Note: Descriptions are shown in the official language in which they were submitted.
~ WO95/14012 211~3 PCr/US94112269
S, 6-- DERIVATI~8 A~ PPnlrv-o~ ~ ~ AND
AN~rIVIR~ AG~r^
1. FIEI,D OF T~Z 1~ ~
The present invention relates to 5,6-di7lydLu~yLu~Je
derivatives that are inhibitors of aspartyl proteases, in
particular the aspartyl proteases f ound in retroviruses
inrlv~;n~ Human T _ . ricipnry Virus (HIV) . The 5,6--
dihydL~yLu-138 are P~P~t~Pd to have utility as antiviral
l0 agents, for the LLCI-j ' of infection caused by EIV or other
retroviruses employing aspartyl proteases, and to be useful in
the LL-:I1 of ~iCPACPC caused by the retroviruses,
; nr~ i nq AIDS .
lS 2 . P~-- OF T~ Ilm liTTOll
ACqUired T '~firiPnry SYI~dL~ (AIDS) was coined in
1982 to describe the ~-l;nirAl manifestations of
^f icie~cy. The e~ ^qi c~ l ag~nt of AIDS was later
associated with a retrovirus, Human T ' 'iciPnry Virus
20 (EIV), from the lentiYirus sllhfAmi ly. At least two infectious
strains of EIV have been identified, HIV-l and HIV-2. Eere,
HIV will be used as a general term describing all strains and
mutants of the Human T ' -i cif~nry Virus. The detailed
study of HIV has given rise to many approaches to antiviral
25 drug devPll, ;nrlll~7inq inhibition of the viral aspartyl
protèase (D. Richman, Control of Virus niC-;~c~s~ 45th
symposium of the Society for General lficrobiology, 261-313
(1990) ) .
Aspartyl proteases have been found in many retroviruses
30 inr~ ;nq the Feline T -' ~iciency Virus (FIV), the
Myeloblastosis Associated Virus (NAV), EIV, and the Rous
sarcoma Virus (RSV) [H. ~oh et al. Nature, 315: 691 (1985); J.
Kay, B. N. Dunn, !3iocl~im. ~3iophys. Acta, 1: 1048 (1990); C.
Cameron, J. P~ ^;ir~7 Che~., 168: 11711-7Z0 (1993) ] . Since
35 there are ::~LLuuLuLeLl similarities among the cnown retroviral
proteases, ~ _ which inhibit the EIV protease may well
inhibit other retroviral proteases.
Wo 9~/14012 ;~ PcrluS94/12269
HIV aspartyl protease is responsible for post-
translational processing of viral p~e- UL~UL polyproteins such
as pol and gag. (M. Graves, Structure ~nd Function of the
Aspartic Proteases, 395-405 tl991) ) . Cleavage of these
5 polyproteins is occ~ tii~ for maturation of the viru6, since
the proteolytic activity n~rOscAry for polyprotein procoqs;n~
cannot be provided by host col lt~ r enzymes. An; L~
finding has been that viruses which lack this protease, or
contain a mutant which is a defective protease, lack
10 infectivity [C. Ping et al., J. Virol, 63: 2550-556 (1989) and
N. Rohl et al., Proc. bati. Acad. Sci. ~7SA, 85: 4686-90
(1987)]. Thus, a selective HIV protea6e inhibitor has been
shown to inhibit viral spread and the production of cytopathic
effects in cultures of acutely infected cells (J. C. Craig,
15 AntivirAl Research, 16: 295-305 (1991) ) . For this reason,
inhibition of HIV protease is believed to be a viable approach
to antivirl~l therapy.
HIV protease inhibitors have been eYtensively reviewed
~see for example A. T, ccOl l; et al., Chimica Oggi, 6-27
20 (1991) and T. Meek, J. Enzyme Inhibition 6: 65-98 (1992) ) .
However, the majority of these inhibitors are peptides and
thus unsuitable as drugs, due to the well known
phaL : l o~ l def it~ j onri ~oc exhibited by most peptide drugs
(biliary excretion, low bioav~;lAh;l;ty and stability in
25 physinlo~ic~l milieu, etc.) Nonpeptidic inhibitors of HIV
protease are thus very; _ L.l.IL, since these may lead to
useful therapeutic agents.
Hei 3-227923 claimed coumarins with anti-HIV activity.
However, only 4 '~LuAyuuu~cLLin was specifically described
30 without d;crllcc;t~n of =- -n;F~ of action.
World Patent 89/07939 claimed eight coumarin derivatives
as HIV reverse transcriptase inhibitors with potential
antiviral activity. ~hese derivatives are hoY~rhl--,ucuu~ rin,
7-acetu--y~;uU~cl~ in, and the structures shown below.
~ WO 95/14012 2 1 7 6 0 4 3 PCT/US94/12269
-- 3 --
Br R ~\ R' ~ N - N ~ 0
5 ~o~O ~~O~O
~r ~\>
R=H, R'=CI; R=H, R'=CF3; R=R'=CI
OH o OH I OH
W `,, i ~
Warfarin (3- (r.-acetonylbenzyl) -4 ~ Ay~uU--~ar in), shown
15 belo~, was reported by R. Nagorny et al. in AIDS 7: 129-130
(1993) as inhibiting cell-free and cell-mediated HIV
infection. However, Warfarin was the only analog pyrone
studied and its ~ ~n; -- of action in HIV inhibition was not
specif ied.
OH Ph O
-/~/~\ Me
25 \~~o ~O
Selected flavones, ~,Lsu~L~ lly different from the 5, 6-
30 dil~ydLu~ysunes of the present invention, were reported by
Fairli et al., (~ioc~em. ~iophys. Res. Comm., 188: 631-637,
(1992) ) to be inhibitors of HIV-1 protease. These
are shown below.
Wo 95/14012 PCrlUS94/12269
2 1 7~0~3
-- 4 --
o OH O
~CO H ~ - '`r~ ~/
OMe OH ~\ '
OH
HO
10 United States Patent Number 3,206,476 describes several
pyrones, specifically 3-substituted-4 ~ydL~ y-G aryl-2-
pyrones, as antihypertensive agents. However, the range of
substituents at the 3-position of these heterocycles is
limited to halo and amino groups and alkanoylamino
15 derivatives.
IJnited states Patent Number 3, 818, 046 describes several
pyrone derivatives, specifically 4 ~lydL~u~y~Lolles with sulfur-
containing carbon chains at the 3-position, as growth stunters
and antimicrobial agents. These pyrones are substituted as
20 follows: R = Ne; M = H or alkali metal; and R' = H, alkyl,
phenyl, h~l~Fho~yl, ni~L~he--yl, lower alkylphenyl, benzyl,
phenethy1, naphthylmethy1, h~1ohon 7yl~ lower alkylbenzyl,
nitrobenzyl, y~ y1, a1lyl, cyclohexyl, lower alkyl, 1ower
thioalkyl, or adamantyl; and n = 0 to 2.
OM
~ S(o)nR~
R~O ~O
R=Me
WO 95/14012 PCT/US94/1220
~ 2 ~ 7~0Q3
-- 5 --
A process for preparing the py~ ones sho~"n above is
claimed in United States Patent No. 3, 931, 235 .
EP 278742 describes several cyclic 2-benzoyl-1,3-diones
with ~rbic;~Al activity. All of these - ' possess 3-
5 benzoyl substituents. Their structu~ es, in the ketotautomeric forms, are shown below:
O O
Y~ Y~ yl or O
1~X~o ~J~ X'CH2.0,S,NR
R2
3 . ~ RY O~
The present invention is based in great part on the
extraordinary discovery of the inventors that novel 5, 6-
di~ v~yLv1-~ derivatives and related `, selected from
a broad ~e- LLu~ of tailored ~ f'171A7- ~LLU~LUL~SI potently
20 inhibit the HIV aspartyl protease blocking infection by HIV.
The present inventivn i5 also based on the insights of the
applicants reqarding the -- ; ~m of action of antiviral
drugs, ~p~ l ly as revealed by their studies on 7LLUVLUL-:-
activity relatjn~ch;ps characteristic of anti-HIV '-
25 that include 5,6-dil.y~u~y~v.,e derivatives.
The invented 5,6-dihy~v~Lv..es are expected to be
e.~LL~ ~1Y useful in the dev~ L of treatments for
infections caused by viruses, ~'Cper;Al ly by retroviruses that
rely on aspartyl protease activities for replication and
3 inf ectivity . One such retrovirus is HIV . For this reason,
the antiviral 5, 6-di1~ydlv~Lvlles are also expected to be very
useful in the treatment of .l;c~c-,c and :~y11~L - associated
with viral pathogens. one such :~y11dLI - is AIDS.
Efficient syntheses of the biologically active 5,6-
35 di~1ydLv~yLvnes involving either de novo AcF ~1 i"c of the 5,6-
di1-ydL V~yL une nucleus or modif ications of suitably
. . ~
WO 95/14012 2 ~ 7 ~ 0 4 3 PCr/US94/12269
funct;nnAl;7scl 5,6-di1lydLv~yLulles~ are ti;cclnsP~l.
nLi - ~, many working ~ l~C outlining the ~L-~alGtion
of specific 5, 6-di1lydLvyyLolles whose structures contain the
desired fllnrt;nnAl groups in proper ., ic aLLClil,_ ~, are
5 given.
me testing of specific 5,6-di11ydLv~rLvlles as inhibitors
of the HIV aspartyl protease, based on the study of the
hydrolysis of an , ~ t ide enzyme substrate, and t_e
testing of the 5,6-di1lydLvv~Lulles as inhibitors of viral
lO growth and infectivity, based on the study of infection of H9
cell lines by the HIV-liLLb strain, are also 1; crl n5ed.
Striking enzyme inhibitions, at n:~r lAr levels, with
corresponding anti-~IV activities were oLs~L v~.
The present illVt:ll-UL~ contemplate the pL~=~ar-tion of
15 pharmaceutically useful antiviral compositions comprising one
or more of the invented 5,6-dih~l v~vyLv1~es and related
and a rhAr~ t;rAlly acceptable carrier. They
also contemplate the use of these compositions, alone or in
combination with other antiviral ~L~ai , in the Le:ai
20 of infections and ~ice~c~c caused by retroviruses, ;r~rlu~s;
AIDS .
The present inventors contemplate t_e ~L~cAvC~L~tion of
pharmaceutically useful ~nt;hAct~rial compositions cmprising
one or more of the invented 5,6 dil1ydLv,vyLv11es and related
25 ~ '- and a rh~ tically acceptable carrier.
The present invention relates to '- or the
pharmaceutically acceptable salts thereof of formula l, shown
below,
R
R'1~ ~
R, Y Z
WO 95/14012 2 1 7 6 ~ 4 3 Pcrlus94/1226s
wherein
X is OR5, NHR5, CH2ORs, CO2R6, or SRs wherein R5 is R6 or
COR6 wherein R6 is ;n~ -.Lly H, a straight chain alkyl
group containing 1 to 6 carbon atoms, a branched or cyclic
5 alkyl grOUp containing 3 to 7 carbon atoms, an
alkylcycloalkyl of 5-9 carbon atoms, benzyl, phenyl or a
heterocycle;
Z is O or S;
Y is O, S, C(R6)2, NF, or NR6;
10 Rl and Rl' are ead i~ --l ly [CH2]Gl-[Wl]D2-[Ar]a2-
~ CII2 ] 1~3- ~WZ ] D~ -R~;
R2 is in~-L-e---lf ,~ ly ~lert~d from the group of
:,L.UL~LuLas from which Rl is selected with the proviso that
if Wl is a heteroatom n7. is an integer of from 1 to 4;
15 R3 is in~ ly selected from the group of
~L~uuL.u~._3 from which Rl is s~l~ctF-cl with the proviso that
if W~ is a heteroatom nl is an integer of from 1 to 4;
R2 and R3 may be taken together to f orm an unsubstituted or
substituted 3-, 4-, 5-, 6-, or 7 - '- e~ ring, wherein the
20 substituents are one or more of the R, groups listed ~elow;
Ri is [CH2]s~ - [w3]n2 - [cH2]n3 - [w4]n~ - [Ar]~2-[cEl2]~3-[w2]l~ - R7;
nl, n2, n3, n4, and n5 are inA_l,.~l~A_..I ly integers of
froF3 0 to 4, 0 to 1, 0 to 4, 0 to 1, and 0 to 2,
respectively;
25 W~, W2, and W4 are i nA~r~n~ ntly o, OCONR" 5 (O) ~5, CO,
C (=NR,) NR" CR,=CR" C5C ~ NR" CS, C----N--R" C=NOR" NR,SO2,
SO2NR7, CsC(R,)2, CR,N(R,)2, CR,OR" C(R~)2, NCO2R" NR,CO2, CO2,
NCON(R,)2, NR,CONR" NCOR" NR,CO, or CONR,;
W3 is i n~ r~-n~l~ntly s~ ct~ from the group of structures from
t0 which Wl is selected, with the further limitation that if
nl in R~ is zero, that W3 is selected from the group of
~LLUULUL~S consi5ting of -CO, -CR,=CR" -C5--C~ -CS~ -C=N-R"
-C----N-R" -C=NOR" -CR,N(R,)2, -CsC(R,)2, -CR,OR,, -C(R,)2, -
CO2, and -CONR" with the left hyphen denoting the point o~
35 attachment to the l~yl-u~-ulle ring;
R, is in~l_L._~ n7 ~y }i, Ar, a straight or branched alkyl
WO 95/14012 ~ 1 7 6 0 ~ 3 PCr/US94/12269
-- 8 --
or alkenyl group containing from 1 to 6 carbon atoms, or
two R7 ' s can be taken together to f orm a ring of 3 -7 atoms,
or a Qubstituted derivative thereof wherein the
substituents are one or more of COzR6, COR6, CON(R6)2,
S NR6CON(R6)2, NR6COR6, ~6~ S(O)=sR6r N(R6)2, Cl~ Br, F, CF3, Ar,
OAr, or S(O) cAr;
Ar is ; n~orQn-lQntly phenyl, naphthyl, a 5- or 6- ~ d
heterocycle containing 1 to 4 heteroatoms, a cycloalkyl
cnnt~in;n~ 3 to 6 atoms, a fused ring system containing 8-
10 10 atoms, or a substituted derivative thereof wherein the
substituents are of F, Cl, Br, CN, NO2, (CH2)n6R6,
(CH2) ,6C(Ne)=CH2, (CH2)sl6N(R6)2, (CH2)"6NR6CON(R6)2,
( CH2 ) ~,6NR6COR6, ( CH2 ) D6OR6 r ( CH2 ) n6OCOR6 r ( CH2 ) ~60CON ( R6 ) 2,
(CH2)~,6CO2R6, (CH2)~6CON(R6)2, (CH2)"6COR6, CF3, (CH2) -6S(O):s
15 OCH2O, or O ( CH2 ) 2O; and
n6 is ;n~ Lly an integer of from O to 3.
More pref erred ~ of the present invention are
those of formula 1 wherein
20 X is ORs wherein Rs is H or COR6 wherein R6 i5 as
def ined above;
Z is O;
Y is O, 5, or CH2;
Rl and Rl' are inr3QrQn~Qntly H, F, (CH2)mCO2R6 (CH2)mOR3, or
25 (CH2) ,lCON(R6) 2;
R2 is [CH2] l-[Wl] 2-[Ar] 2-[CH2] 3--[W2] e~R7 with the
proviso that if Wl is a heteroatom nl is an integer of from
1 to 4;
R3 is ; ~ r~ ly selected from the group of
30 2~LL~L:Lule:s from which R2 is selected;
R2 and R3 can be part of a 5-, 6-, or 7 ~ ' ~d ring
optionally substituted by groups selected from the group of
structures ~rom which R, is selected;
R, is [CH2]~1--[W3]~,2--[CH2]n3--[W~]=~--[Ar]=2--[CH2] ,3--[w2]n~ - R7;
35 nl, n2, n3, n4, and n5 are as defined above;
W~ and W, are ;n~ Q~ ly O, S()n6r COr CR7=CR7, NR" CR,OR"
C(R7)2, NR7CO2, CO2, NR7CONR7, CONR7 or NR7CO;
W095114012 2 ~7~Q43 pCTlUS94/12269
_g _
W~ i~ as d-f ined ~bov~;
w~ ie; C270R" C(R,)~, or CON~;
R, i~ a~ d~inetl above;
Ar 18 as du~ined ~ov-; and
S n6 i6 a~ def inQ~ ~bova
EvQn more ~r LLCI '- of th~ pr~s~nt invention
~re tho6e of ~ormula l wh rein
X i~i OE~;
10 Z is 0;
Y is 0 or CH2;
~nd Rl' are H;
R2 i6 rCH~]nl-tWl~n2-tAr]n2-~C~ nj-tW2~n,-~, with th~ provl~o
that l~ W~ iG ~ h~teroat nl i~ ~n lnt~g~r o~ rrom 1 to 4;
~, is ~CH2~,--tAr]n~-tCE}~]t,~--~W~n~--R,;
R2 ~nd R, ~n bo p~rt of ~ 5-, 6-, or 7 ~ ring
u,~ optto~ y ~ublstitut~d Iby groups E~ ' rr
th~ sroYp rrom which R, is ~ ct~d;
R~ C~, ] n~ ] n~- t c~ ~ n~- t w~ ~ n~ - [ Ar ~ l~2- t cH~ ~ nl--~ w~ R,;
20 nl, n2, n3, n4, and n5 ar~ ~ de~ln~d aboY;
W~ is 0, ~t)ns~ N~7, CONR, or C(R,)~;
Wl is a6 ~in~d abov~;
W, i~ C(~2;
W~ ntly CR,-CR" NR,CONR" C(R,)"
2 5 NR,CO, CO, or CO~;
R~ is a~ derir~ed aJ~ov-;
R, 18 ~ dYfin~d abov~;
Ar i~ a6 d~fin ~d a~ov~; ~nd
n6 19 ~s dQrined abov~
~tlll ~nbr~ pr~f~rr~ld are _ ~ o~ ~'ornul~ 1 wh~rQin
X 16 OH;
~ i~ O;
Y 1~ 0;
3s R~ ~nd R~' aro E~;
R, i~ CH~-Ar-(C~,)n,-[W,I,~,-R" C~-CHI-Ar-(C~,)n,-tW,]",-~" CH,OAr-
~C~,)",-[W,~n,-R,, cyclop~ntylmuthyl, -(CH2),-Ct~O~-N(R,)"
WO 95/14012 ~ ~ .7 ~ 3 PCTIUS94112269
-- lo
cyclohexylmethyl, 2-(2- or 3-tetral,y.lLu~ nyl)ethyl, 2-(2-
or 3-furanyl~ethyl, propyl, butyl, iso-butyl, pentyl, iso-
pentyl, 2-(cyclopropyl)ethyl~ (CH2)2C(CH3)=CH2, Ar-(CH2)n3-
[W2] ,~-R7~ phenyl, or 2-, 3-, or 4-pyridyl;
5 R3 is Ar-(CH2)n3-[W2]n~-R7, phenyl, cyclopentyl, cycloheYyl, 2-
or 3-furanyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl~
isobutyl, pentyl, CH2-CH2-Ar, or isopentyl;
R2 and R3 can be part of an unsubstituted or
substituted 5-, 6-, or to 7 - ~d ring 7iLL~iLuLe where
10 the substituents are ;n~l~p~n~ntly one or more of those
listed for R, above;
R~ is as defined above for the even more preferreed
_ _ of Formula 1;
nl, n2, n3, n4, and n5 are as def ined above;
15 W2, W3 and W~ are as defined for the even more preferred
of the invention above;
R6 is as def ined above;
R~ is as def ined above;
Ar is as def ined above; and
20 n6 is as defined above.
Some of the most pref erred : _ of the present
invention are ;nrl~ Dd in the following:
5,6-Dihydro-4 ~IydLv~y C pl~ellyl~3-t (phenylmethyl)thio-2H]-
25 pyran-2-one;
5,6-Dihydro-4 '~ydLv~.y-G phe,lyl-3-[ (2-phenylethyl)thio]-
2H-pyran-2 -one;
5, 6 -Dihydro-4 hy dL U~Y G P11ellY 1-3 - [ ( 3 -phenylpropy 1 ) thio ] -
2H-pyran-2 -one;
5,6-Dihydro-4-hydroxy-6-phenyl-3-[ (2 phellO~y~L~Iyl)thio]-
2H-pyran-2 -one;
5,6-Dihydro-4-hydroxy-6-(2-methylpropyl) G Ph~11Y1-3-
[ (phenylmethyl ) thio ] -2H-pyran-2 -one;
5, 6-Dihydro-4 -hydroxy-6- ( 2-methylpropyl ) -6 -phenyl-3 - [ ( 2 -
35 phenylethyl)thio]-2H-pyran-2-one;
5 - ( 3 -Chlorophenyl ) -2 - [ ( 2 -phenylethyl ) thio ] -1, 3 -
cyrlrh~YAn~; one;
~ WO95/14012 2 ~ 76~43 PCrlUS94112269
-- 11 --
5, 6-Dihydro-4 -hydroAy-6- ( 4 ~ Ll~VAy~l1e~y 1 ) -3 -
[ tPhenYlmethyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4-hydroAy-6-(4-methyl~hioE~h~yl) -3-
[ (phenylmethyl)thio]-2H-pyran-2-one;
5, 6-Dihydro-4-hydroAy-6- (4-methylphenyl) -3-
[ (phenylmethyl ) thio ] -2H-pyran-2 -one;
5, 6-Dihydro-4 -hydroxy-6- [ 4 - ( l, l-dimethylethyl ) phenyl ] -3 -
[ (phenylmethyl) thio]-21I ~Leln 2-one;
6- (4-Chlorophenyl) -5, 6-dihydro-4 ~ydLVAy-3-
10 [ (phenylmethyl)thio]-21I ~L~II 2-one;
6- (3-Chlv. v~llel~y1) -5, 6-dihydro-4 ~1-vAy-3-
[ (phenylmethyl) thio] -2H-pyran-2-one;
5,6-Dihydro-3-[ (2-phenylethyl)thio]-6-[4-
(phenyl ll~vAy)phenyl]-2lI-pyran-2-one;
5,6-Dil1ydL~ C (4 ''- y~henyl)-3-[ (2-phenylethyl)thio]-
2H-pyran-2 -one;
5, 6--Dil~dLv G (4--methylth; orh~l~yl)--3--[ (2--
phenylethyl)thio]-2II ~yL~ 2-one;
5,6-Dil-ydLv G (4-methylphenyl) -3-[ (2-
20 phsnylethyl)thio]-21I ~yL~ 2-one;
6- [ l, l ' -Biphenyl ] -4 -yl-5, 6-dihydro-3 - [ ( 2 -
phenylethyl)thio]-21I ~yLcLil 2-one;
5,6-Dill~Lv G [4-(l,l-dimethylethyl)phenyl)-3-[(2-
phenylethyl) thio] -2H-pyran-2-one;
2 5 6- ( 3 -ChlUL v ~h_~1y 1 ) -5, 6-dihydro-3- [ ( 2 -phenylethyl ) thio ] -
2H-pyran-2 -one;
6- [ ( [ l, l ' -Biphenyl ] -4 _Y10AY) methyl ] -5, 6-dihydro-3 - [ ( 2 -
phenylethyl ) thio ] -2H-pyran-2 -one;
6- [ l, l ' -Biphenyl ~ -4 -yl -6 -butyl - 5, 6 -dihydro- 4 ~1y ~L VAY - 3 -
[ (2-phenylethyl)thio]-211 ~ n 2-one;
4-[2,3-Dihydro-4 hy~lLvAy-G oxo-5-[ (phenylmethyl)thio]-2H-
pyran-2-yl ] benzonitrile;
6- ( 4 -~rif 1UVL tl~y lphenyl ) -5, 6-dihydro-4 ~IyVL ~ Ay -
3- [ (phenylmethyl) thio] -2H-pyran-2-one;
6-(3,5-Dichlorophenyl)-5,6-dihydro-4 ~ydrvAy-
3- [ (phenylmethyl) thio] -2H-pyran-2-one;
_ _ _ _ . . . .... , .. . _ . _ _ _ _
WO 95114012 2 ~ ~ ~ Q ~ 3 PCrlUS94/12269
-- 12 --
6-(PentafluvLu~ ..yl~ -5, 6-dihydro-4-hydroxy-
3 - [ (phenylmethyl ) thio] -2H-pyran-2 -one;
5,6-Dihydro-4 ~yd-v~y-6-(3-
methylphenyl) -3- [ (2-phenylethyl) thio] -2H-pyran-2-one;
6- ( 2 -ChloL vyl~ ly 1~ -5, 6-dihydro-4 -
hydroxy-3-[ (phenylmethyl)thio]-2II pyL~n 2-one;
6-Butyl-5, 6-dihydro-4 ~y dLU~Y-
6-phenyl-3-[(phenylmethyl)thio]-2II ~yL-,n 2-one;
6 - [ l, l ' -B iphenyl ] - 4 -yl-6 -butyl-5, 6-dihydro-4 ^hydroxy-3 -
10 t (phenylmethyl)thio]-21I ~yLclll 2-one;
5,6-Dihydro-4 ~Y~1LUAY G p~.~= .yl~3~[ (phQnylmethyl)thio]-6-
propyl-2II ~y--,1. 2-one;
5,6-Dihydro-4-hydroxy-6-phenyl-3-[ (2-phenylethyl)thio~-6-
propyl-2H-pyran-2 -one;
~5 5,6-Dihydro-4 ~1ydLu~y G p~-Lyl G ph~1-yl-3-
[ (phenylmethyl)thio]-2II P~ 2-one;
5, 6 -Dihydro-4 lI~1L VAy -C p~ y 1 - 6 -phenyl - 3 - [ ( 2 -
phenylethyl) thio] -2H-pyran-2-one;
5, 6-Dihydro-4 ~ydLu~y-6- (3-methylbutyl) G phel.y1-3-
20 [ (phenylmethyl)thio]-2E-pyran-2-one;
5,6-Dihydro-4-hydroxy-6-(3-methylbutyl) G phe..yl-3-t (2-
phenylethyl) thio] -2H-pyran-2-one;
5, 6-Dihydro-4 11~ u,.y-6, 6-diphenyl-3-
[ (phenylmethyl)thio]-2E-pyran-2-one;
5,6-Dihydro-4 ~1~ lLu,.y-6,6-diphenyl-3-[ (2-
phenylethyl) thio] -2II ~yLcln 2-one;
5, 6-Dihydro-4 ~1ydLu~y-6-phenyl-6- (2-phenylethyl) -3-
[ (phenylmethyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4-hydroxy G ph~l~yl-6-(2-phenylethyl)-3-[ (2-
30 phenylethyl)thio]-2H-py-ran-2-one;
5, 6 -Dihydro-4 ~i d- u~y - 6 - [ 4 - [ 2 - ( 4 -
morpholinyl) ethoxy]phenyl] -6- (2-phenylethyl) -3-[ (2-
phenylethyl ) thio ] -2H-py-ran-2 -one;
1-[4-[3,6-Dihydro-4 ~1ydLv~.y-6-oxo-5-[ (2-
35 phenylethyl) thio] -2H-py-ran-2-yl]phenyl] -5-phenyl-lH-pyrrole-2-
propanoic acid;
Wo 95/14012 PCT/US94112269
-- 13 _
5,6-Dihydro-4 h~dLuAy-6-(3-methylbutyl)-3-t[2-(
methylethyl ) phenyl ] thio ] G p11el.y 1-2II elyL <1~1 2-one;
5, 6-Dihydro-4-11~ 1L U~y - G phenyl-6- t 2 -phenylethyl ) -3- [ [ 3 -
(phenylmethoxy) phenyl ] methyl ] -2H-pyran-2 -one;
5, 6-Dihydro-4-hydroxy-3 - [ 5-methyl-2 - ( l-
methylethyl ~ phenoxy] -6-phenyl-6- ( 2-phenylethyl ) -2H-pyran-2 -
one;
N- ( 1, l -D imethylethyl ) - l- [ t 3, 6-dihydro-4 h~ 1~ u,.y -6 -oxo- 2 -
phenyl-5-[ (2-phenylethyl)thio]-2H-pyran-2-yl]methyl]-
10 cy~lclh~
6-8utyl-3- [ ( l-ethyl-lH-indol-3-yl) thio] -5, 6-dihydro-4-
,Ay 6 ~ .-y 1-2H-pyran-2 -one;
5, 6--Dihydro--4 1IY~1LUAY--6--(4 ~Iy 1L u~y~11~llyl)--3--
t (phenylmethyl ) thio] -2H-pyran-2-one;
5,6-Dihydro-4 hylLuAy-6-(4 ~dLu~sy~henyl)-3-[(2
phenylethyl ) thio ] -2H-pyran-2 -one;
t4-[5, 6-Dihydro-4-hydroxy-2-oxo-3-t (phenylmethyl) thio] -
2II ~yL~-n G yl]phenoxy]acetic acid;
t4-t5~6-Dihydro-4-hydLvAy-2-oxo-3-[ (2-phenylethyl)thio]-
2 o 2H-pyran-6-yl ] phenoxy ] acetic acid;
[4-[5,6-Dihydro-4-hydroxy-2-oxo-3-t (phenylmethyl)thio]-
2H-pyran-6-yl]phenoxy]acetic acid ethyl ester;
[ 4 - [ 5, 6 -Dihydro-4 ~1~ uay -2 -oxo-3 - [ ( 2 -phenylethyl ) thio ] -
2II e,yLc.n G yl]phenoxy]acetic acid ethyl ester
5,6-Dihydro-4 h ydLu~y~6-t4-(2 h~v,-yethoxy)phenyl]-3-
[ (phenylmethyl ) thio ] -2H-pyran-2 -one;
5,6-Dihydro-4-hydroxy-6-[4-(2-hy~u~y~thoxy)phenyl]-3
t (2-phenylethyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4 :lydLu,.y-3-[(phenylmethyl)thio]-6-[4-[2-(4
30 1-h;l ~llolinyl)ethoxy]phenyl]-2H-pyran-2-one-S,S-dioxide;
5, 6-Dihydro-4 hy~L u,.y -3 - [ ( 2 -phenylethyl ) thio ] -6- [ 4 - [ 2 - ( 4 -
t-h i o ~holinyl ) ethoxy ] phenyl ] -2H-pyran-2 -one-S, S-dioxide;
4-[5,6-Dihydro-4-hydroxy-2-oxo-3-[ (phenylmethyl)thio]-2H-
pyran-6-yl ] benz o ic acid;
4-[5,6-Dihydro-4 ~ydLu.sy-2-Oxo-3-[ (2-phenylmethyl)thio]-
2H-pyran-6-yl ] benzoic acid;
WO 95114012 2 1 7 ~ ~ 4 3 pCT/US94/12269
-- 14 --
5, 6-Dihydro-4 ~ydLu~.y-6-[4-(l~y~lL~.~y '` yl)phenyl]-3-
[ (phenylmethyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4 hyllLu~y-6-[4-(hy-lLu-~y U.yl)phenyl]-3-[ (2-
phenylethyl)thio]-2H-pyran-2-one;
5, 6 -D ihydro-4 }.y~ u~.y -6 - ( 3 -methylbuty 1 ) -3 - [ 5 -methy 1-1-
(phenylmethyl) hexyl] G ph6,-yl-2H-pyran-2-one;
3-[l-(cyclohexylthio)-e r hylhexyl]-5,6-dihydro-4-
hydroxy-6-(3-methylbutyl) G pllelly1-21I ~yLan 2-one;
3-t2-CYclohexyl-l-[ (3-methylbutyl)amino]ethyl]-5,6-
dihydro-4 hydLu~y-6-(3-methylbutyl) G ph~ 1-2H ~L~I 2-one;
5, 6-Dihydro-4 -hydroxy-6- ( 3 -methylbutyl ) -3 - [ ( 4 -
methylpentyl) (phenylmethyl~amino] G ph_.-yl-2~ ~yLall 2-one;
5,6-Dihydro-4 hydLu~.y-G pl~ellyl~3~[ (phenylmethyl)thio]-6-
[ (tetrahydro-3-furanyl)methyl]-2H-pyran-2-one;
2, 3--Dihydro--4 l'lydLu~y G .JAU 2--phenyl--5--
[ (phenylmethyl)thio]-2H-pyran-3-acetamide;
2, 3-Dihydro-4 ~y~ u~y-6-oxo-2-phenyl-5-
[ (phenylmethyl) thio] -2H-pyran-3-butAn~
5--(4--HydLu~y~u~yl)--5,6--dihydro--4 }y-lLu.~Ly-G pl~ -yl--3-
20 [ (phenylmethyl) thio] -2H-pyran-2-one;
5, 6-Dihydro-4 I'~ydL UAy - G ~llelly 1-3 - [ ( 2 -phenylethyl ) thio ] -
2 (lH) -pyridinone;
5,6-Dihydro-4 I.ydLu.~y-l-methyl G plle~lyl~3~[ (2-
phenylethyl ) thio ] -2 ( lH~ -pyridinone;
Phenylmethyl 2-(1-methylethyl)-2-[[3,6-dihydro-4-hydroxy-
6-oxo-2-phenyl-5- [ (2-phenylethyl) thio] -2H-pyran-2-
yl]methyl]hydrA7;n~cArboxylate;
N-[l-[ [3, 6-Dihydro-4 ~-ydLu..y-6-oxo-2-phenyl-5-[ (2-
phenylethyl ) thio ] -2H-pyran-2-yl ] methyl ] cyclopentyl ] ur~a;
N-[1-[ [3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[ (2-
phenylethyl)thio]-2H-pyran-2-yl]methyl]cyclopentyl]-N'-
(phenylmethyl ) urea;
Phenylmethyl [1-[ [3,6-dihydro-4 1~y~Lu~y-6-oxo-2-phenyl-5
[ ( 2 -phenylethyl ) thio ] -2H-pyran-2 -
3S yl]methyl]cyclopentyl]~,aLl,au~e;
6-[ (2,3-Dimethyl-lH-pyrrol-1-yl)methyl]-5,6-dihydro-4-
hydroxy-6-phenyl-3- [ (2-phenylethyl) thio] -2H-pyran-2-one;
~ WO 95/14012 2 ~ 7 6 ~ ~ ' PCI/US94/1226s
5,6-Dihydro-4-llydLu~y-G-[2-(l-piperazinyl)ethyl] -6-
phenyl-3 - t ( 2 -phenylethyl ) thio ] 2H-pyran-2 -one;
5, 6-Dihydro-4 h~ 1L c ,.y-6- r 2 - ( 4 -morpholinyl ) ethyl ] -6-
phenyl-3 - [ (phenylmethyl ) thio ] -2H-pyran-2 -one;
5,6-Dihydro-4-hydroxy-6-r3-(4-morpholinyl)propyl]-6-
phenyl-3-[ (phenylmethyl) thio] -2H-pyran-2-one;
5, 6-Dihydro-4 h~ 1L u~y G [ 4 - ( 4 -morpholinyl ) butyl ] -6-
phenyl-3-[ (phenylmet_yl)thio]-2H-pyran-2-one;
5,6-Dihydro-4 ~ydL~ y-G [2-(4-thit 1holinyl)ethyl]-6-
10 phenyl-3-[ (phenylmethyl)thio]-2H-pyran-2-one;
5,6--Dihydro--4 }:~lL~y--6--[3--(4-~hi~ ~I.olinyl)propyl]--6--
phenyl-3-[ (phenylmethyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4 l~ydL~Ay-6-[4-(4-thi~ ~,holinyl)butyl]-6-
phenyl-3-[ (phenylmethyl)thio]-2H ~JyL.51- 2-one;
5,6-Dihydro-4-hydroxy-6-[2-(1-piperazinyl)ethyl]-6-
phenyl-3-[ (phenylmethyl)thio~-2H-pyran-2-one;
5,6-Dihydro-4-hydroxy-6-[3-(1-piperazinyl)propyl]-6-
phenyl-3-[ (phenylmethyl)thio]-2H-pyran-2-one;
5, 6 -D ihydro-4 hy 1L u~y -6 - [ 4 - ( 1 -piperaz inyl ) butyl ] - 6 -
2 O phenyl-3 - [ (phenylmethyl ) thio ] -2~-pyran-2 -one;
5, 6 -Dihydro-4 ~1L .~-y -6 - [ 2 - ( 4 -methyl -1-
piperazinyl) ethyl] -6-phenyl-3- [ (phenylmethyl) thio] -2H-pyran-2-
one;
5, 6-Dihydro-4 -hydroxy-6- [ 3 - (4-methyl-1-
2 5 p iperaz inyl ) propyl ] -6 -phenyl -3 - [ (phenylmet_yl ) thio ] -2 H-pyran-
2-one;
5, 6 -Dihydro-4 hy dL ~ y - 6 - [ 4 - ( 4 -methyl -1-
piperazinyl)butyl]-6-phenyl-3-[ (phenylmethyl)thio]-2H-pyran-2-
one;
5~6-Dihydro-4-hydroxy-6-t2-(4-morpholinyl)ethyl]-6
phenyl-3-[ (2-isopropylphenyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4 h~lL.,--y-6-[3-(4-morpholinyl)propyl]-6-
phenyl-3 - [ ( 2 -isopropylphenyl ) thio] -2H-pyran-2 -one;
5,6-Dihydro-4 hylLu,.y-6-[4-(4-morpholinyl)butyl]-6-
35 phenyl-3- [ (2-isopropylphenyl) thio] -2H-pyran-2-one;
5,6-Dihydro-4 hydL~y-6-[2-(4-thi~ ~holinyl)ethyl]-6-
phenyl-3-[ (2-isopropylphenyl)thio]-2H-pyran-2-onei
_ _ _ _ . , . _ .. .. _ _ _ _ . ,
WO 95/14012 2 1 ? ~ 3 PCrlU594/12269 ~
5, 6 -Dihydro-4 ~.~1L v,-y -6 - t 3 - ( 4 -~h; ~hol inyl ) propy 1 ] - 6 -
phenyl-3-[ (2-isopropylphenyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4 ~ydLu~y-6-[4-(4-thi~ ~holinyl)butyl]-6-
pheny l- 3 - [ ( 2 - i sopropy lphenyl ) thio ] - 2 H-pyran-2 -one;
s 5, 6 -Dihydro-4 -hydroxy- 6- [ 2 - ( 1-p ipera z inyl ) ethyl ] - 6 -
phenyl-3 - t ( 2-isopropylphenyl ) thio ] -2H-pyran-2 -one;
5,6-Dihydro-4 hy~u.~y-6-[3-(1-piperazinyl)propyl]-6-
phenyl-3-[ (2-isopropylphenyl)thio]-2H-pyran-2-one;
5,6-Dihydro-4 ~ydLu~y-6-[4-(l-piperazinyl)butyl]-6
phenyl-3-[ (2-isopropylphenyl) thio] -21I pyL~ 2-one;
5, 6-Dihydro-4 ky-lL u~y-6- [ 2 - ( 4 -methyl-1-
piperazinyl)ethyl] G phe~lyl-3-[ (2-isopropylphenyl)thio]-2H-
pyran-2-one;
5, 6 -D ihydro-4 hy 1L u,,y -6 - [ 3 - ( 4 -methyl -1-
lS piperazinyl)propyl] G ~ yl-3-[ (2-isopropylphenyl)thio]-2H-
pyran-2-one;
5, 6-Dihydro-4 -hydroxy-6 - [ 4 - ( 4 -methyl-1-
piperazinyl)butyl]-6-phenyl-3-[ (2-isopropylphenyl)thio]-2H-
pyran-2-one;
5,6-Dihydro-4 1IY-1LU~Y3-[ (2-isopropylphenyl)thio]-6-(3-
morpholin-4-yl-3 ~".UyL v~y 1 ) G pherly 1-2H-pyran-2 -one;
5,6-Dihydro-4 ~IydLu~y-3-[ (2-isopropylphenyl)thio]-6-(4-
morpholin-4-yl-4-oxobutyl) G pherlyl-2H-pyran-2-one;
5,6-Dihydro-4 hydLuAy-3-[ (2-isopropylphenyl)thio]-6-(5-
25 morpholin-4-yl 5 u~u~erlLyl) G p~ llyl-2H-pyran-2-one;
5,6-Dihydro-4 ~IydLu~y-3-[ (2-isopropylphenyl) thio]-6-(3-
~hi~ ~holin-4-yl-3 ul~v~L~yl) G phellyl-2H-pyran-2-one;
5,6-Dihydro-4-hydroxy-3-[ (2-isopropylphenyl)thio]-6-(4-
thiomorpholin-4-yl-4 o~v~uLyl)-6-phenyl-2H-pyran-2-one;
5, 6-Dihydro-4-hydroxy-3-[ (2-isopropylphenyl)thio]-6- (5-
1-h;~ ~hvlin-4-yl 5-vxuy6:llLyl) G ph~lyl-2H-pyran-2-one;
5, 6-Dihydro-4 -hydroxy-3 - [ ( 2 -isopropylphenyl ) thio ] -6- ( 3 -
piperazin-l-yl-3 oxvl,Lv~l)-6-phenyl-2H-pyran-2-one;
5, 6-Dihydro-4 hydL v-~y-3 - [ ~ 2 -isopropylphenyl ) thio ] -6- ( 4-
3s piperazin-1-yl-4 ~ u~lLyl) G p~lel.yl-2H-pyran-2-one;
5,6-Dihydro-4 1IYdLU~Y-3-[ (2-isopropylphenyl)thio]-6-(5-
piperazin-1-yl 5 ~v~ Lyl)-6-phenyl-2H-pyran-2-one;
~ W095/14012 2~Q43 PCr/US94112269
1~ --
5, 6-Dihydro-4 }Iydr~.y ~3 ~ [ (2 -isopropylphenyl) thio ~ -6- r 3 ~
(4-methylpiperazin-1-yl) _3_VAU~LUL,Y1] -6-phenyl-2H-pyran-2-one;
5, 6-Dihydro-4 hyllLu~.y-3-[ (2-isopropylphenyl) thio] -6-[4-
(4-methylpiperazin-1-yl) -4-oxobutyl] -6-phenyl-2H-pyran-2-one;
5,6-Dihydro-4 liyJ~vAy-3-[ (2-isopropylphenyl)thio]-6-[5-
(4-methylpiperazin-1-yl)-5 ~/AV~ .~yl] G phe,.yl-2H-pyran-2-one;
5, 6-Dihydro-4-~1y.lL~Ay-3- [ (phenylmethyl) thio] -6- (3~
morpholin-4-yl-3 .~LU~L~yl) G phc~yl-2H-pyran-2-one;
5, 6-Dihydro-4 ~1~lL~lAy-3- t (phenylmethyl) thio] -6- (4-
10 morpholin-4-yl-4 ~ LuLyl) G ph_.~yl-2~-pyran-2-one;
5,6-Dihydro-4-:.ydL~Ay-3-t (phenylmethyl)thio]-6-(5-
morpholin-4-yl 5 ~AU~ ILyl) G ph~"2 1-2H-pyran-2-one;
5, 6-Dihydro-4 -hydroxy-3 - t (phenylmethyl ) thio ] -6- ( 3 -
thi- ~l,olin-4-yl-3 VAV~LV~,2'1) G p~ y1-2H-pyran-2-one;
5,6-Dihydro-4 ~y~Ay~3~[ (phenylmethyl)thio]-6-(4-
thi~ ~I,olin-4-yl-4 v~-vL--~yl) G pl~el~l-2H-pyran-2-one;
5, 6-Dihydro-4 hy~lL ~.Ay-3 - [ (phenylmethyl) thio] -6- (5-
~hiomorpholin-4-yl 5 ~,Av~_,,Lyl)-6-phenyl-2H-pyran-2-one;
5, 6-Dihydro-4 ~1ylL~Ay-3- [ (phenylmethyl) thio] -6- (3-
20 piperazin-1-yl-3 ~ V~JL-~yl) G pll~.-yl-2H-pyran-2-one;
5,6-Dihydro-4-hydroxy-3-t (phenylmethyl)thio]-6-(4-
piperazin-1-yl-4 ~Au~uLyl) G phc-lyl-2II pyL~,l 2-one;
5,6-Dihydro-4-hydroxy-3-t (phenylmethyl)thio]-6-(5-
piperazin-1-yl 5 oxv~ yl) G pl.~-.yl-2H-pyran-2-one;
5,6-Dihydro-4-hydroxy-3-t (phenylmethyl)thio]-6-t3-(4
methypiperazin-1-yl)-3 ~AU~LU~yl] G-pl~-lyl-21I ~lL~l~ 2-one;
5,6-Dihydro-4-hydroxy-3-t (phenylmethyl)thio]-6-[4-(4-
methylpiperazin-l-yl)-4 ~,AvLu-yl]-6-phenyl-2II ~L-n 2-one;
5,6-Dihydro-4-hydroxy-3-[ (phenylmethyl)thio]-6-[5-(4-
methylpiperazin-1-yl) 5 uAu~c,.~yl]-6-phenyl-2H-pyran-2-one;
Methyl 2-t-butyl-3 - [ [ 5, 6-dihydro-4 hydL UAy-2 -oxo-6-
phenyl-6-(2-phenylethyl) -2H-pyran-3-yl]thio]benzoate;
5 - [ 3, 6 -Dihydro-4 -hy 1L UAy -5- [ [ 5 -methyl -3 - ( 3 -
pyridinylmethoxy) -2 -isopropylphenyl ] thio ] -6-oxo-2 -phenyl-2~-
35 pyran-2-yl]pentanoic acid;
3-[[5-Ethyl-2-(1-methyl-2 hy~LuAyc-llyl)phenyl]thiO]-5~6
dihydro-4 ~yd~uAy -6,6-dipheny1-2II ~y r-~1 2-one;
, _ _ _ , . . . . . . _ _ _ _ . _ _ _
WO 95/14012 2 ~ 7 6 Q 4 3 PCT/US94/12269
-- 18 --
5 - [ 5 - [ ( 2 -Cyclopenty l-5 -isopropylpheny l ) thio ] -3, 6 -dihydro-
4 llylLu~y-6-oxo-2-phenyl-2II ~yLCIII 2-yl]pentanoic acid;
5, 6-Dihydro-4 }IydL u~y -6- ( 3 -methylbutyl ) G phe~ly 1-3- [ [ 2 -
[2-(3-pyridinyl)ethyl]phenyl]thio]-2II ~yLan 2-one;
5,6-Dihydro-4-~.ydLu,.y-3-[[5-(2 ~.ydLu,.yethyl)-3-(2-
phenylethyl)-2-isopropylphenyl]thio] G ~1le-,yl-6-(2-
phenylethyl ) -2H-py-ran-2 -one;
4 - [ [ 5, 6 -Dihydro-4 hy ~ u~y -2 -oxo-6, 6 -diphenyl-2H-pyran-3 -
yl]thio]-2 ~ylLu~yindarle;
3-[[4,5-Diethyl-2-(1 l.ydLu~yeLllyl)phenyl]thio]-5,6-
dihydro-4 h~lLv~.y-G p~.e..yl-6-(2-phenylethyl)-2II pyL-Il 2-one;
5,6-Dihydro-4 ~I~u~.y-3-[ (2-isopropyl-5-
methylphenyl)methyl]-6-(2-phenylethyl) G p~. ..yl-2H-pyran-2-
one;
5,6-Dihydro-4 hy~u~.y-3-[ (3 ~ly~U~y l.l-yl-2-isopropyl-5-
methylphenyl)methyl]-6,6-diphenyl-2II ~yLCIII 2-one;
5, 6 -Dihydro-4 h ~ ~ UAy - 3 - [ [ 4 -
( l-y dL u~y Lhyl ) phenyl ] methyl ] G pell ~y 1-6 -phenyl - 2H-pyran-2 -
one;
5,6-Dihydro-4 ~IydLu.~y-3-[ (3-llylLu~y~llellyl)methyL]-6-(2
phenylethyl ) G phelly 1-2H-pyran-2-one;
5, 6-Dihydro-4 -hydroxy-G -pellLy 1-6-pheny1-3 - [ [ 4 - (pyridin-3 -
yLmethoxy) phenyl] methyl ] -2H-pyran-2-one;
5, 6-Dihydro-4 hy dL u..y - 3 - [ [ 2 - isopropyl-3 - [ 2 - (morphol in-4 -
25 yl) ethoxy~phenyl]methyl]-6- (2-phenylethyl) G phe--yl-2H-pyran-
2-one;
5, 6-Dihydro-4 hy-lL u~y -3 - ( 3 -methyl- 1-phenyl-but-2 -enyl ) -
6, 6-diphenyl-2H-pyran-2-one;
3-[ (1,4-Di-tert-butyl-lH-imidazol-2-yl)thio]-5,6-dihydro-
30 4-hydroxy-6-(2-phenylethyl) G pher~yl-2H-pyran-2-one;
5, 6 -Dihydro-4 hy dL u~y - 6 - ( 3 -methylbutyl ) - 3 - ( 3 -methyl - 1-
propyl-but-2 -enyl ) -6-phenyl-2H-pyran-2 -one;
5, 6-Dihydro-4 ~IydL u~.y-3 - [ [ 2 -
(1IY~1L~J~Y 'c` yl)phenyl]~nethyl]-6- (2-phenylethyl) G phellyl-2H-
35 pyran-2-one;
3-Diisobutylamino-5, 6-dihydro-4 ~IydLu~.y~6~ 6-diphenyl-2H-
pyran-2-one;
~ Wo 951t40t2 2 ~ 7 6 ~ 4 ~ PCT/US9411226s
-- 19 --
5,6-Dihydro-4 IydLu~y-6-(2-phenylethyl) G pl~ yl-3-tN-
phenyl -N-propylamino ) -2H-pyran-2 -one;
3- (3, 4-Dihydro-2H-quinolin-1-yl) -6-hexyl-5, 6-dihydro-4-
hydroxy-6-phenyl-2H-pyran-2 -one;
5,6-Dihydro-4 hyviu~y-3-[ (2-isopropyl-5-
methylphenyl) amino] -6, 6-diphenyl-2H-pyran-2-one;
6 -Butyl - 3 - [ ( 1, 4 -di-tert-buty l -lH-imidazol -2 -yl ) amino ] -
5,6-dihydro-4 ~ v~y G p~.~..y1-2H-pyran-2-one;
6-Butyl -3 - ( 3, 5-dimethylphenyl ) -5, 6-dihydro-4 hy lL v~y -6-
10 phenyl-21I ~yL~n 2-one;
3-[4-[ (Phenylr-l~u-.y)methyl]-l-tert-butyl-lH-imidazol-2
yl]-5,6-dihydro-4 h~lLuAy-6-(2-phenylethyl) G ph~:llyl-2H p
2-one;
3- (1-tert-Butyl-4-methyl-lH-pyrrol-2-yl) -5, 6-dihydro-4-
15 hydroxy-6,6-diphenyl-2II pyL<I~I 2-one;
6- [ 2- r 4 - ( 5, 5-Dimethyl-4, 5-dil~ ~ v .,..~zo1-2-
yl)phenyl]ethyl]-5,6-dihydro-4-hydLu~y-3-[ (2-isopropyl-5-
methylphenyl) thio] -6-phenyl-2H-pyran-2-one;
6 - [ 2 - [ 4 - ( 4, 4 -Dimethyl-4, 5-dil~ ~L U ~ CI Z ol-2 -
2 0 yl ) phenyl ] ethyl ] -5, 6-dihydro-4 ~ ~ u3Ly-3~ [ ( 2-isopropyl-5-
methylphenyl) thio]-6-phenyl-2H-pyran-2-one;
6- [ 2 - [ 4 - ( 1, l-Dioxoth i 1 ~ullolin-4-yl ) phenyl ] ethyl ~ -5, 6-
dihydro-4 ~l~dLu~.y-3-[ (2-isopropyl 5 - ylphenyl)thio]-6-
phenyl-2H-pyran-2 -one;
1-Hydroxy-4-[2-[4 ~IydLu~y-5-[ (2-isopropyl-5-
methylphenyl) thio] -6-oxo-2-phenyl-3, 6-dihydro-2H-pyran-2-
yl ] ethyl ] -lH-pyridin-2 -one;
5, 6 -Dihydro-4 h~ ~ v,~y -6- [ 2 - ( lH-indol-5-yl ) ethyl ] -3 - [ ( 2 -
isopropyl ~ - Lhylphenyl)thio] G ph~.-yl-2H ~yLC-II 2-one;
3o 5, 6-Dihydro-4-hydroxy-6- (2-phenylethyl) -6-phenyl-3- (2-
phenyl- [ 1, 3 ] dithiolan-2 -yl ) -2H-pyran-2 -one;
5, 6-Dihydro-4 ~Iy IL u~y - 3 - [ ( 2 -isopropyl-5-
methylphenyl)thio]-6-(2-phenylethyl) -6-[4-[ (pyridin-3-
yl ) methoxy ] phenyl ] -2H-pyran-2 -one;
5,6-Dihydro-4 ~ v.~y-3-[(2-isopropylphenyl)thio]-6-
phenyl-6- [ 5- (phenylmethyl ) amino-2, 2 -dimethyl-pentyl ] -2H-pyran-
2-one;
.. .. . _ .. . _ . . _ _ _ _ _ . .
