Note: Descriptions are shown in the official language in which they were submitted.
~ WO95/14014 PCT~S94/12367
~17~1~4
- 1 -
r~.... .....~ DERIV~rVE8 A8 ~.~A8~ I~h~ ~K~ AND A~ ~v-KA~ AGENT8
1. FIRT-n OF $9~ INVEN~IO~
S The present invention relates to ~y~ a derivatives that
are inhibitors of aspartyl proteases, in part;c~ r the
aspartyl prote~C~e found in ~LlGviruses including Human
Immnn~A~ficiency Virus (HIV). The pyrones are expected to
have utility as antiviral agents, for the treatment of
10 infection caused by HIV or other ~L~oviruses employing
aspartyl prote~C~C~ and to be useful in the treatment of
~;-CD~ces caused by the LeLl~viruses, including AIDS.
2 . R~ r-~,O~ OF TB ~..V~lU..
Acquired Immunodeficiency Syl~dlume (AIDS) was coined in
1982 to describe the clinical manifestations of
imml~n~ficiency. The etiological agent of AIDS was later
associated with a LeL~ovirus, Human Immllno~ficiency Virus
(HIV), from the lentivirus subfamily. At least two infectious
20 strains of HIV have been identified, HIV-1 and HIV-2.. Here,
HIV will be used as a general term describing a variety of
strains and mutants of the Human Immunodeficiency Virus. The
detailed study of HIV has given rise to many appro~h~C to
antiviral drug de~elopment including inhibition of the viral
2S aspartyl protease (D. Richman, Control of Virus Diseases, 45th
Symposium of the Society for General Microbiology, 261-313
(1990) ) .
Aspartyl prote~s~C have been found in many l~LLuviruses
including the Feline Immunodeficiency Virus, the
30 Myeloblastosis Associated Virus, HIV, and the Rous Sarcoma
Virus tH. Toh et al., Nature, 315: 691 (1985); J. Ray, B. M.
Dunn, Biochlm. Biophys. Acta, 1: 1048 (1990); C. Cameron et
al., J. Biological Chem., 168, 11711-720 (1993)]. Since there
are structural similarities among the known ~LLvviral
35 prot~ , com~ which inhibit the HIV protease may well
inhibit other leL.~viral prote~c~c.
HIV aspartyl protease is responsible for post-
translational processing of ~iral ~L~ sor polyproteins such
Wo95/14014 PCT~S94/12367 ~
: ` .
~7~12~ 2 -
as pol and gag. (N. Graves, Structure and Function of the
Aspartic P~oteases, 395-405 (l99l)). Cleavage of these
polyproteins by this protease is essential for maturation of
the virus, since the proteolytic activity ~PcPcs~ry for
5 polyprotein processing cannot be provided by host cellular
enzymes. An important f; n~; n~ has been that viruses which
lack this protease, or contain a mutation which pro~tlce~ a
defective protease, lack infectivity ~C. Peng et al., ~.
Virol, 63: 2550-2556 (1989) and N. ~ohl et al., Proc. Nati.
lO Acad. sci. USA, 85: 4689-90 (1987)]. Thus, a selective HIV
protease inhibitor has been shown to inhibit viral spread and~
the production of cytopathic effects in cultures of acutely
infected cells (J. C. Craig et al., Antiviral ~esearch, 16:
295-305 (l99l)). For this reason, inhibition of HIV protease
15 is believed to be a viable approach to antiviral therapy.
HIV protease inhibitors have been extensively reviewed
(see for example A. Tomasselli et al., C~imica Oggi, 9: 6-27
(l99l) and T. Meek, J. Enzyme Inhibition 6: 65-98 (19g2)).
However, the majority of these inhibitors are peptides and
20 thus unsuitable as drugs, due to the well known
pharmacological deficiencies exhibited by most peptide drugs
(biliary e~r~Lion, low bioavailability and stability in
physiological milieu, etc.) No~ idic inhibitors of HIV
protease are thus very important, since these may lead to very
25 useful therapeutic agents.
Hei 3-227923 claimed coumarins with anti-HIV activity.
However, only 4-hyd~ coumarin was specifically described
without discussing its mec~ni~m of action.
World Patent 89/07939 claimed eight coumarin derivatives
30 as Hrv reverse transcriptase inhibitors with potential
antiviral activity. These derivatives are hexachlorocoumarin,
7-acetoxycoumarin, and the structures shown below.
3s
WO95/14014 ~ 1 7 4 1 2~ PCT/US94/12367
Br ~ N~\R~ N~N~
~`O ~O~o
." ,~.
R=H, R'=Cl; R=H, R'=CF3; R=R'=Cl ~Fe)~
OH o OH . OH
~O~o ~J ~o~ooJio~
Warfarin (3-(~-acetonylbenzyl)-4-hydLo~ycoumarin), shown
5 below, was Le~olLed by R. Nagorny et al. in AIDS, 7: 129-130
(1993) as inhibiting cell-free and cell-mediated HrV
infection. However, Warfarin was the only pyrone studied and
itS ~rh~ni ~m of action in HIV inhibition was not specified.
2 0 OH Ph O
~\ Me
~0~0
Selected flavones, structurally different from the
25 pyrones of the present invention, were ~e~L Led by Fairli et
al. (Biochem. Biop~ys. ~es. Comm., 188: 631-637 (1992)) to be
inhibitors of HIV-l protease. These compounds are shown
below.
O OH O
1'. HO~
~ OlCO2H '~~ OH
OMe OH ~
1 OH
HO
WO95tl4014 PCT~S94/12367
United States Patent Number 3,206,476 describes several
pyrones, specifically 3-substituted-4-hyd~o~y-6-aryl-2-
pyrones, as antihypertensive agents. However, the range of
substituents at the 3-position of these heterocycles is
5 limited to halo and amino yL 0~ and ~lk~noylamino
derivatives.
,..
United States Patent Number 3,818,046 describes several
pyrone derivatives, specifically 4-h~dko~y~yLolles with sulfur-
cont~; n; n~ carbon ~hA i nc at the 3-position, as growth stunters
10 and antimicrobial agents. The substitution at the 6-position
of these hetelG~ycles is limited to the methyl group. The
pyrones, which are shown below, are substituted as follows: R
s Me; M = H or ~lkAl; metal; and R' = H, alkyl, phenyl,
halophenyl, nitrophenyl, phenyl substituted with lower alkyl,
15 benzyl, phenethyl, naphthylmethyl, halobenzyl, benzyl
substituted with lower alkyl, nitrobenzyl, propargyl, allyl,
cyclohexyl substituted with lower alkyl, thioalkyl cont~;ni ng
a lower alkyl group, lower alkyl, or adamantyl; and n=0 to 2.
.
OM
~,S(O)nR'
R " ~`O ~ O
R--M~
A process for preparing the pyrones shown above is
30 claimed in United States Patent No. 3,931,235.
3. 8~MMARY OF ~ INVENTION
The present invention is based in great part on the
extraordinary discovery of the inventors that novel tri- and
35 tetrasubstituted pyrones and related com~oullds, selected fro~
a very broad spectrum of tailored molecular stru~ es~
potently inhibit the HIV aspartyl protease blocking infection
by HIV. The present invention is also based on the insights
,
~ WO95/14014 2 1 7 ~ 1 ~4 PCT~Sg4/12367
- 5 -
of the inventors regarding the mec~ism of action of
antiviral drugs, especially as revealed by their studies on
structure-activity relatio~ch i rS characteristic of anti-HIV
compounds that include pyrones.
The invented pyrones are expected to be extremely useful
in the development of treatments for infections caused by
viruses, especially by ~eLLoviruses that rely on aspartyl
protease activities for replication and infectivity. One such
LeL.~irus is HIV. As virus blockers, the pyrones are also
l0 expected to be very useful in the treatment of diseases and
syndromes associated with viral pathogens. One such ~y~dlome
is AIDS.
Efficient syntheses of the biologically active pyrones,
involving either de novo assemblies of the ~L olle nucleus or
~5 modifications of suitably functio~Al;~ed pyrones, are
disclosed. Furthermore, ~any working examples outlining the
preparation of specific ~yLo~,as whose structures contain the
desired functional yL O~p-- ' in proper geometric arrangements are
given.
The testing of specific pyrones as inhibitors of the HIV
aspartyl protease, h~ on a study of the hydrolysis of an
n~c~eptide enzyme substrate, and the testing of the pyrones
as inhibitors of viral growth and infectivity, based on a
study of infection of H9 cell lines by the HIV~ strain,
2S are also disclosed. Striking enzyme inhibitions, at nanomolar
levels, with corres~o~i ng anti-~IV activities, were observed.
The present inventors contemplate the preparation of
pharmaceutically useful antiviral compositions comprising one
or more of the invented pyrones and related compounds and a
30 pharmaceutically acceptably carrier. They also contemplate
the use of these compositions, alone or in combination with
other antiviral treatments, in the treatment of infections and
es caused by retroviruses, including AIDS.
The present invention relates to compounds, or the
35 pharmaceutically acceptable salts thereof, of Formula l, shown
below,
,
WO95/14014 ~ 2 ~ PCT~Ss4tl~67
-- 6 --
,.
R5 W2Al(CH2 )mW3 R3
R3 Wl (CH2 )mW(CH2 )nA Y Z
wherein
X is oRl, NHRl, SRl, Co2R4 or CHzORl wherein Rl is R4 or CoR4
15 wherein R4 is as defined below;
Y is oxygen or sulfur;
Z is oxygen or sulfur;
A and Al are ind~r~n~tly a chemical bond, an
unsubstituted or substituted phenyl, naphthyl, a 5- or 6-
20 membered heterocyclic ring, cycloalkyl, or a fused ring systemof from 8 to 10 atoms or a substituted derivative thereof
wherein the substituents are one or more of F, Cl, Br, oR4,
N(R4) 2, Co2R4, CoN(R4) 2, coR4~ R4, OCH2O, OCH2CH20, or C--N wherein
R4 is ~ r~n~ntly hydloyen, substituted on unsubstituted
2s alkyl, cycloalkyl, alkylcycloalkyl or phenyl wherein the
substituents are one or more of CO2R2, CON(R2)2, F, oR2~ SR2,
N(R2)2, CN, phenyl, naphthyl, a heterocycle or CF3 wherein R2
is indep~n~ntly alkyl, cycloalkyl, or hydrogen;
Rs is hydLoyen, alkyl, cycloalkyl, alkylcycloalkyl,
30 phenyl, or the substituted derivatives thereof wherein the
substituents are one or more of CO2R2, CON (R2) 2 ~ F, oR2~ phenyl,
naphthyl, CF3, oRl, NHRl, SRl, or CH20Rl wherein Rl is as
defined above;
R3 is ;n~F~n~ently h~dloyen, (CH2)pR4 or (CH2)iA wherein p
35 is an integer of from 0 to 2 and R4 and A are as defined
above;
W, W1, and W3 are each independently a chemical bond,
oxygen, NR3, C(R3) 2~ C~ CR3=CR3, C2C, CR30R3, C(=NR3)NR3, S(O)p,
-
~ WO95/14014 217~24 PCT/US94/12367
CR3N (R3 ) 2 ~ So2NR3, C2 ~ NR3COVgA and NCov~R3 wherein g is either
or 1, and V is oxygen, sulfur, NR3, or CHR3;
W2 is an oxygen, NR3, S(O)p, So2NR3, -OCO, NR3COV~a and
NCOVgR3 wherein g is either 0 or 1 and V is 0, S, NR3 or CHR3;
m and n are each in~P~ ntly an intéger of from 0 to 4
with the provision that when W and Wl are both heteroatoms or
when w2 and W3 are both heteroatoms, m is an integer of from 2
to 4; and with the further proviso that R3Wl(CH2)mW(CH2~nA
cannot be methyl or ethyl.
Preferred com~o~l~s of the instant invention are those of
Formula 1 shown above wherein
X is hydk~yl, amino, or h~ko~ymethyl;
Z is oxygen;
Y is oxygen or sulfur;
W, W1, and W3 are each in~r~ tly oxygen, NR3, NCoV5R3,
CR3=CR3, 5O2NR3, sulfur, or C(R3) 2 and w2 is selected from the
group consisting of O, NR3, S, and NCov~R3~ wherein V is
oxygen, NR3 or CHR3 wherein R3 is independently hyd-oyel~,
(CH2)pR4 or (CH2)p A wherein p is an integer of from 0 to 2, g
20 is 0 or 1, and A is ;n~p~n~ently phenyl, naphthyl, a 5- or 6-
membered hete.~y~le having one or two heteroatoms, a fused
ring system of from 8 to 10 atoms, cyclopentyl, cyclohexyl or
a substituted derivative thereof wherein the substituents are
one or more of F, Cl, Br, oR4, N(R4)2, CO2R~, CON(R~)2, R4,
25 OCH20, or OCH2CH20 wherein R~ is i~Pr~n~tly l~Loyen, a
straight or br~nçhe~ alkyl of from 1 to 5 atoms, a cycloalkyl
group of 3 to 6 carbon atoms, a CH2cycloalkyl group of 4 to 8
carbons, phenyl, or a substituted derivative which
substituents are of CO2R2, F, oR2~ phenyl, or CF3 wherein R2 is
30 hydrogen, methyl, ethyl, isobutyl, t-butyl, or cycloalkyl
contA;~ing 3 to 6 carbon atoms, wherein Al is as previously
defined; and
R5 is hydrogen, methyl, ethyl, propyl, cyclo~l u~yl,
hydLoxyl, carboxyl, or hy~o~ymethyl.
3s More preferred compounds of the present invention are
those of Formula 1 shown above wherein
X is hy~G~.yl;
Z is oxygen;
WO95/14014 ~1 7~ 2~ PCT~S94/12367 ~t
Y is oxygen;
W, Wl, and W3 are each ;n~ep~n~tly oxygen, sulfur,
So2NR3 ~ NR3 ~ or C(R3) 2 and w2 is O, S or NR3, wherein R3 is
~n~pen~ently hydrogen, (CH2)pR~, or (CH2)~A wherein p is an
5 integer of from 0 to 2, Rg is hydrogen, methyl, ethyl,
isu~Lo~yl, isobutyl, CYC1O~L~Y1~ cyclohexyl,
cyclu~lo~ylmethyl, cyclohexylmethyl, CH2CO2R2, phenyl or
benzyl; R2 is H, methyl, ethyl isobutyl or t-butyl; A is
phenyl, 2,3- or 4-pyridyl, 2,4- or 5-thiazolyl, morpholinyl, 2
10 or 3-furyl, cyclopentyl, cyclohexyl, indanyl, or a substituted
derivative thereof wherein the substituents are one or more of
F, Cl, Br, oR4 R~, Co2R4 or OCH2O, wherein Al is as previously
defined; and
R5 is hyd~oyen, methyl, ethyl, or hydlGxymethyl;
Some of the most preferred compounds of the present
invention are included in the following:
3-[(Cyclohexylthio)phenylmethyl]-4-hy~oxy-6-
phenyl-2H-pyran-2-one;
4-Hydlox~-3-[[(2-methoxyphenyl)thio]phenyl-
methyl]-6-phenyl-2H-pyran-2-one;
3-(3-Methoxybenzoyl)-6-(3-methoxyphenyl)-2H-
pyran-2,4(3H)-dione;
6-~4-[(3,5-Dimethyl-4-; CQYA 701yl ) methoxy]phenyl]-
4-hydk~xy-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydloxy-3-~3-methyl-1-(phenylthio)butyl]-6-
phenyl-2H-pyran-2-one;
4-Hydroxy-3-~(2-phenylethyl)thio]-6-[4-
(phenylsulfinyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[phenyl[(phenylmethyl)thio]
methyl]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-hydroxy-3-t(2-
phenylethyl)thio]-2H-pyran-2-one;
4-Hydlo~y-6-(3-phenoxyphenyl)-3-[(2-
3S phenylethyl)thio]-2H-pyran-2-one;
3-~2-Cyclohexyl-1-(phenylthio)ethyl]-4-hy~Gx~-6-
phenyl-2H-pyran-2-one;
WO95/14014 ~74124 PCT~S9411~67
4-Hy~Lo~y-6-t3-methoxy-4-(phenylmethoXy)phenyl]-
3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hy& oxy-3-t(2-oxo-2-phenylethyl)thio]-6-phenyl-
2H-pyran-2-one;
54-Hy~Lùxy-6-phenyl-3-[phenyl(phenylthio)methyl3-
2H-pyran-2-one;
3-[Bis(2-naphthalenylmethyl)amino]-4-hydroxy-6-
phenyl-2H-pyran-2-one;
4-HydLo~y-6-phenyl-3-[(phenylmethyl)thio]-2H-
pyran-2-one;
(S)-l,3-Dih-y~O N-(4-hy~lGxy-2-oxo-6-phenyl-2H-
pyran-3-yl)-2-(phenylmethyl)-2H-isoindol-2-acetamide;
N-(l,l-Dimethylethyl)-N'-(4-hy~loxy-2-oxo-6-
phenyl-2H-pyran-3-yl)-N'-(phenylmethyl)urea;
~54-Hy~oxy-3-[(2-~h~nQYyethyl)thio]-6-phenyl-2H-
pyran-2-one;
(E)-4-Hy~koxy-6-phenyl-3-t(3-phenyl-2-
propenyl)thio]-2H-pyran-2-one;
4-Hydku~y-3-ph~oYy-6-phenyl-2H-pyran-2-one;
202-Oxo-6-phenyl-3-[(phenylmethyl)thio]-2H-
pyran-4-yl-3-methylbutanoic acid ester;
6-(3,4-Dichlorophenyl)-4-hy~L~xy-3-
[(phenylmethyl)thio]-2II ~yLan-2-one;
6-(3-Chlorophenyl)-4-hydroxy-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
2-Oxo-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-4-
yl propanoic acid, ester;
4-Hydroxy-6-(3-methylphenyl)-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
304-Hydroxy-6-(3-hydroxy~henyl)-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(2-phenylethyl)-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hyd~o~y-6-(4-hy~xy~henyl)-3-[(2-
phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-
(phenylmethoxy)phenyl]-2H-pyran-2-one;
WO95/14014 2 1 ~ 4 1 2 ~ PCT~S94/12367 ~
-- 10 --
4-Hy~loAy-6-~4-(2-phenylethoxy)phenyl]-3-t(2-
phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[3-(2-phenylethoxy)phenyl]-3-[(2-
phenylethyl)thio]-2H-pyran-2-one;
4-HY~VAY-6-(2-hYd1OAY~henY1)-3
~(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(3-methoxyphenyl)-3-
t(phenylmethyl)thio]-2~-pyran-2-one;
6-(3-Chlorophenyl)-4-hydlu~y-3-[~2-
phenylethyl)thio]-2H-pyran-2-one;
4-Hy~y--6-(4-methoxy-3-methylphenyl)-3-
~(phenylmethyl)thio]-2H-pyran-2-one;
6-(3-Chloro-4-methoxyphenyl)-4-1.y~o~y-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
4 IIydLoAy-3-[(2-phenylethyl)thio]-6-t3-
(phenylmethoxy)phenyl]-2H-pyran-2-one;
4-Hy~lo~y--3-t[2-(4-methoxyphenyl)ethyl]thio]-6-
phenyl-2H-pyran-2-one;
3-[(Cyclohexylmethyl)thio]-4-hydLu~y-6-phenyl-2H-
pyran-2-one;
4-Hydroxy-3-[(phenylmethyl)thio]-6-[3-
(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-Ey~lo~y-3-[(2-phenylethyl)thio]-6-[3-
(trifluoromethyl)phenyl]-2H-pyran-2-one;
6-(2,3-Dihy~.o l,4-benzodioxin-6-yl)-4-hyd~o~y-3-
t(phenylmethyl)thio]-2H-pyran-2-one;
4 -Hydl u~y - 3 - [ ( 2-phenylethyl)thio]-6-[3-methyl-4-
(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
t4-[4-Hy~koxy-2-oxo-3-[(2-phenylethyl)thio]-2H-
pyran-6-yl]phenoAy]acetic acid;
t4-[4-Hy~Gxy-2-oxo-3-[(2-phenylethyl)thio~-2H-
pyran-6-yl]phenoxy]acetic acid, ethyl ester;
4-Hydroxy-6-(4-phPnn~yphenyl)-3-~(2
phenylethyl)thio]-2H-pyran-2-one;
4-HydroAy-3-t(2-phenylethyl)thio]-6-[4-(2-
pyridinylmethoxy)phenyl]-2H-pyran-2-one;
4_HY~AY_3_[(2-PhenY1ethY1)thiO]-6-[4-(3
pyridinylmethoxy)phenyl]-2H-pyran-2-one;
~ WO9S/14014 21~4124 PCT~S94/12367
-- 11 --
4 ~I~dl~y--6-t4-(2-methoxyphenyl)methoxy]phenyl]
3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hy~l uXy-3 - [2-naphthalenyl(phenylthio)methyl]-6-
phenyl-2H-pyran-2-one;
54-H~dLoxy-3-t(2-naphthalenylthio)phenylmethyl~-6-
phenyl-2H-pyran-2-one;
4-Hydloxy-3-t(2-phenylethyl)thio]-6-t4-
(phenylthio)phenyl]-2H-pyran-2-one;
6-(l,3-Benzodioxol-5-yl)-4-hydroxy-3-
r(phenylmethyl)thio~-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-hydroxy-3-
t(phenylmethyl)thio]-2H-pyran-2-one;
4-hydLGxy-6-(2-naphthalenyl)-3
t(phenylmethyl)thio3-2H-pyran-2-one;
154-hydloxy-6-(4-hyd~y~lenyl)-3-
t(phenylmethyl)thio]-2H-pyran-2-one;
6-(2-Chlorophenyl)-4-hydLo~-3-
t(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[2-(3-methylbutyl)phenyl]-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-(hydroxymethyl)-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
t4-t4-Hydlûxy-5-(hyd~ohy-methyl)-2-oxo-3-[(2-
phenylethyl)thio~-2H-pyran-6-yl~ rh~Yy] acetic acid;
256-(3,5-Dimethylphenyl)-4-hydlo~y-5-methyl-3-[2-
phenyl-l-r(phenylmethyl)thio]ethyl]-2H-pyran-2-one;
4-Hydroxy-6-[4-(2-methoxyphenoxy)phenyl]-3-
[phenylr(phenylmethyl)thio]methyl]-2H-pyran-2-one;
[4-[3-r2-Cyclopentyl-l-(phenylmethoxy)ethyl~-4-
hydL~xy-2-oxo-2H-pyran-6-yl]phenoxy]acetic acid;
4-Hydroxy-6-[4-t(l-methylethoxy)methyl]-2-
thiazolyl~-2-oxo-3-~2-phenyl-l-
[t(phenylmethyl)thio]ethyl]-2H-pyran-2-one;
4-[4-Hydk~y-3-[l-(l-hyd~o~y-2-phenylethyl)-3-
methylpentyl]-2-oxo-2H-pyran-6-yl]benzenepropanoic
acid;
6-(3,5-Dimethylphenyl)-4-hydLoxy-3-[l-hydkoxy-2
methyl-l-(phenylmethyl)propyl]-2H-pyran-2-one;
WO95tl4014 PCT~S94/12367 ~
217412~
~ .~., c A ' h: -
- 12 -
6-t3-Fluoro-4-(3-pyridinylmethoxy)phenyl]-4-
hydloxy-3-[3-methyl-1-[(phenylmethyl)thio]butyl]-2H-
pyran-2-one;
[2-(Hyd~oxymethyl)-4-[4-hydroXy-3-[1-(1-
methylethoxy)-2-(phenylthio)ethyl]-2-oxo-2H-pyran-6-
yl]ph~noxy]acetic acid;
[4-t4-~dLoxy-3-[3-methyl-2-(phenylthio)butyl]-2-
oxo-2H-thiopyran-6-yl]phenoxy]acetic acid;
4-Hy~oxy-6-[(4-methoxyphenyl)methyl]-3-[[1-
(phenylmethyl)butyl]thio]-2H-pyran-2-one;
t2 IIydlGxy-4-[4-h~dloxy-2-oxo-3-[2-
(phenylmethylene)pentyl]-2H-pyran-6-yl]phenoxy]acetic
acid;
[[5-[2-Oxo-4-hydroxy-3-[(3-methyl-1-
phenylbutyl)thio]-2H-pyran-6-yl]-2-
pyridinyl~oxy]acetic acid;
4-HydL-,~y-6-[5-(r~eroxymethyl)-2-furanyl]-3-t2-
phenyl-1-[(phenylmethyl)thio]ethyl]-2H-pyran-2-one;
[4-t4-Hydroxy-2-oxo-3-[2-phenyl-1-[(phenyl-
methyl)amino]ethyl]-2H-pyran-6-yl]phenoxy]acetic
acid;
4-Hy~Gxy-3-[2-phenyl-1-tphenyl(phenyl-
methyl)amino]ethyl]-6-t4-(3-pyridinylmethoxy)phenyl]-
2H-pyran-2-one;
tt4-t4-Hy~lu~y-2-oxo-3-t(phenylmethyl)thio]-2H
pyran-6-yl]cyclohexyl]oxy]acetic acid;
Cis-6-(3,5-Dimethylphenyl)-4-h~d~ ~y-3 -t 3 -methyl-
1-[2, 3 -dihydro-1-hyd~oxy-lH-inden-2-yl)thio]butyl]-2H-
pyran-2-one;
4-Hydroxy-3-t(2-isopropylphenyl)thio]-6-phenyl~
2H-pyran-2-one;
4 ~Iydl GXy-3 - [ [ ( 2-methylpropyl)phenyl]thio]-6-
phenyl-2H-pyran-2-one;
3-[(2-Cyclo~opylmethyl)phenyl)thio]-4-hydroxy-6-
phenyl-2H-pyran-2-one;
4-Hy~loxy-3-t(2-is~Lu~ylphenyl)thio]-6-(2, 3-
dihydro-1,4-benzodioxin-6-yl)-2H-pyran-2-one;
WO9~/14014 ~ 7~2~ PCT~S94/1~67
- 13 -
3-~(2,5-Diis~o~ylphenyl)thio]-4-hyd~ox~-6-t(3-
phenyl)phenyl]-2H-pyran-2-one;
6-t4-(3-Furanylmethoxy)phenyl]-4-hydLox~-3-t3-
- methyl-l-t(phenylmethyl)thio]butyl]-2H-pyran-2-one;
56-t4-(Cyclohexylmethoxy)phenyl]-4-hy~Lo~y-3-t(2-
phenylethyl)thio]-2H-pyran-2-one;
4-Hyd~u~y-3-t(2-phenylethyl)thio]-6-t4-
(phenylsulfonyl)phenyl}-2H-pyran-2-one;
4-Hyd~y-3-t(2-phenylethyl)thio]-6-t4-
benzoyloxy)phenyl]-2H-pyran-2-one;
4-Hy~o~y-3-t(2-phenylethyl)thio]-6-t4
(phenylsulfinyl)phenyl]-2H-pyran-2-one;
4-~ydlGxy-3-t(2-phenylethyl)thio]-6-(4
pyridinyl)-2H-pyran-2-one;
153-tl,4-Bis(phenylthio)butyl]-4-hy& o~y-6-phenyl-
2H-pyran-2-one;
4-Hy~o~-6-phenyl-3-
tphenylt(phenylmethyl)thio]methyl]-2H-pyran-2-one;
4-Hydrox-y-3-tt(2-
methoxyphenyl)thio]phenylmethyl]-6-phenyl-
2H-pyran-2-one;
4-Hyd~o~y-3-t3-methyl-1-(phenylthio)butyl]-6-
phenyl-2H-pyran-2-one;
3-t2-Cyclohexyl-1-(phenylthio)ethyl]-4-hydl uxy-6-
phenyl-2H-pyran-2-one;
4-Hydloxy-6-(3-phenoxyphenyl)-3-t(2-
phenylethyl)thio]-2H-pyran-2-one;
4-Hyd~oxy-6-t3-methoxy-4-(phenylmethoxy)phenyl]-
3-t~2-phenylethyl)thio]-2H-pyran-2-one;
3 06- ( 3,5-Dimethylphenyl)-4-hydroxy-3-t(2-
phenylethyl)thio]-2H-pyran-2-one;
4-Hydrox-y-3-tt(3-methoxyphenyl)methyl]thio]-6-
phenyl-2H-pyran-2-one;
4-Hydroxy-3-t4-methyl-1-(phenylthio)pentyl]-6-
phenyl-2H-pyran-2-one;
4-Hydloxy-6-PhenYl-3~t[t3~
(phenylmethoxy)phenyl]methyl]thio]-2H-pyran-2-one;
WO95/14014 PCT~S94/12367 ~1
~1~4~
- 14 -
3-t(1,3-Benzodioxol-5-ylmethyl)thio]-4-h~dLu~y-6-
phenyl-2H-pyran-2-one;
4-Hyd~ vXy-3- t~(2-methoxyphenyl)methyl]thio]-6-
phenyl-2H-pyran-2-one;
4-Hy~lo~y-3-t[(2-methylphenyl)methyl]thio]-6-
phenyl-2H-pyran -2-one;
4-HydlGxy-3-[[(3-methylphenyl)methyl]thio]-6-
phenyl-2H-pyran-2-one;
4-HydLo~yy-3-tt(4-methylphenyl)methyl]thio]-6-
phenyl-2H-pyran-2-one;
6-[1,1~-Biphenyl]-3-yl-4-hy~o~y-3-t(2-
phenylethyl)thio]-2H-pyran-2-one;
4-Ey~loxy-3-t[(4-methoxyphenyl)methyl]thio]-6-
phenyl-2H-pyran-2-one;
3-[2-cyclohexyl-l-(cyclohexylthio)ethyl]-4
h~dlv~y-6-phenyl-2H-pyran-2-one;
3-[1-[(2,6-Dimethylphenyl)thio]-3-methylbutyl]-4-
h~dloxy-6-phenyl-2H-pyran-2-one;
3-[1-(Cyclohexylthio)-2-cyclo~Lo~-ylethyl]-4-
hydLv~y-6-phenyl-2H-pyran-2-one;
3-[1-t(2,6-Dichlorophenyl)thio]-3-methylbutyl]-4-
hy~loxy-6-phenyl-2H-pyran-2-one;
3-[1-Cyclohexylthio)-3,3-dimethylbutyl]-4-
hy~lvxy-6-phenyl-2H-pyran-2-one;
[4-t4 IIy~Lv~y-2-oxo-3-t(2-phenylethyl)thio]-
2H-pyran-6-yl]-2-methylph~noxy], acetic acid, ethyl
ester;
6-[3,5-Dimethyl-4-[[dimethyl(1,1-
dimethylethyl)silyl]oxy]phenyl]-4-hydroxy-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-t4-(4-
pyridinylmethoxy)phenyl]-2H-pyran-2-one;
3-[1-(Cyclopentylthio)-3-methylbutyl]-4-hyd~vxy-
6-phenyl-2H-pyran-2-one;
[4-[4-Ey~loxy-2-oxo-3[(2-phenylethyl)thio]-
2H-pyran-6-yl]-2-methylphenoxy acetic acid;
3-tl-(Cyclohexylthio)-2-(cyclopentyl)ethyl]-4-
hydlo~y-6-phenyl-2H-pyran-2-one;
~ WO95/14014 2 1 7 4 L ~4 PCT~S94~12367
4-HY'~1G~Y-6-(4-hy~G~y-3,5-dimethylphenyl)-3-
t(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[[~3-(2-
phenylethoxy)phenyl]methyl]thio]-2H-pyran-2-one;
4-Hy~lo~y-6-[4-(2-phenylethynyl)phenyl]-3-[(2-
phenylethyl)thio]-2H-pyran-2-one;
4-H~dloxy--6-[4-(2-phenylethyl)phenyl]-3-[(2-
phenylethyl)thio]-2H-pyran-2-one;
3-[(Cyclohexylthio)phenylmethyl]-4-1~yd~o~y-6-
phenyl-2H-pyran-2-one;
4 I1Y~L~Y-_3_~(phenylmethyl)thio]-6-~3-
(trifluoromethoxy)phenyl]-2H-pyran-2-one;
3-t(Cyclohexylmethyl)thio]-4-hy~Loxy-6-phenyl-2H-
pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[3-methyl-4-
(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
6-(2,3-DihydLO l,4-benzodioxin-6-yl)-4-hydL~y-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
4-~ydloxy-3-[(2-phenylethyl)thio]-6-[3-
(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(phenylmethyl)thio]-6-[3-
(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-~ydloxy-3-[(phenylmethyl)thio]-6-(2,3,4-
trimethoxyphenyl)-2H-pyran-2-one;
N-[4-[4-IIydL~-2-oxo-3-[(2-phenylethyl)thio]-2H
pyran-6-yl]phenyl]benzenesulfonamide;
6-[4-[(3,5-Dimethyl-4-isoxazolyl)methoxy]phenyl]-
4-hydLoxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
3-t(Cyclohexylthio)phenylmethyl]-4 hyd~ GXy -6-[3-
methyl-4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
2-[[(4-HydLoxy-2-oxo-6-phenyl-2H-pyran-3-
yl)thio]methyl]-benzoic acid methyl ester;
3-[l-(Cyclohexylthio)-3-methylbutyl]-6-(2,3-
dihydro-l,4-benzodioxin-6-yl)4-hydL~y-2H-pyran-2-one;
2-[[4-(4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-
2H-pyran-6-yl]phenoxy]methyl-benzoic acid methyl
ester;
WO 95/14014 PCT/US94/12367 ~
21741~4 - 16 ~
4-HydlGxy-3-~(2-phenylethyl)thio]-6-[4-(lH-
tetrazol-5-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydlu~y-6-~3 -methyl-4-(2-
pyridinylmethoxy)phenyl]-3 ~ t ( 2-phenylethyl)thio]-2H-
pyran-2-one;
3 - [ 2-CyclG~Lopyl-1-t(phenylmethyl)thio]ethyl]-4-
l~y~Lo~y-6-phenyl-2H-pyran-2-one;
4-Hyd~ O~y~3 ~ [ 1- t(2-methoxyphenyl)thio]-3-
methylbutyl]-6-phenyl-2H-pyran-2-one;
104 ~IydLo~y-3-~ (phenylmethyl)thio]-3-
methylbutyl]-6-phenyl-2H-pyran-2-one;
4-tt4-Hyd~o~y-2-oxo-3-[(2-phenylethyl)thio]-2H
pyran-6-yl]ph~noYy]methyl]benzoic acid methyl ester;
3-~t4-[4-~d~u~y-2-oxo-3-[(2-phenylethyl)thio]-
2H-pyran-6-yl]ph~oxy]methyl]benzoic acid methyl
ester;
6-[4-[(3,4-Dichlorophenyl)methoxy]phenyl]-4-
hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
3-[[(4-Hy~ko~y-2-oxo-6-phenyl-2H-pyran-3-
yl)thio]methyl]benzoic acid methyl ester;
4-[[(4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-
yl)thio]methyl]benzoic acid methyl ester;
6-[3,5-Bis(trifluoromethyl)phenyl]-4-h~Lo~y-3-
[(phenylmethyl)thio]-2H-pyran-2-one;
253-[1-(Cyclohexylthio)-3-methylbutyl]-4-hydroxy-6-
phenyl-2H-pyran-2-one;
[4-[4-Hyd~o~y-2-oxo-3-[(2-phenylethyl)thio]-2H-
pyran-6-yl]phenoxy]acetonitrile;
6-Phenyl-4-hy~ Gxy-3-[(cyclo~lo~ylmethyl)thio]-
2H-pyran-2-one;
6-(3-Chlorophenyl)-4-hydroxy-3-[(4-
phenylbutyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-hydroxy-2-phenylethyl)thio]-6-
phenyl-2H-pyran-2-one;
356-Phenyl-4-hydroxy-5-methyl-3-(phenylthio)-2H-
pyran-2-one;
t4-t4-Hydroxy-2-oxo-3-(phenylthio)-2H-pyran-6-
yl ] ph~no~y ] acetic acid;
WO95/14014 ~ ~ 7 4 1 2 ~ PCT~S94112367
- 17 -
[4-[4-Hydlo~y-5-methyl-2-oxo-3-(phenylthio)-2H-
pyran-6-yl]phP~oYy]acetic acid;
4-Hydroxy-3-t(phenylmethyl)thio]-6-(3-pyridinyl)-
- 2H-pyran-2-one;
56-(2,6-Dimethyl-4-pyridinyl)-4-hydroxy-3-
(phenylmethyl)thio]-2H-pyran-2-one;
4-~y~lo~y-3-t(phenylmethyl)thio]-6-(3-thienyl)
2H-pyran-2-one;
4-~y~lGxy-3-t(2-isopropylphenyl)thio]-6-tl-(2-
methylpropyl)cyclopentyl]-2H-pyran-2-one;
4-HydLo~y-3-[(2-isG~Lopylphenyl)thio]-6-[l-(3
methylbutyl)cyclopentyl]-2H-pyran-2-one;
4-HydLoxy-3-[(2-iso~l~ylphenyl)thio]-6-[l-(4-
methylpentyl)cyclopentyl]-2H-pyran-2-one;
lS4-~y~r~y-3~t(2 -iSv~l O~y lphenyl)thio]-6-tl-
(phenylmethyl)cyclopentyl]-2H-pyran-2-one;
4 IIy~o~y-3-[(2 -iSO~l ~ylphenyl)thio]-6-tl-(2-
phenylethyl)cyclopentyl]-2H-pyran-2-one;
4-HydLoxy-3-t(2-iso~Lu~ylphenyl)thio]-6-tl- (3-
phenylpropyl)cyclopentyl]-2H-pyran-2-one;
4-~ydL~xy-3-[(2 -iSO~l o~ylphenyl)thio]-6-tl-(2-
methylpropyl) CyClG~ ]-2H-pyran-2-one;
4-Hyd~oxy-3-t(2 -iSGp r ~y lphenyl)thio]-6-tl-(3-
methylbutyl)cyclo~y-l]-2H-pyran-2-one;
254-Hydroxy-3-t(2-iso~Lo~ylphenyl)thio]-6-tl-(4
methylpentyl)cyclopropyl]-2H-pyran-2-one;
4-HydLoxy-3-[(2-isopropylphenyl)thio]-6-tl-
(phenylmethyl)cyclo~o~yl]-2H-pyran-2-one;
4-Hyd~o~y-3-t(2-isc,~Lo~ylphenyl)thio]-6--tl-(2-
phenylethyl)cyclopropyl]-2H-pyran-2-one;
4-Hyd~oxy-3-[(2-isopropylphenyl)thio]-6-[l-(3
phenylpropyl)cyclopropyl]-2H-pyran-2-one;
4-Hydluxy-6-(3-hydLuxy~henyl)-3-t(2-
iso~lo~ylphenyl)thio]-2H-pyran-2-one;
354-Hydroxy-3-[(2-isopropylphenyl]thio]-6-(pyridin-
4-yl)-2H-pyran-2-one;
4-Hyd~o~y-3-[(2-iso~lo~ylphenyl)thio]-6-(pyridin-
2-yl)-2H-pyrân-2 -one;
WO9S/14014 ~ 1 7 ~ 1 2 ~ PCT~Ss
- 18 -
4 ,.ydluxy-3-t(2-isopropylphenyl)thio]-6-(4
nitrophenyl)-2H-pyran-2-one;
6-(4-Fluorophenyl)-4-hy~uxy-3-t(2-
iso~v~ylphenyl)thio]-2H-pyran-2-one;
S4-Hydroxy-3-t(2-isopropylphenyl)thio]-6-(2-
methylphenyl)-2H-pyran-2-one;
4-Hydl~xy-3-[(2-iso~lo~ylphenyl)thio]-6-(2
methoxyphenyl)-2H-pyran-2-one;
6-(2-Chlorophenyl)-4-hydroxy-3-[(2-
isu~u~lphenyl)thio]-2H-pyran-2-one;
4 -~y ~L oAy-3 - ~ ( 2-iso~u~ylphenyl)thio]-6-t4-(N,N-
dimethylamino)phenyl]-2H-pyran-2-one;
4-Hyd~oxy-3-t(2-iso~Lu~ylphenyl)thio]-6-(3-
trifluoromethylphenyl)-2H-pyran-2-one;
154 II~dLo~y-3-[(2-isu~u~ylphenyl)thio]-6-[4-(l-
naphthalenylmethyloxy)phenyl]-2H-pyran-2-one;
4-IIydlo~-3-[(2-iso~Lo~ylphenyl)thio]-6-t4-t2-
(morpholin-4-yl)ethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2-iso~o~ylphenyl)thio]-6-[3-[2-
(morpholin-4-yl)ethoxy)phenyl]-2H-pyran-2-one;
6-(4-Benzyloxy-3-methoxyphenyl)-4-hydroxy-3-[(2-
isopropylphenyl)thio]-2H-pyran-2-one;
6-(4-Benzyloxy-3-chlorophenyl)-4-hydloxy-3-t(2-
is~u~ylphenyl)thio]-2H-pyran-2-one;
254-t4-~ydLo~y-2-ûxo-3-t(2-isu~L~ylphenyl)thio]
2H-pyran-6-yl]-2-methylph~no~y-acetic acid;
4-Hydroxy-6-[4-(2-hy~roxyethox-y)phenyl]-3-t(2-
isopropylphenyl)thio]-2H-pyran-2-one;
2-t3-[4-Hydroxy-5-[(2-iso~lv~ylphenyl)thio]-6-
oxo-6H-pyran-2-yl]phenoxy]acetamide;
4-HydLoxy-3-[(2-iso~Lv~ylphenyl)thio]-6-[4-(2,3-
pyrazinemethoxy)phenyl]-2H-pyran-2-one;
4-Hyd~oxy-3 - t ( 2-isopropylphenyl)thio]-6-[4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
354-Hyd~oxy-3-t(2-isop~o~ylphenyl)thio]-6-[4-
(pyridin-2-ylmethoxy)-3-methylphenyl]-2H-pyran-2-one;
4-~d~ u~y-3- [ ( 2-iso~Lo~ylphenyl)thio]-6-[4-
(pyridin-4-ylmethoxy)phenyl]-2H-pyran-2-one;
~ WO 9Stl4014 PCT/US94/12367
~17412~
-- 19 --
3-~(2-Cyclopropylphenyl)thio]-4-hy~Lo~y-6-[4
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2,5-diisopropylphenyl)thio]-6-[4-
(pyridin 3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2-iso~ro~lphenyl)thio]-6-t4-t2-
