Note: Descriptions are shown in the official language in which they were submitted.
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SELECTIVE MELANIN CONCENTRATING HORMONE-1 (MCH1) RECEPTOR
ANTAGONISTS AND USES THEREOF
BACKGROUND OF THE INVENTION
Throughout this application, various publications are
referenced in parentheses by author and year. Full
citations for these references may be found at the end of
the specification immediately preceding the sequence
listings and the claims. The disclosure of these
publications in their entireties are hereby incorporated by
reference into this application to describe more fully the
state of the art to which this invention pertains.
Melanin-concentrating hormone (MCH) is a cyclic peptide
originally isolated from salmonid (teleost fish)
pituitaries (Kawauchi et al., 1983). In fish the l7,amino
acid peptide causes aggregation of melanin within the
melanophores and inhibits the release of ACTH, acting as a
functional antagonist of ex-MSH. Mammalian MCH (19 amino
acids) is highly conserved between rat, mouse, and human,
exhibiting 1000 amino acid identity, but its physiological
roles are less clear. MCH has been reported to participate
in a variety of processes including feeding, water balance,
energy metabolism, general arousal/attention state, memory
and cognitive functions, and psychiatric disorders (for
reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge
et al., 1996). Its role in feeding or body weight
regulation is supported by a recent Nature publication (Qu
et al., 1996) demonstrating that MCH is overexpressed in
the hypothalamus of ob/ob mice compared with ob/+ mice, and
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that fasting further increased MCH mRNA in both obese and
normal mice during fasting. MCH also stimulated feeding in
normal rats when injected into the lateral ventricles
(Rossi et al., 1997). MCH also has been reported to
functionally antagonize the behavioral effects of a-MSH
(Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al.,
1997); in addition, stress has been shown to increase POMC
mRNA levels while decreasing the MCH precursor preproMCH
(ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may
serve as an integrative neuropeptide involved in the
reaction to stress, as well as in the regulation of feeding
and sexual activity (Baker, 1991; Knigge et al., 1996).
Although the biological effects of MCH are b'e.lieved,;.t,o l~,e ,
~'e~i;:.:t:~. , ''4-.
mediated by specific receptors, binding sites for~MC'H have
not been well described. A tritiated ligand ([3H]-MCH) was
reported to exhibit specific binding to brain membranes'but.
,,., ,
was unusable for saturation analyses, so ne,it,her affinity
nor Bma~ were determined (Drozdz and Eberle, 1995).
Radioiodination of the tyrosine at position thirteen
resulted in a ligand with dramatically reduced biological
activity (see Drozdz and Eberle, 1995). In contrast, the
radioiodination of the MCH analogue [Phez3,Tyr19]-MCH was
successful (Drozdz et al., 1995); the ligand retained
biological activity and exhibited specific binding to a
variety of cell lines including mouse melanoma (B16-F1,
G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the
K~, = 0.118nM and the Bmax 1100 sites/cell. Importantly,
the binding was not inhibited by a-MSH but was weakly
inhibited by rat ANF (Ki = 116 nM vs. 12 nM for native MCH)
(Drozdz et al., 1995). More recently specific MCH binding
was reported in transformed keratinocytes (Burgaud et al.,
1997) and melanoma cells (Drozdz et al., 1998), where
photo-crosslinking studies suggest that the receptor is a
membrane protein with an apparent molecular weight of 45-50
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kDaltons, compatible with the molecular weight range of the
GPCR superfamily of receptors. No radioautoradiographic
studies of MCH receptor localization using this ligand have
been reported as yet.
The localization and biological activities of MCH peptide
suggest that the modulation of MCH receptor activity may be
useful in a number of therapeutic applications. The role
of MCH in feeding is the best characterized of its
potential clinical uses. MCH is expressed in the lateral
hypothalamus, a brain area implicated in the regulation of
thirst and hunger (Grillon et al., 1997); recently orexins
A and B, which are potent orexigenic agents, have been
shown to have very similar localization to MCH in the
lateral hypothalamus (Sakurai et al., 1998). MCH mRNA
levels in this brain region are increased in rats after 24
hours of food-deprivation (Nerve and Fellman, 1997); after
insulin injection, a significant increase in the abundance
and staining intensity of MCH immunoreactive perikarya and
fibres was observed concurrent with a significant increase
in the level of MCH mRNA (Bahjaoui-Bouhaddi et al., 1994).
Consistent with the ability of MCH to stimulate feeding in
rats (Rossi et al., 1997) is the observation that MCH mRNA
levels are upregulated in the hypothalami of obese ob/ob
mice (Qu et al., 1996), and decreased in the hypothalami of
rats treated with leptin, whose food intake and body weight
gains are also decreased (Sahu, 1998). MCH appears to act
as a functional antagonist of the melanocortin system in
its effects on food intake and on hormone secretion within
the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al.,
1998). Together these data suggest a role for endogenous
MCH in the regulation of energy balance and response to
stress, and provide a rationale for the development of
specific compounds acting at MCH receptors for use in the
treatment of obesity and stress-related disorders.
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In all species studied to.date, a major portion of the
neurons of the MCH cell group occupies a rather constant
location in those areas of the lateral hypothalamus and
subthalamus where they lie and may be a part of some of the
so-called "extrapyramidal" motor circuits. These involve
substantial striato- and pallidofugal pathways involving
the thalamus and cerebral cortex, hypothalamic areas, and
reciprocal connections to subthalamic nucleus, substantia
nigra, and mid-brain centers (Bittencourt et al., 1992).
In their location, the MCH cell group may offer a bridge or
mechanism for expressing hypothalamic visceral activity
with appropriate and coordinated motor activity.
Clinically it may be of some value 'to consider the
involvement of this MCH system in movement disorders, such
as Parkinson's disease and Huntingdon's Chorea in which
extrapyramidal circuits are known to be involved.
Human genetic linkage studies have located authentic hMCH
loci on chromosome 12 (12q23-24) and the.variant hMCH loci
on r_hromosome 5 (5q12-13) (Pedeutour et al., 1994). Locus
12q23-24 coincides with a locus to which autosomal dominant
cerebellar ataxia type II (SCA2) has been mapped (Auburger
et al., 1992; Twells et al,, 1992). This disease comprises
neurodegenerative disorders, including an
olivopontocerebellar atrophy. Furthermore, the gene for
Darier's disease, has been mapped to locus 12q23-24
(Craddock et al., 1993). Dariers' disease is characterized
by abnormalities I keratinocyte adhesion and mental
illnesses in some families. In view of the functional and
neuroanatomical patterns of the MCH neural system in the
rat and human brains, the MCH gene may represent a good
candidate for SCA2 or Darier's disease. Interestingly,
diseases with high social impact have been mapped to this
locus. Indeed, the gene responsible for chronic or acute
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forms of spinal muscular atrophies has been assigned to
chromosome 5q12-13 using genetic linkage analysis (Melki et
al., 1990; rnlestbrook et al., 1992). Furthermore,
independent lines of evidence support the assignment of a
major schizophrenia locus to chromosome 5q11.2-13.3
(Sherrington et al., 1988; Bassett et al., 1988; Gilliam et
al., 1989). The above studies suggest that MCH may play a
role in neurodegenerative diseases and disorders of
emotion.
Additional therapeutic applications for MCH-related
compounds are suggested by the observed effects of MCH in
other biological systems. For example, MCH may regulate
reproductive functions in male and female rats. MCH
transcripts and MCH peptide were found within germ cells in
testes of adult rats, suggesting that MCH may participate
in stem cell renewal and/or differentiation of early
spermatocytes (Hervieu et al., 1996). MCH injected
directly into the medial preoptic area (MPOA) or
~0 ventromedial nucleus (VMN) stimulated sexual activity in
female rats (Gonzalez et al., 1996). In ovariectomized
rats primed with estradiol, MCH stimulated luteinizing
hormone (ZH) release while anti-MCH antiserum inhibited L,H
release (Gonzalez et al., 1997). The zona incerta, which
contains a large population of MCH cell bodies, has
previously been identified as a regulatory site for the
pre-ovulatory ZH surge (MacKenzie et al., 1984). MCH has
been reported to influence release of pituitary hormones
including ACTH and oxytocin. MCH analogues may also be
useful in treating epilepsy. In the PTZ seizure model,
injection of MCH prior to seizure induction prevented
seizure activity in both rats and guinea pigs, suggesting
that MCH-containing neurons may participate in the neural
circuitry underlying PT2-induced seizure (Knigge and
Wagner, 1997). MCH has also been observed to affect
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behavioral correlates of cognitive functions. MCH
treatment hastened extinction of the passive avoidance
response in rats (McBride et al., 1994), raising the
possibility that MCH receptor antagonists may be beneficial
for memory storage and/or retention. A possible role for
MCH in the modulation or perception of pain is supported by
the dense innervation of the periaqueductal grey (PAG) by
MCH-positive fibers. Finally, MCH may participate in the
regulation of fluid intake. ICV infusion of MCH in
conscious sheep produced diuretic, natriuretic, and
kaliuretic changes in response to increased plasma volume
(Parkas, 1996). Together with anatomical data reporting
the presence of MCH in fluid regulatory areas of the brain,
the results indicate that MCH may be an importan peptide
involved in the central control of fluid homeostasis in
mammals. ,
As used in this invention, the term "antagonist" refers to
a compound which binds to, and decreases the activity of,
a receptor in the presence of an agonist. In the case of
a G-protein coupled receptor, activation may be measured
using any appropriate second messenger system which is
coupled to the receptor in a cell or tissue in which the
receptor is expressed. Some specific, but by no means
limiting, examples of well-known second messenger systems
are adenylate cyclase, intracellular calcium mobilization,
ion channel activation, guanylate cyclase and inositol
phospholipid hydrolysis. Conversely, the term "agonist°'
refers to a compound which binds to, and increases activity
of, a receptor as compared with the activity of the
receptor in the absence of any agonist.
In one embodiment of this invention, the synthesis of novel
compounds which bind selectively to the cloned human
melanin-concentrating hormone-1 (MCH1) receptor, compared
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to other cloned G-protein coupled receptors, and inhibit
the activation of the cloned receptors as measured in in
vitro assays is disclosed. The in vitro receptor binding
and activation assays described hereinafter were performed
using various cultured cell lines, each transfected with
and expressing only a single cloned receptor.
Furthermore, the compounds of the present invention may
also be used to treat abnormal conditions such as feeding
disorders (obesity, bulimia and bulimia nervosa),
sexual/reproductive disorders, depression, anxiety,
depression and anxiety, epileptic seizure, hypertension,
cerebral hemorrhage, congestive heart failure, sleep
disturbances, or any condition in which antagonism of an
MCH1 receptor may be beneficial. In addition, the
compounds of the present invention may be used to reduce
the body mass of a subject.
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_g_
Summary Of The Invention
This invention provides a compound having the structure:
A O
R1 N~N~R4 F ~R4
H
R2 N~X
I
R3
Rsw N N~ R4
or
. ~ I H
S N R2
V __ ~ ~n
V
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wherein A is
Y2 Y3 Y2 Y
3
r
Y 1 ~~~~ Y . . Y
/ Y4 ,
/ N
y5
Y2
~ Y3
Yi L
S
Y2 Y3 Y2 Y
2 0 y \.~~ N y ~~/ ~N O
/ \~ r 1 ~y w /
X ~ N
y2 y
3
Or ~ ~ .
Y, l
x
wherein each of Y1, Y,,, Y3, YQ and Y5 is independently -H;
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3; -CN; -OR3,
-OCOR3, -COR3, -CON (R3) 2, or -COORS; or any two of Y1, Y2,
Y3, Y9 and Y5 present on adj acent carbon atoms can
constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
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wherein R1 is -H; -N02; -CN; straight chained or branched
C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CHZ) pOR3; -COR3; -C02R3;
-CON ( R3 ) 2; or -COZ ( CH2 ) nV;
wherein R2 is -H; straight~chained or branched C1-C7
alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C~-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; C3-Clo cycloalkyl-C1-Clo-alkyl, C3-Clo
cycloalkyl-C1-Clo-monofluoroalkyl or C3-C1o cycloalkyl-C1-
Clo-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3,
- ( CH., ) nNHR3, -CH2X ( CH2 ) pN ( R3 ) 2 , -CH~X ( CH2 ) pN3 r
-CH~X (CHz) pNHCXR~ ; or -OR3; or wherein R1 and R2 together
may form a lactone ring;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
wherein R4 is
(i)
X~R~
R ~~ 1I I~
O
R ~ Rs
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(ii)
X"R6
R
I~ ~ m ~ O
t N
R ~~../ Rs
V
(iii)
R ~/ Rs
Ny ' m
~'\V~X~R6
R ~m
O
V
(iv) R ~~~Rs
t N
~'\V~X~Rs
R I~I[m
O
(v) R m R
r ~N r V
R U m Rs R
(vi) R V R
m
r \N r V
R C' m Rs R
(vii) R ~ Rs O
N m~N~
N~Ra
~ ..J
R~
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_Z2_
(viii)
O
v
N-R8 9
(ix) Z R~
R
. Or
t
R ~ Rs
Z
(x)
R
,
t N \\
Rs
R
V
wherein the dashed line represents a single bond or a
double bond;
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; -N (R3) ~; -NO~; -CN; -C02R3; -OR3; or
-CON (R3) 2%
wherein each V is independently aryl or heteroaryl,
optionally substituted with one or more F; C1; Br; I;
COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2; -OR3; -SR3;
(CH2) qOR3; (CH2) qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
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wherein each R5 is -H; -N02; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more F;
Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) ~; -OR3;
-SR3; (CH2) qOR3; (CH2) qSR3; straight chained or branched
Cl-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein R6 is -H; straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroa:lkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, optionally substituted with
one or more F; Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -NO.,;
-N (R3) 2; -OR3; -SR3; (CHz) qOR3; (CH2) qSR3; straight chained
or branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein R~ is H; F; Cl; Br; I; -N02; -N3; -CN; straight
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
CyClOalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3; or
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-CON (R3) 2;
wherein R8 is independently straight chained or branched
C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein 2 is naphthyl, quinolinyl, isoquinolinyl,
l0 quinazolinyl, phthalazinyl, quinoxalinyl, indolyl,
benzo[b]furanyl, or benzo[b]thiophenyl; wherein the
naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or
benzo[b]thiophenyl may be substituted with one or more F;
C1; Br; I; COR3; CO.,R3; -CON (R3) ~; CN; -NO2; -N (R3) 2; -OR3;
-SR3; (CH2) qOR3; (CH2) qSR3; straight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched Cz-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein each n is independently an integer from 0 to 5
inclusive;
wherein each p is independently an integer from 1 to 7
inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein r is an integer from 0 to 3 inclusive;
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wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
This invention further provides a compound having the
structure:
15
/R2 R R
-~ /X
M N ~----~ -~N-- ~ m W
Ri Rz R Ri R
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl ; -N (R3 ) ., ; -NOz ; -CN; -SR3 ; -COzR~ ; or
2 0 - OR3 ;
wherein each R1 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
25 C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; - (CHL) pOR3; -COR3; -C02R3; or -CON (R3) z;
wherein each R2 is -H; -N02; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
30 straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -CO2R3;
or -CON(R3)2; or aryl or heteroaryl, optionally
substituted with one or more F; C1; Br; I; COR3; COzR3;
35 -CON (R3) 2: CN; -N02; -N (R3) L; -OR3: -SR3; (CH2) qOR3;
(CH.,) qSR3; straight chained or branched C1-C~ alkyl,
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monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight.chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C~-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
wherein M is aryl or heteroaryl, optionally substituted
with one or more F; Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN;
-N02; -N (R3) 2: -OR3; -SR3; (CH2) qOR3; (CH2) qSR3; straight
chained or branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;
straight chained or branched C2-C~ alkenyl, C2-C~ alkynyl;
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein X is (CHI) n, O, S or NR3;
wherein W is
(a) C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally
substituted with one or more COR3; CO~R3; -CON (R3) 2;
CN; -N02 ; -N ( R3 ) 2 ; - OR3 ; - SR3 ; ( CH2 ) qOR3 ; ( CHI ) qSR3 ;
straight chained or branched C1-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one
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or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN;
-N02 ; -N ( R3 ) 2 ; -OR3 ; - SR3 ; ( CH2 ) qOR3 ; ( CH2 ) qSR3 %
straight chained or branched C1-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C~-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl;
wherein m is an integer from 0 to 4 inclusive;
wherein n is an integer from 0 to 6 inclusive;
wherein p is an integer from 1 to 4 inclusive;
wherein q is an integer from l to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
This invention also provides a compound having the
structure:
O
O R
RS RS C m U
\w
f~'~R
2 5 R ~n R
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; -N (R3) 2; -N02; -CN; -C02R3; -OR3; or
-CON ( R3 ) 2
wherein each R1 is independently -H; F; C1; Br; I; -N02;
-N~; -CN; straight chained or branched C1-C~ alkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C2-C~ alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
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cycloalkenyl; -N (R3) z; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more F;
Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2; -OR3;
-SR3; (CH2) qOR3; (CHZ) ~SR3; straight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C~-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; .
wherein R5 is -H; -N02; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more F;
Cl; Br; I; COR3; C02R3; -CON (R3) ~; CN; -N02; -N (R3) 2; -OR3;
-SR3; (CH2) qOR3; (CH2) qSR3; straight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched Cz-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein V is H; aryl or heteroaryl, optionally
substituted with one or more F; C1; Br; I; COR3; C02R3;
-CON (R3) 2; CN; -NO~; -N (R3) ~; -OR3; -SR3; (CHI) qOR3;
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(CH2)qSR3; straight chained or branched C1-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, CZ-C7 alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein W is
(a) C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally
substituted with one or more COR3; C02R3; -
CON (R3) 2; CN; -N02; -N (R3) 2; -0R3; -SR3;
( CH2 ) qOR3 ; ( CH2 ) qSR3 ; straight chained or
branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched
C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl;
or
(b) aryl or heteroaryl optionally substituted with
one or more F; C1; Br; T; COR3; CO~R3; -CON(R3) ~;
CN ; -N02 ; -N ( R3 ) ~ ; - OR3 ; - SR3 ; ( CHI ) qOR3 ;
(CH2) qSR3; straight chained or branched Cl-C~
alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight
chained or branched C2-C~ alkenyl, C2-C~
alkynyl; C3-C~ cycloalkyl;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein n is an integer from 0 to 2 inclusive;
wherein p is an integer from 1 to 7 inclusive;
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wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
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_2~_
This invention further provides a method of modifying
feeding behavior of a subject which comprises
administering to the subject an amount of a compound
effective to decrease the consumption of food by the
subject wherein the compound has the structure:
A O
II
RI N~N~Ra
P .- R4
H ,
R2 N~X
R3
A O A O
R ~ R
1 I N N~ 4 R3~N N~R4
H . or
R2 N~S ~ I H
S N R2
Ij~ ]n > ~n
V
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-22-
wherein A is
Y~~~Y3 Y~~~Y3
Y r .1 , r..1
Y4 Y1 ~/ ~ y4 ,
/ N
y5
Y2
~ Y3
,
y1 L
S
y2 Y3 y2 Y
3
i
N ~~~ N
y1 ' ~ \~ , y1 r~ ~ ~ ,
~N
Y2 Y
3
Or
3 0 Yj ' ~ X
wherein each of Y1, Y2, Y3, Y4 and Y5 is independently -H;
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -F, -C1, -Br, or -I;
-NO~; -N3; -CN; -OR3, -OCOR3, -COR3, -CON (R3) 2, or -COOR3;
or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent
carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3;
wherein R1 is -H; -N02; -CN; straight chained or branched
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C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CH~) pOR3; -COR3; -C02R3;
-CON ( R3 ) ~ ; or CO~ ( CH2 ) nV;
wherein R2 is -H; straight chained or branched C1-C~
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C2-C7 alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; C3-Clo cycloalkyl-C1-Clo-alkyl, C3-Clo
cycloalkyl-C1-Clo-monofluoroalkyl or C3-Clo cycloalkyl-C1-
Clo-polyfluoroalkyl; -CN; -.CH,,XR3, -CH2X(CH2)pNHR3,
- ( CH2 ) nNHR3, -CH2X ( CH2 ) pN ( R3 ) 2, -CH2X ( CH2 ) pN3,
-CH~X(CH~)pNHCXRS ; -OR3; or wherein R~ and R2 together form
a lactone ring;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
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wherein R4 is
(i)
R ~R5
-~N V
R f~R6
(ii) R7
'm
to R R5
t N
~R '
R ~ m
R7
15 (iii)
Y1
R [ m [
t N . .b ~ ~ Y2
2o R [ m Z
R6 Ya
(iV)
Y1 Y2
2 5 , R6
R [ m [ m \ ~ ~Y3
t N
R [~D _ [d
3o D
(V)
Y2
3 5 Y1 Y3
R [ m R6
4o t N / ~~~d
R [. ,-n ~-Z
(Vi)
O
R m R6
45 R
N
R ~ m ~ W R6 '
o R7
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(vii)
R m R6
Y1
R ~~ II '
B Y2 '
z o . Y3
( viii ) R R6
R m R5
.
R
R R ~ m , 6
R7
(ix)
R U R
m ; or
m ~N m U
2 5 R ~ m Rs R
R ~ R
(X) ~m
9
m LT .
R I m~' Rs R
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C~-C~
alkenyl or alkynyl; -N (R3) 2; -N02; -CN; -C02R3; -OR3; or
-CN ( R3 ) 2
wherein B is N or CYg;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or
CS;
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wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; C1; Br; I;
COR3: CO2R3; -CON (R3) 2; CN; -N02; -N (R3) ?: -OR3: -SR3;
( CH., ) ~OR3; ( CH2 ) qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein V is C (R5) 2; CR5R6; . NR5 or NR6;
wherein W is CRS; CR6 or N;
Z5 wherein 2 is S: 0; C (R3) ~; or NR3;
wherein each R5 is -H; -NO.,; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C~-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
or -CON(R3)~; -XCORB; or aryl or heteroaryl, wherein the
aryl or heteroaryl is optionally substituted with one or
more F; C1; Br; I; COR3; CO~R3; -CON (R3) 2; CN; -N02;
-N (R3) .,; -OR3; -SR3; (CH2) qO.R3; (CH2) qSR3; -XCORB; straight
chained or branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, or aminoalkyl; straight chained or
branched C2-C~ alkenyl, C2-C~.alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocyCloalkyl or
cycloalkenyl;
wherein each R6 is independently -H; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
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cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3; or
-CON (R3) 2%
wherein R~ is -H; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; T; COR3; C02R3;
-CON (R3) 2; CN; -N02; -N (R3) 2; -OR3: -SR3: (CH2) qOR3:
(CHI) ~SR3; -XCORB; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl;
straight chained or branched C~-C~ alkenyl, C2-C~ alkynyl:
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein R$ is -H; straight chained or branched C1-C~
l5 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CHI) pOR3; -COR3; -C02R3; or
-CON(R3)z; aryl or heteroaryl, optionally substituted with
one or more F; Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02;
-N (R3) 2; -OR3; -SR3; (CH2) qOR3; (CH,,) qSR3; straight chained
or branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched C2-C~ alkenyl, C~-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein each n is independently an integer from 0 to 5
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_~8_
inclusive;
wherein each p is independently an integer from 1 to 7
inclusive;
wherein q is an integer from l to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
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This invention further provides a method of reducing the
body mass of a subject which comprises administering to
the subject an amount of a compound effective to reduce
the body mass of the subject wherein the compound has the
structure:
R: R~
F N~ R4
~ ~ ,
R, H
A O
R ~ Rq
N R3w N N~ R4
or
N R2
~n
V
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-30-
wherein A is
Y2 Y3 Y2 Y3
Y1 ~~~~ Y . Y
4 I ~/ ~ Yø r
/ N
y5
Y2
Z 0 \~ Y3
r ~~ ,
Y1
S
Y2 Y3 Y2 Y3
Y1 ~ / \~ ~ Y1 ' w ~O .
x ~~ N
2 0 Y2 y
3
O r'
Y~ ~ ~ > ;
x
wherein each of Y1, Y~, Y3, Y4 and Y5 is independently -H;
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -F, -C1, -Br, or -I;
-NO2; -N3; -CN; -OR3, -OCOR3, -COR3, -CON (R3) 2, or -COOR3;
or any two of Y1, Y2, Y3, Y4 and Y5 present on adj acent
carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
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-3l-
wherein R1 is -H; -N02; -CN; straight chained or branched
C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.,-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON ( R3 ) 2; or C02 ( CH2 ) nV;
wherein R2 is -H; straight chained or branched C1-C~
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C2-C~ alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; C3-Cxo cycloalkyl-C1-Clo-alkyl, C3-Clo
cycloalkyl-C1-Clo-monofluoroalkyl or C3-Clo cycloalkyl-C1-
Clo-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (.CH2) pNHR3,
- ( CH2 ) nNHR3 , -CH2X ( CH2 ) pN ( R3 ) 2 , -CH~X ( CH2 ) pN3 r
-CH2X (CH2) pNHCXRS ; -OR3; or wherein R1 and R2 together form
a lactone ring;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
wherein R4 is
(i)
R ~Rs
3 0 i t N VR '
R f~ s
(ii) R7
R m R5
t N
~ w R6
R ~ m
R7
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(iii)
Y~
R [ m [
N b I Y2 '
R [ m Z
Rs Y3
to (iv)
Y~ Y2
R [ m [ m ~ ~ Y3
-~--N
[ m p , ~ ~d
(V)
Y2
Y~ Ys
' '
R [ m R6
t N .i [~~d
3 o R ~ m //
(vi)
R m R6
R5
t N
R ~ m W R6 '
R~
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(vii)
R m R6
Y~
[~ I i Y
2
Y3
(viii)
R ~ m R5
t [
[ m 6
2 o R7
(ix)
R ~U R
rm y ; or
m ~N m U
R m Rs R
R ~ R
(h) m
m ~ m U
R I ~m Rs R
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C~-C~
alkenyl or alkynyl; -N (R3) ~; -NO~; -CN; -C02R3; -OR3; or
-CN (R3) ~;
wherein B is N or CY4;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or
CS;
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wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; C1; Br; I;
COR3; CO~R3: -CON (R3) 2; CN; -N02: -N (R3) 2% -OR3; -SR3;
( CH2 ) qOR3; ( CH2 ) qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C.,-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein V is C (RS) 2; CRSR6; NRS or NR~;
wherein W is CRS; CR6 or N;
wherein Z is S; 0; C (R3) 2; or NR3;
wherein each RS is -H; -NO~; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
or -CON(R3)~; -XCOR8; or aryl or heteroaryl, wherein the
aryl or heteroaryl is optionally substituted with one or
more F; Cl; Br; T; COR3; CO~R3; -CON (R3) 2; CN; -NO?;
-N (R3) ~; -OR3; -SR3; (CH2) qOR3; (CH2) qSR3; -XCORB; straight
chained or branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, or aminoalkyl; straight chained or
branched C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R6 is independently -H; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
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cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (Rg) 2; -OR3.; - (CHz) pOR3; -COR3; -CO~R3; or
-CON (R3) 2%
wherein R~ is -H; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR3; CO~R3;
-CON (R3) ~; CN; -N02; -N (R3) ?; -OR3; -SR3; (CH2) qOR3;
(CH2)qSR3; -XCORB; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl;
straight chained or branched C~-C~ alkenyl, C2-C~ alkynyl;
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N(R3) 2; -OR3; - (CH2)pOR3; -COR3; -CO2R3; or
-CON(R3)2; aryl or heteroaryl, optionally substituted with
one or more F; Cl; Br; T; COR3; C02R3; -CON (R3) 2; CN; -NO~;
-N (R3) ~; -OR3; -SR3; (CH2) qOR3; (CHI) qSR3; straight chained
or branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein each n is independently an integer from 0 to 5
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inclusive;
wherein each p is independently an integer from 1 to 7
inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In addition, the present invention provides a method of
treating a subject suffering from depression and/or
anxiety which comprises administering to the subject a
compound of the aforementioned formula in an amount
effective to treat the subject's depression and/or
anxiety.
This invention also provides a method of modifying
feeding behavior of a subject which comprises
administering to the subject an amount of a compound
effective to decrease the consumption of food by the
subject wherein the compound is selected from the group
consisting of:
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a) O
N+ O_ (b) O
- ~ N~ N
N
N ~ % ~S ~ N
\ I s ,
to 0
c) F ~ ~ O N~
N NJ ;
20 d) -'\
O ~ S
~5 O N N O O
e) / N \ N~ \ ~ O
~N
35
O
O
N ~ / CI '
CI
g) O N O
N
and
CI
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-38-
h)
F
This invention further provides a method of treating a
feeding disorder in a subject which comprises
administering to the subject an amount of a compound of
the invention effective to decrease the consumption of
food by the subject.
This invention also provides a pharmaceutical composition
comprising a therapeutically effective amount of the
compound of the invention and a pharmaceutically
acceptable carrier.
This invention. further provides a pharmaceutical
composition made by combining a therapeutically effective
amount of the compound of this invention and a
pharmaceutically acceptable carrier. This invention
further provides a process for making a pharmaceutical
composition comprising combining a therapeutically
effective amount of the compound of the invention and a
pharmaceutically acceptable carrier.
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Detailed Description Of The Invention
This invention provides a compound having the structure:
S
A O
R~ N~N~R4 R .Ra
~ N
H ~ H
RZ N X ,
R3
A O A O
R1 N~N~R4 ~ R3w .R4
N ~ ~N
H . or ~ ~ H
R2 N S s N R2
V~ In > ~n
V
CA 02384041 2002-03-05
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wherein A is
Yz Y3 Yz Y
3
r .
Y 1 ~~~~ Y ~ Y ~~ 1
/ Y4 i
/ N
YS
Yz
~ y3
Y1
S
Yz Y3 Y2 Y3
N ~~~ ~N
Y1 l / ~> ~ y~
X ~~ N
Yz Y
3
O r'
Y,
~ X
wherein each of Y1, Y2, Y3, Y9 and Y5 is independently -H;
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -F, -C1, -Br, or -I; -N02; -N3; -CN; -OR3,
-OCOR3, -COR3, -CON (R3) 2, or -COOR3; or any two of Y1, Y2,
Y3, Yq and Y5 present on adjacent carbon atoms can
constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is -H; -N02; -CN; straight chained or branched
CA 02384041 2002-03-05
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C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained br branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) ~; -OR3; - (CHZ) ~OR3; -COR3; -C02R3;
-CON ( R3 ) 2; or -C02 ( CH2 ) nV;
wherein R2 is -H; straight chained or branched C1-C~
alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C~-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cyclc~alkenyl; C3-Clo cycloalkyl-C1-C1o-alkyl, C3-Clo
cycloalkyl-C1-Clo-monofluoroalkyl or C3-Clo cycloalkyl-C1-
Clo-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CHz) pNHR3,
- ( CH2 ) nNHR3, -CH2X ( CH2 ) pN ( R3 ) 2 , -CH2X ( CHg ) pN3 r
-CH2X (CH2) pNHCXR~ ; -OR3; or wherein Rl and R2 together form
a lactone ring;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
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wherein RQ is
(i)
~X~R6
R ~ II
m ~ O
t N
R C~ Rs
(ii)
X~R6
R
y ~m ~ O
t N~--\
R ~~J Rs
V
( iii ) R C~m~~Rs
t N
, ~~\V~X~R6
R ~j~jm
O
(iv) R V
~~~ Rs
t N
~.~V~X~R6
R ~ '~'~' ~m
O
(V)
R R
ym
r ~N r V
R C m Rs R
(vi)
R V R
m~
r \N r V
R C m Rs R
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(vii) R ~ Rs O
m
N ~N~
t ~ ~ N~R$
R m
(viii) R7
~R$
(ix) Z
R
m ; or
,\
R ~ Rs
Z
(x)
R
m
N
~\
R ~ J Rs
V
wherein the dashed line represents a single bond or a
double bond;
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; -N (R3) 2; -N02; -CN; -C02R3; -OR3; or
-CON (R3) 2;
wherein each V is independently aryl or heteroaryl,
optionally substituted with one or more F; C1; Br; I;
COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2; -OR3; -SR3;
(CHI) qOR3; (CH2) qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
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carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or~alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more F;
Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2; -OR3;
-SR3; ( CH2 ) qOR3; ( CH2 ) qSR3; straight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein R6 is -H; straight chained or branched C~-C~
alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C~-C~. alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, optionally substituted with
one or more F; C1; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02;
-N (R3) ~; -OR3; -SR3; (CH2) qOR3; (CH2) qSR3; straight chained
or branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein R~ is H; F; Cl; Br; I; -N02; -N3; -CN; straight
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chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C~-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) ~; -OR3; - (CH2) pOR3; -COR3; -C02R3; or
-CON ( R3 ) 2 ;
Wherein RS is independently straight chained or branched
Cz-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein 2 is naphthyl, quinolinyl, isoquinolinyl,
quinazolinyl, phthalazinyl, quinoxalinyl, indolyl,
benzo[b]furanyl, or benzo[b]thiophenyl; wherein the
naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or
benzo[b]thiophenyl may be substituted with one or more F;
Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2; -QR3;
-SR3; (CH2) qOR3; (CH2) qSR3; straight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein each n is independently an integer from 0 to 5
inclusive;
wherein each p is independently an integer from 1 to 7
inclusive;
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wherein q is an integer from 1 to 3 inclusive;
wherein r is an integer from 0 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention
comprise the (+) enantiomer. In another embodiment, the
compounds comprise the (-) enantiomer.
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In one embodiment, the compound has the structure:
A
~~ R5
R~
N NON
R N~X ~ ~V~X~R6 , or
2 mm
O
R3
A O
m R5
R~ N~N~
R ~ N~X [ ~~V~X R6
Z I m
R3 O
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In another embodiment, the compound has the structure:
A O
Rt ~ ~/\ Rs
I N NON
/O ' \~/~V~X R6 , or
N ~O
H O
A O
Rs
w
RI N~N~
O I ~~ ~X R6
/ N~O V
H O
In a further embodiment, the compound has the structure:
O A O
~O N~N
H
/O N~\O N R6 , o r
H O
H
O A O I \ N~RS
\O N~N/~ ~ ~ ~ ~O
o I ~ /
'~ N O
H
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In yet another embodiment of the present invention variable
A is
Y2
Y3 Y2\ Y
~~~~ ~ o r
Yi L~~J Y4 Yi L.w ~ /O
y / N
s
In an embodiment of the present invention, the compound is
F
F
I
O \ O
\O N~N~N
~ N
N' '_O
0
F
F
I
O \ O
II
~O N~N~N
~ N
N' '-O
~O W I O
F
F
O ~ I O
~O N~N~N
~ N
N' 'O
4 5 ~O . ~ O
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F
O
II
~N~N
0 / N
, or
O
F
O
~N~N
0 i \ N II
2 0 I ./ O
In another embodiment, the compound has the structure:
A O ~X~R6
R~ N~N~ ~ IIO
w
RZ N~X I~~Rg a
I
R3
In further embodiments, the compound has the structure:
A O XuR6
4 0 R i ~ /~/~ ~~ J IO
~N N N
/O
N~O ~ Rs
I
H
In an embodiment, the compound has the structure:
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O A O ~O~ R6
~O N~N~
O
N~O ~ Rs
i
H
In other embodiments, A is
y~~~y3 1'2 y~
y~ ~ ' J y4 ~ or y1
N
ys
In an embodiment of the invention, the compound has the
structure:
F
O
3 0 ~N~N ~ ~
O O ~
O
In other embodiments, the compound has the structure:
R
R 'm
~~N r V
R I m Rs R
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._5~_
In additional embodiments, the compound has the structure:
R
R \
N \N ~ V
R
s R
In one embodiment of the present invention, the compound
has the structure:
R3
O A O R N
_ ~ ~ /~S R3
In another embodiment of,the instant invention, A is
Y2
Y3 y2 y
y1 r\~~~ y ~ o r
3 5 ~ J 4 Yl
N
Ys .,
In other embodiments of the invention, the compound has the
structure:
N-O
I iN
I
O / O
~
. ,..,~N \ I
~O I N- _N / N
N ~1O
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In an embodiment, the compound has the structure:
A O
~.,~ Rs ,.O
R ~ N ~N~/\ ~~ -~\/N
N~R$
R, N~X ~~ \
I -J
3 0
R~
In another embodiment, the compound has the structure:
A ~ ., n
R~
N
2 0 Rs
N O
H c
R~
In yet another embodiment, the compound has the structure:
O A O
II Rs O
\O N~N~/\ ~~N~
~ N_R8
N~O \
R~ c
In an embodiment, A is
Y2 Y3 Y2 Y
4 5 Y, ~~~1 Y . o r f~~~ W
Y, ~ o
N
Y
s
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In a further embodiment, the compound has the structure
F
O
O
~
O
In another embodiment, the compound has the structure:
~Z
R~ A
N N N
R~ N~X ~~ Rs
~ ~ c
R3
In yet another embodiment, the compound has the structure:
Z
A O
R~
~ N N N
O
O R5 a
H
In an additional embodiment, the compound has the
structure:
O
~O
o i
~
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In other embodiments, A is
Y2
~~ Y3 Y2 /Y3
Y I ~ ~~~ Y4 r O r Y r~n~ y
Ys
In an embodiment, the compound has the structure:
O
~N~N
O
~I
In yet another embodiment, the compound is
(+)-1,2,3,6-tetra-hydro-1-{n-[4-(3,-acetamido)-phenyl-
piperidin-1-yl]propyl}carboxamido-4-methoxymethyl-6-(3,4-
difluoro-phenyl)-2-oxopyrimidine-5-carboxylic acid methyl
ester. In a further embodiment, the compound is
(-)-1,2,3,6-tetra-hydro-1-fn-[4-(3,-acet-amido)-phenyl-
piperidin-1-yl]propyl~carboxamido-4-methoxymethyl-6-(3,4-
difluoro-phenyl)-2-oxopyriinidine-5-carboxylic acid methyl
ester.
In a further embodiment, the compound is:
F
O
~N~N
O / NH2
i0 ~ I ,
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In a further embodiment, the compound has the structure:
/R2 R R
XX
M N ~----~. -~---N-~m -W
Ri R2 R RI R
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or '
polyfluoroalkyl; straight chained or branched C2~C~
alkenyl or alkynyl; -N(R3)~; -N02; -CN; -SR3; -C02R3; or
-OR3 ;
wherein each R1 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alk~ynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; - (CH2) pOR3; -COR3; -C02R3; or -CON (R3) 2%
wherein each R2 is -H; -N02; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycldalkyl
or cycloalkenyl; -N (R3) z; -OR3; - (CH2) pOR3; -COR3; ' -CO~R3;
or -CON(R3)2; or aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR3; C02R3;
-CON (R3) 2; CN; -N02; -N (R3) ~; -OR3; -SR3; (CH2) qOR3;
(CH~)qSR3; straight chained or branched C1-C7 alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or~
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R3 is independently -H; straight chained or
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branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
wherein M is aryl or heteroaryl, optionally substituted
with one or more F; Cl; Br; I; COR3; C02R3; -CON (R3) ?; CN;
-N02; -N (R3) 2; -OR3; -SR3; (CH2) qOR3; (CHZ) qSR3; straight
chained or branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;
straight chained or branched CZ-C~ alkenyl, C2-C~ alkynyl;
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein X is (CH2) n, O, S or NR3;
wherein W is
(a) C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally
substituted with one or more COR3; C02R3; -CON (R3) 2
CN ; -N02 ; -N ( R3 ) ~ ; -OR3 ; - SR3 . ( CHZ ) qOR3 ; ( CH2 ) qSR3 ;
straight chained or branched Cl-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C~-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one
or more F; Cl: Br; I; COR3; C02R3; -CON(R3) 2; CN;
3 0 -N02 ; -N ( R3 ) ~ : -OR3 ; - SR3 : ( CHI ) qOR3 : ( CH2 ) qSR3 :
straight chained or branched C1-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl;
wherein m is an integer from 0 to 4 inclusive;
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wherein n is an integer from 0 to 6 inclusive;
wherein p is an integer from 1 to 4 inclusive;
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise
the (+) enantiomer. In another embodiment, the compounds
comprise the (-) enantiomer.