WO 95/14012 PCr/US94/12269
2~ ~6~3
-- 2~ --
5-[4-Hydroxy-5-[ (2-isopropylphenyl)thio]-6-oxo-2-phenyl-
3,6-dihydro-2II ~yLail 2-yl]-4,4-dimethyl p~..Lanoic acid
benzylamide;
1-[2-[4-Hydroxy-5-[ (2-isopropylphenyl)thio]-6-oxo-2-
5 phenyl- 3, 6 -dihydro-2ll ~y L all 2 -yl ] - l -pheny lethyl ] -3 -pyridin- 2 -
ylmethylurea;
5,6-Dihydro-4 hy-lLu~y-6-(5 hydLu.syuahLyl) -3-[ (2-
isopropylphenyl)thio]-6-phenyl-211 ,yLa., 2-one;
5-[4-Hydroxy-5-[ (2-isopropyl 5 Ll~ylphenyl)thio]-6-oxo-
10 2-phenyl-3, 6-dihydro-2H-pyran-2-yl]r^-t~n~ acid, tert-butyl
ester;
6-[4-(4,4-Dimethyl-4,5-di~.y~Lu uAazO1-2~yl)butyl]-5~6
dihydro-4 hydLu~.y-3-[ (2-isopropylphenyl)thio] G phe~lyl-2H-
pyran-2-one;
l-[[3,5-Dihydro-4 ~y-lLu.. y-5-[(2-isopropylphenyl)thio]-6-
oxo-2 -phenyl-2H-pyran-2 -yl ] methyl ] cyclohexyl ] methyl r lr~:~m;
acid phenylmethyl ester;
5,6-Dihydro-4-hydroxy G pl,~l-yl-3-[ (phenylmethyl)thio]-6-
[2- (4-pyridyl) ethyl] -2H-pyran-2-one;
5,6-Dihydro-4-hydroxy-6-[2-(5 ~ydLu~y~2~
methylphenyl) ethyl] -6-phenyl-3- [ (phenylmethyl) thio] -2H-pyran-
2-one;
5, 6-Dihydro-4 }~y dL u~y - G [ 2 - ( 3 - (morpholin-4 -
yl)phenyl)ethyl]-6-phenyl-3-[ (phenylmethyl)thio]-2H-pyran-2
25 one;
5, 6 -D ihydro- 4 -hydroxy- - 6 - [ 2 -phenylethyl ] -3 -
[ (phenylmethyl) thio] -6- (4-pyridyl) -2H-pyran-2-one;
5, 6-Dihydro-4 ~IydL u.~y -6-phenyl-3 - [ (phenylmethyl ) thio ] -6-
[2- (2-thienyl) ethyl] -2r~-pyran-2-One;
6-[2-(2-Furyl)ethyl]-5,6-dihydro-4-hydroxy-6-phenyl-3-
[ (phenylmethyl ) thio ] -2r~-pyran-2 -one;
5, 6-Dihydro-4 -hydroxy-6-phenyl-3 - [ (phenylmethyl ) thio ] -6-
[2-(lH-pyrrol-2-yl) ethyl]-2H-pyran-2-one;
5 - [ 4 -Hydroxy-5- [ ( 2-isopropylphenyl ) thio ] -6-oxo-2 -phenyl-
3, 6-dihydro-211 ~yLan 2-yl]pentanoic acid methyl ester;
5- [4-Hydroxy-5- [ (2-isopropylphenyl) thio] -6-oxo-2-phenyl-
3,6-dihydro-2H-pyran-2-yl]pentanoic acid ethyl ester;
. ~
WO 95/14012 PCT/US94/12269
2 1 1f~3
-- 21 --
5-[4-Hydroxy-5-[ (2-isopropylphenyl)thio]-6-oxo-2-phenyl-
3, 6-dihydro-2H-pyran-2-yl]p~n~ ic acid propyl ester;
5-[4-Hydroxy-5-[ (2-isopropylphenyl) thio] -6-oxo-2-phenyl-
3, 6-dihydro-2H-pyran-2-yl]pentanoic acid isopropyl ester;
s 5 - [ 4 -Hydroxy-5 - [ ( 2 -isopropylphenyl ) thio ] -6 -oxo-2 -phenyl -
3,6-dihydro-2H-pyran-2-yl]pentanoic acid tert-butyl ester;
5-[4 11~-lLu~-y-5-[ (2-isopropylphenyl)thio]-6-oxo-2-phenyl-
3,6-dihydro-2H-pyran-2-yl]pentanoic acid benzyl ester;
[3-[4-Hydroxy-5-[ (2-isopropylphenyl)thio]-6-oxo-2-phenyl-
10 3,6-dihydro-2H-pyran-2-yl]propyl] ~ iC acid tert-butyl
ester;
[3-[4-~1L~Y-5 [ (2-isopropylphenyl) thio] -6-oxo-2-phenyl-
3,6-dihydro-2H-pyran-2-yl]-propyl]-carbamic acid benzyl ester;
l-Benzyl-3-{3-[4 hy~u~y-5~[ (2-isopropylphenyl)thio]-6-
oxo-2-phenyl-3, 6-dihydro-2H-pyran-2-yl] -propyl}-urea;
4-[4-Hydroxy-5-[ (2-isopropylphenyl) thio]-6-oxo-2-phenyl-
3, 6-dihydro-2H-pyran-2 -yl ] -butane-l-sulf onic acid benzylamide;
4-[4 I;YdL~,~Y_5_[ (2-isopropylphenyl)thio]-6-oxo-2-phenyl-
3,6-dihydro-2H-pyran-2-yl]-butane-1-sulfonic acid amide;
4 1IydL~y-3-[ (2-isopropyl, - ylphenyl)thio]-6-phenyl-
5, 6-dihydro-lH-pyridin-2-one;
4-Hydroxy-3-[ (2-isopropyl 5 - Lhylphenyl)thio]-6-phen
6- (2-phenylethyl) -5, 6-dihydro-lH-pyridin-2-one;
3 -Hydroxy-2 - [ ( 2 -isopropyl 5 -- Lhy lphenyl ) thio ] -5-phenyl -
25 5-(2-phenylethyl)-cyclohex-2-enone;
3 -Hydroxy-2 - [ ( 2 -isopropyl-5-methylphenyl ) thio ] -5 -phenyl-
cyclohex-2 -enone;
4-Hydroxy-3 - [ (2-isopropyl-5-methylphenyl ) sulfonyl ] -6-
phenyl-6- ( 2 -phenylethyl ) -5, 6-dihydro-2H-pyran-2-one;
4-Hydroxy-3- (2-isopropylbenzoyl) G pl~ yl-6- (2-
phenylethyl) -5, 6-dihydro-2H-pyran-2-one;
4 -Hydroxy-3 - [ tl~ y imino (phenyl ) methyl ~ -6-phenyl-6 - ( 2 -
phenylethyl) -5, 6-dihydro-2H-pyran-2-one;
4-Hydroxy-3-[methylimino(phenyl)methyl]-6-phenyl-6-(2-
35 phenylethyl) -5, 6-dihydro-2H-pyran-2-one;
2,3-Dihydro-4' hy~L~y-3~3-dimethyl-5~-[ (2-
isopropylphenyl )
. _, . . . ,,, , _, . _ _ _ _ _ . _ , ~
WO9~/14012 2 ~ 43 PCrrUSs4/12269
thio]-spiro[4H-l-benzvi,yL. -. 4,2'-[2H]pyran]-6' (3'H)-one;
2, 3 -Dihydro-4 ' -hydroxy-2, 2 -dimethyl-5 ' - [ ( 5 -methyl-2 -
isopropylphenyl)thio]-spiro[lH-indene-1,2'-[2H]pyran]-6' (3'H)-
one;
2, 3 -Dihydro-4 ' -hydroxy-5 ' - [ ( 5-methyl-2 -
isopropylphenyl)thio]-spiro[lH-indene-1,2'-[2H]pyran]-6' (3'H)-,
one;
4 " -Hydroxy-5 " - [ ( 5-methyl-2 -isopropylphenyl ) thio ] -
dispiro[cycluyLù~an~ 1,2'(3'H)-[lH]indene-1',2"-[2H]pyran]-
10 6" (3"H) -one;
3,4-Dihydro-4' IydLvAy-5~-[ (5-methyl-2-
isopropylphenyl)thio]-spiro[naphthalene-1(2H) ,2'-t2H]pyran]-
6 ' (3 'H) -one;
3, 4-Dihydro-4 ' hy~ u~.y-2, 2-dimethyl-5 ' - [ (5-methyl-2-
15 isopropylphenyl)thio]-spiro[naphthalene-1,2'-[2H]pyran]-
6' (3'H)-one;
3 ', 4 ' -Dihydro-4 " -hydroxy-5" - [ ( 5 -methyl-2 -
isopropylphenyl)thio]-dispiro[cyclopropane-1,2' (l'H)-
naphthalene-l' ,2"[2H]pyran]-6" (3"H)-one;
4-Hydroxy-3- (2-isopropylphenoxy) -6-phenyl-6- (2-
phenylethyl) -S, 6-dihydro-2H-pyran-2-one;
4 TTy~lLv~y-3-(2-isopropyl 5 -- ylphenoxy)-6-phenyl-6-(2-
phenylethyl) -5, 6-dihydro-2H-pyran-2-one;
3-(2-tert-Butylphenoxy)-4 hy-lLv,.y G ~ y1-6-(2-
25 phenylethyl)-5,6-dihydro-2H-pyran-2-one;
5 - [ 5 - ( 2 -Cyc lopenty lphenoxy ) - 4 ~IydL u,.y -6 -oxo-2 -pheny l -3, 6 -
d ihydro- 2H-pyran-2 -yl ] pont;- n~ ic acid;
4 -Hydroxy-3 - ( 2- isopropyl-5 - y lphenoxy) -6- ( 2 -
phenylethyl) -6-propyl-5, 6-dihydro-2H-pyran-2-one;
3 o 6-Cyclopentylmethyl-4 -hydroxy-3 - ( 2-isopropylphenoxy) -6-
phenyl-5, 6-dihydro-2H-pyran-2-one;
3- (Cyclopropylphenylamino) -4-hydroxy-6-phenyl-6- (2-
phenylethyl) -5, 6-dihydro-2H-pyran-2-one;
N- [ 3 - [ Cyclopropyl [ 4 -hydroxy-2 -oxo-6-phenyl-6- ( 2 -
35 phenylethyl) -5, 6-dihydro-2H-pyran-3-
yl]amino]phenyl]~on7Onoslllfonamidei
WO 9S~14012 ~ 4 ~ PCI~/US94/12269
-- 23 --
t3-[CYclopropylt4 hy~lL~Ay-2-oxo-6-(2-phenylethyl)-6-
propyl-5,6-dihydro-2H-pyran-3-yl]amino]phenyl]amide quinoline-
8-sulfonic acid;
3- (Cyclopropylphenylamino) -4-hydroxy-6- (2-phenylethyl) -6-
5 propyl-5, 6-dihydro-2H-pyran-2-one;
4 IIy~LuAy-6-isobutyl-6-(2-phenylethyl)-3-
(phenylpropylamino) -5, 6-dihydro-2H-pyran-2-one;
N- [ 4 -Hydroxy- 2 ~JAU G pl~ y 1 -6 - ( 2 -phenylethyl ) -5, 6 -
dihydro-2H-pyran-3-yl] l~ ph~..yl-met h~n~-s--l fonamide;
N-[6-(2-Benzo[1,3]dioxol-5-yl-ethyl)-4 ~dLuAy-2-oxo-6-
phenyl-5, 6-dihydro-2H-pyran-3 -yl ] -N- ( 3 -
methylbutyl) kor~7~ clll fonamide;
3-[Cyclopentyl(cyclopentylmethyl)amino]-4 ~IydLuAy-6-
phenyl-6- (2-phenylethyl) -5, 6-dihydro-2H-pyran-2-one;
4 II~ dL UAy - 3 - [ methoxy ( phenyl ) methyl ] C ph_.-y 1-6 - ( 2 -
phenylethyl)-5,6-dihydro-2II pyLall 2-one;
3-[Cyclopentyl(cyclopentyloxy)methyl]-4-~,y~LuAy-6-(2
phenylethyl) -6-propyl-5, 6-dihydro-2H-pyran-2-one;
3 - ( 1-Cyclopentyloxy-3 -methylbutyl ) -4 h~ 1L UAY -6- ( 3 -
methylbutyl) -6-phenyl-5, 6-dihydro-2H-pyran-2-one;
6-Cyclopentyl-3 - [ cyclopentyl ( isul~L U~UAy ) methyl ] -4-
hydroxy-6- ( 3 -methylbutyl ) -5, 6-dihydro-2H-pyran-2-one;
4 II~lL UAY-3- [ (2-isopropylphenyl) thio] -6- (2-phenylethyl) -
6-propyl-5, 6-dihydro-2H-pyran-2-one;
4 -Hydroxy-6-isobutyl-3 - [ ( 2 -isopropyl-5-
methylphenyl) thio] -6- (2-phenylethyl) -5, 6-dihydro-2H-pyran-2-
one;
3-[ (2-tert-Butyl-furan-3-yl)thio]-4-hydroxy-6-phenyl-6-
(2-phenylethy1) -5, 6-dihydro-2H ~y L<~11 2-one;
3 0 4 -Hydroxy-3 - [ ( 3 -isopropyl-pyridin-4 -yl ) thio ] -6-phenyl-6-
( 2 -phenylethyl ) -5, 6-dihydro-2H-pyran-2-one;
3-[ (2-Cyclopentyl-pyridin-3-yl)thio]-4 ~IydLuAy G p~llLyl-
6-phenyl-5, 6-dihydro-2H-pyran-2-one;
4 -Hydroxy-6 - isobutyl - 3 - [ ( 3 - isopropyl -isoxaz o l -4 -y 1 ) thio ] -
6- (2-phenylethyl) -5, 6-dihydro-2H-pyran-2-one;
5-[ (2-Isopropyl-~-methylphenyl)thio]-6-oxo-2-phenyl-2-(2-
phenylethyl) -3, 6-dihydro-2H-pyran-4-yl acetic acid ester;
Wo 95/14~12 Pcrluss4ll2269
2~7~4~ --
-- 24 --
2-[2-(3enzo[1,3]dioxol-5-yl)ethyl]-5-[ (2-isopropyl-5-
methylphenyl) thio] -6-oxo-2-phenyl-3, 6-dihydro-2H-pyran-4-yl
propionic acid ester;
5-[4-Isobutyryloxy-5-[ (2-isopropylphenyl)thio]-6-oxo-2-
5 phenyl-3,6-dihydro-2H-pyran-2-yl]-pentanoic acid;
N-[3-[Cyclopropyl[4-(acetyloxy) -5,6-dihydro-2-oxo-6-
phenyl- (2-phenylethyl) -2H-pyran-3-yl]methyl]phenyl] -
k~n~n~c~ll fonamide;
Propanoic acid 5-[cyclopropyl[3-
10 [ (phenylsulfonyl) amino]phenyl]methyl] -3, 6-
di1~ydrv G o,.u 2,2-diphenyl-2H-pyran-4-yl ester;
2,2-Dimethylbutanoic acid 3,5-dil-y~v G OXv 2-(2-
phenylethyl)-5-(1-phenylpropyl)-2-propyl-2H-pyran-4-yl ester
and
~r~n-on~cet;C! acid 5-[cyclopropyl[3-
[ (ethylsulfonyl)amino]phenyl]methyl]-3,6-di1lydLv G .,~v 2- (2-
phenylethyl) -2-propyl-211 ~y ,~n 4-yl ester.
~, . DR~ TT.l2n ~L,O~ OF TlII~ L~ r~
Here, the term "alkyl" means a straight or branched
20 hydrocarbon radical having from 1 to 12 carbon atoms unless
otherwise specified ancl inrl~ C, for example, methyl, ethyl,
n-propyl, isopropyl, n butyl, sec-butyl, isobutyl, tert-butyl,
n-penty1, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decy1,
undecyl, and dodecyl. The alkyl groups may contain one or
25 more sites of u..~tuL,ltion such as double or triple carbon-
carbon bonds. The alkyl group is unsubstituted or substituted
by from 1 to 3 substituents selected from alkyl, alkoxy,
thioalkoxy all as defined herein, hydroxy, thiol, nitro,
halogen, amino, f ormyl, carboxy1, nitrile, -NH-CO-R, -CO-NH-,
30 -CO2R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and
heteroaryl are def ined as herein .
The term "cycloalkyl" means a 1IYdLVVr11~UI~ ring which
contains from 3 to 12 carbon atoms unless otherwise specified,
for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
35 and adamantyl. Where pr~ccihle~ the cycloalkyl group may
contain double bonds. The cycloalkyl ring may be
unsubstituted or substituted by from 1 to 3 substituents
_ _ _ _ _ .. . _ . .. . _ .. . . .. .. _ . _
WO gS114012 PCT~US94n2269
~ 2 ~ 7G~3
-- Z5 --
seloc~od alkyl, alkoxy, thiC~A~lknYy all as defined herein,
hydroYy, thiol, nitro, halo~en, amino, formyl, carbo. yl,
nitrile, -NH-CO-R, -CO-N~R-, -CO,R, -COR, aryl, or heteroaryl
wherein alkyl (R~, aryl, and heteroaryl are defined as herein.
The term alkylcycloalkyl means a cycloalkyl group as
defined above attached directly to an aLkyl group as defined
above .
The terms "alko~y" and "th i OA 1 kf~xyN are O-alkyl or S-
alkyl as defined above for alkyl.
The term spirocycle refers to a .i~-LLo~y~;lic or
heterocyclic ring whose ends meet at a single carbon in a
chain or another ring.
The term NarylN means an aromatic radical which is a
phenyl group, a benzyl group, a naphthyl group, a biphenyl
15 group, a pyrenyl group, an anthracenyl group, a fluarenyl
group or a fused ring resulting from any two of phenyl,
naphthyl, and a 5- or 6- r ~ d ring containing from 0 to 3
heteroatoms soloctod from gll;nnlnno~:, icoqninnlones~ indoles,
indanes, benzofurans, benzoth;nrhono~, hen7~Y~7~1es,
20 benzothiazoles, bon7inyA7olos~ coumarins, bon7;mir~A7~1es and
the like, unsubstituted or substituted by 1 to 3 substituents
selocte~l from alkyl as defined above, alkoYy as defined above,
;oAlknYy as defined above, hydroxy, thiol, nitro, halogen,
amino, formyl, carboYy, nitrile, -N~ICOR, -CO~IR, -CO2R, -COR,
25 aryl, or heteroaryl wherein aLkyl (R), aryl, and heteroaryl
are def ined as above .
The terms "heteroaryl" and "heterocycle", Ll=yLase~,~ed by
an "Ar", mean a heterocyclic radical which is 2- or 3-thienyl,
2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-
30, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-
isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-;~AYA7Q1Y1
3- or 5- 1, 2, 4-triazolyl, 4- or 5- 1, 2, 3-triazolyl,
tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl,
2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, s-, 6-, 7-,
35 or 8-guinolinyl, l-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl,
2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-
benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-hon7~YA7olyl, 2-, 4-, 5-
W095/14012 2 1 7 ~ 3 PCTIUS94/12269
-- 26 --
, 6-, or 7-~hr~n7i~;~9A7clyl~ 2-, 4-, 5-~ 6-, or 7-
benzothiazolyl, 1- or 2-piperazinyl, 2-, 3-, or 4-morpholinyl,
2-, 3-, or 4-th; 1 uholinyl, 1-, 2-, or 3-pyrrolidinyl, 2- or
3-tetrahydrofuranyl, 2-, 3-, or 4-tetral.y~Lu~yLrlllyl~ 2- 3-, or
5 4-piperidinyl, 1-, 2-, 4-, 5-, or 6-tetral.y~L~J~yLimidinyl~ 2-
igYnl ;nyl~ 2-, 4--, or 5-;~ll;AA70l ;t9;nyl, 1-, 2-, 3-, 4-, 5-,
6-, or 7-indolinyl, unsubstituted or substituted by 1 to 2
substituents selected from alkyl as defined above, aryl as
defined above, alkoxy as defined above, ~ h;sAlk~xYy as defined
10 above, hydroYy, thiol, nitro, haloqen, formyl, amino,
carboYyl, nitrile, -NHCOR, -CO2R, -COR, wherein alkyl in as
def ined above or phenyl .
"~Ialogen" is f luorine, chlorine, bromine or iodine .
Some of the . of Formula 1 are capable of further
lS forming rhA~^e~ltically acceptable acid-addition and/or base
salts. All of thesè fol~ms are within the scope of the present
invention.
phArr--~utically acceptable acid addition salts of the
of Formula 1 include salts derived from nnnt nY;c
20 inorganic acids such as hydrochloric, nitric, rhrsphrricr
sulfuric, I~YI1LV~L~ ;C, hydriodic, hydrofluoric, phosphorous,
and the like, as well as the salts derived from nontoxic
organic acids, such as aliphatic mono- and tl;r~rhnyylic acids,
phenyl-substituted ~1 lkAnnir~ acids, hydroxy AlkAnnir acids,
2S AlkAn~r~injr acids, aromatic acids, aliphatic and aromatic
sulfonic acids, etc. Such salts thus include sulfate,
pyrosulfate, bisu1fate, su1fite, bisulfite, nitrate,
phosphate, -h~!~Lu~ L ~ Ate, dilly~Lug~ l-hns~hAte,
~L nSrh~te~ ~yL~-~hg~LhAte~ chloride, bromide, iodid~,
30 acetate, trifluoroacetate, propionate, caprylate, isol:u~yL~te,
oxalate, malonate, succinates suberate, sebacate, fumarate,
maleate, mandelate, ben2oate, chlorobenz02te, methylbenzoate,
dinitrobenzoate, phthalatQ, hr~n7r~ncoll1 fonate,
tol~ n-~slll fonate, phenylacetate, citrate, lactate, maleate,
35 tartrate, methAnr~clll fonate, and the like. Also contemplated
are salts of amino acids such as arginate and the like and
gluconate, galacturonate (see, for eYample, Berge, S.N., et
_ _ _ _ _ _ _ _ _ _ _ _
WO 95/14012 2 1 ~ ~ ~ 4 3 Pcr/rTss4/l2~76s
-- 27 --
al., "Pharmaceutical Salts, " Journal o~ Pha~ uLical
Science, 66: 1-19 (1977).
The acid addition salt of said basic '- are
p.apa.~d by contacting the free base form with a sufficient
5 amount of the desired acid to produce the salt in the
conventional manner.
ph~r7~--eutically acceptable base addition salts are
formed with metals or amines, such as alkali and Alk~l ;nP
earth metals or organic amines. æxamples of _etals used as
10 cations are sodium, potassium, 7~7~~gn-~cjum, calcium, and the
like. Examples of suitable amines are N,N'-
dibenzylethyl~n~ m;n~, ChloLv~7 ~,~,aine, choline,
~;ethAnolamine, dicyclohexylamine, ethyl~n~diAm;n~ N-
methylglucamine, and procaine (see, for example, Berge, 5.,~.,
15 et al., '~phAr7--reutical Salts, " Journal of ph. Lical
Science, 6C: 1-19 (1977).
The base addition salts of said acidic are
prepared by contacting the free acid form with a sufficient
a_ount of t~e desired base to produce the salt in the
20 conventional man~ er.
Certain of the c '- of the present invention can
exist in unsolvated forms as well as solvated forms, ;nrllld;
hydrated forms. In general, the solvated for_s, ;nrl7l;;n~
hydrated forms, are equivalent to unsolvated forms and are
25 intended to be C:ll -csed within the scope of tle present
invention .
Certain of the ~ '- of the present invention possess
one or more chiral centers and each center may exist in the
R(D) or S(L) configuration. The present invention ;nrll7d~c
30 all enantiomeric and epimeric forms as well as the appropriate
mixtures thereof.
The _ _ '- of the present invention can be ~L-~ared
and administered in a wide variety of oral and parenteral
dosage forms. Thus, t~e u.-ds of the present invention
35 can be administered by injection, that is, i-lLLav~luu~ly,
i~lLL, ~ ul i-rly, intracutaneously, subcutaneously,
intrad~r~d~nAl ly, or intraperitoneally. Also, the of
_ _ _ _ _ _ _ . , . ... _ . ~ . , .. , _ _ _ _ _ _
Wo 95/14012 pcrNss4ll2269
~17~0`~3
-- 28 --
the present invention can be administered by inhalation, for
example, intranasally. Additionally, the a_ of the
present invention can be administered trAnC~Prr-11y. It will
be obvious to those skilled in the art that the following
5 dosage forms may comprise as the active L, either a
' of Formula l or a vuLL~ "l;n~ rhArr-~P~ltically
acceptable salt of a _ ' of Formula l.
For preparing rh~r~-~Plltical compositions from the
" of the present invention, rhArr--pl7ticAlly
10 acceptable carriers can be either solid or liquid. sOlid form
pLe:p~L -tions include powders, tablets, pills, cArs~ c,
cachets, suppositories, and dispersible granules. A solid
carrier can be one or more substances which may also act as
tli11~Gntc, flavoring agents, binders, pL ec~L V~ Lives, tablet
15 disintegrating agents, or an Pn~-~rclllAting material.
In powders, the carrier is a f inely divided solid which
is in a mixture with the f inely divided active
In tablets, the active is mixed with the
carrier having the n~c ~c~, y binding properties in suitable
20 proportions and compacted in the shape and size ~lPc;rpd
The powders and tablets preferably contain from five or
ten to about seventy percent of the active '. Suitable
carriers are magnesium v ~LLv..ate, r~n~ci~lm stearate, talc,
sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,
2~ methylc~lln1ose~ sodium clLL~ y ylcellulose, a low melting
wax, cocoa butter, and the like. The term "preparation" is
intended to include the f ormulation of the active ~ '
with PnrArs~ ting material as a carrier providing a capsule
in which the active ~ L with or without other carriers,
30 is ~uLL~u--ded by a carrier, which is thus in association with
it. Similarly, cachets and lozPn~c are inrlllrlP~ Tablets,
powders, cArsl~1pc~ pills, cachets, and lozenges can be used as
solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a
35 mixture of fatty acid glycerides or cocoa butter, is first
melted and the active _ is dispersed ~ -~llc1y
therein, as by stirring. The molten ~ , ~ mixture is
WO 9S/14012 pcTnrs94n2269
2 ~ 7~43
-- 29 --
then poured into convenient sized molds, allowed to cool, and
thereby to solidify.
Liguid form preparations include solutions, 5-lcpPn-i-nc,
and emulsions, for example, water or water propylene glycol
5 solutions. For paL~r.LeL,-l injection liguid pre~a dtions can
be formulated in solution in agueous polyethylene glycol
solution .
Agueous solutions suitable for oral use can be yL~ ed
by dissolving the active _ ~ in water and adding
10 suitable colorants, flavors, stabi1izing and thi~-k-ni1-j agents
as desired.
Agueous sllcr-nci~n~ suitable for oral use can be made by
dispersing the finely divided active L in water with
viscous material, such as natural or, synthetic gums, resins,
15 methylt--111l1ose, sodium caL~ y U1y1~ 1os~, and other
well-known Sllcr_n~lin~ agents.
Also included are solid form preparations which are
intended to be converted, shortly before u6e, to liguid form
~l~paL~-Lions for oral administration. Such liguid forms
20 include -ol~ nc, suspensions, and ~ lcit~nC. These
preparations may contain, in addition to the active ~- -n_nt,
colorants, flavors, st-hi 1 i 7_rS, buffers, artificial and
natural sweeteners, di:,ye.~ Ls, thirk_n_rs, Solllh; 1 i 7in~
agents, and the like.
The ph~rr~c-lltical preparation is preferably in unit
dosage form. In such form the ~ c,tion is divided into unit
doses containing appropriate ~uantities of the active
. The unit dosage f orm can be a p~-k~cd
~LI:~aL~lLion, the package containing discrete guantities of
3o preparation, such as packeted tablets, ~rS-l1_c, and powders
in vials or l--s. Also, the unit dosage form can ~e a
capsules, tablet, cachet, or lozenge itself, or it can be the
appropriate number of any of these in p_t~k~_d form.
The guantity of active in a unit dose
35 preparation may be varied or adjusted from 0. l mg to lO0 mg
preferably 0 . 5 mg to lO0 mg according to the particular
application and the potency of the active -nt. The
. . , _ . , . , , . _ _ _ _ _ ,,
WO 95114012 Pcr~S94112269
~ ~ 7~43
-- 30 --
composition can, if desired, also contain other compatible
therapeutic agQnts.
In therapQutic use as antagonists of a retroviral
protease, as agents f or the trQatment of inf ections causQd by
5 a rQtroVirus in~lu~3ing HIV, or as agents for the treatment of
~;CO~CPC due to AIDS, the ' utilizQd in the
r~ P~tical method of this inVQntion are administerQd at
thQ initial dosage of a]~out 0 . Ol mg to about lO0 mg/kg daily.
A daily dose range of about 0 . Ol mg to about lO mg/kg is
10 preferred. The dosages, howevQr, may be variQd ~PrPn~lin~ upon
the reguirements of the patient, the severity of the condition
being trQated, the ~ ' being employQd. DetQrmination of
thQ proper dosage f or a particular situation is within the
skill of the art. GQnQrally, LL~ai is initiatQd with
15 6mallQr dosages which are less than the optimum dose of thQ
- _ '. Thereafter, thQ dosage is incrQased by small
il'l-,L~ Ls until the optimum, effect under the cir.~Lances is
reached. For convenience, the total daily dosage may be
divided and administered in portions during the day, if
20 desired .
4 . l GenQral Synthetic Approaches
to S . 6-Di~ L ~ L ~lle Derivatives
Scheme I, shown below, illustrates the ~Le:~_L~tiOn of
25 suostituted di1~ylL~yL~,,es ITI.
3S
~ WO95114012 2 ~ 76943 PCr/US94/12269
-- 31 --
SC}I~MR I
CH~ R 2, ~IBuLi R, R2 ~ ute N OH
O OH
0 ~ E~ I~/E
R7~ O~o 1 71\ o~O
II m
E ~
Methyl Ac~to~retate ~I) is treated seql~ntiAlly with a metal
hydride, preferably sodium hydride, in TEIF or ether at -20 C
to +l0 C, and with a a~Lull~el base, usually n-~3uLi, in a
solvent such as THF or ether at -20 C to +l0 C, producing
20 the dianion. The reaction mixture is quenched with an
.Lu~Liately substituted aldehyde or ketone, allowed to react
for an additional 15 minutes to 24 hours, and finally worked
Up, fllrn;chin~ the ,~-keto lactone (dilly~u~yLu~1e) II.
C II is elaborated into target pyrones III via
25 ~ L~:al ' with a suitable electrophile, such as a
thiotosylate, an alkyl halide or the like, in ethanol or DMF
solution containing an inert base such as triethylamine and/or
sodium bicarbonate at 25 C to 80 C.
For ~uL~oses of the above and other synt_eses of the
30 ~ 'C of the present invention, reactive f11nrtirnAl groups
present in starting materials, reaction int~ - iAters, or
reaction products may be protected during cho~irJ~l reactions
using protecting groups which render the reactive functional
groups substantially inert to the reaction conditions. (See
35 f or example , Protective Groups in Organic Synthesis, 2 ed ., T .