(thiomorpholin-4-yl)ethoxy]phenyl]-2H-pyran-2-one;
.,
4-Hydroxy-3-t(2-isG~ o~ylphenyl)thio]-6-~4-t2-
(piperazin-l-yl)ethoxy]phenyl]-2H-pyran-2-one;
4-HYdL u~y-3 ~ t ( 2-isu~o~ylphenyl)thio]-6-t4-t2-
(methylpiperazin-1-yl)ethoxy]phenyl]-2H-pyran-2-one;
4 IIy~oxy-3-t(2-isG~Lo~ylphenyl)thio]-6-t4-t2-
(1,1-dioxothiomorpholin-4-yl)ethoxy~phenyl]-2H-pyran-
2-one;
4-Hy~kuxy-3-t(2-isoy~o~ylphenyl)thio]-6-(l-
phenyl-cyclopentyl)-2H-pyran-2-one;
4-Hydroxy-3-t(2-isu~Lo~ylphenyl)thio]-6-(4
phenyl-piperidin-4-yl)-2H-pyran-2-one;
Isopentanoic acid 2-oxo-6-phenyl-3-t(2-
isopropylphenyl)thio]-2H-pyran-2-one-4-ylester;
Propanoic acid 2-oxo-6-phenyl-3-t(2-
isopropylphenyl)thio]-2H-pyran-2-one-4-ylester;
.Phenylacetic acid 2-oxo-6-phenyl-3-t(2-
iso~o~ylphenyl)thio]-2H-pyran-2-one-4-ylester;
4 IIydLoxy-3-t(2-iso~Lu~yl-5-methylphenyl)thio]-6-
phenyl-2H-pyran-2-one;
4-~yd~O~y-3-t(2-isu~ u~yl-4-methylphenyl)thio]-6-
phenyl-2H-pyran-2-one;
4-Hydroxy-3-t(2-isG~Lo~yl-6-methylphenyl)thio]-6-
phenyl-2H-pyran-2-one;
3-[(4-Chloro-2-iso~Lu~ylphenyl)thio]-4-hydroxy-6-
phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(4-hydroxy-2-iso~lu~ylphenyl)thio]-
6-phenyl-2H-pyran-2-one;
3-t(2-Cyclopropylphenyl)thio]-4-hydroxy-6-phenyl-
2H-pyran-2-one;
3-[(2~5-Diisopropylphenyl)thio]-4-hydroxy-6-
phenyl-2H-pyran-2-one;
WO95/14014 ~ PCT~S94112367 ~
i
- 20 -
4 -HY~L oxy-6-phenyl-3-[(2-tert-butylphenyl)thio]-
2H-pyran-2-one;
3-[(2-Cyclo~Lu~yl-5-isG~v~ylphenyl)thio]-4-
hydLoxyy-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclopentyl-5-iso~Lu~ylphenyl)thio~-4-
1~dL oxy-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclohexyl-5-isv~Lo~ylphenyl)thio]-4-
hY~L ~y-6-phenyl-2H-pyran-2-one;
4-~y~Lv~y-6-phenyl-3-[(2-tert-butyl-5-
isu~Lu~ylphenyl)thio]-2H-pyran-2-one;
3-[(2,5-Di-tert-butylphenyl)thio]-4-1,~Lo~y-6-
phenyl-2H-pyran-2-one;
3-~(2-Cyclopentylphenyl)thio]-4-~ o~y-6-phenyl-
2H-pyran-2-one;
3-~(2-Cyclohexylphenyl)thio]-4-hyd~o~y-6-phenyl-
2H-pyran-2-one;
4 ~ [ t4 IIy~lo~y-2-oxo-6-phenyl-2H-pyran-3-yl]thio]-
2-hydroxy; n~An~;
4-Hydroxy-3-[[2-isop~o~yl-4-(morpholin-4-
ylmethyl)phenyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hy& oxy-3-[(6-iso~Lopyl-indan-5-yl)thio]-6-
phenyl-2H-pyran-2-one;
4-Hy~oxy-3-[(4-iso~Lu~yl-benzo[l,3]dioxol-5-
yl)thio]-6-phenyl-2H-pyran-2-one;
3-[(2-tert-Butyl-4-thiomorpholin-4-
ylmethylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-
one;
4-Hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-3-
[(2-tert-butylphenyl)thio]-2H-pyran-2-one;
3-t~(2-Cyclopropyl-5-isoplopyl)phenyl]thio]-4-
hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-
one;
3-[[(2-Cyclopentyl-5-iso~Lo~yl)phenyl]thio]-4-
hYdL ~y-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-
one;
3-[[(2-Cyclohexyl-5-iso~Lu~l)phenyl]thio]-4-
hyd~oxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-
one;
WO95/14014 ~1~ 4 1 2 ~ PCT~S94tl~67
- 21 -
4-~Iy~loxy-6-t4-(pyridin-3-ylmethoxy)phenyl]-3-
t(2 tert-butyl-5-is~L~ylphenyl)thio]-2H-pyran-2-one;
3-t(2,5-Di-tert-butylphenyl)thio]-4-hydroxy-6-[4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
53-t(2-Cyclopentylphenyl)thio]-4-hyd~x~-6-[4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-t(2-Cyclohexylphenyl)thio]-4-hy~ro~-6-t4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4 IIy~L~y-6-t4-(pyridin-3-ylmethoxy-)phenyl]-3
t(6-tert-butylindan-S-yl)thio]-2H-pyran-2-one;
4 IIydko~y-3-t(2-isopropyl-4-morpholin-4-ylmethyl-
phenyl)thio]-6-~4-(pyrindin-3-ylmethoxy)phenyl]-2H-
pyran-2-one;
Acetic acid 3-t(2-iso~L~ylphenyl)thio]-2-oxo-6-
lS t4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-ylester;
Isobutyric acid 3-t(2-iso~op~lphenyl)thio]-2-
oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-
ylester;
2,2-Dimethylpropionic acid 3-[(2-
isopropylphenyl)thio]-2-oxo-6-[4-(pyridin-3-
ylmethoxy)phenyl]-2H-pyran-4-ylester;
4-~y~lo~y-3-[(2-isopropylphenyl)sulfonyl]-6-[4
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4 IIy-dLoxy-3-(2-iso~Lopylbenzoyl)-6-[4-(pyridin-3
ylmethoxy)phenyl]-2H-pyran-2-one;
3-[(2-tert-Butylphenyl)sulfonyl]-4-hy~l~y-6
phenyl-2H-pyran-2-one;
6-(l-Benzylpropyl)-4-hyd~y-3-[(2-
iso~L ~ylphenyl)sulfonyl]-2H-pyran-2-one;
306-(l-Benzylpropyl)-4-hydroxy-3-[(2-
isopropylphenyl)thio~-2H-pyran-2-one;
6-(l-Benzylpropyl)-3-[(2-tert-butylphenyl)thio]-
4-hyd~G~y-2H-pyran-2-one;
N-[3-[[6-(l-Benzylpropyl)-4-hy~oxy-2-oxo-2H-
pyran-3-yl]thio]-2-iso~o~ylphenyl]
benzenesulfonamide;
WO9Stl4014 7~ 1~4; i PCT~Ss4/12367 ~
- 22 -
6-tl-Cycl~lo~ylmethyl-2-(tetrahyd~o pyran-3-
yl)ethyl]-4-hy~Loxy-3-[(2-iso~Lu~ylphenyl)thio]-2H-
pyran-2-one;
4-~ydlo~y-3-(2-iso~ yl-rh~no~y)-6-t4-(pyridin-
3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-HydLGky-3-(2-iso~Lv~yl-rh~noxy)-6-phenyl-2H
pyran-2-one;
3-(2-tert-8utyl-ph~nQxy)-4-hydLo~y-6-~4-(pyridin-
3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-(2-tert-Butyl-5-methyl-rh~noYy)-4-hydLu~y-6-t4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
6-(1-Benzylplo~1)-4 1LY~1 O~Y_3_(2_
isG~l u~yl ph~noYy) -2H-pyran-2-one;
6-(1-Benzylpropyl)-3-(2-tert-butylphenoxy)-4-
hyd~G~y-2H-pyran-2-one;
- 3-Benzyloxy-4-Hyd~u~y-6-~4-(pyridin-3-
ylmethoxy)phenyl]-2H-pyran-2-one;
2-t4-HydlO~y-2-o~O G t4-(py-ridin-3-
ylmethoxy)phenyl]-2H-pyran-3-yloxy-methyl]benzoic acid
methyl ester;
2-[t[6-(1-Benzylpropyl)-4-hydroxy-2-oxo-2H-pyran-
3-yl]oxy]methyl] benzoic acid ethyl ester;
6-(1-Benzylpropyl)-4-h~dlo~y-3-(1-phenylbutoxy)-
2H-pyran-2-one;
6-(1-8enzyl~ u~yl) -3-(cyclo~Lu~ylphenylamino)-4-
hydroxy-2H-pyran-2-one;
N-t3-[[6-(l-Benzylpropyl)-4-hydLuxy-2-oxo-2H-
pyran-3-yl] CYC1O~L u~ylamino]phenyl]benzenesulfonamide;
3-[Cyclo~lu~ylphenylamino]-4-hydroxy-6-(pyridin-
3-ylmethoxy)-2H-pyran-2-one;
3-(Bis-cyclopentylmethyl-amino)-4-hydroxy-6-
(pyridin-3-ylmethoxy)-2H-pyran-2-one;
3-[Cyclo~ell~ylmethyl(cyclo~ u~ylmethyl)amino]-4-
hydlo~y-6-(pyridin-3-ylmethoxy)-2H-pyran-2-one;
6-[l-cyclo~Lu~ylmethyl-2-(tetrallydLo pyran-3-
yl)ethyl]-3-(cyclo~lo~ylphenylamino)-4-hyd~o~y-2H-
pyran-2-one;
~ Wos5/I4014 PCT~S94/1~67
~:~7~12~
- 23 -
CyclopropA~r~rboxylic acid cyclopentylmethyl-[4-
hydLo~y-2-oxo-6-[(pyridin-3-ylmethoxy)phenyl]-2H-
pyran-3-yl]amide;
CyclopentAn~c~rboxylic acid cyclo~ellLylmethyl-[4-
h~dlox~-2-oxo-6-t4-(pyridin-3-ylmethoxy)phenyl]-2H-
pyran-3-yl]amide;
N-Cyclo~ ylmethyl-N-[4-hydLoxy-2-oxo-6-~4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]
cyclopentanesulfonamide;
3-(Cyclv~L~ylphenylmethyl)-4-hyd~v~y-6-[4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
N - [3 - [CYC1V~LV~1[4 - hydlU~ - 2 ~AO G [4-(pyridin-
3-ylmethoxy)phenyl]-2H-pyran-3-
yl]methyl]phenyl]benzenc~l f onamide;
4 ~Iy~Loxy-3-(1-phenylpropyl)-6-[4-(pyridin-3-
ylmethoxy)phenyl]-2H-pyran-2-one;
6-(1,1-Dimethyl-3-phenylpropyl)-4-hyd~o~y-3-[(2-
iso~Lo~ylphenyl)thio]-2H-pyran-2-one;
N-[3-t CYC1G~, o~yl[6-(1,1-dimethyl-3-
phenylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-[3-[Cyclo~l v~yl [ 4-hy~Yoxy-2 o~o G-[1-(2-
phenylethyl)cyclopentyl]-2H-pyran-3-yl]methyl]phenyl]-
benzenesulfonamide;
3-(Cyclo~lv~ylphenylmethyl)-6-(1,1-dimethyl-3-
phenylpropyl)-4-hy~lo~y-2H-pyran-2-one;
N-[3-[~6-(1-Benzylcyclo~v~yl)-4-hydroxy-2-oxo-
2H-pyran-3-yl]cycl~ o~ylmethyl]phenyl]-
benzenesulfonamide;
6-(1-Benzylpropyl)-4-hydroxy-3-(2-isobutyl-5-
isopropylphenyl)-2H-pyran-2-one;
6-(1-Benzylpropyl)-4-hyd~vxy-3-(2-methyl-5,6,7,8-
tetr~lyd~o naphthalen-l-yl)-2H-pyran-2-one;
3-(3-Cyclopropylmethyl-5-iso~lv~ylphenyl)-4-
hy~lox~-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2
one;
3-(3,5-Diiso~lv~lphenyl)-4-hydroxy-6-t4-
(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one
WOgS/14014 PCT~S94112367 ~
,
- 24 -
6-(Benzo[l,3]-dioxol-5-yl)-4-hydroxy-3-[(2-
iso~Lu~y~lphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-t(2-isop~o~ylphenyl)thio]-6-~l-
(phenylmethyl)cyclobutyl]-2H-pyran-2-one;
4-Hyd~oxy-3-t(2-is~lo~ylphenyl)thio]-6-[l-(2-
phenylethyl)cyclobutyl]-2H-pyran-2-one;
4-Hy~luxy-3-t(2-isopLu~ylphenyl)thio]-6-[l-( 3 ~
phenyl~o~y~l)cyclobutyl]-2H-pyran-2-one;
4-HydL vXy-3~ [ ( 2-iso~Lopyl-5-methylphenyl)thio]-6-
(l-benzylcyclu~u~yl)-2H-py~an-2-one;
4-Hy~o~y-3-~(2-iso~L~l-5-methylpheny1)thio]-6-
tl-(2-phenylethyl)cyclu~L u~yyl ] -2H-pyran-2-one;
4 IIyd~uxy-3-t(2-iso~Lo~yl-5-methylphenyl)thio]-6-
~l-(3-phenyl~Lo~y.l)cyclo~ u~yl ] -2H-pyran-2-one;
4 IIy~loxy-3-t(2-iso~Lopyl-5-methylphenyl)thio]-6-
(l-benzylcyclobutyl)-2H-pyran-2-one;
4-Hyd~uxy-3-t(2 -iSG~ o~yl-5-methylphenyl)thio]-6-
tl-(2-phenylethyl)cyclobutyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2-iso~Lo~yl-5-methylphenyl)thio]-6-
[l-(3-phenylpropyl)cyclobutyl]-2H-pyran-2-one;
4-~y~l~xy-3-t(2-isopLu~yl-5-methylphenyl)thio]-6-
(l-benzylcyclopentyl)-2H-pyran-2-one;
4-Hydko~y-3-[(2-iso~Lu~yl-5-methylphenyl)thio]-6-
tl-(2-phenylethyl)cyclopentyl]-2H-pyran-2-one;
4-Hydlo~-3-t(2-isû~o~yl-5-methylphenyl)thio]-6-
[l-(3-phenylpropyl)cyclopentyl]-2H-pyran-2-one;
6-(l,l-Dimethyl-3-phenylpropyl)-4-hydluxy-3-t(2-
iso~L~ylphenyl)thio]-2H ~yLan-2-one;
6-(l~l-Dimethyl-2-phenylethyl)-4-hydroxy-3-[(2
iso~L~ylphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(l-
methyl-l-phenylethyl)-2H-pyran-2-one;
6-(l,l-Diethyl-3-phenylpropyl)-4-hydroxy-3-t(2-
iso~lo~ylphenyl)thio]-2H-pyran-2-one;
3s 6-(l-Benzyl-l-èthylpropyl)-4-hydroxy-3-t(2-
isoy~ylphenyl)thio]-2H-pyran-2-one;
6-(l-Ethyl-l-phenylpropyl)-4-hydroxy-3-[(2-
isu~Lu~ylphenyl)thio]-2H-pyran-2-one;
WO95/14014 ~ 4 ~ ~ 4 PCT~Ss4/1~67
- 25 -
N-[3-tCyclo~u~lt6-(l,l-dimethyl-3-
phenylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-t3-tCyclv~.o~ylt6-(1,1-dimethyl-2-phenylethyl)-
4-h~dlo~r-2-oxo-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-[3-tCyclo~.o~ylt4-hydroxy-6-(1-methyl-1-
phenylethyl)-2-oxo-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-t3-tCyclv~.v~ylt6-(~ diethyl-3-phenylpropyl)-
4-hy~.~y-2-oxo-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-[3-tCyclo~v~yl[6-tl-ethyl-l-
(phenylmethyl)propyl]-4-hy~Lu~y-2-oxo-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-t3-tCyclo~Lo~lt6-(1-ethyl-1-phenylpropyl)-4-
hydroxy-2-oxo-2H-pyran-3-
yl]methyl]phenyl~benzenesulfonamide;
N-t3-[Cyclo~ylt4-hydLo~-2-oxo-6-tl-(2-
phenylethyl)cyclopentyl]-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-t3-tt6-(1-Benzylcyclopentyl)-4 hydlu~y-2-oxo-
2H-pyran 3-
yl]cycl~v~ylmethyl]phenyl]benzenesulfonamide;
N-t3-tCyc 1V~L V~Y 1 t4-l~y~.o~-2-oxo-6-tl-(3-
phenylpropyl)cyclopentyl]-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-[3-[Cyclo~Lu~lt4-h~d~o~-2-oxo-6-[l-(2-
phenylethyl)cyclobutyl]-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
N-[3-tt6-(1-Benzylcyclobutyl)-4-hyd~v~y-2-oxo-2H-
pyran-3-
yl]cyclo~.o~yl]methyl]phenyl]benzenesulfonamide;
N-[3-[cyclo~lo~l[4-hydroxy-2-oxo-6-tl-(3
phenylpropyl)cyclobutyl]-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
W095/14014 ~ ~ 4 PCT~S94/12367
- 26 -
N-~3-~Cyclu~.o~ylt4-1~yd~v~y-2 - oxo-6- [ 1 - (2-
phenylethyl)cyclo~lu~yl]-2H-pyran-3-
yl~methyl]phenyl]benzenesulfonamide;
N-~3-[[6-(l-BenzylcyclG~lv~yl)-4-hyd~o~y-2-oxo-
2H-pyran-3-
yl]cyclu~u~y-lmethyl]phenyl]benzenesulfonamide;
N-[3-[Cyclo~ r u~yl~ 4-hy ~LV~y -2 oxo ~ (3-
phenylpropyl)cyclo~lu~yl]-2H-pyran-3-
yl]methyl]phenyl]benzenesulfonamide;
103-(Cyclo~Lv~ylphenylmethyl)-6-(1,1-dimethyl-3-
phenylpropyl)-4 hy~lu~y-2H-pyran-2-one;
3-(Cyclu~u~ylphenylmethyl)-6-(l,l-dimethyl-2-
phenylethyl)-4-hyd~u~y-2H-pyran-2-one;
3-(cyclf~Lu~ylphenylmethYl) -4 1~Y~1L~Y-6- (l-
methyl-l-phenylethyl)-2H-pyran-2-one;
3-(cyclo~Lù~ylphenylmethyl)-6- ( 1 ~ l-diethyl-3-
phenylpropyl) -4-hy~L uxy-2H-pyran-2-one;
6- (l-Benzyl-l-ethylpropyl)-3-
(cyclG~Lu~lphenylmethyl)-4-hydroxy-2H-pyran-2-one and
203-(Cyclo~Lv~ylphenylmethyl)-6-[l-ethyl-l-
phenylpropyl~-4-hy~Lo~y-2H-pyran-2-one.
4. ~ TT.~n n~pTpTIoN OF T~ INVENTION
Here, the term "alkyl", usually represented by an
"R", means a straight or br~n~h~ dlGcarbon radical
having from l to 12 carbon atoms unless otherwise
specified and includes, for example, methyl, ethyl, n-
~,u~yl, iso~-u~yl, n-butyl, sec-butyl, isobutyl, tert-
butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,
n-decyl, undecyl, and dodecyl. The alkyl ~,uu~ may
contain one or more sites of unsaturation such as
double or triple carbon-carbon bonds. The alkyl group
is unsubstituted or substituted by from l to 3
substituents selected from alkyl, alkoxy, thioalkoxy
all as defined herein, hydroxy, thiol, nitro, halogen,
amino, formyl, carboxyl, nitrile, -N~-CO-R, -CO-NH-, -
CO2R, -COR, aryl, or heteroaryl wherein alkyl (R),
aryl, and heteroaryl are defined as herein.
~ WO95/14014 PCT~S94/1~67
24
- 27 -
The term "cycloalkyl", also represented by an
"R", means a hydlo~arbon ring which contains from 3 to
12 carbon atoms unless otherwise specified, for
example, cyclo~lo~yl~ cyclobutyl, cyclopentyl,
S cyclohexyl, and adamantyl. Where possible, the
cycloalkyl group may contain a single double bond.
The cycloalkyl ring may be unsubstituted or
substituted by from 1 to 3 substituents selected
alkyl, alkoxy, thioAlkoYy all as defined herein,
~ O~y~ thiol, nitro, halogen, amino, formyl,
carboxyl, nitrile, -NH-CO-R, -CO-NHR-, -CO2R, -COR,
aryl, or ~eteroaryl wherein alkyl (R), aryl, and
heteroaryl are defined as herein.
The terms "alkoxy" and '~thio~lkoxy~ are O-alkyl
lS or S-alkyl as defined above for alkyl.
The term alkylcycloalkyl means a cycloalkyl
attached to an alkyl chain where the terms cycloalkyl
and alkyl are defined above.
The term spirocycle refers to a carbocyclic or
heterocyclic ring whose ends meet at a single carbo~
in a ring or chain. Examples of such spirocycles are
ring A in the following:
~O ~O ~ A~
~,S/-\Ph ~ \Ph
~ o~`O or ~ ~,
A
\N~
The term "aryl" means an aromatic radical which
is a phenyl group, a benzyl group, a naphthyl group, a
biphenyl 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- membered ring
con~; n; ng from 0 to 3 heteroatoms selected from
wogs/14014 ~ 7 ~ PCT~S94/12367 ~
s ,.
- 28 -
quinolones, isoquinolones, indoles, in~e
benzofurans, benzothiorhenec, benzoxazoles,
benzothiazoles, benz; ~OF~ 7oles, coumarins,
benzimidazoles and the like, unsubstituted or
s substituted by 1 to 3 substituents selected from alkyl
as defined above, alkoxy as defined above, thioalkoxy
as defined above, hydlo~, thiol, nitro, halogen,
amino, formyl, carboxy, nitrile, -NHCOR, -CONHR, -CO2R,
-COR, aryl, or heteroaryl wherein alkyl (R), aryl, and
heteroaryl are defined as above.
The terms "heteroaryl" and "hetelG~y~le", llCll~l ly
represented by an "A", mean a heteroatom con~; n i ng
ring radical which is 2- or 3-thienyl, 2- or 3-
furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-
, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-,
or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or
s-;~Y~olyl, 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-, 5-, 6-, 7-, or 8-quinolinyl,
1-, 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, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl,
2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-,
or 7-benzothiazolyl, 1- or 2- piperazinyl, 2-, 3-, or
4-morpholinyl, 2-, 3-, or 4-thiomorpholinyl, 1-, 2-,
or 3-pyrrolidinyl, 2- or 3-tetrahydofuranyl, 1-, 2-,
-, 4-, 5-, 6-, 7- or 8-tetrahydroquinolinyl, and the
like, all of which may be unsubstituted or substitut.ed
by 1 to 2 substituents selected from alkyl as defined
above, aryl as defined above, alkoxy as defined above,
thioalkoxy as defined above, hydroxy, thiol, nitro,
halogen, formyl, amino, carboxyl, nitrile, -NHCOR,
-CO2R, -COR, wherein alkyl in as defined above or
phenyl.
"Halogen" is fluorine, chlorine, bromine or
~odine.
-
WO9S/14014 PCT~S94/1~67
~17~12~
- 29 -
Some of the compounds of Formula 1 are capable of
further forming pharmaceutically acceptable acid-
addition and/or base salts. All of these forms are
within the scope of the present invention.
S Pharmaceutically acceptable acid addition salts
; of the compounds of Formula 1 include salts derived
from nontoxic inorganic acids such as hydrochloric,
nitric, phosphoric, sulfuric, hydrobromic, hydriodic,
hydrofluoric, phosphorous, and the like, as well as
the salts derived from nontoxic organic acids, such as
aliphatic mono- and dicalbo~lic acids, phenyl-
substituted A 1 kAnoic acids, hydl~y A 1kAnoic acids,
alkA~; oic acids, aromatic acids, aliphatic and
aromatic sulfonic acids, etc. Such salts thus include
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,
nitrate, phosphate, monohydloypnphosphate~
dihydLGyenphosphate, metaphosphate, pyrophosphate,
chloride, bromide, iodide, acetate, trifluoroacetate,
propionate, caprylate, iso~uLyLdte, oxalate, malonate,
succinates suberate, sebacate, fumarate, maleate,
mandelate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, phthalate, benzensoulfonate,
toluenesulfonate, phenylacetate, citrate, lactate,
maleate, tartrate, methanesulfonate, and the like.
Also contemplated are salts of amino acids such as
arginate and the like and gluconate, galacturonate
(see, for example, Berge, S.M., et al.,
"Pharmaceutical Salts,~' Journal of Pharmaceutical
Science, 66: 1-19 ( 1977 ) .
The acid addition salt of said basic compounds
are prepared by contacting the free base form with a
sufficient amount of the desired acid to produce the
salt in the conventional manner.
Pharmaceutically acceptable base addition salts
are formed with metals or amines, such as alkali and
alkaline earth metals or organic amines. Examples of
metals used as cations are sodium, potassium,
mag~esiU~ ~al~ium, and the like. ~xamples of
W09Stl4014 ~ 24 PCT~S94/1~67 ~
- 30 -
suitable amines are N,N'-~;h~n7-ylethylenediamine,
chlo~ u~2 ocaine, choline, diethanolamine,
dicyclohexylamine, ethylenediamine, N-methylglucamine,
and procA;ne (see, for example, Berge, S.M., et al.,
"Pharmaceutical Salts," Journal of Pharmaceutical
Science, 66: 1-19 (1977).
The base addition salts of said acidic compounds
are prepared by contacting the free acid form with a
sufficient amount of the desired base to produce the
salt in the conventional manner.
Certain of the compounds of the present invention
can exist in unsolvated forms as well as solvated
forms, including hydrated forms. In general, the
solvated forms, including hydrated forms, are
equivalent to unsolvated forms and are int~n~ to be
encomp~se~ within the scope of the present invention.
Certain of the compounds 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 includes all enantiomeric and epimeric forms
as well as the a~o~.iate mixLule~ thereof.
The compolln~C of the present invention can be
prepared and administered in a wide variety of oral
and parenteral dosage forms. Thus, the compo~n~c of
the present invention can be administered by
injection, that is, intravenously, intraml~cc~llArly,
intracutaneously, subcutaneously, intr~ o~PnAlly, or
intraperitoneally. Also, the compounds of the present
invention can be administered by ;nh~l~tion, for
example, intr~n~cAlly. Additionally, the compounds of
the present invention can be administered
transdermally. It will be obvious to those skilled in
the art that the following dosage forms may comprise
as the active comro~nt, either a compound of Formula
1 or a corr~pon~;ng pharmaceutically acceptable salt
of a compound of Formula 1.
For preparing pharmaceutical compositions from
the com~u~lds of the present invention,
~ WO95tl4014 ~7 ~1 2 ~ pcT~ss~/l2367
.
- 31 -
pharmaceutically acceptable carriers can be either
solid or liquid. Solid form preparations include
powders, tablets, pills, capsules, cachets,
~o~itories, and dispersible granules. A solid
carrier can be one or more substances which may also
act as diluents, flavoring agents, binders,
preservatives, tablet disintegrating agents, or an
~nc~r~ulating material.
In powders, the carrier is a finely divided solid
which is in a mixture with the finely divided active
component.
In tablets, the active component is mixed with
the carrier having the ~ece~FAry b; n~; n~ properties in
suitable ~Lv~oLLions and compacted in the shape and
size desired.
The powders and tablets preferably contain from
five or ten to about seventy percent of the active
compound. Suitable carriers are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose,
sodium caL~G~ymethylcellulose, a low melting wax,
cocoa butter, and the like. The term "preparation" is
inten~ to include the formulation of the active
compound with ~nc~pculating material as a carrier
providing a capsule in which the active component with
or without other carriers, is ~uLLoul~ded by a carrier,
which is thus in association with it. Similarly,
cachets and lozenges are included. Tablets, powders,
capsules, 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 mixture of fatty acid glycerides or cocoa
butter, is first melted and the active component is
dispersed homogeneously therein, as by stirring. The
molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby
to solidify.
WO95/14014 PCT~S94/1~67 ~
2 4
- 32 -
Liquid form preparations include solutions,
suspensions, and emulsions, for example, water or
water ~-o~ylene glycol solutions. For parenteral
injection liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be
prepared by dissolving the active component in water
and ~; n~ suitable colorants, flavors, stabilizing
and thiCkPn i ng agents as desired.
Aqueous suspensions suitable for oral use can be
made by ~i~p~sing the finely divided active component
in water with vis~o~c material, such as natural or,
synthetic gums, resins, methylcellulose, sodium
caL~ymethylcellulose, and other well-known
5 s~ pen~ i ng agents.
Also included are solid form preparations which
are inte~ to be coll~el~ed, shortly before use, to
liquid form preparations for oral administration.
Such liquid forms include solutions, suspensions, and
emulsions. These preparations may contain, in
addition to the active component, colorants, flavors,
stabilizers, buffers, artificial and natural
sweeteners, dispersants, thick~n~s, solubilizing
agents, and the like.
2S The pharmaceutical preparation is preferably in
unit dosage form. In such form the preparation is
divided into unit doses contA; n; ng a~L O~L iate
guantities of the active component. The unit dosage
form can be a packaged preparation, the package
con~; n; ng discrete quantities of preparation, such as
packeted tablets, capsules, and powders in vials or
ampoules. Also, the unit dosage form can be a
c~pC?lles~ tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged
form.
The quantity of active component in a unit dose
preparation may be varied or adjusted from O.l mg to
lO0 mg preferably 0.5 mg to lOo mg according to the
,
~ WO g5/14014 ~ ~ 7 4 ~ ~4 PCT~S94J1~67
- 33 -
particular application and the potency of the active
comron~nt. The composition can, if desired,talso
contain other compatible therapeutic agents.
In therapeutic use as antagonists of a LeL.~viral
protease, as agents for the treatment of infections
caused by a LeLlvvirus including HlV, or as agents for
the treatment of diseases due to AIDS, the compounds
utilized in the pharmaceutical method of this
invention are administered at the initial dosage of
about O.O1 mg to about 100 mg/kg daily. A daily dose
range of about 0.01 mg to about 10 mg/kg is preferred.
The dosages, however, may be varied ~p~n~; n~ upon the
requirements of the patient, the severity of the
condition being treated, the com~o~.d being employed.
Determination of the proper dosage ~or a particular
situation is within the skill of the art. Generally,
treatment is initiated with smaller dosages which are
less than the optimum dose of the compound.
Thereafter, the dosage is increased by small
increments until the optimum effect under the
circumstAnr~s is reached. For convenience, the total
daily dosage may be divided and administered in
portions during the day, if desired.
WO9S/14014 PCT~S94/12367 ~
~7~124
- 34 -
.1 G~neral ~ynthetic Appr~-~h~Q
to ~6~ DQrivatives
Scheme I, shown below, illustrates the
S preparation of 6-substituted-3-substituted pyrones.
S~$~A~ I
O 1. B~e OSiMe3
`~ C ~ TMS-OTf ~~\_rr'RS
H ~Rs ( NEt3 )
I
OH R
CO2Et ~ ~ /
`C02Et ~\o~O
m
Ketone I is treated with a suitable base, such as
lithium diiso~Lu~ylamide or lithium
bis(trimethylsilyl)amide, at -78 C to -45 C, in
ether or THF solution and, when deprotonation is
complete, quenched with chlorotrimethylsilane (TMS-
Cl), at -78 C to 0 oc, producing the silyl enol ether
II. Alternatively, compound I is treated with
trimethylsilyltrifluorome~h~n~culfonate (TMS-OTf) and
triethylamine at 0 C in dichloromethane solution, to
effect transformation to intermediate II. Compound II
is then reacted with an appropriately substituted
malonate and heated either neat or in xylene at 130-
160 C to give the desired product III.
For ~uu~G~es of the above and other syn~h~cec of
the compounds of the present invention, reactive
functional yL~U~ present in starting materials,
reaction intermediates, or reaction products may be
WO95/14014 ~1 7 ~ ~ 2 4 PCT~S94~1~67
- 3s -
protected during chemical reactions using protecting
ylOU~ which render the reactive functional yl~u~
substantially inert to the reaction conditions. (See
for example, Protective Groups ln Organic Synthesis,
2 ed., T. W. Green and P. G. Wuts, John Wiley & Sons,
New York, NY l99l). Thus, for example, protecting
y~Ou~S such as the following may be utilized to
protect suitable amino, hy~ko~yl, and other groups of
related reactivity: car~oxylic acyl y~Ou~S, such as
formyl, acetyl, trifluoroacetyl; alkoxycarbonyl
yL UU~ ~ such as ethoxycarbonyl, t-butoxycarbonyl
(BOC), ~ -trichloroethoxycarbonyl (TCEC), ~-
iodoethoxycarbonyl; aryloxycarbonyl yLo~, such as
benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,
phenoxycarbonyl; trialkyl silyl ylOU~, such as
trimethylsilyl and t-butyldimethylsilyl (TBDMS); and
yL~u~ such as trityl, tetral~ydl U~l anyl,
vinyloxycarbonyl, o-nitrophenylsulfenyl,
diphenylphosphinyl, p-toluenesulfonyl, and benzyl, may
all be utilized. The protecting group may be removed,
after completion of the synthetic reaction of
interest, by ~ r o~e~ules known to those skilled in the
art. For example, the BOC group may be removed by
acidolysis, the trityl group by hydLoyenolysis, TBDMS
2s by treatment with fluoride ions, and TCEC by treatment
with zinc.
An alterna~ive approach to functionalized pyrones
is outlined in Scheme II.
WO95/14014 2 1 ~ PCT~S94/1236
- 36 -
sr~ II
OH
OSiMe3 ,COCI Rs , h~
~`"``'~--S `COCI '' CH~-- so2sR2
~ -78C
II IV
OH
R5 ~/sR2
V
The trimethyl silyl enol ether II is reacted with
malonyl dichloride in a dry solvent such as ether or
THF at low temperature, preferably -78 C to -35 C,
to give pyrone IV, which is converted to the sulfur
derivative V using an a~-o~Liately substituted p-
toluenethiosulfonate, as disclosed in U.S. Patent
3,931,235 (1976). Alternatively, the thiotosylate
reagents were prepared as described by M. G.
Ranasinghe and P. L. Fuchs in Syn. Comm. 18 (3): 227
(1988). The requisite thiols can be prepared ~rom the
corresponding phenol via the Newman-Kwart
rearrangement (see, for example, H. Kwart and H.
Omura, J. Amer. Chem. Soc. 93: 7250 (1971); M. S.
Newman and F. W. Hetzel, Org. Synth. Coll. Vol. ~I:
824 (1988); M. S. Newman and H. A. Karnes, J. Org.
~ WO95/14014 2 1 7 ~ 1 2 ~ PCT~ss4/1~67
- 37 -
Chem. 31: 3980 (1966)) or from the corresponding
io~oh~n7ene via a nucleophilic displacement with
~hiourea in the pr~ce~ce of a nickel catalyst (~.
Takagi, Chem. Letters, 1307 (1985)).
S A synthesis of pyrones such as VIII is shown
below, in Scheme III. Here, substituent R6 of
structure VTI can be aryl, alkyl, or substituted
alkyl.
S~ R III
!l
CH 3 ~R6
i; ~1 1. NaH
OEt 2. RLi ~ OCH3
R5 R3
VI
OH
O 5~ ,~ 3
R6/~ `OEt R6~ O--~O
R R
VII VIII
Substituted ~-ketoester VI is deprotonated with
one equivalent of a suitable base, e.g. a metal
hydride such as sodium hydride, in a suitable solvent,
e.g. ether or THF.. A second equivalent of a stronger
base, e.g. an alkyllithium such as n-butyllithium or
lithium diiso~Lu~ylamide, is added to the malonate
solution to produce the dianion, which is then reacted
with a suitable acylating agent, e.g. an amide, at
O C to 25 C producing dione ester VII. Compound VII
WO95tl4014 I PCT~S94/12367 ~
~1 7~ 1~4
- 38 -
may then be cyclized to the pyrone VIII in a variety
of ways, e.g. by using a sL,o~.y acid such as H2SO4 or
CH3SO3H, by heating the reaction mixture in a high
boiling solvent such as xylene, or by using a small
s amount of a base, preferably a hindered base like
l,8-~;A~hicyclo[5.4.0]undec-7-ene. If R3 = H, then
pyrone VIII can be further derivatized, as shown in
Scheme II above.
Scheme IV describes the preparation of O-acyl
pyrone analogues.
SC~M~ IV
OH OCR7
R5~ 1~ ,R3 R5~ ",R3
Base, CICR7 1' ~
R6' `a'~) R6' `~`O
VIII
The pyrone, e.g. VIII, is treated with a suitable
base, e.g. a metal hydride such as sodium hydride, or
an alkoxide, in a suitable solvent, e.g. THF, dioxane,
or ether, and the resulting anion is reacted with an
acyl chloride or other acylating agent producing the
desired acyl derivative IS.
Scheme V, shown below, illustrates the
preparation of several 3-alkyl pyrone derivatives.
