U.S. patent application number 10/825643 was filed with the patent office on 2004-12-02 for selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof.
This patent application is currently assigned to Synaptic Pharmaceutical Corporation. Invention is credited to Deleon, John E., Gluchowski, Charles, Lagu, Bharat, Marzabadi, Mohammad R., Nagarathnam, Dhanapalan, Noble, Stewart, Wetzel, John.
Application Number | 20040242609 10/825643 |
Document ID | / |
Family ID | 26910798 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242609 |
Kind Code |
A1 |
Marzabadi, Mohammad R. ; et
al. |
December 2, 2004 |
Selective melanin concentrating hormone-1 (MCH1) receptor
antagonists and uses thereof
Abstract
This invention is directed to compounds which are selective
antagonists for melanin concentrating hormone-1 (MCH1) receptors.
The invention provides a pharmaceutical composition comprising a
therapeutically effective amount of the compound of the invention
and a pharmaceutically acceptable carrier. 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 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. This invention also provides a method of modifying feeding
behavior of 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 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. In an embodiment of the invention, the feeding disorder is
bulimia, bulimia nervosa or obesity.
Inventors: |
Marzabadi, Mohammad R.;
(Ridgewood, NJ) ; Wetzel, John; (Fairlawn, NJ)
; Deleon, John E.; (North Bergen, NJ) ; Lagu,
Bharat; (Belle Mead, NJ) ; Gluchowski, Charles;
(Danville, CA) ; Noble, Stewart; (Lake Forest,
IL) ; Nagarathnam, Dhanapalan; (Bethany, CT) |
Correspondence
Address: |
John P. White
Cooper & Dunham LLP
1185 Avenue of the Americas
New York
NY
10036
US
|
Assignee: |
Synaptic Pharmaceutical
Corporation
|
Family ID: |
26910798 |
Appl. No.: |
10/825643 |
Filed: |
April 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10825643 |
Apr 15, 2004 |
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09899635 |
Jul 5, 2001 |
|
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6720324 |
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60216218 |
Jul 5, 2000 |
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Current U.S.
Class: |
514/269 ;
544/316 |
Current CPC
Class: |
C07D 211/52 20130101;
C07D 401/12 20130101; C07C 2601/14 20170501; C07D 471/10 20130101;
C07D 211/58 20130101; C07D 471/04 20130101; C07C 233/79 20130101;
C07D 401/14 20130101; C07D 491/10 20130101; C07D 295/073 20130101;
C07D 417/06 20130101; C07D 491/04 20130101; C07D 413/14
20130101 |
Class at
Publication: |
514/269 ;
544/316 |
International
Class: |
A61K 031/513; C07D
239/02 |
Claims
1-39. (cancelled)
40. A compound having the structure: 155wherein each R is
independently --H; --F; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
--N(R.sub.3).sub.2; --NO.sub.2; --CN; --CO.sub.2R.sub.3;
--OR.sub.3; or -CON(R.sub.3).sub.2; wherein each R.sub.1 is
independently --H; F; Cl; Br; I; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; aryl or
heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; wherein each R.sub.3 is
independently --H; straight chained or branched C.sub.1-C.sub.7
alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or
branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; wherein R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON (R.sub.3) .sub.2; aryl or
heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON (R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3) .sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; wherein V is H; aryl or
heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR.sub.3; CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; wherein W is (a)
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally substituted with
one or more COR.sub.3; CO.sub.2R.sub.3; --CON (R.sub.3).sub.2; CN;
--NO.sub.2; --N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl; or (b) aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON (R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
--(CH.sub.2).sub.qOR.sub.3; --(CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 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.
41. The (+) enantiomer of the compound of claim 40.
42. The (-) enantiomer of the compound of claim 40.
43. The compound of claim 40 having the structure: 156
44. The compound of claim 43 having the structure: 157
45. The compound of claim 44 wherein W is phenyl optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
--(CH.sub.2).sub.qOR.sub.3; --(CH.sub.2).sub.qSR.sub.3; or straight
chained or branched C.sub.1-C.sub.7 alkyl groups.
46. The compound of claim 45 having the structure: 158
47-81. (cancelled)
82. A pharmaceutical composition comprising a therapeutically
effective amount of the compound of claim , or 40 and a
pharmaceutically acceptable carrier.
83. The pharmaceutical composition of claim 82, wherein the amount
of the compound is an amount from about 0.01 mg to about 500
mg.
84. The pharmaceutical composition of claim 83, wherein the amount
of the compound is an amount from about 0.1 mg to about 60 mg.
85. The pharmaceutical composition of claim 84, wherein the amount
of the compound is an amount from about 1 mg to about 20 mg.
86. The pharmaceutical composition of claim 82, wherein the carrier
is a liquid and the composition is a solution.
87. The pharmaceutical composition of claim 82, wherein the carrier
is a solid and the composition is a tablet.
88. The pharmaceutical composition of claim 82, wherein the carrier
is a gel and the composition is a suppository.
89. A pharmaceutical composition made by combining a
therapeutically effective amount of the compound of claim 40 and a
pharmaceutically acceptable carrier.
90. A process for making a pharmaceutical composition comprising a
therapeutically effective amount of the compound of claim 40 and a
pharmaceutically acceptable carrier.
91. A method of treating a subject from suffering from bulimia,
obesity or bulimia nervosa which comprises administering to the
subject an amount of a compound of claim 40 and a pharmaceutically
acceptable salt.
92. A method of treating a subject from suffering from depression
and/or anxiety which comprises administering to the subject an
amount of a compound of claim 40 and a pharmaceutically acceptable
salt.
Description
BACKGROUND OF THE INVENTION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/216,218, filed Jul. 5, 2000, the contents of
which are hereby incorporated by reference.
[0002] 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.
[0003] Melanin-concentrating hormone (MCH) is a cyclic peptide
originally isolated from salmonid (teleost fish) pituitaries
(Kawauchi et al., 1983). In fish the 17 amino acid peptide causes
aggregation of melanin within the melanophores and inhibits the
release of ACTH, acting as a functional antagonist of .alpha.-MSH.
Mammalian MCH (19 amino acids) is highly conserved between rat,
mouse, and human, exhibiting 100% 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 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 .alpha.-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).
[0004] Although the biological effects of MCH are believed to be
mediated by specific receptors, binding sites for MCH have not been
well described. A tritiated ligand ([.sup.3H]-MCH) was reported to
exhibit specific binding to brain membranes but was unusable for
saturation analyses, so neither affinity nor B.sub.max 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
[Phe.sup.13, Tyr.sup.19]-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, G-4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the
K.sub.=0.118 nM and the B.sub.max =.about.1100 sites/cell.
Importantly, the binding was not inhibited by .alpha.-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 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.
[0005] 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
(Herv 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.
[0006] 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.
[0007] Human genetic linkage studies have located authentic hMCH
loci on chromosome 12 (12q23-24) and the variant hMCH loci on
chromosome 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 forms
of spinal muscular atrophies has been assigned to chromosome
5q12-13 using genetic linkage analysis (Melki et al., 1990;
Westbrook 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.
[0008] 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
ventromedial nucleus (VMN) stimulated sexual activity in female
rats (Gonzalez et al., 1996). In ovariectomized rats primed with
estradiol, MCH stimulated luteinizing hormone (LH) release while
anti-MCH antiserum inhibited LH 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 LH 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 PTZ-induced seizure (Knigge and
Wagner, 1997). MCH has also been observed to affect 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 (Parkes, 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 important peptide
involved in the central control of fluid homeostasis in
mammals.
[0009] 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.
[0010] 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 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.
[0011] 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.
SUMMARY OF THE INVENTION
[0012] This invention provides a compound having the structure:
1
[0013] wherein A is 2
[0014] wherein each of Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4 and
Y.sub.5 is independently --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --F, --Cl, --Br, or --I;
--NO.sub.2; --N.sub.3; --CN; --OR.sub.3, --OCOR.sub.3, --COR.sub.3,
--CON(R.sub.3).sub.2or --COOR.sub.3; or any two of Y.sub.1,
Y.sub.2, Y.sub.3, Y.sub.4 and Y.sub.5 present on adjacent carbon
atoms can constitute a methylenedioxy group;
[0015] wherein each X is independently S; O; or NR.sub.3;
[0016] wherein R.sub.1 is --H; --NO.sub.2; --CN; straight chained
or branched C.sub.2-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2)OR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; --CON (R.sub.3).sub.2; or
--CO.sub.2(CH.sub.2).sub.nV;
[0017] wherein R.sub.2 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-alkyl,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-monofluoroalkyl or
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-polyfluoroalkyl; --CN;
--CH.sub.2XR.sub.3, --CH.sub.2X(CH.sub.2).sub.pNHR.sub.3,
--(CH.sub.2).sub.nNHR.sub.3,
--CH.sub.2X(CH.sub.2).sub.pN(R.sub.3).sub.2,
--CH.sub.2X(CH.sub.2).sub.pN- .sub.3,
--CH.sub.2X(CH.sub.2).sub.pNHCXR.sub.7; or --OR.sub.3; or wherein
R.sub.1 and R.sub.2 together may form a lactone ring;
[0018] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0019] wherein R.sub.4 is 3
[0020] wherein the dashed line represents a single bond or a double
bond;
[0021] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--CO.sub.2R.sub.3; --OR.sub.3; or --CON(R.sub.3).sub.2;
[0022] wherein each V is independently aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2; --N
(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0023] wherein each R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; aryl or
heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0024] wherein R.sub.6 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; --CON(R.sub.3) ; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3; (CH).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0025] wherein R.sub.7 is H; F; Cl; Br; I; --NO.sub.2; --N.sub.3;
--CN; straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON (R.sub.3).sub.2;
[0026] wherein R.sub.8 is independently straight chained or
branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0027] wherein Z 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; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl; C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0028] wherein each m is independently an integer from 0 to 3
inclusive;
[0029] wherein each n is independently an integer from 0 to 5
inclusive;
[0030] wherein each p is independently an integer from 1 to 7
inclusive;
[0031] wherein q is an integer from 1 to 3 inclusive;
[0032] wherein r is an integer from 0 to 3 inclusive;
[0033] wherein L is an integer from 2 to 6 inclusive;
[0034] or a pharmaceutically acceptable salt thereof.
[0035] This invention further provides a compound having the
structure: 4
[0036] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--SR.sub.3; --CO.sub.2R.sub.3; or --OR.sub.3;
[0037] wherein each R.sub.1 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--(CH.sub.2).sub.pOR.sub.3; --COR.sub.3; --CO.sub.2R.sub.3; or
--CON(R.sub.3).sub.2;
[0038] wherein each R.sub.2 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2; or aryl or
heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR.sub.3; CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0039] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0040] wherein M is aryl or heteroaryl, optionally substituted with
one or more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0041] wherein X is (CH.sub.2).sub.n, O, S or NR.sub.3;
[0042] wherein W is
[0043] (a) C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally substituted with
one or more COR.sub.3; CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN;
--NO.sub.2; --N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.2-C.sub.7 cycloalkyl; or
[0044] (b) aryl or heteroaryl optionally substituted with one or
more F; Cl; Br; I; COR.sub.3; CO.sub.3R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,
or carboxamidoalkyl; straight chained or branched C.sub.1-C.sub.7
alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7 cycloalkyl;
[0045] wherein m is an integer from 0 to 4 inclusive;
[0046] wherein n is an integer from 0 to 6 inclusive;
[0047] wherein p is an integer from 1 to 4 inclusive;
[0048] wherein q is an integer from 1 to 3 inclusive;
[0049] or a pharmaceutically acceptable salt thereof.
[0050] This invention also provides a compound having the
structure: 5
[0051] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--CO.sub.2R.sub.3; --OR.sub.3; or --CON (R.sub.3).sub.2;
[0052] wherein each R.sub.1 is independently --H; F; Cl; Br; I;
--NO.sub.2; --N.sub.3; --CN; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; aryl or heteroaryl,
wherein the aryl or heteroaryl is optionally substituted with one
or more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0053] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0054] wherein R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; aryl or
heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3),; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.- 3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0055] wherein V is H; aryl or heteroaryl, optionally substituted
with one or more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0056] wherein W is
[0057] (a) C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally substituted with
one or more COR.sub.3; CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN;
--NO.sub.2; --N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl; or
[0058] (b) aryl or heteroaryl optionally substituted with one or
more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl;
[0059] wherein each m is independently an integer from 0 to 3
inclusive;
[0060] wherein n is an integer from 0 to 2 inclusive;
[0061] wherein p is an integer from 1 to 7 inclusive;
[0062] wherein q is an integer from 1 to 3 inclusive;
[0063] wherein t is an integer from 2 to 6 inclusive;
[0064] or a pharmaceutically acceptable salt thereof.
[0065] 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: 6
[0066] wherein A is 7
[0067] wherein each of Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4 and
Y.sub.5 is independently --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --F, --Cl, --Br, or --I;
--NO.sub.2; --N.sub.3; --CN; --OR.sub.3, --OCOR.sub.3, --COR.sub.3,
--CON(R.sub.3).sub.2or --COOR.sub.3; or any two of Y.sub.1,
Y.sub.2, Y.sub.3, Y.sub.4 and Y.sub.5 present on adjacent carbon
atoms can constitute a methylenedioxy group;
[0068] wherein each X is independently S; O; or NR.sub.3;
[0069] wherein R.sub.1 is --H; --NO.sub.2; --CN; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR; --CH.sub.2).sub.pO.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; or
CO.sub.2(CH.sub.2).sub.nV;
[0070] wherein R.sub.2 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-alkyl,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-monofluoroalkyl or
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-polyfluoroalkyl; --CN;
--CH.sub.2XR.sub.3, --CH.sub.2X(CH.sub.2).sub.pNHR.sub.3,
--(CH.sub.2).sub.nNHR.sub.3,
--CH.sub.2X(CH.sub.2).sub.pN(R.sub.3).sub.2,
--CH.sub.2X(CH.sub.2).sub.pN- .sub.3,
--CH.sub.2X(CH.sub.2).sub.pNHCXR.sub.5; --OR.sub.3; or wherein
R.sub.1 and R.sub.2 together form a lactone ring;
[0071] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0072] wherein R.sub.4 is 8
[0073] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--CO.sub.2R.sub.3; --OR.sub.3; or --CN (R.sub.3).sub.2;
[0074] wherein B is N or CY.sub.4;
[0075] wherein each D is independently C(R.sub.3).sub.2; O; S;
NR.sub.3; CO; or CS;
[0076] wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7-alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0077] wherein V is C(R.sub.5).sub.2; CR.sub.5R.sub.6; NR.sub.5 or
NR.sub.6;
[0078] wherein W is CR.sub.5; CR.sub.6 or N;
[0079] wherein Z is S; O; C(R.sub.3).sub.2; or NR.sub.3;
[0080] wherein each R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2;
--XCOR.sub.8; or aryl or heteroaryl, wherein the aryl or heteroaryl
is optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON (R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7alkyl, monofluoroalkyl,
polyfluoroalkyl, or aminoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0081] wherein each R.sub.6 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; --N(R.sub.3).sub.2; --OR.sub.3;
--(CH.sub.2).sub.pOR.sub.3; --COR.sub.3; --CO.sub.2R.sub.3; or
--CON(R.sub.3).sub.2;
[0082] wherein R.sub.7 is --H; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0083] wherein R.sub.8 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2; aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0084] wherein b is 1 or 2;
[0085] wherein d is an integer from 0 to 2 inclusive;
[0086] wherein each m is independently an integer from 0 to 3
inclusive;
[0087] wherein each n is independently an integer from 0 to 5
inclusive;
[0088] wherein each p is independently an integer from 1 to 7
inclusive;
[0089] wherein q is an integer from 1 to 3 inclusive;
[0090] wherein t is an integer from 2 to 6 inclusive;
[0091] or a pharmaceutically acceptable salt thereof.
[0092] 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: 9
[0093] wherein A is 10
[0094] wherein each of Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4 and
Y.sub.5 is independently --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --F, --Cl, --Br, or --I;
--NO.sub.2; --N.sub.3; --CN; --OR.sub.3, --OCOR.sub.3, --COR.sub.3,
--CON(R.sub.3).sub.2, or --COOR.sub.3; or any two of Y.sub.1,
Y.sub.2, Y.sub.3, Y.sub.4 and Y.sub.5 present on adjacent carbon
atoms can constitute a methylenedioxy group;
[0095] wherein each X is independently S; O; or NR.sub.3;
[0096] wherein R.sub.1 is --H; --NO.sub.2; --CN; straight chained
or branched C.sub.2-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; or
CO.sub.2(CH.sub.2).sub.nV;
[0097] wherein R.sub.2 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-alkyl,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-monofluoroalkyl or
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10 -!polyfluoroalkyl;
--CN; --CH.sub.2XR.sub.3, --CH.sub.2X(CH.sub.2).sub.pNHR.sub.3,
--(CH).sub.2).sub.nNHR.sub.3,
--CH.sub.2X(CH.sub.2).sub.pN(R.sub.3).sub.2,
--CH.sub.2X(CH.sub.2).sub.pN- .sub.3,
--CH.sub.2X(CH.sub.2).sub.pNHCXR.sub.5; --OR.sub.3; or wherein
R.sub.1 and R.sub.2 together form a lactone ring;
[0098] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0099] wherein R.sub.4 is 11
[0100] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--CO.sub.2R.sub.3; --OR.sub.3; or --CN(R.sub.3).sub.2;
[0101] wherein B is N or CY.sub.4;
[0102] wherein each D is independently C(R.sub.3).sub.2; O; S;
NR.sub.3; CO; or CS;
[0103] wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0104] wherein V is C(R.sub.5).sub.2; CR.sub.5R.sub.6; NR.sub.5 or
NR.sub.6;
[0105] wherein W is CR.sub.5; CR.sub.6 or N;
[0106] wherein Z is S; O; C(R.sub.3).sub.2; or NR.sub.3;
[0107] wherein each R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.1-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(PR.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2;
--XCOR.sub.8; or aryl or heteroaryl, wherein the aryl or heteroaryl
is optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0108] wherein each R.sub.6 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; --N(R.sub.3).sub.3; --OR.sub.3;
--(CH.sub.2).sub.pOR.sub.3; --COR.sub.3; --CO.sub.2R.sub.3; or
--CON(R.sub.3).sub.2;
[0109] wherein R.sub.7 is --H; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0110] wherein R.sub.8 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2; aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0111] wherein b is 1 or 2;
[0112] wherein d is an integer from 0 to 2 inclusive;
[0113] wherein each m is independently an integer from 0 to 3
inclusive;
[0114] wherein each n is independently an integer from 0 to 5
inclusive;
[0115] wherein each p is independently an integer from 1 to 7
inclusive;
[0116] wherein q is an integer from 1 to 3 inclusive;
[0117] wherein t is an integer from 2 to 6 inclusive;
[0118] or a pharmaceutically acceptable salt thereof.