W. Green and P. G. Wuts, John Wiley ~ Sons, New York, NY
l99l). Thus, for example, protecting groups such as the
. _ _ _ _ _ , . . . _ . . _ _ . .,
Wo 95114012 2 l ~ ~ 13 4 ~ PcrluS94/12269 ~
following may be u~ili7--~ to protect suitable amino, hydroxyl,
and other groups of related reactivity: carboxylic acyl
groups, such as formyl, acetyl, trifluoroacetyl;
alkoxycarbonyl groups, such as ethu,.yvc-lLul~yl, t- -
S butoxycarbonyl (BOC), ,~, ~"B-trichluLu~-l.u~y. aLLG..yl (TCEC), ,B-
io~ YyuclLLv1-yl; arylu--yuarLv--yl groups, such as
benzylu..y-,aLLu..yl~ p ~ Lhu~yL.al~zylu~yuaLLullylr
pl.o.~v~.y~ LLv.1yl; trialkyl silyl groups, such as trimethylsilyl
and t-butyld;- Lhylsilyl (TBDNS); and groups such as tri~yl,
10 tetrall~ dL u ~yrally 1~ vinylu~y~;a~ Lu--y l, o-ni ~L uy1-e1-y lsulf enyl,
diphenylrh(~srh;nyl~ p-~ n~c~lfonyl, and benzyl, may all be
Ut~ 1; 7-~d- The protecting group may be removed, after
completion of the synthetic reaction of interest, by
yLvcedur~:s known to those skilled in the art. For example,
15 the BOC group may be removed by acidolysis, the trityl grour
by IIYdLU~.IO1YSiS~ TBDMS by treatment with fluoride ions, and
TCEC by ~L ea i - with z inc .
scheme II describes an alternate synthesis of
dil1ydLv~yLùiles which are substituted at C-3.
WO 95/14012 2 1 7 6 0 4 3 PCT/US94/12269
SCHEN13 II
O O O O
5 R~ CH3 RO CH 3
Cl n
1. ba~e HSR
2. X-CH2-R4 4
l0 \ V /NaOR
\~ O O ~ 4
RO ' CH 3
Y-R4
V
Y = CHl r S r or O
R~ s unsubstituted or substituted
aL~yl or aryl
R = aLlcyl
O OH
/~` 1. diL NaOH ~ \\/' 4
V Ba~e (2 equiv~, R~ R2 ~ 2. d}L HCI ~ R
R2
Vl
wo 95/14~12 2 ~ ~ ~ 0 4 ~ PCr/US94112269
-- 34 --
The acetoacetate T is treated with a base, such as sodium
hydride or sodium ethoxide, in a suitable solvent such as THF,
ether, or alcohol at -20 C to 10 C, and the resulting anion
5 is qll ~n~-h~ with an appropriately substituted alkyl or benzyl
halide, usually the bromide or iodide, to give ketoester V (Y
= CH2). Alternatively, chloroacetoacetate IV is rQacted with
a thiol, preferably in the ~ sence of a suitable base such as
triethylamine, piperidine, or pyridine, in a suitable solvent
10 such as dichluL. -n~, at -10 C to +25 C, affording
ketoester V (Y = S) (see Z. Yoshida et al., l'etrahedron 26:
2987 (1970) ) . The requisite thiols can be ~L~aL~ from the
LV.L~ iin~ phenol via the li - Rwart leaLL~-~g L (see,
for example, H. Kwart and H. Omura, J. Amer. Chem. Soc. ~3:
15 72S0 (1971); M. S. Newman and F. W. ~etzel, Org. Syn. Coll.
Vol. V~: 824 (1988); N. 5. Newman and H. A. Rarnes, J. Org.
Chem. 3': 3980 (1966) ) or from the CVLL ~ ;n~ ior~rO~C~n7~n~
via a nucl~nrhil;c diSplA t with thiourea in the ~L~=s~nc~
of a nickel catalyst (R. Takagi, Chem. Letters, 1307 (1985) ) .
20 similarly, reaction of IV with an ~lkr~Yitl~ in a suitable
solvent such as benzene, DMF, or mixtures of THF and H~PA, at
-10 C to 25 C, yields ~-etoacet:~te V (Y = O) (see T. Sasaki
et al., T~ hed~v~l 38: 85 (1982)). Tnt~ te V is
s~hc~Tl~ntly elaborated into dih~lLu~-v--e~ ~rI using the
25 general yLvc~duL~ outlined in Scheme I above.
Analogs possessing amino substituents at the 3-position
can be ~L~ ed as shown in Scheme III.
3S
WO 9S/140~2 ~ 1 7 6 0 4 3 PCI'IUS94J12269
~ 35 --
S III
R5 ` OH O O
R6 / ~ O-- l. LDA ~ R1 ~ ` ~
VII R2 , N ~
OH R5 R6
10 2. ! !~
R~OR
R2 VIII
OH R5
~N<
R1 '` ' O"~ O
R2
X
Ester VII is treated with a suitable base, such as
25 lithium diisopropylamide, in a suitable solvent such as TH~ or
ether, at -78 C to 0 C, and the resulting anion is reacted
with an appropriately substituted acylating agent such as
ester VIII, producing ketoester I~. Cyclization of IX by e . g .
I_Lt~ t L with a suitable base such as sodiu_ hydroxide or
30 sodium ~lk~Yi~.o yields desired dihy~u~yLunes X.
Any of the 4 hy~v~y-2iI pyLCLlJ 2-ones such as III, VI, or
X can be constructed to contain an dy~Lu~riate leaving group
(such as halogen, acetate, tosylate, etc. ) in one of the R1 or
R2 substituents. Such leaving groups can be displaced by
35 pri_ary or 50~ r y amines to further c~mhol l; -:h the Rl or R2
substituents. Such disp~ would be carried out in
alcohol or DNF or DNSO at -10 to 125C. Likewise, if Rl or
Wo 95/14012 PCr/US94/12269
~t760~
-- 36 --
R2 contain a carboYylic acid related group, then further
chemistry on that group would further omhol 1; Qh the R1 or R
substituents. Such reactions would include esterification or
amide formation using methods well known in the 2rt.
S Fur~ , 4 ~,ylLu--y--2t~ pyri~;nnn~c such as SI,
shown below, are known in the art (e.g. see ~.J. Ashton et
al ., ~eterocycles 28: (2) 1015 (1989) ), and can be converted to
desired protease inhibitors and antiviral agents ~n~loq~llc to
the 5,6-dillydLu~yLulles by using rol~tionQ similar to that used
l0 for conversion of II ~ III shown in Scheme I above.
OH
R-- N/~O
R'
substituted 1, 3-cy~ nh~Y5~n~1; nn~-c can be prepared as
described by Werbel (see J. I~ed. Cl~em. 35: 3429-47 (1992) and
references cited therein). The l~3-cy~lnhoY~In~9innoc can be
converted to substituted analogues using reactions similar to
25 those used for conversions II ~ III.
Tetrahydro (thio) pyran-2, 4-dione derivatives can be
prepared as described in United States Patent 4, 842, 638 and
references cited therein. The tetrahydro(thio)pyran-2,4-
diones can be converted to various substituted analogues using
30 reactions similar to those used for conversions of II -- III.
Derivatives containing a thio moiety at the 3-position
can also be ,~)L epO~L ~d as shown in Scheme IV:
WO 95~14012 ~ ~ 7 6 ~ ~ 3 PCr/US94/1226s
-- 37 --
SCHEME IV
s~
OH ~ ~
~ NEIS ~"
R~ 0 ~0
0 R2 R b
II X~l
OH
~5~ ,x
--7`o ~0
R2
XIII
DillydLu~yLune II is treated with a suitable brominating
agent, such as N bL~ _ nim;d~, in a suitable solvent, such
as t-butanol, for l to 18 hours. The resulting bromo
i nt ~ ~ '; ate XII is reacted with a thiol, usually in the
pl ~=st1.ce of an a~L U~L iate base such as pyridine or
25 piperidine, in a suitable solvent such as dichloromethane at
0C to +25C to afford desired product XIII.
An alternate synthesis of derivatives containing a carbon
substituent at the 3-position is shown in Scheme V.
wo 95/14012 2 ~ 7 ~ PcrluS94/12269
-- 38 --
SCHRMR V
o
OH o O ~ R
R-Asyl: HoX CN, CH3 CI~
/~ R/'`~Cl, b~se ~"~ R-Alkyl: D~P, 0CH3
R2 R2
II ~ XlV
OX o OH
~R N.1~3H ~ R
5 ~O ~0 3 R
R2 R2
X V XVI
The di}~ydL~ylulle II is reacted with a suitable acid
chloride, and the product is rearranged to give int~ ';Ate
XV according to ~OCP~L~S outlined in l~.S. Patent 4,842,638
(1989). The keto group of XV is reduced to the methylene with
an a~L-~riate reducing agent, such as sodium ~ y-~lOb~lL~Iy-lLide
25 or 11YdLUgt~i~ in the presence of a catalyst, to afford
XVI .
In Scheme VI, an optional method f or preparing certain 4 -
hydroxy-2H-pyran-2-ones (such as III or VI) with complex amide
containing side chains as R. or R2 is shown.
~o 95/14012 2 1 7 ~ 0 4 3 PCT/IJ594/12269
-- 39 --
SCE~EME V
R8 R8
o~ DMF~C~2C~
XVIII
XVII
,R5
~ R
O "~/
Rs ~ I \ ~'
~ ~ O ~0 dianion ~\
0 R8 R8 R7 R6
XX XIX
The prerequisite acid XVII ~ .red by literature
conditions is cyclized to the lactone XVIII in DMF and
dichl~,L. Ll~clne at t~ ~ILuL.., of 0 to 75C. l~e lactone is
25 ring opened by the appropriately substituted amine either neat
or in solvents such as toluene, at 75 - 110C to produce
ketone amide XIX. This amide XIX is treated with the dianion
as descri~ed in Scheme I to produce the lactone XX which is
; dF~nt i c 1 l to II where R1 is equal to the new amide containing
30 chain. XX can be converted to the target ,_ ' using
- conditions described in Scheme I.
The , JUII"15 of the present invention can exist in their
tautomeric forms, i.e. the enol and keto forms shown in Scheme
I. Both such forms as well as their mixtures are preferred
3 ,; aspects of the instant invention .
WO95/140i2 2 1 76~ PCrlUS94/12269
-- 40 --
The substituted phenylpropioph~n~na~ were ~L~paLed by
llydL~y~llation of the cuLr~ l;n~ chalcones in
tetra~lydLuruLGll with 5% Pd on BaSû~ as cata~yst.
The rh~lr~nas were prepared according to Rohler and
5 Chadwell Org. Synth. Coll. Vol. I, 78, 1941.
.2 P --? ~ for the PL~ . of
5, 6-Dih2~1Lvr~Lv..e Deriv~tives
Gener~ tho~ 1.
, ~ Nethyl ~r~to~retate was added dropwise to a slurry of
exane was,.ed sodium hydride in ~ y.lL~ tetrallydL~,LuLa.. at
o oc and the reaction stirred at 0 C (15 minutes to 1 hour).
n-Butyl lithium was then added at 0 C and the reaction
stirred at 0 C (15 minutes to 1 hour). The aldehyde or
,5 ketone, in tetra~ly~L~,LuL~Il, was added to the dianion and the
reaction stirred at 0 C (15 minutes to 24 hours) and allowed
to warm to room t~ ~LUL~: (15 minutes to 24 hours). To the
reaction mixture was a~ded water and the mixture allowed to
stir 15 minutes to overnight. After extracting with diethyl
20 ether, the aqueous layer at 0 C was acidified with acid(2-6N
HCl) to pH 1-2 and the aqueous layer extracted with ethyl
acetate or CH2C12. The organic extracts of the acid solution
were, ` in~d, dried over NgSO~ and c .,.- l ~ted.
25 Esample A.
s,6-Dih~d _ ~-h2~v~2 6 r~ 2~-pyr~n-2-on- t~)
The title c ' was prepared as described in General
Method 1 using 13.67 g methyl ~reto~cetate, 8.5 g of NaH 60%
dispersion in oil, 73 . 6 mL of 1. 6 M n-butyl lithium in hexane,
30 10 g of ~an7~1dahyde, and 300 mL of tetrallydL~LuLan. After
addition of the aldehyde, the reaction was stirred 15 minutes
at -78 C then allowed to warm to room ~ ~- atuL~ overnight.
A solid was filtered off after cu.. ellLLe.tion (m.p. 145-
146 C). lH N~ (CDC13) ~ 2.8-3.05 (m, 2 H), 3.5 (d, 1 H),
35 3.7 (d, 1 H), 5.7 (dd, 1 H), 7.3-7.5 (m, 5 H).
~ WO95114012 21 760~3 PCr/US94112269
-- 41 --
lS~mple B.
5~ 6-Dihy~lro-~ 1L~A~- 6 (2-methylpropyl) 6 r~ yl-2~ .. n 2-
one ~ I )
The title _ ' was pL ~pal ed as described in Genera
5Nethod 1 using 12 g methyl acetoacetate, 4 . 3 g of NaH 60%
dispersion in oil, 64.5 mL of 1.6M n-butyl lithium in hexane,
10 g of iso-valerorhQn~n~, and 300 mL of tetral y~LvruLal-.
After addition of the phenone, the reaction was stirred 15
minutes at -78 C and 2 hours at room t~ aLuL~a. The crude
10 reaction was f lash chromatographed using hexane/ethyl ace~ate
6/40-40/60 as eluent. The solid was triturated from diethyl
ether (m.p. 123.5-125 C). 1H NNR (CDCl3) ~ 0.81 (d, 3 H),
0.89 (d, 3 H), 1.6-1.7 (N, 1 H), 1.91 (m, 2 H), 2.90 (d, 1 H),
2.95 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.25-7.45 (m, 5
15 H)-
E~ample C.
5, 6-Dihydro-~ k~lL~,, 6 (4-metkv~, yl) -2~E~p,~--h 2-one, t I )
The title _ was ~L ~paL t:d as described in General
20 Method 1 usinq 5 mL of methyl acetoacetate, 2 . 0 g of NaH 60%
dispersion in oil, 25 mL of 2.0 M n-butyl lithium in hexane,
7. 0 mL of 4-methvAy~v~ ohyde and 150 mL of tetra~.y lLuruLan.
After addition of the aldehyde, the reaction was stirred for
15 minutes at 0 C then allowed to warm to room temperature
25 overnight. The crude product was triturated from diethyl
ether to afford a solid (m.p. 159-162 C (dec. ) ) . 1H NMR
(CDCl3) ~ 2.91 (dd, 2 H), 3.57 (dd, 2 H), 3.83 (s, 3 H), 5.66
(dd, 1 H), 6.93-6.97 (m, 2 H), 7.30-7.34 (m, 2 H).
30 E~ample D.
5, 6-Dihydro-~ -hydroxy-6- r ~- (methylthio) phenyl] -2~ ~ LC~l 2 -one,
~ -- )
~he title ~ ' was prepared as described in General
Method 1 using 10 mL of methyl ~eto~retate, 4 . o g of NaH 60%
35 dispersion in oil, 60 mL of 1.6 N n-butyl lithium in hexane,
18.8 mL of 4-methylthioh~n7~ hyde and 200 mL of
tetral,~ùLuLa~.. After addition of the aldehyde, the reaction
. . ~
WO 95/14012 PCr/USs4/12269
2~Q~ --
-- 42 --
was stirred for 15 minutes at 0 C then allowed to warm to
room t - ~ Lu~ e overnight . The crude product was triturated
from diethyl ether to afford a solid (m.p. 139-141 C). lH
NMR (CDC13) ~ 2.51 (s, 3 H), 2.92 (dd, 2 H), 3.58 (dd, 2 H),
5 5.68 (dd, l H), 7.27-7.31 (m, 4 H).
r
E~ pl~ E
5,6-Dihydro-~ h~d.v,~ 6 (4-DIethylphenyl)-2I[ E~ ~ 2-on~
The title ' was prepared as described in General
10 Method l using lO mL of methyl acetoacetate, 3.7 g of NaH 60%
dispersion in oil, 58 mL of l. 6 M n-butyl lithium in hexane,
10.9 mL of p-tolu~ lDhyde and 250 mL of tetrah~ur~,~
After additiûn of the aldehyde, the reaction was stirred for
15 minutes at 0 C thQn allowed to warm to room t~ CltULCI
15 overnight. The crude product was triturated from diethyl
ether to afford a solid (m.p. 138-139 C). lH NMR (CDCl3) ô
2.39 ~s, 3 H), 2.93 (dd, 2 H), 3.58 (dd, 2 H), 5.69 (dd, 1 H),
7.23-7.31 (m, 4 H).
2 0 B~npl~ F .
6-t~-~1,1-Dimethylethyl)phe~yl]-5,6-dih~dlv ~-h~dLV~-2~-
pyr~n-2 -one, ~ t ~
The title ~- _ ' was pL"~7 ~=d as described in General
Method l using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60%
25 dispersion in oil, 31.5 m.. of 1.6 M n-butyl lithium in hexane,
9.0 g of 4-(l,l-dimetllylethyl)kDn7~ Dhyde and 100 mL of
tetral.yv~LvLuL~l~l. After addition of the aldehyde, the reaction
was stirred for 15 minutes at 0 C then allowed to warm to
room ~ ~LUL-: overnight. The crude product was triturated
from diethyl ether to afford a solid (m.p. 164-165 C). lH
NMR (CDCl3) ô 1.33 (s, 9 H), 2.94 (dd, 2 H), 3.59 (dd, 2 H),
5.69 (dd, 1 H), 7.31-7.47 (m, 4 H).
I~mple e.
6-(~-ChloL-~ ~1)-5,6-~ihy~ro-4 h~dlv~ 21E-pyran-2-ono, (~ )
The title ~ _ ' was prepared as described in General
Method 1 using 10 mL of methyl ~cet~re~te, 3.9 g of NaH 60%
~ WO95/14012 2 ~ 7~3 PCrlUS94ll226s
-- 43 --
dispersion in oil, 58 mL of 1.6 M n-butyl lithium in hexane,
13.5 g of 4-chluL ~h~ hyde and 250 mL of tetra~ly.llvLuLi~n.
After addition of the aldehyde, the reaction was stirred for
15 minutes at 0 C then allowed to warm to room temperature
5 overnight. The crude product was triturated from diethyl
ether to afford a solid (m.p. 149-150 C). ~H NMR (CDCl3)
2.83 (dd, 1 H), 2.95 (dd, 1 H), 3.60 (dd, 2 H), 5.67 (dd, 1
H), 7.33-7.44 (m, 4 H).
10 ~ple ~.
6-~3-Chl~,Lv~k_r-~1)-5,6-dihydro-~ ~alv~ 21r ~l~ 2-one, ~+)
The title _ ' was ~ar~d as described in General
Method 1 using 5 . O mL of methyl A~ eto~ret~te, 2 . O g of NaH 60%
dispersion in oil, 25 mL of 2. 0 M n-butyl lithium in hexane,
15 6.5 mL of 3-chluL ~ hyde and 150 mL of tetrahydLvLuL~
After addition of the aldehyde, the reaction was stirred for
15 minutes at 0 C then allowed to warm to room t~ ~LULC:
overnight. The crude product was triturated from diethyl
ether to afford a solid (m.p. 122-124 C). lH NMR (CDCl3) ô
20 2.83 (dd, 1 H), 2.96 (dd, 1 H), 3.60 (dd, 2 H), 5.68 (dd, 1
H), 7 . 25-7 . 42 (m, 4 H) .
r4pl~ I
5,6-Dihy~ro-~ L~arv~ 6 [~-~ph~nyl Lk~,")ph~nyl]-211 ~ . 2-
25 on~, ~+)
The title ~ _ ' was prepared as described in General
Method 1 using 5 . 0 mL of met_yl acetoacetate, 2 . 0 g of NaH 60%
dispersion in oil, 25 mL of 2. 0 M n-butyl lithium in hexane,
12 . 0 g of 4-benzyloxybenzaldehyde and 150 mL of
30 tetral,y-lLvLuLcl~l. After addition of the aldehyde, the reaction
was stirred for 15 minutes at 0 C then allowed to warm to
room t~, o.LUL~ overnight. The crude product was triturated
from diethyl ether to afford a solid (m,p. 165-166 C). ~H
NMR (CDCl3) ô 2.91 (dd, 2 H), 3.56 (dd, 2 H), 5.09 (s, 2 H),
35 5.65 (dd, 1 H), 6.98-7.04 (m, 2 H), 7.30-7.44 (m, 7 H).
W095/14012 2 l 7 6 0 ~ j PCTIUS94/~269
-- 44 --
B~pl~ J
6-[~ -Biphony~ -yl-5r6-~ihycro-~ h~.v,~-2~ L~.n 2-one,
( _ )
me title c ~, u~ was prepared as described in General
S Method 1 using 13.0 g of ethyl a~ etoAcetate, 5.3 g of NaH 50%
dispersion in oil, 60 mL of 1.6 M n-butyl lithium in hexane,
16.3 g of 4-biphenylcarb~YAl~hyde and 300 mL of
tetrahydLuruLa~. After addition of the aldehyde, the reaction
was stirred f or 15 minutes at 0 C then allowed to warm to
10 room t~ aLuL~ overnight. me crude product was triturated
from diethyl ether to afford a solid (m.p. 150-152 C). 'H
NMR (CDCl3) ~ 2.97 ldd, 2 H), 3.60 (dd, 2 H) 5.77 (dd, 1 H),
7.27-7.68 (m, 9 H).
15 E~ple l;
6-[[~1,1'-Biphcnyl)-~-ylo~y]r4 thyl]-5,6-tli~d v ~ .v,~-2H-
pyran-2-one, ~t)
The title ~ ' was pL~aled as described in General
Method 1 using 4.76 g of methyl acetoacetate, 1.97 g of NaH
20 50% dispersion in oil, 19.5 mL of 2.1 M n-butyl lithium in
heYane, 8.~ g of [[1,1'-biphenyl]-4-yloxy]-AcetAl~lGhyde and
200 mL of tetrally lLuruL~-. After addition of the aldehyde,
the reaction was stirred for 60 minutes at 0 C then allowed
to warm to room t~ ~It.UL a overnight . The crude product was
25 triturated from diethyl ether to afford a solid (m.p. 152-
154 C). lH NNR (CDCl3) ~ 2.83 (dd, 1 H), 2.95 (dd, 1 H) 3.61
(dd, Z H), 4.23 (dd, 1 H), 4.38 (dd, 1 H), 5.03-5.07 (m, 1 H),
6.94-6.98 (m, 2 H), 7.30-7.57 (m, 7 H).
30 Esample L.
6- t l, l ~ -Biph~nyl] - ~ -yl-6-~utyl-5, 6-dihydro-~ h / ~- v,~ -2~ n
2-one ~ I )
The title ~ was ~L~ Led as described in General
Method 1 using 13 g ethyl AretoacetAte, 5.3 g of NaH 60%
35 dispersion in oil, 60 mL of 1.6M n-butyl lithium in hexane,
21 g of 1-[1,1'-biphenyl]-4-yl-1 p~ llul.e and 300 mL of
tetrally lLvruL~-Il. After addition of the ketone, the reaction
= = = = = = = , =, , = _ ~
W0 95/14012 2 ~ 7 6 ~ 4 3 pCr/lTS94/12269
-- 45 --
was stirred 15 minutes at -78 C and 2 hours at room
t~ ~ILuLe. The crude reaction mixture afforded a solid
which was washed with CH2Cl2 and two times with ethyl acetate
-(m.p. 165-170 C~. lH N~(d6-DNSO) ô 0.7-1.9 (m, 7 H), 2.0
5(m, 2 H), 3.0 (s, 2 H), 4.9 (s, 1 H~, 7.3-7.8 (m, 9 H),
11.3 (s, 1 H).
~ample 11.
~-[2,3-Dihydro-~ ~v.l 6 ~v 2~-pyr~n-2-yl]-11ensonitrile,
10 (1)
The title was ~Lèpar~ as described in General
Method 1 using 5 . O mL of methyl ~cetoAC-etate, 2 . O g of NaH 60%
dispersion in oil, 25 mL of 2.0 M n-butyl lithium in hexane,
7 . 6 g of 4-cyAn~lh~n7s~ hyde and 150 mL of tetral.y lLvr~,Lal,.
15 After addition of the aldehyde, the reaction was stirred for
10 minutes at 0 C then allowed to warm to room t~ ~LuLè
overnight. The crude product was triturated from diethyl
ether to afford a solid (m.p. 149-152 C). 'H N~ (CDCl3)
2.80 (dd, 1 H), 2.99 (dd, 1 H), 3.65 (dd, 2 H), 5.75 (dd,
20 1 H), 7.55 (d, 2 H), 7.75 (d, 2 H).
EJcampl~ N.
6-~ rrifluol~ Lh~lphenyl)-5,6-dih~d v ~ ~v,~
2~ p~r..n 2-one, ~
The title _ _ ' was ~Le~ar ~d as described in General
Method 1 using 10 mL of methyl acetoacetate, 3.7 g of NaH 60%
dispersion in oil, 58 rL of 1. 6 N n-butyl lithium in hexane,
11.5 g of 4-trifluu., ~ ylh~n~ldehyde and 250 mL of
tetrallydLufu~ After addition of the aldehyde, the reaction
30 was stirred for 10 minutes at 0 C then 30 minutes at room
temperature. The crude product was triturated from diethyl
ether to afford a solid (m.p. 155-156 C). lH N~ (CDCl3)
2.83 (dd, 1 H), 2.99 (dd, 1 H), 3.58 (dd, 2 H), 5.76 (dd,
1 H), 7.50-7.76 (m, 4 H).
WO 95/14012 2 ~ ~ ~ O ~ 3 PcrluS94112269
-- 46 --
Ex~mpl~ 0.
6-~3,5-Dichlor.p~ 11)-5,6-Cihy~ro-~-h~Lv.~ 2~ n 2-one,
/ )
The title ~ _ was prepared as described in General
5 Nethod 1 using 2.5 mL of methyl acefoAretate, 1.0 g of NaH 60%
dispersion in oil, 12 . 5 mL of 2 . 0 M n-butyl lithium in hexane,
5.1 g of 3,5-dichlorohPn7Al~Phyde and 75 mL of
tetra}ly lL~,LuLall. After addition of the aldehyde, the reaction
was stirred for 10 minutes at 0 C then allowed to warm to
10 room t~ _ a~uL~ overnight. The crude product was triturated
i~rom diethyl ether to afford a solid (m.p. 135-137 C). lH
NMR (CDCl~) ~ 2.78 (dd, 1 H), 2.97 (dd, 1 H), 3.63 (dd, 2 H),
5.64 (dd, 1 H), 7.31--7.40 (m, 3 H).
15 Bs~ple P.
5,6-Dihy~ro-~ LV~ p~nf~f~ v~he_l1)-21~-pyr;~n-2-one,
~f/ )
The title ~ _ ' was L.Le:~aled as described in General
Method 1 using 2.5 mL oE methyl Aref~ArPfAte, 1.0 g of NaH 60%
20 dispersion in oil, 12.5 mL of 2.0 M n-butyl lithium ip hexane,
3.4 mL of pentafluor~hPn7~1~Phyde and 75 mL of
tetral-y-lLuruLa~l. After addition of the aldehyde, the reaction
was stirred for 10 minutes at 0 C then allowed to warm to
room f.' ~ UL~ overnight. The crude product was triturated
25 from diethyl ether to afford a solid (m.p. 176-178 C). IH
NMR (C~Cl3) ~ 2.89 (dd, 1 H), 3.15 (dd, 1 H), 3.70 (dd, 2 H),
6.02 (dd, 1 H).
E x~mple Q .
30 5,6-Dihyaro-4-~1 ~LV~ 6 ~3-methylph~nyl)- 231-pyran-2-one,
The title ~ _ ' was l.L~:~ared as described in General
Method 1 using 2.0 mL of methyl AcefoacPtate, 0.8 g of NaH 60%
dispersion in oil, 10 mL of 2.0 M n-butyl lithium in hexane,
35 2.6 mL of 3-methylhPn7~ hyde and 100 mL of tetrallydLoruLan.
After addition of the aldehyde, the reaction was stirred for
10 minutes at 0 C then allowed to warm to room t~ al ULe
WO 95/14012 PCI`/US941~2~69
2 1 76043
-- 47 --
overnight. The crude product was triturated from diethyl
ether to afford a solid (m.p. 137-138 C). lH NMR (CDC13) ~
2.38 (s, 3 H), 2.88 (dd, 1 H), 2.95 (dd, 1 H), 3.57 (dd, 2 H),
- 5 . 68 (dd, 1 H), 7 .16-7 . 33 (m, 4 H) .
lSlc~pl~ R.
C- ~2-Chlo~ o, hP ~ 5, 6-dihydro-4 k~d.v-~ 2E-pyran-2-one,
/ )
The title ' was prepared as described in General
Method 1 using 2.5 mL of methyl Ac~to~e1Ate, 1.0 g of NaH 60%
dispersion in oil, 12.5 mL of 2.0 M n-butyl lithium in hexane,
3.3 mL of 2- chl~,L ~ hyde and 75 mL of téLLallydL~ruLcln~
After adaition of the aldehyde, the reaction was stirred for
10 minutes at 0 C then stirred for 2 hours at room
15 t~ ~sLu~e.. The crude product was triturated from diethyl
ether to afford a solid (m.p. 124-125 C). lH NMR (CDCl3)
2 . 63 (dd, 1 H), 3 .10 (dd, 1 H), 3 . 68 (dd, 2 ~), 6 . 07 (dd,
1 H), 7 . 3-7 . 65 (m, 4 H) .
20 E~a~plc 8.
6-Butyl-5,6-di~ydro-1 h~d.~ Fk 11-2~ .. 2-on~, ~+/-)
The title c _ ' was prepared as described in General
Method 1 using 2.7 mL of methyl acet~ace~t~, 1.1 g of NaH 60%
dispersion in oil, 12.5 mL of 2.0 N n-butyl lithium in hexane,
25 5.1 mL of valeroFh~nnn~ and 125 mL of tetrallydL~ruLan~ After
addition of the ketone, the reaction was stirred for 10
minutes at 0 C then allowed to warm to room t~ aLu~e
overnight. The crude product was triturated from diethyl
ether to afford a solid (m.p. 124-126 C). ~H NMR (CDCl3) ~
30 0.85 (t, 3 H), 1.28 (m, 4 H), 1.97 (m, 2 H), 2.90 (dd, 2 H),
3.30 (dd, 2 ~), 7.28-7.42 (m, 5 H).
E~cample T.
5,6-Dihydro-~ d.v~ 6 pk~ Lv~l-2~-pyran-2-one, ~+/-)
The title ~ _ was prepared as described in the
General Method 1 using 5 mmol of methyl AC-~a~-el ~te, 5.5 mmol
of NaH 6096 dispersion in oil, 5.5 mmol of 1.6 M n-butyl
_ _ _ _ _ _ _ _ _ _ . ,, ... . . . . _ _ _ _ _ _ _ _ _ _ _ _ _
WO95/14012 2 1 7~3 PcrluS94/12269
-- 48 --
lithium in hexane, 5.5 m~ol of LuLyL~JL~ n~n~ and 14 mL of
tetr~7lydL~rurGI-. After addition of the ketone, the reaction
was stirred for 90 minutes at 0 C. The reaction was poured
into saturated NH;Cl solution and extracted with ethyl
5 acetate. The organic layer was dried over MgSO4,
, L c-ted, and the residue flash ~ , toyLa~hed using
hexane/ethyl acetate 80/20 as eluent. The aldol product was
stirred at room t~ a~uL~ in 100 mL of 0.1N NaOH for 3.5
hours. The reaction was worked up as in General Method 1 and
10 the product triturated from diethyl ether to afford a solid
(~.p. 131.5--132 C) lH NNR (CDCl3) ô 0.88 (t, 3 H), 1.1--1.4
(m, 2 H), 1.95 (m, 2 H), 2.90 (d, 1 H), 2.92 (d, 1 H),
3.25 (a, l H), 3.35 (d, 1 ~), 7.2-7.4 (m, 5 H).
15 l~x~pl~ lJ.
5,6-DiL~o 6 ~e~ll 6 F~ 2~ r~ 2-on~, (~/-)
The title ~ _ was prepared as described in General
Method 1 using 10 mmol of methyl acetoacetate, 11 mmol of NaH
60% dispersion in oil, 10 . 5 mmol of 1. 6 M n-butyl lithium in
20 hexane, 10 mmol of hP~ ho ~ ~ and 28 mL of tetral.y LoLIlLcn.
Upon c~".c~ Lc~ing the reaction a solid precipitated out which
was triturated with ether and filtered (m.p. 123-124 C). IEI
NMR (CDCl3) ~ 0.83 (t, 3 H), 1.1-1.4 (m, 6 H), 1.9-2.0 (m,
2 ~), 2.90 (d, 1 H), 2.92 (d, 1 H), 3.25 (d, 1 H), 3.35 (d,
25 l H), 7 . 2-7 . 5 (m, 5 H) .
Example V.
5,6-Dih,~ c (3-methy~utyl) 6 phcL~1-2~-p~ ..~ 2-one, ~
The title ~ _ ' was prepared as described in Generzl
30 Method 1 using 25 mmo~ o~ methyl acetoacetate, 27.5 mmol of
NaH 60% dispersion in oil, 26.25 mmol of 1.6 ~ n-butyl lithium
in hexane, 25 mmol of i c h_~ hPn~ and 70 mL of
tetral-y-lLuLuLall. Upon ~ ~,..cen~LGting the reaction a solid
precipitated out which was triturated with ether and f iltered
35 (m.p. 134-136 C). ~H NMR (CDCl3) ~ 0.83 (dd, 6 H), 1.1-1.3
(m, 2 H), 1.4-1.6 (m, 1 H), 1.9-2.1 (m, 2 H), 2.90 (d, 1 H),
2.92 (d, 1 H), 3.25 (d, 1 H), 3.35 (d, 1 H), 7.2-7.5 (m, 5 ~).
. . ,,, _ _ , . . .
WO 95/14012 2 ~ 7 60 ~ 3 PCTNS9411n69
-- 49 --
~pl~
5,6-Dihy~lro-6,6-~iph~nyl-2~ ~Ll.n 2-one
The title ~ ' was prepared as described in General
- Method 1 using 20 mmol of methyl Aretoa~re~te, 22 mmol of NaH
5 60~6 dispersion in oil, 21 mmol of 1.6 M n-butyl lithium in
- hexane, 20 mmol of benz.~ and 70 mL of tetral.ydL~.LuL~n.
Upon c.,~ e,--La~ing the reaction a solid precipitated out which
was triturated with ether and filtered (m.p. 170.5-173 C).
lH NMR (CDCl3) ~ 3.18 (s, 2 H), 3.4 (s, 2 H), 7.3-7.5 (m,
10 10 H).
~plo S.
S,6-Di~ LV 6 F' ~1-6-~2-phenylethyl)-2~ F~ LL~ 2-one, ~
The title - _ ' was ~L ~yal ed as described in General
Method 1 using 2S mmol of methyl acetoacetate, 27.5 mmol of
NaH 609~ dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium
in hexane, 25 mmol of 3-phenylpropiorh~nne and 70 mL of
tetral,y lLuLuLel~l. Upon ~ v..cer. Lelting the reaction a solid
precipitated out which was triturated with ether and f iltered
20 (m.p. 130-130.55, oc). lH NMR (CDCl3) ô 2.2-2.4 (m, 2 H),
2.4-2.6 (m, 1 H), 2.6-2.8 (m, 1 H), 2.9 (d, H), 3.0 (d,
1 H), 3 . 3 (d, 1 H), 3 . 4 (d, 1 H), 7 . 0-7 . 5 (m, 15 H) .
~Ws lZ Y.
25 5,6-Dih~l.o ~ L~ 6 r~ yl-2~ pyri~linone ~l~
The title was ~Le~a~ed by decarboxylation of
methyl 6-phenyl-2-, 4-~1; n~rnpip~ridine-3 _aL~-".ylate (prepared
as per Ashton et al., ~eterocycles 28: (2) 1015 (1989) ) by
r-~flllY;n~ in acetonitrile (as per Toda et al., J. Antibiotics
30 23: (2) 173 (1980) ) . Removal of the solvent gave a solid
(m.p. 166-169 C). lH N~R (CDCl3) ~ 2.77 (dd, 1 H), 2.90 (dd,
1 H), 3.38 (s, 2 H), 4.80 (dd, 1 H), 6.40 (s, 1 H), 7.32-7.46
(m, 5 H).
35 ~mple 8
5, 6--Dihydro--~ L1~L~ 6 r ~ ~hyl c r' 2 1--21r E~L~ 2
one, ~/-)
_ _ _ _ _ _ _ _ _ _ _ _ _
Wo95/14012 2 ~ 3 PCr/US94/12269
-- 50 --
The title ' was prepared as described in General
Method l using 0.85 mL of methyl Ace~n~ et~te, 350 mg of NaH
60% dispersion in oil, 5 mL of 1. 6 M n-butyl lithium in
hexane, 2.0 g of 2-phenoxy-1-phenyl ethanone and 60 mL of
5 tetrallydL.,ruL,-n. After addition of the ketone, the reaction
was stirred for 15 minutes at 0C then allowed to warm to room
t c-~u-~ and stirred for 1 hour. The crude product was
triturated from diethyl ether to afford a solid (m.p. 133-135
C) lH NMR (DMS0-d6) ~ 3 . 03 (d, l H), 3 . 35 (d, l H), 4 . 18
10 (dd, 2 H), 4.90 ~s, l H), 6.92-6.95 (m, 3 H), 7.24-7.49 (m, 7
H), 11.56 (s, 1 H).
Exampl~ Al
6--~2--Bon~otl,3]~io~ol--5--yl--ethyl)--5, 6--aiL~I~LV ~--h~dLV~ 6
15 phenyl-2~ ~L~ 2-on~
The title ll~ was ~Le~al~=d as described in General
Method 1 using 0.22 mL of methyl acetoacetate, 90 mg of NaH
60% dispersion in oil, l mL of 2.1 M n-butyl lithium in
hexane, 500 mg of 3-(3,4-methyl~nP~ ryphenyl)pr-)pioFh~nnne
20 and 15 mL of t~LLa~lydLvruLcLIl. After addition of the ketone,
the reaction was stirred for 15 minutes at 0C then allowed to
warm to room t~ C~LUL~ and stirred for 2 hours. The crude
product was triturated from diethyl ether to afford a solid
(m.p. 112-114 C ). lH NIIR (CDCl3) ~ 2.20-2.28 (m, 2 H),
2.37-2.44 (m, 1 H), 2.61-2.69 (m, l H), 2.95 (dd, 2 H), 3.32
(dd, 2 H), 5.90 (s, 2 H), 6.52-6.70 (m, 3 H), 7.33-7.44 (m, 5
H) ~
E~mplo B1
6-t2-~3,~-Dichlo~ l)-ethyl]-5,6-dih~.v ~ h~dLv~
phenyl-2~ ~ ~ 2-one, ~tl-)
The title ~ ' was prepared as described in General
Method l using 1.7 mL of methyl acetoacetate, 630 mg of NaH
60~ dispersion in oil, 9.85 mL of 1.6 M n-butyl lithium in
35 hexane, 4.0 g of 3-(3~4-dichlvr~l~h~:llyl)propiorh~nnn~ and 150
mL of tetrallydLvruLcLl-. After addition of the ketone, the
reaction was stirred for 15 minutes at 0C then allowed to
, _ , _ . . , . . _ .. _ _ . . . . = . ... . . ~ = = _ _
~ wo95n40l2 2 ~ 76~43 PCTIUS94/12269
-- 51 --
warm to room t~ clL.lLæ and stirred for 4 hours. The crude
product was triturated from diethyl ether to afford a solid
(m.p. 145-147 C ). lH NMR lCDCl3) ~ 2.18-2.3S (m, 2 H),
-2.3g-2.50 (m, l H), 2.68-2.80 (m, 1 H), 2.96 (dd, 2 H), 3.36
5(dd, 2 H), 6.90-7.50 (m, 8 H).
}:~ple C1
6-t2-~-Fluo v~he ~l)-ethyl~-5,6-dih~ù -h~d~ 6 r~
21I ~ n 2-one ~I/-)
me title _ ' was ~L~:~aI~d as described in General
Nethod 1 using 3 . l mL of methyl ?~ce1 oa~et:~te, 1.2 g of NaH 60%
dispersion in oil, 18 mL of 1. 6 M n-butyl lithium in hexane,
6.0 g of 3-(4-fluorophenyl)propi~ph~n~n~ and 200 mL of
tetral.y~Lu~ . After addition of the ketone, the reaction
lS was stirred for 15 minutes at 0C t_en allowed to warm to room
tr aLu~ and stirred for 4 hours. The crude product was
triturated from diethyl ether to afford a solid (m.p. 155-157
C ). lH NMR (CDCl~) ~ 2.23-2.29 (m, 2 H), 2.42-2.52 (m, l
H), 2.67-2.78 (m, 1 H), 2.97 (dd, 2 H), 3.35 (dd, 2 H), 7.34-
20 7.47 (m, 5 H), 6.91-7.07 (m, 4 H).
I~ple Dl
5,6-DiL~d.o 6 ' 21-~ h~d.~ 1-2~ ~.~ 2-on- (+)
The title ~- '' was prepared as described in General
25 Method 1 using 25 mmol of methyl ac~ c~:-aLe, 27.S mmol of
NaH 60% dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium
in hexane, 25 mmol of hep~n~rh~n~ and 70 mL of
tetrally~uLu~ln. Upon c~ L~ c.Ling the reaction, a solid
precipitated out which was triturat~sd with et_er and f iltered
30 (m.p. 119-120.5 C). ~H NMR (CDCl3) ~ 0.84 (t, 3 H~, 1.1-1.4
(m, 8 H), 1.9-2.0 (m, 2 H), 2.89 (d, 1 H), 2.93 (d, 1 H), 3.24
(d, 1 H), 3.35 (d, 1 H), 7.2-7.5 (m, ~ H).
