CA 02283575 1999-09-09
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CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
COMBINATION THERAPY EMPLOYING ILEAL BILE ACID TRANSPORT
INHTBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS
This application claims the benefit of priority of
U.S. provisional application Serial No. 60/040,660, filed
March 11, 1997. This application is also a continuation-
in-part application of U.S. Serial No. 08/831,284, filed
March 31, 1997, which is a continuation application of
U.S. Serial No. 08/517,051, filed August 21, 1995, which
is a continuation-in-part application of U.S. Serial No.
08/305,526 filed September 12, 1994; and is a
continuation-in-part application of U.S. Serial No.
08/816,065, filed March 11, 1997, which claims priority
from U.S. provisional application Serial No. 60/013,119,
filed March 11, 1996.
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to novel
benzothiepines, derivatives and analogs thereof, in
combination with HI~IG Co-A reductase inhibitors,
pharmaceutical compositions containing them, and use of
these compositions in medicine, particularly in the
prophylaxis and treatment of hyperlipidemic conditions
such as is associated with atherosclerosis or
hypercholesterolemia, in mammals.
Description of Related Art
It is well-settled that hyperlipidemic conditions
associated with elevated concentrations of total
cholesterol and low-density lipoprotein cholesterol are
major risk factors for coronary heart disease and
particularly atherosclerosis. Interfering with the
circulation of bile acids within the lumen of~the
intestinal tract is found to reduce the levels~of serum
cholesterol in a causal relationship. Epidemiological
data has accumulated which indicates such reduction
leads to an improvement in the disease state of
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WO 98/40375 PCT/US98/03792
atherosclerosis. Stedronsky, in "Interaction of bile
acids and cholesterol with nonsystemic agents having
hypocholesterolemic properties," Hiochimica et
Bio_phvsica Acta, 1210 (1994) 255-287 discusses the
biochemistry, physiology and known active agents '
surrounding bile acids and cholesterol.
Pathophysiologic alterations are shown to be
consistent with interruption of the enterohepatic
circulation of bile acids in humans by Heub_i, J.E., et
al. See "Primary Bile Acid Malabsorption: Defective
in Vitro Ileal Active Bile Acid Transport",
Gastroenteroloav, 1982:83:804-11.
In fact, cholestyramine binds the bile acids in
the intestinal tract, thereby interfering with their
normal enterohepatic circulation (Reihner, E. et al, in
°Regulation of hepatic cholesterol metabolism in
humans: stimulatory effects of cholestyramine on HMG-
CoA reductase activity and low density lipoprotein
receptor expression in gallstone patients", Journal of
Lipid Research, Volume 31, 1990, 2219-2226 and Suckling
el al, "Cholesterol Lowering and bile acid excretion in
the hamster with cholestyramine treatment",
Atheroscleros~s, 89(1991) 183-190). This results in an
increase in liver bile acid synthesis by the liver
using cholesterol as well as an upregulation of the
liver LDL receptors which enhances clearance of
cholesterol and decreases serum LDL cholesterol levels.
In another approach to the reduction of
recirculation of bile acids, the ileal bile acid
transport system is a putative pharmaceutical target
for the treatment of hypercholesterolemia based on an
interruption of the enterohepatic circulation with
specific transport inhibitors (Kramer, et al,
"Intestinal Bile Acid Absorption" The Journa~~of
Hiolouical Chemi~t~-..~ Vol. 268, No. 24, Issue of August
25, pp. 18035-18046, 1993).
o~,
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WO 98/40375 PCT/US98/03792
In a series of patent applications, eg Canadian
Patent Application Nos. 2,025,294; 2,078,588;
2,085,782; and 2,085,830; and EP Application Nos. 0 379
161; 0 549 967; 0 559 064; and 0 563 731, Hoechst
Aktiengesellschaft discloses polymers of various
naturally occurring constituents of the enterohepatic
circulation system and their derivatives, including
bile acid, which inhibit the physiological bile acid
transport with the goal of reducing the LDL cholesterol
level sufficiently to be effective as pharmaceuticals
and', in particular for use as hypocholesterolemic
agents.
In vitro bile acid transportinhibition is
disclosed to show hypolipidemic activity in The
Wellcome Foundation Limited disclosure of the world
patent application number WO 93/16055 for
"Hypolipidemic Benzothiazepine Compounds"
Selected benzothiepines are disclosed in world
patent application number W093/321146 for numerous uses
including fatty acid metabolism and coronary vascular
diseases.
Other selected benzothiepines are known for use as
hypolipaemic and hypocholesterolaemic agents,
especially for the treatment or prevention of
atherosclerosis as disclosed by application Nos. EP
508425, FR 2661676, and WO 92/18462, each of which is
limited by an amide bonded to the carbon adjacent the
phenyl ring of the fused bicyclo benzothiepine ring.
The above references show continuing efforts to
find safe, effective agents for the prophylaxis and
treatment of hyperlipidemic diseases and their
usefulness as hypocholesterolemic agents.
Additionally selected benzothiepines are disclosed
' for use in various disease states not within the
present invention utility. These are EP 568 898A as
abstracted by Derwent Abstract No. 93-351589; WO
89/1477/A as abstracted in Derwent Abstract No. 89-
3
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WO 98/40375 PCT/US98/03792
370688; U.S. 3,520.891 abstracted in Derwent 507018-B;
US 3,287,370, US 3,389,144; US 3,694,446 abstracted in
Derwent Abstr. No. 65860T-B and WO 92/18462.
HMG Co-A reductase inhibitors have been used as
cholesterol-lowering agents. This class of compounds
inhibits 3-hydroxy-3-methylglutaryl-coenzymE A (HMG Co-
A) reductase. This enzyme catalyzes the conversion of
HMG Co-A to mevalonate, which is an early and rate-
limiting step in the biosynthesis of cholesterol.
' Benzothiazepine anti-hyperlipidemic agents are
disclosed in WO 94/18183, WO 94/18184, WO 96/05188, WO
96/16051, AU-A-30209/92, AU-A-61946/94, AU-A-61948/94,
and AU-A- 61949/94.
The present invention furthers such efforts by
providing novel pharmaceutical compositions and methods
for the treatment of hyperlipidemic conditions.
SUN~IARY OF THE INVENTION
Accordingly, among its various apects, the present
invention provides compounds of formula (I):
O
J R'
_S~ R8
R'
~R~a I ~ ~ ~ 3 ~\ ( I >
R2
n R3
Rs \ 5 Ra
R
wherein:
q is~an integer from 1 to 4;
n is an integer from 0 to 2;'
R1 and R2 are independently selected from~the
group consisting of H, alkyl, alkenyl, alkynyl,
haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,
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dialkylamino, alkylthio, (polyalkyl)aryl, and
° cycloalkyl,
wherein alkyl, alkenyl, alkynyl, haloalkyl,
alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,
dialkylamino, alkylthio, (polyalkyl)aryl, and
cycloalkyl optionally are substituted with one or more
substituents selected from the group consisting of OR9,
~9R1 ~ , N'R'Rl°RWA~ , SR9. S+R9R1~A~ p'R'Ri°RuA- ~ S _( 0 ) R9
. S02 R9 .
S03R9, C02R9, CN, halogen, oxo, and CONR9R10,
wherein alkyl, alkenyl, alkynyl, alkylaryl,
alkoxy, alkoxyalkyl, (polyalkyl)a~yl, and cycloalkyl _
optionally have one or more carbons replaced by O, NR9,
N+R9R10A-, S, SO, 502, S+R9A-, P+R9Rl0A-, or phenylene,
wherein R9, R10, and Rw are independently selected
from the group consisting of H, alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, acyl, heterocycle, heteroaryl,
ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; or
Rl and R2 taken together with the carbon to which
they are attached form C~-C1° cycloalkylidene;
R3 and R4 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl,
acyloxy, aryl, heterocycTe;~ldR9, NR9R10, SR9, S(O)R9,
S02R9, and S03R9, wherein R' and Ri° are as defined
above; or
R3 and R4 together form =0, =NOR11, =S, =~g11R12,
=NR9, or =CRZZR12,
wherein R11 and R12 are independently selected
from the group consisting of H, alkyl, alkenyl,
alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl,
heterocycle, car 1
icyalkyl, carboalkoxyalkyl,~
cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(O)R9,
S02R9, S03R9, C02R9, CN, halogen, oxo, and CONR9R10,
S
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wherein R9 and R10 are as defined above, provided that
both R3 and R4 cannot be OH, NH2,and SH, or
R11 and R12 together with the nitrogen or carbon
atom to which they are attached form a cyclic ring;
R5 and R6 are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heter cy~ e~quaternary heterocycle,
quaternary
~heteroaryl, SR9,S(O)R9, S02R9, and S03Rg,
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
hete~roaryl,
heterocycle,/~quaternary heterocycle, and quaternary
heteroaryl can be substituted with one or more
substituent groups independently selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle,heteroaryl
arylalkyl, quaternary heterocycle, quaternary
heteroaryl, halogen, oxo, OR13, NRI3R14~ SR13~ S(O)R13~
S02R13, S03R13, NR130R14, NR13NR14R15~ N02, C02R13, CN,
OM, S020M, S02NR13R14, C(O)NR13R14, C(O)OM, COR13,
P (O) R13R14~ P+R13R14R15A_~ P (OR1') ORI~, S'R1'R"A-, and
N+R9R11R12A
wherein:
A- is a pharmaceutically acceptable anion and M is
a pharmaceutically acceptable cation,
said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, ~t~cycle and heteroaryl
can be further substituted with one or more substituent
groups selected from the group consisting of ORS,
NR~RB, SRS, S(O)RB, S02R~, S03R~,,C02R~, CN, ~o~co,
CONR~R8, N+R~R8R9A-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, hetezoazyl, azylalkyl, quaternary
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heterocycle, quaternary heteroaryl, P(O)R~Ra,
P+R~R8R9A , and P(0)(OR~)OR8, and
wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether , aryl , haloalkyl , cycloalkyl , hetemcycle and heteroaiyl
can optionally have one or more carbons replaced by 0,
NR~, N+R~R8A-, S, SO, S02, S+R~A-, PRA. P(0)R~.
P+R~R8A-, or phenylene, and R13, R14, and R15 are
independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl,
arylalkyl, cycloalkyl, heterocycle, heteroaryl
quaternary heterocycle, quaternary heteroaryl, and
quaternary heteroarylalkyl,
wherein alkyl, alkenyl, alkynyl, arylalkyl,
hetexoaryl,
heterocycle,~ and polyalkyl optionally have one or more
carbons replaced by 0, NR', N+R9R10A-, S, S0, S02,
S+R9A , PR9, P+R9R10A-, P(O)R', phenylene, carbohydrate,
amino acid, peptide, or polypeptide, and
R13~ R14~ and R15 are optionally substituted with
one or more groups selected from the group consisting
of sulf a7.tkcqua erna ~
ry heterocycle, quaternary
heteroaryl, OR9, NR9R10, N+R9R11R12A , SR9. S(0)R9,
S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S020M,
S02NRgR10, p0(OR16)ORl~, P+R9R10R11A-~ S+R9R10A-~ and C(O)C~'I.
wherein R16 and R1~ are independently selected
from the substituents constituting R9 and M; or
R14 and R15, together with the nitrogen atom to
which they are attached, form a cyclic ring;
R~ and RB are independently selected from the
group consisting of hydrogen and alkyl; and
one or more Rx are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl,
polyalkyl, acyloxy, aryl, arylalkyl, halogen,
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haloalkyl, cycloalkyl, heterocycle, heteroaryl~
polyether, quaternary heterocycle, quaternary
heteroaryl, OR13, ~13R14~ SR13, S(O)R13, S(0)2R13,
S03R13, S+R13R14A-~ ~130R14~ ~13~14R15~ N02. C02R13,
CN, OM, S020M, S02NR13R14 ~ ~1.C (0) R1', C (O) NR13RI4
NR14C(O)R13, C(0)OM, COR13, OR18, S(O)nNRlB, ~13R18~
~180R14~ N+R9R11R12A-~ P+R9R11R12A-~ amino acid,
peptide, polypeptide, and carbohydrate,
- wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
h teroaxyl,
polyalkyl, heterocycle,n acyloxy, arylalkyl, haloalkyl,
polyether, quaternary heterocycle, and quaternary
heteroaryl can be further substituted with OR9, NR9R10,
N+R9R11R12A-, SR9, S(O)R9, S02R9, S03R9, oxo, C02R9,
CN, halogen, CONR9R10, S020M, S02NR9R10, PO(OR1')OR1',
P+R9R11R12A-, S'R'R1°A-, or C (O) OM, and
wherein R18 is selected from the group consisting
of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,
heter~oa=yl, alkyl, quaternary heterocycle, and quaternary heteroaryl
wherein acyl, arylalkoxycarbonyl, arylalkyl,
heterocycle, heteroaryl, alkyh quaternary heterocycle,
and quaternary heteroaryl optionally are substituted
with one or more substita.st~ selected from the group
consisting of OR9, NR9R10, N+R9R11R12A-~ SR9, S(0)R9,
S02R9, S03R9, oxo, C02R9, CN, halogen, CONR9R10, S03R9,
S020M, S02NR9R10, PO(OR16)OR1~, and C(O)OM,
wherein in Rx, one or more carbons are optionally
replaced by O, NR13, N+R13R14A-~ S, S0, S02, S+R13A-,
PR13, ~ p(0)R13 P+R13R14A-~ phenylene, amino acid,
peptide, polypeptide, carbohydrate, polyether, or
polyalkyl,
8
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WO 98/40375 PCT/US98I0379Z
wherein in said polyalkyl, phenylene, amino acid,
peptide, polypeptide, and carbohydrate, one or more
carbons are optionally replaced by 0, NR9, N+R9R10A-,
S, SO, S02, S+R9A-, PR9, P+R9R10A-, or P(O)R';
wherein quaternary heterocycle and quaternary
heteroaryl are optionally substituted with one or more
groups selected from the group consisting of alkyl,
alkenyl, alkynyl, polyalkyl, polyether, aryl,
~haloalkyl, cycloalkyl, heterocyc e,n li-ylalkyl, halogen,
oxo-, OR13, NR13R14, SR13, S(O)R13, S02R13, S03R13,
NR130R14, NR13NR14R15, N02. C02R13, CN, OM, S020M,
S02NR13R14~ C(0)NR13R14~ C(0)OM, COR13, p(O)R13R14~
P+R13R14R15A_~ p(ORIS)OR1', g'Rl'R~'A , and N+R9R11R12A-
provided that both R5 and R6 cannot be hydrogen,
OH, or SH~and when R5 is OH, R1, R2, R3, R4, R~ and R8
cannot be all hydrogen;
provided that when R' or R' is phenyl, only one of
R1 or R= is H;
provided that when q = 1 and R" is styryl,
anilido, or anilinocarbonyl, only one of R' or R' is
alkyl; or
a pharmaceutically acceptable salt, solvate, or
prodrug thereof.
Preferably, RS and R6 can independently be
selected from the group consisting of H, aryl,
heterocyc e,~ a'ternary heterocycle, and quaternary
heteroaryl,
wherein said aryl, heterocycle, heteroaryl, quaternary
heterocycle, and quaternary heteroaryl can be.
- 30 substituted with one or more subs'tituent groups
independently selected from the group consisting of
alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,
haloalkyl, cycloalkyl, hetero~~rc~e,'larylalkyl, halogen,
oxo, OR13, NR13R14, SR13, S(O)R13,~S~02R13, S03R13,
9
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NR130R14~ ~I3NR14R15~ N02, C02R13, CN, OM, S020M,
S02NR13R14~ C(O)NR13R14~ C(O)OM,,COR13, p(O)R13R14~
P+R13 R14.R15A- ~ p ( OR1' ) OR1' , S+Rl'R~.A- ~ and N+R9R11R12A-
wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle and het~yl
can optionally have one or more carbons replaced by O,
NR~, N+R~R8A-, S, SO, S02, S+R~A-, PRA, P(O)RE
~P+R~R8A-, or phenylene,
wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle and he~yl
can be further substituted with one or more substituent
groups selected from the group consisting of ORS,
NR~R8, SRS, S(O)RB, S02R~, S03R~, C02R~, CN, oxo,
CONR~R8, N+R~R8R9A-, alkyl, alkenyl, alkynyl, aryl,
hete~aryl,
cycloalkyl, heterocycle,narylalkyl, quaternary
heterocycle, quaternary heteroaryl, P (O) R~RB, P+R~R8RgA-,
and P ( O ) ( OR' ) OR° .
More preferably, RS or R' has the formula:
-Ar- ( RY ) t
wherein:
t is an integer from 0 to 5;
Ar is selected from the group consisting of
phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl,
pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl,
.isoquinolinyl, quinoxalinyl, isnidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl,
triazolyl, isothiazolyl, indolyl,~benzoimidazolyl.
benzoxazolyl, benzothiazolyl, and benzoisothiazolyl;
and
one or more Ry are independently selected from the
group consisting of H, alkyl, alkenyl, alkynyl, aryl,
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cycloalkyl, heterocycle, ~t~~,l, quaternary heterocycle.
,, quaternary heteroaryl OR9, SR9, S(O)R9, S02R9, and S03R9,
wherein alkyl, alkenyl, alkynyl, aryl, cycloalkvl.
_ heterocycle, and heteroaryl can be substituted with one or more
substituent groups independently selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle, he~yl.
arylalkyl, halogen, oxo, OR13, ~13R14~ SR13~ S(0)R13~
.S02R13. S03R13, NR130R14, NR13NR14R15, N02. C02R13, CN,
OM,.S020M, S02NR13R14~ C(0)~13R14~ C(O)OM, COR13,
P (0) R13R14 ~ p+R13R14R15A_ ~ p (OR1') OR1', S'R1'R"A-, and
N+R9R11R12A-
wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl,~~. aid heGa~a~Yl
can be further substituted with one or more substituent
groups selected from the group consisting of ORS,
NR~R8, SRS, S(O)RB, S02R~, S03R~, C02R~, CN, oxo,
CONR~R8, N+R~R8R9A-, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycle, he~yl, a~y7allcyl, g_sb~y
heterocycle, quaternary heteroaryl, P (0) R~R8, P R~RBF~A-,
and P ( 0 ) ( OR' ) ORS , and
wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle, and heteroaryl
can optionally have one or more carbons replaced by 0,
NR~, N+R~RBA-, S, S0, 502, S+R~A-, PRA, P(O)R',
P+R~RBA-, or phenylene._
Most preferably, RS or R6 has the formula (II):
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(II)
(Ry)t
The invention is further directed to a compound
selected from among:
Rio - R19 - Ru
(Formula DI)
R"
Z0 19 21
R - R - R (Formula DII),
and
R~=
2 0 Rso - R19 - Rsl
(Formula DIII)
R~'
wherein Rl' is selected from the group
consisting of alkane diyl, alkene diyl, alkyne diyl,
polyalkane diyl, alkoxy diyl, polyether diyl,
polyalkoxy diyl, carbohydrate, amino acid, peptide, and
polypeptide, wherein alkane diyl,~alkene diyl,.alkyne
diyl, polyalkane diyl, alkoxy diyl, polyether diyl,
polyalkoxy diyl, carbohydrate, amino acid, peptide, and
polypeptide can optionally have one or more carbon
atoms replaced by O, NR~, N+R~RB, S, SO, S02. S+R~R8,.
~a
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PRA, P+P~R8, phenylene, heterocycle, heteroaryl, quatern~yy
heterocycle, quaternary heteroaryl, or aryl,
wherein alkane diyl, alkene diyl, alkyne diyl,
polyalkane diyl, alkoxy diyl, polyether diyl,
. 5 polyalkoxy diyl, carbohydrate, amino acid, peptide, and
polypeptide can be substituted with oae or more
aubetituent groups independently selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle,heteroaryl,
arylalkyl, halogen, oxo, OR13, ~13R14~ SR13~ s~0)R13~
sOZRl3, so3Rl3, NAl3oRl4, NR13NR14R15~ Via. COZR13, cN.
OM, SOZOM, S02NRl'~R14, C(O)NR13R14, C(O)OM, COR13,
P (O) R13R14 ~ ptR13R14.R15A_ I p (OR" ) OR", S'R"RmA., and
NtR9R11R12A ~
wherein R" further comprises functional linkages
by which R'.' is bonded to R'°, R", or R" in the compounds
of Formulae DII and DIII, and R" in the compounds of
Formula DIII. Each of R'°, R", or R" and R" comprises a
benzothiepine moiety as described above that is
therapeutically'effective in inhibiting ileal bile acid
transport.
The invention is also directed to a compound
selected from among Formula DI, Formula DII and Formula
DIII in which each of R", R", R" and R" comprises a
benzothiepine moiety corresponding to the Formula:
(off
tR'~ '
a
1
~ (Formula DIY)
ar:
13
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(Oh R7
S 8
(RX~
(Formula DIVA)
wherein R', R', R', R', Rs, R', R', R°, R", q, and n are as
defined in Formula I as described above, and R's is
either a covalent bond or arylene.
In compounds of Formula DIV, it is particularly
preferred that each of R'°, R", and R" in Formulae DII
and DIII, and R" in Formula DIII, be bonded at its 7-
or 8-position to R". In compounds of Formula DIVA, it
is particularly preferred that Rs' comprise a phenylene
moiety bonded at a m- or p-carbon thereof to R".
Examples of Formula DI include:
Re R~ R2 ..
R~~ ~~ Rs
-..
R O11I
,e
(III)
(R'~q (R'u°,)r
4~
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;3A
R~ ~~' (IV)
RBA
,. . ,q _ . ' ~n
R
O O
d a
and
(R
R8 Ri R2 R4A
R7~ ~ R3 RsA
Ra R~s~ ~ R2A
(v)
--. ' RBA
g Ren
(R"A)~ ' RBA
O
~R~c a
(R'~q
In any of the dimeric or multimeric structures
discussed~immediately above, benzothiepine compounds of
the present invention can be used'alone or iri various
combinations.
In any of the compounds of the present invention,
R1 and R' can be ethyl/butyl or butyl/butyl.
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Other compounds useful in the present invention as
ileal bile acid transport inhibitors are shown in
Appendix A.
In another aspect, the present invention provides
a pharmaceutical composition for the prophylaxis or
treatment of a disease or condition for which a bile
acid transport inhibitor is indicated, such as a
hyperlipidemic condition, for example, atherosclerosis.
Such compositions comprise any of the compounds
disclosed above, alone or in combination, in an amount
effective to reduce bile acid levels in the blood, or
to reduce transport thereof across digestive system
membranes, and a pharmaceutically acceptable carrier,
excipient, or diluent.
In a further aspect, the present invention also
provides a method of treating a disease or condition in
mammals, including humans, for which a bile acid
transport inhibitor is indicated, comprising
administering to a patient in need thereof a compound
of the present invention in an effective amount in unit
dosage form or in divided doses.
In yet a further aspect, the present invention
also provides processes for the preparation of
compounds of the present invention.
In yet another aspect, the present invention
provides a combination therapy comprising the use of a
first amount of an ileal bile acid transport.inhibitor
and a second amount of a HMG Co-A reductase inhibitor
useful to treat hyperlipidemic disorders, wherein said
first and second amounts together comprise an anti-
hyperlipidemic condition effective amount of said
compounds.
HMG Co-A reductase inhibitor~compounds useful in
the present invention are shown in Appendix B.-.
Further scope of the applicability of the present
invention will become apparent from the detailed
description provided below. However, it should be
tb
CA 02283575 1999-09-09
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understood that the following detailed dscription and
examples, while indicating preferred embodiments of the
invention, are given by way of illustration only since
various changes and modifications within the spirit and
scope of the invention will beomce apparent to those
skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description is provided to
aid those skilled in the art in practicing the present
invention. Even so, this detailed description should
not be construed to unduly limit the present invention
as modifications and variations in the emobadiments
discussed herein can be made by those of ordinary skill
in the art without departing from the spirit or scope
of the present inventive discovery.
The contents of each of the references cited
herein, including the contents of the references cited
within these primary references, are herein
incorporated by reference in their entirety.
Definitions
In order to aid the reader in understanding the
following detailed description, the following
definitions are provided:
"Alkyl", "alkenyl," and "alkynyl" unless otherwise
noted are each straight chain or branched chain
hydrocarbons of from one to twenty carbons for alkyl or
two to twenty carbons for alkenyl and alkynyl in the
present invention and therefore mean, for example,
methyl, ethyl, propyl, butyl, pentyl or hexyl,and
ethenyl, propenyl, butenyl, pentenyl, or hexenyl and
ethynyl, propynyl, butynyl, pentynyl, or hexyriyl
- respectively and isomers thereof.
"Aryl" means a fully unsaturated mono- or multi-
ring carbocyle, including, but not limited to,
I~
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substituted or unsubstituted phenyl, naphthyl, or
anthracenyl.
"Heterocycle" means a saturated or unsaturated
mono- or multi-ring carbocycle wherein one or more
carbon atoms can be replaced by N, S, P, or 0. This
includes, for example, the following structures:
Z
i-~... ,-~ Z"'
i
ry ~ ~ ~ r ~
or Z
wherein Z, Z', Z" or Z"' is C, S, P, O, or N, with the
proviso that one of Z, Z', Z" or Z"' is other than
carbon, but is not O or S when attached to another Z
atom by a double bond or when attached to another 0 or
S atom. Furthermore, the optional substituents are
understood to be attached to Z, Z', Z" or Z"' only when
each is C.
The term "heteroaryl" means a fully unsaturated
heterocycle.
In either "heterocycle" or "heteroaryl," the point
of attachment to the molecule of interest can be at the
heteroatom or elsewhere within the ring.
The term "quaternary heterocycle" means a
heterocycle in which one or more of the heteroatoms,
for example, O, N, S, or P, has such a number of bonds
that it is positively charged. The point of attachment
of the quaternary heterocycle to the molecule of
interest can be at a heteroatom or elsewhere.
The term "quaternary heteroaryl" means a.
heteroaryl in which one or more of the heteroatoms, for
example, O, N, S, or P, has such a number of bonds that
it is positively charged. The point of attachment of
the quaternary heteryaryl to the molecule of interest
can be at a heteroatom or elsewhere.
I$
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The term "halogen" means a fluoro, chloro, bromo
or iodo group.
The term "haloalkyl" means alkyl substituted with
one or more halogens.
The term "cycloalkyl" means a mono- or multi-
ringed carbocycle wherein each ring contains three to
ten carbon atoms, and wherein any ring can contain one
or more double or triple bonds.
The term "diyl" means a diradical moiety wherein
said moiety has two points of attachment to molecules
of -interest.
The term "oxo" means a doubly bonded oxygen.
The term "polyalkyl" means a branched or straight
hydrocarbon chain having a molecular weight up to about
20,000, more preferably up to about 10,000, most
preferably up to about 5,000.
The term "polyether" means a polyalkyl wherein one
or more carbons are replaced by oxygen, wherein the
polyether has a molecular weight up to about 20,000,
more preferably up to about 10,000, most preferably up
to about 5,000.
The term "polyalkoxy" means a polymer of alkylene
oxides, wherein the polyalkoxy has a molecular weight
up to about 20,000, more preferably up to about 10,000,
most preferably up to about 5,000.
The term "cycloaklylidene" means a mono- or multi-
ringed carbocycle wherein a carbon within the ring
structure is doubly bonded to an atom which is not
within the ring structures.
The term "carbohydrate" means a mono-, di-, tri-,
or polysaccharide wherein the polysaccharide can have a
molecular'weight of up to about 20,000, for example,
- hydroxypropyl-methylcellulose or chitosan.
The term "peptide" means polyamino acid~c.ontaining
up to about 100 amino acid units.
The term "polypeptide" means polyamino acid
containing from about 100 amino acid units to about
~9
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1000 amino acid units, more preferably from about 100
amino acid units to about 750 amino acid untis, most
preferably from about 100 amino acid units to about 500
amino acid units.
The term "alkylammoniumalkyl" means a NHz group or
a mono-, di- or tri-substituted amino group, any of
which is bonded to an alkyl wherein said alkyl is
bonded to the molecule of interest.
The term "triazolyl" includes all positional
isomers. In all other heterocycles and heteroaryls
which contain more than one ring heteroatom and for
which isomers are possible, such isomers are included
in the definition of said heterocycles and heteroaryls.
The term "sulfoalkyl" means an alkyl group to
which a sulfonate group is bonded, wherein said alkyl
is bonded to the molecule of interest.
The term "active compound" means a compound of the
present invention which inhibits transport of bile
acids.
When used in combination, for example "alkylaryl"
or "arylalkyl," the individual terms listed above have
the meaning indicated above.
The term "a bile acid transport inhibitor" means a
compound capable of inhibiting absorption of bile acids
from the intestine into the circulatory system of a
mammal, such as a human. This includes increasing the
fecal excretion of bile acids, as well as reducing the
blood plasma or serum concentrations of cholesterol and
cholesterol ester, and more specifically, reducing LDL
and VLDL cholesterol. Conditions or diseases which
benefit from the prophylaxis or treatment by bile acid
transport~inhibition include, for example, a
hyperlipidemic condition such as atherosclerosis.
The phrase "combination therapy" refers to the
administration of an ileal bile acid transport
inhibitor and a HMG Co-A reductase inhibitor to treat a
hyperlipidemic condition, for example atherosclerosis
~,o
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and hypercholesterolemia. Such administration
encompasses co-administration of these inhibitors in a
substantially simultaneous manner, such as in a single
capsule having a fixed ratio of active ingredients or
in multiple, separate capsules for each inhibitor
agent. In addition, such administration also
encompasses use of each type of inhibitor in a
sequential manner. In either case, the treatment
regimen will provide beneficial effects of the drug
combination in treating the hyperlipidemic condition.
The phrase "theraputically effective° is intended
to qualify the combined amount of inhibitors in the
combination therapy. This combined amount will achieve
the goal of reducing or eliminating the hyperlipidemic
condition.
Compounds
The compounds of the present invention can have at
least two asymmetrical carbon atoms, and therefore
include racemates and stereoisomers, such as
diastereomers and enantiomers, in both pure form and in
admixture. Such stereoisomers can be prepared using
conventional techniques, either by reacting
enantiomeric starting materials, or by separating
isomers of compounds of the present invention.
Isomers may include geometric isomers, for example
cis isomers or trans isomers across a double bond. All
such isomers are contemplated among the compounds of
the present invention.
The compounds of the present invention also
include tautomers.
The compounds of the present invention as
discussed below include their salts, solvates.and
prodrugs.
compound syntheses
a~
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The starting materials for use in the preparation
of the compounds of the invention are known or can be -
prepared by conventional methods known to a skilled
person or in an analogous manner to processes described
in the art.
Generally, the compounds of the present invention
can be prepared by the procedures described below.
For example, as shown in Scheme I, reaction of
aldehyde II with formaldehyde and sodium hydroxide
yields the hydroxyaldehyde III which is converted to
mes~rlate IV with methanesulfonyl chloride and
triethylamine similar to the procedure described in
Chem. Ber. 98, 728-734 (1965). Reaction of mesylate IV
with thiophenol V, prepared by the procedure described
in WO 93/16055, in the presence of triethylamine yields
keto-aldehyde VI which can be cyclized with the
reagent, prepared from zinc and titanium trichloride in
refluxing ethylene glycol dimethyl ether (DME), to give
a mixture of 2,3-dihydrobenzothiepine VII and two
racemic steroisomers of benzothiepin-(5H)-4-one VIII
when R1 and R~ are nonequivalent. Oxidation of VII with
3 equivalents of m-chloro-perbenzoic acid (MCPBA) gives
isomeric sulfone-epoxides IX which upon hydrogenation
with palladium on carbon as the catalyst yield a
mixture of four racemic stereoisomers of 4-hydroxy-
2,3,4,5-tetrahydrobenzothiepine-1,1-dioxides X and two
racemic stereoisomers of 2,3,4,5-tetrahydro-
benzothiepine-1,1-dioxides XI when R1 and R= are
nonequivalent.
Optically active compounds of the present
invention can be prepared by. using optically active starting
material III or by resolution of compounds X with optical
resolution agents well known in the art as described in J.
Org. Chem., 39, 3904 (1974), ibid., 42, 2781 (1977), and
ibid., 44, 4891 (1979).
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1
Rt Rs --~. i~ip Rt Rs ~~ ~,rp Rt R:
- p ~ ~ 0 't 0
R R~ ~ R R8
N
~$ RtR
Rt R ~N '! s H
' R, ~ llio s , O
o se%
~I, ~R'~ R R'
v N
w
~-, ~b
ø, RS
Rt
Rt
~ i. R= ~ ~ R=
O
z, ~a
~ooolls ~ACPSA ~ R ~ ~ R t
R= li=lPd-C ~ ~ Rs
---~ --'-
~, b fix)
8
x
Rt
R
s
CR )$
>e
Alternatively, xeto-aldehyde VI where R' is H can be
prepared by reaction of thiophenol V with a 2-
substituted acrolein.
5
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WO 98/40375 PCT/US98/03792
St! O ~ H
R R1 ~N H
s , ~ p
O
~x~ ~; ~ R ~
H
Benzothiepin-(5H)-4-one VIII can be oxidized with MCPBA
to give the benzothiepin-(SH)-4-one-1,1-dioxide XII
Which can be reduced with sodium borohydride to give
, four racemic stereoisomers of X. The two stereoisomers
of X, Xa and Xb, having the OH group and R' on the
opposite sides of the benzothiepine ring can be
converted to the other two isomers of X, Xc and Xd,
having the OH group and R'Ion the same side of the
benzothiepine ring by reaction in methylene chloride
with 40-50~ sodium hydroxide in the presence of a phase
transfer catalyst (PTC). The transformation can also
be carried out with potassium t-butoxide in THF.
~4
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WO 98/40375 PCT/IJS98/03792
\ R' 2~ R ~s
R: ~ Ra ~- ~ R:
x _ ~0 ~.~ .OH
((Z ~ t~ i
x
H
~t
.,~~ ~t
a0 R1
sp Rt
~'~ R:
...n.~~ R=
(~x~ . __ ~" ~ ..
R1 OOH,. PT~f~I =as ~L" R OH
t
xs
a t ~, Rt
a0 Rt
R~
~d R=
.wi R=
H
~s xs
wiwnR ~~ Bu,R=~~,R ~~Ph,X~tl.q~4
e~ ~ Xr
~b ~ 7m
8c ~ xc
Ed~Xd
The compounds of the present invention where R' is OR,
' or S ~O)aR and R' is hydroxy can be prepared by
reaction of epoxide IX where R' is H with thiol,
alcohol, or amine in the presence of a base.
~S
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WO 98/40375 PGT/US98/0379Z
R~ R1
~ R'
x
S R=
~ R~ ~ v
HOR, or HNRRI or HS(O) R base
n
R' Re
S= R'
..~u Rt
~ R~ ~ ~ ~ Ohl
R' - OR, NRRI, S(O)~R
Another route to Xc and Xd of the present invention is
shown in Scheme 2. Compound VI is oxidized to compound
XIII with two equivalent of m-chloroperbenzoic acid.
Hydrogenolysis of compound XIII with palladium on
IO carbon yields compound XIV which can be cyclized with
either potassium t-butoxide or sodium hydroxide under
phase transfer conditions to a mixture of Xc and Xd.
Separation of Xc and Xd can be accomplished by either
HPLC or fractional crystallization.
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The thiophenols XVIII and V used in the present
invention can also be prepared according to the Scheme
3. Alkylation of phenol XV with an arylmethyl chloride
- s in a nonpolar solvent according to the procedure in ~T.
Chain. Soc., 2431-2432 (1958) gives the ortho
substituted phenol XVI. The phenol XVI can be
converted to the thiophenol XVIII via the thiocarbamate
XVII by the procedure described in J. Org. Chem., 31,
3980 (1966). The phenol XVI is first reacted with
dimethyl thiocarbamoyl chloride and triethylamine to
give thiocarbamate XVII which is thermally rearranged
at 200-300 °C, and the rearranged product is hydrolyzed
with sodium hydroxide to yield the thivphenol XVIII.
Similarly, Thiophenol V can also be prepared from 2-
acylphenol XIX via the intermediate thiocarbamate XX.
s~ 1
9 3
R I R1 R? ~~~ RI ~ p~? ~Y r
R R.~.
1 ~ ~ ~ O~ ~ N Oy ~ N
2 ~, ~ WdIG
R5 ~ R5 ~ ~ 5
R
! ~R'~~c~ ~R''~~ ~~x~ xiv
lCOtBu
1'1 R3 Y R~ R3
d RI SO RI
al R~ '~" ~~,ul
~~,~~ =RS off ~Rx,~ R~ off
~7
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OH
f RaCti=d ~ Ra
~P~"~ XV CR~'~ XH
8
oJi- trw = t. 0
2 N~OH 8H
Ra I Ra ~ ~ R
/ /
CR"~ ~Rx~~ xvn
m
s
O ~~ ~ ~ O
2~ ~ O
Ra ~, ~ / Ri ---~ ( ~ Ra
( R~~ me ~ g~ ~ roc CR~'~ ~
Scheme 4 shows another route to benzothiepine-1,1-
dioxides Xc and Xd starting from the thiophenol XVIII.
Compound XVIII can be reacted with mesylate IV to give
the sulfide-aldehyde XXI. Oxidation of XXI with two'
equivalents of MCPBA yields the sulfone-aldehyde XIV
which can be cyclized with potassium t-butoxide to a
mixture of Xc and Xd. Cyclyzation of sulfide-aldehyde
with potassium t-butoxide also gives a mixture of
benzothiepine XXIIc and XXIId.
~:8
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4
_ 1H ~~ t~~ ~ Rs R, Rg Rt
. ~ Rs Hs0 R1 ~ H a0= ~ H
~ Ri 'he 0
~ct~X)$ " ~ i \'~ ~ ~ R
'~' "' CR")$ CRX~~
goo ~av
IOD~u l~f8u
~,~~ R s
R1 a0 Rt
w~~n ."~1 R:
,"« ~
+ ~~/~/
Ctv )~ Rs :%OH CRX~~ Rs ON CR~i~ Rs SON
-~ x
xo
' ~~ R s'
R~
~~~111 R=
R,
xe
Examples of amine- and hydroxylamine-containing
compounds of the present invention can be prepared~as
shown in Scheme 5 and Scheme 6. 2-Chloro-5-
nitrobenzophenone is reduced with triethylsilane and
trifluoromethane sulfonic acid to 2-chloro-5-
nitrodiphenylmethane 3Z. Reaction of 32 with lithium
sulfide followed by reacting the resulting sulfide with
mesylate IV gives sulfide-aldehyde XXIII. Oxidation of
- 10 XXIII with 2 equivalents of MCPBA yields sulfone-
aldehyde XXIV which can be reduced by hydrogenation to
the hydroxylamine XXV. protecting the hydroxylamine XXV
with di-t-butyldicarbonate gives the N,D-di-(t-
a~
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butoxycarbonyl)hydroxylamino derivative XXVI.
Cyclization of XXVI with potassium t-butoxide and
removal of the t-butoxycarbonyl protecting group gives
a mixture of hydroxylamino derivatives XXVIIc and
XXVIId. The primary amine XXXIIIc and XXXIIId
derivatives can also be prepared by further
hydrogenation of XXIV or XXVIIc and XXVIId.
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s~ s
a Ct O
_ r_
1 ~s NOZ 3: NOx
- ~ p' Z~eJsloco-s-V
nitx~a~a~e
. iv
p2 2 Yc~ ~ p2
S
~ I
HZ NOZ ~ N70mr Hs'~1C
R~ p2
csa~o
I N(HOC)O(HOG~
1 pu~am c-butopde~ NHOH ~y
2 add ~
~, O
l Qs O
HOHN i ~~ ' E''~ R
Ph OH HOHN Ph OH
JoNad
Rvc-x~ ioo ~, x ~c ~cxz.ioo ~, so ~c
Q, o
p,~ Q, O
~ ~t + pt
H2N i az
Ph OH H2N OH
Ph
In Scheme 6, reduction of the sulfone-aldehyde XXV
with hydrogen followed by reductive alkylation of the
resulting amino derivative with hydrogen and an
aldehyde catalyzed by palladium on carbon in the same
reaction vessel yields the substituted amine derivative
31
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WO 98/40375 PCT/US98/03792
a
0
H~ooH
o-~ ~ ~
0 0
XX~/ ~~ 70No
IOD~eu
hf
r
0
~o
'aN
N ~ OH
XXVIII. Cyclization of XXVIII with potassium t-butoxide
yields a mixture of substituted amino derivatives of
this invention XXIXc and XXIXd.
Scheme 7 describes one of the methods of
introducing a substituent to the aryl ring at the 5-
position of benzothiepine. Iodination of 5-phenyl
l0 derivative XXX with iodine catalyzed by mercuric
triflate gives the iodo derivative XXXI, which upon
palladium-catalyzed carbonylation in an alcohol yields
the carboxylate XXXII. Hydrolysis of the carboxylate
3~
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8dmer T
v ~ ° ~'~ 6
_ o
''~ rt, R,
Ho(~ s
»u111 R= .
t= . 2s C
N
II \/
Pd a~y~
° ~.~ CQI R~OH
100 C
I
N
~0a1
and derivatization of the resulting acid to acid
derivatives are well known in the art.