[0119] 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.
[0120] 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: 1213
[0121] 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.
[0122] This invention also provides a pharmaceutical composition
comprising a therapeutically effective amount of the compound of
the invention and a pharmaceutically acceptable carrier.
[0123] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0124] This invention provides a compound having the structure:
14
[0125] wherein A is 15
[0126] wherein each of Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, and
Y.sub.5 is independently --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.1-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --F, --Cl, --Br, or --I;
--NO.sub.2; --N.sub.3; --CN; --OR.sub.3, --OCOR.sub.3, --COR.sub.3,
--CON(R.sub.3).sub.2, or --COOR.sub.3; or any two of Y.sub.1,
Y.sub.2, Y.sub.3, Y.sub.4 and Y.sub.5 present on adjacent carbon
atoms can constitute a methylenedioxy group;
[0127] wherein each X is independently S; O; or NR.sub.3;
[0128] wherein R.sub.1 is --H; --NO.sub.2; --CN; straight chained
or branched C.sub.2-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; or
--CO.sub.2(CH.sub.2).sub.nV;
[0129] wherein R, is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-alkyl,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-monofluoroalkyl or
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-polyfluoroalkyl; --CN;
--CH.sub.2XR.sub.3, --CH.sub.2X(CH.sub.2).sub.pNHR.sub.3,
--(CH.sub.2).sub.nNHR.sub.3,
--CH.sub.2X(CH.sub.2).sub.pN(R.sub.3).sub.2,
--CH.sub.2X(CH.sub.2).sub.pN.sub.3,
--CH.sub.2X(CH.sub.2).sub.pNHCXR.sub.- 7; --OR.sub.3; or wherein
R.sub.1 and R.sub.2 together form a lactone ring;
[0130] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0131] wherein R.sub.4 is 16
[0132] wherein the dashed line represents a single bond or a double
bond;
[0133] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--CO.sub.2R.sub.3; --OR.sub.3; or --CON(R.sub.3).sub.2;
[0134] wherein each V is independently aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0135] wherein each R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; aryl or
heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.2;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0136] wherein R.sub.6 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0137] wherein R.sub.7 is H; F; Cl; Br; I; --NO.sub.2; --N.sub.3;
--CN; straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2;
[0138] wherein R.sub.8 is independently straight chained or
branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0139] wherein Z 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; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0140] wherein each m is independently an integer from 0 to 3
inclusive;
[0141] wherein each n is independently an integer from 0 to 5
inclusive;
[0142] wherein each p is independently an integer from 1 to 7
inclusive;
[0143] wherein q is an integer from 1 to 3 inclusive;
[0144] wherein r is an integer from 0 to 3 inclusive;
[0145] wherein t is an integer from 2 to 6 inclusive;
[0146] or a pharmaceutically acceptable salt thereof.
[0147] In one embodiment the compounds of this invention comprise
the (+) enantiomer. In another embodiment, the compounds comprise
the (-) enantiomer.
[0148] In one embodiment, the compound has the structure: 17
[0149] In another embodiment, the compound has the structure:
18
[0150] In a further embodiment, the compound has the structure:
19
[0151] In yet another embodiment of the present invention variable
A is 20
[0152] In an embodiment of the present invention, the compound is
2122
[0153] In another embodiment, the compound has the structure:
23
[0154] In further embodiments, the compound has the structure:
24
[0155] In an embodiment, the compound has the structure: 25
[0156] In other embodiments, A is 26
[0157] In an embodiment of the invention, the compound has the
structure: 27
[0158] In other embodiments, the compound has the structure: 28
[0159] In additional embodiments, the compound has the structure:
29
[0160] In one embodiment of the present invention, the compound has
the structure: 30
[0161] In another embodiment of the instant invention, A is 31
[0162] In other embodiments of the invention, the compound has the
structure: 32
[0163] In an embodiment, the compound has the structure: 33
[0164] In another embodiment, the compound has the structure:
34
[0165] In yet another embodiment, the compound has the structure:
35
[0166] In an embodiment, A is 36
[0167] In a further embodiment, the compound has the structure
37
[0168] In another embodiment, the compound has the structure:
38
[0169] In yet another embodiment, the compound has the structure:
39
[0170] In an additional embodiment, the compound has the structure:
40
[0171] In other embodiments, A is 41
[0172] In an embodiment, the compound has the structure: 42
[0173] 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-methoxym-
ethyl-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-
-{n-[4-(3,-acet-amido)-phenyl-piperidin-1-yl]propyl}carboxamido-4-methoxym-
ethyl-6-(3,4-difluoro-phenyl)-2-oxopyrimidine-5-carboxylic acid
methyl ester.
[0174] In a further embodiment, the compound is: 43
[0175] In a further embodiment, the compound has the structure:
44
[0176] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--SR.sub.3; --CO.sub.2R.sub.3; or --OR.sub.3;
[0177] wherein each R, is independently --H; straight chained or
branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2;
[0178] wherein each R.sub.2 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2; or aryl or
heteroaryl, optionally substituted with one or more F; Cl; Br; I;
COR.sub.3; CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0179] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0180] wherein M is aryl or heteroaryl, optionally substituted with
one or more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0181] wherein X is (CH.sub.2).sub.n, O, S or NR.sub.3;
[0182] wherein W is
[0183] (a) C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally substituted with
one or more COR.sub.3; CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN;
--NO.sub.2; --N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl; or
[0184] (b) aryl or heteroaryl optionally substituted with one or
more F; Cl; Br; I; COR.sub.3; CO.sub.2CR.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl;
[0185] wherein m is an integer from 0 to 4 inclusive;
[0186] wherein n is an integer from 0 to 6 inclusive;
[0187] wherein D is an integer from 1 to 4 inclusive;
[0188] wherein q is an integer from 1 to 3 inclusive;
[0189] or a pharmaceutically acceptable salt thereof.
[0190] In one embodiment the compounds of this invention comprise
the (+) enantiomer. In another embodiment, the compounds comprise
the (-) enantiomer.
[0191] In an embodiment, the compound has the structure: 45
[0192] In a further embodiment, W is phenyl optionally substituted
with one or more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3; or
(CH.sub.2).sub.qSR.sub.3.
[0193] In another embodiment, the compound has the structure 46
[0194] In one embodiment, the compound has the structure: 47
[0195] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--CO.sub.2R.sub.3; --OR.sub.3; or --CON(R.sub.3);
[0196] wherein each R.sub.1 is independently --H; F; Cl; Br; I;
--NO.sub.2; --N.sub.3; --CN; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; --CON(R.sub.3).sub.3; aryl or heteroaryl,
wherein the aryl or heteroaryl is optionally substituted with one
or more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.2; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0197] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0198] wherein R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; aryl or
heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3); --OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.- 3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0199] wherein V is H; aryl or heteroaryl, optionally substituted
with one or more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0200] wherein W is
[0201] (a) C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl optionally substituted with
one or more COR.sub.3; CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN;
--NO.sub.2; --N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl; or
[0202] (b) aryl or heteroaryl optionally substituted with one or
more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3;
--CON(R.sub.3).sub.2; CN; --NO.sub.2; --N(R.sub.3).sub.2;
--OR.sub.3; --SR.sub.3; (CH.sub.2).sub.qOR.sub.3;
(CH.sub.2).sub.qSR.sub.3; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7
cycloalkyl;
[0203] wherein each m is independently an integer from 0 to 3
inclusive;
[0204] wherein n is an integer from 0 to 2 inclusive;
[0205] wherein p is an integer from 1 to 7 inclusive;
[0206] wherein q is an integer from 1 to 3 inclusive;
[0207] wherein t is an integer from 2 to 6 inclusive;
[0208] or a pharmaceutically acceptable salt thereof.
[0209] In one embodiment the compounds of this invention comprise
the (+) enantiomer. In another embodiment, the compounds comprise
the (-) enantiomer.
[0210] In an additional embodiment, the compound has the structure:
48
[0211] In a further embodiment, the compound has the structure
49
[0212] In yet another embodiment, W is phenyl optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; or straight
chained or branched C.sub.1-C.sub.7 alkyl groups.
[0213] In yet another embodiment, the compound has the structure
50
[0214] 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.
[0215] 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.
[0216] 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, maleic 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, ethylenediamine, hydroxyethylamine, morpholine,
piperazine and guanidine. This invention further provides for the
hydrates and polymorphs of all of the compounds described
herein.
[0217] 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 emcompass 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.
[0218] 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.
[0219] 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 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.
[0220] This invention provides a pharmaceutical composition made by
combining a therapeutically effective amount of he compound of this
invention and a pharmaceutically acceptable carrier.
[0221] 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.
[0222] 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.
[0223] 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.
[0224] A solid carrier can include one or more substances which may
also act as flavoring agents, lubricants, solubilizers, 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 99% 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.
[0225] 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 compositions for parenteral administration. The liquid
carrier for pressurized compositions can be halogenated hydrocarbon
or other pharmaceutically acceptable propellent.
[0226] Liquid 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.
[0227] The compound can be administered orally in the form of a
sterile solution or suspension containing other 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.
[0228] 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.
[0229] 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: 51
[0230] wherein A is 52
[0231] wherein each of Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4 and
Y.sub.5 is independently --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --F, --Cl, --Br, or --I;
--NO.sub.2; --N.sub.3; --CN; --OR.sub.3, --OCOR.sub.3, --COR.sub.3
, --CON(R.sub.3 ).sub.2, or --COOR.sub.3 ; or any two of Y.sub.1,
Y.sub.2, Y.sub.3, Y.sub.4 and Y.sub.5 present on adjacent carbon
atoms can constitute a methylenedioxy group;
[0232] wherein each X is independently S; O; or NR.sub.3;
[0233] wherein R.sub.1 is --H; --NO.sub.2; --CN; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3 ; --CON(R.sub.3).sub.2; or
CO.sub.2(CH.sub.2).sub.nV;
[0234] wherein R, is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-alkyl,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-monofluoroalkyl or
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-polyfluoroalkyl; --CN;
--CH.sub.2XR.sub.3, --CH.sub.2X(CH.sub.2).sub.pNHR.sub.3,
--(CH.sub.2).sub.nNHR.sub.3,
--CH.sub.2X(CH.sub.2).sub.pN(R.sub.3).sub.2,
--CH.sub.2X(CH.sub.2).sub.pN- .sub.3,
--CH.sub.2X(CH.sub.2).sub.pNHCXR.sub.5; --OR.sub.3; or R.sub.1 and
R.sub.2 together form a lactone ring;
[0235] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0236] wherein R.sub.4 is 53
[0237] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; --N(R.sub.3).sub.2; --NO.sub.2; --CN;
--CO.sub.2R.sub.3; --OR.sub.3; or --CN(R.sub.3).sub.2;
[0238] wherein B is N or CY.sub.4;
[0239] wherein each D is independently C(R.sub.3).sub.2; O; S;
NR.sub.3; CO; or CS;
[0240] wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0241] wherein V is C(R.sub.5).sub.2; CR.sub.5R.sub.6; NR.sub.5 or
NR.sub.6;
[0242] wherein W is CR.sub.5; CR.sub.6 or N;
[0243] wherein Z is S; O; C(R.sub.3).sub.2; or NR.sub.3;
[0244] wherein each R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2;
--XCOR.sub.8; or aryl or heteroaryl, wherein the aryl or heteroaryl
is optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
[0245] --N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.- 3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0246] wherein each R.sub.6 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; --N(R.sub.3).sub.2; --OR.sub.3;
--(CH.sub.2).sub.pOR.sub.3; --COR.sub.3; --CO.sub.2R.sub.3; or
--CON(R.sub.3).sub.2;
[0247] wherein R.sub.7 is --H; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0248] wherein R.sub.8 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl,
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2; aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl,
[0249] monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
[0250] wherein b is 1 or 2;
[0251] wherein d is an integer from 0 to 2 inclusive;
[0252] wherein each m is independently an integer from 0 to 3
inclusive;
[0253] wherein each n is independently an integer from 0 to 5
inclusive;
[0254] wherein each p is independently an integer from 1 to 7
inclusive;
[0255] wherein q is an integer from 1 to 3 inclusive;
[0256] wherein t is an integer from 2 to 6 inclusive;
[0257] or a pharmaceutically acceptable salt thereof.
[0258] In one embodiment, the compound has the structure 54
[0259] In a further embodiment, the compound has the structure
55
[0260] In an additional embodiment, the compound has the structure
56
[0261] In a further embodiment, at least one R.sub.5 group is an
aryl or heteroaryl group optionally substituted with one or more F;
Cl; Br; I; --NO.sub.2; --N(R.sub.3).sub.2; --OR.sub.3;
--XCOR.sub.8; or straight chained or branched C.sub.1-C.sub.7
alkyl.
[0262] In another embodiment, A is: 57
[0263] In further embodiments, the compound is selected from the
group consisting of: 5859
[0264] In other embodiments, the compound has the structure 60
[0265] In a further embodiment, the compound has the structure
61
[0266] In additional embodiments, A is 62
[0267] and R.sub.7 is phenyl, optionally substituted with one or
more F; Cl; Br; I; COR.sub.3; CO.sub.2R.sub.3; --CON
(R.sub.3).sub.2; CN; --NO.sub.2; --N (R.sub.3).sub.2; --OR--.sub.3;
--SR.sub.3; (CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3;
--XCOF.sub.8; or straight chained or branched C.sub.1-C.sub.7
alkyl.
[0268] In one embodiment, the compound has the structure 63
[0269] In an embodiment of the present invention, the compound has
the structure 64
[0270] In yet another embodiment, the compound has the structure
65
[0271] In further embodiments, A is 66
[0272] and Z is O or CH.sub.2.
[0273] In an additional embodiment, the compound is selected from
the group consisting of 67
[0274] In one embodiment, the compound has the structure 68
[0275] In a further embodiment, the compound has the structure
69
[0276] In another embodiment, A is 70
[0277] In yet another embodiment, the compound is 71
[0278] In a further embodiment, the compound has the structure
72
[0279] In another embodiment, the compound has the structure 73
[0280] In yet another embodiment, the compound has the structure
74
[0281] In one embodiment, the compound has the structure 75
[0282] In another embodiment, the compound has the structure 76
[0283] In another embodiment, the compound has the structure 77
[0284] This invention further provides a method of reducing the
body mass of a subject which comprises administering to he subject
an amount of a compound effective to reduce the body mass of the
subject wherein the compound has the structure: 78
[0285] wherein A is 79
[0286] wherein each of Y.sub.1, Y.sub.2, Y.sub.3, Y.sub.4, and
Y.sub.5 is independently --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --F, --Cl, --Br, or --I
--NO.sub.2; --N.sub.3; --CN; --OR.sub.3, --OCOR.sub.3, --COR.sub.3,
--CON(R.sub.3).sub.2, or --COOR.sub.3; or any two of Y.sub.1,
Y.sub.2, Y.sub.3, Y.sub.4 and Y.sub.5 present on adjacent carbon
atoms can constitute a methylenedioxy group;
[0287] wherein each X is independently S; O; or NR.sub.3;
[0288] wherein R.sub.1 is --H; --NO.sub.2; --CN; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; --N
(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3- ;
--COR.sub.3; --CO.sub.2R.sub.3; --CON (R.sub.3).sub.2; or
CO.sub.2(CH.sub.2).sub.nV;
[0289] wherein R.sub.2 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-alkyl,
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-monofluoroalkyl or
C.sub.3-C.sub.10 cycloalkyl-C.sub.1-C.sub.10-polyfluoroalkyl; --CN;
--CH.sub.2XR.sub.3, --CH.sub.2X(CH.sub.2).sub.pNHR.sub.3,
--(CH.sub.2).sub.nNHR.sub.3,
--CH.sub.2X(CH.sub.2).sub.pN(R.sub.3).sub.2,
--CH.sub.2X(CH.sub.2).sub.pN- .sub.3,
--CH.sub.2X(CH.sub.2).sub.pNHCXR.sub.5; --OR.sub.3; or wherein
R.sub.1 and R.sub.2 together form a lactone ring;
[0290] wherein each R.sub.3 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched C.sub.2-C.sub.7
alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
[0291] wherein R.sub.4 is 80
[0292] wherein each R is independently --H; --F; straight chained
or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7-alkenyl or alkynyl; --N(R.sub.3)2; --NO.sub.2;
--CN; --CO.sub.2R.sub.3; --OR.sub.3; or --CN(R.sub.3).sub.2;
[0293] wherein B is N or CY.sub.4;
[0294] wherein each D is independently C(R.sub.3).sub.2; O; S;
NR.sub.3; CO; or CS;
[0295] wherein each U is independently aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0296] wherein V is C(R.sub.5).sub.2; CR.sub.5R.sub.6; NR.sub.5 or
NR.sub.6;
[0297] wherein W is CR.sub.5; CR.sub.6 or N;
[0298] wherein Z is S; O; C(R.sub.3).sub.2; or NR.sub.3;
[0299] wherein each R.sub.5 is --H; --NO.sub.2; --N.sub.3; --CN;
straight chained or branched C.sub.1-C.sub.7, alkyl,
monofluoroalkyl or polyfluoroalkyl; straight chained or branched
C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7 cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
--N(R.sub.3).sub.2; --OR.sub.3; --(CH.sub.2).sub.pOR.sub.3;
--COR.sub.3; --COR.sub.3; or --CON(R.sub.3).sub.2; --XCOR.sub.8; or
aryl or heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0300] wherein each R.sub.6 is independently --H; straight chained
or branched C.sub.1-C.sub.7 alkyl, hydroxyalkyl, aminoalkyl,
alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl or alkynyl; C.sub.3-C.sub.7
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl; --N(R.sub.3).sub.2; --OR.sub.3;
--(CH.sub.2).sub.pOR.sub.3; --COR.sub.3; --CO.sub.2R.sub.3; or
--CON (R.sub.3).sub.2;
[0301] wherein R.sub.7 is --H; aryl or heteroaryl, optionally
substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; --XCOR.sub.8;
straight chained or branched C.sub.1-C.sub.7 alkyl,
monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0302] wherein R.sub.8 is --H; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C.sub.2-C.sub.7 alkenyl or alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl; --N(R.sub.3).sub.2;
--OR.sub.3; --(CH.sub.2).sub.pOR.sub.3; --COR.sub.3;
--CO.sub.2R.sub.3; or --CON(R.sub.3).sub.2; aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I; COR.sub.3;
CO.sub.2R.sub.3; --CON(R.sub.3).sub.2; CN; --NO.sub.2;
--N(R.sub.3).sub.2; --OR.sub.3; --SR.sub.3;
(CH.sub.2).sub.qOR.sub.3; (CH.sub.2).sub.qSR.sub.3; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained
or branched C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl;
C.sub.3-C.sub.7 cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
[0303] wherein b is 1 or 2;
[0304] wherein d is an integer from 0 to 2 inclusive;
[0305] wherein each m is independently an integer from 0 to 3
inclusive;
[0306] wherein each n is independently an integer from 0 to 5
inclusive;
[0307] wherein each p is independently an integer from 1 to 7
inclusive;
[0308] wherein q is an integer from 1 to 3 inclusive;
[0309] wherein t is an integer from 2 to 6 inclusive;
[0310] or a pharmaceutically acceptable salt thereof.
