U.S. patent application number 10/345063 was filed with the patent office on 2006-02-23 for substituted alkyl amido piperidines.
Invention is credited to Chien-An Chen, Yu Jiang, Kai Lu, Mohammad R. Marzabadi, John M. Wetzel.
Application Number | 20060041139 10/345063 |
Document ID | / |
Family ID | 32069536 |
Filed Date | 2006-02-23 |
United States Patent
Application |
20060041139 |
Kind Code |
A9 |
Marzabadi; Mohammad R. ; et
al. |
February 23, 2006 |
SUBSTITUTED ALKYL AMIDO PIPERIDINES
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 reducing the body
mass of a subject which comprises administering to the subject an
amount of a compound of the invention effective to reduce the body
mass of the subject. This invention further provides a method of
treating a subject suffering from depression and/or anxiety which
comprises administering to the subject an amount of a compound of
the invention effective to treat the subject's depression and/or
anxiety.
Inventors: |
Marzabadi; Mohammad R.;
(Ridgewood, NJ) ; Wetzel; John M.; (Fairlawn,
NJ) ; Chen; Chien-An; (Fresh Meadows, NY) ;
Jiang; Yu; (Jersey City, NJ) ; Lu; Kai;
(Elmwood Park, NJ) |
Correspondence
Address: |
DARBY & DARBY P.C.
P. O. BOX 5257
NEW YORK
NY
10150-5257
US
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20040073036 A1 |
April 15, 2004 |
|
|
Family ID: |
32069536 |
Appl. No.: |
10/345063 |
Filed: |
January 14, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10188434 |
Jul 3, 2002 |
6727264 |
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10345063 |
Jan 14, 2003 |
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60346997 |
Jan 9, 2002 |
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60303091 |
Jul 5, 2001 |
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Current U.S.
Class: |
546/194 ;
546/207; 546/229 |
Current CPC
Class: |
C07D 211/28 20130101;
C07D 401/10 20130101; C07D 409/06 20130101; C07D 409/10 20130101;
A61P 25/18 20180101; C07D 211/90 20130101; C07D 231/12 20130101;
A61P 25/24 20180101; C07D 417/06 20130101; C07D 233/56 20130101;
A61P 3/00 20180101; C07D 401/06 20130101; C07D 405/06 20130101;
C07D 405/12 20130101; C07D 249/08 20130101; C07D 417/10 20130101;
C07D 401/04 20130101; C07D 409/14 20130101; C07D 413/12 20130101;
A61P 7/12 20180101; A61P 13/00 20180101; A61P 25/22 20180101; C07D
401/12 20130101; C07D 495/04 20130101; A61P 43/00 20180101; C07D
471/04 20130101; C07D 211/26 20130101; A61P 25/00 20180101; C07D
401/14 20130101; C07D 409/12 20130101; A61P 13/02 20180101; A61P
3/04 20180101 |
Class at
Publication: |
546/194 ;
546/207; 546/229 |
International
Class: |
C07D 41/02 20060101
C07D041/02; C07D 211/80 20060101 C07D211/80 |
Claims
1. A compound having the structure: ##STR201## wherein each R.sub.1
is independently hydrogen; --F; --Cl; --Br; --I; --CN; --NO.sub.2;
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; C.sub.3-C.sub.7 cycloalkyl or C.sub.5-C.sub.7
cycloalkenyl; aryl; heteroaryl; --N(R.sub.5).sub.2;
--(CH.sub.2).sub.mOR.sub.5; --COR.sub.5; --CO.sub.2R.sub.5;
--OCOR.sub.5; --CON(R.sub.5).sub.2; --N(R.sub.5)COR.sub.5;
--N(R.sub.5)CON(R.sub.5).sub.2; --OCON(R.sub.5).sub.2 or
--N(R.sub.5)CO.sub.2R.sub.5; wherein R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Cl; --Br; --I; --CN;
--(CH.sub.2).sub.mOR.sub.5; --(CH.sub.2).sub.mSR.sub.5; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with one or more R.sub.1; or wherein R.sub.2 and
R.sub.3 together can be --(CH.sub.2).sub.p--; wherein R.sub.4 is
straight chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl
or polyfluoroalkyl, C.sub.3-C.sub.6 cycloalkyl, --N(R.sub.5).sub.2
or --(CH.sub.2).sub.mOR.sub.5; wherein each R.sub.5 is
independently hydrogen; aryl; heteroaryl or straight chained or
branched C.sub.1-C.sub.7 alkyl, wherein the alkyl may be
substituted with aryl or heteroaryl; wherein each R.sub.6 is
independently hydrogen; straight chained or branched
C.sub.1-C.sub.7 alkyl; wherein each R.sub.7 is independently
hydrogen; phenyl or straight chained or branched C.sub.1-C.sub.7
alkyl, wherein the alkyl may be substituted with phenyl; wherein
each m is independently an integer from 0 to 5 inclusive; wherein n
is an integer from 1 to 5 inclusive; wherein p is an integer from 2
to 7 inclusive; wherein q is an integer from 0 to 2 inclusive;
wherein X is CH or N; or a pharmaceutically acceptable salt
thereof.
2. The compound of claim 1, wherein each R.sub.1 is independently
hydrogen; straight chained or branched C.sub.1-C.sub.7 alkyl; --F;
--Cl; --Br; --I; --CN; --NO.sub.2; straight chained or branched
C.sub.1-C.sub.4 alkyl or polyfluoroalkyl;
--(CH.sub.2).sub.mOR.sub.5; --COR.sub.5; --CO.sub.2R.sub.5;
--OCOR.sub.5; --CON(R.sub.5).sub.2; --N(R.sub.5)COR.sub.5 or
--N(R.sub.5)CON(R.sub.5).sub.2; wherein R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Cl; --Br; --I; --CN;
--(CH.sub.2).sub.mSR.sub.5; straight chained or branched
C.sub.1-C.sub.7 alkyl; aryl or heteroaryl, wherein the aryl or
heteroaryl may be substituted with one or more R.sub.1; or wherein
R.sub.2 and R.sub.3 together can be --(CH.sub.2).sub.p--; wherein
R.sub.4 is straight chained or branched C.sub.1-C.sub.7 alkyl;
C.sub.3-C.sub.6 cycloalkyl; --N (R.sub.5).sub.2 or
--(CH.sub.2).sub.mOR.sub.5; wherein each R.sub.5 is independently
hydrogen or straight chained or branched C.sub.1-C.sub.3 alkyl,
wherein the alkyl may be substituted with phenyl; wherein m is 0 to
3; wherein n is 1 to 3; wherein p is an integer from 2 to 5
inclusive; wherein q is 0; and wherein X is CH.
3. The compound of claim 2, wherein the compound has the following
structure: ##STR202##
4. The compound of claim 3, wherein the compound has the following
structure: ##STR203##
5. The compound of claim 4, wherein R.sub.1 is hydrogen; --F; --Cl;
--Br; --I or straight chained or branched C.sub.1-C.sub.7 alkyl;
and wherein R.sub.2 is hydrogen or straight chained or branched
C.sub.1-C.sub.7 alkyl.
6. The compound of claim 5, wherein R.sub.4 is straight chained or
branched C.sub.1-C.sub.7 alkyl.
7. The compound of claim 6, wherein the compound has the structure:
##STR204##
8. The compound of claim 7, wherein the compound is selected from
the group consisting of: ##STR205##
9. The compound of claim 7, wherein the compound is selected from
the group consisting of: ##STR206##
10. The compound of claim 7, wherein the compound is selected from
the group consisting of: ##STR207##
11. The compound of claim 4, wherein R.sub.4 is C.sub.3-C.sub.6
cycloalkyl.
12. The compound of claim 11, wherein the compound is selected from
the group consisting of: ##STR208##
13. The compound of claim 2, wherein R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Br or straight chained or branched
C.sub.1-C.sub.7 alkyl.
14. The compound of claim 13, wherein R.sub.2 and R.sub.3 are
independently hydrogen or straight chained or branched
C.sub.1-C.sub.7 alkyl.
15. The compound of claim 14, wherein the compound has the
structure: ##STR209##
16. The compound of claim 13, wherein R.sub.2 and R.sub.3 are
independently hydrogen; --F or --Br.
17. The compound of claim 16, wherein the compound has the
structure: ##STR210##
18. The compound of claim 2, wherein R.sub.2 and R.sub.3 together
are --(CH.sub.2).sub.p--;
19. The compound of claim 18, wherein the compound has the
structure: ##STR211##
20. The compound of claim 19, wherein R.sub.4 is straight chained
or branched C.sub.1-C.sub.7 alkyl.
21. The compound of claim 20, wherein the compound is selected from
the group consisting of: ##STR212##
22. The compound of claim 20, wherein the compound is selected from
the group consisting of: ##STR213##
23. The compound of claim 2, wherein the compound has the following
structure: ##STR214##
24. The compound of claim 23, wherein the compound has the
following structure: ##STR215##
25. The compound of claim 24, wherein the compound has the
structure: ##STR216##
26. The compound of claim 1, wherein the compound is
enantiomerically pure.
27. The compound of claim 1, wherein the compound is
diastereomerically pure.
28. The compound of claim 26, wherein the compound is
enantiomerically and diastereomerically pure.
29. The compound of claim 27, wherein the compound is
enantiomerically and diastereomerically pure.
30. A pharmaceutical composition that comprises a therapeutically
effective amount of the compound of claim 1 and a pharmaceutically
acceptable carrier.
31. A pharmaceutical composition made by admixing a compound of
claim 1 and a pharmaceutically acceptable carrier.
32. A process for making a pharmaceutical composition comprising
admixing a compound of claim 1 and a pharmaceutically acceptable
carrier.
33. A method of treating a subject suffering from a disorder
mediated by the MCH1 receptor comprising administering to a subject
in need of such treatment a therapeutically effective amount of the
compound of claim 1.
34. The method of claim 33, wherein the therapeutically effective
amount is between about 0.03 and about 300 mg.
35. The method of claim 33, wherein the disorder is depression.
36. The method of claim 33, wherein the disorder is anxiety.
37. The method of claim 33, wherein the disorder is obesity.
38. The method of claim 33, wherein the disorder is urge
incontinence.
39. A method of treating a subject suffering from a disorder
selected from the group consisting of depression, anxiety, urge
incontinence or obesity, comprising administering to the subject a
therapeutically effective amount of the compound of claim 1.
40. The method of claim 39, wherein the therapeutically effective
amount is between about 0.03 and about 300 mg.
41. The method of claim 39, wherein the disorder is depression.
42. The method of claim 39, wherein the disorder is anxiety.
43. The method of claim 39, wherein the disorder is obesity.
44. The method of claim 39, wherein the disorder is urge
incontinence.
Description
[0001] This application is a continuation-in-part of PCT
International Application No. PCT/US02/21063 filed Jul. 3, 2002,
the contents of which are hereby incorporated by reference into the
subject application.
BACKGROUND OF THE INVENTION
[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, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the
K.sub.D=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
(Herve 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] The identification of a G-protein coupled receptor for MCH
has recently been published (Chambers et al., 1999; Saito et al.,
1999). These groups identified MCH as the endogenous ligand for the
human orphan G-protein coupled receptor SLC-1 (Lakaye et al.,
1998). The rat homologue of this receptor (now called MCH-1) was
reported to be localized in regions of the rat brain associated
with feeding behavior (e.g. dorsomedial and ventromedial
hypothalamus). The link between MCH-1 and the effects of MCH on
feeding has been strengthened by recent reports on the phenotype of
MCH-1 knockout mice. Two groups have shown independently (Marsh et
al, 2002; Chen et al, 2002) that the targeted disruption of the
MCH-1 receptor gene (MCH-1 knockout) in mice results in animals
that are hyperphagic but are lean and have decreased body mass
relative to wild-type littermates. The decrease in body mass is
attributed to an increase in metabolism. Each group demonstrated
that the MCH-1 knockout mice are resistant to diet-induced obesity,
and generally exhibit weights similar to littermates maintained on
regular chow.
[0010] Finally, synthetic antagonist molecules for the MCH-1
receptor have now been described in the literature. Bednarek et al.
(2002) have reported on the synthesis of high affinity peptide
antagonists of MCH-1. In addition, a small molecule antagonist of
MCH-1 has been described by Takekawa et al. (Takekawa et al.,
2002). This compound, T-226296, exhibits high affinity for the
MCH-1 receptor (.about.5-9 nM for rat and human MCH-1), and was
shown to inhibit food intake induced by the intracerebroventricular
application of MCH. These data validate the strategy of using an
MCH-1 receptor antagonist to treat obesity.
[0011] Furthermore, in our own studies, we have tested MCH-1
antagonists in several animal models that are well known as
predictive for the efficacy of compounds in humans, see Borowsky,
et al. (2002). These experiments indicate that MCH1 antagonists are
useful to treat obesity, depression, anxiety, as well as urinary
disorders.
[0012] 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.
[0013] 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 assays described hereinafter were
performed using various cultured cell lines, each transfected with
and expressing only a single cloned receptor.
[0014] 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. Furthermore, the compounds of the present invention may be
used to treat urinary disorders.
SUMMARY OF THE INVENTION
[0015] The present invention provides for a compound having the
structure: ##STR1## [0016] wherein each R.sub.1 is independently
hydrogen; --F; --Cl; --Br; --I; --CN; --NO.sub.2; 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; C.sub.3-C.sub.7 cycloalkyl or C.sub.5-C.sub.7
cycloalkenyl; aryl; heteroaryl; --N(R.sub.5).sub.2;
--(CH.sub.2).sub.mOR.sub.5; --COR.sub.5; --CO.sub.2R.sub.5;
--OCOR.sub.5; --CON(R.sub.5).sub.2; --N(R.sub.5)COR.sub.5; --N
(R.sub.5)CON(R.sub.5).sub.2; --OCON (R.sub.5).sub.2 or --N
(R.sub.5)CO.sub.2R.sub.5; [0017] wherein R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Cl; --Br; --I; --CN;
--(CH.sub.2).sub.mOR.sub.5; --(CH.sub.2).sub.mSR.sub.5; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with one or more R.sub.1; or [0018] wherein
R.sub.2 and R.sub.3 together can be --(CH.sub.2).sub.p--; [0019]
wherein R.sub.4 is straight chained or branched C.sub.1-C.sub.7
alkyl, monofluoroalkyl or polyfluoroalkyl, C.sub.3-C.sub.6
cycloalkyl, N(R.sub.5).sub.2 or --(CH.sub.2).sub.mOR.sub.5; [0020]
wherein each R.sub.5 is independently hydrogen; aryl; heteroaryl or
straight chained or branched C.sub.1-C.sub.7 alkyl, wherein the
alkyl may be substituted with aryl or heteroaryl; [0021] wherein
each R.sub.6 is independently hydrogen; straight chained or
branched C.sub.1-C.sub.7 alkyl; [0022] wherein each R.sub.7 is
independently hydrogen; phenyl or straight chained or branched
C.sub.1-C.sub.7 alkyl, wherein the alkyl may be substituted with
phenyl; [0023] wherein each m is independently an integer from 0 to
5 inclusive; [0024] wherein n is an integer from 1 to 5 inclusive;
[0025] wherein p is an integer from 2 to 7 inclusive; [0026]
wherein q is an integer from 0 to 2 inclusive; [0027] wherein X is
CH or N; or a pharmaceutically acceptable salt thereof.