Abbreviations used in the foregoing description
have the following meanings:
TfiF---tetrahydrofuran
33
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WO 98/40375 PCT/US98/03792
PTC---phase transfer catalyst
Aliquart 336---methyltricaprylylammonium chloride
MCPBA---m-chloroperbenzoic acid
Celite--- a brand of diatomaceous earth filtering
aid
DMF---dimethylformamide
DME----ethylene glycol dimethyl ether
BOC---t-butoxycarbonyl group
Rl and R' can be selected from among substituted
and unsubstituted C1 to Cla alkyl wherein the
substituent(s) can be selected from among
alkylcarbonyl, alkoxy, hydroxy, and nitrogen-containing
heterocycles joined to the Ci to Clo alkyl through an
ether linkage. Substituents at the 3-carbon can
include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl,
i sopropyl , -CHzC ( =O ) C~HS , -CHzOCzHs , and -CH=0- ( 4 -
picoline). ~thyl, n-propyl, n-butyl, and isobutyl are
preferred. In certain particularly preferred
compounds of the present invention, substituents R1 and
RZ are identical, for example n-butyl/n-butyl, so that
the compound is achiral at the 3-carbon. ~liminating
optical isomerism at the 3-carbon simplifies the
selection, synthesis, separation, and quality control
of the compound used as an ileal bile acid transport
inhibitor. In both compounds having a chiral 3-carbon
and those having an achiral 3-carbon, substituents (R")
on the benzo- ring can include hydrogen, aryl, alkyl,
hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, haloalkyl, haloalkoxy, (N)-hydroxy-
carbonylalkyl amine, haloalkylthio, haloalkylsulfinyl,
haloalkylsufonyl, amino, N-alkylamino, N,N-
dialkylamino, (N)-alkoxycarbamoyl, (N)-
aryloxycarbamoyl, (N)-aralkyloxycarbamoyl, trialkyl-
ammonium (especially with a halide counterion), (N)-
amido, (N)-alkylamido, -N-alkylamido, -N,N-
3'~
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dialkylamido, (N)-haloalkylamido, (N)-sulfonamido, (N)-
- alkylsulfonamido, (N)-haloalkylsulfonamido,
carboxyalkylamino, trialkyl-ammonium salt, (N)-carbamic
_ acid, alkyl or benzyl ester, N-acylamine,
hydroxylamine, haloacylamine, carbohydrate, thiophene a
trialkyl ammonium salt having a carboxylic acid or
hydroxy substituent on one or more of the alkyl
substituents, an alkylene bridge having a quaternary
ammonium salt substituted thereon, -[O(CH,)'"]x-X where x
is 2 to 12, w is 2 or 3 and X is a halo or a quaternary
ammonium salt, and (N)-nitrogen containing heterocycle
wherein the nitrogen of said heterocycle is optionally
quaternized. Among the preferred species which may
constitute R" are methyl, ethyl, isopropyl, t-butyl,
hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo,
bromo, fluoro, methylsulfinyl, methylsulfonyl,
ethylthio, amino, hydroxylamine, N-methylamino, N,N-
dimethylamino, N,N-diethylamino,
(N)-benzyloxycarbamoyl, trimethylammonium, A,
2 0 -NHC ( =0 ) CHI , -NHC ( =O ) CSHI~ , -NHC ( =O ) C6H1, ,
carboxyethylamino, (N)-morpholinyl, (N)-azetidinyl,
(N)-N-methylazetidinium A~, (N)-pyrrolidinyl, pyrrolyl,
(N)-N-methylpyridinium A , (N)-N-methylmorpholinium A ,
and N-N'-methylpiperazinyl, (N)-bromomethylamido, (N)-
N-hexylamino, thiophene, -N'(CH~)~COzH I~, -NCHsCH=COSH, -
(N)-N'-dimethylpiperazinium I-, (N)-t-
butyloxycarbamoyl, (N)-methylsulfonamido, (N)N'-
methylpyrrolidinium, and - (OCHZCH~) ~I, where A' is a
pharmaceutically acceptable anion. The benzo ring
can be mono-substituted at the 6, 7 or 8 position, or
disubstituted at the 7-and -8 positions. Also
included are the 6,7,8-trialkoxy compounds, for example
the 6,7,8-trimethoxy compounds. A variety of other
substituents can be advantageously present on the 6, 7,
8, and/or 9- positions of the benzo ring, including,
for example, guanidinyl, cycloalkyl, carbohydrate
(e.g., a 5 or 6 carbon monosaccharide), peptide, and
i
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quaternary ammonium salts linked to the ring via
poly ( oxyalkylene ) 1 inkages , a . g . , - ( OCHzCHs ) x-N~RI'R1~R~SA-,
where x is 2 to 10. Exemplary compounds are those set
forth below in Table 1.
3~
CA 02283575 1999-09-09
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TABLE 1
Alt eraative compcuads $3 (Fa=..: ly F101. xxx . yyyj
- 0~ i0
~z) i s ~ S ~ ..,... R2
R
.. ~~~ OFi
R
pre;'-s C5~* Rl=A2 Rg
'
(~ '
F.s~. vw)
t 101. OQ'- n-propy'- P!:- 7-w~C::yI
O1
02 n-p=opy'- Pr- 7-et:wl
03 a-propyi P::- 7-iso-p_opyl
04 n-p~apyl Ph- 7-tee -~L~p
OS n-propy= Ph- 7-0::
06 n-p;opv~ Ph- 7-ccs3
07 n-gropyl Pa- 7-0(-so-~:Opy!)
OS n-psopyl Ph- 7-SC'.-'.3
09 n-propy? P::- 7-SCGa3
It-p~opyl Ph- 7-S02Gs3
* General Notes
In the description of the substituents '(N)' indicates
that a nitrogen bearing substituent is bonded to the rinc
structure via the nitrvgen'atom. -
Similarly, 2-thiophene indicates a bond in the 2 position
of the thiophene ring. A similar convention is used for other
heterocyclic substituents.
Abbreviations and Definitions
NFi-CBZ is defined as -HNC (=O) OCIiZPh
31
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11 n-propyl Ph- 7-SCH2CH3
12 n-propyl Ph- 7-NH2
13 n-propyl Ph- 7-NHOH
14 n-propyl Ph- 7-NHCH3
15 n-propyl Ph- 7-N(CH3)2
16 n-propyl. Ph- 7-N+(CH3)3, I
17 n-progyl Ph- 7-NHC(-0)CH3
18 n-propyl Ph- 7-N(CH2CH3)2
19 n-propyl Ph- ?-NMeCH2C02H
20 n-propyl ph- 7-N'(Me)~CH2C02H, I-
21 n-propyl ph- 7-(N)-morpholine
22 n-propyl Ph- 7-(N)-azetidine
23 n-propyl Ph- 7-(N)-N-ssethylazetidinium, I-
24' n-propyl Ph- ?-(N)-pyrrolidine
25 n-propyl Ph- 7- (N) -N-methyl-pyrrolidiniu.-.t,
I-
26 n-prooyl Ph- 7-(N)-N-methyl-morpholiniu.-a, I'
27 n-propyl Ph- 7-(N)-N'-methylpiperazine
28 n-propyl Ph- 7-(N)-N'-dia:ethylpiperaziniL-z,
I'
29 n-propyl Ph- 7-NL-CBZ
30 n-propyl Ph- 7-N~e(0)C5H11
31 n-gropyl Ph- 7-NYC(0)CH28r
32 n-propyl Ph- 7-NH-C(NH)NH2
33 n-propyl Ph- 7-(2)-thiophene
34 n-propyl Ph- 8-methyl
35 a-propyl Ph- 8-ethyl
36 n-propyl Ph- 8-iso-propyl
37 n-propyl Ph- 8-tent-butyl
38 n-propyl Ph- 8-OH
39 n-propyl Ph- 8-OCH3
40 n-propyl Ph- 8-0(iso-propyl)
41 n-propyl Ph- 8-SCH3
42 n-propyl Ph- 8-SOCH3
43 n-propyl Ph- 8-S02CH3
44 n-propyl Ph- 8-SCH2CH3
45 a-propyl Ph- 8-NH2
46 n-propyl Ph- 8-NHOH
47 n-propyl Ph- 8-NHCH3
48 a-propyl Ph- 8-N(CH3)2
49 n-propyl Ph- 8-N~fCH3)3, I-
50 n-pzopyl Ph- B-NHC(~Q)CH3
51 n-propyl Ph- 8-N(CH2CH3)2
52 a-propyl Ph- 8-NMeCH2COZH
3~
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53 n-propyl Ph- 8-N~ (Me) =CH2C02H~~'~1T
54 n-propyl Ph- 8-(N)-morpholine
55 n-propyl Ph- 8-(N)-azetidine
- 56 n-propyl Ph- 8-(N)-N-methylazetidinium
I-
57 n-ProPyl Ph- ,
8-(N)-pyrrolidine
- 58 n-propyl Ph- 8-(N)-N-methyl-pyrrolidinium
Z'
59 n-propyl Ph- ,
8-(N)-N-methyl-morpholinium
Z'
60 n-propyl Ph- ,
8-(N)-N'-methylpiperazine
6i n-propyl Ph- 8-(N)-N'-dimethylpiperazinium
Z-
62 n-propyl Ph- ,
8-NH-CHZ
63 n-propyl Ph- 8-NHC(O)C5H11
64 n-propyl Ph- 8-NHC(0)CH2Hr
65 n-propyl Ph- 8-NH-C(NH)NH2
66 n-propyl Ph- 8-(2)-thiophene
67 n-propyl Ph- 9-methyl
68 n-propyl Ph- 9-ethyl
69 n-propyl Ph- 9-iso-propyl
70 n-propyl Ph- 9-tent-butyl
71 n-propyl ph_
~.-
72 n-propyl Ph- 9-OCH3
73 n-propyl Ph- 9-O(iso-propyl)
74 n-propyl Ph- 9-SCx3
75 n-propyl Ph- 9-SOCH3
76 n-propyl Ph- 9-S02C::3
77 n-propyl Ph- 9-SCH2CH3
78 n-propyl Ph- 9-Nv2
79 n-propyl Ph- 9-NHOH
80 n-propyl Ph- 9-NHCH3
8I n-propyl Ph- 9-N(CH3)2
82 n-propyl Ph- 9-N+(CH3)
I-
83 n-propyl Ph- 3.
9-NHC(~0)CH3
84 n-propyl Ph- 9-N(CH2CH3)2
85 n-propyl Ph- 9-NMeCH2C02H
86 n-propyl Ph- 9-N(Me)ZCH2C02H, I-
87 n-propyl Ph- 9-(N)-morpholine
88 n-propyl Ph- 9-(N)-azetidine
89 n-propyl Ph- g-(N)-N-methylazetidiniuin
Z-
90 n-propyl Ph- ,
9-(N)-pyrrolidine
91 n-propyl Ph- 9-(N)-N-methyl-pyrrolidiniuas,
I-
92 n-propyl Ph- 9-(N)-N-methyl-morpholinium,
Z-
93 n-propyl Ph- 9-(N)-N'-methylpiperazine
93 n-propyl Ph- 9-(N)-N-d~thylpiperazinium,
I-
95 n-propyl ph- 9-NH-C82
39
CA 02283575 1999-09-09
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96 n-propyl Ph- 9-NHC(0)C5H11
97 n-propyl Ph- 9-NHC(0)CH28r
g8 n-propyl Ph- 9-NH-C(NH)NH2
gg n-pzopyl Ph- 9-(2)-thioghene
100 n-propyl Ph- 7-oCH3, 8-OCH3
101 n-propyl Ph- 7-SCH3, 8-OCIi3
I02 n-propyl Ph- 7-SCH3, 8-SCH3
103 n-pronvl Ph- 6-OCH3, 7-OCH3, 8-OCH3
Bzetis Cpd~ Rl=R2 RS (Rx)q
(FFF s~ ~ wv)
r10I.002 Ol n-butyl Ph- 7-rethyl
_
02 n-butyl Ph- 7-ethyl
03 n-butyl Ph- 7-iao-propyl
04 n-butyl Ph- 7-tent-5uty1
OS n-butyl Ph- 7-OH
06 n-butyl Ph- 7-OCH3
07 n-butyl Ph- 7-t~(iso-propyl)
08 n-butyl Ph- 7-~3 ..
09 n-butyl Ph- 7-SOC'.-'.3
n-butyl Ph- 7-S02CS3
11 n-butyl Ph- 7-SC:i2C 3
12 n-butyl Ph- 7-Nii2
13 n-butyl Ph- 7-NHOH
14 n-butyl Ph- 7-NF:C:~3
n-butyl Pr- 7-N (C:i3) 2
16 n-butyl Ph- 7-N+(Cv3)3. I
17 n-butyl Ph- 7-NHC(=0)CH3
18 n-butyl Ph- 7-:~ (CH2CH3) 2
lg n-butyl Ph- 7-N:leCHyC02H
n-butyl Ph- 7-N'(Me)ZCHZC02H, I-
21 n-butyl Ph- 7-(N)-morpholine
22 n-butyl Ph- 7-(N)-azetidine
23 n-butyl Ph- 7-(N)-N-methylazetidinium, I'
24 n-butyl Ph- 7-(N)-pyrrolidine
n-butyl Ph- 7-(N)-N-methyl-pyrzolidinium,
I'
26 n-butyl Ph- 7-(N)-N-methyl-morpholinium,
I'
27 n-butyl Ph- 7-(N)-N'-methylpiperazine
28 n-butyl Ph- 7-(N)-N'-dimethylpiperazinium,
I'
29 n-butyl Ph- 7-NH-C9Z
n-butyl Ph- 7-NHC(0)CgHll
31 n-butyl Ph- 7-NHC(0)CH2Br
L~..O
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32 n-butyl Ph- 7-NH-C(NH)NH2
33 n-butyl Ph- 7-(2)-thiophene
- 34 n-butyl Ph- 8-methyl
35 n-butyl Ph- 8-ethyl
36 n-butyl Ph- 8-iso-propyl
- 37 n-butyl Ph- 8-tart-butyl
38 n-butyl Ph- 8-OH
39 n-butyl Ph- 8-OCH3
40 n-butyl Ph- 8-O(iso-propyl)
41 n-butyl Ph- 8-SCH3
42 n-butyl Ph- 8-SOCH3
43 n-butyl Ph- 8-S02CH3
44 n-butyl Ph- 8-SCH2CH3
45 n-butyl Ph- 8-NH2
46 n-butyl Ph- 8-NHOH
47 n-butyl Ph- 8-NHCh3
48 n-butyl Ph- 8-N(Ca3)2
49 n-butyl Ph- 8-~+(CH3)3. I'
50 n-butyl ph- 8 ~ ~ a v
-H:C ( 0 ) C..3
51 n-butyl ph_ 8-N (Cu2CH3 ) 2
52 n-butyl Ph- 8-NMeCH2C02H
53 n-butyl Ph- 8-N (,!e) =Ca2C02H, I'
54 n-butyl Ph- 8-(N)-mo~roline
55 n-butyl Ph- 8-(N)-azetidine
56 n-butyl Ph- 8- (N) -N-~ ethylazetidiniu.-.t
I'
57 n-butyl Ph- ,
8-(N)-pyrrolidine
58 n-butyl Ph- 8-(N)-N-methyl-pyrrolidiai
I-
59 n-butyl Ph- um,
8-(N)-N-aethyl-morpholini
I'
60 n-butyl Ph- uia,
8-(N)-N'-c~ethylpiperazine
61 n-butyl Ph- 8-(N)-N'-dimethylpiperazinium
I'
62 n-butyl Ph- ,
8-NH-C8Z
63 n-butyl Ph- 8-NHC(O)CSH11
64 n-butyl Ph- 8-NHC(0)CH28r
65 n-butyl Ph- 8-NH-C (NH) NH2
66 n-butyl Ph- 8-(2)-thiophene
67 n-butyl Ph- 9-methyl
68 n-butyl ~Ph- 9-ethyl
69 n-butyl Ph- 9-iso-propyl
70 n-butyl Ph- 9-tart-butyl
71 n-butyl ph- 9~H .
72 a-butyl ph- 9-~H3
73 n-butyl Ph- 9-0(iso-propyl)
4~
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WO 98/40375 PCTNS98/03792
74 n-butyl Ph- 9-SCH3
75 n-butyl Ph- 9-SOCH3
76 n-butyl Ph- 9-502CH3
77 n-butyl Ph- 9-SCH2CH3
78 n-butyl Ph- 9-NH2
79 n-butyl Ph- 9-NHOH
80 n-butyl Ph- 9-NHCH3
81 n-butyl Ph- 9-N(CH3)2
82 n-butyl Ph- g-N+(CH3)3, I-
83 n-butyl Ph- 9-NHC(-0)CH3
84 n-butyl Ph- 9-N(CH2CH3)2
85 n-butyl ~Ph- 9-NMeCH2C02H
86 n-butyl Ph- 9-N' (,!e) ZCH2C02H, I-
87 n-butyl Ph- 9-(N)-morpholine
88 n-butyl Ph- 9-(N)-azetidine
8 n-butyl Ph- 9- (N) -N-methylazetidiniurs,
9 I'
90 n-butyl Ph- 9-(N)-pyrrolidine
91 n-butyl Ph- g- (N) -;~-~ ethyl-pyr rolidinis:ri,
I'
92 n-butyl Ph- 9-(,~~) jN-~-ethyl-r..o_pholinium,
I-
93 n-butyl Ph- 9-(Nrj~-N'-r..ethylpiperazine
93 n-butyl Ph- g-(N)-N~-di-ethylpiperaziniu~,
I'
95 n-butyl Ph- 9-NH-C3Z
96 n-butyl Ph- 9-NsC (0) C5:~11
97 n-butyl Ph- 9-Ni:C (0) C::23=
98 n-butyl Ph- 9-NE-C(NH)N82
99 n-butyl Ph- 9-(2)-thiophene
100 n-butyl Ph- 7-OCH3, 8-GCH3
101 n-butyl ph- 7-SCH3, 8-OCH3
102 n-butyl Ph- ~-SCH3, 8-SCH3
103 n-butyl Ph- 6-OCH3, 7-OCH3, 8-OCH3
pre~is Cpd~ R1~R2 R5 (Rz)
q
(1~'f'F' . sa
. YYY)
F101.003 O1 n-pentyl Ph- 7-methyl
02 n-pentyl Ph- 7-ethyl
03 n-pentyl ph- 7-iso-propyl
04 n-pentyl ph- 7 -tent-butyl
05 n-pentyl ph- 7~g
06 n-pentyl ph- 7-OCH3
07 n-pentyl Ph- 7-0(iso-propyl)
08 n-pentyl ph- 7-SCH3
09 n-pentyl ph- 7-SOCH3
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n-pentyl Ph- 7-SO2CH3
11 n-pentyl Ph- 7-SCH2CH3
12 n-pentyl Ph- 7-NH2
13 n-pentyl ' Ph- 7-NHOH
14 n-pentyl Ph- 7-NHCH3
- 15 n-pentyl ph- 7-N(CH3)2
16 n-pentyl Ph- 7-N+ICH3)3, _-
17 n-pentyl Ph- 7-N'dC(-0)CH3
18 n-pentyl Ph- 7-N(CHZCH3)2
19 n-pentyl Ph- 7-NMeCH2COyH
n-pentyl Ph- 7-N'(Me)=CH2C02H, I-
- 2I n-pentyl Ph- 7-(N)-csorpho line
22 n-pentyl Ph- 7-(N)-azetidine
23 n-pentyl Ph- 7- (N) -N-methylazetidiniuri
I-
24 n-pentyl Ph- ,
7-(N)-pyrrolidine
n-pentyl Ph- 7-(N)-N-methyl-pyrrolidiniu.-z
I-
26 n-pentyl Ph- ,
7-(N)-N-:.-.ethyl-~orpholiaium,
I-
27 n-pentyl Ph- 7-(N)-N'-rethylpiperazine
28 n-pentyl Ph- 7- (at) -N' -dig ethylpiperaziniu.~,
I-
29 n-pentyl Ph- 7-:~~'=~HZ ..
n-pentyl Ph- 7-N C (0) C5::11
31 n-pentyl Ph- 7-:~'.-C (0) C::23r
32 n-peatyl Ph- 7-NH-C (:li:) Ni:2
33 n-pentyl Ph- 7-(2)-thiophene
34 n-pentyl Ph- 8-methyl
n-pentyl Ph- 8-ethyl
36 n-pentyl Ph- 8-iso-propyl
37 n-pentyl Ph- 8-tent-butyl
38 n-pentyl Ph- 8-OH
39 n-pentyl Ph- B-OCH3
n-pentyl Ph- 8-0(iso-propyl)
41 n-pentyl Ph- 8-SCH3
42 n-pentyl Ph- 8-SOCH3
43 n-pentyl Ph- 8-SOZCH3
44 n-pentyl Ph- 8-SCH2CH3
n-pentyl ph- 8-
46 n-pentyl Ph- 8-NHOH
47 n-pentyl Ph- 8-NHCHg
48 n-pentyl ph- 8-N(CH3)2
49 n-pentyl Ph- 8-N+(CH3) 3
I-
n-pentyl Ph- ,
8-NHC(-0)CH3
51 n-pentyl Ph- 8-N(CHyCH3)2
43
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52 n-pentyl Ph- 8-NMeCH2C02H
53 n-pentyl Ph- 8-N'(Me)2CH2C02H, I'
54 n-pentyl Ph- 8-(N)-morpholine
55 n-pentyl Ph- 8-(N)-azetidine
56 n-pentyl Ph- 8-(N)-N-methylazetidinium,
I'
57 n-pentyl Ph- 8-(N)-pyrrolidine
58 n-pentyl Ph- 8-(N)-N-methyl-pyrrolidiniu:a,
I'
5g n-pentyl Ph- 8-(N)-N-cethyl-morpholinium,
I'
60 n-pentyl Ph- 8-(N)-N'-methylpiperazine
61 n-pentyl Ph- 8-(N)-N'-dimethylpiperazinium,
I' '
62 n-pentyl Ph- 8-NH-CBZ
63 n-pentyl Ph- 8-NHC(0)CgHll
64 n-pentyl Ph- 8-NHC(0)CH2Br
65- n-pentyl Ph- 8-NH-C(NH)NH2
66 n-pentyl Ph- 8-(2)-thiophene
67 n-pentyl Ph- 9-~ethyl
68 n-pentyl Ph- 9-ethyl
69 n-pentyl Ph- 9-iso-propyl
70 n-gentyl Ph- 9-tent-butyl
7I n-pencyl Ph- 9-Of:
72 n-pentyl Ph- 9-OCH3
73 n-pentyl Ph- 9-0(iso-gropyl)
74 n-pentyl Ph- 9-SCH3
75 n-pencyl Ph- 9-SCCH3
76 n-pentyl Ph- 9-SC2CH3
77 n-pentyl Ph- 9-SCH2CH3
78 n-pentyl Ph- 9-NH2
79 n-pentyl Ph- 9-NHOH
80 n-pentyl Ph- 9-NHCH3
81 n-pentyl Ph- 9-N(CH3)2
82 n-pentyl Ph- 9-N+ (CH3) 3, I
83 n-pentyl Ph- 9-NHC(-O)CH3
84 n-pentyl Ph- 9-N(CH2CH3)2
85 n-pentyl Ph- 9-NMeCH2C02H
86 n-gentyl Ph- 9-N'(Me)~CH2C02H, I'
87 n-pentyl Ph- 9-(N)-morpholine
88 n-pentyl Ph- 9-(N)-azetidine
8g n-pentyl Ph- 9-(N)-N-methylazetidinium,
I'
90 n-pentyl Ph- 9-(N)-pyrrolidine .
9I n-pentyl Ph- 9-IN)-N-methyl-pyrrolidinium,
I'
92 n-pentyl Ph- 9-(N)-N-methyl-morpholinium,
I'
g3 n-pentyl Ph- 9-(N)-N'-methylpiperazine
g3 n-pentyl Ph- g-(N)-N'-dimethylpiperazinium,
I'
CA 02283575 1999-09-09
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95 n-pentyl Ph- 9-NH-CSZ
96 n-pentyl Ph- 9-NHC(O)CgHIl
97 n-pentyl 8h- 9-NHC(O)CH2Hr
98 n-pentyl Ph- 9-NH-C(NH)NH2
99 n-pentyl Ph- 9-(2)-thiophene
I00 n-pentyl ph- 7-OCH3, 8-OCH3
101 n-pentyl ph- 7-SCH3, 8-CCH3
102 n-pentyl Ph- 7-SCH3, 8-SCH3
103 n_Dentvl Ph- 6-OCH3, 7-OCH3, 8-OCH3
Pret3~c . Cpd~ R1~R2
(FFF . x~oc . vw)
F101.004 0I ~ n-hexyl Ph- 7-methyl
02 n-hexyl Ph- 7-ethyl
03 n-hexyl Ph- 7-iso-propyl
04 n-hexyl Ph- 7-te_~-butyl
OS n-hexyl Ph- 7-OH
06 n-hexyl Ph- 7-OCH3
07 n-hexyl Ph- 7-Ofiao-prooyl)~
. 08 n-hexyl P:1- 7-SC:?3
09. n-hexyl Ph- 7-SOCH3
IO n-hexyl Ph- 7-S02CH3
I1 n-hexyl Ph- 7-SCH2CH3
I2 n-hexyl ph_ ~-N1,2
13 n-hexyl Ph- 7-NHOH
14 n-hexyl Ph- 7-NHCH3
15 a-hexyl Ph- 7-N(CH3)2
16 n-hexyl Ph- 7_N+(CH3)
I-
I7 n-hexyl Ph- 3,
7-NHC(~0)CH3
18 n-hexyl Ph- 7-N(CHZCH3)2
19 n-hexyl Ph- 7-NMeCHZC02H
20 n-hexyl Ph- 7-N+(Me)ZCH2C02H, I-
21 n-hexyl Ph- 7-(N)-morpholine
22 n-hexyl Ph- 7-(N)-azetidine
23 n-hexyl Ph- 7-(N)-N-methylazetidinium
I'
24 n-hexyl Ph- ,
7-(N)-pyrrolidine
25 n-hexyl Ph- 7-(N)-N-methyl-pyrroliainium
I'
26 n-hexyl Ph- ,
7-(N)-N-methyl-morpholiniuta
I'
27 n-hexyl Ph- ,
7-(N)-N'-methylpiperazine
28 n-hexyl Ph- 7-(N)-N'-dimethylpiperazinium
I'
29 n-hexyl Ph- ,
7-NH-CSZ
30 n-hexyl Ph- 7-NHC(O)CgHll
$5
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31 n-hexyl ph- 7-NHC(O)CH28r
32 n-hexyl ph- 7-NH-C(NH)NH2
33 n-hexyi ph- 7-(2)-thiophene
34 n-hexyl Ph- 8-methyl
35 n-hexyl Ph- 8-ethyl
36 n-hexyl Ph- 8-iso-propyl
37 n-hexyl Ph- 8-tert-butyl
38 n-hexyl Ph- 8-OH
39 n-hexyl ph- 8-OCH3
40 n-hexyl ph- 8-0(iso-propyl)
41 n-hexyl Ph- 8-SCH3
.42 n-hexyl Ph- 8-SOCH3
43 n-hexyl Ph- 8-S02CH3
-
44 n-hexyl Ph- 8-SCH2CH3
45 n-hexyl Ph- 8-NH2
46 n-hexyl Ph- 8-Ne:OH
47 n-hexyl Ph- 8-NHC:?3
48 n-hexyl Ph- 8-N(CH3)2
4 n-hexyl p!~- 8 +~
9 -N. (CH3) 3, I' ..
50 n-hexy l Ph- 8-NHC(=O)CH3
51 n-he:cyl Ph- 8-N (CH2CH3) 2
52 n-hexyl Ph- 8-NMeC::2CO2H
53 n-hexyl Ph- g-N+(;~e)2CH2C02H, I-
54 n-hexyl Ph- 8-(N)-morpholine
55 n-hexyl Ph- 8-(N)-azetidine
56 n-hexyl Ph- 8-(N)-N-methylazetidiniuni, I-
57 n-hexyl Ph- 8-(N)-pyrrolidine
58 n-hexyi Ph- 8-(N)-N-methyl-pyrrolidiniurl, I'
59 n-hexyl Ph- 8-(N)-N-methyl-morpholiniur~, I'
60 n-hexyl Ph- 8-(N)-N'-methylpiperazine
61 n-hexyl Ph- 8-(N)-N'-dimethylpiperazinium, I-
62 n-hexyl Ph- 8-NH-CeZ
63 n-hexyl ph- ~ 8-NHC(0)C5H11
64 n-hexyl Ph- 8-NHC(0)CH28r
65 n-hexyl Ph- 8-NH-C(NH)NH2
66 n-hexyl Ph- 8-(2)-thiophene
67 n-hexyl Ph- 9 -methyl
68 n-hexyl Ph- 9-ethyl
69 n-hexyl Ph- 9-iso-propyl
70 n-hexyl ph- 9-tert-butyl
71 n-hexyl Ph- 9-OH
72 n-hexyl Ph- 9-OCH3
4- ~
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73 n-hexyl Ph- 9-O(iso-propyl)
74 n-hexyl Ph- 9-SCH3
~
_ 75 n-hexyl Ph- 9-SOCH3
76 n-hexyl Ph- 9-S02CH3
77 n-hexyl Ph- 9-SCH2CH3
- 78 n-hexyl Ph- 9-NH2
7g n-hexyl Ph- 9-NHOH
80 n-hexyl Ph- 9-NHCH3
81 n-hexyi Ph- 9-N(CH3)2
82 n-hexyl Ph- 9-N~(CH3)
3.
83 n-hexyl Ph- g-NHC(-O)CH3 _
84 n-hexyl Ph- 9-N(CH2CH3)2
85 _ a-hexyl Ph- 9-N.!eCH2C0yH
86 n-hexyl Ph- g-N*(Me)2CH2COZH, Z'
8? n-hexyl Ph- g-(N)-morpholine
88 n-hexyl Ph- 9-(N)-azetidine
89 n-hexyl Ph- g-(N)-N--ethylazetidiniura
I-
90 n-hexyl Ph- ,
9-(N)-py.=olidine
9I n-hexyl Ph- g- (;y) -N-methyl-py;=olidinit:~s
I'
92 n-hexyl Ph- ,
g- ~~t -N-r..ethyl-morpholiniu
-
93 n-hexyl Ph- .~~, I
g-(N)-N~-methylpiperazine
93 n-hexyl Ph- g-(N)-N~-di.Tethylpiperaziniu
~
I-
95 n-hexyl Ph- .
,
9-Ni:-C32
96 n-hexyl Ph- 9-NrC(0)CgHll
97 n-hexyl Ph- g-NHC (0) C::28r
98 n-hexyl Ph- 9-N::-C (N ) NH2
99 n-hexyl Ph- 9-(2)-thiophene
100 n-hexyl Ph- 7-OCv3, 8-OCH3
101 n-hexyl Ph- 7-SCH3, 8-OCH3
102 n-hexyl Ph- 7-SCH3, 8-SCH3
103 n-hexvl Ph- 6-OCH3, 7-CCH3, 8-OCH3
8refix Cpd$ R1=g2
fFfF.za. )
F101.005 O1 iso-propyl Ph- '7-methyl
02 iso-propyl Ph- 7-ethyl
03 iso-propyl Ph- 7-iso-propyl
04 iso-propyl Ph- 7-tert-butyl
05 iso-propyl Ph- 7-OFI
06 iso-propyl Ph- 7-OCH3
07 iso-propyl Ph- 7-O(iao-propyl)
08 iso-propyl Ph- 7-SCH3
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WO 98/40375 PCT/US98/03792
09 iso-propyl Ph- 7-SOCH3
iso-propyl Ph- 7-502CH3
il iso-propyl Ph- 7-SCH2CH3
I2 iso-propyl Ph- 7-NH2
13 iso-propyl Ph- 7-NHOH
14 iso-propyl Ph- 7-NHCH3
iso-propyl Ph- 7-N(CH3)2
16 iso-propyl Ph- 7-N+(CH3)3, Z
17 iso-propyl Ph- 7-NHC(~O)CH3
18 iso-propyl Ph- 7-N(CH2CH3)2
19 iso-propyl Ph- 7-NMeCH2C02H
iso-propyl Ph- 7-N*(Me)ZCH2C02H, Z'
21 iso-propyl Ph- 7-(N)-morpholine
22~ iso-propyl Ph- 7-(N)-azetidine
23 iso-propyl Ph- 7-(N)-N-aethylazetidiniu.-1,
I-
24 iso-propyl Ph- 7-(N)-pyrrolidine
iso-propyl Ph- 7-(N)-N-methyl-pyrrolidinium,
I'
26 iso-propyl Ph- 7-(N)-N-ethyl-marpholiniu.~.i,
I-
27 iso-propyl Ph- 7,(Nl-N'-~:ethylpiperazine
28 iso-propyl Ph- 7-*N7 -.1' -dimethylpipezaziniu.~a,
I'
29 iso-propyl Ph- 7-NH-C3Z
iso-propyl Ph- 7-NEC (0) C5~:11
31 iso-propyl Ph- 7-Ni:C (O) CHZBr
32 iso-propyl Ph- 7-NiT.-C (N:i) NH2
33 iso-propyl Ph- 7-(2) -t::iophene
34 iso-propyl Ph- 8-methyl
iso-propyl Ph- 8-ethyl
36 iso-propyl Ph- 8-iso-propyl
37 iso-propyl Ph- 8-tent-butyl
38 iso-propyl Ph- 8-OH
39 iso-propyl Ph- 8-0CH3
iso-propyl Ph- ~ 8-0(iso-propyl)
41 iso-propyl Ph- B-SCH3
42 iso-propyl Ph- 8-SOCH3
43 iso-propyl Ph- 8-S02CH3
44 iso-propyl Ph- 8-SCH2CH3
iso-propyl .Ph- 8-NH2
46 iso-propyl Ph- 8-NHOH
4? iso-propyl Ph- 8-NHCH3
48 iso-propyl Ph- 8-N(CH3)2
49 iso-propyl Ph- 8-N+(CH3)3, I'
iso-propyl Ph- 8-NHC(-O)CH3
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5i iso-propyl Ph- 8-N(CH2CH3)2
52 iso-propyl Ph- 8-NMeCH2C02H
53 iso-propyl Ph- 8-N'(Me)=CH2C02H, I-
54 iso-propyl Ph- 8-(N)-morpholine
55 iso-propyl Ph- 8-(N)-azetidine
- 56 iso-propyl Ph- 8-(N)-N-methylazetidinium
I-
57 iso-propyl Ph- ,
8-(N)-pyrrolidine
58 iso-propyl Ph- e-(N)-N-methyl-pyrrolidinium
I-
59 iso-propyl Ph- ,
8-(N)-N-methyl-morpholinium
I-
60 iso-propyl Ph- ,
8-(N)-N'-methylpiperazine
61 iso-propyl Ph- 8-(N)-N'-dimethylpiperazinium,
I'
62 iso-propyl Ph- 8-NH-CBZ
63 iso-propyl Ph- 8-NHC(0)C5H11
64 iso-propyl Ph- 8-NHC(0)CH28r
65 iso-propyl Ph- 8-NH-C(NH)NH2
66 iso-propyl Ph- 8-(2)-thiophene
67 iso-propyl Ph- 9-methyl
68 iso-propyl Ph- 9-ethyl
69 iso-propyl Ph- 9-is
o'-propyl
70 iso-propyl Ph- _
9-tert-butyl
71 iso-propyl Ph- 9-OH
72 iso-propyl Ph- 9-OCH3
73 iso-propyl Ph- 9-O(iso-propyl)
74 iso-propyl Ph- 9-SCH3
75 iso-propyl Ph- 9-SOCH3
76 iso-propyl Ph- 9-502CH3
77 iso-propyl Ph- 9-SCH2CH3
78 iso-propyl Ph- 9-NH2
79 iso-propyl Ph- 9-NHOH
80 iso-propyl Ph- 9-NHCH3
81 iso-propyl Ph- 9-N(CH3)2
82 iso-propyl Ph- g-N+(CH3)3, I-
83 iso-propyl Ph- 9-NHC(-O)CH3
84 iso-pzopyl Ph- 9-N(CH2CH3)2
85 iso-propyl Ph- 9-NMeCH2C02H
86 iso-propyl Ph- 9-N'(Me)1CH2C02H, I-
87 iso-propyl Ph- 9- (N) -rnorpholine
88 iso-propyl Ph- 9-(N)-azetidine
89 iso-propyl Ph- 9-tN)-N-methylazetidinium
I'
90 iso-propyl Ph- ,
9-tN)-pyrrolidine
91 iso-propyl Ph- g-tN)-N-methyl-pyrrolidinium,
I-
92 iso-propyl Ph- g-(N)-N-methyl-morpholinium,
I-
93 iso-propyl Ph- 9-(N)-N'-methylpiperazine
49
CA 02283575 1999-09-09
WO 98/40375 PGT/IJS98/03792
93 iso-propyl ph- 9-(N)-N'-diraethylp$iaiu
-
95 iso-propyl ph- m, I
9-NH-C82
96 iso-propyl ph- 9-NHC(0)C5H11
97 iso-propyl Ph- 9-NHC (O) C'rI2Br
98 iso-propyl Ph- 9-NH-CiNH)NH2
99 iso-propyl Ph- 9-f2)-thiopheae
100 iso-propyl Ph- 7-OCH3, 8-OCH3
101 iso-propyl ph- 7-SCH3, 8-OCH3
102 iso-propyl ph- 7-SCH3, 8-SCH3
103 iso-nroDVl Ph- 6-OCH3, 7-OCH3, 8-OCH3
8ret3s Cpd; R1=R2 R5 x
(R
(F'F'F . s~oc ) q
. )
F181. 00 6 iso-butyl Ph- 7-methyl
Ol
02 iso-butyl Ph- 7-ethyl
03 iso-butyl Ph- 7-iso-propyl
04 iso-butyl Ph- 7-tent-butyl
05 iso-butyl Ph- 7-0L
06 iso-butyl P::- 7-0CL3
.
07 iso-butyl Ph- 7-0(iso-propyl)
08 iso-butyl Ph- 7-SC33
Og iso-butyl Ph- 7-SOCa3
iso-butyl Ph- 7-502CH3
Il iso-butyl Pr.- 7-SCi~2Cag
12 iso-butyl p:~_ 7-NH2
13 iso-butyl Pr- 7-NHOH
14 iso-butyl Ph- 7-NHCH3
iso-butyl Ph- 7-N(CH3)2
16 iso-butyl Ph- 7-N+fCH
-
17 iso-butyl Ph- 3)3. I
7-
NHC(-O)CH3
i8 iso-butyl Ph- 7-N(CHZCH3)2
19 iso-butyl ph- 7-NMeCH2C02H
iso-butyl Ph- 7-N'(Me)=CH2C02H, I-
21 iso-butyl Ph- 7-(N)-morpholfne
22 iso-butyl Ph- 7-(N)-azetidine
23 iso-butyl Ph- 7-fN)-N-methylazetidiai
-
24 iso-butyl Ph- tua, I
7-(N)-pyrrolidine
iso-butyl Ph- 7-(N)-N-methyl-pyrrolidini
-
26 iso-butyl Ph- um, I
7-(N)-N-methyl-morpholiniu
I-
27 iso-butyl ph- ia,
7-(N)-N'-methylpiperazine
28 iso-butyl ph- 7-(N)-N'-dimethylpiperaziaium
I-
29 iso-butyl ph- ,
7-NH-C8Z
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
30 iso-butyl ph- 7-NHC(0)CSHii -
31 iso-butyl ph- 7-NHCIO)CH2Br
32 iso-butyl Ph- 7-NH-C(NH)NH2
33 iso-butyl Ph- 7-(2)-thiophene
34 iso-butyl ph- 8-methyl
35 iso-butyl ph- 8-ethyl
36 iso-butyl Ph- 8-iso-propyl
37 iso-butyl Ph- 8-tert-butyl
~ a ~,~yl ;P~~~ -8-Ai~-
39 iso-butyl ph- 8-OCH3
40 iso-butyl ph- 8-O(iso-propyl)
- 41 iso-butyl Ph- 8-SCH3
42 . iso-butyl ph- 8-SOCH3
43 iso-butyl Ph- 8-S02CH3
44 iso-butyl Ph- 8-SC::2CH3
45 iso-butyl Ph- 8-NH2
46 iso-butyl ph- 8-N'r'.OH
47 iso-butyl Ph- 8-NHCH3
48 iso-butyl ph- 8=N (C~i3 ) 2
49 iso-butyl ph_ 8-N+(CH3)3. I- ..
50 iso-butyl ph- 8-NFC(-0)CH3
51 iso-butyl Ph- 8-N(CH2Ci3)2
52 iso-butyl Ph- 8-NMec~:2co2H
53 iso-butyl Ph- 8-N'(Me)=CH2C02H, I-
54 iso-butyl Ph- 8-(N)-corpho line
55 iso-butyl Ph- 8-(N)-azetidine
56 iso-butyl Ph- 8-(N)-N-methylazetidinium,
I-
57 iso-butyl Ph- 8-(N)-pyrrolidine
58 iso-butyl Ph- 8-(N)-N-methyl-pyrrolidinium,
I-
59 iso-butyl Ph- 8-(N)-N-methyl-morpholiniu~,
I'
60 iso-butyl Ph- 8-(N)-N'-methylpiperazine
61 iso-butyl Ph- 8- (N) -N'-dirscthylpiperaziniuas,
I-
62 iso-butyl ph- -NH-CBZ
8
63 iso-butyl ph- 8-NHC(0)CgHil
64 iso-butyl ph- B-NHC(0)CH28r
65 iso-butyl ph- 8-NH-C(NH)NH2
66 iso-butyl Ph- 8-(2)-thiophene
67 iso-butyl Ph- 9-methyl
68 iso-butyl ph- 9-ethyl
69 isv-butyl Ph- 9-iso-propyl
70 iso-butyl Ph- 9-tort-butyl
71 iso-butyl Ph- 9-OH
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
72 iso-butyl Ph- 9-OCH3
73 iso-butyl Ph- 9-O(iso-propyl)
74 iso-butyl Ph- 9-SCH3
75 iso-butyl Ph- 9-SOCH3
76 iso-butyl Ph- 9-502CH3
?7 iso-butyl Ph- 9-SCH2CH3
78 iso-butyl Ph- 9-NH2
'
79 iso-butyl Ph- 9-NHOH
80 iso-butyl Ph- 9-NHCH3
81 iso-butyl ph- 9-N(CH3)2
82 iso-butyl Ph- g-N+(CH3)3, I'
83 iso-butyl Ph- 9-NHC(-0)CH3
84 iso-butyl Ph- 9-N(CH2CH3)2
85 iso-butyl Ph- 9-NMeCH2C02H
86 iso-butyl Ph- g-Ni(Ne)ZCH2C02H, I-
87 iso-butyl Ph- 9-(N)-r..orpholine
88 iso-butyl Ph- 9-(N)-azetidine
89 iso-butyl Ph- g-(N)-N-"tethylazetidiniu.-.1,
I'
90 iso-butyl Ph- g-(PL) -pyrrolidine
91 iso-butyl ph- g~'
-~EN) -N-methyl-pyrrolidiniu.~a,
I'
92 iso-butyl Ph- g-(N)-V-methyl-morpholiniu.-n,
I'
93 iso-butyl Ph- 9-(N)-N'-r..ethylpiperazine
93 iso-butyl Ph- g-(N)-N'-di.~ethylpiperazinium,
I'
95 iso-butyl Ph- g-NF:-G5Z
96 iso-butyl Ph- g-Ni:C (0) C5~T11
97 iso-butyl Ph- g-NFiC (0) CH2Hs
98 iso-butyl P::- 9-NE-C (NF:) NH2
99 iso-butyl Ph- 9-(2)-thiophene
100 iso-butyl Ph- 7-OCV3, 8-CCH3
101 iso-butyl Ph- 7-SCH3, 8-OCH3
102 iso-butyl ph- 7-SCH3, 8-SCH3
103 iso-butyl Ph- 6-OCH3, 7-OCH3, 8-OCH3
pretis Cpd~ R1=R2 RS (R=)
Q
_I~'~'S' . ~oo~
. 5~y1
F10 1.007 O1 iso-pentyl Ph- 7-methyl
~
02 iso-pentyl ph- 7-ethyl
03 iso-pentyl Ph- 7-iso-propyl
04 iso-pentyl ph- 7-tent-butyl
OS iso-pentyl Ph- 7-OH
06 iso-gentyl ph- 7-OCH3
07 iso-pentyl Ph- 7-0(iso-propyl)
CA 02283575 1999-09-09
WO 98/40375 PCT/tJS98/03792
08 iso-pentyl Ph- 7-SCH3
09 iao-pentyl ph- ?-SOCH3
isa-pentyl ph- 7-S02CH3
11 iso-pentyl ph- 7-SCHZCH3
12 iao-pentyl ph- 7-NH2
- 13 iso-pentyl ph- 7-NHOH
14 iso-pentyl ph- 7-NHCH3
iso-pentyl ph- 7-N(CH3)2
16 _-_iso-pentyl Ph- 7-ri~(.CH3.?~,-I- _
17 iso-pentyl ph- 7-NHC(~O)CH3
18 iso-pentyl Ph- 7-N(CH2CH3)2
19 iso-pentyl Ph- 7-N.!eCH2C02H
20- iso-pentyl Ph- 7-N'(Me)=CH2C02H, I-
21 iso-pentyl Ph- 7- (N) -:.-.orpholine
22 iao-pentyl Ph- 7-(N)-azetidine
23 iso-pentyl Ph- 7- (N) -N-r:ethylazetidiniurn, I-
24 iso-pentyl ph- 7-(N)-pyrrolidine
iso-pentyl P::- 7-(N)-N-methyl-pyrrolidiniu.-t
I'
26 iso-pentyl Ph- ,
7- (N) -N-met::yl-. :rorpholiniu.-1,
I-
27 iao-pentyl Ph- ?-(:4r-N'-r..ethylpiperazine
28 isa-pentyl Ph- 7- (N) -N'-d=.~ethvlpiperaziniu.~.i,
I-
29 iso-pentyl Ph- 7-Nri-C3Z
iso-pentyl Ph- 7-NHC(O)C5~11
31 i~o-pentyl Ph- 7-NEC(0)CHZHr
32 iso-pentyl Ph- 7-Ns-C(NH)N:i2
33 iso-pentyl Ph- 7-(2)-thiophene
34 iso-pentyl Ph- 8-r.,ethyl
iso-pentyl Ph- 8-ethyl
36 iso-pentyl Ph- 8-iso-propyl
37 iso-pentyl Ph- 8-ter;.-butyl
38 iso-pentyl Ph- 8-OH
39 iso-pentyl Ph- 8-OCH3
iso-pentyl Ph- 8-O(iso-propyl)
41 iso-pentyl ph- 8-SCH3
42 iao-pentyl Ph- 8-SOCH3
43 iso-pentyl ph- 8-S02CH3
44 iso-pentyl Ph- 8-SCH2CH3
iso-pentyl Ph- 8-NH2
46 iso-pentyl Ph- 8-NHOH
47 iso-pentyl Ph- 8-NHCH3
48 iso-pentyl Ph- 8-N(CH3)2
49 iso-pentyl ph- 8-N+(CH3) 3, I-
53
CA 02283575 1999-09-09
WO 98/40375 PCT/I1S98/03792
50 iso-pentyl Ph- 8-NHC(-O)CH3
51 iso-pentyl Ph- 8-N(CH2Cx3)2
52 iso-pentyl Ph- 8-NMeCH2C02H
53 iso-pentyl Ph- 8-N'(Me)=CH2C02H, I'
54 iso-pentyl Ph- 8-(N)-morpholine
55 iso-pentyl Ph- 8-(N)-azetidine
56 iso-pentyl Ph- 8-(N)-N-methylazetidinium
I'
57 iso-pentyl Ph- ,
8-(N)-pyrrolidine
58 iso-pentyl Ph- 8-(N)-N-methyl-p,~rrolidinium,-I-
- ~-
$~ s =pentyl Ph- 8-(N)-N-methyl-morpholinium
I'
60 iso-pentyl Ph- ,
8-(N)-N'-methylpiperazine
61 iso-pentyl Ph- 8-(N)-N'-dimethylpiperaziniurs
I'
62 iso-pentyl Ph- ,
8-Nx-C8Z
63 iso-pentyl Ph- 8-NHC(0)CgHll
.