WO95/14014 ~7 ~12~ PCT~S94J1~67
- 39 -
S~P!MF~ V
OH O OH R 8
~R8CH,HSRg or H2NRg R5~,~ R
~ r., HOAc R /~0~)
VIrI X
(wh~x Y= N,S)
OH ~8
R6 a~
XI
Intermediate pyrone VIII in an alcoholic medium, such
as ethanol, is combined with a suitable aldehyde and a
suitable nucleophile, such as HSRg or NH2Rg, in the
presence of a mixture of an acid, such as acetic acid,
and a base, such as piperidine. The resulting mixture
is heated at 60 C to 90 C to produce a pyrone X,
which may itself be a preferred compound.
Alternatively, for the case of Y = S, S may be reduced
via a dissolving metal reduction, e.g. by using sodium
in liquid ammonia, or via a reduction employing a
Raney nickel system in a solvent such as acetone, to
- give desired 3-alkyl pyrones SI.
Scheme VI summarizes the synthesis of certain 3-
amino pyrones.
WO95/14014 PCT~S94/12367 ~1
~1 ~4~ ~
-- 40 --
S~u~ Z VI
OH OH
Rs~;HNO3, HOAc Rs~ ~2 Sn, H
"HOAc jl I
R8~ ' ` R8/~ 0~0
vm OH
Rs NH2 ~
R6/l~O~'O R~2NC
1. RloCHO,D~F,/ g~ OH 1
HO~C/ R-1 CO2H Rs~ NHCNRt2
~/~ NaCNBH3 MeN O, ~N
OH N{:~NEt
~H-- R5~/ NHCR
XV
Nitration of pyrone VIII is effected with nitric
acid, preferably fuming nitric acid in acid solution,
e.g. as described in US Patent 3,206,476 (1965).
Reduction of ni LL ~yL one XII with tin and acid
furn;sh~s aminopyrone XIII. Intermediate 2III can now
be elaborated into a variety of derivatives. For
example, XIII may be treated with an a~L U~L iately
substituted aldehyde in the presence of a reducing
agent, such as sodium borohydride or, preferably,
sodium cyanoborhydride, to give the N-alkylated
analogues xrv. Acylation of compound ~III may be
achieved via one of several routes: l. By treatment
with sodium hydride, followed by coupling with a
mixture of a suitable carboxylic acid, N-
methylmorpholine, and a suitable co~n~ing agent,
such as l-(3-dimethylaminu~}~yl)-3-ethylcarbodiimide,
at a suitable temperature, e.g. -35 C - o oc; 2. By
~17 412A
- WO95/14014 - PCT~S94~12367
reaction with a suitable acid chloride or other
acylating agent in the presence of a base, such as
triethylamine, and 4-dimethylaminopyridine; or 3. By
- deprotonation with sodium hydride, followed by
reaction with a suitable acid chloride in the presence
of excess of an amine base, usually triethylamine, at
elevated temperatures, e.g. 40-60 C. Ureas such as
XVI may be prepared from aminopyrone XIII by reaction
with a suitable isocyanate and a base, e.g. N-
methylmorpholine, in an inert solvent such as ethyl
acetate.
Scheme VII ou~l ineC an alternate approach for the
preparation of C-6 substituted analogs.
sr~2 VII
OR OR OR
R3 NBS ~, Rs~ ~ - R3 R13SNa ~ R5 ~ ~" R3
H C 0/~0 ~~C ~0 '~O'~O
2 0 ~ Br ~ SR~3 X$[1:
1. 2~nv.ba~l 1. N~N3 1 ~ NaOH
2. ~ 7 ~dudr~
~
OR OR OR
F~5 ~"R3 RS--~ R3 R5~ ~,R3
E ~NH2 ~ OH m
3 (E ~ alkyl groups: C~ H: PhCO)
The 6-methyl pyrone XVII is treated with
2 equivalents of a strong base, e.g. sodium amide in
35 liquid ~mmonia or lithium diisopropylamide in THF
solution, followed by ~l~nch;ng with one of a great
variety of electrophiles, e.g. alkyl halides,
acylating agents, etc., furnishing pyrone XVIII (see
_
WO 95114014 PCT/US94/12367 1ll
~17~
.
- 42 -
M.P. Wachter and T.M. Harris, ~etrahedron 26: 1685
tl970)). Alternatively, allylic bromination of SVII
under free radical conditions, e.g. using N-
bromosuccinimide (NBS) in the presence of a free
radical initiator and light, affords intermediate XIS,
which can be further elaborated to amine X~ as
described in Jones et al., Tetrahedron Letters, 30:
3217 (1989), converted to alcohol ~XI as described in
R. Bacardit et al ., J . Heterocycl ic Chem . 19 : 157
(1982.), and ultimately transformed to sulfide ~SII as
described in R. Bacardit et al., J. Heterocyclic Chem.
26: 1205 (1989). The amino and hyd~o~y substituents
of structures ~ and ~SI can be further derivatized
using s~n~rd reactions known in the art, e.g. via
alkylation, acylation, etc..
The synthesis of several 4-substituted pyrone
derivatives is shown in Scheme VIII below.
WO95114014 ~ 7 ~ ~ 2 ~ PCT~S94/1~67
- 43 -
St'~MF VIII
S OH OTs SR1"
R5~R3 T~CI R5~ RaRl~SNa Rs~ ~ R3
R~O~O '~
vm ~m ~v
P8r3 /DMF
Br CO2C~ ~OH
R5~R3 1P50Cps~(cPora)2 R5~f; R5~RJ
l~ I NEt3, M~OH l! 11 !
R6/~O~o R~3 Rjf~O~O
lS XXV ~ ~v~
N~
t
N3 NH2
R5 ~R3 H2~d R5
2 0R6 'J~ RB
2S~V111 2~
Pyrone VIII is activated, e.g. by tosylation to
YYTTT using p-toluenesulfonyl chloride (TsCl) in
pyridine. The tosylate is then reacted with a
suitable sulfur nucleophile (see A.M. Bittencourt et
al., Tetra~edron, 27: 1043 (1971)) to give sulfide
- 30 XSIV. In a similar fashion, pyrone VIII is converted
to the 4-bromo analog A~V, using a brominating agent
such as phosphorous-tribromide/dimethylformamide
(DMF). Displacement of the bromine of X$V with azide
followed by reduction (e.g. preferably hydrogenation
over a palladium/triaryl-phosphine catalyst in a
suitable solvent) gives 4-amino derivative SSI~.
Further functionalization of the amine moiety of X~I~
is achieved as described above in Scheme VI.
WO95/14014 PCT~S94/12367 ~
- 44 -
Alternatively, 4-bromo~L~l.e ~SV can be reacted
with a palladium triarylphosphine catalyst and
methanol in a carbon monoxide atmosphere to give ester
~XVI. The ester can be further hydrolyzed, e.g. in
s acid solution at 0-25 C, to the corresponding
carboxylic acid, or reduced, e.g. using a hydride t
reagent such as lithium aluminum hydride in THF or
ether solution at 0 C-25 C, to the alcohol (XSVII~.
Scheme IX illustrates the preparation of 2H-
l0 thiopyran-2-one derivatives.
S~U~HR IX
Cl OH
~ + R3 ~ E~2C~ ~ R3
R6 SH Cl`- ~" S'~`O
OH
1. OH- ~"R3
2. PhNO2/quinolone~ ~ ,
1, j
~00~11
An a~o~iately substituted ~-mercapto acrylate, e~g.
XXS, is condensed with the desired malonyl dichloride
in an inert solvent, e.g. toluene, at a temperature
between 0 C and the boiling point of the reaction
solvent, to afford the thiopyran-2-one XS~I.
Thiopyrone ~S~I may be converted to derivative ~X~II
under suitable conditions, e.g. by basic hydrolysis
followed by deca~bo~ylation (for example, see F. K.
Splinter and H. Arold, J. Prakt . Chem ., 38 : 3-4 ,
142-6). Thiopyrones XS~II (R3 = H) can be converted to
~ WO95tl4014 PCT~S94/12367
~17~12~
- 45 -
their substituted derivatives, using the ~oced~es of
Schemes II, X, and VI for derivatization of the
analogous pyrones.
Suitably protected pyrones, e.g. SVII, as well as
their analogs possessing S instead of 0 at position 1
of the pyrone ring, may be thiated, i.e. the carbonyl
at position-2 of the heterocycle may be replaced by a
thiocarbonyl (C=O - C=S), using st~n~Ard group
modification te~h~; ques, e.g. employing a thiation
reagent such as Lawesson's reagent under suitable
reaction conditions (see Monatsh . Chem ., 1~5: 769
(1984) and Chem. Rev. 8~: 17 (1984)).
~.2 General r~ ure8 for the
Pre~aratson of Function~ ed PYrones
Met~od A: 8ynthesis ~ia Reaction of 8ilyl Enol Bthers
with 2-~ubstituted Prop~nq~;oic Acid ~sters
i) Preparation of Trimethylsilyl enol ~thers
To a solution of an appropriate ketone (lo mmol,
1 equivalent) in dry tetrahydrofuran (100 ml) at 7& C
was added lithium hexamethyldisilazide (11 mmol, 1.1
equivalents). The reaction mixture was stirred at
-78 C for 1 hour and at -35 C for 0.5 hour.
Trimethylchlorosilane was then added dropwise at
-78 C, and the resulting mixture was stirred for 1 h
at -78 C and for 0.5 h at 0 C. The reaction was
stirred at -78 oc for 1 h., and at o C for 0.5 h.
The reaction was interrupted by addition of saturated
sodium bicarbonate solution and the reaction mixture
extracted with ethyl acetate (300 ml). The ethyl
acetate layer was washed with saturated sodium
bicarbonate solution and brine, and dried further over
anhydrous sodium sulfate. The ethyl acetate solution
was concentrated under reduced pressure and the
material isolated was dried in vacuo for 1 hour and
used without purification.
WO95/14014 2 17 ~ 12 4 PCT~S94/12367 ~
,,, !
- 46 -
~i) CQn~n~ation of Triuethylsilylonol ethers with
Dialkyl Bsters of 2-8ubstituted Pro~ns~;oic Acid
Crude trimethylsilyl enol ether (11 mmol, 1.1
equivalents), prepared as described above, was
5 combined with a dialkyl ester of a 2-substituted
pro~n~;oic acid, (10 mmol, 1.O eguivalent) and the T
resulting mixture was heated at 150 C with continuous
passage of nitrogen gas through the reaction mixture,
overnight. The reaction mixture was cooled to room
10 temperature and the product was purified by
chromatography on silica gel. Elution with 10-15%
ethyl acetate/h~An~s removed unreacted starting
material and other impurities and elution with 30-50%
ethyl acetate/5% methylene chloride/h~YAnPs effected
further purification furn; ~h; ng the desired pyrones in
20 - 75% yield.
~etho~ B: 8ulfenylation of 6-Aryl-~-hy~.oAy-2~-pyra~
2-one
i) Preparation of 6-Aryl-4-hy~ 6~y~2 ~y~6he
The trimethylsilyl enol ether (20 mmol, 1 equivalent),
prepared as described in Method A (or ob~ e~
commercially), was taken in anhydrous ethyl ether and
cooled to -78 C to -40 C. To it malonyl dichloride
(30-40 mmol, 1.5-2 equivalents) was added dLV~ ise.
The reaction mixture was warmed up gradually to room
temperature and stirred at room temperature overnight.
The solid obt~in~ was filtered and washed with
anhydrous ether.
ii) 8ulfenylation of 6-Aryl-4-hydroxy-2~-pyran-2-one
The 6-ary1-4-hydroxy-2-pyrone prepared as described
above (1.62 mmol, 1 equivalent) was dissolved in
ethanol. To this solution was added lN sodium
hy~Loxide (1.72 mL, 1.04 equivalents) or 2 equivalents
of triethylamine, followed by the a~ ~ iate
thiolsulfonate (1.72 mmol, 1.04 equivalents). The
reaction mixture was heated at reflux for overnight.
WO9S/14014 PCT~S94/12367
~ 74~24
- 47 -
The solvents were evaporated, acidified with lN HCl
and the product was extracted with ethyl acetate.
After evaporation of the solvents, the crude product
was purified by chromatography (silica gel-230 to 400
mesh) using 30-50% of ethyl acetate in h~x~nec to
yield the desired product. ~ields: 40-80%.
Mothod C: Pr~paration of ~6-Aryl~ o~y-
2-oxo-2~-pyran-3-yl) ~rylthiometh~no~
To the 6 aryl-4-~1y~luxy-2H-pyran-2-one
(2.16 mmol; 1 eq) in 10 mL of ethyl alcohol, the
appropriate aldehyde (2.37 mmol, 1.1 equivalents),
appropriate thiol (5.62 mmol, 2.6 equivalents),
piperidine (0.50 mL), and acetic acid (0.50 mL) were
lS added. The reaction mixture was kept at 80 oc for 24
hours. The ethyl alcohol was evaporated, acidified
with lN HCl and the residue was purified by
chromatography (silica gel-230 to 400 mesh) to yield
35-60% of the desired product.
~ethod D: Preparation of 6-Aryl-3-al~ylamino-~-
hydroxy-2~-pyran-2-on~
i) 6-Aryl-~ dLvAy-3-nitro-2H-pyran-2-one
The method used was adapted from the pro~ule
described in U.S. Patent 3,206,476 (1965) for
nitration and reduction. To a suspension of 6-aryl-4-
hydroxy-2H-pyran-2-one (2.65 mmol, ) in acetic acid
(2.77 ml) at room temperature was added fuming nitric
acid (0.222 ml). After stirring for 5 minutes, the
reaction mixture was cooled to 0 C and the product
filtered. The product was purified by
recrystallization from boiling acetic acid. lH NMR
(2S0 MHz, d-TFA) ~ 7.02 (s,lH), 7.65 (s, 3 H), 7.99
(m, 2 H).
ii) 3-A~ino-6-aryl-~-hy~roxy-2H-pyran-2-one
To a suspension of 6-aryl-4-hy~,o~y-3-nitro-2H-pyran-
2-one (10.5 mmol, 1 equivalent) in acetic acid (15 ml)
WO95/14014 PCT~S94/12367 ~
~17~
.
- 48 -
and concentrated HCl (7.34 ml) was added mossy tin
(20.6 mmol, l.96 equivalents). This mixture was then
heated to reflux and a homogeneous mixture resulted.
The reaction mixture was refluxed for 7 minutes, and
then cooled in an ice bath. Concentrated HCl was
added to precipitate the 3-amino-6-aryl-4-hydroxy-2H-
pyran-2-one hydrochloride, which was collected and
dried. lH NMR (250 MHz, D20) ~ 6.74 (s,lH), 7.53 (m,
3 H), 7.84 (m, 2 H).
iii) 3-Alkylamino-6-aryl-~-hydroxy-2~-pyran-2-ones
To a solution of 3-amino-6-aryl-4-hy~v~y-2H-pyran-2
one hydrochloride (2 mmol, l equivalent) in dimethyl
formamide cont~;n;~ 1% acetic acid (20ml) was added
~5 the aldehyde (2.l to 4.2 mmol, l.05-2.l equivalents)
followed by sodium cyanoborohyride (2.1 to 4.2 mmol,
l.05-2.l equivalents). The reaction was stirred for
minutes, quenche~ with water and con~-~ntrated in
vacuo. The oily residue was diluted with lO0 ml of
ethyl acetate, washed with water, then saturated
sodium chloride, and dried over anhydrous magnesium
sulfate. After evaporation of the solvents in vacuo
the crude product was either purified by column
chromatography (silica gel-230 to 400 mesh) or
2S recrystallization to yield the desired product.
Method B: 3-Acylamino-6-aryl-~-hydroYy-2~-pyran-2-
ones
The following pLou~dures were used for amidation of
the 3-amino-6-aryl-4-hydroxy-2H-pyran-2-ones.
a) To a solution of 3-amino-6-aryl-4-hydroxy-2H-pyran-
2-one hydrochloride (0.84 mmol, l.0 equivalent) in THF
(10 ml) was added 60% sodium hydride (0.92 mmol, l.l
equivalent) followed by stirring at room temperature
for 30 min. In a separate flask, to the a~L O~L iate
carboxylic acid (l.67 mmol, 2 equivalents) in THF (20
ml) at -20 C was added N-methyl morpholine (0.92
WO95/14014 PCT~S94J1~67
~ 4~2~
- 49 -
mmol, 1.1 equivalent) followed by 1-(3-
dimethylamino~.~yl)-3-ethylcarbodiimide hydrochloride
(0.92 mmol, 1.1 equivalent). The reaction mixture was
stirred at -20 C for 1 hr. This solution was added
to the above 3-amino-6-aryl-4-hydlo~y-2H-pyran-2-one
followed by more N-methyl morpholine (0.918 mmol, 1.1
equivalent). The reaction mixture was stirred at room
temperature overnight. The reaction was qll~n~he~ by
adding brine and diluting with ethyl acetate. The
organic layer was washed in s~sc~c-sion with 1 N HCl,
water, saturated sodium chloride, and was then dried
over anhydrous magnesium sulfate. After evaporation
of the solvents in vacuo, the crude product was
purified by column chromatography (silica gel-230 to
400 mesh) to yield the desired product.
~) To a suspension of 3-amino-6-aryl-4-hydko~y-2H-
pyran-2-one, monohydrochloride (0.83 mmol, 1.0
equivalent) in methylene chloride (8mL) was added
triethylamine (3.3 mmol, 4.0 equivalents) followed by
a catalytic amount of 4-dimethylaminopyridine (0.08
mmol, o.l equivalent) and the a~Lo~iate acid
chloride (0.92 mmol, 1.1 equivalent). The reaction
was stirred at room temperature for 6 hours. The
reaction was qll~nch~ with lN hydrochloric acid and
then diluted with methylene chloride. The organic
layer was washed with water and saturated sodium
chloride, and then dried over anhydrous magnesium
sulfate. After evaporation of the solvents in vacuo,
the crude product was recrystallized from boiling
acetic acid.
c~ To a solution of 3-amino-6-aryl-4-hydroxy-2H-pyran-
2-one monohydrochloride (O.63 mmol, 1.0 equivalent) in
tetrahydrofuran (6mL) at 0 C was added 60% sodium
hydride (0.69 mmol, 1.1 equivalents). The resulting
mixture was stirred at room temperature for 15
minutes. To the reaction mixture, the corr~spo~
WO9S/14014 ~ 1 2~ PCT~S94112367 ~
-- 50 --
acid chloride (0.69 mmol, 1.1 equivalents) was added.
The reaction mixture was heated to 50 C for 1 hour
and overnight at room temperature. The reaction was
quenched with lN hydrochloric acid and diluted with
ethyl acetate. The organic layer was washed with
saturated sodium chloride, dried over anhydLous t
magnesium sulfate. After evaporation of the solvents
in vacuo, the crude product was recrystallized from
boiling nitromethane to yield the pure product.
Nethod F: Preparation of 3-Al~yl-6-aryl-~-hydrosy-2~-
pyr~n-2-ones
The (6-aryl-4-hyd~o~-2-oxo-2H-pyran-3-yl)arylthio-
meth~nes were prepared as described in Method C.
Raney-Nickel (Grace 3100) was boiled in acetone for 45
- minutes and the acetone was replaced with ethanol (20
ml). The (4-h~d~Gxy-6-substituted-2-oxo-2H-pyran-
3-yl)arylthiomethane (1.0 mmol, 1 equivalent) was
added and the resulting slurry was heated to reflux
overnight. The mixture was filtered through Celite
and washed with hot ethanol. The filtrate was
~onc~ntrated in vacuo to yield pure products.
Method G: Preparation of ~-Acylo~y Esters of ~-
~ydro~y-3-aryl(or arylal~yl)thio-6-aryl-2~-pyran-2-one
The 4-hydroxy-3-aryl(or arylakyl)thio-6-aryl-2H-pyran-
2-one (3 mmol, 1 equivalent) was dissolved in 20mL of
tetrahydrofuran and cooled to 0 C. To this mixture
was added sodium hydride ( 3.3 mmol, 1.1 equivalent)
slowly and the resultant mixture was stirred at room
temperature for 15 minutes. The corresponding acid
chloride (6 mmol, 2 equivalents) was added drop-wise
and the reaction was stirred at room temperature
overnight. The reaction was ~l~nche~ with saturated
sodium chloride solution and was diluted with lOOmL of
ethyl acetate. The combined organic layer was washed
with sodium bicarbonate solution, brine, and dried
over anhydrous sodium sulfate. After evaporation of
~ WO95/14014 PCT~S94/12367
~ ~4~2~
- 51 -
the solvents, the crude product was purifed by column
chromatography (silica gel-230 to 400 mesh) using 10
ethyl acetate in h~Y~n~ as eluents afforded the enol
ester in 70-85% yields.
4.3 PreParation of 8tartin~ Materials
Esamples A-B: Pr~p~r~tion of propane~ ioic Acid~
The following key intermediates were synthesized
according to the proceduLe described in Comptus rendus
2S5: 2611 (1962).
ksampl~ A
Diethyl ester of l(phenylmethyl)thio3-pro~n~ ;oic
acid : b.p. 160-162 C/6 mm Hg;
lH NMR (250 MHz, DMSO-d6) ~ 1.18 (t, 6 H), 3.93 (s, 2
H), 4.13 (q, 4 H), 4.44 (s, 1 H), 7.31 (m, 5 H).
Example B
D~methyl e~ter of t~2-naphthale~yl~ethyl)thio]-
pro~ne~;oic ~ci~: The crude product was purified by
silica gel chromatography (silica gel 230-400 mesh). lH
NMR (250 MHz, DMSO-d6) ~ 3.65 (s, 6 H), 4.10 (s, 2 H),
4.55 (s, 1 H), 7.51 (m, 3 H), 7.87 (m, 4 H).
~ s~mpl~ C
Diothyl ester of ~3-phenylpropyl)thio]-proF~ns~ioic
acid: b.p. 185-190 C/1 mm Hg;
lH NMR (400 MHz, DMSO-d6) ~ 1.17 (t, 6 H), 1.82 (m, 2
H), 2.65 (q, 4 H), 4.14 (q, 4 H), 4.62 (s, 1 H), 7.23
(m, 5 H).
Example D
Diethyl ester of t~2-n~phth~lenyl)thio] ~ GL~n~;oic
acid: The crude product was purified by silica gel
chromatography (silica gel 230-400 mesh). lH NMR (250
MHz, DMSO-d6) ~ 1.09 (t, 6 H), 4.12 (q, 4 H), 5.27
(s, 1 H), 7.58 (m,-3 H), 7.90 (m, 3 H), 8.80 (s, 1 H).
WO95/14014 ~ 2 ~ PCT~S94/12367 ~
,
- 52 -
~s~ple E
Di~thyl ~st~r of t(2-ph~nyl~thyl)thio] ~ro~a~o~ioic
acid: b.p.: 160-165 C/lmm of Hg.
lH NMR (400 MHz), DMSO-d6) ~ 1.19 (t, 6 H), 2.89 (m, 2
H), 4.16 (q, 4 H), 4.68 (s, 1 H), 7.25 (m, 5 H).
Es~mples F-M: Prep~r~tio~ of p-ToluenQthiosulfon~tes
The following p-toluenethiosulfonates were synthesized
according to the procedure described in U.S. Patent
3,931,235 (1976).
Es~mple F
2-Phe~G~y~Lhyl p-Toluenethiosulfon~te: lH NMR (400
MHz, DNSO-d6) ~ 2.41 (s, 3 H), 3.41 (t, 2 H), 4.13 (t,
2 H), 6.83 (d, 2 H), 6.94 (t, 1 H), 7.27 (t, 2 H),
7.48 (d, 2 H), 7.85 (d, 2 H).
~xample G
3-Phenyl-2-propenyl p-Toluenethiosulfon~te: lH NMR
(400 MHz, DMSO-d6) ~ 2.32 (s, 3 H), 3.93 (d, 2 H), ~.00
(dt, 1 H), 6.58 (d, 1 H), 7.29 (m, 5 H), 7.38 (d, 2
H), 7.81 (d, 2 H).
Example H
2-t2-Methosyp~nyl~thyl p-Toluenethiosulfo~atQ: lH NMR
(400 MHz, DMSO-d6) ~ 2.43 (s, 3 H), 2.80 (t, 2 H), 3.19
(t, 2 H), 3.75 (s, 3 H), 6.83 (t, 1 H), 6.93 (d, 1 H),
7.02 (d, 1 H), 7.21 (t, 1 H), 7.49 (d, 2 H), 7.81 (d,
2 H)-
ExamplQ I
~-Ph~nylbutyl p-Toluenethiosulfonate: lH NMR (400 MHz,
DMSO-d6) ~ 1.53 (m, 4 H), 2.43 (s, 3 H), 2.50 (t, 2 H),
3.03 (t, 2 H), 7.12 (d, 1 H), 7.18 (d, 2 H), 7.25 (t,
2 H), 7.45 (d, 2 H), 7.80 (d, 2 H).
Es~mple J
WO95/14014 ~1 7~ PCT~S94/12367
2-~3-Netho~yphenyl]ethyl p-Toluenothiosulfon~t~: lH
NMR (400 MHz, DMSO-d6) ~ 2.43 (s, 3 H), 2.79 (t, 2 H),
3.25 (t, 2 H), 3.73 (s, 3 H), 6.73 (m, 3 H), 7.19
(m, 1 H), 7.49 (d, 2 H), 7.83 (d, 2 H).
kx~mple R
2-~-~Qtho~yphenyllethyl p-Tolue~et~iosulfonate: lH
NMR (400 MHz, DMSO-d6) ~ 2.50 (s, 3 H), 2.76 (t, 2 H),
3.21 (t, 2 H), 3.71 (s, 3 H), 6.83 (t, 2 H), 7.03 (d,
2 H), 7.50 (t, 2 H), 7.82 (d, 2 H).
E~c~pl~
2-(2-Chlorophenyl)ethyl p-Toluenethio~ulfonate: lH NMR
(400 MHz, DMS0-d6) ~ 2.43 (s, 3 H), 2.86 (t, 2 H), 3.28
(t, 2 H), 7.22 (m, 4 H), 7.49 (d, 2 H), 7.83 (d, 2 H).
Esampl~ M
t~-~Phenylmetho~y)phe~yl]methyl p-
Toluenethiosulfonate: lH NMR (400 MHz, DMSO-d6) ~ 2.41
(s, 3 H), 4.28 (s, 2 H), 5.06 (s, 2 H), 6.87 (d, 2 H),
7.13 (d, 2 H), 7.37 (m, 7 H), 7.72 (d, 2 H).
~x~mpl~ N
6-(3-Chlorophenyl)-~-~y~L VA~ 2E-pyran-2-one.
A slurry of 60% NaH (0.790 g, 19.7 mmol) in THF (50
mL) under a N2 atmosphere was cooled to 0 C and
treated with ethyl acetoacetate (2.51 mL, 19.7 mmol).
The resulting solution was subsequently treated with
n-BuLi (12.3 mL, 19.7 mmol) and stirred for 20 min. at
0 C to provide an orange solution which was treated
via cannula with a solution of 3-chloro-N-methoxy-N-
methylbenzamide (2.50 g, 15.15 mmol) in THF (5.0 mL).
The mixture was allowed warm to ambient temperature
where it was stirred for 14 h before being ~l~n~h~
with 2.0 N HCl. The product was extracted with
ethylacetate (3 x 50 mL), the layers combined, dried
Wos5/l4ol4 PCT~S94/12367
~ 54 _
with Na2SO~, and the solvent removed in vacuo. The
residue was then treated with conc. H2SO~ (20 mL) and
the resulting mixture stirred for 18 h at room
temperature before being diluted with H20 (200 mL).
The product was then extracted with ethylacetate (3 x
100 mL) being sure to collect all solids. The layers
were then combined and diluted with acetone to provide
a homogenous solution which was dried with Na2S0~. The
solvent was then removed in vacuo and the resulting
lo solid recryst~ ed from acetone-hexane to provide
the title compound (1.33 g, m.p. 254 - 256 C). lH NMR
(400 NHz, DNSO-d6) ~ 11.957 (bs, 1 H), 7.889 (t, 1 H, J
= 1.5 Hz), 7.839 - 7.813 (m, 1 H), 7.598 - 7.524 (m, 2
H), 7.876 (d, 1 H, J = 2 Hz), 5.450 (d, 1 H, J = 2
Hz).
~r~mple O
6-(~-Chlorophenyl)-4-hydroxy-2H-pyran-2 -O~Q .
The title compound (1.56 g, m.p. 247 - 249 C) was
prepared in a similar manner as that demol,~LLated in
the preparation of Example N using the following: 60%
NaH (0.904 g, 22.6 mmol), THF (50 mL), ethyl
acetoacetate (3.00 g, 22.6 mmol), lithium
diis~o~ylamine in THF (39.8 mL, 24 mmol), 4-chloro-
N-methoxy-N-methylbenzamide (3.73 g, 22.6 mmol), 90~
H2S04 (20 mL). H NMR (300 MHz, DMSO-d6) ~ 11.950 (bs,
1 H), 7.878 (d, 1 H, J = 9 Hz), 7.584 (d, 1 H, J = 9
Hz), 6.812 (d, 1 H, J = 2 Hz), 5.409 (d, 1 H, J = 2
Hz).
Example P
~Cy¢lopropylmethyl)-p-toluenethiosulfonate.
To a solution of methylcyclopropyl bromide (4.00 g,
29.6 mmol) in ethanol (20.0 mL) was added potassium
thiotosylate (10.0 g, 44.4 mmol) and the mixture
heated to 90 C for 10 h. The mixture was then
~uP~he~ into a 1 : 1 mixture of H20 (50.0 mL) and
diethyl ether (50.0 mL). The layers were separated
~ WO 95/1~014 PCT/US94/12367
~ 7~2~
- 55 -
and the organic layer washed with brine (50.0 mL).
The organic layer was then dried with MgS04 and
concentrated in vacuo to yield the title compound as a
solid (5.2 g, m.p. 46 - 48 C). lH NMR (400 MHz,
s CDCl3) ~ 7.816 (d, 2 H, J = 8.8 Hz), 7.308 (d, 2 H, J
= 8.8 Hz), 2.945 (d, 2 H, J = 7.6 Hz), 2.451 (s, 3 H),
1.010 - 0.933 (m, 1 H), 0.592 - 0.545 (m, 2 H), 0.236 -
0.197 (m, 2 H).
E~a~pl~ Q
~et~yl-[~-~l G~C~ Lhyl)rh~r~-~] Acetate.
A mixture of 4-hydL~Ay~io~h~nnnP (10.0 g, 60.24
mmol), CsC03 (21.6 g, 66.3 mmol), and acetone (150.0
mL) under an N2 atmosphere was treated with
methylbromoacetate (7.26 mL, 78.3 mmol) and the
mixture heated to reflux for 4 h. The mixture was
then allowed to cool to ambient temperature, diluted
with H20 (150 mL) and extracted with CHzClz (2 x 300
mL). The organic layers were combined, dried with
Na2S04, and the solvent removed in vacuo to provide the
title compound (12.75 g, m.p. 64 - 66 C). lH NMR (400
MHz, DMSo-d6) ~ 9.35 (d, 2 H, J = 8.9 Hz), 7.040 (d, 2
H, J = 809 Hz), 4.920 (s, 2 H), 3.715 (s, 3 H), 2.981
(q, 2 H, J = 7.2 Hz), 1.071 (t, 3 H, J = 7.2 Hz).
~7~
WO95/14014 PCT~S94/1~67
- 56 -
4 . 4 prQparation of SPecif ic ~y ;)~ Derivatives
E:S~pl~ 1
6-(3-Chlorophenyl)-~-hy~ro~y-3-t(phenylmethyl)thio]-
2~-pyr~n-2-one.
Following method A a solution of 3'-chloroacetophenone
(1.50 g, 11.6 mmol) in THF (10.0 mL) was cooled to -
78 C (N2 atmosphere) and treated with a 1.0 M solution
of lithium hexamethyldisilazide (12.5 mL, 12.5 mmol)
in THF. The solution was warmed to 0 C, allowed to
stir for 15 min., then treated with
trimethylsilylchloride (1.47 mL, 11.6 mmol) The
reaction mixture was then allowed to stir for 0.5 h
(ambient temperature) and subsequently ~lenche~ into a
~S mixture of diethyl ether (50 mL) and saturated aqueous
NaHCO3 (20 mL). The layers were separated and the
organic layer washed with a 1 : 1 mixture of brine :
saturated NaHCO3 (20 mL). The ethereal solution was
then dried with Na2SO4 and the solvent removed in
vacuo. The resulting silyl enol ether was then
transferred to a flask con~in;ng diethyl -2-
(thiobenzyl)propane-1,3-dioate (1.63 g, 5.80 mmol),
the resulting mixture heated to 160 C for 16 h. and
then allowed to cool to room temperature where it was
diluted with diethyl ether (20 mL) and extracted with
saturated Na2CO3 (3 x 20 mL). The aqueous layer was
then acidifed with conc. HCl to pH 0 and then
extracted with ethyl acetate (3 x 100 mL). The
organic layers were combined, dried with Na2SO4 and the
solvent removed in vacuo. The resulting residue was
then submitted to chromatography (SiO2-230 to 400 mesh,
100% CH2Cl2 to 1% MeOH / CH2Cl2) to provide a solid
which was recrystallized from acetone / h~Y~n~c to
provide 0.436 g (m.p. 136 - 137 C) of the title
compound. lH NNR (400 NHz, DMSO-d6) ~ 11.950 (bs, 1
H), 7.814 (s, 1 H~, 7.761 (d, 1 H, J = 7.5 Hz), 7.616
- 7.534 (m, 2 H), 7.271 - 7.185 (m, 5 H), 6.811 (s, 1
H), 4.023 (s, 2 H).
WO951l4014 217 ~12 L~ PCT~S9411~67
- 57 -
~ ~pl~ 2
6-(2-Chlorophonyl)-~-h~LG~-3-ttphQnylmeth~l)thio]-
2H-pyr~n-2-one. The title compound (0.210 g, m.p. 99 -
101 C) was prepared by method A using 2'-
chloroacetophenone (1.50 mL, 11.6 mmol), 1.87 M
potassium hexamethyldisilazide (6.80 mL, 12.7 mmol),
trimethylsilylchloride (1.47 mL, 11.6 mmol), THF (10.0
mL), diethyl 2-(thiobenzyl)propane-1,3-dioate (1.3 g,
4.63 mmol). lH NMR (400 MHz, DMSO-d6) ~ 12.153 (bs, 1
H), 7.639 (t, 2 H, J = 9 Hz), 7.572 - 7.477 (m, 2 H),
7.276 - 7.206 (m, 5 H), 6.558 (s, 1 H), 4.029 (s, 2
H).
E~mpl~ 3
6-~3,4-Dichlorophonyl)-~ o,~ 3-
t~p~enylmothyl)thio]-2~-pyran-2-on~. The title
compound (0.201 g, m.p. 18S-186 oc) was prepared by
method A using 3',4'-dichloroacetophenone (1.5 g, 7.9
mmol), 1.0 M lithium hexamethyldisilazide (8.7 mL,
24 8.69 mmol), trimethylsilylchloride (1.0 mL, 7.9 mmol),
THF (10.0 mL), diethyl 2-(thiobenzyl)propane-1,3-
dioate (0.89 g, 3.2 mmol). lH NNR (400 MHz, DMSO-d6)
12.000 (bs, 1 H), 8.018 (s, 1 H), 7.784 (s, 2 H),
7.265 - 7.179 (m, 5 H), 6.839 (s, 1 H), 4.017 (s, 2
H).
Exa~ple ~
~-~yd ~A~ ~- (3-met~osyphenyl)-3-[(phenylmethyl)thio~-
2~-pyran-2-ono. The title compound (0.400 g, m.p. 146
- 147 C) was prepared by method A using 3'-
methoxyacetophenone (1.5 mL, 10.9 mmol), potassium
hexamethyldisilazide (6.41 mL, 12.0 mmol),
trimethylsilylchloride (1.38 mL, 10.9 mmol), THF (10.0
mL), diethyl 2-(thiobenzyl)propane-1,3-dioate (1.23 g,
4.36 mmol). lH NMR (400 MHz, DMSO-d6) ~ 11.880 (bs, 1
H), 7.445 (t, 1 H, J = 8 Hz), 7.370 (d, 1 H, J = 8
Hz), 7.286 - 7.094 (m, 6 H), 7.109 (m, 1 H), 6.770 (s,
1 H), 4.020 (s, 2 H), 3.831 (s, 3 H).
WO95/14014 PCT~S94/12367
58 -
ES~pl~ 5
~-~ydro~y-3-~(phenylm~t~yl)thio]-6-(3,~,5-
trimethoxyphenyl)-2~-pyr~n-2-one. The title compound
(0.385 g, m.p. 156 - 157 C) was prepared by method A
using 3', 4', 5'-trimethoxyacetophenone (2.0 g, 9.5
mmol), potassium hexamethyldisilazide (5.6 mL, 10.45
mmol), trimethylsilylchloride (1.2 mL, 9.5 mmol), THF
(15 mL), diethyl 2-(thiobenzyl)propane-1,3-dioate
(1.07 g, 3.80 mmol). lH NMR (400 MHz, DMS0-d6) ~
11.778 (bs, 1 H), 7.265 - 7.181 (m, 5 H), 7.054 (s, 2
H), 6.792 (s, 1 H), 3.997 (s, 2 H), 3.861 (s, 6 H),
3.727 (s, 3 H).
Example 6
6-(3-Chloroph~nyl)-~-hy~rosy-3-t~2-ph~nylethyl)thiO]-
2~-pyr~-2-one. The title comrolln~ (0.138 g m.p. 125 -
127 C) was prepared by method B using 6-(3-
chlorophenyl)-4-hy~xy-2H-pyran-2-one (0.250 g, 1.10
mmol), phenethyl-p-toluenethiosulfonate (0.43 g, 1.46
mmol), triethylamine (0.35 mL, 2.5 mmol), ethanol (5.0
mL) lH NMR (400 MHz, CDCl3) 8 7.838 (t, 1 H, J = 1.5
Hz), 7.710 (d, 1 H, J = 8 Hz), 7.530 (bs, 1 H), 7.475
-7.392 (m, 2 H), 7.308 - 7.260 (m, 2 H), 7.207 - 7.171
(m, 3 H), 6.604 ts, 1 H), 3.125 (t, 2 H, J = 7 Hz),
2.897 (t, 2 H, J z 7 Hz).
kxample 7
6-(4-Chlorophenyl)-~-hydro~y-3-tt2-phenylethyl)thio]-
2~-pyr~n-2-one. The title compound (0.242 g, m.p. 161
- 163 C) was prepared by method B using 6-(4-
chlorophenyl)-4-hydroxy-2H-pyran-2-one (0.250 g, 1.12
mmol), phenethyl-p-toluenethiosulfonate (0.390 g, 1.35
mmol), triethylamine (0.31 mL, 2.24 mmol), ethanol
(10.0 mL). lH NMR (400 MHz, DMSO-d6) ~ 12.085 (bs, 1
H), 7.827 (d, 2 H, J = 9 Hz), 7.605 (d, 2 H, J = 9
Hz), 7.259 - 7.142 (m, 5 H), 6.830 (s, 1 H), 3.017 (t,
2 H, J = 7.5 Hz), 2.785 (t, 2 H, J = 7.5 Hz).
~ WO95/14014 PCT~S94112367
~74~
- 59 -
~ mpl~ 8
~-n~.G~ 6-phcnyl-3-t(phe~ylmethyl)~thio]-2H-pyr~-2-
one: The title compound was prepared by Method A using
1-phenyl-1-(trimethylsilyloxy)ethylene (1.00 g, 5.19
mmol) and the diethyl ester of t(phenylmethyl)thioJ-
propandioic acid (0.977 g, 3.46 mmol). m.p. 155-
160 C; lH NMR (250 MHz, DMSO-d6) ~ 4.00 (s, 2H), 6.74
(s, 1 H), 7.23 (m, 5 H), 7.53 (m, 3 H), 7.78 (m,2 H).