WO 95/14012 2 1 7 6 ~ 4 ~ PcrluS94112269
~c ple ~1
5, 6--Dihy~ro--~ .VA~ --~t~ylpentyl) 6 p ~1--211 PlL-,L 2--
onc (I)
The title ' was prepared as described in General Nethod
5 1 using 14 . 2 mmol of methyl ACetOaCetate, 15. 6 mmol of NaH 60%
dispersion in oil, 14 . 9 mmol of 1. 6 M n-butyl lithium in
hexane, 14 . 2 mmol o~ isohep~nnrh~"nn~ and 50 mL of
tetral~ uruLan. Isohept~ was ~L~ yar~d by reacting
the appropriate acid chloride with AlCl~ in benzene as
10 described by Vogel in Practical Organic Chemistry 1978, 770-
775. Upon c ~ ting the reaction, a solid precipitated
out which was r~.Ly_~ ~11; 79~1 from ethyl acetate (m.p. 124-125
C). lH NMR (CDCl,) ô 0.80 (d,d, 6 H), 1.1-1.2 (m, 2 H),
1.15-1. 40 (m, 2 H), 1. 4-1. 5 (m, 1 H), 1. 9-2 . 0 (m, 2 H), 2 . 88
15(d, 1 H), 2.9 (d, 1 H), 3.2 (d, 1 H), 3.3 (d, 1 H), 7.2-7.5
(m, 5 H).
lxample F1
6- (Cyc1 ~ ~lmethyl) -5, 6-Cihyl~ro-~ h~ VA,~ 6 P~ 1-2}~
20 2-on- ( I )
The title ' was prepared as described in General
Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of
NaH 60~c dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium
in hexane, 25 mmol of 2-cyclopentyl-1-phenyl-e~hAnon~ and 70
25 mL of tetral.y lLu~uL-~I. 2-Cyclopentyl-l-phenyl-eth~nnn~ was
~ _L~d by reacting the appropriate acid chloride with AlCl3
in benzene as described by Vogel in Practical Organic
Chemistry 1978, 770-775. Upon u ullC~I.LL~ting the reaction, a
solid precipitated out which was l~c;Ly:,L~llized from ethyl
acetate (m.p. 158-160 C). lH NMR (DMSO-d6) ~ 0.8-0.9 (m, 1
H), 1.0-1.1 (m, 1 H~, 1.2-1.8 (m, 7 H), 1.9-2.1 (m, 2 H), 2.9
(ABq, 2 H), 4.8 (s, 1 H), 7.2-7.4 (m, 5 H), 11.3 (s, 1 H).
~a~plo G1
3,~-Dihy~ro-~' hJ~I~ v~ iro[-~rht~ 1(2~) ,2'-[2~]pyr~n]-
6' ~3'~-one ~ I )
WO95114012 ~ 1 761D43 PCIIUS94112269
The title ' was prepared as described in General
Nethod 1 using 25 mmol of methyl acetoacetate, 27.S mmol of
NaH 60% dispersion in oil, 26.25 mmol of 1.6 ~ n-butyl lithium
in hexane, 25 mmol of ~-tetralone and 70 mL of
5 tetrallydL.,ruLc,n. The product was recryst~ from ethyl
acetate/diethyl ether (m.p. 117-119 C). ~H NMR (CDCl3) ~
1.7-1.9 (m, 1 H), 1.9-2.1 (m, 2 H), 2.1-2.3 (m, 1 H), 2.7-3.0
(m, 2 E), 2.95 (d, 1 H), 3.1 (d, 1 H), 3.5 (s, 2 H), 7.1-7.2
(m, 1 H), 7.2-7.3 (m, 2 H), 7.4-7.5 (m, 1 H).
~pl~
3--(3~4i--Di~ V 'I~ LV~ 6 __v 2--phenyl--211 E~ ~ 2--yl)
aci~ (_)
The title . ' was pL ~aL ed as described in Genera
lS Method 1 using 25 mmol of methyl acetoacetate, 27 . 5 mmol of
NaH 609~ dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium
in hexane in 50 mL of tetrallydL-,ru, ln and 25 mmol of 3-
benzoylpropionic acid sodium salt in 60 mL of tetral.ydL~ruL~
3-Benzoylpropionic acid sodium salt was E~L~llLad by reacting
20 the acid (25 mmol) with hexane washed NaH (26.25 mmol) in
tetral.ydLvruL~ln at 0C for 30 minutes. The crude product was
flash chromatoyL~yhed using CH2Cl2/MeOH/CH3C02H (90/10/0.2) to
give a viscous gum. lH 1~ (CDCl~) ô 2.1-2.6 (m, 4 H), 2.9
(d, 1 H), 3.0 (d, 1 H), 3.3 (d, 1 H), 3.4 (d, 1 H), 7.2-7.5
25 (m, 5 H).
Ex~ple I1
~-~3,6-Dihyaro-~ aLvA~ 6 ~, 2-phenyl-2~ r~n 2-yl) butyric
~cia ~ ' ~
The title ~ d was pLc:~ar~d as described in General
Method 1 using 25 mmol o~ methyl aceto~~etate, 27 . 5 mmol o~
NaH 60% dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium
in hexane in 50 mL of tetrally-lLvruLe-n and 25 mmol of 4-
benzoylbutyric acid acid sodium salt in 100 mL of
35 tetrahydrofuran. 4-Benzoylbutyric acid sodium salt was
pl~yaled by reacting the acid (25 mmol) with hexane ~ashed NaH
(17.5 mmol) in tetrai~lLoruL~l at 0C for 25 minutes. The
Wo 95114012 2 ~ 7 ~ ~1 4 3 PCrlUS94/12269
crude product was flash chromatoyL lphed using
CH2Cl2/NeOH/CH3C02H (99/1/0.1-97.5/2.5/0.1) to give a solid
which was 1~LY~ l 1; 70~9 from ethyl acetate (m.p. 134-137 C) .
IH NMR (DMSO-d6) ô 1.1-1.2 (m, 1 H), 1.4-1.6 (m, 1 H), 1.8-2.0
5(m, 2 H), 2.0-2.2 (m, 2 H), 2.9 (ABq, 2 H), 4.85 (s, 1 H),
7.2-7.4 (m, 5 H).
~mple J1
5-~3,6-Dihydro-~ LJALvAl 6 ~o 2-phenyl-2}1 ,,JL~ 2-yl)
10 p~nt~n^i~ ~cid ~)
The title was ~JL e:~a~ e:d as described in General
Nethod 1 using 25 mmol of methyl ~ otoAretate, 27.5 mmol of
NAH 60% dispersion in oil, 26 . 25 mmol of 1. 6 M n-butyl lithium
in hexane in 50 mL of tetrallydLuruLan and 25 mmol of 5-
15 benzoyl r~nt-An~-ic acid sodium salt in 100 mL of
tetral.y lLuruLan. 5 ~hz.ylpentanoic acid sodium salt was
yL~par~d by reacting the acid (25 mmol) with hexane washed NaH
(27.5 mmol) in tetral~y-lL-,ruL-n at 0C for 25 minutes. The
crude solid was recrystAl 1 i 70d from ethyl acetate (m.p. 136-
20 140 C). IH NMR (DNSO-d6) ~ 0.8-1.0 (m, 1 H), 1.1-1.3 (m, 1
H), 1.3-1.5 (m, 2 H), 1.8-2.0 (m, 2 H), 2.1 (t, 2 H), 2.9
(ABq, 2 H), 4.85 (s, 1 I~), 7.2-7.4 (m, 5 H), 11.4 (bs, 1 H),
12.0 (bs, 1 H).
z5 E~ Ipl~ ~1
5, 6--Dihy~ro--~--L~L~ t p~ ~1--6--pyri~in--~--yl--21} ~L~IL~ 2--one
~)
The title ' was prepared as described in General
Method 1 using 90 mmol of ethyl acetoacetate, 99 mmol of NaH
30 60% dispersion in oil, 95 mmol of 1.6 M n-butyl lithium in
hexane and 90 mmol of 4-benzoylpyridine and 250 mL of
tetrallylL~rllLan. The reaction mixture was acidified with
acetic acid and the crude solid was washed with ice water
(m.p. 148-150 ~C).
~ WO 95~14012 2 1 7 6 0 4 3 PCr/US94/12269
~ampl~ L1
5,6-Di~,~LV ~ v~ thylphenylamino)~ethyl] 6 r~
2l}-pyr~n-2-one ~ I )
The 2- (methylphenylamino) -l-phenyl-e~hAn~n~ was prepared
5 by reacting N-methy~Anil;n~ (50 mmol~ etnph~"on~ (S0
mmol), triethylamine (55 mmol) in diethyl ether at room
t~, aLuLe overnight. The diethyl ether was ~ va~vLated,
replaced with p-dioxane, and the mixture refluxed for 15
hours . The solid triethylamine hydrochloride was f iltered .
10 The filtrate was ~ r~) L ated and the solids were
r~VLy~ 1 1; 7~1 from ethyl acetate to afford the desired
' as a solid (m.p. 118-120 C).
The title _ ' was yL ~:paL ~d as described in General
Method 1 using 6.7 mmol of methyl acetoacetate, 7.3 mmol of
15 NaH 6096 dispersion in oil, 7.0 mmol of 1.6 M n-butyl lithium
in hexane, 6 . 7 mmol of 2- (methylphenylamino) -1-phenylethanone
and 40 mL of tetrahy lLvruLan. The reaction mixture was
acidif ied to pH 7 with conc . HCl and then taken to pH 3 with
acetic acid. The product was flash vl r~ tOyLaphed using
20 CH2Cl2/MeOH (99/1) to give a solid (m.p. 152-153 C). lH N~
(CDCl3) ô 2.9 (d, 1 H), 3.05 (s, 3 H), 3.1 (d, 1 H), 3.2 (d, 1
H), 3.3 (d, 1 H), 3.7 (ABq, 2 H), 6.7-6.8 (m, 3 H), 7.2-7.3
(m, 2 H), 7 . 3-7 . 5 (m, 5 H) .
25 E~pl~ Xl
N-Benzyl-~-~3,6-aihydro-~ h~d.v,~ 6 ~ v 2-phenyl-2~-pyr~n-2-
yl) N -- ~h~ Ly ~ iae ~ I )
The 5-oxo ~ plle:.,ylpentanoic acid benzyl-methyl amide was
prepared by r~ ;n~ N-methylbenzylamine (10.5 mmol) and 6-
30 phenyl-3,4-dil.ylLu S,yLan-2-one (10.5 mmol) in toluene for one
hour. The reaction was allowed to stir overnight at room
t,~ ~ ~ILUL~. It wa6 poured into 100 mL of ethyl acetate and
100 mL of lN HCl. The organic ~--LL~C,L~ were washed with 100
mL of lN NaOH, 100 mL of water and dried over MgSO~. The
35 crude product was flash chromatvyLa~l-ed (CH2Cl,/MeOH 98/2) to
a~ford a liquid. lH NNR (CDCl3) ô 2.0--2.2 (m, 2 H), 2.5 (t, 2
~ _ _ _ _ _ _ _ _ _ _ .. . . . . . .. _ . . _ _
Wo sstl40l2 PCT/US94/1226~
2 ~ 7 ~ 3
-- 56 --
H), 2.93/2.96 (s/s, 3 H), 3.0-3.2 (m, 2 H), 4.5/4.6 (s/s, 2
H), 7 .1-7 . 6 (m, 8 H), 7 . 8-8 . 0 (m, 2 H) .
The title ~ ' was ~Le:yaIe~ as described in General
Method 1 using 5. 6 mmol of methyl ~etoAret~te, 6.1 mmol of
5 NaH 60% dispersion in oil, 5.9 mmol of 1.6 1~ n-butyl lithium
in hexane, 5.6 mmol of 5 ~,~. 5 phe,.ylront~nnic acid benzyl-
methyl amide and 25 mL of tetral.~LuLuL~.n. The product was
~lash chromatoyL~phed using CH2Cl2/MeOH (98/2) to give a 601id
(m.p. 47-S1 C). lH N~R (DMSO-ds) ~ 1.1-1.3 (m, 1 H), 1.4-1.6
lO (m, l H), 1.8-2.0 (m, 2 H), 2.2-2.4 (m, 2 H), 2.75/2.81 (s/s 3
H), 2.85-3.1 (m, 2 H), 4.4/4.5 (s/s, 2 H), 4.85/4.9 (5/5 1 H),
7.1-7.4 (m, 10 H), 11.36/11.38 (s/s, 1 H).
G~n~ral ll~thod 2
The thiotosylate reagents were ~Le~L.d by reacting Qgual
molar guantities of alkyl halide and potassium thiotosylate in
absolute ethanol and rofl~lying for 24 hours or in DNF and
stirring at room t~ - aL~t: for 12 to 72 hours. The solvent
20 was stripped of~ and the residue was taken up in ethyl acetate
and washed with water. Alternatively, water was added and the
aqueous layer was extracted with diethyl ether or ethyl
acetate. The organic ~.LL j~-_LS were dried over NgS0~ and
~1 c~ ed in vacuo.
Alternatively, the thiotosylate reagents were prepared as
described by M. G. Ranasinghe and P. L. Euchs in Sy~. Com~.
18~3): 227 (1988).
Lsample AA. Benzyl-p-toluenethiosul~onato
The title c ' was ~Le~r.2d as described in General
Method 2 using 0.05 mol of benzyl chloride, 0.05 moles of
potassium thiotosylate in 150 mL of ethanol. The residue was
dissolved in heYane and seeded with a crystal of the product
to afford 10.8 g (77%) of benzyl-p-tolllor~o~hios~lfonate (m.p.
52--56.5 C). lH NNR (CDCl~) ô 2.45 (s, 3 H), 4.26 (s, 2 H),
7.18-7.30 (m, 7 H), 7.74 (d, 2 H).
WO 95114012 PC'rlUS94112269
~ 2~ 760~3
-- 57 --
l~pl~ BB. 2-Phenyl-thyl-p-tol~ h;~ lfon~t~
The title ~ ' was ~L~paLe:d according to General
Method 2 using phenethyl bromide (0 . 088 mmol), potassium
thiotosylate(o.088 mol), and absolute ethanol (250 mL). A
5 clear liquid was obtained which was used without purif ication .
'H N~ (CDCl3) ~ 2.47 (s, 3 H), 2.92 (t, 2 E}), 3.24 (t, 2 H),
7 . 1-7 . 4 (m, 7 H), 7 . 84 (d, 2 X) .
Fsampl- CC. 3-Ph~nylpropyl-p-tolu~nefhio~ 1 fn~-te
The title was ~L e:~J L ed as described in General
Method 2 using 1-bromo-3-phenylpropane (0. 044 mmol), potassium
thiotosylate (0.044 mmol) and Ahsol~lt~ ethanol (125 mL) to
give an oil which was used without purification. lH Nl~1
(CDCl3) ô 1.95 (quint., 2 H), 2.459 (s, 3 H), 2.63 (t, 2 ~I),
15 2.95 (t, 2 H), 7.0-7.4 (m, 8 Ei), 7.7 (d, 2 H).
E~cample DD. 2-~ ~- thll-p-tol~ hi~_ 1f ona.te
The title ~ ' was prepared as described in General
Method 2 using 2-ph~llv~.yeLllyl bromide (0.025 mmol), potassium
20 thiotosylate (0.025 mmol) and DMF (100 mL) to give a solid.
1H NMR (CDCl3) ~ 2.45 (s, 3 H), 3.34 (t, 2 ~), 4.14 (t, 2 H),
6.80 (d, 2 H), 6.95 (t, 1 H), 7.26 (t, 2 H), 7.35 (d, 2 H),
7 . 82 (d, 2 H) .
G~n~r~l lSetho~ 3
The 3-bromo-5, 6-dihydro-4 hy~lLv~y-2H-pyran-2-one int~ tes
were pL~=~aLed by reacting equimolar amounts of the requisite
6-substituted 5,6-dihydro-4 i~dLv.~y-2H-pyran-2-ones (prepared
in General Method 1) with N_bL, ~ n;m;~ (1.0 equiv.) in
dry t-butanol in the dark. The solvent was ~=v~LaLed, and the
30 residue was partitioned between chloroform and water. The
organic layer was washed with brine, dried (MgS0~), and
vllLe~l ~L a ~ed .
ple AAA. 3-Bromo-5,6-dih~d~v ~-h~lL.,~ ~,6-aiphenyl-2~-
35 pyr~n-2-one
The title _ ' was ~Lt ~ed as described in General
Method 3 using 4 . O mmol of 5, 6-dihydro-4 hyd2 v~y-6, 6-
_ _ _ ... . _ _ _ ... _ _ _ _ _ _ _ _ _ _ _ _ .
WO95/14012 ~l7~a,~3 PcrruS94/12269
-- 58 --
diphenyl-2H-pyran-2-one (~le~r~d in Example W) and 4 . 0 mmol
of NBS. The product was obtained as a solid. lH NMR ~DMS0-d6)
~ 3.68 (s, 2 H), 7.27-7.40 (m, 10 H).
5 Es~ple BBB. 3--BL 5,6--~ihy~ro--~ ,v--~--6 r~ 6--~2--
phcnylcthyl) -2}{ ~,L..n 2-one, ~ L/_)
The title ~- ' was prepared as described in General
Method 3 using 2.0 mmol of 5,6-dihydro-4 l~ydL~.y C pllellyl~6~
(2-phenylethyl)-2II p~LC.il 2-one (~-a~aLad in Example X) and 2.0
10 mmol of NBS. lH NMR (DNSO-d6) ~ 2.16-2.58 (m, 4 H), 3.30 (m, 2
H), 7 . 04-7 . 60 (m, 10 H) .
IS~plo CCC. 3-B.. ~ 5,6-~iL~hv ~ Lv~-(3-m~thylbutyl)-6-
p~enyl-21} E~L~ 2-on~, ~+/-)
The title ~ ' was pLel.ared as described in General
Method 3 using 2.0 mmol of 5,6-dihydro-4 ~IydL~l~.y-6-(3-
methylbutyl)-6-phenyl-211 ~yLclil 2-one (y-e~al~d in Example V)
and 2.0 mmol of NBS. 1H NMR (DMS0-d6) ~ 0.80 (m, 6 H), 1.00
(m, 1 H), 1.14 (m, 1 H), 1.42 (m, 1 H), 1.95 (m, 2 H), 3.35
20 (m, 2 H), 7 . 25-7 . 52 (m, 5 H) .
2sample DDD. 5-~5 B~ LV~ C _.~V 2-phenyl-3,6-dihydro-
211 E,~L~n 2-yl]~ cid, ~t-t-)
The title _ ' was l~LeyeL~d as described in General
25 Method 3 using 1.4 mmol of 5-[4 ~l~dL~ y-6-oxo-2-phenyl-3~6-
dihydro-2H-pyran-2-yl]pentanoic acid (~Lépared in Example J1)
and 1.4 mmol of NBS. lH` NMR (DMS0-d6) ~ 0.94 (m, 1 H), 1.22-
1 . 40 (m, 3 H), 1 . 92 (m, 2 H), 2 . 13 (t , 2 H), 3 . 28 (q, 2 H),
7.16-7.52 (m, 5 H).
General M~tho~l ~
The desired ~ were E~L e~red by adding the 5, 6-dihydro-
35 2II py~ 2-one, absolute ethanol, the p-t~ n~thinc~llfonate
reagent, and Et3N to a reaction vessel. The solution was
stirred at room t~ LuLe to reflux for 4 hours to one week.
_ _ _ _ _ _
WO 95/14012 PCr~US94112269
2 ~ 76~3
59
The solvent was stripped off and the residue partitioned
between lN HCl and CH,Cl2 or ethyl acetate. The layers were
separated and the aqueous layer was extracted with CH2Cl2 or
ethyl acetate. The organic layers were combined and dried
5 over MgSO~.
l~ple 1.
5,6-Dih~dLV ~ hid~v~-~ ph~ l-3-r(phenylm~thyl)thio]-2~1-
pyran-2-on~ ( J ),
The title . ' was prepared as described in General
Nethod 4 using 2 .1 mmol of 5, 6-dihydro-4 h~ y-G ~he,.~ 1-2H-
pyran-2-one, 10 mL of absolute EtOH, 2 . 3 mmol of benzyl-p-
tol~ noth;oF-~lfonate and 2.3 mmol of Et3N in 5 mL of absolute
EtOH. The solution was stirred for 3 days at room
15 f~ LuLe. Cu-.~ e--LL~tion in vacuo gave a solid which was
broken up and made into a slurry in diethyl ether and ethyl
acetate. The solid was filtered off and the mother liquors
were ~ 5r~L~ ~:ted and flash chromatographed on silica gel
using CH2Cl2/NeOH (99/1 to 97/3) as eluants. The '1n~C1
20 crops gave 0 . 365 g (559~) of the desired product as a solid
(m.p. 150-151.5 C). lH NMR (CDCl3) ~ 2.65 (dd, 1 H),
2.78 (dd, 1 H), 3.85 (d, 1 H), 3.94 (d, 1 H), 5.29 (dd, 1 H),
7.2-7.4 (m, 11 H).
25 ibcullpl- 2.
5,6-Dihydro-~ h~d.v.~, O' phe..yl-3-~(2-phenylethyl)thio]-21I-
pyr~n-2-on~
The title ~ ' was ~Leyalc:d as described in General
Method 4 using 2.1 mmol of 5,6-dihydro-4 ~y-lL~l~.y-~ pl.e..yl-2H-
3c pyran-2-one, 6 mL of absolute EtOH, 2 . 3 mmol) of 2-
phenylethyl-p-toluenethiosulfonate in 6 m1 of absolute EtOH
and 2 . 3 mmol o E triethylamine in 3 mL of absolute EtOH. The
reaction was stirred at room t ~ILUL-2 for 4 days. The
product was purif ied by f lash chromatography using
35 CH2Cl2/MeOH(99/1 to 97/3) as eluants. The viscous paste which
was isolated was triturated from ether to yield a solid (m.p.
Wo 9S/14012 ~ PCrlU594112269
2 ~ ~6~
-- 60 --
98-99 C). lH NMR (CDCl3) ~ 2.8-3.1 (m, 6 H), 5.3 (dd, 1 H),
7.1-7.7 (m, 11 H).
l~s ple 3.
5 5,6-Dihy~ro-~ h~l v,~ 6 r~ 3-[ (3-phenylpropyl)thio]-2}~-
pyr~n-2 -one ~ t ) .
The title ' _ _ ' was ~ al ed as described in General
Method 4 using 2.63 mmol of 5,6-dihydro-4 hydLuAy-~ phellyl~2H~
pyran-2-one, 7 mL of absolute EtOH, 2.76 mmol of 3-
10 phenylpropyl-p-toluenethiosl~fonate in 6 mI, of Ahsolllt~ EtOX
and 2 . 89 mmol of triethylamine in 2 mL of ~hsol~t~ EtOH. Thê
reaction was stirred at room t~ -~UL~ for 2 days. The
product was triturated from ethyl acetate as a solid (m. p .
134-135 C). lH NNR (CDCl3) ~ 1.8 (quint., 2 H), 2.6-2.8 (m,
S 4H), 2.87 (dd, l H), 3.01 (dd, 1 H), 5.43 (dd, 1 H), 7.1-
7 . 5 (m, 10 H), 7 . 81 (bs , 1 H) .
13sampl~ ~.
S, 6-Dihy~ro-~-L~ r~ 3-~ ~2 r ~,t.hyl) thio] -2}1-
20 pyran-2-one ~t ) .
The title ~ ' was ~LC:UaL~:~ as described in General
Method 4 using 0.54 mmol of 5,6-dihydro-4 ~IydLu~y-C pllt:llyl-2H-
pyran-2-one, 7 mL of AhColllt~ EtOH, 0.57 mmol of 2-
yLel-v,.y~Lhyl-p-tol~l~n~hios~lfonate in 6 mL of Ahs~lllt~ EtOH
25 and 0 . 06 mmol of triethylamine in 2 mL of absolute EtOH. The
reaction was stirred at room t~ UL~ for 2 days. The
product was flash chromatographed and triturated from diethyl
ether to give a solid (m.p. 107-108 C). lH NMR (DMSO-d6)
2.80(dd, 1 H), 2.9-3.0 (m, 2 H~, 3.08 (dd, 1 H), 4.07 (t,
30 2 H), 5.47 (dd, 1 H), 6.9-7.0 (m, 3 H), 7.2-7.5 (m, 7 H).
~ple 5.
s,6-DiL~tlLo ~-h~ c ~2-m~thylpropyl) 6 r~ 2.1-3-
[ ~ph~nylm~thyl) thio] -21I ~ ~n 2-one ~ I )
~he title ' was prepared as described in General
Method 4 using 0.61 mmol of 5,6-dihydro-4 ~ylLUAy~6~(2~
methylpropyl ) -6-phenyl-2H-pyran-2-one, 5 mL of absolute EtOH,
.. . ..... .. . . _ _ _ _
WO 95/14012 2 1 7 6 0 ~ 3 PCT/US94112269
-- 61 --
0.67 mmol of benzyl-p-~o~ nP~h;~ fonate in 3 mL of absolute
EtOH and 0. 67 mmol of triethylamine in 2 mL of absolute EtOH.
The reaction was stirred at room t _ ~UL~: for 18 hours.
The product was flash chromatographed (CH,Cl2/MeOH 99.5/0.5)
5 to aford a viscous oil. lH N~ (CDCll) ô 0. 72 (d, 3 H), 0 . 90
- (d, 3 H), 1.5-1.7 (m, 1 H), 1.81 (dd, 1 H), 1.91 (dd, 1 H),
2.95 (ABg, 2 H), 3.53 (d, 1 H), 3.75 (d, 1 H), 6.8-6.9 (m,
2 H), 7 . 1-7. 4 (m, 8 H) .
10 l~pl~ 6.
5,6-Dih~d o ~ LV~,~ 2- -thylpropyl)-6 r~ 2~1-3-~2-
ph~nyl<~thyl) thiol -2~ n 2-onc ~)
The title ' was ~L~ya~ed as described in General
Method 4 using 0.61 mmol of 6-i-butyl-5,6-dihydro-4 hylLu~.y~6-
15 (2-methylpropyl) G pl~ellyl~2LI pyL~ 2-one, 5 mL of absolute
EtOH, 0.67 mmol of 2-phenylethyl-p-tol~ne~hios~lfonate in 3
mL of absolute EtOH and 0 . 67 mmol of triethylamine in 2 mL of
absolute EtOH. Ihe reaction was stirred at room temperature
for 18 hours. The product was flash chromato~L~l~hed
20 (CH2Cl2/MeOH 99.5/0.5) to a~ford a viscous oil. lH liMR (CDCl3)
~ 0.75 (d, 3 H), 0.89 (d, 3 H), 1.5-1.7 (m, 1 H), 1.87 (dd,
1 H), 1.95 (dd, 1 H), 2.2-2.3 (m, 1 Ei), 2.4-2.5 (m, 1 H), 2.6-
2.8 (m, 1 H), 3.13 (ABg, 2 H), 6.90-6.95 (m, 2 H), 7.1-7.4 (m,
8 H).
Es~ple 7.
5- ~ 3-Chlo~ y l) ~2 ~ [ (2-ph~nylethyl 1 thio-1, 3 -cyol~
5-(3-Chlorophenyl)-1,3-cyclnh~Y~ nr~;ODr' can be ~ aLed
as described in J. Med. C_em. 1992, 35, 19, 3429-3447.
To a 50 mL reaction flask was added 0.30 g (1.35 ~mol) of
5-(3-chlv~uyh~ yl)-l~3-cy~ h~y~np~ in 5 mL of absolute
EtOH, 0 . 43 g (1. 48 mmol) o~ 2-phenylet_yl-p-
toluene~ hi~s~ onate in 3 mL of absolute EtOH and 0.16 g (1.62
mmol ) of EtlN in 2 mL of absolute EtOH . The reaction was
35 stirred at room t~ UL` for 27 hours. The EtOH was
removed in vacuo and the residue dissolved in 200 mL of
diet_yl ether and 100 mL of lN HCl. The agueous layer was
., . . _, . . . _ . , _ _ _ _ _ _ _ .
WO95/14012 ~ 3 PCrlUS94/12269
-- 62 --
extracted with 2xlO0 mL of diethyl ether. The organic
extracts were in~l, dried over MgS0~, and c,~ .,LLc,Led.
The residue was flash chromatoyLa~hed using CH2Cl2/MeOH 99/1
to give a solid (m.p.69-73 C). lH NMR(CDCl3~ ô 2.5-3.1 (m,
5 8 H), 3.3 (m, 1 H), 7.1-7.4 (m, 9 H), 7.9 (bs, 1 H).
lss~ple 8.
5,6-Dih~ h~v~ 6 ~-~etk_..y, r 21)-3-
[ ~phenylm~Jthyl) thio] -211 E~L~U. 2-ono, ~+/-)
The title _ ' was ~L~ L~=~ as described in General
Nethod 4 using 300 mg of 5,6-dihydro-4 hydLuA.~ G (4-
y~ 2H-pyran-2-one~ 500 mg of benzyl-p-
to~ n~th;os~lfonate and l.0 mL of triethylamine in 10 mL of
absolute ethanol. The C~]ution was stirred overnight at room
15 temperature . Purif ication by f lash chromatography using
CH?Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oil
which was trituratea with diethyl ether to afford a solid
(m.p.168-170 C). lH NklR (CDCl,) ô 2.60 (dd, 1 H), 2.77 (dd,
1 H), 3.82 (s, 3 H), 3.39 (dd, 2 H), 5.23 (dd, 1 H), 6.89-7.33
20 (m, 10 H).
~mplc 9.
5,6--Dih~ --h~f., 6 ~-- ~thylth~ 1)--3-
~phenylmethyl)thio]-211 ~...a 2-on, (+/-)
The title ~ ' was ~L~uared as described in General
~ethod 4 using 480 mg of 5,6-dihydro-4-hydroxy-6-(4-
methylth; orh~nyl) -2H-pyran-2-one, 620 mg of benzyl-p-
toluene~hioc~lfonate and 0.34 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred for 3 days at room
30 t~ aL~a. Purification by flash chromatography using
CH2Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
(m.p. 185-188 C). lH llMR (CDCl3) ô 2.49 (s, 3 H), 2.62 (dd,
1 H), 2.75 (dd, 1 H), 3.90 (dd, 2 H), 5.25 (dd, 1 H), 7.19-
35 7 . 32 (m, 10 H) .
E~ple 10.
WO 9S/14012 2 1 7 ~ ~ 4 ~ PCT/US94ll226s
-- 63 --
S,6-Dihydro-~ ~v,~ thylph-~yl)-3-
[ ~ph~nyl~lothyl) thio] -2~-pyr~m-2-ono,
The title ~ ' was prepared as described in General
Nethod 4 using 123 mg of 5,6-dihydro-4 ilydL~y-6-(4-
S methylphenyl)-2H-pyran-2-one, 170 mg of benzyl-p-
f~ n~h;o~ulfonate and 0.90 mL of triethylamine in 3 mL of
i~hsolute ethanol. The solution was stirred for 18 hours at
room t~ a LUL ~:: . The crude product was triturated with
diethyl ether to afford a solid (m.p. 166-167 C). lH NlfR
10 (CDCl3) ~ 2.36 (s, 3 H), 2.62 (dd, 1 H), 2.77 (dd, 1 ~), 3.94
(dd, 2 H), 5.25 (dd, 1 H), 7.19-7.32 (m, 10 H).
E~ple 11.
s, 6-Dihydro-~ h~ ,,J ~ li~ thylethyl)ph~yl]-3-
15 ~ (phcnyll-~thyl) thio]-2~ ~ 2-. ,~, ~+/-)
The title _ was ~L~a~ ~ as described in General
Method 4 using 445 mg of 5,6-dihydro-4 ~ydL-.~y-6-[4-(1,1~
dimethylethyl)phenyl]-2H-pyran-2-one, 550 mg o~ benzyl-p-
toluorvth;osulfonate and 0.3 mL of triethylamine in 10 mL o~
20 ;`hcolut~ ethanol. The solution was stirred for 3 days at room
~ , ~ a~ . The crude product was triturated with diethyl
ether to afford a solid (m.p. 140-142 C). lH NNR (CDCl3) ~
1.32 (s, 9 H), 2.65 (dd, 1 H), Z.79 (dd, 1 lI), 3.89 (dd, 2 H~,
5 . 27 (dd, 1 H), 7 .18-7 . 43 (m, 10 H) .
E~ple 12.
6-(~-Chlo~ 1)-5,6-dihy~ro-~ ," 3-
tphenyll-ethyl) thio] -2~ . 2-olle, (+/-)
The title _ _ was ~L~aL~d as described in General
30 Method 4 using 250 mg of 6-(4-chl~,Luyh_~yl)-5,6-dihydro-4-
hydroxy-211 ~ yLaL~ 2-one, 315 mg of benzyl-p-
tol ~ n~t h; osul~onate and 0 .16 mL of triethylamine in 8 mL of
absolute ethanol. The solution was stirred overnight at room
1-~ , a~UL~. Purification by flash ~ t, LGS~La~hy using
35 CH2Cl,/methanol (100/0 to 95/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
, .. . .. _ _ _ _ _ _ _ . . ,
WO95tl4012 2 ~ 3 PC~IUS94/12269
-- 64 --
(m.p. 167-170 C) . lH NMR (CDCl~) ~ 2 . 62 (dd, 1 H), 2 . 74 (dd,
1 H), 3.90 (dd, 2 H), 5.21 (dd, 1 H), 7.23-7.41 (m, 10 H).
Es~mple 13.
S 6-l3-Chlorophenyl)-5,6-~ihydro-4 hld~ 3-
[ ~phenylmethyl) thio] -2}~ L~ 2-one,
The title _--d was ~Lc:~GL~ d as described in General
Method 4 using 300 mg of 6-(3-chlorophenyl)-5,6-dihydro-4-
hydroxy-2H-pyran-2-one, 450 mg of benzyl-p-
10 tolueneth; o5~l fonate and 1. 0 mL of triethylamine in 10 mL of:~hSol~te ethanol. The solution was stirred overnight at room
t~ aLuL~. Purifi~t;nn by flash chromatography using
CH2Clz/methanol (100/0 to 95/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
15 (m.p. 139-142 C). lH N~ (CDCl3) ~ 2.64 (dd, 1 H), 2.73 (dd,
1 H), 3.89 (dd, 2 H), 5.25 (dd, 1 H), ~.18-7.41 (m, 10 H).
B~c~ple 1~.
5,6-Dihydro-3-[ ~2-ph~nylethyl~thio]-6-t~-
20 (phenylmethosy)phenyl]-21I ~ ~.~ 2-one, (~/-)
The title = llld was yr~:yal-~d as described in Gener21
Method 4 using 109 mg of 5,6-dihydro-4 ~1L~)2.Y-6-[4-
(phenyl- ` y)phenyl]-2lI ~yLan 2-one, 114 mg of 2-
phenylethyl-p-toluenethiosl~lfonate and 0.06 mL of
25 triethylamine in 3 mL of absolute ethanol. The solution was
stirred overnight at room temperature . Purif ication by f lash
chromatography using CH2Cl2/methanol (100/0 to 95/5) as eluent
gave a viscous oil which was triturated with diethyl ether to
afford a solid (m.p. 99-101 C). lH llNR (CDCl3) ~ 2.7~ (dd,
30 1 H), 2.85 (dd, 1 H), 2.92-3.11 (m, 4 H), 5.07 (s, 2 H), 5.30
(dd, 1 H), 6.97-7.44 (m, 14 H), 7.62 (s, 1 H).
E~a~ple~ 15.
5,6-Di~ld o 6 (4 ~ ~ 1)-3-[~2-phenylethyl)
35 thio]-2~ ~L..n 2-one, ~
The title ~ ' was ~Le:p~rt:~ as described in General
Nethod 4 using 300 mg of 5,6-dihydro-4 ~ly~LU~Ly-6-(4-
WO 95/14012 P~IUS94~ 69
1- 2~76~
-- 65 --
r '' y~,~.e..yl)-2H-pyran-2-one, 500 mg of 2-phenylethyl-p-
toll~n~hios~llfonate and 1.0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
t~ - ~UL e . The crude product was triturated with diethyl
ether to afford a solid (m.p. 112-115 C). lH NMR (CDCl3) ~
- 2.78 (dd, 1 H), 2.86 (dd, 1 H), 2.92-3.11 (m, 4 H), 3.81 ~s,
3 H), 5.31 (dd, 1 H), 6.91-7.35 (m, 10 H~.
E~pl~ 16.
10 5,6--DiL~ ~thyl~ h;~ 1)--3--t (2--
ph~nyl~thyl) thio] -211 ~ 2-on~l, (+/-)
The title _ a was prepared as described in General
Method 4 using 430 mg of 5,6-dihydro-4 hyL~JAy-6-(4-
methylth;oFh~nyl)-2H-pyran-2-one, 585 mg of 2-phenylethyl-p-
15 toluene~h;osl~lfonate and 0.3 mL of triethylamine in 10 mL ofabsolute ethanol. The soll7~ n was stirred for 3 days at room
t~ ~u~. The crude product was triturated with diethyl
ether to afford a solid (m.p. 135-137 C). lH NMR (CDCl3) ~
2.48 (s, 3 H), 2.77-3.10 (m, 6 H), 5.32 (dd, 1 H), 7.16-7.33
20 (m, 9 H), 7.63 (s, 1 H).
E~a~plc 17.
5,6-Di~ . 6 (~ thylphenyl)-3-~(2-phonyl~thyl)thio]-2~-pyra
n-2-on~, (+/-)
25 The title ~ _ ' was ~Le~aled as described in General
Method 4 using 500 mg of 5,6-dihydro-4 ~IydL~y-6-(4-
methylphenyl)-2H-pyran-2-one, 720 mg of 2-phenylethyl-p-
toluene~h;nculfonate and 0.4 mL of triethylamine in 12 mL of
absolute ethanol. The solution was stirred overnight at room
30 temperature. Purification by flash chromatography using
CH2Cl2lmethanol (100/0 to 95/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
(m.p. 112-113 C). lH N~ (CDCl3) ~ 2.36 (s, 3 H), 2.79 (dd,
1 H), 2.84 (dd, 1 X), 2.91-3.10 (m, 4 H), 5.33 (dd, I H),
35 7.16-7.33 (m, 9 H), 7.61 (s, 1 H).
WO95/14012 ~7t~a43 PCT~594/12269~
-- 66 --
~mplo 18. 6-[1,1'-Biphonyl]-~-yl-5,6-l~ihy~ro-3-[ ~2-
phonyl~tbyl)thio]-2~ LI-n 2-on~, (~/-)
me title ' was yL e~arêd as described in General
Method 4 using 200 mg cf 5,6-dihydro-4 hydLu~y-6-[~
5 biphenyl]-4-yl-2H-pyran-2-one, 300 mg of 2-phenylethyl-p-
tol~ h; osulf onate and 1. O mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
t~ --~UL ~ rif ication by f lash ,ILL ~ tCYL ~ y using
CH2Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oil
10 which was triturated with diethyl ether to afford a solid
(m.p. 130-133 C). 1H ~ (CDCl3) ~ 2.84-2.89 (m, 2 H), 2.96-
3.12 (m, 4 H), 5.42 (dd, 1 H), 7.08-7.67 (m, 15 H).
E~ample 19.
15 5,6-Dih~dLo 6 [~-(1,1-di~ethylethyl)ph~nyl)-3-
[ ~2-phenyl~tbyl) thio~ -2~ L~I 2-on~, ~ I /-)
The title ' was ~L e ~ared as described in General
Nethod 4 using 430 mg of 5,6-dihydro-4 hy-lLu.~y-6-[4-(1,1-
dimethylethyl)phenyl]-2H-pyran-2-one, 560 mg of 2-phenylethyl-
20 p-t~ thir~s~lfonate and 0.28 mL of triethylamine in 10 mL
of absolute ethanol. The solution was stirred for 3 days at
room t CI~UL~=. The crude product was triturated with
diethyl ether to afford a solid (m.p. 130-131 C). lX NNR
tCDC13) ~ 1-31 (s, 9 H), 2.79-2.88 (m, 2 H), 2.94-3.11 (m,
25 4 H), 5.34 (dd, 1 }i), 7.16-7.43 (m, 9 H), 7.61 (s, 1 H).
Example 20.
6-~3-Chlo..~l~ yl)-5,6-dihydro-3-[ ~2-
ph~nylethyl) thio] -2~ ~L--n 2-on~
The title ~ ' was ~ Led as described in General
Method 4 using 300 mg of 6-(3-chlorophenyl)-5,6-dihydro-4-
hydroxy-2H-pyran-2-one, S00 mg of 2-phenylethyl-p-
toluenethiosulfonate and 1. 0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
35 t~ ULe. Purification by flash ~l r, tOyLC~ y using
CH2Cl2/methanol (100/0 to g5/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
~ ~095114012 2 ~ 76~43 PCTJUS94~12269
67 --
(m.p. 99-100 C) . lH Nl~ (CDC13) ô 2 . 78-2 . 91 (m, 2 H), 2 . 97-
3.13 (m, 4 H), 5.32 (dd, 1 H), 7.17-7.43 (m, 9 H), 7.62 (s,
1 H).
5 I!~cample 21.
6- [ t ( ~ -siph~ny~ -ylos~ thyll -5 ~ 6-dihydro-3
~2-phenylethyl) thio]-21r ~,~ 2-one, (+/-)
The title _ -_ ' was prepared as described in General
Nethod 4 using 150 mg of 6-[[(1,1'-biphenyl)-4-yloxy]methyl]-
0 5,6-dihydro-4 ~.~JL.",y-2H-pyran-2-one, 185 mg of 2-phenylethyl-
p-toluene~ h;r~s~lfonate and 1.0 mL of triethylamine in 5 mL of
absolute ethanol. The soll7t;~n was stirred overnight at room
t~ aL~Le. Purification by flash chromatography using
CH,Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oi
15 which was triturated with diethyl ether to afford a solid
(m.p. 124-126 C). lH NMR (CDCl3) ~ 2.77 (dd, 1 H), 2.88 (dd,
1 H), 2.95-3.10 (m, 4 H), 4.19-4.28 (m, 2 H), 4.71-4.76 (m,
1 H), 6.96--7.56 (m, 14 H), 7.65 (s, 1 H).
20 EsaD~pl~ 22.
6- [ 1, 1 ' -~3iph~nyl ] -~ -yl-6 -butyl-5, 6 -dihydro-~ k~ dL ~ 3 - t ~ 2 -
phenylethyl) thio]-2~-~,L..n 2-on~
The title _ ' was ~Lepal~d as described in General
Method 4 using (0.388 mmol) of 6-[1,1'-biphenyl]-4-yl-6-butyl-
25 5,6-dihydro-4 ~yJL~ y-2H-pyran-2-one~ 5mL of absolute EtOH,
(0.407 mmol) of 2-phenylethyl-p-t~ol-lonoth;oc--~fonate in 3 mL
of absolute EtOH and (0.426 mmol) of triethylamine in 2 mL of
absolutê EtOH. The reaction was stirred at room temperature
overnight. The product was flash chromatographed(CH2Clz/~eOH
30 99/1) to afford a solid which was re~Ly:~Lalized from ethyl
acetate/diethyl ether. (m.p. 100-104 C). lH N~ (CDCl3)
ô 0.86 (t, 3 H), 1.15-1.5 (m, 4 H) ,1.9-2.1(m, 2 H) ,2.2-2.5 (m,
2 H), 2.5-2.8 (m, 2 H), 3.2 (ABSI, 2 H), 6.8-6.9 (m, 2 E~) ,7.1-
7 . ~ (m, 3 H), 7 . 3-7 . 7 (m, 9 H) .