[0311] 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.
[0312] 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: 8182
[0313] 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.
[0314] 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.
[0315] 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.
[0316] 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.
[0317] 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.
[0318] 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.
[0319] 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.
[0320] This invention will be better understood from the
Experimental Details which follow. However, one skilled in 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.
[0321] Experimental Section
[0322] I. Synthetic Methods for Examples
[0323] General Methods:
[0324] 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 .sup.1H and .sup.13C NMR spectra were recorded
at 300 and 75 MHz (QE Plus) with CDCl.sub.2 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.
[0325] Procedures for the Synthesis of the Dihydropyrimidine
Intermediates
[0326]
5-Methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-d-
ifluorophenyl)-pyrimidine:
[0327] 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) in 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.times.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, 97%). .sup.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).
[0328]
(+)-5-Methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3-
,4-difluorophenyl)-pyrimidine:
[0329] 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.times.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-2oxo-6-(3,4-difl-
uorophenyl)-pyrimidine (40-42 wt % isolation of the desired
enantiomer from the racemate); [.alpha.].sub.D=+83.8 (c=0.5,
chloroform). The (-)-isomer was also isolated as the later eluting
fraction from the chiral chromatography column.
[0330]
(+)-5-Methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3-
,4-difluorophenyl)-1-[(4-nitrophenyloxy) carbonyl]pyrimidine:
[0331] To a solution of
(+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetr-
ahydro-2-oxo-6-(3,4-difluorophenyl)-pyrimidine (1.98 g, 6.34 mmol)
in anhydrous THF (20 mL) at -78.degree. 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.degree. C. Stirring was continued for 10 min.
and the mixture was poured onto ice (50 g) and extracted with
chloroform (2.times.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%): .sup.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).
[0332] Benzyl
3-[(3,4-difluorophenyl)methylene]-4-oxopentanoate:
[0333] 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 for 5 h. The solvent
was removed in vacuo and the residue was dissolved in ErOAc. The
reaction mixture was washed with water (100 mL), followed by brine
(100 mL) and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
evaporated, giving a pale yellow syrup (60.2 g). The product was
used in the next step without further purification.
[0334]
5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-di-fluor-
ophenyl)pyrimidine:
[0335] A suspension of benzyl
3-[(3,4-di-fluorophenyl)methylene]-4-oxopent- anoate (16.0 g, 48.0
mmol), O-methylisourea hydrogen sulfate (16.7 g, 97.0 mmol) and
NaHCO.sub.3 (16.3 g, 130 mmol) in DMF (190 mL) was stirred at
70.degree. 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 (4.times.100 mL), brine (200 mL) and
dried over Na.sub.2SO.sub.4. 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, 58%). The NMR
analysis showed it to be a mixture of amine/imine tautomers and was
used as is in the next step.
[0336]
5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-di-fluor-
ophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0337] To a stirring solution of
5-(benzyloxycarbonyl)-1,6-dihydro-2-metho-
xy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine (17.0 g, 44.0 mmol) and
4-dimethylaminopyridine (7.00 g, 57.3 mmol) in CH.sub.2Cl.sub.2
(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), giving
5-(benzyloxycarbonyl)-4-ethyl-1,6-dih-
ydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimi-
dine as a colorless viscous oil (12.6 g, 50%). .sup.1H NMR d 12 (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).
[0338]
5-(Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[1-phenyl)ethyl]}-ca-
rboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine:
[0339] To a stirred mixture of
5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-
-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine
(12.6 g, 22.9 mmol) in THF (150 mL) was added a solution of
R-(+)-.alpha.-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% K.sub.2CO.sub.3
solution (2.times.30 mL). The organic layer was dried over
Na.sub.2SO.sub.4, 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)pyrimid-
ine. Colorless oil; Rf=0.31 (petroleum ether/ether, 4/1); yield:
3.8 g (31%); [.alpha.];=+267.05 (c=0.76, CHCl.sub.3); .sup.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 major product
to elute was
(-)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carbo-
xamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine. Colorless oil;
Rf=0.22 (petroleum ether/ether, 4/1); yield: 3.20 g (26%);
[.alpha.].sub.D=-146.89 (d=0.38, CHCl.sub.3); .sup.1H NMR .delta.
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).
[0340] (+)-5-(Benzyloxycarbonyl)
-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-di--
fluorophenyl)pyrimidine:
[0341] To a stirred solution of
(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihy-
dro-1-{N-[2-phenyl)ethyl]}carbox-amido-2-methoxy-6-(3,4-difluorophenyl)pyr-
imidine (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%).
[0342]
(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-Methoxy-6-(3,4-difl-
uorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0343] To a stirring solution of
(+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-m-
ethoxy-4-ethyl-6-(3,4-difluorophen-yl)pyrimidine (17.0 g, 44.0
mmol) and 4-dimethylaminopyridine (6.99 g, 57.3 mmol) in
CH.sub.2Cl.sub.2. (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]pyr-
imidine as a viscous colorless oil (19.3 g, 76%).
[0344] 5-Methylbenzfuroxan:
[0345] 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% yield) as a pale
yellow solid: .sup.1H NMR d 2.39 (s, 3 H), 6.90-7.40 (br m, 3
H).
[0346] 5-Methylbenzofurazan:
[0347] To 5-Methylbenzfuroxan (88.2 g, 0.590 mol) in refluxing EtOH
(75 mL) was added dropwise P(OEt).sub. (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%) as white
needles; .sup.1H NMR .delta. 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).
[0348] 5-Dibromomethylbenzofurazan:
[0349] 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.times.500 mL), dried (NaSO.sub.4), and the solvent was removed
in vacuo. The residue was chromatograghed (EtOAc/hexane, 1/150),
giving 122 g (80%) of the title compound as a white solid: .sup.1H
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).
[0350] 5-Formylbenzofurazan:
[0351] AgNO.sub. (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 reflux temperature was continued for 2 h. The
mixture was cooled, the precipitated AgBr was removed by filtration
through Celite, and the solvent was concentrated. The resulting
solution was extracted with toluene (10.times.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, 78%) as a white solid: .sup.1H NMR .delta. 7.92
(m, 2H), 8.39 (s, 1 H), 10.10 (s, 1 H).
[0352] Methyl 2-{(benzofuran-5-yl)methylene}-3-oxobutyrate:
[0353] 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 mmol),
and acetic acid (0.014 g, 0.23 mmol) in benzene (30 mL) was heated
at reflux temperature (equipped with a Dean-Stark trap) for 8 h.
Benzene was evaporated in vacuo, 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, 98%) and was used
in the next step without any further characterization.
[0354]
6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxylcarbonyl-4-me-
thylpyrimidine:
[0355] 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 mmol), and
NaHCO.sub.3 (1.30 g, 16.4 mmol) in DMF (15 mL) was stirred and
heated at 70 C for 16 h. The mixture was cooled, diluted with EtOAc
(50 mL) and washed with washed with water (5.times.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, 43%):
[0356] .sup.1H NMR .delta. 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).
[0357]
6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-met-
hoxy-1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0358] To a solution of
6-(benzofuran-5-yl)-1,6-dihydro-2-methoxy-5-methox-
ycarbonyl-4-methylpyrimidine (0.485 g, 1.6 mmol) and
4-dimethylaminopyridine (0.200 g, 1.64 mmol) in CH.sub.2Cl.sub.2
(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, 89%); mp
180-183.degree.0 C.; .sup.1H NMR .delta. 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).
[0359] (+) and
(-)-6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxyca-
rbonyl-1-[N-(S)-1-(1-phenylethyl)]-4-methylpyrimidione:
[0360] A solution of
6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxy-
carbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (800 mg,
1.71 mmol) 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 10% aqueous KCO solution (3.times.50 mL) , brine (50 mL)
and dried (Na.sub.2SO.sub.4) After removal of the solvent, the
residue was purified by chromatography (EtOAc/hexane, 1/20 to
3/20), separating the two diastereomers. The isomers of
6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl--
1-[N-(S)-1-(1-phenylethyl)]-4-methylpyrimidine were obtained as
colorless oils. 1st Isomer (367 mg, 47.7%):
[0361] [.alpha.]=+278 (c=0.50, CHCl.sub.3); .sup.1H NMR .delta.
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, 26.6%): [.alpha.]:=-81
(c=0.43, CHCl.sub.3) ; .sup.1H NMR .delta.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)
[0362]
6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-met-
hylpyrimidine:
[0363] A solution of the 1st isomer of
6-(benzofurazan-5-yl)-1,6-dihydro-2-
-methoxy-5-methoxycarbonyl-1-[N-(S)-1-(1-phenylethyl)]-4-methylpyrimidine
(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.degree. 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-methylpyr-
imidine was obtained as a colorless oil (635 mg, 98.3%). .sup.1H
NMR .delta. 2.38 (s, 3H), 3.66 (s, 3H), 3.74 (s, 3H), 5.68 (s, 1H),
6.32 (br s, 1H) 7.0-7.8 (m, 3H)
[0364]
6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-met-
hyl-1-(4-nitrophenoxy)carbonylpyrimidine:
[0365] To a solution of
6-(benzofuran-5-yl)-1,6-dihydro-2-methoxy-5-methox-
ycarbonyl-4-methylpyrimidine (0.485 g, 1.60 mol and
4-dimethylamino-pyridine (0.200 g, 1.60 mmol) in CH.sub.2Cl.sub.2
(20 mL), at 0-5.degree. 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, 89%): mp 180-183.degree. C.;
.sup.1H NMR .delta.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);
[a].sub.D=+266 (c=2.70, CH.sub.2Cl.sub.2).
[0366] Methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate:
[0367] 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.
6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpy-
rimidine:
[0368] A mixture of methyl
2-{(3,4-difluorophenyl)-methylene}-3-oxobutyrat- e (8.80 g, 36.3
mmol), O-methylisourea hydrogen sulfate (9.40 g, 546 mmol, and
NaHCO.sub.3 (12.3 g, 146 mol) in DMF (30 mL) was heated at 70 C
with stirring for 16 h. The mixture was cooled, diluted with EtOAc
(300 mL) and washed with water (5.times.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, 35%).
[0369]
6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-me-
thyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0370] 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-methoxycarbony-
l-4-methylpyrimidine (2.82 g, 9.46 mmol) and
4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH.sub.2Cl.sub.2 (50
mL) , at 0-5.degree. 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, 85%):
mp 172-174 C.
[0371]
6-(3,4-Difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbon-yl--
4-methyl-1-(4-Nitrophenoxy)carbonylpyrimidine:
[0372] Aqueous 6 N hydrochloric acid (10 mL) was added to a
stirring solution of
6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbony-
l-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 g, 100%): mp
185-186.degree. C.
[0373]
(+)-1-(3-Bromo-propylcarbamoyl)-6-(3,4-difluorophenyl)-4-methyl-2-o-
xo-1,6-dihydro-pyrimidine-5-carboxylic Acid Methyl Ester:
[0374] A solution of 10% aqueous HCl (5 mL) was added to a stirring
solution of
(+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycar-
bonyl-4-methyl-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine (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.times.20 mL),
washed with brine (10 mL) and then dried over Na.sub.2SO.sub.4. The
solvent was removed in vacuo, giving
(+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-m-
ethyl-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
NaHCO.sub.3 (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.times.20 mL). The EtOAc
extracts were combined, dried over Na.sub.2SO.sub.4, 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, 83%):
.sup.1H NMR .delta. 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
C.sub.17H.sub.18N.sub.2O.sub.54 FBr: C, 45.76; H, 4.07; N, 9.42.
Found: C, 45.70; H, 3.99; N, 9.16.
[0375] 3-{(3,4,5-Trifluorophenyl)methylene}-2,4-pentanedione:
[0376] 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
(equipped with a Dean-Stark Wrap) 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.
[0377]
6-(3,4,5-Trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methylpy-
rimidine:
[0378] A mixture of
2-{(3,4,5-trifluorophenyl)methylene}3-2,4-pentanedione (26.2 mmol),
O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO.
(6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at
95-100 .degree. 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, 36%).
[0379]
6-(3,4,5-Trifluorophenyl)-1,6-dihydro-2-methoxyl-5-acetyl-4-methyl--
1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0380] 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-me-
thylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in
CH.sub.2Cl.sub.2 (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%).
[0381]
6-(3,4,5-Trifluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-acetyl-4-methy-
l-1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0382] A solution of 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-me-
thyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (4.00 g, 8.63 mmol:
in THF (100 mL) at 0-5.degree. 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, 100%).
[0383] Procedures for the Synthesis of the Piperidine
Intermediates
[0384] (reference for the general procedure for Pd coupling of
vinyl triflate and boronic acids or tributyl tin reagents: See,
Wuston, Wise Synthesis (1991), 993)
[0385] Tert-butyl
4-{[(Trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1--
pyridinecarboxylate:
[0386] 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.degree. C. and stirred for 20 minutes. The
reaction mixture was cooled to -78.degree. 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 30 minutes.
Tf.sub.2NPh (15.0 g, 42.0 mmol) in THF (40 mL) was added dropwise
to the reaction mixture and the mixture was stirred at 0.degree. 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 concentrated to yield 16.5 g of the desired product that was
contaminated with a small amount of Tf.sub.2 Nph. .sup.1H NMR
.delta. 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).
[0387] Tert-butyl
4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinec-
arboxylate:
[0388] A mixture of saturated of aqueous Na.sub.2CO solution (25
mL), tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-teterahydro-1-pyrid-
ine-carboxylate (20 mmol), 3-acetamidophenylboronic 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 (3.times.). The
combined organic extracts were dried and concentrated in vacuo. The
crude product was chromatograghed, giving the desired product
.sup.1H NMR .delta. 8.11 (br s, 1 H), 7.57 (br s, 1 H), 7.41
(br.delta., 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).
[0389] 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-pyridinecarboxylate
(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).
.sup.1H NMR .delta. 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)
[0390] Tert-butyl N-(3-bromopropyl)carbamate:
[0391] Prepared from 3-bromopropylamine hydrobromide and BOC.sub.2O
in the presence of base in dichloromethane: .sup.1H NMR .delta.
5.07 (br, 1 H), 3.31 t, 2 , J=6.6 Hz), 3.12 (apparent br q, 2 H,
J=6.0 Hz), 1.92 (p, 2 H, J=6.6 Hz), 1.30 (s, 9H)
[0392] Reaction of
N1-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide with
tert-butyl N-(3-bromopropyl)carbamate
[0393] Tert-butyl
N-(3-{4-[3-(acetylamino)phenyl]-,2,3,6-tetrahydro-1-pyri-
dinyl}propyl)carbamate:
[0394] 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 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). .sup.1H NMR .delta. 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).
[0395] Deprotection of BOC:
[0396]
N1-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl)acet-
amide:
[0397] A 1:1 solution of TFA:CH.sub.2Cl.sub.2 (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 NaHCO.sub.3
was added until pH>6, the organic layer was separated, and dried
in vacuo, giving the desired product (45 mg): .sup.1H NMR .delta.
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).
[0398] Tert-butyl
4-[3-(acetylamino)phenyl]-1-piperidinecarboxylate:
[0399] A mixture tert-butyl
4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-
-pyridinecarboxylate (710 mg) and 5% 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). .sup.1H NMR .delta. 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).
[0400] N1-[3-(4-piperidyl)phenyl]acetamide:
[0401] A solution of HCl in dioxane (4N, 5 mL) was added to
tert-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; .sup.1H NMR
.delta. 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).
[0402] Tert-butyl
N-(3-{4-[3-(acetylamino)phenyl]piperidino}propyl)-carbam- ate:
[0403] A solution of N1-[3-(4-piperidyl)phenyl]acetamide (550 mg,
0.210 mmol), tert-butyl N-(3-bromopropyl)-carbamate (550 mg, 0.230
mmol), K.sub.2CO (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 product (340 mg). .sup.1H NMR
.delta. 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).