64 iso-pentyl Ph- 8-NHC(0)CH29r
65 iso-pentyl Ph- 8-N::-C (NH) NH2
66 iso-pentyl Ph- 8-(2)-thiophene
67 iso-pentyl Ph- 9--Methyl
68 iso-pentyl Ph- 9-e~hyl
69 iso-pentyl Ph- 9-iso-propyl
70 iso = 9-tent-butyl
pentyl Ph-
71 iso-pentyl Ph- g-OH
72 3so-pentyl Ph- 9-OCH3
73 iso-pentyl Ph- 9-0(isa-propyl)
74 iso-pentyl Ph- 9-SCx3
75 iso-pentyl Ph- g-SOCH3
76 iso-pentyl Ph- 9-S02CH3
77 iso-pentyl Ph- 9-SCH2CH3
78 iso-pentyl Ph- 9-NH2
79 iso-pentyl Ph- 9-NHOH
80 iso-pentyl Ph- 9-NHCH3
81 iso-pentyl Ph- 9-N(CH3)2
82 iso-pentyl Ph- 9-N+(CH3)3
I-
83 iso-pentyl Ph- .
9-NHC(-0)CH3
84 iso-pentyl Ph- 9-N(CHZCH3)2
85 iso-pentyl Ph- 9-NMeCH2C02H
86 iso-pentyl Ph- 9-N'(Me)2CHZC02H, I'
87 iso-pentyl Ph- 9-(N)-morpholine
88 iso-pentyl Ph- 9-(N)-azetidine
8 9 iso-pentyl Ph- 9- (N) -N-~thylazetidinium
I'
90 iso-pentyl Ph- , _
9-(N)-pyrrolidine
91 iso-pentyl Ph- g-(N)-N-methyl-pyrrolidinium,
I'
92 iso-pentyl Ph- g-(N)-N-methyl-morpholinium
I'
,
~J ~'
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
93 iso-pentyl Ph- 9-(N)-N'-methylpie
93 iso-pentyl Ph- g_(N)_N'-dimethylpiperazini
-
95 iso-pentyl Ph-. um, I
9-NH-C8Z
96 iso-pentyl Ph- 9-NHC(C)C;HlI
97 iso-pentyl Ph- 9-NHC(C)CH28r
98 iso-pentyl Ph- 9-NH-C(NH)NH2
99 iso-pentyl Ph- 9-(2)-thiophene
IO_0 _ iso-pentyl Ph- 7_OCx~B~CH_~
_
~
101 iso-pentyl Ph- 7-SCH3, 8-CCH3
102 iso-pentyl Ph- 7-SCH3, 8-SCH3
I03 iso-oeatvl Ph- 6-OCH3, ?-OCH3, 8-OCH3
8re~iz Cpd~ R1~R2 RS (Rx)
'
'
q
F
F.me. wy)
_(F
r 101. 008 OI CHZC (=O) C=H;Ph- ?-methyl
02 CH=Ct-OJCZHS Ph- ?-ethyl
03 CH2C(-0)C=H; Ph- ?-iso-prooyl
04 CHIC(=0)CIH; Ph- ?-pert-butyl
'
os cH2c (-o) c2H;ph_ ?~,.
os cHZC t-o) c2x;Ph- ?-acJ3
07 CHIC(-0)C2H; Ph- ?-O(iso-psopyl)
08 CHZC(-O)CZH; Ph- ?-SCH3
09 CH2C (-0) C=H;ph- 7-SCCH3
IO CH=C (=O) CZH;Ph- ?-S02Ci?3
Il cH2c(=o)c=H; Ph- ?-scH2cH3
I2 CH2C(=O)CZHS Ph- ?-NH2
13 CsZC(=o)CZH; Ph- ?-NHOH
14 CHIC (=O) C2H;Ph- 7-NHCH3
IS CHIC(=O)CZHS Ph- ?-N(CH3)2
16 cxZc(=o)c=H; Ph- ?-N+tcH3)
I-
17 cH=c (=o) czHSPh- 3,
7-NHC (=o) cH3
18 CH2C (-O) C=H;Ph- 7-N (CH2CH3) 2
19 CHIC(-O)C=H5 ph- 7-NMeCH2C02H
20 CHIC (=O) CZH;Ph- 7-Na (~!e) 2CH2C02H, I'
21 CHZC(-O)C=Hg Ph- 7-(N)-morpholine
22 CHIC(-O)CIHS Ph- 7-(N)-azetidine
23 CH2C(-O)CIHS Ph- 7-(N)-N-caethylazetidinium,
I-
24 CHIC(=O)CZHS Ph- 7-(N)-pyrrolidine
25 CH=C(-O)CIHS Ph- ?-(N)_N-methyl-pyrrolid3nium
I'
26 CHZC(-O)C=HS Ph- ,
7-(N)-N-methyl-morpholiniurn,
I'
27 CHIC (=O) CZH;Ph- 7- (N) -N' -ctethylpiperazine
28 CH2C(-O)CIHS Ph- 7-(N)-N'-d~ethylpiperazinium,
I-
CA 02283575 1999-09-09
WO 98140375 PGTNS98/03792
29 CHIC(-O)CZHs Ph- 7-NH-C3Z
30 CH=C(-O)C=HS Ph- 7-NHC(0)C5H11
31 CHIC(-O)CZHg Ph- 7-NHC{0)CH2Br
32 CHIC(-O)C=HS Ph- 7-NH-C{NH)NH2
33 CH=C (-O) C=Hg ph- 7- (2 ) -thiophene
34 CH=C(D)C=Hg Ph- 8-methyl
35 CH2C(-O)C=Hg ph- 8-ethyl
3 6 CHZC(-O)CZHS ph- 8-ino-propyl_
37 CHI C 8-tcrt-butyl
(=O)C=Hg Ph-
38 cHZC(=o)C=HS Ph- 8-off
_
39 CHIC(-O)C=H5 Ph- 8-OCH3
40 CHIC(=O)CZHS Ph- 8-a{iao-propyl)
41 CH=C(-O)C=H3 h- 8-SCH3
P
42 CHIC(=O)C=HS Ph- 8-SOCH3
43 CvZC{=O)CZHg Ph- 8-so2cx3
44 C'c:ZC (=O) Ph- 8-SCH2CH3
ClHg
45 C:?ZC (=O) C2 Ph- 8-NH2
H3
46 CH=C {-O) C2H5 ph- 8-IJHOH
47 CiiZC (-O) CZH;Ph- 8=~~t'r,:CH3
48 C:iZC (-O) C=H5Ph- 8-:1 (Cag) Z
49 CHyC{=O)C=HS Ph- g-N+(Cs3)
I'
50 CH=C (=O) C=HS Ph- 3,
8-Ni:C (=O) CH3
51 CHZC(-O)C=Hs Ph- 8-N(CHZCH3)2
52 CHIC (=0) C2H; Ph- 8 :'~1:!eC::ZC02H
53 CHIC{-O)CZHS Ph- 8-N'(Ne)=CH2C02H, I-
54 CH=C(-O)C=Hg Ph- 8-{N)-morpholine
55 CHIC(=O)CZH3 Ph- 8-(N)-azetidine
56 Ci:~C (=O) C1H5Ph- 8- {N) -N-methylazetidinium
I'
57 Cli=C (=0) C=HgPh- ,
8- {N) -pyr rolidine
58 CH=C{=O)CZHg Ph- 8-(N)-N-methyl-pyrrolidinium,
I-
59 CHZC(-0)CZHg Ph- 8-(N)-N-methyl-morpholinium,
I-
60 CHIC(=O)C=H3 Ph- 8-(N)-N~-methylpiperazine
61 CHIC {=O) C=Hg Ph- 8- (N) -N' -dimethylpiperazinitua,
I'
62 CHIC(=O)CZHB Ph- 8-NH-C8Z
63 CH=C(=O)C=Hg Ph- 8-NHC(O)C5H11
64 CHIC{=0)CZHS Ph- 8-NHC(0)CHZer
65 CHIC (=0) CZHS ' Ph- 8-NH-C {NH) NH2
66 CHIC (-O) CZHS Ph- 8- (2) -thiophene
67 CH=C(=O)C=HS Ph- 9-methyl
58 CH=C(=C)CZHS Ph- 9-ethyl
69 CHZC(-O)CIHS Ph- 9-iso-propyl
~6
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
?0 cH~c(=O)C=HS ph- 9-tert-butyl
71 cH=c(-o)czHS Ph- 9-off
72 CH=C(-O)CZHS ph- 9-OCH3
?3 CHIC(-O)CZHj ph- 9-O(iso-propyl)
?4 CH=C(=O)CZH~ ph- 9-SCH3
75 CHIC(-O)CZH3 Ph- 9-SOCH3
? 6 CHIC (=O) CZHg Ph- 9-502CH3
?7 cHic(=o)ciHS ph- 9-5cH2cH3
78 CH=c (-oI C=HS ph-
?9~ __-CH=C (=0.).CZi,F~__gh_ -~NHOH-_
80 cHZC(-o)c2H5 ph- g-NHCH3
81 CHIC(=O)CZHS Ph- 9-N(CH3)2
82 CHIC(-0)C=H3 Ph- 9-N+(CH
3)3,
83 CHIC(=0)C=H5 ph- 9-N
HC(=O)CH3
84 cHZc(=o)cZHS Ph- 9-N(cH2cH3)Z
85 cHZc (=o) cZHS Ph- g .~rr:ecH2CO2x
86 CHIC(=0)CIHq Ph- 9-N'(Me)~Ca2C02H, I-
87 CH2C (=O) CZH3 ph- 9- (N) -..~aorpholine
88 CHIC(=O)CZHg Ph- g-fR)-azetidine
89 CH2C (=O) C2H5 Ph- 9- ~~~ :.N-r.,ethylaietidiniur
-
90 CH=C(=O)CZHS Ph- i, I
9-(N)-py_rolidine
. 91 CH2C (-0) C=H5 Ph- 9- (N) -N-aethyl-PYrrolidini
-
92 CH=C (=0) CIH; Ph- ura, I
g- (N) -N-methyl-mo~holiai
I-
93 CHIC(=O)C=H~ Ph- u~,
9-(N)-N'-methylpigerazine
93 CHIC (=0) C=H: ph- g-(N) -N-dy~ethylpiperaziniu
-
95 cxZC(=o)c2H~ Ph- ri, I
9-NH-Caz
96 CHIC(=0)C=H5 Ph- 9-NHC(0)C5HI1
97 CHIC (=0) CZ Ph- g-N::C (0) CHZar
Hg
g8 CHIC (=0) CzHS Ph- 9-NH-C (NH) NH2
cH~c (=0) CZ ph- g- (2 ) -thiophene
HS
100 CH=C(=0)CZHS ph- 7-OCH3, 8-OCH3
i01 cHzc(=o)czHS Ph- ~-5cH3, 8-ocH3
102 CHIC(=O)C=HS Ph- 7-5CH3, 8-5CH3
103 cHlc (-o) c ph- s-ccH3, ~-ccH3, e-ocH3
Hs
Cpd# RhR2 R5 ~
~R
~ q
FIOI
009 O1
. CHIOC1H5 Ph- 7-methyl
02 cH2oc=HS Ph- 7-ethyl
03 cH~ocZHS ph- 7-iso-propyl .
04 CHIOCZHS ph- ?-tert-butyl
J~
CA 02283575 1999-09-09
WO 98/40375 PCT/US98103792
05 CH=OCIxs Ph- 7-off
06 CH=OC=H5 Ph- 7-ocH3
07 CHZOC~Hg Ph- 7-O(iso-propyl)
08 CHZOCZHS Ph- 7-SCH3
09 CHZOCZHS Ph- 7-SOCH3
to cH~ac=Hg Ph- 7-S02CH3
11 cHZ0cIH5 Ph- 7-5cH2CH3
12 CHZOCZHS Ph- 7-NH2
_-
I3 CHZOCZHg Ph- 7-NHOH
14 CH=OC=HS Ph- 7-N'riCH3
15 CH~OC=HS Ph- 7-N(CH3)2
16 CH2oczH5 Ph- 7-N+(cH3)3, __
17 cHZOC=H5 Ph- 7-NHC(-o)cH3
.
18 CHIOCZHS Ph- 7-N(CH2CH3)2
is CHZOCZHS Ph- 7-N:feCH2C02H
20 CHZOCIHS Ph- 7-N* (We) ZC:i2C02H, I-
21 CHZOCZHg Ph- 7-(N)-morpholine
22 CH20CIH5 Ph- 7-(N)-azeti~.i.ne
23 CHZOCZHS Ph- 7- (~1) =N-methylazetidiniu.~a,
I'
24 CH=OCZH3 Ph- 7-(N)-pyrrolidine
25 CHZOCIHS Ph- 7-(N)-N-methyl-PYrrolidinit:.~n,
I'
26 C~i=OCIHS Ph- 7-(N)-N-methyl-morpholiniu.~n,
I'
27 CHIOCZHg Ph- 7-(N)-N'-~ethylpiperazine
28 CH=OCZHS Ph- 7- (N) -N -~~ethylpiperazini~~a,
I'
29 CHZOC=H5 Ph- 7-NH-C3Z
30 CF:=OCZHS Ph- 7-NHC(0)CgHlI
31 Ca20C~Hg Ph- ?-NHC(0)CH23r
32 Ca~OCZHS Ph- 7-NH-C(NH)NH2
33 CHZOCZH3 Ph- 7-(2)-thiophene
34 CHZOCZHS Ph- 8-methyl
35 CH=OC=Hg Ph- 8-ethyl
.
36 CH=0C=HS Ph- 8-iso-propyl
37 CHZOC~HS Ph- 8-tert-butyl
38 CH=OCZHS Ph- 8-OH
39 CHZOCZHg Ph- 8-OCH3 .
40 Cx~oCZHS Ph- 8-O(iso-propyl)
41 CH20C=H5 Ph- 8-SCH3
42 CH~OC2Hg ph- 8-SOCHg
43 CH=OCZHS Ph- 8-502CH3
44 CHZOC=HS Ph- 8-SCH2CH3
45 CHIOC=Hg Ph- 8-N~t2
46 CH=OC=Hg Ph- 8-NHOH
58
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
47 CHZOC~HS ph- 8-NHCH3
48 CHZOC=HS ph- 8-N(CH3)2
49 CHZOC=HS Ph- 8-Nf(CH3)3, I-
50 CH=OCZHS Ph- 8-NHC(-O)CH3
51 CH=OC=HS ph- 8-N(CH2CH3)2
52 cH2ocZHS ph- e-NMecH2co2H
53 CH=OC=HS Ph- 8-N'(Me)~CHZC02H, I-
54 CH~OCIHS ph- 8-(N)-aorpholine
55 CH=OCIHg Ph- 8-(N)-azetidine
_ _
56 CH=OCZHS __ _ _
Ph- 8-(N)-N-methylazetidinium
I-
57 CH20CZH5 ph- ,
8-(N)-pyrrolid.ine
58 CHZOCZHS ph- 8-(N)-N-r..ethyl-pyrrolidiniuca
I-
59 CH=OC2H5 Ph- ,
8-(N)-N-saethyl-morpholiniuia,
I-
60 - CHZOC=HS Ph- 8-(N)-N'-methylpiperazine
61 CH2OCIH5 Ph- 8-(N)-N'-dimethylpperaziniu.-a,
Z-
62 CHZOCZHS Ph- 8-NH-C3Z
63 CH=OCZHS ph- 8-N:~C (O) C5H11
64 CHZOC2H5 Ph- a-NHC (0) C::ZBr
65 CH=OC2H5 Ph- 8-NL'-C (N ) NeI2
66 CH20CZH5 Ph- 8-(2)--thioohene
67 CH20C2H5 Ph- 9-s:ethvl
68 C.T-IZOC2Hg P::- 9-ethyl
69 CHIOC=H5 Ph- 9-iso-propyl
70 CH20CZHg Ph- 9-tent-bLLyl
71 CHZOCZHS Ph- 9-OH
72 CH=OCZHS Ph- 9-OCj3
73 CH20C=HS Ph- 9-0(iso-propyl)
74 CHZOCZHS Ph- 9-SCHg
75 CHZOCZHg Ph- 9-SOCH3
76 CH=OC=HS Ph- 9-so2cH3
77 CHIOCZHS Ph- 9-SCH2CH3
78 CHZOC=HS Ph- 9-NHZ
79 CHZOC=H5 ph- 9-NHOH
80 CHZOC=HS Ph- 9-NHCH3
81 CH=OCZHg Ph- 9-N(CH3)2
82 CH=OC2Hg Ph- 9-N+(CH3)3, I-
- B3 CH20C=HS ph- 9-NHC(0)CH3
84 cHZOCZHS ph- 9-N(cH2cH3)2
85 . CH=OC=HS ph- 9-NMeCH2C02H
86 CH=OC=HS ph- 9-N' (Me) =CH2C02H, I- .
87 CHIOCZHS Ph- 9-(N)-morpholine
Sg
CA 02283575 1999-09-09
WO 98/40375 PCTNS98/03792
88 cHSOC=H; Ph- 9-(N)-azetidine
89 CHIOCZHS Ph- g-(N)-N-r..ethylazetidinium,
I'
90 CH~OCZHg Ph- 9-(N)-pyrrolidine
91 CHZOCZHS Ph- 9-(N)-N-aethyl-pyrrolidiniura,
I-
92 CH~OCZHS Ph- 9-(N)-N-methyl-morpholiniurs,
Z-
93 CHIOC=H; Ph- 9-(N)-N'-methylpiperazine
93 CH=OCZH; Ph- g-(N)-N'-dimethylpiperazinium,
I'
95 CHIOC=H; Ph- 9-NH-CBZ
_~g~.... _.Cx=OCZHS _.P.h_ ..9-NHC-(OrCgiill
_
97 cHiociH; Ph- 9-NHC(o)cH2sr
98 cH~oc=Hs Ph- 9-NH-C(NH)NH2
' 99 CH20CyH; Ph- 9-(2)-thiophene
100 CH20C1H; Ph- 7-OCHg, 8-OCH3
101 CH~OC=H; Ph- 7-SCH3, 8-0CH3
i02 CHZOC2H; Ph- 7-SCH3, 8-SCH3
103 CH20CZH5 Ph- 6-0C::3, 7-OCH3, 8-OCH3
Pre=is Cpd'~ R1.R2 RS (R=~~ .
_SF'~'.sa.
wv)
FIO 1. 0 IO C'ZCa (OH) C2H;Ph- 7-:.~,ethyl
O1
02 CHZCH(OH)CZH; Ph- 7-ethyl
03 CH=CH(OH)C=H; Ph- 7-iso-propyl
04 CHlCa(OH)CZH; Pa- 7-tent-butyl
05 CHZCH(OH)C=H; Ph- 7-OH
06 CH=CH (OH) C=H;Ph- 7-OCF:3
07 C:iICH (OH) Ph- 7-0 (i3o-propyl)
CIH;
08 CVZCH(OH)CZH; Ph- 7-SCH3
09 CH=CH(OH)CZH; Ph- 7-SOCH3
CHZCH (OH) CZH;Ph- 7-S02CF:3
11 CH~CH(OH)C=H; Ph- 7-SCH2CH3
12 CHZCH(OH)CZH; Ph- 7-NH2
13 CH=CH(OH)CZH; Ph- 7-NHOH
14 CHICH(OH)CZHS Ph- 7-NHCH3
CH=CH(OH)C=H; Ph- 7-N(CH3)2
i6 cH~cx tax) ciHSPh- ~-N+ (cH3 ) 3, I-
17 CHZCH(OH)CZH; Ph- ~-NHC(-o)cH3
18 CH=CH(OH)C~HS Ph- 7-N(cH2cH3)2
19 CHZCH(OH)C=HS Ph- 7-NMeCHzC02H
CH=CH(OH)C2H5 Ph- 7-N'(Me)~cH2CO2H, I-
21 CH=CH(OH)CZH; Ph- 7-(N)-morpholine
22 cHZCx(oH)c=HS Ph- 7-(N)-azetidine
d
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
23 CH=CH (OH) CZHS8h- 7- (N) -N-rethylaze~un,
24 CH=CH(OH)CIHS Bh- 7-(N)-pyrrolidine
25 CH=CH(OH)C=HS Ph- 7-(N)-N-methyl-pyrrolidiaium,
I'
- 26 CHICH(OH)C=HS Ph- 7-(N)-N-methyl-morpholiniu.-n,
I-
27 CHZCH(OH)C=HS Ph- 7-(N)-N'-methylpiperaziae
_ 28 CHZCH (OH) C=HgPh- ?- (N) -N' -ditnethylpiperaziniu.~n,
I'
29 CH2CH (OH) C=H5Ph- 7-Nii-CHz
30 CHICH (OH) C=HsPh- 7-NFiC (0) CSHll
31 CH2CH(OH)C=Hg Ph- 7-NHC(0)CH2Hr
~~_.- _ --CHiCH ___Ph_-7=NH-C-(NH) NF~2 -
(OH)~CzHS _.._ _
-
.33 CH=CH (OH) CyHSPh- 7- (2) -thiophene
34 CHZCH(OH)CZHS Ph- 8-methyl
35 - CH=CH(OH)C=HS Ph- 8-ethyl
36 CH=CH(OH)CZHS Ph- 8-iso-propyl
37 CHZC:i(OH)C=H3 Ph- 8-ter:-butyl
38 cxzc~:(OH)C=H3 Ph- 8-off
39 GH2C:i (OH) Ph- 8-OC3g
CZHS
40 C::ZC.'-'.(OH)CZHSPh- 9-fl.(~so-propyl)
41 G:?=CH (OH) Ph- 8-Si.:i3
C=H3
42 cH=G::(oH)czs~ Ph- 8-sacx3
43 C::ICa (OH) Ph- 8-S02C:i3
C=H5
44 C:i2C (OH) CZHSPh- 8-SCHZC:i3
45 CHZC::(OH)CZH~ Ph- B-NH2
46 CH2CH(OH)CZHS Ph- 8-NHOH
47 CH=C::(OH)C=H~ Ph- 8-NHCH3
48 CuZCa(OH)CZH3 Ph- 8-N(GH3)2
49 CJZCi: (OH) Ph- 8-N'~' (Cii3) 3, I-
C=H3
50 C::ZC:( (OH) Ph- 8-NF~C (~0) CH3
C2H3
51 C::=C:: (OH) Ph- 8-N (CH2CH3) 2
CZHS
52 CF:=CH (OH) Ph- 8-NMeCii2C02H
C~HS
53 CH=CH(OH)C=Hg Ph- 8-N'(Me)ICHZC02H, I-
54 CH2CH(OH)CZHS Ph- 8-(N)-morpholine
55 CHICH(OH)C1H5 Ph- 8-(N)-azetidine
56 CHZCH(OH)CZHS Ph- 8-(N)-N-methylazetidiniuas,
I-
57 CHICH(OH)CIHS Ph- 8-(N)-pyrrolidiae
58 CH=CH(OH)C=HS Ph- 8-(N)-N-methyl-pyrrolidinium,
I'
59 CH2CH (OH) CIHSPh- 8- (N) -N-methyl-saorpholini~,ua,
I-
60 CHZCH(OH)CZHS ph- 8-(N)-N'-methylpiperaziae
61 CHiCH(OH)C=HS Ph- 8-(N)-N'-dimethylpiperazinium,
I-
- 62 cx2cH(oH)C=HS Ph- a-NH-CHz
63 CHZCHiOH)CIHg Ph- 8-NHC(0)C5H11
64 CH=CH(OH)C=HS Ph- 8-NHC(0)CH2Hr
CA 02283575 1999-09-09
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65 CH=CH(OH)C=H; ph- 8-NH-C(NH)NH2
66 CH=CH(OH)C=HS Ph- 8-(2)-thiophene
67 , CHZCH(OH)CZHSph- 9-methyl
68 CHZCH(OH)CIH; ph- 9-ethyl
69 CHICH(OH)C=H; ph- 9-iso-propyl
70 CH=CH(OH)CIH; Ph- 9-tent-butyl
71 CH=CH(OH)C=H; ph- g-OH
72 _._ __ ~x2cH ph- _g-__ac~3____
c_ox) cix;
73 CH2CH(OH)C=H5 Ph- 9-0(iso-propyl)
74 CH=CH(OH)CZHS Ph- 9-SCH3
75 CHZCH(OH)CIH; Ph- 9-sOCH3
76 CHICH (OH) CZHSPh- 9-sO2CH3
77 CH~CH(OH)C2H3 Ph- 9-sCH2CH3
78 CHZCH (OH) C2H5Ph- 9-NH2
79 CsZCH (OH) CZH;Ph- 9-NHOH
80 CH2CH (OH) C2H;Ph- 9-NHCi3
81 CF:ICT. (OH) Ph- 9-N (C::3) 2
CZH;
82 C'.-:ZCH (oH) ph- g-N(C,3) 3, r
Cih;
83 CH2CH (OH) CI::;Ph- 9-Nc~.'C'(-O) CH3 ..
84 CvZC~ (OH) C= Ph- 9-N (CsZCu3) Z
;
85 Cz=C:: (Ox) Ph- 9-~1:~!eC.'-2COZH
CZc;
86 Cs2CH (OH) CZeT.~Ph- 9-Nf (Me) =Cs2C02F:, I-
87 C::ZCH (OH) Ph- 9-!N) -morpholine
C=Fr;
88 CHZCH (OH) CZi~;Ph- 9- (N) -azetidine
89 CH=CH (OH) CZr;Ph- 9-!N) -N-methylazetidiaii..m,
I-
90 Cs2C: (OH) CZi!;Ph- g- (N) -pyrrolidine
91 CHZCHlOH)CZH; Ph- g-(N)-N-methyl-pyrrolidinium,
Z-
92 CHZCF! (OH) Ph- g-(N) -N-methyl-morpholinium,
CIF:; Z-
93 CHZCH (OH) CZH;Ph- 9- (N) -N~ -methylpiperazine
93 CH=CH(OH)C=H; Ph- 9-(N)-N'-dimethylpiperazinium,
I-
95 CHZCH(oH)CZH; Ph- g-NH-CaZ
.
96 CHZCH(OH)CZH: Ph- 9-NHC(O)CgHll
97 CH~CH(oH)CZHS Ph- 9-NHC(0)CH29r
98 CHICH(OH)CZH; ph- 9-NH-C(NH)NH2
99 CH=CH(OH)ClHg ph- 9-(2)-thiophene
I00 CH=CH(OH)CIH; P h- 7-OCH3, 8-OCH3
ioi cH2cx(oH)c=H; ph- 7-scH3, 8-ccH3
102 CHICH(OH)C=H5 Ph- 7-SCH3, 8-SCH3
103 CHZCH(oH)cZHS Ph- 6-OCH3, 7-OCH3, 8-OCH3
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Bret3s Cpd~ R1~R2 Rs (Rx)
Q
(FF'F . r~ . YYY)
F101.011 01 CHZO-(4-picoline)ph- 7-methyl
02 CH20-(4-picoline)Ph- 7-ethyl
03 CH10-(4-picoline)ph- 7-iso-propyl
04 CH=O-(4-picoline)Ph- 7-tent-butyl
OS CH=0-(4-picoline)ph- 7-OH
06 CHZO-(4-picoline)ph- '7-OCH3 ,
-QT- -CHZO= C4-picTine)_.ph-?-O ( so-propyl)
08 CH=0-(4-picoline)Ph- 7-SCH3
09 CH=0-(4-picoline)Ph- 7-SOCH3
~i0 CHZO-(4-picoline)Ph- 7-S02CH3
11 . CHZO-(4-picoline)Ph- 7-SCH2CH3
12 CH10-(4-picaline)ph- 7-Nv2
13 CH20-(4-picoline)Ph- 7-NHOH
14 CH20- ( 4-picoline)Ph- 7-Ni:CH3
15 CHZO-(4-picoline)Ph- 7-N(CH3)2
16 CHZO- ( 4-picoline)Ph- 7-~t (~H3 ) 3
.
17 CHID- I4-picoline)Ph- 7-.~fie (-O) CH3 ..
18 CHZO-(4-picoline)Ph- 7-N(CH2Cs3)2
19 CH20- ( 4-picoline)Ph- ?-N.:eC~:2C02H
20 CHzO- ( 4-picoline)Ph- 7-N' (::e) ~C::2C02H, I-
21 CHID- (4-picoline)P::- 7- (N) -morpholine
22 CHZO-(4-picoline)Ph- ?-(N)-azetidiae
23 CHZO-(4-picoline)Ph- 7-(N)-N-Tethylazetidinium, I-
24 CHZO-(4-picoline)ph- 7-(N)-pyrrolidine
25 CH=0-(4-picoline)Ph- 7-(N)-N-methyl-pyrrolidiniu.-z,
I'
26 CH20-(4-picoline)Ph- 7-(N)-N-methyl-morpholinium, I-
27 CHZO-(4-picoline)ph- 7-(N)-N'-methylpiperazine
Z8 CH10- ( 4-picoline)Ph- 7- (N) -N' -dir.:ethylpiperazinima,
I'
29 CH~O-(4-pieoline)Ph- 7-NH-CSZ
30 CH10-(4-picoline)Ph- 7-NHC(O)CgHll
31 CH=O-(4-picoline)Ph- 7-NHC(O)CH28r
32 CH=O-(4-picoline)Ph- 7-NH-C(NH)NH2
33 CH=O-(4-picoline)Ph- 7-(2)-thiophene
34 CHZO-(4-picoliae)Ph- 8-methyl
35 CH=O-(4-picoline)Ph- 8-ethyl
36 CHZO-(4-picoline)Ph- 8-iso-propyl
- 37 CHZO-(4-picoline)Ph- 8-tent-butyl
38 CHZO-(4-picoline)Ph- 8-OH
39 CH=O-(4-picoline)Ph- 8-OCH3
~3
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
40 CH=O-(4-picoline)Ph- 8=0(iao-propyl)
41 CHZO-(4-picoline)Ph- 8-SCH3
42 CH10-(4-picoline)Ph- 8-SOCH3
43 CH=O-(4-picoline)Ph- 8-S02CH3
44 CHZO-I4-picoline)Ph- 8-SCH2CH3
45 CH20-(4-picoline)Ph- 8-NHZ
46 CHZO-(4-picoline)Ph- 8-NHOH
47 CH=O-(4-picoline)Ph- 8-NECH3
48 CHZO-(4-picoline)Ph- 8-N(CH3)2
49 CH=O-(4-picoline)Ph- g-N+;CH3)3, I-
50 CH=0-(4-picoline)Ph- 8-NHC(-O)CH3
51 CHZO- ( 4-picoline)Ph- 8-N (CH2C:13 ) 2
52 CH=O-(4-picoline)Ph- 8-NMeCH2CO2H
.
53 CH20-(4-picoline)Ph- 8-N'(Me)2CH2C02H, I-
54 CHZO- ( 4-picoline)Ph- g- (N) -no ~holine
55 CHZO-(4-picoline)Ph- 8-(N)-azetidine
56 CH=O-(4-picoline)Ph- g-(N)-N-~ethylazetidinium,
I-
57 CH20-(4-picoline)Ph- 8-(N)-py==olidine
58 CH=O-(4-picoline)Ph- 8-EN)-N-methyl-pyrroiidiniura,
I-
._
.
;
59 CHZO-(4-picoline)Ph- .
,
g-(N)-N-methyl-morpholinium,
I'
60 CH10-(4-picoline)Ph- g-(N)-N'-~ethylpiperazine
61 CHZO-(4-picoline)Ph- g-(N)-N'-dir.ethylpiperaziniun,
I'
62 CH20-(4-picoline)Ph- 8-N:i-C3Z
63 CH~O-(4-picoline)Ph- 8-NHC(O)C5H11
64 CHZO-(4-picoline)Ph- 8-NHC(0)CH2Hr
65 CH=O-(4-picoline)Ph- 8-NH-C(Nr)NH2
66 CHyO-(4-picoline)Ph- 8-(2)-thiophene
67 CHZO-(4-picoline)Ph- 9-crethyl
68 CHZO-(4-picoline)Ph- 9-ethyl
69 CHZO-(4-picoline)Ph- 9-iso-propyl _
70 CHID-(4-picoline)Ph- 9-tert-butyl
71 CH=O-(4-picoline)ph- g-OH
72 CH20-(4-picoline)Ph- 9-OCH3
73 OHIO-(4-picoline)Ph- 9-O(iso-propyl)
74 CH=O-(4-picoline)Ph- 9-SCH3
75 cH~o-(4-picoiine)Ph- 9-socH3~
76 CHZO-(4-picoline)Ph- 9-SO2CH3
77 CH=O-(4-picoline)Ph- 9-SCH2CH3
78 CH=O-(4-picoline)Ph- 9-NH2 . .
.
79 CH=O-(4-picoline)Ph- 9-NHpH
80 CHZO-(4-picoline)Ph- 9-NHCH3
81 CH=O-(4-picoline)Ph- 9-N(CH3)2
CA 02283575 1999-09-09
WO 98140375 PCT/US98/03792
82 CH=O-(4-picoline)ph- 9-N+(CH3)3. _-
83 cH=o-(4-picoiins)Ph- 9-NHC(-o)cH3
84 CH~o-(4-picoline)Ph- 9-N(CH2CH3)2
85 CHZO-(4-picoifne)Ph- 9-NMeCH2C02H
86 CHZO-(4-picoiine)Ph- 9-N'(Me)ZCH2CO2H, Z'
87 CHZO-(4-picoline)Ph- 9-(N)-morpholine
88 CH~O-(4-picoline)ph- 9-(N)-azetidine
89 CHZO- (4-picoline)Ph- 9- (N) -N-methylazetidiniuin
_-
- 90- CHZO-(4-pico-l-ine-)--Ph-_.,
. ..9--(N)wpyrro3idine-_ _..
__
91 CHZO-(4-picoline)Ph- 9-(N)-N-methyl-pyrrolidinium
I'
92 CHZO-(4-picoline)Ph- ,
9-(N)-N-methyl-morpholiniur.~
Z'
93 CHZO-(4-picoline)Ph- ,
9-(N)-N'-methylpiperazine
93 CHZO-(4-picoline)Ph- 9-(N)-N'-dimethylpiperazini~a,
~ I'
95 CH20-(4-picoline)ph- 9-NH-C3Z
96 CHZO-(4-picoline)Ph- 9-NHC(O)C5H11
97 CHIO- (4-picoline)Ph- 9-N::C (O) C::28r
98 CH=O-(4-picoline)Ph- 9-NH-C(N::)NH2
99 CH=O-(4-picoline)Ph- 9-(2)-thiophene
100 CHZO-(4-picoline)Ph- 7-OCF3, 8-OCH3
101 CHIO-(4-picoline)Ph- 7-SCH3, 8-OC:a3
I02 CJ20-(4-picoline)Ph- 7-SC3, 8-SCH3
I03 CH20-(S-picoline)ph- 6-OC::3, 7-OC::3, 8-CCa3
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
vv
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CA 02283575 1999-09-09
WO 98/40375 PCT/US98/0379Z
L, w PA
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CA 02283575 1999-09-09
WO 98!40375 PCT/US98/03792
P
o
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C '~ x O fl x ~~ Q 0 x Xv =' = r =_'3~ = C
s = Q ss ~ ~ ~ ~c ~ '~ x x ov ~ ~c ~ ~ s ~
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CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
PA1~
c c °c ' '
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71
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
C C = C C
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCTIUS98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/I1S98/03792
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WO 98!40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 . PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
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WO 98/A0375 PCT/US98/03792
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CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PCT/US98/03792
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WO 98/40375 PGT/US98/03792
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WO 98/40375 PCT1US98/0379Z
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WO 98/40375 PCT/US98/03792
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v v v v v
~ E E E E E
'r
i ~ _
w
i v i
t U = U
Z N V t Z V Z
t t Z = t
tm t Z
...
O
O
O _, ~ O
O .
Z Z t Z Z
O O O O O
a, a. =. a. a.
> > z > >
c c c c c
a, a. a, _a. ~ ~,
.~0~ ~ 3 = ~ '
c c c C ~ c
e~~f ~"~ ~ ao
r- ..
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
3 ~ o
c c
s a ' ,~e ~ a
'' a. ~ a,
E v
E E E
t~ e~ , 'v
_ ' Z
U
U
'- ,_ ' + ev
O ,_
_ O _
O
1 v
T
O
r
.'3~ 3 ?
C C C
~_
.O
C C C C
t13
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
a ~ o ~ o
w
R R R R R
E E
' ~ , 'q
x
,
~ i ~Z/ \
_ \
v z/+ ~_
Z N Z +
_Z
, ,
,
0 ,
0
x
x
C
C C C
C
a. a'
C C C C a
_
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
-.
' ' ~ = a
c
a R ~E ~E
a ~ ~ a R
c a C v
;Q E
:yo
i' ' x
x
U ~+ ~ U
+Z
Z- +~ U
+z
o
' 0 0
0
zx
x
0 0
~,'
.a
c c
's
.o
C c '
c
c~
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
c C° °
°e a
~rs R R .R .R
~1 ~1 ~1 ~1
" E ~y ~ a
;v .E' .a E
t~
Z
x
O
O-~-O
U
O
v
'~' t
Z
N
ti O
O
u. O
x x
O
~' ~ i
C C C C C
~1
C C C
1 _
! !
CA 02283575 1999-09-09
WO 98/403?5 PCT/US98103?92
° ~ a
'° s
av a, a, a.
s
a
E c
ev ~ 'Q
z
Z ~ t ~ ~ U
m Z +
N Z
0
o ~
0
a c
c
a
a
3 ;
c c a c
''
.. ..
1 I''1
CA 02283575 1999-09-09
WO 98/40375 PCTNS98/03792
C C C
s _R .E .E
_R fi
S ~ ~ iv
.a
Z
a z
\ + z' O
U
U ~ Z
t d.
,Z N
N
U - O ~s O
= u. O
ti O
Z
O
O
O
a a,
3
a c
a. a,
.o .o
c a a a
.°.
a a
CA 02283575 1999-09-09
WO 98140375 PCT/IJS98/03792
n
U
~Zf ~ ~ Z ~ + U
t' 2
.~2
t
- a
s
a a a
a
z
~z
i~q
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
0
C C C
.a .R a .E
r
s
a
E E E E
w
'Q :a
o
x
0
_~
z '- i
N
ti x 1
U
~i-?~
x
' \ U
u. O O- U
x
0 O
a.
c a
_a, ~, ~
C c
a' a r, t~
a
tao
CA 02283575 1999-09-09
WO 98/40375 PCT/US98103792
E E ° ~ c
~E
a, a, s R
a ~~
E .~~. y ~ =
w c E_ E
.,
_~ _ _ _
,_ ~, .;
z z
V _N
U
U
+Z
~Z
2~
+ +
. O
zx ~c' ~- ~ ~- n
o a _
c
x y x
z
0 0 0 0
0
s z
;c ' c ~ a
c c
a ~ z ~ s
c ~ a,
c c . c
N
T q N !
! !
~, !
tai
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
0 0
a c
R '° a a
a, a. a, a, a.
v y y y
C E E E C
x
0
N x
+Z
_O n
h
-F Z
~c' V ' ..
C
O
x
T
0
r ~ ~ _!~
> >
C C C
.7 'J . 7
t1 .O
C C C C
H
N
T
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
c °c ~ ~ a
.,: .~ .R c E
a~ i~ R rs
s ~ s
y
n
O x
O
II,O
Z N ~ +,~ '-'Z O ,- U
Z N Z C'1
O ~- O
O / ~ O . ~ O
1
z
x
T_
O O O
r _?v
'.S1 .0 .7
C C = C
~_ r
'.~ ~ > > .