In an embodiment, the compound has the structure:
X
M N W
i ~
H N~ ; or
R ~ R~ ~R
M
N W
H N--~
RI R R c
In a further embodiment, W is phenyl optionally
substituted with one or more F; Cl; Br; I; COR3; C02R3;
3 5 - CON ( R3 ) 2 ; CN; -N02 ; -N ( R3 ) 2 ; -OR3 ; - SR3 ; ( CH2 ) qOR3 ; or
( CH2 ) qSR3 .
In another embodiment, the compound has the structure
w ~ ~ ,''\\ N
'N N
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In one embodiment, the compound has the structure:
O
O R
RS RS ~ m U
\w /
C .,
R ~n R
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; -N (R3) L; -NO~; -CN; -C02R3; -OR3; or
-CON ( R3 ) 2
wherein each R1 is independently -H; F; C1; Br; I; -N02;
-N3; -CN; straight chained or branched C1-C~ alkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C2-C7 alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) ~; -OR3; - (CH.,) pOR3; -COR3; -CO2R3;
-CON(R3)2; aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more F;
C1; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2; -OR3;
-SR3; (CH2) qOR3; (CH2) qSR3; straight chained or branched
C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C7 alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
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or cycloalkenyl;
wherein R5 is -H; -N02; -N3; -CN; straight chained or
branched C~-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) ~; -OR3; - (CHZ) pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more F;
C1; Br; I; COR3; C02R3; -CON (R3) 2; CN; -NO2; -N (R3) z; -OR3;
-SR3; (CH2) qOR3; (CH2) qSR3; straight chained or branched
Cz-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,.aminoalkyl,
or carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, Cz-C~ alkynyl; C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein V is H; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; Z; COR3; C02R3;
2 0 -CON ( R3 ) 2: CN: -N02; -N ( R3 ) ~ : -OR3; -SR3: ( CH2 ) qOR3;
(CH2)qSR3; straight chained or branched C1-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein. W is
(a) C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally
substituted with one or more COR3; C02R3;
-CON (R3) 2: CN: -N02: -N (R3) ~; -OR3; -SR3;
( CHI ) qOR3 ; ( CH2 ) qSR3 ; straight chained or
branched Cl-C~ alkyl, monofluoroalkyl,
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polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched
C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl;
or
(b) aryl or heteroaryl optionally substituted with
one or more F; C1; Br; I; COR3; C02R3; -CON(R3)2%
CN; -N02 ; -N ( R3 ) 2 ; -OR3 ; - SR3 ; ( CH2 ) qOR3 ;
(CH2) qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight
chained or branched Cz-C~ alkenyl, C2-C~
alkynyl; C3-C~ cycloalkyl;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein n is an integer from 0 to 2 inclusive;
wherein p is an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise
the (+) enantiomer. In another embodiment, the compounds
comprise the (-) enantiomer.
In an additional embodiment, the compound has the
structure:
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O
R U ~W
~/~N
N
R3
R ~ Rs
In a further embodiment, the compound has the structure
O
R N~ W
N
R3
R
'
In yet another embodiment, V~l is phenyl optionally
substituted with one or more F; Cl; Br; I; COR3; C02R3;
- CON ( R3 ) 2 ; CN; -N02 ; =N ( R3 ) 2 ; -OR3 ; - SR3 ; ( CH2 ) qOR3 ;
(CH2) qSR3; or straight chained or branched C1-C~ alkyl
groups.
In yet another embodiment, the compound has the structure
/i
N
Nr~ O
0
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In the present invention, the term "aryl" includes phenyl
and naphthyl and the term "heteroaryl" is used to include
five and six membered unsaturated rings that may contain
one or more heteroatoms such as oxygen, sulfur, and
nitrogen. Examples of heteroaryl groups include, but are
not limited to, furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, and triazinyl.
In addition the term "heteroaryl" is used to include fused
bicyclic ring systems that may contain one or more
heteroatoms such as oxygen, sulfur and nitrogen. Examples
of such heteroaryl groups include, but are not limited to,
indolizinyl, indolyl, isoindolyl, benzo[b]furanyl,
benzo[b]thiophenyl, indazolyl, benzimidazolyl,
benzthiazolyl, purinyl, imidazo[2,1-b]thiazolyl,
quinolinyl, isoquinolinyl, quinolizinyl, and 2,1,3-
benzothiazolyl.
Included in this invention are pharmaceutically acceptable
salts and complexes of all of the compounds described
herein. The salts include but are not limited to the acids
and bases listed herein. The salts include, but are not
limited to the following inorganic acids: hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid and
boric acid. The salts include, but are not limited to the
following organic acids; acetic acid, malonic acid,
succinic acid, fumaric acid, tartaric acid, malefic acid,
citric acid, methanesulfonic acid, benzoic acid, glycolic
acid, lactic acid and mandelic acid. The salts include,
but are not limited to the inorganic base, ammonia. The
salts include, but are not limited to the following organic
bases: methylamine, ethylamine, propylamine,
dimethylamine, diethylamine, trimethylamine, triethylamine,
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ethylenediamine, hydroxyethylamine, morpholine, piperazine
and guanidine. This invention further provides for the
hydrates and polymorphs of all of the compounds described
herein.
The present invention includes within its scope prodrugs of
the compounds of the invention. In general, such prodrugs
will be functional derivatives of the compounds of the
invention which are readily convertible in vivo into the
required compound. Thus, in the present invention, the
term "administering" shall encompass the treatment of the
various conditions described with the compound specifically
disclosed or with a compound which may not be specifically
disclosed, but which converts to the specified compound in
vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable
prodrug derivatives are described, for example, in Design
of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
The present invention further includes metabolites of the
compounds of the present invention. Metabolites include
active species produced upon introduction of compounds of
this invention into the biological milieu.
This invention further provides a pharmaceutical
composition comprising a therapeutically effective amount
of the compound of the invention and a pharmaceutically
acceptable carrier. In one embodiment, the amount of the
compound is an amount from about 0.01 mg to about 800 mg.
In another embodiment, the amount of the compound is an
amount from about 0.01 mg to about 500 mg. In another
embodiment, the amount of the compound is an amount from
about 0.01 mg to about 250 mg. In another embodiment, the
amount of the compound is an amount from about 0.1 mg to
about 60 mg. In another embodiment, the amount of the
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compound is an amount from about 1 mg to about 20 mg. In
a further embodiment, the carrier is a liquid and the
composition is a solution. In another embodiment, the
carrier is a solid and the composition is a tablet. In a
further embodiment, the carrier is a gel and the
composition is a suppository.
This invention provides a pharmaceutical composition made
by combining a therapeutically effective amount of the
compound of this invention and a pharmaceutically
acceptable carrier.
This invention provides a process for making a
pharmaceutical composition comprising combining a
therapeutically effective amount of the compound of this
invention and a pharmaceutically acceptable carrier.
In the practice of this invention the "pharmaceutically
acceptable carrier" is any physiological carrier known to
those of ordinary skill in the art useful in formulating
pharmaceutical compositions.
In one preferred embodiment the pharmaceutical carrier may
be a liquid and the pharmaceutical composition would be in
the form of a solution. In another equally preferred
embodiment, the pharmaceutically acceptable carrier is a
solid and the composition is in the form of a powder or
tablet. In a further embodiment, the pharmaceutical carrier
is a gel and the composition is in the form of a
suppository or cream. In a further embodiment the compound
may be formulated as a, part of a pharmaceutically
acceptable transdermal patch.
A solid carrier can include one or more substances which
may also act as flavoring agents, lubricants, solubilizers,
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suspending agents, fillers, glidants, compression aids,
binders or tablet-disintegrating agents; it can also be an
encapsulating material. In powders, the carrier is a
finely divided solid which is in admixture with the finely
divided active ingredient. In tablets, the active
ingredient is mixed with a carrier having the necessary
compression properties in suitable proportions and
compacted in the shape and size desired. The powders and
tablets preferably contain up to 990 of the active
ingredient. Suitable solid carriers include, for example,
calcium phosphate, magnesium stearate, talc, sugars,
lactose, dextrin, starch, gelatin, cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange
resins.
Liquid carriers are used in preparing solutions,
suspensions, emulsions, syrups, elixirs and pressurized
compositions. The active ingredient can be dissolved or
suspended in a pharmaceutically acceptable liquid carrier
such as water, an organic solvent, a mixture of both or
pharmaceutically acceptable oils or fats. The liquid
carrier can contain other suitable pharmaceutical additives
such as solubilizers, emulsifiers, buffers, preservatives,
sweeteners, flavoring agents, suspending agents, thickening
agents, colors, viscosity regulators, stabilizers or
osmo-regulators. Suitable examples of liquid carriers for
oral and parenteral administration include water (partially
containing additives as above, e.g. cellulose derivatives,
preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric
alcohols, e.g. glycols) and their derivatives, and oils
(e.g. fractionated coconut oil and arachis oil). For
parenteral administration, the carrier can also be an oily
ester such as ethyl oleate and isopropyl myristate.
Sterile liquid carriers are useful in sterile liquid form
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compositions for parenteral administration. The liquid
carrier for pressurized compositions can be halogenated
hydrocarbon or other pharmaceutical7_y acceptable
propellent.
Ziquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by for example,
intramuscular, intrathecal, epidural, intraperitoneal or
subcutaneous injection. Sterile solutions can also be
administered intravenously. The compounds may be prepared
as a sterile solid composition which may be dissolved or
suspended at the time of administration using sterile
water, saline, or other appropriate sterile injectable
medium. Carriers are intended to include necessary and
inert binders, suspending agents, lubricants, flavorants,
sweeteners, preservatives, dyes, and coatings.
The compound can be administered orally in the form of a
sterile solution or suspension containing othex solutes or
suspending agents (for example, enough saline or glucose to
make the solution isotonic), bile salts, acacia, gelatin,
sorbitan monoleate, polysorbate 80 (oleate esters of
sorbitol and its anhydrides copolymerized with ethylene
oxide) and the like.
The compound can also be administered orally either in
liquid or solid composition form. Compositions suitable
for oral administration include solid forms, such as pills,
capsules, granules, tablets, and powders, and liquid forms,
such as solutions, syrups, elixirs, and suspensions. Forms
useful for parenteral administration include sterile
solutions, emulsions, and suspensions.
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The present invention also provides a method of modifying
feeding behavior of a subject which comprises administering
to the subject an amount of a compound effective to
decrease the consumption of food by the subject wherein the
compound has the structure:
R N ~ R4 F R4
N
H , I ,
R- H
A O
R~ R4
R3~N N~R4
or
R; ~ ~ H
S N Rz
~n
V
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wherein A is
Y2 Y3 Y2 Y3
Y ~ ~~~~ Y . ' Y j ~~~~ Y
4 ~I ~ 4 r
~ YS ~N
Y2
Y3
Yf L
I S
Y~~~Y3 N Y~~~Y~N~
\~
Y1 ~ / ~ Y~ ~. w /O
X ~~ N
. Y2 Y
3
n
Or w
2 0 Y'
X
wherein each of Ys, Y2, Y3, YQ and Y5 is independently -H;
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -F, -C1, -Br, or -I; -NO2; -N3; -CN; -OR3,
-OCOR3, -COR3, -CON (R3) 2, or -COOR3; or any two of Y1, Y2,
Y3, YQ and Y5 present on adjacent carbon atoms can
constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is -H; -N02; -CN; straight chained or branched
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C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CHI) pOR3; -COR3; -C02R3;
-CON ( R3 ) 2; or C02 ( CH2 ) nV;
wherein R2 is -H; straight chained or branched C1-C~
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C2-C~ alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; C3-C1o cycloalkyl-Cz-Clo-alkyl, C3-Clo
cycloalkyl-C1-Clo-monofluoroalkyl or C3-Clo cycloalkyl-C1-
Clo-polyfluoroalkyl; -CN; -CH2XR3, -CH2X(CH2)pNHR3,
- ( CH2 ) nNHR3, -CH2X ( CH2 ) pN ( R3 ) z, -CH~X ( CH2 ) pN3 i
-CH.,X (CH2) pNHCXRS ; -OR3; or R1 and R2 together form a
lactone ring;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
wherein R4 is
(i) R y'mX"5
-E~--N V
R firs
(ii)
R~
R m R5
N '
t R
R ~ m
R7
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(iii)
R
( m [
N b ~ Y2
R [ m Z
Rs y3
(1V)
1o Y~ Y2
R6
R ~ m. j m ~ Y3
t N~' ~
R ( 'f m ' D, ~d
D
Y2
(V)
2 o Y~ Ys
R [ m R6 -
t N [~ ~ d
R [ m /'l-Z
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(vi)
R m R6
N R5
t
R ~ m R6
R7
'(vii)
z o R m R6
N ~~ Y~
R m B Y
2
~ 5 Y3
(viii)
R R6 R
20 ~ m R5
t f n N
~ m R6
R R
R7
25 (ix)
R U R
m ; or
m ~N m U
R ~ m Rs R
R ~ R
~m
m ~ m U
R ~ ~I m Rs R
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wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; -N (R3) ?: -N02; -CN; -C02R3; -OR3; or
-CN ( R3 ) 2 ;
wherein B is N or CY4;
wherein each D is independently C (R3) 2; O; S; NR3; C0; or
CS;
wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; C1; Br; I;
COR3: C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2; -OR3; -SR3:
(CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched C2-C~
alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein V is C (RS) 2; CRSR6; NRS or NR6;
wherein W is CRS; CR6 or N;
wherein Z is S; O; C (R3) 2; or NR3;
wherein each RS is -H; -N02; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3;
or -CON(R3)2; -XCOR8; or aryl or heteroaryl, wherein the
aryl or heteroaryl is optionally substituted with one or
more F; C1; Br; I; COR3; C02R3; -CON (R3) ~; CN; -N02;
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-N (R3) 2; -OR3; -SR3; (CH2) qOR3; (CH2) qSR3; -XCOR8; straight
chained or branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, or aminoalkyl; straight chained or
branched C2-C~ alkenyl, C~-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R6 is independently -H; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~.alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CH2)pOR3; -COR3; -C02R3;
or -CON (R3) z;
wherein R~ is -H; aryl or heteroaryl, optionally
substituted with one or more F; C1; Br; I; COR3; C02R3;
-CON (R3) 2; CN; -N02; -N (R3) 2; -OR3; -SR3; (CH2) qOR3;
(CHI) qSR3; -XCORB; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl;
straight chained or branched C2-C~ alkenyl, C2-C~ alkynyl;
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorooycloalkyl or
cycloalkenyl; -N (R3) 2; -OR3; - (CH2) pOR3; -COR3; -C02R3; or
-CON(R3)2; aryl or heteroaryl, optionally substituted with
one or more F; Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02;
-N (R3) 2; -OR3; -SR3; (CH2) qOR3; (CH2) qSR3; straight chained
or branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
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monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein each n is independently an integer from 0 to 5
inclusive;
wherein each p is independently an integer from 1 to 7
inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound has the structure
A O Rs
R~ ~ R
~N H I t N ~Rs ; or
R ~~\ R
R2 r \'X
R~
R3
Rs
R
Ri A
N H I t N ~C~Rs)z
R yv
RZ N~X R5
3 5 R3 R~
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In a further embodiment, the compound has the structure
A O
R ~ ~,.~ R Y ' m kR5
N H I t N VR
R [~ s
R2 N X
I . R~
Rs
In an additional embodiment, the compound has the structure
A
Rt
N H~N N Rs
~ O Z'
R2 N- \ O
R5
A O
R' N~N~
N~~(Rs)2
R2 N ~.~~/O
2 5 H R5
In a further embodiment, at least one R5 group is an aryl
or heteroaryl group optionally substituted with one or
more F; C1; Br; I; -N02; -N (R3) 2; -OR3; -XCOR8; or straight
chained or branched C1-C~ alkyl.
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In another embodiment, A is:
Y~~ Y3 Y2 3
Y
y1 r \~1 Y4 ~ or
J Y' 1.
N a
Ys
In further embodiments, the compound is selected from the
group consisting of:
F
(a) ~ F
O ~ O
II
~O I N~N~N
N ~O O
i0
(b)
F
O
~N~N O
O N ~N
~s
(C)
F
O
~N~N
O
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(d) F
F
O \ O
~O N~N~N %
N ~O
~O
F
(e)
F
O '
~N~N
and
O ~ ~ F
F
F
(f)
F
O
~N~N .
O ~ I N II
a
In other embodiments, the compound has the structure
R R5
R1 ' m
_~ H t N
R ~ m. ~Rs
R2 N X
R3 R~ s
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In a further embodiment, the compound has the structure
R5
NON
H
Rs
R~
In additional embodiments, A is
y2
y3 ' y2
Y, r~~~~ y ~ o r ~~~yW
y' L~ ~ ~ ~° ;
N
ys
and R~ is phenyl, optionally substituted with one or more F;
Cl; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02; -N (R3) 2%
-OR3; -SR3; (CH2 )qOR3 ; (CH2 )q SR3 ; -XCORg ; or straight chained
or branched C1-C~ alkyl.
In one embodiment, the compound has the structure
F
O O
~O N~N~N
i0 N~O . ~ w N II
O
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In an embodiment of the present invention, the compound has
the structure
A O ~ Y~
~ [R ~ m
R ~ N H~N , b I Y2
Z
. R2 N~X R ~ m R6 Y
3
R3
In yet another embodiment, the compound has the structure
A ~ , Y~
R~
N HEN I Yz
Z
R2 N~O
Y3
H
In further embodiments, A is
Y2
~~ Y3 Y2 Y3
Y~ r \~1 y4 ~ or
J Y ~ l.~ ~o
~ N
Ys
and 2 is 0 or CH2.
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In an additional embodiment, the compound is selected from
the group consisting of
O ~ O
~O N~N~N
N O
N-
/I
O O
~O N~N~N
\ ~ ; and
N O
F
F
O O
N N~N~N
N O
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In one embodiment, the compound has the structure
Y2
3
A O
R~
N
R2 N~X ,
R3
In a further embodiment, the compound has the structure
Y2
3
A O
R~ ~
N~N~
H
N~O
I
H a
In another embodiment, A is
Y2
Y3 YZ Y
Yi ~~~~ Y ~ or
Y~
N ,
Ys .
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In yet another embodiment, the compound is
N-O
N
O
~N~N ; or
., ~O
O
F
O
~N~N
.~ O
O
In a further embodiment, the compound has the structure
R
2 0 Rs
Ri m
N N N~ Y~
R t ~~ Y
R2 N X B 2
R3 Y3
In another embodiment, the compound has the structure
R~
3 0 ~~ Y2
r3
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In yet another embodiment, the compound has the structure
F
O
~N~N
0
~O N ~ ( ~
In one embodiment, the compound has the structure
R
'
R.
25
In another embodiment, the compound has the structure
A O
R~
N~N N
H
N~O
H
In another embodiment, the compound has the structure
N-O
N
O
~N / N
/~\~N ~
'O
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This invention further provides a method of reducing the
body mass of a subject which comprises administering to the
subject an amount of a compound effective to reduce the
body mass of the subject wherein the compound has the
5~ structure:
A O
R R4
R3~N N~ R4
H
Rv X N R2
R3
R N~ R4
N~ R4
or
R, H
V
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wherein A is
Y2 Y3 Y2 Y3
r
Y 1 ~~/~ y ~ y
4 1 '/ ~ Y4 r
/j \\ / N
y5
y2
~~ Y3
r ~~ ,
y1
S
Y2 Y3 Y2 Y3
~~/ N ~%~/
y1 ~ / \~ ~ y1 L~ ~ w ~O r
X ~ N
2 0 y2 Y
3
or
Y1 ~ / ~> >
X
wherein each of Y1, Y2, Y3, . Yq and Y5 is independently -H;
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C2-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -F, -C1, -Br, or -I;
-N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON (R3) 2, or -COOR3;
or any two of Y1, Y2, Y3, Y4 and Y5 present on adj acent
carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3;
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wherein R1 is -H; -N02; -CN; straight chained or branched
C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N (R3) ~; -OR3; - (CH2) pOR3; -COR3; -C02R3;
-CON ( R3 ) ~; or CO~ ( CH2 ) nV;
wherein RZ is -H; straight chained or branched C1-C~
alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C2-C~ alkenyl or.alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; C3-Clo cycloalkyl-C1-Clo-alkyl, C3-Clo
cycloalkyl-C1-Clo-monofluoroalkyl or C3-Clo cycloalkyl-C1-
Clo-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3,
- ( CH2 ) nNHR3, -CH2X ( CH2 ) pN ( R3 ) 2, -CH2X ( CH2 ) PN3 r
-CH2X(CH2)pNHCXRS ; -OR3; or wherein Rl and R2 together form
a lactone ring;
wherein each R3 is independently -H; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl;
wherein R4 is
R ~~_~ ~
(i) N~5
R firs
3o R~
R , m Rs
(ii) N '
t R
R ~ m
R7
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(iii)
Y~
m
N ~ b ~ Y2
t \Z
( m
Rs Y3
(iv)
Y~ Y2
R6
R ( m [ m \ ~ Y3
t N~~ ~
R ('im' D_ [d
D
(V)
Y2
2o Y~ Ys
R . ~ m R6 ;
t N ~ ~~ ~ d
R ~ m
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(vi)
R m R6
R5
t
R ~ m W R6
~(V1.1)
1 o R m Rs
t
f~~
R B Y
2
Y3
(viii)
2o R R6 R R5
~m
t ~ n N
n
R R ~ m R6
R7
(ix)
R U R
m ; or
m ~N m U
3 0 R ~ m Rs R
R R
~m
\N m U
(x) R ~~ Rs R
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wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched Cz-C~
alkenyl or alkynyl; -N (R3) z; -NOz; -CN; -C02R3; -OR3; or
-CN ( R3 ) z
wherein B is N or CY4;
wherein each D is independently C(R3)z; O; S; NR3; CO; or
CS;
wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I;
COR3; C02R3; -CON (R3) z; CN; -NOz; -N (R3) z; -OR3; -SR3;
(CHz) qOR3; (CHz) qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched Cz-C~
alkenyl, Cz-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein V is C (RS) z; CRSR6; NRS or NRS;
wherein W is CRS; CR6 or N;
wherein Z is S; O; C (R3) z; or NR3;
wherein each RS is -H; -NOz; -N3; -CN; straight chained or
branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched Cz-C~ alkenyl or alkynyl; C3-
C~ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) z; -OR3; - (CHz) pOR3; -COR3; -COzR3;
or -CON(R3)z; -XCORB; or aryl or heteroaryl, wherein the
aryl or heteroaryl is optionally substituted with one or
more F; C1; Br; I; COR3; COzR3; -CON (R3) z; CN; -NOz;
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-N (R3) ~; -OR3; -SR3; (CH2) qOR3; (CH2) qSR3; -XCOR8; straight
chained or branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, or aminoalkyl; straight chained or
branched C2-C~ alkenyl, Cz-C~ alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each R6 is independently -H; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C2-C~ alkenyl ~or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyf.luorocycloalkyl or cycloalkenyl;
-N (R3) 2; -OR3; - (CH2) pOR3: -COR3; -C02R3; Or
-CON (R3) 2%
wherein R~ is -H; aryl or heteroaryl, optionally
substituted with one or more F; C1; Br; I; COR3; C02R3;
-CON ( R3 ) 2; CN; -N02; -N ( R3 ) 2: -OR3; -SR3: ( CH2 ) qOR3:
(CHZ) qSR3; -XCORB; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl;
straight chained or branched C2-C~ alkenyl, C2-C~ alkynyl;
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; -N(R3) ~; -OR3; - (CH2)pOR3; -COR3; -C02R3; or
-CON(R3)2; aryl or heteroaryl, optionally substituted with
one or more F; C1; Br; I; COR3; C02R3; -CON (R3) 2; CN; -N02;
-N (R3) 2; -OR3; -SR3; (CH2) qOR3; (CH2) qSR3; straight chained
or branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched C2-C~ alkenyl, C2-C~ alkynyl; C3-C~ cycloalkyl,
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monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein each n is independently an integer from 0 to 5
inclusive;
wherein each p is independently an integer from 1 to 7
inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In addition, the present invention provides a method of
treating a subject suffering from depression and/or anxiety
which comprises administering to the subject a compound of
the aforementioned formula in an amount effective to treat
the subject's depression and/or anxiety.
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This invention also provides a method of modifying feeding
behavior of a subject which comprises administering to the
subject an amount of a compound effective to decrease the
consumption of food by the subject wherein the compound is
selected from the group consisting of:
.a) O,
N~ O_ (b) O
N;N N / / I \
~ ~ O N ~ ; ~S ~N~
s// - \ ,
0
c) F ~ ~ O Ni
N J ;
N
d)
O ~ S
O N N O
O
e) / N ~ - N/ ~ / O ;
~N
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O
O
f) I \ N ~ / CI '
CI
g) O N O
N
\ ~ ~
and
F
h) N
U
F
This invention further provides a method of modifying
feeding behavior of a subject which comprises administering
to the subject an amount of a compound of the present
invention effective to decrease the consumption of food by
the subject.
This invention also provides a method of treating a feeding
disorder in a subject which comprises administering to the
subject an amount of a compound of the present invention
effective to decrease the consumption of food by the
subject. In an embodiment of the present invention, the
feeding disorder is bulimia, obesity or bulimia nervosa.
In a further embodiment, the subject is a vertebrate, a
mammal, a human or a canine. In yet another embodiment,
the compound is administered in combination with food.
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In the subject invention a "therapeutically effective
amount" is any amount of a compound which, when
administered to a subject suffering from a disease against
which the compounds are effective, causes reduction,
remission, or regression of the disease.
One skilled in the art will readily appreciate that
appropriate biological assays will be used to determine the
therapeutic potential of the claimed compounds for treating
the above noted disorders.
Optimal dosages to be administered may be determined by
those skilled in the art, and will vary with the particular
compound in use, the strength of the preparation, the mode
of administration, and the advancement of the disease
condition. Additional factors depending on the particular
subject being treated will result in a need to adjust
dosages, including subject age, weight, gender, diet, and
time of administration.
This invention further provides compositions which need not
be pharmaceutical as that term is understood in the art .
Such compositions comprise a compound in accordance with
the subject invention in an amount effective to antagonize
an MCH1 receptor and a suitable carrier.
Still further, the invention provides a method of agonizing
and/or antagonizing an MCH1 receptor which comprises
contacting the receptor, e.g. in vitro or in in vivo, with
an amount of a compound of this invention effective to
agonize and/or antagonize the receptor.
This invention will be better understood from the
Experimental Details which follow. However, one skilled in
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the art will readily appreciate that the specific methods
and results discussed are merely illustrative of the
invention as described more fully in the claims which
follow thereafter.
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Experimental Section
I. Synthetic Methods for Examples
General Methods: All reactions (except for those done by
parallel synthesis reaction arrays) were performed under an
Argon atmosphere and the reagents, neat or in appropriate
solvents, were transferred to the reaction vessel via
syringe and cannula techniques. The parallel synthesis
reaction arrays were performed in vials (without an inert
atmosphere) using J-KEM heating shakers (Saint Louis, MO).
Anhydrous solvents were 'purchased from Aldrich Chemical
Company and used as received. The examples described in the
patent (1-37) were named using ACD/Name program (version
2.51, Advanced Chemistry Development Inc., Toronto,
Ontario, M5H2L3, Canada). Unless otherwise noted, the 1H
and 13C NMR spectra were recorded at 300 and 75 MHz (QE
Plus) with CDC13 as solvent and tetramethylsilane as
internal standard. s = singlet; d = doublet; t = triplet;
q - quartet; p = pentet; sextet; septet; br = broad; m =
multiplet. Elemental analyses were performed by Robertson
Microlit Laboratories, Inc. Unless otherwise noted, mass
spectra were obtained using low-resolution electrospray
(ESMS) and MH+ is reported. Thin-layer chromatography (TLC)
was carried out on glass plates precoated with silica gel
60 F254 (0.25 mm, EM Separations Tech.). Preparative
thin-layer chromatography was carried out on glass sheets
precoated with silica gel GF (2 mm, Analtech). Flash
column chromatography was performed on Merck silica gel 60
(230 - 400 mesh). Melting points (mp) were determined in
open capillary tubes on a Mel-Temp apparatus and are
uncorrected.
Procedures for the Synthesis of the Dihydropyrimidine
Intermediates
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5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-2-
OXO-6- (3,4-DIFLUOROPHENYL)-PYRIMIDINE: To a stirring
mixture of methyl 4-methoxyacetoacetate (50.0 g, 0.342
mol), 3,4-difluorobenz-aldehyde (51.4 g, 0.362 mol), and
urea (31.6 g, 0.527 mole) ir~ THF (300 mL) at room
temperature were added copper(I) oxide (5.06 g, 0.035 mole)
and acetic acid (2.05 mL), sequentially, followed by
dropwise addition of boron trifluoride diethyl etherate
(56.0 mL, 0.442 mole). The mixture was stirred and
refluxed for 8 h, whereupon TLC (1/1 EtOAc/hexanes)
analysis indicated completion of the reaction. The reaction
mixture was cooled and poured into a mixture of ice and
sodium bicarbonate (100 g) and the resulting mixture was
filtered through Celite. The Celite pad was washed with
dichloromethane (400 mL). The organic layer was separated
from the filtrate and the aqueous layer was extracted with
more dichloromethane (3 X.300 mL). The combined organic
extracts were dried (sodium sulfate) and the solvent
evaporated. The crude product was purified by flash column
(ethyl acetate/hexanes, 1/1; then ethyl acetate), giving
the product as pale yellow foam, which on trituration with
hexane became white powder (103 g, 970). 1H NMR d 3.48 (s,
3H), 3.65 (s, 3H), 4.65 (s, 2H), 5.39 (s, 1H), 6.60 (br s,
1H, NH), 7.00 - 7.20 (m, 3H), 7.72 (br s, 1H, NH).
(+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-2-
OXO-6-(3,4-DIFLUOROPHENYL)-PYRIMIDINE: The racemic
intermediate 5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-
tetrahydro-2-oxo-6- (3,4-difluorophenyl)pyrimidine was
resolved by chiral HPLC. [Chiralcel OD 20 X 250 mm
#369-703-30604; lambda 254 nm; hexanes/ethanol 90/10; 85 mg
per injection; retention time of the desired enantiomer:
16.94 min., the first enantiomer peak to elute], giving
(+)-5-methoxycarbonyl-4-methoxymethyl-
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1,2,3,6-tetrahydro-2oxo-6-(3,4-difluorophenyl)-pyrimidine
(40-42 wto isolation of the desired enantiomer from the
racemate); [a,]p - + 83.8 (c - 0.5, chloroform). The
(-)-isomer was also isolated as the later eluting fraction
from the chiral chromatography column.
(+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-
2-OXO- 6-(3,4-DIFLUOROPHENYL)-1-[(4-NITROPHENYLOXY)
CARBONYL]PYRIMIDINE: To a solution of
(+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-
tetrahydro-2-oxo-6-(3,4- ~difluorophenyl)-pyrimidine (1.98
g, 6.34 mmol) in anhydrous THF (20 mL) at -78 °C under argon
atmosphere, a solution of lithium hexamethyldisilazide in
THF ( 1M, 18 . 0 mL, 18 . 0 mmol ) was added over 2-3 min . and
the mixture was stirred for 10 min. This solution was
added over 6 min., via a cannula, to a stirred solution of
4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20
mL) at -78 °C. Stirring was continued for 10 min. and the
mixture was poured onto ice (50 g) and extracted with
chloroform (2 X 50 mL). The combined extracts were dried
(sodium sulfate) and the. solvent was evaporated. The
residue was purified by flash column chromatography
(hexanes/ethyl acetate, 4/1 to 3.5/1) as the eluent. The
product was obtained as yellow syrup which upon trituration
with hexanes became a white powder (2.40 g, 79%): 1H NMR d
3.52 (s, 3H) , 3.74 (s, 3H) , 4 . 65-4.80 (q, J=16.5 Hz, 2H) ,
6.32 (s, 1H), 7.10-7.30 (m, 4H), 7.36 (d, J=9 Hz, 2H), 8.27
(d, J=9 Hz, 2H) .
BENZYL 3-[(3,4-DIFLUOROPHENYL)METHYLENE]-4-OXOPENTANOATE:
A solution of benzyl propionylacetate (36.3 g, 176 mmol),
3,4- difluorobenzaldehyde (25.0 g, 176 mmol), piperidine
(0.86 mL, 9.0 mmol) and acetic acid (0.49 mL, 9.0 mmol) was
refluxed with removal of water using a Dean-Stark apparatus
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for 5 h. The solvent was removed in vacuo and the residue
was dissolved in EtOAc. The reaction mixture was washed
with water (100 mL), followed by brine (100 mL) and dried
over anhydrous Na2S04. The solvent was evaporated, giving a
pale yellow syrup (60.2 g). The product was used in the
next step without further purification.
5-(BEN~YLOXYCARBONYL)-1,6-DIHYDRO-2-METHOXY-4-ETHYL-6-(3,
4-DI-FLUOROPHENYL)PYRIMIDINE: A suspension of benzyl
3-[(3,4-di-fluorophenyl)methylene]-4-oxopentanoate (16.0 g,
48.0 mmol), O-methylisourea hydrogen sulfate (16.7 g, 97.0
mmol) and NaHC03 (16.3 g, 130 mmol) in DMF (190 mL) was
stirred at 70 °C for 20 h. After cooling to room
temperature, the mixture was filtered and the filtrate was
diluted with EtOAc (300 mL) and then washed with water
(4X100 mL), brine (200 mL) and dried over Na2S04. After
removal of solvent, the residue was purified by column
chromatography (EtOAc/Hexane, 1/9 to 3/7), giving the title
compound as a colorless oil (10.6 g, 580). The NMR
120 analysis showed it to be a mixture of amine/imine tautomers
and was used as is in the next step.
5-(BENZYLOXYCARBONYL)-4-ETHYL-1,6-DIHYDRO-2-METHOXY-6-(3,
4-DI-FLUOROPHENYL)-1-[(4-NITROPHENYLOXY)CARBONYL]
PYRIMIDINE: To a stirring solution of
5-(benzyloxycarbonyl)-1,6-dihydro-2- methoxy-4-ethyl-6-
(3,4-difluorophenyl)pyrimidine (17.0 g, 44.0 mmol) and
4-dimethylaminopyridine (7.00 g, 57.3 mmol) in CHzClz (200
mL) was added 4-nitrophenyl chloroformate as a powder (11.5
g, 57.1 mmol) at room temperature. The reaction mixture was
stirred for 12 h and then the solvent was removed in vacuo.
The residue was purified by chromatography (EtOAc/Hexane,
1 / 9 t o 3 / 7 ) , g i v i n g
5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2- methoxy
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6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyr-
imidine as a colorless viscous oil (12.6 g, 500). 1H NMR d
1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H),
5.14 (ABq, A=5.08, B= 5.20, J= 12.3 Hz, 2H), 6.28 (s,
3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d,
J=9.2 Hz, 2H).
5-(BENZYLOXYCARBONYL)-4-ETHYL-1,6-DIHYDRO-1-{N-[1-PHENYL)
ETHYL]}-CARBOXAMIDO-2-METHOXY-6-(3,4-DIFLUOROPHENYL)
PYRIMIDINE: To a stirred mixture of
5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-
methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbo
nyl]pyr-imidine. (12.6 g, 22.9 mmol) in THF (150 mL) was
added a solution of R-(+)-a-methyl benzylamine (3.53 mL,
27.1 mmol) at room temperature. The stirring was continued
for 12 h and the solvent was removed in vacuo. The yellow
residue was dissolved in chloroform (200 mL) and was washed
with 10 o K2C03 solution (2x30 mL) . The organic layer was
dried over Na2S04, filtered and solvent was removed in
vacuo. The resulting mixture of diastereomers was
separated by column chromatography (petroleum ether/ether,
9/1 to 4/1). The first major product to elute was
(+)-5-(benzyloxycarbonyl)-4-ethyl-
1,6-dihydro-1-{N-[1- phenyl)-ethyl]}carboxamido-2-
methoxy-6-(3,4-difluorophenyl)pyrimidine. Colorless oil;
Rf= 0.31 (petroleum ether/ether, 4/1); yield: 3.8 g (310);
[a,]~ _ +267.05 (c = 0.76, CHC13) ; 1H NMR d 1.22 (t, J=7.5 Hz,
3H), 1.52 (d, J=6.9 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H), 3.99
(s, 3H), 4.99 (m, 1H), 5.09 (ABq, A=5.00, B= 5.19, J=
12.6 Hz, 2H), 6.66 (s, 1H), 6.99-7.36 (m, 13H). The second
m a j o r p r o d a c t . t o a 1 a t a w a s
(-)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-
[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophe
nyl)pyr-imidine. Colorless oil; Rf= 0.22 (petroleum
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ether/ether, 4/1); yield: 3.20 g (260); [a]p = -146.89 (c =
0 . 38, CHC13 ) ; 1H NMR 8 1 . 22 (t, J=7 .2 Hz, 3H) , 1 . 49 (d,
J=6. 6 Hz, 3H) , 2. 88 (q, J=6. 0 Hz, 2H) , 3. 94 (s, 3H) , 5 . 03
(m, 1H), 5.11 (ABq, A=5.02, B= 5.19, J= 12.6 Hz, 2H),
6. 68 (s, 1H) , 6. 91-7.34 (m, 13H) .
(+)-5-(BENZYLOXYCARBONYL)-.1,6-DIHYDRO-2-METHOXY-4-ETHYL-6
-(3,4-DI-FLUOROPHENYL)PYRIMIDINE: To a stirred solution of
(.+)-5-(bent-yloxycarbonyl)-4-ethyl-1,6-dihydro-1-
{N-[2-phenyl)ethyl]}carbox-amido-2-methoxy-6-
(3,4-difluorophenyl)pyrimidine (1.00 g, 1.83 mmol) in
toluene (10 mL) was added 1,8-diazabicyclo[5,4,0]-undec-
7-ene (0.120 mL, 0.810 mmol) at room temperature and the
resulting solution was heated at reflux temperature for 5
h and then stirred for 12 h at room temperature. The
solvent was evaporated and the residue was purified by
flash column (EtOAc/Hexanes, 1/3), giving
(+)-5-(benzyloxycarbonyl)-1,6- dihydro-2-methoxy-4-ethyl
-6- (3,4-difluorophenyl)pyrimidine (0.560 g, 77%).