B~pl~ 9
~-~ydlO~y 6-ph~nyl-3-t(phenylmethyl)amino]-2~-pyr~n-2-
one: The title compound was prepared by method D using
3-amino-4-hydlosy-6-phenyl-2H-pyran-2-one
hydrochloride (0.500 g, 2.08 mmol), 1% acetic acid in
dimethylformamide (20 mL), benzaldehyde (0.233mL, 2.29
mmol), sodium cy~n~h~rohydride (0.144 g, 2.29 mmol).
m.p. dec. 205 C, 1 H NMR (250 MHZ, DMSO-d6) ~ 4.37 (s,
2 H), 6.56 (s, 1 H), 7.27 (m, 5 H), 7.45 (m, 3 H),
7.67 (m, 2 H).
E~ple 10
N-(1,1-Dimethyl~thyl)-N'-(4-hydrosy-2 G~ 6-phenyl-2H-
pyran-3-yl)-N'-~phenylmethyl) ~rea: To a suspension
of 4-hyd~ox~-6-phenyl-3-(phenylmethyl)amino-
2H-pyran-2-one, mono~dlG~hloride (0.153 mmol) in
ethyl acetate (10 ml) was added N-methylmorpholine
(2.0 ml) and tert-butyl isocyanate (2.0 ml). The
reaction was allowed to stir for 2.5 hrs and then
quenched by dilution with ethyl acetate. The organic
layer was washed with 5% citric acid and saturated
sodium chloride and was dried over anhydrous magnesium
sulfate. After evaporation of the solvents in vacuo ,
the crude product was purified by column
chromatography (silica gel-230 to 400 mesh) using 5%
methanol in dichloromethane as eluents.
lH NNR (250 MHz, DMSO-d6) ~ 1.24 (s, 9H), 4.47 (dd, 2
H), 5.45 (bs, 1 H), 7.23 (m, 5 H), 7.51 (m, 3 H), 7.75
(m, 2 H).
W095/14014 2 ~ PCT~S94/12367 ~
- 60 -
E~ample 1~
~ ~ v~-3-~2-naphthalenylmethyl)thio]-6-phenyl-
2H-pyran-2-o~: The title compound was prepared by
Method A using l-phenyl-1-(trimethylsilyloxy)ethylene
S (0.475 g, 2.46 mmol) and dimethyl ester of t(2-
naphthalenylmethyl)thio~propanedioic acid (0.500 g,
1.64 mmol). m.p. dec>250 C; lH NMR (250 MHz, DMSO-d6)
4.06 (s, 2 H), 6.47 (s, 1 H), 7.46 (m, 6 H), 7.78
(m, 6 H).
~s~mple 12
~ 6.y 3-t(2-naphthalonylthio]-6-phonyl-
2~ -2-one: The title compound was prepared by
Method A using l-phenyl-1-(trimethylsilyloxy)
ethylene (1.33, 6.90 mmol) and diethyl ester of [(2-
naph~hAle~yl)thio]-prop~ne~;oic acid (2.00 g, 6.29
mmol). m.p. dec. 246 C; lH NMR (250 MHz, DMSO-d6)
6.95 (sl), 7.38 (m, 3 H), 7.56 (m, 4 H), 7.85
(m, 5 H).
Exampl~ 13
LG"~-3-[(phonylmethyl)thio]-6-
(2,~,6-trimethylphenyl)-2~-pyran-2-ono: The title
compound was prepared by Nethod A using 2',4',6'-
trimethylacetoph~nnne (1.86 g, 11.5 mmol), lithium
bis(trimethylsilyl)amide (2.11 g, 12.65 mmol),
chlorotrimethylsilane tl.60 mL, 12.65 mmol), THF (127
mL), and diethyl ester of
[(phenylmethyl)thioJpropAn~;oic acid (2.95 g, 10.4
mmol). m.p. 134-136 C; 'H NMR (250 MHz, DMSO-d6)
2.11 (s, 6 H), 2.26 (s, 3 H), 3.98 (s, 2 H), 6.03
(s, 1 H), 6.96 (s, 2 H), 7.25 (m, 5 H), 11.85
(bs, 1 H).
Esampl~ 1~
~-Hyarosy-6-t4-[2-(4-morpholinyl)etho~y~phe~yl]-3-
~tphonylmethyl~thio]-2~-pyr~n-2-one: The title
compound was prepared by Method A using 4'-~2-(4-
WO 95/14014 ~ 1 7 ~ 1 2 ~ PCT~US94/12367
-- 61 --
morpholinyl)ethoxy]acetophenone (1.31 g, 5.29 mmol),
lithium bis(trimethylsilyl)amide (0.972 g, 5.81 mmol),
chlorotrimethylsilane (0.738 mL, 5.81 mmol), THF (58
mL), and diethyl ester of [(phenylmethyl)thio]
propanedioic acid (1.35 g, 4.80 mmol). m.p. dec.
207 C; lH NMR (2S0 MHz, DMSO-d6) ~ 2.54 (s, 2 H), 6.89
(m, 4 H), 2.83 (t, 2 H), 3.55 (m, 4 H), 3.96 (s, 2 H),
4.22 (t, 2 H), 6.58 (s, 1 H), 7.08 (d, 2 H), 7.23
(m, 5 H), 7.73 (d, 2 H).
~s~mple 15
~-~y~rosy-6-(2-naphthalenyl)-3-~(phenylmethyl)thio]-
2~-pyr~n-2-ono: The title compound was prepared by
Method A using 2-acetyl naphthalene (1.97 g, 11.6
mmol), lithium bis(trimethylsilyl)amide (2.13 g, 12.76
mmol), chlorotrimethylsilane (1.61 mL, 12.76 mmol),
THF (127 mL), and diethyl ester of
[(phenylmethyl)thio]-propanedioic acid (2.90 g, 10.5
mmol). m.p. dec. 203 C; lH NMR (250 MHz, DMSO-d6) ~
4.04 (s, 2 H), 6.89 (s, 1 H), 7.23 (m, 5 H), 7.61 ~m,
2 H), 7.84 (d, 2 H), 8.05 (m, 3 H), 8.43 (s, 1 H),
11.95 (bs, 1 H).
EKample 16
4-Hydroxy-6-phonyl-3-t(phenylthio)methyl]-
2~-pyra~-2-one : The title compound was prepared by
Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
g, 5.31 mmol), ethanol (10 mL), paraformaldehyde
(0.175 g, 5.80 mmol), thiophenol (1.40 mL, 13.8 mmol),
piperdine (0.5 mL), acetic acid (0.5mL). m.p. dec.
211 C; lH NMR (400 MHz, DMSO-d6) ~ 3.98 (s, 2 H), 6.73
(s, 1 H), 7.17 (m, 1 H), 7.30 (m, 2 H), 7.37 (m, 2 H),
7.54 (m, 3 H), 7.77 (m, 2 H), 12.05 (bs, 1 H).
~xample 17
~-~y~rosy-6-(~-hy~rosyphenyl)-3-~(phenylmethyl)thio]-
2~-pyr~n-2-one: The title compound was prepared by
Method A using 4'-hydroxyacetophenone (0.722 g, 5.31
WO95/14014 ~i 7 ~ ~ 2 ~ PCT~S94/12367
- 62 -
mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6
mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF
(116 mL), and diethyl ester of
[(phenylmethyl)thio~prop~n~;oic acid (1.00 g, 3.54
S mmol). m.p. dec. 204 C; lH NNR t250 MHz, DMSO-d6) 8
3.96 (s, 2 H), 6.55 (s, 1 H), 6.88 (d, 2 H), 7.39
(m, 5 H), 7.63 (d, 2 H), 10.28 (s, 1 H), 11.75
(bs, 1 H).
~ample 18
~-~ydro~y-6-~-metho~yphenyl)-3-t(phe~yl~ethyl)thio]-
2~-pyr~n-2-one : The title compound was prepared by
Method A using 4'-methoxyacetophenone (0.797 g, 5.31
mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84
mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol),
THF (58 mL), and diethyl ester of
[(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54
mmol). m.p. dec. 187 C; lH NMR (400 MHz, DMSO-d6) ~
3.83 (s, 3 H), 3.98 (s, 2 H), 6.62 (s, 1 H), 7.06 (m,
2 H), 7.22 (m, 5 H), 7.73 (m, 2 H), 11.76 (bs, 1 H).
13s~pl~ 9
~-~y~rosy-6-(~-methylphenyl)-3-~phonylmethyl)thio~-
2~-pyr~n-2-one : The title compound was prepared by
Method A using 4'-methylacetophenone (0.712 g, 5.31
mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84
mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol),
THF (58 mL), and diethyl ester of
[(phenylmethyl)thio]-prop~e~;oic acid (1.00 g, 3.54
mmol). m.p. dec. 205 oc; lH NMR (400 MHz, DMSO-d6) 8
2.37 (s, 3 H), 3.99 (s, 2 H), 6.69 (s, 1 H), 7.26
(m, 7 H), 7.68 (m, 2 H), 11.83 (bs, 1 H).
Exampl~ 20
3-[Bislphcnyl~ethyl)~cino]-~-hydroxy-6-phenyl-
2~-pyr~n-2-one: The title compound was prepared by
Method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-
one hydrochloride (0.150 g, 0.626 mmol), 1% acetic
WO 95/14014 ~ ~ 7 4 1 2~ PCT/US94/12367
- 63 -
acid in dimethylformamide (7 mL), benzaldehyde (0.133
mL, 1.33 mmol), sodium cyanoborohydride (0.083 g, 1.31
mmol). m.p. 130-135 C; lH NMR (400 MHz, DMSO-d6)
4.26 (s, 4 H), 6.44 (s, 1 H), 7.24 (m, 6 H), 7.44
s (m, 7 H)j 7.69 (m, 2 H).
t
pl~ 21
~-Hydroxy-6-phenyl-3-~2-phenylethyl)thio]-
2~-pyr~n-2-on~: The title compound was prepared by
Me~hod B using 4-hydloxy-6-phenyl-2H-pyran-2-one
(0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
~yd~oxide (2.65 mL), 2-phenylethyl-p-
toluenethiosulfonate (0.770 g, 2.65 mmol). m.p.
121-124 C; lH NMR (400 MHz, DMSO-d6) ~ 2.78 (t, 2 H),
2.99 (t, 2 H), 6.80 ~s, 1 H), 7.24 (m, 5 H), 7.54 (m,
3 H), 7.80 (m, 2 H).
Ex~mpl~ 22
4-~ydro~y-6-phenyl-3-tt3-phenylpropyl)thio]-
2H-pyra~-2-one : The title compound was prepared by
Method A using 1-Phenyl-l-(trimethylsilyloxy)ethylene
(0.922 g, 4.83 ol) and diethyl ester of [(3-
phenylpropyl)thio]prorAne~i~oic acid (1.00 g, 3.22
mmol). m.p. 114-116 C; lH NMR (400 MHz, DMSO-d6)
~ 1.74 (m, 2 H), 2.71 (m, 4 H), 6.82 (m, 1 H), 7.16
(m, 3 H), 7.25 (m, 2 H), 7.54 (m, 3 H), 7.81 (m, 2 H),
11.95 (bs, 1 H).
E~mple 23
~-~y~ro~y-3-t(2-pheno~yethyl)thio]-6-phenyl-
2~-pyran-2-one : The title co~ou~ld was prepared by
Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one
(o.SOO g, 2.65 mmol), ethanol (7 mL), lN sodium
hydroxide (2.65 mL, 2.65 mmol), 2-phenoxyethyl-p-
toluenethiosulfonate (0.816 g, 2.65 mmol). m.p.
146-149 C; lH NMR (400 MHz, DMSO-d6) ~ 3.12 (t, 2 H),
4.11 (t, 2 H), 6.81 (s, 1 H), 6.88 (m, 3 H), 7.24 (m,
2 H), 7.54 (m, 3 H), 7.81 (m, 2 H)~ 12.04 (bs, 1 H).
W095tl4014 ~ PCT~S94/1~67
- 64 -
Illpl8 2~
~-Hyd.v~ 6-(2-methylphen~ 3-t~phenyluethyl)thio~-
2H-pyran-2-one: The title compound was prepared by
Method A using 2'-methylacetophenone (0.712 g, 5.31
mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84
mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol),
THF (58 mL), and diethyl ester of
[(phenylmethyl)thio]propanedioic acid (1.00 g, 3.S4
mmol). lH NMR (400 NHz, DMSO-d6) ~ 2.34 (s, 3 H), 4.01
(s, 2 H), 6.32 (s, 1 H), 7.32 (m, 9H).
Es~mpl~ 25
4-Ryd~o~y 6 ~2-phenylethyl)-3-[~phenylm~thyl)thio]-
2~-pyr~n-2-one: The title compound was prepared by
Method A using 4-phenethylacetorh~nnn~ (0.786 g, 5.31
mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84
mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol),
THF (58 mL), and diethyl ester of
[(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54
mmol). m.p. 164-166 C; lH NMR (400 MHz, DMSO-d6)
2.75 (t, 3 H), 2.85 (t, 2 H), 3.92 (s, 2 H), 5.92
(s, 1 H), 7.23 (m, 9H), 11.69 (bs, 1 H).
~mple 26
~ d v~ 6-(3-~ v~henyl)-3-~(phenylmethyl)thio]-
2~-pyra~-2-one : The title compound was prepared by
Method A using 3'-hydroxyacetophenone (0.722 g, 5.31
mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6
mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF
(116 mL), and diethyl ester of
[(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54
mmol). m.p. dec. 185 C; lH NMR (400 MHz, DNSO-d6)
4.00 (s, 2 H), 6.66 (s, 1 H), 6.92 (m, 1 H), 7.21
(m, 7 H), 7.32 (m, 1 H).
E~ple 27
~-~ydrosy-6-(~-hydroxyphenyl)-3-l(phenylethyl)thio]-
2H-pyran-2-one : The title compound was prepared by
WO 95/14014 ~ ~ 7 4 ~ ~ 4 PCTIUS94112367
-- 65 --
Method A using 4'-hy~lo~yacetophenone (0.688 g, 5.06
mmol), lithium bis(trimethylsilyl)amide (1.84 g, 11.1
mmol), chlorotrimethylsilane (1.41 mL, 11.1 mmol), THF
(111 mL), and diethyl ester of [(2-
phenylethyl)thio]propAne~;oic acid (1.00 g, 3.37
mmol). H NMR (400 MHz, DMSO-d6) ~ 2.78 (t, 2 H), 2.95
(t, 2 H), 6.62 (s, 1 H), 6.89 (dd, 2 H), 7.21
(m, 5 H), 7.65 (d, 2 H), 10.22 (s, 1 H), 11.05
(bs, 1 H).
Es~mple 28
4-~ydkoA~ ~-phenyl-3-[3-(phenyl-2-propenyl)thio]-
2~-pyr~n 2-one, ~E)-: The title compound was prepared
by Method B using 4-hyd~ -6-phenyl-2H-pyran-2-one
~5 (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
hydroxide (2.65 mL), 3-phenyl-2-~o~enyl-p-
toluenethiosulfonate (0.808 g, 2.65 mmol). m.p.
133-136 C; lH NMR (400 MHz, DMSO-d6) ~ 3.57 (d, 2 H),
6.24 (dt, 2 H), 6.76 (s, 1 H), 7.24 (m, 5 H), 7.51 (m,
3 H~, 7.78 (m, 2 H).
- Esampl~ 29
3-tt2-phenylethyl)thio]-6-t~-
~phenylm~tho~y)phe~yl]-2~-pyran-2-one : The title
com~o~,d was prepared by Method A using 4'-
benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium
bis(trimethylsilyl)amide (0.930 g, 5.56 mmol),
chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57
mL), and diethyl ester of [(2-
phenylethyl)thio~propanedioic acid (1.00 g, 3.37
mmol). m.p. 139-142 C; lH NMR (400 MHz, DMSO-d6)
2.77 (t, 2 H), 2.98 (t, 2 H), 5.19 (s, 2 H), 6.68
(s, 1 H), 7.26 (m, 7 H), 7.43 (m, 5 H), 7.76 (d, 2 H).
3s Exampl~ 30
~-Hyd.o~ 6-[~-t2-phenylethoxy)phenyl]-3-
[~2-phenylethyl)thio]-2H-pyran-2-one: The title
compound was prepared by Method A using 4'-(2-
WO9S/14014 PCT~S94/12367 ~
- 66 -
phenylethoxy)acetoph~no~ (1.21 g, 5.06 mmol), lithium
bis(trimethylsilyl)amide (0.930 g, 5.56 mmol),
chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF t57
mL), and diethyl ester of ~(2-
phenylethyl)thio]propanedioic acid (l.oo g, 3.37
mmol). m.p. 103-106 C; lH NMR (400 MHz, DMSO-d6) ~ r
2.76 (t, 2 H), 2.97 (t, 2 H), 3.06 (t, 2 H), 4.27 (t,
2 H), 6.67 (s, 1 H), 7.21 (m, 12 H), 7.73 (d, 2 H).
~o E~mple 31
~-~y~roxy-3-tt2-phe~ylethyl)thio~-6-t4-(3-phenyl~ ~o~
y)phenyl]-2~-pyr~n-2-one: The title compound was
prepared by Method A using 4'-(3-
phenyl~l~o~)aceto~heno~e (1.28 g, 5.06 mmol),
lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol),
chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57
mL), and diethyl ester of ~(2-
phenylethyl)thio]propanedioic acid (1.00 g, 3.37
mmol). m.p. 139-142 C; lH NMR (400 MHz, DMSO-d6) ~
2.04 (m, 2 H), 2.84 (m, 4 H), 2.98 (t, 2 H), 4.40 (t,
2 H), 6.68 (s, 1 H), 7.18 (m, 12 H), 7.75 (d, 2 H),
11.86 (bs, 1 H).
~mple 32
~-~y~O~ 6-t2-h~ henyl)-3-[tphenylmethyl)thio3-
2~-pyran-2-one: The title compound was prepared by
Method A using 2'-hydroxyacetophenone (0.722 g, S.31
mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6
mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF
(116 mL), and diethyl ester of
[(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54
mmol). m.p. dec. 189 C; lH NMR (400 MHz, DMSO-d6)
4.01 (s, 2 H), 6.97 (s, 1 H), 7.25 (m, 7 H), 7.71
(d, 1 H), 10.75 (s, 1 H), 11.85 (bs, 1 H).
~s~pl~ 33
4-Hydrosy-6-t3-t2-phenyletho~cy)phenyl]-3-[ t2-Phen
ethyl)thio~-2H-pyr~n-2-one: The title compound was
~ WO g5/14014 ~ i 7 4 1 2~ PCT~S94/1~67
- 67 -
prepared by Method A using 3'-(2-phenylethoxy)-
acetoph~o~e (0.336 g, 1.40 mmol), lithium
bis(trimethylsilyl)amide (0.257 g, 1.54 mmol),
chlorotrimethylsilane (0.195 mL, 1.54 mmol), THF (15
mL), and diethyl ester of ~(2-phenylethyl)thio~-
propanedioic acid (0.417 g, 1.40 mmol). m.p.
104-106 C; lH NMR (400 MHz, DMSO-d6) ~ 2.75 (t, 2 H),
2.97 (t, 2 H), 3.04 (t, 2 H), 4.25 (t, 2 H), 6.79
(s, 1 H), 7.25 (m, 14H), 11.95 (bs, 1 H).
E~mpl~ 3~
4-~ydro~y-6-phenyl-3-tphenyl~phenylthio)mQthyl~-
2~-pyran-2-oue ,~/-)-: The title compound was
prepared by Method E using 4-hydkuxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
benzaldehyde (0.593 mL, 5.84 mmol), thiop~nol (1.40
mL, 13.8 mmol), piperdine (0.5 mL), acetic acid
(O.5mL). m.p. dec. >220 C; lH NNR (400 MHz, DMS0-d6)
~ 5.80 (s, l H), 6.70 (s, 1 H), 7.23 (m, 8H), 7.54
(m, 4 H), 7.74 (m, 2 H).
E~mpl~ 35
~-Hydro~y-3-tt2-(2-~etho~yphenyl)sthyl]thio]-6-phenyl-
2H-pyran-2-one: The title compound was prepared by
Method B using 4-hy~lo~y-6-phenyl-2H-pyran-2-one
(0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
hydroxide (2.65 mL), 2-(2-methoxyphenyl)ethyl p-
toluenethiosulfonate (0.856 g, 2.65 mmol). m.p.
114-115 C; lH NMR (400 MHz, DMSO-d6) ~ 2.74 (t, 2 H),
2.94 (t, 2 H), 3.73 (s, 1 H), 6.85 (m, 3 H), 7.15 (m,
2 H), 7.54 (m, 3 H), 7.82 (m, 2 H).
Es~mpl~ 36
4-Hydroxy-6-phenyl-3-~(4-phenylbutyl)thio]-
2~-pyr~n-2-one: The title compound was prepared by
Method B using 4-hy~Lu~y-6-phenyl-2H-pyran-2-one
(0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
hydroxide (2.65 m~), 4-phenylbutyl-p-
-
WO 95/14014 PCT/US94/12367
- 68 -
toluenethiosulfonate (0.851 g, 2.65 mmol). m.p.
103-105 C; lH NMR (400 MHz, DMSO-d6) 8 1.47 (m, 2 H),
1.66 (m, 2 H), 2.54 (t, 2 H), 2.77 (t, 2 H), 6.80
(s, 1 H), 7.17 (m, 5 H), 7.53 (m, 3 H), 7.81 (m, 2 H).
s
Ex~mpl~ 37
~-L~d~GA~-3-t~2-~3-methoxyphenyl)ethyl]thio]-6-phenyl-
28-pyran-2-on~: The title compound was prepared by
Method B using 4-hyd~ux~-6-phenyl-2H-pyran-2-one
(0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
hy~u~ide (2.65 mL), 2-(3-methoxyphenyl)ethyl-p-
toluenethiosulfonate (0.856 g, 2.65 mmol). m.p.
112-113 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.75 (t, 2 H),
3.01 (t, 2 H), 3.34 (s, 3 H), 6.75 (s, 1 H), 7.16
(t, 1 H), 7.54 (m, 3 H), 7.80 (m, 2 H).
Bx~ple 38
~-8ydrosy-3-tt2-~-~etho~yphenyl)ethyl~thio]-6-phen~
28-pyran-2-one: The title compound was prepared by
Method B using 4-hydlo~-6-phenyl-2H-pyran-2-one
(0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
h~dLGxide (2.65 mL), 2-(4-methoxyphenyl)ethyl-p-
toluenethiosulfonate (0.856 g, 2.65 mmol). m.p.
144-145 C; lH NMR (400 MHz, DMSO-d6) ~ 2.71 (t, 2 H),
2.96 (t, 2 H), 3.66 (s, 3 H), 6.77 (s, 1 H), 6.80 (d,
2 H), 7.12 (d, 2 H), 7.54 (m, 3 H), 7.80 (m, 2 H).
Example 39
3-[t2-13-Chlorophenyl)ethyl~thio]-~ 6-phenyl-
28-pyran-2-one: The title compound was prepared by
Method B using 4-hydLo~y-6-phenyl-2H-pyran-2-one
(0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
hydroxide (2.65 mL), 2-(2-chlorophenyl)ethyl-p-
toluenethiosulfonate (0.868 g, 2.65 mmol). m.p.
3s 133-134 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.79 (t, 2 H),
3.02 (t, 2 H), 6.77 (s, 1 H), 7.25 (m, 4 H), 7.55 (m,
3 H), 7.81 (m, 2 H).
WO95/14014 ~1 7 ~ 1 24 PCT~Sg4~1~3C7
- 69 -
~plQ ~0
y~ro~y-6-ph~nyl-3-(2-ph~nyl~thyl)-2~-pyran-2-one:
The title compound was prepared by Method F using
Raney-Nickel (Grace 3100), ethanol (20 mL), 4-hydlo~y-
6-phenyl-3-~2-phenyl-1-(phenylthio)ethyl]-2H-pyran-2-
one (0.425 g, 1.06 mmol). m.p. dec. >2S5 C; lH NNR
(400 MHz, DNS0-d6) ~ Z.65 (dd, 2 H), 2.71 (dd, 2 H),
6.68 (s, 1 H), 7.23 (m, 3 H), 7.52 (m, 3 H), 7.76 (m,
2 H), 11.85 (bs, 1 H).
k~a~pl~ 41
~ ~y~v~ 6 ~he~yl-3-(3-ph~nylpropyl)-2~-pyran-2-onQ:
The title compound was prepared by Method F using
Raney-Nickel (Grace 3100), ethanol (15 mL), 4-hyd~o~-
6-phenyl-3-t3-phenyl-1-(phenylthio)propyl]-2H-pyran-2-
one ~( 0.150 g, 0.362 mmol). m.p. 195-196 C; lH NMR
(400 MHz, DMSO-d6) ~ 1.73 (m, 2 H), 2.40 (t, 2 H), 2.60
(t, 2 H), 6.68 (s,,l H), 7.23 (m, 5 H), 7.52 (m, 3 H),
7.74 (m, 2 H).
Esampl~ ~2
6-~2,6-Dimethylphenyl)-~-hydroxy-3-t(phenylmethyl)thio
~-2~-pyran-2-one: The title com~o~.d was prepared by
Method A using 2',6'-dimethyl acetophPnone (0.785 g,
5.31 mmol), lithium bis(trimethylsilyl)amide (~.977 g,
5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84
mmol), THF (58 mL), and diethyl ester of
[(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54
mmol). m.p. 140-143 C; lH NMR (400 MHz, DMSO-d6) ~
2.15 (s, 6 H), 3.99 (s, 2 H), 6.12 (s, 1 H), 7.22 (m,
8H).
Exa~plQ 43
~-~ydro~y-6-t2-hydrosy-3-mQthyl-4-~ph~nylmothosy)
phenyl]-3-[(2-phenylQthyl)thio~-2~-pyr~-2-onQ: The
title compound was prepared by Method A using 4'-
benzyloxy-2'-hydroxy-3'-methylacetophenone (1.29 g,
5.06 mmol), lithium bis(trimethylsilyl)amide (2.11 g,
WO 95/14014 ~ 1 7 4 1 2 4 PCT~S94/1~67 ~
~ - 70
12.6 mmol), chlorotrimethylsilane (1.60 mL, 12.6
mmol), THF (127 mL), and diethyl ester of t(2-
phenylethyl)thio]prop~n~ioic acid (1.00 g, 3.37
mmol). m.p. 147-148 oc; lH NMR (400 MHz, DMSO-d6)
2.14 (s, 3 H), 2.77 (t, 2 H), 2.98 (t, 2 H), 5.17 (s,
2 H), 5.29 (s, 1 H), 6.79 (d, 1 H), 7.30 (m, 13H),
9.36 (s, 1 H), 11.85 (bs, 1 H).
E:~c~pl~ ~
~-n~d v~ 3-t~2-phenylethyl)thio]-6-[3-(phe~ylmetho~y)
ph~nyl]-2H-pyr~n-2-onQ: The title compound was
prepared by Method A using 3'-benzyloxyacetoph~no~e
(1.14 g, 5.06 mmol), lithium bis(trimethylsilyl) amide
(0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL,
5.56 mmol), THF (57 mL), and diethyl ester of [(2-
phenylethyl)thio]prop~ne~;oic acid (1.00 g, 3.37
mmol). m.p. 126-127 C; lH NMR (400 MHz, DMSO-d6)
2.78 (t, 2 H), 3.01 (t, 2 H), 5.20 (s, 2 ~), 6.81
(s, 1 H), 7.22 (m, 6 H), 7.41 (m, 7 H).
Ex~mpl~ ~5
G~ 6- ~ 2-naphthalenyl~etho~y)ph~yl~-3-
~2-phenylethyl)thio]-2H-pyran-2-one: The title
compound was prepared by Method A using 4'-(2-
naphthalenylmethoxy)acetophenone (1.39 g, 5.06 mmol),
lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol),
chlorotrimethylsilane (0.705 mL, 5.56 mmol), ~ (57
mL), and diethyl ester of t(2-
phenylethyl)thio]propanedioic acid (1.00 g, 3.37
mmol). m.p. 152-154 C; lH NMR (400 NHz, DNSO-d6)
2.77 (t, 2 H), 2.98 (t, 2 H), 5.38 (s, 2 H), 6.68
(s, 1 H), 7.21 (m, 7 H), 7.54 (m, 2 H), 7~60 (d, 1 H),
7.96 (m, 4 H).
3s ~sampl~ ~6
6-(3-chloro-~-~etho~yphenyl)-4-~ o~-3-~(phonyl-
m~t~yl)thio]-2H-pyr~n-2-on~: The title compound was
prepared by Method A using 3'-chloro-4'-methoxy
~ WO95/14014 PCT~S94/1~67
~ ~ 7 ~
- 71 -
acetophenone (0.979 g, 5.31 mmol), lithium
bis(trimethylsilyl)amide (0.977 g, 5.84 mmol),
chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58
mL), and diethyl ester of ~(phenylmethyl)-
thio]prop~ne~ioic acid (1.00 g, 3.54 mmol). m.p. dec.
171 oc; lH NMR (400 MHz, DMSO-d6) ~ 3.93 (s, 3 H), 3.99
(s, 2 H), 6.68 (s, 1 H), 7.32 (m, 6 H), 7.77 (d, 1 H),
7.83 (d, 1 H).
~sampl~ ~7
~ .6~y 6 ~snyl-3-[(phenylmethyl)su~fonyl]-2~-
pyr~n-2-one: This compound was prepared by oxidation
of 4-hyd~o~-6-phenyl-3-~(phenylmethyl)thio]-2H-Pyran-
2-one (1 mmol, 310mg) with oxone (3 mmol, l.99g) at
room temperature in lOmL of methanol and lOmL of
water. After stirring the reaction mixture at room
temperature for 4 hours the mixture was diluted with
water and extracted with 50mL of dichloromethane. The
organic layer was dried over anhydrous magnesium
sulfate. Solvents were evaporated. The residual,
a solid was pure by tlc. Isolated yield: 90%. m.p.
152-153 C lH NMR (400 MHz, CDCl3) ~ 11.34 (s, 1 H),
7.8 (m, 2 H), 7.5 (m, 3 H), 7.37 (m, 3 H), 7.27 (m, 2
H), 6.37 (s, 1 H), 6.23 (s, 1 H), 4.75 (s, 1 H), 4.34
(q, 2 H); IR (KBr) 3421, 3059, 1726, 1698, 1628, 1559,
1497, 1230, 957, 770, 689 cm~1; MS (CI) m/e 343 (6.8),
327 (15.54), 278 (15.99), 219 (40.99), 91 (100).
Es~mpl~ ~8
4-Hydroxy-6-(3-methylphenyl)-3-[~phenylmethyl)thio]-
2H-pyr~n-2-one: This compound was prepared by the
condensation of the diethyl ester of
~(phenylmethyl)thio]-pro~ne~ioic acid (1 g, 3.54
~mol) with the colLe~ ding trimethylsilyl enol ether
of 3~-methyl acetophenone (7.09 mmol, 1.46g) as
described in general procedure A. Isolated Yield: 65%
m.p. 137-138 oc lH NMR (400 MHz, DMS0-d6) ~ 11.9
(brs, 1 H), 7.6 (m, 2 H), 7.39 (t, 1 H), 7.35
,
WO9S/14014 PCT~S94/1~67
- 72 -
(d, 1 H), 7.25 (d, 4 H), 7.2 (m, 1 H), 6.7 (s, 1 H),
4.0 (s, 2 H), 2.38 (s, 3 H); IR (KBr) 3030, 2585,
1617, 1536, 1402, 1100, 787, 696 cm-1; MS (CI) m/e 325
(65), 291 (2), 233 (4), 119 (9), 91 (100).
s
B ~mple 49
2-O~c 6 ~,henyl-3-ttphenylm~thyl)thioJ-2H-pyr~n-4-
ylprop~noic aci~ ~ster: This compound was prepared by
the treatment of sodium salt of 4 l-~dloxy-6-phenyl-
3-[(phenylmethyl)thio]-2H-pyran-2-one (310m g, 1 mmol)
with propionyl chloride (2.4 mmol, 222mg) as described
in the general proce~ e G. Isolated Yield: 72%. :
lH NMR (400 MHz, DMS0-d6) d 7.77 (m, 2 H), 7.51.m (3),
7.22 (m, 4 H), 7.17 (m, 1 H), 6.7 (s, 1 H), 3.98 (s, 2
H), 2.19 (q, 2 H), 0.96 (t, 3 H); IR (KBr) 3438, 3027,
2923, 1772, 1731, 1617, 1528, 1494, 1453, 1323, 1153,
1087, 1045, 979, 873, 767, 702 cm-1; MS (CI) m/e 366
(4), 311 (79), 189 (26), 105 (20), 91 (100).
Exampl~ So
4-~ydro~y-6-t3-methyl-4-(phe~yl~ethyloYy)phQ~yl]-3-
~2-phenylethyl)thio]-2H-pyr~n-2-one : Co~P~cAtion
of diethylester of ~(phenylethyl)thio]prop~n~;oic
acid (1.06 g, 3.6 mmol) with the trimethylsilyl enol
ether of 3'-methoxy-4'-benzyloxyacetorhDnone (2.24 g,
7.2 mmol) was performed as described in general
procedure A. Isolated yield: 78%. m.p. 147-148 C: lH
NMR (400 MHz, DMS0-d6) ~ 7.63 (m, 2 H), 7.11-7.S3 (m,
llH), 6.68 (s, 1 H), 5.22 (s, 1 H), 2.98 (t, 2 H),
2.77 (t, 2 H), 2.27 (s, 3 H); IR (KBr) 3432, 3030,
2922, 1717, 1626, 1503, 1408, 12~2, 1140, 1024, 696
cm-1; MS (CI) m/e 445 (2.12), 3553.34, 309 (3.81), 189
(8.33), 156 (14.78), 137 (16.19), 105 (94.34), 91
(100); Analysis calc'd for : C, 72.95; H, 5.44;
found: C, 72.25; H, 5.43.
Ex~mple 51
~ WO95/14014 2 ~ ~ 4 ~ ~ PCT~S94112367
- 73 -
~ .6~ 6-(~-hydrosy-2-~ethylphenyl)-3-t2-
phenylethyl)thio~-2H-pyr~n-2-o~e : This compund is
prepared by the condensation of diethyl ester of
~(phenylethyl)thio]propanedioic acid (1 g, 3.38 mmol)
with the correspo~; ng trimethylsilyl enol ether of
4'-hyd-u~-2'-methyl acetophPno~e (2.94 g, 10 mmol) as
described in the general procedure A. Isolated yield:
52% m.p. 85-87 C lH NMR (400 MHz, DMSO-d6) ~ 11.89
(brs, 1 H), 9.97 (s, 1 H), 7.35 (d, 1 H), 7.23
(m, 5 H), 6.72 (s, 2 H), 6.33 (s, 1 H), 3.o (t, 2 H),
2.78 (t, 2 H), 2.34 (s, 3 H); IR (KBr) 3300, 2926,
1672, 1604, 1541, 1244, 1194, 1120, 698 cm-1; MS (CI)
m/e 355 (36), 250 (27), 105 (93), 91 (30), 85 (100);
Analysis calc'd for: C, 67.78; H, 5.12; found: C,
67.53; H, 5.40.
E~ple 52
~-~ydrosy-6-(~-metho~y-3-m~thylphenyl)-3-
~phenylmethyl)thio]-2H-pyr~n-2-one: This com~o~,d is
prepared by the con~nC~tion of diethyl ester of
[(phenylmethyl)thio]propAn~;oic acid (1 g, mmol) with
the COL r e~ol~ding trimethylsilylenol ether of 4~-
methoxy-3'-methylacetophenone as described in general
pro~e~l~re A. Isolated Yield: 68%. m. p. 159-106 C lH
NMR (400 MHz, CDCl3) ~ 7.67 (dd, 1 H), 7.61 (s, 1 H),
7.2 (m, 5 H), 6.8 (d, 1 H), 6.38 (s, 1 H), 3.96 (s, 2
H), 3.89 (s, 3 H), 2.25 (s, 3 H); IR (KBr) 3432, 2945,
1613, 1507, 1402, 1262, 1142, 1030, 812, 704 cm-1; MS
(CI) m/e 355 (78.3), 263 (lg.6), 235 (11.8), 149
(12.7), 91 (100); Analysis calc'd for : C, 67.78; H,
5.12; found: C, 67.35; H, 5.17.
Ex~mple 53
2-O~ 6 ~henyl-3-~(phenylmethyl)thio]-2~-pyr~n-~-
yl~cetic acid ester: This compound was prepared by the
treatment of sodium salt of 4-hydroxy-6-phenyl-3-
[(phenylmethyl)thio]-2H-pyran-2-one, (310 mg, 1.00
mmol) with acetyl chloride (188mg, 2.4 mmol) as
WO95/14014 PCT~S94/12367 ~
~ 17 ~
- 74 -
described in general ~Lv~c~ e G. Isolated yield: 72~.
lH NNR (400 MHz, DMSO-d6) ~ 7.81 (m, 2 H), 7.53 (m,
3 H), 7.22 (m, 4 H), 7.16 (m, 1 H), 3.99 (s, 2 H),
1.92 (s, 3 H).
~xample 5~
2-Oso-6-phenyl-2~-pyran-~-yl-1-naphthal~nsca~lG-yliC
acid ester: This com~v~,d was prepared by Method G
using 4-h~L~y-6-phenyl-2H-pyran-2-one (0.250 g, 1.32
mmol), THF (15 mL), 60% sodium hydride (0.585 g, 1.46
mmol), 1-naphthoyl chloride (0.278 g, 1.46 mmol).
m.p. 123.5-125; lH NMR (250 MHz, DMSO-d6) ~ 6.54
(s, 1 H), 7.49 (s, 1 H), 7.65 (m, 6 H), 7.95 (m, 2 H),
8.13 (d, 1 H), 8.34 (d, 1 H), 8.50 (d, 1 H).
E~mplQ S5
3,3'-Thiobis[~-hyd.G~y 6 ~henyl-2~-pyr n-2-one~: This
compound was synthesized by the following method:
4-hydroxy-6-phenyl-2H-pyran-2-one (0.250 g, 1.33 mmol)
was gradually added to thionyl chloride (0.585 ml).
The reaction was allowed to stir at room temperature
overnight. The unreacted thionyl chloride was removed
in vacuo and residue was recrystallized from boiling
methanol. m.p. >240C; lH NMR (250 MHz, d-TFA) ~ 7.03
(s, 2 H), 7.56 (m, 6 H), 7.89 (m, 4 H).
Example 56
3,3'-Dithiobis~-hyd.~y ~-phenyl-2X-pyran-2-one]:
Sul~ur monochloride (0.105 mL, 1.32 mmol) was
dissolved in benzene (1 ml), and the solution was
added dropwise to a suspension of 4-hydroxy-6-phenyl-
2H-pyran-2-one (0.500 g, 2.65 mmol) in benzene (7 ml)
while the 5l~cr~ncion was being refluxed. The reflux
was continued for 1.5hrs. The reaction was ~l~nch~
with a few drops of water, and the light tan product
was collected by filtration. The solid was
recrystallization from boiling acetic acid. m.p.
W095/14014 ~ 17 ~ 1 Z4 PCT~S94/1~67
- 75 -
dec~280 C; lH NMR (250 MHz, DMSO-d6) ~ 6.77 (s, 2 H),
7.52 (m, 6 H), 7.81 (m, 4 H).
Es~mpl~ 57
S 3-r~n~yl-~-hyd 6Ay 6-phQnyl-2H-pyran-2-one: To a
solution of ethyl benzoylacetate (150 g, 0.88 mmol) in
1,2-dichlorobenzene (150mL) was added a trace amount
of sodium bicarbonate. The reaction mixture was
heated to reflux. A distillate of ethanol
(a~-o~imately 20mL) was collected. The reaction
mixture was cooled to O C. Ether (lOOmL) was added
to induce crystallization. The reaction mixture was
kept in the refrigerator overnight. The solid formed
was collected and washed with ether: m.p. 171-173 C;
lH NMR (250 MHz, DMSO-d6) ~ 6.91 (s, 1 H), 7.59
(m, 6 H), 7.87 (m, 4 H).