C C C C ~ C
c1
l~~f
t~3
CA 02283575 1999-09-09
WO 98!40375 PCT/US98/03792
0 0 0
c c a a
c
.s .R .E
s ~ s
a, a, a, a, ~, a,
s
E E E c E c
r
s t
0
_o
' ~ U
0
Z " Z
t : _ _ _ U
tZ
U U e~,
V t Z H t Z « \ t
a z
N
t
0
u. o
1 \ /
z z z T z
0 0 0 0 0 0
.z ~ ~ = ''
.0 3
a c c c
a, a, a, ;,
3 = 3 3
c a a ''
c c
a
a~ v .r
..
~ aø
CA 02283575 1999-09-09
WO 98/40375 PCTNS98/0379Z
0
c c° o _c
'~' ~ ~ x ~ E
s '' a. °- s a,
a y y y o s
E
'°
Z
a z
R
z Z +
~~'
_ _ \+ ~ ~ o
u- o
"' ° ~ \ °
\ ~ ~ / \ /
\ / ~ \ /
l
z
0 0 0 0
a
C C G C C C
T. _?v
3
,d ~ = 7
C C C C Ji .
C
N
T
i~ ' ~ a
~ as
CA 02283575 1999-09-09
WO 98/40375 PCTNS98/03792
c c a
.E R .~ rs
.C t. a,
V
E
E
r
+Z
r-,
o/ ~ ~ a
,r O
z Z
o O 00
s
c ~ c c
a. y. - i,
c ~ ~ C
C
T a ~ 1f1
T a
1~6
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
,N
V
PEG = 3400 molecular weight polyethylene glycol polymer chain
PE~
V ~H~
O O
O
O
PEG = 3400 molecular weight polyethylene glycol polymer chain
~a-t
CA 02283575 1999-09-09
WO 98/40375 PCTIUS98/03792
N~EG~N
H H
O.
O
,N
- O
PEG = 3400 molecular weight polyethylene glycol polymer chain
O
S
'N \
':.
~~OH
cag
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03'192
' C2= Nt! N 0~ i
' lt7.Sl~
~f
a
n
czz Nxs N a3 s
ass.s~s
;.
a
vx.sa
0 0
Er
n-8u
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/0379Z
auras oa s
sss.~us
o~ / o
aZ tao o s ;
310. Z3
n-8u
:T
Ph
ax rae o s
s~o.sa
n-Bu
.T
t 3~
.- . _
Ph OH
~/
OH
Ph
CA 02283575 1999-09-09
WO 98/40375 PCTNS98/03792
cu sac ov s
ass.us
o~ c~ o
_.._._~ . 3u
Pn OH ""
az ~z os s . cxz Kzs o3 s
»s. oes
~~ 4
~w
,a ~.
a
Ei
n-8u
i r~n
131
ax wx~ a: s
~c. us
0~ ~0
i
CA 02283575 1999-09-09
WO 98140375 PCT/US98/03792
ue w,~ ~ oa s
o~.so,
LT
°-C~IIf
a~ quo as s
aa.sa
~4
'~.
tr
-w
t 3 a-
C2Z iQl T 03 f
.lft. Q7
0'\ / 0
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
cis gas H o~ s
~roa.s~n
cr
a
Ho - ~r
c?Z tfZ! N o1 s
~Qa.3t7
~r
0
N0 ~- IH
rnw
o~.ro,
w
aw
~"'~s"sa
t 33
i
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
a~n,oo~s
~vi. us
O
n-8u
~ Er
_.___ _.._o ___ ~~~~'' 0~ ___ .._-_... _
r
n-C6H~3 Ph
a~ rua as s
130.Ea1
0
II n-Au
Er
H
C3i
117.~07
4
a
~-w
o~~~
~Er
0
1A
t 3 ~.
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
cta Sao o, s
,ox.sss
' o
aimo,s
aea.oxa
0
o~~~.
~~BV
Et /
i ~-8u
Ph
~ 35
Ph pH
VA
Ph
a,~nxo.s
,m.sei
o
o~ ~~
i
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
cu axe o3 s
sri. sa
~~~ //~
Er
~-8u
OH
as quo o~ s
,oi.sss
0
Er
~ 3~
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
cti gas a, s . cu ~s os s
~c~.oao
ae.
. ~~ ~.
w
s czz ~aa oa s:
~o~. ssi
ors/ o . o\ s/ o
''' Er ,''~ Er
.~
~ ~ v
n-8u ~~8u
HO
S 01i ~ 5
phi ' Ph
i 3'~
i i
CA 02283575 1999-09-09
WO 98/40375 PCTNS98/03792
ax las tx o3 s
a~.axx
'~ c
0 0
_ . . __ __
i _
QI 11x~ 0.1 t
~f,. his
~3g
Ph OH
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
as N~o o~ s
,cx.su
0
o~ ~~
n-Bu
Er
0
Ph
CZ3 N70 C~1 f
,Qt.53i
I Ph
13q
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
cti Hzo oa s
31i.Q1
0 0
Er
Phl
cti Ino oa s
~ti.Qt
0 0
Er
Ph -..
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
crt gas o: s
ao.zzs
P
MBu
CZt Irt~ 03 S
7n.sis
t
- I O
0
Er
Er
n-8u
Ph pH
V
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
In further compounds of the present invention, Rs
and R' are independently selected from among hydrogen
and ring-carbon substituted or unsubstituted aryl,
thiophene, pyridine, pyrrole, thiazole, imidazole,
pyrazole, pyrimidine, morpholine, N-alkylpyridinium, N-
alkyl-piperazinium, N-alkylmorpholinium, or furan in
which the substituent(s) are selected from among halo,
hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino,
N,N-dialkylamino, quaternary ammonium salts, a C1 to C'
alkylene bridge having a quaternary ammonium salt
substituted thereon, alkoxycarbonyl, aryloxycarbonyl,
alkylcarbonyloxy and arylcarbonyloxy, (O,O)-
dioxyalkylene, -[0(CH~)"]~X where x is 2 to 12, w is 2
or 3 and X comprises halo or a quaternary ammonium
I5 salt, thiophene, pyridine, pyrrole, thiazole,
imidazole, pyrazole, or furan. The aryl group of R5 or
R' is preferably phenyl, phenylene, or benzene triyl,
i.e., may be unsubstituted, mono-substituted, or di-
substituted. Among the species which may constitute
the substituents on the aryl ring of R' or R' are
fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy,
trimethylammonium (preferably with an iodide or
chloride counterion), methoxycarbonyl, ethoxycarbonyl,
formyl, acetyl, propanoyl, (N)~-hexyldimethylammonium,
hexylenetrimethylammonium, tri(oxyethylene)iodide, and
tetra(oxyethylene)trimethylammonium iodide, each
substituted at the p-position, the m-position, or both
of the aryl ring. Other substituents that can be
present on a phenylene, benzene triyl or other aromatic
ring include 3,4-dioxymethylene (5-membered ring) and
3,4-dioxyethylene (6- membered ring). Among compounds
which have been or can be demonstrated to have
desirable ileal bile acid transport inhibiting.
properties are those in which R' or R' is selected from
phenyl, p-fluorophenyl, m-fluorophenyl, p-
hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m-
methoxyphenyl, p-N,N-dimethylaminophenyl, m-N,N-
I~I~
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
diiaethylaminophanyl , I' p- ( cH~ ),-N'-phenyl . I' m- ( Qi, ) ,-N'-
phenyl. I' m- (GHQ) ~-1if-~~_ (OCH,CFi,I,-O-ghanyl. I' p-
( CFI, ) ,-N -CH~Cii.,- ( OCH~Gii' ) ,-O-phenyl , I' na- (N, N-diiae thyl-
piperazinium) - (N' ) -CHI- (pCFi~CH~)a-O-phenyl, 3-methoxy~4-
' S fluorophenyl, thienyl-2-yl, 5-cholorothienyl-2-yl,
3,4-difluorophenyl, I' p-(N,N-dimethylpiperazinium)-
tN' )-CIi~-(OCH,CH,),-O-phenyl, 3-fluoro-4-iaethoxyphenyl, -
d-pyridinyl. 2-pyridinyl,- 3-pyridinyl, N-methyl-d-
pyridinium, I' N-metlsyl-3-pyridinium, 3, 4-
dioxymethylenephenyl. 3,d-dioxyethylenephenyl, and p-
methvxycarbonylphenyl. Preferred compounds include 3-
ethyl-3-butyl and 3-butyl-3-butyl compounds having each
of the above preferzed R' substituents in combination
with the R' substituents shown in Table 1. It is
particularly preferzed that one but not both of R' and
R' is hydrogen.
It is especially preferzed that R' and R' be
hydrogen, that R' and R' riot be hydrogen, and that R'
and R' be oriented in the same direction relative to
ZO the plane of the molecule, i.e., both in o~ or both in
i3-configuration. It is further praferrcd that, where
R' is butyl and R' is ethyl , then R' has the saxte
orientation relative to the plane of the molecule as R'
and R' .
Sat forth in Table lA are lists of species of
R'/B'. H'/R' and B'_
143
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
P ~-G. ~ 14.~.-
t ~~ E-N ~ W N,~~..~ ;
Las ~~-r~ ~
199
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Table ~ ; ALteraative A groups
O' ~O
~x~ ~ a ~ s .,.A Rl
q - % . s . R2
s ...~~ R3
.,,.
Rs Ra Ra
R R R .R R tRs) a
eChyl BO- Ph- 7-aethyl
a-propyl _. ._g- ~y-?h4_. . __ _...._... ~-ethyl-._ __.
. ...
a-butyl m-F-Ph- 7-iso-propyl
n-~a=Yl p-CH3Q-?h- 7-cer:-butyl
a-hexyl
iso-prop'yl m-cq~a-?h- 7-CCl
,
iso-bueyl
p-tCH~)=N-?h- 7-Otisa-propyl)
iso-peatyi
m-t~~)=N-?h- 7-SC~
CSIC t OI C=H~ -
I T-SOC ~
Cs=cc=as P- IC ) -N-?h-
> >
-
cs=cs tos) c=ss
. ~- tc~) ~-:r-~h- ?-so=c~
I
-
C8=O-tt-plea-ine)
I T-sC=C3~
p-tC~)~-N-C_~C~=-
tCCZC=)=-o-?- T-NH=
I m-IC~I ~-:J'-CIC=- = T-NOti
~
tCC=C=1 =-0-?h- T-NFC~ ..
~'~~
I-. p-tNN- 7-~tC~~)_
di~eLhy_ape:azisel- 7-NICI>> I-
tN')-C1-tCCIC=)Z-0- T-aBCt-O)C3~
Ph- 7-N tC=C::~) _
I -tN,:l- 7-N:!eC3=CO=ti
diae:..ylpipe:aziaa)- 7-a't:!e)=C=CO=n. I-
t~~)-Cz-tccxiC~=)=-o- T-tN)-~:pholi~e
p~- ?-tN)-azecidine
m-:. p-C~C-?..- T-tN)-N-=echylazecidiniua
I-
74dioxywe:,,yiee-?h 1-tN)-py::olidirte
m-C~C-. p-:-?.-. T-t,t)-N-~et..yl-pyrrolidiniua,
I-
1-oy:iCize 7-tN)-N-aechyl-ao:pholinium.
I-
N-~aechyl-i-oy:idW iua I- T-IN)-Y-aechylpiperaziae
I-py:id:ae 7-IN)-a-di~e:..ylpi?eraziniua
I-
N-es:~yl-3-~y_fGialc:, I- T-:~-C=2
Z-PY:id=ae T-a~tCtO)CSH1I
p-CIO=C-?h- 7-dliCt .o )CIi=Dr
C.~3say1-2-yl 7-NH-CIa)NH=
S-C1-chieayl-I-yl 7-t=)-:hiophene
3.t-ditluoro .
~-F.p-~3C-ph eonttacad nexr page...
(øs
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
1-aechyl
1-ethyl
e-iso-propyl
1-CeK-butyl
1-OH
1-CCH~ .
1-Oliso-propyl)
1-sCS~
1-svC8~
e-so=cs3
1-sc3~ca~
1-NH=
e-Ngoa
e-Neca~
_ _-_._..___ --.~__a-N.(c$~)_= _ _ _
1-N'tcg3)~. I-
1-NECf-O)Cs3
1-N fC~=Clip ) _
1-IINeCHZCO=E
1-N' ftisl =CF=CO=3, I-
1-f;f)-eorpholias
8-fN)-azscidiae
8-fN)-N-ae=hylazet'_diaiu~, r
8-fNl-pY=:o--~-ae
e-cN)-N-ses:~yl-ayrsolid'-aiua. I-
9-ta)-a-aetayl-~o:pholLztu~, I-
A-fN)-N'-aaC'ylpiperaziae
A-f:11-N'-d'__staylpfperaziaiua. I-
A-Ne-C3t
1-!1~C f01 Cs311
A-NECfO)CH=3_
8-Ye.-C f:IHI NH=
A-f3 ) -c:ae~hera
eont_auad asst papa...
l4-6
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
9-eechyl
9-ethyl
9-iso-propyl
9-tart-butyl
9-OB
9-CC81
9-Otiso-propyl)
9-SCr~
9-SOC:i3
9-50=C»x
9-SCS=C)i~
9-NFI=
4-N~OH
9-N»C»x
9-N (C'~3) _
9=a'tCa~)j~'_
4-N8C t~0) C'~
9-N tC»=C)i~ ) _
9-N,!eC3=CO=8
9-a't:!e)ZC»=CO=x, I-
9-lN)-~orpholine
9-tN)-azecidine
9-IY)-N-r.echylazetidinia~, I-
9-tN)-pyrrolidine
9-tN)-N-aethyl-pyrrolidiniua, I-
9-ta) -,t-:eechyl-worpholiniu~s, I-
' 9-Ia)-H'-we:hylpiperazine
9-ta) -N~ -Ciwec.'.ylpigeraz i nii:a, I-
9-NH-C3Z
9-yi:C t0) C;~:1
9-N»C t01 C »i3r
4-Ni:-C INf:1 Ne:=
9-t2)-chiophene
7-CC y, 8-CC»~
7-SC»~, 8-CC~~
7-3~»~. 8-SC3~ .
6-CCJI, 7-CC»l, A-OCaI
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Further preferred compounds of the present invention
comprise a core structure having two or more
pharmaceutically active benzothiepine structures as
described above, covalently banded to the core moiety via
functional linkages. Such active benzothiepine structures
preferably comprise:
_ _c_~ ~, . ~
(r~' s
i
"2
4 (Formula DIV)
or:
cod R7
s
cR"~
~5~4 ~'3
(Formula DIVA)
where R1, R~, R', R~, R', R', R', R', R°, X, q and n are as
defined above, and Rss is either a covalent bond or.
arylene.
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
The core moiety can comprise alkane diyl, alkene
diyl, alkyne diyl, polyalkane diyl, alkoxy diyl,
polyether diyl, polyalkoxy diyl, carbohydrate, amino
acid, and peptide, polypeptide, wherein alkane diyl,
alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl,
polyether diyl, polyalkoxy diyl, carbohydrate, amino
acid, and peptide polypeptide, can optionally have one
or more carbon replaced by_O, NR',___.N'R'R°, S, SO, gp2
S'R'R°, pR~ , p+R~R8 , phenylene, heterocycle, quatarnary
heterocycle, quaternary heteroaryl, or aryl,
-wherein alkane diyl, alkene diyl, alkyne diyl,
polyalkane diyl, alkoxy diyl, polyether diyl,
polyalkoxy diyl, carbohydrate, amino acid, peptide, and
polypeptide can be substituted with one or more
substituent groups independently selected from the
group consisting of alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, heterocycle,
arylalkyl, halogen, oxo, OR13, NR13R14~ SR13~ S(0)R13~
S02R13, S03R13, NR130R14, NR13NR14R15~ N02. C02R13, CN,
OM, S020M, S02NR13R14~ C(0)NR13R14, C(O)OM, COR13,
P (0) R13R14 ~ p+R13R14;R15A- ~ p (OR" ) OR1', S~RI'Rl'A~, and
N+R9R11R12A-
wherein said alkyl, alkenyl, alkynyl, polyalkyl,-
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle
can be further substituted with one or more substituent
groups selected from the group consisting of ORS,
NR~R8, SRS, S(O)RB, S02R~, S03R~, C02R~, CN, oxo,
CONR~RB, N+R~R8R9A-, alkyl, alkenyl, alkynyl,.aryl,
cycloalkyl, heterocycle, arylalkyl, quaternary
1 ~I 9
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
heterocycle, quaternary heteroaryl, P(O)R~R8, P+R~RBA ,
and P ( O ) ( OR' ) ORS , and
wherein said alkyl, alkenyl, alkynyl, polyalkyl,
polyether, aryl, haloalkyl, cycloalkyl, and heterocycle
can optionally have one or more carbons replaced by O,
NR7, N+R~RBA-, S, SO, 502, S+R~A-, PRA, P(O)R',
P+-R~R$A-; or phenylene. -
Exemplary core moieties include:
26
R2 5
~~~_~~2 7
0 ~27
k0
26
~27
0
k
R28
0
R26 ~ 'Sl 27
k
29
yd
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R2 ~R27
wherein:
R" is selected from the group consisting of C and
N, and
R" and R" are independently selected from the
group consisting of:
(O)x
-N- ~ ~T_. _p_. _.S_.~ -~. -CFi2_
o s o s
~I~ ~-~ I h~ 11
-c -c -~ -
R31
-g f .. .~1H Slii _. -~p ~ . and ~N~
~t32 Z '~ ~NH2
wherein R". R", R'° aad R" are independently
selected from alkyl, alkenyl, alkylaryl, aryl,
arylalkyl. ~ cycloalkyl._ hetero:c,~c~:e: and
-hate=ocycl alkyl,
Z5 A is a pharmaceutically acceptable anion, and k =
1 to 10.
I s~
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In compounds of Formula DIV, Rs°, R'l, R=' in
Formulae DII and DIII, and R" in Formula DIII can be
bonded at any of their 6-, 7-, 8-, or 9- positions to
Rl'. In compounds of Formula DIVA, it is preferred that
R" comprises a phenylene moiety bonded at a m- or p-
position thereof to R1'.
In another embodiment, a core moiety backbone, R",
as discussed herein in Formulas DII and DIII can be
multiply substituted with more than four pendant active
benzothiepine units, i . a . , R'°, R'1, R", and R" as
discussed above, through multiple functional groups
within the core moiety backbone. The core moiety
backbone unit, Rl', can comprise a single core moiety
unit, multimers thereof, and multimeric mixtures of the
different core moiety units discussed herein, i.e.,
alone or in combination. The number of individual core
moiety backbone units can range from about one to about
100, preferably about one to about 80, more preferably
about one to about 50, and even more preferably about
one to about 25. The number of points of attachment of
similar or different pendant active benzothiepine units
within a single core moiety backbone unit can be in the
range from about one to about 100, preferably about~one
to about 80, more preferably about one to about 50, and
even more preferably about one to about 25. Such
points of attachment can include bonds to C, S, O, N,
or P within any of the groups encompassed by the
definition of Ri'.
The more preferred benzothiepine moieties
comprising R'°, R=l, R~= and/or R" conform to the
preferred structures as outlined above for Formula I.
The 3-carbon on each benzothiepine moiety can be
achiral, and the substituents R', R=, R', R~, R' and R"
~ sz
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can be selected from the preferred groups anct
combinations of substituents as discussed above. The
core structures can comprise, for example,
poly(oxyalkylene) or oligo(oxyalkylene), especially
poly- or oligo(oxyethylene) or poly- or
oligo(oxypropylene).
Dosasres, Formulations, and Routes of Administration
The ileal bile acid transport inhibitor compounds
of the present invention can be administered for the
prophylaxis and treatment of hyperlipidemic diseases or
conditions by any means, preferably oral, that produce
contact of these compounds with their site of action in
the body, for example in the ileum of a mammal, e.g., a
human.
For the prophylaxis or treatment of the conditions
referred to above, the compounds of the present
invention can be used as the compound per se.
Pharmaceutically acceptable salts are particularly
suitable for medical applications because of their
greater aqueous solubility relative to the parent
compound. Such salts must clearly have a
pharmaceutically acceptable anion or cation. Suitable
pharmaceutically acceptable acid addition salts of the
compounds of the present invention when possible
include those derived from inorganic acids, such as
hydrochloric, hydrobromic, phosphoric, metaphosphoric,
nitric, sulfonic, and sulfuric acids, and organic acids
such as acetic, benzenesulfonic, benzoic, citric,
ethanesulfonic, fumaric, gluconic, glycolic,
isothionic, lactic, lactobionic, malefic, malic,
methanesulfonic, succinic, toluenesulfonic, tartaric,
and trifluoroacetic acids. The chloride salt is
X53
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particularly preferred for medical purposes. Suitable
pharmaceutically acceptable base salts include ammonium
salts, alkali metal salts such as sodium and potassium
salts, and alkaline earth salts such as magnesium and
calcium salts.
The anions of the definition of A in the present
invention are, of course, also required to be
pharmaceutically acceptable and are also selected from
the above list.
The compounds of the present invention can be
presented with an acceptable carrier in the form of a
pharmaceutical composition. The carrier must, of
course, be acceptable in the sense of being compatible
with the other ingredients of the composition and must
not be deleterious to the recipient. The carrier can
be a solid or a liquid, or both, and is preferably
formulated with the compound as a unit-dose
composition, for example, a tablet, which can contain
from 0.05 to 95~ by weight of the active compound.
Other pharmacologically active substances can also be
present, including other compounds of the present
invention. The pharmaceutical compositions of the
invention can be prepared by any of the well known
techniques of pharmacy, consisting essentially of
admixing the components.
These compounds can be administered by any
conventional means available for use in conjunction
with pharmaceuticals, either as individual therapeutic
compounds or as a combination of therapeutic compounds.
The amount of compound which is required~to
achieve the desired biological effect will, of course,
depend on a number of factors such as the specific
compound chosen, the use for which it is intended, the
I5~
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mode of administration, and the clinical condition of
the recipient.
In general, a daily dose can be in the range of
from, about 0.3 to about 100 mg/kg bodyweight/day,
preferably from about 1 mg to about 50 mg/kg
bodyweight/day, more preferably from about 3 to about
mg/kg bodyweight/day. This total daily dose can be
administered to the patient in a single dose, or in
proportionate multiple subdoses. Subdoses can be
10 administered 2 to 6 times per day. Doses can be in
sustained release form effective to obtain desired
results.
Orally administrable unit dose formulations, such
as tablets or capsules, can contain, for example, from
about 0.1 to about 100 mg of benzothiepine compound,
preferably about 1 to about 75 mg of compound, more
preferably from about 10 to about 50 mg of compound.
In the case of pharmaceutically acceptable salts, the
weights indicated above refer to the weight of the
benzothiepine ion derived from the salt.
Oral delivery of an ileal bile acid transport
inhibitor of the present invention can include
formulations, as are well known in the art, to provide
prolonged or sustained delivery of the drug to the
gastrointestinal tract by any number of mechanisms.
These include, but are not limited to, pH sensitive
release from the dosage form based on the changing pH
. of the small intestine, slow erosion of a tablet or
capsule, retention in the stomach based on the physical
properties of the formulation, bioadhesion of the
dosage form to the mucosal lining of the intestinal
tract, or enzymatic release of the active drug from the
dosage form. The intended effect is to extend the time
IJJ
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period over which the active drug molecule is delivered
to the site of action (the ileum) by manipulation of
the dosage form. Thus, enteric-coated and enteric-
coated controlled release formulations are within the
scope of the present invention. Suitable enteric
coatings include cellulose acetate phthalate,
polyvinylacetate phthalate,
hydroxypropylmethylcellulose phthalate and anionic
polymers of methacrylic acid and methacrylic acid
methyl~ester.
When administered intravenously, the dose can, for
example, be in the range of from about 0.1 mg/kg body
weight to about 1.0 mg/kg body weight, preferably from
about 0.25 mg/kg body weight to about 0.75 mg/kg body
weight, more preferably from about 0.4 mg/kg body
weight to about 0.6 mg/kg body weight. This dose can
be conveniently administered as an infusion of from
about 10 ng/kg body weight to about 100 ng/kg body
weight per minute. Infusion fluids suitable for this
purpose can contain, for example, from about 0.1 ng to
about 10 mg, preferably from about 1 ng to about 10 mg
per milliliter. Unit doses can contain, for example,
from about 1 mg to about 10 g of the compound of the
present invention. Thus, ampoules for injection can
contain, for example, from about 1 mg to about 100 mg.
Pharmaceutical compositions according to the
present invention include those suitable for oral,
rectal, topical, buccal (e.g., sublingual), and
parenteral (e. g., subcutaneous, intramuscular,.
intradermal, or intravenous) administration, although
the most suitable route in any given case will..depend
on the nature and severity of the condition being
treated and on the nature of the particular compound
IS (o
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which is being used. In most cases, the preferred
route of administration is oral.
Pharmaceutical compositions suitable for oral
administration can be presented in discrete units, such
as capsules, cachets, lozenges, or tablets, each
containing a predetermined amount of at least one
compound of the present invention; as a powder or
granules; as a solution or a suspension in an aqueous
or, non-aqueous liquid; or as an oii-in-water or water-
in-oil emulsion. As indicated, such compositions can
be prepared by any suitable method of pharmacy which
includes the step of bringing into association the
active compounds) and the carrier (which can
constitute one or more accessory ingredients). In
IS general, the compositions are prepared by uniformly and
intimately admixing the active compound with a liquid
or finely divided solid carrier, or both, and then, if
necessary, shaping the product. For example, a tablet
can be prepared by compressing or molding a powder or
granules of the compound, optionally with one or more
assessory ingredients. Compressed tablets can be
prepared by compressing, in a suitable machine, the
compound in a free-flowing form, such as a powder or
granules optionally mixed with a binder, lubricant,
inert diluent and/or surface active/dispersing
agent(s). Molded tablets can be made by molding, in a
suitable machine, the powdered compound moistened with
an inert liquid diluent.
Pharmaceutical compositions suitable for buccal
(sub-lingual) administration include lozenges
comprising a compound of the present invention in a
flavored base, usually sucrose, and acacia or
tragacanth, and pastilles comprising the compound in an
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inert base such as gelatin and glycerin or sucrose and
acacia.
Pharmaceutical compositions suitable for
parenteral administration conveniently comprise sterile
aqueous preparations of a compound of the present
invention. These preparations are preferably
administered intravenously, although administration can
also be effected by means of subcutaneous,
~intramuscular, or intradermal injection. Such
preparations can conveniently be prepared by admixing
the compound with water and rendering the resulting
solution sterile and isotonic with the blood.
Injectable compositions according to the invention will
generally contain from 0.1 to 5~ w/w of a compound
disclosed herein.
Pharmaceutical compositions suitable for rectal
administration are preferably presented as unit-dose
suppositories. These can be prepared by admixing a
compound of the present invention with one or more
conventional solid carriers, for example, cocoa butter,
and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical
application to the skin preferably take the form of an
ointment, cream, lotion, paste, gel, spray, aerosol, or
oil. Carriers which can be used include vaseline,
lanoline, polyethylene glycols, alcohols, and
combinations of two or more thereof. The active
compound is generally present at a concentration of
from 0.1 to 15~ w/w of the composition, for example,
from 0.5 to 2~.
Transdermal administration is also possible.
Pharmaceutical compositions suitable for transdermal
administration can be presented as discrete patches
15~
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adapted to remain in intimate contact with the
epidermis of the recipient for a prolonged period of
time. Such patches suitably contain a compound of the
present invention in an optionally buffered, aqueous
solution, dissolved and/or dispersed in an adhesive, or
dispersed in a polymer. A suitable concentration of
the active compound is about 1% to 35%, preferably
about 3% to 15%. As one particular possibility, the
compound can be delivered from the patch by
electrotransport or iontophoresis, for example, as
described in Pharmaceutical Research, 3(6), 318 (1986).
In any case, the amount of active ingredient that
can be combined with carrier materials to produce a
single dosage form to be administered will vary
depending upon the host treated and the particular mode
of administration.
The solid dosage forms for oral administration
including capsules, tablets, pills, powders, and
granules noted above comprise one or more compounds of
the present invention admixed with at least one inert
diluent such as sucrose, lactose, or starch. Such
dosage forms may also comprise, as in normal practice,
additional substances other than inert diluents, e.g.,
lubricating agents such as magnesium stearate. In the
case of capsules, tablets, and pills, the dosage forms
may also comprise buffering agents. Tablets and pills
can additionally be prepared with enteric coatings.
Liquid dosage forms~for oral administration can
include pharmaceutically acceptable emulsions,
solutions, suspensions, syrups, and elixirs containing
inert diluents commonly used in the art, such as water.
Such compositions may also comprise adjuvants, such as
W9
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wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile
injectable aqueous or oleaginous suspensions may be
formulated according to the known art using suitable
dispersing or setting agents and suspending agents. .
The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
.parenterally acceptable diluent or solvent, for
example, as a solution in I,3-butanediol. Among the
acceptable vehicles and solvents that may be employed
are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending
medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in
the preparation of injectables.
Pharmaceutically acceptable carriers encompass all
the foregoing and the like.
In combination therapy, administration of the
ileal bile acid transport inhibitor and HI~IG Co-A
reductase inhibitor may take place seguentially in
separate formulations, or may be accomplished by
simultaneous administration in a single formulation or
separate formulations. Administration may be
accomplished by oral route, or by intravenous,
intramuscular, or subcutaneous injections. The
formulation may be in the form of a bolus, or in the
form of aaqueous or non-aqueous isotonic sterile
injection solutions or suspensions. These solutions
and suspensions may be prepared from sterile powders or
granules having one or more pharmaceutically-acceptable
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carriers or diluents, or a binder such as gelatin or
hydroxypropylmethyl cellulose, together with one or
more of a lubricant, preservative, surface active or
dispersing agent.
For oral administration, the pharmaceutical
composition may be in the form of, for example, a
tablet, capsule, suspension, or liquid. Capsules,
tablets, etc., can be prepared by conventional methods
resell known in the art. The pharmaceutical composition
is preferably made in the form of a dosage unit
containing a particular amount of the active ingredient
or ingredients. Examples of dosage units are tablets
or capsules. These may with advantage contain one or
more ileal bile acid transport inhibitors in an amount
described above. In the case of HI~lG Co-A reductase
inhibitors, the dose range may be from about 0.01 mg to
about 500 mg or any other dose, dependent upon the
specific inhibitor, as is known in the art.
The active ingredients may also be administered by
injection as a composition wherein, for example,
saline, dextrose, or water may be used as a suitable
carrier. A suitable daily dose of each active
inhibitor is one that achieves the same blood serum
level as produced by oral administration.as described
above.
The active inhibitors may further be administered
by any dual combination of oral/oral, oral/parenteral,
or parenteral/parenteral~route.
Pharmaceutical compositions for use in the'
treatment methods of the present invention may be
administered in oral form or by intravenous
administration. Oral administration of the combination
therapy is preferred. Dosing for oral administration
Ib1
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may be with a regimen calling for single daily dose, or
for a single dose every other day, or for multiple,
spaced doses throughout the day. The inhibitors which
make up the combination therapy may be administered
simultaneously, either in a combined dosage form or in
separate dosage forms intended for substantially
simultaneous oral administration. The inhibitors which
make up the combination therapy may also be
administered sequentially, with either inhibitor being
administered by a regimen calling for two-step
ingestion. Thus, a regimen may call for sequential
administration of the inhibitors with spaced-apart
ingestion of the separate, active agents. The time
period between the multiple ingestion steps may range
from a few minutes to several hours, depending upon the
properties of each inhibitor such as potency.
solubility, bioavailability, plasma half-life and
kinetic profile of the inhibitor, as well as depending
upon the age and condition of the patient. The
inhibitors of the combined therapy whether administered
simultaneously, substantially simultaneously, or
sequentially, may involve a regimen calling for
administration of one inhibitor by oral route and the
other inhibitor by intravenous route. Whether the
inhibitors of the combined therapy are administered by
oral or intravenous route, separately or together, each
such inhibitor will be contained in a suitable
pharmaceutical formulation of pharmaceutically=
acceptable'excipients, diluents or other formulations
components. Examples of suitable pharmaceutically-
acceptable formulations containing the inhibitors for
oral administration are given above.
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Treatment Recimen
The dosage regimen to prevent, give relief from,
or ameliorate a disease condition having hyperlipemia
as an element of the disease, e.g., atherosclerosis, or
to protect against or treat further high cholesterol
plasma or blood levels with the compounds and/or
compositions of the present invention is selected in
accordance with a variety of factors. These include
the type, age, weight, sex, diet, and medical condition
of the patient, the severity of the disease, the route
of administration, pharmacological considerations such
as the activity, efficacy, pharmacokinetics and
toxicology profiles of the particular compound
employed, whether a drug delivery system is utilized,
and whether the compound is administered as part of a
drug combination. Thus, the dosage regimen actually
employed may vary widely and therefore deviate from the
preferred dosage regimen set forth above.
Initial treatment of a patient suffering from a
hyperlipidemic condition can begin with the dosages
indicated above. Treatment should generally be
continued as necessary over a period of several weeks
to several months or years until the hyperlipidemic
disease condition has been controlled or eliminated.
Patients undergoing treatment with the compounds or
' compositions disclosed herein can be routinely
monitored by, for example, measuring serum LDL and
total cholesterol levels by any of the methods well
known in the art, to determine the effectiveness of the
combination therapy.. Continuous analysis of such data
permits modification of the treatment regimen during
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therapy so that optimal effective amounts of each type
of inhibitor arE administered at any point in time, and
so that the duration of treatment can be determined as
well. In this way, the treatment regimen/dosing
schedule can be rationally modified over the course of
therapy so that the lowest amount of ileal bile acid
transport inhibitor and HIMG Co-A reductase inhibitor
which together exhibit satisfactory effectiveness is
administered, and so that administration is continued
only so long as is necessary to successfully treat the
hyperlipidemic condition.
A potential advantage of the combination therapy
disclosed herein may be reduction of the amount of
ileal bile acid transport inhibitor, HI~IG Co-A reductase
inhibitor, or both, effective in treating
hyperlipidemic conditions such as atherosclerosis and
hypercholesterolemia.
The following non-limiting examples serve to
illustrate various aspects of the present invention.
~(o~-
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EXAMPLES OF SYNTHETIC PROCE_DVRES
15 _~_ _
Pre~ara~ ion 1 ~3c ~ '~ ~ NZ a
~ 4~
2-Ethyl-2-(mesyloxymethyl)hexanal (1)
To a cold (10 °C) solution of 12.6 g (0.11 mole) of
rnethanesulfonyl chloride and 10.3 g (0.13 mole) of
20 triethylamine was added dropwise 15.8 g of 2-ethyl-2-
(hydroxymethyl)hexanal, prepared according to the
procedure described in Chem. Ber. 98, 728-734 (1965),
while maintaining the reaction temperature below 30 °C.
The reaction mixture was stirred at room temperature
25 ' for 18 h, quenched with dilute HC1 and extracted with
methlyene chloride. The methylene chloride extract was
dried over MgSO, and concentrated in vacuo to give 24.4
g of brown oil.
30 Pre~a=ation 2
2-((2-Henzoylphenylthio)methyl)-2-ethylhexanal (2)5 °
A mixture of 31 g (0.144,mo1) of 2- a a N
- mercaptobenzophenone, prepared according to the
c>>
procedure described in WO 93/16055, 24.4 g (0.1 mole)
35 of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14:8 g
(0.146 mole) of triethylamine, and 80 mL of 2-
methoxyethyl ether was held at reflux for 24 h. The
reaction mixture was poured into 3N HC1 and extracted
t b'S
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with 300 mL of methylene chloride. The methylene
chloride layer was washed with 300 mL of 10% NaOH,
dried over MgSO, and concentrated in vacuo to remove 2- _
methoxyethyl ether. The residue was purified by HPLC
(10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.
Example 1
3-Hutyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine (3),
cis-3-Hutyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-
~ (5X)4-one (4a) and traps-3-Hutyl-3-ethyl-5-phenyl-2,3-
,dihydro-benzothiepin-(5X)4-one (4b) ~S S~~
0
a a
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g
(0.047 mole) of TiCl~ and 80 mL of anhydrous ethylene
IS glycol dimethyl ether (DME) was held at reflux for 2 h.
The reaction mixture was cooled to 5 °C. To the
reaction mixture was added dropwise a solution of 3.54
g (0.01 mole) of 2 in 30 mL of DME in 40 min. The
reaction mixture was stirred at room temperature for 16
h and then was held at reflux for 2 h and cooled before
being poured into brine. The organic was extract into
methylene chloride. The methylene chloride extract was
dried over MgSO, and concentrated in vacuo. The residue
was purified by HPLC (hexane) to give 1.7 g (43%) of 3
as an oil in the first fraction. The second fraction
was discarded and the third fraction was further
purified by HPLC (hexane) to give 0.07 g (2%) of 4a in
the earlier fraction and 0.1 g (3%) of 4b in the later
fraction. .
Fxar~ple 2
cis-3-Hutyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepin-
(SX)4-one-1,1-dioxide (5a) and traps-3-Hutyl-3-ethyl-5-
phenyl-2,3-dihydro-benzothiepin-(5X)4-one-1,1-dioxide
( 5b ) Sos . ~ -
° ~ SQ, S b
o -o
To a solution of 1.2 g (3.5 mm e) of 50-60% MCPBA in
20 mL of methylene chloride was added 0.59 g (1.75
i 6f~
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mmole) of a mixture of 4a and 4b in 10 mL of methylene
chloride. The reaction mixture was stirred for 20 h. An
additional 1.2 g (i.?5 mmole) of 50-60% MAPBA was added
and the reaction mixture was stirred for an additional
3 h then was triturated with 50 mL of 10% NaOH. The
insoluble solid was filtered. The methylene chloride
layer of the filtrate was washed with brine, dried over
MgSO,, and concentrated in vacuo. The residual syrup
was purified by HPLC (5% EtOAc-hexane) to give 0.2 g
(30%)of 5a as an oil in the first fraction and 0.17 g
~(26%) of 5b as an oil in the second fraction.
o a _. _
z Sci O W
Eacam~le 3 0 off tlea~ \ ~'~oH ~66'
Q 0
(3a,4a,5b) 3-Hutyl=3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (6a), (3a,4b,5a) 3-
Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-tetrahydro- -S''~-
~E
benzothiepine-1,1-dioxide (6b), (3a,4a,5a) 3-Hutyl-3-
ethyl-4-hydroxy-5-phenyl-2,3,4,5- ~ ou
tetrahydrobenzothiepine-1,1-dioxide (6c), and ~ ~~I)
(3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (6d)
A. Reduction of 5a and Sb With Sodium Horohydride
To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of
ethanol was added 0.24 g (6.4 mmole) of sodium
borohydride. The reaction mixture was stirred at room
temperature for 18 h and concentrated in vacuo to
remove ethanol. The residue was triturated With water
and extracted with methylene chloride. The methyleae
chloride extract was dried over MgSO, and concentrated
in vacuo to give 0.2 g of syrup. In a separate
experiment, 0.45 g of 5a.was treated with 0.44 g of
sodium borohydride in 10 mL of ethanol and was worked
up as described above to give 0.5 ~ of syrup which was
identical to the 0.2 g of syrup obtained above. These
two materials were combined and purified by HPLC using
10% EtOAc-hexane as eluant. The first fraction was 0.18
g (27%) of 6a as a syrup. The second fraction was 0.2 g
1 ~"l
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(30%) of 6b also as a syrup. The column was then eluted
with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in
the third fraction as a solid. Recrystallization from
hexane gave a solid, mp 179-181 °C. Finally, the column
was eluted with 30% EtOAc-hexane to give 0.08 g (12%)
of 6d in the fourth fraction as a solid.
Recrystallization from hexane gave a solid, mp 160-161
°C.
B. Conversion of 6a to 6c and 6d With NaOH and PTC
To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL
CH~C1= , was added 9 g of 40% NaOH. The reaction mixture
was stirred for 0.5 h at room temperature and was added
one drop of Aliquat-336 (methyltricaprylylammonium
chloride) phase transfer catalyst (PTC). The mixture
was stirred for 0.5 h at room temperature before being
treated with 25 mL of ice-crystals then was extracted
with CH=C1= ( 3x10 ml ) , dried over MgSO, and concentrated
in vacuo to recover 0.17 g of a colorless film. The
components of this mixture were separated using an HPLC
and eluted with EtOAc-hexane to give 12.8 mg (4%) of 2-
(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the
first fraction, 30.9 mg (11%) of 6c in the second
fraction and 90.0 mg (31%) of 6d in the third fraction.
Oxidation of 6a to 5b
To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of
CH,C1~ was added 0.23 g (1.0 mmole) of pyridinium
chlorochromate. The reaction mixture was stirred for 2
h then was treated with additional 0.23 g of pyridinium
chlorochromate and stirred overnight. The dark reaction
mixture was poured into a ceramic filterfrit containing
silica gel and was eluted with CH=C1,. The filtrate was
concentrated in vacuo to recover 167 mg (87%) of 5b as
a colorless oil.
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~xamDle 4
3-Butyl-3-ethyl-5-phenyl-2,3-dihydrobenzothiepine-1,1-
~ _ _
dioxide ( 7 ) ~ Soi
0
To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of
CH~Cl,was added 10 g (31.9 mmole)of 50-60% MCPBA (m-
chloroperoxybenzoic acid) portionwise causing a mild
reflux and formation of a white solid. The reaction
mixture was allowed to stir overnight under N= and was
triturated with 25 mL of water followed by 50 mL of 10%
~NaOH solution. The organic was extracted into CH=Cl=
(4x20 mL). The CH=Cl=extract was dried over MgSO, and
evaporated to dryness to recover 4.9 g (87%) of an
opaque viscous oil.
IS
~~,amD 1 a 5
(laa,2b,Bba ) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-
tetrahydro-benzothiepino[4,5-b]oxirene-4,4-dioxide (8a)
(laa,2a,8ba) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-
tetrahydro-benzothiepino [4,5-b]oxirene-4,4-dioxide
( 8b ) Soy st~i
~4--
g~ ° c~b~
To 1.3 4.03 mole) of in 25 mL of CHC1~ was added
portionwise 5 g (14.1 mmole) of 50-60 % MCPBA causing a
mild exotherm. The reaction mixture was stirred under
N= overnight and was then held at reflux for 3 h. The
insoluble white slurry was filtered. The filtrate was
extracted with 10% potassium carbonate (3x50 mL), once
with brine, dried over MgSO,, and concentrated in vacuo
to give 1.37 g of a light yellow oil. Purification by
HPLC gave 0.65 g of crystalline product. This product
is a mixture of two isomers. Trituration of this
crystalline product in hexane recovered 141.7 mg (10%)
of a white crystalline product. This isomer was
characterized by NMR and mass spectra to be the
(laa,2b,8ba) isomer 8a. The hexane filtrate was
concentrated in vacuo to give 206 mg of white film
which is a mixture of 30% 8a and 70% 8b by 'H NMR.
