-
compoundsrepresentimportantleadsforfurtherdevelopmentof
rmodificationsof
theamideandaryloxymoietieswillbereported.
tal./.20(2010)346–349
349
O
OO
O
NH
a or b
Br
N
40
ROH
OO
O
NH
c
Br
N
42
ROH
OO
O
NH
NC
N
43
tsandconditions:(a)R=alkyl,RMgX,THF,À20°Ctoroom
temperature,4h,40–75%;(b)R=H,NaBH
4
,MeOH,roomtemperature,1h,quant.;
(c)Zn(CN)
2
,Pd
2
dba
2
,dppf,dimethylacetamide,microwaveirradiation,60W,
200°C,1h,37–73%.
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azolesynthesis—Generalmethod1:Amixtureof2(1.05mmol),2-
aminophenolderivative(1.05mmol)andboricacid(1.37mmol)ino-xylene
(60mL)washeatedatrefluxunderaDean–
thistimethereactionmixturewasdilutedwithEtOAc(50mL),washed
successivelywithsaturatedNaHCO
3
(50mL),H
2
O(50mL),andbrine(50mL),
dried(Na
2
SO
4
)s
purifiedbyflashchromatographyand/orreversedphaseHPLCtoaffordthe
desiredbenzoxazole.
Generalmethod2:Amixtureof2(0.307mmol),2-aminophenolderivative
(0.430mmol)andboricacid(0.430mmol)ino-xylene(2.5mL)wassubjected
tomicrowaveirradiation(300W,270°C,60min).Thereactionmixturewas
dilutedwithEtOAc(25mL),washedsuccessivelywithsaturatedNaHCO
3
(25mL),H
2
O(25mL),andbrine(25mL),dried(MgSO
4
)andconcentratedin
spurifiedbyflashchromatography
and/orreversedphaseHPLCtoaffordthedesiredbenzoxazole.
Generalmethod3:Asolutionofoxalylchloride(2MinCH
2
Cl
2
,1.40mmol)was
addedtoastirredsuspensionof2(0.702mmol)inCH
2
Cl
2
(11mL)followedby
afewdropsofDMFatroomtemperatureunderN
2
.Thereactionwasstirredat
reactionmixturewasconcentratedinvacuoandazeotropedwithtoluene
(10mL).Thecrudeacidchlorideand2-aminophenol(1.05mmol)were
dissolvedin1,4-dioxane(20mL)andheatedatrefluxfor4hunderN
2
.The
reactionwasdilutedwithEtOAc(50mL)andwater(50mL)andtheaqueous
layerwasextractedwithEtOAc(2Â50mL).Thecombinedorganicextracts
werewashedwithbrine(50mL),dried(Na
2
SO
4
)andconcentratedinvacuoto
reofthecrudeamideandpyridinium
p-toluenesulfonate(0.0702mmol)ino-xylene(30mL)washeatedatreflux
underaDean–StarkapparatusovernightunderN
2
.Thereactionwasdiluted
withEtOAc(100mL)andwashedsuccessivelywithsaturatedNaHCO
3
(50mL),
water(50mL)andbrine(50mL),dried(Na
2
SO
4
)andconcentratedinvacuoto
spurifiedbyflashchromatographyand/or
reversedphaseHPLCtoaffordthedesiredbenzoxazole.
2024年3月27日发(作者：尹棠华)
Bioorganic&MedicinalChemistryLetters20(2010)346–349
ContentslistsavailableatScienceDirect
Bioorganic&MedicinalChemistryLetters
journalhomepage:/locate/bmcl
2-ArylbenzoxazolesasCETPinhibitors:Substitutionofthebenzoxazolemoiety
a,
*
,AmjadAli
a
,LiyaChen
a
,d
a
,on
b
,YingChen
b
,
d
b
,QiuGuo
b
,
b
,
b
,w
b
,
b
,ir
a
a
b
DepartmentofMedicinalChemistry,MerckResearchLaboratories,RahwayNJ07065,UnitedStates
DepartmentofCardiovascularDiseases,MerckResearchLaboratories,RahwayNJ07065,UnitedStates
articleinfo
abstract
Aseriesof2-arylbenzoxazoleinhibitorsofthecholesterolestertransferprotein(CETP)isdescribed.
Structure–activitystu-
tionatthe5-and7-positionsofthebenzoxazolemoietywasfoundtobebeneficialforCETPinhibition.