(+)-5-(BENZYLOXYCARBONYL)-.4-ETHYL-1,6-DIHYDRO-2-METHOXY-6
-(3,4-DI-FLUOROPHENYL)-1-[(4-NITROPHENYLOXY)
CARBONYL]PYRIMIDINE: To a stirring solution of
(+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-
methoxy-4-ethyl-6-(3,4-difluorophen-yl)pyrimidine (17.0 g,
44.0 mmol) and 4-dimethylaminopyridine (6.99 g, 57.3 mmol)
in CHZC12 (200 mL) was added 4-nitrophenyl chloroformate
(11.6 g, 57.3 mmol) at room temperature. The reaction
mixture was stirred for 12 h and then the solvent was
removed .in vacuo. The residue was purified by
chromatography (EtOAc/Hexane, 1/9 to 3/7), giving
(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6
-(3,4- difluorophenyl)-1-[(4-nitrophenyloxy)
carbonyl]pyrimidine as a viscous colorless oil (19.3 g,
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760) .
5-METHYLBENZFUROXAN: 4-Methyl-2-nitroaniline (100 g, 0.650
mol) was suspended in saturated methanolic sodium hydroxide
solution (1.50 L). This suspension was cooled (5 °C) and
aqueous sodium hypochlorite until the red color
disappeared. The resulting fluffy yellow precipitate was
filtered, washed with cold water and recrystallized from
ethanol, giving 5-methylbenzfuroxan (88.2 g, 89 o yield) as
a pale yellow solid: 1H NMR d 2.39 (s, 3 H), 6.90-7.40 (br
m. 3 H) .
5-METHYLBENZOFURAZAN: To 5-Methylbenzfuroxan (88.2 g, 0.590
mol) in refluxing EtOH (75 mL) was added dropwise P(OEt)3
(150 mL). Heating was continued at reflux temperature for
1 h. The solvent was removed in vacuo and the residue was
shaken with water (200 mL) and allowed to stand overnight
at (0-5 °C). The resulting brown solid was filtered, washed
with water. The crude product was purified by flash
chromatography, giving 5-methylbenzofurazan (70.0 g, 87 0)
as white needles; 1H NMR 8 2.41 (s, 1 H), 7.19 (dd, J=9.3,
1.1 Hz, 1 H), 7.48 (d, J=1.1 Hz, 1 H), 7.66 (d, J=9.3 Hz,
1 H) .
5-DIBROMOMETHYLBENZOFURAZAN: An anhydrous solution of
5-methylbenzofurazan (70.0 g, 0.520 mol),
N-bromosuccinamide (325 g), and benzoyl peroxide (0.50 g)
in carbon tetrachloride (1.5 L) was heated at reflux
temperature with stirring for 30 h. The reaction mixture
was washed with water (2 X 500 mL), dried (NaS09), and the
solvent was removed in vacuo. The residue was
chromatograghed (EtOAc/hexane, 1/150), giving 122 g (800)
of the title compound as a white solid: '-H NMR d 6.69 (s, 1
H), 7.69 (d, J=9.6 Hz, 1 H), 7.77 (s, 1 H), 7.89 (d, J=9.6
Hz, 1 H) .
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5-FORMYLBENZOFURAZAN: AgN03 (163 g) in 2 L of water was
added to a refluxing mixture of dibromomethylbenzofurazan
(122 g, 418 mmol) in EtOH (1 L). Heating at reflex
temperature was continued for 2 h. The mixture was cooled,
the precipitated Agar was removed by filtration through
Celite, and the solvent was concentrated. The resulting
solution was extracted with toluene (10 X 100 mL), dried
over magnesium sulfate, and the solvent was removed in
vacuo. The residue was chromatograghed (EtOAc/hexane,
1/125), giving the title aldehyde (48.2 g, 780) as a white
solid: 1H NMR 8 7.92 (m, 2H), 8.39 (s, 1 H), 10.10 (s, 1 H).
METHYL 2-{(BENZOFURAN-5-YL)METHYLENE}-3-OXOBUTYRATE: A
mixture of 5-formylbenzofurazan (0.60 g, 4.1 mmol), methyl
acetoacetate (0.52 g, 4.5 mmol), piperidine (0.019 g, 0.23
mmo1), and acetic acid (0.014 g, 0.23 mmol) in benzene (30
mL) was heated at reflex temperature (equipped with a
Dean-Stark trap) for 8 h. Benzene was evaporated in sracuo,
the residue was dissolved in ethyl acetate (80 mL) and
washed with brine (50 mL), saturated potassium bisulfate
solution (50 mL), and saturated sodium bicarbonate
solution. The ethyl acetate solution was dried over
magnesium sulfate, the solvent removed under reduced
pressure and the residue was purified by column
chromatography (EtOAc/hexane, 1/9 to 3/20). The desired
product was obtained as oil (0.98 g, 980) and was used in
the next step without any further characterization.
6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB
ONYL-4- METHYLPYRIMIDINE: A mixture of methyl
2-{(benzofuran-5-yl)-methylene}-3-oxobutyrate (1.02 g, 4.10
mmol), O-methylisourea hydrogen sulfate (1.06 g, 6.20
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-105-
mmol ) , and NaHC03 ( 1. 3 0 g, 16 . 4 mmol ) in DMF ( 15 mL ) wa s
stirred and heated at 70 °C for 16 h. The mixture was
cooled, diluted with EtOAc (50 mL) and washed with water
(5X 50 mL), brine (50 mL) and dried over magnesium sulfate.
The solvent was evaporated and the crude product was
purified by flash chromatography (EtOAc/hexane, 1/9 to
1/5), giving the desired product as an oil (0.520 g, 430):
~HNMR 8 2.38 and 2.42 (2 s, 3 H), 3.60 and 3.66 (2 s, 3 H),
3 . 74 and 3. 82 (2 s, 3 H) , 5.53 and 5. 68 (2 s, 1 H) , 6.31
and 6.32 (br s, 1 H), 7.0-7.8 (m, 3 H).
6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB
ONYL-4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE:
To a solution of 6-(benzofuran-5-yl)-1,6-dihydro-
2-methoxy-5-methoxycarbonyl-4- methylpyrimidine (0.485 g,
1.6 mmol) and 4-dimethylaminopyridine (0.200 g, 1.64 mmol)
in CH2C12 (20 mL) at 0-5 °C was added 4-nitrophenyl
chloroformate (0.307 g, 1.52 mmol). The mixture was then
allowed to warm to room temperature. After 12 h, the
solvent was evaporated and the residue was purified by
'flash chromatography (EtOAc/hexane, 1/9 to 3/20), giving
the desired product as white crystals (0.665 g, 89o); mp
180-183 °C; 1H NMR 8 2.54 (s, 3 H) , 3.75 (s, 3 H) , 3. 98 (s,
3 H), 6.37 (s, 1 H), 7.40 (d, J=9.3 Hz, 2 H), 7.52 (d,
J=9.0 Hz, 1 H), 7.68 (s, 1 H), 7.84 (d, J=9.0 Hz, 1 H),
8.32 (d, J=9.3 Hz, 2 H).
(+) and (-)-6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-
METHOXYCARBONYL-1-[N-(S)-1-(1-PHENYLETHYL)]-4-METHYLPYRIM
IDINE: A solution of 6-(benzofurazan-5-
yl)-1,6-dihydro-2-methoxy-5- methoxycarbonyl-4-methyl-
1- (4-nitrophenoxy) carbonylpyrimidine (800 mg, 1.71 mmol)
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and (S)-(-)-a-methylbenzylamine (269 mg, 2.22 mmol) in
THF (50 mL) was stirred at room temperature for 12 h.
The THF was removed in vacuo and the residue was
dissolved in EtOAc (100 mL), washed by 10o aqueous KzC03
solution (3x50 mL) , brine (50 mL) and dried (NaZS09) .
After removal of the solvent, the residue was purified by
chromatography (EtOAc/hexane, 1/20 to 3120), separating
the two diastereomers. The isomers of
6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarb
onyl-1-[N-(S)-1-(1-phenylethyl)]- 4-methylpyrimidine were
obtained as colorless oils. 1st Isomer (367 mg, 47.70):
[a,] ~, = +278 (c=0.50, CHC13) ; 1H NMR 8 1. 54 (d, J=6. 9 Hz,
3H), 2.45 (s, 3H), 3.68 (s, 3H), 3.99 (s, 3H), 5.02
(quintet, J=6.9 Hz, 1H) , 6.71 (s, 1H) , 6.89 (d, J=6. 6 Hz,
1H) , 7.2-7.9 (m, 8H) . ' 2nd Isomer (205 mg, 26.60) : [a.]L,
--81 (c=0.43, CHC13) ; 1H NMRb 1.52 (d, J=6.6 Hz, 3H) ,
2.48 (s, 3H), 3.71 (s, 3H), 3.96 (s, 3H), 5.00 (quintet,
J=6. 6 Hz, 1H) , 6.74 (s, 1H) , 6. 90 (d, J=6.5 Hz, 1H) ,
7.2-7.9 (m, 8H).
6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB
ONYL-4- METHYLPYRIMIDNE: A solution of the 1st isomer of
6-(benzofura-zan-5-yl)-1,6-dihydro-2-methoxy-
5-methoxycarbon-yl-1-[N-(S)-1-(1-phenylethyl)]-4-methylpy
rimidine (960 mg, 2.14 mmol) and 1,8-diazabicyclo
[5,4,0]undec-7-ene (107 mg, 0.705 mmol) in toluene (50 mL)
was stirred at 100 °C for 5 h. After cooling to room
temperature, toluene was removed in vacuo and the residue
was purified by chromatography (EtOAc/hexane, 1/9 to 3/7).
6-(Benzofurazan-5- yl)-1,6-dihydro-2-methoxy-
5-methoxycarbonyl- 4-methylpyrimidine was obtained as a
colorless oil ( 635 mg, 98 . 3 0 ) . 1H NMR 8 2 . 38 ( s, 3H) , 3 . 66
(s, 3H), 3.74 (s, 3H), 5.68 (s, lH), 6.32 (br s, 1H),
7.0-7.8 (m, 3H).
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6-(BENZOFURAZAN-5-YL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCARB
ONYL-4-METHYL-1-(4-NITROPHENOXY)CARBONYLPYRIMIDINE: T o
a solution of 6-(benzofuran-5-yl)-1,6-dihydro-2-methoxy-
5-methoxycarbonyl- 4-methylpyrimidine (0.485 g, 1.60 mmol)
and 4-dimethylamino-pyridine (0.200 g, 1.60 mmol) in CH=Cl
(20 mL), at 0-5 °C, was added 4-nitrophenyl chloroformate
(0.307 g, 1.52 mmol). After addition, the mixture was
allowed to warm to room temperature. After 12 hours, the
solvent was evaporated and the residue was purified by
flash column chromatography (EtOAc/hexane, 1/9 to 3/20),
giving the desired product as white crystals (0.665 g,
890): mp 180-183 °C; sH NMR82.54 (s, 3 H), 3.75 (s, 3 H),
3.98 (s, 3 H) , 6.37 (s, 1 H) , 7.40 (d, J = 9.3 Hz, 2 H) ,
7.52 (d, J = 9.0 Hz, 1 H) , 7. 68 (s, 1 H) , 7.84 (d, J = 9.0
Hz, 1 H), 8.32 (d, J = 9.3 Hz, 2 H); [a]D = +266 (c=2.70,
CH_Cl., ) .
METHYL 2-{(3,4-DIFLUOROPHENYL)METHYLENE}-3-OXOBUTYRATE: A
mixture of 3,4-difluorobenzaldehyde (14.2 g, 0.100 mol),
methyl acetoacetate (12.2 g, 0.105 mol), piperidine (0.430
g, 5 mmol ) , and acetic acid ( 0 . 30 g, 5 mmol ) in benzene
(150 mL) was stirred and heated at reflux temperature
(equipped with a Dean-Stark trap) for 8 h. The benzene was
evaporated and the residue was dissolved in ethyl acetate
(200 mL). The resulting solution was washed with brine (50
mL), saturated potassium bisulfate solution (50 mL), and
saturated sodium bicarbonate solution. The ethyl acetate
solution was dried over magnesium sulfate and the solvent
was removed under reduced pressure. The residue was
purified by column chromatography (EtOAc/hexane, 1/9 to
3/20), giving the desired product as a yellow oil (9.80 g,
41%) which was used in the subsequent step without any
further characterization.
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6-(3,4-DIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCAR
BONYL-4-METHYLPYRIMIDINE: ~A mixture of methyl 2-{(3,4-
difluorophenyl)-methylene}-3-oxobutyrate (8.80 g, 36.3
mmol), 0-methylisourea hydrogen sulfate (9.40 g, 546 mmol),
and NaHC03 (12.3 g, 146 mol) in DMF (30 mL) was heated at
70 °C with stirring for 1~ h. The mixture was cooled,
diluted with EtOAc (300 mL) and washed with water (5 X 300
mL), brine (300 mL), and dried over magnesium sulfate. The
solvent was evaporated and the crude product was purified
by flash chromatography (EtOAc/hexane, 1/9 to 3/7) as the
gradient eluent, giving the desired product as an oil (3.82
g, 350) .
6-(3,4-DIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-METHOXYCAR
BONYL-4-METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE:
4-Nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added
to a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-
2-methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g,
9.46 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol)
in CHzCl? (50 mL), at 0-5 °C and the mixture was then allowed
to warm to room temperature. After 12 h, the solvent was
evaporated and the residue was purified by flash
chromatography (EtOAc/hexane, 1/9 to 3/20), giving the
desired product as white crystals (3.72, 850): mp 172-174
°C.
6-(3,4-DIFLUOROPHENYL)-1,2,3,6-TETRAHYDRO-2-OXO-5-METHOXY
CARBON-YL-4-METHYL-1-(4-NITROPHENOXY)CARBONYLPYRIMIDINE:
Aqueous 6 N hydrochloric acid (10 mL) was added to a
stirring solution of 6-(3,4-difluorophenyl)-1,6- dihydro-
2-methoxy-5-methoxycarbonyl- 4-methyl-1-
(4-nitrophenoxy)carbonylpyrimidine (10.0 g) in THF (200 mL)
at room temperature. The stirring was continued for 3 h.
The solvent was evaporated and the residue was dried under
vacuum, giving the desired product as a white powder (9.70
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g, 1000) : mp 185-186 °C.
(+)-1-(3-BROMO-PROPYLCARBAMOYL)-6-(3,4-DIFLUOROPHENYL)-4-
METHYL- 2-OXO-1,6-DIHYDRO-PYRIMIDINE-5-CARBOXYLIC ACID
METHYL ESTER: A solution of 10o aqueous HCl (5 mL) was
added to a stirring solution of (+)-6-(3,4-
difluorophenyl)-1,6-dihydro- 2-methoxy-5-methoxycarbonyl-
4-methyl-1-[(4-nitrophenyloxy)-carbonyl]pyrim-idine (4.10
g, 9.10 mmol) in THF (20 mL) at room temperature and the
resulting solution was stirred overnight. The THF was
removed in vacuo and the. resulting residue was extracted
with EtOAc (3 X 20 mL), washed with brine (10 mL) and then
dried over Na2S04. The solvent was removed in vacuo, giving
(+)-6-(3,4-di-fluorophenyl)-1,6-dihydro-2- oxo-5-
methoxycarbonyl-4-methyl-1- [(4-nitrophenyloxy)carbonyl]
pyrimidine as a viscous oil (3.8~g, 8.5 mmol). The oil was
dissolved in THF (20 mL) and 3-bromo-propylamine
hydrobromide (2.33 g, 10.8 mmol) and NaHC03 (1.81 g, 21.5
mmol) were added. The resulting suspension was stirred at
room temperature overnight.. The THF was removed in vacuo
and the resulting residue was dissolved in water (10 mL)
and then extracted with EtOAc (3 X 20 mL). The EtOAc
extracts were combined, dried over NazS04, filtered and the
solvent was removed , giving (+)-1-(3-bromo-
propylcarbamoyl)-6- (3,4-difluorophenyl)-
4-methyl-2-oxo-1,6-dihydropyrimidine-5-carboxylic acid
methyl ester (3.28 g, 830): 1H NMRB 2.05-2.15 (m, 2 H), 2.43
(s, 3 H), 3.40-3.56 (m, 4 H), 3.72 (s, 3 H), 6.69 (s, 1 H),
7 . 08-7 . 27 (m, 3 H) , 7 .57 (br s, 1 H) , 8. 84 (br t, 1 H) .
Anal. Calcd for C1~H18N3Oq F~Br: C, 45.76; H, 4.07; N, 9.42.
Found: C, 45.70; H, 3.99; N, 9.16.
3-{(3,4,5-TRIFLUOROPHENYL)METHYLENE}-2,4-PENTANEDIONE: A
stirring mixture of 3,4,5-trifluorobenzaldehyde (4.20 g,
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26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol),
piperidine (0.430 g, 5.00 mmol) in benzene (150 mL) was
heated at reflux temperature (equipped with a Dean-Stark
trap) for 8 h. The benzene was evaporated and the yellow
oily residue, 2-{(3,4,5-trifluorophenyl)methylene}
2,4-pentanedione, was used in the next step without further
purification.
6-(3,4,5-TRIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-ACETYL-
4-METHYLPYRIMIDINE: A mixture of 2-{(3,4,5-
trifluorophenyl)methylene}- 2,4-pentanedione (26.2 mmol),
O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and
NaHC03 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and
heated at 95-100 °C for 6 h. The mixture was filtered and
the solid residue was .washed with ethanol (100 mL) . The
solvent was evaporated from the combined filtrates and the
crude product was purified by flash column chromatography
(EtOAc/hexane, 1/9 to 1/4), giving the desired product as
an oil (2.80 g, 36o) .
6-(3,4,5-TRIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-ACETYL-
4-METH-YL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE:
4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was added
to a solution of 6-(3,,4,5-trifluorophenyl)-1,6-
dihydro-2-methoxy-5-acetyl-4-meth-ylpyrimidine (2.80 g,
9.38 mmol) and pyridine (10 mL) in CHzClz (200 mL) at 0-5 °C,
and the resulting mixture was allowed to warm to room
temperature. After 12 h, the solvent was evaporated and
the residue was purified by . flash chromatography
(dichloro-methane/EtOAc, 1/9 to 3/20), giving the desired
product as a white powder ( 4 . 00 g, 92 0 ) .
6-(3,4,5-TRIFLUOROPHENYL)-1,2,3,6-TETRAHYDRO-2-OXO-5-ACET
YL-4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE: A
solution of 6 N aqueous HC1 (4 mL) was added to a stirring
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solution of 6- (3,4,5-trifluorophenyl)-1,6-
dihydro-2-methoxy-5-acetyl-4-methyl- 1-[(4-
nitrophenyloxy)carbonyl]pyrimidine (4.00 g, 8.63 mmol) in
THF (100 mL) at 0-5 °C, and the mixture was allowed to warm
to room temperature. After 2 h, solvent was evaporated and
the product dried under vacuum. The product was obtained
as a pure single component and used in the next step
without any further purification (3.88 g, 1000).
Procedures for the Synthesis of the Piperidine
Intermediates
(reference for the general procedure for Pd coupling of
vinyl triflate and boronic acids or tributyl tin reagents:
See, Wuston, Wise Synthesis (1991), 993)
TERT-BUTYL 4-{[(TRIFLUOROMETHYL)SULFONYL]OXY}-
1,2,3,6-TETRA-HYDRO-1-PYRIDINECARBOXYLATE: n-Butyllithium
(17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a
solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL
of dry THF at 0 °C and stirred for 20 minutes. The reaction
mixture was cooled to -78 °C and tert- butyl
4-oxo-1-piperidinecarboxylate (40.0 mmol) in THF (40 mL)
was added dropwise to the reaction mixture and stirred for
minutes. Tf2NPh (15.0 g, 42.0 mmol) in THF (40 mL) was
25 added dropwise to the reaction mixture and the mixture was
stirred at 0 °C overnight. The reaction mixture was
concentrated in vacuo, re-dissolved in hexanes/EtOAc (9/1),
passed through a plug of alumina and washed with
hexanes/EtOAc (9/1). The combined extracts were
30 concentrated to yield 16.5 g of the desired product that
was contaminated with a small amount of Tf2 Nph. 1H NMRb
5.77 (s, 1 H), 4.05 (dm, 2 H, J=3.0 Hz), 3.63 (t, 2 H,
J=5.7 Hz), 2.45 (m, 2 H), 1.47 (s, 9 H).
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TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1,2,3,6-
TETRAHYDRO-1- PYRIDINECARBOXYLATE: A mixture of saturated
of aqueous Na2C03 solution (25 mL), tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}- 1,2,3,6-
tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acet-
amidophenylboronic acid (30 mmol) and tetrakis-
triphenylphosphine palladium (0) (1.15 g) and
dimethoxyethane (40 mL) was heated at reflux temperature
overnight. The organic layer of the cooled reaction
mixture was separated and the aqueous layer was washed with
ethyl acetate (3X). The combined organic extracts were
dried and concentrated in vacuo. The crude product was
chromatograghed, giving the desired product 1H NMRB 8.11
(br s, 1 H) , 7 .57 (br s, 1 H) , 7 .41 (br 8 , 1 H, J=7 .8 Hz) ,
7 .25 (apparent t, 1 H, J=7 .8 Hz) , 7 .08 (br d, 1 H, J=7 . 8
Hz), 5.99 (b s, 1 H), 4.03 (br m, 2 H, J=2.7 Hz), 3.59 (t,
2 H, J=5.7 Hz) , 2.46 (m, 2. H, ) , 2.16 (s, 3 H) , 1.49 (s, 9
H) .
N1-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]ACETAMIDE: A
solution of 4 M HCl in dioxane (10 mL) was added to
tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-
tetrahydro-1-pyridinecarboxyl-ate (8.25 mmol) in
dichloromethane (30 mL). The reaction mixture was stirred
at room temperature overnight, concentrated in vacuo,
giving the desired product as the hydrochloride salt (2.1
g) . 1H NMR b 7 . 41-7. 00 (m, 4 H) , 6. 10 (br, 1 H) , 3 .55 (m,
2 H), 3.16 (t, 2 H, J = 5.7 Hz), 2.44 (m, 2 H), 2.19 (s, 3
H) .
TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE: Prepared from
3-bromopropylamine hydrobromide and BOC20 in the presence of
base in dichloromethane: 1H NMR ~ 5.07 (br, 1 H), 3.31 (t,
2 ~H, J=6. 6 Hz) , 3.12 (apparent br q, 2 H, J=6.0 Hz) , 1 . 92
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(p, 2 H, J=6. 6 Hz) , 1 .30 (s, 9H) .
REACTION OF N1-j3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]
ACETAMIDE ~nIITH TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE
TERT-BUTYL N-(3-{4-[3-(ACETYLAMINO)PHENYL]-
1,2,3,6-TETRAHYDRO- 1-PYRIDINYL}PROPYL)CARBAMATE: A
solution of N1-[3-(1,2,3,6- tetrahydro-4-pyridinyl)
phenyl]acetamide hydrochloride (8.24 mmol), tert-butyl
N-(3-bromopropyl)carbamate and potassium carbonate (33
mmol) in dry dioxane (30 mL) was heated at reflux
temperature overnight. The solids were removed by
filtration, the solution was concentrated in vacuo and the
product was chromatographed, giving the desired product
(110 mg) . 1H NMRB 7 . 65 (s, 1 H) , 6. 98 (s, 1 H) , 7 . 45 (d, 1
H, J=7.8 Hz), 7.16 (apparent t, 1 H, J=7.8 Hz), 7.10 (d, 1
H, J=7 .8 Hz) , 6.02 (s, 1 H) , 5.23 (b, 1 H) , 3.40 (b, 2 H) ,
3.30-1.80 (m, 10 H), 2.18 (s, 3 H), 1.45 (s, 9 H).
Deprotection of BOC:
N1-{3-[1-(3-AMINOPROPYL)-1.,2,3,6-TETRAHYDRO-4-PYRIDINYL]P
HENYL}ACETAMIDE: A 1:1 solution of TFA:CHzClz (5 mL) was
added to tert-butyl N-(3-{4-[3-(acetylamino)phenyl]-
1,2,3,6-tetrahydro-1- pyridinyl}propel)carbamate in
dichloromethane (5 mL). The resulting solution was stirred
at room temperature for 1-3 days, saturated NaHC03 was
added until pH > 6, the organic layer was separated, and
dried in vacuo, giving the desired product (45 mg) : 1H NMR
7.68 (br, 1 H), 7.35 (dm, 1 H, J=7.8 Hz), 7.25 (apparent
t, 1 H, J=7.8 Hz), 7.15 (dm, 1 H, J=7.8 Hz), 6.12 (m, 1 H),
3.22 (m, 2 H), 3.03 (t, 2 H, J=7.3 Hz), 2.78 (t, 2 H, J=5.5
Hz), 2.70-2.50 (m, 4 H), 2.10 (s, 3 H), 1.87 (p, 2 H, J=7.3
Hz) .
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TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1-
PIPERIDINECARBOXYLATE: A mixture tart-butyl
4-[3-(acetylamino)phenyl]-1,2,3,6-tetra-hydro-1-
pyridinecarboxylate (710 mg) and 5o Pd/C (100 mg) in EtOH
(10 mL) was hydrogenated (balloon technique) at room
temperature overnight. The reaction mixture was passed
through a pad of Celite 545 and the pad of Celite was
washed with ethanol. The combined ethanol extracts were
concentrated and chromatograghed, giving the desired
product (660 mg). 1H NMR ~ 7.80 (s, 1 H), 7.41-7.20 (m, 3
H) , 6. 94 (d, 1 H, J=7.5 Hz)., 4 .21 (m, 2 H) , 2.75 (m, 2 H) ,
2.62 (m, 1 H), 2.16 (s, 3 H), 1.78 (m, 2 H), 1.56 (m, 2 H),
1.48 (s, 9 H) .
N1-[3-(4-PIPERIDYL)PHENYL]ACETAMIDE: A solution of HC1 in
dioxane (4N, 5 mL) was added to tart-butyl 4-[3-
(acetylamino)-phenyl]-1-piperidinecarboxylate (660 mg) in
dry dichloromethane (15 mL). The reaction mixture was
stirred at room temperature overnight and concentrated in
vacuo, giving the desired product (550 mg): mp 102-104 °C;
1H NMR 8 2.02 (d, J=13.2 Hz, 2H), 2.11-2.45 (m, 5H),
2.67-2.77 (m, 1H), 3.00-3.10 (m, 2H), 3.51 (d, J=10.5 Hz,
2H), 6.94 (d, J=7.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.60 (s,
1H) .
TERT-BUTYL N-(3-{4-[3-(ACETYLAMINO)PHENYL]
PIPERIDINO}PROPYL)-CARBAMATE: A solution of
N1-[3-(4-piperidyl)phenyl]acetamide (550 mg, 0.210 mmol),
tart-butyl N-(3-bromopropyl)-carbamate (550 mg, 0.230
mmol) , K2C03 (1.10 g, 0. 890 mmol) , diisopropylethyl amine
(1.50 mL) and a few crystals of KI in dioxane (20 mL) was
heated at reflux temperature for 2 days. The precipitated
salts were removed by filtration, concentrated in vacuo and
the crude product was chromatographed, giving the desired
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product (340 mg) . 1H NMR ~ 8 . 15 (s, 1 H) , 7. 47-7. 44 (m, 2
H), 7.22 (t, 1 H, J=7.8 Hz), 6.94 (d, 1 H, J=7.8 Hz), 5.53
(b, 1 H), 3.23 (b, 6 H), 2.80-1.60 (m, 9 H), 2.20 (s, 3 H),
1.45 (s, 9 H) .
N1-{3-[1-(3-AMINOPROPYL)-4-PIPERIDYL]PHENYL}ACETAMIDE: TFA
(1.0 mL) was added to a solution of tert-butyl
N-(3-{4-[3-(acetyl-amino)phenyl]piperidino}
propyl)carbamate (340 mg) in dry dichloromethane (10 mL)
and stirred at room temperature for 5 h. A 10o aqueous
solution of KOH was added to the reaction mixture until pH
> 6 and then the dichloromethane was removed in vacuo. The
aqueous layer was frozen and lyophilized, giving a solid
which was then extracted with methanol. Removal of
methanol gave the desired product (120 mg) as an oil. 1H
NMR 8 8.56 - 8.46 (s, 1H), 7.43 - 7.30 (m, 2H), 7.23 - 7.16
(apparent t, 1H, J=7.5 Hz), 6.95 - 6.92 (m, 1H), 3.03
2.99 (m, 2H), 2.77 - 2.73 (t, 2H, J = 6.6 Hz), 2.50-1.60
(m, 10 H) , 2 .13 (s, 3 H) .
1-BENZYL-4-HYDROXY-4-(4-FLUORO-2-METHYLPHENYL)PIPERIDINE:
1H NMR 8 7.40-7.26 (M, 5 H), 6.91-6.76 (m, 3 H), 3.57 (s,
2 H), 2.83- 2.72 (m, 2 H), 2.61 (s, 3 H), 2.58-2.43 (m, 2
H), 2.23-2.12 (m, 2 H).
1-BENZYL-4-(4-FLUORO-2-METHYLPHENYL)-1,2,3,6-TETRAHYDROPY
RIDINE: 1H NMR 8 7.41-7.26 (m, 5 H), 7.05 (dd, 1 H, J=6.0,
8 .1 Hz) , 6.87-6.80 (m, 2 H) , 5.52-5.50 (m, 2 H) , 3.65 (s,
2 H), 3.13 (q, 2 H, J=3.3 Hz), 2.69-2.66 (t, 2 H, J=5.1
Hz), 2.35-2.31 (m, 2 H), 2.27 (s, 3 H).
4-(4-FLUORO-2-METHYLPHENYL)PIPERIDINE: 1H NMR 8 7.17 (t, 1
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H, J=7.2 Hz), 6.83-6.80 (m, 2 H), 3.22 (m, 2 H), 2.82-2.73
(m, 2 H), 2.66 (br s, 1 H), 2.33 (s, 3 H), 1.80-1.60 (m, 4
H) .
1-BENZYL-4-(3,4,5-TRIFLUOROPHENYL)-1,2,3,6-TETRAHYDROPYRI
DINE: 1H NMR 8 7.50-7.20 (m, 7 H), 5.67 (m, 1 H), 3.69 (s,
2 H), 3.19 (apparent q, 2 H, J=2.7 Hz), 2.75 (t, 2 H, J=5.7
Hz) , 2.34 (m, 2 H) .
4-(3,4,5-TRIFLUOROPHENYL)PIPERIDINE: mp 197-199 °C; 1H NMR
cS 2.05 (d, J=13.2 Hz, 2H), ), 2.33 (dd, J=25.5 Hz, J=12.9
Hz, 2H), 3.06-3.23 (m, 3H), 3.73 (d, J=12.0 Hz, 2H),
6.94-7.04 (m, 2H).
4-(3,4,5-TRIFLUOROPHENYL)PIPERIDINE: 1H NMR ~ 7.20-6.80 (m,
2 H), 3.73 (m, 2 H), 3.14 (m, 3 H), 2.33 (m, 2 H), 2.05 (m,
2 H) .
TERT-BUTYL N-3-[4-(3,4,5-TRIFLUOROPHENYL)PIPERIDINO]
PROPYL-CARBAMATE: 1H NMR 8 6.91 (m, 2 H), 5.62 (b, 1 H),
4 .31 (t, 2 H, J=5.4 Hz) , 3. 63 (m, 2 H) , 3.39 (dt, 2 H, J=
2.1, 6.0 Hz), 3.40-2.70 (m, 7 H), 2.46 (t, 2 H, J=6.9 Hz),
2.10-1.60 (m, 4 H), 1.45 (s, 9 H).
3-[4-(3,4,5-TRIFLUOROPHENYL)PIPERIDINO]-1-PROPANAMINE: 1H
NMR x6.93 (m, 2 H), 4.30 (b, 1 H), 3.36 (b, 1 H), 3.06 (m,
2 H), 2.77 (m, 2 H), 2.43 (m, 2 H), 2.20-1.40 (m, 9 H).
1-BENZYL-4-(5-FLUORO-2-METHOXYPHENYL)-4-PIPERIDINOL: 1H NMR
cS7.40-6.80 (m, 8 H), 3.94 and 3.85 (s, 3 H), 3.61 and 3.58
(s, 2 H), 2.80-1.90 (m, 8 H).
1-BENZYL-4-(5-FLUORO-2-METHOXYPHENYL)-1,2,3,6-TETRAHYDROP
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YRIDINE: 1H NMR 8 7.40-6.70 (m, 8 H), 5.84 (m, 1 H), 3.77
(s, 3 H), 3.64 (s, 2 H), 3.17 (m, 2 H), 2.68 (t, 2 H, J=5.7
Hz), 2.54 (m, 2 H).
4-(5-FLUORO-2-METHOXY)PHENYL PIPERIDINE: mp 254-258 °C; 1H
NMR 81.53-1.68 (m, 2H), 1.79 (d, J=11.7 Hz, 2H), 2.12 (dt,
J=2.1 Hz, J=11.7 Hz, 1H), 2.77 (dt, J=1.8 Hz, J=12.3 Hz,
1H), 2.90-3.05 (m, 1H), 3:10-3.22 (m, 2H), 3.68 (s, 1H),
3.79 (s, 3H), 6.72-6.93 (m, 3H). Anal. Calcd. For
C1~H1~NOFC1 + 0.14 CHzCl2: C, 56.60; H, 6.76; N, 5.44.
Found: C, 56.60; H, 6.92;~N, 5.28.
TERT-BUTYL N-3-[4-(5-FLUORO-2-METHOXYPHENYL)PIPERIDINO]
PROPYL-CARBAMATE: 1H NMR 8 6.90-6.70 (m, 3 H), 5.76 (b, 1
H), 3.80 (s, 3 H), 3.68 (m, 1 H), 3.40-2.90 (m, 4 H), 2.45
(t, 2 H, J=6.6 Hz), 2.20-1.60 (m, 9 H), 1.45 (s, 9 H).
3-[4-(5-FLUORO-2-METHOXYPHENYL)PIPERIDINO]-1-PROPANAMINE:
1H NMR 8 7.00-6.80 (m, 3 H) , 3.80 (s, 3 H) , 3.05 (d, 2 H,
J=11.4 Hz), 2.76 (t, 2 H, J=6.9 Hz), 2.43 (dd, 2 H, J=7.8
Hz), 2.05 (dt, 2 H, J=2.4, 11.7 Hz), 1.90-1.20 (m, 10 H).
TERT-BUTYL 4-(1-NAPHTHYL)-1,2,3,6-TETRAHYDRO-1-
PYRIDINECARBOXYL-ATE: 1H NMR88.00-7.80 (m, 2 H), 7.76 (d,
1 H, J=8.1 Hz), 7.50-7.44 (m, 2 H), 7.42 (d, 1 H, J=8.1
Hz) , 7 .27 (d, 1 H, J=8. 1 Hz) , 5.76 (br, 1 H) , 4.14 (m, 2
H) , 4 or 3.29 (t, 2 H, J=5.7 Hz) , 2.52 (br m, 2 H) , 1.53
(s, 9H) .
4-(1-NAPHTHYL)PIPERIDINE: HCl salt; mp 330-332 °C; 1H NMRB
1.66-1.70 (m, 2H), 2.20-2.26 (m, 2H), 2.30-2.43 (m, 2H),
2.72-2.84 (m, 1H), 3.15-3.26 (m, 2H), 7.42-7.56 (m, 4H),
7.78 (d, J=8.1 Hz, 1H), 7.90 ( d, J=8.1 Hz, 1H), 8.04 (d,
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J=8 . 1 Hz, 1H) . Anal . CalCd. For C1~H18NOC1 + 0 . 20 CHZC1~ : C,
68.96; H, 7.00; N, 5.29. Found: C, 68.64; H, 7.04; N,
5.24.
TERT-BUTYL N-3-[4-(1-NAPHTHYL)PIPERIDINO]PROPYLCARBAMATE:
1H NMR 8 8 . 0 9 ( 1 H, J=8 Hz 7 . ( 1 J=1 7
d, . 4 ) 8 dd, H, . 8 .
, 6 , 5
Hz), 7.71 (dd, 1 H, J=2.4,6.9 Hz), 7.60-7.30(m, H),
4
6. 31 (br, 1 H) 5.75 (br, 1 4 .26 (t, 1 J=5 Hz)
, H) H, . 4 ,
,
3.40-3.00 (m, 6 H), 2.54 2 J=6.9 Hz) , 4 (dt, 2
(t, H, 2.2 H,
J= 3.0, 11.4 Hz), (m, 6 H), 1.45(s, 9 H).
2.00-1.60
4-(3-METHYL-2-PYRIDYL)-4-PTPERIDINOL: 1H NMR88.21 (dd, 1 H,
J=1.2, 4.5 Hz), 7.36 (dd, 1 H, J=6.6, 7.8 Hz), 7.02 (dd, 1
H, J=4.8, 7.5 Hz), 3.07 (dt, 2 H, J=2.7, 12.3 Hz), 2.89 (m,
2 H) , 2.46 (s, 3 H) , 2.22 (dt, 2 H, J=4 . 8, 12 .3 Hz) , 1.39
( dm, 2 H, J=12 . 3 Hz ) .
TERT-BUTYL 4-(3-METHYL-2-PYRIDYL)-1,2,3,6-TETRAHYDRO-
1-PYRIDINE-CARBOXYLATE: 1H NMRB 8.16 (dd, 1 H, J=1.2, 3.3
Hz) , 7.51 (clm, 1 H, J=7.5 Hz) , 7.15 (dd, 1 H, J=4.8, 7.5
Hz) , 5. 73 (br, 1 H) , 4.01 (m, 2 H) , 3.59 (t, 2 H, J=5.7
Hz) , 2.40 (m, 2 H) , 1.44 (s, 9 H) .
T E R T - B U T Y Z
N-3-[4-(3-METHYL-2-PYRIDYL)PIPERIDINO]PROPYLCARBAMATE: 1H
NMR 8 8.37 (dd, 1 H, J=4.2,. 4.8 Hz) , 7.51 (dd, 1 H, J=7.2,
7.5 Hz), 7.20 (dd, 1 H, J=4.5, 7.5 Hz), 6.73 (br, 1 H),
3.26 (m, 4 H) , 3.05 (d, 2 H, J=12.0 Hz) , 2. 80-2. 40 (m, 4
H) , 2. 61 (s, 3 H) , 1. 82 (p, 2 H, J=6.3 Hz) , 1.54 (d, 2 H,
J= 12.0 Hz) .