16g
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s°z
v ,y ~S~h . S~
~nr O
Example 6 ° C~a~ ~cl~
cis-3-Hut 1-3-eth 1-5- hea 1-2 3~ 5-tetrah dro-
Y Y p Y ~ ~ ~ Y C
benzothiepine-1,1-dioxide (9a), traps-3-Hutyl-3-ethyl
5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(9b), and 3-Hutyl-3-ethyl-4-hydroxy-5-cyclohexylidine-
2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (10)
A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a
and 8b was dissolved in 15 ml MeOH in a 3 oz.
~Fisher/Porter vessel, then was added 0.1 g of l0% Pd/C
catalyst. This mixture was hydrogenated at 70 psi H=
for 5 h and filtered. The filtrate was evaporated to
dryness in vacuo to recover 0.117 g of a colorless oil.
This material was purified by HPLC eluting with EtOAc-
hexane. The first fraction was 4.2 mg (3%) of 9b. The
second fraction, 5.0 mg (4%), was a 50/50 mixture of 9a
and 9b. The third fraction was 8.8 mg (6%) of 6a . The
fourth fraction was 25.5 mg (18%) of 6b. The fifth
fraction was 9.6 mg (7%) of a mixture of 6b and a
product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-
phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
based on mass spectrum. The sixth fraction was 7.5 mg
(5%) of a mixture of 6d and one of the isomers of 10,
10a.
Example 7
In another experiment, a product (3.7 g) from
epoxidation of 3 with excess MCPBA in refluxing CHC1,
under air was hydrogenated in 100 mL of methanol using
1 g of 10% Pd/C catalyst and 70 psi hydrogen. The
product was purified by HPLC to give 0.9--g--(25%) of 9b,
0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of
6b,Ø02 g (1%) of 6c, 0.06 g (2%.) of one isomer of 10,
l0a and 0.03 g (1%) of another isomer of 10, i0b.
l'7 l~ .
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S ~ , .~~d
H
v
Example 8 ~ ~~~~
2-((Z-Benzoylphenylthio)methyl)butyraldehyde (11)
To an ice bath cooled solution of 9.76 g (0.116 mole )
of 2-ethylacrolein in 40 mL.of dry THF was added 24.6 g
(0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF
followed by I3 g (0.128 mole) of triethylamine. The
reaction mixture was stirred at room temperature for 3
days , diluted with ether, and was washed successively
with dilute HC1, brine, and 1 M potassium carbonate.
The ether layer was dried over MgSO, and concentrated
in vacuo. The residue was purified by HPLC (10% EtOAc-
hexane) to give 22 g (64%) of il in the second
fraction. An attempt to further purifiy this material
by kugelrohr distillation at 0.5 torr (160-190 °C) gave
a fraction (12.2 g) which contained starting material
indicating a reversed reaction during distillation.
This material was dissolved in ether (100 mL) and was
washed with SO mL of 1 M potassium carbonate three
times to give 6.0 g of a syrup which was purified by
HPLC (10% EtOAc-hexane) to give 5.6 g of pure il.
Exam lp a 9
O
3-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12)
m
a
To a mixture of 2.61 g (0.04 mole) of zinc dust and 60
mL of DME was added 7.5 g (0.048 mole) of TiCl,. The
reaction mixture was held at reflex for 2 h. A solution
of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h.
The reaction mixture was held at reflex for 18 h,
___ cooled and poured into water. The organic was extracted
into ether. The ether layer was washed with brine and-
filtered through Celite. The filtrate was dried over
MgSO, and concentrated. The residual oil (2.5 g) was
purified by HPLC to give 2.06 g (77%) of 12 as an oil
in the second fraction.
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S°z
Example 10
v ~ ~13~
(laa,2a,8ba) 2-Ethyl-8b-phenyl-1a,2,3,8b-tetrahydro-
benzothiepino-j4,5-b]oxirene-4,4-dioxide (13)
To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of
CHC1, was added 6.8 g (19.4 mmole) of 50-60% MCPB
portionwise causing an exothem and formation of a white
solid. The mixture was stirred at room temperature
overnight diluted with 100 ml methylene chloride and
washed successively with 10% K,CO, (4x50 ml), water
'(twice with 25 ml) and brine. The organic layer was
then dried over MgSO, and evaporated to dryness to
recover 1.47 g of an off white solid. 1H NMR indicated
that only one isomer is present. This solid was
slurried in 200 ml of warm Et,O and filtered to give
0.82 g (46%) of 13 as a white solid, mp 185-186.5 °C.
Example 11
(3a,4b,5a)- 3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydro-benzothiepine-1,1-dioxide (14a), (3a,4b,5b)
3-Ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (14b), aad cis-3-
Ethyl-5-phenyl-2,3,4,5-tetrahydro-benzothiepine-1,1-
dioxide ( 15 ) ~ ''t ft ~5~~ ft Ns°L ~ E
C~~~ i 4 ~'~b~ ~,~ t
O o H C q~ Q o H C S,
A mixture of 0.5 g (1.6 mole) of 13, 50 ml of ace is
acid and 0.5 g of 10% Pd/C catalyst was hydrogenated
with 70 psi hydrogen for 4 h. The crude. reaction slurry
was filtered and the filtrate was stirred with 150 ml
of a saturated NaHCO, solution followed by 89 g of
NaHCO,.powder portionwise to neutralize the rest of
acetic acid. The mixture was extracted with methylene
chloride (4x25 mI), then the organic layer was dried
over MgSO, and concentrated in vacuo to give 0.44 g
(8?%) of a voluminous white solid which was purified by
HPLC (EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the
first fraction, 272 mg (54%) of 14a as a solid, mp 142-
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143.5 °C, in the second fraction, and 35 mg (7%) of
impure 14b in the third fraction.
Ex~ple 12
2-Ethyl-2-((2-Hydroxymethylphenyl)thiomethyl)hexenal
(16) "'1s
p
~'C~ 67
°H H
A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl
alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of
~triethylamine and 25 mL of 2-methoxyethyl ether was
held at reflux for 7 h. Additional 1.1 g of
mercaptobenzyl alcohol and 0.72 g of triethylamine was
added to the reaction mixture and the mixture was held
at reflux for additional 16 h. The reaction mixture was
cooled and poured into 6N HCl and extracted with
methylene chloride. The methylene chloride extract was
washed twice with 10% NaOH, dried over MgSO, and
concentrated in vacuo to give 9.6 g of residue.
Purification by HPLC (20% EtOAc-hexane) gave 3.7 g
(41%)of 16 as an oil.
~5 - ~~C"
Example 13 ° 'o
2-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17)
A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of
pyridinium chlorochromate, 2 g of Celite and 30 mL of
methylene chloride was stirred for 18 h and filtered
through a bed of silica gel. The silica,gel was eluted
3o with methylene chloride. The combined methylene
chloride eluant was purified by HPLC (20% ETOAc-hexane)
to give 2.4 g (66%) of an oil. -
Example 14
C1 ~,
3-Butyl-3-ethyl-2,3-dihydrobenzothiepiae (18)
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g
(0.047 mole) of TiCl,, and 50 mL of DME was held at
x'13
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reflex for 2 h and cooled to room temperature.. To this
mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of
DME in 10 min. The reaction mixture was stirred at room
temperature for 2 h and held at reflex for 1 h then was
let standing at room temperature over weekend. The
reaction mixture was poured into dilute HC1 and was
stirred with methylene chloride. The methylene
chloride-water mixture was filtered through Celite. The
methylene chloride layer was washed with brine, dried
over MgSO,, and concentrated in vacuo to give 3.0 g of
~a residue. Purification by HPLC gave 0.41 g (20%) of 18
as an oil in the early fraction.
Example 15
IS (laa,2a,8ba ) 2-Butyl-2-ethyl-1a,2,3,8b-tetrahydro-
benzothiepino[4,5-b7oxirene-4,4-dioxide (19a) and
(laa,2b,8ba) 2-Butyl-2-ethyl-8b-phenyl-1a,2,3,8b-
tetrahydro-benzothiepino[4,5-b7oxirene-4,4-dioxide
(19b) a Sc1 ,~ ~S°i 6~.
~ _ ''« Et
0 ~'~ =o'
To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30
mL of methylene chloride was added 2.2 g (3.2 mmole) of
50-60% MCPBA. The reaction mixture was stirred for 2 h
and concentrated in vacuo. The residue was dissolved in
3 0 mL of CHC1, and was held at ref lux f or 18 h under N~ .
The reaction mixture was stirred with 100 mL of 10%
NaOH and 5 g of sodium sulfite. The methylene chloride
layer was washed with brine, dried over MgSO, and
concentrated in vacuo. The residue was purified by HPLC
(20% EtOAc-hexane) to give a third fraction cahich was
further purified by HPLC (10% EtOAc-hexane) to give
0.12 g of syrup in the first fraction.
Recrystallization from hexane gave 0.08 g (17%) of 19a,
mp 8.9.5-105.5 °C. The mother liquor from the first
fraction was combined with the second fraction~and was
further purified by HPLC to give additional 19a in the
first fraction and 60 mg of 19b in the second fraction.
1 '7 ~-
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Crystallization from hexane gave 56 mg of a white
solid.
Example 16
3-Hutyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-
tetrahydro-benzothiepine-1,1-dioxide (20) ~~So1
O
This product was isolated along with 6b from H a
hydrogenation of a mixture of 8a and 8b. " (2uj
~'~amflle 17
3-Hutyl-3-ethyl-4-hydroxy-5-phenylthio-2,3,4,5-
Sv1 8
tetrahydro-benzothiepine-1,1-dioxide (21) p
~'s c N
A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 (Z1~
mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium
carbonate, and 4 mL of DMF was stirred at room
temperature under N, for 19 h. The reaction mixture was
poured into water and extracted with methylene
chloride. The methylene chloride layer was washed
successively with 10% NaOH and brine, dried over MgSO,,
and concentrated in vacuo to give 0.19 g of semisolid
which contain substantial amounts of diphenyl
disulfide. This material was purified by HPLC (5%
EtOAc-hexane) to remove diphenyl disulfide in the first
fraction. The column was then eluted With 20% EtOAc-
hexane to give 17 mg of a first fraction, 4 mg of a
second fraction and 11 mg of a third fraction which.
were three different isomers of 21, i.e. 21a, 21b, and
21c, respectively, by iH NMR and mass spectra.
Example 18
Alternative Synthesis of 6c and 6d
A. Preparation from 2-((2-Henzoylphenylthio)methyl)-2-
ethylhexanal (2)
Step 1. 2-((2-Henzoylphenylsulfonyl)methyl)-2
ethylhexaaal (44) SOt eK
o J Et
L ~1~ ''
c~-~
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To a solution of 9.0 g (0.025 mole) of compound 2 in
100 ml of methylene chloride was added 14.6 g (0.025
mol) of 50-60% MCPBA portionwise. The reaction mixture
was stirred at room temperature for 64 h then was
stirred with 200 ml of 1 M potassium carbonate and
filtered through Celite. The methylene chloride layer
was washed twice with 300 ml of 1 M potassium
carbonate, once with 10% sodium hydroxide and once with
brine. The insoluble solid formed during washing was
removed by filtration through Celite. The methylene
.chloride solution was dried and concentrated in vacuo
to give 9.2 g (95%)of semisolid. A portion (2.6 g) of
this solid was purified by HPLC(10% ethyl acetate-
hexane) to give 1.9 g of crystals, mp 135-I36 °C
Step 2. 2-((2-Henzylphenylsulfonyl)methyl)-2-
S ~Z~EE
ethylhexanal (45)
A solution of 50 g (0.13 mole) of crude 44 in 250 ml of
methylene chloride was divided in two portions and
charged to two Fisher-Porter bottles. To each bottle
was charged 125 ml of methanol and 5 g of 10% Pd/C. The
bottles Were pressurized with 70 psi of hydrogen and
the reaction mixture was stirred at room temperature
for 7 h before being charged with an additional 5 g of
10% Pd/C. The reaction mixture was again hydrogenated
with 70 psi of hydrogen for 7 h. This procedure was,
repeated one more time but only 1 g of Pd/C was charged
to the reaction mixture. The combined reaction mixture
was filtered and concentrated in vacuo to give 46.8 g
of 45 as brown oil.
Step 3. (3a,4a,5a) 3-8uty1-3-ethyl-4-hydroxy-5-phenyl-
2,3,4,5-tetrahydrobenzothiepine-l,l-dioxide (6c), aad
(3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydrobenzothiepiae-1,1-dioxide (6d)
1'1 ~
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To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of
anhydrous THF cooled to 2 °C with an ice bath was added
9.7 g (73.4 mmole) of 95% potassium t-butoxide. The
reaction mixture was stirred for 20 min, quenched with
300 ml of 10% HC1 and extracted with methylene
chloride. The methylene chloride layer was dried over
magnesium sulfate and concentrated in vacuo to give
24.7 g of yellow oil. Purification by HPLC (ethyl
acetate-hexane) yielded 9.4 g of recovered 45 in the
first fraction, 5.5 g (20%) of 6c in the second
fraction and 6.5 g (24%) of 6d in the third fraction.
H. Preparation from 2-hydroxydiphenylmethana
Step 1. 2-iaercaptodiphenyhaethane (46) ~ C
is
To a 500 ml flask was charged I6 g (0.33 mol) of 60%
sodium hydride oil dispersion. The sodium hydride was
washed twice with 50 ml of hexane. To the reaction
flask was charged 100 ml of DID'. To this mixture was
added a solution of 55.2 g (0.3 mol) of 2-
hydroxydiphenylmethane in 200 ml of DMF in 1 h while
temperature was maintained below 30 °C by an ice-water
bath. After complete addition of the reagent, the
mixture was stirred at room temperature for 30 min then
cooled with an ice bath. To the reaction mixture was
added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl
chloride at once. The ice bath was removed and the
reaction mixture was stirred at room temperature for l8
h before being poured into 300 ml of water. The organic
was extracted into 500 ml of toluene. The toluene layer
_was washed..successively with 10% sodium hydroxide and
brine and.was concentrated in vacuo to give 78.6 g of a
yellow oil which was 95% pure dimethyl 0-2-benzylphenyl
thiocarbamate. This oil was heated at 280-300 ~°C in a
kugelrohhr pot under house vacuum for 30 min. The
residue was kugelrohr distilled at 1 torn (180-280 °C).
The distillate (56.3 g) was crystallized from methanol
to give 37.3 g (46%) of the rearranged product dimethyl
l "1'l
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S-2-benzylphenyl thiocarbamate as a yellow solid. A
mixture of 57 g (0.21 mole) of this yellow solid, 30 g
of potassium hydroxide and 150 ml of methanol was
stirred overnight then was concentrated in vacuo. The
residue was diluted with 200 ml of water and extracted
with ether. The aqueous layer was made acidic with
concentrate HC1, The oily suspension was extracted into
ether. The ether extract was dried over magnesium
sulfate and concentrated in vacuo. The residue was
crystallized from hexane to give 37.1 g (88%) of 2
mercaptodiphenylmethane as a yellow solid.
Step 2. 2-((2-Henzylphenylthio)methyl)-2-ethylhexanal
(47) v ~S~Et
~s ~ H J c
A mixture of 60 g (03 mole) of yellow solid from step
1, 70 g (0.3 mole) of compound 1 from preparation 1,
32.4 g (0.32 mole) of triethylamine, 120 ml of 2-
methoxyethyl ether was held at reflux for 6 hr and
concentrated in vacuo. The residue was triturated with
-500 ml of water and 30 ml of concentrate HC1. The
organic was extracted into 400 ml of ether. The ether
layer was washed successively with brine, 10% sodium
hydroxide and brine and was dried over magnesium
sulfate and concentrated in vacuo. The residue (98.3 g)
was purified by HPLC with 2-5% ethyl acetate-hexane as
eluent to give 2-((2-benzylphenylthio)methyl)-2-
ethylhexanal 47 as a yellow syrup.
Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2-
ethylhexanal - ( 4 5 ) ~ S ~'L
Et
~~ s~
To a solution of 72.8 g (0.21 mole) of yellow syrup
from step 2 in 1 liter of methylene chloride cooled to
10 °C was added 132 g of 50-60% MCPBA in 40 min. The
reaction mixture was stirred for 2 h. An additional 13
g of 50-60% MCPHA was added to the reaction mixture.
The reaction mixture was stirred for 2 h and filtered
(1$
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through Celite. The methylene chloride solution was
washed twice with 1 liter of 1 M potassium carbonate
then with 1 liter of brine. The methylene chloride
layer was dried over magnesium sulfate and concentrated
to 76 g of 2-((2-benzylphenylsulfonyl)methyl)-2-
ethylhexanal 45 as a syrup.
Step 4. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-
2,3,4,5-tetrahydrobenzothiepiae-1,1-dioxide (6c), and
(3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (6d)
Reaction of 45 with potassium t-butoxide according to
the procedure in step 3 of procedure A gave pure 6c and
6d after HPLC. S Ete~
~J v
Exams 1 a 19 ~c O a b ~ C 22'
(3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-8-methoxy-5-
phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (25)
and (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-B-methoxy-5-
phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (26)
Step 1. Preparation of 2-((2-benzoyl-4-methoxy
phenylthio)methyl)-2-ethylhexanal (22)
2-Hydroxy-4-methoxybenzophenone was converted to the
dimethyl 0-2-benzoyphenyl thiocarbamate by methods
previously described in example 18. The product can be
isolated by recrystallization from ethanol. Using this
improved isolation procedure no chromatography was
needed. The thermal rearrangement was performed by
reacting the thiocarbamate( 5 g) in diphenyl ether at
260 °C as previously described. The improved isolation
procedure which avoided a chromatography step was
described below.
-_ 35
The crude pyrolysis product was then heated at 65 °C in
100 ml of methanol and 100 ml of THF in the presence of
3._5 g of KOH for 4 h. After removing THF and methanol
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by rotary evaporation the solution was extracted with 5
~ NaOH and ether. The base layer was acidified and
extracted with ether to obtain a 2.9 g of crude
thiophenol product. The product was further purified by
titrating the desired mercaptan into base with limited
KOH. After acidification and extraction with ether pure
2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.
2~mercapto-4-methoxybenzophenone can readily be
IO converted to the 2-((2-benzoyl-4-
~methoxyphenylthio)methyl)-2-ethylhexanal (22) by
reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as
previously described.
Step 2. 2-((2-Henzoyl-5-methoxyphenylsulfonyl)methyl)-
et
y~ g k
2-ethylhexanal (23) i;3 °
° (z3)
v
v
Substrate 22 was readily oxidized to 2-((2-benzoyl-5-
methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (23) as
described in example 18 . ~y ~~ 5~1-.cue tt
j v o ~~ a ~, ~ 2 4~
0
Step 3. 2-((2-benzyl-5-methoxyphenylsulfonyl)methyl)-2-
ethylhexanal (24)
Sulfone 23 was then reduced to 2-((2-benzyl-5-
methoxyphenyl-sulfonyl)methyl)-2-ethylhexanal (24) as
described in example 18. t~3 °~~sv''
_ ''~ ('I5>
oN
Step 4. (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-8-methoxy-
5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(25) and (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-8-
methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1=
dioxide (26) ~~~5~'L
0
O
A 3-neck flask equipped with a powder addition"°u
funnel, thermocouple and nitrogen bubbler was charged
with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry
THF. The reaction was cooled to -1.6 °C internal
($O
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temperature by means of ice/salt bath. Slowly add 5.61
g (0.05 mole) of potassium t-butoxide by means of the
powder addition funnel. The resulting light yellow
solution was maintained at -1.6 °C. After 30 min
reaction 400 ml of cold ether was added and this
solution was extracted with cold 10 ~ HCl. The acid
layer was extracted with 300 ml of methylene chloride.
The organic layers were combined and dried over
magnesium sulfate and after filtration stripped to
dryness to obtain 19.9 g of product. iH nmr and glpc
indicated a 96% conversion to a 50/50 mixture of 25 and
26. The only other observable compound was 4$ starting
sulfone 24.
The product was then dissolved in 250 ml of 90/10
hexane/ethyl acetate by warming to 50 °C. The solution
was allowed to cool to room temperature and in this way
pure 26 can be isolated. The crystallization can be
enhanced by addition of a seed crystal of 26. After 2
crystallizations the mother liquor which was now 85.4
and has a dry weight of 8.7 g. This material was
dissolved in 100 ml of 90/10 hexane/ethyl acetate and
10 ml of pure ethyl acetate at 40 C. Pure 25 can be
isolated by seeding this solution with a seed crystal
25 of 25 after storing it overnight at 0 C.
~t o S°t 8
~1.~ o ok
(3a,4a,5a) 3-Hutyl-3-ethyl-4,8-dihydroxy-5-phenyl-
2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (27)
In a _25 ml -round _bottomed_ flask, 1 g of 26 ( 2.5 mmoles)
and 10 ml methylene chloride were cooled to - 78 °C
with stirring. Next 0.7 ml of boron tribromide(7.5
mmole) was added via syringe. The reaction was allowed
to slowly warm to room temperature and stirred for 6 h.
The reaction was then diluted with 50 ml methylene
chloride and washed with saturated NaCI and then
water. The organic layer was dried over magnesium
CA 02283575 1999-09-09
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sulfate. The product (0.88g) 27 was characterized by
NMR and mass spectra.
Example 21
General Alkylation of phenol 27
A 25 ml flask was charged with 0.15 g of 27(0.38
mmole), 5 ml anhydrous DI~', 54 mg of potassium
carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9
mmole). The reaction was stirred at room temperature
,overnight. The reaction was diluted with 50 ml ethyl
ether and washed with water (25 ml) then 5~ NaOH (20
ml) and then sat. NaCl. After stripping off the solvent
the ethoxylated product 28 was obtained in high yield.
The product was characterized by NNgt and mass spectra.
This same procedure was used to prepare products listed
in table 1 from the corresponding iodides or bromides.
For higher boiling alkyl iodides and bromides only one
equivalent of the alkyl halide was used.
0 0
Ro \ : S ,'
i
~,, off
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Table 1
Compound No. R
27 H
26 Me
28 Et
29 hexyl
30 Ac
31 (CH2)6-N-pthalimide
(3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-7-hydroxyamino-5-
phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (37)
and (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-7-
hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-
IS 1,1-dioxide (38)
Step 1. Preparation of 2-chloro-5-nitrodiphenylmethane
cv
(32) 1
0
Nvi
Procedure adapted from reference :Synthesis -Stuttgart
9 770-772 (1986) Olah G. Et al
Under nitrogen, a 3 neck flask was charged with 45 g
(0.172 mole ) of 2-chloro-5-nitrobenzophenone in 345 ml
methylene chloride and the solution was cooled to
ice/water temperature. By means of an additional
funnel, 150 g( 0.172 mole) of trifluoromethane sulfonic
acid in 345 ml methylene chloride was added slowly.
Next 30 g of triethylsilane (0.172 mole) in 345 ml
methylene chloride was added dropwise to the chilled
solution. Both addition steps( trifluoromethane
sulfonic acid and_triethylsilane)were repeated. After
the additions were completed the reaction was allowed
to slowly warm up to room temperature and stirred for
12 h under nitrogen. The reaction. mixture was then
poured into a chilled stirred solution of 1600 ml of
saturated sodium bicarbonate. Gas evolution occurred.
Poured into a 4 liter separatory funnel and separated
layers.. The methylene chloride layer was isolated and
(83
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combined with two 500 ml methylene chloride extractions
of the aqueous layer. The methylene chloride solution
was dried over magnesium sulfate and concentrated in
vacuo. The residue was recrystallized from hexane to
give 39 g product. Structure 32 was confirmed by mass
spectra and proton and carbon NMR.
~~r
G -v
Step 2. Preparation of 2-((2-benzyl-4-~iN
nitropheaylthio)methyl)-2-ethylhexanal (33) (33,
The 2-chloro-5-nitrodiphenylmethane product 32 (40 g,
0.156 mole) from above was placed in a 2 liter 2 neck
flask with water condenser. Next 150 ml DMSO and 7.18 g
(0.156 mole) of lithium sulfide was added and the
solution was stirred at 75 °C for 12 h. The reaction
was cooled to room temperature and then 51.7 g of
mesylate IV was added in 90 ml DMSO. The reaction
mixture was heated to 80 °C under nitrogen. After 12 h
monitored by TLC and added more mysylate if necessary.
Continued the reaction until the reaction was
completed. Next the reaction mixture was slowly poured
into a 1900 ml of 5~ acetic aqueous solution with
stirring, extracted with 4 X 700 ml of ether, and dried
over MgS04. After removal of ether, 82.7 g of product
was isolated. The material can be further purified by
silica gel chromatography using 95~ hexane and 5 %
ethyl acetate. If pure mysylate was used in this step
there was no need for further purification. The
product 33 was characterized by mass spectra and NMR.
Step 3. Oxidation of the vitro product 33 to the
sulfoae 2-((2-benzyl-4-aitrophenylsulfonyl)methyl)-2-
ethylhexanal (34)
The procedure used to oxidize the sulfide 33 to the
sulfone 34 has been previously described.
S°L sk
o ~ C-E
ON
t ~ ~ N C34
1~~-
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WO 98/40375 PCT/US98103792
~~i' r,.,i ... '
~E
ik~~Ju
Step 4. Reduction of 34 to 2-((2-benzyl-4-
hydroxyaminophenylsulfonyl)methyl)-2-ethylhexanal (35)
A 15 g sample of 34 was dissolved in 230 ml of ethanol
and placed in a 500 ml rb flask under nitrogen. Next
1.5 g of 10 wt.% Pd/C was added and hydrogen gas was
bubbled through the solution at room temperature until
the nitro substrate 34 was consumed. The reaction could
be readily monitored by silica gel TLC using 80/20
to hexane/EtOAc. Product 35 was isolated by filtering off
the Pd/C and then stripping off the EtOH solvent. The
product was characterized by Nl~t and mass spectra.
Step 5. Preparation of the 2-((2-benzyl-4-N,O-di-(t-
butoxy-carbonyl)hydroxyaminophenylsulfonyl)methyl)-2 5~~
a thylhexanal ( 3 6 ) . a°c ° ~ ° ~ Et
cl~c o- ~'
A 13.35 g sample of 35 (0.0344 mole) in 40 ml of dry '~
THF was stirred in a 250 ml round bottomed flask. Next
added 7.52 g (0.0344 mole) of di-t-butyl dicarbonate in
7 ml THF. Heated at 60 °C overnight. Striped off THF
and redissolved in methylene chloride. Extracted with
1 % HCl; and then 5% sodium bicarbonate.
The product was further purified by column
chromatography using 90/IO hexane/ethyl acetate and
then 70/30 hexane/ethyl acetate. The product 36 was
obtained (4.12 g) which appeared to be mainly the di-
( t-butoxycarbonyl ) derivatives by proton NIA. ~~S°~ 8;,~
Ii~N~ ~'~E
Step 6. (3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-7-
- (31
- 30 hydroxyamino-5-phenyl-2,3,4,5-tetrahydrobenzothiepine
I,1-dioxide (37) and (3a,4b,5b) 3-Hutyl-3-ethyl-4-
hy~oxy-7-hYdroxyamino-5-phenyl-2,~3, 4, 5- -. __ sat
tetrahydrobenzothiepine-1,1-dioxide (38)ItoNk ~
oc~ (3s~
A 250m1 3-neck round bottomed flask was charged with 4
g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and
cooled to -78 °C under a nitrogen atmosphere. Slowly
add 2,.29 g potassium tent-butoxide(20.4 mmoles) with
~ ~5
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stirring and maintaining a -78 °C reaction te.-nperature.
After 1 h at -78 °C the addition of base was completed
and the temperature was brought to -10 °C by means of a
ice/salt bath. After 3 h at -10 °C, only trace 36
remained by TLC. Next add 35 ml of deionized water to
the reaction mixture at -10 °C and stirred for 5 min.
Striped off most of the THF and added to separatory
funnel and extracted with ether until all of the
organic was removed from the water phase. The combined
ether phases were washed with saturated NaCl and then
dried over sodium sulfate. The only products by TLC and
NMR were the two BOC protected isomers of 37 and 38.
The isomers were separated by silica gel chromatography
using 85~ hexane and 15 ~ ethyl acetate; BOC-37 (0.71
g) and BOC- 38 (0.78 g).
Next the BOC protecting group was removed by reacting
0.87 g of HOC-38 (1.78 mmoles) with 8.7 ml of 4 M HC1
(34.8 mmoles)in dioxane for 30 min. Next added 4.74 g
of sodium acetate (34.8 mmoles) to the reaction mixture
and 16.5 ml ether and stirred until clear. After
transferring to a separatory funnel extracted with
ether and water and then dried the ether layer with
sodium sulfate. After removing the ether, 0.665 g of 38
was isolated. Isomer 37 could be obtained in a similar
procedure . o s~z
~EE
no"~'~ ° I+( v ( 3q, _
Fxam~le 23
(3a,4a,5a) 3-Butyl-3-ethyl-7-(a-hexylamino)-4-hydroxy-
5-phenyl-2,3,4,5-tetrahydrcbenzothiepine-1,1-dioxide
(40) and (3a,4b,5b) 3-Butyl-3-ethyl-7-(a-hexylamino)-4-
hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (41)
Step 1. 2-((2-Henzyl-4-(n-
hexylamino)phenylsulfonyl)methyl)-2-ethylhexanal (39)
In a Fischer porter bottle weighed out 0.5 g of 34 (1.2
mmoles) and dissolved in 3.8 ml of ethanol under
l$6
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nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of
hexanal. Seal and pressure to 50 psi of hydrogen gas.
Stirred for 48 h. After filtering off the catalyst and
removing the solvent by rotary evaporation 39 was
~ isolated by column chromatography (0.16 g) using 90/10
hexane ethyl acetate and gradually increasing the
mobile phase to 70/30 hexane/ethyl acetate. The product
was characterized by N1~ and mass spectra.
,Step 2. (3a,4a,5a) 3-Hutyl-3-ethyl-7-(n-hexylamino)-4-
hydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (40) and (3a,4b,5b) 3-Hutyl-3-ethyl-7-(n-
hexylamino)-4-hydroxy-5-phenyl-2,3,4,5- p s~z Rq
tetrahydrobenzothiepine-l, l-dioxide (41) HeF~''~
IS ~ a 4 C4o
A 2-neck, 25 ml round bottomed flask with stir bar was
charged with 0.158 g 39 (0.335 mmole) and 5 ml
anhydrous THF under nitrogen. Cool to -10 °C by means
of a saltwater bath. Slowly add 0.113 g of potassium
tert butoxide (0.335 mmole). After 15 min at -10 °C all
of the starting material was consumed by TLC and only
the two isomers 40 and 41 were observed. Next added 5
ml of chilled 10% HC1 and stirred at -10 °C for 5 min.
Transferred to a separatory funnel and extract with
ether. Dried over sodium sulfate. Proton NN~ of the
dried product (0.143 g) indicated only the presence of
the two isomers 40 and 43. The two isomers were
separated by silica gel chromatography using 90/10
hexane ethyl acetate and gradually increasing the
mobile phase to 70/30 hexane/ethyl acetate. 40 ( 53.2
mg): 41(58.9 mg). 5°~
u4' - ~, C 4 ~
Example 24~
v
Quateraization of amine substrates 40 and 41
Amine products such as 40 and 41 can be readily
alkylated to quaternary salts by reaction with alkyl
halides. For example 40 in DMF with 5 equivalents of
l ~'1
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methyl iodide in the presence of 2.6 dimethyl lutidine
produces the dimethylhexylamino quaternary salt.
.~S°y,
...,E ( 42~
~xamnle 25 ou
(3a,4b,5b) 3-Hutyl-3-ethyl-4-h~ydroxy-5-(4-iodophenyl)-
2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (42)
In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d
0.67 g of mercuric triflate were dissolved in 20 ml
of dry methylene chloride with stirring. Next 0.34 g of
Iodine was added and the solution was stirred at room
temperature for 30 h. The reaction was then diluted
with 50 ml methylene chloride and washed with 10 ml of
1 M sodium thiosulfate; 10 ml of saturated KI ; and
IS dried over sodium sulfate. See Tetrahedron, Vo1.50.
No. I7, pp 5139-5146 (1994) Bachki. F. Et al. Mass
spectrum indicated a mixture of 6d , mono iodide 42 and
a diiodide adduct. The mixture was separated by column
chromatography and 42 was characterized bt NMR and mass
Sv
spectra. V
'w Et
o ~l~
Examble 26
o-
(3a,4b,5b) 3-Hutyl-5-(4-carbomethoxyphenyl)-3-ethyl-4-
hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(43)
A 0.1 g sample of 42 ( 0.212 mmole). 2.5 ml dry
methanol, 38 ul triethylamine (0.275 mmole) . 0.3 ml
toluene and 37 mg of palladium chloride (0.21 mmole)
3o was charged to a glass lined mini reactor at 300 psi
carbon monoxide. The reaction was heated at 100 °C
overnight. The catalyst was filtered and a high yield
of product was isolated.
The product was characterized by NMR and mass spectra.
Note the ester functionalized product 43 can be
converted to the free acid by hydrolysis.
l~$
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WO 98140375 PCT/US98/03792
Fxamule 27
(3a,4a,5a) 3-Hutyl-3-ethyl-4-hydroxy-7-methoxy-5-
phenyl-2,3,4,5-tetzahydrobenzothiepiae-1,1-dioxide
(48), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-
methoxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (49)
Step 1. 2-Mercapto-5-methoxybenzophenone (50) ~ a
ac~t~ (5=
Reaction of 66.2 g of 4-methoxythiophenol with 360 ml
l0 of 2.5 N n-butyllithium, 105 g of
~tetramethylethylenediamine and 66.7 g of benzonitrile
in 600 ml cyclohexane according to the procedure in WO
93/16055 gave 73.2 g of brown oil which was kugelrohr
distilled to remove 4-methoxythiophenol and gave 43.86
g of crude 50 in the pot residue.
Step 2. 2-((2-Henzoyl-4-methoxyphenylthio)methyl)-2-
ethylhexanal (51) c ~s
o ~_~ h~= E<
J
Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g
(0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of
triethylamine in 50 ml of diglyme according to the
procedure for the preparation of 2 gave 10.5 g of crude
product which was purified by HPLC (5~ ethyl acetate-
hexane) to give 1.7 g (22$) of 51.
Step 3. 2-((2-Henzoyl-4-methoxypheaylsulfonyl)methyl)-
2-ethyl-hexanal (52) o s°~ B:.
ta; ~ ° ~ Et Cs~~
o r~
A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of
methylene chloride was reacted with 2.0 g (6.2 mmoles)
' of 50-60% MCPBA according to the procedure of step 2 of
procedure~A in example 18 gave 1.16 g (90$) of 52 as a
yellow oil.
Step 4. 2-((2-Henzyl-4-methoxyphenylsulfonyl)methyl)-
2-ethylhexanal (53) 0 5°Z
B
i~3 v a EE
1.1 ~°
pq C53,
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WO 98140375 PCT/US98/03792
Hydrogenation of 1.1 g of 52 according to the procedure
of step 3 of procedure A of example 18 gave 53 as a
yellow oil (1.1 g).
Step 5. (3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-
5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide
(48), and (3a,4b,5b) 3-Hutyl-3-ethyl-4-hydroxy-7-
methoxy-5-phenyl-2,3,4,5-tetrahydrobeazothiepine-1,1-
dioxide (49) o srl 6~ ~S°~d.,
~'C-E u~c:J~>~_ "Et (~~i,
v o « ~,rEg 3 ' cH.
A solution of 1.1 g of 53, , .36 g o~potassium t-
butoxide and 25 ml of anhydrous THF was held at reflux
for 2 h and worked up as in step 4 of procedure A of
example 18 to give 1.07 g of a crude product which was
purified by HPLC to give 40 mg (4%) of 48 as crystals,
mp 153-154 °C and 90 mg (8%) of 49 as solid, mp 136-140
°C ~ ~s~t lk O
v
y 4
l~xam~le 28 v S'?~ ~ C5
5-Phenyl-2,3-dihydrospirobenzothiepine-3,1'-cyclohexane
(57)
Step 1. 1-(Hydroxymethyl)-cyclohexanecarboxaldehyde
(54)
To a cold (O~C'mixture of 100 g (0.891 mole) of
cyclohexanecarboxaldehyde, 76.5 g of 37% of
formaldehyde in 225 ml of methanol was added dropwise
90 ml of 1 N Sodium hydroxide in 1 h. The reaction
mixture was stirred at room temperature over 48 then
was evaporated to remove methanol. The reaction mixture
was diluted with water and extracted with__methylene
chloride. The organic layer was washed with water,
brine, and~dried over sodium sulfate and concentrated
under vacuum to give 75 g (59.7%) of thick oil. Proton
NNgt and mass spectra were consistent with the product.
Step 2. 1-(mesyloxymethyl)cyclohexaaecarboxaldehyde
(55) 0
. i~3 C _ S _ c3~~
1 °~ o
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To a cold (O~C'mixture of alcohol 54 (75 g, 0.54 mole)
and 65.29 g (0.57 mole) of methanesulfonyl chloride in
80 ml of methylene chloride was added a solution of
pyridine (47.96 g, 0.57 mole) in 40 ml of methylene
- chloride. The reaction mixture was stirred at room
temperature for 18 h then quenched with water,
acidified with conc. HC1 and extracted with methylene
chloride. The organic layer was washed with water,
brine, and dried over sodium sulfate and concentrated
under vacuum to give 91.63 g (77.8%) of thick oil.
Proton NI~t and mass spectra were consistent with the
product. o S
Step 3. 1-((2-
Heazoylphenylthio)methyl)cyclohexanecarboxaldehyde (56)
A mixture of 69 g (0.303 mole) of 2-
mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55,
32 g of triethylamine, and 150 ml of diglyme was
stirred and held at reflux for 24 h. The mixture was
cooled, poured into dil. HC1 and extracted with
methylene chloride. The organic layer was washed with
10% NaOH, water, brine, and dried over sodium sulfate
and concentrated under vacuum to remove excess diglyme.
This was purified by silica gel flush column (5% EtOAc:
Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton
NMR and mass spectra were consistent with the product.
Step 4. 5-Pheayl-2,3-dihydrospirobeazothiepine-3,1~-
cyclohexane ( S7 ) _ _ ~ S
.,_ C 5'?
To a mixture of 6.19 g of zinc dust and 100 ml of dry
DME was added TiCl,(I6.8 g, 0.108 mole) . The reaction
- 35 mixture was heated to reflux for 2 h. A solution of
compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was
added dropwise to the reaction mixture in 1 h and the
mixture was held at reflux for 18 h. The mixture was
lei
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cooled, poured into water and extracted with ether. The
organic layer was washed with water, brine, and dried
over sodium sulfate, filtered through celite and
concentrated under vacuum. The residue was purified by
HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white
solid, mp 90-91 ~C. Proton and carbon NMR and mass
spectra were consistent with the product.
~So1
° ' ~ c5~~
Exa_mnle 29
'8b-Phenyl-1a,2,3,8b-tetrahydrospiro(benzothiepino[4,5-
b]oxirene-2,1'-cyclohexane)-4,4-dioxide (58)
To a solution of 57 (4.6 g, 15 mmole) in 50 ml
chloroform under nitrogen was added 55% MCPBA (16.5 g,
52.6 mmole) portionwise with spatula. The reaction was
held at reflux for 18 h and washed with 10% NaOH(3X),
water, brine, and dried over sodium sulfate and
concentrated under vacuum to give 5 g of crude product.
This was recrystallized from Hexane/EtOAc to give 4.31
g (81%) of yellow solid, mp 154-155 ~C. Proton and
carbon NMR and mass spectra were consistent with the
5°z
product. G
Cs~~
Fxam~l a 3 0 ~ 011
tzans-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro
spiro(benzothiepine-3,1'-cyclohexane)-1,1-dioxide (59)
A mixture of 0.5 g (1.4 mmoles) of 58 , 20 ml of
ethano1.10 ml of methylene chloride and 0.4 g of 10%
Pd/C catalyst was hydrogenated with 70 psi hydrogen for
3 h at room temperature. The crude reaction slurry was
filtered through Celite and evaporated to dryness. The
residue was purified by HPLC (10%,EtOAc-Hexane, 25%
EtOAc-Hexane). The first fraction was 300 mg (60%) as a
white solid, mp 99-100 ~C. Proton NMR showed this was
a trans isomer. The second fraction gave 200 mg of
solid which was impure cis isomer.
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SJl
0
l6 0~
Fxam~le 31 p o N
cis-4-Hydroxy-5-phenyl-2,3,4,5-tetrahydro
spiro(benzothiepine-3,1'-cyclohexane)-l,l-dioxide (60)
s
To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of
CH,C1,, was added 8 g of 50% NaOH and one drop of
Aliquat-336 (methyltricaprylylammonium chloride) phase
transfer catalyst. The reaction mixture was stirred for
,10 h at room temperature. Twenty g of ice was added to
the mixture and the mixture was extracted with CH,Cl=
(3x10 ml) washed with water, brine and dried over MgSO,
and concentrated in vacuo to recover O.I5 g of crude
product. This was recrystallized from Hexane/EtOAc to
give 125 mg of white crystal, mp 209-210 'C . Proton
and carbon NMR and mass spectra were consistent with
the product. S Bw 5
C~ ~ ', Et ~ r~ ~t ~' 6 2
~u (6!,
~amr,~le 32
(3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydrobenzothiepine (61), and (3a,4b,5b) 3-Butyl-3-
ethyl-4-hydroxy-5-phenyl-2,3,4,5-
tetrahydrobenzothiepine (62)
To a solution of 0.5 g (1.47 mmole) of compound 47 in 5
ml of anhydrous THF was added 0.17 g (1.47 mmole) of
95% potassium t-butoxide. The reaction mixture was
stirred at room temperature for 18 h and quenched with
10 ml of 10% HC1. The organic was extracted into
methylene chloride. The methylene chloride extract was
_ dried over magnesium sulfate and concentrated in vacuo.
The residue was purified by HPLC (2% EtOAc-hexane) to
give 47 mg of 61 in the second fraction and 38 mg of 62
in the third fraction. Proton NMR~and mass spectra were
consistent with the assigned structures.
S0~
Fxam~ 1 a 3 3 ~ g,~ ~ 5~' g,,
n,, E~
~~'' oh
6 3~
C~93 ~~~)
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(3a,4a,5a) 3-Hutyl-3ethyl-4-hydroxy-7-amino-5-pheayl-
2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide (63) and
(3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-7-amino-5-phenyl-
2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide(64)
An autoclave Was charged with 200 mg of 37 in 40 cc
ethanol and .02 g 10 % Pd/C. After purging with
nitrogen the clave was charged with 100 psi hydrogen
and heated to 55 C. The reaction was monitored by TLC
and mass spec and allowed to proceed until all of 37
was consumed. After the reaction was complete the
catalyst was filtered and the solvent was removed in
vacuo and the only observable product was amine 63.