Compound47wasfoundtobethemostpotentinhibitorinthisseriesandinhibitedCETPwithanIC
50
of
28nM.
Óhtsreserved.
Articlehistory:
Received26June2009
Revised23October2009
Accepted26October2009
Availableonline29October2009
Keywords:
Cholesterylestertransferprotein
CETP
Highdensitylipoprotein
HDL
Benzoxazole
Coronaryheartdisease(CHD)isnowtheleadingcauseofdeath
edlevelsoflow-density
lipoprotein-cholesterol(LDL-C)hasbeenidentifiedasamajorrisk
elopmentofthestatinshassignificantly
helpedtoreduceLDL-ClevelsinpatientsatriskforCHD.
1,2
There
isnowagrowingbodyofepidemiologicalevidencelinkingin-
creasedlevelsofhighdensitylipoprotein-cholesterol(HDL-C)with
decreasedriskofdevelopmentofCHD.
3–6
Somecholesterollower-
ingdrugs,includingniacin,fibratesandstatins,haveamodestef-
fectonincreasingHDL-Clevels.
7–10
Regardless,niacinremainsthe
frontlinetherapyforraisingHDL-Clevelsdespiteitsmodesteffi-
cacy($20%increase).Consequentlythereisaneedforbetterther-
apiestoaddressthisproblem.
Thebeneficialeffectsofhighdensitylipoprotein(HDL)are
thoughttoarisefromitsparticipationinreversecholesteroltrans-
port(RCT)aswellasitsanti-inflammatoryandanti-oxidantprop-
erties.
11,12
Cholesterylestertransferprotein(CETP)mediatesthe
exchangeofcholesterylester(CE)fromHDLwithtriglyceridespri-
marilyfromverylow-densitylipoprotein(VLDL).
11,12
Inhibitionof
CETPwouldthereforebeexpectedtoincreaseserumHDL-Clevels.
ClinicalstudiesinhumanswiththeCETPinhibitors,dalcetrapib
(JTT-705),
13,14
torcetrapib,
15–19
andanacetrapib
20–22
established
thatpharmacologicalinhibitionofCETPleadstosignificantin-
ethisobservation,imaging
OO
O
NHS
O
F
3
C
O
O
F
3
CCF
3
N
dalcetrapib (JTT-705)
OF
torcetrapib
F
3
C
O
N
O
CF
3
F
3
C
anacetrapib
*.:+;fax:+.
E-mailaddress:cameron_smith@().
0960-894X/$-seefrontmatterÓhtsreserved.
doi:10.1016/.2009.10.099
studieswithtorcetrapibshowedthecompoundhadnoeffecton
theprogressionofatherosclerosis.
23–25
Additionally,thetorcetra-
pibphaseIIItrialwasprematurelyhaltedaftertheobservationof
tal./.20(2010)346–349
347
increasedmortalityinpatientsreceivingtorcetrapibandatorva-
statinrelativetotheatorvastatin-onlygroup.
19
Thisadverseeffect
mayhavebeenrelatedtotheobservationofanincreaseinmean
scur-
rentlysignificantdebateoverwhethertheadverseeffectsobserved
withtorcetrapibwerecausedbymechanismbasedfactorsoroff-
targetactivities.
26–28
Despitetheuncertaintyregardingtheviabil-
ityofCETPinhibitors,thereiscontinuedinterestinthedevelop-
communicationdetailstheidentificationandoptimizationofaser-
iesof2-arylbenzoxazolebasedCETPinhibitors.
InhibitionofCETPmediatedCEtransferwascharacterized
invitrousingafluorescencetransferassay.
29
Theassayusessyn-
theticHDLdonorparticlesthatcontainself-quenchingBODIPYla-
beledCEalongwithanadditionalfl
BODIPYlabeledCEistransferredfromthedonorparticletoan
acceptorlipoproteinbyCETP,fluorescenceisobservedandquanti-
fitionofCETPmediatedCEtransferwascharacterizedby
adecreaseinlevelsoffluorescenceobservedrelativetocontrol.
AhighthroughputscreenofcompoundsintheMerckcollection
at2
l
Musingtheaboveassaywasconductedandhitswerecon-
firmedbytitration.2-Arylbenzoxazole1wasidentifiedasascreen-
adclasswasalsoindependentlyidentifiedby
researchersatBristol–MyersSquibbandpublishedsubsequentto
ourstudies.