[0028] In a sub-class of the invention, are the compounds wherein
each R.sub.1 is independently hydrogen; straight chained or
branched C.sub.1-C.sub.7 alkyl; --F; --Cl; --Br; --I; --CN;
--NO.sub.2; straight chained or branched C.sub.1-C.sub.4 alkyl or
polyfluoroalkyl; --(CH.sub.2).sub.mOR.sub.5; --COR.sub.5;
--CO.sub.2R.sub.5; --OCOR.sub.5; --CON(R.sub.5).sub.2;
--N(R.sub.5)COR.sub.5 or --N (R.sub.5)CON (R.sub.5).sub.2; [0029]
wherein R.sub.2 and R.sub.3 are independently hydrogen; --F; --Cl;
--Br; --I; --CN; --(CH.sub.2).sub.mSR.sub.5; straight chained or
branched C.sub.1-C.sub.7 alkyl; aryl or heteroaryl, wherein the
aryl or heteroaryl may be substituted with one or more R.sub.1; or
[0030] wherein R.sub.2 and R.sub.3 together can be
--(CH.sub.2).sub.p--; [0031] wherein R.sub.4 is straight chained or
branched C.sub.1-C.sub.7 alkyl; C.sub.3-C.sub.6 cycloalkyl;
--N(R.sub.5).sub.2 or --(CH.sub.2).sub.mOR.sub.5; [0032] wherein
each R.sub.5 is independently hydrogen or straight chained or
branched C.sub.1-C.sub.3 alkyl, wherein the alkyl may be
substituted with phenyl; [0033] wherein m is 0 to 3; [0034] wherein
n is 1 to 3; [0035] wherein p is an integer from 2 to 5 inclusive;
[0036] wherein q is 0; and [0037] wherein X is CH.
[0038] In a subclass of the invention are the compounds of the
formula: ##STR2##
[0039] In one embodiment of the invention are the compounds having
the following structure: ##STR3##
[0040] In one embodiment of the invention, R.sub.1 is hydrogen;
--F; --Cl; --Br; --I or straight chained or branched
C.sub.1-C.sub.7 alkyl; and [0041] R.sub.2 is hydrogen or straight
chained or branched C.sub.1-C.sub.7 alkyl.
[0042] In one embodiment of the invention R.sub.4 is straight
chained or branched C.sub.1-C.sub.7 alkyl.
[0043] In one embodiment of the invention, the compound has the
structure: ##STR4##
[0044] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR5##
[0045] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR6##
[0046] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR7##
[0047] In one embodiment of the invention, R.sub.4 is
C.sub.3-C.sub.6 cycloalkyl.
[0048] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR8##
[0049] In one embodiment of the invention, R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Br or straight chained or branched
C.sub.1-C.sub.7 alkyl.
[0050] In one embodiment of the invention, R.sub.2 and R.sub.3 are
independently hydrogen or straight chained or branched
C.sub.1-C.sub.7 alkyl.
[0051] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR9##
[0052] In one embodiment of the invention, R.sub.2 and R.sub.3 are
independently hydrogen; --F or --Br.
[0053] In one embodiment of the invention, the compound has the
structure: ##STR10##
[0054] In one embodiment of the invention, R.sub.2 and R.sub.3
together are (CH.sub.2).sub.p--;
[0055] In one embodiment of the invention, the compound has the
structure: ##STR11##
[0056] In one embodiment of the invention, R.sub.4 is straight
chained or branched C.sub.1-C.sub.7 alkyl.
[0057] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR12##
[0058] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR13##
[0059] In one embodiment of the invention, the compound has the
following structure: ##STR14##
[0060] In one embodiment of the invention, the compound has the
following structure: ##STR15##
[0061] In one embodiment of the invention, the compound has the
structure: ##STR16##
[0062] In one embodiment of the invention, the compound is
enantiomerically pure.
[0063] In one embodiment of the invention, the compound is
diastereomerically pure.
[0064] In one embodiment of the invention, the compound is
enantiomerically and diastereomerically pure.
[0065] The present invention also provides a pharmaceutical
composition that comprises a therapeutically effective amount of a
compound of the present invention and a pharmaceutically acceptable
carrier.
[0066] The present invention further provides a pharmaceutical
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier.
[0067] The present invention also provides a process for making a
pharmaceutical composition comprising admixing a compound of the
present invention and a pharmaceutically acceptable carrier.
[0068] The present invention also provides a method for treating a
subject suffering from a disorder mediated by the MCH1 receptor
comprising administering to the subject a therapeutically effective
amount of a compound of the present invention.
[0069] In one embodiment, the therapeutically effective amount is
between about 0.03 and about 300 mg.
[0070] In one embodiment, the disorder is depression, anxiety,
obesity or urge incontinence.
[0071] The present invention also provides a method of treating a
subject suffering from a disorder selected from the group
consisting of depression, anxiety, urge incontinence or obesity
comprising administering to the subject a therapeutically effective
amount of a compound of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0072] As used in the present invention, the term "heteroaryl" is
used to include five and six membered unsaturated rings that may
contain one or more oxygen, sulfur, or nitrogen atoms. Examples of
heteroaryl groups include, but are not limited to, carbazole,
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and
triazinyl.
[0073] 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,
purinyl, benzoxazolyl, benzisoxazolyl, benzo[b]thiazolyl,
imidazo[2,1-b]thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl,
1,8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
phthalimidyl and 2,1,3-benzothiazolyl.
[0074] The term "heteroaryl" also includes those chemical moieties
recited above which may be substituted with one or more of the
following: --F, --Cl, --Br, --I, CN, --NO.sub.2, straight chained
or branched C.sub.1-C.sub.7 alkyl, straight chained or branched
C.sub.1-C.sub.7 monofluoroalkyl, straight chained or branched
C.sub.1-C.sub.7 polyfluoroalkyl, straight chained or branched
C.sub.2-C.sub.7 alkenyl, straight chained or branched
C.sub.2-C.sub.7 alkynyl; C.sub.3-C.sub.7 cycloalkyl,
C.sub.3-C.sub.7 monofluorocycloalkyl, C.sub.3-C.sub.7
polyfluorocycloalkyl, C.sub.5-C.sub.7 cycloalkenyl,
[0075] The term "heteroaryl" further includes the N-oxides of those
chemical moieties recited above which include at least one nitrogen
atom.
[0076] In the present invention, the term "aryl" is phenyl or
naphthyl.
[0077] The invention provides for each pure stereoisomer of any of
the compounds described herein. Such stereoisomers may include
enantiomers, diastereomers, or E or Z alkene or imine isomers. The
invention also provides for stereoisomeric mixtures, including
racemic mixtures, diastereomeric mixtures, or E/Z isomeric
mixtures. Stereoisomers can be synthesized in pure form (Nogradi,
M.; Stereoselective Synthesis, (1987) VCH Editor Ebel, H. and
Asymmetric Synthesis, Volumes 3 B 5, (1983) Academic Press, Editor
Morrison, J.) or they can be resolved by a variety of methods such
as crystallization and chromatographic techniques (Jaques, J.;
Collet, A.; Wilen, S.; Enantiomer, Racemates, and Resolutions,
1981, John Wiley and Sons and Asymmetric Synthesis, Vol. 2, 1983,
Academic Press, Editor Morrison, J).
[0078] In addition the compounds of the present invention may be
present as enantiomers, diasteriomers, isomers or two or more of
the compounds may be present to form a racemic or diastereomeric
mixture.
[0079] The compounds of the present invention are preferably 80%
pure, more preferably 90% pure, and most preferably 95% pure.
Included in this invention are pharmaceutically acceptable salts
and complexes of all of the compounds described herein. The acids
and bases from which these salts are prepared include but are not
limited to the acids and bases listed herein. The acids include,
but are not limited to, the following. inorganic acids:
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid
and boric acid. The acids 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 bases include, but are not limited to ammonia,
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.
[0080] The present invention includes within its scope prodrugs of
the compounds of the invention. In general, such prodrugs will be
functional derivatives of the compounds of the invention which are
readily convertible in vivo into the required compound. Thus, in
the present invention, the term "administering" shall encompass the
treatment of the various conditions described with the compound
specifically disclosed or with a compound which may not be
specifically disclosed, but which converts to the specified
compound in vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in Design of Prodrugs, ed.
H. Bundgaard, Elsevier, 1985.
[0081] 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.
[0082] 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 from about 0.01 mg to
about 800 mg. In another embodiment, the amount of the compound is
from about 0.01 mg to about 500 mg. In yet another embodiment, the
amount of the compound is from about 0.1 mg to about 250 mg. In
another embodiment, the amount of the compound is from about 0.1 mg
to about 60 mg. In yet another embodiment, the amount of the
compound is 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 another embodiment, the carrier is a
gel and the composition is a capsule, suppository or a cream. In a
further embodiment the compound may be formulated as a part of a
pharmaceutically acceptable transdermal patch. In yet a further
embodiment, the compound may be delivered to the subject by means
of a spray or inhalant.
[0083] This invention also provides a pharmaceutical composition
made by combining a therapeutically effective amount of the
compound of this invention and a pharmaceutically acceptable
carrier.
[0084] 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.
[0085] A solid carrier can include one or more substances which may
also act as endogenous carriers (e.g. nutrient or micronutrient
carriers), 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.
[0086] 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, coloring agents, viscosity regulators,
stabilizers or osmoregulators. 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 or isopropyl
myristate. Sterile liquid carriers are useful in sterile liquid
form compositions for parenteral administration. The liquid carrier
for pressurized compositions can be a halogenated hydrocarbon or
other pharmaceutically acceptable propellent.
[0087] 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. 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.
[0088] 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.
[0089] 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.
[0090] In the subject application 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. In a subject application, a "subject" is a vertebrate, a
mammal or a human.
[0091] This invention provides a method of treating a subject
suffering from an abnormality wherein the abnormality is alleviated
by decreasing the activity of an MCH1 receptor which comprises
administering to the subject an amount of a compound of the
invention which is an MCH1 receptor antagonist effective to treat
the subject=s abnormality.
[0092] In separate embodiments, the abnormality is a regulation of
a steroid or pituitary hormone disorder, an epinephrine release
disorder, a gastrointestinal disorder, a cardiovascular disorder,
an electrolyte balance disorder, hypertension, diabetes, a
respiratory disorder, asthma, a reproductive function disorder, an
immune disorder, an endocrine disorder, a musculoskeletal disorder,
a neuroendocrine disorder, a cognitive disorder, a memory disorder
such as Alzheimer=s disease, a sensory modulation and transmission
disorder, a motor coordination disorder, a sensory integration
disorder, a motor integration disorder, a dopaminergic function
disorder such as Parkinson=s disease, a sensory transmission
disorder, an olfaction disorder, a sympathetic innervation
disorder, an affective disorder such as depression and anxiety, a
stress-related disorder, a fluid-balance disorder, a seizure
disorder, pain, psychotic behavior such as schizophrenia, morphine
tolerance, opiate addiction, migraine or a urinary disorder such as
urinary incontinence.
[0093] The following description of depressive and anxiety
disorders is for the purpose of illustrating the utility of the
compounds of this invention. The definitions of depressive and
anxiety disorders given below are those listed in Diagnostic and
Statistical Manual of Mental Disorders. 4th ed. (DSM-IV; American
Psychiatric Association, 1994a) or Diagnostic and Statistical
Manual of Mental Disorders. 3rd ed. Revised (DSM-III-R; American
Psychiatric Association, 1987). Additional information regarding
these disorders can be found in this reference, as well as the
others cited below, all of which are incorporated herein by
reference.
[0094] Depressive disorders include major depressive disorder and
dysthymic disorder (American Psychiatric Association, 1994a;
American Psychiatric Association, 1994b). Major depressive disorder
is characterized by the occurrence of one or more major depressive
episodes without manic or hypomanic episodes. A major depressive
episode is defined as a prominent and relatively persistent
depressed or dysphoric mood that usually interferes with daily
functioning (nearly every day for at least 2 weeks); it should
include at least 4 of the following 8 symptoms: change in appetite,
change in sleep, psychomotor agitation or retardation, loss of
interest in usual activities or decrease in sexual drive, increased
fatigue, feelings of guilt or worthlessness, slowed thinking or
impaired concentration, and a suicide attempt or suicidal ideation
(Medical Economics Company, 2002). Dysthymic disorder involves a
type of depression that is not severe enough to be called a major
depressive episode, but that lasts much longer than major
depressive disorder, without high phases.
[0095] It is contemplated that the compounds of this invention will
be effective in treating depression in patients who have been
diagnosed with depression by administration of any of the following
tests: Hamilton Depression Rating Scale (HDRS), Hamilton depressed
mood item, Clinical Global Impressions (CGI)-Severity of Illness.
It is further contemplated that the compounds of the invention will
be effective in inducing improvements in certain of the factors
measured in these tests, such as the HDRS subfactor scores,
including the depressed mood item, sleep disturbance factor and
anxiety factor, and the CGI-Severity of Illness rating. It is also
contemplated that the compounds of this invention will be effective
in preventing relapse of major depressive episodes.
[0096] Anxiety disorders include panic disorder, agoraphobia with
or without history of panic disorder, specific phobia, social
phobia, obsessive-compulsive disorder, post-traumatic stress
disorder, acute stress disorder and generalized anxiety disorder.
It is contemplated that the compounds of this invention will be
effective in treating any of all of these disorders in patients who
have been diagnosed with these disorders.
[0097] Obsessive compulsive disorder is characterized by recurrent
and persistent ideas, thoughts, impulses or images (obsessions)
that are ego-dystonic and/or repetitive, purposeful and intentional
behaviors (compulsions) that are recognized by the person as
excessive or unreasonable (American Psychiatric Association,
1994a). The obsessions or compulsions cause marked distress, are
time-consuming, or significantly interfere with social or
occupational functioning.
[0098] It is contemplated that the compounds of this invention will
be effective in treating obsessions and compulsions in patients who
have been diagnosed with obsessive compulsive disorder by
administration of appropriate tests, which may include, but are not
limited to any of the following: Yale Brown Obsessive Compulsive
Scale (YBOCS) (Goodman, 1989) (for adults), National Institute of
Mental Health Global OCD Scale (NIMH GOCS), CGI-Severity of Illness
scale. It is further contemplated that the compounds of the
invention will be effective in inducing improvements in certain of
the factors measured in these tests, such as a reduction of several
points in the YBOCS total score. It is also contemplated that the
compounds of this invention will be effective in preventing relapse
of obsessive compulsive disorder.
[0099] Panic disorder is characterized by recurrent unexpected
panic attacks and associated concern about having additional
attacks, worry about the implications or consequences of the
attacks, and/or a significant change in behavior related to the
attacks (American Psychiatric Association, 1994a). A panic attack
is defined as a discrete period of intense fear or discomfort in
which four (or more) of the following symptoms develop abruptly and
reach a peak within 10 minutes: (1) palpitations, pounding heart,
or accelerated heart rate; (2) sweating; (3) trembling or shaking;
(4) sensations of shortness of breath or smothering; (5) feeling of
choking; (6) chest pain or discomfort; (7) nausea or abdominal
distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9)
derealization (feelings of unreality) or depersonalization (being
detached from oneself); fear of losing control; (11) fear of dying;
(12) paresthesias (numbness or tingling sensations); (13) chills or
hot flushes. Panic disorder may or may not be associated with
agoraphobia, or an irrational and often disabling fear of being out
in public.
[0100] It is contemplated that the compounds of this invention will
be effective in treating panic disorder in patients who have been
diagnosed with panic disorder on the basis of frequency of
occurrence of panic attacks, or by means of the CGI-Severity of
Illness scale. It is further contemplated that the compounds of the
invention will be effective in inducing improvements in certain of
the factors measured in these evaluations, such as a reduction in
frequency or elimination of panic attacks, an improvement in the
CGI-Severity of Illness scale or a CGI-Global Improvement score of
1 (very much improved), 2 (much improved) or 3 (minimally
improved). It is also contemplated that the compounds of this
invention will be effective in preventing relapse of panic
disorder.