WO 9S/14012 PCr/US94112269
-- 68 --
~pl~ 23.
~ - [ 2, 3 -Dihy~ro-~ ~ ~ Vd.~ - 6 ~IA~. _ [ (phenyl~llcthyl ~ thio ~ -2}{-
p~!rnn-2-yl]~enzonitri~
The title ` was E~LC:~a~ ~d as described in General
5 Nethod 4 using 250 mg of 4-[2,3-dihydro-4-hydroxy-6-oxo-2H-
pyran-2-yl]benzonitrile, 385 mg of benzyl-p-
toluenethiosulfonate and 1. 0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
temperature . Purif ication by f lash chromatography using
10 CH2Cl2/methanol (100/0 to 9S/5) as eluent gave a viscous oil
which was triturated with diethyl ether to af f ord a solid
(m.p. 148-151 C). lH NMR (CDCl~) ~ 2.66-2.75 (m, 2 H), 3.91
(dd, 2 H), 5.33 (dd, 1 H), 7.20-7.72 tm, 10 H).
lS ~ample 2~.
6-~ rifluv~ lph~nyl)-5,6-~ih~-v ~ '2
3-~phenylmethyl)thio]-2~-pyran-2-one, ~+/-)
The title ~ was prepared as described in General
Nethod 4 using 211 mg of 6-(4-trifluur ~lphenyl)-
20 5, 6-dihydro-4 ~lydLul~y-2H-pyran-2-one~ 273 mg of benzyl-p-
tolueneth i ~c~ onate and 1. 0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
t- c~LuLæ. Puri~icâtion by flash chromatography using
CH2Cl2/methanol (100/0 to 95/5) as eluent gave a vi6cous oil
25 which was triturated with diethyl ether to afford a solid
(m.p. 183-186 C). lH N~R (CDCll) ~ 2.65-2.77 (m, 2 H), 3.92
(dd, 2 H), 5.35 (dd, 1 H), 7.19-7.68 (m, 10 H).
l~nple 25 .
30 6-(3,5-Dil:hlv~ 1)-5,6-dihy~ro-~ d-VA,~-
3-~ (phenylm~thyl)thio]-2II E~ 2-one,
The title - ~1' was ur~:uaLe~ as described in General
Nethod 4 using 250 mg of 6-(3,5-dichluLuyh~..yl)-5,6-dihydro-4-
hydroxy-2II ~yLall 2-one, 320 mg of benzyl-p-
35 t~ n~-thioclllfonate and 1.0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
t~ aLuL~:. Purification by flash chromatography using
_ _ _ _ _ _ _ _ _ _
~ Wo 95114012 2 1 7 f; (~4 ~ PcrluS94/12269
CH2Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
(m.p. 147-149 C). lH N2~ (CDCl~) ~ 2.61-2.74 (m, 2 H), 3.90
(dd, 2 H), 5.21 (dd, 1 H), 7.18-7.36 (m, 9 H).
~c~mple 26.
C-~Pent~fluo~ 21)-5~6-dihld-v ~-k~d-VA~
3-t~phonylmethyl)thio]-211 ~,L~n 2-one, ~-It-)
The title ~ _ was ~L c:y_L æd as described in General
10 Nethod 4 using 226 mg of 6-(ppllt~f~ u~ yl)-5~6-dihydro-4
lly~uAy-2II pyLa.l 2-one, 269 mg of benzyl-p-
toluPnPthi~el1lfonate and 1.0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
t~ aLuL~. Purification by flash d,L, t~yLa~lly using
15 CH2Cll/-- ~1 (100/0 to 95/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
(m.p. 113-115 C). 'H NMR (CDCl3) ~ 2.50 (dd, 1 H), 3.14 (dd,
1 H), 3.90 (dd, 2H), 5.57 (dd, 1 H), 7.19-7.365 (m, 6H).
20 Es~ple 27.
5, 6-Dihl d- v ~ hl ~- v~r -6 - ( 3 -methylphenyl ) -3 -
[ ~2-ph~nylethyl) thio] -2~-pyr~n-2-one, (+/-)
The title ~ was y-~yar~d as described in General
Method 4 using 300 mg of 5,6-dihydro-4 ~Iy~lLuAy-6-(3-
25 methylphenyl)-2H-pyran-2-one, 515 mg of 2-phenylethyl-p-
tol~lPnpthirlslllfonate and 1.0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
t~ atuL~. Purification by flash chromatography using
CH2Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oil
30 which was triturated with diet~hyl ether to afford a solid
(m.p. 81-83 C). lH NMR (CDCl3) ~ 2.38 (s, 3H), 2.78-3.10 (m,
6 H), 5.35 (dd, 1 H), 7.17-7.34 (m, 9H), 7.61 (s, 1 H).
E~C2Ullpl8 28.
35 6-(2-Chlor,,' ~1)-5,6-dihy~ro-~ h~ v~ 3-
[ (pheny~ ethyl) thio] -2~ L~ 2-one, (~t-)
WO 95114012 Pcrluss4ll2269
2~ 3
-- ~o
The title ' was ~Le~aLed as described in General
Method 4 using 200 mg of 6-(2-chlorophenyl)-5,6-dihydro-4-
hydroxy-2H-pyran-2-one, 300 mg of benzyl-p-
toluene~hios~lfonate and 1.0 mL of triethylamine in 10 mL of
S absolute ethanol. The solution was 5tirred overnight at room
tt ~L~Lu~ ~. Purification by flash chromatography us ng
CH2Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oil
which was triturated with diethyl ether to afford a solid
(m.p. 89-91 C). 'H N~R (CDCl~) ~ 2.58 (dd, 1 H), 2.80 (dd,
10 1 H), 3.92 (dd, 2H), 5.64 (dd, 1 H), 7.20-7.67 (m, 10 H).
pl~ 29.
6--BUtY1--5~6--dih~dLO ~ dL~ ; r'
3-[ ~phenylm~thyl) thio]-2~ ~JL.,n 2-one (+/-)
lS The title ' was pL c:yared as described in General
Method 4 using 400 mg of 6-butyl-5,6-dihydro-4 ~Iy~v~y-
6-phenyl-2H-pyran-2-one, 540 mg of benzyl-p-
toluene~hios~lfonate and 1.0 mL of triethylamine in 10 mL of
absolute ethanol. The solution was stirred overnight at room
20 t~,eL Lu~=. Purification by flash ~1 L- t.OyLa~l~y using
CH2Cl2/methanol (100/0 to 95/5) as eluent gave a viscous oil.
H N~R (CDCl3) ~ 0.82 (t, 3 H), 1.0-1.4 (m, 4 H), 1.83-1.99
(m, 2 H), 2.97 (dd, 2 H), 3.63 (dd, 2 H), 6.83-7.41 (m, 11 H).
2S
E~ ~pl- 30.
6-tl,1'-Biphenyl~-~-yl-6-~utyl-5,6-dihydro-~ h,dL~, 3-
[ ~phenylmethyl)thio]-211-pyr~n-2-one ~_)
The title ~ _ was prepared as described in General
30 ~ethod 4 using (0.388 mmol) of 6-[1,1'-biphenyl]-4-yl-6-butyl-
5, 6-dihydro-4-hydroxy-2~-pyran-2-one, 5 mL of absolute EtOH,
(0.407 mmol) of benzyl-p-toluenethi~c~lfonate in 3 mL of
absolute EtOH and (0.425mmol) of triethylamine in 2 mL of
absolute EtOH. The reaction was stirred at room r~, CILUL-:
3S overnight. The product was flash .;1~-, h~Le1Y1~ed (ClI2C12/MeOH
99/1) to afford a solid (m.p. 45-52 C). lH NlR (CDCl3)
(S 0.85 (t, 3 H), 1.15-1.7 (m, 5 H), 1.9-2.1 (m, 2 H), 3.0
~ WO 95/14012 2 1 7 6 0 ~ 3 PCT/US94/12269
~ABq, 2 H), 3.5 (d, 1 H), 3.7 (d, l H), 6.8-6.9 (m, 2 H), 7.0-
7 . 7 (m, 12 H) .
~c~ple 31.
5 5,6-Dihydro- h~Lv,I 6 r~ ~1-3-t (phcnylmethyl)thio]-6-
propyl-2~ 2-one ~+)
The title _ ' was prepared as described in General
Nethod 4 using 1. 08 mmol of 5, 6-dihydro-4-hydroxy-6-phenyl-6-
propyl-2II FYL~I 2-one, 5 mL of absolute EtOH, 1.29 mmol of
0 benzyl-p-toluenethiosulfonate in 10 mL of absolute EtOH and
1. 51 mmol of triethylamine in 5 mL of absolute EtOH. The
reaction was stirred at room ~ aLuL~ overnight. The
product was flash 1~., Lùy.a~hed (hexane/ethyl acetate 75/25)
to afford a viscous oil. 'H NNR (CDCl3) ~ 0.83 (t, 3 H), 1.0-
5 1.2 (m, 1 H) ,1.3-1.5 (m, 1 H) ,1.8-2.0(m, 2 H) ,2.97 (ABq, 2 H),
3.5 (d, 1 H), 3.7 (d, 1 H), 6.8-6.9 (m, 2 H) ,7.0-7.5 (m, 9 H) .
mple 32.
5,6-Dihydro-~ hl~LV,~ 6 r' i~1-3-lt2-phenYlethYl)thio]-6-
20 propyl-28-pyr~n-2-one (I)
The title . ' was p. ~pal ed as described in General
Method 4 using 1. 08 mmol of 5, 6-dihydro-4 hydL u~y-6-phenyl-6-
propyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.29 mmol of 2-
phenylethyl-p-toluenethiosulfonate in 10 mL of absolute EtOH
25 and 1. 51 mmol of triethylamine in 5 mL of absolute EtOH. The
reaction was stirred at room t~ , ~ aLuLe: overnight. The
product was flash chromatographed (hexane/ethyl acetate 60/40)
to afford a viscous oil. lH N~ (CDCl3) ~ 0.85 (t, 3 H), 1.1-
1. 3 (m, 1 H) ,1. 3-l . 5 (m, l H), 1. 8-2 . 0 (m, 2 H), 2 . 2-2 . 3 (m,
30 1 H), 2.3-2.5 (m, 1 H), 2.6-2.8 (m, 2 H), 3.1 (ABq, 2 H),
6.9 (d, 2 H), 7.1-7.5 (m, 9 H).
E a lpll- 33.
5,6-Dihydro-~ hl~Lv~ 6 p_.,Lyl 6 ph~rl-3-
35 1 (phenylm~thyl) thio] -2}l-pyr~n-2-on~
The title ~ was ~L.~,a> ed as described in General
Method 4 using 0.96 mmol of 5,6-dihyd~v G p~llLyl-6-phenyl-
. , . . _ . .. .. _ _ _ _ _ .
WO 95/14012 PCr/US94/12269
~ ~b~43
-- 72 --
2H-pyran-2-one, 5 mL of absolute EtOH, 1.05 mmol of benzyl-p-
tolu~n~th;~culfonate in 10 mL of absolute EtOH and 1.05 mmol
of triethylamine in 5 mL of absolute EtOH. The reaction was
stirred at room t a ~UL _ overnight . The product was f lash
5 chromatographed (hexane/ethyl acetate 75/25) to afford a
viscous oil. lH NMR (C~C13) ~S 0.81(t, 3 H), 1.0-1.4 (m, 6 H),
1.8-2.0 (m, 2 H), 2.97 (A8q, 2 ~), 3.5 (d, 1 H), 3.7 (d, 1 H),
6.8-6.9 (m, 2 H), 7.0-7.4 (m, 9 H).
10 l~c~pl~- 3~.
5,6-Di~3LV ~-~d ~ 6 F yl 6 Fl~ ~1-3-[ ~2-
ph~nyl~thyll thiol-2~ L. 2-one ~ ~ )
The title was ~uL~uared as described in General
Method 4 using 0.96 mmol of 5~6-di~lydLu G p~..Lyl G ph~llyl-
15 2II pyL-II 2-one, 5 mL of absolute EtOH, 1.05 mmol of 2-
p~,_..~Lhyl-p-toluene~h;os~ onate in 10 mL of absolute EtOH and
1. 05 mmol of triethylamine in 5 mL of ~hcol~t~ EtOH. The
reaction was stirred at room t~ ~tUL~ overnight. The
product was flash chromatoyL~.y1.ed (hexane/ethyl acstate 70/30)
20 to afford a viscous oil. 'H NMR (CDCl,) S 0.82 (t, 3 H), 1.0-
1.4 (m, 6 H~, 1.8-2.0(m, 2 H), 2.2-2.3 (m, 1 E~), 2.3-2.5 (m,
1 H), 2.6-2.8 (m, 2 H) 3.13 (A~8q, 2 H), 6.8-6.9 (m, 2 ~), 7.1-
7 . 5 (m, 9 H) -
25 Ex ple 3s.
5, 6--Dih~ a. v ~ L~A~ 6- ~3-m~thylbutyl) -6 p~e.. ~1--3--
t ~ph~nylm~thyl) thio]-2}{-pyran-2-on~
The title was pL~:uaLed as described in General
Method 4 using 0.96 mmol of 5,6-dil.~lLu G (3-methylbutyl)-
30 6-phenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.05 ol of
benzyl-p-toluenethiosulf onate in 10 mL of absolute EtOH and
1.15 mmol of triethylamine in 5 mL of absolute EtOH. The
reaction was stirred at room t~ ~ULe3 overnight. The
product was flash chromatGyL~E,l.ed (hexane/ethyl acetate 80/20)
35 to afford a viscous oil. ~H N~ (CDCl3) ~ 0.80 (d,d, 6 H),
0.9-1.1 (m, 1 H), 1.2-1.3 (m, 1 H), 1.3-1.5 (m, 1 H), 1.8-2.0
,
-
~ WO 95/14012 2 1 7 ~ 0 4 3 pCrf0S94/12269
-- 73 --
(m, 2 H), 2.97 (1~3~, 2 H), 3.5 (d, 1 H), 3.7 (d, 1 H), 6.8-
6 . 9 (m, 2 H), 7 . 0-7 . 4 (m, 9 H) .
E~ ple 36.
5 5,6-Dihydro-~ h~ AI 6 ~3-m~thylbutyl) 6 r' ~1-3-t(2-
- ph~nyl~thyl) thio] -2~-pyran-2-on~ (_ )
The title ~ _ ' was ~. ~alcd as described in General
Nethod 4 using 0.96 mmol of 5,6-dil-y-lL~ G-(3-methylbutyl)-
6-phenyl-2E-pyran-2-one, 5 mL of Ahsolnte EtOH, 1.05 mmol of
10 2-phenylethyl-p-toluenethiosulfonate in 10 mL of absolute EtOH
and 1. 05 mmol of triethylamine in 5 mL of absolute EtOH. The
reaction was stirred at room t GLu- ~ oYernight. The
product was flash chromatographed (hexane/ethyl acetate 80/20)
to afford a viscous oil. lH l~lR (CDCl3) ~ 0.80(d,d, 6H), 1.0-
15 1 . 15 (m, 1 H), 1 . 2-1 . 3 (m, 1 H), 1 . 4-1 . 5 (m, 1 H), 1 . 9-2 . 0 (m,
2 H), 2.2-2.3 (m, 1 H), 2.3-2.5 (m, 1 H), 2.6-2.8 (m, 2 H),
3.15 (ABq, 2 H), 6.8--6.9 (m, 2 H), 7.1-7.5 (m, 9 H).
35~ ple 37.
20 5,6-Dihydro-~-h~ 6,6-diphenyl-3-
[ ~phonylmethyl) thio] -2~ E~.L 2-one
The title r _ ' was y- c:yared as described in General
Method 4 using 0. 94 mmol of 5, 6-dihydro-4 ~y~ .y-G, 6-
diphenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.13 mmol of
25 benzyl-p-toluene~h;os~lfonate in 10 mL of absolute EtOH and
1. 31 mmol of triethylamine in 5 mL of absolute EtOH. The
reaction was stirred at room ~ u.~: overnight. The
product was flash chromatographed (CH2Cl2/ MeOH 100/0-98/2) to
afford a solid (m.p. 44-47.5 C). lH N~R (CDCl3) ~ 3.34 (s,
30 2 H), 3.63 (5, 2 H), 6.8-6.9 (m, 2 H), 7.1-7.5 (m, 14 H).
E~ample 38.
5, 6-Dihydro-4 h~dr~ 6~ 6-diphenyl-3-
[ (2-phenyl~thyl) thio] -211 E~' 2-on~
The title ~ _ was yL~yGL~d as described in General
Nethod 4 using 0.94 mmol of 5,6-dihydro-4 11~ 1ru~y~6~6~
diphenyl-2H-pyran-2-one, 5 mL of absolute EtOH, 1.13 mmol of
.. _ . . . . . _ .. _ _ _, _ _ _ _ _ _ _ _
WO 9S/14012 PcrluS94112269
2 ~ 7~
-- 74 --
2-pheylnethyl-p-toluenethiosulfonate in 10 mL of absolute EtOH
and 1. 31 mmol of triethylamine in 5 mL of absolute EtOH. The
reaction was stirred at room tl, aLULe overnight. The solid
product was triturated from diethyl ether to afford a solid
5 (m.p. 153-154.5 C). lX N~ (CDCl3) ~ 2.3 (t, 2 H), 2.6 (t,
2 H), 3.49 (s, 2 H), 6.8-6.9 (m, 2 H), 7.1-7.6 (m, 14 H).
E~ple 39.
5, 6 -Dihydro-~ -h~ d. v,~ 6 r ~ 6- ~ 2 -ph~nyl~thyl ) -3 -
o ~ (ph~nyl~cthyl) thio] -2E-pyr~n-2-onc ~+)
The title, ~ _--d was ~- ~ya~ed as described in General
Method 4 using 0.85 mmol of 5,6-dihydro-4 h~ l~v~y-G p~ yl-6-
(2-phenylethyl)-2H-pyran-2-one, 5 mL of absolute EtOH, 1.02
mmol of benzyl-p-toluenethiosulfonate in 10 mL of absolute
15 EtOH and 1.19 mmol of triethylamine in 5 mL of absolute EtOH.
The reaction was stirred at room t~ aLuL-~ overnight. ~he
product was flash chromatographed (hexane/ethyl acetate 80/20)
to afford a viscous oil. ~H N2~(CDC13) ô 2.1-2.4 (m, 3 H),
2.7-2.8 (m, 1 H), 3.0(ABq, 2 H), 3.5 (d, 1 H), 3.8 (d, 1 H),
20 6.8-6.9 (m, 2 H), 7.0-7.5 (m, 14 H).
E~pl~ ~0.
5,6-Dihydro-~ h~d.~ 6 r~ ~1-6-(2-ph~nyl~thyl)-3-[ ~2-
phenylothyl) thio]-21/ ~ .. 2-one (+)
The title _ was yl~:ya~ed as described in General
Method 4 using 0.85 mmol of 5,6-dihydro-4 ~Iy~u~y-6-phenyl-6-
(2-phenylethyl)-2H-pyran-2-one, 5 mL of absolute EtOH, 1.02
mmol of 2-phenylethyl-p-tolll~n~thinc~llfnn~te in 10 mL of
absolute EtOH and 1.19 mmol of triethylamine in 5 mL of
30 absolute EtOH. The reaction was stirred at room t~, aLu~e
overnight. The solid product was triturated from ether to
afford a solid (m.p. 56-58 C). lH N~l(CDCl3) ~ 2.2-2.5 (m,
5 H), 2.6-2.8 (m, 3 H), 3.2 (ABq, 2 H), 6.8-6.9 (m, 2 H), 7.0-
7 . 5 (m, 14 H) .
Wo 95114012 PCTIUS94~12269
a~3
-- 75 --
15sample ~1
5, 6-Di~ LV ~ h~l v.~ ~-F' ~1-3-l (2-phenyl~thyl~ thio] -2 ~1~1) -
pyridinone ( ~ )
- The title ~ d was prepared as described in General Nethod
S 4 using 105 mg of 5,6-dihydro-4 ~lydLw.y-C ph~lyl-2(1H)-
pyridinone, 175 mg of 2-phenylethyl-p-toluenethiosulfonate and
0.1 ML of triethylamine in 5 mL of absolute ethanol. The
solution was stirred overnight at room temperature.
Purification by flash chromatography using CH2Cl2/methanol
10 (100/0 to 9~/3) as eluent gave a viscous oil which was
triturated with diethyl ether to afford a solid (m.p. 111-113
C). lH NMR (CDCl3) ~ 2.80-3.03 (m, 6 H), 4.70 (t, 1 H), 5.75
(s, 1 H), 7.16-7.40 Im, 11 H).
15 lbc~ple ~2
5, 6--Di~ ~LV ~ ~L~ ~1V~I 6 } ~ hyl ~ r ~1--3--
t (phenylm~thyl) thio] -2}1-pyr~n-2-onc, (+/-)
The title ~ ' was prepared as described in General
Nethod 4 using 200 mg of 5,6-dihydro-4 ~IydLuAy-6-
20 ph~l-u~.y Lh~l G ph~l~yl-2H-pyran-2-one, 210 mg of benzyl-p-
toluenethios~lfonate and 0.125 mL of triethylamine in 5 mL of
absolute ethanol. The solution was stirred overnight at room
ULe:. Purification by flash chromatography using
C~2Cl~ n- l (100/0 to 95/5) as eluent gave a solid (m.p.
25 161--163 oC) lH NMR (CDCl3) ~ 3.10 (d, 1 H), 3.52 (d, 1 H),
3.54 (d, 1 H), 3.75 (d, 1 H), 3.97 (d, 1 H), 4.23 (d, l H),
6 . 84-7 . 52 (m, 16 H) .
E~campln ~3
30 6-[2-(Benzorl~3]dioYol-5-yl)ethyl]-5,6-dihydro-~ ~1.1LVA,~ 6
phenyl-3-l ~phenylmethyl) thio] -211 ~,L~n 2-one, (+/-)
The title was pLe~.lr6:d as described in General
Method 4 using 165 mg o~ 6-[2-(benzo[1,3]dioxol-5-yl)ethyl]-
5,6-dihydro-4-hydLvAy ~ ~henyl-2E-pyran-2-one, 150 mg of
35 benzyl-p-toluenethiosulfonate and 0 . 075 ml of triethylamine in
5 mL of absolute ethanol. The sol~ltion was stirred overnight
at room t~ UL~. Purification by flash ~H1L- tOYL~ Y
Wo 95114012 2 ~ 7 ~ Q ~ 3 PCTIU~94112269
-- 76 --
using CH2Cl,/methanol (100/0 to 95/5) as eluent gave a solid
(m.p. 45-50 C) 'H NMR (CDCl3) ~ 2.08-2.30 (m, 3 H), 2.62-
2.71 (m, 1 H), 2.98 (dd, 2 H), 3.53 (d, 1 H), 3.76 (d, 1 H),
5.89 (s, 2 H), 6.50-6.86 (m, 5 H), 7.06-7.26 (m, 4 ~), 7.33-
5 7.44 (m, 5 H).
B~mple ~
6-t2-(3,4-Dichlo~ l)ethyl]-5~6-dihydro-~ hl~Lv~ 6
phenyl-3-[ ~phenylm~thy~ ~ thio] -2E P~L~n 2-on~, (~/-)
The title ~ ' was pL ~aL e~ as described in General
Method 4 using 365 mg of 6-[2-(3,4-dichl~,L~,~h.:..yl)ethyl]-5,6-
dihydro-4 }~dL~Ay C p~ yl~2II pyLan 2-one, 310 mg of benzyl-p-
toluenethiosulfonate and 0.15 mL of triethylamine in 5 mL of
absolute ethanol. The solution was stirred overnight at room
lS t ~LuLa. Purification by flash chromatography using
CH2Cl2/ ~nr~l (100/0 to 95/5) as eluent gave a solid (m.p.
43-50 C) lH NNR (CDCl3) ~ 2.07-2.16 (m, 1 H), 2.21-2.28 (m,
2 H), 2.71-2.77 (m, 1 E~), 2.99 (dd, 2 H), 3.54 (d, 1 H), 3.78
(d, 1 H), 6.84-6.91 (m, 3 H), 7.10-7.45 (m, 11 H).
ple ~5
6-[2-(4-FlU~ Jl)ethyl]-5~6-dihydro-~ SL~J-~-}-' ~1-3-
t ~phenylmethyl) thio] -2~ L~ 2-on-, ~ I /-)
The title ' was ~Le~a~e~ as described in General
25 Nethod 4 using 312 mg of 6 t2-(4-fluorophenyl)ethyl]-5,6-
dihydro-4 ~.ydL~Ay-6-phenyl-2H-pyran-2-one, 310 mg of benzyl-p-
tolueneth; 0s~ onate and 0 .15 mL of triethylamine in 5 mL of
absolute ethanol. The solution was stirred overnight at room
~- aLuL~. Purification by flash ~ , LO~L~ IY using
30 CHzCl2/methanol (100/0 to 95/5) as eluent gave a solid (m.p.
86-90 C) lH NNR (CDCl3) ô 2.08-2.35 (m, 3 H), 2.70-2.77 (m,
1 H), 2.99 (dd, 2 H), 3.54 (d, 1 H), 3.77 (d, 1 H), 6.85-7.44
(m, lS H).
WO 95tl4012 ~ ~ 7 6~4 ~ PCT/US94/12269
-- 77 --
~ple ~6
5,6-Di~dL~ ~ k ~ -h~LVA~ ~ r~ 3-[~ph~nylmethyl~thio]-
2~1-pyr~n-2-one ( t)
The title _ ' was prepared as described in General
5Method 4 using 0.91 mmol of 5,6-dillydLu G hexyl-4 hidLu~y-6-
phenyl-2H-pyran-2-one (+), 5 mL of absolute EtOH, 1.1 mm301 of
benzyl-p-tolueneth;oc~lfonate in 5 mL of absolute EtOH and
1. 27 mmol of triethylamine in 5 mL of absolute EtO~. The
reaction was stirred at room tL. ~LaL~La overnight. The
10 product was flash ~_1 L~ tc,yL~pl~e~ using CH2Cl2/MeOH (99.5/0.5)
to afford a viscous gum. lH N~ (CDCl3) ~ 0.81 (t, 3 EI), 1.0-
1.4 (m, 8 H), 1.8-2.0 (m, 2 H), 2.97 (ABq, 2 H), 3.5 (d, 1 H),
3 . 7 (d, 1 H), 6 . 8-6 . 9 (m, 2 H), 7 . 0-7 . 4 (m, 9 ~I) .
15 ~al~pl~ ~7
5,6-Di~d v ~ ' ~1 4-h~d v~-6 F' ~1-3-t (2-
phenylethyl) t:hiol-2~ ~l a~. 2-on~ (+)
The title ' was prepared as described in General
Method 4 using 0.91 mmol of 5~6-dillydL~. G hexyl-4-hydroxy-6-
20 phenyl-ZH-pyran-2--one (+), 5 mL o~ absolute EtOH, 1. 09 mmol of
phenethyl-p-tnlll~nF~h;~ onate in 5 mL of absolute EtOH and
1. 27 mmol of triethylamine in 5mL of absolute EtOH. The
reaction was stirred at room t ~uLæ overnight. The
product was flash chromatGyL. ~hed using CH2Cl2/MeOH
25 (99.75/0.25-99/1) to afford a viscous gum. 3H N~ (CDCll) ~
o . 84 (t, 3 H), 1. 0-1. 4 (m, 8 H), 1. 8-2 . 0 (m, 2 H), 2 . 2-2 . 3 (m,
1 H), 2.3-2.5 (m, 1 H), 2.6-2.8 (m, 2 H) 3.13 (ABq, 2 H), 6.9
(dd, 2 H), 7 . 1-7 . 5 (m, 8 H) .
30 E~cample 48
5,6-Dihyl~ro-~ h~d v~ -methylpentyl) 6 pl:e ~1-3-
t (phenyl~ethyl) thio]-2II F'IL~ 2-one (+)
The title ~ _ ' was ~3L epar~=d as described in General
Nethod 4 using 1 mmol of 5,6-dihydro-4-hy~L~,.y-6-(4-
35 methylpentyl) G p~._..yl-2H-pyran-2-one (+), 5 mL of absolute
EtOH, 1.2 mmol of benzyl-p-tol-~FnF~h;osulfonate in 5 mL of
absolute EtOH and 4 mmol of NaHCO3 in 5 mL of absolute EtOH.
_ _ _ . _ _ _ . . _ _ _ _ _ . _ _ _ _ _ _
Wo ss/14012 PCr/US94/12269
2 1 7~3
-- 78 --
The reaction was heated to 50 C for 1.5 hours then stirred at
room t~ uLa overnight. The product was flash
chromatographed using CH2Cl2/MeOH (100/0-99/1) to afford a
viscous gum. lH NNR (CDCl3) ~ 0.78 (d, 6 H), 1.0-1.5 (m, 5
5 H), 1.8-2.0 (m, 2 H), 2.97 (ABq, 2 H), 3.5 (d, 1 H), 3.7 (d, 1
H), 6 . 8-6 . 9 (m, 2 H), 7 . 0-7 . 4 (m, 9 H) .
~ca~pl~ ~9
5,6-Dihy~ro-~ d ~ 6-l~,-mothylp~ntyl) 6 r' Jl-3-[ ~2-
10 ph~nylothyl)thio]-211 r~rL~n 2-on~
The title _ ~ was ~le~ed as described in General
Nethod 4 using 1 mmol of 5,6-dihydro-4 ~41L~AY-6-(4-
methylpentyl) C pl~el~yl-2H-pyran-2- one (+), 5 mL of absolute
EtOH, 1.2 mmol of phenethyl-p-toluenethiosulfonate in 5 mL of
15 absolute EtOH and 1. 4 mmol of triethylamine in 5mL of absolute
EtOH. The reaction was stirred for 2 hours at 50 C. The
product was flash chromatographed using hexane/ethyl acetate
(80/20) to afford a viscous gum. lH NMR (CDCl3) ~ 0.79 (d, 6
H), 1.0-1.5 (m, 5 EI), 1.8-2.0 (m, 2 H), 2.2-2.3 (m, 1 H), 2.3-
20 2.5 (m, 1 H), 2.6-2.8 (m, 2 H) 3.14 (ABq, 2 H), 6.9 (~d, 2 H),
7 .1-7 . 5 (m, 8 H) .
ES~pl~ 50
6-Cyclop~ntylmothyl-5,6-dihy~ro-~ h~dL.,,~ 6-p' 11-3-
25 [~ph~nylm~thyl)thio]-2II ~ L. 2-onc ~+)
~ he title _ ' was ~Le~aL~:d as described in General
~ethod 4 using 1 mmol of 6-cyclopentylmethyl-5, 6-dihydro-4-
hydroxy-6-phenyl-2H-pyran-2 -one (+), 5 mL of absolute EtOH,
1. 2 mmol of benzyl-p-toluenethiosulf onate in 5 mL of absolute
30 EtOH and 4 mmol of NaHCO3 in 5 mL of absolute EtOH. The
reaction was heated to 120 C for 15 minutes. The product was
flash chromatographed using hexane/ethyl acetate (75/25) and
then CH2Cl-2/MeOH (99.5/0.5) to afford a viscous gum. 1H NMR
(CDCl~) ~ 0.8-1.0 (m, 1 H), 1.0-1.2 (m, 1 H), 1.3-1.6 (m, 5
35H), 1.6-1.8 (m, 2 H), 1.97 (dd, 1 H), 2.07 (dd, 1 H), 2.97
(ABq, 2 H), 3.5 (d, 1 H), 3.7 (d, 1 H), 6.8-6.9 (m, 2 H), 7.0-
7 . 4 (m, 9 H) -
~0 95/14012 PCrll~S94~12269
~ ~ 76a43
,9
~aDlple 51
6-Cyrl~, ty~ thyl-5~6-dihr~ro-~-h~Lv~ 6 r~ 3-[~2-
phenyl~thyl~ thio]-2~ ~L~L. 2-one l+)
The title ~ ' was ~L è~ared as described in General
5 Method 4 using 1 mmol of 6-cyclopentylmethyl-5, 6-dihydro-4-
hydroxy-C pherlyl-2H-pyran -2-one (+), 5 mL of absolute EtOH,
1.2 mmol of phenethyl-p-toluene~hios~lfonate in 5 mL of
absolute EtOE~ and l . 4 mmol of triethylamine in 5mL of absolute
EtOH. The reaction was stirred at room t c~L lLe for 2
10 days. The product was flash el~ ~ LcyLa~hed using
hexane/ethyl acetate (75/25-60/40) to afford a viscous gum.
H NNR (DMSO-d6) ô 0.8-1.0 (m, 1 H), 1.0-1.1 (m, 1 H), 1.2-1.8
(m, 7 H), 1.9--2.1 (m, 2 H), 2.3 (t, 2 H), 2.5--2.6 (m, 2 H)
3.25 (s, 2 H), 6.95 (d, 2 H), 7.1-7.4 (m, 8 H).
Example 52
3, ~ -Dihy~ro-~ ' -h~ 5 ' - [ ( phenylmethyl ) thio ] -
~piro[naph~ 2E) ,2'-[2}1]pyran]-6' (3'~)-one (+)
The title ' was pLe~led as describêd in General
20 Method 4 using 1.1 mmol of 3,4-dihydro-4' I~ydLu~y-
spiro[naphthalene-1(2H) ,2'-[2H]pyran]-6' (3'H)-one (+), 5 mL of
absolute EtOH, 1.3 mmol of benzyl-p-toluenethiosulfonate in 5
mL of absolute EtOH and 1. 5 mmol of triethylamine in 5 mL of
absolute EtOH. The reaction was stirred overnight at room
25 ~ uLè. The product was flash chromatographed using
hexane/ethyl acetate (g0/10-60/40) and then triturated from
ether to afford a solid (m.p. 143-145 DC). ~H NlqR (CDCl3) ~
1.5-1.8 (m, 2 H), 1.8-2.1 (m, 2 H), 2.6 (d, 1 H), 2.7-2.9 (m,
2 H), 3.0 (dd, 1 H), 3.9 (A;3q, 2 H), 7.0-7.2 (m, 1 H), 7.2-7.4
30 (m, 7 H), 7 . 4-7 . 5 (m, 1 H) .
E~cample 53
3, ~-Dihrdro-~ aL~-~ 5 ' - [ (2 -ph~nyl~thyl) thio] -
spiro[naph~ 1(211) ,2'-[2~]pyran]-6' (3'~)-one ( I )
The title __ ' was ~~ e~ Lèd as described in General
Method 4 using 1.1 mmol of 3, 4-dihydro-4 ' ~ILUaY~
spiro[naphthalene-1(2H) ,2'-[2H]pyran]-6' (3'H)-one (+), 5 mL of
_ _ _ _ _ _ _ _ _ _ _ _ , . , , , . _ . ,,,,, . .. ,, _
Wo 95114012 pcrN~94ll2269
2~ 7~)43
-- 80 --
bsolute EtOH, 1.3 mmol of phenethyl-p-tolueneth;os~lfonate in
5 mL of absolute EtOH and 1. 5 mmol of triethylamine in 5mL of
absolute EtOE. The reaction was stirred at room temperature
overnight . The product was f lash chromatographed using
5 CH2Cl,/MeOH (100/0-98/2) to afford a solid which was
recrystAl 1; 7~ from CH2Cll/diethyl ether to ~fford a solid
(m.p. 125-126.5 C). lH N~ (CDCl~) ~ 1.6-1.9 (m, 1 H), 1.9-
2.1 (m, 1 H), 2.1-2.3 (m, 2 H), 2.7-3.3 (m, 8 H), 7.1-7.4 (m,
7 H), 7 . 5-7 . 7 (m, 2 H) .
~ample 5~
3- ~3, 6-Dihydro-~-hldcv~l 6 _~v 2-phenyl-5-1 ~2-
ph~nylethyl)thio]-2~ p~L~. 2-yl)pr.,~ cid (I)
The title ' was prepared as described in General
15 Method 4 using 0.95 mmol of 3-(3,6-dihydro-4 hy~uAy-6-oxo-2-
phenyl-2H-pyran-2-yl) pl~ IOiC acid (+), 5 mL of absolute
EtOH, 1.1 mmol of ph=..æthyl-p-tol~ n~h;t~culfonate in 5 mL of
solllte EtOH and 2 . 3 mmol of triethylamine in 5mL of absolute
EtOH. The reaction was refluxed for 2 hours. The product was
20 flash chromatographed using CH2Cl2/MeOH/MeCO2H (95/5/0~ 05) to
afford a solid which was r~Ly~l -l l; 7e~1 from ethyl acetate
(m.p. 150.5-152 C). lH NMR (CDCl3) ~ 2.1-2.9 (m, 8 ~), 3.15
(ABq, 2 H), 6.9 (d, 2 H), 7.1-7.4 (m, 8 H).
25 E~ple 55
4-~3,6-Dih~l.v ~-h~LVA~ ~ _,v 2-phenyl-5-~2-
phenylethyl) thio] -21E ~ u. 2-yl) butyric Acid ~+)
The title ' was prepared as described in General
Method 4 using 1.8 mmol of 4-(3,6-dihydro-4 hyll~-Ay-6-oxo-2-
30 phenyl-2H-pyran-2-yl)-butyric acid (+), 5 mL of absolute EtOH,
2.1 mmol of phenethyl-p-tolll~nQ~h;~cl~lfonate in 5 mL of
absolute EtOH and 4 . 3 mmol of triethylamine in 5mL of absolute
EtOH. The reaction was refluxed for 3 hours. The product was
flash chromatographed using CH2Cl2/MeOH/MeCO2H (95/5/0.05) to
35 afford a ~hv-La solid. 1H NMR (CDCl3) ~ 1.4-1.6 (m, 1 H),
1 . 6-1 . 8 (m, 1 H), 1 . 9-2 . 1 (m, 2 H), 2 . 2--2 . 4 (m, 3 H), 2 . 4-2 . 5
WO 95/14012 PCrlUS94/12269
~ 2 ~ 760~3
-- 81 --
(m, 1 H), 2.6-2.8 (m, 2 H), 3.15 (A;3q, 2 H), 6.9 (d, 2 H),
7 .1-7 . 5 (m, 8 H) .
- ~mple 56
5 5-13,6-Dih~ v J~-h~aLV--2 6 ~,~v 2-pho~yl-5-t ~2-
- phenyletllyl)thio]-2~ $~,rL~ ~ 2-yl)p. ~ -ic ~cia (+)
The title _ was ~L~ ualed as described in General
Method 4 using 1.8 mmol of 5-(3,6-dihydro-4 ~ydLu~y-G u,.u 2-
phenyl-211 ~yL-.. 2-yl) p~--L~.ûic acid (+), 10 mL of absolute
10 EtOH, 2.2 mmol of pl.~ Ll.yl-p-tol~n~hio ~lfonate in 10 mL of
absolute EtOH and 4 . 3 mmol of triethylamine in 10 mL of
absolute EtOH. The reaction was refluxed for 3 hours. ~he
product was flash chromatuyL~l,l.ev using CH~Cl2/NeOH/MeCO~H
(99/1/0.05) to afford a solid (m.p. 113-119.5 C). lH N~
15 (CDCl3) ô 0.8-1.1 (m, 1 H), 1.1-1.3 (m, 1 H), 1.3-1.5 (m, 2
H), 1.8-2.0 (m, 2 H), 2.1 (t, 2 H), 2.2 (t, 2 H), 2.5-2.8 (m,
2 H), 3 . 2 (Ai3q, 2 H), 6 . 9 ~d, 2 H), 7 . 1--7 . 4 (m, 8 H), 11 . 5
(bs , 1 H), 11 . 9 (bs , 1 H) .
2 o E:r ple 57
5,6-Dihydro-~ k~lV~ ~; p~_..yl-3-~(2-phenylethyl)thio]-6
pyri~in-~-yl-2}{ ~ n 2-o~ (+)
me title was ~L~yaL.:~ as described in General
Method 4 using 0.47 mmol of 5,6-dihydro-4 h~Lv~y-6-phenyl-6-
25 pyridin-4-yl-2H-pyran-2-one (+), 0.56 mmol of ~hel.~Llyl-p-
toluenethiosulfonate in 5 mL of absolute EtOH, 2 mmol of
NaHCO3, and 0 . 65 mmol of triethylamine in 5 mL of absolute
EtOH. The reaction ~as stirred overnight at room temperature.
The solid product was triturated from ethyl acetate (m.p. 203-
30 205 C). IH N~ (DMSO--d6) ô 2.1 (t, 2 H), 2.5 (t, 2 H), 3.7(ABq, 2 H), 6.9 (d, 2 H), 7.1-7.6 (m, 10 H), 8.6 (d, 2 H).