This same procedure was used to produce 64 from 38.
SJ
~5~~ g~ p ~ t 8
D
'''EC
~rco
j /~3co ''ON
Example 34 ~ G~ (b5> U
ocu
(3a,4a,5a) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'-
methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (65), and (3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-
7-methoxy-5-(3'-methoxyphenyl)-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (66).
Alkylation of e-methoxyphenol with 3-methoxybenzyl
chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3'-
methoxybenzyl)phenol in 35% yield. This material was
converted to compound 65, mp 138.5-141.5 °C, and
compound 66, mp 115.5-117.5 °C, by the procedure
similar to that in Example 18 method B.
~,,xample 35
(3a,4a,5a) ~3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5-(3'- -
(trifluoromethyl)phenyl)-2,3.4,5-
tetrahydrobenzothiepine-1,1-dioxide (67), and~~
(3a,4b;5b) 3-Butyl-3-ethyl-4-hydroxy-7-methoxy-5~-(3'-
(trifluoromethyl)phenyl)-2,3,4,5-
tetrahydrobenzothiepine-l,l-dioxide (68).
s°t 6
V e~, ~ ~., E~
c~~c o ~ ~~.EE 3 0
F c ~ a a (6'l~ ~ o ~
I q'~ 3 ~3' C& ~~
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WO 98/40375 PCT/US98/03792
Alkylation of 4-methoxyphenol with 3-
(trifluoromethyl)benzyl chloride according to the
procedure described in J. Chem. Soc. 2431 (1958) gave
4-methoxy-2-(3'-(trifluoromethyl)benzyl)phenol. This
material was converted to compound 67, mp 226.5-228 °C,
and compound 68, mp 188-190°C, byu the procedure
similar to that in Example 18 method B.s~
s~i 8c, v 3_~r
Ex~ple 36~~
''
0
l0 (3a,4a,5a) 3-B ty -3-ethyl-5-(4'-.fluorophenyl)-4
Ihydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (69), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-
fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (70).
IS
Alkylation of 4-methoxyphenol with 4-fluorobenzyl
chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4'-
fluorobenzyl)phenol. This material was converted to
20 compound 69 and compound 70 by the procedure similar to
that in Example 18 method B. v i°t cJ 5''z
c o'~ B..
y~'~ ~ Y_
Example 37 F ° °H (-~11~ F
(3a,4a,5a) 3-Butyl-3-ethyl-5-(3'-fluorophenyl)-4-
25 hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (71), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(3'-
fluorophenyl)-4-hydroxy-7-methoxy-2,3,4,5-
tetrahydrobenzothiepine-l,l-dioxide (72).
30 Alkylation of 4-methoxyphenol with 3-fluorobenzyl
chloride according to the procedure described in J.
- Chem. Soc,.2431 (1958) gave 4-methoxy-2-(3'-
- fluorobenzjrl)phenol. This material was converted to
compound 71 and compound 72 by the~procedure similar to
35 that in Example 18 method B.
~s~c
8~ o B4
Exams 1 a 3 8 N~ v \ '~~ ~ Et ~\ 'c,
F & c3
~ F d ~''ou
c 3) ~ C-~ ~-~
(AS
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(3a,4a,5a) 3-Butyl-3-ethyl-5-(2'-fluorophenyl)-4-
hydroxy-7-methoxy-2,3,4,5-tetrahydrobenzothiepine-l,l-
dioxide (73), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(2'-
fluorophenyl)-4-hydroxy-7-methoxy-2,3.4.5-
tetrahydrobenzothiepine-1,1-dioxide (74).
Alkylation of 4-methoxyphenol with 2-fluorobenzyl
chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2'-
fluorobenzyl)phenol. This material was converted to
. compound 73 and compound 74 by the procedure similar to
s~~ S°1 Ci,..
that in Example 18 method B. ~ ~ Et'~ pr ~ , "~
8r
v 01-~
~'xam~le 39 V a~~°~ ~'!S~ ~o~N x-76
(3a,4a,5a) 3-Butyl-7-bromo-3-ethyl-4-hydroxy-5-(3'- 3
methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (75), and (3a,4b,5b) 3-Butyl-7-bromo-3-ethyl-4-
hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-
tetrahydrobenzothiepine-l,l-dioxide (76).
Alkylation of 4-bromophenol with 3-methoxybenzyl
chloride according to the procedure described in J.
Chem. Soc. 2431 (1958) gave 4-bromo-2-(3'-
methoxybenzyl)phenol. This material was converted to
compound 75, mp 97-101.5 °C, and compound 76, mp 102-
106 °C, by the procedure similar to that in Example 18
G O
method B . ~~ 5 i g,,
gxamDla 40 ° 6
F F
(3a,4a,5a) 3-Butyl-3-ethyl-7-fluoro-5-(4'-
fluorophenyl)-4-hydroxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (77), and
(3a,4b,5b) 3-Butyl-3-ethyl-7-fluoro-5-(4'-
fluorophenyl)-4-hydroxy-2,3,4,5- .
tetrahydrobenzothiepine-1.1-dioxide (78).
Alkylation of 4-fluorophenol with 4-fluorobenzyl
chloride according to the procedure described in J.
tq6
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Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4'-
fluorobenzyl)phenol. This material was converted to
compound 77, mp 228-230 °C, and compound 78, mp 134.5-
139 °C, by the proced vre similar to that in Example 18
me thod B . ~ L B,,
-
F ''' Et F ''
Example 41.' ~ c~~ ~~q' ~ ot~4 ~$0~
'~3 °'~3
(3a,4a,~5a) 3-Butyl-3-ethyl-7-fluoro-4-hydroxy-5-(3'-
methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-l,l-
dioxide (79), and (3a,4b,5b) 3-Butyl-3-ethyl-7-fluoro-
40hydroxy-5-(3'-methoxyphenyl)-2,3,4,5-
tetrahydrobenzothiepine-l,l-dioxide (80).
Alkylation of 4-fluorophenol with 3-methoxybenzyl
chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3'-
methoxybenzyl)phenol. This material was converted to
compound 79, as a solid and compound 80, mp 153-155 °C,
by the procedure similar to that in Example 18 method
L n
g . So
vL
(~(~G O icy
Example 42 a 1.~
r=
(3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-
hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-
l,l-dioxide (81).
A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5
mmol) of sodium methanethiolate and 15 ml of anhydrous
DMF was stirred at room temperature for I6 days. The
reaction mixture was dilute with ether and washed with
water and brine and dried over MoSO,. The ether
. solution was concentrated in vacuo. The residue was
purified by HPLC (20% ethyl acetate in hexanes). The
first fraction was impure (3a,4a,5a) 3-butyl-3-ethyl-4-
hydroxy-7-methylthio-5-(4'-fluorophenyl)-2,3,4',5-
tetrahydrobenzothiepine-l,l-dioxide. The second
fraction was compound 81, mp 185-186.5 °C.
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a
W .n EE
~N
a rt
Examflle 43
(3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-flu rophenyl)-4-
hydroxy-7-(1-pyrrolidinyl)-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (82).
A mixture of 0.53 g (1.30 mmol) of compound 78 and S ml
of pyrrolidine was held at reflux for 1 h. The
reaction mixture was diluted with ether and washed with
water and brine and dried over MaSO,. The ether
solution was concentrated in vacuo. The residue was
crystallized from ether-hexanes to give comipound 82, mp
s~l
174.5-177 °C.
c~~ ~~4> 3 ~ bra CyS
x
(3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4- ~,,i 8~
hydroxy-7- (1-morpholinyl) -2, 3, 4, 5- ~N.~°~ ,'''EE
tetrahydrobenzothiepine-1,1-dioxide (83). J ''
~~3)
r
A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g
(56 mmol) of morpholine was held at reflux for 2 h and
concentrated in vacuo. The residue was diluted with
ether (30 ml) and washed with water and brine and dried
over MaSO,. The ether solution was concentrated in
vacuo. The residue was recrystallized from ether-
hexanes to give compound 83, mp 176.5-187.5 °C.
~xam~le 45
(3a,4a,5a) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-
hydroxy-7-methyl-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (84), and (3a,4b,5b) 3-Butyl-3-ethyl-5-(4'-
fluorophenyl)-4-hydroxy-7-methyl-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (85).
Alkylation of 4-methylphenol with 4-fluorobenzyl~
chloride according to the procedure described in J.
Chem. Soc, 2431 (1958) gave 4-methyl-2-(4'-
fluorobenzyl)phenol). This material was converted to
J9a
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compound 84 and compound 85 by the rocedure similar to
that in Example 18 method u.'o ' ~~,E~ ~o
E~
ou
Exampla 46
e!4
(3a,4b,5b) 3-Butyl-3-ethyl-4-hydroxy-5-(4'- oN
- hydroxyphenyl)-7-methoxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (86), and
(3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-
hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-
1~1 dioxide ( 87 ) .
To a solution of 0.52 (1.2 mmol) of compound 66 in 20
ml of methylene chloride was added 1.7 g (6.78 mmol) of
born tribromide. The reaction mixture was cooled to -
IS 78 °C and was stirred for 4 min. An additional 0.3 ml
of boron tribromide was added to the reaction mixture
and the reaction mixture was stirred at -78 °C for 1 h
and quenced with 2 N HCl. The organic was extracted
into ether. The ether layer was washed with brine,
20 dried over MaSO,, and concentrated in vacuo. The
residue (0.48 g) was purified by HPLC (30~ ethyl
acetate in hexanes). The first fraction was 0.11 g of
compound 86 as a white solid, mp 17I.5-173 °C. The
second fraction was crystallized from chloroform to
25 give 0.04 g of compound 87 as a white solid, mp 264 °C
(dec) .
O S t 13:
nv~ "~CE
Example 47 ~ ~ « ~$$)
(3a,4b,5b) 3-Butyl-3-ethyl-4,7-dihydroxy-5-(4'-
30 fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-
dioxide (88).
Reaction of compound 70 with excess boron tribromide at
room. temperature and worked up as.in Example ;46 gave
35 compound 88 after an HPLC purification.
Sol
example 48 B4
Coq
o c~
r
t ~l °I
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(3a,4b.5b) 3-Butyl-3-ethyl-5-(4'-fluorophenyl)-4-
hydroxy-7-(1-azetidinyl)-2,3,4.5-
tetrahydrobenzothiepine-1,1-dioxide (89).
A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0
g (35 mmol) of aztidine was held at reflux for 3 h and
concentrated in vacuo. The residue was diluted with
ether (30 ml) and washed with water and brine and dried
over MgS04. The ether solution was concentrated on a
steam bath. The separated crystals were filtered to
ive 0.136 g of 89 as risms, mp 196.5-199.5 °C.
g o ~'z Bu ~ s°z ' 9w
,«,Ef ~t3cs .,Ct
Example 49 3 Clo~ ~ ~'1 ~'( ~'
V ~~j ock
(3a,4a,5a) 3-Butyl-3-et~yl-5-(3'-methoxypheny~)-4-
>j hydroxy-7-methylthio-2,3,4,5-tetrahydrobenzothiepine-
1.1-dioxide (90). (3a.4b,5b) 3-Butyl-3-ethyl-5-(3'-
methoxyphenyl)-4-hydroxy-7-methylthio-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide (91).
'0 A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g
(1.14 mmol) of sodium methanethiolate and I5 ml of
anhydrous DMF was stirred at 60 °C for 2 h. An
additional 1.4 mmol of sodium methanethiolate was added
to the reaction mixture and the mixture was stirred at
25 60 °C for an additional 2 h. The reaction mixture was
triturated with 100 ml of water and extracted methylene
chloride. The methylene chloride water mixture was
filtered through Celite and the methylene chloride ,
layer was dried over M9S0, and concentrated in vacuo.
30 The first fraction (0.1 g) was compound 90, mp 117-121
°C. The second fraction (0.16 g) was compound 91, mp
68-76-.oC:
~Q O
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10
Example 50
Preparation of polyethyleneglycol functionalized
benzothiepine 8.
Ho
ocH3 i ( ,,.~
/ \
..
..._ _.._ = 'OH
phf',. S~ ~\--__..__
HO''~
No . 141 '~.Et No .
136
A 50 ml rb flash under a nitrogen atmosphere was
_ charged with 0.54 g of M-Tres-5000 (Polyethyieneglycol
,1.0 1
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Tresylate [methoxy-PEG-Tres,MW 5000] purchased from
Shearwater Polymers Inc., 2130 Memorial Parkway. SW,
Huntsville, Alabama 35801). 0.055 g Compound No. 136,
0.326 C,CO, and 2cc anhydrous acetonitrile. The
reaction was stirred at 30 C for 5 days and then the
solution was filtered to remove salts. Next, the
acetonitrile was removed under vacuum and the product
was dissolved in THF and then precipitated by addition
of hexane. The polymer precipitate was isolate by
,filtration from the solvent mixture (THF/hexane). This
precipitation procedure was continued until no Compound
No. 136 was detected in the precipitated product (by
TLC Si02). Next, the polymer precipitate was dissolved
in water and filtered and the water soluble polymer was
dialyzed for 48 hours through a cellulose dialysis tube
(spectrum~ 7 ,45 mm x 0.5 ft, cutoff 1,000 MW). The
polymer solution was then removed from the dialysis
tube and lyophilized until dried. The NMR was
consistent with the desired product A and gel
permeation chromatography indicated the presence of a
4500 MW polymer and also verified that no free Compound
No. 136 was present. This material was active in the
IBAT in vitro cell assay.
1d ~
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Examp 1 a ~1
Preparation of Compound 140
0
. ~ nOH ~~~'~. O
/ ,,~ HO1~" S~
\ ~ .il \ / ...~ \
i \ ~.
O-polyethyleneglycol-O
~2
2
No. 140
0
O~S ...pH
\
H
H2 No. 111
A 2-necked 50 ml round bottom Flask was charged with
0.428 of Tres-3400 (Polyethyleneglycol Tresylate [Tres-
PEG-Tres,MW 3400) purchased from Shearwater Polymers
Inc., 2130 Memorial Parkway, SW, Huntsville, Alabama
35801), 0.1 potassium carbonate, O.100g of Compound No.
111 and 5 ml anhydrous DMF. Stir for 6 days~at 27 °C.
TLC indicated the disappearance of the starting
Compound No. 111. The solution waS transferred to a
separatory funnel and diluted with 50 cc methylene
chloride and then extracted with water. The organic
layer was evaporated to dzyness by means of a rotary
X03
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evaporator. Dry wgt. 0.4875 g. Next, the polymer was
dissolved in water and then dialyzed for 48 hours at 40
°C through a cellulose dialysis tube (spectrum~ 7 ,45mm
x 0.5 ft, cutoff 1,000 MW). The polymer solution was
then removed from the dialysis tube and lyophilized
until dried 0.341 g). NIA was consistent with the
desired product B.
Example 52
0~~ ~ 0
v ~
~'ox
No. 134
A 10 cc vial was charged with 0.21 g of Compound No.
136 (0.5mmoles), 0.17g (1.3 mmoles)potassium carbonate,
0.6g (1.5 mmoles) of 1,2-bis-(2-iodoethoxy)-ethane and
10 cc DMF. The reaction was stirred for 4 days at room
temperature and then worked up by washing with
ether/water. The ether layer was stripped to dryness
and the desired product Compound No. 134 was isolated
on a silica gel column using 80/20 hexane ethyl
acetate:
20 ~-
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Example 53
o=s
..~oH
~ ~"'"~ ~ I Hpn.,.
' \ /~o ~'~O ~o s ~
2
\ .
No. I12
Example 54
pig ...,~uIOH
... .. ..
/ \
i \
No. 113
2o S
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A two necked 25 ml round bottom Flask was charged with
0.58 (1.24mmoles) of 69462, 13 mls of anhydrous DMF,
0.0558 of 60% NaH dispersion and 0.2308 (0.62 mmoles)
of 1,2-Bis [2-iodoethoxylethane) at 10 °C under
nitogen. Next, the reaction was slowly heated to 40
°C. After 14 hours all of the Compound No. 113 was
consumed and the reaction was cooled to room
temperature and extracted with ether/water. The ether
layer was evaporated to dryness and then
chromatographed on Silicage (80/20 ethyl
acetate/hexane). Isolated Compound No. I12 (0.28 g)
was characterized by NMR and mass spec.
Example 55
o,.°
/ \
~OH
\ / 0~ 0
~S~
i
~OH
\ / No . 13 5
0' S O ,
H ~ ....1
~'bH
' No. 136
a.o ~
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In a 50 ml round bottom Flask, add 0.78 (1.8 mmoles) of
Compound No. 136, 0.6218 of potassium carbonate, 6 ml
DMF, and 0.338 of 1,2-Bis [2-iodoethoxylethane]. Stir
_ 5 at 40 °C under nitrogen for 12 hours. The workup and
isolation was the same procedure for Compound No. 112.
Examples 56 and 57 (Compound Nos 131 and 137)
The compositions of these compounds are shown in Table
3.
The same procedure as for Example 55 except appropriate
benzothiepine was used.
Example 58 (Compound No. 139)
The composition of this compound is shown in Table 3.
Same procedure as for Example 55 with appropriate
benzothiepine 1,6 diiodohexane was used instead of 1,2-
Bis [2-iodoethoxylethane].
Example 59 (Compound No. 10~)
_ .~ ..
O S ,~~'OH o~s/ ..~uOH
ii
O
\ ....~~ /
......
I \t
w
__ _d. . ,H No .
lol
This compound is prepared by condensing the 7-NH=
benzothiepine with the 1,12-dodecane dicarboxylic acid
or acid halide.
~v'?
I i
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Example 60 fCom~ound No. 104)
a
."npFi
. y
''
~'~ ~ No . 10 4
2-Chloro-4-nitrobenzophenone is reduced with
triethylsilane and trifluoromethane sulfonic acid to 2-
chloro-4-nitrodiphenylmethane 32. Reaction of 32 with
lithium sulfide followed by reacting the resulting
sulfide with mesylate IV gives sulfide-aldehyde XXIII.
Oxidation of XXIII with 2 equivalents of MCPBA yields
sulfone-aldehyde XXIV (see Scheme 5). Reduction of the
sulfone-aldehyde XXV formaldehyde and 100 psi hydrogen
and 55 C for 12 hours catalyzed by palladium on carbon
in the same reaction vessel yields the substituted
dimethylamine derivative XXVIII. Cyclization of XXVII
with potassium t-butoxide yields a mixture of
substituted amino derivatives of this invention
Compound No. 104.
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Scheme 6
~
~: N
~~ N1. f 1 l C- Il' C ~ N
~:
/ /
N ~' \
N K~, IY
XXI V N
IN~ ~ TNf
~ 1 1
\\S/ Itt \\ // !t1
/ ~~ / ~2
..11 ~~~~~1
\ \
~,~ ~H ~~N 111
H P~ H Ph
xx~ xc xx~ x~
Example 61
0
.S ..,~IIpH
/ ...~y \'
I /
1.
~ ~ No. 102
A 1 oz. Fisher-porter bottle was charged with 0.14 g
(0.34 mmoles) of 70112, 0.97 gms (.6.8 mmoles) of methyl
- iodide, and 7 ml of anhydrous acetonitrile. Heat to 50
°C for 4 days. The goat. Salt Compound No. 192 was
X09
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isolated by concentrating to 1 cc acetonitrile and then
precipitating with diethyl ether.
;LSO
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Example 62
0
o 's~
,.l
OH
N
No. 125
A 0.1 g (0.159 mmoles) sample of Compound No. 134 was
dissolved in 15 ml of anhydrous acetonitrile in a
Fischer-porter bottle and then trimethylamine was
bubbled through the solution for 5 minutes at 0 °C and
then capped and warmed to room temperature. The
reaction was stirred overnight and the desired product
was isolated by removing solvent by rotary evaporation.
Example 63 (Compound No. 2951
0
//.
~~~DH
_.. w ~o ~ ~
__. ._ H2 No. 295
~~1
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WO 98140375 PCT/US98/03792
0
rr
0
-- ,"OOH
\ ..~~r
i \ H
No. 113
Sodium Hydride 60~ (11 mg, 0.27 mmoles) in 1 cc of
acetonitrile at 0 °C was reacted with 0.248 mmoles (.10
g) of Compound No. 54 in 2.5cc of acetonitrile at 0 °C.
Next, 0.(9808 2.48 mmoles) of 1,2-Bis [2-
iodoethoxylethaneJ. After warming to room temperature,
stir for 14 hours. The product was isolated by column
chromatography.
Example 64 (Compound No. 286)
o _ ,~o
PhCH2
No. 286
Following a procedure similar to the one described
in Example 86, infra (see Compound No. 118), the title
compound was prepared and purified as a colorless
24 solid; mp 180-181 °C; 1H NI~t (CHC1~) S 0.85 (t, J = 6
Hz, 3H_, 0.92 (t, J = 6 Hz, 3H), 1.24-1.42 (m, 2H),
1.46-1.56 (m, 1H), 1.64-1.80 (m, 1H), 2.24-2.38 (m,
1H), 3.15 (AB, J", = 15 Hz, Ov = 42 Hz, 2H), 4.20 (d, J
'~ 1~.
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- 8 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.46 (s, 1H),
6.6E (s, 1H), 7.29-7.51 (m, lOH), 7.74 (d, J = 8 Hz,
1H), 8.06 (d, J = 8 Hz, 1H). FARMS m/z 494 (M+H), HRMS
calcd for (M+H) 494.2001, found 494.1993. Anal. Calcd.
for C"H"NOsS: C, 68.13; H, 6.33; N, 2.84. Found: C,
68.19; H, 6.56; N, 2.74.
~~3
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Example 65 fCom~ound No. 2871
0
O~S/
HZ .~OH
No. 287
Following a procedure similar to the one described
in Example 89, infra (see Compound No. 121), the title
compound was prepared and purified as a colorless
solid: mp 245-246 °C, 1H NMR (CDC1,) 8 0.84 (t, J = 6
Hz, 3H), 0.92 (t, J = 6 Hz, 3H), 1.28, (d, J = 8 Hz,
1H), 1.32-1.42 (m, 1H), 1.48-1.60 (m, 1H), 1.64-1.80
(m, 1H), 2.20-2.36 (m, 1H), 3.09 (AB, J", = 15 Hz, w =
42 Hz, 2H), 3.97 (bs, 2H), 4.15 (d, J = 8 Hz, 1H), 5.49
(s, 1H), 5.95 (s, 1H), 6.54 (d, J = 7 Hz, 1H), 7.29-
7.53 (m, 5H), 7.88 (d, J = 8 Hz, 1H); ESMS 366 (M+Li).
Anal. Calcd. for C~oHssNO~S: C, 66.82; H, 7.01; N. 3.90.
Found: C, 66.54; H, 7.20; N, 3.69.
Example 66 (Compound No. 2881
o\~
H ~ i
~~'bH
i
No. 288
~1~
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Following a procedure similar to the one described
in Example 89, infra (see Compound No. 121), the title
compound was prepared and purified by silica gel
chromatography to give the desired product as a
colorless solid: mp 185-186°C; 1H NMR (CDC1,) 81.12 (s,
3H), 1.49 (s, 3H), 3.00 (d, J = 15 Hz, 1H), 3.28 (d, J
- 15 Hz, IH), 4.00 (s, 1H), 5.30 (s, 1H), 5.51 (s, 1H),
5.97 (s, 1H), 6.56 (dd, J = 2.1, 8.4 Hz, 1H). 7.31-7.52
(m, 5H), 7.89 (d, J = 8.4 Hz, 1H). MS (FAH+) (M+H) m/z
332.
Example 67 (Compound No. 289)
o~~ P
I /
2.
bH
No. 289
Following a procedure similar to the one described
in Example 89 (see Compound No. 121), the title
compound was prepared and purified by silica gel
chromatography to give the desired product as a white
solid: mp 205-205 °C; iH NMR (CDC1~) 8 0.80-0.95 (m,
6H), 1.10-1.70 (m, 7H), 2.15 (m, 1H), 3.02 (d, J = 15.3
Hz, 2H), 3.15 (d; J = 15.1 Hz, 2H); 3.96 (s,' br, 2H),
4.14 (d, J~ = 7. 8 Hz, 1H) , 5.51 (s, 1H) , 5.94 (d, J =
2.2, IH), 6.54 (dd, J = 8.5, 2.2 Hz, 1H), 7.28-7.50 (m,
6H), 7.87 (d, J = 8.5 Hz, 1H). MS (FAB): m/z 388 (M+H).
Examnle68 (Compound No. 2901
~l5
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
O~S
W \
H
~OH
r
No. 290
~ Following a procedure similar to the one described
in Example 89, infra (see Compound No. 121), the title
compound was prepared and purified as a colorless
solid: mp = 96-98 °C, 1H NMR (CDC1~) b 0.92 (t, J = ?
Hz, 6H), 1.03-1.70 (m, 11H), 2.21 (t, J = 8 Hz, 1H),
3.09 (AB, J", = 18 Hz, w = 38 Hz, 2H), 3.96 (bs, 2H),
4.14 (d, J = 7 Hz, 1H), 5.51 (s, 1H), 5.94 (s, 1H),
6.56 (d, J = 9 Hz, 1H), 7.41-7.53 (m, 6H), 7.87 (d, J =
8 Hz, 1H); FARMS m/z 416 (M+H).
Example 69
0
o~si
O W \
PhCH20~N
H ~~OH
No. 291
Follo~ring a procedure similar to the one described
in Example 86, infra (see Compound~No. 118), the title
compound was prepared and purified as a colorless
solid: iH NMR (CDC1,) S 0.91 (t, J = 7 Hz, 6H), 1.02-
1.52 (m, I1H), 1.60-1.70 (m, 1H), 2.23 (t, J = 8 Hz,
~lL
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1H), 3.12 (AB, Ju = 18 Hz, w = 36 Hz, 2H), 4.18 (d, J
- 7 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 1H), 6.43 (s, 1H),
6.65 (s, 1H), 7.29-7.52 (m, lOH), 7.74 (d, J = 9 Hz,
1H), 8.03 (d, J = 8 Hz, 1H); ESMS m/z 556 (M+Li).
'x.11
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WO 98/40375 PCT/US98/03792
Examine 70 (Compound No. 292)
0
H / V~
~~bH
No. 292
Following a procedure similar tb the one descried
in Example 89, infra (see Compound No. 121), the title
compound was prepared and purified as a colorless
solid: mp = 111-112.5°C, 1H NMR (CDC1~) b 0.90 (t, J = 8
Hz, 6H), 1.03-1.50 (m, lOH), 1.55-1.70 (m, 2H), 2.18
(t, J = 12 Hz, 2H) , 3 .07 (AB, J,,, = 15 Hz, Ov = 45 Hz,
2H), 4.09 (bs, 2H), 5.49 (s, 1H), 5.91 (s, 1H), 6.55
(d, J = 9 Hz, 1H), 7.10 (t, J = 7 Hz, 2H), 7.46 (t, J =
6 Hz, 2H), 7.87 (d, J = 9 Hz, 1H).
Example 71 (Compound No. 293)
0
w w
PhCH
~bH
No. 293
During the preparation of Compound No. 290 from
Compound No. 291 using BBr,, the title compound was
~ 1~
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isolated: 'H NMR (CDC1~) 8 0.85 (t, J = 6 Hz, 6H), 0.98-
1.60 (m, lOH), 1.50-1.66 (m, 2H), 2.16 (t, J = 8 Hz,
1H), 3.04 (AB, J", = 15 Hz, w = 41 Hz, 2H), 4.08 (s,
1H), 4.12 (s, 1H),.5.44 (s, 1H), 5.84 (s, 1H), 6.42 (d,
J = 9 Hz, 1H), 7.12 (d, J = 8 Hz, 2H), 7.16-7.26 (m,
lOH), 7.83 (d, J = 8 Hz, 1H); ESMS m/z 512 (M+Li).
Example 72 (Comr~ound No 2941
Following a procedure similar to the one described
in Example 60 (Compound No. 104), the title compound
was prepared and purified as a colorless solid: 1H NMR
(CDC1~) 8 0.90 (t, J = 6 Hz, 6H), 1.05-1.54 (m, 9H),
1.60-1.70 (m, 1H), 2.24 (t, J = 8 Hz, 1H), 2.80 (s,
6H), 3.05 (AB, J,,, = 15 Hz, w = 42 Hz, 2H), 4.05-4.18
(m, 2H), 5.53 (s, 1H), 5.93 (s, 1H), 6.94 (d, J = 9 Hz,
1H), 7.27-7.42 (m, 4H), 7.45 (d, J = 8 Hz, 2H), 7.87
(d, J - 9 Hz, 1H); ESMS m/z 444 (M+H).
Structures of the compounds of Examples 33 to 72
are shown in Tables 3 and 3A.
Examples 73-79, 87, 88 and 91-10
Using in each instance a method generally
described in those of Examples 1 to 72 appropriate to
the substituents to be introduced, compounds were
prepared having the structures set forth in Table 3.
The starting materials illustrated in the reaction
schemes shown above were varied in accordance with
principles of organic synthesis well known to the art
to introduce the'indicated substituents in the 4- and
5- positions (R', R', R', R') and in the indicated
position on the benzo ring (R").
~~9
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Structures of the the compounds produced in
Examples 73-102 are set forth in Tables 3 and 3A.
Examples 80-84
Preparation of 115, 116, 111, 113
Preparation of 4-chloro-3-[4-methoxy-
phenylmethyl~-nitrobenzene.
In a 500 ml 2-necked rb flask weigh out 68.3 gms
phosphorus pentachloride (0.328 mole 1.1 eq). Add 50
mls chlorobenzene. Slowly add 60 gms 2-chloro-5
nitrobenzoic acid (0.298 mole). Stir at room temp
overnight under N2 then heat 1 hr at 50C.
Remove chlorobenzene by high vacuum. Wash residue
with hexane. Dry wt=55.5 gms.
In the same rb flask, dissolve acid chloride (55.5
g 0.25 mole) from above with 100 mls anisole (about 3.4
eq). Chill solution with ice bath while purging with
N2. Slowly add 40.38 aluminum chloride (1.2 eq 0.3
mole). Stir under N~ for 24 hrs.
After 24 hrs, the solution was poured into 300 mls
1N HC1 soln. (cold). Stir this for 15 min. Extract
several times with diethyl ether. Extract organic
layer once with 2~ aqueous NaOH then twice with water.
Dry organic layer with MgS04, dry on vac line. Solid
is washed well with ether and then ethanol before
drying. Wt=34.578 (mixture of meta, ortho and para).
Elemental theory found
C 57.65 57.45
H 3.46 5.51
N 4.8 4.8
C1 12.15 12.16
2 ~o
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With the next step of the reduction of the ketone
with trifluoromethane sulfonic aid and triethyl silane,
crystallization with ethyl acetate/hexane affords pure
4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.
4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene
was then reacted as specified in the synthesis of 117
and 118 from 2-chloro-4-nitrophenylmethane. From these
procedures 115 and 116 can be synthesized. Compounds
111 and 113 can be synthesized from the procedure used
to prepare compound 121.
Compound 114 can be prepared by reaction of 116
with ethyl mercaptan and aluminum trichloride.
Examples 85 and 86
Preparation of 117 and 118
2-Chloro-4-nitrobenzophenone is reduced with
triethylsilane and trifluoromethane sulfonic acid to 2-
chloro-4-nitrodiphenylmethane 32. Reaction of 32 with
lithium sulfide followed by reacting the resulting
sulfide with mesylate IV gives sulfide-aldehyde XXIII.
Oxidation of XXIII with 2 equivalents of MCPBA yields
sulfone-aldehyde XXIII. Oxidation of XXIII with 2
equivalents of MCPBA yields sulfone-aldehyde XXIV (see
Scheme 5).
The sulfone-aldehyde (31.8 g) was dissolved in
ethanol/toluene and placed in a parr reactor with 100
ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C
and heated to 55 C and 100 psi of hydrogen gas for 14
hours. The reaction was then filtered to remove the
catalyst. The amine product (.076 moles, 29.5 g) from
this reaction was then reacted with benzyl
chloroformate (27.4g) in toluene in the presence of 35
g of potassium carbonate and stirred at room
~a-l
i
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temperature overnight. After work up by extraction
with water, the CBZ protected amine product was further
purified by precipitation from toluene/hexane.
The CBZ protected amine product was then reacted
with 3 equivalents of potassium t-butoxide in THF at O
C to yield compounds 117 and 118 which were separated
by silica gel column chromatography.
Examples 89 and 90
Preparation of 121 or 122
Compound 118 (.013 moles, 6.79g) is dissolved in
135 ml of dry chloroform and cooled to -78 C, next 1.85
ml of boron tribromide (4.9 g) was added and the
reaction is allowed to warm to room temperature.
Reaction is complete after 1.5 hours. The reaction is
quenched by addition of 10$ potassium carbonate at 0 C
and extract with ether. Removal of ether yields
compound 121. A similar procedure can be used to
produce 122 from 117.
Examples 93-96
Compounds 126, 127, 128 and 129 as set forth in
Table 3 were prepared substantially in the manner
described above for compounds 115, 116, 111 and 113,
respectively, except that fluorobenzene was used as a
starting material in place of anisole.
~~:2
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TABLE 3
Specific compounds (x102-111,113-130,132-
134,136,138,142-144,262-296)
S 1
,,,,~ R
(g")q ~ ~ ~ 4' ~ R2
~~~~, R3
4
Rs. Rs R
C=, . Ri RZ R3 R~ RS R6 (R=) a
Dc.
61 302 . Et- n-8u- HO- H- Ph- H' I-, ?-
. : ( C3 ~ 3N+_
73 103 n-3u- Et- FO- F:- Ph- F.- I-, ?-
{Ci:3 ) 3N~_
60 104 Et- n-Hu- FO- F- Ph- , H- ?- (C'.-'.3)
2N-
.-:.~:
74. 105 Et- n-Hu- HO- H- Ph- F:- ?-
C 3S02N.'-'.'.-
''75 106 Et- n-3u- F.0- H- Ph- H- ?-3r-C 2-
CONz-
76 10? n-3u- Et- Fi0- F:- p-n-CiaFZi- F- 7_NHZ-
-0-Ph-
77 108 Et- n-Hu- F:0- F:- Ph- H- 7-
. CSH1ICONr-
78 109 Et- n-3u- f0- H- p-n-CipFZi- H- ?-N'~2_
-0-Ph-
7g 110 Et- n-Hu- HO- H- Ph- H- ?-CH3CONF-
80 111 n-8u- Et- HO- H- p-EO-Ph- F~- ?-NH2-
81 113 Et- n-Hu- HO- H- p-HO-Ph- H- ?-NHZ-
82 114 Et- n-Bu- fi0- F- p-CH30-Ph- H- ?-NHZ_
83 115 n-3u- Et- HO- H- p-CH30-Ph- H- 7-N~-CBZ
84 116 Et- n-Hu- HO- H- p-Cfi30-Ph- H- ?-NH-CH2
~.~.3
I I
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85 11? n-Hu- Et- HO- H- Ph- H- 7-NH-CHZ
86 118 Et- n-Bu- HO- H- ph- H- ?-NH-CHZ
87 119 Et- n-Hu- HO- H- ph- H- ?-NHC02-t-
' Bu
88 120 n-Bu- Et- HO- H- ph- H- ?-NHCOZ-t-
Bu
89 121 Et- n-Bu- HO- H- Ph- H- ?-NHZ-
90 122 n-Hu- Et- HO- H- Ph- H- ?-NH2-
. ~'
91 123 Et- n-Bu- Fi0-H- Ph- H- ?-n-C6H13-
NH-
92 124 n-Bu- Et- HO- H- Ph- H- ?-n-C6~13-
NF:-
62 125 Et- n-3u- FO- H- Ph-~ H- I-, 8-
.. (CH3) 3 N+(
C ZCFZO) 3-
93 126 n-3u- Et- EO- H- p-=-?h- H- ?-NFi-C32
94 12? n-Bu- Et- HO- H- p-: -?h- H- ?-N =2-
95 128 Et- n-Hu- F:O-E- p-F-?h- E- ?-NF:-CBZ
96 129 Et- n-Bu- HO- H- p-F-?h- H- ?-NH2-
97 130 Et- n-BL- HO- H- Ph- F:- I-, 8-
(CH3) 3N~
C6H120-
98 132 Et- n-9u- HO- H- Ph- H- 8-phthal-
imidyl-
C sH 120-
99 133 Et- n-Bu- HO- H- Ph- H- _.______8-n-C~pH21-
52 134 Et- n-Hu- HO- H- Ph- H- 8- I-
(C2H44)3-
100 136 Et- n-Bu- HO- H- Ph- H- 8- HO-
aa~
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101 138 n-Bu- Et- HO- H- Ph- H- 8- CH3C02-
49 90 Et- n-Bu- H- HO- H- m-CH30-Ph- 7-CH3S-
49 91 Et- n-Hu- HO- H- m-CH30-Ph- H- 7-CH3S-
48 89 Et- n-Hu- HO- , H- p-F-Ph- H- 7- (N) -
azetidine
34 66 Et- n-Bu- HO- H- m-Cr30-?h- H- 7-C30-
34 65 Et- n-Hu- H- EO- H- n-C 30-Ph- 7-C.'-'.30-
35 68 Et- n-Hu- F:0-F:- n-CF 3-Ph- H- 7-C 30-
35 67 Et- n-Hu- F:- F:O- H- -- m-C= 3-Ph- 7-C30-
46 87 Et- n-3u- F:O-F:- r.,-'.-:0-?h-F:- 7-.'-0-
46 86 Et- n-3u- F:O-F:- n-'.-0-?h- F:- 7-Ct
30-
36 70 Et- n-3u- HO- F:- p-F -?h- F:- 7-C:~30-
36 69 Et- n-8u- H- F:O- F- p-=-Bh- 7-Ct30-
47 88 Et- n-Bu- FO- Fi- p-F -Ph- F:- 7-HO-
39 76 Et- n-8u- EO- H- n-C:i30-Ph-H- 7-Br-
39 75 Et- n-Hu- H- HO- F~'.- m-Cc:30-Ph- 7-Hr-
40 77 Et- n-3u- H- HO- H- p-F-Ph- ?-F-
40 78 Et- n-Bu- HO- H- p-F-Ph- H- 7-F-
41 79 Et- n-Hu- H- HO- H- m-CH30-Ph- 7-F-
41 80 Et-~ ~ n-Hu-HO- H- m-CH30-Ph- ~ H- 7-F-
37 ?2 Et- n-Bu- HO- H- n-F-Ph- H- 7-CH30-
38 73 Et- n-Bu- H- HO- H- o-F-Ph- 7-CH30-
37 71 Et- n-Hu- H- F~:O-H- m-F-Ph- 7-CH30-
a a.5
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38 74. Et- n-Hu- HO- H- o-F-Ph- H- ?-CH30-
42 81 Et- n-Bu- HO- H- p-F-Ph- H- 7-CH3S-
45 85 Et- n-Hu- HO- H- p-F-Ph- H- 7-CH3-
45 84 Et- n-Hu- H- HO- H- p-r-Ph- 7-CH3-
44 83 . Et- 'n-Hu- HO- H- p-F-Ph- H- 7- (N) -
morpholine
43 82 Et- n-Hu- HO- H- p-F-Ph- H- 7-(N)-
pyrroli -
dine
64 286 Et-~ Et- HO- H- Ph- H- 7-Nr-C3Z
65 287 Et- Et- HO- F:- Ph- H- 7-N'.-'.Z_
~
66 288 CH3- CH3- HO- F- Ph- H- 7-Nr2-
67 289 n= n- EO- H- Ph-. H- 7_N2_
C3r7_ C3r7-
68 290 n-Hu- n-3u- HO- H- Ph- H- 7-N=2-
69 291 n-3u- n-3u- H0- L- Ph- H- 7-Nr-C3Z
70 292 n-Hu- n-3u- HO- H- p-F-Ph- H- 7-NHZ-
71 293 n-8u- n-Hu- F:0-H- Ph- H- 7-PhCHZN-
72 294 n-3u- n-3u- HO- H- Ph- H- 7- (C H3)
2N-
63 295 Et- n-Hu- HO- H- p-I- H- 7-NF:2-
(C2Hq0)3-
Ph-
102 296 Et- n-Bu- HO- H- I-, p- H- 7-NH2-
(CH3) 3N+(C2
Hq0) 3-Ph-
~a~
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TABLE 3A
Bridged Eenzothiepheaes (;101,112,131,135,137,139-14I)
r
O
HN~
O
CPD T101 (Dc. 59)
C? D ~ I 12 ( E5c . 53 )
CPDs131 (Dc. 56)
a a~
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CPD X135 (Dt. 55)
CPD 1137 (Fx. 57)
CPD X139 (Dc. 58)
aag
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O
oiyethyleneglycol
3400 MW polyethyleneglycol bridge CPD 1140 (~c. 51)
~O~O~
OCH3 ~' N C
O
HO
~" E~ C? D T 1 41 ( Dc . 50 )
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Examples 104-231
Using in each instance a method generally
described in those of Examples 1 to 72 appropriate to
the substituents to be introduced, including where
necessary other common synthesis expedients well known
to the art, compounds are prepared having the
structures set forth in Table 4. The starting
materials illustrated in the reaction schemes shown
above are varied in accordance with principles of
organic synthesis well known to the art in order to
introduce the indicated substituents in the 4- and 5-
positions (R', R', Rs, R') and in the indicated position
on the benzo ring (R").
X30
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TABLE 4
Alternative compounds ~1 (a302-312, 314-430)
S
s ~ ~ ..~,,. Ec
n-Bu
J
~.
Rs ox
Cpd# RS
(Rx)
302 p-F-Ph- ?-(1-aziridine)
303 p-F-Ph- 7-EtS-
304 p-F-Ph- 7-Ci:3S (0)-
305 p-F-Ph- ~_CL3S(0)2-
306 p-F-Ph- '.~.- 7-PhS-
307 p-F-Ph- 7-Cz3S-
g-Cg3S-
3 0 8 p-F-P h- 7-C:i30-
g-CL30-
309 p-F-Ph- 7-Et-
310 p-F-Ph- 7-iPr-
311 p-F-Ph-
7-t-Bu-
312 p-F-Ph- 7-(1-pyrazole)-
314 m-CH30-Ph 7-(1-azetidine)
315._...____ .. ..__._m_-~H3~-Ph-7-(1-aziridine).
._.