[0101] Social anxiety disorder, also known as social phobia, is
characterized by a marked and persistent fear of one or more social
or performance situations in which the person is exposed to
unfamiliar people or to possible scrutiny by others (American
Psychiatric Association, 1994a). Exposure to the feared situation
almost invariably provokes anxiety, which may approach the
intensity of a panic attack. The feared situations are avoided or
endured with intense anxiety or distress. The avoidance, anxious
anticipation, or distress in the feared situation(s) interferes
significantly with the person's normal routine, occupational or
academic functioning, or social activities or relationships, or
there is marked distress about having the phobias Lesser degrees of
performance anxiety or shyness generally do not require
psychopharmacological treatment.
[0102] It is contemplated that the compounds of this invention will
be effective in treating social anxiety disorder in patients who
have been diagnosed with social anxiety disorder by administration
of any of the following tests: the Liebowitz Social Anxiety Scale
(LSAS), the CGI-Severity of Illness scale, the Hamilton Rating
Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression
(HAM-D), the axis V Social and Occupational Functioning Assessment
Scale of DSM-IV, the axis II (ICD-10) World Health Organization
Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability
Scales, the Schneier Disability Profile, the World Health
Organization Quality of Life-100 (WHOQOL-100), or other tests as
described in Bobes, 1998, which is incorporated herein by
reference. It is further contemplated that the compounds of the
invention will be effective in inducing improvements as measured by
these tests, such as the a change from baseline in the Liebowitz
Social Anxiety Scale (LSAS), or a CGI-Global Improvement score of 1
(very much improved), 2 (much improved) or 3 (minimally improved).
It is also contemplated that the compounds of this invention will
be effective in preventing relapse of social anxiety disorder.
[0103] Generalized anxiety disorder is characterized by excessive
anxiety and worry (apprehensive expectation) that is persistent for
at least 6 months and which the person finds difficult to control
(American Psychiatric Association, 1994a). It must be associated
with at least 3 of the following 6 symptoms: restlessness or
feeling keyed up or on edge, being easily fatigued, difficulty
concentrating or mind going blank, irritability, muscle tension,
sleep disturbance. The diagnostic criteria for this disorder are
described in further detail in DSM-IV, which is incorporated herein
by reference (American Psychiatric Association, 1994a).
[0104] It is contemplated that the compounds of this invention will
be effective in treating generalized anxiety disorder in patients
who have been diagnosed with this disorder according to the
diagnostic criteria described in DSM-IV. It is further contemplated
that the compounds of the invention will be effective in reducing
symptoms of this disorder, such as the following: excessive worry
and anxiety, difficulty controlling worry, restlessness or feeling
keyed up or on edge, being easily fatigued, difficulty
concentrating or mind going blank, irritability, muscle tension, or
sleep disturbance. It is also contemplated that the compounds of
this invention will be effective in preventing relapse of general
anxiety disorder.
[0105] Post-traumatic stress disorder (PTSD), as defined by
DSM-III-R/IV (American Psychiatric Association, 1987, American
Psychiatric Association, 1994a), requires exposure to a traumatic
event that involved actual or threatened death or serious injury,
or threat to the physical integrity of self or others, and a
response which involves intense fear, helplessness, or horror.
Symptoms that occur as a result of exposure to the traumatic event
include re-experiencing of the event in the form of intrusive
thoughts, flashbacks or dreams, and intense psychological distress
and physiological reactivity on exposure to cues to the event;
avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general
responsiveness manifested as diminished interest in significant
activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal
including hypervigilance, exaggerated startle response, sleep
disturbance, impaired concentration, and irritability or outbursts
of anger. A PTSD diagnosis requires that the symptoms are present
for at least a month and that they cause clinically significant
distress or impairment in social, occupational, or other important
areas of functioning.
[0106] It is contemplated that the compounds of this invention will
be effective in treating PTSD in patients who have been diagnosed
with PTSD by administration of any of the following tests:
Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-rated
Impact of Event Scale (IES) (Medical Economics Company, 2002, p.
2752). It is further contemplated that the compounds of the
invention will be effective in inducing improvements in the scores
of the CAPS, IES, CGI-Severity of Illness or CGI-Global Improvement
tests. It is also contemplated that the compounds of this invention
will be effective in preventing relapse of PTSD.
[0107] In a preferred embodiment, the subject invention provides a
method of treatment or management of the following indications:
depressive disorders, anxiety disorders, eating/body weight
disorders, and urinary disorders. Examples of depressive disorders
are major depressive disorder or dysthymic disorder. Examples of
anxiety disorders are panic disorder, agoraphobia without history
of panic disorder, specific phobia, social phobia,
obsessive-compulsive disorder, post-traumatic stress disorder,
acute stress disorder or generalized anxiety disorder. Examples of
eating/body weight disorders are obesity, weight gain, bulimia,
bulimia nervosa or anorexia nervosa. Examples of urinary disorders
include, but are not limited to urinary incontinence overactive
bladder, urge incontinence, urinary frequency, urinary urgency,
nocturia or enuresis. Overactive bladder and urinary urgency may or
may not be associated with benign prostatic hyperplasia.
[0108] This invention provides a method of modifying the 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 also provides a
method of treating an eating disorder in a subject, which comprises
administering to the subject an amount of a compound of the
invention effective to treat the eating disorder. In an embodiment
of the present invention, the eating disorder is obesity, bulimia,
bulimia nervosa or anorexia nervosa.
[0109] The present invention further provides a method of reducing
the body mass of a subject, which comprises administering to the
subject an amount of a compound of the invention effective to
reduce the body mass of the subject. This invention also provides a
method of managing obesity in a subject in need of weight loss,
which comprises administering to the subject an amount of a
compound of the invention effective to induce weight loss in the
subject. This invention also provides a method of managing obesity
in. a subject who has experienced weight loss, which comprises
administering to the subject an amount of a compound of the
invention effective to maintain such weight loss in the
subject.
[0110] The present invention also provides a method of treating
depression in a subject, which comprises administering to the
subject an amount of a compound of the invention effective to treat
the subject's depression. This invention also provides a method of
treating anxiety in a subject, which comprises administering to the
subject an amount of a compound of the invention effective to treat
the subject's anxiety. This invention also provides a method of
treating depression and anxiety in a subject, which comprises
administering to the subject an amount of a compound of the
invention effective to treat the subject's depression and anxiety.
This invention also provides a method of treating major depressive
disorder in a subject, which comprises administering to the subject
an amount of a compound of the invention effective to treat the
subject's major depressive disorder. This invention also provides a
method of treating dysthymic disorder in a subject, which comprises
administering to the subject an amount of a compound of the
invention effective to treat the subject's dysthymic disorder. This
invention also provides a method of treating obsessions and
compulsions in a subject with obsessive compulsive disorder, which
comprises administering to the subject an amount of a compound of
the invention effective to treat the subject's obsessions and
compulsions. This invention also provides a method of treating
panic disorder, with or without agoraphobia, in a subject, which
comprises administering to the subject an amount of a compound of
the invention effective to treat the subject's panic disorder. This
invention also provides a method of treating social anxiety
disorder in a subject, which comprises administering to the subject
an amount of a compound of the invention effective to treat the
subject's social anxiety disorder. This invention also provides a
method of treating generalized anxiety disorder in a subject, which
comprises administering to the subject an amount of a compound of
the invention effective to treat the subject's generalized anxiety
disorder. This invention also provides a method of treating
post-traumatic stress disorder in a subject, which comprises
administering to the subject an amount of a compound of the
invention effective to treat the subject's post-traumatic stress
disorder.
[0111] It is contemplated that the compounds of this invention will
be effective in treating obesity, including weight loss and
maintenance of weight loss in patients, who have been diagnosed
with obesity by the one or more of the following measurements: an
increased body mass index, increased waist circumference (an
indicator of intra-adominal fat), Dual Energy X-Ray Absorptiometry
(DEXA) and trucal (android) fat mass. It is further contemplated
that the compounds of the invention will be effective in inducing
improvements in certain factors measured in these tests.
[0112] It is contemplated that the compounds of this invention will
be effective in treating urinary disorders in patients who have
urge or mixed (with a predominance of urge) incontinence as
evidenced by the number of unnecessary episodes per week, the
number of unnecessary micturitions per day and a low volume voided
per micturition. It is further contemplated that the compounds of
the invention will be effective in inducing improvements in certain
factors measured in these tests.
[0113] The present invention also provides a method of treating a
subject suffering from bipolar I or II disorder, schizoaffective
disorder, a cognitive disorder with depressed mood, a personality
disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep
disorder, nightmare disorder, sleep terror disorder or sleepwalking
disorder.
[0114] The present invention provides a method of treating
overactive bladder with symptoms of urge urinary incontinence,
urgency and/or frequency in a subject, which comprises
administering to the subject an amount of a compound of the
invention effective to treat the subject's overactive bladder. This
invention also provides a method of alleviating urge urinary
incontinence in a subject suffering from overactive bladder, which
comprises administering to the subject an amount of a compound of
the invention effective to alleviate the subject's urge urinary
incontinence. This invention further provides a method of
alleviating urinary urgency in a subject suffering from overactive
bladder, which comprises administering to the subject an amount of
a compound of the invention effective to alleviate the subject's
urinary urgency. Additionally, this invention provides a method of
alleviating urinary frequency in a subject suffering from
overactive bladder, which comprises administering to the subject an
amount of a compound of the invention effective to alleviate the
subject's urinary frequency.
[0115] The present invention also provides a method of treating a
subject suffering from a urinary disorder, which comprises
administering to the subject an amount of a compound of the
invention effective to treat the subject's urinary disorder. In
some embodiments the urinary disorder is urinary incontinence,
overactive bladder, urge incontinence, urinary frequency, urinary
urgency, nocturia or enuresis.
[0116] The present invention provides a method of alleviating the
symptoms of a disorder in a subject, which comprises administering
to the subject an amount of an MCH1 antagonist effective to
alleviate the symptoms, wherein the MCH1 antagonist is any of the
compounds of the invention.
[0117] In an embodiment of the invention, the subject is a
vertebrate, a mammal, a human or a canine. In another embodiment,
the compound is administered orally. In yet another embodiment, the
compound is administered in combination with food.
[0118] This invention will be better understood from the
Experimental Details In a preferred embodiment, the .subject
invention provides a method of treatment for the following
indications: depression, anxiety, eating/body weight disorders, and
urinary disorders. Examples of eating/body weight disorders are
obesity, bulimia, or bulimia nervosa. Examples of urinary disorders
include, but are not limited to, urinary incontinence, overactive
bladder, urge incontinence, urinary frequency, urinary urgency,
nocturia, or enuresis. Overactive bladder and urinary urgency may
or may not be associated with benign prostatic hyperplasia.
[0119] This invention provides a method of modifying the 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.
[0120] This invention also provides a method of treating an eating
disorder in a subject which comprises administering to the subject
an amount of a compound of this invention effective to decrease the
consumption of food by the subject. In an embodiment of the present
invention, the eating disorder is bulimia, obesity or bulimia
nervosa. In an embodiment of the present invention, the subject is
a vertebrate, a mammal, a human or a canine. In a further
embodiment, the compound is administered in combination with
food.
[0121] The present invention further provides a method of reducing
the body mass of a subject which comprises administering to the
subject an amount of a compound of the invention effective to
reduce the body mass of the subject.
[0122] The present invention also provides a method of treating a
subject suffering from depression which comprises administering to
the subject an amount of a compound of this invention effective to
treat the subject's depression. The present invention further
provides a method of treating a subject suffering from anxiety
which comprises administering to the subject an amount of a
compound of this invention effective to treat the subject's
anxiety. The present invention also provides a method of treating a
subject suffering from depression and anxiety which comprises
administering to the subject an amount of a compound of this
invention effective to treat the subject's depression and
anxiety.
[0123] The present invention also provides a method of treating a
subject suffering from major depressive disorder, dysthymic
disorder, bipolar I and II disorders, schizoaffective disorder,
cognitive disorders with depressed mood, personality disorders,
insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder,
nightmare disorder, sleep terror disorder, sleepwalking disorder,
obsessive-compulsive disorder, panic disorder, with or without
agoraphobia, posttraumatic stress disorder, social anxiety
disorder, social phobia and generalized anxiety disorder.
[0124] The present invention also provides a method of treating a
subject suffering from a urinary disorder which comprises
administering to the subject an amount of a compound of this
invention effective to treat the subject's a urinary disorder. In
some embodiments, the urinary disorder is urinary incontinence,
overactive bladder, urge incontinence, urinary frequency, urinary
urgency, nocturia, or enuresis.
[0125] 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.
[0126] The present invention further provides for a compound having
the structure: ##STR17## [0127] wherein each R.sub.1 is
independently hydrogen; --F; --Cl; --Br; --I; --CN; --NO.sub.2;
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; C.sub.3-C.sub.7 cycloalkyl or C.sub.5-C.sub.7
cycloalkenyl; aryl; heteroaryl; --N(R.sub.5).sub.2;
--(CH.sub.2).sub.mOR.sub.5; --COR.sub.5; --CO.sub.2R.sub.5;
--OCOR.sub.5; --CON(R.sub.5).sub.2; --N(R.sub.5)COR.sub.5;
--N(R.sub.5)CON(R.sub.5).sub.2; --OCON(R.sub.5).sub.2 or
--N(R.sub.5)CO.sub.2R.sub.5; [0128] wherein R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Cl; --Br; --I; --CN;
--(CH.sub.2).sub.mOR.sub.5; --(CH.sub.2).sub.mSR.sub.5; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with one or more R.sub.1; or [0129] wherein
R.sub.2 and R.sub.3 together can be --(CH.sub.2).sub.p--; [0130]
wherein R.sub.4 is hydrogen; straight chained or branched
C.sub.1-C.sub.7 alkyl, monofluoroalkyl or polyfluoroalkyl;
C.sub.3-C.sub.6 cycloalkyl; --N(R.sub.5).sub.2 or
--(CH.sub.2).sub.mOR.sub.5; [0131] wherein each R.sub.5 is
independently hydrogen; aryl; heteroaryl or straight chained or
branched C.sub.1-C.sub.7 alkyl, wherein the alkyl may be
substituted with aryl or heteroaryl; [0132] wherein each R.sub.6 is
independently hydrogen; straight chained or branched
C.sub.1-C.sub.7 alkyl; [0133] wherein each R.sub.7 is independently
hydrogen; phenyl or straight chained or branched C.sub.1-C.sub.7
alkyl, wherein the alkyl may be substituted with phenyl; [0134]
wherein R.sub.8 is hydrogen or straight chained C.sub.1-C.sub.7
alkyl; [0135] wherein R.sub.4 and R.sub.8 together can be
--(CH.sub.2).sub.r--; [0136] wherein each m is independently an
integer from 0 to 5 inclusive; [0137] wherein n is an integer from
1 to 5 inclusive; [0138] wherein p is an integer from 2 to 7
inclusive; [0139] wherein q is an integer from 0 to 2 inclusive;
[0140] wherein each X is independently CH or N; [0141] wherein Z is
CO; SO2 or may be absent or a pharmaceutically acceptable salt
thereof.