[0404] N1-{3-[1-(3-aminopropyl)-4-piperidyl]phenyl}acetamide:
[0405] 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 10% 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. .sup.1H NMR .delta.
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), 3.0-2.99 (m, 2H), 2.77-2.73 (t, 2H,
J=6.6 Hz), 2.50-1.60 (m, 10 H), 2.13 (s, 3 H).
[0406]
1-Benzyl-4-hydroxy-4-(4-fluoro-2-methylphenyl)piperidine:
[0407] .sup.1H NMR .delta. 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).
[0408]
1-Benzyl-4-(4-fluoro-2-methylphenyl)-1,2,3,6-tetrahydropyridine:
.sup.1H NMR .delta. 7.41-7.26 (m, 5 H), 7.05 (dd, 1 H, J=6.0, 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).
[0409] 4-(4-Fluoro-2-methylphenyl)piperidine: .sup.1H NMR .delta.
7.17 (t, 1 H, J=7.2 Hz), 6.83-6.80 (m, 2 H), 3.22 (m, 2 H),
2.81-2.73 (m, 2 H), 2.66 (br s, 1 H), 2.33 (s, 3 H), 1.80-1.60 (m,
4 H).
[0410]
1-benzyl-4-(3,4,5-trifluorophenyl)-1,2,3,6-tetrahydropyridine:
[0411] .sup.1H NMR .delta. 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).
[0412] 4-(3,4,5-trifluorophenyl)piperidine:
[0413] mp 197-199 C; .sup.1H NMR .delta. 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).
[0414] 4-(3,4,5-trifluorophenyl)piperidine: .sup.1H NMR .delta.
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).
[0415] Tert-butyl
N-3-[4-(3,4,5-trifluorophenyl)piperidino]propyl-carbamat- e:
[0416] .sup.1H NMR .delta. 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).
[0417] 3-[4-(3,4,5-trifluorophenyl)piperidino]-1-propanamine:
[0418] .sup.1H NMR .delta.6.93 (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).
[0419] 1-benzyl-4-(5-fluoro-2-methoxyphenyl)-4-piperidinol:
[0420] .sup.1H NMR .delta.7.40-6.80 (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).
[0421]
1-benzyl-4-(5-fluoro-2-methoxyphenyl)-1,2,3,6-tetrahydropyridine:
[0422] .sup.1H NMR .delta. 7.40-6.70 (m, 8 H), 5.84 (m, 1 H), 3.7
(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).
[0423] 4-(5-fluoro-2-methoxy)phenyl piperidine:
[0424] mp 254-258 C; .sup.1H NMR .delta.1.53-1.68 (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 CH--NOFCl
+0.14 CH.sub.2Cl.sub.2: C, 56.60; H, 6.76; N, 5.44. Found: C,
56.60; H, 6.92; N, 5.28.
[0425] Tert-butyl
N-3-[4-(5-fluoro-2-methoxyphenyl)piperidino]propyl-carba- mate:
[0426] .sup.1H NMR .delta. 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).
[0427]
3-[4-(5-fluoro-2-methoxyphenyl)piperidino]-1-propanamine:
[0428] .sup.1H NMR .delta. 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).
[0429] Tert-butyl
4-(1-naphthyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate:
[0430] .sup.1H NMR.delta.8.00-7.80 (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).
[0431] 4-(1-naphthyl)piperidine:
[0432] HCl salt; mp 330-332.degree. C.; .sup.1H NMR.delta.
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, J=8.1 Hz, 1H). Anal. Calcd.
For C.sub.15H.sub.2--NOCl+0.20 CH.sub.2Cl.sub.2: C, 68.96; H, 7.00;
N, 5.29. Found: C, 68.64; H, 7.04; N, 5.24.
[0433] Tert-butyl
N-3-[4-(1-naphthyl)piperidino]propylcarbamate:
[0434] H NMR.delta.8.09 (d, 1 H, J=8.4 Hz), 7.86 (dd, 1 H, J=1.8,
7. 5 Hz), 7.71 (dd, 1 H, J=2.4, 6.9 Hz), 7.60-7.30 (m, 4 H), 6.31
(br, 1 H), 5.75 (br, 1 H), 4.26 (t, 1 H, J=5.4 Hz), 3.40-3.00 (m, 6
H), 2.54 (t, 2 H, J=6.9 Hz), 2.24 (dt, 2 H, J=3.0, 11.4 Hz),
2.00-1.60 (m, 6 H), 1.45 (s, 9 H).
[0435] 4-(3-methyl-2-pyridyl)-4-piperidinol:
[0436] .sup.1H NMR.delta.8.21 (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).
[0437] Tert-butyl
4-(3-methyl-2-pyridyl)-1,2,3,6-tetrahydro-1-pyridine-car-
boxylate:
[0438] .sup.1H NMR.delta.8.16 (dd, 1 H, J=1.2, 3.3 Hz), 7.51 (dm, 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).
[0439] Tert-butyl
N-3-[4-(3-methyl-2-pyridyl)piperidino]propylcarbamate:
[0440] .sup.1H NMR.delta.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).
[0441] Tert-butyl
4-(3-methoxyphenyl)-1,2,3,6-tetrahydro-1-Pyridinecarboxy- late:
[0442] .sup.1H NMR.delta.7.23 (t, 1 H, J=8.1 Hz), 6.96 (d, 1 H,
J=7.5 Hz), 6.89 (d, 1 H, J=1.8 Hz), 6.80 (dd, 1 H, J=4, 8.1 Hz),
6.02 (br, 1 H), 4.20-4.00 (m, 3 H), 3.80 (s, 3 H), 3.6 2 (t, 2 H,
J=5.7 Hz), 2.51 (br, 2 H), 1.49 (s, 9 H,
[0443] 1-benzyl-4-methyl-piperidin-4-ol:
[0444] 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
Et.sub.2O (3.times.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 (87%) of
the desired product as a colorless oil: .sup.1H NMR.delta.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:); C NMR .delta. 30.44, 39.37, 50.39, 63.80, 68.50, 127.56,
128.80, 129.80, 139.17.
[0445] 1-benzyl-4-methyl-4-phenylpiperidine:
[0446] 1-Benzyl-4-methyl-piperidin-4-ol (4.81 g, 23.4 mmol) was
added to a suspension of AlCl.sub.3 (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.degree.
C., and extracted with EtOAc (3.times.100 mL). The combined organic
solutions were dried over magnesium sulfate and concentrated. The
residue was chromatographed (hexane-Et.sub.2O, 19/1 to 9/1,
followed by hexane-EtOAc 3/1), giving the desired product (3.23 g,
52%) as a brown oil: H NMR.delta.1.25 (s, 3 H), 1.80 (m, 2 H), 2.17
(m, 2 H), 2.44 (m, 2 H), 2.55 (m, 2 H), 3.50 (s, 2 H), 7.25 (m, 1
H), 7.35 (m, 4 H); .sup.13C NMR.delta.36.82, 37.65, 50.95, 54.93,
64.08, 126.19, 126.51, 127.59, 128.83, 128.95, 129.05, 129.89,
139.24.
[0447] 4-methyl-4-phenylpiperidine:
[0448] 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 10%
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) , H.sub.2O (15 mL) , CH.sub.2Cl (30 mL) and MeOH
(15 mL). The combined filtrate and washings were concentrated, and
the residue was dissolved in CH.sub.2Cl.sub.2 (50 mL) and H.sub.2O
(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 (CHCl.sub.3/MeOH/2 N NH.sub.3 in MeOH 100/4/0 to
100/20/10), giving 1-benzyl-4-methyl-4-phenylpiperidine (1.20 g)
and 1.10 g (51%, 82% based on consumed starting material) of
4-methyl-4-phenylpiperidine: .sup.1 NMR .delta. 1.24 (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); C NMR .delta. 37.22, 38.54, 43.44, 47.74,
126.31, 127.43, 129.01, 149.73.
[0449] 3-aminopropyl-4-methyl-4-phenylpiperidine:
[0450] 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 with CH.sub.2Cl.sub.2
(150 mL+3.times.100 mL). The combined organic solutions were dried
over magnesium sulfate and concentrated. The residue was purified
by flash chromatography (CHCl.sub.3/MeOH/2 N NH.sub.3 in MeOH
100/20/10), giving the desired product as a colorless oil (241 mg,
184): .sup.1H NMR.delta.1.18 (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),
7.30 (m, 4 H); .sup.13C NMR.delta.30.28, 36.78, 37.64, 41.51,
50.96, 57.51, 126.16, 126.40, 128.91, 149.20.
[0451] Preparation of
3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine
[0452] 4-(4-fluorophenyl)piperidine hydrochloride:
[0453] 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
.sup.1H NMR and TLC analysis. .sup.1H NMR.delta. 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).
[0454] 4-(4-fluorophenyl)piperidine:
[0455] mp C; 1H NMR.delta.1.51-1.66 (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).
[0456] Anal. Calcd. For C.sub.11H.sub.14NF+C.sub.4H.sub.4O.sub.4:
C, 58.70; H, 5.83; N, 4.18.
[0457] Found: C, 58.72; H, 5.84; N, 3.98.
[0458] 3-[4-(4-Fluorophenyl)piperidin-1-yl]propylphthalimide:
[0459] 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 80% of the solvent was evaporated under reduced
pressure. The residue was diluted with ethyl acetate (200 mL) and
washed with brine (3.times.100 mL) and dried (Na.sub.2SO.sub.4).
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, 88%).
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). .sup.1H NMR.delta.
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.
[0460] 3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine:
[0461] Hydrazine (4 mL) was added to a solution of
3-[4-(4-fluorophenyl)pi- peridin-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 combined filtrates to leave the
crude product as an oil. The oil was purified by column
chromatography (dichloromethane/methanol/2 M ammonia in methanol,
10/3/1), giving the desired product (2.70 g, 93%). .sup.1H NMR
.delta. 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).
[0462] 4-(4-methyl-4-(3,5-dimethylphenyl)piperidine:
[0463] hygroscopic; .sup.1H NMR.delta.1.20 (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).
[0464] Piperidine Side Chain Intermediates
[0465] Tert-butyl 4-{[(trifluoromethyl)
sulfonyl]oxy}-1,2,3,6-tetrahydro-1- -pyridinecarboxylate:
[0466] 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.degree. C. and stirred for 20 minutes. The
reaction mixture was cooled to -78.degree. 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. Tf.sub.2NPh (42.0 mmol, 15.0 g) in THF (40
mL) was added dropwise to the reaction mixture and stirred at
.degree. 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
Tf.sub.2NPh.
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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).
[0468] Tert-butyl
4-[3-(amino)phenyl]-1,2,3,6-tetrahydro-1-pyridinecarboxy- late:
[0469] A mixture of 2 M aqueous Na.sub.2CO.sub.3 solution (4.2 mL),
tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridi-
ne-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 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 (3.times.). The combined organic extracts were dried and
concentrated in vacuo. The crude product was chromatograghed
(silica, hexanes:EtOAc:dichloromethane (6:1:1) with 1% added
isopropylamine to protect the BOC group from hydrolysis) to give
0.330 g of the desired product in 81% yield:
[0470] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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).sup.+.
[0471] Anal. Calc. for C.sub.16H.sub.24N.sub.2O.sub.2: C, 70.04; H,
8.08; N, 10.21. Found: C, 69.78; H, 7.80; N, 9.92
[0472] Tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate
[0473] A mixture of 3.10 g of tert-butyl
4-(3-aminophenyl)-1,2,3,6-tetrahy- dropyridine-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 1%
isopropylamine added to protect the BOC group from hydrolysis) to
give 2.63 g of the desired product (84%).
[0474] Tert-butyl
4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate
[0475] .sup.1H NMR (400 MHz, CHCl.sub.3) .delta. 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.sub.4H.sub.8).sup.+.
[0476] 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine:
[0477] Into a stirred solution of 5.00 g (16.0 mmol) of tert-butyl
1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylate in 100
ml of 1,4-dioxane at 0.degree. C. was bubbled HCl gas for 10
minutes. The reaction mixture was allowed to warm to room
temperature and the bubbling of the HCl 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.times.80
mL of dichloromethane and the combined organic extracts were dried
(MgSO.sub.4), 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
(87.5% yield) of the desired product: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 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), 3.14 (t, 2H, J=5.6 Hz), 2.54-2.46 (m,
2H)
[0478] Tert-butyl
3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propylc-
arbamate:
[0479] A mixture of 2.80 g (14.0 mmol) of
1,2,3,6-tetrahydro-4-(3-nitrophe- nyl)pyridine, 3.60 g (15.0 mmol)
of tert-butyl N-(3-bromopropyl)carbamate, 11.6 g (84.0 mmol) of
K.sub.2CO.sub.3, 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
(MgSO.sub.4), concentrated in vacuo and the residue was purified by
column chromatography (silica, 9:1, dichloromethane:methanol+1%
isopropyl amine) to afford 4.35 g (85.7% yield) of the desired
product: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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).sup.+.
[0480]
3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine:
[0481] 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.degree. C. was bubbled HCl 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.times.80 mL of
dichloromethane, the combined organic extracts were dried
(MgSO.sub.4) , filtered and concentrated in vacuo. The residue was
purified by column chromatography (silica, 9:1,
dichloromethane:methanol+- 1% isopropyl amine) to afford 3.05 g
(97.0% yield) of the desired product: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.24 (t, 1H, J=1.8 Hz), 8.09 (dd, 1H, J=1.8,
8.2 Hz), 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); ESMS m/e: 262.2
(M+H).sup.30 ; Anal. Calc. for C.sub.14H.sub.19N.sub.3O.sub.2 (0.06
CHCl.sub.3): C, 62.90; H, 7.16; N, 15.65. Found: C, 63.20; H, 7.16;
N, 15.65.
[0482] Methyl
(4S)-3-[({3-[4-(3-aminophenyl)-1-piperidinyl]propyl}amino)ca-
rbonyl]-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro--
5-pyrimidinecarboxylate:
[0483] 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)-p-
yrimidinedicarboxylate, 1.50 g (5.80 mmol) of
3-(4-(3-nitrophenyl)-3,6-dih- ydro-1(2H)-pyridinyl)-1-propanamine,
7.94 g (75.5 mmol) of K.sub.2CO.sub.3 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.times.50 mL of 5% aqueous NaOH solution, the
organic layer was dried (MgSO.sub.4) and concentrated in vacuo. The
residue was dissolved in 100 mL of anhydrous ethanol containing
0.50 g 10% 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 (MgSO.sub.4) and concentrated in
vacuo. The residue was purified by column chromatography (silica,
9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford
1.65 g (52.0% yield) of the desired product.
[0484] Tert-butyl
4-[3-(isobutyrylamino)phenyl]-3,6-dihydro-1-(2H)-pyridin-
ecarboxylate:
[0485] 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 (MgSO.sub.4) , and concentrated in vacuo.
The residue was purified by column chromatography (silica,
50:46:3:1, hexanes:dichloromethane:methano- l:isopropyl amine) to
afford 2.90 g (52.0% yield) of the desired product: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 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).sup.+. Anal.
Calc. for C.sub.20H.sub.28N.sub.2O.sub.3+0.175 CHCl.sub.3: C,
66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88
[0486] Tert-butyl
4-[3-(isobutyrylamino)phenyl]-1-piperidinecarboxylate:
[0487] 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 10% 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 (MgSO.sub.4) and concentrated in vacuo. The residue was
purified by column chromatography (silica, 9.5:0.5,
dichloromethane:methanol+1% isopropyl amine) to afford 2.40 g
(84.0% yield) of the desired product: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.49-7.44 (m, 2H), 7.24 (t, 1H, J=7.6 Hz), 6.93
(d, 1H, J=7.6 Hz), 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).sup.+; Anal. Calc. for
C.sub.20H.sub.30N.sub.2O.sub.3+0.3H.sub.2O: C, 68.27; H, 8.77; N,
7.96. Found: C, 68.25; H, 8.54; N, 7.84.
[0488] 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide:
[0489] 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.degree. C. was bubbled HCl gas for 10 minutes. The
reaction mixture was allowed to warm to room temperature and the
bubbling of the HCl 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.times.80 mL of dichloromethane, the
combined organic extracts were dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was purified by column
chromatography (silica, 9:1, dichloromethane:methanol+- 1%
isopropyl amine) to afford 0.700 g (46.0% yield) of the desired
product: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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).sup.+;
[0490] The hydrochloride salt was used for the combustion analysis:
Anal. Calc. for C.sub.15H.sub.22N.sub.2O+HCl+0.15 CHCl.sub.3: C,
60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N, 8.88.
[0491] 3-(4-piperidinyl)aniline:
[0492] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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, 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).sup.+.
[0493] Tert-butyl
4-(4-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate:
[0494] To a 25-mL RB flask, equipped with a condensor, was added
tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinec-
arboxylate (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.degree. 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 (3.times.20 mL) and the
combined organic extracts were washed with sat NH.sub.4Cl (20 mL)
and brine (20 mL) , dried over MgSO.sub.4 and concentrated under
reduced pressure. The residue was purified by chromatography
(6:1=hexane:ethyl acetate with 1% NH.sub.3) to afford the product
(0.55 g, 59.9%) as a yellow oil. The compound is not stable at room
temperature and should be used as prompt as practical: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 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), 1.49 (s, 9H).
[0495] 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine:
[0496] 4-(4-Nitrophenyl)-1,2,3,6-tetrahydropyridine was prepared by
a similar procedure to that used for the 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.
[0497] Dihydropyrimidine Intermediates
[0498] 3-(3,4,5-trifluorobenzylidene)-2,4-pentanedione:
[0499] 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.
[0500]
1-[2-methoxy-4-methyl-6-(3,4,5-trifluorophenyl)-1,6-dihydro-5-pyrim-
idinyl]ethanone:
[0501] A mixture 3-(3,4,5-trifluorobenzylidene)-2,4-pentanedione
(26.2 mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol),
and NaHCO.sub.3 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and
heated at 95-100.degree. C. for 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 crude 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, 36%).