30
Theirworkshowedtheimportanceofsubstitution
workdescribedinthispublicationisconsistentwiththatdescribed
byBMS,butalsoshowsthatfurthersubstitutionofthebenzoxaz-
olemoietyatthe7-positionleadstocompoundswithadditional
enhancementofCETPinhibition.
O
O
O
NH
Cl
N
1
Thedevelopmentofleadcompound1beganwiththeinvestiga-
tionoftheeffectofvariationofthesubstitutionofthebenzoxazole
OO
a
O
O
HOCl
34
OO
b
O
NH
HO
2
O
O
c
O
R
NH
NH
OH
6
d
R
O
O
O
or 2
e
NH
N
7
tsandconditions:(a)(COCl)
2
,,CH
2
Cl
2
,room
temperature,1h,quant.;(b)4-aminobenzoicacid,i-Pr
3
NEt,CH
2
Cl
2
,roomtemper-
ature,30min,87%;(c)(i)(COCl)
2
,,CH
2
Cl
2
,roomtemperature,2h;(ii)2-
aminophenolderivative,1,4-dioxane,reflux,2h;(d)PPTS,xylene,
refluxunderDean–Stark,16h,10–53%;(e)2-aminophenolderivative,boricacid,
xylene,reflux,24h,7–37%,ormicrowaveirradiation,270°C,1h,7–33%.
carboxylicacid2wassynthesizedfromphenoxyaceticacid3by
firsttreatingwithoxalylchloridetoformthecorrespondingacid
ngwith4-aminobenzoicacidaffordedcarboxylic
azoleswerethensynthesizedbyoneofthreemeth-
ods.
31
Activationof2asthecorrespondingacidchlorideusingoxa-
lylchloridefollowedbycouplingwitharangeofsubstituted2-
-
tionofamides6inxylenewasheatedatrefluxinaDean–Stark
apparatuswitheitherp-tolenesulfonicacidorpyridiniump-tolu-
enesulfonicacid,toafford2-arylbenzoxazolesofgeneralstructure
atively,asolutionofcarboxylicacid2,a2-aminophenol
andboricacidinxylenecouldbeheatedatrefluxorsubjectedto
microwaveirradiationat270°Ctoaffordthecorresponding2-aryl-
benzoxazole.2-Aminophenolswereeithercommerciallyavailable
orobtainedbyreductionofthecorresponding2-nitrophenolusing
eitherheterogeneouspalladiumorplatinumoxidecatalyzed
hydrogenationortreatmentwithtin(II)chloride(Scheme2).Some
2-nitrophenolswereobtainedbynitrationofthecorresponding
phenols.
TheCETPinhibitiondataforaseriesofcompoundsofdifferent
benzoxazolephenylringsubstitutionisshowninTable1anditcan
beseenthatsubstitutionofthisringappreciablyaltersCETPinhib-
ubstitutedbenzoxazole(8)was10-foldless
yofaseriesofbenzoxazole
substituents(compounds9–22)showedaclearpreferenceforsub-
icularthe5-nitroand5-cyano
OHOH
R
a
R
b, c, d or e
OH
R
NO
2
NH
2
tsandconditions:(a)90%HNO
3
,AcOH,40°Ctoroomtemper-
ature,1h,16–70%;(b)H
2
,10%Pd/C,EtOH,roomtemperature,5–15h,97–99%;(c)
HCO
2
NH
4
,10%Pd/C,MeOH,roomtemperature,15h,quant.;(d)H
2
,PtO
2
,EtOH,
roomtemperature,2–15h,99%;(e)SnCl
2
Á2H
2
O,concdHCl,MeOH,roomtemper-
ature,15h,38–97%.
Table1
SARof2-arylbenzoxazoles
R
4
R
3
6
7
O
NH
R
2
5
4
N
R
1
OO
CompdR
1
R
2
R
3
R
4
CE
a
IC
50
a
(
l
M)%Max
8HHHH1379
1HClHH1.194
9HHClHn.d.
b
32
10HHHCl2171
11MeHHH2362
12HMeHH2.089
13HHMeHn.d.
b
34
14NO
2
HHHn.d.
b
42
15HNO
2
HH0.9479
16HHNO
2
H3.271
17HFHH1.991
18HHFH7.550
19HHHFn.d.
b
36
20HCNHH0.1390
21HHCNH0.4197
22HHHCN5.289
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
b
IC
50
notdeterminedif%maxinhibitionwas<50%.