[0142] The present invention provides for a compound having the
structure: ##STR18## wherein each R.sub.1 is independently
hydrogen; --F; --Cl; --Br; --I; --CN; --NO.sub.2; 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; C.sub.3-C.sub.7 cycloalkyl or C.sub.5-C.sub.7
cycloalkenyl; aryl; heteroaryl; --N(R.sub.5).sub.2;
--(CH.sub.2).sub.mOR.sub.5; --COR.sub.5; --CO.sub.2R.sub.5;
--OCOR.sub.5; --CON(R.sub.5).sub.2; --N(R.sub.5)COR.sub.5;
--N(R.sub.5)CON(R.sub.5).sub.2; --OCON(R.sub.5).sub.2 or
--N(R.sub.5)CO.sub.2R.sub.5; [0143] wherein R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Cl; --Br; --I; --CN;
--(CH.sub.2).sub.mOR.sub.5; --(CH.sub.2).sub.mSR.sub.5; straight
chained or branched C.sub.1-C.sub.7 alkyl, monofluoroalkyl,
polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl
may be substituted with one or more R.sub.1; or [0144] wherein
R.sub.2 and R.sub.3 together can be --(CH.sub.2).sub.p--; [0145]
wherein R.sub.4 is straight chained or branched C.sub.1-C.sub.7
alkyl, monofluoroalkyl or polyfluoroalkyl, C.sub.3-C.sub.6
cycloalkyl, N(R.sub.5).sub.2 or --(CH.sub.2).sub.mOR.sub.5; [0146]
wherein each R.sub.5 is independently hydrogen; aryl; heteroaryl or
straight chained or branched C.sub.1-C.sub.7 alkyl, wherein the
alkyl may be substituted with aryl or heteroaryl; [0147] wherein
each R.sub.6 is independently hydrogen; straight chained or
branched C.sub.1-C.sub.7 alkyl; [0148] wherein each R.sub.7 is
independently hydrogen; phenyl or straight chained or branched
C.sub.1-C.sub.7 alkyl, wherein the alkyl may be substituted with
phenyl; [0149] wherein each m is independently an integer from 0 to
5 inclusive; [0150] wherein n is an integer from 1 to 5 inclusive;
[0151] wherein p is an integer from 2 to 7 inclusive; [0152]
wherein q is an integer from 0 to 2 inclusive; [0153] wherein X is
CH or N; or a pharmaceutically acceptable salt thereof.
[0154] In a sub-class of the invention, are the compounds wherein
each R.sub.1 is independently hydrogen; straight chained or
branched C.sub.1-C.sub.7 alkyl; --F; --Cl; --Br; --I; --CN;
--NO.sub.2; straight chained or branched C.sub.1-C.sub.4 alkyl or
polyfluoroalkyl; --(CH.sub.2).sub.mOR.sub.5; --COR.sub.5;
--CO.sub.2R.sub.5; --OCOR.sub.5; --CON(R.sub.5).sub.2;
--N(R.sub.5)COR.sub.5 or --N(R.sub.5)CON(R.sub.5).sub.2; [0155]
wherein R.sub.2 and R.sub.3 are independently hydrogen; --F; --Cl;
--Br; --I; --CN; --(CH.sub.2).sub.mSR.sub.5; straight chained or
branched C.sub.1-C.sub.7 alkyl; aryl or heteroaryl, wherein the
aryl or heteroaryl may be substituted with one or more R.sub.1; or
[0156] wherein R.sub.2 and R.sub.3 together can be
--(CH.sub.2).sub.p--; [0157] wherein R.sub.4 is straight chained or
branched C.sub.1-C.sub.7 alkyl; C.sub.3-C.sub.6 cycloalkyl;
--N(R.sub.5).sub.2 or --(CH.sub.2).sub.mOR.sub.5; [0158] wherein
each R.sub.5 is independently hydrogen or straight chained or
branched C.sub.1-C.sub.3 alkyl, wherein the alkyl may be
substituted with phenyl; [0159] wherein m is 0 to 3; [0160] wherein
n is 1 to 3; [0161] wherein p is an integer from 2 to 5 inclusive;
[0162] wherein q is 0; and [0163] wherein X is CH.
[0164] In a subclass of the invention are the compounds of the
formula: ##STR19##
[0165] In one embodiment of the invention are the compounds having
the following structure: ##STR20##
[0166] In one embodiment of the invention, R.sub.1 is hydrogen;
--F; --Cl; --Br; --I or straight chained or branched
C.sub.1-C.sub.7 alkyl; and [0167] R.sub.2 is hydrogen or straight
chained or branched C.sub.1-C.sub.7 alkyl.
[0168] In one embodiment of the invention R.sub.4 is straight
chained or branched C.sub.1-C.sub.7 alkyl.
[0169] In one embodiment of the invention, the compound has the
structure: ##STR21##
[0170] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR22##
[0171] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR23##
[0172] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR24##
[0173] In one embodiment of the invention, R.sub.4 is
C.sub.3-C.sub.6 cycloalkyl.
[0174] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR25##
[0175] In one embodiment of the invention, R.sub.2 and R.sub.3 are
independently hydrogen; --F; --Br or straight chained or branched
C.sub.1-C.sub.7 alkyl.
[0176] In one embodiment of the invention, R.sub.2 and R.sub.3 are
independently hydrogen or straight chained or branched
C.sub.1-C.sub.7 alkyl.
[0177] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR26##
[0178] In one embodiment of the invention, R.sub.2 and R.sub.3 are
independently hydrogen; --F or --Br.
[0179] In one embodiment of the invention, the compound has the
structure: ##STR27##
[0180] In one embodiment of the invention, R.sub.2 and R.sub.3
together are (CH.sub.2).sub.p--;
[0181] In one embodiment of the invention, the compound has the
structure: ##STR28##
[0182] In one embodiment of the invention, R.sub.4 is straight
chained or branched C.sub.1-C.sub.7 alkyl.
[0183] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR29##
[0184] In one embodiment of the invention, the compound is selected
from the group consisting of: ##STR30##
[0185] In one embodiment of the invention, the compound has the
following structure: ##STR31##
[0186] In one embodiment of the invention, the compound has the
following structure: ##STR32##
[0187] The one embodiment of the invention, the compound has the
structure: ##STR33##
[0188] In one embodiment of the invention, the compound is
enantiomerically pure.
[0189] In one embodiment of the invention, the compound is
diastereomerically pure.
[0190] In one embodiment of the invention, the compound is
enantiomerically and diastereomerically pure.
[0191] The present invention also provides a pharmaceutical
composition that comprises a therapeutically effective amount of a
compound of the present invention and a pharmaceutically acceptable
carrier.
[0192] The present invention further provides a pharmaceutical
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier.
[0193] The present invention also provides a process for making a
pharmaceutical composition comprising admixing a compound of the
present invention and a pharmaceutically acceptable carrier.
[0194] The present invention also provides a method for treating a
subject suffering from a disorder mediated by the MCH1 receptor
comprising administering to the subject a therapeutically effective
amount of a compound of the present invention.
[0195] In one embodiment, the therapeutically effective amount is
between about 0.03 and about 300 mg.
[0196] In one embodiment, the disorder is depression, anxiety,
obesity or urge incontinence.
[0197] The present invention also provides a method of treating a
subject suffering from a disorder selected from the group
consisting of depression, anxiety, urge incontinence or obesity
comprising administering to the subject a therapeutically effective
amount of a compound of the present invention.
Experimental Section
[0198] I. Synthetic Methods for Examples
General Methods:
[0199] 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 compounds described herein were named using
ACD/Name program (version 4.0, Advanced Chemistry Development Inc.,
Toronto, Ontario, M5H2L3, Canada). The .sup.1H NMR spectra were
recorded at 400 MHz using a Bruker Avance spectrometer with
tetramethylsilane as internal standard. Splitting patterns were
designated as follows: s=singlet; d=doublet; t=triplet; q=quartet;
quintet; sextet; septet; br=broad; m=multiplet. Elemental analyses
were performed by Robertson Microlit Laboratories, Inc. Mass
spectra were obtained on a Platform II (Fisons) or Quattro Micro
(Micromass) spectrometer with electrospray (ESMS) ionization and
MH.sup.+ is reported. Thin-layer chromatography (TLC) was carried
out on glass plates precoated with silica gel 60 F.sub.254 (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.
[0200] The examples described in the experimental section are
merely illustrative of the methods used to synthesize MCH1
antagonists. Additional compounds of the invention can be obtained
by the general synthetic procedures described herein or by
incorporating variations into these methods that would be obvious
to someone skilled in the art. ##STR34## ##STR35## ##STR36##
##STR37## ##STR38## ##STR39## ##STR40## ##STR41## ##STR42##
##STR43## ##STR44## ##STR45## ##STR46## ##STR47## ##STR48##
EXAMPLE 1
[0201] ##STR49##
N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]phenyl}-
-2-methylpropanamide
[0202] Example 1 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.63 (s, 1H), 7.39-7.31 (m, 3H), 7.29-7.21
(m, 5H), 7.02-6.96 (m, 4H), 4.80 (s, 1H), 3.40 (q, 2H, J=4.5 Hz),
2.94 (d, 2H, J=10.2 Hz), 2.51-2.38 (m, 4H), 1.97(dt, 2H, J=1.8,
10.4 Hz), 1.81 (m, 2H) 1.68 (quintet, 2H, J=6.8 Hz,), 1.59 (m, 3H),
1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 534.3 (M+H).sup.+; Anal. Calc.
For (HCl salt) C.sub.32H.sub.37F.sub.2N.sub.3O.sub.2.HCl.0.20
CHCl.sub.3: C, 65.11; H, 6.48; N, 7.07. Found: C, 65.30; H, 6.50;
N, 6.96.
EXAMPLE 2
[0203] ##STR50##
-N-{3-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]phenyl-
}-2-methylpropanamide
[0204] Example 2 was prepared from bis(4-chlorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.64 (s, 1H), 7.34-7.13 (m, 12H), 4.75 (s,
1H), 3.41 (q, 2H, J=4.5 Hz), 2.94 (d, 2H, J=10.2 Hz), 2.51-2.40 (m,
4H), 1.97 (m, 2H), 1.82 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz), 1.59
(m, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 566.2 (M+H).sup.+.
EXAMPLE 3
[0205] ##STR51##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2-diphenylacetamid-
e
[0206] Example 3 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 8: .sup.1 H NMR (400 MHz,
CDCl.sub.3) .delta. 7.70 (s, 1H), 7.40 (s, 1H), 7.32-7.20 (m, 12H),
6.96 (t, 1H, J=4.8 Hz), 6.91 (d, 1H, J=7.6 Hz), 4.87 (s, 1H), 3.39
(dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.43 (m, 1H),
2.36 (t, 2H, J=6.4 Hz), 2.11 (s, 3H), 1.94 (m, 2H), 1.76 (d, 2H,
J=12.4 Hz), 1.68 (t, 2H, J=6.8 Hz), 1.60 (dd, 2H, J=1.2, 8.4 Hz);
ESMS m/e: 470.3 (M+H).sup.+.
EXAMPLE 4
[0207] ##STR52##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-4-methylphenyl]-2-
-methylpropanamide
[0208] Example 4 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 8: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.39-7.23 (m, 12H), 7.14 (br, 1H),
7.08 (d, 1H, J=8.4 Hz), 6.90 (br, 1H), 4.91 (s, 1H), 3.41 (dd, 2H,
J=6.4, 12.4 Hz), 2.95 (d, 2H, J=12.4 Hz), 2.66 (m, 1H), 2.47 (m,
1H), 2.40 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 2.03-1.97 (m, 2H),
1.74-1.62 (m, 6H), 1.22 (d, 6H, J=7.2 Hz); ESMS m/e: 512.3
(M+H).sup.+.
EXAMPLE 5
[0209] ##STR53##
N-[3-(1-{3-[(2,2-diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]butanam-
ide
[0210] Example 5 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 8: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.49 (s, 1H), 7.35-7.23 (m, 12H), 7.20 (s, 1H),
6.95 (d, 2H, J=7.6 Hz), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6
Hz), 2.94 (d, 2H, J=11.6 Hz), 2.48 (m, 1H), 2.40 (t, 2H, J=6.4 Hz),
2.34 (t, 2H, J=7.2 Hz), 1.98 (t, 2H, J=11.2 Hz), 1.82-1.60 (m, 8H),
1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 498.3 (M+H).sup.+.
EXAMPLE 6
[0211] ##STR54##
N-[6-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-2-pyridinyl]-2-me-
thylpropanamide
[0212] Example 6 was prepared from diphenylacetyl chloride and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 8: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.07 (d, 1H, J=8.0 Hz), 7.71-7.63 (m, 3H),
7.42-7.23 (m, 10H), 6.89 (d, 1H, J=7.6 Hz), 4.96 (s, 1H), 3.41 (dd,
2H, J=5.6, 7.6 Hz), 3.00 (d, 2H, J=11.6 Hz), 2.60 (m, 1H), 2.47 (t,
2H, J=6.4 Hz), 2.45 (m, 1H), 2.06-2.01 (m, 2H), 1.89-1.64 (m, 6H),
1.13 (d, 6H, J=6.8 Hz); ESMS m/e: 499.3 (M+H).sup.+.
EXAMPLE 7
[0213] ##STR55##
2-(4-chlorophenyl)-2-methyl-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidin-
yl}propyl)propanamide
[0214] Example 7 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.86 (s, 1H), 7.50 (s, 1H), 7.34-7.19 (m, 6H),
6.96 (d, 1H, J=7.8 Hz), 6.72-6.67 (m, 1H), 3.42 (q, 2H, J=7.1 Hz),
3.31 (q, 3H, J=5.4 Hz), 2.49-2.35 (m, 5H), 2.08-1.95 (m, 2H),
1.82-1.74 (m, 2H), 1.71-1.62 (m, 3H), 1.56 (s, 6H), 1.24 (t, 3H,
J=7.8 Hz); ESMS m/e: 470.3 (M+H).sup.+.
EXAMPLE 8
[0215] ##STR56##
2-(4-chlorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)-2-methylpropanamide
[0216] Example 8 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamid- e
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.53 (s, 1H), 7.32-7.24 (m, 7H), 6.91 (d,
1H, J=7.2 Hz), 6.67 (m, 1H), 3.31 (q, 2H, J=5.5 Hz), 2.92-2.85 (m,
2H), 2.53 (septet, 1H, J=6.7 Hz), 2.43 (tt, 1H, J=11.6, 3.0 Hz),
2.33 (t, 2H, J=6.7 Hz), 1.91 (dt, 2H, J=11.7-1.8 Hz), 1.78-1.72 (m,
2H), 1.65-1.59 (m, 2H), 1.56 (s, 6H), 1.52-1.45 (m, 2H), 1.25 (d,
6H, J=6.7 Hz); ESMS m/e: 484.3 (M+H).sup.+; Anal. Calc. for (HCl
salt) C.sub.28H.sub.38ClN.sub.3O.sub.2.HCl.0.30 CHCl.sub.3: C,
61.10; H, 7.12; N, 7.55. Found: C, 60.90; H, 7.20; N, 7.64.
EXAMPLE 9
[0217] ##STR57##
N-{3-[1-(3-{[bromo(phenyl)acetyl]amino}propyl)-4-piperidinyl]phenyl}-2-met-
hylpropanamide
[0218] Example 9 was prepared from bromo(phenyl)acetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: ESMS m/e: 500.0
(M+H).sup.+.
EXAMPLE 10
[0219] ##STR58##
N-[3-(1-{3-[(2-bromo-2-phenylacetyl)amino]propyl}-4-piperidinyl)phenyl]pro-
panamide
[0220] Example 10 was prepared from bromo(phenyl)acetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: ESMS m/e: 486.1
(M+H).sup.+.
EXAMPLE 11
[0221] ##STR59##
N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propyl)-2,2-diphenylhept-
anamide
[0222] Example 11 was prepared from 2,2-diphenylheptanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.65 (s, 1H), 7.45 (s, 1H), 7.40 (m, 1H),
7.37-7.19 (m, 11H), 6.88 (d, 1H, J=7.3 Hz), 6.34 (t, 1H, J=4.5 Hz),
3.34-3.27 (m, 3H), 2.94-2.87 (m, 2H), 2.52 (septet, 1H, J=6.9 Hz),
2.46-2.34 (m, 4H), 2.27 (t, 2H, J=6.9 Hz), 2.00-1.91 (m, 2H),
1.77-1.69 (m, 2H), 1.69-1.52, (m, 5H), 1.30-1.20 (m, 12H); ESMS
m/e: 568.4 (M+H).sup.+.