T E R T - B U T Y L
4-(3-METHOXYPHENYL)-1,2,3,6-TETRAHYDRO-1-PYRIDINECARB-
OXYLATE: 1H NMR S 7.23 (t, 1 H, J= 8.1 Hz) , 6.96 (d, 1 H,
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J=7 .5 Hz) , 6.89 1 J=1.8 Hz) , 6. 80 (dd, 1 J=2
(d, H, H, .4,
8.1 Hz), 6.02 (br, H), 4.'20-4.00 (m, 3 H), 3.80 3
1 (s, H),
3. 62 (t, 2 H, J=5.7Hz) 2.51 (br, 2 H) , 1.49 (s, H)
, 9 .
1-BENZYL-4-METHYL-PIPERIDIN-4-OL: Methyllithium (1.4 M in
Et.,O, 54.0' mL) was added to a solution of 1-benzyl-
4-piperidone (5.00 mL, 27.0 mmol) in anhydrous ether at
-78 °C under argon. Stirring was continued at -78 °C for
1.5 hours. Ether (200 mL) and water (40 mL) were added,
and the two phases were separated. The aqueous solution
was extracted with Et20 (3 x 50 mL). The combined organic
solutions were dried over magnesium sulfate and
concentrated. The residue was chromatographed (EtOAc to
EtOAc-MeOH 9/1), giving 4.81 g (870) of the desired product
as a colorless oil: 1H NMR 8 1 .21 (s, 3 H) , 1.56 (dt, J =
13, 3 Hz, 2 H) , 1 . 65 (td, ~J = 10, 4 Hz, 2 H) , 2.35 (td, J
- 10, 3 Hz, 2 H) , 2 . 53 (m, 2 H) , 7 .24 (m, 1 H) , 7 .29 (m, 4
H); 13C NMR 8 30.44, 39.37, 50.39, 63.80, 68.50, 127.56,
128.80, 129.80, 139.17.
1-BENZYL-4-METHYL-4-PHENYLPIPERIDINE: 1-Benzyl-4-methyl-
piperidin-4-of (4.81 g, 23.4 mmol) was added to a
suspension of A1C13 (15.62 g, 117 mmol) in benzene (100 mL)
at room temperature under argon. The mixture was stirred
at reflux for 24 hours, then cooled and poured cautiously
into ice water (100 g of ice, 50 mL of water). The aqueous
phase was adjusted to pH 11-12 by addition of 6 N aqueous
NaOH at 0 °C, and extracted with EtOAc (3 x 100 mL). The
combined organic solutions were dried over magnesium
sulfate and concentrated. The residue was chromatographed
(hexane- Et20 1911 to 9/1, followed by hexane-EtOAc 3/1),
giving the desired product (3.23 g, 520) as a brown oil:
1H NMR ~ 1.25 (s, 3 H) , 1.80 (m, 2 H) , 2.17 (m, 2 H) , 2. 44
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(m, 2 H), 2.55 (m, 2 H), 3.50 (s, 2 H), 7.25 (m, 1 H), 7.35
(m, 4 H); 13C NMR836.82, 37.65, 50.95, 54.93, 64.08, 126.19,
126.51, 127.59, 128.83, 128.95, 129.05, 129.89, 139.24.
4-METHYL-4-PHENYLPIPERIDINE: Freshly prepared methanolic
formic acid solution (4.4% by weight, 70 mL) was added to
1-benzyl-4-methyl-4-phenylpiperidine (3.23 g, 12.2 mmol).
To the resulting solution was added 10o palladium on carbon
(2.00 g). The mixture was stirred at room temperature for
24 hours. The solid was filtered out and washed with MeOH
(30 mL), H20 (15 mL), CHzCl? (30 mL) and MeOH {15 mL). The
combined filtrate and washings were concentrated, and the
residue was dissolved in CH2C1., (50 mL) and H20 (10 mL) . The
aqueous phase was adjusted to pH 11 by addition of 1 N
aqueous NaOH. The organic phase was separated, dried over
magnesium sulfate and concentrated. The residual oil was
purified by flash chromatography (CHC13/MeOH/2 N NH3 in MeOH
100/4/0 to 100/20/10), giving 1-benzyl-4- methyl-4-
phenylpiperidine {1.20 g) and 1.10 g (510, 82o based on
consumed starting material) of 4-methyl-4-phenylpiperidine:
1H NMR81.24 (s, 3 H), 1.71 (m, 2 H), 2.06 (m, 2 H), 2.82
(m, 3 H) , 2 . 94 {m, 2 H) , 7 . 19 (m, 1 H) , 7 .32 {m, 4 H) ; 1jC
NMR ~ 37.22, 38.54, 43.44, 47.74, 126.31, 127.43, 129.01,
149.73.
3-AMINOPROPYL-4-METHYL-4-PHENYLPIPERIDINE: A solution of
4-methyl-4-phenylpiperidine (1.00 g, 5.70 mmol), 3-bromo-
propylamine hydrobromide (1.87 g, 8.55 mmol) and potassium
carbonate {1.97 g, 14.2 mmol) in refluxing dioxane (20 mL)
was stirred for 36 hours. After removal of the solvent,
water {50 mL) was added and the pH adjusted to 11-12 by the
addition of 1 N aqueous NaOH. The mixture was extracted
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with CHZClz (150 mL + 3 x 100 mL) . The combined organic
solutions were dried over magnesium sulfate and
concentrated. The residue was purified by flash
chromatography (CHC13/MeOH/2 N NH3 in MeOH 100/20/10),
giving the desired product as a colorless oil (241 mg,
18%) : 1H NMR81.18 (s, 3 H) , 1.61 (p, J = 7 Hz, 2 H) , 1.75
(m, 2 H) , 2. 10 (m, 2 H) , 2 . 33 (t, J = 7 Hz, 2 H) , 2 . 40 (m,
2 H), 2.45 (m, 2 H), 2.72 (t, J = 6 Hz, 2 H), 3.02 (br s,
2 H) , 7 . 14 (m, 1 H) , 7 .3,0 ~ (m, 4 H) ; 13C NMR 8 30.28, 36. 78,
37.64, 41.51, 50.96, 57.51, 126.16, 126.40, 128.91, 149.20.
Preparation of
3-[4-(4-Fluorophenyl)piperidin-1-yl]propylamine
4-(4-FLUOROPHENYL)PIPERIDINE HYDROCHLORIDE: To a solution
of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine
hydrochloride (10 g) in methanol (200 mL) was added 10%
palladium on charcoal (0.5 g) and the mixture was
hydrogenated at 50 psi for 3 h. The catalyst was removed
by filtration and solvent was evaporated, leaving the
product (10.0 g) as a white powder, which was used in the
next step without purification. The product appeared to
be pure based on 1H NMR and TLC analysis. 1H NMR~
1.95-2.03 (br d, 2H), 2.14-2.29 (m, 2H), 2.70-2.80 (m,
1H), 2.91-3.07 (br q, 2H), 3.60-3.64 (br d, 2H),
6.96-7.03 (m, 2H), 7.19-7.22 (m, 2H), 9.60 (br s, 1H),
9.71 (br s, 1H).
4-(4-FLUOROPHENYL)PIPERIDINE: mp °C; 1H NMR81.51-1.66 (m,
2H), 1.80 (d, J=7.2 Hz, 2H), 2.53-2.64 (m, 1H), 2.67-2.77
(m, 2H), 3.17 (d, J=12.0 Hz, 2H), 6.94-7.03 (m, 2H),
7.13-7.21 (m, 2H) .
Anal. Calcd. For C11H19NF + C~H404: C, 58.70; H, 5.83; N,
4.18.
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Found: C, 58.72; H, 5.84; N, 3.98.
3-[4-(4-FLUOROPHENYL)PIPERIDIN-1-YL]PROPYLPHTHALIMIDE: A
mixture of 4-(4-fluorophenyl)piperidine hydrochloride
(5.08 g, 23.2 mmol), 3-bromopropylphthalimide (6.22 g,
23.2 mmol), and potassium carbonate (15 g) in DMF (100
mL) was stirred at 95-100 °C for 12 h. About 800 of the
solvent was evaporated under reduced pressure. The
residue was diluted with ethyl acetate (200 mL) and
washed with brine (3 X 100 mL) and dried (NazS09) . The
solvent was evaporated from the ethyl acetate solution
and the residue was purified by column chromatography
(1/1 hexane-ethyl acetate to 100% ethyl acetate), giving
crude product (7.50 g, 880). This crude product was
crystallized from isopropanol, giving a white crystalline
solid (4.50 g, 1st crop). This material was used in the
next step. Concentration of the mother liquor and cooling
gave the second crop of desired product (1.0 g). 1H NMRB
1.43-1.52 (m, 2H), 1.67-1.75 (m, 2H), 1.80-1.96 (m, 4H),
2.33-2.46 (m, 3H), 2.94-2.99 (br d, 2H), 3.78 (t, J=7 Hz,
2H), 6.90-7.04 (m, 4H), 7.70-7.74 (m, 2H), 7.84-7.87 (m,
2H) .
3-[4-(4-FLUOROPHENYL)PIPERIDIN-1-YL]PROPYLAMINE:
Hydrazine (4 mL) was added to a solution of 3-[4-
(4-fluorophenyl)piperidin- 1-yl]propylphthalimide (4.50
g, 12.3 mmol) in methanol '(200 mL), and the mixture was
stirred at reflux for 8 h. The solution was cooled to
room temperature, and the resulting white solid which
formed was filtered and washed with methanol (20 mL).
The solvent was evaporated from the filtrate and residue
was dried under vacuum for 4 h. The crude product was
dissolved in 50 mL of chloroform, stirred for 1 h, and
filtered. The white solid was washed with additional
chloroform (20 mL), the solvent was evaporated from the
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combined filtrates to leave the crude product as an oil.
The oil was purified by column chromatography
(dichloromethane / methanol / 2 M ammonia in methanol,
1013/1), giving the desired product (2.70 g, 930). 1H NMR
cS 1 . 60-1 . 83 (m, 6H) , 1. 96-2. 07 (m, 4H) , 2 . 40-2 .55 (m,
3H), 2.70-2.85 (br t, 2H), 3.03-3.07 (br d, 2H),
6.93-7.00 (m, 2H), 7,14-7.20 (m, 2H).
4-(4-METHYL-4-(3,5-DIMETHYLPHENYL)PIPERIDINE:
hygroscopic; 1H NMR81.20 (s, 3H), 1.74-1.80 (m, 2H),
2.08-2.16 (m, 2H), 2.30 (s, 6H), 2.50-2.56 (m, 2H),
2.64-2.68 (m, 2H), 2.97-3.04 (m, 1H), 6.87 (s, 1H), 6.94
(s, 2H) .
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Piperidine Side Chain Interneediates
TERT-BUTYh 4-{[(TRIFhUOROMETHYh)SUhFONYh]OXY}-I,2,3,6-
TETRAHYDRO-1-PYRIDINECARBOXYLATE:
n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes)
was added to a solution of diisopropyl amine (96.2 mL,
44.2 mmol) in 40 mL of dry THF at 0 °C and stirred for 20
minutes . The reaction mixture was r_ooled to -7 8 °C and
tert-butyl 4-oxo-1-piperidinecarboxylate (Aldrich
Chemical Company, 40.0 mmol) in THF (40 mL) was added
dropwise to the reaction mixture and stirred for 30
minutes. Tf2NPh (42.0 mmol, 15.0 g) in THF (40 mL) was
added dropwise to the reaction mixture and stirred at °C
overnight.. The reaction mixture was concentrated in
vacuo, re-dissolved in hexanes:EtOAc (9:1), passed
through a plug of alumina and the alumina plug was
washed with hexanes:EtOAc (9:1). The combined extracts
were concentrated to yield 16.5 g of the desired product
that was contaminated with some starting Tf2NPh.
1H NMR (400 MHz, CDC13) 8 5.77 (s, 1 H) , 4 .05 (dm, 2 H,
J=3.0 Hz), 3.63 (t, 2 H,~J=5.7 Hz), 2.45 (m, 2 H), 1.47
(s, 9 H) .
TERT-BUTYh 4-[3-(AMINO)PHENYh]-1,2,3,6-TETRAHYDRO-1-
PYRIDINECARBOXYI~ATE:
A mixture of 2 M aqueous NazC03 solution (4 .2 mL) , tert-
butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-
tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol),
3-aminophenylboronic acid hemisulfate (0.393 g, 2.11
mmol), lithium chloride (0.191 g, 4.50 mmol) and
tetrakis-triphenylphosphine palladium (0) (0.080 g,
0.075 mmol) in dimethoxyethane (5 mL) was heated at
reflux temperature for 3 hours, under an inert
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atmosphere (an initial degassing of the mixture is
recommended to prevent the formation of
triphenylphosphine oxide). The organic layer of the
cooled reaction mixture was separated and the aqueous
layer was washed with ethyl acetate (3X). The combined
organic extracts were dried and concentrated in vacuo.
The crude product was chromatograghed (silica,
hexanes:EtOAc:dichloromethane (6:1:1) with 1o added
isopropylamine to protect the BOC group from hydrolysis)
to give 0.330 g of the desired product in 81% yield:
1H NMR (400 MHz, CDC13) ~ 7.12 (t, 1H, J= 7.60 Hz), 6.78
(d, 1H, J= 8.4 Hz), 6.69 (t, 1H, J= 2.0 Hz), 6.59 (dd,
1H, J= 2.2, 8.0 Hz), 6.01 (m, 1H), 4.10-4.01 (d, 2H, J=
2.40 Hz), 3.61 (t, 2H, J= 5.6 Hz), 2.52-2.46 (m, 2H),
1.49 (s, 9H); ESMS m/e . 275.2 (M + H)~.
Anal. Calc. for C16Hz4N20z: C, 70.04; H, 8.08; N, 10.21.
Found: C, 69.78; H, 7.80; N, 9.92
TERT-BUTYL 4-[3-(AMINO)PHENYh]-1-PTPERIDINECARBOXYI~ATE
A mixture of 3.10 g of tert-butyl 4-(3-aminophenyl)-
1,2,3,6-tetrahydropyridine-1-carboxylate (11.3 mmol) and
1.0 g of 10% Pd/C in 200 mL of ethanol was hydrogenated
at room temperature using the balloon method for 2 days.
The reaction mixture was filtered and washed with
ethanol. The combined ethanol' extracts were
concentrated in vacuo and the residue was
chromatographed on silica (dichloromethane: methanol
95:5 with to isopropylamine added to protect the BOC
group from hydrolysis) to give 2.63 g of the desired
product ( 8 4 0 ) .
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TERT-BUTYIa 4- (3-NITROPHENYI~) -3, 6-DIHYDRO-1 (2H) -
- PYRIDINECARBOXY7~ATE
~H NMR (400 MHz, CHC13) $ 8.23 (s, 1H) , 8.11 (d, 1H,
J=8.0 Hz), 7.69 (d, 1H, J=8.0 Hz), 7.51 (t, 1H, J=8.0
Hz), 6.20 (m, 1H), 4.17-4.08 (m, 2H), 3.67 (t, 2H, J=5.6
Hz), 2.61-2.52 (m, 2H), 1.50 (s, 9H); ESMS m/e . 249.1
(M + H - C~He)+.
1,2,3,6-TETRAHYDRO-4-(3-NITROPHENYI,)PYRIDINE: Into a
stirred solution of S.OO.g (16.0 mmol) of tert-butyl
I,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-
carboxylate in 100 ml of 1,4-dioxane at 0°C was bubbled
HCl gas for 10 minutes. The reaction mixture was
allowed to warm to room temperature and the bubbling of
the HC1 gas was continued for an additional 1 hour. The
solvent was removed in vacuo, the residue was dissolved
in 50 mL of water and was neutralized by the addition of
KOH pellets. The aqueous solution was extracted with 3
X 80 mL.of dichloromethane and the combined organic
extracts were dried (MgSOq), filtered and concentrated in
vacuo. The residue was purified by column
chromatography (silica, 9 . 1 ,dichloromethane .
methanol + 1% isopropyl amine) to afford 2.85 g (87.50
yield) of the desired product: 1H NMR (400 MHz, CDC13)
8.24 (s, 1H), 8.09 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=8.0
Hz~), 7.49 (t, 1H, J=8.0 Hz), 6.35-6.25 (m, 1H), 3.58
( apparent q, 2H, J=3 .'0 Hz j , 3 . 14 ( t, 2H, J=5 . 6 Hz ) ,
2.54-2.46 (m, 2H).
TERT-BUTYL 3- (4- (3-NITROPHENYI,) -3, 6-DIHYDRO-1 (2H) -
PYRIDINYZ)PROPYI,CARBAMATE: A mixture of 2.80 g (14.0
mmol) of 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine,
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3 . 60 g ( 15 . 0, mmol ) of tert-butyl N- ( 3-
bromopropyl)carbamate, 11.6 g (84.0 mmol) of K2C03, 14.6
mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00
mmol) of tetrabutylammonium iodide in 250 mL of 1,4-
dioxane was heated at reflux temperature for 14 hours.
The reaction mixture was filtered and the filtrate was
dried (MgS04), concentrated in vacuo and the residue was
purified by column chromatography (silica, 9:1,
dichloromethane: methanol + 1o isopropyl amine) to
afford 4.35 g (85.7% yield) of the desired product: 1H
NMR (400 MHz, CDC13) 8 8.24 (t, 1H, J=1.9 Hz), 8.09 (dd,
1H, J=1.9, 8.0 Hz), 7.70 (apparent d, 1H, J=8.0 Hz),
7.49 (t, 1H, J=8.0 Hz), 6.23 (m, 1H), 3.29-3.18 (m, 4H),
2.75 (t, 2H, J=5.6 Hz), 2.64-2.54 (m, 4H), 1.82-1.70 (m,
2H), 1.44 (s, 9H); ESMS m/e . 362.2 (M + H)+.
3- (4- (3-NITROPHENYI~) -3, 6-DIHYDRO-I (2H) -PYRIDINYI~) -1-
PROPANAMINE: Into a stirred solution of 4.35 (12.0 mmol)
of tert-butyl 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-
pyridinyl)propylcarbamate in 100 ml of 1,4-dioxane at
0°C was bubbled HC1 gas for 10 minutes. The reaction
mixture was allowed to warm to room temperature and the
bubbling was continued for an additional 1 hour. The
solvent was removed in vacuo, the residue was dissolved
in 50 mL of water and was neutralized by the addition of
KOH pellets. The aqueous solution was extracted with 3
X 80 mL of dichloromethane, the combined organic
extracts were dried (MgSOq), filtered and concentrated in
vacuo. The residue was purified by column
chromatography (silica, 9 . 1 ,dichloromethane .
methanol + 1o isopropyl amine) to afford 3.05 g (97.0%
yield) of the desired product: 1H NMR (400 MHz, CDC13) 8
8.24 (t, 1H, J=1.8 Hz), 8.09 (dd, 1H, J=1.8, 8.2 Hz),
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7.69 (dd, 1H, J=1.8, 8.2 Hz), 7.48 (t, 1H, J=8.2 Hz),
6.24 (m, 1H), 3.21 (d, 2H, J=3.6 Hz), 2.84 (t, 2H, J=6.6
Hz), 2.75 (t, 2H, J=5.8 Hz), 2.64-2.54 (m, 4H), 1.76
(m,
2H); ESM S . 262.2 (M + H)+; Anal. Calc. for
m/e
C14H19 N302 (0.06CHC13) : C, 62.90; H, 7.16; N, 15.65.
Found: 63 0; H, 7 . 16; N, 15 . 65 .
C, ,
2
' METHYL (4S) -3- [ ( ~ 3- [4- (3-AMINOPHENYL) -1-
PIPERIDINYL]PROPYL}AMINO)CARBONYL]-4-(3,4-
DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-
TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: A mixture of 3.02 g
( 6. 33 mmol) 5-methyl 1- ( 4-nitrophenyl) ( 6S) -6- (3, 4-
difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-
1,5(2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of
3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-
propanamine, 7 . 94 g ( 75 . 5 mmol ) of K2C03 and 1 , 00 mL of
methanol in 200 mL dichloromethane (under argon) was
stirred at room temperature for 1 hour. The reaction
mixture was filtered and concentrated in vacuo. The
residue was dissolved in 100 mL of ethyl acetate and
washed 3 X 50 mL of 5o aqueous NaOH solution, the
organic layer was dried (MgS09) and concentrated in
vacuo. The residue was dissolved in 100 mL of anhydrous
ethanol containing 0.50 g 10o Pd/C and the reaction
mixture was stirred under a hydrogen balloon for 24
hours. The reaction mixture Was passed through a column
of Celite 545 filtering agent, washed with ethanol, the
filtrate was dried (MgSOq) and concentrated in vacuo.
The residue was purified by column chromatography
(silica, 9.5 . 0.5 ,dichloromethane . methanol + 10
isopropyl amine) to afford 1.65 g (52.0o yield) of the
desired product.
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TERT-BUTYL 4-[3-(ISOBUTYRYhAMINO)PHENYh]-3,6-DIHYDRO-
1(2H)-PYRIDINECARBOXYhATE: Into a solution of 4.00 g
(16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-
1 (2H) -pyridinecarboxylate and 5. 60 mL (~32. 0 mmol) of
diisopropylethylamine in 100 mL dichloromethane was
slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride.
The reaction mixture was stirred at room temperature for
2 hours, washed with water, dried (MgS04), and
concentrated in vacuo. The residue was purified by
column chromatography (silica, 50 . 46 . 3 . 1, hexanes
. dichloromethane . methanol . isopropyl amine) to
afford 2.90 g {52.0o yield) of the desired product: 1H
NMR (400 MHz, CDC13) 8 7.69 (s, 1 H), 7.34 {d, 1 H, J=7.8
Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz),
6.04 (s, 1H) , 4 .05 (s, . 2H) , 3. 62 (apparent t, 2. H, J=4 . 9
Hz), 2.51.(m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4 Hz);
ESMS m/e: 345.5 {M + H)+. Anal. Calc. for
C=oH28N~03+0.175 CHC13: C, 66.33; H, 7.77; N, 7.67. Found:
C, 66.20; H, 7.41; N, 7.88
TERT-BUTYh 4- [3- (ISOBUTYRY7~AMINO) PHENYh] -1-
PIPERIDINECARBOXY?~ATE: A mixture of 2.90 g {8.40 mmol)
of tert-butyl 4-[3-(isobutyrylamino)phenyl]-3,6-dihydro-
1(2H)-pyridinecarboxylate and 0.80 g of 10o yield Pd/C
in 100 mL of ethanol was stirred under a hydrogen
balloon for 24 hours. The reaction mixture was passed
through a column of Celite 545 filtering agent, the
filtrate was dried (MgS09) and concentrated in vacuo.
The residue was purified by column chromatography
(silica, 9.5 . 0.5 ,dichloromethane . methanol + 10
isopropyl amine) to afford 2.40 g (84.0o yield) of the
desired product: 1H NMR (400 MHz, CDC13) 8 7.49-7.44 (m,
2H) , 7.24 (t, 1H, J=7. 6 Hz) , 6. 93 (d, 1H, J=7. 6 Hz) ,
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4.20-4.10 (m, 2H), 2.86-2.45 (m, 4H), 1.86-1.75 (m, 4H),
1.48 (s, 9H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e . 345.2
(M + H) ~; Anal. Calc. for C~oH3oN203+0.3H20: C, 68.27; H,
8.77; N, 7.96. Found: C, 68.25; H, 8.54; N, 7.84.
2-METHYL-N- [3- (4-PIPERIDINYL) PHENYL],PROPANAMIDE: Into a
stirred solution of 2.20 (6.50 mmol) of tert-butyl 4-[3-
(isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100
ml of 1,4-dioxane at 0 °C was bubbled HCl gas for 10
minutes. The reaction mixture was allowed to warm to
room temperature and the bubbling of the HC1 gas was
continued for 1 hour. The solvent was removed in vacuo,
the residue was dissolved in 50 mL of water and was
neutralized by the addition of KOH pellets. The aqueous
solution was extracted with 3 X 80 mL of
dichloromethane, the combined organic extracts were
dried (MgS04), filtered and concentrated in vacuo. The
residue was purified by column chromatography (silica, 9
. 1 ,dichloromethane . methanol + 1o isopropyl amine) to
afford 0.700 g (46.0o yield) of the desired product: 1H
NMR (400 MHz, CDC13) 8 7.47 (s, 1H), 7.40 (d, 1H, J=7.8
Hz), 7.24 (t, 1H, J=7.8 Hz), 7.00 (d, 1H, J=7.8 Hz),
3.23-3.14 (m, 5H), 2.82-2.57 (m, 4H), 1.20 (d, 6H, J=6.8
Hz); ESMS m/e . 247.2 (M + H)~;
The hydrochloride salt was used for the combustion
analysis: Anal. Calc. for C15H22NZO+HCl+0.15 CHC13: C,
60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N,
8.88.
3-(4-PIPERIDINYI,)ANII,INE: 1H NMR (400 MHz, CDC13) 8 7.01
(t, 1H, J=7.6 Hz), 6.62-6.54 (m, 3H), 3.16 (br d, 2H,
J=10.3 Hz), 2.75 (dt, 2H, J=2.7, 12.3 Hz), 2.56 (tt, 1H,
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J=3.6, 12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq,
2H, J=4.0, 12.3 Hz); ESMS m/e . 177.2 (M + H)~.
TERT-BUTYL 4- (4-NITROPHENYh) -3, 6-DIHYDRO-1 (2H) -
PYRIDINECARBOXY7~ATE: To a 25-mL RB flask, equipped with
a condensor, was added tert-butyl 4-
{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-
pyridinecarboxylate (1.0 g), 4-nitrophenylboronic acid
(0.71 g), sodium carbonate (0.430 mL of 2M solution),
lithium chloride (0.382 g),
tetrakis(triphenylphosphine)- palladium (0) (0.173 g)
and ethylene glycol dimethyl ether (10 mL). The
reaction mixture was flushed with Argon three times,
then the reaction mixture was heated to 100 °C for 3 hrs.
After cooling to room~temperature, the reaction mixture
was diluted with methylene chloride (30 mL) and water
(30 mL) and the organic layer was separated. The
aqueous layer was extracted with methylene chloride
(3x20 mL) and the combined organic extracts were washed
with sat NH9C1 (20 mL) and brine (20 mL), dried over
MgS04 and concentrated under reduced pressure. The
residue was purified by chromatography (6:1=hexane: ethyl
acetate with to NH3) to afford the product (0.55 g,
59.90 as a yellow oil. The compound is not stable at
room temperature and should be used as prompt as
practical: 1H NMR (400 MHz, CpCl3) ~ 8.20 (d, 2H, J=8.6
Hz), 7.51 (d, 2H, J=8.6 Hz), 6.24 (m, 1H), 4.13 (m, 2H),
3.67 (apparent t, 2H, J=5.5 Hz), 2.55 (m, 2H), 2.49 (s,
9H)
4-(4-NITROPHENYI~)-1,2,3,6-TETRAHYDROPYRIDINE:
4-(4-Nitrophenyl)-1,2,3,6-tetrahydropyridine was
prepared by a similar procedure to that used for the
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preparation of 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide using HCl gas and tert-
Butyl 4- ( 4-Nitrophenyl) -3, 6-dihydro-1 (2H) -
pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room
temperature. The reaction mixture was concentrated in
vacuo to give the crude product (69.8 mg) that used in
the next reaction without further purification.
Dihydropyrimidine Intermediates
3-(3,4,5-TRIFIrUOROBENZYhIDENE)-2,4-PENTANEDIONE: A
stirring mixture of 3,4,5-trifluorobenzaldehyde (4.20 g,
26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol),
piperidine (0.430 g, 5.00 mmol) in benzene (150 mL) was
heated at reflux temperature in a Dean-Stark apparatus
for 8 h. The benzene was evaporated and the yellow oily
residue was used in the next step without further
purification.
1-[2-METHOXY-4-METHYh-6-(3,4,5-TRIFhUOROPHENYh)-1,6-
DIHYDRO-5-PYRIMIDINYh]ETHANONE: A mixture 3-{3,4,5-
trifluorobenzylidene)-2,4-pentanedione (26.2 mmol), 0-
methylisourea hydrogen sulfate {3.22 g, 39.3 mmol), and
NaHC03 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred
and heated at 95-100 °C far 6 h. The mixture was
filtered and the solid filter cake was washed with
ethanol {100 mL). The solvent was evaporated from the
combined filtrates and the prude product was purified by
flash column chromatography (EtOAc/hexane, 1/9 to 1/4),
to afford the desired product as an oil (2.80 g, 360).
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4-NITROPHENYL 5-ACETYL-2-METHOXY-4-METHYL-6-(3,4,5-
TRIFLUOROPHENYL)-1(6H)-PYRIMIDINECARBOXYLATE:
4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was
added to a solution of 1-[2-methoxy-4-methyl-6-(3,4,5-
trifluorophenyl)-1,6-dihydro-5-pyrimidinyl]ethanone
( 2 . 8 0 g, 9 . 38 mmol ) and pyridine ( 10 mL) in CH2C1~ ( 200
mL) at 0-5 °C, and the resulting mixture was allowed to
warm to room temperature. After 12 h, the solvent was
evaporated and the residue was purified by flash
chromatography (dichloromethane/EtOAc, 1/9 to 3120), to
give the desired product as a white powder (4.00 g,
92 ~ ) .
4-NITROPHENYL 5-ACETYL-4-METHYL-2-OXO-6-(3,4,5-
TRIFLUOROPHENYL)-3,6-DIHYDRO-1(2H)-
PYRIMIDINECARBOXYLATE:
A solution of 6 N aqueous HC1 (4 mL) was added to a
well-stirred solution of 4-nitrophenyl 5-acetyl-2-
methoxy-4-methyl-6-(3,4,5-trifluorophenyl)-1(6H)-
pyrimidinecarboxylate (4.00 g, 8.63 mmol) in THF (100
mL) at 0-5 °C, and the mixture was allowed to warm to
room temperature. After 2 h, solvent was evaporated and
the product dried under vacuum. The product was
obtained as a pure single component and used in the next
step without further purification (3.88 g, 100%).
. 1H NMR (DMSO) 8 10.29 (s, 1H), 8.23 (d, 2H, J=9.1 Hz),
7.51 (d, 2H, J=9.1 Hz), 7.15-7.07 (m, 2H), 6.18 (s, 1H),
2.30 (s, 3H), 2.28 (s, 3H); ESMS m/e: 450.2 (M + H)+;
Anal. Calc. for CZOH14F3N30~: C, 53.46 H, 3.14 N, 9.35.
Found: C, 53.261 H, 3.21; N, 9.35.
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BENZYL 2-PROPIONYL-3-(3,4,5-TRIFLUOROPHENYL)-2-
- PROPENOATE. A solution of benzyl propionylacetate (36.3
g, 176 mmol), 3,4-difluorobenzaldehyde (25.0 g, 176
mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid
(0.49 mL, 9.0 mmol) were heated at reflux temperature
with removal of water using a Dean-Stark apparatus for
5h. The solvent was removed in vacuo and the residue was
,dissolved in EtOAc. The organic layer was washed with
water (100 mL) followed by brine (100 mL) and dried over
20 anhydrous Na~S09. The solvent was evaporated to afford a
pale yellow syrup (60.2 g), which was used in the next
step without further purification.
BENZYL 6-(3,4-DIFLUOROPHENYL)-4-ETHYL-2-METHOXY-1,6-
DIHYDRO-5-PYRIMIDINECARBOXYLATE. A suspension of benzyl
2-propionyl-3-(3,4,5-trifluorophenyl)-2-propenoate (16.0
g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65
g, 97.02 mmol), NaHC03 (16.3 g, 130.2 mmol) in DMF (190
mL) was stirred at 70 °C for 20h. After cooling to room
temperature, the reaction mixture was filtered and the
filtrate was diluted with EtOAc (300 mL) and then washed
with water (4X100 mL), brine (200 mL) and dried over
Na~~S09. After removal of solvent, the residue was
purified by column chromatography (Si02, EtOAc/Hexane,
100-300) to afford benzyl 6-(3,4-difluorophenyl)-4-
ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate as a
colorless oil (10.6 g, 58% yield). The product was
directly used in the next step after 1H NMR spectroscopy
which showed it to be a mixture of amine/imine
tautomers.
5-BENZYL 1-(4-NITROPHENYLj 6-(3,4-DIFLUOROPHENYL)-4-
ETHYL-2-METHOXY-1,5(6H)-PYRIMIDINEDICARBOXYLATE.
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Into a well-stirred solution of benzyl 6-(3,4-
difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-
pyrimidinecarboxylate (27.5 g, 68.75 mmol) and pyridine
(9.2 mL) in CH2C1~ (300 mL) was added 4-nitrophenyl
chloroformate (14.49 g, 82.5 mmol) at room temperature.
The reaction mixture was stirred for 4 h and then washed
with 10o aqueous KOH solution (2,X 150 mL). The organic
layer was separated and dried over Na2S04. The solvent
was removed in vacuo and the residue was used in the
next step without further purification: 1H NMR (CDC1~) cS
1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H),
5.14 (ABq, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d,
J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
BENZYL 6-(3,4-DIFLUOROPHENYI,)-4-ETHYL-2-METHOXY-1-
({[(2R)-1-PHENYLETHYLjAMINO}CARBONYL)-1,6-DIHYDRO-5-
PYRIMIDINECARBOXYLATE.
Into a stirred mixture of 5-benzyl 1-(4-nitrophenyl) 6-
(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,5(6H)-
pyrimidinedicarboxylate (12.6 g, 22.86 mmol) in THF (150
mL) was added a solution of R-(+)-a-methyl benzylamine
. (3.53 mL, 27.44 mmol) at room temperature. The stirring
was continued for 12 h and the solvent was removed in
vacuo. The yellow residue was dissolved in chloroform
(200 mL) and was washed with 10o KzC03 solution (2 x 30
mL). The organic layer was dried over Na~S04, filtered
and the solvent was removed in vacuo. The resulting
mixture of diastereomers was separated by column
chromatography over silica gel with 9:1 pet. ether: ether
to 4:1 pet. ether: ether. First major product to elute
was (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-
1-({[(1R)-Z-phenylethyl]amino)carbonyl)-1,6-dihydro-5-
pyrimidinecarboxylate: Colorless oil,. Rf= 0.31(4:1 pet
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ether:ether); wt.= 3.8 g (60o yield); [a]D = +267.05 (c
- 0.76, CHC13) ; 1H NMR (CDC13) 8 1.22 (t, J=7.5 Hz, 3H) ,
1.52 (d, J=6.9 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H), 3.99 (s,
3H), 4.99 (m, 1H), 5.09 (ABq, 2H), 6.66 (s, 1H), 6.99-
7.36 (m, 13H); The second major product to elute was (-
-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1-
({[(1R)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5-
pyrimidinecarboxylate: Colorless oil; Rf= 0.22 (4:1 pet
ether: ether); wt.= 3.2 g (51.20 yield); [a]D = -146.89
(c = 0.38, CHC13) ; 1H NMR (CDC13) cS 1.22 (t, J=7.2 Hz,
3H), 1.49 (d, J=6.6 Hz, 3H), 2.88 (q, J=6.0 Hz, 2H),
3. 94 (s, 3H) , 5.03 (m, 1H) , 5. 11 (ABq, 2H) , 6. 68 (s, 1H) ,
6.91-7.34 (m, 13H).
(+) -BENZYI~ 6- ( 3 , 4-DIFI~UOROPHENYI,) -4-ETHYL-2-METHOXY-1 , 6-
DIHYDRO-5-PYRIMIDINECARBOXYI~ATE. Into a stirred solution
of (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-
1-({[(1R)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5-
pyrimidinecarboxylate (17.1 mmol, 9.35 g) in CHzCl2 was
added 1,8-diazabicyclo[5,4,0]-undec-7-ene (17.1 mmol,
2.56 mL) and stirring was continued for 16 h at room
temperature. The solvent was evaporated and the residue
was purified by flash column chromatography on silica
gel with 3:1 EtOAc/Hexanes as the eluting system. 5.27 g
of the (+)-benzyl 6-(3,4-difluorophenyl)-4-ethyl-2-
methoxy-1,6-dihydro-5-pyrimidinecarboxylate was obtained
(77 o yield) .
(+) -5-BENZYI~ 1- (4-NITROPHENYI~) 6- (3, 4-DIFI~UOROPHENYI~) -4-
ETHYL-2-METHOXY-1,5(6H)-PYRIMIDINEDICARBOXYI~ATE. Into a
well-stirred solution of (+)-benzyl 6-(3,4-
difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-
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pyrimidinecarboxylate (6.4 g, 16.0 mmol) and pyridine
(1.5 mL) in CHaCl2 (150 mL) was added 4-nitrophenyl
chloroformate (3.41 g, 19.2 mmol) at room temperature.
The reaction mixture was stirred for 4 h and then it was
washed with 10% aqueous KOH solution (2 X 100 mL). The
organic layer was separated and dried over Na2S09. The
solvent was removed in vacuo. The residue of (+)-5-
benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-ethyl-
2-methoxy-1,5(6H)-pyrimidinedicarboxylate was used in
the next step without further purification.
a. 2-(4-METHOXYBENZYL)-2-THIOPSEUDOUREA HYDROCHLORIDE.
Into a well-stirred suspension of thiourea (7.6 g, 0.1
mol) in THF (50 mL) at 0 °C, 4-methoxybenzyl chloride (16
g, 0.1 mol) was added in 10 min and the reaction mixture
was allowed to warm to room temperature. After 2 hours
the reaction mixture was heated to 65 °C and kept at that
temperature for 5 hours. The reaction mixture was
cooled to room temperature and diluted with diethyl
ether (200 mL). The white precipitate that formed was
filtered and dried (22.5 g, 96o yield); m. p. 161-163 °C.
b. METHYL 2-((4-NITROPHENYL)METHYLENE)-3-OXOBUTYRATE.
A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol),
methyl acetoacetate (12.773 g, 0.11 mol), piperidine
(0.41.g, 4.80 mmol), and acetic acid (0.288 g, 4.8 mmol)
in 2-propanol (400 mL) was stirred at room temperature
for 48 hours. The resulting white solid, methyl 2-{(4-
nitrophenyl)methylene}-3-oxobutyrate was filtered,
washed with 2-propanol (2 X 50 mL) and dried (21.8 g,
- w 93o yield).
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c.
1, 6-DIHYDRO-5-METHOXYCARBONYL-2- [ { (4-METHOXYPHENYL) METHY
L}THIO]-4-METHYL-6-(4-NITROPHENYL)PYRIMIDINE.
A mixture of methyl 2-{(4-nitrophenyl)methylene}-3-
oxobutyrate (8.96 g, 0,04 mol), 2-(4-methoxybenzyl)-2-
thiopseudourea hydrochloride (9.28 g, 0.04 mol), and
NaOAc (3.28 g, 0.04 mol) in DMF (100 mL) was stirred and
heated at 70-75 °C for 4.5 hours. The reaction mixture
was cooled to room temperature, poured into ice-water
(300 mL) and extracted with EtOAc (2 X 400 mL). The
combined EtOAc extracts were washed with 10% NaHC03
solution (2 X 60 mL), brine (100 mL), and then dried
(MgS09). The solvent was evaporated and the crude
product was purified by flash column chromatography on
silica gel using 10o through 30o EtOAc in hexane as the
gradient eluent. The desired product was obtained as an
oil, which on trituratiom with EtOAc/hexane became a
yellow solid (11.4 g, 66.70 yield) which was shown by 1H
NMR to be a mixture of tautomers: m.p. 138-139 °C; 1H NMR
(CDC13) 8 2. 15 (s, 3 H) , 3. 62 (s, 3 H) , 3. 72 (s, 3 H) ,
4.05 and 5.78 (s and d, J=3 Hz, 1 H), 4.08, 4.20 (AB q,
J=12.5 Hz, 2 H), 4.21 and 6.40 (s and d, J=3 Hz, 1 H),
6.66 (2 d, J=8.5 Hz, 2 H), 7.08 (2 d, J=8.5 Hz, 2 H),
7 . 37 (2 d, J=8 . 8 Hz, 2 H) , 8.7 (2 d, J=8. 8 Hz, 2 H) ;
Anal. Calcd. for C21H~1N305S: C, 59,00; H, 4.95; N, 9.83.