[0502] 4-nitrophenyl
5-acetyl-2-methoxy-4-methyl-6-(3,4,5-trifluorophenyl)-
-1(6H)-pyrimidinecarboxylate:
[0503] 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 (2.80 g, 9.38 mmol) and pyridine (10 mL) in
CH.sub.2Cl.sub.2 (200 mL) at 0-5.degree. 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 3/20), to give the
desired product as a white powder (4.00 g, 92%.
[0504] 4-nitrophenyl
5-acetyl-4-methyl-2-oxo-6-(3,4,5-trifluorophenyl)-3,6-
-dihydro-1(2H)-pyrimidinecarboxylate:
[0505] A solution of 6 N aqueous HCl (4 mL) was added to a
well-stirred solution of 4-nitrophenyl
5-acetyl-2-methoxy-4-methyl-6-(3,4,5-trifluorop-
henyl)-1(6H)-pyrimidinecarboxylate (4.00 g, 8.63 mmol) in THF (100
mL) at 0-5.degree. 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%).
[0506] : .sup.1H NMR (DMSO) .delta. 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).sup.+; Anal.
Calc. for C.sub.20H.sub.14F.sub.3N.sub.3O.sub.6: C, 53.46; H, 3.14;
N, 9.35. Found: C, 53.26; H, 3.21; N, 9.35.
[0507] Benzyl
2-propionyl-3-(3,4,5-trifluorophenyl)-2-propenoate.
[0508] 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
5 h. 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 anhydrous Na.sub.2SO.sub.4. The
solvent was evaporated to afford a pale yellow syrup (60.2 g),
which was used in the next step without further purification.
[0509] Benzyl
6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyrim-
idinecarboxylate.
[0510] A suspension of benzyl
2-propionyl-3-(3,4,5-trifluorophenyl)-2-prop- enoate (16.0 g, 48.0
mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol),
NaHCO.sub.3 (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at
70.degree. C. for 20 h. After cooling to room temperature, the
reaction mixture was filtered and the filtrate was diluted with
EtOAc (300 mL) and then washed with water (4.times.100 mL), brine
(200 mL) and dried over Na.sub.2SO.sub.4. After removal of solvent,
the residue was purified by column chromatography (SiO.sub.2,
EtOAc/Hexane, 10-30%) to afford benzyl
6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-pyri-
midinecarboxylate as a colorless oil (10.6 g, 58% yield). The
product was directly used in the next step after .sup.1H NMR
spectroscopy which showed it to be a mixture of amine/imine
tautomers.
[0511] 5-benzyl
1-(4-nitrophenyl)6-(3,4-difluorophenyl)-4-ethyl-2-methoxy--
1,5(6H)-pyrimidinedicarboxylate.
[0512] Into a well-stirred solution of benzyl
6-(3,4-difluorophenyl)-4-eth-
yl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate (27.5 g, 68.75
mmol) and pyridine (9.2 mL) in CH.sub.2Cl.sub.2 (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 10% aqueous KOH solution (2.times.150 mL). The organic
layer was separated and dried over Na.sub.2SO.sub.4. The solvent
was removed in vacuo and the residue was used in the next step
without further purification: .sup.1H NMR (CDCl.sub.3) .delta. 1.24
(t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (AB.sub.q,
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).
[0513] Benzyl
6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1-({[(1R)-1-phenyle-
thyl]amino}carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate.
[0514] 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-(+)-.alpha.-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 10% K.sub.2CO.sub.3
solution (2.times.30 mL). The organic layer was dried over
Na.sub.2SO.sub.4, 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)-1-phenyleth-
yl]amino}carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate: Colorless
oil, Rf=0.31(4:1 pet ether:ether); wt.=3.8 g (60% yield);
[.alpha.].sub.D=+267.05 (c=0.76, CHCl.sub.3); .sup.1H NMR
(CDCl.sub.3) .delta. 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, 2H, 4.99 (m, 1H) , 5.09
(AB.sub.q, 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}ca-
rbonyl)-1,6-dihydro-5-pyrimidinecarboxylate: Colorless oil;
R.sub.f=0.22 (4:1 pet ether:ether); wt.=3.2 g (51.2% yield);
[.alpha.].sub.D=-146.89 (c=0.38, CHCl.sub.3); .sup.1H NMR
(CDCl.sub.3) .delta. 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
(AB.sub.q, 2H), 6.68 (s, 1H), 6.91-7.34 (m, 13H).
[0515] (+)-benzyl
6-(3,4-difluorophenyl)-4-ethyl-2-methoxy-1,6-dihydro-5-p-
yrimidinecarboxylate.
[0516] Into a stirred solution of (+)-benzyl
6-(3,4-difluorophenyl)-4-ethy-
l-2-methoxy-1-({[(1R)-1-phenylethyl]amino}carbonyl)-1,6-dihydro-5-pyrimidi-
necarboxylate (17.1 mmol, 9.35 g) in CH.sub.2Cl.sub.2 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-pyrimidinecarboxyl-
ate was obtained (77%, yield).
[0517] (+)-5-benzyl 1-(4-nitrophenyl)
6-(3,4-difluorophenyl)-4-ethyl-2-met-
hoxy-1,5(6H)-pyrimidinedicarboxylate.
[0518] Into a well-stirred solution of (+)-benzyl
6-(3,4-difluorophenyl)-4-
-ethyl-2-methoxy-1,6-dihydro-5-pyrimidinecarboxylate (6.4 g, 16.0
mmol) and pyridine (1.5 mL) in CH.sub.2Cl.sub.2 (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.times.100 mL). The
organic layer was separated and dried over Na.sub.2SO.sub.4. 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.
[0519] a. 2-(4-methoxybenzyl)-2-thiopseudourea Hydrochloride.
[0520] Into a well-stirred suspension of thiourea (7.6 g, 0.1 mol)
in THF (50 mL) at 0.degree. 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.degree. 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, 96% yield); m. p. 161-163.degree.
C.
[0521] b. Methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate.
[0522] 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.times.50 mL) and dried (21.8 g,
93% yield).
[0523] c.
1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]--
4-methyl-6-(4-nitrophenyl)pyrimidine.
[0524] 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.degree. C. for 4.5 hours. The reaction mixture was
cooled to room temperature, poured into ice-water (300 mL) and
extracted with EtOAc (2.times.400 mL). The combined EtOAc extracts
were washed with 10% NaHCO.sub.3 solution (2.times.60 mL), brine
(100 mL), and then dried (MgSO.sub.4). The solvent was evaporated
and the crude product was purified by flash column chromatography
on silica gel using 10% through 30% EtOAc in hexane as the gradient
eluent. The desired product was obtained as an oil, which on
trituration with EtOAc/hexane became a yellow solid (11.4 g, 66.7%
yield) which was shown by .sup.1H NMR to be a mixture of tautomers:
m.p. 138-139.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 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 C.sub.21H.sub.21N.sub.3O.sub.5S: C, 59.00; H, 4.95; N, 9.83.
Found: C, 59.02; H, 4.93; N, 9.77.
[0525] d.
1,6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl}thio]--
4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.
[0526] Into a well-stirred mixture of
1,6-dihydro-5-methoxycarbonyl-2-[{(4-
-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)pyrimidine
(4.50 g, 10.5 mmol), NaHCO.sub.3 (3.69 g, 0.044 mol),
CH.sub.2Cl.sub.2 (200 mL), and water (50 mL) at 0-5.degree. 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.sub.2Cl.sub.2 layer was washed with saturated aqueous
NaHCO.sub.3 solution (3.times.50 mL) , dried (MgSO.sub.4) , and the
solvent evaporated. The residue was recrystallized from
CH.sub.2Cl.sub.2 and hexane to give the product as white crystals
(5.50 g, 88.4% yield) : m.p. 156-157.degree. C.; .sup.1H-NMR
(CDCl.sub.3) .delta. 2.53 (s, 3 H), 3.70 (s, 3 H), 3.81 (s, 3 H),
4.06, 4.36 (AB.sub.q, 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 C.sub.28H.sub.24N.sub.4O.sub.9S: C,
56.75; H, 4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25.
[0527] a.
6-(benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-brom-
omethyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine.
[0528] Into a well-stirred solution of
6-(benzofurazan-5-yl)-1,6-dihydro-2-
-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimid-
ine (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.degree. 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 CHCl.sub.3 (10 mL) and washed with
brine. The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered and the solvent was removed in vacuo to
obtain 0.15 g (88% yield) of 6-(benzofurazan-5-yl)-1,-
6-dihydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyl-oxy)carb-
onyl]pyrimidine as a yellow foam. The crude product was used in the
next step without purification. .sup.1H NMR (CDCl.sub.3) .delta.
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, 1 H), 7.80 (s, 1 H), 7.92 (d, J=9.1 Hz, 1
H), 8.30 (d, J=9.1 Hz, 2 H).
[0529] c. 4-nitrophenyl
4-(2,1,3-benzoxadiazol-5-yl)-2,5-dioxo-1,2,5,7-tet-
rahydrofuro[3,4-D]pyrimidine-3(4H)-carboxylate.
[0530]
6-(3,4-Benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bro-
momethyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.27 mmol, 0.15
g) was heated in oil bath for 3 h (bath temperature 130.degree. C.
The brownish-yellow residue thus obtained was washed with
CHCl.sub.3 and 4-nitrophenyl
4-(2,1,3-benzoxadiazol-5-yl)-2,5-dioxo-1,2,5,7-tetrahydrofu-
ro[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, 93% yield): .sup.1H NMR (DMSO-d.sub.6) .delta.
8.38-7.56 (m, 7H), 6.33 (s, 1H), 5.02 (s, 2H); Anal. Calc. for
C.sub.19H.sub.11N.sub.5O.sub.- 8+2.3H.sub.2O: C, 47.85; H, 3.28; N,
14.63. Found: C, 47.73; H, 2.51; N, 14.77.
[0531] 5-methyl
1-(4-nitrophenyl)4-(bromomethyl)-6-(3,4-difluorophenyl)-2--
oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate:
[0532] Into a well-stirred solution of
6-(3,4-Difluorophenyl)-1,6-dihydro--
2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimid-
ine (1.5 mmol, 0.66 g) in 5 mL of chloroform was added a solution
of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0.degree.
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 CHCl.sub.3 (20 mL) and washed with brine. The organic
layer was separated, dried over Na.sub.2SO.sub.4, 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.
.sup.1H NMR .delta. 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).
[0533] 4-nitrophenyl
4-(3,4-difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydrofu-
ro[3,4-D]pyrimidine-3(4H)-carboxylate.
[0534] 5-methyl 1-(4-nitrophenyl)
4-(bromomethyl)-6-(3,4-difluorophenyl)-2-
-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate (1.5 mmol, 0.81 g)
was heated in an oil bath for 3 h (bath temperature 130.degree.
C.). The brown residue thus obtained was washed with CHCl.sub.3 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): .sup.1H NMR (DMSO-d.sub.6) .delta. 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).
[0535] 4-nitrophenyl
4-(1,3-benzodioxol-5-yl)-2,5-dioxohexahydrofuro[3,4-D-
]pyrimidine-3(4H)-carboxylate:
[0536] .sup.1H NMR (DMSO) .delta. 11.35 (s, 1H), 8.16 (d, 2H, J=9.5
Hz), 7.32 (d, 2H, J=8.9 Hz), 6.81-6.65 (m, 3H) , 5.88 (s, 1H) ,
4.85 (ABq, 2H); ESMS m/e: 440.1 (M+H).sup.+; Anal. Calc. for
C.sub.20H.sub.15N.sub.3- O.sub.9+1.5H.sub.2O: C, 51.29; H, 3.87; N,
8.97. Found: C, 51.38; H, 2.85; N, 8.73.
[0537] 5-methyl 1-(4-nitrophenyl)
(6S)-6-(3,4-difluorophenyl)-4-methyl-2-o-
xo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate:
[0538] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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).sup.+; Anal. Calc. for
C.sub.20H.sub.15F.sub.2N.sub.3O.sub.7: C, 53.70; H, 3.38; N, 9.39.
Found: C, 53.35; H, 3.36; N, 9.27.
[0539] Benzyl
[0540]
4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexylcarbamate:
[0541] Oxalyl chloride (1.1 equivalents) was added dropwise to a
mixture of
4-[[(tert-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.degree. 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.degree. 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.).
[0542] A solution of benzyl
4-{[(tert-butoxycarbonyl)amino]methyl}-cyclohe- xyl carbamate in
MeOH containing 10% 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-aminocyclohexylmethylcar- bamate (95%).
[0543] 9H-9-fluorenylmethyl
N-[4-(aminomethyl)cyclohexyl]carbamate:
[0544] .sup.1H NMR.delta.8.02 (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).
[0545] N1-[4-(aminomethyl)cyclohexyl]-1-naphthamide:
[0546] 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: .sup.1H NMR .delta.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).
[0547] Tert-butyl
N-(4-[(1-naphthylcarbonyl)amino]-cyclohexylmethyl)-carba- mate:
[0548] 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
tert-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): .sup.1H NMR.delta.8.29 (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).
[0549] 4-acetyl-1-(3-aminopropyl)-4-phenylpiperidine:
[0550] 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 CH.sub.2Cl.sub.2 (100
mL+3.times.50 mL). The combined organic solutions were dried over
magnesium 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, 40%): H NMR.delta.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); .sup.13C NMR.delta. 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.
[0551] For the preparation of benzo-4',5'[H]furanpiperidine refer
to W. E. Parham et al, J. Org. Chem. (1976) 41, 2268.
[0552]
Tert-butoxy{[3-(benzo-4',5'[H]furanpiperidin-1-yl)propyl]amino}meth-
anol:
[0553] To a stirred solution of the
N-[4-(benzo-4',5'[H]furanpiperidine (0.566 g, 3.27 mmol) in dioxane
(20 mL), N-(tert-butoxycarbonyl)-3-bromop- ropylamine (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%); .sup.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).
[0554] 3-(4-methyl-4-phenyl-1-piperdinyl)propylamine:
[0555] Trifluoroacetic acid (1 mL) was added to
tert-butoxy{[3-(4-methyl-4-
-phenyl-1-piperdinyl)propyl]-amino}methanol (0.500 g, 1.51 mmol) in
dichloromethane (5 mL) and the solution was stirred at room
temperature for 1 h. The solution was concentrated, neutralized
with 10% 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.
[0556] Procedures for the Reaction of the Amine Side Chains with
the p-Nitrophenylcarbamate Intermediates:
[0557] General Procedure:
[0558] An equimolar solution of an amine side chain such as
3-(4-methyl-4-phenyl-1-piperdinyl)propylamine and a
p-nitrophenylcarbamate intermediate such as
5-methoxycarbonyl-4-methoxyme-
thyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)-
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.
[0559] 2-oxo-3-{spiro[1H-indane-1,4'-piperdine]propylamine (0.03,
19 g, 0.123 mmol) was added to
(.+-.)-6-(3,4-difluorophenyl)-1,6-dihydro-2-meth-
oxy-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 HCl (2
mL). After neutralization with aqueous 10% KOH solution, the
reaction mixture was extracted into dichloromethane (3.times.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.
[0560] 1 M 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 product was
recrystallized from ether, giving the desired compound (0.042 g,
99%) as a pale yellow solid; mp 178-182.degree. C.; Anal. Calcd.
for C.sub.H.sub.34F.sub.2N.sub.4O.sub.5C- l.sub.2+0.6 H.sub.2O: C,
57.87; H, 5.73, N 9.31. Found: C, 58.11; H 5.90; N 8.95.
[0561] General Procedure for the reaction of the piperidines and
piperazines with
1-(3-bromo-propylcarbamoyl)-6-(3,4-difluoro-phenyl)-4-me-
thyl-2-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid methyl
ester:
[0562] 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 NaHCO.sub.3 (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 HCl in Et.sub.2O (1 M, 0.5 mL) was added at room temperature.
The solvent was removed in vacuo, giving the desired compound as an
HCl salt.
EXAMPLE 1
(-)-1,2,3,6-tetrahydro-1-{N-[4-(3,-acetamido)-phenyl-piperidin-1-yl]propyl-
}carboxamido-4-methoxymethyl-6-(3,4-difluoro-phenyl)-2-oxopyrimidine-5-car-
boxylic Acid Methyl Ester
[0563] ESMS, 612.25 (M+1); .sup.1H NMR.delta.1.76-1.87 (m, 6H),
2.03-2.13 (m, 2H), 2.18 (s, 3H), 2.49 (t, J=6.9 Hs, 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-pyridinylpropy-
l)amino]carbonyl-4-(3,4-difluorophenyl)-6-(methoxy-methyl)-2-oxo-1,2,3,4-t-
etrahydro-5-pyrimidinecarboxylate
[0564] .sup.1H NMR.delta.8.90 (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-O-acetyl)-4-phenylpiperidin-1-yl]propyl}-
carboxamido-5-methoxycarbonyl-4-methoxymethyl-6-(3,4-difluorophenyl)-2-oxo-
pyrimidine
[0565] 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 mixture was stirred at room
temperature for 12 h. The reaction mixture was quenched with
aqueous 6 N HCl. 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 or Na CO, the
layers were separated, and the aqueous layer was extracted with
dichloromethane (3.times.30 mL). The combined organic extracts were
dried (Na.sub.2SO.sub.4) and the product was chromatographed,
giving the desired product. The HCl salt was prepared by the
addition of 1 M HCl in ether to a solution of the product in
CH.sub.2Cl.sub.2. The precipitated salt was filtered, washed with
ether and dried in vacuo, giving
(1)-1,2,3,6-tetrahydro-1-{N-[3-(4-O-acetyl)-4--
phenylpiperidin-1-yl]propyl}carboxamido-5-methoxycarbonyl-4-methoxymethyl--
6-(3,4-difluorophenyl)-2-oxopyrimidine (170 mg, 47%) as the
hydrochloride salt: (C.sub.31H.sub.36NF.sub.2O-+HCl+0.6
CH.sub.2Cl.sub.2) ; mp 82-84.degree. C.