WO 95/14012 ~ 3 PCr/US94/12269
-- 82 --
~ampl~ 58
S,6-Dihydro-~ ~d ~ 6-[~thylphenyl ino~othyl] 6 ph_~y1-
3-1 ~2-ph~J~yll~t~yl) thio]-2~ E~L~n 2-ono ~+)
The title ' was prepared as described in General
5 Method 4 using 0.55 mmol of 5,6-dihydro-4 1IYdLU~Y-~-
[ (methylphenylamino)methyl]-6-phenyl-2H-pyran-2-one ( ), 0.61
mmol of p~ thyl-p-toluenethioslllfonate in 5 mL of ~hsolut~
EtOH, 2.2 mmol of NaHCO3, and 0.61 mmol of triethylamine in 5
mL of absolute EtOH. The reaction was stirred overnight at
10 room t~ ~L-: then 2 hours at 50 C. The solid product was
flash ûhromatographed using CH2Cl2/MeOH (99/1) to afford a
solid tm.p. 48-57 C). lH NMR (CDCl~) ~ 2.2-2.3 (m, 1 H),
2.3-2.5 (m, 1 H), 2.6-2.8 (m, 2 H), 3.08 (s, 3 H), 3.15 (d, 1
H), 3.35 (d, 1 H), 3.7 (A3q, 2 H), 6.7-6.9 (m, 3 H), 7.1-7.6
15 (m, 12 H).
~c~mpl~ 59
3,6-Dihydro-~ ~d v,.~ 6 o~_ 2-phenyl-5-
[ ~ph~nylm~thyl) thio] -2E~-pyrnn-2-yl) 1. ltyl~- id~
To a 50 mL reaction flask was added 0.75 mmol of 4-(3,6-
dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl) propanoic acid
(+), 1.5 mmol of 4-methylmorpholine, and 7-5 mL of CH2C12.
The reaction was cooled to 0OC and 1.5 mmol of methyl
chloroformate in 3 . 5 mL of CH2Cl2 was added . The reaction was
2 5 stirrred at 0 C f or 2 hours . Ammonia was bubbled into the
vessel for 10-15 minutes and the reaction allowed to stir for
3 0 min at 0 C then 1. 5 hours at room t~ 1 ~ e . The
reaction was poured into ethyl acetate and lN HCl, the aqueous
layer extracted with 2x ethyl acetate, dried over MgSO4, and
30 ~ LL-ted. The crude reaction mixture was flash
chromatoyL,~phed using CH2Cl2/MeOH/MeCO2H (98/2/0.05) to a~ford
4- ( 3, 6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2 -
yl)hutyramide (+) as a solid (m.p. 51-54 C). lH NMR (DMSO-
d6) ~ 1.0-1.2 (m, 1 H), 1.3-1.6 (m, 1 H), 1.8-2.0 (m, 4 H),
35 2.9 (ABq, 2 H), 4.8 (s, 1 H), 6.6 (s, 1 H), 7.2 (s, 1 H), 7.2-
7.5 (m, 5 H), 11.4 (bs, 1 H).
_ _ _ _
~ WO 95/14012 2 ~ 7 6 ~ 4 3 PCT~S94/l226s
-- 83 --
me title was prepared as described in General
Nethod 4 using 0 . 42 mmol of 4- (3, 6-dihydro-4 ~lydL~ y-6-oxo-2-
phenyl-2H-pyran-2-yl) bu~yLaluide (+) S mL of absolute EtOH,
o . 58 mmol of benzyl-p-toluenethiosulfonate in 5 mL of absolute
5 EtOH, 1. 67 mmol NaHCO" and 0 . 42 mmol of triethylamine in 5mL
of absolute EtOH. The reaction was stirred at room
te ~ aLuL~ overnight. The product was flash chromato~La~hed
using CH2Cl2/MeOH (90/10) to afford the desired . ' as a
solid ~m.p. 47.5-53 C). lH NNR (DNSO-d6) ô 1.0-1.3 (m, 1 H),
10 1.3-1.6 (m, 1 H), 1.7-2.1 (m, 4 H), 3.1 (s, 2 H), 3.5 (ABq, 2
H) 6.7 (s, 1 H) 7.0-7.5 (m, 11 H), 11.4 (s, l H).
Esa~pl~ 60
5 - ~ 3, 6 -Di~ d, ~ i .,~., 2 -ph~nyl-5- [ ~ 2 -
15 ph~nyl~thyl)thio]-2~ ~,~ 2-yl)~ -ic acid amid~ ~+)
To a 50 mL reaction flask was added 1.2 mmol of 5-(3,6-
dihydro-4-hydroxy-6-oxo-2-phenyl-2~-pyran-2-yl)pentanoic acid
(+), 2.4 mmol of 4-methylmorpholine, and 10 mL of CH2Cl2. The
reaction was cooled to 0C and 2 . 4 mmol of methyl
20 chloroformate in 3 mL of CH2Cl2 was added. The reaction was
stirrred at 0C for 2 hours. Ammonia was bubbled into the
vessel for 10-15 minutes and the reaction allowed to stir for
30 minutes at 0C. The reaction was poured into ethyl acetate
and lN HCl, the agueous layer extracted with ethyl acetate,
25 dried over MgSO~, and ~ ~...c~.,L- ated. The crude solid was
triturated using CH2C12 to af~ord 5-(3,6-dihydro-4 hydL~y-6-
oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid amide (+) as a solid
(m.p. 173-174 C). ~H NNR (DMSO-d6) ~ 0.8-1.0 (m, 1 H), 1.1-
1.3 (m, 1 H), 1.3-1.5 (m, 2 H), 1.8-2.0 (m, 4 H), 2.9 (ABg, 2
30 H), 4.8 (s, 1 H), 6.6 (s, 1 H), 7.2 (s, 1 H), 7.2-7.5 (m, 5
H), 11.4 (s, 1 H).
The title ~ "~ was prepared as described in General
Method 4 using 0 . 60 mmol of 5- (3, 6-dihydro-4 ~ ~ILU~-Y-6-OXO-2-
phenyl-2H-pyran-2-yl)pentanoic acid amide (+) 5 mL of absolute
35 EtOH, 0.85 mmol of pl~ eLl.-yl-p-toluenethiosulfonate~ 2.4 mmol
NaHCO3, and 0 . 60 mmol of triethylamine in 5mL of absolute
EtOH. The reaction was stirred at room t aL~ overnight.
_ . ,, . , _ . , . , ,, _ . . , ., _ . _ _ _ _ _ _ _ , _ _ _ _ _ _
WO95/14012 2 ~ 3 PCr/U594112269
-- 84 --
me product was flash chromat~L~yl~d using CH2Cl~/MeOH
(90/10) then triturated from ether to afford a solid (softened
100-105 C, melted ~ letaly at 120 C). 'H NMR (DMSO-d6)
0.9-1.1 (m, l H), 1.1-1.3 (m, 1 H), 1.3-1.5 (m, 2 H), 1.8-2.0
S (m, 4 H), 2.2 (t, 2 H), 2.5-2.6 (m 2 H), 3.2 (s, 2 H), 6.6 (s,
1 H), 6.9 (d, 2 H), 7.1--7.6 (m, 9 H), 11.5 (bs, 1 H).
E~spl~ 61
~--B~nzyl~ 3, 6-dih~v ~ h~dLv~ 6-v~v 2-ph~nyl-5-
10 [~ph~nyll~t~jl)t~io]-2~ ~L~ 2-yl~L LYL~ .de (I)
To a 50 mL reaction flask was added 0.75 mmol of 4-(3,6-
dihydro-4 ~l~dLvAy-C ~,,v 2-phenyl-2H-pyran-2-yl)propanoic acid
(_), 1.5 mmol of 4-methylmorpholine, and 7-5 mL of CH2Cl2-
The reaction was cooled to 0 C and 1. 5 mmol of methyl
lS chloroformate in 3 . 5 mL of CH2Cl2 was added. The reaction was
stirrred at 0 C for 2 hours. Benzyl amine (1.6 mmol) in
CH2Cl2 (5 mL) was added and the reaction allowed to stir for
30 min at 0 C then 1.5 hours at room t~ ULe. The
reaction was poured into ethyl acetate and lN HCl, the aqueous
20 layer extracted with 2x ethyl acQtate, dried oYer MgSO~, and
c "~ ted. The crude reaction mixture was f lash
chromatG ~L~pl.ed usinq CH2Cl,/MeOH (99/1) .
The resulting e ~LLcuuaLe (200mg) was hydrolized by
LLeak with 0.1N HCl (20 mL) in p-dioxane (4 mL) for 1 hour
25 at room t~ c.LULe to afford N-benzyl-4-(3,6-dihydro-4-
hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)-~uLyLa~l~ide (+/-).
The title ` was pLe~a~6d as described in General
Method 4 using 0.33 mmol of N-benzyl-4-(3,6-dihydro-4-hydroxY-
6-oxo-2-phenyl-2H-pyran-2-yl) butyramide (_), 5 mL of absolute
30 EtOH, 0.47 mmol of benzyl-p-tolueneth;os~ onate in 5 mL of
absolute EtOH, 1.33 mmol NaHCO3, and 0.33 mmol of
triethylamine in 5mL of absolute EtOH. The reaction was
stirred at room t~ ~Lu~e overnight. The product was flash
chromat~yL-~hed using CH2Cl2/MeOH (95/5) to afford the desired
' as a solid (m.p. 48-52 C). ~H NMR (DNSO-d6) ~ 1.1-
1.3 (m, 1 H), 1.4-1.6 (m, 1 H), 1.8-1.9 (m, 2 H), 2.0-2.2 (m,
,
~ ~IV095/14012 2~16~43 PC~IUS94/12269
-- 85 --
2 H), 3.1 (s, 2 H), 3.6 (ABq, 2 H), 4.2 (d, 2 H), 7.0 (m, 2
H), 7.1-7.5 (m, 13 H), 8.3 (t, 1 H), 11.4 (bs, 1 H).
l~ample 62
5 5-~3,6-Dihydro-~ ~:,d,.,,~ ~ ~,,.. 2-phonyl-5-1~2-
p~enylethyl)thio]-2~ L~J_ 2-yl)pentanoic ~cid benzyl~mide ~_)
To a 50 mL reaction flask was added 0.83 mmol of 5-(3,6-
dihydro-4 }'IydLVAy ~ JAV 2-phenyl-2H-pyran-2-yl)pentanoic acid
(+), 1 . 65 mmol of 4-methylmorpholine, and 10 mL of CH2Cl2 .
10 The reaction was cooled to 0C and 1. 65 mmol of methyl
chlo~vfuL..-aLe in 5 mL of CH,Cl2 was added. The reaction was
stirrred at 0C for 2 hours. Benzyl amine (1.7 mmol) in
CH2Cl2 (5 mL) was added and the reaction allowed to stir for 2
hours at room ~ a~ . The reaction was poured into et~yl
15 acetate and lN HCl, the aqueous layer extracted with 2x ethyl
acetate, dried over MgSO1, and cv..~-erl~LGLed. The crude
reaction mixture was carried on without purification.
The resulting ~a~L._luate (200mg) was hydrolized by
treatment with 0. lN HCl ~20 mL) in p-dioxane (4 mL) for 8
20 hours at room temperature to afford 5- (3, 6-dihydro-4 l~YdLV
6-oxo-2-phenyl-2H pyLan 2-yl)-pentanoic acid benzylamide (+).
'NMR (DMSO-d6) ~ 0.8-1.0 (m, 1 H), 1.1-1.3 (m, 1 H), 1.3-1.5
(m, 2 H), 1.8-2.0 (m, 2 H), 2.0-2.2 (m, 2 H), 2.9 (ABq, 2 H),
4.2 (ABq, 2 H), 4.85 (s, 1 H), 7.1-7.5 (m, 10 H), 8.2 (bt, 1
25H), 11.4 (s, 1 H).
The title ~ ' was prepared as described in General
Method 4 using 0 . 58 mmol of N-benzyl-5- ( 3, 6-dihydro-4 ~y~ VAy-
6-oxo-2-phenyl-2H-pyran-2-yl)-pentanoic acid amide (+), 5 mL
of absolute EtOH, 0.82 mmol of benzyl-p-toluenethiosulfonate,
30 2.34 mmol NaHCO3, and 0.82 mmol o~ triethylamine in 5mL of
absolute EtOH. The reaction was stirred at room temperature
overnight. The product was flash chromatGyLaphed using
CH2Cl2/lleOH (g9/1) to afford the desired _ ' as a solid
(m.p. 47-49 C). ~H NMR (CDCl3) ô 1.0-1.2 (m, 1 H), 1.3-1.5
35 ~m, 1 H), 1.5-1.7 (m, 2 H), 1.8-2.0 (m, 2 H), 2.0-2.2 (m, 2
H), 2.9 (ABq, 2 H), 3.5 (d, 1 H), 3.7 (d, 1 H), 4.4 (m, 2 H),
5.7 (bt, 1 H), 6.8-6.9 (m, 2 H), 7.0-7.5 (m, 13 H).
WO95/14012 2 ~ 3 PCTIUS94/12269
-- 86 --
~ple 63
N-B~nzyl-~-~3,6-Cihydro-~ h~ ~L-IA~ 6 ~ , 2-phenyl-5-
[ ~phonylnlethyl) thio] -2~1 p~ L. 2-yl) -N-~thylL~L~ +)
The title ' was yL eya~èd as described in General
5 MêthOd 4 using 0.66 mmol of N-benzyl-4-(3,6-dihydro-4-hydroxy-
6-oxo-2-phenyl-2H-pyran-2-yl) ~ -- thylbutyramide (+), 0.92
mmol of benzyl-p-toluenethiosulf onate in 5 mL of absolute
EtOH, 2.63 mmol of NaHCO3, and 0.92 mmol of triethylamine in
5 mL of absolute EtOH. The reaction was hêatêd for 2 hours at
10 50 C. The solid product was flash ~1LL~ ~uyL~phed using
CH2Cl2/MêOH (99/1-98/2) to afford a solid (m.p. 47-49 C). ~H
NMR (CDCl3) ô 1.5--1.8 (m, 2 H), 1.9-2.1 (m, 2 H), 2.3 (A;3q, 2
H), 2.84/2.91 (s/s 3 H), 2.98-3.02 (m, 2 H), 3.5 (dd, 1 H),
3.7 (dd, 1 H), 4.46/4.55 (s/s, 2 H), 6.8-6.9 (m, 2 H), 7.0-7.5
15 (m, 13 H).
General ~et~o~ 5.
The desired ~ _ - were yLè~aled by adding the
20 appropriatê acid chloride (1_05 equiv.) to a solution of thê
5, 6-dihydro-2H-pyran-2-one ( 1. 0 equiv . ), triethylamine ( 1. 05
equiv. ), and THF at 5 C. The sllcpQnC;-~n was stirred overnight
at room t~ LuL e and then diluted with ethyl acetate and
water. The organic phase was washed with ice-cold 1 N HCl and
25 brine, dried over MgSO4, and cu--c~ L-ted. The residue was
dissolved in toluene, treated with catalytic DNAP, and heated
at 80-85 ~C for 4 to 8 hours. The solution was cooled to room
t~ ~ltUL e and diluted with water . The organic phase was
washed with ice-cold 1 N HCl and brine, dried (MgSO~), and
30 cul.cel,LL~lted. The product was chrûmatographed on silica gel,
eluting with 5:1 hexane:ethyl acetate, to give the 3-acylated
int~ te. This material was dissolved in glacial acetic
acid, treated with sodium cyano~uLoh~lLide (2 equiv), and
stirred at room t~ tlLuLe for two hours. The reaction
35 mixture was diluted with water, acidified with conc. HC1, and
extracted with ethyl acetate. The extract was washed with
Wo95/14012 2 i 7~ 3 PCTIUS94/12269
-- 87 --
brine, dried (MgS0~), and cul,c~ Lc~ted to afford the desired
~campl~ 64
5 5,6-Dil.~d~e J-k~lL~ ,6-diphenyl-3-~2-phenylethyl)-2
- 2-one
The title _ ' was pL- ~aled as described in General
Method 5 using 2 . 0 mmol of 5, 6-dihydro-4-hydroxy-6, 6-diphenyl-
2H-pyran-2-one, 2.1 mmol of phenylacetyl chloride, 2.1 mmol of
10 triethylamine, and 10 mL of THF, followed by 10 mL of toluene
and catalytic DNAP. Chromatography of the residue afforded 1.5
mmol of the i nt- ~; Ate 3-acyl ~ - ~P~ rtion of this
acyl derivative was A. l; chPd with 3 mmol of sodium
cyanobuLo~ly~ide~ The product was triturated from ether (m.p.
15 158-159 C). ~H NMR (DMSO-d6) ~ 2.31 (m, 4 H), 3.37 (m, 2 H),
6.g3 (d, 1 ~1), 7.07-7.17 (m, 3 H), 7.24-7.28 (m, 2 ~I), 7.35
(m, 8 H).
Alternatively, the title ~ ' could be pL~pa~d as
follows. A suqpPnqion of 0.25 g (6.2 mmol) of sodium hydride
20 in 5 mL of dry THF was cooled to 0C under nitrogen and
treated with a solution of 1.40 g (6.0 mmol) of ethyl 2-(2-
phenylethyl) acetoacetate in T~IF (2 mL) . The solution was
stirred at 0C for ten minutes, treated with 4.3 mL of 1.4 M
n-butyllithium, and stirred for another fifteen minutes. A
25 solution of 0.55 g (3.0 mmol) of ~Pn~orhPn~nP in THF (3 mL)
was added all at once, and the reaction mixture was stirred at
room t-, at~ for two hours. Water (75 mL) was added, and
the mixture was stirred overnight at room t~t~PLaLuLc. The
solution was washed with ether. The agueous layer was
30 acidified to pH 2 with 6 N HCl and extracted with ethyl
acetate; the extract was washed with brine, dried over
magnesium sulfate, and .once-l-Lated. The residue was
triturated with ether : hexane 1:1, and the solids were
f iltered and dried to give the title , _ .
E~pl~ 65
_, _ _ _
Wo 95/14012 PCr/US94/12269
~tl~ 3
-- 88 --
5,6-Di~ LV l~ LV~ 6 ~3-methylbutyl) 6-F ~1-3-~2-
ph~nylethyl)-21} P~L~ 2-one, ~+/-)
The title, ' was prepared as described in General
Method S using 2.0 mmol of 5,6-dihydro-4 hydLv~y-6-(3-
5 methylbutyl) G pl.~.,yl-2H-pyran-2-one, 2.1 mmol of phenylacetyl
chloride, 2.1 mmol of triethylamine, and 10 mL of THF,
followed by 10 mL of toluene and catalytic DNAP.
Chromatography of the residue afforded 1.0 mmol of the
int ~; lte acyl - - RF~ r~;nn of this intermediate
10 was effected with 2 mmol of sodium ~yalloboLullydLide. The
product was rht~inc-d as a solid (m.p. 125-126 C). lH N~
(DMS0-d6) ~ 0.~6 (m, 7 I~), 1.12 (m, 1 H), 1.38 (m, 1 H), 1.87
(m, 2 H), 2.27-2.46 (m, 4 H), 2.97 (q, 2 H), 6.98-7.38 (m, 10
H) .
Esampl~ 66
5,6-Dih~ dL V S h~l v.~ 6,6-aiphenyl-3-~3-ph~nylpropyl)-2}1-
pyrAn-2-one
The title ` was ~Lt:yaL~=~ as described in General
20 Method 5 using 2.5 mmol of 5,6-dihydro-4 hylL~,~y-6,6-diphenyl-
2H-pyran-2-one, 2.7 mmol of phenylacetyl chloride, 2.8 mmol of
triethylamine, and 20 mL of THF, followed by 20 mL of toluene
and catalytic DMAP . Chromatography of the residue af f orded 1. 0
mmol of the in~ te 3 -acyl ,_ - . I~e~ t i nn of this
25 acyl derivative was ac~omplished with 3 mmol of sodium
~;yanobvLv~lydLide. The product was triturated from ether to
give the title ' (m.p. 61-63 C). lH N}IR (D~ISO-d6) ~
1.35 (m, 2 H), 2.05 (t, 2 H), 2.14 (t, 2 H), 3.42 (bs, 2 H),
6.92 (m, 2 H), 7.17-7.40 (m, 13 H).
lS~ple 67
5,6-Dihydro-~ c phe ~1-3,6-bi~2-phenylet~yl)-2~-
pyr~n-2-one, ~ +/-)
The title ~ ' was E.L~a-~d as described in General
35Method 5 using 3.0 mmol of 5,6-dihydro-4 ~IydLv~.y-G pl~ yl-6-
(2-phenylethyl)-2H-pyran-2-one, 3.2 mmol of hydrsrinn
chloride, 3.2 mmol of triethylamine, and 30 mL of THF,
~ WO 95/14012 2 ~ 7 ~ ~ ~3 PCrlUS94/12269
-- 89 --
followed by 30 mL of toluene and catalytic DMAP.
Chromatography of the residue afford~d 1.5 mmol of the
int~ te 3-acyl ~ ~. Reduction of this acyl
derivative was accomplished with 3 m~ol of sodium
5 cyanobuLo1lydLide~ The product was triturated from ether:hexane
- (1:5) to give the title _ ' (m.p. 68-70 C). lH ~T~
(DMS0-d6) ~ 2.20 (m, 2 H), 2.35 (m, 2 H), 2.42-2.59 (m, 4 H
plus DMS0), 3 . 06 (q, 2 H), 7 . 00 (dd, 2 H), 7 . 07-7 . 43 (m, ~3
H)
General JS-tl~od 6.
The desired _ were p~ Led by adding piperidine
(1.05 equiv) to a cold (ice bath) solut;nn of the 3-bromo-5,6-
dihydro-4 hydLv~y-2H-pyran-2-ones (1. 0 mmol, p~e~are-l in
15 General Method 3), the requisite thiol (1.05 mmol), and
dichlvr~ (20 mL). The mixture was stirred at room
t~ -~UL~ for 8 to 48 hours. Water was added, and the
organic phase was separated, dried over MgS0~, and
CVIIC~ L ,ited .
3~mple 68
4-1~.v.,-3-(2-i~opropylehenylthio) -5,6-dihrdro-6,6-diphenyl-
211 ~/L,~.. 2-one
The title ~ .u-.~ was ~L~ red as described in General
25 Method 6 from 1.0 mmol of 3-LLI ~ .,6-dihydro-4-hydLu~y-6~6
diphenyl-2H-pyran-2-one (~L~pa~d in example AAA), 1.05 mmol
of 2-isopropylh~n7~n~thiol, and 1.05 mmol of piperidine in 20
mL of dichloromethane. The product was triturated with ether
to afford a solid (m.p. 216-217 oC). lH NNR (DMSO-d6) ô 1.17
30 (d, J = 6.8 Hz, 6 H), 3.20 (m, 1 H), 3.77 (bs, 2 H), 5.64 (d,
1 H), 6.45 (t, 1 H), 6.g2 (t, 1 H), 7.12 (d, 1 H), 7.32 -
7 . 48 (m, 10 H) .
ple 69
35 5, 6-Dih~,dLV ~-h~-lLV ~ ~, 6-~liph~nyl-3-phenrlthio-2~-pyran-2-one
The title _ ' was prepared as described in General
Method 6 from 0 . 96 mmol of 3-bromo-5, 6-dihydro-4-hydroxy-6, 6-
_ _ _ _ _ _
Wo 9~/14012 PCr/USs4lI2269
-- 90 --
diphenyl-2H pyL~I~ 2-one (prepared in example AAA), 1 . 0 mmol of
benzenethiol, and 1.0 mmol of piperidine in 20 mL of
dichloromethane. The product was triturated with hexane:ether
(1:1~ to afford a solid (m.p. 78-80 C). lH N~ (DNSO-d6) ~
5 3.37 (bs, 2 H), 6.35 (m, 2 H), 6.93 (m, 3 H), 7.29-7.49 (m, 10
H)
.
l~ple 70
5, 6-Dihy~ro-~ LvA~ -3 - ~ 3 -methylphenylthio ) -6, 6-~iphenyl-2~-
10 pyran-2-one
The title ~ ' was ylepaLed as described in General
Nethod 6 from 1.3 mmol of 3 bL~ 5,6-dihydro-4 ~1~lLv~y-6,6-
diphenyl-2Ii yyLeln 2-one (yLe:~aL~:d in example AAA), 1.4 mmol of
3-methylh~n7~n~thiol, and 1.4 mmol of piperidine in 25 mL o~
15 dichlvL, 'An~. The product was triturated with hexane:ether
(1:1) to afford a solid which was dissolved in 2 N NaOH,
washed with ether, acidif ied to pH 2, and extracted with ethyl
acetate. The extract was washed with water, dried over MgS04,
and ~ V~ l.LLclted to give a solid (m.p. 58-60 C) . lH NNR
20 (DNSO-d6) ~ 2.07 (s, 3 H), 3.77 (s, 2 E), 6.06 (m, 1 ~), 6.45
(s, 1 H), 6.78 (m, 2 H), 7.25-7.47 (m, 10 H).
E~mpl- 71
5~6-Dih~ LV ~-h~lLV~ pl;__~l-6-(2-phenylethyl)-3-phenylthio-
25 2~ ~ L~ 2-one l~/-)
The title _ ' was prepared as described in General
Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4 hydLv~y~6-
phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example
BBB), 1 . 60 mmol of benzenethiol , and 1 . 60 mmol of piperidine
30 in 30 mL of dichloromethane. The product was triturated with
hexane:ether (1:1) to afford a solid. The crude product was
chromatographed on silica gel, eluting first with chloroform
and then with 5% methanol in chloroform, to give the title
~ _ (m.p. 58-60 C). lH NMR (DMSO-d6) ô 2.22-2.39 (m, 3
35 H), 2.62 (m, 1 H), 3.46 (q, 2 H), 6.48 (m, 2 H), 6.98 (m, 3
H), 7 . 15 (m, 3 H), 7 . 25 (m, 2 H), 7 . 46 (m, 5 H) .
~ W095/14012 ~ D43 PCT/US94112269
-- 91 --
D~plo 72
5, 6-Dihydro-~-h~Lv..~ 3- t2-i~opropylphenylthio) 6 r- - yl-6- (2-
phnnyl~thyl ) -2}1 ~ L ~ 2 -one ( +/ - )
The title __ was prepared as described in General
5 Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4-ilyvLu~y-G-
phenyl-6- (2-phenylethyl) -2H-pyran-2-one (p-e u~red in example
BBB), 1. 60 mmol of 2-isopropyl h~n7~nPthiol, and 1. 60 mmol of
piperidine in 30 mL of dichlvLI thane. The product was
triturated with hexane:ether (1:1) to afford a solid. The
10 crude product was .l-r, toyL~yhed on silica gel, eluting first
with chloroform and then with 5% r '~-nAl in chloroform, to
give the title _ ' (m.p. 66-67 C). lH NMR (DMSO-d6) ~
1.16 (t, 6 H), 2.21-2.35 (m, 3 H), 2.60 (m, 1 H), 3.21 (m, 1
H), 3.42 (q, 2 H), 5.88 (d, 1 H), 6.56 (t, 1 H), 6.94 (t, 1
15H), 7 . 13 (m, 4 H), 7 . 25 (m, 2 H), 7 . 45 (m, 5 H) .
ES~pl~ 73
5,6-Dil.~Lv ~-h~d.v..y-3-(3-~thylphenylthio) 6 r' ~1-6-(2-
ph~nyl~thyl) -21r ~"~ n 2-one (+/-)
The title ~ _ ~ was prepared as described in General
Method 6 from 2. 0 mmol of 3-bromo-5, 6-dihydro-4-hydroxy-6-
phenyl-6- (2-phenylethyl) -2H-pyran-2-one (prepared in example
BBB), 2. 2 mmol of 3--methylh~n7~ hi ol ~ and 2 .2 mmol of
piperidine in 30 ~nL of dichlv~ ne. The crude product was
25 ~1... ~vyLc~phed on silica gel, eluting first with chloroform
and then with 5% methanol in chloroform, to give the title
' (m.p. 68-70 C). lH NMR (DNSO-d6) ~ 2.06 (s, 3 H),
2 . 18-2 . 36 (m, 3 H), 2 . 60 (m, 1 H), 3 . 38 (2 H + H20), 6. Z6 (d,
1 H), 6.46 (s, 1 H), 6.75 (m, 1 H), 6.83 (t, 1 H), 7.15 (m, 3
30 H), 7 . 24 (m, 2 H), 7 . 45 (m, 5 H) .
B~pl~ 7~
5-t3,6-Dihydro~ .v-~-5 (2-i~opropylph~nylthio)-6-o~co-2-
ph~nyl-2~ p/,rL~ 2-yl]p~nt~ acid (+/-)
The title _ was ~L~y~l~d as described in General
Nethod 6 from 1.1 mmol of 5-[5 ~'LI 3,6-dihydro-4 h~.lLu~y-6-
oxo-2-phenyl-2H-pyran-2-yl]pentanoic acid (pl- ~ared in example
_ _ _ _ _ . . . . . .. . . _ . _ _ _ _ _ . _ _
WO gS/14012 PcrluS94/12269
~6Q~
-- 92 --
DDD), 1.3 mmol of 2-isopropylh~n7Qn~th;ol, and 1.3 mmol of
piperidine in 20 mL of dichluL -n~. The crude product was
chromatographed on silica gel, eluting first with 596 methanol
in chloroform and then with 9:1:0.S chloroform:methanol:acetic
S acid, to give the title __ ', (m.p. 145-146 C). lH N~R
(DMS0-d6) ~ 1.07-l.19 (t plus m, 7 H), 1.25 (m, l H), 1.43
~m, 2 H), 1.91 (m, 2 H), 2.15 (t, 2 H), 3.19 (m, 1 H), 3.41 (2
H + H,0), 5.81 (d, 1 H), 6.54 (t, 1 H), 6.93 (t, 1 H), 7.12
(d, 1 H), 7.29-7.44 (m, 5 H).
pl~ 75
5,6-Dih,~L~ ~-hi~LVA~ 6 ~3-methylbutyl) 6 r ~1-3-~2-
l--p helly l th io )--2 IE ~ ,r L -~L. 2--o ne, ~ + /--)
The title ~ _ ' was prepared as described in General
15 Method 6 from 2.0 mmol of 3 bLI - 5,6-dihydro-4 ~lydLu~y-6-(3-
methylbutyl) C pl,_.-yl-2II pyL~n 2-one (I Le~.lLe~ in example
CCC), 2 . 2 mmol of 2 -isopropyl h~ h ; ~l , and 2 . 2 mmol of
piperidine in 3 0 mL of dichloromethane . The crude product was
chromatGyL~hed on silica gel, eluting first with chloroform
20 and then with 5% methanol in chloroform, to give the title
' (m.p. 64-66 C). lH NMR (DMSO-d6) ~ 0.80 (m, 6 H),
0.95(m, 1 H), 1.17 (t, 7 H), 1.42 (m, 1 H), 1.93 (m, 2 H),
3.20 (m, 1 H), 3.45 (2 H + H20), 5.84 (d, 1 H), 6.55 (t, 1 H),
6.93 (t, 1 H), 7.12 (d, 1 H), 7.40 (m, 5 H).
mpl~ 76
s~6-Dihy~ro-~-h~ v~ 3-m~tbylbutyl) 6-F' ~l-3-ph~nylthio-
2~ L~ 2-one, ~+/-)
The title _--d was ~Le~L~d as described in General
30 Method 6 from 1.5 mmol of 3-bromo-5,6-dihydro-4 hy~lu~y-6-(3-
methylbutyl)-6-phenyl-2H-pyran-2-one (~L~:~ared in example
CCC), 1 . 6 mmol of benzenethiol , and 1 . 6 mmol of piperidine in
2 0 mL of dichloromethane . The crude product was
chromatG~Lc~ ed on silica gel, eluting first with chloroform
35 and then with 5% methanol in chloroform, to give the title
', (m.p. 154-155 C). lH li~ (DMSû-d6) ~ 0.80 (m, 6
H), 0.97 (m, 1 H), 1.16 (m, 2 H), 1.42 (m, l H), 1.91 (m, 2
~ WO gS/14012 ~ 3 PCrlllS94/12269
-- 93 --
H), 3 . 40 (2 H + H20), 6 . 45 (m, 2 H), 6 . 93 (m, 3 H), 7 . 37 (m, 5
H) .
Es~ple 77
5 3~ethyl 2-tt5,6-~ihydro- h~lL~ 6 ~3-~ethylbutyl)-2-oYo-6-
- phenyl-2~-pyr~-3 -yl] thio] b ~ ~ t ~
The title _ ' was ~Lt~aLCd as described in General
Method 6 from 1.9 mmol of 3 1SL~ - 5,6-dihydro-4 ~lydLv~y-6-~3-
methylbutyl) C p~ yl-2H-pyran-2-one (yL.r,aLed in example
10 CCC), 2.2 mmol of methyl t~;ocal icylate and 2.1 mmol of
piperidine in 30 m~, of dichlor I ~n-~, The crude product was
~_1~ to.~L~ d on silica gel, eluting first with chloroform
and then with 5~ methanol in chloroform, to give the title
_ _ ' (m.p. 115-116 C). lH NMR (DMSO-d6) ô 0.80 (m, 6 H),
~5 1.0 (m, 1 H), 1.17 (m, 1 H), 1.43 (m, 1 H), 1.96 (m, 2 H), 3.4
(2 H + H20), 3.81 (s, 3 H), ~.02 (bd, 1 H), 6.88 (t, 1 H),
7.05 (t, 1 H), 7.42 (m, 5 H), 7.80 (dd, 1 H).
Ex~ple 78
20 2-t[5,6-Dihydro-4-l~L~ 6 (3-m~thylbutyl)-2-~.,v C-ph~ r1-2}E-
pyr~n-3-yl]thio]bellzoic ~cid ~
A solution of 0 . 3 mmol of the prepared in
Example 77 in 15 mL of l N sodium hydroxide was stirred at
room temperature f or 3 hours . The solution was washed with
z5 ether and then acidi~ied to pH 2. 0 with 6 N hydrochloric acid.
The solution was extracted with ethyl acetate, and the extract
was washed with brine, dried over magnesium sulfate, and
..LLa~ed to give the title ~ - ' (m.p. 99-lO1 C). lH
N~R (DMSO-d6) ~ 0 . 80 (m, 6 H~, 0 . 95 (m, 1 H), 1. 15 (m, 1 H),
30 1.43 (m, 1 H), l.91 (m, 2 H), 3.4 (2 H + H~0), 6.05 (d, 1 H),
6.85 (bt, l H), 7.03 (t, 1 H), 7.42 ~m, S H), 7.79 (dd, l H).
Wo 95/14012 PcrrlJS94/12269
~16~3
-- 94 --
ES~pl~ 79
5,6-Dihy~ro-3-~2 9~ Lylphenylthio)-~-h~ v~ 6,6-aiphenyl-
2~ 2-ono ~
The title _ ' was prepared as described in General
5 Method 6 from 1. 6 mmol of 3-bromo-5, 6-dihydro-4-hydroxy-6, 6-
diphenyl-2H-pyran-2-one (prepared in example AAA), 1 . 7 mmol of
2-sec-butylhDn~nPthiol, and 1.7 mmol of piperidine in 25 mL
of dichloromethane. The product was ~ tvyLaphed on silica
gel, eluting first with chloroform and then with 5% methanol
10 in chloroform, to give t_e title ' (m.p. 161-162 C).
H NMR (DMSO-d6) ~ 0.81 (t, 3 H), l.lS (d, 3 H), 1.43-1.64 (m,
2 H), 2.98 (m, 1 H), 3.77 (s, 2 H), 5.65 (dd, 1 H), 6.47 (t, 1
H), 6.92 (t, 1 H), 7.07 (d, 1 H), 7.34-7.48 (m, 10 H), 12.4
(bs, 1 H).
E~pl~ 80
5,6-Dihyaro-~ .v.. ~ 3-~2 -- b ~,- ylthio)-6,6-diphenyl-2~-
pyran-2 -ono
The title ~ _ '' was ~UL~:~aL~d as described in General
20 Method 6 from 1. 5 mmol of 3-bromo-5, 6-dihydro-4 ~y~LV~-y-6, 6-
diphenyl-211 ~yLcln 2-one (~L~alæd in example AAA), 1.6 mmol of
2-methoxybenzenethiol, and 1.6 mmol of piperidine in 25 mL of
dichlvL- ` ~nP. The product was chromato~L~h~d on silica
gel, eluting first with chloroform and then with 5% methanol
2S in chloroform, to give the title - ' (m.p. 170-172 ~C
dec.). ~H NMR (DMSO-ds) ~ 3.76 (bs, 5 H), 5.44 (dd, 1 H),
6.26 (t, 1 H), 6.85 (m, 1 H), 6.91 (t, 1 H), 7.34-7.50 (m, 10
H) ~
30 E:xample 81
5,6-Dihy~ro-3-~2 ~e~ `v~lphenylthio)-~ h~ 1LV~ ph_ yl~6~~2~
phenylethyl)-211 ~.~ 2-on~
The title ~, ul~d was ~L~:~aLæd as described in General
Method 6 from 2.0 mmol of 3 L/L~ J,6-dihydro-4-hydroxy-6-
35 phenyl-6- (2-phenylethyl) -2H-pyran-2-one (~re:~aLed in example
BBB), 2.1 mmol of 2-sec-butylhPn~Pn~thiol, and 2.1 mmol of
piperidine in 25 mL of dichlu~ P. The product was
_ _ _ _ .
WO95~14012 ~ l 7~D~ ~ PCrrUS94112269
-- 95 --
chromatographed on silica gel, eluting first with chloroform
and then with 5% methanol in chloroform, to give the title
__ ' (m.p. 67-68 C) . ~H NMR (DNSO-d6) ~ 0 . 82 (g, 3 H),
1.09 (t, 3 H), 1.46-1.61 (m, 2 H), 2.26 (m, 2 H), 2.35 (m, l
5 H), 2.62 (m, 1 H), 2.98 (m, 1 H), 3.47 (g, 2 H), 5.90 (t, 1
H), 6.56 (t, 1 H), 6.94 (t, 1 H), 7.07-7.18 (m, 4 H), 7.25 (m,
2 H), 7 . 45 (m, 5 H) .
E~ple 82
10 S,6-Dihydro-~ L~d-V--I 3-~- ethyl-2-isopropylphenylthio)-6,6-
diphenyl-21~ ~ 2-.~ ~
The title ~ _ ' was lJL~aI-'d as described in General
Nethod 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4 hydLv~y-6,6-
diphenyl-2~ p~La~l 2-one (pLe~aLed in example AAA), 2.1 mmol of
lS 4-methyl-2-isopropyl hon . o7Othiol, and 2 .1 mmol of piperidine
in 30 mL of dichluL (~al~e. The product was chromatG7La~hed
on silica gel, eluting first with chloroform and then with 5%
methanol in chloroform (m.p- 185-186C)- IH N~ (DMSO-d6) ~
1.17 (d, J = 10 Hz, 6 H), 2.15 (s, 3 H), 3.17 (m, 1 H), 3.76
(bs, 2 H), 5.56 (d, 1 H), 6.29 (d, 1 H), 6.94 (s, l ~), 7.32
- 7 . 47 (m, 10 H) .
}:xample 83
5, 6 -Dihrdro-~ dl v,l - 3 - t 3 -meth~ lthio ) -6, 6 -dipl~enyl -2~-
25 pyr~n-2-one
The title ,r ~ ' was pL ~paLed as described in General
Method 6 from 1.8 mmol of 3-bromo-5,6-dihydro-4 .IydLu~.y-6~6-
diphenyl-2H-pyran-2-one (pL~yaLed in example AAA), 2 . 0 mmol of
3-methoxy}~enzenethiol, and 2 . O mmol of piperidine in 25 mL of
30 dichloromethane. The product was ULLI toyLa~hed on silica
gel, eluting first with chloroform and then with 5% methanol
in chloroform (m.p. 61-62 C). IH N~IR (DMSO-d6) ~ 3.63 (s, 3
H), 3.76 (s, 2 H), 5.64 (bd, 1 H), 6,42 (s, 1 H), 6.54 (d, 1
H), 6.74 (t, 1 H), 7.32-7.47 (m, lO H).
Ex~ple 84
_ _ _ _ _
WO 95/14012 PcrluS94112269
2~7~4`~ ~
-- 96 --
5,6-Dihy~ro-~ hyd~ ,~ 3-~5-~othyl-2-isopropylph~nylthio)-6,6-
~iph~nyl-2~ n 2-on~
The title ~ ' was ~L~ared as described in General
Method 6 from 2.0 mmol of 3 bL- r,6-dihydro-4-hydroxy-6,6-
5 diphenyl-2H-pyran-2-one (~ ~yaL~d in example AAA~, 2 .1 mmol of
5-methyl-2-isopropylhor7onothiol~ and 2.1 mmol of piperidine
in 30 mL of dichloromethane. The product was chromatographed
on silica gel, eluting first with chloroform and then with 5%
methanol in chloroform ~m.p. 183-184 C). lH NMR ~DMSO-d6)
10 1.15 (d, 6 H), 1.85 ~s, 3 H), 3.22 (m, 1 H), 3.80 ~bs, 2 H),
5.88 ~bs, 1 H), 6.77 (d, 1 H), 7.03 (d, 1 H), 7.32-7.47 (m, 10
H)
.