Found: C, 59.02; H, 4.93; N, 9.77,
d. 1,6-DIHYDRO-5-METHOXYCARBONYL-2-[{(4-METHOXYPHENYL)
METHYL}THIO] -4-METHYL-6- (4-NITROPHENYL) -1- [ (4-NITROPHENY
LOXY)CARBONYL]PYRIMIDINE..
Into a well-stirred mixture of 1,6-dihydro-5-methoxy
carbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4
-nitrophenyl)pyrimidine (4.50 g, 10.5 mmol), NaHC03 (3.69
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g, 0.044 mol), CHZC12 (200 mL), and water (50 mL) at 0-5
. °C, 4-nitrophenyl chloroformate (2.40 g, 12.0 mmol) was
added over a 5 min period and the reaction mixture was
allowed to warm to room temperature. After 10 hours,
the TLC analysis of the reaction mixture showed the
presence of a small amount of starting pyrimidine,
therefore, more 4-nitrophenyl chloroformate (0.65 g,
0.0032 mol) was added and the stirring was continued for
an additional 4 hours. The two layers were separated,
the CH~C12 layer was washed with saturated aqueous NaHCO;
solution (3 X 50 mL), dried (MgS04), and the solvent
evaporated. The residue was recrystallized from CH~C1
and hexane to give the product as white crystals (5.50
g, 88.40 yield): m.p. 156-157 °C; 1H-NMR (CDC13) 8 2.53
(s, 3 H), 3.70 (s, 3 H), 3.8I (s, 3 H), 4.06, 4.36 (ABq,
J=13.5 Hz, 2 H), 6.30 (s, 1 H), 6.78 (d, J=8.6 Hz, 2 H),
7.17 (d, J=8.6 Hz, 2 H), 7.20 (d, J=8.8 Hz, 2 H), 7.32
(d, J=8. 8 Hz, 2 H) , 7 . 97 (d, J=8 . 8 Hz, 2 H) , 8 .25 (d,
J=8. 8 Hz, 2 H) ; Anal. Calcd. for C28H24NgO9S: C, 56. 75; H,
4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25.
a. 6-(BENZOFURAZAN-5-YI~)-~,6-DIHYDRO-2-OXO-5-
METHOXYCARBONYI~-4-BROMOMETHYh-1-((4-NITROPHENYL-
OXY) CARBONYI~J PYRIMIDINE .
Into a well-stirred solution of 6-(benzofurazan-5-yl)-
1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-
nitrophenyl-oxy)~carbonyl]pyrimidine (0.310 mmol, 0.140
g) in 1.5 mL of chloroform was added a solution of
bromine (0.310 mmol, 0.020 mL) in 1.5 mL of chloroform
at 0 °C and the solution was allowed to attain room
temperature over 1.5 h. The solvent was removed in
vacuo and the residue was again dissolved in CHC13 (10
mL) and washed with brine. The organic layer was
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separated, dried over Na2S04, filtered and the solvent
was removed in vacuo to obtain 0.15
g (88 o yield) of 6-
(benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-
4-bromomethyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine
as a yellow foam. The crude product was used in the
next step without purification. 1H NMR (CDC13) 8 3.79
(s, 3 H), 4.72 (ABq, 2 H), 6.47 (s, 1 H), 7.37 (d, J=9.1
Hz, 2 H), 7.51 (d, J=7.8 Hz, Z H), 7.80 (s, 1 H), 7.92
(d, J=9.1 Hz, 1 H), 8.30 (d, J=9.1 Hz, 2 H).
c. 4-NITROPHENYI~ 4- (2, 1, 3-BENZOXADIAZOL-5-YI~) -2, 5-DIOXO-
1,2,5,7-TETRAHYDROFURO(3,4-D]PYRIMIDINE-3(4H)-
CARBOXYI~ATE .
6-(3,4-Benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxy-
carbonyl-4-bromomethyl'-1-[(4-
nitrophenyloxy)carbonyl]pyrimidine (0.27 mmol, 0.15 g)
was heated in oil bath for 3 h (bath temperature 130 °C.
The brownish-yellow residue thus obtained was washed
with CHC13 and 4-nitrophenyl 4-(2,1,3-benzoxadiazol-5-
yl)-2,5-dioxo-1,2,5,7-tetrahydrofuro[3,4-d]pyrimidine-
3(4H)-carboxylate was obtained as an off-white solid
which was used in the next step without further
purification (crude wt. 0.11 g, 93o yield): 1H NMR (DMSO-
d6) 8 8.38-7.56 (m, 7H), 5.33 (s, 1H), 5.02 (s, 2H);
2~5 Anal. Calc. for C19H11N508+2.3H~0: C, 47.85; H, 3.28; N,
14.63. Found: C, 47.73; H, 2.51; N, 14.77.
5-METHYL 1- (4-NITROPHENYI~) 4- (BROMOMETHYI~) -6- (3, 4-
3 0 DIFI~UOROPHENYI~) -2-OXO-3 , 6-DIHYDRO-1, 5 (2H) -
PYRIMIDINEDICARBOXYI~ATE: Into a well-stirred solution of
6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-1-[(4-
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nitrophenyloxy)carbonyl]pyrimidine (1.5 mmol, 0.66 g) in
mL of chloroform was added a solution of bromine (1.5
mmol, 0.09 mL) in 3 mL of chloroform at 0 °C and the
solution was allowed to attain room temperature over 1.5
5 h. The solvent was removed in vacuo and the residue was
again dissolved in CHC13 (20 mL) and washed with brine.
The organic layer was separated, dried over Na~S04,
filtered and the solvent was removed in vacuo to afford
the desired product as a yellow foam, which was used in
. the next step without purification. 1H NMR 8 3.75 (s, 3
H), 4.67 (ABq, 2 H), 6.35 (s, 1 H), 7.09-7.19 (m, 4 H),
7 .37 (d, J=9.0 Hz, 2 H) , 8 .27 (d, J=9. 0 Hz, 2 H) .
4-NITROPHENYh 4-(3,4-DIFI~UOROPHENYI~)-2,5-DIOXO-1,2,5,7-
TETRAHYDROFURO[3,4-D]PYRIMIDINE-3(4X)-CARBOXYI~ATE.
5-methyl 1-(4-nitrophenyl) 4-(bromomethyl)-6-(3,4-
difluorophenyl)-2-oxo-3,6-dihydro-1,5(2X)-
pyrimidinedicarboxylate (1.5 mmol, 0.81 g) was heated in
an oil bath for 3 h (bath temperature 130 °C). The brown
residue thus obtained was washed with CHC13 and the
desired product was obtained as a pale brown solid which
was used in the next step without~further purification
(crude wt. 0.51 g): 1H NMR (DMSO-d6) 8 4.94 (br s, 2 H),
6.08 (s, 1 H), 7.20-7.43 (m, 4 H), 8.35 (d, J=10.2 Hz, 2
H) .
4-NITROPHENYI~ 4-(1,3-BENZODIOXOh-5-YL)-2,5-
DIOXOHEXAHYDROFURO[3,4-D]PYRIMIDINE-3(4H)-CARBOXYLATE: 1H
NMR (DMSO) 8 11.35 (s, 1H), 8.16 (d, 2H, J=9.5 Hz), 7.32
3.0_ -(d,__2H, J=8 . 9__Hz) ,__ 6. 81-6. 65 (m, 3H) , 5. 88 (s,. 1H_)-.-4-.-8-
5_
(ABq, 2H); ESMS mle . 440.1 (M + H)+; Anal. Calc. for
CZ°H15N309+1.5H20: C, 51.29; H, 3.87; N, 8.97. Found: C,
51.38; H, 2.85; N, 8.73.
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5-METHYL 1- (4-NITROPHENYI~) (6S) -6- (3, 4-DIFI,UOROPHENYI~) -
4-METHYL-2-OXO-3,6-DIHYDRO-1,5(2H)-
PYRIMIDINEDICARBOXYI~ATE: 1H NMR (400 MHz, CDC13) ~ 8.29
(d, 2H, J=9.1 Hz), 7.36 (d, 2H, J=8.9 Hz), 7.25-7.11 (m,
3H), 6.37 (s, 1H), 3.75 (s, 3H), 2.46 (s, 3H); ESMS m/e:
448.1 (M + H)+; Anal. Calc. for CzoHz5F~N30~: C, 53.70; H,
3.38; N, 9.39. Found: C, 53.35; H, 3.36; N, 9.27.
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BENZYL
4-{[(TERT-BUTOXYCARBONYL)AMINO]METHYL}CYCLOHEXYLCARBAMATE
. Oxalyl chloride (1.1 equivalents) was added dropwise to
a mixture of 4-[[(tart-butoxycarbonyl)-amino]methyl]-
cyclohexanecarboxylic acid (1 equivalent, Maybridge) in
toluene. The reaction mixture was stirred at room
temperature for 2-6 h. The solvent was removed in vacuo,
the residue was dissolved in acetone and the resulting
mixture was added dropwise to an aqueous solution of
sodium azide (1.2 equivalents) at a rate such as to
maintain a temperature of 10-15 °C. After the completion
of the reaction, the reaction mixture was extracted with
ethyl acetate, the combined extracts were dried and
concentrated in vacuo. The residue was dissolved in
acetone and added slowly to warm (60 °C) benzene. After
the completion of the reaction, benzyl alcohol was added
to the reaction mixture, stirred for 2 days and the
desired product was isolated (For Typical References,
See: G. Schroeter Ber. 1909, 42, 3356; and Allen, C.F.H.;
Bell, A. Org. Syn. Coll. Vol. 3 (1955) 846.).
A solution of benzyl 4-{[(tent-butoxycarbonyl)amino]
methyl}-cyclohexyl carbamate in MeOH containing 10o Pd/C
was hydrogenated at 50 psi overnight. The reaction
mixture was filtered through Celite 545 and the Celite
545 was washed with methanol. The combined methanol
extracts were concentrated. in vacuo, giving trans-
tert-butyl 4-aminocyclohexylmethylcarbamate (95 0).
9H-9-FLUORENYLMETHYL N-[4-(AMINOMETHYL)CYCLOHEXYL]
CARBAMATE: . 1H NMR88.02 (br, 1 H), 7.33 (m, 5 H), 5.07
(s, 2 H), 3.71 (s, 1 H), 3.40 (br m, 1 H), 2.80 (br m, 2
H), 1.94 (ABq, 4 H), 1.68 (br, 1 H), 1.30-1.00 (m, 5 H).
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N1-[4-(AMINOMETHYL)CYCLOHEXYL]-1-NAPHTHAMIDE: HCl in
dioxane (10 mL, 4 N) was added to a solution of tert-
butyl[4-(1-naphthoyl-amino)cyclohexyl]methylcarbamate
(0.350 g) in dichloromethane (20 mL), stirred overnight,
concentrated in Vacuo, giving the desired product: 1H NMR
b 8 .24 (dd, 1 H, J=1.2, 8 .7 Hz) , 7 .85 (dt, 2 H, J=2 .7, 9.7
Hz), 7.60-7.30 (m, 4 H), 5.98 (m, 1 H), 4.02 (m, 1 H),
3.80-3.40 (m, 4 H), 2.53 (d, 2 H, J=6.0 Hz), 2.02 (ABq, 4
H), 1.41-1.90 (m, 4 H).
TERT-BUTYL N-(4-[(1-NAPHTHYLCARBONYL)AMINO]-
CYCLOHEXYLMETHYL)-CARBAMATE: A mixture of 1-naphthoic
acid (1.00 mmol, 0.172 g), DMAP (2.00 mmol, 0.250 g) and
ECD (0.383 g, 2.00 mmol) in dry dichloromethane (20 mL)
was stirred at room temperature for 0.5 h followed by the
addition of tent-butyl(4-amino)cyclohexyl)methyl-
carbamate amine (1.09 mmol, 0.250 g). The reaction
mixture was stirred at room temperature overnight and
purified by flash chromatography, giving the desired
product as a white solid (0.160 g): 1H NMR88.29 (dd, 1
H, J=1.8, 9.1 Hz), 7.89 (m, 2 H), 7.60-7.40 (m, 4 H),
5.85 (br d, 1 H, J=6.3 Hz), 4.65 (m, 1 H), 4.04 (m, 1 H),
3. 02 (t, 1 H, J=6.3 Hz) , 2. 05 (ABq, 4 H) , 1. 62 (m, 2 H) ,
1.46 (s, 9 H), 1.40-1.10 (m, 4 H).
4-ACETYL-1-(3-AMINOPROPYL)-4-PHENYLPIPERIDINE: A solution
of 4-Acetyl-4-phenylpiperidine (7, 1.53 g, 7.50 mmol),
3-bromo-propylamine hydrobromide (1.64 g, 7.50 mmol) and
potassium carbonate (1.24 g, 9.00 mmol) was stirred in
refluxing 1,4-dioxane (50 mL) for 12 h. After removal of
dioxane, water (50 mL) was added and the pH was adjusted
to 11-12 by addition of 1 N aqueous NaOH. The mixture
was extracted with CHzCl,, (100 mL + 3 x 50 mL). The
combined organic solutions were dried over magnesium
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sulfate and concentrated. The residue was purified by
flash chromatography (EtOAc-MeOH-Et3N 100/40/20), giving
the desired product as a colorless oil (780 mg, 400): 1H
NMRB 1.56 (p, J = 7 Hz, 2 H) , 1.84 (s, 3 H) , 1. 98 (m, 2
H), 2.15 (br t, J = 12 Hz, 2 H), 2.29 (t, J = 7 Hz, 2 H),
2.41 (br d, J = 12 Hz, 2 H), 2.66 (t, J = 7 Hz, 4 H),
7.18 - 7.30 (m, 5 H) ; 13C NNlR~ 26.28, 31.11, 33.43,
41.47, 51.62, 55.31, 57.19, 77.32, 77.74, 78.17, 126.95,
127.69, 129.44, 142.25, 210.15.
For the preparation of benzo-4',5'[H]furanpiperidine
refer to W.E.Parham et al, J. O.rg. Ch em. (1976) 41, 2268.
TERT-BUTOXY{[3-(BEN20-4',5'[H]FURANPIPERIDIN-1-YL)PROPYL]
AMINO}METHANOL: To a stirred solution of the N-[4-(benzo-
4',5'[H]furanpiperidine (0.566 g, 3.27 mmol) in dioxane
(20 mL), N-(tart-butoxycarbonyl)-3-bromopropylamine
(0.772 g, 3.27 mmol) and potassium carbonate (0.904 g,
6.54 mmol) were added and the solution was refluxed for
24 h. The reaction mixture was cooled to room
temperature, concentrated and partitioned between
chloroform (40 mL) and water (5 mL). The organic layer
was dried over sodium sulfate, filtered and concentrated.
The crude product was purified by column chromatography
(ethyl acetate/ methanol; 4.5/0.5), giving the desired
product as a colorless oil (0.856 g, 79 0); '-H NMR (1.45
(s, 9 H), 1.63-2.04 (m, 6 H), 2.33-2.52 (m, 4 H), 2.87
(d, J=11.0 Hz, 2 H), 3.2 (br s, 2 H), 5.07 (s, 2 H), 5.6
(br s, 1 H), 7.13-7.28 (m, 4 H).
3-(4-METHYL-4-PHENYL-1-PIPERDINYL)PROPYLAMINE:
Trifluoroacetic acid (1 mL) was added to te.rt-butoxy{[3-
(4-methyl-4-phenyl-1-piperdinyl)propyl]-amino}methanol
(0.500 g, 1.51 mmol) in dichloromethane (5 mL) and the
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solution was stirred at room temperature for 1 h. The
solution was concentrated, neutralized with 10 o KOH
solution and extracted with dichloromethane (25 mL). The
organic layer was dried over sodium sulfate, filtered and
concentrated, giving 0.340 g (98%) of 3-(4-methyl-4
phenyl-1-piperdinyl)propylamine which was used without
further purification in the subsequent step.
Procedures for the Reaction of the Amine Side Chains with
the p-Nitrophenylcarbamate Intermediates:
General Procedure:
An equimolar solution of an amine side chain such as 3-
(4-methyl-4-phenyl-l-piperdinyl)propylamine and a
p-nitrophenylcarbamate intermediate such as
5-methoxycarbonyl-4-methoxymethyl- 1,2,3,6-
tetrahydro-2-oxo-6-(3,4-difluorophenyl)-1-[(4-nitrophen-
yloxy)carbonyl]pyrimidine and 1-2 equivalents of a base
such as diisopropylethylamine in dichloromethane were
stirred at room temperature overnight. The reaction
mixture was concentrated and purified by flash
chromatography, giving the desired product. In case of
2-methoxy intermediates, conversion to the oxo
derivatives was accomplished by treatment of the
2-methoxy product with HCl.in dioxane.
2-OXO-3-{SPIRO[1H-INDANE-1,4'-PIPERIDINE]PROPYLAMINE(0.03
19 g, 0.123 mmol) was added to (~)-6-(3,4
-difluorophenyl)-1,6-dihydro- 2-methoxy-5-
methoxycarbonyl-4-ethyl-1-(4-nitrophenoxy)carbonyl-
pyrimidine (0.052 g, 0.112 mmol) in dry dichloromethane
(10 mL) and the solution was stirred at room temperature
for 24 h. The reaction mixture was stirred for another 1
h after addition of 6 N HC1 (2 mL). After neutralization
with aqueous loo KOH solution, the reaction mixture was
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extracted into dichloromethane (3 x 10 mL). The organic
layer was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by flash
chromatography (EtOAc/ MeOH, 4.5/0.5), giving of the
desired product (0.040 g) as a syrup.
1 N HCl in ether (5 mL) was added to the free base (0.040
g, 0.072 mmol) in dichloromethane (4 mL) and the solution
was concentrated under reduced pressure. The crude
l0 product was recrystallized from ether, giving the desired
compound (0.042 g, 99 %) as a pale yellow solid; mp
178-182 °C; Anal. Calcd. for CZ9H34F~NQO,C1~ + 0.6 HzO: C,
57.87; H,5.73, N 9.31. Found: C, 58.11; H 5.90; N 8.95.
General Procedure for the reaction of the piperidines and
piperazines with 1-(3-bromo-propylcarbamoyl)-6-{3,4-
difluoro-phenyl)-4-methyl-2-oxo-1,6-dihydro-pyrimidine-
5-carboxylic acid methyl ester:
The amine {0.15 mmol) was added to a solution of
1-(3-bromo- propylcarbamoyl)-6-(3,4-difluorophenyl)-4-
methyl-2-oxo-1,6-di-hydropyrimidine-5-carboxylic acid
methyl ester (43.0 mg, 0.100 mmol) in anhydrous acetone
(10 mL), followed by NaHC03 (41 mg, 0.3 mmol) and KI (16
mg, 0.1 mmol). The resulting suspension was heated to
reflux for 10 h and then cooled to room temperature. The
solvent was removed in vacuo and the residue was purified
by flash column chromatography (EtOAc, followed by
EtOAc/MeOH, 9/1). The product was then dissolved in 2 mL
of chloroform, acetone or EtOAc and HC1 in EtcO (1 M, 0.5
mL) was added at room temperature. The solvent was
removed in vacuo, giving the desired compound as an HCl
salt.
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Example 1
(-)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,-ACETAMIDO)-PHENYL-
PTPERIDIN-1- YL]PROPYL}CARBOXAMIDO-4-METHOXYMETHYL-6-
(3,4- DIFLUORO-PHENYL)-2- OXOPYRIMIDINE-5-CARBOXYLIC ACID
METHYL ESTER: ESMS, 612.25 (M+1); 1H NMR81.76-1.87 (m,
6H), 2.03-2.13 (m, 2H), 2.18 (s, 3H), 2.49 (t, J=6.9 Hz,
3H), 3.10 (d, J=11.1 Hz, 2H), 3.30-3.42 (m, 2H), 3.45 (s,
3H) , 3.71 (s, 3H) , 4 . 68 (s, 2H) , 6. 68 (s, 1H) , 6.96 (d,
J=7.5 Hz, 1H), 7.04-7.11 (m, 2H), 7.16-7.26 (m, 2H), 7.34
(d, J=6.3 Hz, 1H), 7.45 (s, 1H), 7.94 (s, 1H), 8.98 (t,
J=5.4 Hz, 1H) .
Example 2
METHYL 3-[(3-4-[3-(ACETYLAMINO)PHENYL]-1,2,3,6-
TETRAHYDRO-1-PYR-IDINYLPROPYL)AMINO]CARBONYL-4-(3,4-
DIFLUOROPHENYL)-6-(METHOXY-METHYL)-2-OXO-1,2,3,4-
TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 1H NMRb8.90 (t, 1 H,
J=3.6 Hz), 7.75 (s, 1 H), 7.50-7.00 (m, 8 H), '6.68 (s, 1
H) , 6. 03 (br s, 1 H) , 4. 67 (s, 2 H) , 3.71 (s, 3 H) , 3. 47
(s, 3 H), 3.38 (ABm, 2 H), 3.16 (m, 2 H), 2.71 (t, 2 H, J
=5.4 Hz), 2.56 (m, 4 H), 2.35-1.90 (br, 2 H), 2.17 (s, 3
H), 1.82 (p, 2 H, J=7.2 Hz); ESMS, 612.25 (M+1).
Example 3
(1)-1,2,3,6-TETRAHYDRO-1-{N-[3-(4-0-ACETYL)-4-PHENYLPIPER
IDIN-1- YL]PROPYL}CARBOXAMIDO-5-METHOXYCARBONYL-
4-METHOXYMETHYL-6-(3,4- DIFLUOROPHENYL)-2-OXOPYRIMIDINE:
4-Acetyl-1-(3-aminopropyl)- 4-phenylpiperidine (190 mg,
0.687 mmol) was added to a stirring solution of 5-methoxy
carbonyl-4-methoxymethyl- 1,2,3,6-tetra-hydro-2-oxo-
6-(3,4-difluorophenyl)-1-[~(4-nitrophenyloxy)carbon-
yl]pyrimidine (281 mg, 0.573 mmol) in dry
dichloromethane (3 mL) and THF (4 mL). The reaction
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mixture was stirred at room temperature for 12 h. The
reaction mixture was quenched with aqueous 6 N HC1. The
. reaction mixture was concentrated to a small volume,
partitioned between dichloromethane and water (100 mL
each), the mixture was adjusted to pH 8 by addition of
Na~C03, the layers were separated, and the aqueous layer
was extracted with dichloromethane (3 x 30 mL). The
combined organic extracts were dried (NazS04) and the
product was chromatographed, giving the desired product.
The HC1 salt was prepared by the addition of 1 N HC1 in
ether to a solution of the product in CH~C12. The
precipitated salt was filtered, washed with ether and
dried in vacuo, giving (1)-1,2,3,6-tetrahydro-1-{N-
[3-(4-0-acetyl)-4- phenylpiperidin-1-yl]propyl}
carboxamido-5-methoxycarbonyl-4- methoxymethyl-6-
(3,4-difluorophenyl)-2-oxopyrimidine (170 mg, 47o) as the
hydrochloride salt: (C31H36N4F.,0., + HCl + 0. 6 CH~Clz) ; mp
82-84 °C.
Example 4
Benzyl ester precursor to the product of Example 4:
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(BENZO-4',5'(H)FURAN)PIPER
IDIN-1- YL]PROPYL}-CARBOXAMIDO-4-ETHYL-6-(3,4-
DIFLUOROPHENYL)-2-OXO- PYRIMIDINE-5- CARBOXYLIC ACID
PHENYLMETHYL ESTER: 1H NMR87.60-7.00 (m, 12 H), 6.85 (br,
1 H), 6.62 (s, 1 H), 5.10 (ABq, 2 H), 5.67 (s, 2 H), 4.03
(br, 1 H), 4.01 (s, 3 H), 3.40 (apparent q, 2 H, J=6.8
Hz), 3.20-1.60 (m, l2 H), 2.86 (q, 2 H, J=2.5 Hz), 1.19
(t, 3 H, J=7.5 Hz).
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(BEN20-4',5'(H)FURAN)PIPER
IDIN-1-YL]PROPYL}-CARBOXAMIDO-4-ETHYL-6-(3,4-
DIFLUOROPHENYL)-2-OXO- PYRIMIDINE-5 CARBOXYLIC ACID
HYDROCHLORIDE: 1H NMRB 8.95 (br s, 1 H) , 8.22 (br s, 1 H) ,
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7.40-6.95 (m, 7 H), 6.95 (s, 1 H), 6.63 (s, 1 H),
5.10-4.95 (m, 2 H), 3.40-3.20 (m, 4 H), 3.10-2.80 (m, 4
H), 2.55-2.20 (m, 1 H), 2.15 (m, 1 H), 1.85 (m, 2 H),
1.55-1.30 (m, 4 H), 1.20 (t, 3 H, J=7.6 Hz); Anal. Calc.
For C~9H3~N405F~ + HCl + 1.5 H"0: C, 56.36; H, 5.87; N,
8.06. Found: C, 56.72; H, 6.11; N, 7.61.
Example 5
1,2,3,4-TETRAHYDRO-1-OXO-2-NAPHTHACETIC ACID METHYL
ESTER: Under argon, oc-tetralone (5.00 g, 34.2 mmol) in
dry THF (300 mL) was treated with LDA in THF (2 M, 18.8
mL) at -78 °C. The solution was stirred at -78 °C for 1
h. Methyl bromoacetate (15.7 g, 0.103 mole) was then
added to the solution, the mixture was stirred overnight
and allowed to warm to room temperature. The solvent was
evaporated and the residue was dissolved into CHC1; (300
mL), washed with water and saturated brine, and then
dried over Na2S09. After filtration and removal of
solvent, the residue was vacuum distilled. The product,
a colorless oil (7.21 g, 96.50) was collected at 180 °C/1
mm Hg; 1H NMR (400 Mhz) 8 1. 98 (m, 1H) , 2.25 (m, 1H) , 2. 44
(m, 1H), 2.90-3.20 (m, 4H), 3.73 (s, 3H), 7.10-8.10 (m,
4H); EI mass spectrum M+ at m/z 218.
1-HYDROXY-2-(2-HYDROXYETHYL)-1,2,3,4-TETRAHYDRONAPHTHALEN
E: A solution of 1,2,3,4-tetrahydro-1-oxo-naphthacetic
acid methyl ester (6.15 g, 28.2 mmol) in THF (150 mL) was
treated with LiAlH9 (2.82 g, 70.5 mmol) and then the
reaction mixture was heated at reflux temperature for 5
h. The suspension was cooled to 0 °C and quenched by
addition of solid Na~SOQ~10 H~O.. The mixture was stirred
at room temperature for 4 hrs. The solid was removed by
filtration and concentration of the filtrate in vacuo
gave a yellow oil (5.33 g, 98.30); 1H NMR indicated the
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formation of an isomeric mixture. EI mass spectrum M+ at
m/z 192. The mixture was directly used in next reaction
without further purification.
S 2-(2-HYDROXYETHYL)-1,2,3,4-TETRAHYDRO-1-OXO-NAPHTHALENE:
A solution of isomeric mixture of 1-hydroxyl-2-
(2-hydroxyethyl)- 1,2,3,4-tetrahydronaphthalene (3.00 g,
15.6 mmol) in CH~C12 (100 mL) was treated with MnO~ (20.4
g, 0.234 mole). The suspension was stirred at room
temperature for 16 h and the solids were removed by
filtration. Concentration of the filtrate in vacuo gave
a brown oil, which was further purified by flash
chromatography (MeOH/ CHC13 , 5/95), giving a yellow oil
(2.00 g, 67.4%): 1H NMR81.76 (m, 1H), 1.98 (m, 1H), 2.21
(m, 2H), 2.57 (br, 1H), 2.70 (m, 2H), 3.20 (m, 2H), 3.81
(m, 2H), 7.00-8.20 (m, 4H); CI mass spectrum (M+1)+ at
m/z 191.
2-(2-BROMOETHYL)-1,2,3,4-TETRAHYDRO-1-OXONAPHTHALENE: A
solution of 2-(2-hydroxethyl)-1,2,3,4-tetrahydro-
1-oxo-naphthalene (2.00 g, 10.5 mmol) in CH2Clz (100 mL)
was treated with PBr3 (948 mg, 3.50 mmol) at 0 °C. The
mixture was stirred at room temperature for 72 h and then
poured onto 100 g of ice. The organic layer was
separated, washed with aqueous 10o K~C03 solution, H~O,
saturated NaCl and dried over Na~S09. After filtration
and removal of the solvent, the residue was purified by
chromatography (EtOAc/hexane, 1/10), giving a yellow oil
(1.18 g, 44.40); 1H NMRb1..49 (m, 2 H), 2.24 (m, 1H),
2.60 (m, 1H), 2.75 (m, 1H), 3.03 (m, 2H), 3.64 (m, 2H),
7.10-8.10 (m, 4H); EIMS M+ m/z 223, M/M+2=1:1.
2-[2-(4-BENZAMINO-1-PIPERIDYL)ETHYL]-1,2,3,4-TETRAHYDRO-1
-OXO- NAPHTHALENE: A mixture of 2-(2-bromoethyl)-
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1,2,3,4-tetrahydro-1-oxonaphthalene (1.18 g, 4.66 mmol),
4-benzamidopiperidine (952 mg, 4.66 mmol) and KzC03 (1.29
g, 9.32 mmol) in acetone (200 mLj was stirred at room
temperature for 48 h. The solids were removed by
filtration. Concentration.of filtrate in vacuo gave a
yellow solid which was purified by chromatography (MeOH:
CHC13, 5/95). The product was recrystallized from an
EtOAc/hexane mixture, giving a white powder (268 mg,
. 3 0 ) ; mp 158-159 °C; 1H NMR 8 1 . 53 (m, 2H) , 1 . 67 (m, 1H) ,
10 1.91 (m, 1H), 2.02 (m, 2H), 2.21 (m, 4H), 2.50 (m, 3H),
2 . 95 (m, 4H) , 4 . 01 (m, 1H) , 5. 95 (d, J=8 . 0 Hz, 1H) ,
7.20-8.10 (m, 9H); CI MS (M+1) +m/z 377; Anal. Calcd for
C~QHnaN~O~,: C, 76.55; H. 7.51; N, 7.44. Found: C, 76.28; H,
7.4~; N, 7.37.
Example 6
METHYL
4-(2,1,3-BENZOXADTAZOL-5-YL)-3-[(1-[4-(DIBUTYLAMINO)-
BENZYL]-4-PIPERIDYLMETHYL)AMTNO]CARBONYL-6-METHYL-2-OXO-1
,2,3,4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 1H NMR S 7.72
(dd, 1 H, J=0.6, 9.6 Hz), 7.70-7.50 (m, 2 H), 7.11 (d, 2
H, J=8.7 Hz), 6.59 (d, 2 H, J=8.7 Hz), 5.90 (s, 1 H),
3.94 (s, 3 H) , 3. 63 (s, 2h) , 3.24 (t, 4 H, J=7.8 Hz) ,
2.80 (m, 2 H), 2.49 (d, 2 H, J=6.3 Hz), 2.38 (s, 3 H),
2.90-1.00 (m, 5 H), 1.54 (p, 4 H, J= 7.8 Hz), 1.35
(sextet, 4 H, J=7.8 Hz), 0.94 (t, 6 H, J=7.8 Hz).
Example 7
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(N'-ETHYL)-N-BENZIMIDAZOLY
L- PIPERIDIN-1YL]PROPYL}CARBOXAMIDO-4-METHYL-6-(3,4-
DIFLUOROPHENYL)- 2-OXOPYRIMTDINE HYDROCHLORIDE: 1H NMRB
8.95 (t, 1 H, J=3.6 Hz), 7.61 (b, 1 H), 7.60-6.95 (m, 7
H), 6.69 (s, 1 H), 4.36 (m, l H), 3.94 (q, 2 H, J=7.2
Hz), 3.72 (s, 3 H), 3.42 (ABm, 4 H), 3.30 (m , 2 H, 4.76
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(m, 4 H) , 2 .43 (s, 3 H) , 2.13 (m, 2 H) , 1.77 (m, 4 H) ,
1.33 (t, 3 H, J=7.2 Hz) .
Example 8
6-(BEN20FURAZAN-5-YL)-1,2,3,6-TETRAHYDRO-5-METHOXYCARBONY
L-4- METHYL-2-OXO-1-{N-[3-(4-PHENYLPIPERIDIN-1-YL)PROPYL]
}CARBOXAMIDO-PYRIMIDINE: A solution of 6-(benzofurazan-
5-yl)-1,6-dihydro-2- methoxy-5-methoxycarbonyl-
4-methyl-1-{N-[3-(4-phenylpiperidin-1- yl)propyl]}
carboxamidopyrimidine in MeOH was treated with 6 N HC1 at
0 °C. The solution was stirred at room temperature for 2
h and the MeOH was removed in vacuo.
~-(Benzofurazan-5-yl)- 1,2,3,x-tetrahydro-
5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4-
phenylpiperidin-1-yl)propyl]}carboxamidopyrimidine
hydrochloride was obtained as a white powder: mp 134-137
°C .
Example 9
4-(3-METHOXY)-PHENYL PIPERIDINE: HC1 salt; mp 150-154 °C;
1H NMR82.04 (s, br, 2H), 2.25 (s, br, 2H), 2.80 (s, br,
1H), 3.09 (s, br, 2H), 3.66 (s, 2H), 3.78 (s, 3H), 6.79
(s, br, 3H), 7.23 (s, 1H),~9.41 (s, br, 1H). Anal.
Calcd. For C1~H18NOC1 + 0.30 CH~C1~ . C, 58.34; H, 7.40; N,
5.53. Found: C, 58.30; H, 7.71; N, 5.35.
(+)-1,2,3,6-TETRAHYDRO-1-N-[4-(3-METHOXY)-PHENYL}-PIPERID
IN-1- YL]-PROPYL-CARBOXAMIDO-4- METHOXYMETHYL-6- (3,4-
DIFLUOROPHENYL)- 2-OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL
ESTER: mp 80-84 °C; [oc]p = +94.7, (c = 0.25, MeOH); 1H NMR
81.74-1.84 (m, 6H), 1.99-2.09 (m, 2H), 2.38-2.51 (m, 3H),
3.03 (d, J=11.1 Hz, 2H), 3.24-3.43 (m, 2H), 3.48 (s,
3H), 3.71 (s, 3H), 3.80 (s, 3H), 4.72 (s, 2H), 6.68 (s,
1H), 6.72-6.84 (m, 3H), 7.05-7.11 (m, 2H), 7.15-7.27 (m,
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2H), 7.72 (s, 1H), 8.84 (t, J=5.4 Hz, 1H). Anal. Calcd.
For C3°H3~N406F~C1: C, 57.8; H, ~.0; N, 9Ø Found: C,
57.61; H, 6.57; N, 6.97.
Example 10
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,-ACETAMIDO)-PHENYL-PIPE
RIDIN-1-YL]PROPYL}CARBOXAMIDO-4-METHOXYMETHYL-6-(3,4-DIFL
UORO-PHENYL)-2- OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL
ESTER: mp 135-138 °C; [a,]D = +105.5, (c = 0.11, MeOH);
ZO ESMS, 614 .25 (M+1) ; '-H NMR cs 1 .76-1. 87 (m, 6H) , 2.03-2.13
(m, 2H), 2.18 (s, 3H), 2.49 (t, J=6.9 Hz, 3H), 3.10 (d,
J=11.1 Hz, 2H), 3.30-3.42 .(m, 2H), 3.46 (s, 3H), 3.71 (s,
3H), 4.68 (s, 2H), 6.68 (s, 1H), 6.96 (d, J=7.5 Hz, 1H),
7.04-7.11 (m, 2H), 7.16-7.26 (m, 2H), 7.34 (d, J=6.3 Hz,
1H), 7.45 (s, 1H), 7.94 (s, 1H), 8.97 (t, J=5.4 Hz, 1H);
ESMS, M+1 614.25
The compound of Example 10 may also be prepared via
hydrogenation of the compoun of example 2 (HZ balloon
method, methanol, Pd/C, overnight). A synthetic path
analogous to the latter route (Scheme 11) was used in the
preparation of the tritiated analog, which in turn, was
used as a radioligand in the MCH pharmacological assays.
Example 11
3-(4-PHENYLPIPERTDIN-1-YL)PROPIONITRILE: Acrylonitrile
(3.1 mL, 44 mmol, 2.5 eq) was added to a solution of
4-phenylpiperidine (3.00 g, 18.0 mmol) in EtOH (40 mL)
and the mixture was stirred at room temperature for 1.5
h. The volatiles were removed, giving 3.80 g of the
desired product (brown oil, 99a).
3-(4-PHENYLPIPERIDIN-1-YL)PROPYLAMINE: A solution of BH3
in THF (1.0 M, 83.0 mL, 83.0 mmol, 3.5 eq) was added to a
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stirring solution of 3-(4-phenylpiperidin-1-yl)-
propionitrile (5.10 g, 24.0 mmol) in anhydrous THF (20
mL) under argon at room temperature. The mixture was
heated at reflux temperature for 4.5 hours and then
cooled to room temperature. Aqueous 6 N HCl (130 mL) was
added and stirring was continued for 2 hours at 50-70 °C.
The mixture was basified to pH 9 by addition of aqueous 6
N NaOH and extracted with EtOAc (100 mL) and CHzCl~ (3 x
100 mL). The combined organic extracts were dried over
magnesium sulfate and concentrated. The residue was
dissolved in CHzCl2 (20 mL) and treated with HC1 in ether
(1.0 M, 50 mL). The solvents were removed, ether (250
mL) was added, the mixture was filtered, and the filter
cake was washed with ether. Water (60 mL) was added to
the resulting white solid, 1 N NaOH was added until pH
10-11 was reached, and then the aqueous phase was
extracted with CHzCl~ (3 X 50 mL). The combined extracts
were dried over magnesium sulfate and the solvents were
evaporated, giving the desired product (4.50 g, 870).
6-(3,4-DIFLOUROPHENYL)-1,2,3,6-TETRAHYDRO-5-METHOXYCARBON
YL-4- METHYL-2-OXO-1-{N-[3-(4-PHENYLPIPERIDIN-1-YL)
PROPYL]}CARBOXAMIDO-PYRIMIDINE: A solution of 6-(3,4-
difluorophenyl)-1,6-dihydro- 2-methoxy-5-methoxy
carbonyl-4-methyl-1-{N-[3-(4-phenyl-piperidin- 1-yl)
propyl]}carboxamidopyrimidine (100 mg, 0.185 mmol, mp =
43-45 °C) in MeOH (5 mL) was treated with aqueous 6 N HC1
(1.5 mL) at 0 °C. The solution was stirred at room
temperature for 2 hrs and MeOH was removed in vacuo.