EXAMPLE 4
Benzyl Ester Precursor to the Product of Example 4
[0566]
(+)-1,2,3,6-tetrahydro-1-{N-[4-(benzo-4',5'(H)furan)piperidin-1-yl]-
propyl}-carboxamido-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine-5-carb-
oxylic Acid Phenylmethyl Ester:
[0567] .sup.1H NMR.delta.7.60-7.00 (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, 12 H), 2.86
(q, 2 H, J=2.5 Hz), 1.19 (t, 3 H, J=7.5 Hz).
[0568]
(+)-1,2,3,6-tetrahydro-1-{N-[4-(benzo-4',5'(H)furan)piperidin-1-yl]-
propyl}-carboxamido-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine-5
Carboxylic Acid Hydrochloride:
[0569] .sup.1H NMR.delta.8.95 (br s, 1 H), 8.22 (br s, 1 H),
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 CHN.sub.4O.sub.5F.sub.2+HCl+1.5
H.sub.2O: 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
[0570] Under argon, .alpha.-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.degree. C. The solution was stirred at -78.degree. 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 CHCl (300 mL), washed with water and saturated
brine, and then dried over Na.sub.2SO.sub.4. After filtration and
removal of solvent, the residue was vacuum distilled. The product,
a colorless oil (7.21 g, 96.5%) was collected at 180 C/1 mm Hg;
.sup.1H NMR (400 Mhz) .delta.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.
[0571]
1-hydroxy-2-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalene:
[0572] A solution of 1,2,3,4-tetrahydro1-oxo-naphthacetic acid
methyl ester (6.15 g, 28.2 mmol) in THF (150 mL) was treated with
LiAlH.sub.4 (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.degree. C. and quenched by addition of solid Na.sub.2SO.sub.410
H.sub.2O. 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, 98.3%); .sup.1H NMR
indicated the formation of an isomeric mixture. EI mass spectrum M+
at m/z 192. The mixture was directly used in next reaction without
further purification.
[0573] 2-(2-hydroxyethyl)-1,2,3,4-tetrahydro-1-oxo-naphthalene:
[0574] A solution of isomeric mixture of
1-hydroxyl-2-(2-hydroxyethyl)-1,2- ,3,4-tetrahydronaphthalene (3.00
g, 15.6 mmol) in CH.sub.2Cl.sub.2 (100 mL) was treated with
MnO.sub.2 (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/CHCl, 5/95), giving
a yellow oil (2.00 g, 67.4%): .sup.1H NMR.delta.1.76 (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.
[0575] 2-(2-bromoethyl)-1,2,3,4-tetrahydro-1-oxonaphthalene:
[0576] A solution of
2-(2-hydroxethyl)-1,2,3,4-tetrahydro-1-oxo-naphthalen- e (2.00 g,
10.5 mmol) in CH.sub.2Cl.sub.2 (100 mL) was treated with PBr (948
mg, 3.50 mmol) at 0.degree. 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 10% K.sub.2CO.sub.3
solution, H.sub.2O, saturated NaCl and dried over Na.sub.2SO.sub.4.
After filtration and removal of the solvent, the residue was
purified by chromatography (EtOAc/hexane, 1/10), giving a yellow
oil (1.18 g, 44.4%); .sup.1H NMR.delta.1.49 (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.
[0577]
2-[2-(4-benzamino-1-piperidyl)ethyl]-1,2,3,4-tetrahydro-1-oxo-napht-
halene:
[0578] A mixture of
2-(2-bromoethyl)-1,2,3,4-tetrahydro-1-oxonaphthalene (1.18 g, 4.66
mmol), 4-benzamidopiperidine (952 mg, 4.66 mmol) and K.sub.2CO
(1.29 g, 9.32 mmol) in acetone (200 mL) 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:CHCl., 5/95). The product was
recrystallized from an EtOAc/hexane mixture, giving a white powder
(268 mg, 15.3%); mp 158-159.degree. C.; .sup.1H NMR.delta.1.53 (m,
2H) , 1.67 (m, 1H), 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
CHN.sub.2O.sub.2: C, 76.55; H. 7.51; N, 7.44. Found: C, 76.28; H,
7.46; N, 7.37.
EXAMPLE 6
Methyl
4-(2,1,3-benzoxadiazol-5-yl)-3-[(1-[4-(dibutylamino)-benzyl]-4-pipe-
ridylmethyl)amino]carbonyl-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinec-
arboxylate
[0579] .sup.1H NMR .delta. 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, 2 h), 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-benzimidazolyl-piperidin-1yl]p-
ropyl}carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine
Hydrochloride
[0580] .sup.1H NMR.delta. 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, 1 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 (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-(benzofurazan-5-yl)-1,2,3,6-tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo--
1-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamido-pyrimidine
[0581] A solution of
6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxy-
carbonyl-4-methyl-1-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamidopyrim-
idine in MeOH was treated with 6 N HCl at 0.degree. C. The solution
was stirred at room temperature for 2 h and the MeOH was removed in
vacuo.
6-(Benzofurazan-5-yl)-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: mp 134-137 C.
EXAMPLE 9
4-(3-methoxy)-phenyl Piperidine
[0582] HCl salt; mp 150-154 C; H NMR.delta.2.04 (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 CHNOCl+0.30 CH.sub.2Cl.sub.2: C, 58.34; H, 7.40;
N, 5.53. Found: C, 58.30; H, 7.71; N, 5.35.
[0583]
(+)-1,2,3,6-tetrahydro-1-N-[4-(3-methoxy)-phenyl}-piperidin-1-yl]-p-
ropyl-carboxamido-4-methoxymethyl-6-(3,4-difluorophenyl)-2-oxopyrimidine-5-
-carboxylic Acid Methyl Ester:
[0584] mp 80-84.degree. C.; [.alpha.].sub.D=94.7, (c=0.25, MeOH);
.sup.1H NMR .delta.1.74-1.84 (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, 2H), 7.72 (s, 1H) , 8.84
(t, J=5.4 Hz, 1H). Anal Calcd. For CHN.sub.4OF.sub.2Cl: C, 57.8; H,
6.0; N, 9.0. Found: C, 57.61; H, 6.57; N, 6.97.
EXAMPLE 10
(+)-1,2,3,6-tetrahydro-1-{N-[4-(3,-acetamido)-phenyl-piperidin-1-yl]propyl-
}carboxamido-4-methoxymethyl-6-(3,4-difluoro-phenyl)-2-oxopyrimidine-5-car-
boxylic Acid Methyl Ester
[0585] mp 135-138.degree. C.; [.alpha.].sub.D=+105.5, (c =0.11,
MeOH); ESMS, 614.25 (M+1); .sup.1H NMR.delta.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
[0586] The compound of Example 10 may also be prepared via
hydrogenation of the compound of example 2 (H.sub.2 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-phenylpiperidin-1-yl)propionitrile
[0587] 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, 99%).
[0588] 3-(4-phenylpiperidin-1-yl)propylamine:
[0589] A solution of BH in THF (1.0 M, 83.0 mL, 83.0 mmol, 3.5 eq)
was added to a 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 CH.sub.2Cl (3.times.100 mL). The combined organic extracts
were dried over magnesium sulfate and concentrated. The residue was
dissolved in CH.sub.2Cl.sub.2 (20 mL) and treated with HCl 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 CH.sub.2Cl.sub.2 (3.times.50 mL). The
combined extracts were dried over magnesium sulfate and the
solvents were evaporated, giving the desired product (4.50 g,
87%).
[0590]
6-(3,4-diflourophenyl)-1,2,3,6-tetrahydro-5-methoxycarbonyl-4-methy-
l-2-oxo-1-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamido-pyrimidine:
[0591] A solution of
6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methox- y
carbonyl-4-methyl-1-{N-[3-(4-phenyl-piperidin-1-yl)propyl]}carboxamidopy-
rimidine (100 mg, 0.185 mmol, mp=43-45.degree. C.) in MeOH (5 mL)
was treated with aqueous 6 N HCl (1.5 mL) at 0.degree. 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-ox-
o-1-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamidopyrimidine
hydrochloride was obtained as a white powder (89 mg, 86). mp
133-136.degree. C.
EXAMPLE 12
3-{(3,4,5-trifluorophenyl)methylene}-2,4-pentanedione
[0592] 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.
[0593]
6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methylpy-
rimidine:
[0594] A stirring mixture of
2-{(3,4,5-trifluoro-phenyl)methylene}-2,4-pen- tanedione (26.2
mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and
NaHCO (6.60 g, 78.6 mmol) in EtOH (400 mL) was heated at
95-100.degree. 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, 36%).
[0595]
.delta.-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-me-
thyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0596] 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-me-
thylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in
CH.sub.2Cl.sub.2 (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 Cl/EtOAc,
9/1 to 20/3), giving the desired product as a white powder (4.0 g,
92%).
[0597]
6-(3,4,5-trifluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-acetyl-4-methy-
l-1-[(4-nitrophenyloxy)carbonyl]pyrimidine:
[0598] 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-n-
itrophenyloxy) 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, 100%).
[0599] (+/-)-1,2,3,6-tetra
hydro-1-{N-[4-(4-fluorophenyl)-piperidine-1-yl]-
-propyl}carboxamido-5-acetyl-2-oxo-6-(3,4,5-trifluoro
phenyl)-4-methyl Pyrimidine Hydrochloride:
[0600] .sup.1H NMR.delta. 7.20-6.86 (m, 6 H), 6.64 (s, 1 H), 5.56
(s, 1 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-naphthamide
[0601] .sup.1H NMR.delta.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-yl]prop-yl}carboxa-
mido-4-methoxymethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine-5-carboxylic
Acid Methyl Ester
[0602] mp 168-172.degree. C.; [.alpha.]: =+94.7, (c=0.25, MeOH);
.sup.1H NMR.delta.1.75-1.84 (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
[0603] mp 254-258 C; .sup.1H NMR.delta.1.53-1.68 (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 CHNOFCl+0.14
CH.sub.2Cl.sub.2: C, 56.60; H, 6.76; N, 5.44. Found: C, 56.60; H,
6.92; N, 5.28.
[0604]
(+)-1,2,3,6-tetrahydro-1-{N-[4-(5-fluoro-2-methoxy)phenylpiperidin--
1-yl]propyl}carboxamido-4-methoxymethyl-6-(3,4-difluoro-phenyl)-2-oxopyrim-
idine-5-carboxylic Acid Methyl Ester:
[0605] .sup.1H NMR.delta.8.93 (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)-piperidin-1-yl]propyl-
}carboxamido-4-methoxymethyl-6-(3,4-difluorophenyl)-2-oxopyrimidine-5-carb-
oxylic Acid Methyl Ester
[0606] mp 132-135.degree. C.; [.alpha.]: =+94.7, (c =0.25, MeOH);
.sup.1H NMR.delta.1.47 (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, 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
[0607] A solution of 2,4'-dipyridyl (25.0 g, 160 mmol) and
3-bromopropyl-amine hydrobromide (35.0 g, 160 mmol) in DMF (60 mL)
was heated at 90-95.degree. 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 Et.sub.2O and
dried, giving 1-(3-aminopropyl)-4-[2-pyridyl]pyridinium bromide
hydrobromide (60 g, 100%)). .sup.1H NMR (DMSO-d.sub.6)
.delta.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, 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 C.sub.13H.sub.16 N.sub.3Br+HBr+0.5 H.sub.2O:
C, 40.65; H, 4.72; N, 10.94. Found: C, 40.83; H, 4.37; N,
11.05.
[0608]
3-(3',6'-dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-propylamine:
[0609] NaBH.sub.4 (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.times.50 mL). The
combined ether extracts were dried over potassium carbonate and the
solvent was removed, giving
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.
[0610] 3-aminopropyl-4-(2-pyridyl)piperidine:
[0611] A suspension of
3-3',6'-dihydro-2'-H-[2,4']bipyridinyl-1'-yl)-propy- lamine (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]
[0612] (CH.sub.2Cl.sub.2/methanol/2M NH3 in MeOH, 90/8/4 to
90/40/40). The product was obtained as a pale yellow oil (3.21 g,
91%). .sup.1H NMR.delta. (CD.sub.3OD) 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, 1 H).
[0613] Part II
[0614] (+)-6-(3,4-difluorophenyl)-1-{N-[4-(2-pyridyl)piperidin-1
yl-propyl]}carboxamido-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-te-
trahydropyrimidine Dihydrochloride
[0615]
5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-d-
ifluorophenyl)-pyrimidine:
[0616] 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 diethyl etherate (56.0 mL, 0.456 mole). The mixture was
stirred at reflux temperature for 8 h, whereupon TLC
(1/1EtOAc/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.times.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, 1/1; 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, 94%).
.sup.1H NMR.delta.3.476 (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).
[0617]
(+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3-
,4-difluorophenyl)-pyrimidine:
[0618] 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.times.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); [.alpha.].sub.3=+83.8 (c=0.5,
chloroform).
[0619]
(+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3-
,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl ]pyrimidine:
[0620] 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-dif-
luorophenyl)-pyrimidine (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.times.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, 79%).
.sup.1H NMR.delta.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).
[0621]
(+)-6-(3,4-difluorophenyl)-1-{N-[4-(2-pyridyl)piperidin-1-yl]-propy-
l]}carboxamido-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydrop-
yrimidine Dihydrochloride:
[0622] A solution of
(+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahy-
dro-2-oxo-6-(3,4-difluorophenyl)-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 re-dissolved in
ethyl acetate (100 mL). The resulting solution was washed with
ice-cold 1 N NaOH (4.times.50 mL), brine (2.times.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 clean fraction of the desired product (2.45 g, 88%) as
a foam and a slightly impure fraction (0.30 g, 10%). .sup.1H
NMR.delta.1.60-2.00 (m, 6H), 2.05-2.15 (m, 2H), 2.38-2.43 (br t,
2H; t, 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).
[0623] 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: .sup.1H NMR.delta.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), 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; [.alpha.]: =+141.13 (c=0.265, MeOH); Anal. Calcd. for
CHNOF.sub.--Cl+0.6 H.sub.2O: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-3-propyl)car-
boxamido-5-methoxycarbonyl-2-oxo-6-(3,4-benzofurazan)-4-methylpyrimidine
Hydrochloride
[0624]
4-(3,4-benzofurazan)-6-methyl-2-OXO-3-{[3-(4-spiro[isobenzo-furan-1-
(3H),4'-piperidine]propyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylic
Acid Methyl Ester:
[0625] 1-(3-Aminopropyl)-4-spiro[iso-benzofuran-1
(3H),4'-piperidine) (0.028 g, 0.110 mmol) was added to
(.+-.)-6-(benzofurazan)-1,6-dihydro-2--
methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine
(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.times.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%) as a syrup: .sup.1H NMR.delta.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, 1 H).
[0626] HCl 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 ); mp 180-182.degree. C.; Anal. Calcd. for C.sub.29
H.sub.34N.sub.6O.sub.6Cl+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-methylthiophen-2-yl)]-propyl}-amide
[0627] Anal. Calcd. for CHN.sub.4O.sub.5ClF.sub.3+HCl+1.5 H O: C,
55.26; H, 6.03; N, 8.59. Found: C, 55.29; H, 5.95; N, 8.39.
EXAMPLE 20
4-(3,4-difluorphenyl)-6-methyl-2-oxo-3-{([3-(4-spiro[isobenzo-furan-1(3H),-
4'-piperidine]propyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylic
Acid Methyl Ester
[0628] For the preparation of the ether piperidine precursor of the
compound of Example 20,refer to W. E. Parham et al, J. Org. Chem.
(1976) 41, 2268.
[0629]
1-tert-butoxycarbonyl-3-(4-spiro[isobenzofuran-1(3H),4'-piperidine]-
)propylamine:
[0630] N-(tert-butoxycarbonyl)-3-bromo-propylamine (0.772 g, 3.27
mmol) 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%) as a colorless oil; .sup.1H
NMR.delta.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).
[0631] 3-(4-spiro[isobenzo-furan-1(3H),4'-piperidine])
propylamine:
[0632] Trifluoroacetic acid (1 mL) was added to
1-tert-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 concentrated, giving the desired amine (0.340
g, 98%) which was used in the subsequent step without further
purification.
[0633]
4-(3,4-difluorphenyl)-6-methyl-2-oxo-3-{[3-(4-spiro[isobenzo-furan--
1(3H),4'-PIPERIDINE]PROPYL}-1,2,3,4-tetrahydropyrimidine-5-carboxylic
Acid Methyl Ester:
[0634] 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-m-
ethoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine
(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 10% aqueous KOH solution,
the reaction mixture was extracted with dichloromethane (3.times.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%) as a syrup;
[0635] 1H-NMR.delta.1.73-1.78 (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).
[0636] A solution of 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 in vacuo. The product was recrystallized
from ether, giving the dihydrochloride as a pale yellow solid
(0.042 g, 99%); mp 178-182 C; Anal. Calcd. for
CH.sub.34F.sub.2N.sub.4OCl+0.6 H.sub.2O: C, 57.87; H, 5.73, N 9.31.
Found: C, 58.11; H 5.90; N 8.95.
EXAMPLE 21
1,2,3,-tetrahydro-1-{N-[4-(dihydroindene)-1-yl}propyl)carboxamido-5-methox-
ycarbonyl-2-OXO-6-(3,4-benzofurazan)-4-M7-methylpyrimidine
[0637] 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.
[0638]
N-(tert-butoxycarbonyl)3-(4-spiro[isobenzo-furan-1(3H),4'-piperidin-
e])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 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 (0.886 g, 61%) as a colorless
oil; .sup.1H NMR.delta. 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).