EXAMPLE 12
[0223] ##STR60##
N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propyl)-2,2-diphenylbuta-
namide
[0224] Example 12 was prepared from 2,2-diphenylbutanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.45 (s, 1H), 7.44-7.39 (m, 2H), 7.37-7.28
(m, 8H), 7.27-7.20 (m, 3H), 6.89 (d, 1H, J=7.4 Hz), 6.43 (t, 1H,
J=4.5 Hz), 3.35-3.27 (m, 2H), 2.90-2.82 (m, 2H), 2.51 (septet, 1H,
J=6.8 Hz), 2.49-2.35 (m, 4H), 2.24 (t, 2H, J=6.3 Hz), 1.89 (t, 2H,
J=10.2 Hz), 1.75-1.68 (m, 2H), 1.66-1.58 (m, 2H), 1.57-1.45 (m,
2H), 1.24 (d, 6H, J=6.7 Hz), 1.27-1.23 (m, 2H); ESMS m/e: 526.3
(M+H).sup.+.
EXAMPLE 13
[0225] ##STR61##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-3-methylbu-
tanamide
[0226] Example 13 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-3-methylbutanamide
according to the procedures described in Scheme 8: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 10.79-10.51 (br, 1H), 8.85-8.67 (m, 1H),
8.01-7.81 (br, 1H), 7.70 (d, 1H, J=7.2 Hz), 7.47-7.14 (m, 11H),
6.89 (d, 1H, J=7.2 Hz), 5.03 (s, 1H), 3.53-3.26 (m, 4H), 2.96-2.80
(m, 2H), 2.78-2.52 (m, 3H), 2.44-2.14 (m, 2H), 2.26 (d, 2H, J=6.0
Hz), 2.14-1.94 (m, 3H), 1.94-1.76 (m, 2H), 1.10 (d, 6H, J=6.4 Hz);
ESMS m/e: 512.3 (M+H).sup.+; Anal. Calc. (HCl salt)
C.sub.33H.sub.42ClN.sub.3O.sub.2.0.60CH.sub.2Cl.sub.2: C, 67.36; H,
7.27; N, 7.01. Found: C, 67.08; H, 7.57; N, 7.36.
EXAMPLE 14
[0227] ##STR62##
N-[3-(1-{3-[(2-mesityl-2-phenylacetyl)amino]propyl}-4-piperidinyl)phenyl]p-
ropanamide
[0228] Example 14 was prepared from mesityl(phenyl)acetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 9: ESMS m/e: 526.3
(M+H).sup.+.
EXAMPLE 15
[0229] ##STR63##
2,2-diphenyl-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl)butan-
amide
[0230] Example 15 was prepared from 2,2-diphenylbutanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.43-7.38 (m, 1H), 7.37-7.29 (m, 9H), 7.28-7.21
(m, 4H), 6.90 (d, 1H, J=8.2 Hz), 6.43 (t, 1H, J=4.1), 3.32 (q, 2H,
J=6.5 Hz), 2.95-2.89 (m, 2H), 2.45 (q, 2H, J=7.9 Hz), 2.43-2.35 (m,
3H), 2.27 (t, 2H, J=6.5 Hz), 2.01-1.92 (m, 2H), 1.78-1.59 (m, 6H),
1.24 (t, 3H, J=7.9 Hz), 0.79 (t, 3H, J=6.5 Hz); ESMS m/e: 512.3
(M+H).sup.+.
EXAMPLE 16
[0231] ##STR64##
N-{3-[1-(3-{[(ethylsulfanyl)(diphenyl)acetyl]amino}propyl)-4-piperidinyl]p-
henyl}-2-methylpropanamide
[0232] Example 16 was prepared from (ethylsulfanyl)(diphenyl)acetic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: ESMS m/e: 658.6
(M+H).sup.+.
EXAMPLE 17
[0233] ##STR65##
[0234]
N-[3-(1-{3-[(2,2-diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl-
]cyclopropanecarboxamide
[0235] Example 17 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 8: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.26-9.09 (br, 1H), 8.12-7.91 (br, 1H),
7.69 (d, 1H, J=7.2 Hz), 7.63-7.42 (br, 1H), 7.43-7.12 (m, 11H),
6.88 (d, 1H, J=7.2 Hz), 5.03 (s, 1H), 3.53-3.27 (m, 4H), 2.99-2.84
(m, 2H), 2.84-2.58 (m, 3H), 2.40-2.16 (m, 2H), 2.16-1.98 (m, 2H),
1.98-1.83 (m, 2H), 1.78-1.64 (m, 1H), 1.10-0.97 (m, 2H), 0.90-0.76
(m, 2H); ESMS m/e: 496.3 (M+H).sup.+.
EXAMPLE 18
[0236] ##STR66##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-2,2-dimeth-
ylpropanamide
[0237] Example 18 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2,2-dimethylpropanamide
according to the procedures described in Scheme 8: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.51-7.41 (s, 1H), 7.34-7.10(m, 13H),
6.99-6.80 (m, 2H), 4.81 (s, 1H), 3.40-3.26 (m, 2H), 2.96-2.78 (m,
2H), 2.50-2.25 (m, 3H), 1.98-1.82 (m, 2H), 1.79-1.68 (m, 2H),
1.68-1.45 (m, 4H), 1.23 (s, 9H) ; ESMS m/e: 512.3 (M+H).sup.+.
EXAMPLE 19
[0238] ##STR67##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-3,3-dimeth-
ylbutanamide
[0239] Example 19 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl
)-4-piperidinyl]phenyl}-3,3-dimethylbutanamide according procedures
described in Scheme 8: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
10.73-10.50 (br, 1H), 8.63-8.48 (m, 1H), 7.97-7.77 (br, 1H), 7.70
(d, 1H, J=7.2 Hz), 7.45-7.11 (m, 11H), 6.89 (d, 1H, J=7.2 Hz), 5.01
(s, 1H), 3.46-3.26 (m, 4H), 2.97-2.77 (m, 2H), 2.77-2.50 (m, 3H),
2.42-2.17 (m, 2H), 2.25 (s, 2H), 2.14-1.94 (m, 2H), 1.93-1.78 (m,
2H), 1.00 (s, 9H); ESMS m/e: 526.4 (M+H).sup.+; Anal. Calc. (HCl
salt) C.sub.34H.sub.44ClN.sub.3O.sub.2.0.31CHCl.sub.3: C, 68.77; H,
7.45; N, 7.01. Found: C, 68.51; H, 7.40; N, 7.39.
EXAMPLE 20
[0240] ##STR68##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-4-methoxyphenyl]--
2-methylpropanamide
[0241] Example 20 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanami-
de according to the procedures described in Scheme 8: ESMS m/e:
528.3 (M +H).sup.+.
EXAMPLE 21
[0242] 98597 ##STR69##
N-{3-[1-(3-{[2,2-bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nyl}propylanamide
[0243] Example 21 was prepared from bis(4-fluorophenyl)acetic acid
and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide
according to the procedures described in Scheme 10: ESMS m/e: 520.3
(M+H).sup.+.
EXAMPLE 22
[0244] 98600 ##STR70##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-4-methoxyphenyl]b-
utanamide
[0245] Example 22 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide
according to the procedures described in Scheme 8: ESMS m/e: 528.4
(M+H).sup.+.
EXAMPLE 23
[0246] 98607 ##STR71##
N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-meth-
oxyphenyl}-2-methylpropanamide
[0247] Example 23 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanami-
de according to the procedures described in Scheme 9: ESMS m/e:
564.4 (M+H).sup.+.
EXAMPLE 24
[0248] 98616 ##STR72##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-4-fluorophenyl]-2-
-methylpropanamide
[0249] Example 24 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 8: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.95 (s, 1H), 7.47 (dd, 1H, J=2.4,
6.4 Hz), 7.34-7.21 (m, 11H), 7.06 (t, 1H, J=4.8 Hz), 6.91 (t, 1H,
J=10.0 Hz), 4.90 (s, 1H), 3.38 (dd, 2H, J=6.0, 11.6 Hz), 2.90-2.87
(m, 2H), 2.74 (m, 1H), 2.50 (m, 1H), 2.36 (t, 2H, J=6.8 Hz), 1.96
(dt, 2H, J=2.8, 12.0 Hz), 1.73-1.62 (m, 6H), 1.20 (d, 6H, J=6.8
Hz); ESMS m/e: 516.3 (M+H).sup.+.
EXAMPLE 25
[0250] ##STR73##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-4-fluorophenyl]bu-
tanamide
[0251] Example 25 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}butanamide
according to the procedures described in Scheme 8: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.71 (s, 1H), 7.39 (dd, 1H, J=2.8, 6.8
Hz), 7.33-7.21 (m, 11H), 7.00 (t, 1H, J=5.6 Hz), 6.92 (t, 1H, J=9.2
Hz), 4.89 (s, 1H), 3.38 (dd, 2H, J=6.4, 12.0 Hz), 2.91-2.88 (m,
2H), 2.74 (m, 1H), 2.36 (t, 2H, J=6.4 Hz), 2.29 (t, 2H, J=7.6 Hz),
1.97 (dt, 2H, J=2.4, 11.6 Hz), 1.77-1.62 (m, 8H), 0.97 (t, 3H,
J=7.2 Hz); ESMS m/e: 516.3 (M+H).sup.+.
EXAMPLE 26
[0252] ##STR74##
N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-meth-
oxyphenyl}butanamide
[0253] Example 26 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide
according to the procedures described in Scheme 9: ESMS m/e: 564.4
(M+H).sup.+.
EXAMPLE 27
[0254] ##STR75##
N-{3-[1-(3-{[2,2-bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nyl}butanamide
[0255] Example 27 was prepared from bis(4-fluorophenyl)acetic acid
and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.14 (s, 1H), 7.69 (t, 1H, J=5.2 Hz),
7.52 (s, 1H), 7.38 (d, 1H, J=8.0 Hz), 7.30-7.27 (m, 4H), 7.20 (t,
1H, J=8.0 Hz), 7.00-6.95 (m, 4H), 6.89 (d, 1H, J=8.0 Hz), 4.90 (s,
1H), 3.37 (dd, 2H, J=6.0, 11.6 Hz), 3.05 (d, 2H, J=11.2 Hz), 2.55
(t, 2H, J=6.8 Hz), 2.49 (m, 1H), 2.33 (t, 2H, J=7.2 Hz), 2.17 (m,
2H), 1.79-1.69 (m, 8H), 0.97 (t, 3H, J=7.6 Hz); ESMS m/e: 534.4
(M+H).sup.+.
EXAMPLE 28
[0256] ##STR76##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2-bis(4-fluorophen-
yl)acetamide
[0257] Example 28 was prepared from bis(4-fluorophenyl)acetic acid
and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.25 (s, 1H), 7.83 (br s, 1H),
7.41-7.85 (m, 12H), 4.90 (s, 1H), 3.36 (dd, 2H, J=5.6, 12.0 Hz),
3.18 (d, 2H, J=11.6 Hz), 2.69 (t, 2H, J=6.4 Hz), 2.53 (m, 1H), 2.34
(m, 2H), 2.15 (s, 3H), 1.96-1.79 (m, 6H); ESMS m/e: 506.4
(M+H).sup.+.
EXAMPLE 29
[0258] ##STR77##
N-{6-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2-pyri-
dinyl}-2-methylpropanamide
[0259] Example 29 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.06 (d, 1H, J=8.4 Hz), 7.99 (m, 1H),
7.84 (s, 1H), 7.63 (t, 1H, J=8.0 Hz), 7.39-7.32 (m, 4H), 7.03-6.97
(m, 4H), 6.87 (d, 1H, J=7.6 Hz), 4.91 (s, 1H), 3.39 (dd, 2H, J=5.2,
11.2 Hz), 3.07 (d, 2H, J=11.6 Hz), 2.62 (m, 1H), 2.55 (t, 2H, J=6.4
Hz), 2.34 (m, 1H), 2.16 (t, 2H, J=11.2 Hz), 1.93-1.73 (m, 6H), 1.16
(d, 6H, J=6.8 Hz); ESMS m/e: 535.4 (M+H).sup.+.
EXAMPLE 30
[0260] ##STR78##
N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propyl)-2,2-diphenylprop-
anamide
[0261] Example 30 was prepared from 2,2-diphenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.46 (s, 1H), 7.42 (s, 1H), 7.39-7.18 (m,
12H), 6.89 (d, 1H, J=7.7 Hz), 6.23 (m, 1H), 3.35 (q, 2H, J=6.4),
2.85 (d, 2H, J=10.8 Hz), 2.5 (quintet, 1H, J=7.4 Hz), 2.45-2.36 (m,
1H), 2.28 (t, 2H, J=6.4 Hz), 1.99 (s, 3H), 1.91-1.82 (m, 2H),
1.75-1.68 (m, 2H), 1.65 (t, 2H, J=6.4 Hz), 1.60-1.47 (m, 2H), 1.23
(d, 6H, J=7.0 Hz); ESMS m/e: 512.4 (M+H).sup.+.
EXAMPLE 31
[0262] ##STR79##
1-(4-chlorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l) cyclopentanecarboxamide
[0263] Example 31 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.45-7.42 (m,1H), 7.33-7.24 (m, 7H), 6.94
(d, 1H, J=7.1 Hz), 6.58-6.52 (m, 1H), 3.26 (q, 2H, J=6.1 Hz), 2.90
(d, 2H, J=10.8 Hz), 2.56-2.40 (m, 4H), 2.29 (t, 2H, J=6.3 Hz),
2.03-1.87 (m, 6H), 1.83-1.76 (m, 4H), 1.60 (dd, 4H, J=6.8, 4.6 Hz),
1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 510.4 (M+H).sup.+.
EXAMPLE 32
[0264] ##STR80##
N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]-amino}propyl)-4-piperidinyl]-4-met-
hylphenyl}-2-methylpropanamide
[0265] Example 32 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.09 (s, 1H), 7.98 (s, 1H), 7.59 (d,
1H, J=1.8 Hz), 7.54-7.51 (m, 1H), 7.32 (m, 3H), 7.21-7.18 (m, 1H),
6.99-6.94 (m, 5H), 4.87 (s, 1H) 3.36 (q, 2H, J=5.8 Hz), 2.92-2.97
(m, 2H), 2.68-2.58 (m, 1H), 2.5 (quintet, 1H, J=7.2 Hz), 2.37 (t,
2H, J=5.7 Hz), 2.25 (s, 3H), 2.01-1.92 (m, 2H), 1.71-1.52 (m, 6H),
1.16 (d, 6H, J=7.2 Hz); ESMS m/e: 548.4 (M+H).sup.+.
EXAMPLE 33
[0266] ##STR81##
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-2-methylphenyl]-2-
-methylpropanamide
[0267] Example 33 was prepared from diphenylacetyl chloride and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-2-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 8: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.49 (d, 1H, J=8.0 Hz), 7.35-7.19 (m,
11H), 7.09-7.02 (m, 3H), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6
Hz), 2.99 (d, 2H, J=12.8 Hz), 2.72 (m, 1H), 2.59 (m, 1H), 2.43 (t,
2H, J=6.4 Hz), 2.19 (s, 3H), 2.06-2.00 (m, 2H), 1.75-1.60 (m, 6H),
1.30 (d, 6H, J=6.8 Hz); ESMS m/e: 512.5 (M+H).sup.+.