6-(3,4-Diflourophenyl)- 1,2,3,6-tetrahydro-
5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4-
phenylpiperidin-1-yl)propyl]}carboxamidopyrimidine
hydrochloride was obtained as a white powder (89 mg,
860) . mp 133-136 °C.
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Example 12
3-{(3,4,5-TRIFLUOROPHENYL)METHYLENE}-2,4-PENTANEDIONE: A
stirring mixture of 3,4,5-trifluorobenzaldehyde (4.2 g,
26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol),
piperidine (0.430 g, 5 mmol) in benzene (150 ml) was
heated at reflux temperature (equipped with a Dean-Stark
trap) for 8 h. The benzene was evaporated, the yellow
oily residue, 2-{(3,4,5-trifluorophenyl)-methylene}-2,4-
pentanedione, was used in the next step without further
purification.
~-(3,4,5-TRIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-ACETYL-
4- METHYLPYRIMIDINE: A stirring mixture of 2-{(3,4,5-
trifluoro-phenyl)methylene}-2,4-pentanedione (26.2 mmol),
O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and
NaHC03 (6.60 g, 78.6 mmol) in EtOH (400 ml) was heated at
95-100 °C for 6 h. The mixture was filtered, the solid
residue was washed with ethanol (100 ml). The solvent
was evaporated from the combined filtrates and the crude
product was purified by flash column chromatography
(EtOAc/hexane, 9/1 to 4/1), giving the desired product as
an oil (2.80 g, 360).
6-(3,4,5-TRIFLUOROPHENYL)-1,6-DIHYDRO-2-METHOXY-5-ACETYL-
4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE:
4-Nitrophenyl chloroformate (1.886 g, 9.38 mmol) was
added to a solution of 6-(3,4,5-trifluorophenyl)-
1,6-dihydro-2-methoxy-5-acetyl-4- methylpyrimidine (2.80
g, 9.38 mmol) and pyridine (10 ml) in CHzClz (200 ml) at
0-5 °C and then the mixture was allowed to warm to room
temperature. After 12 h, the solvent was evaporated and
the residue was purified by flash chromatography
(CH~C1~/EtOAc, 9/1 to 20/3) , giving the desired product as
a white powder (4.0 g, 920).
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6-(3,4,5-TRIFLUOROPHENYL)-1,2,3,6-TETRAHYDRO-2-OXO-5-ACET
YL-4- METHYL-1-[(4-NITROPHENYLOXY)CARBONYL]PYRIMIDINE:
Aqueous 6 N aqueous HCl (4 mL) was added to a stirring
solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro-
2-methoxy-5-acetyl-4- methyl-1-[(4-nitrophenyloxy)
carbonyl]pyrimidine (4.0 g, 8.63 mmol) in THF (100 mL) at
0-5 °C, and the mixture was allowed to warm to room
temperature. After 2 h, the solvent was evaporated and
the product was dried under vacuum, giving the desired
product as a pure single component which was used in the
next step without further purification (3.88 g, 1000).
(+)- 1,2,3,6- TETRA HYDRO-1-{N-[4- (4-FLUOROPHENYL)-
PIPERIDINE- 1-YL]- PROPYL} CARBOXAMIDO- 5- ACETYL- 2-
OXO-6-( 3,4 ,5-TRI FLUORO PHENYL)- 4- METHYL PYRIMIDINE
HYDROCHLORIDE: 1H NMRB 7.20-6.86 (m, 6 H), 6.64 (s, 1
H), 5.56 (s, Z H), 3.70-3.80 (m, 2 H), 3.43-3.35 (m, 2
H), 3.19-2.98 (m, 2 H), 2.40 (s, 3 H), 2.28 (s, 3 H),
2.50-1.60 (m, 8 H).
Example 13
N1-[4-([4-(DIBUTYLAMINO)BENZYL]AMINOMETHYL)CYCLOHEXYL]-1-
NAPHTH-AMIDE: 1H NMRB 8.26 ,(dd, 1 H, J=2.1, 7.2 Hz) , 7.87
(m, 2 H), 7.51 (m, 2 H), 7.40 (apparent t, 1 H, J=7.8
Hz), 7.17 (d, 1 H, J=8.7 Hz), 6.61 (d, 2 H, J=8.7 Hz),
5.94 (d, 1 H, J=8,1 Hz), 4.04 (m, 1 H), 3.76 (m, 1 H),
3.63 (m, 2 H), 3.21 (t, 4 H, J=7.6 Hz average), 2.53 (d,
2 H, J=6.7 Hz), 2.10, ABm, 4 H), 1.55 (p, 4 H, J=7.7 Hz
average), 1.34 (sept, 4 H, J=7.6 Hz average), 1.17 (m, 4
H), 0.95 (t, 6 H, J=7.6 Hz average).
Example 14
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(1-NAPHTHYL)-PIPERIDIN-1-Y
L]PROP -YL}CARBOXAMIDO-4- METHOXYMETHYL-6-(3,4-
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DIFLUOROPHENYL)-2-OXO-PYRIMIDINE-5-CARBOXYLIC ACID METHYL
ESTER: mp 168-172 °C; [a]" _ +94.7, (c = 0.25, MeOH); 1H
NMRb1.75-1.84 (m, 2H), 1.87-2.01 (m, 4H), 2.14-2.28 (m,
2H), 2.47 (t, J=7.2 Hz, 2H), 3.10 (d, J=11.1 Hz, 2H),
3.28-3.45 (m, 3H), 3.48 (s, 3H), 3.71 (s, 3H), 4.68 (s,
2H), 6.70 (s, 1H), 7.05-7.12 (m, 2H), 7.16-7.24 (m, 1H),
7.42-7.54 (m, 4H), 7.69-7.75 (m, 2H), 7.85 (d, J=11.4 Hz,
1H), 8.09 (d, J=11.1 Hz, 1H), 8.91 (t, J=5.4 Hz, 1H).
Example 15
4-(5-FLUORO-2-METHOXY)PHENYL PIPERIDINE: mp 254-258 °C; 1H
NMR81.53-1.68 (m, 2H), 1.79 (d, J=11.7 Hz, 2H), 2.12 (dt,
J=2.1 Hz, J=11.7 Hz, 1H), 2.77 (dt, J=1.8 Hz, J=12.3 Hz,
1H), 2.90-3.05 (m, 1H), 3.10-3.22 (m, 2H), 3.68 (s, 1H),
3.79 (s, 3H), 6.72-6.93 (m, 3H). Anal. Calcd. For
C1~H1~NOFC1 + 0.14 CH~Cl~: C, 56.60; H, 6.76; N, 5.44.
Found: C, 56.60; H, 6.92; N, 5.28.
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(5-FLUORO-2-METHOXY)PHENYL
PIPERI-DIN-1-YL]PROPYL}CARBOXAMIDO-4- METHOXYMETHYL-6-
(3,4-DIFLUORO-PHENYL)-2-OXOPYRIMIDINE-5-CARBOXYLIC ACID
METHYL ESTER: 1H NMR88.93 (t, 1 H, J=5.4 Hz), 7.76 (br, 1
H), 7.30-6.69 (m, 7 H), 4.69 (s, 2 H), 3.79 (s, 3 H),
3.71 (s, 3 H), 3.48 (s, 3 H), 3.38 (m, 2 H), 3.10-2.80
(m, 3 H), 2.42 (t, 2 H, J=7.2 Hz), 2.07 (dt, 2 H, J=3.0,
8.4 Hz), 2.00-1.60 (m, 6 H).
Example 16
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-HYDROXY-4-(2-PYRIDYL)-PIPE
RIDIN-1-YL]PROPYL}CARBOXAMIDO-4- METHOXYMETHYL-6-
(3,4-DIFLUOROPHENYL)-2- OXOPYRIMIDINE-5-CARBOXYLIC ACID
METHYL ESTER: mp 132-135 °C; [a]D = +94.7, (C = 0.25,
MeOH); '-H NMR 81.47 (d, J=11.7 Hz, 2H), 1.74-1.85 (m, 2H),
2.43-2.63 (m, 9H), 2.87 (d, J=10.2 Hz, 2H), 3.30-3.47 (m,
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2H), 3.49 (s, 3H), 3.71 (s, 3H), 4.69 (s, 2H), 6.69 (s,
1H), 7.04-7.21 (m, 4H), 7.49 (dd, J=0.6 Hz, J=6.9 Hz,
1H), 7.72 (s, br, 1H), 8.36 (dd, J=1.2, 4.8 Hz, 1H), 8.89
(t, J=5.4 Hz, 1H).
Example 17
1-(3-AMINOPROPYL)-4-[2-PYRIDYL]PYRIDINIUM BROMIDE
HYDROBROMIDE: A solution.of 2,4'-dipyridyl (25.0 g, x_60
mmol) and 3-bromopropyl-amine hydrobromide (35.0 g, 160
mmol) in DMF (60 mL) was heated at 90-95 °C for 10 h.
After cooling to room temperature, anhydrous ether (500
mL) was added to the mixture, the resulting white solid
was filtered, washed with Et20 and dried, giving
1-(3-aminopropyl)-4-[2-pyridyl]pyridinium bromide
hydrobromide ( 60 g, 100 0 ) ) . 1H NMR ( DMSO-d6) ~ 2 . 35-2 . 44
(m, 2 H), 3.08-3.13 (m, 2 H), 4.76-4.81 (m, 2 H), 7.58
(dd, J=4.8 Hz, J=7.5 Hz, 1 H), 8.03 (dt, J=1.8 Hz, J=7.8
Hz, 1 H), 8.32 (d, J=7.8 Hz, 1 H), 8.77-8.81 (m, 3 H),
9.12 (d, J=6.3 Hz, 2 H) . Anal. Calcd. for C13H16N3Br + HBr
+ 0.5 H~O: C, 40.65; H, 4.72; N, 10.94. Found: C, 40.83;
H, 4.37; N, 11.05.
3-(3',6'-DIHYDRO-2'-H-[2,4']BIPYRIDINYL-1'-YL)-PROPYLAMIN
E: NaBH4 (2 g, 53 mmol) in small portions was added to a
solution of 1-(3-aminopropyl)-4-[2-pyridyl]pyridinium
bromide hydrobromide (6 g, 16 mmol) in MeOH (150 mL) at
0-5 °C over a period of 2 h. The reaction mixture was
stirred overnight at room temperature and then the
solvent was evaporated. The residue was suspended in
ether (200 mL) and treated~with aqueous 50% NaOH solution
(100 mL). The ether layer was separated and the aqueous
layer was extracted with additional ether (2 X 50 mL).
The combined ether extracts were dried over potassium
carbonate and the solvent was removed, giving
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3-(3',6'-dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-
propylamine (3.48 g) as an oil. The crude product was
used in the next step immediately without further
purification.
3-AMINOPROPYL-4-(2-PYRIDYL)PIPERIDINE: A suspension of
3-(3',6'-dihydro-2'-H-[2,4~']bipyridinyl-1'-yl)-propylamin
a (3.48 g crude, 15.9 mmol) and Pearlman's catalyst (1.0
g) in MeOH (40 mL) was hydrogenated under 120 psi for 10
h, after which the reaction mixture was filtered through
a pad of Celite and the solvent was removed. The residue
was purified by column chromatography over silica gel (30
g) [Note: If a large excess of silica gel is used the
recovery of the product will be very low]
(CH=C12/methanol/2M NH3 in MeOH, 90/8/4 to 90/40/40). The
product was obtained as a pale yellow oil (3.21 g, 910).
~H NMRB(CD30D) 1.50-1.99 (m, 10 H), 2.02-2.06 (m, 2 H),
2.37-2.75 (m, 3 H), 3.02-3.06 (br m, 2 H), 7.05-7.09 (m,
4 H), 7.16 (dt, J=0.9 Hz, J=8.7 Hz, 1 H), 8.48 (dd, J=0.9
Hz, J=4.2 Hz, l H).
Part II
(+)-6-(3,4-DIFLUOROPHENYL)-1-{N-[4-(2-PYRIDYL)PIPERIDIN-1
_yL] _
PROPYL]}CARBOXAMIDO-5-METHOXYCARBONYL-4-METHOXYMETHYL-2-O
XO- 1,2,3,6-TETRAHYDROPYRIMIDINE DIHYDROCHLORIDE
5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-2-OX
O-6- (3,4-DIFLUOROPHENYL)-PYRIMIDINE: Copper(I) oxide
(5.06 g, 0.035 mole) and acetic acid (2.05 mL) were added
sequentially to a stirring solution of methyl
4-methoxyacetoacetate (50.0 g, 0.351 mol),
3,4-difluorobenzaldehyde (51.4 g, 0.351 mmol), and urea
(31,6 g, 0.527 mole) in THF (300 mL) at room temperature,
followed by dropwise addition of boron trifluoride
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diethyl etherate (56.0 mL, 0.456 mole). The mixture was
stirred at reflux temperature for 8 h, whereupon TLC (1/1
EtOAc/hexanes) indicated completion of the reaction. The
reaction mixture was cooled and poured into a mixture of
ice and sodium bicarbonate (100 g) and the resulting
mixture was filtered through Celite. The Celite pad was
washed with dichloromethane (400 mL). The organic layer
was separated from the filtrate and the aqueous layer was
extracted with more dichloromethane (3 X 300 mL). The
combined organic extracts were dried (sodium sulfate) and
the solvent was evaporated. The crude product was
purified by flash chromatography (ethyl acetate/hexanes,
1/l;then ethyl acetate), giving the desired product as~a
pale yellow foam. The foam was triturated with hexanes,
giving a white powder (103.3 g, 940). 1H NMR83.476 (s,
3H), 3.651 (s, 3H), 4.653 (s, 2H), 5.39 (s, 1H), 6.60 (br
s, 1H, NH), 7.00-7.20 (m, 3H), 7.72 (br s, 1H, NH).
(+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-
2-OXO-6-(3,4-DIFLUOROPHENYL)-PYRIMIDINE: The racemic
intermediate 5-methoxycarbonyl-4-methoxymethyl-
1,2,3,6-tetrahydro-2-oxo-6- (3,4-difluorophenyl)
pyrimidine was resolved by chiral HPLC [Chiralcel OD 20 X
250 mm #369-703-30604; lambda 254 nm; hexanes/ethanol
90/10 ; 85 mg per injection; retention time of the
desired enantiomer: 16.94 min., the first enantiomer
peak to elute], giving (+)-5-methoxycarbonyl-4-
methoxymethyl-1,2,3,6- tetrahydro-2-oxo-6-(3,4-
difluorophenyl)-pyrimidine (40-42 wt% isolation of the
desired enantiomer from the racemate); [a]p = +83.8 (c =
0.5, chloroform) .
(+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-1,2,3,6-TETRAHYDRO-
2-OXO-6-(3,4-DIFLUOROPHENYL)-1-[(4-NITROPHENYLOXY)CARBONY
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L]PYRIMIDINE: A solution of lithium hexamethyldisilazide
in THF (1M, 18.0 mL, 18.0 mmol) was added over 2-3 min.
to a solution of (-~-)-5-methoxycarbonyl-4-methoxymethyl-
1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorophenyl)-pyrimidin
a (1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at -78 °C
under argon atmosphere and the mixture was stirred for 10
min. The resulting solution was added over 6 min., via a
cannula, to a stirred solution of 4-nitrophenyl
chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at -78
°C. The mixture was stirred for an additional 10 min. and
the mixture was poured onto ice (50 g) and extracted with
chloroform (2 X 50 mL). The combined extracts were dried
(sodium sulfate) and the solvent evaporated. The residue
was purified by flash chromatography (hexanes/ethyl
acetate, 4/1 to 3.5/1), giving the product as a yellow
syrup, which on trituration with hexanes became a white
powder (2.40 g, 790). ~H NMR83.52 (s, 3H), 3.74 (s, 3H),
4.65-4.80 (q, J=16.5 Hz, 2H), 6.32 (s, 1H), 7.10-7.30 (m,
4H), 7.36 (d, J=9 Hz, 2H), 8.27 (d, J=9 Hz, 2H).
(+)-6-(3,4-DIFLUOROPHENYL)-1-{N-[4-(2-PYRIDYL)PIPERIDIN-1
-YL]-PROPYL]}CARBOXAMIDO-5-METHOXYCARBONYL-4-
METHOXYMETHYL-2-OXO- 1,2,3,6-TETRAHYDROPYRIMIDINE
DIHYDROCHLORIDE: A solution of (+)-5-methoxycarbonyl-
4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorop
henyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (2.38 g,
5 mmol), 3-aminopropyl-4-(2-pyridyl)piperidine (1.21 g,
5.5 mmol) in THF (20 mL) was stirred at room temperature
for 12 h. The solvent was evaporated and the residue was
30, re-dissolved in ethyl acetate (100 mL). The resulting
solution was washed with ice-cold 1 N NaOH (4 X 50 mL),
brine (2 X 50 mL) and dried over potassium carbonate.
The solvent was evaporated in vacuo and the residue was
purified by flash chromatography (dichloromethane/MeOH/2
M ammonia in MeOH, 980/10/10 to 940/30/30 ), giving a
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clean fraction of the desired product (2.45 g, 880) as a
foam and a slightly impure fraction (0.30 g, 100). '-H NMR
81.60-2.00 (m, 6H), 2.05-2.15 (m, 2H), 2.38-2.43 (br t,
2H), 2.65-2.80 (m, 1H), 3.05-3.06 (br d, 2H), 3.30-3.45
(m, 2H), 3.48 (s, 3H), 3.704 (s, 3H), 4.68 (s, 2H), 6.68
(s, 1H), 7.05-7.20 (m, 5H), 7.58-7.63 (dt, 1H), 7.70 (s,
1H, NH), 8.50-8.52 (dd, 1H), 8.88 (br t, 1H).
The HCl salt was prepared by treatment of a solution of
the free base in ether with 1 N HCl in ether. The white
powder was dried under reduced pressure: 1H NMRB
2.05-2.20 (m, 4H), 2.77-2.88 (m, 2H), 3.00-3.20 (m, 4H),
3.35-3.47 (m, 2H), 3.47 (s, 3H), 3.64-3.70 (m, 2H), 3.71
(s, 3H) , 4 . 05 (br t, 1H) , 4 . 67 (s, 2H) , 6.59 (s, 1H) ,
l5 7.05-7.20 (m, 3H), 7.79 (t, 1H), 8.00 (d, 1H), 8.43 (dt,
1H), 8.96 (br t, 1H, NH), 12.4 (br s, 1H), m.p. 188-191
°C; [a]D = ~-141.13 (c = 0.265, MeOH) ; Anal. Calcd. for
C.,~Hj4N,0~F~Cl + 0.6 H20:C, 52.36; H, 5.84; N, 10.90. Found:
C, 52.24; H, 5.96; N, 10.80. (Note: NMR analysis of this
product did not show the presence of any water. However,
it was noted by the lab that performed the elemental
analysis that this sample gains weight during handling by
absorbing water from the atmosphere).
Example 18
(1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(ISOBENZOFURAN)PIPERIDINE-
1-YL]-PROPYL}CARBOXAMIDO-5-METHOXYCARBONYL-2-OXO-
6-(3,4-BENZOFURAZAN)- 4-METHYLPYRIMIDINE HYDROCHLORIDE
4-(3,4-BENZOFURAZAN)-6-METHYL-2-OXO-3-{[3-(4-SPIRO[ISOBEN
ZO-FURAN-1(3H),4'-PIPERIDINE]PROPYL}-1,2,3,4-
TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER .
1-(3-Aminopropyl)-4- spiro[iso-benzofuran-1 (3H),4'-
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piperidine] (0.028 g, 0.110 mmol) was added to
(~)-6-(benzofurazan)-1,6-dihydro-2-methoxy-
5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyri
midine (0.047 g, 0.100 mmol) in. dry dichloromethane (10
mL) and the solution was stirred at room temperature for
24 h. Aquesous 6 N HCl (2 mL) was added to the reaction
mixture which was stirred for another 1 h. The reaction
mixture was basified with aqueous 10% KOH solution (pH =
9) and extracted into dichloromethane (3 x 10 mL). The
organic layer was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by flash
chromatography (EtOAc/ MeOH, 4.5/0.5), giving the desired
product (41.0 mg, 73 0) as a syrup: 1H NMRc~1.76-1.81
(m, 7 H), 1.94-2.04 (m, 6 H), 2.32-2.48 (m, 1 H), 2.83
(d, J=10.6 Hz, 2 H), 3.36-3.43 (m, 2 H), 3.75 (s, 3 H),
5.05 (s, 2 H), 6.83 (s, 1 H), 7.07-7.27 (m, 4 H), 7.54
(d, J=9.5 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J=9.5 Hz, 1
H) , 8 . 85 (d, J=5 . 2 Hz, l H) .
HC1 in ether (1 N, 5 mL) was added to the free base
(0.041 g, 0.073 mmol) in dichloromethane (4 mL), and the
solution was concentrated under reduced pressure. The
product was recrystallized from ether, giving the
hydrochloride salt as a pale yellow solid (42.0 mg, 96
0) ; mp 180-182 °C; Anal. Calcd. for C29H34N6O6C1 + 0.5 moles
H~O: C, 57.47; H, 5.65; N, 13.87. Found: C, 57.42; H,
5.71; N, 13.70.
Example 19
2-(3,4-DIFLUOROPHENYL)4,5-DIHYDROIMIDAZOLE-1-CARBOXYLIC
ACID {3-[4-PHENYL-4-(4-BROMO-5-METHYLTHIOPNEN-2-YL)]
-PROPYL}-AMIDE: Anal. Calcd. for C3pH3oNqO,CIF3 + HC1 + 1.5
H.,O: C, 55.26; H, 6.03; N, 8.59. Found: C, 55.29; H, 5.95;
N, 8.39.
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Example 20
4-(3,4-DIFLUORPHENYL)-6-METHYL-2-OXO-3-{[3-(4-SPIRO[ISOBE
N20-FURAN-1(3H),4'-PIPERIDINE]PROPYL}-1,2,3,4-
TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER
For the preparation of the ether piperidine precursor of
the compound of Example 20,refer to W.E.Parham et a1, J.
Org. Ch em. (1976) 41, 2268.
1-TERT-BUTOXYCARBONYL-3-(4-SPIRO[ISOBENZOFURAN-1(3H),4'-
PIPERIDINE])PROPYLAMINE: N-(tent-utoxycarbonyl)-3-bromo-
propylamine (0.772 g, 3.27~mmo1) and potassium carbonate
(0.904 g, 6.54 mmol) were added to a stirring solution of
the amine (0.566 g, 3.27 mmol) in dioxane ( 20 mL) and
the reaction mixture was heated at reflux temperature for
24 h. The reaction mixture was cooled to room
temperature, concentrated and partitioned between
chloroform (40 mL) and water (5 mL). The organic layer
was dried over sodium sulfate, filtered and concentrated.
The crude product was purified by column chromatography
(ethyl acetate/ methanol, 4.5/0.5), giving the desired
product (0.856 g, 79 0) as a colorless oil; 1H NMR~ 1.45
(s, 9 H), 1.63-2.04 (m, 6 H), 2.33-2.52 (m, 4 H), 2.87
(d, J=11.0 Hz, 2 H), 3.2 (br s, 2 H), 5.07 (s, 2 H), 5.6
(br s, 1 H) , 7 . 13-7 .28 (m, 4 H) .
3-(4-SPIRO[ISOBENZO-FURAN-1(3H),4'-PIPERIDINE])
PROPYLAMINE: Trifluoroacetic acid (1 mL) was added to
1-tent-butoxycarbonyl 3-(4-spiro[isobenzo-furan-
1(3H),4'-piperidine])propylamine (0.500 g, 1.51 mmol) in
dichloromethane (5 mL) and the solution was stirred at
room temperature for 1 h. The reaction mixture was
concentrated, neutralized with 10 % KOH solution and
extracted into dichloromethane (25 mL). The organic
layer was dried over sodium sulfate, filtered and
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concentrated, giving the desired amine (0.340 g, 980)
which was used in the subsequent step without further
purification.
4-(3,4-DIFLUORPHENYL)-6-METHYL-2-OXO-3-{[3-(4-SPIRO[ISOBE
N20-FURAN-1(3H),4'-PIPERIDINE]PROPYL}-1,2,3,4-
TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER:
3-(4-spiro[isobenzo-furan-1(3H),4'-piperidine])
propylamine (0.0319 g, 0.123 mmol) was added to
(~)-6-(3,4-Difluorophenyl)-1,6-dihydro- 2-methoxy-5-
methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimi
dine (0.052 g, 0.112 mmol) in dry dichloromethane (10 mL)
and the solution was stirred at room temperature for 24
h. Aqueous 6 N HCl (2 mL) was added and the reaction
mixture was stirred for an~additional 1 h. After
neutralization with 10o aqueous KOH solution, the
reaction mixture was extracted with dichloromethane (3 x
10 mL). The organic layer was dried over sodium sulfate,
filtered and concentrated. The crude product was
purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5),
giving the desired product (0.040 g, 64 0) as a syrup;
1H-NMR81.73-1.78 (m, 7 H), 1.93-2.04 (m, 2 H), 2.33-2.48
(m " 6 H), 2.83 (d, J=11.8 Hz, 2 H), 3.35-3.41 (m, 2 H),
3.71 (s, 3 H), 5.06 (s, 2 H), 6.75 (s, 1 H), 7.04-7.26
(m, 7 H), 8.82 (t, J=5.1 Hz, 1 H).
A solution of 1 N HC1 in ether (5 mL) was added to the
free base (0.040 g, 0.072 mmol) in dichloromethane (4 mL)
and the solution was concentrated in ~racuo. The product
was recrystallized from ether, giving the dihydrochloride
as a pale yellow solid (0.042 g, 99 0); mp 178-182 °C;
Anal. Calcd. for CZ9H3qF~N40~Cli + 0.6 H20: C, 57.87; H,
5.73, N 9.31. Found: C, 58.11; H 5.90; N 8.95.
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Example 21
1,2,3,6-TETRAHYDRO-1-{N-[4-(DIHYDROINDENE)-1-YL}PROPYL}CA
RBOXAMIDO-5-METHOXYCARBONYL- 2-OXO-6-(3,4-BENZOFURAZAN)-
4-METHYLPYRIMID-INE
For the preparation of the indane piperidine precursor of
the compound of Example 21, refer to M.S.Chambers J. Med.
Chem. (1992) 35,2033.
Z0 N-(tent-butoxycarbonyl)3-(4-spiro[isobenzo-furan-
1(3H),4'- piperidine])propylamine(1.10 g, 4.64 mmol) and
potassium carbonate (1.17 g, 8.44 mmol) were added to a
stirring solution of the amine (0.790 g, 4.22 mmol) in
dioxane (20 ml), and the resulting solution was heated at
l5 reflux temperature for 24 h. The reaction mixture was
cooled to room temperature, concentrated and partitioned
between chloroform (40 mL) and water (5 mL). The organic
layer was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by column
20 chromatography (ethyl acetate/ methanol, 4.510.5), giving
the desired product (0.886 g, ~1 0) as a colorless oil; 1H
NMRB 1.46 (s, 9 H), 1.55 (d, J = 11.3 Hz, 2 H), 1.69 (t,
J = 6.3 Hz, 2 H), 1.88-2.47 (m, 6 H), 2.47 (t, J = 6.3
Hz, 2 H), 2.88 (t, J = 3.3 Hz, 4 H), 3.23 (d, J = 5.6 Hz,
25 2 H), 5.85 (br s, 1 H), 7.18 (s, 4 H).
Trifluoroacetic acid (1 ml) was added to 1-tert-
butoxycarbonyl-3-(4-spiro[isobenzo-furan-1(3H),4'-
piperidine])propylamine(0.180 g, 0.52 mmol) in
30 dichloromethane (5 ml) and the resulting solution was
stirred at room temperature for 1 hour. The solution was
concentrated, neutralized with 10o KOH solution and
extracted into dichloromethane (25 m1). The organic
layer was dried over sodium sulfate, filtered and
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concentrated, giving propylamine (0.156 g, 1000) which
was used in the subsequent step without further.
purification.
(~)-4-(3,4-BENZOFURAZAN)-6-METHYL-2-OXO-3-{SPIRO[1H-INDAN
E-1,4'-PIPERIDINE]PROPYL}-1,2,3,4-TETRAHYDROPYRIMIDINE-5-
CARBOXYLIC ACID METHYL ESTER HYDROCHLORIDE: To
(~)-4-(3,4-benzofurazan)-1,6- dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)-
carbonylpyrimidine (0.059 g, 0.126 mmol) in dry
dichloromethane (10 mL), 1-(3-aminopropyl)spiro
[1H-indane-1,4'- piperidine] (0.062 g, 0.252 mmol) was
added and the solution was stirred at room temperature
for 24 h. The reaction mixture was stirred for another 1
h after addition of 2 mL of 6N HCl. The reaction mixture
was basified with 10% aqueous KOH solution (pH = 9) and
extracted with dichloromethane (3 x 10 mL). The combined
organic extracts were dried over sodium sulfate, filtered
and concentrated. The crude product was purified by
flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 0.070
g (100x) of the desired product as a syrup: 1H NMR81.51
(d, J=12.5 Hz, 2 H), 1.76-2.08 (m, 4 H), 2.12 (t, J=10.3
Hz, 2 H), 2.45 (s, 5 H), 2.86-2.91 (m, 4 H), 3.30-3.45
(m, 2 H) , 3.75 (s, 3 H) , 6.83 (s, 1 H) , 7.02 (br s, 1 H) ,
7 .0 (m, 4 H) , 7.54 (d, J=9. 6 Hz, 1 H) , 7. 69 (s, 1 H) ,
7.78 (d, J=9.2 Hz, 1 H), 8.84, (t, J=5.2 Hz, 1 H).
To the free base (0.070 g, 0.125 mmol) in 4 mL of
dichloromethane, 5 mL of 1 N HCl in ether was added, and
the solution was concentrated under reduced pressure.
Recrystallization from ether gave 0.088 g (100 0) of
(~)-4-(3,4-benzofurazan)-~-methyl-2-oxo-3-{spiro[2H-indan
e- 1,4'-piperidine]propyl}-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid methyl ester hydrochloride
as a white solid: m.p. 155-157 °C; Anal. Calcd. for
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C~aH36N60,C1: C, 57.12; H, 5.76; N, 13.33. Found: C, 57.40;
H, 5.96; N, 13.02.
Example 22
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(BENZO-4',5'(H)FURAN)PIPER
IDIN-1- YL]PROPYL}CARBOXAMIDO-4-ETHYL- 6-(3,4-
DIFLUOROPHENYL)-2-OXO- PYRIMIDINE-5-CARBOXAMIDE
HYDROCHLORIDE: DMAP~ ECD (0.250 mmol, 0.050 g) was added
to a stirred mixture of (+)-1,2,3,6-tetra-hydro-1-
{N-[4-(benzo-4',5'(h)furan)piperidin-1-yl]propyl}carbox-
amido-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine-5-c
arboxyl-is acid hydrochloride (0.100 mmol, 0.055 g) and
N-methylmorpholine (0.330 mL) in dry dichloromethane (10
mL). The resulting mixture was stirred at room
temperature for 1 h and quenched with NH3. The reaction
mixture was stirred at room temperature overnight,
concentrated and chromatographed, giving the desired
product. The HC1 salt was prepared by the addition of
HC1 in ether to a solution of the product in
dichloromethane, followed by evaporation of the solvents.
Anal. Calc. For C~9H33N~Oq F~ + HCl + 0.7 CHC13 . C, 52. 96; .
H, 5.29; N, 9.40. Found: C, 52.81; H, 5.69; N, 8.97.
Example 23
(1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,4-DIHYDRO-2-OXOSPIRO-
NAPHTHALENE-1(2H))-PIPERIDINE-1-YL]PROPYL}CARBOXAMIDO-5-
METHOXYCARBONYL-2- OXO-6-(3,4-BEN20FURAZAN)-4-
METHYLPYRIMIDINE HYDROCHLORIDE
1-(3-TERT-BUTOXYCARBONYLAMINOPROPYL)SPIRO[ISOCHROMAN-3,4'
PIPERIDIN]-1-ONE: To a stirred solution of spiro
[piperidine-4,1'-tetralin] To a stirred solution of
spiro[isochroman-3,4'-piperidin]-1-one (K.Hashigaki et
a1. Chem.Pharm.Bull. (1984) 32, 3568.) (0.587 g, 2.58
mmol) in dioxane ( 20 mL), N-(tert- butoxycarbonyl)-
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3-bromopropylamine (0.615 g, 2.84 mmol) and potassium
carbonate (0.714 g, 5.17 mmol) were added and the
solution was refluxed for 24 h. The reaction mixture was
cooled to room temperature, concentrated and partitioned
between 40 mL chloroform and 5 mL water. The organic
layer was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by column
chromatography (ethyl acetate/ methanol, 4.5/0.5) to
yield 0.465 g (47 0) of the desired product as a
colorless oil; ~H NMR81.45 (s, 9 H), 1.64-2.18 (m, 7 H),
2.45-2.84 (m, 6 H), 3.19-3.95 (m, 4 H), 6.01 (br s, 1 H),
7.13-7.26 (m, 3 H), 7.42 (d, J=7.7 H).
Step B.
1-(3-AMTNOPROPYL)SPIRO[ISOCHROMAN-3,4'PIPERIDIN]-1-ONE:
To 1-(3-tert-Butoxycarbonylaminopropyl)spiro
[isochroman-3,4'-piperidin]-1-one (0.144 g, 0.375 mmol)
in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid
was added and the solution stirred at room temperature
for 1 h. The solution was concentrated, neutralized with
10 o KOH solution and extracted into 25 mL of
dichloromethane. The organic layer was dried over sodium
sulfate, filtered and concentrated, giving 0.110 g (1000)
of the product which was used as such for the subsequent
step.
(~)-4-(3,4-BENZOFURAZAN)-6-METHYL-2-OXO-3-{(SPIRO[ISOCHRO
MAN- 3,4'-PIPERIDIN]-1-ONE)PROPYL}-1,2,3,4-
TETRAHYDROPYRIMIDINE-5- CARBOXYL-IC ACID METHYL ESTER:
To (~)-4-(3,4-Benzofurazan)-l,6- dihydro-2-methoxy-
5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)-
carbonylpyrimidine (40.0 mg, 0.0865 mmol) in 10 mL of dry
dichloromethane, spiro[isochroman-3,4'piperidin]-1-one
(44.0 mg, 0.173 mmol) was added and the solution was
stirred at room temperature for 24 h. The reaction
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mixture was stirred for another 1 h after addition of 2
mL of 6N HC1. The reaction mixture was basified with 100
aqueous KOH solution (pH = 9) and extracted into
dichloromethane (3 x 10 mL). The organic layer was dried
over sodium sulfate, filtered and concentrated. The
crude product was purified by flash chromatography
(EtOAc/ MeOH, 4.5/0.5), giving 50.0 mg (1000) of the
desired product as a syrup: 1H NMR~1.~7-2.13 (m, 8 H),
2.45 (m, 5 H), 2.70 (t, J=7.4 Hz, 2 H), 2.72-2.75 (m, 2
H), 3.19 (t, J=7.4 Hz, 2 H), 3.34-3.45 (m, 2 H), 3.75 (s,
3 H) , 6.82 (s, 1 H) , 6.87 (s, 1 H) , 7.13-7.44 (m, 3 H) ,
7.54 (d, J=9.~ Hz, 1 H), 7.43 (d, J=7.4 Hz, 1 H), 7.~9
(s, 1 H), 7.79 (d, J=9.6 Hz, 1 H), 8.87 (t, J=5.2 Hz, 1
H) .
To the free base (50.0 mg, 0.084 mmol) in 4 mL of
dichloromethane, 5 mL of 1 N HCl in ether was added, and
the solution concentrated under reduced pressure.
Recrystallization from ether gave 30.0 mg (86 0) of the
product as a white solid: m.p. 165-167 °C; Anal. Calcd.
for C31H36N6~6C~- + 1.5 H20: C, 57.81; H, 5.95. Found: C,
57.75; H, 5.91.
Example 24
(1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,4-DIHYDRO-2-OXOSPIRO-
NAPHTHALENE-1(2H))-PIPERIDINE-1-YL]PROPYL}CARBOXAMIDO-5-M
ETHOXY-CARBONYL-2- OXO-6-(3,4-DIFLUOROPHENYL)-4-METHYL-
PYRIMIDINE
(~)-4-(3,4-DIFLUOROPHENYL)-6-METHYL-2-OXO-3-{(SPIRO[ISOCH
ROMAN- 3,4'PIPERIDIN]-1-ONE)PROPYL}-1,2,3,4-TETRAHYDRO-
PYRIMIDINE-5- CARBOXYLIC ACID METHYL ESTER: To
(~)-4-(3,4-Difluorophenyl)- 1,6-dihydro-2-methoxy-5-
methoxycarbonyl-4-methyl-1-(4-nitrophen-oxy)carbonyl-
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pyrimidine (40.0 mg, 0.0865 mmol) in 10 mL of dry
dichloromethane, spiro[isochroman-3,4'piperidin]-1-one
(44.0 mg, 0.173 mmol) was added and the solution was
stirred at room temperature for 24 h. The reaction
mixture was stirred for another 1 h after addition of 2
mL of 6N HCl. The reaction mixture was basified with 100
aqueous KOH solution (pH = 9) and extracted into
dichloromethane (3 x 10 mL). The organic layer was dried
over sodium sulfate, filtered and concentrated. The
ZO crude product was purified by flash chromatography
(EtOAc/ MeOH, 4.5/0.5), giving 45.0 mg (900) of
(~)-4-(3,4-difluorophenyl)- 6-methyl-2-oxo-3-{(spiro-
[isochroman-3,4'piperidin]-1-one)propyl}-1,2,3,4-tetrahyd
ropyrimi-dine-5-carboxylic acid methyl ester as a syrup;
l5 '-H NMR b 1 .75-1 .94 (m, 9H) , 2. 05-2. 13 (m, 4 H) , 2 .36-2 . 41
(m, 5 H), 2.70 (t, J=7.35 Hz, 2 H), 2.77 (m, 2 H), 3.19
(t, J=7.4 Hz, 2 H), 3.39-3.43 (m, 2 H), 6.69 (s, 1 H),
7.04-7.45 (m, 8 H), 8.82 (t, J=5.2 Hz, 1 H).
20 To the free base (45.0 g, 0.077 mmol) in 4 mL of
dichloromethane, 5 mL of 1 N HC1 in ether was added, and
the solution was concentrated in vacuo.
Recrystallization from ether gave 0.050 g (1000) of
(-1-)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-3-{(spiro-
25 [isochroman-3,4'piperidin]- 1-one)propyl}-1,2,3,4-
tetrahydro-pyrimidine-5-carboxylic acid methyl ester
hydrochloride as a white solid: m.p. 150-152 °C; Anal.
Calcd. for C31H3gF2N40C1 + 2 H~O: C, 56. 49; H, 5. 96. Found:
C, 56.40; H, 5.95.