EYampl~ 58
N-~-n~ o~ 2-oxo-6-phenyl-2~-pyran-3-yl)benzene-
~cot~mide: The title com~.d was prepared by Method E
using 3-amino-4-hydlGs~-6-phenyl-2H-pyran-2-one
hydrochloride (0.150 g, 0.626 mmol), methylene
chloride (6 mL), triethylamine (0.348 mL, 2.50 mmol),
catalytic 4-dimethylaminopyridine, ph~n~cetyl chloride
(0.106 g, 0.626 mmol). m.p. dec. 213 C; lH NMR (250
MHz, DMSO-d6) ~ 3.69 (s, 2 H), 6.85 (s, 1 H), 7.29
(m, 4 H), 7.53 (m, 3 H), 7.83 (m, 2 H), 9.40
(bs, 1 H).
Example 59
2-oxo-6-phenyl-2~-pyran-4-yl-2-naphthal~n~c~rh~Yylic
~cid e~ter: The title compound was prepared by Method
G using 4-hydlox~-6-phenyl-2H-pyran-2-one (0.200 g,
0.835 mmol), methylene chloride (8 mL), triethylamine
(0.348 mL, 2.50 mmol), catalytic 4-
dimethylaminopyridine, 2-naphthoyl chloride (0.175 g,
0.918 mmol). m.p. 143.5-144 C; lH NMR (250 MHz,
WO95/14014 PCT~S94/12367
- 76 -
DMSO-d6) ~ 6.51 (s, 1 H), 7.51 (m, 3 H), 7.72 (m, 3 H),
8.80 (m, 7 H), 8.89 (bs, 1 H).
mpl~ CO
3-r8is~2-n~phthalenylmethyl)amino]-4-hy~kG~ 6 ~henyl-
2~-pyran-2-one: The title compound was prepared by
Method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-
one hydrochloride (0.250 g, 1.04 mmol), 1% acetic acid
in dimethylformamide (10 mL), 2-naphthaldehyde (0.407
g, 2.60 mmol), sodium cyanoborohydride (0.164 g, 2.60
mmol). m.p. dec. 209; lH NMR (250 MHz, DMSO-d6) ~ 4.46
(s, 4 H), 6.38 (s, 1 H), 7.44 (m, 8H), 7.77 (m, 13H).
Ex~mpl~ 61
N-(~-~ydroxy-2 o~o 6-phenyl-2H-pyran-3-yl)-
2-naphthalenea~tamide : The title compound was
prepared by Method E using 3-amino-4-hydLu~y-6-phenyl-
2H-pyran-2-one hydrochloride (0.200 g, 0.835 mmol),
THF (9 mL), 60 % sodium hydride (0.037 mL, 0.918
mmol), oxalyl chloride (0.080 mL, 0.918 mmol), 2-
naphthalyl acetic acid (0.170 g, 0.918 mmol). m.p.
dec. 227 C; lH NMR (250 MHz, DMSO-d6) ~ 4.17 (s, 2 H),
6.84 (s, 1 H), 7.50 (m, 6 H), 7.83 (m, 4 H), 7.93
(d, 1 H), 8.17 (d, 1 H), 9.58 (s, 1 H).
Example 62
N-(~-Hydro~y-2 o~o 6-phenyl-2H-pyran-3-yl)-
2-n~phth~lQn~c~-boxamide: The title compound was
prepared by Method E using 3-amino-4-hydroxy-6-phenyl-
2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol),
THF (6 mL), 60 ~ sodium hydride (0.028 mL, 0.688
mmol), 2-naphthoyl chloride (0.131 g, 0.688 mmol).
m.p. dec. 219 C; lH NMR (250 MHz, DMSO-d6) ~ 6.92
(s, 1 H), 7.61 (m, 5 H), 7.97 (m, 6 H), 8.62 (s, 1 H),
9.61 (s, 1 H).
Example 63
N-(4-Hydroxy-2 O~G ~-phenyl-2H-pyran-3-yl3benzene-
WO g5/14014 PCTJUS94~12367
~74~24
- 77 -
pror~n-~ido: The title compound was prepared by Method
E using 3-amino-4-hy~ox~-6-phenyl-2H-pyran-2-one
hydrochloride (0.150 g, 0.626 mmol), THF (6 mL~, 60 %
sodium hydride (0.028 mL, 0.688 mmol), hydrocinnamyl
S chloride (0.131 g, 0.688 mmol). m.p. 191-193 C; lH
NMR (250 MHz, DMSO-d6) ~ 2.65 (t, 2 H), 2.89 (t, 2 H),
6.86 (s, 1 H), 7.26 (m, 5 H), 7.53 (m, 3 H), 7.84 (m,
2 H), 9.28 (s, 1 H).
Bsample 6~
6~ 3-Ren~ Yol-5-yl) -4-hydro2y-3-
ttphenylmethyl)thio]-2~-pyr~n-2-one: The title
compound was prepared by Method A using 3',4'-
(methylenedioxy)acetophenone (0.871 g, 5.31 mmol),
lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol),
chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58
mL), and diethyl ester of [(phenylmethyl)thio]
propanedioic acid (1.00 g, 3.54 mmol). m.p. dec.
170 C; 1H NMR (400 MHz, DMSO-d6) ~ 3.98 (s, 2 H), 6.13
(s, 2 H), 6.61 (s, 1 H), 7.0S (d, 2 H), 7.27 (m, 7 H).
E~ample 65
6-t~-(Benzoyloxy)phenyl~-~-h~GAy-3-~(phenylmethyl)
thio]-2~-pyran-2-o~e: The title compound was prepared
by Method A using 4'-benzoyloxyacetophPn~ne (1.27 g,
5.31 mmol), lithium bis(trimethyl-silyl)amide (0.977
g, 5.84 mmol), chlorotrimethyl-silane (0.741 mL, 5.84
mmol), THF (58 mL), and diethyl ester of
t(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54
mmol). m.p. dec. 205 C; 'H NMR (400 MHz, DMSO-d6)
4.01 (s, 2 H), 6.75 (s, 1 H), 7.21 (m, 1 H), 7.25
(d, 4 H), 7.47 (d, 2 H), 7.63 (t, 2 H), 7.77 (t, 1 H),
7.90 (d, 2 H), 8.16 (d, 2 H).
~xample CC
3-tCyclohe~yl(phenylthio)methyl]-~-hyd~G~ ~-phenyl-2
-pyran-2-one: The title compound was prepared by
Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
WO95/14014 PCT~S94/1~67 ~
~17~1~4
- 78 -
g, 5.31 mmol), ethanol (10 mL), cyclnh~Y~e-
carboxaldehyde (0.707 mL, 5.84 mmol), thiophenol (1.40
mL, 13.8 mmol), piperdine (0.5 mL), acetic acid
(0.5mL). m.p. 87-90 C; lH NMR (400 MHz, DMSO-d6)
1.46 (m, 5 H), 1.61 (m, 4 H), 2.15 (m, 1 H), 2 . 31
(d, 1 H), 4.26 (d, 1 H), 6.65 (s, 1 H), 7.16 (t, 1 H),
7.27 (t, 2 H), 7.37 (d, 2 H), 7.52 (m, 3 H), 7.74 (m,
2 H), 11 . 80 (bs , 1 H) .
IS~c~ple 67
~-~y~ v..2~-3-[ t2-phenylethyl)thio~-6-t4-(phe~ylthio)-
phe~yl]-2H-pyr~n-2-one: The title compound was
prepared by Method A using 4'-(phenylthio)acetophenone
(1.15 g, 5.06 mmol), lithium bis(trimethylsilyl)amide
(0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL,
5.56 ,~ol), THF (56 mL), and diethyl ester of r(2-
phenylethyl)thio]prop~ne~;oic acid (1.00 g, 3.37
mmol). m.p. 120-121 C; lH N~ (400 MHz, DMSO-d6) 8
2.76 (t, 2 H), 2.98 (t, 2 H), 6.72 (s, 1 H), 7.24
(m, 7 H), 7.45 (m, 5 H), 7.74 (d, 2 H).
kY~mpl~ 68
os~-6-t4-t~2-m~thox~he~yl)m~thosy]phenyl~-3-
t~2-phenylethyl)thio]-2H-pyr~n-2-one: The title
compound was prepared by Method A using 4'-t (2-
methoxyphenyl)methoxy]phenylacetoph~none (1. 2 9 g, 5.06
mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56
mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol),
THF (56 mL), and diethyl ester of t(2-
phenylethyl)thio]propanedioic acid (1.00 g, 3.37
mmol). m.p. 138-139 C; lH N~ (400 MHz, DMSO-d6) ~
2.77 (t, 2 H), 2.98 (t, 2 H), 3.83 (s, 3 H), 5.14 (s,
2 H), 6.68 (s, 1 H), 6.97 (t, 1 H), 7.08 (d, 1 H),
7 . 20 (m, 7 H), 7 . 53 (t, 1 H), 7 . 40 (d, 1 H), 7 . 76 (d,
2 H), 11.85 (bs, 1 H).
~xampl~ 69
WO95/14014 ~174:L2~ rcT/usg4J~2367
-- 79 --
~-~ydrosy-6-t4-~2-metho~cyp~Qnyl)metho~y]-3-
methylphonyl]-3-t(2-phenylethyl)thio]-2H-pyr~n-2-ono:
The title compound was prepared by Method A using 4'-
[(2-methoxyphenyl)methoxy]-3'-methylacetophenone (1.36
g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930
g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56
mmol), THF (56 mL), and diethyl ester of [(2-
phenylethyl)thio]prop~n~ioic acid (1.00 g, 3.37
mmol). m.p. dec. 170 C; lH NMR (400 MHz, DMSO-d6) ~
2.25 (s, 3 H), 2.77 (t, 2 H), 2.g7 (t, 2 H), 3.84 (s,
3 H), 5.17 (s, 2 H), 6.67 (s, 1 H), 6.98 (t, 1 H),
7.70 (d, 1 H), 7.27 (m, 6 H), 7.41 (t, 1 H), 7.43
(d, 1 H), 7.65 (m, 2 H), 11.81 (bs, 1 H).
E~pl~ 70
6-(3,5-Dimethylphenyl) -4-~lG_~ 3-t(phenylmethyl)-
thio~-2~-pyran-2-one: The title compound was prepared
by Method A using 3',5'-dimethylacetophenone (0.785 g,
5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g,
5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84
mmol), THF (58 mL), and diethyl ester of
~(phenylmethyl)thio]propAn~Aioic acid (1.00 g, 3.54
mmol). m.p. dec. 170 C; lH NMR (400 MHz, DMSO-d6)
2.33 (s, 6 H), 3.99 (s, 2 H), 6.67 (s, 1 H), 7.21
(m, 6 H), 7.39 (s, 2 H).
E2~mpl~ 71
4-~ydroxy-6-(4-ph~y~henyl)-3-[(2-phenylethyl)thio]-
2~-pyran-2-one: The title compound was prepared by
Method A using 4'-phenoxyacetophenone (1.07 g, 5.06
mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56
mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol),
THF (56 mL), and diethyl ester of [(2-
phenylethyl)thio]propanedioic acid (1.00 g, 3.37
3s mmol). m.p. 127-128 C; lH NMR (400 MHz, DMSO-d6) ~
2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.18 (m,
lOH), 7.46 (t, 2 H), 7.82 (d, 2 H).
WO95/14014 PCT~S94/1~67
- 80 -
Ex~mpl~ 72
~-~ydrosy-6-phenyl-3-~t[4-~phenylmetho~y)phenyl]
methyl]thio]-2~-pyran-2-one: The title compound was
prepared by Method B using 4-hydroxy-6-phenyl-2H-
pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN
sodium hyd~oxide (2.65 mL), [4-
(phenylmethoxy)phenyl]methyl-p-toluenethiosulfonate
(1.01 g, 2.65 mmol). m.p. 185-186 C; lH NMR (400 MHz,
DMS0-d6) ~ 3.94 (s, 2 H), 5.03 (s, 2 H), 6.72 (s, 1 H),
6.89 (d, 2 H), 7.18 (d, 2 H), 7.34 (m, 5 H), 7.46 (m,
3 H), 7.80 (m, 3 H).
Example 73
~-~ydroxy-3-~2-phenylethyl)thio]-6-
~-(2-pyridinylnethoxy)phanyl]-2~-pyran-2-one: The
title compound was prepared by Method A using 4'-(2-
pyridinylmethoxy)acetophenone (1.14 g, 5.06 mmol),
lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol),
chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56
mL), and diethyl ester of [(2-phenylethyl)thio]-
propanedioic acid (1.00 g, 3.37 mmol). m.p. dec.
179 C; lH NMR (400 MHz, DMS0-d6) ~ 2.77 (t, 2 H), 2.98
(t, 2 H), 5.27 (s, 2 H), 6.68 (s, 1 H), 7.22 (m, 7 H),
7.36 (m, 1 H), 7.53 (d, 1 H), 7.77 (d, 2 H), 7.85
(t, 1 H), 8.60 (d, 2 H), 11.88 (bs, 1 H).
~xampl~ 74
~-t~-~ydrosy-2-o~o-3-t~2-phenylethyl)thio]-
2~-pyran-6-yl~phenoxy acetic acid ethyl e~ter: To a
methanol solution (3 ml) of the 4-hydroxy-
6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-
2H-pyran-2-one (0.500 g, 1.47 mmol) was added cesium
- carbonate (0.955 g, 2.94 mmol). The reaction was
stirred for 3 hrs. and is then concentrated in vacuo .
Next, dimethylformamide (15 mL) is added and the
residue is reconcentrated in vacuo to dryness. The
solid is then diluted with dimethylformamide (3 mL)
and bromoethylacetate (0.491 mL, 2.94 mmol) is added.
WO 95114014 PCT/US94/12367
~7~2~
- 81 -
The slurry is then stirred for 3 hrs. The reaction is
quenched by dilution with ethyl acetate (100 mL). The
organic layer is washed in sllcce~ion with; 1 N HCl,
water, saturated sodium chloride; dried over anhydrous
S magnesium sulfate. After evaporation of the solvents
in vacuo, the crude product was purified by flash
column chromatography (sioz-23o to 400 mesh) using a
gradient of 15% ethyl acetate/he~n~s to 50% ethyl
acetate/h~Y~nec to 30~ ethyl acetate/30~ h~Y~nP~/40%
methylene chloride.: m.p. 169-171 C; lH NMR (400 MHz,
DMS0-d6) ~ 1.20 (t, 3 H), 2.75 (t, 2 H), 2.96 (t, 2 H),
4.16 (q, 2 H), 4.87 (s, 2 H), 6.69 (s, 1 H), 7.06 (d,
2 H), 7.19 (m, 5 H), 7.73 (d, 2 H), 11.85 (bs, 1 H).
~xa~ple 75
~-~ydroxy-3-~2-~aphth~le~yl~phenylthio)methyl]-6-
phenyl 2H-pyran-2-one: The title compound was
prepared by Method ~ using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), 2-
naphthaldehyde (0.912 g, 5.84 mmol), thiophenol (1.40
mL, 13.8 mmol), piperdine (0.5 mL), acetic acid
(0.5mL). m.p. 98-101 C; lH NMR (400 MHz, DMSO-d6)
5.96 (s, 1 H), 6.73 (s, 1 H), 7.18 (t, 1 H), 7.36
(m, 4 H), 7.52 (m, 5 H), 7.88 (m, 3 H), 8.07 (s, 1 H).
Example 76
~-Hydroxy-3-t~2-naphth-l~nylthio)phenylmethyl]-6-
phe~yl-2~-Pyran-2-one: The title compound was prepared
by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one
(1.00 g, 5.31 mmol), ethanol (10 mL), benzaldehyde
(0.593 mL, 5.84 mmol), 2-naphthalenethiol (2.21 gL,
13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL).
m.p. dec. 200 C; lH NMR (400 MHz, DMSO-d6) ~ 5.9
(s, 1 H), 6.71 (s, 1 H), 7.20 (m, 5 H), 7.44 (m, 7 H),
7.75 (m, 3 H), 7.82 (m, 2 H).
~xample 77
WO95114014 PCT~S94/12367
- 82 -
~-t~ ~y~v~ 2-oso-3-[(2-phenylethyl)thio]-2~-
pyr~n-6-yl]ph~o~c~tic acid: To a tetrahydrofuran
(10 ml) solution of 4-[4-hydroxy-2-oxo-
3-[(2-phenylethyl)thio]-2H-pyran-6-yl]ph~noxyacetic
s acid, ethyl ester (0.939 mmol) was added lN sodium
hydroxide (2.34 mmol). The reaction was stirred for 5
hrs, and then quenched by addition of water (lo ml)
followed by acidification with conc. hydrochloric acid
to pH 2. The aqueous layer was then extracted with 2X
with ethyl acetate (100 ml). The combined organic
extracts were then washed with saturated sodium
chloride and dried over anhy~Luus magnesium sulfate.
After evaporation of the solvents in vacuo, the crude
product was purified by column chromatography (silica
gel-230 to 400 mesh) using 94/5/1 methylene
chloride/methanol/acetic acid as the eluent. m.p.
182-183 C; lH NMR (400 MHz, DNSO-d6) ~ 2.76 (t, 2 H),
2.97 (t, 2 H), 4.78 (s, 2 H), 6.67 (s, 1 H), 7.06 (d,
2 H), 7.21 (m, 5 H), 7.75 (d, 2 H).
E~mple 78
~-~ydroxy-3-~t2-phe~ylethyl)thio]-6-
[~-(3-pyridinylmethoxy)phenyl]-2~-pyran-2-o~e:
The title compound was prepared by Method A using 4'-
(3-pyridinylmethoxy)acetophenone (1.14 g, 5.06 mmol),
lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol),
chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56
mL), and diethyl ester of [(2-phenylethyl)thio]pro-
p~ne~;oic acid (1.00 g, 3.37 mmol). m.p. 178-179 C;
lH NMR (400 MHz, DMSO-d6) ~ 2.76 (t, 2 H), 2.98 (t, 2
H), 5.25 (s, 2 H), 6.69 (s, 1 H), 7.21 (m, 7 H), 7.45
(q, 1 H), 7.77 (d, 2 H), 7.91 (d, 1 H), 8.57
(bs, 1 H), 8.70 (bs, 1 H).
Example 79
6-r~-(Cyclohe~ylmethoxy)phenyl]-~-hydro~y-3-[(2-
phenylcthyl)thio]-2~-pyran-2-o~e: The title com~o~,ld
was prepared by Method A using 4'-(cyclohexylmethoxy)
~WO95/14014 2~7~ PCT~S94/12367
, - 83 -
acetophenone (2.50 g, 10.77 mmol), lithium
bis(trimethylsilyl)amide (2.70 g~ 16.16 mmol),
chlorotrimethylsilane (2.05 mL,16.16 mmol), THF (107
mL), and diethyl ester of t(2-
phenylethyl)thio]prop~n~;oic acid (1.00 g, 3.37
mmol). m.p. 130-132 C; lH NMR (400 MHz, DMS0-d5) ~
1.15 (m, 5 H), 1.81 (m, 6 H), 2.77 (t, 2 H), 2.97 (t,
2 H), 3.85 (d, 2 H), 6.67 (s, 1 H), 7.21 (m, 5 H),
7.45 (q, 1 H), 7.74 (d, 2 H).
Example 80
~-~ydro~y-3-t~2-pheuylethyl)thio]-6-t~-
~phe~ylsul~onyl)phenyl]-2~-pyran-2-one: The title
compound was prepared by Method A using 4 ' -
(phenylsulfonyl)acetophenone (2.50 g, 9.61 mmol),
lithium bis(trimethylsilyl)amide (2.41 g, 14.42 mmol),
chlorotrimethylsilane (1.83 mL, 14.42 mmol), THF (96
mL), and diethyl ester of [(2-
phenylethyl)thio]pror~n~ioic acid (1.00 g, 3.37
mmol). m.p. 194-195 C; lH NMR (400 MHz, DMS0-d6)
2.76 (t, 2 H), 3.01 (t, 2 H), 6.87 (s, 1 H), 7.19
(m, 5 H), 7.68 (m, 3 H), 8.04 (m, 6 H), 12.05
(bs, 1 H).
~sa~pl~ 81
J. -~ydrosy-3 - ~ ~ 2 -phenylethyl ) thio 1 -6- t ~ ~
be~zoyloxy) phenyl ~ -2~-pyr~n-2 -ono: The title compound
was prepared by Method A using 4'-
benzoyloxyacetophenone (2.50 g, 10.41 mmol), lithium
bis(trimethylsilyl)amide (2.61 g, 15.62 mmol),
chlorotrimethylsilane (1.98 mL,15.62 mmol), THF (100
mL), and diethyl ester of [~2-
phenylethyl)thio]propanedioic acid (1.00 g, 3.37
mmol). m.p. 164-166 C; lH NMR (400 MHz, DMSO-d6)
2.78 (t, 2 H), 3.01 (t, 2 H), 6.81 (s, 1 H), 7.21
(m, S H), 7.49 (d, 2 H), 7.63 (t, 2 H), 7.77
(t, 1 H) ,7.92 (d, 2 H) ,12.00 (bs, 1 H)
wos5/14014 ~7~ PCT~S94/12367
- 84 -
kX~pl~ 82
d.~-3-t(2-phonylethyl)thio]-6-t~-
~ph~nylsulfinyl)phenyl]-2H-pyran-2-one: The title
compound was prepared by Method A using 4'-
(phenylsulfinyl)acetophenone (2.50 g, 10.24 mmol),
lithium bis(trimethylsilyl)amide (2.57 g,15.36 mmol),
chlorotrimethylsilane (1.94 mL,15.36 mmol), THF (100
mL), and diethyl ester of [(2-phenylethyl)thio]-
propAnP~ioic acid (1.00 g, 3.37 mmol). m.p. 171-
173 C; lH NMR (400 MHz, DMSO-d6) S 2.76 (t, 2 H), 3.01
(t, 2 H), 6.83 (s, 1 H), 7.19 (m, 5 H), 7.54 (m, 3 H),
7.75 (d, 2 H), 7.86 (d, 2 H), 7.95 (d, 2 H), 12.05
(bs, 1 H).
k~ample 83
~-Hydrosy-3-[~2-phenylethyl)thio]-6-~-pyridinyl)-
2H-pyran-2-one: The title compound was prepared by
Method A using 4-acetylpyridine (2.50 g, 20.63
mmol), lithium bis(trimethylsilyl)amide (5.17 g, 30.94
mn ol), chlorotrimethylsilane (3.92 mL, 30.94 mmol),
THF (200 mL), and diethyl ester of [(2-
phenylethyl)thio]-propanedioic acid (1.00 g, 3.37
mmol). m.p. dec. 149-152 C; lH NMR (400 MHz, DMSO-d6)
S 2.78 (t, 2 H), 3.04 (t, 2 H), 6.98 (s, 1 H), 7.20
(m, 5 H), 7.74 (d, 2 H), 8.74 (d, 2 H).
~x~mple 8~
3-[1,4-Bis(phenylthio)butyl]-4-hydrosy-6-phQnyl-
2H-pyran-2-one, (~/-): The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 ml),
cycl~yl~yl carboxaldehyde (0.436 mL, 5.84 mmol),
thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL),
acetic acid (0.5mL). m.p. 75-77 C; 7H NMR (400 MHz,
DMS0-d6) S 5.9 (s, 1 H), 6.71 (s, 1 H), 7.20 (m, 5 H),
7.44 (m, 7 H), 7.75 (m, 3 H), 7.82 (m, 2 H).
Esa~pl~ 85
WO95/14014 ~ 24 PCT~S94112367
- 85 -
-L~ dlv~-6-phenyl-3-
~phenyl~tph~nylmothyl)thio]methyl]-2H-pyran-2-one,
~+/-): The title compound was prepared by Method C
using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31
mmol), ethanol (10 mL), benzaldehyde (0.593 mL, 5.84
mmol), benzylmercaptan (1.62 mL, 13.8 mmol), pipe~dine
(0.5 mL), acetic acid (0.5mL). m.p. 189-191 C; lH NMR
(400 MHz, DMSO-d6) S 3.70 (dd, 2 H), 5.29 (s, 1 H),
6.65 (s, 1 H), 7.23 (m, 8H), 7.50 (m, 5 H), 7.73 (m, 2
H), 11.96 (bs, 1 H).
E~mple 86
~-~yd~v~y~3~~ t~2-metho~yphenyl)thiolphenylmethyl]-6-
phenyl-2H-pyr~n-2-onQ, (I/-) The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
benzaldehyde (0.593 mL, 5.84 mmol), 2-
methoxythiophenol (1.93 mL, 13.8 mmol), piperdine (0.5
mL), acetic acid (0.5mL). m.p. 165-170 C; lH NMR (400
MHz, DMSO-d6) S 3.870 (s, 3 H), 5.81 (s, 1 H), 6.70
(s, 1 H), 6.84(t, 1 H), 7.19 (m, 3 H), 7.28 (t, 2 H),
7.53 (m, 3 H), 7.75 (m,2H), 12.13 (bs, 1 H).
Es~mple 87
4-Hyaroxy-3-t3-mQthyl-l-(phenylthio)butyl]-6-phenyl-
2~-pyran-2-o~e, (~/-) The title compound was prepared
by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one
(1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde
(0.626 mL, 5.84 mmol), thiophenol (1.40 mL, 13.8
mmol), piperdine (O.S mL), acetic acid (O.SmL). m.p.
154-156 C; lH NMR (400 MHz, acetone-d6) S O.89 (d,
3 H), 0.93 (d,3H), 1.63 (m,lH), 1.80 (m, 1 H), 2.32
(m,lH), 4.82 (dd, 2 H), 6.70 (s, 1 H), 7.24 (m,
3 H), 7.82 (m, 2 H), 10.49 (bs, 1 H).
3~
~xample 88
3-t2-Cyclohexyl-l-(phenylthio)ethyl]-~-h~ -6-
phenyl-2~-pyran-2-one, ~/-) The title compound was
wos5ll4ol4 PCT~S94/12367 ~1
~ 4 - 86 -
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
cyclohexylmethyl carboxaldehyde (0.735 mL, 5.84 mmol),
thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL),
S acetic acid (0.5mL). m.p. dec. 205 C; lH NNR (400
MHz, acetone-d6) ~ 0.91 (d, 3 H), 1.25 (m, 5 H), 1.73
(m, 5 H), 2.58 (m, 1 H), 4.83 (dd, 1 H), 6.69
(s, 1 H), 7.22 (m, 3 H), 7.48 (m, 5 H), 7.82 (m, 2
H).
Exa~ple 89
~ ~d~o~ 6-~3-rhn-o-~he~yl)-3-[~2-phenylethyl)thio~-
2~-pyran-2-one: The title compound was prepared by
Method A using 3'-rh~Yyacetophenone (2.00 g, 9.43
mmol), lithium bis(trimethylsilyl)amide (2.36 g, 14.15
mmol), chlorotrimethylsilane (1.79 mL, 14.15 mmol),
THF (100 mL), and diethyl ester of [(2-
phenylethyl)thio]-prop~e~;oic acid (1.00 g, 3.37
mmol). m.p. 114-115 C; lH NMR (400 MHz, DMS0-d6)
2.76 (t, 2 H), 2.99 (t, 2 H), 6.76 (s, 1 H), 7.09
(m, 7 H), 7.34 (s, 1 H), 7.44 (t, 2 H), 7.56 (m, 2 H).
I~pl~ 90
~-n~d,v~y~6-t3-metho~y~ phe~ylmetho~y)phenyl]-3-~2-
phenylethyl)thio]-2H-pyran-2-o~e: The title compound
was prepared by Method A using 4'-benzyloxy-3'-
methoxyacetophenone (2.00 g, 7.81 mmol), lithium
bis(trimethylsilyl)amide (1.96 g, 11.71 mmol),
chlorotrimethylsilane (1.48 mL, 11.71 mmol), THF (80
mL), and diethyl ester of [(2-
phenylethyl)thio3propanedioic acid (1.00 g, 3.37
mmol). m.p. 114-115 C; lH NMR (400 MHz, DMSO-d6)
2.77 (t, 2 H), 2.98 (t, 2 H), 3.86 (s, 1 H), 6.75
(s, 1 H), 7.21 (m, 7 H), 7.40 (m, 6 H).
~ pl~ 91
6-S3,5-Dimethylphenyl)-~-hy~ro~y-3-t~2-
phenylethyl)thio~-2~-pyr~-2-one: The title compound
WO95/14014 ~ ~q~ ~ PcT~S94112367
- 87 -
was prepared by Method A using 3',5'-dimethyl
acetophenone (1.75 g, 11.82 mmol), lithium
diisopropylamide (1.89 g, 17.73 mmol),
chlorotrimethylsilane (2.25 mL, 17.73 mmol), THF (120
mL), and diethyl ester of [(2-phenylethyl)thio]-
prop~n~;oic acid (1.00 g, 3.37 mmol). m.p. 155-
157 C; lH NMR (400 MHz, DMSO-d6) ~ 2.34 (s, 6 H), 2.77
(t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.21 (m, 6 H),
7.41 (s, 2 H), 8.74 (d, 2 H).
~mple 92
ydroYy-3-ttt3-metho~cyphenyl)methyl]thio]-6-phenyl-
2~-pyran-2-one: The title compound was prepared by
Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide
(5.31 mL), ~3-(methoxy)phenyl]methyl p-
toluenethiosulfonate (2.12 g, 6.90 mmol). m.p.
134-136 C; lH NMR (400 MHz, DMSO-d6) ~ 3.69 (s, 3 H),
3.99 (s,2H), 6.75 (m, 2 H), 6.83 (m, 2 H), 7.16
(t, 1 H), 7.53 (m, 3 H), 7.79 (m, 2 H).
Example 93
~-~ydroxy-3-~-methyl-1-(phenylthio)pentyl]-6-phQnyl-
2~-pyran-2-one, (~/-) The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), 4-
methylpentanal (0.584 mL, 5.84 mmol), thiophenol (1.40
mL, 13.8 mmol), piperdine (0.5 mL), acetic acid
(O.SmL). m.p. 144-145 C; lH NMR (400 MHz, DMSO-d6)
0.80 (d, 3 H), 0.81 (d, 3 H), 1.07 (m, 1 H), 1.18
(m, 1 H), 1.49 (m, 1 H), 1.89 (m, 1 H), 2.19 (m, 1 H),
4.51 (dd, 1 H), 6.68 (s, 1 H), 7.19 (t, 1 H), 7.29
(t, 2 H), 7.35 (d, 2 H), 7.53 (m, 3 H), 7.76 (m, 2 H).
3s Example 9
~-Hydro~y-6-ph~nYl-3~[[t3~
(ph~nylmethoxy)phenyl]methyl]thio]-2~-pyran-2-one: The
title compound was prepared by Method B using 4-
WO95/14014 PCT~S94/1~67
- 88 -
hydl~y-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol),
ethanol (15 mL), lN sodium hy~Loxide (5.31 mL), [3-
(benzoxyl)phenyl]methyl p-toluenethiosulfonate (2.65
g, 6.90 mmol). m.p. 140-141 C; lH NMR (400 MHz,
DMSO-d6) ~ 3.98 (s, 2 H), 5.01 (s, 2 H), 6.75 (s, 1 H),
6.83 (m, 2 H), 6.91 (m, 1 H), 7.28 (t, 1 H), 7.34
(m, 4 H), 7.52 (m, 3 H), 7.80 (m, 2 H).
E~mpl~ 95
3-t~1,3~ n7~i~1-5-ylm~thyl)thio]-4-hydroxy-6-
phenyl-2~-pyr~n-2-one : The title compound was
prepared by Method B using 4-hydL~xy-6-phenyl-2H-
pyran-2-one (l.00 g, 5.31 mmol), ethanol (15 mL), lN
sodium hyd~oxide (5.31 mL), 1,3-benzodioxoyl-5-yl
methyl p-toluenethiosulfonate (2.22 g, 6.90 mmol).
m.p. 162-164 C; lH NMR (400 MHz, DMSO-d6) ~ 3.92 (s, 2
H), 5.95 (s, 2 H), 6.75 (m, 4 H), 7.53 (m, 3 H), 7.79
(m, 2 H).
E~mpl~ 96
~-~ydroxy-3-t~2-methoxyphenyl~methyl]thio]-6-phenyl-
2~-pyran-2-on~: The title compound was prepared by
Method B using 4-hy~L~y-6-phenyl-2H-pyran-2-one
(0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium
hydroxide (2.65 mL), [(2-methoxyphenyl)methyl] p-
toluenethiosulfonate (0.816 g, 2.65 mmol). m.p.
152-153 C; lH NMR (400 MHz, DMSO-d6) ~ 3.73 (s, 3 H),
3.95 (s, 2 H), 6.71 (s, 1 H), 6.81 (t, l H), 6.91
(d, 1 H), 7.13 (d, l H), 7.17 (t, 1 H), 7.53 (m, 3 H),
7.79 (m, 2 H).
Exampl~ 97
4-Hydrosy-3-[t(2-methylphenyl)methyl]thio]-6-phenyl-
2H-pyr~n-2-one: The title compound was prepared by
Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide
(5.31 mL), [(2-methylphenyl)methyl] p-
toluenethiosulfonate (1.55 g, 5.31 mmol). m.p. 176-
~ W095rl4014 ~17 ~ ~ 2~ PCT~Ss4/l2367
- 89 -
178 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.42 (s, 3 H), 3.99
(s, 2 H), 6.74 (s, 1 H), 709 (m, 4 H), 7.53 (m, 3 H),
7.79 (m, 2 H).
Esample 98
4-ny~lG~-3-t[~3-methylphenyl)methyl]thio]-6-phenyl-
2~-pyran-2-one: The title compound was prepared by
Me~hod B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
g, 5.31 mmol), ethanol (lS mL), lN sodium hyd~o~ide
(5.31 mL), t(3-methylphenyl)methyl~ p-
toluenethiosulfonate (1.55 g, 5.31 mmol). m.p. 139-
140 C; lH NMR (400 MHz, DMSO-d6) ~ 2.23 (s, 3 H), 3.96
(s, 2 H), 6.74 (s, 1 H), 7.07 (m, 4 H), 7.54 (m, 3 H),
7.79 (m, 2 H).
~sample 99
4-~y~6~y-3-tt(~-mQthylphenyl)m~thyl]thio~-6-phen
2~-pyr~n-2-one: The title compound was prepared by
Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide
(5.31 mL), [(4-methylphenyl)methyl] p-
toluenethiosulfonate (1.5S g, 5.31 mmol). m.p. 164-
165 C; lH NMR (400 MHz, DMSO-d6) ~ 2.23 (s, 3 H), 3.g6
(s, 2 H), 6.74 (s, 1 H), 7.06 (d, 2 H), 7.14 (d, 2 H),
7.53 (m, 3 H), 7.79 (m, 2 H).
~ xa~ple 100
6-t1,1'-Biphenyl]-3-yl-~-hydro~y-3-~(2-
phenylethyl)thio~-2H-pyran-2-one : The title compound
was prepared by Method A using 3~-phenylacetophenone
(2.00 g, 10.21 mmol), trimethylsilyltriflate (2.36 mL,
1~.24 mmol), triethylamine (2.84 mL, 20.40 mmol),
methylene chloride (26 mL), and diethyl ester of ~(2-
phenylethyl)thio]prop~n~ ;oic acid (1.00 g, 3.37
mmol). m.p. 93-94 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.79
(t, 2 H), 3.01 (t, 2 H), 6.92 (s, 1 H), 7.21 (m, 5 H),
7.42 (t, 1 H), 7.52 (t, 2 H), 7.64 (t, 1 H), 7.75 (d,
2 H), 7.82 (t, 2 H), 8.02 (s, 1 H).
~17~ 12~1
WO 9Stl4014 PCI/US94112367
-- 90 --
E~a~plQ 101
~-~ydroxy-3-~ -~Qthosyphenyl)methyl]thio]-6-phenyl-
2~-pyr~n-2-one: The title compound was prepared by
Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide
(5.31 mL), [(4-methox~phenyl)methyl] p-
toluenethiosulfonate (2.21 g, 6.90 mmol). m.p. 168-
170 C; lH NMR (400 MHz, DMSO-d6) ~ 3.96 (s, 3 H), 3.95
(s, 2 H), 6.73 (s, 1 H), 6.81 (d, 2 H), 7.17 (d, 2 H),
7.53 (m, 3 H), 7.79 (m, 2 H).
E~mpl~ 102
3-t2-Cyclohexyl-l-(cyclohe~ylthio)ethyl]-4-~ -6-
phenyl-2H-pyr~n-2-one, (~ : The title compound was
lS prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
cyclohexylmethyl carboxaldehyde (0.735 g, 5.84 mmol),
cyclohexylmercaptan (1.60 g, 13.8 mmol), piperdine
(0.5 mL), acetic acid (0.5mL). m.p. dec. 220 C; lH
NMR (400 MHz, DMSO-d6) ~ 0.86 (m, 2 H), 1.18 (m, 9H),
1.66 (m, lOH), 2.03 (m, 2 H), 2.58 (m, 2 H), 4.25
(m, 1 H), 6.68 (s, 1 H), 7.53 (m, 3 H), 7.75 (m,2H).
Esampl~ 103
3-[1- r (2,6-Dimethylphenyl)thio3-3-methylbutyl]-4-
~y~y 6-phenyl-2H-pyran-2-one, ~/-) : The title
compound was prepared by Method C using 4-hydk oxy-6-
phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10
mL), isovaleraldehyde (0.63 mL, 5.84 mmol), 2,6-
dimethylthiophenol (1.90 g, 13.8 mmol), piperdine (0.5
mL), acetic acid (0.5mL). m.p. 166-167 C; lH NMR (400
MHz, DMSO-d6) ~ 0.78 (d, 3 H), 0.83 (d, 3 H), 1.42
(m, 1 H), 1.47 (m, 1 H), 2.46 (m, 1 H), 2.51
(s, 6 H), 4.37 (m, 1 H), 6.51 (s, 1 H), 7.70 (m,
3 H), 7.52 (m, 3 H), 7.74 (m,2H).
E~C~pl~ 10
WO 95tl4014 PCT/US94J12367
3-t1-(Cycloh y lthio~-2-cyclopropylethyl~-4-Ly~ ~y~6~
pho~yl-2H-pyr~n-2-o~ The title compound
was prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
cycl~u~ylmethyl carboxaldehyde (0.67 g, 5.84 mmol),
cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperdine
(0.5 mL), acetic acid (0.5mL). m.p. 69-71 C; lH NMR
(400 MHz, DMS0-d6) ~ -0.02 (m, 1 H), 0.05 (m, 1 H),
0.34 (m, 2 H), 0.64 (m, 2 H), 1.22 (m, 5 H), 1.52
(m, 1 H), 1.67 (m, 3 H), 1.84 (m, 1 H), 1.97 (m, 2
H), 2.64 (m, 1 H), 4.21 (t, 1 H), 6.69 (s, 1 H), 7.52
(m, 3 H), 7.75 (m, 2 H).