316 m-CH30-Ph-. 7-EtS-
317 m-CH30-Ph- _ '7-CF:3S (0) -
_ 318 m-CH30-Ph- 7-CH3S(0)2-
319 m-CH30-Ph- 7-PhS-
~3~
I I
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320 m-CH34-Ph 7-CH3S-
9-CH3S-
321 m-CH30-Ph 7-CH30-
9-CH30-
322 m-CH30-Ph 7-Et-
323 m-CH30-Ph 7-iPr-
324 m-CH30-Ph 7-t-Bu-
325 p-F-Ph- 6-CH30-
7-CH30-
8-CH30-
326 p-F-Ph- 7-(1-az~tidine)
9-CH3-
327 p-r-ph- 7-EtS-_
c_CH3-
328 p-F-Ph- 7-C 3S (O)-
9-CH3-
329 p-F-Ph- 7-CL3S(O)2-
9-CH3-
330 p-F-Ph- 7-PhS-
g-CH3-
331 p-F-Ph- 7-CH3S-
9-CH3-
332 p-F-Ph- 7-CH30-
g-CH3-
333 p-F-Ph- 7-CH3-
9-CH3-
_. 3 p-F-P h- _ _? -CH3o_ _
3 4
9-CH3o-
335 p-F-Ph- 7-(1-pyrrole)
336 p-F-Ph- 7- (N)-.~1' -methylpiperazine
~ 3 ~-
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337 p-F-Ph- Ph-
338 p-F-Ph- 7-CH3C (=CH2) -
339 p-F-Ph- 7-cyclpropyl
340 p-F-Ph- 7- (CH3) 2NH '
341 p-F-Ph- 7-(N)-azetidine
9-CH3S-
342 p-F-Ph- 7-(N-pyrrolidine)
9-CH3S-
343 p-F-Ph- 7-(CH3)2N-
9-CH3S-
344 m-CH30-Ph- 7-(1-pyrazole)
345 m-C 30-Ph- 7- (Ny~1' =methyl piperazine
34 6 m-CH30-Ph- Ph-
347 m-CH30-Ph- ?-C3C (C~=2) -
348 m-C'.-'.30-Ph- 7-cycl opropyl
349 m-CH30-Ph- 7- (C 3) ZNH -
350 m-CH30-Ph- 7-(N)-azetidine
9-cH3s-
351 m-CH30-Ph- 7-(N-pyrrolidine)-
9-CH3S-
352 m-CH30-Ph- 7- (CH3) 2N-
9-CH3S-
353 m-CH30-Ph- 6-CH30-
7-CH30-
8-CH30-
354 m-CH30-Ph- ?-(1-azetidine)
9-CH3-
~ 33
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355 m-CH30-Ph- 7-EtS-
9-CH3_
356 m-CH30-Ph- 7-CH3S (0) -
9-cH3-
357 m-CH30-Ph- ~ 7-CH3S (O) 2-
9-CH3-
358 m-CH30-Ph- 7-PhS-
9-CH3_
359 m-CH30-Ph- 7-cH3S-
9-cH3-
360 m-CH30-Ph- 7-CH30-
9-CH3-
361 m-CH30-Ph- 7-CH3-
9-CH3_
362 m-CH30-Ph- 7-CH34- _
9-CH30-
363 thien-2-yl 7-(1-aziridine)
364 thien-2-yl 7-EtS-
365 thien-2-yl 7-CH3S(O)-
366 thien-2-yl 7-CH3S(O)2-
367 thien-2-yl 7-PhS-
368 thien-2-yi 7-CH3S- -
9-CH3S-
369 thien-2-yl 7-CH30-
9-CH30-
370 thien-Z-yl 7-Et- .
371 thien-2-yl 7-iPr-
372 thien-2-yl ~ 7-t-Bu-
373 thien-2-yl 7-(1-pyrrole)-
374 thien-2-yl 7-CH3~-
' a3ø
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3?5 thien-2-yl ?-CH3S-
3?6 thien-2-yl ?-(1-azetidine)
3?? thien-2-yl ?-Me-
3?8 5-C1-thien-2-yl ?-(1-azetidine)
3?9 5-C1-thien-2-yl ?-(1-aziridine)
380 5-Cl-thien-2-yl ?-EtS-
381 5-Cl-thien-2-yl ?-CH3S(O)-
382 5-C1-thien-2-yl ?-CH3S(O)2-
383 5-Cl-thien-2-yl 7-PhS-
384 5-Cl-thien-2-yl ?-CH3S-
9-CH3S-
385 5-Cl-thien-2-yl ?-CH3~-
9-CH30-
386 5-C1-thien-2-yl ?-Et-
38? 5-Cl-thien-2-yl 7-iPr-
388 5-Cl-thien-2-yl ?-t-3u-
389 5-C1-thien-2-.;' 7-CH30-
390 5-C1-thien-2-yl ?-CH3S-
391 5-Cl-thien-2-yl ?-Me
392 thien-2-yl ?-(1-azetidine)
9-CH3-
393 thien-2-yl ?-EtS-
-_ ~ g-CH3-
3 g4 thien-2-yl ?-CIi3S (0) -
9-CH3-
395 thien-2-yl ?-CH3S (0) 2-
g-CH3-
a 35
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396 thien-2-yl 7-PhS-
9-CH3-
397, thien-2-yl 7-CH3S-
9-cH3_
398 thien-2-yl ?-CH30-
9-CHg-
399 thien-2-yl 7-CH3-
9-CH3-
400 thien-2-yl 7-CH30-
9-CH30-
401 thien-2-yl 7-(1-pyrazrole)
402 thien-2-yl ?- (NrV'-sethylpiperazine
403 thien-2-yl Ph-
404 thien-2-yl 7-CL3C(=CH2)-
405 thien-2-yl 7-cyclpropyl
40fi thien-2-yl 7-(CH3)2NH -
407 thien-2-yl 7-(N)-azetidine
9-CH3S-
408 thien-2-yl 7-(N-pyrrolidine)
9-CH3S-
409 thien-2-yl 7-(CH3)yN-
9-CH3S- .
411 5-CI-thien-2-yl 7-(1-pyrazrole)
412 5-C1=thiea-2---yl- ----- 7= (N)~.~1' -methylpiperazine
---
413 5-C1-thien-2-yl Ph-
414 5-C1-thien-2-yl '7-CH3C(=CH2)-
415 5-C1-thien-2-yl 7-cyclopropyl
416 5-C1-thien-2-yl 7- (CH3) 2NH -
~3~
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417 5-Cl-thien-2-yl 7-(N)-azetidine
- 9-CH3s-
418 5-Cl-thien-2-yl 7-(N-pyrrolidine)-
9-cH3s-
419 5-Cl-thien-2-yl 7-(CH3)2N-
9-CH3S-
420 5-CI-thien-2-yl 7-(1-azetidine)
g_CH3_
421 5-C1-thien-2-yl ?-EtS-
9-CH3_
422 5-Cl-thien-2-yl 7-CH3S(O)-
9-CH3-
423 5-Cl-thien-2-yl "'7-CH3S(0)2-
g-CH3-
424 5-C1-thien-2-yl ?-PhS-
9-CHg-
425 5-C1-thien-2-yl 7-CH3S-
9-CH3-
426 5-C1-thien-2-yl 7-CH30-
9-CH3-
427 5-C1-thien-2-yl 7-CH3-
9-CH3-
428 5-C1-thien-2-yl 7-CH30-
9-CH30-
429 thien-2-yl 6-CH30-
?-cH3o-
_8-CH30=_
430 5-Cl-thien-2-yl 6-CH30-
7-CH30-
8-CH30-
23~
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Fxamules 232-1394
Using in each instance a method generally
described in those of Examples 1 to 72 appropriate to
the substituents to be introduced, including where
necessary other common synthesis expedients well known
to the art, compounds are prepared having the
structures set forth in Table 1. The starting
materials illustrated in the reaction schemes shown
above are varied in accordance with principles of
organic synthesis well known to the art in order to
introduce the indicated substituents in the 4- and 5-
positions (R', R', Rs, R') and in the indicated position
on the benzo ring (R").
Example 1395
Dibutyl 4-fluorobenzene dialdehyde
O~~ ~%
/S ,,Bu
,"
Bu
OHC
F
Br
Preparation of dibutyl 4-fluoro benzene
dialdehyde
To a stirred solution of 17.5 g (123 mmol) of 2.5-
difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at
ambient temperature was added 6.2 g (135 mmol) of
lithium sulfide (Aldrich). The dark red solution was
stirred at 75 C for 1.5 hours, or until-the starting
material was completely consumed, ar_d then 34 g 1135
mmol) of dibutyl mesylate aldehyde was added at. about
50 C. The reaction mixture was stirred at 75 C for
three hours or until the reaction was completed. The
cooled solution was poured into water and extracted
with ethyl acetate. The combined extracts were washed
with water several times, dried (MgSO,) and
a 3B
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concentrated in vacuo. Silica gel chromatographic
purification of the crude product gave 23.6 g (59%) of
fluorobenzene dialdehyde as a yellow oil: 1H NMR
-. (CDC13) d 0.87 (t, J = 7.05 Hz, 6H), 1.0-1.4 (m, 8H),
1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H), 7.S-
7.6 (m, 2H) , 9.43 (s, 1H) , 10.50 (d, J = 2.62 Hz. 1H) .
Preparation of dibutyl 4-fluorobenzyl alcohol
To a solution of 22.6 g (69.8 mmol) of the dialdehyde
obtained from Step 1 in 650 mL of THF at -60 C was
added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a
syringe. The reaction mixture was stirred at -40 C for
hours. To the cooled solution at -40 C was added
sufficient amount of ethyl acetae to quench the excess
15 of DIBAL, followed by 3 N HC1. The mixture was
extracted with ethyl acetate, washed with water, dried
(MgSO,), and concentrated in vacuo. Silica gel
chromatographic purification of the crude product gave
13.5 g (58%) of recovered starting material, and 8.1 g
20 (36%) of the desired fluorobenzyl alcohol as a
colorless oil: 1H NMR (CDC13) d 0.88 (t, J = 7.05 Hz,
6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s,
1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J = 8.46,
3.02 Hz, 1H), 7.20 (dd, J = 9.47, 2.82 Hz, 1H). 7.42
(dd, J = 8.67, 5.64, 1H), 9.40 (s, 1H).
Preparation of dibutyl 4-fluorobenzyl bromide
To a solution of 8.1 g (25 mmol) of benzyl alcohol
obtained from Step 2 in 100 mL of DMF at -40 C was
added 47 g (50 mmol) of bromotriphenyphosphonium
bromide (Aldrich). The resulting solution was stirred
cold for 30 min, then was allowed to warm to 0 C:--To-~
the mixture was added 10% solution of sodium sulfite
and ethyl acetate. The extract was.washed a few~times
with water, dried (MgS04), and concentrated in'vacuo.
The mixture was stirred in small amount of ethyl
acetate/hexane mixture (1:4 ratio) and filtered through
a pad of silica gel, eluting with same solvent mixture.
a3°t
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The combined filtrate was concentrated in vacuo to give
9.5 g (98%) of the desired product as a colorless oil:
1H NMR (CDC13) d 0.88 (t, J =.7.05 Hz, 6H). 1.0-1.4 (m,
8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H),
S 7.02 (dt, J = 8.46, 3.02 Hz, 1H), 7.15 (dd, J = 9.47,
2.82 Hz, 1H), 7.46 (dd, J = 8.67, 5.64, 1H), 9.45 (s,
1H ) .
Step 4: Preparation of sulfonyl 4-fluorobenzyl
bromide
To a solution of 8.5 g (25 mmol) of sulfide obtained
from Step 3 in 200 mL of CH,C1= at 0 OC was added 15.9 g
(60 mmol) of mCPBA (64$ peracid). The resulting
solution was stirred cold for 10 min, then was allowed
to stirred ambient temperature for 5 hours. To the
mixture was added 10~ solution of sodium sulfite and
ethyl acetate. The extract was washed several times
with saturated NasCO,, dried (MgSO,), and concentrated
in vacuo to give 10.2 g (98~) of the desired product as
a colorless oil: IH NMR (CDC13) d 0.91 (t, J = 7.05 Hz,
6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m,
2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, IH),
7.30 (dd, J = 8.87, 2.42 Hz, 1H), 8.03 (dd, J = 8.86,
5.64, 1H), 9.49 (s, 1H).
~~.0
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Example 1396
o ~oH
a~ ~
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Generic Scheme X
F 1. Li S, DMSO, heat S ,R'
2 x _..! \ R2
Rx ~ ~ R ~~ CHO
2. mesylate aldehyde, heat CHO
CHO
I. BuLi. PMETA
-40 °C, THF
2. DMF
I DIBAL, THF
Nw N
w F PMETA: iN''~ ~ ' -40 °C
Rx ~~
r
S Rt BrPh3PBr, -40 °C R I ~ S 'R' Rz
Rx , ~ R2 x ~ CHO
i OHC DMF
HO
Br
mCPBA
O, S~O ,Rt RS B(OR~, heat O: S'~R 2
i
Rx ~ O~ R2 ~ Rx / OHC R
Pd(Ph3P),t, Na2C03
gr EtOH, toluene or DME
R
or
RS SnR3, heat
Pd(Ph3P)4, solvent . base; e.g. KOtBu
R = H, or short alkyl (C1-C6)
O; S'O Rt
_.. _. _~ :___.___
Rx , R2
/ ~~~OH
R5.
Generic Scheme X: The nucleophilic substitution of an
appropriately substituted 2-fluorobenzaldehyde with
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lithium sulfide or other nucleophilic sulfide anion in
polar solvent (such as DMF, DMA, DMSO, etc), followed
_ by the addition of dialkyl mesylate aldehyde (X),
provided a dialkyl benzene dialdehyde Y. DIBAL
reduction of the dialdehyde at low temperature yielded
benzyl alcohol monoaldehyde Z. Conversion of benzyl
alcohol to benzyl bromide, followed by oxidation of
sulfide to sulfone yielded the key intermediate W.
~~g~aration of N-DroDVlsulfonic acid
To a solution of 51 mg (111 dun) Compound X in ethanol
(400 ul) was added 1,3 propane sultone (19.5 ul, 222
dun). The reaction was stirred in a sealed vial at 55
for 25 hr. Sample was concentrated under a nitrogen
stream and purified by reversed phase chromatography
using acetonitrile/water as eluent (30-45%) and
afforded the desired material as an off-white solid
(28.4 mg, 44%): 'H NMR (CDCL,) d 0.82-0.96 (m, 6H),
1.11-1.52 (m of m, 10H), 1.58-1.72 (m, 1H), 2.08-2.21
(m, 1H), 2.36-2.50 (m, 2H), 2.93 (s, 6H), 3.02-3.22 (m
of m, 5H), 3.58-3.76 (m, 2H), 4.15 (s, 1H), 5.51 (s,
1H), 6.45-6.58 (m, IH), 6.92-7.02 (m, 1H), 7.35-7.41
(m, 1H), 7.41-7.51 (m, 2H), 8.08 (d, J = 8.1 Hz, 1H),
8.12-8.25 (m, 1H); MS ES- M-H m/z 579.
3 0 F'.xamn a 13 9 7
The 7-fluoro, 9-fluoro and 7,9-difluoro analogs of
benzothiepine'compounds of this invention can-be
reacted with sulfur and nitrogen nucleophiles to give
the corresponding sulfur and nitrogen substituted
analogs. The following example demonstrates the
synthesis of these analogs.
3,3-Dibutyl-5a-(4'-fluoropheayl)-4a-hydroxy-7-
methylthio-2,3,4,5-tetrahydrobeazothiepiae-1,1-dioxide.
a~3
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O' /O
\ S~ Bu
Bu
MeS
~OH
i
F
A mixture of 0.4 g Of 3,3-dibutyl-7-fluoro-5a-(4'-
fluorophenyl)-4a-hydroxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide, prepared by
previously described method, 0.12 g of sodium
methanethiolate and 20 ml of DMF was stirred at 50 C
for 3 days. An additional 0.1 g of sodium
methanethiolate was added to the reaction mixture and
the mixture was stirred for additional 20 h at 50 C
then was concentrated in vacuo. The residue was
triturated with water and extracte wiith ether. The
ether extract was dried over MgS04 and concentrated in
vacuo to 0.44 g of an oil. Purification by HPLC (10%
EtOAc in hexane) gave 0.26 g of needles, mp 164-165.5
%C.
3,3-Dibutyl-9-dimethylamino-7-fluoro-5a-(4'-
fluorophenyl)-4a-hydroxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide and ?,9-
Bis(dimethylamino)-3,3-dibutyl-5a-(4'-fluorophenyl)-4a-
hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide.
Me2N Oy /O Me2N .os O
Bu \ \iBu
~ Bu
~ Bu Me 2N
F ~OH
~OH
1 i
i
F
F
~4~
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A solution of 0.105 g of 3,3-dibutyl-7,9-difluoro-
5a-(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide, prepared by the
method described previously, in 20 ml of 2 N
dimethylamine in THF was heated at 160 C in a sealed
Parr reactor overnight. The reaction mixture was cooled
and concentrated in vacuo. The residue was triturated
with 25 ml of water and extracted with ether. The ether
extract was dried over MgS04 and concentrated in vacuo.
The resdue was purified by HPLC (10% EtOAc in hexane)
to give 35 mg of an earlier fraction which was
identified as 3,3-dibutyl-9-dimethylamino-7-fluoro-5a-
(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 480
(M+ +1), and 29 mg of a later fraction which was
identified as 7,9-bis(dimethylamino)-3,3-dibutyl-5a-
(4'-fluorophenyl)-4a-hydroxy-2,3,4,5-
tetrahydrobenzothiepine-1,1-dioxide, MS (CI) m/e 505
(M+ +1) .
The compounds of this invention can also be
synthesized using cyclic sulfate (A, below) as the
reagent as shown in the following scheme. The following
example describes a procedure for using the cyclic
sulfate as the reagent.
ass
I I
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R2 R2
R SOC12 Rt 2 RuCl3, NaI04 Rt
1 ' ~ '
OH OH O\ /O O\ /O
O~ O
O
A
SH
I.NaH, diglyme t2
(Rx)q f(Rx)c PCC,
/ c 1~,,Gti
Rt R2
(RY)P ~ ln. !
P
2.
O\ /O
OS O
3. H2S04
Rt O
O~S~ Rt
R2 MCPBA / /
RZ
(Rx)c
O H (Rx)q H
O
p _
KOtBu
R2
(Rx)i
(RY)P
Dibutyl cyclic sulfites
~. 46
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R.
,S.
A solution of 2,2-dibutyl-1,3-propandiol
(1038, 0.548 mol) and triethylamine (2218, 2.19 mol)
in anhydrous methylene chloride (500 ml) and was
stirred at 0 degrees C under nitrogen. To the mixture,
thionyl chloride (97.8 g, 0.82 mol) was added dropwise
and within 5 min the solution turned yellow and then
turned black when the addition was completed within
half an hour. The reaction mixture was stirred for 3
hrs. GC showed that there was no starting material
left. The mixture was washed with ice water twice then
with brine twice. The organic phase was dried over
magnesium sulfate and concentrated under vacuum to give
the cyclic sulfite 128 g (100~s) as a black oil. Mass
spectrum (MS) was consistent with the product.
To a solution of the above compound (127.58 , 0.54
mol) in 600 ml acetonitrile and 500 ml of water cooled
in an ice bath under nitrogen was added ruthenium(III)
chloride (1 g) and sodium periodate (233 g, 1.08 mol).
The reaction was stirred overnight and the color of
the solution turned black. GC showed that there was-no
starting material left. The mixture was extracted with
300 ml of ether and the ether extract was washed three
-.-times.withbrine.._The_organic_phase was dried over
magnesium sulfate and passed through celite. The
- 30 filtrate was concentrated under vacuum and gave the
cyclic sulfate 133 g (97.80 as an~oil. Proton, carbon
NMR and MS were consistent with the product.
2-((2-(4~-Fluorobenzyl)-4-
methylpheaylthio)methyl -2-butylhexanol:
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F
Sodium hydride (60% oil dispersion), 0.27 g (6.68
mmole), was washed with hexane and the hexane wash was
decanted. To the washed sodium hydride was added 20 ml
of 2-methoxyethyl ether (diglyme) and the mixture was
cooled in an ice bath. A solution of 1.55 g (6.68
mmole) of 2-(4'-fluorobenzyl)-4-methylbenzenethiol in
10 ml of 2-methoxyethyl ether was added dropwise to the
reaction mixture in 15 min. A mixture of 2.17 g (8.68
mmole) of the dibutyl cyclic sulfate in 10 ml of 2-
methoxyethyl ether was added once and stirred for 30
min at 0 C then at room temperature for 1 hr under
nitrogen. GC showed that there was no thiol left. The
solvent was evaporated and triturated wth water then
was extracted with ether twice. The water layer was
separated, treated with 20 ml of 10% NaOH then was
boiled for 30 min and cooled, acidified with 6N HC1 and
boiled for 10 min. The reaction mixture was cooled and
extracted with ether. The organic layer was washed
successively with water and brine, dried over magnesium
25- -sulfate and ~ concentrated under vacuum -to--give--2._.47 g (
92.5%) of an oil. Proton NNgt , 13C NMR and MS were
consistent with the product.
2-[(2-(4'-Fluorobenzyl)-4-
methylphenylthio)methyl]-2-butylhexanal:
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I-i3C A~
off
I
F
To a solution of the above product (2 g , 9.9
mmol) in 40 ml methylene chloride cooled in an ice bath
under nitrogen was added pyridinium chlorochromate
(2.18 g, 9.9 mmol) at once. The reaction was stirred
with 3 hrs and filtered through a bed of silica gel.
The filtrate was concentrated under vacuum to give 1.39
g (70%) of an oil. Proton, carbon Nt~t and MS were
consistent with the product.
2-[(Z-(4~-Fluorobenzyl)-4-
methylphenylsulfonyl)methyl]-2-butylhexanal
0
~°s
H3C f~ p H
L
I
,r F..
To a solution of the above product (0.44 g ,l.l
- mmole) in 20 ml methylene chloride solution cooled in
an ice bath under nitrogen was added 70% m-
chloroperbenzoic acid (0.54 g, 2.2 mmol) at once. The
reaction mixture was stirred for 18 hrs and filtered.
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The filtrate was washed successively with 10% NaOH
(3X), water and brine, dried over magnesium sulfate and
concentrated under vacum to give 0.42 g (90%) of an
oil. Proton, carbon NMR and MS were consistent with
the product.
3,3-Dibutyl-7-methyl-Sa-(4~-fluorophenyl)-4a-
hydroxy-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide:
H 3 C ~ off
i
F
A mixture of 0.37 g (0.85 mmol) of the above
product in 30 ml of anhydrous THF was stirred at 0 %C.
Then potassium t-butoxide (102 mg, 0.85 mmol) was
added. After 3 hrs, TLC showed that there was a product
and some starting material left. The crude reaction
mixture was acidified with 10% HC1 and extracted with
ether. The ether extract was washed successively with
water and brine, dried with MgS04 and concentrated
under vacuum. The residue was purified by HPLC (10%
EtOAc-Hexane). The first fraction was 0.1 g of starting
material as an oil and the second fraction was a white
' solid. 0.27 g (75%). Proton NMR and carbon NMR were
consistent with._the desired product. Mass.spectrum (CI) _
also confirmed the product, m/e 433 (M+ 1).
as o
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Step 1
CmHioClNO, fw=291.69
In an inert atmosphere, weigh out 68.3 gms
phosphorus pentachloride (0.328mo1e Aldrich 15,777-5)
into a 2-necked 500m1 round bottom flask. Fit flask
with a N= inlet adapter and subs seal. Remove from
inert atmosphere and begin N= purge. Add 50m1s
anhydrous chlorobenzene (Aldrich 28,451-3) to the PC1,
via syringe and begin stirring with magnetic stir bar.
Weigh out 60 gms 2-chloro-5-nitrobenzoic acid
(0.298 mole Aldrich 12,511-3). Slowly add to the
chlorobenzene solution while under N= purge. Stir at
room temperature overnight. After stirring at room
temperature for -20hrs,.place in oil bath and heat at
50C for lhr. Remove chlorobenzene by high vacuum. Wash
residue with anhydrous hexane. Dry acid chloride
wt=61.95gms. Store in inert and dry atmosphere.
In inert atmosphere, dissolve acid chloride with
105m1s anhydrous anisole (0.97 mole Aldrich 29,629-5).
__--_P.1_ace__ solution in-__a .2-necked..-50-Oml_ round- bottom flask-.
Weigh out 45.lgms aluminum chloride (0.34 moles
Aldrich 29,471-3) and place in a solid addition funnel.
Fit reaction flask with addition funnel and a N= inlet
adapter. Remove from inert atmosphere. Chill reaction
solution with ice bath and begin N= purge. Slowly add
AlCl, to chilled solution. After addition is complete,
allow to warm to room temperature. Stir overnight .
oc5 ~
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Quench reaction by pouring into a solution of 300
mls 1N HC1 and ice. Stir 15 min. Extract twice with
ether. Combine organic layers and extract twice with
2% NaOH, then twice with deionized H=O. Dry with MgSO,,
filter and rotovap to dryness. Remove anisole by high
vacuum. Crystalize product from 90% ethanol 10% ethyl
acetate. Dry on vacuum line. Wt=35.2gms. Yield 41%.
Obtain NMR and mass spec (m/z=292).
Step 2
Dissolve 38.lOgms (0.131 moles) of the
benzophenone from step 1 in 250m1s anhydrous methylene
chloride. Place in a 3 liter flask fitted with N=
inlet, addition funnel and stopper. Stir with magnetic
stir bar. Chill solution with ice bath.
Prepare a solution of 39.32 gms trifluoromethane
sulfonic acid (0.262 mole Aldrich 15,853-4) and 170
mls anhydrous methylene chloride. Place in addition
funnel and add dropwise to chilled solution under N,.
Stir 5 minutes after addition is complete.
Prepare a solution of 22.85 gms triethyl silane
(0.197mo1e Aldrich 23,019-7) and 170m1s anhydrous
iriethyleae chloride-- Place in-addition funnel-and add
dropwise to chilled solution under N=. Stir 5 minutes
after addition is complete.
Prepare a second solution of 39.32 gms
trifluoromethane sulfonic acid and~170m1s anhydrous
methylene chloride. Place in addition funnel and add
dropwise to chilled solution under N=. Stir 5 minutes
after addition is complete.,
as~-
Cl,HISC1N0, fw=277.71
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wo 9s~ao3~s rcr~s9sio3~n
Prepare a second solution of 22.85 gms triethyl
silane and 170m1s anhydrous methylene chloride. Place
in addition funnel and add dropwise to chilled solution
under N,. After all additions are made allow to slowly
warm to room temperature overnight. Stir under N,
overnight.
Prepare 1300 mls saturated NaHCO, in a 4 liter
beaker. Chill with ice bath. While stirring
vigorously, slowly add reaction mixture. Stir at
chilled temperature for 30 min. Pour into a separatory
funnel and allow separation. Remove organic layer and
extract aqueous layer 2 times with methylene chloride.
Dry organic layers with MgSO,. Crystallize from
ethanol. Dry on vacuum line. Dry wt=28.8gms. Confirm
by NMR and mass spec (m/z=278).
Step 3
C=sH"NO,S fw=443.61
Dissolve 10.12 gms (0.036 moles) of product 2 with
200 mls anhydrous DMSO. Place in a 500 ml round bottom
flask with magnetic stir bar. Fit flask with water
condenser, N, inlet, and stopper. Add 1.84 gms Li=S
(0.040 moles Aldrich 21,324-1). Place flask in oil
bath and heat at 75°C under N, overnight then cool to
room temperature.
Weigh out 10.59 gms dibutyl mesylate (0.040
moles). Dissolve with anhydrous DMSO and add to
reaction solution. Purge well with N,, heat overnight
a53
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at 80'C.
Cool to room temperature. Prepare 500 mls of 5%
acetic acid in a 2 liter beaker. While stirring.
slowly add reaction mixture. Stir 30 min. Extract
with ether 3 times. Combine organic layers and extract
with water and sat'd NaCl. Dry organic layer with
MgSO,, filter and rotovap to dryness. Dry oil on vacuum
line. Obtain pure product by column chromatography
using 95% hexane and 5% ethyl acetate as the mobile
phase. Dry wt=7.8 gms. Obtain NMR and mass spec
(m/z=444).
Step 4
C,SH~~N06S fw=47 5 . 61
Dissolve 9.33 gms (0.021 moles) of product 3 with
12D mls anhydrous methylene chloride. Place in a 250
ml round bottom flask with magnetic stir~bar. Fit
flask with N, inlet and stopper. Chill solution with
ice bath under N= purge.. Slowly add 11.54_gms 3-
chloroperbenzoic acid (0.0435 moles, Fluka 25800,
-65%). After addition is complete warm to room
temperature and monitor reaction by TLC. Reaction goes
quickly to the sulphoxide intermediate but takes 8 hrs
to convert to the sulphone. Chill solution over night
in freezer. Filter solid from reaction, extract
filtrate with 10% K~CO,. Extract aqueous layer twice
with methylene choride. Combine organic layers and dry
asp
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with MgSO,. Filter and rotovap to dryness. Obtain
pure product by crystallizing from ethanol or isolating
-. by column chromatography. Obtain NMR and mass spec
(m/z=476).
Step 5
Reaction is done in a 300 ml stainless steel Parr
stirred mini reactor. Place 9.68 gms (0.02'04 moles) of
product 4 in reactor base. Add 160 mls ethanol. For
safety reasons next two compounds are added in a N~
atmosphere glove bag. In glove bag, add 15.3 mls
formaldehyde (0.204 moles, Aldrich 25,254-9, about 37
wt% in water) and 1.45 gms 10% Pd/Carbon (Aldrich
20,569-9). Seal reactor before removing from glove
bag_ Purge reactor three times with H=. Heat to 55°C
under H=. Run reaction at 200 psig H,, 55°C, and a stir
rate of 250 rpm. Run overnight under these conditions.
Cool reactor and vent H=. Purge with N=. Check
progress of run by TLC. Reaction is a mixture of
. desired product and intermediate. Filter reaction
mixture over a bed of celite washing well with ether.
Rotovap and redissolve with ether., Extract with water.
Dry organic layer with MgSO,, filter and rotovap to
dryness. Dry on vacuum line.
Charge reactor again with same amounts, seal
reactor and run overnight under same conditions.
C"H"NO,S fw=473.68
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After second run all of the material has been converted
to the desired product. Cool and vent H, pressure.
Purge with N,. Filter over a bed of celite, washing
well with ether. Rotovap to dryness. Dissolve with
ether and extract with water. Dry organic layer with
MgSO,, filter and rotovap to dryness. Dry on vacuum
line. Obtain Nt~t and mass spec (m/z=474).
Step 6
'N
Z O HaC' \CH~
Cs,H"NO,S fw=473.68
Dissolve 8.97 gms (0.0189 mole) of product 5 with
135 mls anhydrous THF. Place in a 250 ml round bottom
flask with magnetic stir bar. Fit flask with N= inlet
and stopper. Chill solution with ice/sait bath under
N= purge. Slowly add 2.55 gms potassium t-butoxide
(0.227 mole Aldrich 15,667-1). After addition is
complete, continue to stir at -10°C monitoring by TLC.
Once reaction is complete, quench by adding 135 mls
10$ HC1 stirring 10 min. Extract three times with
ether. Dry organic layer with MgSO,, filter and
rotovap to dryness. Crystallize from ether. Obtain
NMR and mass spec (m/z=474).
Step 7
a56
CA 02283575 1999-09-09
WO 98!40375 PC"T/US98/03792
C"H"NO,S fw=459.65
Dissolve 4.67 gms (0.01 moles) of product 6 with
100 m1s anhydrous chloroform. Place in a 250 ml round
bottom flask with magnetic stir bar. Fit flask with N=
inlet adapter and suba seal. Chill solution with dry
ice /acetone bath under a N= purge. Slowly add, via
syringe, 2.84 mls boron tribromide (0.03 moles Aldrich
20,220-7). Stir at cold temperature for 15 min after
addition then allow to warm to room temperature.
Monitor reaction progress by TLC. Reaction is usually
complete in 3 hrs.
Chill solution with ice bath. Quench with 100 mls
10% K,CO, while stirring rapidly. Stir 10 min. then
transfer to sep funnel and allow separation. Remove
aqueous layer. Extract organic layer once with 10%
HC1, once H=O, and once with saturated NaCl solution.
Dry organic layer with MgSO,, filter and rotovap to
dryness. Crystallize product from ether. Obtain NMR
and mass spec (m/z=460).
Step 8
asp
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Weigh 0.38 gms NaH (9.57 mmoles Aldrich 19,923-0
60% disp. in mineral oil) in a 250 ml round bottom
flask with magnetic stir bar. Fit flask with N, inlet
and stopper. Chill NaH with ice bath and begin N,
purge.
Dissolve 4.0 gms (8.7 mmoles) of product 7 with 60
mls anhydrous DMF. Add to the cold NaH. Stir at cold
temperature for 30 min. Add 1.33 gms K=C0, (9.57 mmoles
Fisher P-208).
Dissolve 16.1 gms 1,2-bis-(2-iodoethoxy)ethane
(43.5 mmoles Aldrich 33,343-3) with 60 mls anhydrous
DMF. Add to cold reaction mixture. Warm to room
temperature then heat to 40°C overnight under N~.
Cleanup by diluting with ether and extracting
sequentially with 5% NaOH, HBO, and saturated NaCl.
Dry organic layer with MgSO,, filter and dry. Obtain
pure product by column chromatography using 75% hexane
25% ethyl acetate as the mobile phase. Obtain NNtR and
mass spec (m/z=702).
Step 9
~~8
C1=H"NO,SI fw=701.71
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Dissolve 1.0 gms (1.43 mmoles) of product 8 with
10 mls anhydrous acetonitrile. Place in a 3 ounce
Fischer-Porter pressure reaction vessel with magnetic
stir bar. Add 2.9 gms tri~ethyl amine (28.6 mmoles
Aldrich 23,962-3) dissolved in 10 mls anhydrous
acetonitrile. Purge well with N, then close system .
Heat at 45°C. Monitor reaction by TLC. Reaction is
usually complete in 48 hrs.
Perform cleanup by removing acetonitrile under
vacuum. Redissolve with anhydrous chloroform and
precipitate quaternary ammonium salt with ether.
Repeat several times. Dry to obtain crystalline
product. Obtain NMR and mass spec (m/z=675).
X55
C"H~,N~O,SI fw=802.90
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~~amnle 1399
Step 1. Preparation of 1
r -
OCH 3
To a solution of 144 g of KOH (2560 mmol) in 1.1 L of
DMSO was added 120 g of 2-bromobenzyl alcohol (641
mmol) slowly via addition funnel. Then was added 182 g
of methyliodide (80 mL. 1282 mmol) via addition funnel.
Stirred at ambient temperature for fifteen minutes.
Poured reaction contents into 1.0 L of water and
extracted three times with ethyl acetate. The organic
layer was dried over MgSO, and concentrated n vacuo.
Purified by silica-gel chromatography through a 200 mL
plug using hexanes (100$) as elutant yielded 103.2 g
(80$) of 1 as a clear colorless liquid. 1H NMFt (CDC1,) d
3.39 (s~ 3H). 4.42 (s. 2H), 7.18-7.27 (m, 2H), 7.12 (d~
- 7.45, 1H). 7.50 (s, 1H).
Step 2. Preparation of 2
3
To a cooled (-78 °C) solution of 95 g (472 mmol) of 1
in 1.5 L THF was added 240 mL of 2.5 M n-butyl lithium
(576 mmol). The mixture was stirred for one hour, and
then to it was added 180 g of zinc_iodide (566 mmol)
dissolved in 500 ml THF.~ The mixture was stirred
thirty minutes, allowed to warm to 5 C, cooled to -10
°C and to it was added 6 g of Pd(PPh,), (5.2 mmol) and
125 g 2,5-difluorobenzoyl chloride (708 mmol). The
mixture was stirred at ambient temperature for 18
hoursand then cooled to 10 °C, quenched with water,
partitioned between ethyl acetate and water, and washed
a.6 o
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organic layer with 1N HCL and with 1N NaOH. The
organic layer was dried over MgSO, and concentrated ~
vacuo. Purification by silica gel chromatography
(Waters Prep-500) using 5% ethyl acetate/hexanes as
elutant gave 53.6 g (43 %) of 2 as an orange oil. 1H
NMR (CDC1,) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m,
3H), 7.47 (t, J = 7.50, 1H), 7.57 (d, J = 7.45, 1H),
7.73 (d, J = 7.45, 1H), 7.80 (s, 1H).
Step 3. Preparation of 3
Bu
~Bu
,~O 'OH
3
A solution of 53 g (202.3 mmol) of 2 and 11.2 g Li2S
(242.8 mmol) in 250 mL DMF was heated to 100 °C for 18
hours. The reaction was cooled (0 °C) and 60.7 g of X
(the cyclic sulfate compound of example 1397) (242.8
mmol) in 50 mL DMF was added. Stirred at ambient
temperature for 18 hours then condensed in vacuo.
Added 1 L water to organic residue and extracted twice
with diethyl ether. Aqueous layer acidified (pH 1) and
refluxed 2 days. Cooled to ambient temperature and
extracted with methylene chloride, dried organic layer
over MgSO, and condensed ~n vacuo. Purification by
silica gel chromatography (Waters Prep-500) using 10%
ethyl acetate / hexanes as elutant gave 42.9 g (48-%)
of 3 as a yellow oil. 1H NMR (CDC1,) d 0.86 (t, J = 7.25
Hz, 6H), 1.10 - 1.26 (m, 12H), 2.83 (s, 2H), 3.32 (s,
2H), 3.40 (s, 3H), 4.48 (s, 3H), 7.02 (dd, J = 8.26 Hz
and 2.82 Hz, 1H), 7.16 (dt, J = 8.19 Hz and 2.82 Hz,
1H), 7.45 (t, J = 7.65 Hz, 1H), 7.56-7.61 (m, 2H), 7.69
(d, J = 7.85 Hz, 1H), 7.74 (s, 1H),
Step 4. Preparation of 4
etlr t
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S~ gu
~Bu
CH zOH
3
To a cooled (-40 °C) solution of 42.9 g (96.2 mmol) of
3 in 200 mL of methylene chloride was added 21.6 g
trifluoromethane sulfonic acid (12.8 mL, 144 mmol)
followed by the addition of 22.4 g triethyl silane
(30.7 mL, 192.4 mmol). Stirred at -20 °C for two hours,
quenched with water and warmed to ambient temperature.
Partitioned between methylene chloride and water,
dried the organic layer over MgSO, and condensed ~i
vacu Purification by silica gel chromatography
(Waters Prep-500) using 10$ ethyl acetate/ hexanes as
elutant gave 24.2 g (60~)of 4 as a oil. 'H NNgt (CDC1~) d
0.89 (t, J = 7.05 Hz. 6H), 1.17 - 1.40 (m, 12H), 1.46
(t, J = 5.84 Hz, 1H), 2.81 (s, 2H), 3.38 (s, 3H), 3.43
(d, J = 5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80
(d, J = 9.67 Hz, 1H), 6.90 (t, J = 8.46 Hz, 1H), 7.09
(d, J = 7.45 Hz, 1H), 7.15 - 7.21 (m, 2H), 7.25 - 7.32
(m, 2H), 7.42 (m, 1H).
Step 5. Preparation of 5
Bu
S~Bu
CHO
3
To a cooled (15-18 °C) solution of 24.2 g (55.8 mmol)
of 4 in 100 mL DMSO was added 31.2 g sulfur trioxide
pyridine complex (195 mmol). Stirred at ambient
temperature for thirty minutes. Poured into cold water
and extracted three times with ethyl acetate. Washed
organics with 5~ HC1 (300 mL) and then with brine (300
mL), dired organics over MgSO, and condensed ~n vacuo
to give 23.1 g (96 ~) of 5 as a light brown oil. 'H NMR
a.6 ~.
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(CDCl,) d 0.87(t, J 7.05 Hz, 6H),
= 1.01 - 1.32 (m.
8H). 1.53 - 65 (m, 3.38 (s, 3H),
1. 4H),
2.98
(s, 2H),
4.15 (s, 2H).4.43 (s, 2H), 6.81 (dd. = 9.66 Hz and
J
2.82 Hz, 1H).6.91 (t, J = 8.62 Hz. 1H),7.07 (d, J =
46 Hz 1H) 7.14 (s. 1H). 7.19 (d, 7.65 Hz, 1H),
7 J =
, , .42 (dd, J = 8.66Hz and 5.64
. - 32 Hz,
7.26 7. (m,
1H),
7
1H). 9.40 1H).
(s,
Step 6. Preparation of 6
Bu
~Bu
_ CHO
3
To a cooled (0 °C) solution of 23.1 g (53.6 mmol) of 5
in 200 mL methylene chloride was added 28.6 g meta
cholorperoxy-benzoic acid (112.6 mmol). Stirred at
ambient temperature for 24 hours. Quenched with 100 mL
10% Na,SO,, partitioned between water and methylene
chloride. Dried organic layer over MgSO, and condensed
;n~acuo to give 24.5 g (98%) of 6 as a light yellow
oil. 1H NMR (CDCl,) d 0.86 - 1.29 (m, 14H), 1.58 - 1.63
(m. 2H), 1.82 - 1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s.
3H), 4.44 (s, 2H). 4.50 (s, 2H), 6.93 (d, J = 9.07 Hz.
1H). 7.1D - 7.33 (m, 5H). 8.05 (s. 1H). 9.38 (s, IH).
Step 7. Preparartion of 7
Bu
~J ~Bu
CHO
Me
J~ ~oLh 3
To a solution of 24.5 g (52.9 mmol) of 6 in 20 mL of
THF contained in a stainless steel reaction vessel was
added 100 mL of a 2.0 M solution of dimethyl amine and
X63
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20 mL of neat dimethyl amine. The vessel was sealed
and heated to 110 °C for 16 hours. The reaction vessel
was cooled to ambient temperature and the contents
concentrated ~n-. Purification by silica gel
chromatography (Waters Prep-500) using 15 % ethyl
acetate/hexanes gave 21.8 g (84 %) of 7 as a clear
colorless oil. 1H Nf~t (CDC1,) d 0.85 (t, J = 7.25 Hz,
6H), 0.93 - 1.29 (m, 8H), 1.49 - 1.59 (m, 2H), 1.70 -
1.80 (m, 2H), 2.98 (s, 8H), 3.37 (s, 3H), 4.41 (s, 2H),
4.44 (s, 2H), 6.42 (s, 1H), 6.58 (dd, J - 9.0 biz and
2.61 Hz, 1H), 7.13 (d, J = 7.45 Hz, 1H), 7.21 (s, 1H),
7.28 (t, J = 7.85 Hz. 1H), 7.82 (d, J = 9.06 Hz, 1H),
9.36 (s, 1H) .
Step 8. Preparation of 8
O..S
Bu
Me 2N
OH
OCH 3
A solution of 21.8 g (44.8 mmol) of 7 in 600 mL of THF
was cooled to 0 °C. 58.2 mL of a 1 M solution of
potassium
t-butoxide was added slowly, maintaining the
temperature at <5 °C. Stirred for 30 minutes, then
quenched with 50 mL of saturated ammonium chloride.
The organic layer was partitioned between ethyl acetate
and water, dried over MgS04 and concentrated ~n vacuo.