Example 25
5-[(2)-1-(1-ETHYL-2,2,4-TRIMETHYL-1,2-DIHYDRO-6-QUINOLINY
L)-METHYLIDENE]-2-THIOXO-1,3-THIAZOLAN-4-ONE
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Example 26
1-[BIS(4-FLUOROPHENYL)METHYL]-4-(3-PHENYL-2-PROPENYL)PIPE
RA2INE
Example 27
4-[(4-IMIDAZO[1,2-A]PYRIDIN-2-YLPHENYL)IMINO]METHYL-5-MET
HYL-1,3-BENZENEDIOL
Example 28
l0 1-[3-(4-CHLOROBENZOYL)]PROPYL-4-BENZAMIDOPIPERIDINE
Preparation of
1-[3-(4-chlorobenzoyl)propyl]-4-benzamidopiperidine
1-[3-(4-CHLOROBENZOYL)PROPYL]-4-BENZAMIDOPIPERIDINE: A
mixture of 3-(4-chlorobenzol)propyl bromide (640 mg, 2.45
mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K~C03
(1.01 g, 7.34 mmol) in 50 ml of acetone was heated at
reflux temperature for 48 h. The cooled reaction mixture
was filtered to remove the solids, concentrated in vacuo,
giving a yellow solid, which was purified by
chromatography (MeOH/CHC13, 5/95). The product (320 mg ,
33.90) was isolated as a white powder: 1H NMR81.46 (dq,
J1=1.0 Hz, J2=8.4 Hz, 2H), 1.90-2.10 (m, 4H), 2.16 (m,
2H), 2.43 (t, J=6.9 Hz, 2H), 2.80-2.90 (m, 2H), 2.97 (t,
J=6.9 Hz, 2H), 3.97 (m, 1H), 5.92 (d, J=7.8 Hz, 1H, N-H),
7.40-8.00 (m, 9H). The product was converted to the HC1
salt and recrystallized from MeOH/Et20, m.p. 243-244 °C;
Anal. Calcd for C~zH~,ClN~O~ + HC1 + HBO: C, 60.15; H, 6.37;
N, 6.37; Found: C, 60.18; H, 6.34; N, 6.29.
Example 29
4-[4-(4-CHLOROPHENYL)-4-HYDROXY-1-PIPERIDINYL]-1-(4-CHLOR
OPHEN-YL)-1-BUTANONE
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Example 30
N-METHYL-8-[4-(4-FLUOROPHENYL)-4-OXOBUTYL]-1-PHENYL-1,3,8
-TRI-AZASPIRO-[4.5]DECAN-4-ONE
Example 31
1H-1,2,3-BENZOTRIAZOL-1-YL (2-NITROPHENYL) SULFONE
Example 32
(1)-1,2,3,6-TETRAHYDRO-1-{N-[4-(DIHYDROINDENE)-1-YL}PROPY
L}-
CARBOXAMIDO-5-METHOXYCARBONYL-2-OXO-6-(3,4-DIFLUORO)-4-ME
THYL-PYRIMIDINE
1-(3-TERT-BUTOXYCARBONYLAMINOPROPYL)SPIRO[1H-INDANE-1,4'-
PIPERIDINE]: To a stirred solution of spiro[1H-indane-
1,4'-piperidine] (M.S.Chambers et a1. J. Med. Chem.
(1992) 35, 2033.) (0.790 g, 4.22 mmol) in dioxane (20
mL), N-(tert-butoxy-carbonyl)-3-bromopropylamine (1.1 g,
4.64 mmol) and potassium carbonate (1.17 g, 8.44 mmol)
were added and the resulting solution was heated at
reflux temperature for 24 h. The reaction mixture was
cooled to room temperature, concentrated and partitioned
between 40 mL of chloroform and 5 mL of water. The
organic layer was dried over sodium sulfate, filtered and
concentrated. The crude product was purified by column
chromatography (ethyl acetate/ methanol, 4.5/0.5) to
yield 0.886 g (61 0) of the required product as a
colorless oil: 1H NMR~ 1.46 (s, 9 H) , 1.55 (d, J=11.3 Hz,
2 H) , 1. 69 (t, J=6.3 Hz, 2 H) , 1. 88-2. 47 (m, 6 H) , 2 . 47
(t, J=6.3 Hz, 2 H), 2.88 (t, J=3.3 Hz, 4 H), 3.23 (d,
J=5.6 Hz, 2 H), 5.85 (br s, 1 H), 7.18 (s, 4 H).
1-(3-AMINOPROPYL)SPIRO[1H-INDANE-1,4'-PIPERIDINE]: To
1-(3-tert- Butoxycarbonylaminopropyl)spiro[1H-indane-
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1,4'-piperidine] (0.180 g, 0.52 mmol) in 5 mL of
dichloromethane, 1 mL of trifluoroacetic acid was added
and the solution stirred at room temperature for 1 h.
The solution was concentrated, neutralized with 10 o KOH
solution and extracted into 25 mL of dichloromethane.
The organic layer was dried over sodium sulfate, filtered
and concentrated, giving 0.156 g (1000) of the product
which was used as such for the subsequent step.
(~)-4-(3,4-DIFLUORO)-6-METHYL-2-OXO-3-{SPIRO[1H-INDANE-1,
4'-PIPERIDINE]PROPYL}-1,2,3,4-TETRAHYDROPYRIMIDINE-5-CARB
OXYLIC ACID METHYL ESTER: To (~)-4-(3,4-difluoro)1,6-
dihydro-2-methoxy- 5-methoxycarbonyl- 4-methyl-1-
(4-nitrophenoxy)carbonylpyrimidine (50.0 g, 0.108 mmol)
in 10 mL of dry dichloromethane, 1-(3- aminopropyl)
spiro[1H-indane-1,4'-piperidine] (53.0 mg, 0.216 mmol)
was added and the solution was stirred at room
temperature for 24 h. The reaction mixture was stirred
for another 1 h after addition of 2 mL of 6N HCl. The
reaction mixture was basified with 10o aqueous KOH
solution (pH = 9) and extracted into dichloromethane (3 x
10 mL). The organic layer was dried over sodium sulfate,
filtered and concentrated. The crude product was
purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5),
giving 60.0 mg (1000) of the product as a syrup: 1H NMRB
1.52 (d, J=13.2 Hz, 2 H), 1.70-2.07 (m, 8 H), 2.12 (t,
J=10.3 Hz, 2 H), 2.42 (s, 4 H), 2.86-2.91 (m, 3 H),
3.32-3.43 (m, 2 H), 3.72 (s, 3 H), 6.71 (s, 1 H), 6.81
(br s, 1 H), 7.04-7.19 (m, 7 H), 8.82 (t, J=5.2 Hz, 1 H).
To the free base (0.060 g, 0.108 mmol) in 4 mL of
dichloromethane, 5 mL of 1 N HC1 in ether was added, and
the solution was concentrated under reduced pressure.
Recrystallization from ether gave 0.070 g (1000) of the
product as a white solid; m.p. 150-153 °C; Anal. Calcd.
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for C3°H36F~NQ06C1: C, 54 . 86; H, 5 .53; N, 8 .54 . Found: C,
54.96; H, 5.57; N, 8.27.
Example 33
(+)-1,2,3,6-TETRAHYDRO-1-{N-[4-(3,4,5-TRIFLUORO)-PHENYL-P
IPER-IDIN-1-YL]PROPYL}CARBOXAMIDO-4- METHOXYMETHYL-6-
(3,4- DIFLUOROPHENYL)-2-OXOPYRIMIDINE-5-CARBOXYLIC ACID
METHYL ESTER: mp °C; [a]D = +123.0, (c = 0.15, MeOH); 1H
NMR81.70-1.82 (m, 6H), 1.97-2.08 (m, 2H), 2.40 (t, J=6.9
Hz, 2H), 2.74-2.87 (m, 1H), 3.01 (d, J=11.1 Hz, 2H),
3.29-3.40 (m, 2H), 3.49 (s, 3H), 3.71 (s, 3H), 4.69 (s,
2H), x.68 (s, 1H), 6.88-6.95 (m, 2H), 7.05-7.11 (m, 2H),
7.15-7.22 (m, 1H), 7.71 (s, 1H), 8.90 (t, J=5.4 Hz, 1H).
Example 34
(+)-1,2,3,6-TETRAHYDRO-1-{N-[2-(S)-METHYL)-4-(2-NITROPHEN
YL)-PIPERAZIN-1YL]PROPYL}-CARBOXAMIDO-4-METHYL-6-(3,4-
DIFLUOROPHEN-YL)-2-OXO-PYRIMIDINE
(S)-(+)-3-METHYL-1-(2-NITROPHENYL)-PIPERAZINE: To a
solution of 2-bromonitrobenzene (0.600 g, 3.00 mmol) in
1,4-dioxane (15 mL) was added (S)-(+)-2-methylpiperazine
(0.500 g, 0.500 mmol) and powdered K.,C03 (15.0 mmol, 1.50
g) and the resulting suspension was heated at reflux for
10 h. After the suspension was cooled, it was filtered
through a sintered glass funnel and the solvent was
removed in vacuo. The resulting residue was purified by
column chromatography (1/1 hexane/EtOAc followed by 4/1
EtOAc/MeOH), giving
(S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an
orange oil (0.53 g, 800).
(+)-1,2,3,6-TETRAHYDRO-1-{N-[2-(S)-METHYL)-4-(2-NITROPHEN
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YL)PIPERAZIN-1YL]PROPYL}-CARBOXAMIDO-4-METHYL-6-(3,4-DTFL
UOROPHENYL)-2-OXO-PYRTMIDINE: To a solution of (+)-1-(3-
bromo-propylcarbamoyl)- 6-(3,4-difluorophenyl)-4-methyl-
2-oxo-1,6-dihydro-pyrimidine-5- carboxylic acid methyl
ester (0.200 g, 0.500 mmol) and (S)-(+)-3-methyl-1-(2-
nitrophenyl)-piperazine (0.170 g, 0.750 mmol) in 20 mL of
anhydrous acetone was added powdered K~CO~ {0.34 g, 3.5
mmol) and KI (0.07 g, 0.5 mmol) and the resulting
suspension was heated at reflux temperature for 10 h.
TLC indicated a new spot for the product (Rf = 0.3, 3/0.5
EtOAc/MeOH) and mostly the starting material. The
suspension was cooled, filtered and the solvent was
evaporated and the residue was purified by column
chromatography (EtOAc/MeOH, 5/1). (+)-1,2,3,6-
Tetrahydro-1-{N-[2-(S)-methyl)-4-(2-nitrophenyl)piperazin
-1-yl]-propyl}-carboxamido-4-methyl-6-(3,4-
difluorophenyl)-2-oxo-pyr-imidine was obtained as yellow
oil (0.030 g, 10o yield). The HCl salt was prepared by
the addition of HC1 in ether to a solution of the product
in dichloromethane, followed by evaporation of the
solvents; mp 150-153 °C; [a]v = 58.3 (c = 0.3, MeOH); 1H
NMR (CD30D) d 1 . 04 (d, J=6. 0 Hz, 3 H) , 1 .71-1 .78 (m, 2 H) ,
2.33-2.49 (m, 3 H), 2.42 (s, 3 H), 2.55-2.92 (m, 5 H),
3.00-3.10 (m, 3 H), 3.34 -3.42 (m, 2 H), 3.72 (s, 3 H),
6.71 (s, 1 H), 7.01-7.32 (m, 6 H), 7.46 (dt, J=0.7 Hz,
J=8.4 Hz, 1 H), 7.74 (dd, J=1.5, 8.4 Hz, 1 H), 8.82 (t,
J=3.9 Hz, 1 H) . Anal calcd. for C28H33N6F~06 + 0.20 CH~Cly
C, 52.92; H, 5.26; N, 13.13. Found: C, 52.84; H, 5.68; N,
12.94.
Example 35
1,2,3,6-TETRAHYDRO-1{N-[4-(2'-METHYL-PHENYL)PIPERA2IN-1-Y
L]-PROPYL}-CARBOXAMIDO-4-METHYL-6-(3,4-
DIFLUOROPHENYL)-2-OXO- PYRIMIDINE: The amine used was
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4-(2'-methyl-phenyl)piperazine. 1H NMR81.75-1.80 (m, 2
H), 2.29 (s, 3 H), 2.42 (s; 3 H), 2.41-2.48 (m, 2 H),
2.58-2.62 (m, 4 H), 2.91-2.97 (m, 4 H), 3.35 -3.42 (m, 2
H) , 3.72 (s, 3 H) , 6.71 (s, 1 H) , 6. 97-7 .26 (m, 8 H) ,
8.81 (t, J=3.9 Hz, 1 H). .The product was dissolved in
ether and 1 N HC1 in ether was.added. The ether was
evaporated, giving the dihydrochloride salt; mp 66-71 °C.
Anal calcd. for C~aH3~N~F~04 Cl~ + 1.75 acetone: C, 55.73;
H, 6.40; N, 9.78. Found: C, 56.16; H, 6.29; N, 10.06.
Example 36
(+)-1,2,3,6-TETRAHYDRO-5-METHOXYCARBONYL-4-METHOXYMETHYL-
2-OXO-1-{N-[3-(4-METHYL-4-PHENYL PIPERIDINE-1-YL]PROPYL}-
6-(3,4-DIFLUOROPHENYL) PYRIMIDINE: Hygroscopic; [a,]D = +
82.1(c = 0.31, MeOH); 1H NMR 51.14 (s, 3 H), 1.61-1.72
(m, 4 H), 2.03-2.08 (m, 2 H), 2.25 (t, J=7.2 Hz, 2 H),
2.30-2.42 (m, 4 H), 3.19-3.31 (m, 2 H), 3.40 (s, 3 H),
3.63 (s, 3 H), 4.60 (s, 2 H), 6.60 (s, 1 H), 6.97-7.29
(m, 8 H) , 7 . 63 (br s, 1 H) , 8 .78 (t, J=5.7 Hz, 1 H) .
Anal calcd. for C3oH3~N40~F~C1 + CH~C1~ . C, 53.80; H, 5.68;
N, 8.10. Found: C, 53.79; H, 6.03; N, 7.83.
EXAMPLE 37
5-(5-BUTYL-2-THIENYL)PYRIDO[2,3-d]PYRIMIDINE-
2, 4, 7 (1H, 3H, 8H) -TRIONE
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General Procedure for the reaction ~o(f,llpyrimidine-3-
carboxylic acid-4-nitrophenyl esters with amines:
A solution of substituted pyrimidine-3-carboxylic acid-
4-nitrophenyl ester ((0.29 mmol) and a substituted 4-
phenyl-1-(3-propylaminopiperidine (0.30 mmol) in 10 mL
of anhydrous THF was stirred overnight at room
temperature. The solvent was removed in vacuo and the
residue was purified by column chromatography.
Example 38
METHYL (4S)-3-[({3-[4-(3-AMINOPHENYL)-1-
PIPERIDINYL]PROPYL}AMINO)CARBONYL]-4-(3,4-
DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-0X0-1,2,3,4-
TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 1H NMR (400 MHz,
CDCI;) 8 7 . 80 (s, 1H) , 7.22-7 . 02 (m,. 2H) , 6. 95 (t, 2H,
J=8.7 Hz), 6.63-6.44 (m, 4H), 4.56 (ABq, 2H), 3.62 (s,
3H), 3.33 (s, 3H), 3.32 (m, 4H), 2.96 (br s, 2H), 2.34
(t, 2H, J=7.5 Hz), 2.11-1.94 (m, 3H), 1.81-1.64 (m, 4H);
ESMS m/e: 572.3 (M + H)~.
Example 39
The product was obtained according to the method
described for Example 40.
METHYL (4S) -4- (3, 4-DIFLUOROPHENYL) -3- ( { [3- (4-{3-
[(METHOXYACETYL)AMINO]PHENYL}-1-
PIPERIDINYL)PROPYL]AMINO}CARBONYL)-6-(METHOXYMETHYL)-2-
OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 15.6 mg
(69o yield); 1H NMR (400 MHz, CDCI;) 8 9.01 (s, 1H), 8.25
(s, 1H), 7.60 (s, 1H), 7.37 (d, 1H, J=7.2 Hz), 7.30-7.05
(m, 5H) , 7.02 (d, 1H, J=8.0 Hz) , 6.71 (s, 1H) , 4.70 (s,
2H), 4.03 (s, 2H), 3.73 (s, 3H), 3.53 (s, 3H), 3.47 (s,
3H), 3.42-3.33 (m, 2H), 3.08 (br s, 2H), 2.49 (br s,
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2H), 2.20 (s, 2H), 2.07 (br s, 1H), ,1.97-1.75 (m, 4H);
ESMS m/e: 644.3 (M + H)+
Example 40
METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-3-({ [3-(4-{3-[ (3,3-
DIMETHYLBUTANOYL)AMINO]PHENYL}-1-
PIPERIDINYL)PROPYL]AMINO}CARBONYL)-6-(METHOXYMETHYL)-2-
OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE
To the 20 ml vial was added methyl (4S)-3-[({3-[4-(3-
aminophenyl)-1-piperidinyl]propyl}amino)carbonyl]-4-
(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-
tetrahydro-5-pyrimidinecarboxylate (0.035 mmol), an acid
chloride or sulfonyl chloride (1.5 eq), N,N-
diisopropylethylamine (5 eq) and dichloromethane (2 ml)
at room temperature. The reaction mixture was stirred at
room temperature for 24 h, at which time the TLC
analysis indicated the reaction was completed. The
reaction mixture was concentrated to a small volume and
purified by preparative TLC (silica, 2000 microns, 95:5
- dichloromethane . methanol with 10 of isopropylamine)
to give 5.6 mg of methyl (4S)-4-(3,4-difluorophenyl)-3-
({[3-(4-{3-[(3,3-dimethylbutanoyl)amino]phenyl}-1-
piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-
oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate: 24.60
yield; 1H NMR (400 MHz, CDC1;) b 7.50 (s, 1H), 7.26 (d,
1H, J=8.3 Hz), 7.15-7.02 (m, 5H), 6.88 (d, 1H, J=8.3
Hz), 6.55 (s, 1H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.32
(s, 3H), 3.25 (t, 4H, J=9.0 Hz), 2.99 (d, 2H, J=10.8
Hz), 2.49-2.37 (m, 3H), 2.08 (t, 2H, J=11.7 Hz), 1.78-
1.65 (m, 14H); ESMS m/e: 670.4 (M + H)+.
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Example 41
The product was obtained according to the method
described for methyl (4S)-4-(3,4-difluorophenyl)-3-({[3-
(4-{3-[(3,3-dimethylbutanoyl)amino]phenyl}-1-
piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-
oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-
OXO-3-{[(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)AMINO]CARBONYL}-1,2,3,4-TETRAHYDRO-5-
PYRIMIDINECARBOXYLATE: 9.9 mg (45o yield) 8 1H NMR (400
MHz, CDC13) 8 7.36 (s, 1H), 7.28 (d, 1H, J=8.0 Hz), 7.16-
7 .02 (m, 5H) , 6.86 (d, 1H, J=7 . 6 Hz) , 6.54 (s, 1H) , 4.56
(ABq, 2H), 3.62 (s, 3H), 3.32 (s, 3H), 3.27-3.19 (m,
4H), 2.95 (d, 2H, J=10.3 Hz), 2.41 (m, 1H), 2.34 (t, 2H,
J=7.7 Hz), 2.28 (q, 2H, J=7.6 Hz), 2.01 (t, 2H, J=11.1
Hz), 1.73-1.64 (m, 8H); ESMS m/e: 628.4 (M + H)+
Example 42
The product was obtained according to the method
described for methyl (4S)-4-(3,4-difluorophenyl)-3-({[3-
(4-{3-[(3,3-dimethylbutanoyl)amino]phenyl}-1-
piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-
oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-3-
({[3-(4-{3-[(3-METHYLBUTANOYL)AMINO]PHENYL}-1-
PIPERIDINYL)PROPYL]AMINO}CARBONYL)-2-OXO-1,2,3,4-
TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 10.4 mg (45o yield)
cS 1H NMR (400 MHz, CDC1;) 8 7.36 (s, 1H), 7.28 (d, 1H,
J=7.9 Hz), 7.16-7.03 (m, 5H), 6.88 (d, 1H, J=7.4 Hz),
6.56 (s, 1H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.32 (s,
3H), 3.25 (t, 4H, J=6.7 Hz), 2.98 (d, 2H, J=11.1 Hz),
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2.43 (m, 1H), 2.38 (t, 2H, J=7.5 Hz), 1.13 (d, 2H, J=7.5
Hz), 2.10-2.01 (m, 2H), 1.75-1.64 (m, 6H), 0.91 (d, 6H,
J=5.8 Hz); ESMS m/e: 656.4 (M + H)+
Example 43
The product was obtained according to the method
described for methyl (4S)-4-(3,4-difluorophenyl)-3-({[3-
(4-{3-[(3,3-dimethylbutanoyl)amino]phenyl}-1-
piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-
oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
METHYL (4S)-4-(3,4-DIFLUOROPHENYL)-3-{[(3-{4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)AMINO]CARBONYL}-6-(METHOXYMETHYL)-2-
OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 16.4 mg
(73o yield) 8 1H NMR (400 MHz, CDC13) 8 7.37 (s, 1H) , 7.28
(d, 1H, J=7.3 Hz), 7.16-7.01 (m, 5H), 6.88 (d, 2H, J=7.3
Hz), 6.54 (s, 1H), 4.56 (ABq, 2H), 3.62 (s, 3H), 3.32
(s, 3H), 3.25 (t, 2H, J=6.8 Hz), 3.23-3.18 (m, 2H), 3.03
(d, 2H, J=11.7 Hz), 2.57-2.48 (m, 1H), 2.43 (t, 2H,
J=8.0 Hz), 2.14 (t, 2H, J=9.4 Hz), 1.8-1.65 (m, 5H),
1.09 (d, 6H, J=6.3 Hz); ESMS m/e: 642.4 (M + H)+
Example 44
The product was obtained according to the method
described for methyl (4S)-4-(3,4-difluorophenyl)-3-({[3-
(4-{3-[(3,3-dimethylbutanoyl)amino]phenyl}-1-
piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-
oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
METHYL ( 4 S ) -3- { [ ( 3- { 4- [ 3- ( BUTYRYLAMINO) PHENYL] -1-
PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(3,4-
DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-
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TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 14.7 mg (65.50
yield) b 1H NMR (400 MHz, CDCt;) $ 7.38 (s, 1H) , 7.26 (s,
1H), 7.17-6.99 (m, 5H), 6.87 (s, 1H), 6.55 (s, 1H), 4.56
(ABq, 2H), 3.63 (s, 3H), 3.33 (s, 3H), 3.28-3.17 (m,
6H), 3.0 (br s, 2H), 2.51-2.36 (m, 3H), 2.25 (t, 2H,
J=5.0 Hz), 2.10 (br s, 2H), 1.8-1.56 (m, 6H), 0.90 (t,
3H, J=5.0 Hz); ESMS m/e: 642.4 (M + H)+,
Example 45
(4R)-N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)-4-(3,4-DIFLUOROPHENYL)-6-
(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE
Method:
(4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-
1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid: A
stirred mixture of one mole equivalent of methyl (4R)-4-
(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-
tetrahydro-5-pyrimidinecarboxylate (10.0 g, 32.0 mmol)
and lithium hydroxide (2 equivalents, 1.53 g, 64.0 mol)
in Hz0-THF (2:1, 300 mL) was heated at reflux temperature
for 1 h. The reaction mixture was concentrated,
dissolved in water, washed with ethyl acetate and
acidified (1 N HC1) to pH 3-4~(pH paper). The
precipitated product was collected, washed with water
and dried under reduced pressure to give the desired
product in 90o yield.
(4R) -4- (3, 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -N- [3- (4-
(3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINYL)PROPYL]-2-
OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE: A
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solution of (4R)-4-(3,4-difluorophenyl)-6-
(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-
pyrimidinecarboxylic acid (1.2 eq), EDC (1.5 Eq.), N-
methylmorpholine (2.0 Eq.) in dichloromethane was
stirred at room temperature for 15 minutes, followed by
addition of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-
pyridinyl)-1-propanamine (1.0 eq.) to the reaction
mixture. The resulting solution was stirred for 18
hours, concentrated and chromatographed on silica to
give (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-[3-
(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-
2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide.
(4R) -N-{3- [4- (3-AMINOPHENYI~) -1-PIPERIDINYI~] PROPYI~}-4-
( 3 , 4-DIFhUOROPHENYI~) -6- (METHOXYMETHYI~) -2-OXO-1; 2 , 3 , 4-
TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE: A mixture of (4R)-4-
( 3, 4-difluorophenyl) -6- (methoxymethyl) -N- [3- (4- (3-
nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-2-oxo-
1,2,3,4-tetrahydro-5-pyrimidinecarboxamide, loo PdIC in
ethanol was hydrogenated .(balloon method) for 2 days.
The reaction mixture was filtered through Celite 545,
washed with ethanol and concentrated to give the desired
product.
(4R) -N- (3-{ 4- [3- (BUTYRYI~AMINO) PHENYL] -1-
PIPERIDINYI~}PROPYta) -4- (3, 4-DIFI~UOROPHENYI~) -f-
(METHOXYMETHYI~) -2-OXO-1, 2 , 3 , 4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE: Into a 20 mL vial was added(4R)-
N-~3-[4-(3-aminophenyl)-1-piperidinyl]propyl}-4-(3,4-
difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-
tetrahydro-5-pyrimidinecarboxamide (0.040 mmol), acid
chloride (1.5 eq) and N,N-diisopropylethylamine (5.0 eq)
in 2.0 mL of dichloromethane at room temperature. After
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24 hrs, the xeaction mixture was concentrated in vacuo
and purified by preparative TLC (silica, 2000 microns,
95:5 = dichloromethane ..methanol with 10 of
isopropylamine) to give 9.2 mg (45% yield) of the
desired product: 1H NMR (400. MHz, CD30D) 8 7.49 (s, 1H),
7.25 (d, 1H, J=7.6 Hz), 7.20-7.02 (m, 5H), 6.91 (d, 1H,
'J=8 Hz), 5.29 (s, 1H), 4.24 (ABq, 2H), 3.30 and 3.24
(two s, 3H), 3.46-3.12 (m, partially hidden by three s,
4H), 2.74 (br s, 4H), 2.25 (t, 2H, J=8.2 Hz), 2.04-1.69
(m, 7H), 1.63 (sextet, 2H, J=7.4 Hz), 0.91 (t, 3H, 7.4
Hz); ESMS m/e: 584.4 (M + H)+.
Exaiaple 46
The product was obtained according to the method
described for (-4R) -N- (3-{4- [3- (butyrylamino) phenyl] -1-
piperidinyl}propyl)-4-(3,4-difluorophenyl)-6-
(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-
pyrimidinecarboxamide.
(4R)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-N-
(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-
1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE: 5.6 mg
(24 . 6% yield) ; 1H NMR (40.0 MHz, CD30D) 8 7 .56 (s, 1H) ,
7.35 (d, 1H, J=6.9 Hz), 7.3-7.03 .(m, 4H), 7.17 (br s,
1H), 6.99 (d, 1H, J=7.0 Hz), 5.45 (s, 1H), 4,.33 (ABq,
2H), 3.41 (s, 3H), 3.37-3.23 (m, partially hidden, 4H),
2.8 (br s, 4H), 2.39 (d, 2H, J=9.3 Hz), 2.14-1.78~(m,
7H) , 1.21 (t, 3H, J=7. 6 Hz) ; ESMS m/e: 570. 4 (M + H) +.
Example 47
The product was obtained according to the method
described for (4R)-N-(3-(4-[3-(butyrylamino)phenyl]-1-
piperidinyl}propyl)-4-(3,4-difluorophenyl)-6-
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(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-
pyrimidinecarboxamide.
(4R)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-N-[3-(4-
{3-[(3-METHYLBUTANOYL)AMINO]PHENYL}-1-
PIPERIDINYL)PROPYL]-2-OXO-1,2,3,4-TETRAHYDRO-5-
,PYRIMIDINECARBOXAMIDE: 11.1 mg (46o yield): 1H NMR (400
MHz, CD30D) S 7.81 (d, 1H, J=8 .5 Hz) , 7. 6 (s, 1H) , 7 .55 (s,
1H), 7.36 (br s, 1 H), 7.31-7.17 (m, 3H), 7.01 (t, 1H,
J=6.7 Hz) 6.64-6.61 (m, 1H), 5.45 (br s, 1H), 4.32 (ABq,
2H), 3.94 and 3.87 ,(two s, 3H), 3.42-3.12 (m, partially
hidden, 2H), 3.1 (br s, 2H), 3.0 (t, 2H, J=11.1 Hz),
2.79-2.57 (m, 4H), 2.27-1.73 (m, 8H), 1.19 and 1.01 (two
d, 6H, J=6.6 Hz); ESMS m/.e: 598.4 (M + H)+.
Example 48
The product was obtained according to the method
described for (4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-
piperidinyl}propyl)-4-(3,4-difluorophenyl)-6-
(methoxymethyl)-2-oxo-1,2;3,4-tetrahydro-5-
pyrimidinecarboxamide. . ,
(4R)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-N-[3-(4-
{3-[(2-METHYLBUTANOYL)AMINO]PHENYL}-1-
PIPERIDINYL)PROPYL]-2-OXO-1,2,3,4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE: 6.7 mg (28o yield); 1H NMR (400
MHz, CD30D) 8 7.59 (s, 1H), 7.35 (br s, 1H), 7.3-7.2 (m,
3H), 7.17 (br s, 1H), 7.01 (d, 1H, J=6.8 Hz), 5.45 (s,
1H), 4.33 (ABq, 2H), 3.39 (s, 3H), 3.29 (m, 2H), 2.84
(br s, 4H), 2.42 (m, 1H), 2.14-1.78 (m, 9H), 1.7 (m,
1H), 1.49 (m, 1H), 1.20 (d, 3H, J=6.7 Hz), 0.95 (t, 3H,
J=6.6 Hz); ESMS m/e: 598.4 (M + H)+.
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Example 49 .-
The product was obtained according to the method
described for (4R)-N-(3-{4-[3-(butyrylamino)-phenyl]-1-
piperidinyl}propyl)-4-(3,4-difluoropheriyl~)=6-
(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-
pyrimidinecarboxamide. .
(4R)-4-(3,4-DIFLUOROPHENYL)-N-[3-(4-{3-[(3,3-
DIMETHYLBUTANOYL)AMINO]PHENYL}-1-PIPERIDINYL)PROPYL]-6-
(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE: 1.1 mg (4.4o yield): 1H NMR (400
MHz, CD30D) 8 7 . 6-6. 91 (m, 7H) , 5.43 (s, 1H) , 4 .31 (ABq,
2H), 3.40 (s, 3H), 3.27-1.26 (m, 17 H), 1.09 (s, 9H);
ESMS m/e: 612.4 (M + F~)+.
Example 50
The product was obtained according to the method
described for (4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-
piperidinyl}propyl)-4-(3,4-difluorophenyl)-6-
-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-
pyrimidinecarboxamide.
( 4R) -4- ( 3, 4-DIFLUOROPHENYL) -N- ( 3- { 4- [ 3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-6-
(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE:. 12.7 mg (54o yield); iH NMR (.400..
MHz, CD30D) 8 7.59(s, 1H),,7.36 (d, 1H, J=8.6 Hz), 7.31-
7.07 (m, 4H), 7.01 (d, 1H, J=6.5 Hz), 5.39 (s, 1H), 4.34
(ABq, 2H), 3.35 (s, 3H), 3.33-3.19 (m, partially hidden,
2H), 3.08-2.72 (m, 4H), 2.63 (t, 2H, J=7.2 Hz), 2.14-
1.82 (m, 8H), 1.19 (d, 6H, J=6.9 Hz); ESMS m/e: 5.84.4 (M
+ H) *.
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Example 51
The synthetic method is the same as described for the
synthesis of ( 4S) -N- (3-{ 4- [3- (acetyl amino) phenyl] -1-
piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
5-ACETYL-N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-
IPIPERIDINYL}PROPYL)-4-METHYL-2-OXO-6-(3,4,5-
TRIFLUOROPHENYL)-3,6-DIHYDRO-1(2H)-
PYRIMIDINECARBOXAMIDE: 14.5 mg (46% yield); 1H NMR (400
MHz, CDC13) 8 9.56 (s, 1H), 9.20 (s, 1 H), 8.21 (s, 1H),
7.52 (s, 1H), 7.18 (t, 1H, J=7.8 Hz), 7.07-6.75 (m, 5H),
3.59-3.37 (m, 1H), 3.48-3.38 (m, 1H), 3.08 (br s, 2H),
2.57-2.39 (m, 5H), 2.25 (s, 3H), 2.21 (s, 3H), 2.19-1.59
(m, 9H)~ ESMS m/e: 586.3 (M + H)+; Anal. Calc. for
C30H34F3N5~4'f'O.1CHC13: C, 60.50; H, 5'.75; N, 11.72. Found:
C, 60.59; H, 5.40; N, 11.73.
Example 52
The synthetic method is the same as described for the ~~
synthesis of (4S) -N- (3-{ 4- [3- (acetyl amino) phenyl] -1-
piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
BENZYL 3-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(2,4-
DIFLUOROPHENYL)-6-ETHYL-2-OXO-1,2,3,4-TETRAHYDRO-5-
PYRIMIDINECARBOXYLATE: 14.8 mg (41o yield); 1H NMR (400
MHz, CDC13) 8 9.05 (br s, 1H) , 8.14 (s, 1H) , 7 .47 (s, 1H) ,
7.37-7.21 (m, 8H), 7.18 (t, 1H, J=7.7 Hz), 6.94 (d, 1H,
J=6.9 Hz), 6.87 (d, 1H, J=7.4 Hz), 6.7-6.62 (m, 3H),
5.09 (q. 2H, J=17.8 Hz), 3.48-3.24 (m, 2H), 3.04 (ABq,
2H), 2.88-2.71 (m, 2H), 2.52-2.39 (m, 2H), 2.19 (s, 3H),
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2.17-1.88 (m, 3H), 1.77-1.58 (m, 3H), 1.19 (t, 3H, J=7.5
Hz); ESMS mle: 674.4 (M + H)+.
Example 53
The synthetic method is the same as described for the
synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl]-1-
piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-4-
(1,3-BENZODIOXOL-5-YL)-2,5-DIOXO-1,2,5,7-
TETRAHYDROFURO[3,4-D)PYRIMIDINE-3(4H)-CARBOXAMIDE: 8.75
mg (28% yield); 1H NMR (400 MHz, CDC13) ~ 9.81 (s, 1H),
8.14 (s, 1H), 7.53 (s, 1H). 7.21 (t, 1H, J=7.7 Hz), 6.99
(d, 1H, J=7.7 Hz) , 6. 91-6.7 (m, 4H) , 6.42 (s, 1'H) , 5. 9
(s, 2H), 4.75 (s, 2H), 3.61-3.5 (m, 1H), 3.37-3.27 (m,
1H), 3.08 (br s, 2H), 2.56-2.40 (m, 3H), 2.18 (s, 3H),
2.16-1.85 (m, 4H), 1.78-1.6 (m, 5H); ESMS m/e: 57.3 (M
+ H)+.
Example 54
The synthetic method is the same as described for the
synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl]-1-
piperidinyl}propyl)-4-(3,-5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
METHYL 1-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)AMINO]CARBONYL}-2-[(4-
METHOXYBENZYL)SULFANYL]-4-METHYL-6-(4-NITROPHENYL)-1,6-
DIHYDRO-5-PYRIMIDINECARBOXYLATE: 10.1 mg (26o yield); 1H
NMR (400 MHz, CDC13) 8 8.02 (d, 2H, J=7 .5 Hz) , 7.53 (br s,
1H), 7.44-7.27 (m, 6H), 7.14 (d, 2H, J=8.5 Hz), 6.99 (d,
1H, J=7.6 Hz), 6.75 (d, 2H, J=8.5 Hz), 6.2 (s, 1H), 4.23.
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(ABq, 2H) , 3.78 (s, 3H) , 3.7 (s, 3H) , 3. 58-3..48 (m, 1H)
3.37-3.26 (m, 2H), 3.04 (m, 2H), 2.61-2.43 (m, 3H), 2.41
(s, 3H), 2.16 (s, 3H), 2.15-1.64 (m, 8H); ESMS m/e:
729.3 (M + H)+.
Example 55
The synthetic method is the same as described for the
' synthesis of (4S) -N- (3-{ 4- [3- (acetyl amino) phenyl] -1-
piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-4-
(2,1,3-BENZOXADIAZOL-5-YL)-2,5-DIOXO-1,2,5,7-
TETRAHYDROFURO[3,4-D]PYRIMIDINE-3(4H)-CARBOXAMIDE: 7.7
mg ( 12 o yield) ; 1H NMR (400 MHz, CDC13) 8 7 . 97-6. 83 (m,
7H) , 6. 49 (s, 1H) , 5.51 (s, 1H) , 3. 43-2.02 (m, 17 H) ,
1.82 (s, 3H); ESMS m/e: 574.3 (M + H)+.
Example 56
The synthetic method is the same as described for the
synthesis of (4S)-N-(3-{4-[3-(acetylamino)phenyl]-1-
piperidinyl}propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
METHYL (4S)-3-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(3,4- , a
DIFLUOROPHENYL)-6-METHYL-2-OXO-1,2,3,4-TETRAHYDRO-5-
PYRIMIDINECARBOXYLATE: 16.6 mg (52o yield); 1H NMR (400
MHz, CDC13) 8 9. 55 ' (br s, 1H) , 9. 07 (s, 1H) , 8.19 (s,
1H), 7.54 (s, 1H), 7.25-6.98 (m; 4H), 6.95 (d, 1H, J=8.0
Hz) , 6.81 (d, 1H, J=7.5 Hz) , 6. 69 (s, 1H) , 3.70 (s, 3H) ,
3.57-3.34 (m, 2H), 3.06 (t, 2H, J=11.6 Hz), 2.47 (t, 2H,
J=8.1 Hz), 2.42 (s, 3H), 2.20 (s, 3H), 2.18-1.61 (m,
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191
9H); ESMS m/e: 584.3 (M + H)+; Anal. Calc. for
CsoHssFzNsO+0.25CHC13: C, 59.23; H, 5.79; N, 11.42. Found:
C, 59.61; H, 5.31; N, 11.48.
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Peptide Synthesis:
Abbreviations: Fmoc: 9-Fluorenyloxycarbonyl-; Trityl:
triphenylmethyl-; tBu-. tertiary butyl ester; OtBu-.
tertiary butyl ether; Ng: N-guanidinyl; Nin: N-Indole;
MBHA . methylbenzhydlamine; DMF: N,N-dimethylformamide;
NMP: N-Methylpyrrolidinone; DIEA: diisopripylethyl
amine; TFA: trifluoroacetic acid.