[0639] 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 dichloromethane (5 ml) and the resulting solution was
stirred at room temperature for 1 hour. The solution was
concentrated, neutralized with 10% KOH solution and extracted into
dichloromethane (25 ml). The organic layer was dried over sodium
sulfate, filtered and concentrated, giving propylamine (0.156 g,
100%) which was used in the subsequent step without further
purification.
[0640]
(.+-.)-4-(3,4-benzofurazan)-6-methyl-2-oxo-3-{spiro[1h-indane
-1,4'-piperidine]propyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylic
Acid Methyl Ester Hydrochloride:
[0641] To
(.+-.)-4-(3,4-benzofurazan)-1,6-dihydro-2-methoxy-5-methoxycarbo-
nyl-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.times.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 (100%) of the
desired product as a syrup: .sup.1H NMR.delta.1.51 (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).
[0642] 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%) of
(.+-.)-4-(3,4-benzofurazan)-6-methyl-2-oxo-3-{spiro[1H-indane-1,4'-pip-
eridine]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 C HNOCl: C, 57.12; H, 5.76; N, 13.33. Found: C, 57.49;
H, 5.96; N, 13.02.
EXAMPLE 22
(+)-1,2,3,6-tetrahydro-1-{N-[4-(benzo-4',5'(H)furan)piperidin-1-yl]propyl}-
carboxamido-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine-5-carboxamide
Hydrochloride
[0643] 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]propy-
l}carboxamido-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine-5-carboxylic
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 NH.sub.3.
The reaction mixture was stirred at room temperature overnight,
concentrated and chromatographed, giving the desired product. The
HCl salt was prepared by the addition of HCl in ether to a solution
of the product in dichloromethane, followed by evaporation of the
solvents.
[0644] Anal. Calc. For C.sub.29 H.sub.33NO.sub.4 F_+HCl+0.7
CHCl.sub.3: 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-benzofur-
azan)-4-methylpyrimidine Hydrochloride
[0645]
1-(3-tert-butoxycarbonylaminopropyl)spiro[isochroman-3,4'piperidin]-
-1-one:
[0646] 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 al. Chem. Pharm. Bull. (1984) 32, 3568.) (0.587 g,
2.58 mmol) in dioxane (20 mL),
N-(tert-butoxycarbonyl)-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%) of the desired product as a colorless oil; .sup.1H
NMR.delta.1.45 (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).
[0647] Step B.
[0648] 1-(3-aminopropyl)spiro[isochroman-3,4'piperidin]-1-one:
[0649] 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% KOH solution and extracted into
25 mL of dichloromethane. The organic layer was dried over sodium
sulfate, filtered and concentrated, giving 0.110 g (100%) of the
product which was used as such for the subsequent step.
[0650]
(.+-.)-4-(3,4-benzofurazan)-6-methyl-2-oxo-3-{(spiro[isochroman-3,4-
'-piperidin]-1-one)propyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylic
Acid Methyl Ester:
[0651] To
(.+-.)-4-(3,4-Benzofurazan)-1,6-dihydro-2-methoxy-5-methoxycarbo-
nyl-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 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 into dichloromethane (3.times.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 (100%) of the
desired product as a syrup: .sup.1H NMR.delta.1.67-2.13 (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 (3, 1 H), 7.13-7.44 (m, 3 H), 7.54 (d, J=9.6 Hz, 1 H),
7.43 (d, J=7.4 Hz, 1 H), 7.69 (s, 1 H), 7.79 (d, J=9.6 Hz, 1 H),
8.87 (t, J=5.2 Hz, 1 H).
[0652] 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%) of the product as a white solid: m.p.
165-167.degree. C.; Anal. Calcd. for CH.sub.36N.sub.6O.sub.6Cl+1.5
H.sub.2O: 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-methoxycarbonyl-2-oxo-6-(3,4-difluoro-
phenyl)-4-methylpyrimidine
[0653]
(.+-.)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-3-{(spiro[isochroman-3-
,4'piperidin]-1-one)propyl}-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic
Acid Methyl Ester:
[0654] To
(.+-.)-4-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycar-
bonyl-4-methyl-1-(4-nitrophenoxy)carbonyl-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 10% aqueous
KOH solution (pH=9) and extracted into dichloromethane (3.times.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 45.0 mg (90%) of
(.+-.)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-3-{(spiro-[isochroman-3,4'pi-
peridin]-1-one)propyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid methyl ester as a syrup;
[0655] .sup.1H NMR.delta.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).
[0656] To the free base (45.0 g, 0.077 mmol) in 4 mL of
dichloromethane, 5 mL of 1 N HCl in ether was added, and the
solution was concentrated in vacuo. Recrystallization from ether
gave 0.050 g (100%) of
(.+-.)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-3-{(spiro-[isochroman-3,4'pi-
peridin]-1-one)propyl}-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic
acid methyl ester hydrochloride as a white solid: m.p.
150-152.degree. C.; Anal. Calcd. for C.sub.31
H.sub.36F.sub.2N.sub.4OCl+2 H_O: C, 56.49; H, 5.96. Found: C,
56.40; H, 5.95.
EXAMPLE 25
5-[(Z)-1-(1-ethyl-2,2,4-trimethyl-1,2-dihydro-6-quinolinyl)-methylidene]-2-
-thioxo-1,3-thiazolan-4-one
EXAMPLE 26
1-[bis(4-fluorophenyl)methyl)-4-(3-phenyl-2-propenyl)piperazine
EXAMPLE 27
4-[(4-imidazo[1,2-a]pyridin-2-ylphenyl)imino)methyl-5-methyl-1,3-benzenedi-
ol
EXAMPLE 28
1-[3-(4-chlorobenzoyl)]propyl-4-benzamidopiperidine
[0657] Preparation of
1-[3-(4-chlorobenzoyl)propyl]-4-benzamidopiperidine
[0658] 1-[3-(4-chlorobenzoyl)propyl]-4-benzamidopiperidine:
[0659] A mixture of 3-(4-chlorobenzol)propyl bromide (640 mg, 2.45
mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K:CO, (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/CHCl, 5/95). The product (320 mg
33.9%) was isolated as a white powder: .sup.1H NMR.delta.1.46 (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 HCl salt and recrystallized from
MeOH/Et.sub.2O, m.p. 243-244 C; Anal. Calcd for
C.sub.22HC.sub.11N.sub.2O.sub.1+HCl+H.sub.2O: 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-chlorophenyl)-1-butano-
ne
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}propyl}-carboxamido-5--
methoxycarbonyl-2-oxo-6-(3,4-difluoro)-4-methyl-pyrimidine
[0660]
1-(3-tert-butoxycarbonylaminopropyl)spiro[1H-indane-1,4'-piperidine-
]:
[0661] To a stirred solution of spiro[1H-indane-1,4'-piperidine]
(M. S. Chambers et al. 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%) of the required product as a colorless oil: .sup.1H
NMR.delta.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).
[0662] 1-3-aminopropyl)spiro[1H-indane-1,4'-piperidine]:
[0663] To
1-(3-tert-Butoxycarbonylaminopropyl)spiro[1H-indane-1,4'-piperid-
ine] (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% KOH solution and extracted into 25 mL of dichloromethane.
The organic layer was dried over sodium sulfate, filtered and
concentrated, giving 0.156 g (100%) of the product which was used
as such for the subsequent step.
[0664]
(.+-.)-4-(3,4-difluoro)-6-methyl-2-oxo-3-{spiro[1H-indane-1,4-piper-
idine]propyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid Methyl
Ester:
[0665] 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 10% aqueous KOH
solution (pH=9) and extracted into dichloromethane (3.times.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 (100%) of the
product as a syrup: .sup.1H NMR.delta.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).
[0666] To the free base (0.060 g, 0.108 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 0.070 g (100%) of the product as a white solid;
m.p. 150-153.degree. C.; Anal. Calcd. for
CHF.sub.2N.sub.4O.sub.6Cl: 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-pipepidin-1-yl]pro-
pyl}carboxamido-4-methoxymethyl-6-(3,4-difluorophenyl)-2-oxopyrimidine-5-c-
arboxylic Acid Methyl Ester
[0667] mp .degree. C.; [.alpha.].sub.D=+123.0, (c=0.15, MeOH);
.sup.1H NMR.delta.1.70-1.82 (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), 6.68
(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-nitrophenyl)-piperazin-1yl-
]propyl}-carboxamido-4-methyl-6-(3,4-difluorophen-yl)-2-oxo-pyrimidine
[0668] (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine:
[0669] 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.sub.2CO.sub.3 (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, 80%).
[0670] (+)-1,2,3,6-tetrahydro-1-{N-[2-(S)-methyl)-4-(2-nitrophenyl)
piperazin-1yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-p-
yrimidine:
[0671] To a solution of
(+)-1-3-bromo-propylcarbamoyl)-6-(3,4-difluorophen-
yl)-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.sub.2CO.sub.3
(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)-meth-
yl)-4-(2-nitrophenyl)piperazin
-1-yl]-propyl}-carboxamido-4-methyl-6-(3,4--
difluorophenyl)-2-oxo-pyrimidine was obtained as yellow oil (0.030
g, 10% yield). The HCl salt was prepared by the addition of HCl in
ether to a solution of the product in dichloromethane, followed by
evaporation of the solvents; mp 150-153.degree. C.; [.alpha.]:=58.3
(c=0.3, MeOH); .sup.1H NMR (CD.OD)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 CH.sub.32N.sub.6F.sub.2O.sub.6+0.20 CH.sub.2Cl.sub.2: 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'-methylphenyl)piperazin-1-yl]-propyl}-carboxa-
mido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine
[0672] The amine used was 4-(2'-methyl-phenyl)piperazine. .sup.1H
NMR.delta.1.75-1.80 (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 HCl in ether was added. The ether was evaporated, giving the
dihydrochloride salt; mp 66-71 C. Anal calcd. for
C.sub.28H.sub.35N.sub.5F.sub.2O.sub.4. Cl.sub.2+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
[0673] Hygroscopic; [.alpha.]=+82.1(c=0.31, MeOH); .sup.1H NMR
.delta.1.14 (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 CHN.sub.4O.sub.5F.sub.1Cl+CH.sub.3Cl.- sub.2: 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
[0674] General Procedure for the reaction of
pyrimidine-3-carboxylic acid-4-nitrophenyl esters with amines:
[0675] A solution of substituted pyrimidine-3-carboxylic
acid-4-nitrophenyl ester ((0.29 mmol) and a substituted
phenyl-1-(3-propylaminopiperidine (0.30 mmol) in 10 m of anhydrous
THF was stirred overnight at room temperature. The solvent was
removed in vacuo and 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-oxo-1,2,3,4-tetrahydro-5-pyrim-
idinecarboxylate
[0676] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 39
[0677] The product was obtained according to the method described
for Example 40.
[0678] Methyl
(4S)-4-(3,4-difluorophenyl)-3-({[3-(4-(3-[(methoxyacetyl)ami-
no]phenyl}-1-piperidinyl)propyl]amino)carbonyl)-6-(methoxymethyl)-2-oxo-1,-
2,3,4-tetrahydro-5-pyrimidinecarboxylate:
[0679] 15.6 mg (69% yield); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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, 2H), 2.20 (s,
2H), 2.07 (br s, 1H), 1.97-1.75 (m, 4H); ESMS m/e: 644.3
(M+H).sup.+
EXAMPLE 40
Methyl
(4S)-4-(3,4-difluorophenyl)-3-({[3-(4-{3-[(3,3-dimethylbutanoyl)ami-
no]phenyl}-1-
piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-oxo-1-
,2,3,4-tetrahydro-5-pyrimidinecarboxylate
[0680] To the 20 ml vial was added methyl
(4S)-3-[({3-[4-(3-aminophenyl)-1-
-piperidinyl]propyl}amino)carbonyl]-4-(3,4-difluorophenyl)-6-(methoxymethy-
l)-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 1% of isopropylamine) to give
5.6 mg of methyl
(4S)-4-(3,4-difluorophenyl)-3-({[3-(4-{3-[(3,3-dime-
thylbutanoyl)amino]phenyl}-1-piperidinyl)propyl]amino}carbonyl)-6-(methoxy-
methyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate: 24.6%
yield; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.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).sup.+.
EXAMPLE 41
[0681] The product was obtained according to the method described
for methyl
(4S)-4-(3,4-difluorophenyl)-3-({[3--(4-{3-[(3,3-dimethylbutanoyl)a-
mino]phenyl}-1-piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)
-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
[0682] Methyl
(4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-3-{[(3-{-
4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl)amino]capbonyl}-1,2,3,4--
tetrahydro-5-pyrimidinecarboxylate:
[0683] 9.9 mg (45% yield) .delta. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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).sup.+
EXAMPLE 42
[0684] The product was obtained according to the method described
for methyl
(4S)-4-(3,4-difluorophenyl)-3-({[3-(4-{3-[(3,3-dimethylbutanoyl)am-
ino]phenyl}-1-piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-oxo-1-
,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
[0685] 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:
[0686] 10.4 mg (45% yield) .delta..sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.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), 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).sup.-
EXAMPLE 43
[0687] The product was obtained according to the method described
for methyl
(4S)-4-(3,4-difluorophenyl)-3-({[3-(4-{(3-[(3,3-dimethylbutanoyl)a-
mino]phenyl}-1-piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-oxo--
1,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
[0688] methyl
(4S)-4-(3,4-difluorophenyl)-3-{[(3-{4-[3-(isobutyrylamino)ph-
enyl]-1-piperidinyl}propyl)amino]carbonyl}-6-(methoxymethyl)-2-oxo-1,2,3,4-
-tetrahydro-5-pyrimidinecarboxylate:
[0689] 16.4 mg (73% yield) .delta. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 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).sup.+
EXAMPLE 44
[0690] The product was obtained according to the method described
for methyl
(4S)-4-(3,4-difluorophenyl)-3-({[3-(4-{3-[(3,3-dimethylbutanoyl)am-
ino]phenyl}-1-piperidinyl)propyl]amino}carbonyl)-6-(methoxymethyl)-2-oxo-1-
,2,3,4-tetrahydro-5-pyrimidinecarboxylate.
[0691] Methyl
(4S)-3-{[(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl-
)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-te-
trahydro-5-pyrimidinecarboxylate:
[0692] 14.7 mg (65.5% yield) .delta. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 45
(4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-4-(3,4-difluor-
ophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamid-
e
[0693] Method:
[0694] (4R)
-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrah-
ydro-5-pyrimidinecarboxylic Acid:
[0695] 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 H.sub.2O-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 HCl) 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 90% yield.
[0696] (4R)
-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-[3-(4-(3-nitrophen-
yl)-3,6-dihydro-1(2h)-pyridinyl)propyl]-2-oxo-1,2,3,4-tetrahydro-5-pyrimid-
inecarboxamide:
[0697] A 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-pyrimidinecarbo-
xamide.
[0698]
(4R)-N-{3-[4-(3-aminophenyl)-1-piperidinyl)propyl}-4-(3,4-difluorop-
henyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamide:
[0699] 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-tetrahyd-
ro-5-pyrimidinecarboxamide, 10% Pd/C 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.
[0700]
(4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-4-(3,4--
difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecar-
boxamide:
[0701] Into a 20 mL vial was
added(4R)-N-{3-[4-(3-aminophenyl)-1-piperidin-
yl]propyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahyd-
ro-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 24 hrs, the reaction mixture was
concentrated in vacuo and purified by preparative TLC (silica, 2000
micons, 95.5=dichloromethane: methanol with 1% of isopropylamine)
to give 9.2 mg (45% yield) of the desired product: .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 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).sup.+.
EXAMPLE 46
[0702] The product was obtained according to the method described
for
(4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-4-(3,4-difluo-
rophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxami-
de.
[0703]
(4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-N-(3-{4-[3-(pro-
pionylamino)phenyl]-1-piperidinyl}propyl)-1,2,3,4-tetrahydro-5-pyrimidinec-
arboxamide:
[0704] 5.6 mg (24.6% yield) ; .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 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).sup.-.
EXAMPLE 47
[0705] The product was obtained according to the method described
for
(4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-4-(3,4-difluo-
rophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxami-
de.
[0706]
(4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-(3-(4-{3-[(3-methyl-
butanoyl)amino]phenyl)-1-piperidinyl)propyl]-2-oxo-1,2,3,4-tetrahydro-5-py-
ridimidinecarboxamide:
[0707] 11.1 mg (46% yield); .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 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).sup.+.
EXAMPLE 48
[0708] The product was obtained according to the method described
for
(4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-4-(3,4-difluo-
rophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxami-
de.
[0709] (4R)
-4-(3,4-difluorophenyl)-6-(methoxymethyl)-N-[3-(4-{3-[(2-methy-
lbutanoyl)amino]phenyl}-1-piperidinyl)propyl]-2-oxo-1,2,3,4-tetrahydro-5-p-
yrimidinecarboxamide:
[0710] 6.7 mg (28% yield); .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 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).sup.+.
EXAMPLE 49
[0711] The product was obtained according to the method described
for
(4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-4-(3,4-difluo-
rophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxami-
de.
[0712]
(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:
[0713] 1.1 mg (4.4% yield); .sup.1H NMR (400MHz, CD.sub.3OD)
.delta. 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+H).sup.+.
EXAMPLE 50
[0714] The product was obtained according to the method described
for
(4R)-N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-4-(3,4-difluo-
rophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxami-
de.
[0715]
(4R)-4-(3,4-difluorophenyl)-n-(3-{4-[3-(isobutyrylamino)phenyl]-1-p-
iperidinyl}propyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidine-
carboxamide:
[0716] 12.7 mg (54% yield); .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 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:
584.4 (M+H.sup.+.
EXAMPLE 51
[0717] 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-difluor-
ophenyl)-2-oxo-1,3-oxazolidine-3-carboxamide.
[0718]
5-acetyl-N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl)propyl)-4-me-
thyl-2-oxo-6-(3,4,5-trifluorophenyl)-3,6-dihydro-1-(2H)-pyrimidinecarboxam-
ide:
[0719] 14.5 mg (46% yield); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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).sup.+;
Anal. Calc. for CH.sub.34F.sub.3N.sub.5O.sub- .4+0.1CHCl.sub.3: C,
60.50; H, 5.75; N, 11.72. Found: C, 60.59; H, 5.40; N, 11.73.