EXAMPLE 34
[0268] ##STR82##
N-{3-[1-(3-{[bis(4-methylphenyl)acetyl]amino}propyl)-4-piperidinyl]phenyl}-
-2-methylpropanamide
[0269] Example 34 was prepared from bis(4-methylphenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.50 (s, 1H), 7.29 (d, 2H, J=6.1 Hz), 7.13
(m, 8H), 6.93 (d, 1H, J=7.5 Hz), 6.83-6.78 (m, 1H), 7.27-7.21 (m,
1H), 4.81 (s, 1H), 3.40-3.34 (m, 2H), 2.91 (d, 2H, J=11.6 Hz),
2.53-2.41 (m, 2H), 2.36 (t, 2H, J=6.6 Hz), 2.29 (s, 6H), 1.99-1.88
(m, 2H), 1.78 (d, 3H, J=12.9 Hz), 1.67 (t, 2H, J=6.6 Hz), 1.62-1.56
(m, 1H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 526.4 (M+H).sup.+.
EXAMPLE 35
[0270] ##STR83##
N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluo-
rophenyl}-2-methylpropanamide
[0271] Example 35 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylipropanami-
de according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.58 (dd, 1H, J=2.8, 6.4 Hz), 7.53
(s, 1H), 7.49 (br s, 1H), 7.31-6.92 (m, 10H), 4.81 (s, 1H), 3.40
(dd, 2H, J=5.6, 11.2 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.76 (m, 1H),
2.49 (m, 1H), 2.42 (t, 2H, J=6.0 Hz), 2.02-1.96 (m, 2H), 1.77 (d,
2H, J=11.6 Hz), 1.69-1.62 (m, 4H), 1.22 (d, 6H, J=6.8 Hz); ESMS
m/e: 552.3 (M+H).sup.+.
EXAMPLE 36
[0272] ##STR84##
1-(4-fluorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)cyclopentanecarboxamide
[0273] Example 36 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.53 (s, 1H), 7.33 (dd, 2H, J=5.8, 3.6
Hz,), 7.29-7.26 (m, 2H), 7.25-7.20 (m, 1H), 7.02-6.95 (m, 2H), 6.93
(d, 1H, J=7.1 Hz), 6.54-6.49 (m, 1H), 3.26 (q, 2H, J=6.5 Hz),
3.22-3.14 (m, 1H), 2.90 (d, 1H, J=12.0 Hz), 2.55-2.37 (m, 4H), 2.29
(t, 2H, J=6.5 Hz), 2.06 (s, 4H), 2.00-1.90 (m, 3H), 1.82-1.75 (m,
4H) 1.73-1.66 (m, 3H), 1.65-1.57 (m, 4H), 1.25 (d, 6H, J=6.7 Hz);
ESMS m/e: 494.3 (M+H).sup.+; Anal. Calc. for
C.sub.30H.sub.40FN.sub.3O.sub.2.0.10 CHCl.sub.3.0.650 DMF: C,
70.92; H, 8.27; N, 8.64. Found: C, 70.83; H, 8.11; N, 8.93.
EXAMPLE 37
[0274] ##STR85##
2-(4-chlorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)propanamide
[0275] Example 37 was prepared from 2-(4-chlorophenyl)propanoic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.61 (d, 2H, J=6.5 Hz), 7.26 (s, 6H),
7.05-6.99 (m, 1H), 6.94 (d, 1H, J=7.1 Hz), 3.37-3.25 (m, 2H), 2.89
(d, 1H, J=9.6 Hz), 2.57-2.43 (m, 2H), 2.37 (t, 2H, J=6.1 Hz),
2.22-2.16 (m, 2H), 2.00-1.91 (m, 2H), 1.89-1.77 (m, 2H), 1.69-1.58
(m, 4H), 1.48 (d, 3H, J=7.0 Hz), 1.24 (d, 6H, J=7.0 Hz); ESMS m/e:
470.3 (M+H).sup.+.
EXAMPLE 38
[0276] ##STR86##
1-(2-chloro-4-fluorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidi-
nyl}propyl)cyclopentanecarboxamide
[0277] Example 38 was prepared from
1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.58(s, 1H), 7.52 (s, 1H), 7.45-7.36 (m,
1H), 7.34-7.29 (m, 1H), 7.23 (t, 1H, J=8.0 Hz), 7.17-7.13 (m, 1H),
6.95-6.90 (m, 2H), 6.00-5.94 (m, 1H), 3.30 (q, 2H, J=6.4 Hz),
2.92-2.84 (m, 2H), 2.57-2.38 (m, 3H), 2.47-2.39 (m, 1H), 2.31 (t,
1H, J=7.2 Hz), 1.95-1.73 (m, 7H), 1.68-1.48 (m, 8H), 1.24 (d, 6H,
J=7.2 Hz); ESMS m/e: 528.3 (M+H).sup.+.
EXAMPLE 39
[0278] ##STR87##
N-{3-[1-(3-{[(3,4-dichlorophenyl)(methoxy)acetyl]amino}propyl)-4-piperidin-
yl]phenyl}-2-methylpropanamide
[0279] Example 39 was prepared from (3,4-dichlorophenyl)
(methoxy)acetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamid- e
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.02-7.94 (m, 1H), 7.54 (d, 2H, J=10.1
Hz), 7.41 (d, 1H, J=8.5 Hz), 7.34-7.19 (m, 4H), 6.97 (d, 1H, J=7.0
Hz), 4.56 (s, 1H), 3.83 (s, 3H), 3.09-3.01 (m, 2H), 2.55-2.39 (m,
4H), 2.17 (s, 1H) 2.08-1.95 (m, 3H), 1.91-1.77 (m, 4H), 1.74-165
(m, 2H), 1.22 (d, 6H, J=6.6 Hz); ESMS m/e: 520.2 (M+H).sup.+.
EXAMPLE 40
[0280] ##STR88##
1-(4-fluorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)cyclohexanecarboxamide
[0281] Example 40 was prepared from
1-(4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.56 (s, 2H), 7.42-7.36 (m, 2H), 7.30-7.20
(m, 2H), 7.05-6.96 (m, 3H), 6.85-6.79 (m, 1H), 3.28 (q, 2H, J=6.3
Hz), 2.95-2.87 (m, 2H), 2.57-2.41 (m, 2H), 2.36-2.28 (m, 4H), 2.06
(s, 1H), 1.96-1.84 (m, 4H), 1.83-1.75 (m, 2H), 1.71-1.54 (m, 9H),
1.24 (d; 6H, J=7.1 Hz); ESMS m/e: 508.3 (M+H).sup.+.
EXAMPLE 41
[0282] ##STR89##
1-(2,4-dichlorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}p-
ropyl)cyclopropanecarboxamide
[0283] Example 41 was prepared from
1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.67 (s, 1H), 7.49 (s, 1H), 7.44 (d, 1H,
J=2.0 Hz), 7.35 (s, 1H), 7.28-7.19 (m, 3H), 6.92 (d, 1H, J=7.6 Hz),
5.69-5.62 (m, 1H), 3.26 (q, 2H, J=6.7 Hz), 2.89-2.82 (m, 2H), 2.54
(quintet, 1H, J=6.7 Hz), 2.47-2.37 (m, 1H), 2.32-2.26 (m, 3H),
1.97-1.88 (m, 2H), 1.79-1.69 (m, 4H), 1.66-1.56 (m, 4H), 1.24 (d,
6H, J=6.7 Hz), 1.05-1.01 (m, 1H); ESMS m/e: 516.2 (M+H).sup.+;
Anal. Calc. for C.sub.28H.sub.35Cl.sub.2N.sub.3O.sub.2.0.048
CHCl.sub.3: C, 64.51; H, 6.76; N, 8.05. Found: C, 64.51; H, 6.60;
N, 8.15.
EXAMPLE 42
[0284] ##STR90##
2-(4-fluorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)propylanamide
[0285] Example 42 was prepared from 2-(4-fluorophenyl)propanoic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.58 (s, 2H), 7.32-7.22 (m, 4H), 7.01-6.92
(m, 3H), 6.90-6.83 (m, 1H), 3.50 (q, 1H, J=7.1 Hz), 3.39-3.26 (m,
2H), 2.93-2.86 (m, 1H), 2.55-2.42 (m, 2H), 2.40-2.34 (m, 2H), 2.16
(s, 1H), 2.01-1.91 (m, 2H), 1.89-1.77 (m, 2H), 1.72-1.54 (m, 4H),
1.49 (d, 3H, J=7.0 Hz), 1.24 (d, 6H, J=7.0 Hz); ESMS m/e: 454.3
(M+H).sup.+; Anal. Calc. for C.sub.27H.sub.36FN.sub.3O.sub.2.1.1
CH.sub.3OH: C, 69.04,; H, 8.33; N, 8.60. Found: C, 69.06; H, 8.61;
N, 8.79.
EXAMPLE 43
[0286] ##STR91##
1-(4-chlorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)cyclobutanecarboxamide
[0287] Example 43 was prepared from
1-(4-chlorophenyl)cyclobutanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.56 (s, 1H), 7.41 (s, 1H), 7.34-7.21 (m,
6H), 6.93 (s, 1H), 6.48 (s, 1H), 3.31-3.24 (m, 2H), 2.94-2.86 (m,
2H), 2.86-2.76 (m, 2H), 2.57-2.37 (m, 4H), 2.33-2.26 (m, 2H),
2.12-2.02 (m, 1H), 1.97-1.87 (m, 3H), 1.82 (s, 1H), 1.79 (s, 1H),
1.70-1.56 (m, 4H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 496.3
(M+H).sup.+; Anal. Calc. for C.sub.29H.sub.38ClN.sub.3O.sub.2.0.550
CHCl.sub.3: C, 63.18; H, 6.92; N, 7.48. Found: C, 63.22; H, 6.90;
N, 7.48.
EXAMPLE 44
[0288] ##STR92##
1-(4-chlorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)cyclopropanecarboxamide
[0289] Example 44 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.47 (s, 1H), 7.40 (s, 1H), 7.36-7.30 (m,
5H), 7.27-7.20 (m, 1H), 6.93 (d, 1H, J=7.6 Hz), 5.70-5.63 (m, 1H),
3.24 (q, 2H, J=6.6 Hz), 2.84 (d, 2H, J=11.4 Hz), 2.52 (quintet, 1H,
J=7.2 Hz), 2.47-2.37 (m, 1H), 2.26 (t, 2H, J=7.2 Hz), 1.92 (t, 2H,
J=11.6 Hz), 1.75 (d, 2H, J=12.5 Hz), 1.65-1.53 (m, 6H), 1.25 (d,
6H, J=7.2 Hz), 1.00 (q, 2H, J=2.9 Hz); ESMS m/e: 482.3 (M+H).sup.+;
Anal. Calc. for C.sub.28H.sub.36ClN.sub.3O.sub.2.0.540
CH.sub.2Cl.sub.3: C, 64.93; H, 7.08; N, 7.96. Found: C, 65.00; H,
7.22; N, 7.81.
EXAMPLE 45
[0290] ##STR93##
1-(4-chlorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidinyl}propy-
l)cyclohexanecarboxamide
[0291] Example 45 was prepared from
1-(4-chlorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.57 (s, 1H), 7.52 (s,1H), 7.38-7.35 (m,
2H), 7.30-7.21 (m, 4H), 6.93 (d, 1H, J=7.2 Hz), 6.88-6.83 (m, 1H),
3.28 (q, 2H, J=5.6 Hz), 2.95-2.88 (m, 2H), 2.56-2.41 (m, 2H),
2.35-2.26 (m, 3H), 2.07 (s, 1H), 1.96-1.84 (m, 4H), 1.83-1.76 (m,
2H), 1.70-1.53 (m, 10H), 1.24 (d, 6H, J=7.1 Hz); ESMS m/e: 524.3
(M+H).sup.+.
EXAMPLE 46
[0292] ##STR94##
N-(3-{4-[4-fluoro-3-(isobutyrylamino)phenyl]-1-piperidinyl}propyl)-2-(4-fl-
uorophenyl)propylanamide
[0293] Example 46 was prepared from 2-(4-fluorophenyl)propanoic
acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.38-8.23 (m, 1H), 7.48-7.27 (m, 3H),
7.13-6.94 (m, 4H), 6.94-6.82 (m, 1H), 3.62-3.46 (m, 1H), 3.41-3.26
(m, 2H), 3.17-3.03 (m, 1H), 3.02-2.91 (m, 1H), 2.67-2.35 (m, 4H),
2.24-1.97 (m, 2H), 1.95-1.62 (m, 6H), 1.49 (d, 3H, J=7.2 Hz), 1.27
(d, 6H, J=6.8 Hz); ESMS m/e: 472.4 (M+H).sup.+.
EXAMPLE 47
[0294] ##STR95##
1-(4-chlorophenyl)-N-(3-{4-[4-fluoro-3-(isobutyrylamino)phenyl]-1-piperidi-
nyl}propyl)cyclopropanecarboxamide
[0295] Example 47 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.32-8.18 (m, 1H), 7.43-7.25 (m, 5H),
7.08-6.93 (m, 1H), 6.93-6.79 (br, 1H), 5.74-5.59 (br, 1H),
3.35-3.15 (m, 2H), 3.93-2.75 (m, 2H), 2.65-2.49 (m, 1H), 2.49-2.34
(m, 1H), 2.34-2.19 (m, 2H), 2.00-1.83 (m, 2H), 1.82-1.68 (m, 2H),
1.68-1.48 (m, 4H), 1.36-1.17 (m, 2H), 1.27 (d, 6H, J=6.8 Hz), 1.0
(s, 2H); ESMS m/e: 500.3 (M+H).sup.+; Anal. Calc. for (HCl salt)
C.sub.28H.sub.36Cl.sub.2FN.sub.3O.sub.2.0.45CHCl.sub.3: C, 57.85;
H, 6.22; N, 7.11. Found: C, 57.61; H, 6.37; N, 7.30.
EXAMPLE 48
[0296] ##STR96##
N-{5-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2-fluo-
rophenyl}-2-methylpropanamide
[0297] Example 48 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: ESMS m/e:
552.3 (M+H).sup.+.
EXAMPLE 49
[0298] ##STR97##
2-(4-chlorophenyl)-N-(3-{4-[4-fluoro-3-(isobutyrylamino)phenyl]-1-piperidi-
nyl}propyl)-2-methylpropanamide
[0299] Example 49 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylp-
ropanamide according to the procedures described in Scheme 9:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.34-8.20 (m, 1H),
7.46-7.14 (m, 5H), 7.10-6.95 (m, 1H), 6.92-6.77 (br, 1H), 6.74-6.59
(br, 1H), 3.39-3.25 (m, 2H), 3.00-2.82 (m, 2H), 2.67-2.51 (m, 1H),
2.51-2.40 (m, 1H), 2.40-2.27 (m, 2H), 2.03-1.86 (m, 2H), 1.85-1.71
(m, 2H), 1.71-1.57 (m, 4H), 1.56 (s, 6H), 1.27 (d, 6H, J=6.8 Hz);
ESMS m/e: 502.3 (M+H).sup.+.
EXAMPLE 50
[0300] ##STR98##
N-{6-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2-pyri-
dinyl}-2-methylpropanamide
[0301] Example 50 was prepared from bis(4-chlorophenyl)acetic acid
and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.06 (d, 1H, J=8.0 Hz), 7.96 (br s,
1H), 7.77 (s, 1H), 7.64 (t, 1H, J=8.4 Hz), 7.31-7.26 (m, 8H), 6.88
(dd, 1H, J=0.8, 7.6 Hz), 4.84 (s, 1H), 3.39 (dd, 2H, J=5.6, 11.6
Hz), 2.99 (d, 2H, J=11.6 Hz), 2.59 (m, 1H), 2.47 (t, 2H, J=6.0 Hz),
2.28 (m, 1H), 2.07-2.00 (m, 2H), 1.89 (dd, 2H, J=2.0, 12.4 Hz),
1.76-1.67 (m, 4H), 1.14 (d, 6H, J=6.8 Hz); ESMS m/e: 567.3
(M+H).sup.+.