tal./.20(2010)346–349
derivatives15and20werefoundtobethemostpotentCETP
inhibitorswithIC
50
sof0.94and0.13
l
M,nds
23–29(Table2)representaseriesofsubstitutionsthataretoler-
atedatthe5-positionwithonlymethoxy(compound24)showing
5-substituentssuch
aslargeralkyl,trifluoromethyl,methylester,carboxylicacid,
amides,carbamates,sulfonamides,sulfones,hydroxyl,anilino,
amidine,tetrazoleandsubstitutedphenylwerefoundtohavelittle
ornoinhibitoryactivity(datanotshown).Thebest5-substituted
derivativefoundwastherefore5-cyanoderivative20andthisrep-
sconsistentwith
theworkpublishedbyresearchersatBristol–MyersSquibb.
30
Holdingthecyanogroupconstant,theSARofadditionalbenz-
oxazolesubstitutionwasthenexplored(Table3).Thethreepossi-
bleregioisomericmethylderivatives31,33and35wereprepared
viapalladiumcatalyzedcyanationofthecorrespondingarylha-
lides30,32and34,Pinhibitiondataclearly
showsthatincorporationofamethylgroupispreferredatthe7-
positionandaffordsatwofoldincreaseinpotency(compare35
to20and34to23).Compound35hasaCETPIC
50
-
pounds36–41showthatanumberofothersubstituentsaretoler-
atedatthe7-positionincombinationwitheither5-cyanoor5-halo
themostpotentbeing5-cyano-7-fluoroderivative39withaCETP
IC
50
of62nM.
Thesubstitutionofthe7-positionwasfurtherinvestigatedby
thesynthesisofaseriesofalcohols(compounds44–57,Table4).
Thesecompoundsweresynthesizedfromacetophenone40as
entofketone40withsodiumborohy-
drideoraGrignardreagentaffordedsecondaryortertiaryalcohols
ompoundswerethen
transformedintonitrilesofgeneralstructure43viapalladiumcat-
arge,potencyofCETPinhibitionisinver-
selyproportionaltothesizeofthealkylgroupaddedto
acetophenone40,thebestcompoundbeingmethylderivative47
withaCETPIC
50
ementofthe5-cyanogroupof
47withahydrogentogivecompound57resultsina10-foldloss
inpotencyofCETPinhibitionconfirmingtheimportanceofsubsti-
tutionatboththe5-and7-positions.
Compounds20,35and47wereevaluatedinapharmacody-
namicmodelinmiceexpressingcynomolgusmonkeyCETPand
Table2
SARof5-substituted-2-arylbenzoxazoles
6
7
O
NH
R
1
5
4
N
OO
CompdR
1
CE
a
IC
50
a
(
l
M)
8H13
20CN0.13
23Br1.3
24OMe0.84
25SMe2.9
26COMe1.3
27
b
CH(OH)Me3.4
28
c
Vinyl2.8
29
d
Ethynyl2.0
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
b
Synthesizedbyreductionof26;NaBH
4
,MeOH,roomtemperature,1h,quant.
c
Synthesizedfrom23byStillecoupling;vinyltributyltin.(Ph
3
P)
4
Pd,DMF,80°C,
12h,13%.
d
Synthesizedfrom23bySonagashiracoupling;(i)TMSacetylene,Pd(PPh
3
)
2
Cl
2
,
CuI,Ph
3
P,Et
2
NH,DMF,microwaveirradiation,120°C,75min,(ii)aqNaOH,THF,
roomtemperature,1h,32%.
Table3
SARofdisubstituted-2-arylbenzoxazoles
R
4
R
3
6
7
O
NH
R
2
5
4
N
R
1
OO
CompdR
1
R
2
R
3
R
4
CE
a
IC
50
(
l
M)
30MeBrHH>100
31MeCNHH38
32HClMeH>100
33HCNMeH1.9
34HBrHMe0.51
35HCNHMe0.060
36HCNHCN0.27
37HClHNO
2
0.57
38HBrHF0.91
39HCNHF0.062
40HBrHCOMe0.38
41HCNHCOMe0.086
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
Table4
SARof5,7-disubstituted-2-arylbenzoxazoles
R
2
R
3
OH
6
7
O
NH
R
1
5
4
N
OO
CompdR
1
R
2
R
3
CE
a
IC
50
(
l
M)
44
b
BrHMe0.059
45CNHMe0.046
46BrMeMe0.044
47CNMeMe0.028
48BrMeEt0.11
49CNMeEt0.031
50BrMen-Pr0.20
51CNMen-Pr0.058
52BrMei-Pr0.21
53CNMei-Pr0.080
54BrMeEthynyl0.094
55BrMe1-Propynyl0.21
56CNMe1-Propynyl0.16
57
c
HMeMe0.44
a
Datareportedisderivedfromduplicatewellsandthreeindependentexperi-
50
valuesweredeterminedfrom10-point,one-thirdlogconcen-
trationresponsecurvesandstandarderrorswere610%.