Purification by recrystalization from -10% ethyl
acetate/hexanes gave 15.1 g of 8 as a white solid. The
mother liquor was purified by silica gel chromatography
(Waters Prep-500) using 30% ethyl acetate/hexanes as
the elutant to give 3.0 g of 8 as a white solid. MS
(FABLE) m/e 494.6. HRMS (EI') calculated for M+H
487.2756. Found 487.2746.
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Step 9. Preparation of 9
,S~
~~Bu
8u
Met ' ~yOH
\ Br
A solution of 2.0 g (4.1 mmol) of 8 in 20 mL of
methylene chloride was cooled to -60 °C. 4.1 mL of a
1M solution of boron tribromide was added. Stirred at
ambient temperature for thirty minutes. Cooled
reaction to -10 °C and quenched with 50 mL of water.
The organic layer was partitioned between methylene
chloride and water, dried over MgSO, and concentrated
~n vacuo. Purification by recrystalization from 50%
ethyl acetate/methylene chloride gave 1.95 g (89%) of 9
as a white solid. MS (FABH') m/e 537. HRMS (FAB)
calculated for M 536.1834. Found 536.1822.
Step 10. Preparation of 10
O' SO
~iBu
~ Bu
Me2N
~OH
\ I Br'
A solution of 1.09 g (2.0 mmol) of 9 and 4.9 g (62~
mmol) of pyridine in 30 mL of acetonitrile was stirred
at ambient temperature for 18 hours. The reaction was
concentrated in vacuo. Purification by -.--.--.
recrystallization from methanol/ diethyl ether gave
1.19 g (96%) of 10 as an~off white solid. MS (FAB')
m/e 535.5.
a~~
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Step 1. Preparation of 2
Bu
~8u
CHO
N02
To a solution of 6.0 g of dibutyl 4-fluorobenzene
dialdehyde of Example 1395 (14.3 mmol) in 72 mL of
toluene and 54 mL of ethanol was added 4.7 g 3-
nitrobenzeneboronic acid (28.6 mmol). 0.8 g of tetrakis
(triphenylphosphine) palladium(0) (0.7 mmol) and 45 mL
of a 2 M solution of sodium carbonate in water. This
heterogeneous mixture was refluxed for three hours.
then cooled to ambient temperature and partitioned
between ethyl acetate and water. The organic layer was
dried over MgSO, and concentrated ~n~.
Purification by silica gel chromatography (Waters Prep-
2000) using ethyl acetate/hexanes (25/75) gave 4.8 g
(73%) of the title compound as a yellow solid. 1H NMFt
(CDC1,) d 0.88 (t. J = 7.45 Hz. 6H), 0.99-1.38 (m. 8H).
1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H). 3.20 (s. 2H).
4.59 (s. 2H). 6.93 (dd, J = 10.5 and 2.4 Hz, 1H). 7.15
(dt. J = 8.4 and 2.85 Hz, 1H). 7.46-7.59 (m. 2H). 8.05-
8.16 (m, 3H). 9.40 ~s, 1H~.
arm
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Step 3. Preparation of 3
- Oo
\ S~~Bu
/ ~ Bu
y
OH
NO Z
A solution of 4.8 g (10.4 mmol) of 2 in 500 mL THF was
cooled to 0 °C in an ice bath. 20 mL of a 1 M solution
of potassium t-butoxide was added slowly, maintaining
the temperature at <5 °C. Stirring was continued for
30 minutes, then the reaction was quenched with 100 mL
of saturated ammonium chloride. The mixture was
partitioned between ethyl acetate and water; the
organic layer was washed with brine, then dried (MgSO,)
and concentrated ~.n vacuo. Purification by silica gel
chromatography through a 100 ml plug using CH~C1= as
eluent yielded 4.3 g (90%) of 3 as a pale yellow foam.
1H NMFt (CDC1,) d 0.93 (t, J = 7.25 Hz. 6H) , 1.00-1.55
(m. 8H), 1.59-1.74 (m, 3H). 2.15-2.95 (m. 1H). 3.16
(q~, J~ = 15. 0 Hz, GV = 33 .2 Hz, 2H) . 4.17 (d. J =
6.0 Hz. 1H). 5.67 (s, 1H), 6.34 (dd, J=9.6 and 3.0 Hz,
1H). 7.08 (dt, J = 8.5 and 2.9 Hz,~ 1H). 7.64 (t, J =
8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz. 1H), 8.13 (dd, J =
9.9 and 3.6 Hz. 1H), 8.23-8.30 (m. 1H). 8.44 (s. 1H).
MS(FABH+) m/e (relative intensity) 464.5 (100). 446.6
(65). HRMS calculated for M+H 464.1907. Found
464 .1905 = -___-
1
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Step 4. Preparation of 4
O.. ~O
~ ~S~iBu
~ eu
Me2N ' ~~OH
NOZ
To a cooled (0 °C) solution of 4.3 g (9.3 mmol) of
3 in 30 ml THF contained in a stainless steel reaction
vessel was added 8.2 g dimethyl amine (182 mmol). The
vessel was sealed and heated to 110 °C for 16 hours.
The reaction vessel was cooled to ambient temperature
and the contents concentrated ~n vacuo. Purification
by silica gel chromatography (Waters Prep-2000) using
an ethyl acetate/hexanes gradient (10-40% ethyl
acetate) gave 4.0 g (88%) of 4 as a yellow solid. 'H
NMR (CDC1,) d 0.80-0.95 (m, 6H), 0.96-1.53 (m. 8H).
1.60-1.69 (m, 3H). 2.11-2.28 (m, 1H). 2.79 (s. 6H).
3.09 (qpg~ Jpg = 15.0 Hz, DV= 45.6 Hz, 2H). 4.90 (d, J
9.0 Hz. 1H). 5.65 (s. IH). 5.75 (d. J = 2.1 Hz, 1H),
6.52 (dd, J = 9.6 and 2.7 Hz. 1H). 7.59 (t. J = 8.4 Hz,
1H). 7.85 (d, J = 7.80 Hz, 1H), 7.89 (d. J = 9.0 Hz,
1H), 8.20 (dd, J = 8.4 and 1.2 Hz. 1H), 8.43 (s, 1H).
MS(FABH+) m/e (relative intensity) 489.6 (100). 471.5
(25). HRMS calculated for M+H 489.2423.. Found
489.2456.
a6g
CA 02283575 1999-09-09
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Step 5. Preparation of 5
o,, p
~ ~SI~Bu
Du
Me2N
OH
NH2
To a suspension of 1.0 g (2.1 mmol) of 4 in 100 ml
ethanol in a stainless steel Parr reactor was added 1 g
10% palladium on carbon. The reaction vessel was
sealed, purged twice with H,, then charged with H= (100
psi) and heated to 45 °C for six hours. The reaction
vessel was cooled to ambient temperature and the
contents filtered to remove the catalyst. The filtrate
was concentrated in vacuo to give 0.9 g (96%) of 5. iH
NMR (CDC1,) d 0.80-0.98 (m, 6H), 1.00-1.52 (m, lOH),
1.52-1.69 (m, 1H), 2.15-2.29 (m, 1H), 2.83 (s, 6H),
3 .07 (qAg, ,3p~g = 15.1 Hz, Dv = 44.2 Hz, 2H) , 3 .70 (s,
2H), 4.14 (s, 1H), 5.43 (s, 1H), 6.09 (d, J = 2.4 Hz,
1H), 6.52 (dd, J = 12.2 and 2.6 Hz, 1H), 6.65 (dd, J =
7.8 and 1.8 Hz, 1H), 6.83 (s, 1H), 6.93 (d, J = 7.50
Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.9 Hz,
1H). MS(FABH+) m/e (relative intensity) 459.? (100).
HRMS calculated for M+H 459.2681. Found 459.2670.
02~0~
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Step 6. Preparation of 6
To a solution of 914 mg (2.0 mmol) of 5 in 50 ml THF
was added 800 mg (4.0 mmol) 5-bromovaleroyl chloride.
Next was added 4 g (39.6 mmol) TEA. The reaction was
stirred 10 minutes, then partitioned between ethyl
acetate and brine. The organic layer was dried
(MgSO,) and concentrated ;n.~- Purification by
silica gel chromatography through a 70 ml MPLC column
using a gradient of ethyl acetate(20-50%) in hexane as
eluent yielded 0.9 g (73%) of 6 as a pale yellow oil.
1H ~ (CDC1,) d 0.84-0.95 (m, 6H)' I.02-1.53 (m, lOH),
1.53-1.68 (m, 1H), 1.80-2.00 (m, 4H), 2.12-2.26 (m,
4H). 2.38 (t, J = 6.9 Hz, 2H), 2.80 (s' 6H), 3.07 (qpg,
Jp~ = 15.6 Hz' DV = 40.4 Hz, 2H)' 3.43 (t, J = 6.9 Hz,
2H), 4.10 (s, 1H). 5.51 (s, 1H)' 5.95 (d, J = 2.4 Hz,
1H), 6.51 (dd, J = 9.3 and 2.7 Hz. 1H), 7.28 (s, 1H)'
7.32-7.41 (m. 2H). 7.78 (d, J = 8.1 Hz. 1H), 7.90 (d, J
9.0 Hz, 1H).
Step 7. Preparation of 7
O
O~S~
Bu
~ Bu
Me 2N ~'OH
NEt3TFA
To a solution of 0.9 g (1.45 mmol) of 6 in 25 ml
acetonitrile add 18 g (178 mmol) TEA. Heat at 55 °C
for 16 hours. The reaction mixture was cooled~to
ambient temperature and concentrated ~n vacuo:',
Purification by reverse-phase silica gel chromatography
(Waters Delta Prep 3000) using an acetonitrile /water
gradient containing 0.05% TFA (20-65% acetonitrile)
~'~ G
CA 02283575 1999-09-09
WO 98140375 PG"f/US98/03792
gave 0.8 g (73%) of 7 as a white foam. iH NMR (CDC1,) d
0.80-0.96 (m, 6H), 0.99-1.54 (m. 19H). 1.59-1.84 (m,
3H). 2.09-2.24 (m, 1H), 2.45-2.58 (m. 2H). 2.81 (s.
6H). 3.09 (qpg. JAg = 15.6 Hz, DV = 18.5 Hz, 2H). 3.13-
3.31 (m, SH), 4.16 (s, 1H). 5.44 (s, 1H). 6.08 (d, J =
1.8 Hz, 1H), 6.57 (dd. J = 9.3 and 2.7 Hz, 1H). 7.24
(t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.4 Hz. 1H). 7.56 (d,
J = 8.4 Hz, 1H), 7.74 (s. 1H). 7.88 (d. J = 9.O Hz,
1H), 9.22 (s, 1H). HRMS calcd 642.4304; observed
642.4343.
~?ramnl P 1 400
Step 1
off
\ \
/ ~%
'
C14H1302F fw=232.25
A 12-liter, 4-neck round-bottom flask was equipped with
reflux condenser. N2 gas adaptor, mechanical stirrer,
and an addition funnel. The system was purged with N2.
A slurry of sodium hydride (126.Og/4.988mo1) in
toluene (2.5 L) was added, and the mixture was cooled
to 6 C. A solution of 4-fluorophenol (560.5g/5.000mo1)
in toluene (2.5 L) was added via addition funnel over a
period of 2.5 h. The reaction mixture was heated to
reflux (100 C) for lh. A solution of 3-methoxybenzyl
chloride (783.Og/5.OOOmo1) in toluene (?50 mL) was
added via addition funnel while maintaining reflux.
After 15 h: refluxing, the mixture was cooled to room
temperature and poured into H20 (2.5 L). After 20 min.
stirring, the layers were separated, and the organic
layer was extracted with a solution of potassium
hydroxide (720g) in MeOH (2.5 L). The MeOH layer was
added to 20% aqueous potassium hydroxide, and the
~'1 I
CA 02283575 1999-09-09
WO 98/40375 PC"T/US98/03792
mixture was stirred for 30 min. The mixture was then
washed 5 times with toluene. The toluene washes were
extracted with 20% aq. KOH. All 20% aq. KOH solutions
were combined and acidified with concentrated HC1. The
acidic solution was extracted three times with ethyl
ether, dried (MgS04), filtered and concentrated in
vacuo. The crude product was purified by Kugelrohr
distillation to give a clear, colorless oil (449.Og/39%
yield). b.p.: 120-130 C/50mtorrHg. 1H NMR and MS [(M
+ H)+ = 233] confirmed desired structure.
Step 2
OI~M
C17H18N02FS fw=319.39
A 12-liter, 3-neck round-bottom flask was fitted with
mechanical stirrer and N2 gas adaptor. The system was
purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-phenol
(455.5g/1.961mo1) and dimethylformamide were added.
2D The solution was cooled to 6 C, and sodium hydride
(55.5g/2.197mo1) was added slowly. After warming to
room temperature, dimethylthiocarbamoyl chloride
(242.4g/1.961mo1) was added. After 15 h, the reaction
mixture was poured into H20 (4.0 L), and extracted two
times with ethyl ether. The combined organic layers
were washed with H20 and saturated aqueous NaCl, dried
(MgS04), filtered, and concentrated in vacuo to give
the product (605.3g, 97% yield). 1H NMR and MS [(M+H)+
- 320] confirm desired structure.
a~ ~-
s
/CH ~
CA 02283575 1999-09-09
WO 98/40375 PCTIUS98/03792
Step 3
OMe
C14H130FS fw=248.32
A 12-liter, round-bottom flask was equipped with N2 gas
adaptor, mechanical stirrer, and reflux condenser. The
system was purged with N2. 4-Fluoro-2-(3-
methoxybenzyl)-phenyldimethylthiocarbamate
(605.3g/1.895mo1) and phenyl ether (2.Okg) were added,
and the solution was heated to reflux for 2 h. The
mixture was stirred for 64 h. at room temperature and
then heated to reflux for 2 h. After cooling to room
temperature, MeOH (2.0 L) and THF (2.0 L) were added,
and the solution was stirred for 15 h. Potassium
hydroxide (425-9g/7.590mo1) was added, and the mixture
was heated to reflux for 4 h. After cooling to room
temperature, the mixture was concentrated by rotavap,
dissolved in ethyl ether (1.0 L), and extracted with
H20. The aqueous extracts were combined, acidified
with concentrated HC1, and extracted with ethyl ether_
The ether extracts were dried (MgSO,), filtered, and
concentrated in vacuo to give an amber oil (463.08, 98%
yield). 1H NMR confirmed desired structure.
Step 4
a~3
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
AN
OMe
A 5-liter, 3-neck, round-bottom flask was equipped with
N2 gas adaptor and mechanical stirrer. The system was
purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-
thiophenol (100.Og/403.2mmo1) and 2-methoxyethyl ether
(1.0 L) were added and the solution was cooled to 0 C.
Sodium hydride (9.68g/383.2mmo1) was added slowly, and
the mixture was allowed to warm to room temparature,
2,2-Dibutylpropylene sulfate (110.89g/443.6mmol) was
added, and the mixture was stirred for 64 h. The
reaction mixture was concentrated by rotavap and
dissolved in H20. The aqueous solution was washed with
ethyl ether, and concentrated H2SOq was added. The
aqueous solution was heated to reflux for 30 min,
cooled to room temperature, and extracted with ethyl
ethex_ The ether solution was dried (MgSOq), filtered,
and cone d in vacuo to give an amber oil (143.949/85
yield). 1H NNgt and MS [(M + H)+ = 419] confirm the
desired structure.
Step 5
a~~
F
C25H3502FS fw=418.61
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
.,
OMe
A 2-liter, 4-neck, round-bottom flask was equipped with
N2 gas adaptor, and mechanical stirrer. The system was
purged with N2. The corresponding alcohol
(143.94g/343.8mmo1) and CH2C12 (1.0 L) were added and
cooled to 0 C. Pyridinium chlorochromate
(140.53g/651.6mmol) was added. After 6 h., CH2C12 was
added. After 20 min, the mixture was filtered through
silica gel, washing with CH2C12. The filtrate was
concentrated in vacuo to give a dark yellow-red oil
(110.68, 77% yield). 1H NMR and MS ((M + H)+ = 417]
confirm the desired structure.
Step 6
oMs
A 2-liter, 4-neck, round-bottom flask was equipped with
N2 gas adaptor and mechanical stirrer. The system was
purged with N2. The corresponding sulfide
~1S
F
C25H33~2FS fw=416.59
C25H33~4FS fw=448.59
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
(110.6g/265.5m~nol) and CN2C12 (1.0 L) were added. The
solution waa cooled to 0 C, and 3-chloroperbenzoic acid
(158.21g/531.7mmo1) was added portionwise. After 30
min, the reaction mixture was allowed to warm to room
temperature After 3.5 h, the reaction mixture was
cooled to 0 C and filtered through a fine frizted
funnel. The filtrate was washed with 10% aqueous
R2C03. An emulsion formed which was extracted with
ethyl ether. The oxganic layers were combined, dried
IO (MgS04). filtered, and concenczated in vacuo to give
the product (93.28. 78% yield). 1H Nit eonfizmed the
desired stzucture.
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 7
' o
..
ow
C2r~H33o4FS fw~d4B.59
A 2-liter, 4-neck, round-bottom flask was eguipped with
N2 gas adaptor, mechanical stirrer, and a powder
addition funnel. The system was purged with N2. The
corresponding aldehyde (93.2g/208mmo1) and THE' (1.0 L)
Were added. and the mixtuze was cooled to 0 C.
Potassium zerC-butoxide (23.35g/208.lmmol) was added
via addition tunnel. After ih. 10% aq/ HCl (1.0 L) seas
added. After 1 h, the mixture was extracted three
times with ethyl ether, dried lMgSOa), filtered, and
concentrated in vecuo. ?he crude product was purified
by recryst. from 80!20 hexane/athyl acetate to give a
white solid (32.18 gf. The mother liquor was
concentrated in vacuo and rectystelized from 9515
toluene/ethyl acetate to give a white solid (33.60g/
combined yield: ?icy. 1N hHIt confirmed the desire3
product.
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 8
0
o~
C27H390qNS fw=473.67
A Fisher porter bottle was fitted with N2 line and
magnetic stirrer. The system was purged with N2. The
corresponding fluoro-compound (28.1g/62.6mmo1) was
added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (1?.lg/379mmo1) was condensed via a
C02/acetone bath and added to the reaction vessel. The
mixture was allowed to warm to room temperature and was
heated to 60 C. After 20 h, the reaction mixture was
allowed to cool and was dissolved in ethyl ether. The
ether solution was washed with H20, saturated aqueous
NaCl, dried (MgSOq), filtered, and concentrated in
vacuo to give a white solid (28.Sg/96~ yield). 1H NMR
confirmed the desired structure.
~'1$
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 9
,o
e~
off
C26H3704NS fw=459.64
A 250-mL, 3-neck, round-bottom flask was equipped with
N2 gas adaptor and magnetic stirrer. The system was
purged with N2. The corresponding methoxy-compound
(6.62g/l4.Ommo1) and CHC13 (150 mL) were added. The
reaction mixture was cooled to -78 C, and boron
tribromide (10.50g/41.9mmo1) was added. The mixture
was allowed to warm to room temperature After 4 h, the
reaction mixture was cooled to 0 C and was quenched
with 10% K2C03 (100 mL). After 10 mina the layers were
separated, and the aqueous layer was extracted two
times with ethyl ether. The CHC13 and ether extracts
were combined, washed with saturated aqueous NaCl,
dried (MgS04), filtered, and concentrated in vacuo to
give the product (6.27g/98% yield). 1H NMR confirmed
the desired structure.
a~ 9
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 10
(IijC~
8u
to
O
J
In a 250 ml single neck round bottom Flask with stir
bar place 2- diethylamineoethyl chloride hydochloride
(fw 172.1Og/mole) Aldrich D8, 720-1 (2.4 mmo1,4.12g),
34 ml dry ether and 34 ml of 1N ROH(agueous). Stir 15
minutes and then separate by ether extraction and dry
over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom flask with
stir bar add sodium hydride (60% dispersion in mineral
oil, 100 mg , 2.6 mmol) and 34 ml of DMF. Cool to ice
temperature. Next add phenol product(previous step) 1.1
g (2.4 mmilomoles in 5 ml DMF and the ether solution
prepared above. Heat to 40C for 3 days. The product
which contained no starting material by TLC was diluted
with ether and extracted with 1 portion of 5% NaOH,
followed by water and then brine. The ether layer was
dried over magnesium sulfate and isolated by removing
ether by rotary evaporation (1.3 gms).The product may
be further purified by chromatography (Si02 99% ethyl
acetate/1% NH40H at 5m1/min.). Isolated yield: 0.78 g
(mass spec , and H1 NMR)
X80
~~ /o
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
Step 11
_ ~~ //°
6u
lu
J'-
The product from step 10 ( 0.57gms, 1.02 millimole fw
558.83 g/mole) and 1.6 gms iodoethane (10.02 mmol) was
placed in S ml acetonitrile in a fischer-porter bottle
and heated to 45 C for 3 days. The solution was
evaporated to dryness and redissolved in 5 mls of
chloroform. Next ether was added to the chloroform
solution and the resulting mixture was chilled. The
desired product is isolated as a precipitate 0.7272
gms. Mass spec M-I = 587.9 , H NMR).
Fxamnle 1401
Step 1
OMe
F
C14x13~2F fw=232.25
A 12-liter, 4-neck round-bottom flask was equipped with
a81
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
reflux condenser. N2 gas adaptor, mechanical stirrer,
and an addition funnel. The system was purged with N2.
A slurry of sodium hydride (126.Og/4.988mo1) in
toluene (2.5 L) was added, and the mixture was cooled
to 6 C. A solution of 4-fluorophenol (560.5g/S.OOOmo1)
in toluene (2.5 L) was added via addition funnel over a
period of 2.5 h. The reaction mixture was heated to
reflux (100 C) for lh. A solution of 3-methoxybenzyl
chloride (783.Og/S.OOOmo1) in toluene (750 mL) was
added via addition funnel while maintaining re.flux.
After 15 h. refluxing, the mixture was cooled to room
temperature and poured into H20 (2.5 L). After 20 min.
stirring, the layers were separated, and the organic
layer was extracted with a solution of potassium
hydroxide (720g) in MeOH (2.5 L). The MeOH layer was
added to 20% aqueous potassium hydroxide, and the
mixture was stirred for 30 min. The mixture was then
washed 5 times with toluene. The toluene washes were
extracted with 20% aq. KOH. All 20% aqueous KOH
solutions were combined and acidified with concentrated
HC1. The acidic solution was extracted three times
with ethyl ether, dried over MgS04, filtered and
concentrated in vacuo. The crude product was purified
by Kugelrohr distillation to give a clear, colorless
oil (449.Og/39% yield). b.p.: 120-130 C/50mtorrHg.
1H NMR and MS ((M + H)+ = 233) confirmed desired
structure.
Step 2
a~a-
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
/CH3
OMe
F
C17H18N02FS fw=319.39
A 12-liter, 3-neck round-bottom flask was fitted
with mechanical stirrer and N2 gas adaptor. The system
was purged with N2. 4-Fluoro-2-(3-methoxybenzyl)-
phenol (455.Sg/1.961mo1) and dimethylformamide were
added. The solution was cooled to 6 C, and sodium
hydride (55.5g/2.197mo1) was added slowly. After
warming to room temperature, dimethylthiocarbamoyl
chloride (242.4g/1.961mo1) was added. After 15 h, the
reaction mixture was poured into H20 (4.0 L), and
extracted two times with ethyl ether. The combined
organic layers were washed with H20 and saturated
aqueous NaCl, dried over MgS04, filtered, and
concentrated in vacuo to give the product (605.3g, 97%
yield). 1H NMR and MS [(M+H)+ = 320 confirm desired
structure.
Step 3
OMe
~~3
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
C1QH130FS fw=248.32
A 12-liter, round-bottom flask was equipped with
N2 gas adaptor, mechanical stirrer, and reflux
condenser. The system was purged with N2. 4-Fluoro-2-
(3-methoxybenzyl)-phenyldimethylthiocarbamate
(605.3g/1.895mo1) and phenyl ether (2.Okg) were added,
and the solution was heated to reflux for 2 h. The
mixture was stirred for 64 h. at room temperature and
then heated to reflux for 2 h. After cooling to room
temperature, MeOH (2.0 L) and THF (2.0 L) were added,
and the solution was stirred for 15 h. Potassium
hydroxide (425.9g/7.594mo1) was added, and the mixture
was heated to reflux for 4 h. After cooling to room
temperature, the mixture was concentrated by rotavap,
dissolved in ethyl ether (1.0 L), and extracted with
H20. The aqueous extracts were combined, acidified
with conc. HC1, and extracted with ethyl ether. The
ether extracts were dried (MgSO,), filtered, and
concentrated in vacuo to give an amber oil (463.Og, 98$
yield). 1H NMR confirmed desired structure.
Step 4
nN
OMe
F
C25H3502FS fw=418.61
A 5-liter, 3-neck, round-bottom flask was equipped
with N2 gas adaptor and mechanical stirrer. The system
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
was purged With N2. 4-Fluoro-2-(3-methoxybenzyl)-
thiophenol (100.Og/403.2mmo1) and 2-methoxyethyl ether
(1.0 L) were added and the solution was cooled to 0 C.
Sodium hydride (9.68g/383.2mmo1) was added slowly, and
the mixture was allowed to warm to room temperature
2,2-Dibutylpropylene sulfate (110.89g/443.6mmo1) was
added, and the mixture was stirred for 64 h. The
reaction mixture was concentrated by rotavap and
dissolved in H20. The aqueous solution was washed with
ethyl ether, and cone. H2S04 was added. The aqueous
solution was heated to reflex for 30 min, cooled to
room temperature, and extracted with ethyl ether. The
ether solution was dried (MgS04), filtered, and
concentrated in vacuo to give an amber oil (143.94g/85%
yield). 1H NMR and MS [(M + H)+ = 419 confirm the
desired structure.
Step 5
n
OMe
A 2-liter. 4-neck,~round-bottom flask was equipped
with N2 gas adaptor, and mechanical stirrer.;,The
system was purged with N2. The corresponding.alcohol
(143.94 g/343.8 mmol) and CH2C12 (1.0 L) were added and
cooled to 0 C. Pyridinium chlorochromate
(140.53g/651.6mmo1) was added. After 6 h., CH2C12 was
~$S
C25H3302FS fw=416.59
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
added. After 20 min, the mixture was filtered through
silica gel, washing with CH2C12. The filtrate was
concentrated in vacuo to give a dark yellow-red oil
(110.68, 77% yield). 1H NMR and MS [(M + H)+ = 417)
confirm the desired structure.
age
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
Step 6
our
C25H3304FS fw=448.59
A 2-liter, 4-neck, round-bottom flask was equipped
with N2 gas adaptor and mechanical stirrer. The system
was purged with N2. The correspona~ng 5u~ly~..=
(110.6g/265.5mmo1) and CH2C12 (1.0 L) were added. The
solution was cooled to 0 C, and 3-chloroperbenzoic acid
(158.21g/531.7mmo1) was added portionwise. After 30
min, the reaction mixture was allowed to warm to room
temperature After 3.5 h, the reaction mixture was
cooled to 0 C and filtered through a fine fritted
funnel. The filtrate was washed with 10% aqueous
K2C03. An emulsion formed which was extracted with
ethyl ether. The organic layers were combined, dried
(MgSOq), filtered, and concentrated in vacuo to give
the product (93.2g, 78% yield). 1H NMR confirmed the
desired structure.
a~~
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 7
o~ll
eu
8
OH
s
~l
a
oM.
C25H33~4FS fw=448.59
A 2-liter, 4-neck, round-bottom flask was equipped
with N2 gas adaptor, mechanical stirrer, and a powder
addition funnel. The system was purged with N2. The
corresponding aldehyde (93.2g/208mmo1) and THF (1.0 L)
were added, and the mixture was cooled to 0 C.
Potassium tert-butoxide (23.35g/208.1mmo1) was added
via addition funnel. After lh, 10% aq/ HC1 (1.0 L) was
added. After 1 h, the mixture was extracted three
times with ethyl ether, dried (MgS04), filtered, and
concentrated in vacuo. The crude product was purified
by recrystallized from 80/20 hexane/ethyl acetate to
give a white solid (32.18g). The mother liquor was
concentrated in vacuo and recrystallized from 95/5
toluene/ethyl acetate to give a white solid (33.608,
combined yield: 71%). 1H NMR confirmed the desired
product.
$g
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 8
e~
C27H3904NS fw=473.67
A Fisher porter bottle was fitted with N2 line and
magnetic stirrer. The system was purged with N2. The
corresponding fluoro-compound (28.1g/62.6mmo1) was
added, and the vessel was sealed and cooled to -78 C.
Dimethylamine (l7.lg/379mmo1) was condensed via a
C02/acetone bath and added to the reaction vessel. The
mixture was allowed to warm to room temperature and was
heated to 60 C. After 20 h, the reaction mixture was
allowed to cool and was dissolved in ethyl ether. The
ether solution was washed with H20, saturated aqueous
NaCl, dried over MgS04, filtered, and concentrated in
vacuo to give a white solid (28.Sg/96% yield). 1H NMR
confirmed the desired structure.
aeq
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 9
o
a
ju
eu
Me 2N
A 250-mL, 3-neck, round-bottom flask was equipped
with N2 gas adaptor and magnetic stirrer. The system
was purged with N2. The corresponding methoxy-compound
(6.62g/l4.Ommo1) and CHC13 (150 mL) were added. The
reaction mixture was cooled to -78 C, and boron
tribromide (10.50g/41.9mmo1) was added. The mixture
was allowed to warm to room temperature After 4 h, the
reaction mixture was cooled to 0 C and was quenched
with 10$ K2C03 (100 mL). After 10 min, the layers were
separated, and the aqueous layer was extracted two
times with ethyl ether. The CHC13 and ether extracts
were combined, washed with saturated aqueous NaCl,
. dried over MgS04, filtered, and concentrated in vacuo
to give the product (6.27g/98% yield). ~~1H NMR
confirmed the desired structure.
~9 O
OH
c26H3704N~ fw=459.64
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
Step 10
Bu
' 3u
J
In a 250 ml single neck round bottom flask with
stir bar place 2- diethylamineoethyl chloride
hydochloride (fw 172.1Og/mole) Aldrich D8, 720-1 (2.4
millimoles, 4.12g), 34 ml dry ether and 34 ml of 1N KOH
(aqueous). Stir 15 minutes and then separate by ether
extraction and dry over anhydrous potassium carbonate.
In a separate 2-necked 250 ml round bottom flask
with stir bar add sodium hydride (60% dispersion in
mineral oil, 100 mg, (2.6 mmol) and 34 ml of DMF. Cool
to ice temperature. Next add phenol product (previous
step) 1.1 g (2.4 mmol in 5 ml DMF and the ether
solution prepared above. Heat to 40C for 3 days. The
product which contained no starting material by TLC was
diluted with ether and extracted with 1 portion of 5%
NaOH, followed by water and then brine. The ether layer
was dried over Magnesium sulfate and isolated by
removing ether by rotary evaporation (1.3 gms). The
product may be further purified by chromatography
(silica 99% ethyl acetate/1% NH40H at 5m1/min..).
Isolated yield: 0.78 g (mass spec , and H1 NMR)
Step 11
aq c
CA 02283575 1999-09-09
W O 98/40375 PCT/US98/03792
Bu
3u
J'-
The product from step 10 (0.57gms, 1.02 millimole
fw 558.83 g/mole) and iodoethane (1.6 gms (10.02
mmol)was place in 5 ml acetonitrile in a Fischer-Porter
bottle and heated to 45 C for 3 days. The solution was
evaporated to dryness and redissolved in 5 mls of
chloroform. Next ether was added to the chloroform
solution and the resulting mixture was chilled. The
desired product is isolated as a precipitate 0.7272
gms. Mass spec M-I = 587.9, 1H NMR).
BIOLOGICAL ASSAYS
The utility of the compounds of the present
invention is shown by the following assays. These
assays are performed in vitro and in animal models
essentially using a procedure recognized to show the
utility of the present invention.
In Vitro Assay of compounds that inhibit IHAT-mediated
uptake of Iz~C1-Taurocholate lTC) in H14 Cells
Baby hamster kidney cells (BIiK) transfected with
the cDNA of human IBAT (H14 cells) are seeded-at 60,000
cells/well in 96 well Top-Count tissue culture plates
for assays run within in 24 hours of seeding, 30,000
ag ~
CA 02283575 1999-09-09
WO 98/40375 PCTIUS98/03792
cells/well for assays run within 48 hours, and 10,000
cells/well for assays run within ?2 hours.
On the day of assay, the cell monolayer is gently
washed once with 100 ml assay buffer (Dulbecco's
Modified Eagle's medium with 4.5 g/L glucose + 0.2~
_ (w/v) fatty acid free bovine serum albumin- (FAF)BSA).
To each well 50 ml of a two-fold concentrate of test
compound in assay buffer is added along with 50 ml of 6
mM [1'C]-taurocholate in assay buffer (final
concentration of 3 mM [1'C]-taurocholate). The cell
culture plates are incubated 2 hours at 3?° C prior to
gently washing each well twice with 100 ml 4° C
Dulbecco's phosphate-buffered saline (PBS) containing
0.2~ (w/v) (FAF)BSA. The wells are then gently washed
once with 100 ml 4° C PBS without (FAF)BSA. To each
200 ml of liquid scintillation counting fluid is added,
the plates are heat sealed and shaken for 30 minutes at
room temperature prior to measuring the amount of
radioactivity in each well on a Packard Top-Count
instrument.
~~i 3
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
In Vitro Assa of com ounds that inhibit a take of
j"C~-Alanine
The alanine uptake assay is performed in an
identical fashion to the taurocholate assay, with the
exception that labeled alanine is substituted for the
labeled taurocholate.
In yivo Assa of com ounds that inhibit Rat Ileal
a take of I"Cl-Taurocholate into Hile
(See"Metabolism of 3a,7b-dihydroxy-7a-methyl-5b-
cholanoic acid and 3a,7b-dihydroxy-7a-methyl-5b-
cholanoic acid in hamsters" in Biochimica et Biophysica
Acta 833 (1985) 196-202 by Une et al.)
Male wistar rats (200-300 g) are anesthetized with
inactin @100 mg/kg. Bile ducts are cannulated with a
10" length of PE10 tubing. The small intestine is
exposed and laid out on a gauze pad. A canulae (1/8"
luer lock, tapered female adapter) is inserted at 12 cm
from the junction of the small intestine and the cecum.
A slit is cut at 4 cm from this same junction
(utilizing a 8 cm length of ileum). 20 ml of warm
Dulbecco's phosphate buffered saline, pH 6.5 (PBS) is
used to flush out the intestine segment. The distal
opening is cannulated with a 20 cm length of silicone
tubing (0.02" I.D. x 0.037" O.D.). The proximal
cannulae is hooked up to a peristaltic pump and the
intestine is washed for 20 min with warm PBS at 0.25
ml/min. Temperature of the gut segment is monitored
continuously. At the start of the experiment. 2.0 ml
of control sample (["C]-taurocholate @ 0.05 mi/ml with
5 mM cold taurocholate) is loaded into the gut segment
with a 3 ml syringe and,bile sample collection is
begun. Control sample is infused at a rate of 0.25
ml/min for 21 min. Bile samples fractions are
collected every 3 minute for the first 27 minutes of
the procedure. After the 21 min of sample infusion,
the ileal loop is washed out with 20 ml of warm PBS
(using a 30 ml syringe), and then the loop is washed
out for 21 min with warm PBS at 0.25 ml/min. A second
~9 ~
CA 02283575 1999-09-09
WO 98/40375 PGT/US98/03792
perfusion is initiated as described above but this with
test compound being administered as well (21 min
administration followed by 21 min of wash out) and bile
- sampled every 3 min for the first 27 min. If
necessary, a third perfusion is performed as above that
typically contains the control sample.
Measurement of Hepatic Cholesterol Concentration
(HEPATIC CHOL)
Liver tissue was weighed and homogenized in
chloroform:methanol (2:1). After homogenization and
centrifugation the supernatant was separated and dried
under nitrogen. The residue was dissolved in
is.opropanol and the cholesterol content was measured
enzymatically, using a combination of cholesterol
oxidase and peroxidase, as described by Allain, C. A.,
et a1. (1974) Clin. Chem. 2~, 470.
Measurement of Hepatic HMG CoA-Reductase Activity (HMG
COA
Hepatic microsomes were prepared by homogenizing
liver samples in a phosphate/sucrose buffer, followed
by centrifugal separation. The final pelleted material
was resuspended in buffer and an aliquot was assayed
for HMG CoA reductase activity by incubating for 60
minutes at 37° C in the presence of "C-HMG-CoA (Dupont-
NEN). The reaction was stopped by adding 6N HC1
followed by centrifugation. An aliquot of the
supernatant was separated, by thin-layer
chromatography, and the spot corresponding to the
enzyme product was scraped off the plate, extracted and
radioactivity was determined by scintillation counting.
(Reference: Akerlund, J. and Bjorkhem, I. (1990) J.
Lipid Res: 31, 2159).
Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL
TGI an8 VLDL + LDL)
Total serum cholesterol (SER.CHOL) was measured
enzymatically using a commercial kit from Wako Fine
x.95
CA 02283575 1999-09-09
WO 98/40375 PCT/US98I03792
Chemicals (Richmond, VA); Cholesterol C11, Catalog No.
276-64909. HDL cholesterol (HDL-CHOL) was assayed
using this same kit after precipitation of VLDL and LDL
with Sigma Chemical Co. HDL Cholesterol reagent,
Catalog No. 352-3 (dextran sulfate method). Total
serum triglycerides (blanked) (TGI) were assayed
enzymatically with Sigma Chemical Co. GPO-Trinder,
Catalog No. 337-B. VLDL and LDL (VLDL + LDL)
cholesterol concentrations were calculated as the
difference between total and HDL cholesterol.
Measurement of Hepatic Cholesterol 7-a-Hvdroxvlase
Activitv (7a-OHase)
Hepatic microsomes were prepared by homogenizing
liver samples in a phosphate/sucrose buffer, followed
by centrifugal separation. The final pelleted material
was resuspended in buffer and an aliquot was assayed
for cholesterol 7-a-hydroxylase activity by incubating
for 5 minutes at 37° C in the presence of NADPH.
Following extraction into petroleum ether, the organic
solvent was evaporated and the residue was dissolved in
acetonitrile/ methanol. The enzymatic product was
separated by injecting an aliquot of the extract onto a
Cl, reversed phase HPLC column and quantitating the
eluted material using W detection at 240nm.
(Reference: Horton, J. D., et a1. (1994) J. Clin.
Invest. 93, 2084).
Measurement of Fecal Bile Acid Concentration (FBA
Total fecal output from individually housed
hamsters was collected for 24 or 48 hours, dried under
a stream of nitrogen, pulverized and weighed.
Approximately 0.1 gram was weighed out and extracted
into an organic solvent (butanol/water). Following
separation and drying, the residue was dissolved in
methanol and the amount of bile acid present~was
measured enzymatically using the 3a-hydroxysteroid
steroid dehydrogenase reaction with bile acids to
reduce NAD. (Reference: Mashige, F., et al. (1981)
a~ ~
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03~92
Clin. Chem. 27, 1352).
j'H7taurocholate Uptake in Rabbit Hrush Border Membrane
yesicles (BHMV)
Rabbit Ileal brush border membranes were prepared
from frozen ileal mucosa by the calcium precipitation
method describe by Malathi et al. (Reference: (1979)
Biochimica Biophysica Acta, 554, 259). The method for
measuring taurocholate was essentially as described by
Kramer et a1. (Reference: (1992) Biochimica Biophysica
Acta, 1111, 93) except the assay volume was 200 ul
instead of 100 ul. Briefly, at room temperature a 190
ul solution containing 2uM ('H]-taurocholate(0.75 uCi),
20 mM tris, 100 mM NaCl, 100 mM mannitol pH 7.4 was
incubated for 5 sec with 10 ul of brush border membrane
vesicles (60-120 pg protein). The incubation was
initiated by the addition of the BBMV while vortexing
and the reaction was stopped by the addition of 5 ml of
ice cold buffer (20 mM Hepes-tris, 150 mM KC1) followed
immediately by filtration through a nylon filter (0.2
um poze) and an additional 5 ml wash with stop buffer.
Acvl-CoA;cholesterol Acvl Transferase (ACAT)
Hamster liver and rat intestinal microsomes were
prepared from tissue as described previously
(Reference: (1980) J. Biol. Chem. 255, 9098) and used
as a source of ACAT enzyme. The assay consisted of a-
2.0 ml incubation containing 24 ),1M Oleoyl-CoA (0.05
uCi) in a 50 mM sodium phosphate, 2 mM DTT ph 7.4
buffer containing 0.25 $ BSA and 200 ug of microsomal
protein. The assay was initiated by the addition of
oleoyl-Cod. The reaction went for 5 min at 37° C and
was terminated by the addition of 8.0 ml of chloroform/
methanol (2:1). To the extraction was added 125 ug of
cholesterol oleate in chloroform methanol to'act as a
carrier and the organic and aqueous phases of the
extraction were separated by centrifugation after
thorough vortexing. The chloroform phase was taken to
a9'1
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
dryness and then spotted on a silica gel 60 TLC plate
and developed in hexane/ethyl ether (9:1). The amount
of cholesterol ester formed was determined by measuring
the amount of radioactivity incorporated into the
cholesterol oleate spot on the TLC plate with a Packard
instaimager.
Data from each of the noted compounds in the
assays described above is as set forth in TABLES 5, 6,
7, and 8 as follows:
a9~
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
COMPOUND IC50 In vitro % % % of Control
uM* Inhibition Inhibition Transport of TC in
of TC of Alanine Rat Ileum @ O.lmM
Uptake @ Uptake @ #
100 uM # 100 uM #
Benzothiaze 2 0 45.4 +/- 0.7
pine=
12 25
3 0
4a 3
5a 34
Sb 40 0 72.9 5.4 @ 0.5 mM
4b 9
18 6
14b 18
14a 13
13 23
15 60
19a 0
19b 15
8a 41
Mixture of 69
8a and 8b
Mixture of 6
9a and 9b
6a 5
6b ( ( 85
CA 02283575 1999-09-09
WO 98/40375 PCT/US98/03792
9a 5 0% @ 25 mM 53.7 +/- 3.9
Mixture of 13
6a and 20
Mixture of 0.8 14% @ 25
6d and l0a ~T~M
21a 37
21c 52
21b 45
6c 2 58_5 68.8 +/- 5.7 0.4
at
6d . 0.6 77.7 16.1 +/- 1.1 0.5
@ @
mM 30.2 +/-
0.9
0.15 mM
17 10
7 5p 49.3
l0a 7 77.6 62.4 =/- 2.5 0.2
@
mM
lOb 15 68.6
25 0.1 4% @ 10 mM 26.0 +/- 3.3
26 2 31% @ 25 87.9 +/- 1.5
mM
27 5 7% @ 20 mM
2g g 31% @ 20mM
29 88 @ 50 mM
30 . 96 @ 50 mM
31 41 @ 50 mM
37 3 0% @ 5 mM
38 p,3 11% @ 5mM 20.6 +/- 5.7
40 ~ ~49 @ 50 mM
3oa
CA 02283575 1999-09-09
t
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LA PRESENTS PARTIE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CEC! EST LE TOME ~ DE
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
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