Small scale peptide syntheses were performed either
manually, by using a sintered glass column with argon
pressure to remove solvents and reagents, or by using an
Advanced ChemTech 396-9000 automated peptide synthesizer
(Advanced ChemTech, Louisville, KY). Large scale peptide
syntheses were performed on a CS Bio 536 (CS Bio Inc.,
San Carlos, CA). Fmoc-Alanine-OH,
Fmoc-Cysteine(Trityl)-OH, Fmoc-Aspartic acid(tBu)-OH,
Fmoc-Glutamic acid(tBu)-OH, Fmoc-Phenylalanine-OH,
Fmoc-Glycine-OH, Fmoc-Histidine(Trityl)-OH,
Fmoc-Isoleucine-OH, Fmoc-Lysine(Boc)-OH, Fmoc-Leucine-OH,
Fmoc-Methionine-OH, Fmoc-Psparagine(Trityl)-OH,
Fmoc-Proline-OH, Fmoc-Glutamine(Trityl)-OH,
Fmoc-Arginine(Ng-2,2,4,6,7-Pentamethyldihydrobenzofuran-5
-sulfonyl)-OH, Fmoc-Serine(OtBu-OH,
Fmoc-Threonine(OtBu)-OH, Fmoc-Valine-OH,
Fmoc-Tryptophan(NinBoc)-OH, Fmoc-Tyrosine(OtBu)-OH,
Fmoc-Cyclohexylalanine-OH, and Fmoc-Norleucine , Fmoc
-O-benzyl-phosphotyrosine were used as protected amino
acids. Any corresponding D-amino acids had the same
side-chain protecting groups, with the exception of
Fmoc-D-Arginine, which had a Ng-2,2,5,7,8-pentamethyl-
chroman-6-sulfonyl protecting group.
Peptides with C-terminal amides were synthesized on solid
CA 02384041 2002-03-05
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phase using Rink amide-MBHA resin. The Fmoc group of the
Rink Amide MBHA resin was removed by treatment with 300
piperidine in DMF for 5 and 30 minutes respectively.
After washing with DMF (3 times), methanol (2 times) and
DMF/NMP (3 times), the appropriate Fmoc-protected amino
acid (4 eq.) was coupled for 2 hours with HBTU or HATU
(4eq.) as the activating agent and DIEA (8eq.) as the
base. In manual syntheses, the ninhydrin test was used
to test for complete coupling of the amino acids. The
Fmoc groups were removed by treatment with 30o piperidine
in DMF for 5 and 30 minutes respectively. After washing
with DMF (3 times), methanol (2 times) and DMF/NMP (3
times), the next Fmoc-protected amino acid (4 eq.) was
coupled for 2 hours with HBTU or HATU (4eq.) as the
activating agent and DIEA (8eq.) as the base. This
process of coupling and deprotection of the Fmoc group
was continued until the desired peptide was assembled on
the resin. The N-terminal Fmoc group was removed by
treatment with 30o piperidine in DMF for 5 and 30 minutes
respectively. After washing with DMF (3 times), methanol
(2 times), the resins) was vacuum dried for 2 hours.
Cleavage of the peptide-on-resin and removal of the side
chain protecting groups was achieved by treating with TFA
. ethanedithiol . thioanisole: m-cresol . water .
triisopropylsilane . phenol, 78/5/3/3/3/5/3 (5 mL per 100
mg resin) for 2.5-3 hours. The cleavage cocktail
containing the peptide was filtered into a round bottom
flask and the volatile liquids were removed by rotary
evaporation at 30-40 °C. The peptides were precipitated
with anhydrous ether, collected on a medium-pore sintered
glass funnel by vacuum filtration, washed with ether and
vacuum dried.
Peptides with C-terminal acids were synthesi2ed using
2-chlorotrityl chloride resin. The first amino acid was
CA 02384041 2002-03-05
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attached to the resin by dissolving 0.6-l.2eq. of the
appropriate Fmoc-protected~amino acid described above in
dichloromethane (a minimal amount of DMF was added to
facilitate the dissolution, if necessary). To this was
added DIEA (4 eq. Relative to the Fmoo-amino acid) and
the solution was added to the resin and shaken for 30-120
minutes. The solvents and the excess reagents were
drained and the resin was washed with dichloromethane /
methanol / DIEA (17/2/1) (3 times), dichloromethane (3
times), DMF (2 times), dichloromethane (2 times), and
vacuum dried. The process of deprotection of the Fmoc
group and coupling the appropriate Fmoc-protected amino
acid was continued as described above, until the desired,
fully protected peptide was assembled on the resin. The
process for removal of the final Fmoc group and the
cleavage and deprotection of the peptides was the same as
described above for the peptides with C-terminal amides.
Purification of the peptides was achieved by preparative
high performance column chromatography (HPLC), using a
reverse-phase C-18 column (25 x 250mm) (Primesphere or
Vydac) with a gradient of acetonitrile (0.1% TFA) in
water (0.1% TFA). The general gradient was from 100-900
acetonitrile in water over 40 minutes. The fractions
corresponding to each peak on the HPLC trace was
collected, freeze dried and analyzed by electrospray mass
spectrometery. The fraction having the correct mass
spectral data corresponding to the desired peptide was
then further analyzed by amino acid analysis, if
necessary. All purified peptides were tested for
homogeneity by analytical HPLC using conditions similar
to that described above, but by using a 2.5x250 mm
analytical column, and generally were found to have >950
purity.
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References:
See our published dihydropyrimidinone and oxazolidinone
patents as references for the synthesis of the templates
and the piperidines.
Also, for the synthesis of~the aminopropyl piperidines
and the templates, see:
Lagu, Bharat, et al., Design and synthesis of novel ala
adrenoceptor-selective antagonists. 3. Approaches to
eliminate opioid agonist metabolites by using substituted
phenylpiperazine side chains. J. Med. Chem. (1999),
42(23), 4794-4803. CODEN: JMCMAR ISSN:0022-2623. CAN
132:78527 AN 1999:680975 CAPLUS
Dhar, T. G. Murali, et al., Design and Synthesis of
Novel aza Adrenoceptor-Selective Antagonists. 2.
Approaches To Eliminate Opioid Agonist Metabolites via
Modification of Linker and 4-Methoxycarbonyl-4-phenyl
piperidine Moiety. J. Med. Chem. (1999), 42(23),
4778-4793. CODEN: JMCMAR ISSN:0022-2623. CAN 132:18483
AN 1999:680971 CAPLUS
Nagarathnam, Dhanapalan, et al., Design and Synthesis of
Novel a,za Adrenoceptor-Selective Antagonists. 1.
Structure-Activity Relationship in Dihydropyrimidinones.
J. Med. Chem. (1999), 42(23), 4764-4777. CODEN:
JMCMAR ISSN:0022-2623. CAN 132:18482 AN 1999:680967
CAPLUS
along, Wai C., et al., Design and Synthesis of Novela~a
Adrenoceptor-Selective Antagonists. 4. Structure-Activity
Relationship in the Dihydropyrimidine Series. J. Med.
Chem. (1999), 42(23), 4804-4813. CODEN: JMCMAR
CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
-196-
ISSN:0022-2623. CAN 132:30317 AN 1999:680947 CAPLUS
Marzabadi, Mohammad R., et al., Design and synthesis of
novel dihydropyridine alpha-1A antagonists. Bioorg.
Med. Chem. Lett. (1999), 9(19), 2843-2848. CODEN:
BMCLE8 ISSN:0960-894X. CAN 132:44482 AN 1999:662323
CAPLUS
along, Wai C., et al., Alpha-1a adrenoceptor selective
antagonists as novel agents for treating benign prostatic
hyperplasia. Book of Abstracts, 217th ACS National
Meeting, Anaheim, Calif., March 21-25 (1999),
MEDI-156. CODEN: 67GHA6 AN 1999:92669 CAPLUS
Nagarathnam, D., et al., Design, synthesis and
evaluation of dihydropyrimidinones as alpha-1a selective
antagonists: 7. Modification of the piperidine moiety
into 4-aminocyclohexane; identification and
structure-activity relationship of SNAP 6991 analogs.
Book of Abstracts, 217th ACS National Meeting, Anaheim,
Calif., March 21-25 (1999), MEDI-110. CODEN: 67GHA6
AN 1999:92624 CAPLUS
Lagu, Bharat, et al., Heterocyclic substituted
oxazolidinones for use as selective antagonists for human
a 1A receptors. PCT Int. Appl. (1998), 258 pp.
CODEN: PIXXD2 WO 9857940 A1 19981223 CAN 130:81508
AN 1999:9823 CAPLUS
along, Wai C., et al., Preparation of piperidinylpropyl
aminocarbonyldihydropyrimidones and related compounds as
selective adrenergic a 1A receptor antagonists. PCT
Int. Appl. (1998), 314 pp. CODEN: PIXXD2 WO
9851311 A2 19981119 CAN 130:25077 AN 1998:764290
CAPLUS
CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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Nagarathnam, Dhanapalan, et al., Design and synthesis of
novel a1a adrenoceptor-selective dihydropyridine
antagonists for the treatment of benign prostatic
hyperplasia. J. Med. Chem. (1998), 41(26),
5320-5333. CODEN: JMCMAR ISSN:0022-2623. CAN
130:110137 AN 1998:742998 CAPLUS
For the general procedure for Pd coupling of vinyl
triflate and bononic acids or tributyl tin reagents: See,
Wuston, Wise Synthesis 1991, 993)
(For Typical References, See:Schroeter, G. Ber. (1909)
42, 3356; and Allen, C.F.H.; Bell, A. Org. Syn. Coll.
Vol. 3, (1955) 846) .
For the preparation of the ether N-[4-(benzo-4',5'[H]-
furanpiperidine refer to W.E.Parham et al, J. Org. Chem.
(1976) 41, 2268.
For the preparation of the ether piperidine precursor of
Example 20, refer to W.E.Parham et al, J. Org. Chem.
(1976) 41, 2268.
For the preparation of the indane piperidine precursor of
Example 21, refer to M.S.Chambers J. Med. Chem. (1992)
35, 2033.
For the preparation of the piperidine precursor of
Example 23, (K.Hashigaki et a1. Chem.Pharm.Bull. (1984)
32, 3568.)
For the preparation of the piperidine precursor of
Example 32, spiro[1H-indane-1,4'-piperidine], refer to
M.S.Chambers et al. J. Med. Chem. (1992) 35, 2033.)
CA 02384041 2002-03-05
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cr
(; v
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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w
a.
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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I
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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=Z
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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~- N- N~ N-
x . N. . o N O O
H~-z°~~
z\ z \ \~o O
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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r. r. r.
r.
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r- +
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a
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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x
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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0
n
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n
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m
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m
N.
0
Z / _ . Z 111
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= 0
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O =
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n~ Z
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
-206-
N. N. .
N..
ro O
z~.i~~~ O
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x ~ ~- cr N- O
C7 m <r ~' Q,
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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x r- C < < C r- r- r- r- p O
r. r. r. . C r. r. .
r. r. . . r. . O
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m o ro -n ~< r N
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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o ~ O O O O
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
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s
m
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CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
-210-
D
II
N
rx (D f)
a"' O
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z.0 ~ _
Z ~"'D W
O O
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CA 02384041 2002-03-05
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Scheme 14: Synthesis of Substituted Dihyropyrimidinones and Reverse
Dihydropyrimidinones
N02 I ~ N02
reagent 1
N N
BOC ~ NH2
F 1. base, p-nitropheny!-
F chloroformate F
2, reagent 1
/ 3. H2, Pd/C
O 4. acylate or O''
~O NH sulfonylate ~N~N
H H
N O O ~ N'
~O H ~O n ~ /
From chiral
chromatography
F F
F 1. LiOH, heat F /
/ 2. EDC, reagent 1 ~ O
3. H2, Pd/C
NH 4. acylate or HN . NON H
sulfonylate ~ ~ ~ H
N O O N ~ N'X~l
H H O~ I / O
From chiral
chromatography
EDC = ethyl dimethylaminopropyl carbodiimide hydrochloride
X = C, S(=O)
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II. Synthetic Methods for General Structures
The examples described in Section I are merely illustrative
of the methods used to synthesize MCH1 antagonists.
Further derivatives may be obtained utilizing generalized
methods based on the synthetic methods used to synthesize
the examples.
It may be necessary to incorporate protection and
deprotection strategies for substituents such as amino,
amido, carboxylic acid, and hydroxyl groups in the
generalized synthetic methods to form further derivatives.
Methods for protection and deprotection of such groups are
well-known in the art, and may be found, for example in
Green, T.W. and Wuts, P.G.M. (1991) Protection Groups in
0raanic Synthesis, 2n~ Edition John Wiley & Sons, New York.
III. Oral Compositions
As a specific embodiment of an oral composition of a
compound of this invention; 100 mg of one of the compounds
described herein is formulated with sufficient finely
divided lactose to provide a total amount of 580 to 590 mg
to fill a size 0 hard gel capsule.
IV. Pharmacological Evaluation of Compounds at Cloned
MCH1, NPY, Galanin, and 5-HT2.C Receptors
The pharmacological properties of the compounds of the
present invention were evaluated at one or more of the
cloned human MCH1, NPY1, NPY5, GALR1, GALR2, and GALR3 and
rat 5-HT2C receptors using protocols described below.
Host cells
A broad variety of host cells can be used to study
heterologously expressed proteins. These cells include but
CA 02384041 2002-03-05
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are not restricted to assorted mammalian lines suciz as;
Cos-7, CHO, LM(tk-), HEK293, etc.; insect cell lines such
as; Sf9, Sf2l, etc.; amphibian cells such as xenopus
oocytes; and others.
COS-7 cells are grown on 150 mm plates in DMEM with
supplements (Dulbecco's Modified Eagle Medium with 100
bovine calf serum, 4 mM glutamine, 100 units/ml
penicillin/100 ~g/ml streptomycin) at 37°C, 5o CO2. Stock
plates of COS-7 cells are.trypsinized and split 1:6 every
3-4 days.
Human embryonic kidney 293 cells are grown on 150 mm plates
in DMEM with supplements (loo bovine calf serum, 4 mM
glutamine, 100 units/ml penicillin/100 ~.g/ml streptomycin)
at 37°C, 5o COz. Stock plates of 293 cells are trypsinized
and split 1:6 every 3-4 days.
Mouse fibroblast LM(tk-) cells are grown on 150 mm plates
in D-MEM with supplements (Dulbecco's Modified Eagle Medium
with 10% bovine calf serum, 4 mM glutamine, 100 units/ml
penicillin/100 ~g/ml streptomycin) at 37°C, 5o CO.,. Stock
plates of LM(tk-) cells are trypsinized and split 1:10
every 3-4 days.
Chinese hamster ovary (CHO) cells were grown on 150 mm
plates in HAM's F-12 medium with supplements (10o bovine
calf serum, 4 mM L-glutamine and 100 units/ml penicillin/
100 ~g/ml streptomycin) at 37°C, 5o C02. Stock plates of
CHO cells are trypsinized and split 1:8 every 3-4 days.
Mouse embryonic fibroblast NIH-3T3 cells are grown on 150
mm plates in Dulbecco's Modified Eagle Medium (DMEM) with
supplements (10o bovine calf serum, 4 mM glutamine, 100
units/ml penicillin/100 ~.g/ml streptomycin) at 37°C, 5o CO~.
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Stock plates of NIH-3T3 cells are trypsinized and split
1:15 every 3-4 days.
Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue
culture dishes in TMN-FH media supplemented with 10o fetal
calf serum, at 27°C, no CO.,. High Five insect cells are
grown on 150 mm tissue culture dishes in Ex-Cell 400TM
medium supplemented with L-Glutamine, also at 27°C, no CO2.
In some cases, cell lines that grow as adherent monolayers
can be converted to suspension culture to increase cell
yield and provide large batches of uniform assay material
for routine receptor screening projects.
Transient expression
DNA encoding proteins to be studied can be transiently
expressed in a variety of mammalian, insect, amphibian and
other cell lines by several methods including but not
restricted to; calcium phosphate-mediated, DEAE-dextran
mediated, Liposomal-mediated, viral-mediated,
electroporation-mediated and microinjection delivery. Each
of these methods may require optimization of assorted
experimental parameters depending on the DNA, cell line,
and the type of assay to be subsequently employed.
A typical protocol for the calcium phosphate method as
applied to LM(tk-) cells is described as follows; Adherent
cells are harvested approximately twenty-four hours before
transfection and replated at a density of 1-2 x 10'
cells/cm= in a 100 mm tissue culture dish and allowed to
incubate over night at 37°C at 5o C02. 250 p1 of a mixture
of CaCl2 and DNA (20 ~g DNA in 250 mM CaClz) is added to a
5 ml plastic tube and 250 u1 of 2X HBS (250 mM NaCl, 10 mM
KCl, 1.5 mM Na2HP04, 12 mM dextrose, 50 mM HEPES) is slowly
added with gentle mixing. The mixture is allowed to
CA 02384041 2002-03-05
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incubate for 20 minutes at room temperature to allow a DNA
precipitate to form. The cells are then washed with
complete medium, 10 ml of culture medium is added to each
plate, followed by addition of the DNA precipitate. The
cells are then incubated for 24 to 48 hours at 37°C at 50
CO,, .
A typical protocol for the DEAE-dextran method as applied
to Cos-7 cells is described as follows; Cells to be used
for transfection are split 24 hours prior to the
transfection to provide flasks which are 70-80o confluent
at the time of transfection. Briefly, 8 ug of receptor DNA
plus 8 ~g of any additional DNA needed (e. g. Ga protein
expression vector, reporter construct, antibiotic
resistance marker, mock vector, etc.) are added to 9 ml of
complete DMEM plus DEAE-dextran mixture (10 mg/ml in PBS).
Cos-7 cells plated into a T225 flask (sub-confluent) are
washed once with PBS and the DNA mixture is added to each
flask. The cells are allowed to incubate for 30 minutes at
37°C, 5o CO~. Following the incubation, 36 ml of complete
DMEM with 80 ~M chloroquine is added to each flask and
allowed to incubate an additional 3 hours. The medium is
then aspirated and 24 ml of complete medium containing 10%
DMSO for exactly 2 minutes and then aspirated. The cells
are then washed 2 times with PBS and 30 ml of complete DMEM
added to each flask. The cells are then allowed to
incubate over night. The next day the cells are harvested
by trypsinization and reseeded as needed depending upon the
type of assay to be performed.
A typical protocol for liposomal-mediated transfection as
applied to CHO cells is described as follows; Cells to be
used for transfection are split 24 hours prior to the
transfection to provide flasks which are 70-80o confluent
at the time of transfection. A total of 10~g of DNA which
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may include varying ratios of receptor DNA plus any
additional DNA needed (e. g. Ga protein expression vector,
reporter construct, antibiotic resistance marker, mock
vector, etc.) is used to transfect each 75 cmz flask of
cells. Liposomal mediated transfection is carried out
according to the manufacturer's recommendations
(LipofectAMINE, GibcoBRL, Bethesda, MD). Transfected cells
are harvested 24 h post transfection and used or reseeded
according the requirements of the assay to be employed.
A typical protocol for the electroporation method as
applied to Cos-7 cells is described as follows; Cells to be
used for transfection are split 24 hours prior to the
transfection to provide flasks which are subconfluent at
the time of transfection. The cells are harvested by
trypsinization resuspended in their growth media and
counted. 4 x 106 cells are suspended in 300 ~a.1 of DMEM and
placed into an electroporation cuvette. 8 ug of receptor
DNA plus 8 ~.g of any additional DNA needed (e. g. Ga protein
expression vector, reporter construct, antibiotic
resistance marker, mock vector, etc.) is added to the cell
suspension, the cuvette is placed into a BioRad Gene Pulser
and subjected to an electrical pulse (Gene Pulser settings:
0.25 kV voltage, 950 uF capacitance). Following the pulse,
800 ~1 of complete DMEM is added to each cuvette and the
suspension transferred to a sterile tube. Complete medium
is added to each tube to bring the final cell concentration
to 1 x 10' cells/100 ~1. The cells are then plated as
needed depending upon the type of assay to be performed.
A typical protocol for viral mediated expression of
heterologous proteins is described as follows for
baculovirus infection of insect Sf9 cells. The coding
region of DNA encoding the receptor disclosed herein may be
subcloned into pBlueBacIII into existing restriction sites
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or sites engineered into sequences 5' and 3' to the coding
region of the polypeptides. To generate baculovirus, 0.5
~g of viral DNA (BaculoGold) and 3 ug of DNA construct
encoding a polypeptide may be co-transfected into 2 x 106
Spodoptera frugiperda insect Sf9 cells by the calcium
phosphate co-precipitation method, as outlined in by
Pharmingen (in "Baculovirus Expression Vector System:
Procedures and Methods Manual"). The cells then are
incubated for 5 days at 27°C. The supernatant of the co-
transfection plate may be collected by centrifugation and
the recombinant virus plague purified. The procedure to
infect cells with virus, to prepare stocks of virus and to
titer the virus stocks are as described in Pharmingen's
manual. Similar principals would in general apply to
mammalian cell expression via retro-viruses, Simliki forest
virus and double stranded DNA viruses such as adeno-,
herpes-, and vacinia-viruses, and the like.
Stable expression
Heterologous DNA can be stably incorporated into host
cells, causing the cell to perpetually express a foreign
protein. Methods for the delivery of the DNA into the cell
are similar to those described above for transient
expression but require the co-transfection of an ancillary
gene to confer drug resistance on the targeted host cell.
The ensuing drug resistance can be exploited to select and
maintain cells that have taken up the heterologous DNA. An
assortment of resistance genes are available including but
not restricted to Neomycin, Kanamycin, and Hygromycin. For
the purposes of receptor studies, stable expression of a
heterologous receptor protein is carried out in, but not
necessarily restricted to, mammalian cells including, CHO,
HEK293, LM(tk-), etc.
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Cell membrane preparation .
For binding assays, pellets of transfected cells are
suspended in ice-cold buffer (20 mM Tris.HCl, 5 mM EDTA, pH
7.4) and homogenized by sonication for 7 sec. The cell
lysates are centrifuged at 200 x g for 5 min at 4°C. The
supernatants are then centrifuged at 40,000 x g for 20 min
at 4°C. The resulting pellets are washed once in the
homogenization buffer and suspended in binding buffer (see
methods for radioligand binding). Protein concentrations
are determined by the method of Bradford (1976) using
bovine serum albumin as the standard. Binding assays are
usually performed immediately, however it is possible to
prepare membranes in batch and store frozen in liquid
nitrogen for future use.
Radioligand bindings assays
Radioligand binding assays for the MCH1 receptor were
carried out using plasmid pEXJ.HR-TL231 (ATCC Accession No.
203197). Plasmid pEXJ.HR-TL231 comprises the regulatory
elements necessary for expression of DNA in a mammalian
cell operatively linked to DNA encoding the human MCH1
receptor so as to permit expression thereof. Plasmid
pEXJ.HR-TL231 was deposited on September 17, 1998, with the
American Type Culture Collection (ATCC), 12301 Parklawn
Drive, Rockville, Maryland 20852, U.S.A. under the
provisions of the Budapest Treaty for the International
Recognition of the Deposit of Microorganisms for the
Purposes of Patent Procedure and was accorded ATCC
Accession No. 203197.
Human embryonic kidney 293 cells (A293 cells) were stably
transfected with DNA encoding the MCH1 receptor utilizing
the calcium phosphate method and cell membranes were
prepared as described above. Binding experiments with
membranes from A293 cells transfected with the human MCH1
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receptor were performed with 0.08 nM [3H]Compound 10 (custom
labeled by Amersham) using an incubation buffer consisting
of 50 mM Tris pH 7.4, 10 mM MgCl2, 0.16 mM PMSF, 1 mM 1,10
phenantroline and 0.2o BSA. Binding was performed at 25°C
for 90 minutes. Incubations were terminated by rapid
vacuum filtration over GF/C glass fiber filters, presoaked
in 5o PEI using 50 nM Tris pH 7.4 as wash buffer. In all
experiments, nonspecific binding is defined using 10 ,uM
Compound 10.
The methods to obtain the cDNA of the human NPY1, NPY5,
GALR1, GALR2, and GALR3 and rat 5-HT2C receptors, express
said receptors in heterologous systems, and carry out
assays to determine binding affinity are described in the
following publications and above: human NPY1 (Larhammar et
al., 1992), human NPY5 (U.S. Patent No. 5,602,024, the
disclosure of which is hereby incorporated by reference in
its entirety into this application), human Gall (Habert-
Ortoli et al., 1994), human Gal2 (Smith et al., 1997),
human Gal3 (Smith et al., 1998), and rat 5-HT2C (Julius et
al., 1988).
Functional assays
Cells may be screened for the presence of endogenous
mammalian receptor using functional assays (described in
detail below). Cells with no or a low level of endogenous
receptor present may be transfected with the exogenous
receptor for use in the following functional assays.
A wide spectrum of assays can be employed to screen for
receptor activation. These range from traditional
measurements of phosphatidyl inositol, CAMP, Ca++, and K+,
for example; to systems. measuring these same second
messengers but which have been modified or adapted to be
higher throughput, more generic, and more sensitive; to
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cell based platforms reporting more general cellular events
resulting from receptor activation such as metabolic
changes, differentiation, and cell division/proliferation,
for example; to high level organism assays which monitor
complex physiological or behavioral changes thought to be
involved with receptor activation including cardiovascular,
analgesic, orexigenic, anxiolytic, and sedation effects,
for example.
Functional assay:
Intracellular calcium mobilization assav
Intracellular calcium mobilization assays for the MCH1
receptor were carried out using plasmid pEXJ.HR-TL231 (ATCC
Accession No. 203197). COS-7 cells were transiently
transfected with DNA encoding the MCH1 receptor utilizing
the DEAE-dextran method as described above. The
intracellular free calcium concentration was measured by
fluorescent imaging using the calcium sensitive fluorscent
dye Fluo-3. COS-7 cells expressing the human MCH1 receptor
were seeded onto sterile 96 well plates, washed with Hank's
balanced salt solution (HBSS), containing 20 mM HEPES, 2.5
mM probenecid, and 0.1o BSA, and loaded with the same
buffer containing 3.8 ,uM Fluo-3 for 1 hour at 37°C. After
washing with HBSS to remove the fluo-3 solution, cells were
equilibrated for 10 minutes. Cells were then incubated
with, or without MCH, and the fluorescence is measured
using a Fluorescence Imaging Plate Reader (FLIPR, Molecular
Devices).
Materials
Cell culture media and supplements were from Specialty
Media (Lavallette, NJ). Cell culture plates (150 mm and
96-well microtiter) were from Corning (Corning, NY). Sf9,
Sf2l, and High Five insect cells, as well as the
baculovirus transfer plasmid, pBlueBacIIITM, were purchased
CA 02384041 2002-03-05
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from Invitrogen (San Diego, CA). TMN-FH insect medium
complemented with 10o fetal calf serum, and the baculovirus
DNA, BaculoGoldTM, was obtained from Pharmingen (San Diego,
CA.). Ex-Cell 400TM medium with L-Glutamine was purchased
from JRH Scientific. Polypropylene 96-well microtiter
plates were from Co-star (Cambridge, MA). Commercially
available MCH and related peptide analogs were either from
Bachem California (Torrance, CA) or Peninsula (Belmont,
CA). Bio-Rad Reagent was from Bio-Rad (Hercules, CA).
Bovine serum albumin (ultra-fat free, A-7511) was from
Sigma (St. Louis. MO). All other materials were reagent
grade.
Functional Assa~r Results
The compounds of Examples 1-37 were assayed using the
cloned human MCH1 receptor. The preferred compounds were
found to be selective MCH1 antagonists. The results are
summarized in Table 1.
CA 02384041 2002-03-05
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Tahlp 1
~XAI~L~ No. STRUCTURE
hMCHl
F
/ F
O ~ I O
1 C-) 'I 4 2
~O I N~N~N
N' 'O / I N
~O
F
F
r
2 O ~ 18
~O I N NON
i0 N~O / I ~ N II
r O
F
~ F
O I / O
3 ~ ~ 201
0 I N NON ~ \
NI 'O
~0 O~O
F
r F
4 O ~ 187
O I N NON
N~O _ O
I
N W
O ~ 258
N O
I /
N-O
~ ,N
6 O O~' 42
wO I N~N / I N
N~O /~N~
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I~ (aM)
EXAMPLE No. STRUCTURE hMCHl
F
F
O ~ OI .
~O I N~N~N p 41
~N~
N O N
- ~ /
N_O
~ ,N
O / OI'
~O I N~N~N
N~O /
F
/ F
O \ ~ O
g 35
~O I N~N~N
N~p . . / I O~
,O \
F
/ F
O \ I O
(+) - 0.3
- ~O I N~N~N
N~O / N II
,O \ I O '
F
~ F
11 O ~ ~ 331
~O I ~ NON
N O
CA 02384041 2002-03-05
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-224-
EXAD~LE No. STRUCTURE
hMC81
F
F ~ F
I
O ~ O
12 ~ 29
I N NON
N~O I \
F
13 \ I O N' v . N ' ~ N 284
\I
F
F ..
O \ I p
14 '' 2
~O I N~N~N ~ I
N~O ~ I
~O \
F
/ F ._
I
O \ O
15 w0 I N~N~N 289
N ~O / F
i0 _ OI v
I
F
/ F
O \ ~ 329
16
w0 _ I ~ . N~\/~N
j N O O N
i ~O
CA 02384041 2002-03-05
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-225-
EXAN~LE No. STRUCTURE
hMCHl
F
F
O ~ O
17 ~ 373
~O I N NON
N~O
,O N J
N-O
~ ,N
. . .. _.
18 O / O'I 1
~O I N~N~N
NI 'O O
F
F'
O ~ O
19 -- - ~ 7
~O I N NON
N~O ~ I ..
,O
F
F'
20 . O ~ . 5
~O I N NON '
N~O O
N_O
,N
21 O ~ OII 28
~O I N~N~N
N~O
F
F
22 O ~ 40
N I ~ NON
N O O
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EXAMPLE No. STRUCTURE
hMC$1
N-O
~ ,N
I
23 0 ~ 0
68
~O I . N~N~N ~
N~O
O
F
F
I
24 O i O
I' 102
~O I N~N~N \ I
N~O
O
O
25 ~S/ ~ I '~ 126
S N
F
\ / " / \
26 N 260
U
/ \
F
O
27 , N \ - N/ _ \ / O 279
~N \ /
O N O
28 ~ _ N~ , 60
CI I / W I
O
29 I \ N ~CI
CI ~
CA 02384041 2002-03-05
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-227-
EaCAMPLE No. STRUCTURE
hMC81
O
F ~ ~ O
~N
30 , N~NJ 479
~N~ O.
31 'O' NvN . 7
S-N ~
O
F
F
I .
32 O / OI' 67
~O I N~N~N
N~O
F
/ F
Io'I
33 ~O. I N~N~N 12
N~O / F
i0 _ ~F
F
F
F
I
O ~ O
34 ~O N~N~N~ O'N'~'O 182
I N~O ..,,..~N
.F
~ I F
O ~ O 276
35 II
~O I N~N~N
N~O vN /
. ~I
CA 02384041 2002-03-05
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Kb (nM)
EXAMPLE No. STRUCTURE ~CH1
F
F
36 O \ ~ 406
~O I ~ NON ~ \
~N O
,O
g~ 162
O \ S
N
O~ N- _ N- 'O
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Radioligand Binding' Assay Results
The compounds of Examples 1 to 37 were assayed using cloned
human MCH1, NPY1, NPY5, GALR1, GALR2, and GALR3 and rat 5-
HT2C receptors. The binding affinities of several
compounds are shown in Tables 2 and 3.
The compounds of Examples '38 to 56 were assayed using the
cloned rat MCH1 receptor. The binding affinities (Ki) of
these compounds are shown in Table 4.
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x
'-' U ~ ~ ~ ao0 0 ~ ~ o t~o~o ao 0 0 0
opv--1M tt7N O M ~'O ooO O 01 O e''
E., ~ ,.r>~ o ~ o aom o 0 0 0 ~ o 0
x ~
N . o , . o . . o . ~ o ~ p
It') ,.~1 ~ n r-1t!~01uc'7In C r-1Ln~T u'~
x N M v-'Ir-1n M N n M ~ n M N n N
4a
M ~ O O O O O O O tI7O O O O O O O ~ O
O O O O O O O a1O O O O O O O ~ O
O O O O O O O O O O O O O O O
O O O O O O O . O O O O O O O ~
~ t!7tn~ u'7t17u7~-Itn tt~t!u7uW t7u~ n
n n n n n n n N n n n n n n n
O O M O O O O ~-1O O O O O O O O
O O O O O O O N O O O O O O O N O
~ O O ~ O O O O O1O O O O O O O ~ O
~-I , O O . O O O O O O O O O O O O
O C7 tWu'7N u~trml7ina~uW n tt~tW.W .WI7W 17
n n ~ n n n n ~ n n n n n n n ' n
U
N
O O O O O O O I~O O O O O O O N O
O O O O O O O ~7O O O O O O O ~ O
x O O O O O O O O O O O O O O O N O
' o 0 0 0 0 0 0 . 0 0 0 0 0 0 0 - o
U i w n m .m.n u n ~-Im m n u"mtmn ~ r mn
,~ x n n n n n n n ~ n n n n n n n ~ n
'-'o o 0 o ~.n ~ o o 0 0 o 0 0 o 0
U 0 o o o c~ 0 0 0 0 0 0 0 0 0
~ ~ O O a O O O l M O O O O O O O O O
o 0 o z o o z ~ o 0 0 0 0 0 0 0 0
x ~n~ ~n~n ~ ~ ~n ~n~n~n~n ~n~nu~~n
n n n n ~ ' n n n n n n n n n
U
N ~ O O O O ~ O O O o O O O ~
~ L fl p
U ~ O O l O O a ~ O O o O O O O O
Z o o z o 0 o ~ o 0 0 0 0 0 0 ~ O
N ~ o o . o o z ~ 0 0 0 0 0 0 o
E-, x u~~ t~~ u~ ~ m n u W .Wn ~ u~
n n N n n n n n n n n n n
U
T3
O ~
O
V ~ M N ~ ~ l0N l~ O O1~'01
--I ~ 1 ' ' O N l0a0 l0f~00L~
N ~ r-Ii-1~-IN N N
~~i
O b~
O ot~~'O 01 ~1N l0r-I00LS7t~~' lfll~M O.
(d w ,-1~-Ii-1N ~ N N N M N N ~"~M
pr 't~
z a
0
N
O
N U
E-~
CA 02384041 2002-03-05
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- 231 -
V ~ m o ~ m o ~ m o o a~
OON r-1tI7O M ~,,.~a1M O
~ H '. m ~ ~ o o ao~ ~ o 0
x . . ._. o . ~ . . o O
I,n,,,)W -I N tcyc'701 ~ u7uW O
H x N ~ M ~ n M M N n N
b~
.,-I
M ~ O O O O O O O O ~ O tn
O O O O O O O O O ~1
~ O O O O O O O o ~ O O O
O O O O O O O O ~ O
l 7 ~nw .rm.nu? ~.ntn uo~ u~ ~-I
n n n n n n n n ~ n N U
x
M
rd
~ O O O O O o M O ~ O ~-1
O O O O O O O O N O N ~ .U
O O O O O O lflO ~ O 01
7 O O O O O O . O O
,,~~ntn tr7m tn w7N ~r7~ m 0
n n n n n n ~ n n
U
O O O O O O O O N O l~~ ,N
0 0 0 0 0 0 o O lOO iI7O U
U ~ O o o 0 o 0 0 o N o O
N O O O O O O O O O ~ S-d
,~ L1'7Ln u7Lnt17LnI17L(7r-ILn r-i
n n n n n n n n ~ n
ue, ,r, ~ x
0
U -~-~ ~ o o 0 o 0 0 o ~ O
~ .n U
~I ~ ~~.10 0 o o 0 ~ ~ 0 0
~ 0 0 o O o o o 0
r-I ~ O O o O O ~ 2, o o
x ~ z ~ ~.r~~ ~n~ ~n ~n~ '
U ~ ''~ n n n n n n n '
N
M
rti ~ O O O O O ~ O
o
O O O !~O l 7 O O O
O O O O O ~ O
a 0 0 0 . o ~ ~ o 0
n n n N n n ~ n
~s x
* -~ 3
r1r-1o M
,'T',,~' M ~'~ ~ ~ t~ M I~~ l0
U O r-Ir1M ~'U
-, U ~ x
U
ti) ~ M
-1-~ W ~w 'ri N
O y -I M N ~ ~ N G
~., ',I,' ~ n N ~ ~ r-1
-W ~, ~ o~oo ~,4-i
O r-IN 4-I O
~ ~, rd
-r1 W
(I)
O
t'S Q 61 ~ O ri N VY G~M ~1 lD~' p
-~ ACS
rCf ~-I ,-Ir1 r-IN ~-I ,-IN "'C3 J-~
.u x t3~
0
0
M
* i
N
r-1
.O
rtS
E~
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-232-
Table 4
EXAMPLE No. STRUCTURE Ki (nM)
rMCH1
F
F
O ~O
38 ~ 1.34
~O ' ~ . NI N~N
N~0 ~ ~ N
r0 /
FI
~F
0 I //\ 0
39 ~o . H~N~N 3.33
N~O ~ N O/
/0 ~ / 0
F
F
0 ~0
40 ~ ~ ~ 2.72
0 ~ ' N N N
N 0 ~ N
/p ' r o
F
F
0 ~_ 0
4'I ~ N~N~N 0.04
N 0, I ~
F
F
0 ~0
42 ~ ~ 0.6
0 ~ . H N N
~ N
N_ '0
/0 ~ r
F
F
43 ~O p I rN~H~N 0.23
~ N
N"0
r0 I r
F
F
O ~O
44 i ~ 0.09
~0 ~ H HEN
~ N
N- 'O
,O r
L P 1
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WO 02/06245 PCT/USO1/21286
-233-
I F
~F
r //
45 ~ O 14.69
N ~ NON
O~N I \ N 11
O\ / O
F
~F
(I //' O
46 8.16
NI ~ ~ N~N
O "N \ N
o\
F
~F
r1 //' O
47 N ~ NON ' 34.28
0 "H ~ \ N
~O~ /
F
~F
(~~~' 0
48 N ' I NON 22.15
O~N \ N
O\ /
F
~F
/
49 ' 225.47
N ~ NON
o~N \ N
. O\
F
~F
// 0
50 N ' ~ NON C!h 13.74
0'"N \ N' ~
~CH~
O~CH~ / 00
F
F \ F
51 ~ ~~ 0.79
NI~N~N N
N ~0 I
CA 02384041 2002-03-05
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-234-
F
F
0
52 i I ~ 0 I N~N~N 0~ O
N'~0 ~ IN
0
I/
53 0 0'I 0~ 50.76
N~N~N
0 ~ ~ w N
N _ '_0 I /
o: N..o.
0 0
54 ~o I N~N~~N . \ ~ 29.87
t4~5 , /
/ Oi
N-0
,N
I/
55 ° N~N~N o~ 203.74
o I ~ ~ N
N' '0 I
F
~F
I
5s ° ° °~ 0.26
N~N/~/~N \ N
~~0 I
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Drozdz, R. and Eberle, A.N. (1995) Binding sites for
CA 02384041 2002-03-05
WO 02/06245 PCT/USO1/21286
-236-
melanin-concentrating hormone (MCH) in brain synaptosomes
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