b
Synthesizedbyreductionof40;NaBH
4
,MeOH,roomtemperature,1h,quant.
c
Synthesizedfrom46;LiAlH
4
,THF,roomtemperature,1.5h,14%.
ybeattributed
tothelackoforalbioavailabilityobservedwiththesecompounds
inmousePKstudies.
Insummary,afterhighthroughputscreeningoftheMerckcom-
poundcollectionidentified2-arylbenzoxazole1asalead,itwas
developedintocompounds35and47usingamodularsynthetic
approachthatshowedtheimportanceofsubstitutionatthe7-po-
compoundsrepresentimportantleadsforfurtherdevelopmentof
rmodificationsof
theamideandaryloxymoietieswillbereported.
tal./.20(2010)346–349
349
O
OO
O
NH
a or b
Br
N
40
ROH
OO
O
NH
c
Br
N
42
ROH
OO
O
NH
NC
N
43
tsandconditions:(a)R=alkyl,RMgX,THF,À20°Ctoroom
temperature,4h,40–75%;(b)R=H,NaBH
4
,MeOH,roomtemperature,1h,quant.;
(c)Zn(CN)
2
,Pd
2
dba
2
,dppf,dimethylacetamide,microwaveirradiation,60W,
200°C,1h,37–73%.
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azolesynthesis—Generalmethod1:Amixtureof2(1.05mmol),2-
aminophenolderivative(1.05mmol)andboricacid(1.37mmol)ino-xylene
(60mL)washeatedatrefluxunderaDean–
thistimethereactionmixturewasdilutedwithEtOAc(50mL),washed
successivelywithsaturatedNaHCO
3
(50mL),H
2
O(50mL),andbrine(50mL),
dried(Na
2
SO
4
)s
purifiedbyflashchromatographyand/orreversedphaseHPLCtoaffordthe
desiredbenzoxazole.
Generalmethod2:Amixtureof2(0.307mmol),2-aminophenolderivative
(0.430mmol)andboricacid(0.430mmol)ino-xylene(2.5mL)wassubjected
tomicrowaveirradiation(300W,270°C,60min).Thereactionmixturewas
dilutedwithEtOAc(25mL),washedsuccessivelywithsaturatedNaHCO
3
(25mL),H
2
O(25mL),andbrine(25mL),dried(MgSO
4
)andconcentratedin
spurifiedbyflashchromatography
and/orreversedphaseHPLCtoaffordthedesiredbenzoxazole.
Generalmethod3:Asolutionofoxalylchloride(2MinCH
2
Cl
2
,1.40mmol)was
addedtoastirredsuspensionof2(0.702mmol)inCH
2
Cl
2
(11mL)followedby
afewdropsofDMFatroomtemperatureunderN
2
.Thereactionwasstirredat
reactionmixturewasconcentratedinvacuoandazeotropedwithtoluene
(10mL).Thecrudeacidchlorideand2-aminophenol(1.05mmol)were
dissolvedin1,4-dioxane(20mL)andheatedatrefluxfor4hunderN
2
.The
reactionwasdilutedwithEtOAc(50mL)andwater(50mL)andtheaqueous
layerwasextractedwithEtOAc(2Â50mL).Thecombinedorganicextracts
werewashedwithbrine(50mL),dried(Na
2
SO
4
)andconcentratedinvacuoto
reofthecrudeamideandpyridinium
p-toluenesulfonate(0.0702mmol)ino-xylene(30mL)washeatedatreflux
underaDean–StarkapparatusovernightunderN
2
.Thereactionwasdiluted
withEtOAc(100mL)andwashedsuccessivelywithsaturatedNaHCO
3
(50mL),
water(50mL)andbrine(50mL),dried(Na
2
SO
4
)andconcentratedinvacuoto
spurifiedbyflashchromatographyand/or
reversedphaseHPLCtoaffordthedesiredbenzoxazole.