EXAMPLE 51
[0302] ##STR99##
N-(3-{4-[4-fluoro-3-(isobutyrylamino)phenyl]-1-piperidinyl}propyl)-2,2-dip-
henylpropanamide
[0303] Example 51 was prepared from 2,2-diphenylpropanoic acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.27-8.13 (m, 1H), 8.04 (s, 1H), 7.62
(s, 1H), 7.50-7.39 (m, 1H), 7.39-7.16 (m, 7H), 7.12-6.90 (m, 2H),
6.79-6.60 (br, 1H), 4.94-4.61 (br, 1H), 3.60-3.22 (m, 4H),
2.89-2.76 (m, 2H), 2.76-2.55 (m, 4H), 2.55-2.34 (m, 3H), 2.14-1.82
(m, 3H), 2.00 (s, 3H), 1.26 (d, 6H, J=6.4 Hz) ; ESMS m/e: 530.4
(M+H).sup.+; Anal. Calc. for (HCl salt)
C.sub.33H.sub.41ClFN.sub.3O.sub.2.0.24CHCl.sub.3.0.96H.sub.2O: C,
65.23; H, 7.11; N, 6.86. Found: C, 64.96; H, 7.36; N. 6.87.
EXAMPLE 52
[0304] ##STR100##
N-{3-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-meth-
ylphenyl}-2-methylpropanamide
[0305] Example 52 was prepared from bis(4-chlorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.65 (s, 1H), 7.62 (d, 1H, J=2.4 Hz),
7.53 (t, 1H, J=4.8 Hz), 7.28-7.22 (m, 8H), 7.12 (dd, 1H, J=2.0, 8.4
Hz), 7.03 (d, 1H, J=8.0 Hz), 4.80 (s, 1H), 3.36 (dd, 2H, J=6.0,
11.6 Hz), 2.91 (d, 2H, J=14.0 Hz), 2.64 (m, 1H), 2.47 (m, 1H), 2.38
(t, 2H, J=5.6 Hz), 2.24 (s, 3H), 2.00-1.93 (m, 2H), 1.70-1.56 (m,
6H), 1.16 (d, 6H, J=7.2 Hz); ESMS m/e: 580.3 (M+H).sup.+.
EXAMPLE 53
[0306] ##STR101##
N-{3-[1-(3-{[2,2-bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nyl}butanamide
[0307] Example 53 was prepared from bis(4-chlorophenyl)acetic acid
and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.67 (s, 1H), 7.58 (s, 1H), 7.49 (br
s, 1H), 7.28-7.21 (m, 10H), 6.91 (m, 1H), 4.77 (s, 1H), 3.38 (dd,
2H, J=6.0, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.46 (m, 1H), 2.41
(t, 2H, J=6.0 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.96 (dt, 2H, J=1.6,
12.0 Hz); 1.82-1.66 (m, 6H), 1.58-1.54 (m, 2H), 0.98 (t, 3H, J=7.6
Hz); ESMS m/e: 566.3 (M+H).sup.+.
EXAMPLE 54
[0308] ##STR102##
N-{3-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluo-
rophenyl}-2-methylpropanamide
[0309] Example 54 was prepared from bis(4-chlorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.62-7.57 (m, 3H), 7.27 (s, 8H),
7.23-7.19 (m, 1H), 6.94 (dd, 1H, J=8.8, 10.0 Hz), 4.78 (s, 1H),
3.39 (dd, 2H, J=6.0, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.77 (m,
1H), 2.48 (m, 1H), 2.42 (t, 2H, J=6.0 Hz), 1.99 (dt, 2H, J=1.6,
11.6 Hz), 1.77 (d, 2H, J=11.2 Hz), 1.69-1.61 (m, 4H), 1.22 (d, 6H,
J=6.8 Hz); ESMS m/e: 584.2 (M+H).sup.+.
EXAMPLE 55
[0310] ##STR103##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2-bis(4-chlorophen-
yl)acetamide
[0311] Example 55 was prepared from bis(4-chlorophenyl)acetic acid
and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide
according procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.48 (s, 1H), 7.39 (br s, 1H), 7.31-7.22 (m,
11H), 6.94-6.92 (m, 1H), 4.76 (s, 1H), 3.39 (dd, 2H, J=6.4, 12.0
Hz), 2.97 (d, 2H, J=10.0 Hz), 2.49 (m, 1H), 2.44 (t, 2H, J=6.4 Hz),
2.17 (s, 3H), 2.05-1.99 (m, 2H), 1.83 (d, 2H, J=13.2 Hz), 1.71 (m,
2H), 1.61 (m, 2H); ESMS m/e: 538.3 (M+H).sup.+.
EXAMPLE 56
[0312] ##STR104##
N-[5-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-2-fluorophenyl]-2-
-methylpropanamide
[0313] Example 56 was prepared from diphenylacetyl chloride and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 8: .sup.1H NMR
(400 MHz, CD.sub.3OD,) .delta. 7.80-7.64 (m, 1H), 7.37-7.09 (m,
12H), 7.08-6.98 (m, 1H), 6.98-6.88 (br, 1H), 4.90 (s, 1H),
3.47-3.33 (m, 2H), 3.33-3.18 (m, 2H), 3.01-2.81 (m, 4H), 2.81-2.69
(m, 1H), 2.69-2.54 (m, 1H), 2.10-1.66 (m, 6H), 1.10 (d, 6H, J=6.4
Hz); ESMS m/e: 516.4 (M+H).sup.+. Anal. Calc. For (HCl salt)
C.sub.32H.sub.39ClFN.sub.3O.sub.2.0.16CHCl.sub.3: C, 67.68; H,
6.92; N, 7.36. Found: C, 67.43; H, 6.85; N, 7.17.
EXAMPLE 57
[0314] ##STR105##
N-{3-[1-(3-{[2,2-bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nyl}propanamide
[0315] Example 57 was prepared from bis(4-chlorophenyl)acetic acid
and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide
according to the procedures described in Scheme 10: ESMS m/e: 552.2
(M+H).sup.+.
EXAMPLE 58
[0316] ##STR106##
1-(4-chlorophenyl)-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl-
)cyclobutanecarboxamide
[0317] Example 58 was prepared from
1-(4-chlorophenyl)cyclobutanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: ESMS m/e: 482.3
(M+H).sup.+.
EXAMPLE 59
[0318] ##STR107##
2-methyl-N-[3-(1-{3-[(triphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]p-
ropanamide
[0319] Example 59 was prepared from triphenylacetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.40 (d, 2H, J=10.8 Hz), 7.32-7.17 (m,
17H), 6.87 (d, 1H, J=7.7 Hz), 6.32-6.26 (m, 1H), 3.41 (q, 2H, J=6.0
Hz), 2.83 (d, 2H, J=10.5 Hz), 2.48 (quintet, 1H, J=6.7 Hz),
2.43-2.33 (m, 1H), 2.26 (t, 2H, J=6.7 Hz), 1.89 (t, 2H, J=11.5 Hz),
1.73-1.62 (m, 4H), 1.56-1.44 (m, 2H), 1.22 (d, 6H, J=6.7 Hz); ESMS
m/e: 574.3 (M+H).sup.+; Anal. Calc. for
C.sub.38H.sub.43N.sub.3O.sub.2.0.730 CHCl.sub.3: C, 70.38; H, 6.67;
N, 6.36. Found: C, 70.42; H, 6.57; N, 6.47.
EXAMPLE 60
[0320] ##STR108##
1-(4-fluorophenyl)-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl-
)cyclopentanecarboxamide
[0321] Example 60 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: ESMS m/e: 480.4
(M+H).sup.+.
EXAMPLE 61
[0322] 101108 ##STR109##
1-(4-fluorophenyl)-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl-
)cyclohexanecarboxamide
[0323] Example 61 was prepared from
1-(4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: ESMS m/e: 494.4
(M+H).sup.+.
EXAMPLE 62
[0324] ##STR110##
1-(4-chlorophenyl)-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl-
)cyclopentanecarboxamide
[0325] Example 62 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: ESMS m/e: 496.4
(M+H).sup.+.
EXAMPLE 63
[0326] ##STR111##
1-(4-chlorophenyl)-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl-
) cyclopropanecarboxamide
[0327] Example 63 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according
to the procedures described in Scheme 10: ESMS m/e: 468.3
(M+H).sup.+.
EXAMPLE 64
[0328] ##STR112##
2-(4-fluorophenyl)-N-(3-{4-[3-(propionylamino)phenyl]-1-piperidinyl}propyl-
)propanamide
[0329] Example 64 was prepared from 2-(4-fluorophenyl)propanoic
acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide
according to the procedures described in Scheme 10: ESMS m/e: 440.4
(M+H).sup.+.
EXAMPLE 65
[0330] ##STR113##
N-[5-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-2-fluorophenyl]bu-
tanamide
[0331] Example 65 was prepared from diphenylacetyl chloride and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide
according to the procedures described in Scheme 8: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.33-8.18 (m, 1H), 7.49-7.10 (m, 12H),
7.10-6.93 (m, 1H), 6.90-6.76 (br, 1H), 4.87 (s, 1H), 3.44-3.28 (m,
2H), 3.06-2.89 (m, 2H), 2.56-2.40 (m, 3H), 2.40-2.31 (m, 2H),
2.13-1.93 m, 2H), 1.86-1.52 (m, 8H), 1.01 (t, 3H, J=7.6 Hz) ESMS
m/e: 516.6 (M+H).sup.+; Anal. Calc. For (HCl salt)
C.sub.32H.sub.39ClFN.sub.3O.sub.2.0.25CHCl.sub.3.1.00H.sub.2O: C,
64.49; H, 6.93; N, 6.99. Found: C, 64.23; H, 7.21; N, 6.99.
EXAMPLE 66
[0332] ##STR114##
1-(4-fluorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)cyclopentanecarboxamide
[0333] Example 66 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta. 8.06 (d, 1H, J=8.4 Hz), 7.79 (s, 1H),
7.64 (t, 1H, J=7.6Hz), 7.38-7.34 (m, 2H), 7.01-6.97 (m, 2H), 6.88
(d, 1H, J=7.2 Hz), 6.53 (br s, 1H), 3.27 (dd, 2H, J=6.0, 12.4 Hz),
2.94 (d, 2H, J=14.0 Hz), 2.54-2.48 (m, 4H), 2.32 (t, 2H, J=6.4 Hz),
1.99-1.60 (m, 14H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 495.3
(M+H).sup.+.
EXAMPLE 67
[0334] ##STR115##
1-(4-chlorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)cyclohexanecarboxamide
[0335] Example 67 was prepared from
1-(4-chlorophenyl)cyclohexanecarboxylic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.06 (d, 1H, J=8.4 Hz), 7.78 (br s,
1H), 7.65 (t, 1H, J=8.0 Hz), 7.40-7.38 (m, 2H), 7.30-7.27 (m, 2H),
6.88 (d, 2H, J=7.6 Hz), 3.29 (dd, 2H, J=6.0, 11.6 Hz), 2.96 (m,
2H), 2.56-2.49 (m, 2H), 2.36-2.30 (m, 4H), 2.00-1.75 (m, 8H),
1.64-1.59 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 525.3
(M+H).sup.+.
EXAMPLE 68
[0336] ##STR116##
1-(4-fluorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)cyclohexanecarboxamide
[0337] Example 68 was prepared from
1-(4-fluorophenyl)cyclohexanecarboxylic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.07 (d, 1H, J=8.0 Hz), 7.79 (br s,
1H), 7.66 (t, 1H, J=8.0 Hz), 7.45-7.41 (m, 2H), 7.04-7.00 (m, 2H),
6.89 (d, 1H, J=7.6 Hz), 6.85 (br s, 1H), 3.30 (dd, 2H, J=6.0, 12.0
Hz), 2.97 (d, 2H, J=11.6 Hz), 2.57-2.50 (m, 2H), 2.37-2.32 (m, 4H),
2.01-1.77 (m, 8H), 1.65-1.60 (m, 8H), 1.27 (d, 6H, J=7.2 Hz); ESMS
m/e: 509.3 (M+H).sup.+.
EXAMPLE 69
[0338] ##STR117##
N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)c-
yclopropanecarboxamide
[0339] Example 69 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.53 (s, 1H), 7.45 (s, 1H), 7.36-7.34 (m, 5H),
7.24 (t, 1H, J=8.0 Hz), 6.94 (d, 1H, J=7.6 Hz), 5.69 (br s, 1H),
3.25 (dd, 2H, J=6.8, 12.8 Hz), 2.87 (d, 2H, J=11.6 Hz), 2.44 (m,
1H), 2.35 (t, 2H, J=7.2 Hz), 2.29 (t, 2H, J=6.8 Hz), 1.95 (t, 2H,
J=11.2 Hz), 1.80-1.74 (m, 4H), 1.63-1.59 (m, 6H), 1.03-1.00 (m,
5H); ESMS m/e: 482.3 (M+H).sup.+.
EXAMPLE 70
[0340] ##STR118##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-1-(4-fluorophenyl)cy-
clohexanecarboxamide
[0341] Example 70 was prepared from
1-(4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.47 (m, 2H), 7.43-7.39 (m, 2H), 7.30-7.27 (m,
2H), 7.04-7.00 (m, 2H), 6.96 (d, 1H, J=7.2 Hz), 6.77 (br s, 1H),
3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.49 (m,
1H), 2.34 (t, 4H, J=6.4 Hz), 2.19 (s, 3H), 1.99-1.80 (m, 6H),
1.73-1.60 (m, 10H); ESMS m/e: 480.3 (M+H).sup.+.
EXAMPLE 71
[0342] ##STR119##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)cy-
clopropanecarboxamide
[0343] Example 71 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.51 (s, 1H), 7.39-7.34 (m, 6H), 7.26 (t, 1H,
J=7.2 Hz), 6.96 (d, 1H, J=7.6 Hz), 5.68 (br s, 1H), 3.26 (dd, 2H,
J=6.8, 12.8 Hz), 2.88 (d, 2H, J=13.2 Hz), 2.45 (m, 1H), 2.30 (t,
2H, J=7.2 Hz), 2.19 (s, 3H), 1.96 (t, 2H, J=11.6 Hz), 1.78 (d, 2H,
J=12.8 Hz), 1.65-1.58 (m, 6H), 1.02 (dd, 2H, J=3.6, 6.8 Hz); ESMS
m/e: 454.2 (M+H).sup.+.
EXAMPLE 72
[0344] ##STR120##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-1-(4-fluorophenyl)cy-
clopentanecarboxamide
[0345] Example 72 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.44 (s, 1H), 7.38-7.25 (m, 5H), 7.03-6.97 (m,
3H), 6.49 (br s, 1H), 3.29 (dd, 2H, J=5.6, 12.0 Hz), 2.98-2.94 (m,
2H), 2.55-2.49 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s, 3H),
2.01-1.95 (m, 4H), 1.86-.162 (m, 10H); ESMS m/e: 466.2
(M+H).sup.+.
EXAMPLE 73
[0346] ##STR121##
1-(4-chlorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)cyclobutanecarboxamide
[0347] Example 73 was prepared from
1-(4-chlorophenyl)cyclobutanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.07 (d, 1H, J=8.0 Hz), 7.78 (br s,
1H), 7.66 (t, 1H, J=7.6 Hz), 7.37-7.32 (m, 4H), 6.90 (d, 1H, J=7.6
Hz), 6.65 (br s, 1H), 3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.98 (d, 2H,
J=11.2 Hz), 2.88-2.81 (m, 2H) 2.58-2.43 (m, 4H), 2.36 (t, 2H, J=6.4
Hz), 2.10-1.96 (m, 4H), 1.92-1.78 (m, 4H), 1.64 (m, 2H), 1.25 (d,
6H, J=6.8 Hz); ESMS m/e: 497.2 (M+H).sup.+.