E~P1Q 105
3-~1-t(2,6-~ichlorophenyl)thio~-3-methylbutyl]-~-
hydro~y-6-phenyl-2H-pyran-2-one, (+/-) : The title
com~o~-d was prepared by Method C using 4-hy~ y-6-
phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10
mL), isovaleraldehyde (0.62 mL, 5.84 mmol), 2,6-
dichlorothiophenol (2.74 g, 13.8 mmol), piperdine (0.5
mL), acetic acid (0.5mL). m.p. 158-162 C; lH NMR (400
NHz, DMSO-d6) ~ 0.83 (d, 3 H), 0.87 (d, 3 H), 1.49
(m, 1 H), 1.74 (m, 1 H), 2.39 (m, 1 H), 4.68
(m, 1 H), 6.769 (s, 1 H), 7.49 (m, S H), 7.74 (m,
3 H).
Es~mpl~ 106
3-tl-(Cyclohexylthio)-3,3-dLmethylbutyl]-~-hydroxy-6-
phenyl-2~-pyr~n-2-one, ~+/-): The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), 3,3-
dimethylbutanal (0.73 mL, 5.84 mmol),
cyclohexylmercaptan (1.86 mL, 13.8 mmol), piperdine
(0.5 mL), acetic acid (O.SmL). m.p. >225 C; lH NMR
(400 MHz, DMSO-d6) ~ 0.85 (s, 9H), 1.25 (m, 5 H), 1.65
(m, 7 H), 4.30 (m, 1 H), 6.69 (s, 1 H), 7.54 (m, 3 H),
7.75 (m, 2 H).
wossll40l4 PCT~S94/1~67 \
~7~1~4
- 92 -
E~ample 107
t4~ ydrosy-2-oso-3-~t2-phenylethyl)thio]-
2~-pyr~n-6-yl]-2-methylphenosy], acQtic acid, ethyl
ester: The title compound was prepared by Method A
using ethyl (4-acetyl-2-methylph~noxy)acetate (2.00 g,
8.47 mmol), trimethyl silyltriflate (3.92 mL, 20.33
mmol), triethylamine (4.72 mL, 33.88 mmol), methylene
chloride (22 mL), and diethyl ester of [(2-
phenylethyl)thio]propAnP~;oic acid (1.00 g, 3.37
mmol). m.p. 154-156 C; lH NMR (400 MHz, DMSO-d6) ~
1.22 (t, 3 H), 2.26 (s, 3 H), 2.77 (t, 2 H), 2.97 (t,
2 H), 4.17 (t, 2 H), 4.91 (s, 2 H), 6.66 (s, 1 H),
6.99 (d, 1 H), 7.21 (m, 5 H), 7.61 (m, 2 H).
~xample 108
6-t3,5-Dimethyl~ dimethyl I 1, 1-
~imethyl~thyl)silyl]oxy]phenyl]-~-hydrosy-3-
ttphenylmethyl)thiol-2~-pyra~-2-one: The title
compound was prepared by Method A using 3',5'-
dimethyl-4'-t[dimethyl(1,1-dimethylethyl)silyl]oxy]
acetophenone (1.50 g, 5.39 mmol),
trimethylsilyltriflate (1.24 mL, 6.47 mmol),
triethylamine (1.50 mL, 10.78 mmol), methylene
chloride (13 mL), and diethyl ester of
[(phenylmethyl)thio]propAn~;oic acid (1.00 g, 3.54
mmol). m.p. 137-139 C; lH NMR (400 MHz, DMSO-d6) ~
0.21 (s, 6 H), 0.99 (s, 9H), 2.22 (s, 6 H), 3.96 (s, 2
H), 6.54 (s, 1 H), 6.99 (d, 1 H), 7.21 (m, 5 H), 7.44
(m, 2 H).
E~ample 109
4-~ydroxy-3-t(2-phenylethyl)thio]-6[4-(4-
pyridinylmethoxy)phenyl]-2~-pyran-2-one: The title
compound was prepared by Method A using 4'-(4-
pyridinylmethoxy)acetophenone (2.00 g, 8.81 mmol),
trimethylsilyltriflate (2.04 mL, 10.57 mmol),
triethylamine (2.45 mL, 17.62 mmol), methylene
chloride (22 mL), and diethyl ester of [(2-
WO95/14014 PCT~S94/12367
~7 412~
- 93 -
phenylethyl~thio~prop~n~;oic acid (1.00 g, 3.37
mmol). m.p. dec. 212 C; lH NMR (400 MHz, DMSO-d6)
2.73 (t, 2 H), 2.88 (t, 2 H), 5.29 (s, 2 H), 6.48
(s, 1 H), 7.18 (m, 5 H), 7.45 (d, 2 H), 7.74 (d, 2 H),
8.90 (d, 2 H).
~ c~mpl~ 110
3-tl-~Cyclopentylthio)-3-methylbutyl~ y~ v~-6-
phe~yl-2~-pyr~n-2-o~e (~ The title compound was
prepared by Method C using 4-h~ y-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
isovaleraldehyde (0.62 mL, 5.84 mmol),
cyclopentylmercaptan (1.43 mL, 13.8 mmol), piperdine
(0.5 mL), acetic acid (0.5mL). m.p. 146-149 C; lH NMR
(400 MHz, DMSO-d6) ~ 0.85 (d, 2 H), 0.87 (d, 2 H), 1.32
(m, 1 H), 1.54 (m, 7 H), 1.85 (m, 1 H), 2.00 (m, 2 H),
3.04 (m, 1 H), 4.20 (dd, 1 H), 6.69 (s, 1 H), 7.53 (m,
3 H), 7.76 (m,2H), 11.69 (bs, 1 H).
E~mpl~
t4-t4-Hydro2y-2-oxo-3t(2-phenylethyl)thio]-2H-pyran
-6-yl]-2-methylrho~ acetic acia: To a
tetrahydrofuran (10 ml) solution of ~4-~4-llyd~o~y-2-
oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-2-
methylphenoxy]-, acetic acid, ethyl ester (0.20 g.
o.45 mmol) was added lN sodium hydroxide (1.13 mL,
1.13 mmol). The reaction was stirred for 5 hrs, and
then quenched by addition of water (10 ml) followed by
acidification with conc. hydrochloric acid to pH 2.
The aqueous layer is then extracted with 2X with ethyl
acetate (100 ml). the com~ined organic extracts were
then washed with saturated~sodium chloride; dried over
anhydrous magnesium sulfate. After evaporation of the
solvents in vacuo, the crude product was purified by
column chromatography (silica gel-230 to 400 mesh)
using 94/511 methylene chloride/methanol/acetic acid
as the eluent. m.p. dec. 210 C; lH NMR (400 MHz,
DMS0-d6) ~ 2.26 (S, 3 H), 2.78 (t, 2 H), 2.98 (t, 2 Hl,
WO95tl4014 PCT~S94112367 ~
~7~
- 94 -
4.81 (s, 2 H), 6.67 (s, 1 H), 6.97 (d, 2 H), 7.21
(m, 5 H), 7.61 (d, 2 H).
BY~mpl~ 112
3-ll-(cycloherylthio)-2-cyclope~tylQthyl]-~-h~GAy-6
phenyl-28-pyran-2-one, (I/-): The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
cyclopentylmethylcarboxaldehyde (0.65 g, 5.84 mmol),
cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperdine
(0.5 mL), acetic acid (0.5mL). m.p. 157-160 C; lH NMR
(400 MHz, DMSO-d6) ~ 1.44 (m, 18H), 2.01 (m, 1 H), 2.19
(m, 1 H), 2.60 (m, 1 H), 4.16 (m, 1 H), 6.68 (s, 1 H),
7.53 (m, 3 H), 7.75 (m,2H), 11.66 (bs, 1 H).
E~a~pl~ 113
v~y 6-(~-hy~roxy-3~5-diuethylphenyl)-3-
t~phenyl~ethyl)thio]-2~-pyra~-2-one: To a THF (10 mL)
solution of 6-~3,5-dimethyl-4- r [ dimethyl(1,1-
dimethylethyl)silyl]oxy]phenyl]-4-hydroxy-3-
~(phenylmethyl)thio]-2H-pyran-2-one at 0 C is added 3
N HCl (9.0 mL). The reaction is stirred for 48 hrs.
at room temperature. The reaction is ~l~nch~ by
pouring onto ethyl acetate and washed in succession
with water, saturated sodium chloride; dried over
anhydrous magnesium sulfate. After evaporation of the
solvents in vacuo, the crude product was purified by
flash column chromatography (SiO2-230 to 400 mesh)
using S0 % ethyl acetate/ h~ es. m.p. 174-176 C; lH
NMR (250 MHz, DMSO-d6) ~ 2.21 (s, 6 H), 2.60 (m, 1 H),
3.96 (s, 2 H), 6.52 (s, 1 H), 7.23 (s, 5 H), 7.38 (s,
2 H), 9.06 (s, 1 H).
~xample 11
~-~y~ VAy ~-phenyl-3-t~t3-(2-
phenylethoxy)phe~yl]methyl]thio]-2~-pyran-2-one : The
title compound was prepared by Method B using 4-
hydl~xy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol),
~ WO gS114014 PCT~US94~23C7
~7gl~
- 95 -
ethanol (15 mL), lN sodium hy~oxide (5.31 mL), t3-(2-
(phenylethoxy)phenyl]methyl p-toluenethiosulfonate
(2.11 g, 5.31 mmol). m.p. 85-90 C; lH NMR (400 MHz,
DMSO-d6) ~ 2.96 (t, 2 H), 3.96 (s, 2 H), 4.09 (t, 2 H),
6.77 (m, 4 H), 7.19 (m, 5 H), 7.53 (m, 3 H), 7.77 (m,
2 H).
~amplo 115
~ ~v~y~6~ t ~- (2-phenylethyllyl) phenyl] -3-1 ~2-
ph~ylethyl)thio]-2~-pyr~n-2-on~: The title compound
was prepared by Method A using 4'-(2-
phenethynyl)acetophenone (1.50 g, 6.81 mmol),
trimethylsilyltriflate (1.57 mL, 8.17 mmol),
triethylamine (1.89 mL, 13.62 mmol), methylene
chloride (17 mL), and diethyl ester of [(2-
phenylethyl)thio]propAn~ioic acid (1.00 g, 3.37
mmol). m.p. 181-182 C; lH NMR (400 MHz, DMSO-d6)
2.78 (t, 2 H), 3.02 (t, 2 H), 6.85 (s, 1 H), 7.21
(m, 5 H), 7.45 (m, 3 H), 7.59 (d, 2 H), 7.86 (d, 2 H).
~xample 116
~ G~-6-t~-(2-phenylethyl)ph~nyl]-3-tt2-
phenylethyl)thio]-2~ ~ ~n-2-one: The title compound
was prepared by Method A using 4'-(2-
phenethyl)acetoph~nnn~ (1.50 g, 6.68 mmol),
trimethylsilyltriflate (1.55 mL, 8.02 mmol),
triethylamine (1.86 mL, 13.36 mmol), methylene
chloride (17 mL), and diethyl ester of [(2-
phenylethyl)thio]propanedioic acid (1.00 g, 3.37
mmol). m.p. 122-123 C; lH NMR (400 MHz, DMSO-d6)
2.77 (t, 2 H), 2.93 (m, 4 H), 2.99 (t, 2 H), 6.75
(s, 1 H), 7.26 (m, 5 H), 7.38 (d, 2 H), 7.71 (d, 2 H).
~s~mpl~ 117
3-~(Cyclohe~ylthio)pheuylmethyl]-~-hydroxy-6-phenyl-
2~-pyran-2-one, (~/-): The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1. 00 g, 5 . 31 mmol), ethanol (10 mI ),
WO95114014 PCT~S94/1~67 ~
217 ~
^ - 96 -
benzaldehyde (0.593 mL, 5.84 mmol),
cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperdine
(0.5 mL), acetic acid (O.SmL). m.p. 189-191 C; lH NMR
(400 MHz, DMSO-d6) ~ 1.21 (m, 5 H), 1.52 (m, 1 H), 1.91
(m, 2 H), 2.58 (m, 2 H), 5.37 (s, 1 H), 6.70 (s, 1 H),
7.17 (t, 1 H), 7.53 (m, 5 H), 7.74 (m, 2 H), 11.96
(bs, 1 H).
~mple 118
~ ~y~ 3-~phenylmathyl)thio]-6-~3-
(trifluorom~thoxy)phenyll-2~-pyr~n-2-on~: The title
com~.d was prepared by Method A using
3'trifluoromethoxyacetophenone (3 g, 14.7 mmol),
lithium bis(trimethylsilylamide (2.45 g, 14.7 mmol),
chlorotrimethylsilane (2.47 g, 14.7 mmol) and diethyl
ester Of t(phenylmethyl)thio]propanedioic acid (1.00
g, 3.54 mmol). m.p. 128-132 C; lH NMR (400 MHz,
DMSO-d6) ~ 4.03 (s, 2 H), 6.81 (s, 1 H), 7.2 (m, 2 H),
7.28 (m, 3 H), 7.56 (dd, 1 H), 7.69 (t, 1 H), 7.75
(s, 1 H), 7.86 (d, 1 H); IR (KBr) 2963, 1651, 1550,
1394, 1369, 1395, 1263, 1098, 1024, 800 cm~1; MS (CI):
m/e 395 (M+H, 37), 309 (8), 273 (7), 205 (3), 119
(10); Analysis calc'd for ClgHl304SlF3.H2O: C, 55.34; H,
3.67; found: C, 54.94; H, 4.03.
Example 119
3-t(Cyclohexylm~thyl)thio]-~-hydroxy-6-phe~yl-28-
pyran-2-one: The title compound was prepared by
Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.5
g, 2.66 mmol), ethanol (7 mL), lN sodium hydroxide
(2.66 mL), cyclohexylmethyl-p-toluenethiosulfonate
(0.756 g, 2.66 mmol). m.p. 141-143 C; lH NMR (400 MHz,
DMSO-d6) ~ 0.92 (m, 2 H), 1.14 (m, 3 H), 1.19 (m, l H),
1.61 (m, 3 H), 1.83 (m, 2 H), 2.64 (d, 2 H), 6.78
3S (s, 1 H), 7.53 (m, 3 H), 7.81 (m, 2 H); IR (RBr) 3106,
2922, 1651, 1547, 1396, 1099, 766 cm~l; MS (CI) m/e 317
(M+H, 16), 279 (83), 242 (77), 201 (27), 177 (19), 134
(54), 105 ~65), 97 (100).
WO95/14014 ~7~ PCT~S94112367
- 97 -
2s~ple 120
4-Xy~roxy-3-t~2-ph~ylethyl)thio]-6-[3-methyl-4-(3-
pyridinylmethoxy)phe~yl~-2~-pyr~n-2-one: The title
compound was prepared by Method A using 3r-methyl-4~-
(3-pyridinylmethoxy)acetoph~no~ (2.0 g, 8.29 mmol),
lithium bis(trimethylsilylamide (1.53 g, 9.13 mmol),
chlorotrimethylsilane (1.54 g, 9.13 mmol) and diethyl
ester of [2-(phenylethyl)thio]propanedioic acid (1.00
g, 3.37 mmol). m.p. 149-151 C; lH NMR (400 MHz,
DMSO-d6) ~ 2.25 (s, 3 H), 2.78(t, 2 H), 2.97 (t, 2 H),
5.28 (s, 2 H), 6.69 (s, 1 H), 7.22 (m, 6 H), 7.44
(dd, 1 H), 7.67 (s + d, 2 H), 7.92 (d, 1 H), 8.58
(brs, 1 H), 8.72 (brs, 1 H); IR (KBr) 3430, 2926,
1713, 1626, 1505, 1263, 1136, 1028, 808, 705 cm-l; MS
(CI): m/e 446 (M+H), 341 (15), 200 (6), 105 (100);
Analysis calc'd for C26H23O4SlNl: C, 70.09; H, 5.20; N,
3.14; found: C, 70.31; H, 5.27; N, 2.95.
Example 121
6-~2,3-Dihydro~ ben~o~; OY; n-6-yl) -4-hydro~y-3-
t~phenylmethyl)thio]-2~-pyran-2-one: The title
compound was prepared by Method A using 1,4-
benzodioxin-6-yl methyl ketone (2.5 g, 14.25 ol),
lithium bis(trimethylsilylamide (2.35 g, 14.25 mmol),
chlorotrimethylsilane (2.47 g, 14.25 mmol) and diethyl
ester of t(phenylmethyl)thio]propAne~;oic acid (l.oo
g, 3.55 mmol). m.p. 192-193 C; lH NMR (400 MHz,
DMSO-d6) ~ 3.99 (s, 2 H), 4.17 (m, 4 H), 6.8 (s, 1 H),
7.0 (d, 1 H), 7.2 (m, 1 H), 2.28 (m, 7 H); IR (KBr)
3435, 2924, 1649, 1624, 1508, 1288, 1066, 698 cm~l; MS
(CI): m/e 369 (M+H,), 277 (12), 233 (12), 163 (9), 107
(10), 91 (76); Analysis calc'd for C20Hl6OsS1: C, 65.21;
H, 4.38; found: C, 64.80; H, 4.17.
$~mple 122
o~y-3-t~2-phenylethyl)thio]-6-t3-
(trifluoromethyl)phenyl]-2~-pyran-2-one: The title
compound was prepared by Method A using the
woss/140l4 ~ 4 PCT~S94/12367
- 98 -
corres~on~;ng trimethylsilyl enol ether (4.5 mmol)
and diethyl ester of t(2-phenylethyl)thio]prop~e~;oic
acid (1.33 g, 4.55 mmol). m.p. 117-118(C); lH NMR
(400 MHz, DMSO-d6) ~ 2.8 (t, 2 H), 3.03 (t, 2 H), 6.94
(s, 1 H), 7.2 (m, 5 H), 7.8 (t, 1 H), 7.94 (t, 1 H),
8.08 (s, 1 H), 8.14 (d, 1 H); IR (KBr) 3435, 3026,
2924, 1720, 1635, 1543, 1327, 1171, 1130, 696 cm~l; MS
(CI): m/e 393 (M+H, 100), 373 (9), 288 (38), 256
(20), 224 (11), 105 (62); Analysis calc'd for
C20H~5S,O3F3.H2O: C, 58.53; H, 4.18; found: C, 59.28;
H, 3.81.
~xa~pl~ 123
~ d.o~ 3-[~phenylmethyl)thio]-6-[3-
~trifluoromethyl)phenyl]-2H-pyran-2-one: The title
compound was prepared by Method A using the
correspo~;ng trimethylsilyl enol ether (9.8 mmol) and
diethyl ester of [(phenylmethyl)thio]prop~n~;oic acid
(2.76 g, 9.88 mmol).
m.p. 152-153 C; lH NMR (400 MHz, DMSO-d6) ~ 3.97 (s, 2
H), 6.53 (s, 1 H), 7.25 (m, 5 H), 7.61 (t, 1 H), 7.75
(d, 1 H), 8.03 (d, 1 H), 8.08 (s, 1 H); IR (KBr) 3434,
3244, 1678, 1628, 1535, 1522, 1435, 1341, 1316, 1192,
1132, 936, 706 cm~l; MS (CI) m/e 379 (M+H,), 257 (1),
91 (100); Analysis calc'd for ClgHl3O3SlF3: C, 60.31; H,
3.46; found: C, 60.53; H, 3.57.
~xample 12~
4-nydl6~y-3-tlp~enylmethyl)thio]-6-(2,3,4-
trimethoxyphenyl)-2H-pyran-2-one: The title compound
was prepared by Method A using 2',3',4'-
trimethoxyacetophenone (1.5 g, 7.13 mmol), lithium
bis(trimethylsilyl)amide (1.43 g, 8.56 mmol),
chlorotrimethylsilane (1.8 mL, 10.67 mmol) and diethyl
ester of [(phenylmethyl)thio]prop~ne~;oic acid (1.00
g, 3.54 mmol).
~xampl~ ~25
WO95/14014 PCT~S9411~67
~ 74~
99
N-t~-t~-~y~Lv~ 2-oso-3-~(2-ph~nylothyl)thio3-2~-
pyran-C-yl~phenyl]-b~nzonQsulfonamide: The title
compound was prepared by Method A using the
correspon~;ng benzenesulfonamide (3.0 g, 10.91 mmol),
S lithium bis(trimethylsilylamide (3.65 g, 21.82 mmol),
chlorotrimethylsilane (3.68 mL, 21.82 mmol) and
diethyl ester Of t(phenylethyl)thio]propanedioic acid
(1.00 g, 3.37 ol). m.p. 89-91 C; lH NMR (400 MHz,
DMS0-d6) ~ 2.78 (t, 2 H), 3.03 (t, 2 H), 6.86 (s, 1 H),
7.25 (m, 6 H), 7.72 (t, 3 H), 7.86 (m, 5 H); IR (KBr)
3443, 3335, 1725, 1632, 1543, 1383, 1171, 912, 729,
581, 552 cm~1; Analysis calc'd ~or C2sH21N1S205. H20: C,
60.35; H, 4.66; N, 2.81; found: C, 60.13; H, 4.47;
N, 3.23.
~5
~sample 126
6-~4-~3,5-Dimethyl~ s~lyl)metho~y]phenyl]-~-
h~,G~-3-t~2-phenylethyl)thio]-2~-pyran-2-one: The
title compound was prepared by Method A using 4'-(3,5-
dimethyl-4-isoxazolyl)acetophenone (1.65 g, 6.74
mmol), lithium bis(trimethylsilylamide (1.13 g, 6.74
mmol), chlorotrimethylsilane (1.14mL, 6.74 mmol) and
diethyl ester of t(2-phenylethyl)thio]prop~n~;oic
acid (1.00 g, 3.37 mmol). m.p. 152-154 C; lH NMR
(400 MHz, DMS0-d6) ~ 2.22 (s, 3 H), 2.31 (s, 3 H), 2.78
(t, 2 H), 2.99 (t, 2 H), 5.03 (s, 2 H), 6.69 (s, 1 H),
7.17 (d, 3 H), 7.25 (m, 4 H), 7.78 (d, 2 H); IR (KBr)
2936, 2979, 1640, 1510, 1406, 1182, 988, 820, 764 cm~l;
MS (CI) m/e 450 (M+H), 341 (10), 236 (9), 112 (76),
105 (100); Analysis calc'd for C2sHz3NlOsS1: C, 66.80;
H, 5.16; N, 3.12; found: C, 66.42; H, 5.20; N,
2.74.
~xample 127
3s (~/-) 3-l(cyclohexylthio)phenylmethyl]-~-hydroxy-6-t3
mcthyl-4-(3-pyridinylmQthoxy)phenyl]-2~-pyran-2 -O~Q:
The title compound was prepared by Method C using 4-
hydroxy-6-~3-methyl-4-(3-pyridinylmethoxy)phenyl~-2H-
WO9S/14014 ~ 7~ PCT~S94/12367 ~
-- 100 --
pyran-2-one (0.5 g, 1.62 mmol), benzaldehyde (0.189 g,
1.78 mmol), cyclohexylmercaptan (0.489 g, 4.212 mmol),
piperidine, (0.5 mL), acetic acid (0.5 mL). m.p.
84-87 C (d); IR (KBr) 3059, 2930, 2853, 1676, 1601,
1449, 1260, 1134, 700 cm-l; MS (CI) m/e 446 (2), 331
(9), 226 (61), 205 (24), 135 (44).
E~a~pl~ 128
2~ -hydrosy-2-oxo-6-phenyl-2~-pyr~n-3-
yl)thio]methyl]-be~zoic acid methyl ester : The title
compound was prepared by Method B using 4-hydroxy-6-
phenyl-2H-pyran-2-one (2.0 g, 10.63 mmol), [2-
(carbomethoxy)phenyl]methyl p-toluenethiosulfonate
(3.57 g, 10.63 mmol), lN NaOH (10.63mL), ethanol
(20mL). m.p. 122-123 C; lH NMR (400 MHz, DMSO-d6)
3.81 (s, 3 H), 4.31 (s, 2 H), 6.67 (s, 1 H), 7.25
(d, 1 H), 7.31 (t, 1 H), 7.44 (t, 1 H), 7.44 (m, 3 H),
7.53 (d, 1 H), 7.99 (m, 3 H); IR (KBr) 3005, 2951,
1721, 1653, 1543, 1400, 1267, 1078, 966, 766, 711, 520
cm-1; MS (CI) m/e 397 (M+29, 4), 369 ((M+H), 40), 3~7
(34), 191 (26), 149 (100), 105 (14).
Exa~ple 129
3-[1-(Cyclohexylthio)-3-methylbutyl]-6-(2,3-dihydro-
1~ ~-b~n70~; ~Yi n-6-yl) ~-hydroxy-2~-pyr~n-2-on~
The title compound was prepared by Method C using 4-
hydroxy-6-[1,4-benzodioxin-6-yl]-2H-pyran-2-one (1.0
g, 4.06 mmol), isovaleraldehyde (0.35 g, 4.06 mmol),
cyclohexylmercaptan (0.944 g, 8.12 mmol), piperidine,
(0.5 mL), acetic acid (0.5 mL). m.p. 161-162 C; lH
NMR (400 MHz, DMSO-d6) ~ 0.85 (d, 3 H), 0.88 (d, 3 H),
1.2 (m, 5 H), 1.39 (m, 1 H), 1.53 (m, 2 H), 1.65 (m, 2
H), 1.81 (brm, 1 H), 2.04 (m, 2 H), 4.2 (q, 1 H), 4.32
(brq, 4 H), 6.53 (s, 1 H), 6.99 (d, 1 H), 7.2
(d, 1 H), 7.25 (dd, 1 H); IR (KBr) 1099, 2930, 2853,
1649, 1564, 1510, 1397, 1314, 1289, 1260, 1140, 106g,
891, 771, 608 cm~l.
~ Wos5/14014 ~ 2~ PCT~S94)~67
-- 101 --
k~a~pl~ 130
2 t~4-t4-L~ G~ -2-oxo-3-[(2-phenyl~thyl)t~io]-2~-
pyran-6-yl] phn~ y]~othyl]-b~zoic ~cid methyl ~ster:
The title compound was prepared by Method A using 2-
[[(4-acetyl)phenoxy]methyl]benzoic acid methyl ester
(2.0 g, 7.04 mmol),
trimethylsilyltrifluoromethylsulfonate (1.57 g, 7.04
mmol), triethylamine (1.42 g, 14.08mmol) and diethyl
ester of ~(2-phenylethyl)thio]prop~ne~;oic acid (1.04
g, 3.52 mmol). m.p. 161-162 C; lH NMR (400 MHz,
DMS0-d6) ~ 2.78 (t, 2 H), 2.97 (t, 2 H), 3.81 (s, 3 H),
5.5 (s, 2 H), 6.69 (s, 1 H), 7.14 (m, 3 H), 7.25
(m, 4 H), 7.5 (m, 2 H), 7.78 (m, 2 H), 7.78 (d, 2 H),
7.94 (d, 1 H); IR (KBr) 3028, 2949, 2909, 2675, 1715,
lS 1638, 1510, 1402, 1291, 1267, 1181, 1030, 828, 747
cm-l; MS (CI) m/e 489 (M+H, 51), 384 (3), 353 (1), 149
(100), 135 (47), 105 (33).
~x~mple 131
~-~ydrosy-3-t~2-ph~nylethyl)thio]-6-t~ -tetr~sol-5-
ylmethoxy)phenyl]-2~-pyran-2-o~e: The title compound
was prepared by using example 143 (0.5 g, 1.32 mmol)
and trimethyltin azide (0.543 g, 2.64 mmol), toluene
(lOmL) and ethanol (lOmL) at its reflux temperature
for 24hours. The solvents were evaporated. The
residue was treated with lN HCl and stirred at room
temperature for 2 hours. The residue was taken up in
methanol, the solvents were then evaporated and the
solid obtained was washed with ethyl acetate to obtain
pure compound. m.p. 195-196 C (dec); lH NMR (400 MHz,
DMS0-d6) ~ 2.78 (t, 2 H), 2.99 (t, 3 H), 5.6 (s, 2 H),
6.72 (s, 1 H), 7.22 (m, 7 H), 7.81 (d, 2 H); IR (KBr)
~ 3121, 3028, 1657, 1549, 1512, 1410, 12S6, 1186, 1059,
831, 696 cm~~; MS (CI) m/e 423 (N+H, 8), 341 (3), 137
(11), 105 (100).
WO95/14014 PCT~S94/12367 ~
~17~12~
- 102 -
2~aple 132
~-~ydrosy-6-[3-methyl-~-[(2-pyridinyl)methoxy]phenyl]-
3-~2-phenylethyl)thio]-2~-pyran-2-ono: The title
compound was prepared by Method A using 4-(2-
pyridinylmethoxy)-3-methylacetophenone (2.0 g, 8.29
mmol), trimethylsilyltrifluoromethylsulfonate (1.84 g,
8.29 mmol), triethylamine (1.68 g, 16.58mmol) and
diethyl ester of t(2-phenylethyl)thio]propanedioic
acid (1.22 g, 4.15 mmol). m.p. 75-77 C; lH NMR (400
MHz, DMSO-d6) 8 2.32 (s, 3 H), 2.78 (t, 3 H), 2.97 (t,
2 H), 5.29 (s, 2 H), 6.67 (s, 1 H), 7.14-7.29
(m, 4 H), 7.38 (m, 1 H), 7.56 (m, 2 H), 7.67 (m, 2 H),
7.86 (t, 2 H), 8.61 (d, 1 H); IR (KBr) 3063, 2924,
1719, 1603, 1505, 1267, 1138, 1039, 760 cm~l; MS (CI)
m/e 446 (M+H, 90), 341 (16), 279 (17), 242 (21), 151
(25), 105 (100); Analysis calc'd for C26H2304NlS1: C,
70.09; H, 5.2; N, 3.4; found: C, 70.68; H, 5.28; N,
3.14.
EsamplQ 133
3-t2-CYC1~1G~Y1-1-~(phenyl~thyl)thio~ethyl]-~-
hydrosy-6-phenyl-2~-pyr~n-2-one ~l/-): The title
compound was prepared by Method C using 4-hydroxy-6-
phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), 2-
cyclopropylmethylcarboxaldehyde (0.67 g, 7.98 mmol),
benzylmercaptan (1.98 g, 15.96 mmol), piperidine, (0.5
mL), acetic acid (0.5 mL). m.p. 59-61 c; lH NMR (400
MHz, DMSO-d6) ~ -0.97 (m, 2 H), 0.28 (m, 2 H), 0.58
(m, 1 H), 1.61 (m, 1 H), 2.01 (m, 1 H), 3.72 (ABXq, 2
H), 4.22 (q, 1 H), 6.67 (s, 1 H), 7.18 (t, 1 H), 7.25
(d, 2 H), 7.31 (t, 2 H), 7.53 (m, 3 H), 7.75 (m, 2 H);
IR (KBr) 3061, 2919, 2631, 1649, 1564, 1404, 1267,
766, 691 cm~1; MS (CI) m/e 255 ((M-SBzl), 19), 201 (5),
147 (2); Analysis calc'd for C23H2203Sl: C, 72.99; H,
5.86; found: C, 72.31; H, 6.08.
Esauple 134
WO95114014 Z ~CT~S9411~67
~ ~ 7~12a~
- 103 -
~-~ydroxy-3-tl-t(2-m~tho~yph~nyl)thio~-3-mQthylbUtyl]-
C-phenyl-2~-pyran-2-onQ (+/-) : The title compound
was prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (0.69
s g, 7.98 mmol), 2-methoxythiophenol (2.24 g, 15.96
mmol), piperidine, (1.0 mL), acetic acid (1.0 mL) and
ethanol (15mL). m.p. 75-78 C; lH NMR (400 MHz,
DMSO-d6) ~ 0.86 (d, 3 H), 0.89 (d, 3 H), 1.53 (m, 1 H),
1.69 (m, 1 H), 2.19 (m, 1 H), 3.64 (s, 3 H), 4.69
(g, 1 H), 6.64 (s, 1 H), 6.89 (t, 1 H), 6.94 (d, 1 H),
7.17 (t, 1 H), 7.33 (d, 1 H), 7.53 (m, 3 H), 7.78 (m,
2 H); IR (KBr) 3063, 2955, 2635, 1649, 1564, 1406,
1242, 1026, 768, 750, 691 cm~1; MS (CI) m/e 257
((M-SPh(OMe), 11), 201 (3), 169 (5), 141 (88);
Analysis calc'd for C23H2404Sl: C, 69.67; H, 6.10;
found: C, 69.63; H, 5.92.
~x~mplQ 135
4-Hydroxy-3-t1-t(phenyln~thyl)thio]-3-methylbutyl]-6-
phenyl-2H-pyran-2-one ~ The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (0.69
g, 7.98 mmol), benzylmercaptan (1.98 g, 15.96 mmol),
piperidine, (1.0 mL), acetic acid (1.0 mL). m.p.
153-155 C; lH NMR (400 MHz, DMSO-d6) ~ 0.64 (d, 3 H),
0.81 (d, 3 H), 1.25 (m, 1 H), 1.53 (m, 1 H), 2.04
(m, 1 H), 3.69 (ABXq, 2 H), 4.22 (q, 1 H); IR (KBr)
3086, 2955, 1651, 1566, 1497, 1404, 1311, 1127, 912,
766, (8).
- ~sample 136
~-[t~-[4-hydro~y-2-oso-3-tl2-phQnylQthyl)thio]-2~-
- pyran-C-yl~phQnoxy]m~thyl]bQnzoic aci~ methyl ester :
The title compound was prepared by Method A using 4-
~t(4-acetyl)phenoxy]methyl]benzoic acid methyl ester
(2.0 g, 7.04 mmol), lithium hexamethyldisilazide (2.36
g, 14.08 mmol), chlorotrimethylsilane (2.38 g, 14.08
mmol) and diethyl ester of [(2-
WO 95/1401~ ~ 7 4 1 2 ~ PCT/US94/12367
-- 104 --
phenylethyl)thio]propanedioic acid (1.0 g, 3.05 mmol).
m.p. 157-158 C; lH NMR (400 MHz, DMSO-d6) ~ 2.78 (t, 2
H), 2.97 (t, 2 H), 3.86 (s, 2 H), 5.31 (s, 2 H), 6.67
(s, 1 H), 7.17 (q, 4 H), 7.25 (m, 3 H), 7.61 (d, 2 H),
s 7.78 (d, 2 H), 8.0 (d, 2 H); IR (KBr) 3023, 2936,
2581, 1632, 1510, 1404, 1258, 1184, 1098, 1009, 818,
718 cm~1; MS (CI) m/e 517 (M+29, 7), 489 (M+H, 55), 384
(19), 149 (40), 105 (100).
Es~mple 137
Methyl ester of 3-[t~-~4-hydroxy-2-oxo-3-t~2
phonylethyl)thio]-2H-pyra~-6-yl]rhP~-yl~ethyll-
benzoic acid: The title compound was prepared by
Method A using 3-[[(4-acetyl)phenoxy]methyl]benzoic
acid methyl ester (2.0 g, 7.04 mmol),
lithiumhexamethyldisilazane (2.36 g, 14.08 mmol),
chlorotrimethylsilane (2.38 g, 14.08 mmol) and diethyl
ester of [(2-phenylethyl)thio]propanedioic acid (1.0
g, 3.05 mmol). m.p. 147-149 C; lH NMR (400 MHz,
DMS0-d6) ~ 2.78 (t, 2 H), 2.97 (t, 2 H), 3.86 (s, 2 H),
5.31 (s, 2 H), 6.69 (s, 1 H), 7.2 (m, 7 H), 7.58
(t, l H), 7.75 (m, 3 H), 7.78 (d, 1 H), 7.94 (d, 1 H),
8.08 (s, 1 H); IR (KBr) 3081, 2950, 1726, 1632, 1609,
1512, 1406, 1345, 1406, 1290, 1209, 1098, 1004, 820,
748, 696 cm~l; MS (CI) m/e 489 (M+H, 48), 384 (16), 341
(7), 236 (6), 149 (39), 119 (11), 105 (100).
gx~mple 138
6l~-[3,4-Dichlorophenylmetho~y]ph~yl]-~-hydro~y-3-
t~2-phenylethyl)thio]-2X-pyran-2-one: The title
compound was prepared by Method A using 4-[(3,4-
dichlorophenyl)methoxy]acetophenone (2.0 g, 6.80
mmol), lithium hexamethyldisilazide (2.28 g, 13.61
mmol), chlorotrimethylsilane (2.3 g, 13.61 mmol) and
diethyl ester of ~(2-phenylethyl)thio]propanedioic
acid (1.0 g, 3.40 mmol). m.p. 168-169 C; lH NMR (400
MHz, DMS0-d6) ~ 2.78 (t, 2 H), 2.97 (t, 2 H), 5.22 (s,
2 H), 6.69 (s, 1 H), 7.17 (m, 8H), 7.47 (dd, 1 H),
WO9Stl4014 ~174~ ~L~ PCT~Ss4/12367
- 10S -
7.69 (d, 1 H), 7.78 (d, 1 H); IR (KBr) 3054, 2602,
1713, 1611, 1512, 1399, 1291, 1179, 1109, 1042, 818,
754 cm~l; MS (CI) m/e 501 (17), 499 (24), 394 (12), 353
(1), 161 (20), 159 (27), 105 (100).
E~ple 139
3-tt(~-hydrosy-2-oso-6-phenyl-2~-pyran-3-
yl)thio]methyl]-be~zoic aci~ mQthyle~ter: The title
compound was prepared by Method B using 4-hydroxy-6-
phenyl-2H-pyran-2-one (2.0 g, 10.63 mmol), ~3-
(carbomethoxy)phenyl]methyl p -toluenethiosulfonate
(3.57 g, 10.63 mmol), lN NaOH (10.63mL), ethanol
(20mL). m.p. 170-171 C; lH NMR (400 MHz, DMSO-d6)
3.78 (s, 3 H), 4.06 (s, 2 H), 6.72 (s, 1 H), 7.42
(t, 1 H), 7.53 (m, 4 H), 7.78 (m, 3 H), 7.83 (s, 1 H);
IR (KBr) 3108, 2947, 1716, 1644, 1549, 1400, 1302,
1100, 770, 713, 523 cm~l; MS (CI) m/e 369 (M+H, 7), 337
(8), 235 (6), 189 (4), 149 (11), 85 (100).
~s~pl~ 1~0
Methylester of ~-t~(4-hy~roxy-2-oxo-6-phenyl-2~-pyran-
3-yl)thio]methyl~benzoic aci~: The title compound
was prepared by Method B using 4-hydroxy-6-phenyl-
2H-pyran-2-one (2.0 g, 10.63 mmol), [4-
(carbomethoxy)phenyl~methyl p -toluenethiosulfonate
(3.57 g, 10.63 mmol), lN NaOH (10.63mL), ethanol
(20mL). m.p. 215-216 C; lH NMR (400 MHz, DMSO-d6)
3.81 (s, 3 H), 4.06 ts, 2 H), 6 (69, J=s Hz, 1 H),
7.39 (d, 2 H), 7.67 (m, 3 H), 7.81 (m, 2 H), 7.86 (d,
2 H); IR (RBr) 3110, 3038, 1717, 1644, 1547, 1402,
~ 1279, 1103, 720, 526 cm~l; MS (CI) m/e 369 (M+H, 22),
235 (100), 207 (18), 189 (37), 151 (55), 119 (20), 105
(21), 85 (28).
3s ~xample 1~1
6-~3,5-Bi~(trifluoromQthyl)phenyl]-~-hydrosy-3-
~phenyl-ethyl)thio]-2~-pyr~n-2-one: The title
compound was prepared by Method A using trimethylsilyl
WO95/14014 PCT~S94/1~67
- 106 -
ether of 3~,5/-trifluoromethylacetophenone (2.16 g,
7.1 mmol) [prepared using 3,5-
ditrifluoromethylacetophenone (15 g, 58.55 mmol) and
trimethylsilyltrimethylsulfonate (13.01 g, 58.55 mmol)
and triethylamine (11.84 g, 117.10 mmol) and
distilled], and diethyl ester of
[(phenylmethyl)thio]prop~ne~ioic acid (1.0 g, 3.55
mmol). m.p. 80-82 C; lH NMR (400 MHz, CDCl3) ~ 4.0
(s, 2 H), 6.61 (s, 1 H), 7.22 (m, 2 H), 7.28 (m, 3 H),
7.97 (s, 1 H), 8.25 (s, 2 H); IR (KBr) 3090, 1726,
1682, 1638, 1549, 1530, 1385, 1281, 1182, 1138, 902,
700 cm~l; MS (CI) m/e 475 (M+29, 3), 447 (M+H, 21), 213
(1), 149 (2), 91 (100).