~pl~ 85
15 5,6-Dihld.~ ~-h~dL~ 3-~5-l~ethyl-2-isopropylphenylthio)-6-
phenyl-6- (2-phQnylothyl) -21E ~ L 2-on~ ~+/-)
The title _ ' was ~L ~ared as described in General
Nethod 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4 hydL~ y-6-
phenyl-6- (2-phenylethyl) -2H-pyran-2-one (prepared in example
20 BBB), 2.1 mmol of 5-methyl-2-isopropylhon~ h;ol~ and 2.1
mmol of piperidine in 30 mL of dichloromethane. The product
was .lLLI t~yLa~hed on silica gel, eluting first with
chloroform and then with 59c methanol in chloroform (m.p. 66-67
C). lH N~ (DMSO-d6) ~ 1.16 (m, 6 H), 1.87 (s, 3 H), 2.26
25 (m, 3 H), 2.57 (m, 1 H), 3.23 (m, 1 H), 3.43 (q, 2 H), 6.01
(bs, 1 H), 6.78 (d, 1 H), 7.03-7.27 (m, 6 H), 7.37-7.47 (m,
H) .
mpl~ 8 6
3o 5,6-Dihyl~ro-3-(~-chloro-2-isopropylphenylthio)~~ ~1dI~A~ 6,6-
~liphenyl-2I~ .... 2-on~
The title ~ ~ ' was prepared as described in General
Method 6 from 2 . 0 mmol of 3-bromo-5, 6-dihydro-4-hydroxy-6, 6-
diphenyl-2H-pyran-2-one (~le~L~d in example AAA), 2 . 1 mmol of
35 4-chloro-2-isopropyl h-on ~onothiol, and 2 .1 mmol of piperidine
in 30 mL of dichloromethane. The product was chromatographed
on silica gel, eluting first with chloroform and then with 5%
., .. .. , . . . . . . . . . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ .
WO9~/14012 2 ~ 3 Pcr/uS94~269
_ 97 _
methanol in chloroform Im.p. 95-96 C). lH Nl~ tDMSO-d6) ~
1.16 (d, 6 H), 3.23 (m, 1 H), 3.73 ~bs, 2 ~), 5.60 ~d, 1 H),
6.45 ~d, 1 H), 7.14 ~d, 1 H~, 7.32-7.48 (m, 10 H).
5 8~ample 87
5,6-Dihydro-4 h~ 3-~4-~athyl-2-isopropylphenylthio)-6-
ph~myl-6-(2-phenyl~thyl)-2~ E~L~ 2-one ~+/-)
The title ~ ~ ' was pL e:pared as described in General
Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-l.y~Lv~y ~
10 phenyl-6- 12-phenylethyl) -2H pyL~II 2-one (~L-~ared in example
BBB), 2.1 mmol of 4-methyl-2-isopropylhen7an~t_iol, and 2.1
mmol of piperidine in 3 0 mL of dichluL, . me product
was ~ Lo~L~phed on silica gel, eluting first with
chloroform and then with 5% methanol in chloroform ~m.p.75-76
15 C). H N~ (DMSO-d6) ô 1.15 (m, 6 H), 2.16 ~s, 3 H), 2.19-
2.36 ~m, 3 H), 2.62 ~m, 1 H), 3.21 ~m, 1 H), 3.44 ~q, 2 H),
5.82 ~d, 1 H), 6.40 (dd, 1 H), 6.95 (d, 1 H), 7.10-7.18 ~m, 3
H), 7 . 25 ~m, 2 H), 7 . 44 ~m, 5 H) .
2 0 E~mplo 88
Xethyl 2-[t5,6-dih,dL~ L,d.~ 2-oxo-6-~2-ph~nyl-thyl)-6-
ph~n~!l--2L p~LC~a 3--yllthio~ t ~
The title ~ ' was pL a~ ed as described in General
Method 6 from 1.9 mmol of 3-bromo-5,6-dihydro-4 ~lLv.sy-6-
25 phenyl-6- ~2-phenylethyl) -2H-pyran-2-one ~ce~ared in example
BBB), 2.2 mmol of methyl th;o~ ylate and 2.1 mmol of
piperidine in 30 ~ of dichlvl~ - h~n~. The crude product was
chromatographed on silica gel, eluting first with chloroform
and then with 59c methanol in chloro~orm, to give the titlê
- ' ~m.p. 91-92 C). lH N~ (DMSO-d6) ô 2.25 (m, 2 H),
2.38 (m, 1 H), 2.62 (m, 1 H), 3.44 (q, 2 H), 3.82 (s, 3 H),
6.06 (bd, 1 H), 6.90 (t, 1 H), 7.05-7.52 (m, 11 H), 7.81 (dd,
1 H).
35 Gener~l llethod 7
The desired ~ were p-~yaL~ by adding t_e 5,6 -
dihylLv~yLv 2H-pyran-2-one, absolute ethanol, the p-
Wo 95/14011 PCr/US94112269
~7~3 ~
-- 98 --
tr,lu~.n"~hio$-llfonate reagent (prepared in general method 2),
sodium bi. ~l~ Lv~-ate, an~ Et,N to a reaction vessel . The mixture
was then z,ubse~ut---ly heated to 40 C for 4 to 48 h. The
mixture was then diluted with H20, acidif ied with conc . HCl,
5 and the product extracted with diethyl ether, CH2Cl2, or ethyl
Acetate. The organic layers were combined and dried with
Na250i
l~ple 89
10 5, 6-Dih~ -h~ d. ~ C }~ r l-6- ( 2 -phenylethyl ~ -3- [ ~ 2-
trifluoromethylphenyl)~ethrlthio]-211-pyran-2-one
The title ' was ~L~:yaL ~d as described in General
Method 1 using the following: 5,6-dihydro-4 ~ydL~ y-6-phen
6-(2-phenylethyl)-21I pyLclll 2-one (0.250 g, 0.850 mmol), (2-
15 triflu-,L yl)benzyl-p-toluenethiosulfonate (0.350 g, 1.02
mmol), Et3N (0.280 mL, 2.00 mmol), NaHC03 (0.68 mmol), (0.50
g), absolute ethanol (3.0 mL). The mixture was heated to 40C
for 16 h then diluted ~ith diethyl ether (100 mL), and washed
with H20. The solvent was then removed in vacuo and the
20 residue submitted to column chromatography (sio2, 1009~ CH~Cl,
to 29~ methanol in CH2Cl2) to provide a solid (0. 316 g, m.p.
59 - 62 C). lH N~ (400 MHz, DMSO-d6) ~ 7.603 - 7.581 (m, 1
H), 7.432 - 7.026 (m, 13 H), 3.780 (d, 1 E, J = 14 Hz), 3.69
(d, 1 H, J = 14 Hz), 3.310 (d, 1 H, J = 17.5 Hz), 3.220 (d, 1
25 H, J = 1~.5 Hz), 2.5677 - 2.505 (m, 1 H), 2.253 - 2.157 (m, 3
H) ~
15sample 90
~,6-Dihydro-~ h~ ,A~ 3-[~2,5-~imethylp~enyl)methylthio]-6-
3o phenyl-6-~2-phenylethyl)-2~ n 2-one ~
The title _ ' was ~Lc~clL~d as described in General
Method 7 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-
6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), 2,5-
dimethylbenzyl-p-tolll~n~th;oslllfonate (0.312 g, 1.02 mmol),
35 Et3N (0.230 mL, 1.60 mmol), NaHC03 (0.071 g, 0.85 mmol),
absolute ethanol (3. 0 mL) . The mixture was heated to 40~C for
16 h then diluted with diethyl ether ( 100 mL), and washed with
WO 95/14012 PCr/US94/12269
~ 2 ~ 7~43
99
H20. The solvent was then removed in vacuo and the residue
submitted to column chromatography (SiO" 100% CHzCl2 to 2%
methanol in CH~Cl2) to provide a solid (0.116 g, m.p. 54 -
56C) which was dried in vacuo. 1H NMR t400 MHz, DMS0-d~) ~
S 11.498 ~bs, 1 H), 7.405 - 7.380 (m, 4 H), 7.327 - 7.285 (m, 1
- H), 7.258 - 7.221 (m, 2 H), 7.168 - 7.128 (m, 1 H), 7.090 (d,
2 H, J = 7.5 Hz), 6.970 (d, 1 H, J = 8 Hz), 6.890 (d, 1 H, J =
8 Hz) , 6.821 (s, 1 H) , 3.600 (d, 1 H, J = 11 Hz) , 3.505 (d, 1
H, J = 11 Hz), 3.250 (d, 1 H, J = 17 Hz), 3.176 (d, 1 H, J =
10 17), 2.619 - 2.564 (m, 1 H), 2.235 - 2.168 (m, 9 H).
l~ple 91
5,6-Dih,~.~ 3-~n r`~- lsT~-l-ylmethylthio) 6 p' ~1-6-
~2-ph~nyl~thyl~-2~ n 2-on~ ~+/-).
15 The title ~ _ ' was ~ al ed as described in General
Method 7 using the following: 5,6-dihydro-4-hydroay-6-phenyl-6-
(2-phenylethyl)-2H-pyran-2-one (0.20 g, 0.68 mmol), (1-
naphthalen-l-ylmethyl)-p-toluenethiocl~lfonate (0.27 g, 0.82
mmol), Et3N (0.18 mL, 1.3 mmol), NaHC01 (0.68 mmol) absolute
20 ethanol (3.0 mL). me miature was heated to 40 C for l6 h then
diluted with diethyl ether (100 mL), and washed with H20. The
solvent was then removed in vacuo and the residue submitted to
column chromatography (SiO2, 100% CH2Cl2 ) to provide a solid
(0.158 g, m.p. 132 - 134 C). lH NNR (400 NHz, DMSO-d6) ~ 11.533
25 (bs, 1 H), 8.177 (d, 1 H, J = 8 Hz), 7.886 (dd, 1 H, J = 2 Hz,
J = 7 Hz), 7.761 (d, 1 H, J = 8 Hz), 7.501 - 7.05 ( m, 14 H),
4.120 (d, 1 H, J = 12 Hz), 3.995 (d, 1 H, J = 12 Hz), 3.274 ~d,
1 H, J = 18 Hz), 3.194 ( d, 1 H, J = 18 Hz), 2.636 - 2.581 (m,
1 H), 2.288 - 2.169 (m, 3 H).
E~pla 92
3-~Biphenyl-2-~ thylthio)-5~6-dihydro-4 h~ ~, 6 r~ ~1-6-12-
phenylethyl ) -2}i-pyr~n-2 -one ~ +/ - ) .
The title ~ was p~e~dled as described in General
35 Method 7 using the following: 5,6-dihydro-4 ky~ay-6-phenyl-6-
(2-phenylethyl)-2H-pyran-2-one (0.2S0 g, 0.85 mmol), (biphen-2-
ylmethyl)-p-tolueneth;-~cl~fonate (0.360 g, 1.02 mmol), Et3N
, . ~
Wo 95/14012 P / 269
43 crNs94 12
-- 100 --
(0.14 mL, 1.0 mmol), NaHCO3 (0.85 mmol) ~hCol~lte ethanol (5.0
mL). The mixture was heated to 40 C for 16 h then diluted with
diethyl ether (100 mL), and washed with H20. The solvent was
then removed in vacuo and the residue submitted to colu~n
5 chromatography (SiO2, 100% CH2Cl2 to 1% methanol in CH2Cl2) to
provide a solid (0.317 g, m.p. 58 - 60 C). 1H NMR (400 MHz,
DNS0-d5) ô 11.569 (bs, 1 H), 7.429 -7.066 (m, 19 H), 3.528 (d,
1 H, J = 12 Hz), 3.477 (d, 1 H, J = 12 Hz), 3.280 (dd, 1 H, J =
17 Hz), 3.183 (d, 1 H, J = 17 Hz), 2.607 - 2.502 (m, 1 H), 2.246
10 - 2.144 (m, 3 H).
I~mple g3
3-(2-Chlo~ lmethylthio)-5,6-dih~Lv ~-}3~L~ 2~ ~1-6-
~2-phenylethyl) -2Ir E~,,. n 2-one (+/-) .
The title _ _ ' was ~JL ~a~ed as described in General
15 Method 7 using the following: 5,6-dihydro-4 h'~!lLU~y-G pllellyl-6-
(2-phenylethyl)-21I ~yLa,3 2-one (0.250 g, 0.85 mmol), (2-
cholorbenzyl)-p-tol~l~n~th;-~cl~lfonate (0.320 g, 1.02 mmol), Et3N
(0.14 mL, 1.0 mmol), absolute ethanol (5.0 mL). The mixture was
heated to 40 C for 16 h then diluted with diethyl ether (100
20 mL), and washed with H2O. The solvent was then removed in vacuo
and the residue submitted to column chromatography (sio2~ 100 %
CH,Cl2 to 2 ~6 met~3anol in CH2C12) to provide a solid (0.317 g,
m.p. 53 - 55 C). lH NMR (400 MHz, DNSO-d6) ~ 11.551 (bs, 1 H),
7.435 - 7.005 (m, 13 H), 6.800 (dd, 1 H, J = 1.5 Hz, J = 7.5
25 Hz), 3.750 (d, 1 H, J = 13 Hz), 3.620 (d, 1 H, J = 13 Hz), 3.251
(d, 1 H, J = 17 Hz), 3.171 (d, 1 H, J = 17 Hz) 2.595 - 2.542 (m,
1 H), 2.233 - 2.125 (m, 3 H).
Esample 9~
30 3- ~2-Chlorophenylmethylthio) -5, 6-dihydro-,~-hydrosy-6- t3-
m~thyl~utyl) 6 r' yl~2~ ~,L-.n 2-on~ ~+/-).
The title ' was ~ aIéd as described in General
Method 7 using the following: 5,6-dihydro-4 }-ydLU-~y-G ~lle~-yl-6-
(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.85 mmol), (2-
35 chluL~Lèll~yl)-p-~ol~l~n~th;osul~onate (0.390 g, 1.24 mmol), Et3N
(0.17 mL, 1.24 mmol), absolute ethanol (5.0 mL), NaHC03 (0.5 g).
The mixture was heated to 40 C for 16 h then diluted with
WO 95/14012 2 ~ 7 ~ ~ 4 3 PCT/US94~12269
- -- 101 --
diethyl ether (100 mL), and washed with H20. The solvent was
then removed in vacuo and the residue submitted to column
lILI tGyLcllJIIy (sio2, 100% CH2Cl2 to 2 % ~ --nnl in CH2Cl2) to
provide a thick oil (0.36 g) which was dried in vacuo. lH NMR
5 ~400 MHz, DMS0-d6) ~ 7.388 - 7.267 (m, 6 H), 7.181 (td, 1 H, J
~ 1.5 Hz, J = 7.5 Hz), 7.052 (t, 1 H, J = 7.5 Hz), 6.800 (dd, 1
H, J = 1.5 Hz, J = 7.5 Hz), 3.718 (d, l H, J = 13 Hz), 3.596 (d,
1 H, J = 13 Hz), 3.112 (s, 2 H), 1.921 - 1.797 (m, 2 H), 1.402 -
1.320 (m, l H), 1.156 - 1.065 (m, 1 H), 0.844 - 0.739 (m, 7 H).
~pl~ 9S
3-~Biph-n-2-yl~thylthio)-5,6-~ihy~ro-4-hydroYy-6-~3-
mcthylbutyl) 6-Fhr ~l-z~-pyran-2-o~e ~+~-).
The title . ' was p~- yared as described in General
15 Method 7 using the following: 5,6-dihydro-4 ~ y-6-phenyl-6-
(3-methylbutyl)-2II ~,~L~I 2-one (0.250 g, 0.96 mmol), (2-
methylbiphenyl)-p-toluene1hiosulfonate (0.439 g, 1.24 mmol),
Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL), NaHC03 (0.5
g). The mixture was heated to 40 C for 16 h then diluted with
20 diethyl ether (100 mL), and washed with H20. The solvent was
then removed in vacuo and the residue submitted to column
chromatography (SiO2, 100% CH2Cl2 to 2~6 -- ` -n~l in CH2Cl2) to
provide a solid (0.33 g, m.p. 49-51 C). lH NMR (400 NE~z, DMSO-
d6) ô 7.425 - 7.153 (m, 13 H), 7.74 (dd, 1 H, J = 1 Hz, J = 7
25 Hz), 3.480 (dd, 2 H, J = 12 Hz, J = 17 Hz), 3.149 (dd, 2 H, J =
17 Hz, J = 22 Hz), 1.921 - 1.821 (m, 2 H), 1.402 - 1.336 (m, 1
H), 1. 161 - 1. 071 (m, 1 H), 0 . 847 - 0. 707 (m, 7 H) .
Example 96
30 5,6-Dihydro-3-(2,5-aimethylphenylmethylthio)-~-h~LG~-6 (3-
m~thyl~utyl) -6-phenyl-211-pyran-2-one ( I /-) .
The title a was ~Le~aled as described in General
Method 7 using the following: 5,6-dihydro-4-hydroxy-6-(3-
methylbutyl)-6-phenyl-2H-pyran-2-one (0.250 g, 0.96 mmol), (2,5-
35 dimethylbenzyl)-p-tol-~onothi~s~llfonate (0.380 g, 1.24 mmol),
Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL), NaHC03 (0.5
g). The mixture was heated to 40 C for 16 h then diluted with
_ _ _ _ _ , _ _ , .. . . . . ... .
WO 95/140~2 PCrNSs4/12269
2~6Q~ --
-- 102 --
diethyl ether (100 mL), and washed with H20. The solvent was
then removed in vacuo and the residue submitted to colu~n
_I L~ t~yLa,ully (sio2, 100% CH2C12 to 2% methanol in CH2Cl2) to
provide a thick oil (0.286 g). H NIIR (400 MHz, DMSO-d6)
5 11.433 (bs, 1 H), 7.380 - 7.251 (m, 5 H), 6.973 (d, 1 H, J = 7.5
Hz), 6.905 (d, 1 H, J = 7.5 Hz), 6.187 (s, 1 H), 3.584 (d, 1 H,
J = 11.5 Hz), 3.481 (d, 1 H, J = 11.5 Hz), 3.133 (s, 2 H), 2.209
(s, 3 H), 2.184 (s, 3 H), 1.933 - 1.858 (m, 2 H), 1.421 - 1.355
(m, 1 H), 1.177 - 1.086 (m, 1 H), 0.870 - 0.751 (m, 7 H).
ICplo 97
5,6-Dih~ h,d~," 3-(3 ~ - Jl3~-thylthio) 6 ph~l-6-
t2-ph nyl~thyl)-21r Fr~ n 2-one (~/-).
The title was ~L~Lèd as described in General
15 Nethod 7 using the following: 5,6-dihydro-4 hydLu~y-6-phenyl-
(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol), (3-
Ll~u~.ybè~ yl)-p-~nlnpnp~hio~ fonate (0.340 g, 1.11 mmol), Et3N
(0.25 mL, l.81 mmol), absolute ethanol (3.0 mL), NaHC03 (0.5 g).
The mixture was heated to 40 C ~or 16 h then diluted with
20 diethyl ether (100 mL), and washed with H20. The solvent was
then removed in vacuo and the residue submitted to column
LUYL~ 1Y (Sio2, 100% CH2Cl2 to 2% -nr l in CH2Cl2) to
provide a thick oil (0.286 g). :H NMR (400 MHz, DMS0-d~)
77.411 - 7.376 (m, 4 H), 7.361 - 7.280 (m, l H), 7.235 (t, 2 H,
25 J = 7 Hz), 7.146 (t, 1 H, J = 7 Hz), 7.078 - 7.019 (m, 3 H),
6.769 (d, l H, J = 2 H), 6.762 - 6.698 (m, 1 H), 6.555 (d, 1 H,
J = 7 Hz), 3.694 (s, 3 H), 3.670 (d, 1 H, J = 13 Hz), 3.585 (d,
1 H, J = 13 Hz), 3.220 (d, 1 H, J = 17 Hz), 3.158 (d, 1 H, J =
17), 2.590 - 2.525 (m, 1 H), 2.219 - 2.141 (m, 3 H).
E~mple 98
3 - (Biphenyl-2 -ylmethylthio) -5, 6-dihydro-~ h~ ~lL ~ , 6-diphenyl-
2~ L~ 2-one.
The title ' was ~Le~aLed as described in General
35 Method 7 using the ~ollowing: ~,6-dihydro-4 ~IydLu~y-6~6-
diphenyl-2H-pyran-2-one (0.250 g, 0.94 mmol) ' (2-
methylbiphenyl)-p-toluP~P~hioslllfonate (0.389 g, 1.1 mmol~, Et3N
WO 95/14012 2 ~ t ~ ~ 3 PCrlUS94112269
-- 103 --
(0.26 mL, 1.9 mmol), absolute ethanol (5.0 mL), NaHC03 (0.5 g).
The mixture was heated to 40 C for 16 h, then diluted with
diethyl ether (100 mL) and washed with H20. The solvent was
then removed in vacuo and the residue submitted to colu~n
S chromatography (SiO2, 100% CH2Cl2 to 2% methanol in CH,Cl,) to
provide a thick oil (0.286 g). lH NMR (400 MHz, DMS0-d6)
11.770 (bs, 1 H), 7.434 - 7.148 (m, 18 H), 6.969 (d, 1 H, J = 7
Hz), 3.595 (s, 2 H), 3.407 (s, 2 H).
10 3bc~ple 9~
3-(3-Chlo- ~ lmethylthio)-5,6-~ihydro-~ r~ ~1-6-
(2-phenylethyl)-2~1-pyr~n-2-one (+/-).
The title ~ ' was ~L .~,al ed as described in General
Method 7 using the following: 5,6-dihydro-4 ~lydLu.~y G ph_llyl-
(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol), [ (3-
chluLupl..: - 1-yl)methyl]-p-'r~ ono~hi~lclllfonate (0.340 g, 1.11
mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (3.0 mL),
NaHC03 (0.5 g). The mixture was heated.to 40 C for 16 h, then
diluted with diethyl ether (100 mL) and washed with H20. The
20 solvent was then removed in vacuo and the residue submitted to
column ulll. tuy~ a~y (Siû2, 100% CH2Cl, to 2% methanol in CH,Cl2)
to provide a thick oil (0.155 g). ~H NMR (400 ME~z, DMSû-d~) ~
7 . 420 - 7 . 060 (m, 13 H), 6 . 848 (d, 1 H, J = 7 Hz), 3 . 688 (d, 1
H, J = 13 Hz), 3.597 (d, 1 H, J = 13 Hz), 3.219 (d, 1 H, J = 17
25 Hz), 3.153 (d, 1 H, J = 17 Hz), 2.592 - 2.526 (m, 1 H), 2.241 -
2.120 (m, 3 H).
E~pl~ 100
5, 6 -;~ihydro-~ -hydrosy-6- ~ 2 -p~enylethyl ) -6-ph~nyl-3 - ~ ~ ~ 3-
30 trifluo~ ~h~l~phenyl~ ethylthio~-2~ n 2-one ~+/-).
The title ~ ~,uu.~d was prepared as described in General
Method 7 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-
(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol), [ (3-
trifluu~, ` ylphen-~-yl)methyl]-p-tolllc~nofh;oslllfonate (0.380
35 g, 1.11 mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (3.0
mL), NaHC03 (0.5 g). The mixture was heated to 40 C for 16 h,
then diluted with diethyl ether (100 mL) and washed with H2û.
Wo 9~/14012 PCr/US94/12269
2~7~ 3
-- 104 --
The solvent was then removed in vaçuo and the residue submitted
to column chromatography (SiO2, 100 % CHlClz to 2 % methanol in
CH2Cl~) to provide a thick oil (0.273 g). lH NMR (400 MHZ, DMS0-
d6) ~ 11.60 (bs, 1 H), 7.523 - 7.481 (m, 2 H), 7.392 - 7.124 (m,
5 9 H), 7.064 ~d, 2 H, J = 8 Hz), 3.794 (d, 1 H, J = 13 Hz), 3.703
(d, 1 H, J = 13 Hz), 3.162 (s, 2 H), 2.583 - 2.525 (m, 1 H),
2.233 - 2.124 (m, 3 H).
E~mpl~ 101
10 5,6-Dih2dL_ ~-h~d.v,~-3-~3-~ethylph~nyl3l~ethylthio) 6 r~ yl~6-
2 -phenyl~thyl ) -2~ L ~ 2 -one ( +/ - ) .
The title I ' was pre~uGL ~d as described in General
Method 7 using the following: 5,6-dihydro-4-hydroxy G ~ yl-
(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.85 mmol), [ (3-
15 methylphen-l-yl)methyl]-p-toluenethios~llfonate (0.298 g, 1.02
mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol (5.0 mL),
NaHC0l (0.5 g). The mixture was heated to 40 C for 16 h, then
diluted with diethyl ether (100 mL) and washed with H20. The
solvent was then removed in vacuo and the residue submitted to
20 column chromatography (sio2~ 100% CH2C12 to 2% methanol in CH2C12)
to provide a thick oil (0.242 g). lH NNR (400 MHz, DMSO-d6)
11.427 (bs, 1 H), 7.423 - 7.374 (m, 4 H), 7.330 - 7.288 (m, 1
H), 7.238 (t, 2 H, J = 7 Hz), 7.145 (t, 1 H, J = 8 Hz), 7.086 -
7.007 (m, 2 H), 6.952 (d, 2 H, J = 6 Hz), 6.790 (d, 1 H, J = 7
25 Hz), 3.630 (d, 1 H, J = 12.5 Hz), 3.544 (d, 1 H, J = 12.5 Hz),
3.227 (d, 1 H, J = 17.5 Hz), 3.153 (d, 1 H, J = 17.5 Hz), 2.567
(bt, 1 H, J = 12 Hz), 2 . 244 - 2 . 132 (m, 3 H) .
ple 102
30 3-t~ aL~A~ 2-o~co-6-~Z-phenylethyl)-6-phenyl-5,6-dihydro-2H-
pyran-3-ylth;~ ' hyl]b~nzonitrile ~+/-) .
The title c ' was pL PG~ ~d as described in General
Method 7 using the f ollowing: 5, 6-dihydro-4 ~ydL U~y -6-phenyl-
(2-phenylethyl) -2H-pyran-2-one (0.250 g, 0.85 mmol), [ (3-
35 cyanophen-l-yl)methyl]-p-toluenethios~lfonate (0.309 g, 1.02
mmol), Et3N (0.25 mL, 1.81 mmol), absolute ethanol ~5.0 mL),
NaHC03 ( O . S g ) . The mixture was heated to 4 0 C f or 16 h, then
~ WO 95114012 2 1 7 ~ O ~ 3 PcrluS94/12269
-- 105 --
diluted with diethyl ether (100 mL), and washed with H20. The
solvent was then removed in vacuo and the residue submitted to
column chromatography (SiO2, 100 % CH2Cl2 to 2 96 methanol in
CH2Cl2) to provide a solid (0.242 g, m.p. 58 - 60 C). lH NNR
5 (400 NHz, DMSO-d6) ~ 11.572 (bs, 1 H), 7.585 (d, 1 H, J = 7 Hz),
7.499 (s, 1 H), 7.426 - 7.078 (m, 10 H), 7.066 (d, 2 H, J = 7
Hz), 3.736 (d, 1 H, J 5 13.5 Hz), 3.637 (d, 1 H, J = 13.5 Hz),
3.185 (AB, 2 H, J~D = 17.5 Hz), 2.570 -- 2.511 (m, 1 H), 2.207 -
1. 074 (m, 3 E~) .
~ple 103
3-~2-Chlo~_~h~lm thylt~io)-5,6-dil~o l~ L-~I 6,6-,lliphenyl-
211 Ei~L~. 2-on~.
The title . ' was ~L ~.~ared as described in General Method
~5 7 using the following: 5,6-dihydro-4 h~v.~y-6,6-diphenyl-2H-
pyran-2-one (0.250 g, 0.94 mmol), ~ (2-chluL~,~h~.. l-yl)methyl]-p-
toluenefh;os~llfonate (0.304 g, 1.10 mmol), Et3N (0.26 mL, 1.9
mmol), absolute ethanol (5.0 mL), NaHC03 (0.5 g). The mixture
was heated to 40 C ~or 16 h then diluted with diethyl ether
20 (100 ~nr ), and washed with H20. The solvent was then removed in
vacuo and the residue submitted to column chromatography (sio"
100% CH2Cl2 to 2% methanol in CH2Cl2) to provide a solid (0.123
g, m.p. 153 - 155 C). lH NNR (400 MHz, D~fSO-d6) ô 7.415 - 7.271
(m, 11 H), 7.187 (td, 1 H, J = 1.3 Hz, J 5 7 Hz), 7.047 (td, 1
z5 H, J = 1.3 Hz, J = 1 Hz), 6.658 (dd, 1 H, J = 1.5 Hz, J = 7 HZ),
3.610 (s, 2 H), 3.582 (s, 2 H).
E~c~ple 10~
5,6-Dihydro-~-hy~roxy-6-~3-31~thylbutyl~ -6-phunyl-3-
30 [(tri~luor~ Lhylphenyl)~ethylt~io]-2~ L-... 2-one ~I/-).
The title ~ ~ was prepared as described in General
Method 7 using the following: 5,6-dihydro-4 ~y~ ~y-6-phenyl-6-
(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.94 mmol), (3-
tri~luoromethylbenzyl)-p-toluenethiosul~onate (0.43 g, 1.24
35 mmol), Et,N (0.17 mL, 1.24 mmol), absolute ethanol (5.o mI,),
NaHC03 (0.5 g). The mixture was heated to 40 C ~or 16 h, then
diluted with diethyl ether ( 100 mL) and washed with H20 . The
.
,, _ _ , _ _ , _ _ . . , . _ _ .
WO 9~/14012 2 ~ Q ~ 3 PCTIUS94/12269
-- 106 --
solvent was then removed in vacuo and the residue submitted to
column chromatography (SiO~, 100% CH2C12 to 1. 5% methanol in
CH2Cl2) to provide a thick oil (0.364 g). lH NMR (400 MHz, DNS0-
d6) ~ 7.523 - 7.503 (m, 2 H), 7.318 - 7.232 (m, 6 H), 7.188 (d,
5 1 H, J = 7.5 Hz), 3.781 (d, 1 H, J = 13 Hz), 3.689 (d, 1 H, J =
13 Hz), 3.076 (A~3, 2 H, JA2 = 14 Hz), 1.869 - 1.783 (m, 2 H),
1.380 - 1.314 (m, 1 H), 1.141 - 1.040 (m, 1 H), 0.828 - 0.727
(m, 7 H).
10 B~mpl~ 105
5, 6-Dihydro-~-hydro~y-3- ~methosrph~nyl~ethylthio) -6- t3-
Dlethylbutyl) 6 r~ ~1-2~ Lc~n 2-on~ (+/-).
The title ~ ' was prepared as described in General
Method 7 using the following: 5,6-dihydro-4 }Iy~vAy-6-phenyl-6-
15 (3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.94 mmol), (3-
- U~v~yLæll~yl)-p-toluenethios~llfonate (0.385 g, 1.24 mmol), Et3N
(0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL), NaHC03 (0.5 g).
The mixture was heated to 40 C for 16 h, then diluted with
diethyl ether (100 mL)and washed with H20. me solvent was then
20 removed in vacuo an~d the residue submitted to colu~3n
chromatography (sio2~ 100% CH2Cl2 to 1.5% methanol in CH2Cl2) to
provide a thick oil (0.364 g). lH NMR (400 MHz, DMS0-d6) ~ 7.365
- 7.243 (m, 5 H), 7.071 (t, 1 H, J = 8 HZ), 7.754 - 6.715 (m, 2
H), 6.562 (d, 1 H, J = 7.5 Hz), 3.699 (s, 3 H), 3.651 (d, 1 H,
25 J = 12 Hz), 3.567 (d, 1 H, J = 12 Hz), 3.098 (s, 2 H), 1.869 -
1.819 (m, 2 H), 1.387 - 1.321 (m, 1 H), 1.125 - 1.066 (m, 1 II),
0 . 809 - 0 . 702 (m, 7 H) .
Exampl~ 106
30 5,6-Dihydro-~-hydroxy-3-t3-m~3thylphenylmethylthio~-6-~3-
m~thylbutyl) 6 r~ ~1-211 ~ 2-one (+/-).
The title ' was ~L C!pal ed as described in General
Method 7 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-
(3-methylbutyl)-2H-pyran-2-one (0.250 g, 0.94 mmol), [ (3-
35 methylphen-l-yl ) methyl ] -p-toluenethiosulf onate ( 0 . 3 6 g, 1. 2 4
mmol), Et3N (0.17 mL, 1.24 mmol), absolute ethanol (3.0 mL),
NaHC03 (0.5 g). The mixture was heated to 40 C for 16 h, then
WO 95114012 2 1 ~7 6 0 i 3 PCTJUS94112269
-- 107 --
diluted with diethyl ether ( 100 mL) and washed with H20 . The
solvent was then removed in vacuo and the residue submitted to
column chromatography (sio2l 100% CH2Cl2 to 1.5% methanol in
CH2Cl~) to provide a thick oil (0.290 g). lH NNR (400 NHz, DNS0-
5 d6) ~ 7.384 - 7.262 (m, 5 H), 7.054 (t, 1 H, J = 7.5 Hz), 6.979
(d, 1 H, J s 7.5 Hz), 6.937 (s, 1 H), 6.782 (d, 1 H, J = 7.5
H2), 3.609 (d, 1 H, J = 12.5 Hz), 3.524 (d, 1 H, J = 12.5 Hz),
3.108 (s, 2 H), 2.226 (s, 3 H), 1.902 - 1.803 (m, 2 H), 1.398 -
1.332 (m, 1 H), 1.149 - 1.059 (m, 1 H), 0.849 - 0.709 (m, 7 H).
10 ~pl~ 107
3~ n~otl,3~dio~ol-5-ylm-thylthio~-5,6-dihydro-~ v,.~-~
ph~nyl-6- (2-phenylethyl) -21I pyL~Il 2-one (+~-) .
The title _ ' was prt ~aI e~ as described in General
Nethod 7 using the following: 5,6-dihydro-4 h~ y G pllt:llyl-6-
15 (2-phenylet_yl) -2H-pyran-2-one (0 . 250 g, 0 . 85 mmol),
benzo[1,3~dioxol-5-ylmethyl-p-toluenefhir~s~lfonate ~0.36g, 1.02
mmol), 3~t3N (0.25 mL, 1.81mmol), absolute ethanol (3.0 mL),
NaHC03 (0.5 g). The mixture was heated to 40 C for 16 h then
diluted with diethyl ether (100 mL), and washed with H20. The
20 solvent was then removed in vacuo and the residue submitted to
column .1 ~ l t~JyL~ y (sio2, 100~ CH,Cl2 to 1.5% methanol in
CH2Cl2) to provide a solid (0.290 g, m.p. 53 - 55 C). lH N~
(400 NHz, DMSO-d6) ~ 11.404 (bs, 1 H), 7.449 - 7.249 (m, 5 H),
7.239 - 7.216 (m, 2 H), 7.168 - 7.124 (m, 1 H), 7.077 (d, 2 H,
25 J = 7 Hz), 6.683 (d, 1 H, J = 1.5 Hz), 6.607 (d, 1 H, J = 8 Hz),
6.390 (dd, 1 }1, J = 1.5 Hz, J = 8 Hz), 5.942 (d, 2 H, J = 2 Hz),
3.600 (d, 1 H, J = 13 Hz), 3.509 (d, 1 H, J = 13 Hz), 3.195 (A3,
2 H, J~3 = 17 Hz), 2.595 - 2.511 (m, 1 H), 2.244 - 2.094 (m, 3
H)
Gen~r~l M~thod 8
The desired - '- were ~L~aLed by adding the 5,6-
dihydro-211 ~yLC~n 2-one and dry dichlc,L -nD to a reaction
vessel followed by the addition of the acid chloride and ~t3N.
35 The mixture was allowed to stir for 15 min. and then diluted
with diethyl ether . The mixture was then washed with sat ' d
NaHC03 (2x) and the organic layer dried with NgS0~. The solvent
_ _ _ _ _ _ _,, . . . _ .... .. _ _ _ _ _ _ .
WO 95/14012
2 1 7 ~ O ~ 3 PCrlUS94112269
-- 108 --
was then removed in vacuo, the residue redissolved in CH3CN and
then treated with Et,N and acetone cyanohydrin. The mixture was
allowed to stir for 18 h and then diluted with diethyl ether.
The mixture was then washed with 1. 0 N HCl, dried with NazSO~,
5 and the solvent removed in vacuo. The residue was then
dissolvQd in glacial acetic acid and treated with NaBH3CN. The
reaction was allowed to proceed for 30 min then treated with
brine. The mixture was then extracted with ethyl acetate, the
organic layers ~ ; n~cl, dried with MgS0" and the solvent
10 removed in vacuo.
Esample 108
s,6-Dihydro-4 hJd.~ 6,6-diphenyl-3-phnnylm~thy1-21I-pyr~n-2-
onn .
The title was prepared as described in Genéral
Method 8 using the ~ollowing: 5,6-dihydro-4 ~1ydL~ y~6~6~
diphenyl-2H-pyran-2-one (0.250 g, 0.940 mmol), Et,N (0.13 mL,
0.94 mmol), benzoyl chloride (0.109 mL, 0.94 mmol), CH2Cl2 (2.0
mL), acetonitrile (5.0 mL), acetone ~:yclnGl~y~Lin (0.01 mL, 0.09
20 mmol), Et,N (0.27 mL, 1.9 mmol), glacial acetic acid ~10.0 mL),
sodium ~;ycLnobuLuhy~ide (0.133 g, 2.11 mmol). Purification was
achieved by submitting the ~inal residue to column .1,~ tG~ ~y
(siO2, 4/1 hexane/ ethyl acetate to 3/2 hexane / ethyl acetate)
to provide a solid (0.105 g, 63 - 65 C). lH N~R (400 MHz,
25 DMS0-d6) ~ 11.136 (s, 1 H), 7.501 - 7.280 (m, 11 H), 6.997 -
6.932 (m, 2 H), 6.566 (d, 2 H, J = 7 Hz), 3.530 (s, 2 H), 3.43
(s~ 2 H)
~a~pl~ ~ 09
30 5,6-Dihydro-~ h~ 6 r~ ~1-6-(2-phenylethyl)-3-phe~lylmethyl-
2~ ~LC~ 2-one ~ /-) .
The title - ' was prepared as described in General
Method 8 using the ~ollowing: 5,6-dihydro-4 ~1ylL~,.,y-6-phenyl-6-
(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), Et3N (0.26
35 mL, 1.94 mmol), benzoyl chloride (0.109 mL, 0.94 ;ol), CH2C12
(2.0 mL), acetonitrile (5.0 mL), acetone cyanohydrin (0.04 mL,
0.43 mmol), Et3N (0.26 mL, 1.9 mmol), glacial acetic acid (10.0
~ WO95/14012 ~l 76043 PCT/US94112269
-- 109 --
mL), sodium ;y~ obvlvl.ydride (0.151 g, 2.4 mmol). Purification
was achieved by submitting the f inal residue to column
,IIL~ t.o~L~y (sio2, 100% CH,Cl2 to 2% MeOH in CH2C12) to provide
- a thick oil (0.384 g). lH NMR (400 MHz, D~150-d6) ô 10.922 (bs,
5 1 H), 7.395 - 7.315 (m, 5 H), 7.297 - 7.126 (m, 3 H), 7.084 -
7.028 (m, 5 H), 6.775 - 6.611 (m, 2 H), 3.423 (s, 2 H), 3.248
(d, 1 H, J = 17 Hz), 3.175 (d, 1 H, J = 11 Hz), 2.619 - 2.551
(m, 1 H), 2.292 - 2.227 (m, 3 H).
10 E~ple 110
5,6-Dih~lLo ~-hl~-v~l 3-t (2-methylphenyl)methyl~ 6-r~- ~1-6-~2-
phenyl-thyl)-21I ~~ 2-one (,~/-).
The title ~ ' was ~. .ya~ ed as described in &eneral
Method 8 using the following: 5,6-dihydro-4 ~ LU~ G p~c.lyl-6-
15 (2-phenylethyl)-2II pyL~n 2-one (0.250 g, 0.850 mmol), Et3N (0.12
mL, 0.85 mmol), 2-methylbenzoyl chloride (0.11 mL, 0.85 mmol),
CH2Cl2 (5.0 mL), acetonitrile (4.0 mL), acetone yal~llylLin (0.04
mL, 0.43 mmol), Et3N (0.24 mL, 1.7 mmol), glacial acetic acid
(10.0 mL), sodium ~:y~lobuLullylLide (0.151 g, 2.4 mmol).
20 Purification was achieved by submitting the final residue to
column chromatograpy (Siû2, 100% CH2Cl2 to 2% MeOH in CH2Cl2) to
provide a solid (0.195 g, m.p. 109 - 111 C). lH N~ (400 ~3HZ,
DMSO-d~) ~ 10.886 (bs, 1 H), 7.457 - 7.359 (m, 5 H), 7.242 (t,
2 H, J = 7 Hz), 7.169 - 7.130 (m, 1 H), 7.097 (d, 2 H, J = 7.5
25 Hz), 7.001 td, 1 H, J = 7.5 Hz), 6.937 (t, 1 H, J = 7.5 Hz),
6.695 (t, 1 H, J = 7 Hz), 6.215 (d, 1 H, J = 7.5 Hz), 3.292 (d,
1 H, J = 17 Hz), 3.169 (d, 1 H, J = 17 Hz), 2.643 - 2.584 (m, 1
H), 2.50-2.475 (2 H I solvent) 2.296 - 2.182 (m, 3 H), 2.125 (s,
3 H)-
~mple 111
5, 6-Dih~ h~ 3 - [ ~ 3 -methylphenyl ) methyl ] 6 ph~ 6 - ~ 2 -
phenylethyl) -2~-pyr~n-2-one ~t /-) .
~he title ' ' was prepared as described in General
35 Methûd 8 using the following: 5,6-dihydro-4 ~IylLu~y-C p~ --yl-6-
(2-phenylethyl)-2II pyLGn 2-one (0.250 g, 0.850 mmol), Et3N (0.12
mL, 0.85 mmol), 3-methylbenzoyl chloride (0.12 mL, 0.89 mmol),
_ _ _ , _, _ _, _ _ , _, . . .. . .. .. ... ....... .. . . . . .. . .
WO 95114012 -2 1 7 6 2 ~ 3 PCr/US94112269
-- 110 --
CH2Cl2 (3 . o mL), acetonitrile (5. 0 mL), acetone cyanohydrin
(0.037 mL, 0.40 mmol), Et3N (0.24 mL, 1.8 mF3ol), glacial acetic
acid (5.0 mL), sodium cyanobuLul.ydride (0.16 g, 2.6 mmol).