EXAMPLE 52
[0720] 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-difluor-
ophenyl)-2-oxo-1,3-oxazolidine-3-carboxamide.
[0721] 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-pyrim-
idinecarboxylate:
[0722] 14.8 mg (41% yield); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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), 2.17-1.88 (m, 3H) , 1.77-1.58 (m, 3H) 1.19 (t, 3H, J=7.5 Hz)
ESMS m/e: 674.4 (M+H).sup.+.
EXAMPLE 53
[0723] 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-difluor-
ophenyl)-2-oxo-1,3-oxazolidine-3-carboxamide.
[0724]
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-4-(1,3-benzod-
ioxol-5-yl)-2,5-dioxo-1,2,5,7-tetrahydrofuro[3,4-D]pyrimidine-3(4H)-carbox-
amide:
[0725] 8.75 mg (28% yield); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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 (3, 1H),
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: 576.3 (M+H).sup.-.
EXAMPLE 54
[0726] 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-difluor-
ophenyl)-2-oxo-1,3-oxazolidine-3-carboxamide.
[0727] Methyl
1-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino-
]carbonyl}-2-[(4-methoxybenzyl)sulfanyl]-4-methyl-6-(4-nitrophenyl)-1,6-di-
hydro-5-pyrimidinecarboxylate:
[0728] 10.1 mg (26% yield); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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 (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).sup.+.
EXAMPLE 55
[0729] 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-difluor-
ophenyl)-2-oxo-1,3-oxazolidine-3-carboxamide.
[0730]
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:
[0731] 7.7 mg (12% yield); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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).sup.+.
EXAMPLE 56
[0732] 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-difluor-
ophenyl)-2-oxo-1,3-oxazolidine-3-carboxamide.
[0733] Methyl
(4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-
amino]carbonyl}-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-
-pyrimidinecarboxylate:
[0734] 16.6 mg (52% yield); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 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, 9H); ESMS m/e: 584.3 (M+H).sup.+; Anal. Calc. for
CH.sub.35F.sub.2N.sub.5O+0.25CHCl.sub.3: C, 59.23; H, 5.79; N,
11.42. Found: C, 59.61; H, 5.31; N, 11.48.
[0735] Peptide Synthesis:
[0736] 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:
diisopropylethyl amine; TFA: trifluoroacetic acid.
[0737] 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, Calif.). 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-Asparagine(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-phosphotyr- osine 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.
[0738] Peptides with C-terminal amides were synthesized on solid
phase using Rink amide-MBHA resin. The Fmoc group of the Rink Amide
MBHA resin was removed by treatment with 30% piperidine in DMF for
5 and 30 minutes respectively. After washing with DMF (3 times),
methanol (2 times) and DME/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 30% 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 (4eq.)
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 30% piperidine in DMF for 5 and 30
minutes respectively. After washing with DMF (3 times), methanol (2
times), the resin(s) 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:wate-
r: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.degree. 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.
[0739] Peptides with C-terminal acids were synthesized using
2-chlorotrityl chloride resin. The first amino acid was attached to
the resin by dissolving 0.6-1.2 eq. 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
Fmoc-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.
[0740] Purification of the peptides was achieved by preparative
high performance column chromatography (HPLC), using a
reverse-phase C-18 column (25.times.250 mm) (Primesphere or Vydac)
with a gradient of acetonitrile (0.1% TFA) in water (0.1% TFA). The
general gradient was from 10%-90% 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 2.5.times.250 mm analytical
column, and generally were found to have >95% purity.
[0741] References:
[0742] See our published dihydropyrimidinone and oxazolidinone
parents as references for the synthesis of the templates and the
piperidines.
[0743] Also, for the synthesis of the aminopropyl piperidines and
the templates, see:
[0744] Lagu, Bharat, et al., Design and synthesis of novel .alpha.,
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
[0745] Dhar, T. G. Murali, et al., Design and Synthesis of Novel
.alpha. 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
[0746] Nagarathnam, Dhanapalan, et al., Design and Synthesis of
Novel .alpha..sub.1a 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
[0747] Wong, Wai C., et al., Design and Synthesis of Novel .alpha..
Adrenoceptor-Selective Antagonists. 4. Structure-Activity
Relationship in the Dihydropyrimidine Series. J. Med. Chem. (1999),
42(23), 4804-4813. CODEN: JMCMAR ISSN:0022-2623. CAN 132:30317 AN
1999:680947 CAPLUS
[0748] 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
[0749] Wong, 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., Mar. 21-25 (1999), MEDI-156. CODEN: 67GHA6 AN
1999:92669 CAPLUS
[0750] 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., Mar. 21-25 (1999), MEDI-110. CODEN: 67GHA6 AN 1999:92624
CAPLUS
[0751] 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
[0752] Wong, 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
[0753] Nagarathnam, Dhanapalan, et al., Design and synthesis of
novel .alpha..sub.1a 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
[0754] For the general procedure for Pd coupling of vinyl triflate
and bononic acids or tributyl tin reagents: See, Wuston, Wise
Synthesis 1991, 993)
[0755] (For Typical References, See:Schroeter, G. Ber. (1909) 42,
3356; and Allen, C. F. H.; Bell, A. Org. Syn. Coll. Vol. 3, (1955)
846).
[0756] For the preparation of the ether
N-[4-(benzo-4',5'[H]-furanpiperidi- ne refer to W. E. Parham et al,
J. Org. Chem. (1976) 41, 2268.
[0757] For the preparation of the ether piperidine precursor of
Example 20, refer to W. E. Parham et al, J. Org. Chem. (1976) 41,
2268.
[0758] For the preparation of the indane piperidine precursor of
Example 21, refer to M. S. Chambers J. Med. Chem. (1992) 35,
2033.
[0759] For the preparation of the piperidine precursor of Example
23, (K. Hashigaki et al. Chem. Pharm. Bull. (1984) 32, 3568.)
[0760] 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.) 83 8485 86 87 88 89 90 91 9293
94 95 96 9798
[0761] II. Synthetic Methods for General Structures
[0762] 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.
[0763] It may be necessary to incorporate protection and
deprotection strategies for substituents such as amino, amido,
carboxylic acid, and hydroxyl groups in he 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 Organic Synthesis, 2.sup.nd Edition John Wiley
& Sons, New York.
[0764] III. Oral Compositions
[0765] 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 O
hard gel capsule.
[0766] IV. Pharmacological Evaluation of Compounds at Cloned MCH1,
NPY, Galanin. and 5-HT2C Receptors
[0767] 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.
[0768] Host Cells
[0769] A broad variety of host cells can be used to study
heterologously expressed proteins. These cells include but are not
restricted to assorted mammalian lines such as; Cos-7, CHO,
LM(tk-), HEK293, etc.; insect cell lines such as; Sf9, Sf21, etc.;
amphibian cells such as xenopus oocytes; and others.
[0770] COS-7 cells are grown on 150 mm plates in DMEM with
supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf
serum, 4 mM glutamine, 100 units/ml penicillin/100 .mu.g/ml
streptomycin) at 37.degree. C., 5% CO.sub.2. Stock plates of COS-7
cells are trypsinized and split 1:6 every 3-4 days.
[0771] Human embryonic kidney 293 cells are grown on 150 mm plates
in DMEM with supplements (10% bovine calf serum, 4 mM gilutamine,
100 units/ml penicillin/100 .mu.g/ml streptomycin) at 37.degree.
C., 5% CO.sub.2. Stock plates of 293 cells are trypsinized and
split 1:6 every 3-4 days.
[0772] 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
.mu.g/ml streptomycin) at 37.degree. C., 5% CO.sub.2. Stock plates
of LM(tk-) cells are trypsinized and split 1:10 every 3-4 days.
[0773] Chinese hamster ovary (CHO) cells were grown on 150 mm
plates in HAM's F-12 medium with supplements (10% bovine calf
serum, 4 mM L-glutamine and 100 units/ml penicillin/100 .mu.g/ml
streptomycin) at 37.degree. C., 5% CO.sub.2. Stock plates of CHO
cells are trypsinized and split 1:8 every 3-4 days.
[0774] Mouse embryonic fibroblast NIH-3T, 3 cells are grown on 150
mm plates in Dulbecco's Modified Eagle Medium (DMEM) with
supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml
penicillin/100 .mu.g/ml streptomycin) at 37.degree. C., 5%
CO.sub.2. Stock plates of NIH-3T, 3 cells are trypsinized and split
1:15 every 3-4 days.
[0775] Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue
culture dishes in TMN-FH media supplemented with 10% fecal Cal
serum, at 27.degree. C., no CO . High Five insect cells are grown
on 150 mm tissue culture dishes in Ex-Cell 400 medium supplemented
with L-Glutamine, also at 27.degree. C., no CO.sub.2.
[0776] 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.
[0777] Transient Expression
[0778] 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.
[0779] 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.times.10.sup. cells/cm.sup.2 in a
100 mm tissue culture dish and allowed to incubate over night at
37.degree. C. at 5% CO.sub.2. 250 .mu.l of a mixture of CaCl.sub.
and DNA (20 .mu.g DNA in 250 mMf CaCl.sub.2) is added to a 5 ml
plastic tube and 250 ul of 2.times.HBS (250 mM NaCl, 10 mM KCl, 1.5
mM Na.sub.2HPO.sub.4, 12 mM dextrose, 50 mM HEPES) is slowly added
with gentle mixing. The mixture is allowed to 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.degree. C. at 5% CO.sub..
[0780] 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 70-80% confluent at the time of
transfection. Briefly, 8 .mu.g of receptor DNA plus 8 .mu.g of any
additional DNA needed (e.g. G.sub. 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 T, 225 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, 5% CO.sub.2. Following the incubation, 36 ml of
complete DMEM with 80 .mu.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.
[0781] 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 70-80% confluent at the time of
transfection. A total of 10 .mu.g of DNA which may include varying
ratios of receptor DNA plus any additional DNA needed (e.g. G
protein expression vector, reporter construct, antibiotic
resistance marker, mock vector, etc.) is used to transfect each 75
cm.sup. 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.
[0782] 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.times.10.sup.6 cells are suspended in
300 .mu.l of DMEM and placed into an electroporation cuvette. 8
.mu.g of receptor DNA plus 8 .mu.g of any additional DNA needed
(e.g. G.sub. 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 .mu.F capacitance). Following the pulse, 800 .mu.l 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.times.10 cells/100
.mu.l. The cells are then plated as needed depending upon the type
of assay to be performed.
[0783] 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 or sites engineered into sequences
5' and 3' to the coding region of the polypeptides. To generate
baculovirus, 0.5 .mu.g of viral DNA (BaculoGold) and 3 .mu.g of DNA
construct encoding a polypeptide may be co-transfected into
2.times.10.sup. 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.degree. C. The supernatant of the co-transfection plate may be
collected by centrifugation and the recombinant virus plaque
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.
[0784] Stable Expression
[0785] 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.
[0786] Cell Membrane Preparation
[0787] 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.times.g for 5 min at 4.degree. C. The
supernatants are then centrifuged at 40,000.times.g for 20 min at
4.degree. 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.
[0788] Radioligand Binding Assays
[0789] 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 Sep. 17,
1998, with the American Type Culture Collection (ATCC), 12301
Parklawn Drive, Rockville, Md. 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.
[0790] 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 receptor were performed with 0.08
nM [.sup.3H]Compound 10 (custom labeled by Amersham) using an
incubation buffer consisting of 50 mM Tris pH 7.4, 10 mM
MgCl.sub.2, 0.16 mM PMSF, 1 mM 1,10-phenantroline and 0.2% BSA.
Binding was performed at 25.degree. C. for 90 minutes. Incubations
were terminated by rapid vacuum filtration over GF/C glass fiber
filters, presoaked in 5% PEI using 50 nM Tris pH 7.4 as wash
buffer. In all experiments, nonspecific binding is defined using 10
.mu.M Compound 10.
[0791] The methods to obtain the cDNA of the human NPY1, NP,: 5,
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. Pat. 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).
[0792] Functional Assays
[0793] Cells may be screened for the presence of endogenous 2.5
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.
[0794] A wide spectrum of assays can be employed to screen for
receptor activation. These range from traditional measurements of
phosphatidyl Inositol, cAMP, Ca.sup.++, and K.sup., 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 cell based platforms reporting more general cellular
events resulting from receptor activation such as metabolic
changes, differentiation, and cell division/proliferation, or
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.
[0795] Functional Assay:
[0796] Intracellular Calcium Mobilization Assay
[0797] 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 fluorescent 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 0.1% BSA, and loaded with the same buffer
containing 3.8 .mu.M Fluo-3 for 1 hour at 37.degree. 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).
[0798] Materials
[0799] Cell culture media and supplements were from Specialty Media
(Lavallette, N.J.). Cell culture plates (150 mm and 96-well
microtiter) were from Corning (Corning, N.Y.). Sf9, Sf21, and High
Five insect cells, as well as the baculovirus transfer plasmid,
pBlueBacIII.TM., were purchased from Invitrogen (San Diego,
Calif.). TMN-FH insect medium complemented with 10% fetal calf
serum, and the baculovirus DNA, BaculoGold.TM., was obtained from
Pharmingen (San Diego, Calif.). Ex-Cell 400.TM. 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, Calif. (Torrance, Calif.) or Peninsula (Belmont,
Calif.). Bio-Rad Reagent was from Bio-Rad (Hercules, Calif.).
Bovine serum albumin (ultra-fat free, A-7511) was from Sigma (St.
Louis. Mo.). All other materials were reagent grade.
[0800] Functional Assay Results
[0801] 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.
1TABLE 1 EXAMPLE No. STRUCTURE Kb (nM) hMCH1 1 99 42 2 100 18 3 101
201 4 102 187 5 103 258 6 104 42 7 105 41 8 106 88 9 107 35 10 108
0.3 11 109 331 12 110 29 13 111 284 14 112 2 15 113 289 16 114 329
17 115 373 18 116 1 19 117 7 20 118 5 21 119 28 22 120 40 23 121 68
24 122 102 25 123 126 26 124 260 27 125 279 28 126 60 29 127 9 30
128 479 31 129 7 32 130 67 33 131 12 34 132 182 35 133 276 36 134
406 37 135 162
[0802] Radioligand Binding Assay Results
[0803] 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.
[0804] 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.
2TABLE 2 Antagonist potency (Kb) at the human MCH1 receptor, and
binding affiity (Ki) at NPY, galanin and 5HT2C receptors. hMCH1
hNPY1 hNPY5 hGALR1 hGALR2 hGALR3 r5HT2C Compound Kb (nM) Ki (nM) Ki
(nM) Ki (nM) Ki (nM) Ki (nM) Ki (nM) 10 0.3 >50000 >50000
>50000 >50000 >50000 29,585 18 1 >50000 >50000
>50000 >50000 >50000 32,617 14 2 ND ND >50000 42,603
>50000 663 20 5 27,076 >50000 >50000 >50000 >50000
15,058 19 7 >50000 >50000 >50000 >50000 >50000
11,720 29 9 >50000 46,075 >50000 >50000 >50000
>50000 2 18 ND ND >50000 >50000 >50000 39,837 6 42
6,667 4,735 11,057 14,921 21,095 25,549 1 42 >50000 >50000
>50000 >50000 >50000 >50000 28 60 >50000 >50000
>50000 >50000 >50000 34,087 25 126 >50000 >50000
>50000 >50000 >50000 41,009 37 162 >50000 >50000
>50000 >50000 >50000 >50000 4 187 >50000 >50000
>50000 >50000 >50000 34,798 26 260 >50000 >50000
>50000 >50000 >50000 2,900 27 279 >50000 >50000
>50000 >50000 >50000 >50000 13 284 9,601 >50000
11,262 4,727 5,985 25,030 30 479 >50000 >50000 >50000
>50000 >50000 8,859
[0805]
3TABLE 3 Antagonist potency (Kb) at the human MCH1 receptor, and
binding affiity (Ki) at human MCH1, NPY1, NPY5, GALR1, GALR2,
GALR3, and rat 5HT2C receptors. hMCH1 hMCH1* hNPY1 hNPY5 hGALR1
hGALR2 hGALR3 r5HT2C Compound Kb (nM) Ki (nM) Ki (nM) Ki (nM) Ki
(nM) Ki (nM) Ki (nM) Ki (nM) 10 0.3 0.08 >50000 >50000
>50000 >50000 >50000 29,585 19 7 3 >50000 >50000
>50000 >50000 >50000 11,720 18 1 4 >50000 >50000
>50000 >50000 >50000 32,617 20 5 6 27,076 >50000
>50000 >50000 >50000 15,058 1 42 40 >50000 >50000
>50000 >50000 >50000 >50000 2 18 49 ND ND >50000
>50000 >50000 39,837 14 2 50 ND ND >50000 42,603 >50000
663 4 187 131 >50000 >50000 >50000 >50000 >50000
34,798 13 284 171 9,601 >50000 11,262 4,727 5,985 25,030 29 9
350 >50000 46,075 >50000 >50000 >50000 >50000 6 42
463 6,667 4,735 11,057 14,921 21,095 25,549 *Binding affinity (Ki)
was determined in competition binding assays using membrane
preparations of A293 cells expressing the human MCH1 receptor and
[3H]Compound 10 as the radioligand.
[0806]
4TABLE 4 EXAMPLE No. STRUCTURE Ki (nM) rMCH1 38 136 1.34 39 137
3.33 40 138 2.72 41 139 0.04 42 140 0.6 43 141 0.23 44 142 0.09 45
143 14.69 46 144 8.16 47 145 34.28 48 146 22.15 49 147 225.47 50
148 13.74 51 149 0.79 52 150 0.81 53 151 50.76 54 152 29.87 55 153
203.74 56 154 0.26
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* * * * *