Es~mple 1~2
3-tl-(Cyclohesylthio)-3-methylbutyl]-~-hy~roxy-6-
phenyl-2~-pyran-2-one ~l/-) :
The title compound was prepared by Method C using 4-
hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol),
isovaleraldehyde (076 g, 8.78 mmol),
cyclohexylmercaptan (2.04 g, 17.56 mmol), piperidine,
(1.0 mL), acetic acid (1.0 mL) and ethanol (20mL).m.p.
210-212 C; lH NMR (400 MHz, DMSO-d6) 8 0.89 (t, 6 H),
1.36 (m, 6 H), 1.44 (m, 1 H), 1.56 (m, 2 H), 1.69 (m,
2 H), 1.81 (m, 1 H), 2.08 (m, 2 H), 2.61 (brm, 1 H),
4.22 (m, 1 H), 6.67 (s, 1 H), 7.53 (m, 3 H), 7.78 (m,
2 H); IR (KBr) 3106, 2928, 2851, 1659, 1568, 1404,
1125, 766, 569 cm~l; MS (CI) m/e 259 (50), 257 (49),
201 (46), 189 (16), 147 (8), 105 (28), 83 (100).
Ex~mpl~ 1~3
1~-t~-~y~roxy-2-oso-3-t(2-phenylethyl)thio]-2~-pyra~-
6-yl]phenoYy]acetonitrile:
The title compound was prepared by Method A using the
appropriate acetophenone (3.0 g, 17.12 mmol),
trimethylsilyltrifluoromethylsulfonate (3.8 g, 17.12
mmol), triethylamine (3.46 g, 34.24mmol) and diethyl
ester of [2-(phenylethyl)thio]prop~nP~;oic acid (2.53
WO95114014 ~1 7~ PCT~S94/12367
- 107 -
g, 8.56 mmol). m.p. 157-159 C; lH NMR (400 MHz,
DMS0-d6) ~ 2.92 (t, 2 H), 3.11 (t, 2 H), 4.86 (s, 2 H),
6.56 (s, 2 H), 7.08 (d, 2 H), 7.19 (t, 3 H), 7.3 (m,
3 H), 7.86 (d, 2 H); IR (KBr) 2993, 2577, 1634, 1510,
1404, 1342, 1302, 1226, 1188, 1098, 1051, 833, 717,
sos cm~l; MS (CI) m/e 380 (lO0), 275 (60), 205 (8), 105
)-
~pl~
4-Hydroxy-3-[~2-isG~!o~lph~nyl)thio]-6-phenyl-2H-
pyran-2-one:
The title compound was prepared by Method A using 1-
phenyl-1-(trimethylsilyloxy)ethylene (1.24 g, 6.45
mmol),and diethyl ester of (2-iso~Lo~ylphenyl)thio
pro~Ane~ioic acid (1.0 g, 3.23 mmol). lH NMR (400
MHz, DMSO-d6) ~ 1.25 (d, 6 H), 3.42 (m, l H), 6.89
(s, 1 H), 6.92 (dd, 1 H), 7.06 (t, 1 H), 7.13
(t, 1 H), 7.28 (d, 1 H), 7.56 (m, 3 H), 7.85 (m, 2 H)
; IR (KBr) 3117, 2962, 1661, 1551, 1406, 1365, 1101,
760 cm~l; MS (CI) m/e 339(100), 305 (4), 219 (25), 189
(11), 147 (9), 105 (9); Analysis calc'd for
C20H1803S1: C, 70.98; H, 5.36; found: C, 70.82; H,
5.24.
E~pl~ l~S
3-t(Cycl~ lnethyl)thio]-4-hydroxy-6-phenyl-2H-
py~n-2-one.
The title compound (0.053 g, m.p. 136-137 C) was
prepared by method B using 4-hydroxy-6-phenyl-2H-
pyran-2-one (0.250 g, 1.33 mmol), cyclo~-o~ylmethyl-p-
- toluenethiosulfonate (0.585 g, 2.261 mmol),
triethylamine (0.158 g, 1.46 mmol), sodium bicarbonate
(0.110 g, 1.33 mmol), ethanol (10.0 mL). ~H NMR (250
MHz, CDCl3) ~ 7.994 - 7.726 (m, 2 H), 7.683 - 7.406 (m,
3 H), 6.665 (s, 1 H), 2.724 - 2.694 (d, 2 H, J = 7.3
Hz), 1.063 - 0.903 (m, 1 H), 0.608 - 0.533 (m, 2 H),
0.270 - 0.208 (m, 2 H).
4`
WO95/14014 PCT~S94tl2367 ~
:.
- 108 -
Ex~mpl~ 1~6
6-(3-Chlorophenyl)-4-hydroxy-3-t~-phenylbutyl)thio]-
2H-pyran-2-one.
The title compound (0.024 g, m.p. 123-124 C) was
prepared by method B using 6-(3-chlorophenyl)-4-
hydroxy-2H-pyran-2-one (0.250 g, 1.13 mmol), 4-phenyl-
butyl-p-toluenethiosulfonate (0.45 g, 1.93 mmol),
triethylamine (0.115 g, 1.13 mmol), sodium bicarbonate
(0.094 g, 1.13 mmol), ethanol (5.0 mL). lH NMR (400
MHz, CDC13) ~ 7.848 - 7.839 (m, 1 H), 7.729 (m, 1 H),
7.479 - 7.392 (m, 2 H), 7.276 - 7.239 (m, 2 H), 7.174 -
7.137 (m, 3 H), 6.631 (s, 1 H), 2.831 - 2.794 (t, 2
H), 2.633 - 2.596 (t, 2 H), 1.747 - 1.689 (m, 2 H),
1.649 - 1.591 (m, 2 H).
Exa~ple 1~7
~-Hy~roxy-3-~t2-o~o-2-phenylethyl)thio]-6-phenyl-2H-
pyran-2-one. A solution of 4-hydroxy-3-mercapto-6-
phenyl-2-pyrone (0.175, 0.840 mmol, prepared as in
R.F. Harris, J.E. Dunbar, U.S. 3,818,046) in CH2Cl2
(3.0 mL) under an N2 atmosphere was treated with
triethylamine (0.12 mL, 0.84 mmol) followed by
bromoacetorh~n~ne (0.167 g, 0.840 mmol). The mixture
was allowed to stir for 30 min. at ambient temperature
then the solvent removed in vacuo. The residue was
then diluted with diethyl ether and extracted with
saturated Na2CO3 (3 x 50 mL). The aquous layers were
then combined, acidifed with conc. HCl, and extracted
with CH2Cl2 (3 x 100 mL). The organic layers were
combined, dried with Na2S04, and the solvent removed in
vacuo to give the title compound (0.066 g, m.p. 164 -
166 C) which was dried in vacuo. lH NMR (300 MHz,
CDCl3) ~ 9.900 (bs, 1 H), 7.970 (d, 2 H, J = 7.1 Hz),
7.810 (d, 2 H, J = 8 Hz), 7.615 (t, 1 H, J = 4 Hz),
7.505 - 7.443 (m, 5 H), 6.619 (s, 1 H), 4.334 (s, 2
H).
kx~mplQ 1~8
Wo95/14014 2 ~ PCT~S94/12367
-- 109 --
~-~ydroxy-3-t(2-phQnylethan-2-ol)thio]-6-pho~yl-2
pyr~n-2-on~.
To a stirred solution of 4-hydroxy-3-[(2-oxo-2-
phenylethyl)thio]-6-phenyl-2H-pyran-2-one (0.021 g,
5 o.060 mmol) in THF (1.0 mL) cooled to O oc (N2
atmosphere) was a 1.0 M solution of BH3-DMS (0.05 mL,
O.05 mmol) in THF added via syringe. The mixture was
allowed to stir for 1 h then quenched with a 1 : 1
mixture of 4 N HCl : MeOH. The mixture was then
lo extracted with diethyl ether. The layers were
combined, dried with Na2SO4, and the solvent removed in
vacuo to provide the title compound (0.015 g) as an
oil. lH NMR (200 MHz, CDCl3) 8 7.873 - 7.777 (m, 4 H),
7.516 - 7.153 (m, 6 H), 6.667 (s, 1 H), 4.820 - 4.755
(dd, 1 H, J = 9.8 Hz, 3.2 Hz), 3.212 - 3.127 (dd, 1 H,
J = 13.8 Hz, 3.2 Hz), 2.920 (dd, 1 H, J = 9.8 Hz, 13.8
Hz).
E~mple 149
~ ~ydroxy-5-methyl-6-phenyl-3-~phe~ylthio]-2~-pyran-2
one.
A solution of propiophenone (1.50 mL, 11.3 mmol) in
CH2Cl2 (40.0 mL) was cooled to O oc (N2 atmosphere) and
treated with triethylamine (3.14 mL, 22.6 mmol)
followed by trimethylsilyltriflate (2.60 mL, 13.5
mmol). The solution was then warmed to ambient
temperature, allowed to stir for 15 min., and
subsequently quenched into a mixture of diethyl ether
(50 mL) and saturated aqueous NaHCO3 (20 mL). The
layers were separated and the organic layer washed
with a 1 : l mixture of brine : saturated NaHCO3 (20
mL). The ethereal solution was then dried with Na2SO4
- and the solvent removed in vacuo. The resulting silyl
enol ether was then transferred to a flask cont~;n;ng
diethyl -2-(thiophenyl)propane-1,3-dioate (1.00 g,
3.76 mmol), the mixture heated to 140 C for 16 h.
then allowed to cool to room temperature where it was
diluted with diethylether and extraced with saturated
W095/14014- 2~ 7~124 PCT~S94/12367 ~
. ` -- 110 --
Na2CO3 (3 x 20 mL). The aqueous layers were combined,
washed with diethylether (3 x 75 mL), then carefully
acidified with conc. HCl. The mixture was then
extracted with CH2C12 (3 x 200 mL), the organic layers
combined, dried with Na2SO4, and the solvent removed in
vacuo to provide the title compound (0.350 g, m.p. 166
- 167 oc). lH NMR (400 MHz, DMSO-d6) 8 6.309 - 6.285 (
m, 2 H), 6.227 - 6.211 (m, 3 H), 5.983 (t, 2 H, J = 8
Hz), 5.862 (d, 3 H, J = 8 Hz), 0.705 (s, 3 H).
~ C~IIpl~ 150
t ~- t ~-~y~G~~2~0X0~3~ ~phenylthio)-2~-pyran-6-
yl]pheno~y]-acetic acid.
A solution of methyl-~4-(1-oxoethyl)phenoxy]-acetate
(2.S0 g, 10.86 mmol) in CH2Cl2 (25.0 mL) was cooled to
o oc (N2 atmosphere) and treated with triethylamine
(3.03 mL, 21.7 mmol) followed by
trimethylsilyltriflate (2.52 mL, 13.0 mmol). The
solution was then warmed to ambient temperature,
allowed to stir for 15 min., and subsequently qu~nche~
into a mixture of diethyl ether (50 mL) and saturated
aqueous NaHCO3 (20 mL). The layers were separated and
the organic layer washed with a 1 : 1 mixture of brine
: saturated NaHCO3 (20 mL). The ethereal solution was
then dried with Na2SO4 and the solvent removed in
vacuo. The resulting silyl enol ether was then
transferred to a flask cont~i n; ng diethyl 2-
(thiophenyl)propane-1,3-dioate (0.97 g, 3.6 mmol). The
mixture was then heated to 140 C for 16 h. and
allowed to cool to room temperature where it was
submitted to chromatography (SiO2-230 to 400 mesh, 100%
CH2Cl2 to 2.0% MeOH / CH2Cl2) to provide an impure solid
which was diluted with diethyl ether (20 mL) and
extracted with saturated Na2CO3 (3 x 20 mL). The
3s combined aqueous extracts were washed with diethyl
ether (3x100 mL) and then acidifed with conc. HCl to
pH 0. The mixture was then extracted with ethyl
acetate (3 x 100 mL), the organic layers combined,
WO95/14014 PCT~S94JI~67
2 ~
-- 111
dried with Na2SO4 and the solvent removed in vacuo. to
provide the title compound (0.695 g, m.p. 186 - 188
C). lH NMR (300 MHz, DMSO-d6) ~ 13.175 (bs, 1 H),
12.425 (bs, 1 H), 7.809 (d, 2 H, J = 9 Hz), 7.298 -
s 7.247 (m, 2 H), 7.149 - 7.004 (m, 5 H), 6.785 (s, 1
H), 4.804 (s, 2 H).
~s~mple 151
t~-t~-~ydro~y-5-methyl-2-oxo-3-~phenylthio)-2H-pyr~n-
lo ~-yl]~h~ ]-aoeti¢ acid. The title compound (0.691
g, m.p. 194 - 197 C) was prepared in a similar
manner to that demonstrated in the preparation of [4-
~4-hydroxy-2-oxo-3-(phenylthio)-2H-pyran-6-
yl]phenoxy]-acetic acid using the following: Methyl-
[4-(l-oxoethyl)phenoxy]-acetate (2.00 g, 8.81 mmol),
triethylamine (3.68 mL, 26.4 mmol),
trimethylsilyltriflate (2.38 mL, 12.3 mmol),
dichloromethane (20.0 mL), diethyl 2-
(thiophenyl)propane-1,3-dioate (1.34 g, 5.00 mmol.).
lH NMR (400 MHz, DMSO-d6) ~ 7.585 (d, 2 H, J = 9 Hz),
7.325 - 7.286 (m, 2 H), 7.178 (d, 3 H, J = 7.5 Hz),
7.063 (d, 2 H, J = 9 Hz), 4.784 (s, 2 H), 2.042 (s, 3
H).
Es~ple 152
~-~ydrosy-3-phc~o~y-6-phenyl-2H-pyra~-2-one. To a
pressure reactor was added 2-phenoxyprop~ne~;oicacid
diethylester 8.11 g (0.032 moles) and 1-phenyl-1-
(trimethylsilyloxy)ethylene 12.35 g (0.064 moles).
The vessel was pressurized to 600 psi with N2. The
mixture was heated at 100 C for 8 hours then an
additional 63.5 hours at 147 - 154 C. The vessel was
cooled to room temperature and rinsed with ethyl
acetate. Crude flash chromatography (hexane/ethyl
acetate 1/1) afforded partially purified material
which was then flashed on silica gel using hexane /
ethyl acetate 95/5 - 40/60 as eluents. The resulting
solid was recrystallized from diethyl ether and ethyl
WO95/14014 ~7~ PCT~S94/12367
- 112 -
acetate to afford 1.64g (18%) of the title compound
(mp = 215-219 C). lH NMR (400 MHz, DMSO-d6) ~ 6.90 (s,
1 H), 6.95 (dd, 2 H), 7.02 (t, 1 H), 7.28 - 7.33 (m, 2
H), 7.52 - 7.56 (m, 3 H), 7.80 - 7.856 (m, 2 H), 12.0
(bs, 1 H).
E~ample 153
~-Hydroxy-3-~phcnylmethyllthio]-6-~3-pyridinyl)-2~-
pyran-2-on~. The title compound was prepared from the
lo condensation of the trimethylsilyl enol ether of 3-
acetyl pyridine and diethyl ester of
[(phenylmethyl)thio]prop~ne~;oic acid following the
same procedure outlined in Method A; m.p. 183-184 C.
NMR (DMS0-d6) ~ 4.02 (s, 2 H), 6.83 (s, 1 H), 7.20 (m,
1 H), 7.26 (d, 4 H), 7.55 (m, 1 H), 8.16 (m, 1 H),
8.69 (m, 1 H), 8.98 (d, 1 H).
~sample 154
6-(2~6-DLmethyl-~-pyridinyl)-~-hydroxy-3-
t(phenylmethyl)thio]-2~-pyran-2-one. The title
compound was prepared from the condensation of the
trimethylsilyl enol ether of 4-acetyl-2,6-
dimethylpyridine and the diethyl ester of
~(phenylmethyl)thio~prop~e~;oic acid following the
same procedure outlined in Method A; m.p. 88-90 C.
NMR (DMSO-d6) ~ 2.55 (s, 6 H), 4.02 (s, 2 H), 6.85 (s,
1 H), 7.16-7.28 (m, 5 H), 7.40 (s, 2 H).
ksample 155
~-~ydroxy-3-ttphenylmethyl)thio~-6-~3-thienyl)-2H-
pyran-2-one. The title compound was prepared from the
condensation of the trimethylsilyl enol ether of 3-
acetylthiophene and the diethyl ester of
[(phenylmethyl)thio]propanedioic acid following the
3s same procedure outlined in Method A; m.p. 150-151 C.
NMR (DMSO-d6) ~ 3.98 (s, 2 H), 6.58 (s, 1 H), 7.24 (m,
5 H), 7.48 (m, 1 H), 7.72 (m, 1 H), 8.13 (d, 1 H).
WO95/14014 217~4 PCT~S94/1~67
- 113 -
E~ple 156
3-t(2,6-Di~thylpho~yl)mothyl]thio]-~-hydroxy-6-
phenyl-2H-pyran-2-onQ: The title compound was
prepared by Method B using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN
sodium hydroxide (5.31 mL), (2,6-dimethylphenyl)methyl
p-toluenethiosulfonate (1.62 g, 5.31 mmol). m.p. 231-
233 C; lH NMR (400 MHz, DMSO-d6) ~ 2.34 (6H, s), 4.01
(s, 2H), 6.81 (m, 2H), 7.03 (m, 3H), 7.53 (m, 3H),
7.82 (m, 2H).
Ex~mple 157
~-~y~6~y-6-phenyl-3-tt(3-ph~ henyl)methyl]thio]
2H-pyran-2-one: The title compound was prepared by
Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00
g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide
(5.31 mL), (3-phenoxyphenyl)methyl p-
toluenethiosulfonate (1.96 g, 5.31 mmol). m.p. 131-133
C; lH NMR (400 MHz, DMSO-d6) ~ 3.97 (s, 2H) 6.73 (s,
lH), 6.87 (m, 4H), 7.03 (m, 2H), 7.27 (m, 3H), 7.53
(m, 3H), 7.78 (m,2H).
E~a~pl~ 158
- 3-tl-t~Cyclohexyl~ethyl)thio]-3-methylbutyl]-4-
~ydh~ 6 ~henyl-2~-pyran-2-one, ~/-): The title
compound was prepared by Method C using 4-hydroxy-6-
phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10
mL), isovaleraldehyde (0.462 mL, 5.84 mmol),
cyclohexylmethylthiol (1.79 g, 13.8 mmol), piperidine
(0.5 mL), acetic acid (0.5 mL). m.p. 146-148 C; lH
NMR (400 MHz, DMSO-d6) ~ 0.58 (d, 6H), 1.11 (m, 5H),
1.57 (m, 8H), 2.07 (m, lH), 2.28 (dd, lH), 2.38 (dd,
lH), 4.17 (dd, lH), 6.69 (s, lH), 7.54 (m, 3H), 7.75
(m, 2H), 11.71 (bs, lH).
Ex~mpl~ 159
3-tl-~Cyclohexyl~ethyl)thio]phenylmethyl]-~-hydroxy-
6-phenyl-2H-pyr~n-2-on~, (I/-): The title compound
WO95/14014 ;' PCT~S94/12367 ~
2~7 4 ~ 2~
^ - 114 -
was prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one ~1.00 g, 5.31 mmol), ethanol (10 mL),
benzaldehyde (0.593 mL, 5.84 mmol),
cyclohexylmethylthiol (1.79 g, 13.8 mmol), piperidine
(0.5 mL), acetic acid (0.5mL). m.p. 138-141 C; lH NMR
(400 MHz, DMSO-d6) ~ 0.89 (m, 2H), 1.21 (m, 3H), 1.42
(m, lH), 1.61 (m, 3H), 1.75 (m, 2H), 2.39 (m, 2H),
5.30 (s, lH), 6.71 (s,lH), 7.26 (t,lH), 7.28 (t, 2H),
7.S3 (m, 5H), 7.74 (m, 2H).
kS~pl~ 160
~-~ydroxy-6-t~-(2-hydroxyethoxy)ph~nyl]-3-t(2-
phenylethyl)thio]-2H-pyran-2-one: To a
tetrahydrofuran (7 mL) solution of [4-[4-hydroxy-2-
oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-
phenoxy]acetic acid, ethyl ester (0.30 g, 0.70 mmol)
was added 2.0 M lithium borohydride (0.5 mL, 1.00
mmol). The reaction was stirred overnight. The
reaction was then quenched by addition of lN
hydrochloric acid (2.0 mL) and diluted with ethyl
acetate (50 mL). The organic layer was separated and
washed with saturated sodium chloride and dried over
anhydrous magnesium sulfate. After evaporation of the
solvents in vacuo, the crude product was purified by
column chromatography (silica gel-230 to 400 mesh)
using 50% ethyl acetate/hex~e~ to 100% ethyl acetate
as the eluent. m.p. 123-125 C; lH NMR (400 MHz,
DMSO-d6) ~ 2.77 (t, 2H), 2.97 (t, 2H), 3.37 (m, 2H),
4.07 (t, 2H), 4.92 (bs, lH), 6.68 (s, lH), 7.09
(d,2H), 7.19 (m, 5H), 7.75 (d, 2H).
Exampl~ 161
~3-~-Hydro~y-2-oxo-3-~(2-phenylethyl)thio]-2H-pyran
-6-yl]rh~ y] acetic acid, ethyl ester: The title
compound was prepared by Method A using ethyl (3-
acetylphenoxy)acetate (2.00 g, 9.00 mmol), trimethyl
silyltriflate (4.18 mL, 21.62 mmol), triethylamine
(5.01 mL, 36.00 mmol), methylene chloride (23 mL), and
W095/14014 ~1 7~12~ PCT~S94112367
- 115 -
diethyl ester of [(2-phenylethyl)thio]propanedioic
acid (1.00 g, 3.37 mmol). m.p. 116-119 C; lH NMR (400
MHz, DMSO-d6) ~ 1.22 (t, 3H), 2.77 (t, 2H), 3.05 (t,
2H), 4.89 (d, 2H), 6.80 (s, lH), 7.20 (m, 7H), 7.44
(m, 2H).
Ex~mple 162
~-~ydrosy-6-[~-t(5-methyl-3-phenyl-~-
isoYasolyl)metho~y]phenyl]-3-t~2-phenylethyl)thio]-2H-
p~ran-2-one: The title compound was prepared by
Method A using 4'-[(5-methyl-3-phenyl-4-
isoxaoly)methoxy]acetophenone (2.00 g, 6.51 mmol),
trimethylsilyl triflate (1.51 mL, 7.81 mmol),
triethylamine (1.81 mL, 13.02 mmol), methylene
chloride (16 mL), and diethyl ester of ~(2-
phenylethyl)thio]prop~ne~;oic acid (l.OOg, 3.37 mmol).
m.p. 126-128 C; lH NNR (400 MHz, DMSO-d6) ~ 2.54 (s,
3H), 2.77 (t, 2H), 2.98 (t, 2H), 5.08 (s, 2H), 6.69
(s, lH), 7.21 (m, 7H), 7.49 (m, 3H), 7.71 (m, 2H),
7.77 (d, 2H).
B Iple lC3
6-(3,5-Di~ethylphenyl)-~-hydroYy-3-(phenylthio)-2~-
pyr~n-2-one: The title compound was prepared by
Method A using 3',5'-dimethylacetophenone (1.43 g,
9.70 mmol), trimethylsilyl triflate (2.24 mL, 11.64
mmol), triethylamine (2.70 mL, 19.40 mmol), methylene
chloride (24 mL), and diethyl ester of (phenylthio)-
propanedioic acid (1.00 g, 7.46 mmol). m.p. 210-211
C; H NMR (400 MHz, DMSO-d6) ~ 2.35 (s, 6H), 6.83 (s,
lH), 7.12 (m, 3H), 7.21 (s, lH), 7.27 (t, 2H), 7.46
(s, 2H).
E2~mpl~ 16~
3-tl-tCyclopentylthio]-2-cyclopropylethyl]-4-hydro~y-
6-phenyl-2~-pyran-2-one, (+/-): The title compound
was prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
WO95/14014 21 r7 41~ PCT~S94/12367 ~
- 116 -
cyclo~ylmethylcarboxaldehyde (0.892 g, 10.62 mmol),
cyclopentylthiol (1.43 mL, 13.8 mmol), piperidine (0.5
mL), acetic acid (0.5 mL). m.p.75-80 C; lH NMR (400
MHz, DMSO-d6) ~ 0.04 (m, 2H), 0.07 tm, 2H), 0.66 (m,
lH), 1.53 (m, 7H), 1.94 (m, 3H), 3.19 (m, lH), 4.21
(dd, lH), 6.71 (s,lH), 7.54 (m, 3H), 7.76 (m, 2H).
E~ample 165
N-t3-t4-~y~ 6a~ 2-oxo-3-t~2-phenylethyl)thio]-2~-
pyr~n-C-yl]phenyl]-4-methyl-bensenesulfon~mide: The
title compound was prepared by Method A using 3'-(p-
toluenesulfonamide)acetophenone (1.38 g, 5.06 mmol),
trimethylsilyl triflate (2.34 mL, 12.41 mmol),
triethylamine (2.82 mL, 20.24 mmol), methylene
chloride (18 mL), and diethyl ester of [(2-
phenylethyl)thio]propanedioic acid (1.00 g, 3.37
mmol). m.p. 133-135 C; lH NMR (400 MHz, DMSO-d6)
2.32 (s, 3H), 2.77 (t, 2H), 3.09 (t, 2H), 6.68 (s,
lH), 7.19 (m, 6H), 7.40 (m, 4H), 7.53 (s, lH), 7.67
(d, 2H), 10.50 (s, lH), 12.03 (bs, lH).
E~ample lC6
3-tCyclopentyl(cyclopentylthio)methyl]-~-hy~roxy-6-
phenyl-2~-pyran-2-one, (~ The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL),
cyclopentanecarboxaldehyde (0.780 g, 7.96 mmol),
cyclopentylthiol(1.43 mL, 13.8 mmol), piperidine (0.5
mL), acetic acid (0.5 mL). m.p.139-142 C; lH NMR (400
MHz, DMS0-d6) ~ 1.03 (m, lH), 1.64 (m, 15H), 2.64 (m,
lH), 3.00 (m, lH), 3.84 (d, lH), 6.69 (s, lH), 7.52
(m, 3H), 7.76 (m, 2H), 11.55 (bs, lH).
~ample 167
6-(1,1'-Biphen-3-yl)-~-h~o~-3-~(2-isopropylphenyl)
thio~-2H-pyran-2-one: The title compound was prepared
by Method A using 3'-phenylacetophenone (0.946 g, 4.83
mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol),
W095/14014 - ~ 7~1 2~ PCT~S94/l~67
- 117 -
triethylamine (1.34 mL, 9.66 mmol), methylene chloride
(17 mL), and diethyl ester of t(2-
isopropylphenyl)thio]-propanedioic acid (1.00 g, 3.22
mmol). m.p. 193-195 C; ; lH NMR (400 MHz, DMSO-d6)
1.25 (d, 6H), 3.43 (m, lH), 6.95 (d, lH), 7.02 (s,
r lH), 7.06 (t, lH), 7.13 (t, lH), 7.28 (d, lH), 7.42
(t, lH), 7.51 (t, 2H), 7.66 (t, lH), 7.75 (d,2 H),
7.85 (t, 2H), 8.07 (s, lH).
Es~mpl~ 168
~-~ydroYy-6-phenyl-3-t~2 ~G~lphenyl)thio]-2~-pyran-
2-on~: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990
mL, 4.83 mmol) and diethyl ester of t(2-
propylphenyl)thio]propanedioic acid (1.00 g, 3.22
mmol). m.p. 158-160 C; lH NMR (400 MHz, DMSO-d6)
0.972 (t, 3H), 1.64 (m, 2H), 2.71 (t, 2H), 6.87 (s,
lH), 6.92 (m, lH), 7.06 (m, 2H), 7.16 (m, lH), 7.55
(m, 3H), 7.85 (m, 2H).
Ex~ple 169
6-(3,5-Dimethylphenyl)-~-hydroxy-3-t(2-isopropylphenyl)-
thio]-2~-pyr~n-2-one: The title compound was
prepared by Method A using 3',5'-dimethylacetophenone
(0.714 g, 4.83 mmol), trimethylsilyl triflate (1.12
mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol),
methylene chloride (17 mL), and diethyl ester of t(2-
isopropylphenyl)thio]propanedioic acid (l.OOg, 3.22
mmol) m.p. 154-155 C; lH NMR (400 MHz, DMSO-d6) ~ 1.24
(d, 6H), 2.35 (s, 6H), 3.40 (m, lH), 6.90 (d, lH),
7.05 (t, lH), 7.11 (dt, 2H), 7.20 (s, lH), 7.27 (d,
lH), 7.45 (s, 2H).
~s~mple 170
~-Hydro~y-6-(~-hy~roxyphenyl)-3-t~2-isopropylphenyl)
thio]-2~-pyr~-2-one: The title compound was prepared
by Method A using 4~-hydlo~y~cetophenone (0.657 g,
4.83 mmol), trimethylsilyl=~riflate (2.05 mL, 10.62
WO95/14014 ~ PCT~S94/12367 ~
~ ~ 7~
- 118 -
mmol), triethylamine (2.69 mL, 19.32 mmol), methylene
chloride (20 mL), and diethyl ester of [(2-
isopropylphenyl)thio]propanedioic acid (l.OOg, 3.22
mmol) m.p. 250 C; (dec.) ; lH NMR (400 MHz, DMS0-d6)
1.24 (d, 6H), 3.40 (m, lH), 6.70 (s, lH), 6.90 (t,
3H), 7.05 (t, lH), 7.10 (t, lH), 7.26 (d, lH), 7.70
(d, 2H).
~xampl~ 171
3-tt2-~Cyclopropyl~ethyl)phenyl]thio]-~-hydroxy-6-
phsnyl-2~-pyran-2-one: The title compound was
prepared by Method A using 1-phenyl-1-
(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol), and
diethyl ester of tt2-(cyclopropylmethyl)phenyl]thio]
propanedioic acid (l.OOg, 3.10 mmol) m.p. 165-167 C;
H NMR (400 MHz, DMSO-d6) ~ 0.25 (dd, 2H), 0.52 (dd,
2H), 1.21 (m, lH), 2.50 (d, 2H), 6.87 (s, lH), 6.92
(m, lH), 7.05 (m, 2H), 7.32 (m, lH), 7.56 (m, 3H),
7.86 (m,2H).
E~mple 172
4-~ydro~y-3-t~2-isG~v~lphenyl)thio]-6-t~-(pyridin-
3-yl~ethoxy)ph~nyl]-2~-pyr~n-2-on~: The title
compound was prepared by Method A using 4'-(pyridin-3-
ylmethoxy)acetophenone (1.09 g, 4.83 mmol),
trimethylsilyl triflate (1.12 mL, 5.79 mmol),
triethylamine (1.34 mL, 9.66 mmol), methylene chloride
(17 mL), and diethyl ester of [(2-
isopropylphenyl)thio]-propanedioic acid (1.00 g, 3.22
mmol) m.p. 225 C; ; lH NMR (400 MHz, DMSO-d6) ~ 1.23
(d, 6H), 3.41 (m, lH), 5.26 (s, 2H), 6.78 (s, lH),
6.90 (d, lH), 7.08 (dt, 2H), 7.21 (d, 2H), 7.2g (d,
lH), 7.45 (dd, lH), 7.82 (d, 2H), 7.91 (d, lH), 8.56
(d, lH), 8.71 (s, lH).
E~ampl~ 173
~-[~-HyaroYy-5-[~2-isopropylphenyl)thio]-6-oYo-6H-
pyr~n-2-yl]~h~ ~cetic ~cid ethyl e~tQr: The title
~ WO95/14014 ~ 7 ~ 12 4 PCT~S94/l~67
-- 119 --
com~ound was prepared by Method A using ethyl (4-
acetyl-phenoxy)acetate (2.14g, 9.67 mmol),
trimethylsilyl triflate (4.48 mL, 23.20 mmol),
triethylamine (12.93 mL, 38.6 mmol), methylene
S chloride (20 mL), and diethyl ester of [(2-
isopropylphenyl)thio]propanedioic acid (2.00g, 6.45
mmol) m.p. 194-196 C; ; lH NMR (400 MHz, DMSO-d6)
l.S7 (m, 9H), 3.41 (m, lH), 4.81 (q, 2H), 4.89 (s,
2H), 6.75 (s, lH), 6.90 (d, lH), 7.05 (m, 4H), 7.26
lo (d~ lH), 7.79 (d, 2H).
Ex~mple 17~
~-[4-Hydrosy-5-t (2-iSG~ o~lphenyl)thio]-6-oso-6H-
pyran-2-yl~-phe~o~ acetic acid: To a tetrahydrofuran
(10 ml) solution of 4-t4-Hydroxy-5-t(2-
isopropylphenyl)thio]-6-oxo-6H-pyran-2-yl]phenoxy
acetic acid ethyl ester (0.319 g. 0.75 mmol) was added
lN sodium hydroxide (1.80 mL, 1.81 mmol). The
reaction was stirred for 1.5 h, and then water (10 ml)
was added followed by acidification with conc.
hydrochloric acid to pH 2. The aqueous layer was then
extracted 2X with ethyl acetate (100 ml). the combined
organic extracts were then washed with saturated
sodium chloride and dried over anhydrous magnesium
sulfate. After evaporation of the solvents in vacuo,
the crude product was purified by column
chromatography (silica gel-230 to 400 mesh) using
94/5/1 methylene chloride/methanol/acetic acid as the
eluent. m.p. 217 C; (dec.); 1H NMR (400 MHz, DMSO-d6)
~ 1.25 (d, 6H), 3.42 (m, lH), 4.79 (s, 2H), 6.75 (s,
lH), 6.90 (d, lH), 7.06 (m, 4H), 7.26 (d, lH), 7.79
(d, 2H).
Es~mple 175
4-~ydrosy-3-t~2-isopropylphenyl)thio]-6-(~-
methoxyphenyl)-2~-pyran-2-one:
The title compound was prepared by Method A using 4'-
methoxyacetoph~non~ (2.26 g, 15.1 mmol),
WO 95tl4014 ' PCT/US94/12367 ~l
2174~2~
- 120 -
trimethylsilyl triflate (3.5 mL, 18.1 mmol),
triethylamine (4.26 mL, 30.6 mmol), methylene chloride
(30 mL), and diethyl ester of [(2-
isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0
S mmol) m.p. 221-223 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25
(d, 6H), 3.40 (m, lH), 3.85 (s, 3H), 6.78 (s, lH),
6.92 (m, lH), 7.10 (m, 4H), 7.27 (m, lH), 7.81 (d,
2H), 12.38 (brs, lH).
E~mpl~ 17C
~-nyd,6.y-3-tl2-isopropylphenyl)thio]-6-(~-
methylphenyl)-2~-pyran-2-one:
The title compound was prepared by Method A using 4'-
methylacetoph~none ( 2.02 mL, 15.1 mmol),
trimethylsilyl triflate (3.5 mL, 18.1 mmol),
triethylamine (4.26 mL, 30.6 mmol), methylene chloride
(30 mL), and diethyl ester of t(2-
isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0
mmol) m.p. 191-193 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25
(d, 6H), 2.39 (s, 3H), 3.41 (m, lH), 6.84 (s, lH),
6.92 (m, lH), 7.10 (m, 2H), 7.27 (m, lH), 7.37 (m,
2H), 7.75 (d, 2H).
E~pl~ 177
6-t3,~-Dichlorophenyl)-4-~yd.6~ 3-[~2-
isopropylphenyl)thio]-2~-pyran-2-one:
The title compound was prepared by Method A using
3',4'-dichloroacetophenone ( 2.46 g, 12.8 mmol),
trimethylsilyl triflate (3.0 mL, 15.4 mmol~,
triethylamine (3.6 mL, 26.0 mmol), methylene chloride
(30 mL), and diethyl ester of ~(2-
isopropylphenyl)thio] prop~ne~;oic acid (4.0 g, 12.8
mmol) m.p. 204-207 C; lH NMR (400 MHz, CDCl3) ~ 1.33
(d, 6H), 3.55 (m, lH), 6.71 (s, lH), 7.00 (m, lH),
7.08 (m, lH), 7.20 (m, lH), 7.30 (m, lH), 7.56 (d,
lH), 7.69 (m, lH), 7.74 (br, lH), 7.98 (s, lH).
EK~pl~ 178
WO95/14014 ~ 2~1 PCT~S94112367
- 121 -
6~ Chlorophenyl)-~-hydrosy-3-t(2-
~o~ o~lphenyl)thio]-2~-pyran-2-o~e:
The title compound was prepared by Method A using 4~-
chloroacetoph~no~e ( 2.33 g, 15.1 mmol),
trimethylsilyl triflate (3.5 mL, 18.1 mmol),
triethylamine (4.26 ~L, 30.6 mmol), methylene chloride
(30 mL), and diethyl ester of t(2-
isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0
mmol) m.p. 148-151 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25
(d, 6H), 3.41 (m, lH), 6.86 (s, lH), 6.92 (m, lH),
7.08 (m, 2H), 7.27 (m, lH), 7.62 (m, 2H), 7.86 (m,
2H).
~Yample 179
4-~-Hydro~y-5-t(2-i~opropylphenyl)thio]-6 o~o 6~-
pyr~n-2-yl~benzoic acid ethyl e~ter: The title
compound was prepared`by Method A using ethyl 4-
acetylbenzoate (2.93 g, 15.1 mmol), trimethylsilyl
triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL,
30.6 mmol), methylene chloride (30 mL), and diethyl
ester of [(2-iso~ ylphenyl)thio]propanedioic acid
(3.11 g, 10.0 mmol) m.p. 201-203 C; lH NMR (400 MHz,
DMS0-d6) ~ 1.25 (d, 6H), 1.35 (t, 3H), 3.42 (m, lH),
4.35 (q, 2H), 6.94 (m, lH), 7.00 (s, lH), 7.10 (m,
2H), 7.28 (m, lH), 7.99 (m, 2H), 8.11 (m, 2H).
E~a~pl~ 180
~ ~G~-6-(3-h~G~y~h~yl)-3-t(2-
is~L~ylphenyl)thio]-2~-pyra~-2-one:
The title compound was prepared by Method A using 3'-
hydroxyacetophenone ( 2.06 g, lS.l mmol),
trimethylsilyl triflate (7.0 mL, 36.2 mmol),
triethylamine (8.52 mL, 61.1 mmol), methylene chloride
(30 mL), and diethyl ester of [(2-
iso~ ylphenyl)thio] propanedioic acid (3.11 g, 10.0
mmol) m.p. 201-204 C; lH NMR (250 MHz, DMSO-d6) ~ 1.25
(d, 6H), 3.41 (m, 1~), 6.82 (s, lH), 6.93 (m, 2H),
7.09 (m, 2H), 7.30 (m, 4H), 9.91 (br, lH).
WO95tl4014 2 ~ 7 ~ PCT~S94/1~67
- 122 -
EX~pl~ 181
~-Hydrosy-3-t~2-isG~,G~lp~onyl)thio]-2H-6-(2-
phenylethyl-1-ene)-pyra~-2-one:
The title compound was prepared by Method A using
trans-4-phenyl-3-buten-2-one ( 2.23 g, 15.1 mmol),
trimethylsilyl triflate (3.5 mL, 18.1 mmol),
triethylamine (4.26 mL, 30.6 mmol), methylene chloride
(30 mL), and diethyl ester of [(2-
isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0
mmol) m.p. 190-192 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25
(d, 6H), 3.40 (m, lH), 6.44 (s, lH), 6.89 (m, lH),
7.10 (m, 3H), 7.27 (m, lH), 7.40 (m, 4H), 7.71 (d,
2H).