Purification was achieved by submitting the final residue to
5 column chromatograpy (SiO2, 100 % CH2Cl2 to 2 ~ MeOH in CH2Cl2) to
provide a solid (0.250 g, m.p. 53 - 55 C). lH NMR (400 NHz,
DMSO-d6) ~ 10.884 (bs, 1 H), 7.418 - 7.310 (m, 5 H), 7.231 (t,
2 H, J = 7.5 Hz~, 7.14~3 - 7.122 (m, 1 H), 7.071 (d, 2 H, J = 7
Hz), 6.929 (t, 1 H, J = 7.5 Hz), 6.843 (d, 1 H, J = 7.5 Hz),
10 6.587 (d, 1 H, J = 7.5 Hz), 6.545 (s, 1 H), 3.398 (AB, 2 H, JA;3
= 15.5 Hz), 3.248 (d, 1 H, J = 17 Hz), 3.125 (d, 1 H, J = 17
Hz), 2.607 - 2.511 (m, 1 H), 2.338 - 2.159 (m, 3 H), 2.094 (s,
3 H).
15 ~mple 112
5,6-Dih~d.v ~-h~LV~ 3-[ (3-methylphenyl)~ethyl]-6,6-diphenyl-
2~ ~ ~ 2-on~.
The title ~ _ ' was prepared as described in General
Method 8 using the following: 5,6-dihydro-4 hy-lLu~y-6,6-
20 diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N ~0.16 mL,
1.15 mmol), 3-methylberlzoyl chloride (0.15 mL, 1.13 mmol), CH2Clz
(4.0 mL), acetonitrile (4.0 mL), acetone yc~ol~ylLin (0.05 mL,
0.58 mmol), Et3N (0.32 mL, 2.3 mmol), glacial acetic acid (4.0
mL), sodium cyano~uLu~2lLide (0.28 g, 4.5 mmol). Purification
2~ was achieved by submitting the f inal residue to column
chromatograpy (SiO2, 100% CH2Cl2 to 1% NeOH in CH2Cl2) to provide
a solid (0.223 g, m.p. 57 - 59 C). lH NMR (400 MHz, DNSO-d6)
~ 11.112 (bs, 1 H), 7.414 - 7.270 (m, 10 H), 6.875 - 6.812 (m,
2 H), 6.429 - 6.392 (m, 2 H), 3.527 (s, 2 H), 3.409 (s, 2 H),
30 2.060 (s, 3 H).
mple 113
5,6-Dihydro-~ h~ v..~ 3-~2-methylphenyl)methyl]-6,6-diphenyl-
2~ ..n 2-one.
The title c _ ' was prepared as described in General
35 Method 8 using the following: 5,6-dihydro-4 ~u~y-6,6-
diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.16 mL,
1.15 mmol), 2-methylber~zoyl chloride (0.15 mL, 1.13 mmol), CH2Cl2
~WO95~14012 ~ a43 PCr/US94/12269
-- 111 --
(4.0 mL), acetonitrile (4.0 mL), acetone .yc~nG~ydLin (0.05 mL,
0.58 mmol), Et3N (0.32 mL, 2.3 mmol), glacial acetic acid (4.0
mL), sodium cyanoborohydride (0.28 g, 4.5 mmol). Purification
was achieved by submitting the final residue to column
5 _1 " tVyL~ y (sio2, 100% CH2Cl2 to 1% MeOH in CH2Cl2) to provide
a solid ~0.135 g, m.p. 169 - 171 C). lH NNR (400 NHz, DNSO-d6)
~ 11.102 (bs, 1 H), 7.444 - 7.260 (m, 10 H), 6.981 (d, 1 H, J =
7.5 Hz), 6.900 (t, 1 H, J = 7.5 ~z), 6.577 (t, 1 H, J = 7 Hz),
5.897 (d, 1 H, J = 7.5 Hz), 3.557 (s, 2 H), 3.341 (s, 2 H),
10 2.115 (s, 3 E).
l~mpl~
5,6-Dihydro-4-hydro~y-6-phenyl-6-~2-phcnylethyl)-3-t (2-
trif luorol~ethylph-~yl ) l~ethyl ] -2~ 2 -on~ .
lS The title ~ was pLel~dlêd as dêscribed in General
Nethod 8 using the following: 5,6-dihydro-4 ~Iy~v~y-G pl~ellyl~6~
(2-phenylethyl)-2H-pyran-2-one (0.300 g, 1.02 mmol), Et3N (0.15
mL, 1.1 mmol), 2-trifluv, thylbenzoyl chloride (0.21 mL, 1.02
mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone
20 cyanohydrin (0.04 mL, 0.47 mmol), Et3N (0.29 mL, 2,1 mmol),
glacial acetic acid (3.0 mL), sodium CyanobvLv~ylLide (0.20 g,
3.1 mmol). Purification was achieved by submitting the ~inal
residue to column vl~ tuy~c~y (sio2, 100% CH2Cl2 to 1% MeOH in
CH2Clz) to provide an oil (0.102 g). lH N~ (400 NHz, DMSO-d6)
25 ô 11.21 (bs, 1 H), 7.584 (d, 1 H, J = 8 Hz), 7.457 - 7.030 (m,
12 H), 6.179 (d, 1 H, J = 7.5 Hz), 3.594 (s, 2 H), 3.362 (d, 1
H, J = 17 Hz), 3.249 (d, 1 ~, J = 17 EIz), 2.686 - 2.603 (m, 1
H), 2.374 - 2.182 (m, 3 H).
30 ~Ss~ple 11~
5,6-Dihydro-~-hydrosy-3-~ (2-i~opropylphenyl)methyl]-6,6-
d iphenyl-211 ~ n 2 -one .
The title ~ ' was ~Lè~red as described in General
Method 8 using the following: 5,6-dihydro-4 hyllLv~y-6,6-
35 diphenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2
mmol), 2-isopropylbênzoyl chloride (1.02 mmol), CE~2Cl2 (4.0 mL),
acetonitrile (4.0 mL), acetone ~:ye~o~J~in (0.05 mL, 0.5 mmol),
WO95/14012 ?,~l7~043 PCr/US94112269
-- 112 --
EtlN (0.35 mL, 2.5 mmol), glacial acetic acid (5.0 mL), sodium
cyanoLv.ul,ydLide (0.50 g, 8.5 mmol). Purification was achieved
by submitting the ~inal residue to column chromatograpy ( SiO~,
100% CH2Cl~to 1% MeOH in CH,Cl,) to provide a solid (0.128 g, 224
5 -- 226 C). lH NMR (400 NHz, DMSO-d6) ~ 11.180 (bs, 1 H), 7.445 --
7.235 (m, 10 H), 7.109 (d, 1 H, J = 7.5 Hz), 6.970 (t, 1 H, J
= 7.5 Hz), 6.515 (t, 1 H, J = 7.5 Hz), 5.841 (d, 1 H, J = 7.5
Hzl, 3.560 (s, 2 H), 3.463 (s, 2 H), 1.174 - 1.094 (m, 7 H).
10 ~ ~ple 116
5, 6-Dihy~ro-~.-hyl~ro~y-6- ~ 3 -mothylbutyl ) -3 - [ ~ 3 -
m~thylphonyl~mothyl] 6 r~ 1l-2~ F~ ~ 2-on~ ~+/-~.
The title _ ' was ~L~ L-:d as described in General
Method 8 using the following: 5,6-dihydro-4 hylLu~y G p~ yl-6-
15 (3-methylbutyl)-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17
mL, 1.2 mmol), 3-methylbenzoyl chloride (0.15 mL, 1.15 mmol),
CH~Cl~ (4.0 mL), acetonitrile (4.0 mL), acetone .y-i~o~ydLin (0.05
m~, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid
(4 .0 mL), sodium y~lllobuLullydLide (0.51 g, 8 .1 mmol) .
20 Purification was achieved by submitting the final residue to
column chromatograpy (SiO~, 100% CH~Cl~ to 0.5% MeOH in CH~Cl~) to
provide a solid (0.252 g, 53 - 55 C). lH NMR (400 MHz, DMSO-d6)
~ 7.376 - 7.244 (m, 5 H), 6.915 (t, 1 H, J = 7.5 Hz), 6.831 (d,
1 H, J = 7.5 Hz), 6.549 (d, 1 H, J = 7.5 Hz), 6.509 (s, 1 H),
25 3.369 (AB, 2 H, J,~" = 14.4 Hz), 3.112 (A;3, 2 H, J",3 = 17.5 Hz),
2.088 (s, 3 H), 1.962 (~, 2 H), 1.416 - 1.333 (m, 1 H), 1.152 -
1.061 (m, l H), 0.898 - 0.726 (m, 7 H).
Br~mple 117
5, 6-Dih~aL- J-h~dL~ (3-~ethylbutyl~ 6 r~ ~1-3-phe~ylmethyl-
2~ ~.~ 2-on~
The title: ' was ~L~ yared as described in General
Method 8 using the following: 5,6-dihydro-4 ~lydLu~y~6-(3-
methylbutyl) C ph llyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N
35 (0.17 mI, 1.2 mmol), benzoyl chloride (0.13 mL, 1.15 mmol),
CH,Cl, (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05
mL, 0.5 mmol), Et,N (0.35 mL, 2.5 mmol), glacial acetic acid
~ W09~114012 ~ ~ 7~3 PCT/US94/122C9
-- 113 --
(4.0 mL), sodium uya..obuluhydLide tO.51 g, 8.1 mmoi).
Purification was achieved by submitting the final residue to
column chromatograpy (SiO2, 100% CH2Cl2 to 1% MeOH in CH2Cl2) to
provide a solid (0.215 g, 46 - 48 C). lH NMR (400 MHz, DMSO-d6)
5 ~ 10.864 (bs, 1 H), 7.375 - 7.248 (m, 7 H), 7.026 - 7.000 (m, 2
H), 6.737 - 6.713 (m, 1 H), 3.393 - 3.332 (2 H, O~S- ULL~d by
solvent), 3.110 (Ai3, 2 H, JA3 = 17 Hz), 1.933 - 1.870 (m, 2 H),
1.402 - 1.353 (m, 1 H), 1.132 - 1.084 (m, 1 H), 0.891 - 0.710
(m, 7 H).
Bx~mple 118
5,6-Dihyt~ro-~-hydroYy-6-(3-~ethyl~utyl~-3-~ 12-
mothylph~nyl ~ methyl ] 6 ~ 2 1-2~-pyran-2 -one ( +/ - ) .
The title ~ ~ ' was pL ~:~ared as described in General
15 Method 8 using the following: 5,6-dihydro-4-hydroxy-(3-
methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N
(0.17 mL, 1.2 mmol), 2-methylbenzoyl chloride (0.15 mL, 1.15
mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone
~;yc~llo~LyllLin (O.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol),
20 glacial acetic acid (4.0 mL), sodium CyanobuL~.ylLide (0.51 g,
8.1 mmol). Purification was achieved by submitting the final
residue to column .1-~, LoyLa~y (SiO2, 100% CH2Cl2 to 1% MeOH in
CH2Cl~) to provide a solid (0.215 g, 46 - 48 C). ~H N~ (400
MHz, DMSO-d6) ~ 10.829 (bs, 1 H), 7.395 - ~.303 (m, 5 H), 6.994
25 (d, 1 H, J = 7 Hz), 6.927 (t, 1 H, J = 7 Hz), 6.674 (t, 1 H, J
= 7 Hz), 6.149 (d, 1 H, J = 7 Hz), 3.305 (A;3, 2 H, JA3 = 17 Hz),
3.158 (A;3, 2 ~, JAj3 = 17.5 Hz), 2.115 (s, 3 H), 1.988 - 1.854 (m,
2 H), 1 . 439 - 1 . 356 (m, 1 H), 1 . 177 - 1. 087 (m, 1 H), 0 . 943 -
0.852 (m, 1 H), 0.792 - 0.767 (m, 6 H).
~cample 119
5,6-Dihy~ro-~ h,~dLV~ 3-~3 -- ~ l)methyl] 6 r2 rl-6-~2-
phenylethyl)-2~ ..n 2-one ~+/-).
The title ~ _ ' was ~L~red as described in General
35 Method 8 using the following: 5,6-dihydro-4 hylLu~y-6-phenyl-6-
(2-phenylethyl)-2H-pyran-2-one (0.300 g, 1.02 mmol), Et3N (0.15
mL, 1.1 mmol), 2 -- yL_l~zOyl chloride (0 .17 g, 1. 02 mmol),
WO 95/14012 2 ~ 7 6 0 ~ 3 PCr/U~94/12269
-- 114 --
CH2C12 (4.0 2L), acetonitrile (4.0 mL), acetone ~ytlilo~ydLin (0.05
mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid
(5.0 mL), sodium ~:y~-~oburu~lydr ide (0.47 g, 7.5 mmol) .
Purif ication was achieved by submitting the f inal residue to
5 column chromatograpy (sioz~ 100% CH2C12 to 1% MeOH in CH2Cl2) to
provide a solid (0.227 g, 62 - 64 C). lH NNR (400 MHz, DMSO-d~)
~ 10.823 (bs, 1 H), 7.436 - 7.362 (m, 5 H), 7.265 (t, 2 H, 7.176
- 7.098 (m, 3 H), 7.022 (td, 1 H, J = 1 Hz, J = 8 Hz), 6.815 (d,
1 H, J = 7.5 Hz), 6.400 (td, 1 H, J = 1 Hz, J = 7.5 Hz), 5.952
10 (dd, 1 H, J = 1 Hz, J = 7 Hz), 3.716 (s, 3 H), 3.391 - 3.169 (m,
4 H), 2 . 650 -- 2 . 582 (m, 1 H), 2 . 354 -- 2 . 182 (2, 3 H) .
E~umple 12 0
5~6-Di~SL.~ L ~ 3-t~r~rh~ n-1-yl)~ethyl]-6~6-diphenyl-
152~ L~L. 2--ono.
The title ' was E.IL~_L"~ as described in General
Nethod 8 using the following: 5,6-dihydro-4 ~IydLul~y-6~6-
diphenyl-2H ~JyL<~II 2-one (0.300 g, 1.13 mmol), Et3N (0.160 mL,
1.15 mmol), l-naphthoyl chloride (1.13 mmol), CH2Cl2 (6.0 mL),
20 acetonitrile (4.0 mL), acetone ~ y-i.ohy~in (0.05 mL, n.5 mmol),
Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (6.0 mL), sodium
cyanob~,Lul.ydLide (0.50 g, 7.9 mmol) . Purification was achieved
by submitting the final residue to column chromatograpy (SiO2,
100% CH2Cl2 to 1.5% MeOH in CH2Cl2) to provide a solid (0.120 g,
25 203 - 205 ~C(dec.)). ~H NNR (400 MHz, DNSû-d~) ~ 11.223 (bs, 1
H), 8.057 (d, 1 H, J = 7 Hz), 7.855 - 7.821 (m, 1 H), 7.603 (d,
1 H, J = 8 Hz), 7.514 - 7.302 (m, 12 H), 6.866 (dd, 1 H, J = 6.5
Hz, J = 8 Hz), 5.975 (d, 1 H, J = 7 Hz), 3.874 (s, 2 H), 3.621
(s, 2 H).
3~x~ple 121
5, 6-Dihydro-~-hydroxy-3-[ ~2-isopropylphenyl~ thyl] -6- (3-
methylbutyl) 6 p~ ~1-2~ ~ ~ 2-one ( L/_) .
The title __ was prepared as described in General
35 Nethod 8 using the Eollowing: 5,6-dihydro-4 ~1~u~y-6-(3-
methylbutyl) G phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N
(0.17 mL, 1.2 mmol), 2-isopropylbenzoyl chloride (1.15 mmol),
WO 9Sl14012 2 1 ~6 04 3 PCT/US94/12269
-- 115 --
CH,Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone iy.l..ul.ylrin (0.05
mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid
(5.0 mL), sodium cyano~uLuh~lLide (0.50 g, 8.1 mmol).
- Purif ication was achieved by submitting the f inal residue to
5 column chromatograpy (SiO2, 100% CHiCl2) to provide a solid
(0.118 g, 124 -- 126 C). lH NMR (400 MHz, DMS0--d6) ~ 100855 (bs,
1 H), 7.395 - 7.306 (m, 5 H), 7.115 (dd, 1 H, J = 1 Hz, J = 7.5
Hz), 6.991 (t, 1 H, J = 7 Hz), 6.622 (td, 1 H, J = 1 Hz, J = 7
Hz), 6.123 (d, 1 H, J = 7 Hz), 3.422 (s, 2 H), 3.210 - 3.102 (m,
10 3 H), 1.975 - 1.871 (m, 2 H), 1.437 - 1.371 (m, l H), 1.142 -
1.084 (m, 7 H), 0.938 - 0.807 (m, 1 H), 0.791 - 0.766 (m, 6 H).
E~mpl~ 122
5, 6-Dih~ h~ 3-[ (2-isopropylphenyl)methyl] ) 6 r~ ~1-6-
15 (2-phenylethyl) -2II-pyr~n-2-one ( I t-) -
The title r a was prepared as described in General
Method 8 using the following: 5,6-dihydro-4 hy~vAy C ph_.lyl-6-
(2-phenylethyl)-2H-pyran-2-one (0.300 g, 1.02 mmol), Et3N (0.17
mL, 1.2 mmol), 2-isopropylbenzoyl chloride (1-02 mmol), CH2C12
20 (4.0 mL), acetonitrile (4.0 mL), acetone ~y~no~l~lLin .(0.05 mL,
0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0
mL), sodium cyanoborohydride (0.45 g, 7.1 mmol). Purification
was achieved by submitting the f inal residue to column
~,1 LI LUYLCL~Y (sio2, 100% CH2Cl2) to provide a solid (0.130 g, 73
25 - 74 C). ~H NMR (400 MHz, DMS0-d6) ~ 7.424 - 7.328 (m, 6 H),
7.259 - 7.222 (m, 2 H), 7.197 - 7.082 (m, 3 H), 6.996 (t, 1 H,
J = 7 Hz), 6.638 (td, 1 H, J = 1.5 Hz, J = 8 Hz), 6.195 (d, l H,
J = 7 Hz), 3.440 (s, 2 H), 3.268 - 3.133 (m, 2 H), 2.630 - 2.528
(m, 1 H), 2.332 - 2.147 (m, 3 H), 2.332 - 2.147 (m, 7 H).
E~ ample 123
3-[ t2-chlorophenyl)m~thyl]-5~s-dihydro-~-hydr
mothyl~utyl) C-r' ~1-2~-pyr n-2-on~
The title ' was ~L~aL~3d as described in General
35 Method 8 using the following: 5,6-dihydro-4 hydLu~y-6~(3-
methylbutyl)-6-phenyl-2II }IyL~ 2-one (0.300 g, 1.15 mmol), Et3N
(0.17 mL, 1.2 mmol), 2-chlorobenzoyl chloride (O.lS mL, 1.15
, _ _ _ _ _, _ _ _ .. . .. .... _ . .. . , . , . , _ _ _ _, , .. _ .
Wo 95/14012 2 t 7 ~ ~ 4 3 Pc~rluS94/12269
-- 116 --
mmol), CH2Cl2 (4 . 0 mL), acetonitrile (4 . 0 mL), acetone
uyell~o~lydLin (0.05 mL, 0.5 mmol), Et3N (0.35 rL, 2.5 rmol),
glacial acetic acid (4.0 mL), sodium cyanobuL.,llydLide (0.720 g,
11.5 mmol). Purification was achieved by submitting the final
5 residue to column chromatograpy (Sio2, 100% CH2Cl2) to provide a
solid (0.165 g, 51 - 53 C). lH NMR (400 MHz, DMSO-d6) ~ 11.062
(bs, 1 H), 7.425 - 7.275 (m, 6 H), 7.072 (td, 1 H, J = 1.5 Hz,
J = 7.5 Hz), 6.774 ( td, 1 H, J = 1.2 Hz, J = 7.5 Hz), 6.059
(dd, 1 H, J = 1.2 Hz, J = 7.5 Hz), 3.428 (AS, 2 H, J,~j3 = 16.5
10 Hz), 3.191 (AB, 2 H, Jal3 = 17 Hz), 1.964 - 1.884 (m, 2 H), 1.450
- 1 . 384 (m, 1 H~, 1 . 163 - 1. 118 (m, 1 H), 0 . 951 (m, 1 H), 0 . 802
- 0 . 776 (m, 6 H) .
E~ple 12~
15 3-[~2-Chlolv~_ l)~ethyl]-5,6-diL~aLv ~-h~v,~ ~,6-diphenyl-
2~- pyr~n-2-on~
The title ~ was ~ ~yaL~=d as described in General
Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-
diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.17 mL, 1.2
20 mmol), 2-chlo~ob~zùyl chloride (0.14 mL, 1.15 mmol), CH2Cl2
(4.0 mL), acetonitrile (4.0 mL), acetone yc~nolly~in (0.05 mL,
0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.O
mL), sodium ~y~llo~ }ly~ide (0.50 g, 7.9 mmol). Purification
was achieved by submitting the f inal residue to column
25 I~IILl tCJyLa~y (sio2, 100% CH2Cl2 to 0.5% MeOH in CH2Cl2) to
provide a solid (0.130 g, 185 - 187 C). lH NMR (400 MHz, DMSO-
d6) ~ 11.351 (bs, 1 H), 7.464 - 7.282 (m, 11 H), 7.054 (t, 1 H,
J = 7 Hz), 6.679 ltd, 1 H, J = 1 Hz, J = 7.5 Hz), 5.797 (d, 1 H,
J = 7 Hz), 3.586 (s, 2 H), 3.472 (s, 2 H).
~s Iple 125
6-Cyclopentylmethyl-5, 6-dihy~ro-4-hydrosy-6-phenyl-3-
phenylmethyl -2~ E~. ~ 2-one ~/-).
The title ~ ' was yLe ~red as described in General
35 Method 8 using the following: 6-cyclopentylmethyl-5,6-dihydro-
4 llydLu~y-6-phenyl-2H-pyran-2-one (0.300 g, 1.10 mmol), Et3N
(0.17 mL, 1.2 mmol), benzoyl chloride (0.13 mL, 1.10 mmol),
.
~WO95114012 2~76a~3 PcT~us94/l2269
-- 117 ~
CH,Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone ~yarlol~in (0.05
mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid
(4.0 mL), sodium uyallobuL~}ly~Lide (0.50 g, 7.9 mmol).
Purification was achieved by submitting the final residue to
5 column ~ t.UyLa~y (SiO2, 100% CH2Cl2) to provide a solid
(0.188 g, 53 - 55 DC). lH N~ (400 MHz, DMSO-d6) ~ 10.849 (bs,
1 H), 7.371 - 7.284 (m, 5 H), 7.040 - 7.004 (m, 3 H), 6.747 -
6.724 (m, 2 H), 3.395 (s, 2 H), 3.117 (AB, 2 H, JAB = 17.5 Hz),
2.059 - 1.950 (m, 2 H), 1.652 - 1.578 (m, 2 H), 1.561 - 1.289
(m, 5 H), 1 . 021 - 0 . 844 (m, 2 H) .
lS~pl~ 126
5, 6-Dih~v ~- k~ p_~Lyl ~6 r~ ~1-3-phenylmethyl-2Ir
2-on~ (I/-).
The title ~ ~_ ' was prepared as described in General
Method 8 using the following: 5,6-dihydro-4 ~IyvLu.~y G n p~--Lyl-
6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2
mmol), benzoyl chloride (0.13 mL, 1.15 mmol), CH2Cl2 (4.0 mL),
acetonitrile (4 . 0 mL), acetone cyanohydrin (0 . 05 mL, 0 . 5 mmol),
20 Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium
cyanol,uLu~.y-lLide (0.50 g, 7.9 mmol). Purification was achieved
by submitting the final residue to column chromatograpy (sio2,
100% CH2Clz) to provide an oil (0.215 g). IH Nl~ (400 MHz, DMSO-
d6) ~ 10.850 (bs, 1 E), 7.367 - 7.287 (m, 5 H), 7.018 - 7.002
25 (m, 3 H), 6 . 724 - 6 . 700 (~, 2 H), 3 . 380 (AB, 2 H, J,~2 = 14 Hz),
3.096 (AB, 2 H, JA3 = 17 Hz), 1.950 - 1.820 (m, 2 H), 1.230 -
1. 100 (m, 5 H), 1 . 080 - 0 . 920 (m, 1 H), 0. 775 (t, 3 H, J = 7
Hz) .
30 E~mple 127
3-1 (3-Chloro~ethylph~nyl)~ethyl] -5, 6-~lihydro-~-hydro~y-6, 6-
~ip~enyl -2~-pyr2~n-2 -one .
The title ~ u.-d was ~L~aLed as described in General
Method 8 using the following: 5,6-dihydro-4 ~IYdLU~Y-6~6
35 diphenyl-2II ~YLall 2-one (0.300 g, 1.13 mmol), Et3N (0.17 mL, 1.2
mmol), 3-(chl~)L - yl)benzoyl chloride (0.13 mL, 1.13 mmol),
CH2Cl2 (5.0 mL), acetonitrile (5.0 mL), acetone ~:yai~ohy~in (0.05
WO95114012 ~?6Q~3 PCr/US94/12269
-- 118 --
mL, 0.5 mmol), EtlN (0.35 mL, 2.5 mmol), glacial acetic acid
(6.0 mL), sodium cyanoboLo~.y-lLide (0.50 g, 7.9 mmol).
Purification was achieved by submitting the final residue to
column chromatograpy (SiO~, 4/1 hexane/ethyl acetate to 3/2
5 hexane/ethyl acetate) to provide a solid (0.118 g, 135 - 137
C). lH NMR (400 MHz, DMS0--d6) ~ 11.211 ~s, 1 H), 7.418 -- 7.280 -
(m, 10 H), 7.088 (d, 1 H, 7.5 Hz), 6.975 (t, 1 H, J = 7.5 Hz),
6.689 (s, 1 H), 6.513 (d, 1 H, J = 7.5 Hz~, 4.498 (s, 2 X),
3.540 Is, 2 H), 3.447 (s, 2 H).
1~ ple 128
5, 6-Dihydro-3- ~b~mzoylcarbonyl) -~-L~v,~ 6, 6-~iph~nyl-2~-pyr~n-
2-on<~.
The desired _ '~ were E r-~ared by adding 5,6-dihydro-
15 4 hy~L~y-6,6-diphenyl-2H-pyran-2-one (0.500 g, 1.88 mmol) and
dry dichloromethane (10.0 mL) to a reaction vessel followed by
the addition of the benzoyl chloride (0.22 mL, 1.88 mmol) and
Et3N (0.28 mL, 2.0 mmol). The mixture was allowed to stir for
15 min. and then diluted with diethyl ether. The mixture was
20 then washed with sat'd NaHC03 (2x) and the organic layer dried
with MgSO4. The solvent was then removed in vacuo, the residue
redissolved in CH3CN and then treated with Et3N (0.56 mL, 4.0
mmol) and acetone ~y~ v}~dLin. The mixture was allowed to stir
for 18 h and then diluted with diethyl ether. The mixture was
25 then washed with 1. 0 N HCl, dried with NaSO4, and the solvent
removed in vacuo. Puri~ication was achieved by submitting the
final residue to column chromatograpy (sio~ 3/2 hexane/ethyl
acetate) to provide a solid (0.357 g, 66 - 68 oc)~ ~H NMR (400
MHz, CDCl3) ~ 7.495 - 7.208 (m, 15 H), 3.558 (s, 2 H).
E~pl~ 129
5,6-DiL,~lL~ ~-h~lLV~ 6,6-dipentyl-3-ph~nylmethylt~io-211-pyran-,
2-on~ .
The title ~ d was ~L~al~d as described in General
35 Method 4 to provide an oil. lH NMR (400 MHz, CDCl3) ~ 7.3-7.14
(m, 5 H), 3.8 (s, 2 H), 2.54 (s, 2 H), 1.5-1.35 (m, 4 H), 1.26-
1.11 (m, 12 H), 0.87-0.80 (t, 6 H).
Wo 9S/14012 ~ I 1 6 ~ 4 3 PCr~S94~12269
-- 119 --
lS~a_plo 130.
5, 6-Dihydro-~-hy~lro~y-6-ph~nyl-3- t ~2 -i30propyl-S-
_ethylph~yl) thio]-2 ~1~) -pyridinon~
The title u--d was ~lL ~pa~ed as described in General
5 Method III using 95.6 mg of 5,6-dihydro-4 ~lL~.y-6-phenyl-2
(lH) -pyridinone, 180 mg of toluene-4-thiosulfonic acid S- (2-
isopropyl 5 ~ ` ylphenyl) ester (~L~paced as per ~An~in~h~ and
Fuchs, synthetic c~ ications 18: 227 (1988)) and 0.08 ml o~
triethylamine in 5 ml of absolute ethanol. The solution was
10 stirred overnight at room t~y~:r a-~lL~. Purification by flash
chromatography using CH2Cl~/isu~L~,panol (99/1 to 95/5) as eluent
gave a solid (m.p. 184-186 C) . lH NMR (CDCl3) ~ 1. 28 (d, 3H),
1.29 (d, 3H), 2.23 (s, 3H), 2.98 (d, 2H), 3.52 (qn, lH), 4.85
(t, lH), 5.63 (s, l}I), 6.78 (s, lH), 6.96 (m, lH), 7.14 (d, lH),
1~ 7.35-7.44 (m, 5H), 7.55 (s, lH).
E~ple 131
3-t ~l-isopropyl-~,~-d~ethyl-4,5-dihydro-llE-imi~-7~1-
2-yl)thio] 6 ~' ~1-5,6-dihydro-2~-pyran-2-on~
The desired ~ _ ' were prepared by adding 4 ~ydL~y-
6,6-diphenyl-5,6-dihydro-2H-pyran-2-one (0.250 g, 0.85 l3mol) and
dry t-butanol (4.5 mL) to a reaction vessel followed by the
addition o~ n bL~ - 'n;mi~3~ (0.151 g, 0.850 mmol). The
mixture was allowed to stir for 1 h in the dark and the solvent
25 then removed in vacuo. The residue was then dissolved in CH2Cl2
and the mixture washed with H,0. The organic layer was then
dried with Na2504 and the solvent removed in vacuo. The
resulting residue was then redissolved in CH2Cl2 ( 6 . o mL) and
treated with l-isopropy];m~ olidine-2-thione (0.184 g, 1.28
30 mmol, prepared by the method described by A.F. McKay et al., J.
Am. Chem. Soc., 78: 1618 (1956))) followed by piperidine (0.084
mL, 0.85 mmol). The mixture was allowed to stir for 14 h in the
dark then diluted with additional CH2Cl~ and the mixture washed
with H20. The organic layer was then dried with Na2S04 and the
35 solvent removed in vacuo. the resulting solid was then submitted
to column chromatography (SiO2, 1 / 1 CH2Cl2 / ethyl acetate to
14 / 4 / 1 CH2Cl2 / ethyl acetate / methanol) to provide a solid
. . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
WO9~/14012 2~76a43 PcrluS94112269 ~
-- 120 --
which was redissolved in CH2C12, filtered through a fiberglass
filter, and the solvent removed in vacuo to provide the title
_ ' (0.234 g, m.p. 160 - 162~C (dec.)). lH NMR (400 MHz,
D~S0-d6) ~ 7.732 (s, 1 H), 7.420 - 7.336 (m, 4 H), 7.277 - 7.212
5 (m, 3 H), 7 . 137 (t, 1 H, J = 7 Hz), 7 . 080 - 7 . 060 (m, 2 H),
3.970 - 3.904 (m, 1 H), 3.842 (t, 2 H, J = 10 Hz), 3.602 - 3.517
(m, 2 H), 2.925 (AB, 2 H, JAr3 = 16 Hz), 2.617 - 2.540 (m, 1 H),
2.315 - 2.240 (m, 1 H), 2.160 - 2.025 (m, 2 H), 1.206 - 1.180
(m, 6 H).
3~pl- 132
~-~y~ro~y-3-~ pro~yl-~,4,5,6-t-tr~ o ~I.imicine-2-
yl~thio] 6 E- ~1-5,6-~lihydro-2~r El,~L~ 2-on~.
The title _ ' was ~L~yaL- d as described in example 41
lS using the following: 5,6-dihydro-4 ~IydLv~y 6 ph_..yl-6-(2-
phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), t-butanol
(3.5 mL), n bL- - n;mi~l~ (0.151 g, 0.85 mmol), CH2C12 (6.0
mL), l-isopropyltetral.y-lLv~yLimidine-2-thione (0.270 g, 1.70
mmol, ~L~L~aL~d by the method described by A.F. McKay et al., J.
20 Am. Chem. Soc., 78: 1618 (1956)), piperidine (0.084 mL, 0.85
mmol). Purification was achieved by submitting the final
residue to column chromatograpy (SiO2, 1/1 CH2Cl2/ethyl acetate
to 2/14/1 ethyl acetatelCH2Cl2/r -nnl) to provide a solid which
was redissolved in CH2C12, filtered through a fiberglass filter,
25 and the solvent removed in vacuo to provide the title ~
(0.356 g, m.p. 103 -- 105C) . lH NNR (400 MHz, DMSO-d6) ~ 7.440 --
7.371 (m, 4 H), 7.296 (t, 1 H, J = 7 Hz), 7.233 (t, 2 H, J = 7
Hz), 7.139 (t, 1 H, J = 7 Hz), 7.077 (d, 2 H, J = 7 Hz), 6.515
(bs, 1 H), 4.365 - 4.300 (m, 1 X), 3.335 - 3.308 (m, 2 1~), 3.024
30 - 2.924 (m, 4 H), 2.624 - 2.548 (m, 1 H), 2.341 - 2.265 (m, 1
H), 2.156 - 2.061 (m, 2 H), 1.763 - 1.737 (m, 2 H), 1.201 -
1.180 (m, 6 H).
~amp}e 133
356-~2-Benzo[1,3]dio~Col-5-yl-ethyl)-5,6-~ihy~ro-~ LL".~-6-
phenyl-3-[ (2-i~opropyl-5-methyl-phenylthio~-2~ L. 2-one(+/-
) , .
~ = _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
~ W095/14012 2 ~ 76~ PcrluS~34/12269
-- 121 --
The title ~ d was pL ~ ya~ ed as described in General
Method iii using 400 mg of 6-(2-benzo[1,3]dioxol-5-yl-ethyl~-
5,6-dihydro-4 ~ly~u~y-6-phenyl-2H-pyran-2-one~ 415 mg of
toluene-4-~h i nsUl fonic acid S- (2-isopropyl J - t~,ylphenyl) ester
S and 0.17 ml of triethylamine in 20 ml of Ahsol-lt~P ethanol. The
soll~t i c~n was stirred overnight at room temperature.
Purification by flash chromatography using hexanes/isopropanol
(90/10 to 50/50) as eluent gave a solid (mp=83-85 C) lH NMR
(CDCl3) d 1.21 (d, 3H), 1.25 (d, 3H), 1.93 (s, 3R), 2.20-2.40
10 tm, 3H), 2.60-2.75 tm, lH), 3.30 tdd, 2H), 3.42 tq, lH), 5.89
(8~ 2H), 6.11 ts, lH), 6.52 td, lH), 6.56 ts, lH), 6.69 (d, lH),
6.87 td, lH), 7.07 td, lH), 7.30-7-50 tm, 5H), 7.64 tbr.s, lH).
.3 D~ tion of HIV Protea.:~ Inhil~ition
~.3.1 8t~rting ~teri21s
DTT Buffer: 1. 0 mM dithiothreitol tDTT) was ~Lè~aled fresh
daily in 0.1% polyethylene glycol tmw 8000) 80 mN NaûAc, 160 mM
20 NaCl, 1.0 mM EDTA, and brought to pH 4.7 with HCl.
~V-l Prote~e: The enzyme is obtained from Bachem Rio%c; ~nre
Inc. The undiluted enzyme is thawed from -80 C and diluted 50-
fold with DTT buffer. The solution is always kept at 0 C on
ice water and used in the experiment within 20 minutes after
25 thawing.
Enz~me 8 LL~te: Substrate III from Bachem BiosriPn~e Inc. is
the undecapeptide H-His-Lys-Ala-Arg-Val-Leu-p-
NitLu~h~ ~y~ ninP-Glu-Ala-Norleucine-Ser-NH2 (>97% purity) . A
200 ~LN stock solution in DTT buffer is prepared and stored on
30 ice. Substrate solution is yLc:paLed fresh daily.
~rest c -: 10 mM inhibitor (I) in dimethyl sulfoxide (DMSû)
is diluted to 200 ~M with DTT buffer. From the 200 ~LM stock
solution is made a 10 ~l stock solution with 2% DMSû in DTT
buffer. The ~wo inhibitor solutions are used to make final [I]
35 = 100, 50, 20, 10, 5, 2, 1, 0.5 and 0 ~N with 2% DMS0 in DTT
buffer in each reaction well ~total inhibitor volume of 50 ~
WO9~/14012 ~11G~3 PcrluS94/12269 ~
-- 122 --
~.3.2 A~ay
To each reaction well is added 20 ILl of substrate (f inal
,u..c~..LLction of 40 yM), 50 ~l o~ inhibitor (at a ~,~,..c~ Lction
such that final dilution will proauce the test cu11ce~1LLction)
5 and 20 ~l of DTT buffer. The reaction plate (96 wells) is
incubated at 37 C for at least 5 minutes.
10 ~Ll of the diluted protease is added to the reaction well
while the reaction plate is shaking . Once shaken f or l0
seconds, the plate is r~ ~uL1,ed to the heating block at 37 C.
l0 (final reaction volume l00 ~l. )
The reaction is incubated for 5 minutes at 37 C. The
reaction is stopped by placing the reaction plate on the shaker
and adding 20 ,~l of 10% trifluoroacetic acid (TFA) and shaking
for l0 seconds. The amount of proteolysis is then det~rm;n~d by
15 separation of noncleaved ,,uba~Lcte and two cleaved products with
reverse-phase ~PLC, while measuring Ah~rh~n~e at 220 n~ to
~let~rmin~ the relative peak areas of the three components. The
relative peak areas are used to calculate 96 conversion to
product as a function of inhibitor concentration. The data are
Z0 plotted as % Control (the ratio of % conversion in the presence
and absence of inhibitor x l00) versus inhibitor ~ el,LLction
and fitted with the equation Y=lOO/l+(X/ICso)~, where ICso is the
inhibitor ~oll~ llLrtion at 50% inhibition and A is the slope of
the inhibition curve.
25 The results are listed in Table I.
TA8T E I
E~IV PROTlSA8E RE8~T8
50% IN/II8ITION
EXANpLE CONCENTRATION [~M~
2 l.9
0.40
14 2.5
22 l.l
2g ~ 26
0 . 12
, . . .
WO95/14012 2i ~ PCTn~S94/122C9
-- 123 --
37 0.26
39 0 . 050
0. 060
44 0 . 32
- 50 0 . 088
5Z 2.0
56 0 . 005
57 0 . 65
61 0.22
66 0 . 39
0 . 11
71 0. 10
0 . 028
0 . 14
92 0 . 27
94 0 . 22
1 . 09
107 0. 110
114 0. 079
119 0 . 097
Anti-~IV--1 A~:tivitY
Using the general methods of Pauwels et al., (J.
Virol. Methods, 16, 171-185, 1987) and Mann et al. (AIDS
~esearch and ~uman 2etroviruses, 253-255, 1989 (anti-
viral assays of actue HIV-l infection were peLLI -' in
the H9 cell line. Cultures were batch infected in 1 ml
of RPM1 1640 media/10% fetal calf serum containing 105
infectious doses of HIVl iib for an effective multiplicity
o~ infection of 0 . 01. After 2 hours of viral
absorption, cells were washed once and palted in 96-
35 wellmicrotiter plates at a density of 10~ cells per well.
Test , _ ' c were added to produce the des ired
r "tion of drug and 0 .1% DMS0 in a final volume of
WO95/14012 2 ~ 76~43 PCr/US94112269
-- 12~ --
200 l~l. IJninfected parallel cultures were maintained
for XTT cytotoxicity assay at 7 days post infection.
Cultures were tested for viral replication by reverse
transcriptase assay at 4 and 7 days post infection.
Antivir~l ActivitY in }}9 C~118
Ex le # Cu~ L ,tiOn for 50%
amp Protection [~M]
94 29
39
107 8
114 26
119 59
Combinations of protease inhibitor with other AIDS
~L~l;i Ls, such as (but not limited to) the HIV reverse
transcriptase inhibitors AZT or ddC, may produce
synergistic results. J. C. Craig et al., Aativiral
Chem. Chemother., ~/3: 161-166 (1993); E. V. Connell et
al., Antimicrob. Agents Chemother., 38: 348-352 (1994);
D. M. Lambert et al., Antiviral Res., 21: 327-342
(1993); A. N. ~ n~o et al., Clin. Infect. Dis., 18/~:
516-524 ( 1994 ) .
The u~.~s of the invention display
25 antibacterial activity when tested by the microtitration
dilution method as described in Heif etz, et al .,
Antimicr. Agents. & Chemoth. 6:124 (1974) which is
inCuL UUL Cl ~ed herein by ref erence .
By use of the above ref erenced method, the
30 following minimum inhibitory ~-,...ellL-~tion values (~ICs
in ~Lg/mL) were r~h~A;rl~d for l~u.es,:--Lative, ` of
the invention vs . cl; n; CA 1 l y relevant gram positive
pat}lo~:..s which have become highly resistant to
conv-~nt; onA 1 therapy in recent years .
WO 95/14012 2 f ~ 6 ~ 4 3 PCT/US94/12269
-- 125 --
A~tib~ct~ri~l Activittr u~/ml
Ex. Ex. Ex.
65 114 122
Staphylococc-lc 25 50 12 . 5
5 aureus H228
Staphyl ~cocc~c 25 50 12 . 5
aureus UC-76
Entt:rococ~;us 100 >100 >100
foecalis MGH2
10 SLL-:Yt~ u~ ~ ~ 25 12 . 5 12 . 5
i ~ 5V-l
Strept~coc~c 25 50 25
a C203
It æhould be ~aL...L to those skilled in the art
15 that other compositions not specifically Aicr~o5~ in
the instant specification are, nevertheless,
contemplated thereby. Such other compositions are
cr~nci~ red to be within the scope and spirit of the
present invention. Hence, the invention should not be
20 limited by the description of the 5pecific ~-mhn~
clos~a herein but only by the following claims.