~x~pl~ 182
6-(1,1'-Biphen-4-yl)-~-hydro~y-3-t~2-isopropylphenyl)
thio]-2H-pyr~n-2-one:
The title compound was prepared by Method A using 4-
acetylbiphenyl ( 3.06 g, lS.l mmol), trimethylsilyl
triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL,
30.6 mmol), methylene chloride (30 mL), and diethyl
ester of ~(2-is~v~ylphenyl)thio]prop~n~ioic acid
(3.11 g, 10.0 mmol) m.p. 203-206 C; lH NMR (250 MHz,
DMSO-d6) ~ 1.26 (d, 6H), 3.40 (m, lH), 6.94 (m, 2H),
7.10 (m, 2H), 7.28 (m, lH), 7.51 (m, 3H), 7.77 (m,
2H), 7.91 (q, 4H).
~x~pl~ 183
6-(1,1~-Biphenyl-3-yl)-~-hydroxy-3-t~naphthalen-2-
yl)thio]-2~-pyran-2-one: The title compound was
prepared by Method A using 3'-phenylacetophenone (2 g,
10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20
mmol), triethylamine (2.06 g, 20.40 mmol), methylene t
chloride (20 mL), and diethyl ester of [2-(naphthalen-
2-yl)thio]-propanedioic acid (1.62 g, 5.1 mmol). m.p.
183-185 C; lH NMR (400 MHz, DMS0-d6) ~ 7.07 (s, lH),
7.33 (dd, lH), 7.39-7.58 (m, 5H), 7.66 (s, lH), 7.69
.
~ WO95/14014 PcT~S941~67
21~41~
- 123 -
(d, lH), 7.78 (d, lH), 7.81-7.92 (m, 6H), 8.11 (s,
lH).
EX~pl~ 184
S ~-~ydroxy-3-[~naphthalen-1-yl)thio]-6-phenyl-2~-pyran-
2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g,
10.14 mmol) and diethyl ester of [(1-
naphthyl)thio]prop~n~;oic acid (1.61g, 5.07 mmol).
m.p. 242-243 C; lH NMR (400 MHz, DMSO-d6) ~ 6.83 (s,
lH), 7.19 (d, lH), 7.39 (t, lH), 7.64-7.42 (m, 5H),
7.69 (d, lH), 7.83 (m, 2H), 7.94 (d, lH), 8.28 (d,
lH).
Ex~mple 185
6-(1,1~-Biphenyl-3-yl)-3-t~2-
(cyclopropylmethyl)phenyl]thio]-~-hydrosy-2H-pyran-2-
o~e: The title compound was prepared by Method A
using 3'-phenyl acetophenone (2 g, 10.20 mmol),
trimethylsilyl triflate (2.27g, 10.20 mmol),
triethylamine (2.06g, 20.40 mmol), methylene chloride
(20 mL), and diethyl ester of [[2-
( CYC10~L u~ylmethyl)phenyl]thio]propanedioic acid (1.14
g, 5.1 mmol). m.p. 88 oc; lH NMR (400 MHz, DMSO-d6)
0.25 (d, 2H), 0.53 (dd, 2H), 1.14 (m, lH), 2.67 (d,
2H), 6.94 (m, lH), 7.03 (s, lH), 7.11 (m, 2H), 7.33
(m, lH), 7.44 (d, lH), 7.53 (t, 2H), 7.67 (t, lH),
7.75 (d, 2H), 7.86 (m, 2H), 8.08 (s, lH).
~x~mple 186
3-tt2-(Cyclo~.o~lnethyl1phenyl]thio]-6-(3,5-~imethyl-
phe~yl)-~-hydrosy-2~-pyran-2-one: The title compound
was prepared by Method A using 3,3'-dimethyl
acetophenone (2 g, 13.51 mmol), trimethylsilyl
3s triflate (3 g, 13.1 mmol), triethylamine (2.73 g,
27.02 mmol), methylene chloride (20 mL), and diethyl
ester of tt2-
( CYC10~L v~ylmethyl)phenyl]thio]prop~ne~;oic acid (2.18
21~2~
WO9S/14014 PCT~S94/12367
- 124 -
g, 6.76 mmol). m.p. 168 C; lH NMR (400 MHz, DMSO-d6)
0.28 (d, 2H), 0.39 (dd, 2H), l.i3 (m, lH), 2.36 (s,
6H), 2.67 (d, 2H), 6.85 (s, lH), 6.92 (m, lH), 7.11
(m, 2H), 7.22 (s, lH), 7.33 (m, lH), 7.47 (s, 2H).
~xample 187
6-(l,lJ-Biphenyl-3-yl)-~-hydroxy-3-[~2-isobutylphe~yl)
thio]-2H-pyran-2-one: The title compound was prepared
by Method A using 3'-phenylacetophenone (2 g, 10.20
mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol),
triethylamine (2.06 g, 20.40 mmol), methylene chloride
(20 mL), and diethyl ester Of t(2-
isobutylphenyl)thio~propanedioic acid (1.14 g, 5.1
mmol). m.p. 187-188 C lH NMR (400 MHz, DMSO-d6) ~ 0.83
(d, 6H), 1.78 (m, lH), 2.4 (d, 2H), 7.03 (s, lH), 7.08
(s, 4H), 7.44 (t, lH), 7.53 (t, 2H), 7.67 (t, lH),
7.75 (s, lH), 7.78 (s, lH), 7.86 (m, 2H), 8.08 (s,
lH).
E~ample 188
~ G~-3- ~t2-isobutylphenyl)t~io]-6-phenyl-2~-
pyr~n-2-one: The title compound was prepared by
Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene
(1.96 g, 10.20 mmol) and diethyl ester of [(2-
isobutylphenyl)thio]propanedioic acid (1.64 g, 5.1
mmol). m.p. 195 oc lH NMR (400 MHz, DMSO-d6) ~ 0.83 (d,
6H), 1.64 (m, lH), 2.39 (d, 2H), 6.89 (s, lH), 7.06
(s, 4H), 7.56 (m, 3H), 7.86 (m, 2H).
Esample 189
4-~ydrosy-3-[(2-isopropylphenyl)thio]-6-t4-(pyridin-3- -
yl)phenyl]-2~-pyran-2-one: The title compound was
prepared by using diethyl ester of [2-
(isopropylphenyl)thio]-propanedioic acid (1 g, 3.22
mmol), trimethylsilyltriflate (1.18 g, 5.31 mmol),
triethylamine (0.98 g, 9.66 mmol) and 3-(pyridin-3-
yl)acetophenone (0.95 g, 4.83 mmol) as described by
Method A. m.p.145-147 C lH NMR (400 MHz, DMSO-d6)
WOg~/14014 ~ 2 4 PCT~S94/12367
- 125 -
1.25 (d, 6H), 3.4 (m, lH), 6.89 (s, lH), 6.92 (d, lH),
7.06 (m, 2H), 7.25 (d, lH), 7.53 (m, lH), 7.69 (t,
lH), 7.89 (d, 2H), 8.14 (s, lH), 8.22 (d, lH), 8.61
(brs, lH), 8.97 (brs, lH).
pl~ 190
~-Hydroxy-3-t(2-isopropylph~nyl)thio]-6-(3-
methylphenyl)-2~-pyran-2-one: The title compound was
prepared by Method A using 3'-methylacetophenone (O.87
lo g, 6.46 mmol), trimethylsilyl triflate (1.44g, 6.46
mmol), triethylamine (0.653 g, 6.46 mmol), methylene
chloride (20 mL), and diethyl ester of [(2-
isopropylphenyl)thio]propanedioic acid (1.0 g, 3.23
mmol). m.p. 161-162 oc; lH NMR (400 MHz, DMSO-d6)
1.25 (d, 6H), 2.39 (s, 3H), 3.42 (m, lH), 6.86 (s,
lH), 6.92 (d, lH), 7.07 (t, lH), 7.13 (t, lH), 7.28
(d, lH), 7.39 (d, lH), 7.4 (t, lH), 7.64 (d, lH), 7.67
(s, lH).
~a~pl~ 191
4-~yaroxy-3-(2-i~opropylph~Ay)-6-phenyl-2~-pyran-2
one: The title compound was prepared by Method A
using 1-phenyl-1-trimethylsilyloxy)ethylene (2.62g,
13.6 mmol) and diethyl ester of 2-(is~Lo~yl)phenoxy
propanedioic acid (2.0g, 6.8 mmol). lH NMR (250 MHz,
DMSO-d6) ~ 1.25 (d, 6H), 3.44 (m, lH), 6.67 (d, lH),
6.89 (s, lH), 7.0 (t, lH), 7.09 (t, lH), 7.29 (d, lH),
7.53 (m, 3H), 7.83 (m, 2H).
Example 192
6-(3-Chlorophenyl)-~-hydrosy-3-t(2-
isopropylphenyl)thio]-2~-pyran-2-one: The title
compound was prepared by Method A using 3~-
chloroacetophenone (3 g, 19.41 mmol), trimethylsilyl
triflate (4.31 g, 19.41 mmol), triethylamine (3.92 g,
38.82 mmol), methylene chloride (20 mL), and diethyl
ester of t(2-isopropylphenyl)thio]-propanedioic acid
(3.0 g, 9.71 mmol). Isolated yield: 70% m.p. 177-178
-
2 1 7 4 1 2~ PCT~S94112367 ~
- 126 -
C; lH NMR (400 MHZ, DMSO-d6) ~ 0.28 (d, 6H), 3.42 (m,
lH), 6.92 (d, lH), 6.94 (s, lH), 7.06 (t, lH), 7.13
(t, lH), 7.28 (d, lH), 7.58 (t, lH), 7.63 (t, lH),
7.83 (d, lH), 7.89 (s, lH).
~x~ple 193
6-~3,5-Dichlorophenyl)-~-hydrosy-3-[~2-
isopropylphenyl)thio]-2~-pyran-2-one: The title
compound was prepared by Method A using 3,5-
dichloroacetophenone (2 g, 10.58 mmol), trimethylsilyl
triflate (2.35 g, 10.58 mmol), triethylamine (2.14 g,
21.16 mmol), methylene chloride (20 mL), and diethyl
ester of [(2-iso~rG~ylphenyl)thio]propanedioic acid
(1.64 g, 5.29 mmol). Isolated yield: 70% m.p.l68-16s
C; lH NMR (400 NHz, DMSO-d6) ~ 1.25 (d, 6H), 3.42 (m,
lH), 6.92 (d, lH), 7.01 (s, lH), 7.06 (t, lH), 7.13
(t, lH), 7.28 (d, lH), 7.83 (m, lH), 7.88 (m, 2H).
B ~ple 19~
3-t(2,6-Dimethylphenyl)thio]-4-hydrosy-6-phenyl-2~-
pyran-2-one: The title compound was prepared by
Method A using l-phenyl-l-(trimethylsilyloxy)ethylene
(1.95 g, 10.14 mmol) and diethyl ester of [(2,6-
dimethylphenyl)thio]prop~n~;oic acid (2.0 g, 6.8
mmol). m.p. 248-249 oc; lH NMR (400 MHz, DMSO-d6)
2.47 (s, 6H), 6.75 (s, lH), 7.08 (m, 3H), 7.39 (m,
3H), 7.78 (m, 2H).
Ex~ple 195
~-Hydrosy-3-[(2-methylphenyl)thio]-6-phenyl-2~-pyran-
2-one: The title compound was prepared by Method A
using l-phenyl-l-(trimethylsilyloxy)ethylene (1.95 g,
10.14 mmol) and diethyl ester of t(2-
methylphenyl)thio]prop~ne~;oic acid (1.43 g, 5.07
3s mmol). m.p. 210-211 C; lH NMR (400 MHz, DMSO-d6)
2.47 (s, 3H), 6.82 (s, lH), 6.86 (d, lH), 7.04 (m,
2H), 7.17 (d, lH), 7.56 (m, 3H), 7.86 (m, 2H).
~ WO95/14014 2 ~ ~ 1 1 2 ~ PCT~S94/12367
- 127 -
Bx~ple 196
3-(2,6-Dichloroph~nyl)thio] ~-hydrosy-6-phenyl-2~-
pyr~n-2-on~: The title compound was prepared by
Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene
(1.72 g, 8.93 mmol) and diethyl ester of [(2,6-
dichlorophenyl)thio]propanedioic acid (1.5 g, 4.46
mmol). m.p. 264-26S C; ~H NMR (400 MHz, DMSO-d6) ~
6.75 (s, lH), 7.31(t, lH), 7.49 (d, 2H), 7.56 (m, 3H),
7.78 (m, 2H).
g~ample 197
~-tS-~1-Cyclopentylthio-3-methylbutyl)-~-hy~roxy-6-
oxo-6H-pyr~n-2-yl]b~nzoic ~cid ethyl e~ter (~ The
title compound was prepared by Method C using 4-
hydroxy-6-(4'-carbethoxyphenyl)-2H-pyran-2-one (1.50
g, 5.77 mmol), ethanol (15 mL), isovalaraldehyde
(0.497 g, 5.77 mmol), cyclopentylthiol (1.18 g, 11.54
mmol), piperidine (1.0 mL), acetic acid (1.0 mL). m.p.
174-176 C; lH NMR (400 MHz, DMSO-d6) ~ 1.05-0.72 (m,
lOH), 1.81-1.14(m, 7H), 2.13-1.81(m, 3H), 3.04 (t,
lH), 4.22 (m, lH), 4.36 (q, 2H), 6.8 (s, lH), 7.90 (d,
lH), 7.97 (~, lH), 8.15 (m, 2H).
E~pl~ 198
3-tt~Bensylthio)pyridin-3-yl]m~thyl]-~-hy~roxy-6-
phenyl-2H-pyr~n-2-one ~/-): The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.50 g, 7.98 mmol), ethanol (10 mL),
pyridine-3-carboxaldehyde (0.86 g, 7.98 mmol),
benzylmercaptan (1.98g, 15.96 mmol), piperidine (0.5
mL), acetic acid (0.5 mL). m.p. 103-106 C; lH NMR (400
MHz, DMS0-d6) ~ 3.75 (q, 2H), 5.31 (s, lH), 6.33 (s,
lH), 7.2 (m, lH), 7.28 (m, 5H), 7.36 (m, 3H), 7.72 (m,
2H), 7.89 (d, lH), 8.38 (dd, lH), 8.57 (s, lH).
Es~mple 199
3-~1-Cyclopentylthio-2-cyclopropyl~thyl)-6-(2,3-
di~ydrobenzotl,~]dioxin-6-yl)-~-hydrosy-2~-pyr~n-2-one
woss/l4014 PCT~S94112367 ~
~ 7~
- 128 -
~ The title compound was prepared by Method C
using 4-hydroxy-6-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-
2H-pyran-2-one (l.oo g, 4.06 mmol), ethanol (15 mL),
cyclu~L~ylmethylcarboxaldehyde (0.34 g, 4.06 mmol),
cyclopentylthiol (0.83 g, 8.12 mmol), piperidine (1.0
mL), acetic acid (1.0 mL). m.p. 80-82 C; lH NMR (400
MHz, DMSO-d6) ~ 0.03 (m, 2H), 0.33 (m, 2H), 0.64 (m,
lH), 1.28-1.74 (m, 7H), 1.83-2.06 (m, 3H), 3.06 (m,
lH), 4.2 (m, lH), 4.31 (m, 4H), 6.53 (s, lH), 7.0 (d,
lH), 7.24 (d, lH), 7.24 (dd, 2H).
~s~ple 200
~-tt(~-~ydroxy-6-o~o-5-t(phenylethyl)thio]-6H-pyran-2-
yl)-pheno~y]m~thyl]benzoic acid: To a dioxane (20 mL)
solution of 4-t[4-hydroxy-2-oxo-3-t(2-
phenylethyl)thio]-2H-pyran-6-yl]phenoxy]methyl]benzoic
acid methyl ester (0.25 g) was added 2N sodium
hydroxide, followed by methanol to keep the reaction
homogeneous. Reaction was stirred at room temperature
for 24h. Solvents were evaporated. The residue w s
acidified with 3N hydrochloric acid. The precipitate
formed was filtered and washed with ether and dried
under vacuum. m.p. 227 C; lH NMR (400 MHz, DMSO-d6)
2.78 (t, 2H), 2.97 (t, 2H), 5.29 (s, 2H), 6.72 (s,
lH), 7.14-7.32(m, 7H), 7.58 (d, 2H), 7.78 (d, 2H),
7.97 (d, 2H).
~xample 201
~ -~ydroxy-6-oso-5-t~2-phenylethyl)thio]-6H-pyran-2-
yl)benzoic acid ethyl ester: The title compound was
prepared by Method A using 4-carboethoxy acetophenone
(3 g, 15.61 mmol), trimethylsilyl triflate (3.47 g,
15.61 mmol), triethylamine (3.16 g, 31.22 mmol),
methylene chloride (20 mL), and diethyl ester of [2-
(phenylethyl)thio]-propanedioic acid (2.31 g, 7.81
mmol). m.p. 156-158 C lH NMR (400 MHz, DMSO-d6) ~ 1.36
(t, 3H), 2.78 (t, 2H), 3.01 (t, 2H), 4.35 (q, 2H),
WO95/14014 ~ 2 ~ PCT~S94/12367
- 129 -
6.86 (s, lH), 7.11-7.28 (m, 5H), 7.92 (d, 2H), 8.08
(d, 2H).
Ex~ple 202
~ -Hydro~y-6-oxo-S-t(2-phenylethyl)thio~-6H-pyran-2-
yl)benzoic acid: The compound 4-(4-hydroxy-6-oxo-5-
r (2-phenylethyl)thio-6H-pyran-2-yl)benzoic acid ethyl
ester (0.2 g) was saponified as described in example
200. m.p. 231 C lH NMR (400 MHz, DMSO-d6) ~ 2.94 (t,
2H), 3.03 (t, 2H), 6.64 (s, lH), 7.11-7.33 (m, 5H),
7.92 (d,lH), 7.99 (d,lH), 8.05 (d,lH), 8.08 (d,lH).
Bx~ple 203
6-l2,3-Dihydrobenso~1,4]dio~in-6-yl)-~-hydroxy-3-t(2-
isopropylph~nyl)thio]-2H-pyran-2-one: The title
compound was prepared by Method A using 1,4-
benzodioxin-6-yl methyl ketone (2 g, 11.22 mmol),
trimethylsilyl triflate (2.5 g, 11.22 mmol),
triethylamine (2.27 g, 22.44 mmol), methylene chloride
(20 mL), and diethyl ester of [(2-
isopropylphenyl)thio]propanedioic acid (1.73 g, 5.61
mmol). m.p. 246-248 C; lH NNR (400 MHz, DMSO-d6) ~
1.2S (d, 6H), 3.4 (m, lH), 4.32 (m, 4H), 6.72 (s, lH),
6.89 (d, lH), 7.01 (d, lH), 7.06 (t, lH), 7.11 (t,
lH), 7.26 (d,lH), 7.31 (d, lH), 7.35 (dd, lH).
E~ample 20~
3~ Benzylthio-3-methylbutyl)-6-(2,3-
dihydrobenzo[1,4]~ioxin-6-yl)-~-hydro~y-2~-pyran-2-one
(I/-): The title compound was prepared by Method C
using 4-hydroxy-6-(2,3-dihydrobenzo~1,4]dioxin-6-yl)-
2H-pyran-2-one (1.00 g, 4.06 mmol), ethanol (15 mL),
isovaleraldehyde (0.35 g, 4.06 mmol), benzylmercaptan
(1.0 g, 8.12 mmol), piperidine (0.5 mL), acetic acid
(0.5 mL). lH NMR (400 MHz, DMSO-d6) ~ 0.78 (t, 6H),
1.36 (m, lH), 1.5 (m, lH), 2.06 (m, lH), 4.2 (m, lH),
4.31 (brm, 6H), 6.56 (s, lH), 7.03 (d, 2H), 7.36-7.2s
(m, 6H).
WO95/14~14 ~17~124 PCT~S94/12367 ~
- 130 -
~a~ple 205
3-tt(Cyclo~exylthio)pyridin-~-yl]methyl]-~-hydrosy-6-
phenyl-2H-pyran-2-one(~ The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
s pyran-2-one (1.5 g, 7.98 mmol), ethanol (10 mL),
pyridine-4-carboxaldehyde (0.86 g, 7.98 mmol),
cyclohexylthiol (1.86 g, 7.98 mmol), piperidine (0.5
mL), acetic acid (0.5 mL). lH NMR (400 MHz, DMSO-d6)
1.25 (m, SH), 1.53 (m, lH), 1.67 (m, 2H), 1.92 (m,
2H), 2.71 (m, lH), 5.33 (s, lH), 6.69 (s, lH), 7.5 (m,
5H), 7.75 (m, 2H), 8.47 (d, 2H).
Ex~mple 206
3-tt(Cyclohesylthio)pyridin-3-yl~methyl]-4-hydro~y-6-
phenyl-2~-pyran-2-one (~ The title compound was
prepared by Method C using 4-hydroxy-6-phenyl-2H-
pyran-2-one (1.5 g, 7.98 mmol), ethanol (10 mL),
pyridine-3-carboxaldehyde (0.86g, 7.98 mmol),
cyclohexylthiol (1.86g, 7.98 mmol), piperidine (0.5
mL), acetic acid (0.5 mL). lH NMR (400 MHz, DMSO-d6)
1.25 (m, 5H), 1.53 (m, lH), 1.67 (m, 2H), 1.92 (m,
2H), 2.69 (m, lH), 5.39 (s, lH), 6.72 (s, lH), 7.33
(m, lH), 7.53 (m, 3H), 7.73 (m, 2H), 7.97 (d, lH),
8.39 (d, lH), 8.67 (d, lH).
Esampl~ 207
~-t~ ydrosy-2-oso-6-phenyl-2~-pyran-3-
yl)thio]methyl]benzoic acid: The title compound was
prepared by the saponification of methyl ester of 4-
[t(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-
yl)thio]methyl]benzoic acid (0.1 g) as described in
Example 200. lH NMR (400 MHz, DMSO-d6) ~ 4.06 (s, 2H),
6.72 (s, lH), 7.36 (d, 2H), 7.58 (m, 3H), 7.86 (m,
4H)-
~mple 208
3-ll ~4-A~ 6~y~2 o~o 6 ~henyl-2H-pyran-3-
yl)~hio]methyl~bensoic acid: The title compound was
-
2 1 7 4 :1 2 i P,~,US94,l2367
WO g5/14014
-- 131 --
prepared by the saponification of methyl ester of 3-
[[(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-
yl)thio]methyl~benzoic acid (0.1 g) as described in
Example 200. lH N~ (400 MHz, DMSO-d6) ~ 4.4 (d, lH),
4.72 (d, lH), 6.72 (s, lH), 7.4 (t, lH), 7.44-7.61(m,
SH), 7.74-7.92 (m, 4H).
Ex~ple 209
2-[tt~-~ydro~cy-2-oxo-6-phenyl-2~l-pyr~-3-
10 yl)thio]-lethyl]bellsoic acid: The title compound was
prepared by the saponification of methyl ester of 2-
~ t (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-
yl)thio~methyl~benzoic acid (0.2 g) as described in
Example 200. lH N~ (400 ~z, DMSO-d6) ~ 4.36 (s, 2H),
6.6g (s, lH), 7.18 (d, lH), 7.29 (t, lH), 7.39 (t,
lH), 7.53 (m, 3H), 7.79 (m, 3H).
~ ~pl~ 210
3-t(2-Chlorophenyl)thio]-4-hy~ A~-6-phenyl-2~-pyra~-
20 2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.9S g,
10.14 mmol) and diethyl ester of [(2-
chlorophenyl)thio]propanedioic acid (1.53 g, 5.07
mmol). m.p. 275-280 C; lH N~ (400 NHz, DMSO-d6) ~
6.78 (s, lH), 6.89 (dd, lH), 7.08 (tt, lH), 7.19 (tt,
lH), 7.42 (dd, lH), 7.56 (m, 3H), 8.06 (m, 2H).
ample 211
~-~y~ro~cy-3-~(2-metho~ enyl)thio3-6-phenyl-2~-pyran-
30 2-o~e: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.9~ g,
10.14 mmol) and diethyl ester of ~(2-
methoxyphenyl)thio]propAn~;oic acid (1.51 g, 5.07
mmol). m.p.208-209 C; lH N~ (400 MHz, DMSO-d6) ~ 3.83
(s, 3H), 6.74 (dd, lH), 6.82 (d, lH), 6.86 (s, lH),
6.97 (d, lH), 7.08 (t, lH), 7.56 (m, 3}I), 7.86 (m,
2H).
_ _
WO 95/14014 PCT/US94/12367 ~1
~ 7~2~
- 132 -
~mplo 212
6-(~-Benzyloxyphenyl)-~-hydroYy-3-t~2-isopropyl-
phenyl)thio]-2~-pyran-2-one: The title compound was
prepared by Method A using 4-benzyloxyacetophenone
(0.3 g, 0.675 mmol), trimethylsilyl triflate (0.15 g,
0.675 mmol), triethylamine (0.14 g, 1.35 mmol),
methylene chloride (20 mL), and diethyl ester of [(2-
isG~lo~ylphenyl)thio]propanedioic acid (0.210 g, 0.675
mmol). m.p. 163-165 C; lH NMR (400 MHz, DMSO-d6) ~
1.28 (d, 6H), 3.4 (m, lH), 5.22 (s, 2H), 6.64(s,1H),
6.92 (d, lH), 7.06 (t, lH), 7.11(t, lH), 7.19 (d, lH),
7.28 (d, lH), 7.36 (q, 2H), 7.42 (d, 2H), 7.49 (d,
2H), 7.83 (d, 2H).
Es~ple 213
3-[~3-Chlorophenyl)thio]-~-hydroxy-6-phenyl-2H-pyran-
2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g,
10.14 mmol) and diethyl ester of [(3-
chlorophenyl)thio]prop~ne~;oic acid (1.53 g, 5.07
mmol). m.p.l81-182 C; lH NMR (400 MHz, DMSO-d6) ~ 6.88
(s, lH), 7.13 (dt, 2H), 7.19 (dt, lH), 7.29 (t, lH),
7.56 (m, 3H), 7.86 (m, 2H).
Exa~pl~ 2
~-~yd~vAy~3~ t ~3-metho~ enyl) thio] -6-phenyl-2~-pyran
2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g,
10.14 mmol) and diethyl ester of [(3-
methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07
mmol). m.p. 130-131 C lH NMR (400 MHz, DMSO-d6) ~ 3.69
(s, 3H), 6.69 (dd, lH) , 6.72 (dd, lH), 6.89 (s, lH),
7.2 (dt, 2H), 7.58 (m, 3H), 7.88 (m, 2H).
Eg~mpl~ 215
~-~ydro~y-3-[~3-methylphenyl)thio]-6-ph~nyl-2~-pyr~n-
2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g,
Wo95/14014 ~ 7 4 1 2 i PCT~S94/1~67
- 133 -
10.14 mmol) and diethyl ester of [(3-
methylphenyl)thio]propanedioic acid (1.43 g, 5.07
mmol). m.p. 197-198 C; lH NMR (400 MHz, DMSO-d6)
2.24 (s, 3H), 6.89 (s, lH), 6.93 (t, lH), 6.97 (s,
lH), 7.14 (t, 2H), 7.56 (m, 3H), 7.86 (m, 2H).
~ample 216
3-t~2-~thylphenyl)thio]-~-hydroSy-6-phe~yl-2H-pyran-2-
one: The title compound was prepared by Method A using
l-phenyl-l-(trimethylsilyloxy)ethylene (4.17 g, 21.72
mmol) and diethyl ester of [(2-
ethylphenyl)thio]propanedioic acid (1.5 g, 10.86
mmol). m.p. 190-192 C; lH NMR (400 MHz, DMSO-d6)
1.25 (t, 3H), 2.78 (q, 2H), 6.8g (s, lH), 6.92 (m,
lH), 7.08 (m, 2H), 7.2 (m, lH), 7.58 (m, 3H), 7.86 (m,
2H).
Ex~mpl~ 217
Acetic ~cid 3-~2-iso~L~ylphenyl)thio]-2-o~o-6-
phcnyl-2R-pyran-4-yl e5tQr: This compound was prepared
by the treatment of sodium salt of 4-hydroxy-3-t2-
isopropylphenyl)thio]-6-phenyl-2H-pyran-2-one (0.2 g,
0.59 mmol) with acetyl chloride (0.09 g, 1.18 mmol) as
described in general proce~uLe G. m.p. 113-115C; lH
NMR (400 MHz, DMSO-d6) ~ 1.26 (d, 6H), 1.89 (s, 3H),
3.42 (m, lH), 6.89 (s, lH), 6.94 (dd, lH), 7.04 (dt,
lH), 7.13 (dt, 1~), 7.28 (dd, lH), 7.58 (m, 3H), 7.86
(m, 2H).
Example 218
~-~ydroxy-6-phenyl-3-~(3-trifluoromethylphenyl)thio]-
2~-pyran-2-one: The title compound was prepared by
Method A using 1-phenyl-l-(trimethylsilyloxy)ethylene
(1.72 g, 8.92 mmol) and diethyl ester of [~3-
(trifluoromethyl)phenyl]thio]propanedioic acid (1.5 g,
4.46 mmol). m.p. 228-229 C; lH NMR (400 MHz, DMSO-d6)
~ 6.89 (s, lH), 7.4-7.61 (m, 7H), 7.89 (m, 2H).
WO95tl4014 PCT~S94/12367 ~
~17~124
- 134 -
~ ~mpl~ 219
3-t3,5-Di~ethylphenyl)thio]-4-h~dro~y-6-phenyl-2H-
pyran-2-one: The title compound was prepared by Method
A using l-phenyl-l-(trimethylsilyloxy)ethylene (1.3 g,
6.76 mmol) and diethyl ester of t(3,5-
dimethylphenyl)thio]propanedioic acid (1.0 g, 3.38
mmol). m.p. 214-216 C; lH NMR (400 MHz, D~SO-d6) S 2.2
(s, 6H), 6.75 (brs, 3H), 6.89 (s, lH), 7.56 (m, 3H),
7.86 (m, 2H).
Exampl~ 220
6-t~-(Cyclo~eYyl~etho-y)p~enyl]-~-hy~rosy-3-t(2-
is~ lphenyl~thio]-2H-pyr~n-2-one: The title
compound was prepared by Method A using 4-
cyclohexylmethoxy acetophenone (2.0 g, 8.61 mmol),
trimethylsilyl triflate (1.91 g, 8.61 mmol),
triethylamine (1.74 g, 17.22 mmol), methylene chloride
(20 mL), and diethyl ester of t(2-
iso~lu~ylphenyl)thio]propanedioic acid (4.0 g, 12.92
mmol). m.p. 187-188 C; 'H NMR (400 MHz, DMSO-d6) ~
0.96-1.33 (m + 1.24 d llH), 1.61-1.87 (m, 6H), 3.4 (m,
lH), 3.86 (d, 2H), 6.76 (s, lH), 6.92 (dd, lH), 7.11
(m, 4H), 7.29 (dd, lH), 7.81 (d, 2H).
kxa~pl~ 221
6-~3-Benzylo~yphenyl)-4-hydro~y-3-~2-
isopropylphenyl)thio]-2H-pyr~n-2-o~e: The title
compound was prepared by Method A using 3-
benzyloxyacetophenone (2.0 g, 8.84 mmol),
trimethylsilyl triflate (1.96 g, 8.84 mmol),
triethylamine (1.79 g, 17.68 mmol) and diethyl ester
f t(2-isopropylphenyl)thio] propanedioic acid (0.210
g, 0.675 mmol). m.p. 162-164 C; lH NMR (400 MHz,
DMS0-d6) ~ 1.25 (d, 6H), 3.42 (m, lH), 5.35 (s, 2H),
6.89 (s, lH), 6.92 (d, lH), 7.06 (dt, lH), 7.11 (dt,
lH), 7.22 (dd, lH), 7.28 (dd, lH), 7.39-7.51(m, 8H).
E~mple 222
WO95/14014 2 1 7 ~ 1 2 4 PCT~S94Jl~67
- 135 -
~-~ydro~y-3-tt2-~sopropylphenyl3thio]-6-t~-~3-
phenylp.~)phenyl]-2~-pyr~n-2-one: The title
compound was prepared by Method A using 4-
phenylpropyloxy acetophenone ~2.0 g, 7.86 mmol),
trimethylsilyl triflate (1.75 g, 7.86 mmol),
triethylamine (1.59 g, 15.72 mmol) and diethyl ester
~ of [(2-iso~Lo~ylphenyl)thio]-propanedioic acid (3.~6
g, 11.79 mmol). m.p. 132-133 C; lH NMR (400 MHz,
DMSO-d~) ~ 1.25 (d, 6H), 2.06 (m, 2H), 2.75 (t, 2H),
3.39 (m, lH), 4.08 (t, 2H), 6.78 (s, lH), 6.90 (d,
lH), 7.05 (dt, 2H), 7.08 (q, 2H), 7.11-7.31 (m, 6H),
7.81 (d, 2H).
~xampl~ 223
3-[~2-sec-Butylphenyl)thio]-~-hydroxy-6-phenyl-2~-
pyr~n-2-one (l/-): The title compound was prepared by
Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene
(1.0 g, 6.17 mmol) and diethyl ester of [(2-sec-
butylphenyl)thio]propanedioic acid (1.0 g, 3.09 mmol).
m.p. 170-171 C; lH NMR (400 MHz, DMSO-d6) ~ O.86(t,
3H), 1022 (d, 3H), 1.57 (m, lH), 1.67 (m, lH), 3.22
(m, lH), 6.89 (s, lH), 6.97 (d, lH), 7.06 (t, lH),
7.13 (t, lH), 7.22 (d, lH), 7.56 (m, 3H), 7.86 (m,
2H).
4.5 Deter~ination of ~IV Protea~e Inhibition
~.5.1 ~tartin~ Materials
DTT Buffer: 1.0 mM dithiothreitol (DTT) was
prepared fresh daily in 0.1% polyethylene glycol (mw
8000) 80 mM NaOAc, 160 mM NaCl, 1.0 mM EDTA, and
brought to pH 4.7 with HCl.
!
~IV-I Protease: The enzyme is obtained from Bachem
Bioscience Inc. The undiluted enzyme is thawed from
-80 C and diluted 50-fold with DTT buffer. The
solution is always kept at O C on ice water and used
in the experiment within 20 minutes after thawing.
W095/14014 ~1 7~12~ PCT~S94/12367
- 136 -
Enzy~e 8ubstrate: Substrate III from Bachem Bioscience
Inc. is the und~c~r~ptide H-His-Lys-Ala-Arg-Val-Leu-p-
NitrophenylAl ~n; n~-Glu-Ala-Norleucine-Ser-N}I2 (> 97 %
purity). A 200 ~M stock solution in DTT buffer is
s prepared and stored on ice. Substrate solution is
prepared fresh daily.
Test Compound: l0 mM inhibitor (I) in dimethyl
sulfoxide (DMSO) is diluted to 200 ~M with DTT buffer.
From the 200 ~M stock solution is made a l0 ~M stock
solution with 2% DMSO in DTT buffer. The two
inhibitor solutions are used to make final [I] = l00,
50, 20, l0, 5, 2, l, 0.5 and 0 ~M with 2% DMSO in DTT
buffer in each reaction well (total inhibitor volume
of 50 ~l).
~.5.2 Ass~Y
To each reaction well is added 20 ~l of substrate
(final concentration of 40 ~M), 50 ~l of inhibitor (at
a concentration such that final dilution will produce
the test concentration) and 20 ~l of DTT buffer. The
reaction plate (96 wells) is incubated at 37 oc for at
least 5 minutes.
10 ~1 of the diluted protease is added to the reaction
well while the reaction plate is shaking. Once shaken
for l0 seconds, the plate is returned to the heating
block at 37 C. (Final reaction volume = 100 ~1.
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 determined by separation of
noncleaved substrate and two cleaved products with
reverse-phase HPLC, while measuring absorbance at 220
nm to determine the relative peak areas of the three
WO95/14014 PCT~S94/1~67
~ 7~4
- 137 -
components. The relative peak areas are used to
calculate % conversion to product as a function of
inhibitor concentration. The data is plotted as %
Control (the ratio of % conversion in the presence and
5 absence of inhibitor x loO) versus inhibitor
concentration and fit with the equation Y=
100/l+(X/IC50) A, where IC50 is the inhibitor
concentration at 50% inhibition and A is the slope of
the inhibition curve.
lo Table 1
HIV Protease Inhibition Results
Example # 50% Inhibition
Concentration
(Averaged)
[~M]
1 0.47
3 1.0
4 0.9
6 0.4
20 8 1.7
17 0.69
23 1.7
26 1.2
2527 0 5
28 1.9
29 0.33
33 1.97
34 0.8
3044 0.75
48 0.86
49 1.6
52 0.7
3564 0.6
68 0.45
0.13
71 1.9
WO95/14014 ; PCT~S94/12367 ~
2~ - 138 -
73 0.77
74 0.61
77 0.14
78 1.5
87 0.41
110 0.07
113 0.24
121 0.48
129 0.20
133 0.06
144 0.037
160 0.36
163 0.63
164 0.055
166 0.23
169 0.015
172 0.068
183 0.41
193 0.026
4.6 Anti-~IV-l ActivitY
Using the general methods of Pauwels et al., (J.
Vlrol. Met~ods, 16, 171-185, 1987) and Mann et al.
(AIDS Research and Human ~etroviruses, 253-255, 1989)
anti-viral assays of acute HIV-1 infection were
performed in the H9 cell line. Cultures were batch
infected in 1 ml of RPM1 1640 media/10% fetal calf
serum con~i n; ng 107 cells and 105 infectious doses of
HIV-liiib for an effective multiplicity of infection of
0.01. After 2 hours of viral absorption, cells were
washed once and plated in 96-well microtiter plates at
a density of 10~ cells per well. Test compounds were
added to ~L ~d~ce the desired concentration of drug and
0.2% DMSO in a final volume of 200 ~l. Uninfected
parallel cultures were maint~; n~ for XTT cytotoxicity
assay at 7 days post infection. Cultures were tested
WO 95/14014 21 7 ~ ~ 2 4 PCT~S94/12367
- 139 -
for viral replication by reverse transcriptase assay
at 4 and 7 days post infection.
Table 2
Antiviral ActivitY in H9 Cells
~onrentration for 50%
Example # Protection
~M]
29 17
29
lS78 3
87 15
121 15
166 14
20169 31
172 0.65
Combinations of prot,ease inhibitor with other
AIDS treatments, such as (but not limited to) the HIV
reverse transcriptase inhibitors AZT or ddC, may
produce synergistic results. J. C. Craig et al.,
Antivlral Chem. Chemother., 4/3: 161-166 (1993); E. V.
Connell et al., Antimicrob. Agents Chemother., 38:
348-352 (1994); D. M. Lambert et al., Antiviral ~es.,
21: 327-342 (1993); A. M. Caliendo et al., Clin.
Infect. Dis., 18/4: 516-524 (1994) .
The compounds of the invention display
antibacterial activity when tested by the
microtitration dilution method as described in
Heifetz, et al., Antimicr. Agents. & Chemoth. 6 : 124
(1974) which is incorporated herein by reference.
By use of the above referenced method, the
following minimum inhibitory concentration values
wo gSI14014 ~ 7 ~ PCT~S94/1~67 ~l
- 140 -
(MICs in ~g/mL) were obtained for representative
compounds of the invention vs. clinically relevant
gram positive pathogens which have become highly
resistant to conventional therapy in recent years.
Antibacterial Activity ~g/ml
Ex. 172 Ex. 29 Ex. 167 Ex.
Staphylococcus 50 25 6.2 12.5
aureus H228
Staphylococcus 50 25 6.2 12.5
aureus UC-76
Enterococcus 100 50 12.5 25
foecalis MGH2
Streptococcus 50 25 6.2 12.5
pneumonia 5V-l
~e~Lococcus 50 25 6.2 12.5
pyogenes C203
It should be apparent to those skilled in the art
that other compositions not specifically disclosed in
the instant specification are, nevertheless,
contemplated thereby. Such other compositions are
considered to be within the scope and spirit of the
present invention. Hence, the invention should not be
limited by the description of the specific embodiments
disclosed herein but only by the following claims.