EXAMPLE 74
[0348] ##STR122##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)cy-
clobutanecarboxamide
[0349] Example 74 was prepared from
1-(4-chlorophenyl)cyclobutanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.55 (s, 1H), 7.36-7.26 (m, 7H), 6.97 (d, 1H,
J=7.2 Hz), 6.50 (br s, 1H), 3.30 (dd, 2H, J=6.0, 12.0 Hz),
2.98-2.95 (m, 2H), 2.87-2.80 (m, 2H), 2.53-2.42 (m, 3H), 2.34 (t,
2H, J=6.4 Hz), 2.20 (s, 3H), 2.15-1.82 (m, 6H), 1.74-0.161 (m, 4H);
ESMS m/e: 468.2 (M+H).sup.+.
EXAMPLE 75
[0350] ##STR123##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)cy-
clohexanecarboxamide
[0351] Example 75 was prepared from
1-(4-chlorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.47 (s, 1H), 7.44 (s, 1H), 7.40-7.37 (m, 2H),
7.32-7.25 (m, 4H), 6.96 (d, 1H, J=7.2 Hz), 6.81 (br s, 1H), 3.30
(dd, 2H, J=5.6, 11.6 Hz), 2.94 (d, 2H, J=12.4 Hz), 2.49 (m, 1H),
2.34 (t, 4H, J=6.4 Hz), 2.20 (s, 3H), 1.99-1.81 (m, 6H), 1.72-1.55
(m, 10H); ESMS m/e: 496.2 (M+H).sup.+.
EXAMPLE 76
[0352] ##STR124##
1-(4-chlorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)cyclopropanecarboxamide
[0353] Example 76 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.06 (d, 1H, J=8.0 Hz), 7.83 (s, 1H),
7.64 (t, 1H, J=7.6 Hz), 7.38-7.33 (m, 4H), 6.89 (d, 1H, J=7.6 Hz),
5.68 (br s, 1H), 3.26 (dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6
Hz), 2.58-2.52 (m, 2H), 2.31 (t, 2H, J=6.8 Hz), 1.99 (t, 2H, J=12.0
Hz), 1.85 (d, 2H, J=12.8 Hz), 1.70-1.59 (m, 6H), 1.28 (d, 6H, J=6.8
Hz), 1.01 (dd, 2H, J=3.6, 6.4 Hz); ESMS m/e: 483.3 (M+H).sup.+.
EXAMPLE 77
[0354] ##STR125##
N-{3-[1-(3-{[2-(4-chlorophenyl)propanoyl]amino}propyl)-4-piperidinyl]pheny-
l}butanamide
[0355] Example 77 was prepared from 2-(4-chlorophenyl)propanoic
acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.56 (s, 1H), 7.41 (s, 1H), 7.30-7.27
(m, 6H), 6.96 (m, 2H), 3.51 (q, 1H, J=7.2 Hz), 3.50-3.30 (m, 2H),
3.02 (d, 1H, J=10.8 Hz), 2.92 (d, 1H, J=13.6 Hz), 2.50 (m, 1H),
2.41-2.34 (m, 4H), 1.99-1.94 (m, 2H), 1.86-1.58 (m, 8H), 1.51 (d,
3H, J=7.2 Hz), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 470.3
(M+H).sup.+.
EXAMPLE 78
[0356] ##STR126##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)cy-
clopentanecarboxamide
[0357] Example 78 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.44 (s, 1H), 7.34-7.26 (m, 7H), 6.97 (d, 1H,
J=7.6 Hz), 6.54 (br s, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz), 2.95 (d,
2H, J=12.0 Hz), 2.54-2.48 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s,
3H), 2.00-1.95 (m, 4H), 1.84-1.60 (m, 10H); ESMS m/e: 482.2
(M+H).sup.+.
EXAMPLE 79
[0358] ##STR127##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2-(4-chlorophenyl)-2-
-methylpropanamide
[0359] Example 79 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.43 (s, 2H), 7.34-7.25 (m, 6H), 6.95 (d, 1H,
J=7.2 Hz), 6.65 (br s, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.92 (d,
2H, J=12.0 Hz), 2.45 (m, 1H), 2.36 (t, 2H, J=6.0 Hz), 2.20 (s, 3H),
1.94 (t, 2H, J=12.4 Hz), 1.78 (d, 2H, J=13.2 Hz), 1.65 (m, 2H),
1.57 (s, 6H), 1.55-1.46 (m, 2H); ESMS m/e: 456.2 (M+H).sup.+.
EXAMPLE 80
[0360] ##STR128##
N-{3-[1-(3-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}propyl)-4-piperidi-
nyl]phenyl}butanamide
[0361] Example 80 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 9: ESMS m/e: 484.3
(M+H).sup.+.
EXAMPLE 81
[0362] ##STR129##
1-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-metrylphenyl]-1-piperidi-
nyl}propyl)cyclopentanecarboxamide
[0363] Example 81 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.44 (d, 1H, J=2.0 Hz), 7.37-7.34 (m,
2H), 7.31-7.25 (m, 4H), 7.09 (d, 1H, J=8.0 Hz), 6.50 (br s, 1H),
3.29 (dd, 2H, J=6.4, 12.0 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.66 (m,
1H), 2.54-2.48 (m, 3H), 2.33-2.29 (m, 5H), 2.03-1.94 (m, 4H),
1.83-1.59 (m, 10H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 524.3
(M+H).sup.+.
EXAMPLE 82
[0364] ##STR130##
2-methyl-N-[6-(1-{3-[(triphenylacetyl)amino]propyl}-4-piperidinyl)-2-pyrid-
inyl]propanamide
[0365] Example 82 was prepared from triphenylacetic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.05 (d, 1H, J=8.0 Hz), 7.81 (s, 1H),
7.63 (t, 1H, J=7.6 Hz), 7.30-7.24 (m, 15H), 6.84 (d, 1H, J=7.2 Hz),
6.33 (br s, 1H), 3.44 (dd, 2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, J=11.6
Hz), 2.57-2.49 (m, 2H), 2.31 (t, 2H, J=6.8 Hz), 1.95 (t, 2H, J=12.0
Hz), 1.79-1.58 (m, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 575.3
(M+H).sup.+.
EXAMPLE 83
[0366] ##STR131##
N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl}propyl)-2,2-diphen-
ylpropanamide
[0367] Example 83 was prepared from 2,2-diphenylpropanoic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.05 (d, 1H, J=8.0 Hz), 7.80 (s, 1H),
7.63 (t, 1H, J=7.6 Hz), 7.35-7.24 (m, 10H), 6.85 (d, 1H, J=8.0 Hz),
6.26 (t, 1H, J=4.8 Hz), 3.38 (dd, 2H, J=6.4, 12.4 Hz), 2.92-2.89
(m, 2H), 2.55-2.48 (m, 2H), 2.32 (t, 2H, J=6.8 Hz), 2.00 (s, 3H),
1.96 (t, 2H, J=11.2 Hz), 1.79 (d, 2H, J=11.6 Hz), 1.72-1.61 (m,
4H), 1.27 (d, 6H, 6.8 Hz); ESMS m/e: 513.3 (M+H).sup.+.
EXAMPLE 84
[0368] ##STR132##
1-(4-chlorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)cyclopentanecarboxamide
[0369] Example 84 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.07 (d, 1H, J=8.4 Hz), 7.81 (s, 1H),
7.66 (t, 1H, J=7.6 Hz), 7.36-7.33 (m, 2H), 7.30-7.27 (m, 2H), 6.90
(d, 1H, J=6.8 Hz), 6.60 (br s, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz),
2.95 (d, 2H, J=11.6 Hz), 2.55-2.49 (m, 4H), 2.33 (t, 2H, J=6.4 Hz),
2.00-1.61 (m, 14H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 511.3
(M+H).sup.+.
EXAMPLE 85
[0370] ##STR133##
1-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidi-
nyl}propyl)cyclohexanecarboxamide
[0371] Example 85 was prepared from
1-(4-chlorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.46 (d, 1H, J=1.6 Hz), 7.42-7.39 (m,
2H), 7.31-7.21 (m, 4H), 7.08 (d, 1H, J=8.0 Hz), 6.78 (br s, 1H),
3.29 (dd, 2H, J=6.0, 12.0 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.65 (m,
1H), 2.50 (m, 1H), 2.34-2.30 (m, 4H), 2.28 (s, 3H), 2.00-1.88 (m,
4H), 1.74-1.59 (m, 12H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 538.3
(M+H).sup.+.
EXAMPLE 86
[0372] ##STR134##
1-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidi-
nyl}propyl)cyclobutanecarboxamide
[0373] Example 86 was prepared from
1-(4-chlorophenyl)cyclobutanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.46 (d, 1H, J=1.6 Hz), 7.34 (s, 4H),
7.28-7.23 (m, 2H), 7.10 (d, 1H, J=8.4 Hz), 6.45 (br s, 1H), 3.31
(dd, 2H, J=5.6, 11.6 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.88-2.81 (m,
2H), 2.68 (m, 1H), 2.54-2.44 (m, 3H), 2.33 (t, 2H, J=6.4 Hz), 2.29
(s, 3H), 2.11-1.90 (m, 4H), 1.76-1.63 (m, 6H), 1.26 (d, 6H, J=7.2
Hz) ESMS m/e: 510.3 (M+H).sup.+.
EXAMPLE 87
[0374] ##STR135##
N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-fluorophenyl)c-
yclohexanecarboxamide
[0375] Example 87 was prepared from
1-(4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.52 (s, 1H), 7.44 (s, 1H), 7.41-7.37 (m, 2H),
7.29-7.23 (m, 2H), 7.02-6.97 (m, 2H), 6.93 (d, 1H, J 6.8 Hz), 6.80
(br s, 1H), 3.29 (dd, 2H, J=5.6, 11.6 Hz), 2.92 (d, 2H, J=11.6 Hz),
2.46 (m, 1H), 2.36-2.30 (m, 6H), 1.96-1.30 (m, 18H), 1.01 (t, 3H,
J=7.6 Hz), ESMS m/e: 508.3 (M +H).sup.+.
EXAMPLE 88
[0376] ##STR136##
2-(4-chlorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)-2-methylpropanamide
[0377] Example 88 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylprop-
anamide according to the procedures described in Scheme 10: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d, 1H, J=8.4 Hz), 7.82 (s,
1H), 7.67 (t, 1H, J=7.6 Hz), 7.33-7.27 (m, 4H), 6.88 (d.sub.1H,
J=7.2 Hz), 6.57 (br s, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.94 (d,
2H, J=11.6 Hz), 2.58-2.53 (m, 2H), 2.37 (t, 2H, J=6.4 Hz), 1.97 (t,
2H, J=11.2 Hz), 1.87 (d, 2H, J=13.2 Hz), 1.67-1.58 (m, 4H), 1.57
(s, 6H), 1.28 (d, 6H, J=7.2 Hz); ESMS m/e: 485.3 (M+H).sup.+.
EXAMPLE 89
[0378] ##STR137##
1-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidi-
nyl}propyl)cyclopropanecarboxamide
[0379] Example 89 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.40-7.32 (m, 7H), 7.08 (d, 1H, J=8.4
Hz), 5.70 (br s, 1H), 3.27 (dd, 2H, J=6.4, 12.4 Hz), 2.88 (d, 2H,
J=11.6 Hz), 2.64 (m, 1H), 2.53 (m, 1H), 2.31 (t, 2H, J=6.8 Hz),
2.28 (s, 3H), 1.99 (dt, 2H, J=2.8, 11.2 Hz), 1.67-1.60 (m, 8H),
1.27 (d, 6H, J=6.8 Hz), 1.03 (dd, 2H, J=4.0, 6.8 Hz); ESMS m/e:
496.3 (M+H).sup.+.
EXAMPLE 90
[0380] ##STR138##
2-(4-chlorophenyl)-N-(3-{4-[6-(isobutyrylamino)-2-pyridinyl]-1-piperidinyl-
}propyl)propylanamide
[0381] Example 90 was prepared from 2-(4-chlorophenyl)propanoic
acid and
N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide
according procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.06 (d, 1H, J=8.0 Hz), 7.75 (s, 1H), 7.64 (t,
1H, J=7.6 Hz), 7.34-7.27 (m, 4H), 7.22 (br s, 1H), 6.89 (d, 1H,
J=7.6 Hz), 3.53 (q, 1H, J=7.2 Hz), 3.36 (m, 1H), 3.29 (m, 1H), 3.05
(d, 1H, J=11.6 Hz), 2.95 (d, 1H, J=10.4 Hz), 2.58 (m, 1H),
2.45-2.40 (m, 3H), 2.02-1.63 (m, 8H), 1.50 (d, 3H, J=7.2 Hz), 1.22
(dd, 6H, J=1.6, 6.8 Hz); ESMS m/e: 471.2 (M+H).sup.+.
EXAMPLE 91
[0382] ##STR139##
2-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidi-
nyl}propyl)-2-methylpropanamide
[0383] Example 91 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylp-
ropanamide according to the procedures described in Scheme 10:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.27 (m, 7H), 7.09
(d, 1H, J=8.0 Hz), 6.59 (br s, 1H), 3.34 (dd, 2H, J=6.4, 12.0 Hz),
2.93 (d, 2H, J=11.6 Hz), 2.64 (m, 1H), 2.54 (m, 1H), 2.37 (t, 2H,
J=6.4 Hz), 2.28 (s, 3H), 1.98 (t, 2H, J=12.4 Hz), 1.71-1.64 (m,
4H), 1.59 (s, 6H), 1.61-1.55 (m, 2H), 1.28 (d, 6H, J=6.8 Hz); ESMS
m/e: 498.3 (M+H).sup.+.
EXAMPLE 92
[0384] ##STR140##
1-(4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidi-
nyl}propyl)cyclohexanecarboxamide
[0385] Example 92 was prepared from
1-(4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.46-7.43 (m, 3H), 7.26-7.22 (m, 2H),
7.10 (d, 1H, J=8.4 Hz), 7.06-7.01 (m, 2H), 6.74 (br s, 1H), 3.31
(dd, 2H, J=6.0, 12.0 Hz), 2.96 (d, 2H, J=11.6 Hz), 2.68 (m, 1H),
2.52 (m, 1H), 2.36-2.32 (m, 4H), 2.29 (s, 3H), 2.03-1.90 (m, 4H),
1.74-1.61 (m, 12H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 522.3
(M+H).sup.+.
EXAMPLE 93
[0386] ##STR141##
1-(4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidi-
nyl}propyl)cyclopentanecarboxamide
[0387] Example 93 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.43-7.37 (m, 3H), 7.29-7.27 (m, 2H),
7.09 (d, 1H, J=8.4 Hz), 7.04-7.00 (m, 2H), 6.47 (br s, 1H), 3.29
(dd, 2H, J=5.6, 12.0 Hz), 2.94 (d, 2H, J=12.0 Hz), 2.66 (m, 1H),
2.54-2.48 (m, 3H), 2.33-2.30 (m, 2H), 2.29 (s, 3H), 2.03-1.95 (m,
4H), 1.84-1.60 (m, 10H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 508.3
(M+H).sup.+.
EXAMPLE 94
[0388] ##STR142##
2-methyl-N-[4-methyl-3-(1-{3-[(triphenylacetyl)amino]propyl}-4-piperidinyl-
)phenyl]propanamide
[0389] Example 94 was prepared from triphenylacetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.39 (dd, 1H, J=1.6, 8.0 Hz),
7.35-7.27 (m, 15H), 7.22-7.20 (m, 2H), 7.09 (d, 1H, J=8.0 Hz), 6.25
(br s, 1H), 3.45 (dd, 2H, J=6.8, 12.4 Hz), 2.90 (d, 2H, J=10.8 Hz),
2.63 (m, 1H), 2.52 (m, 1H), 2.33-2.29 (m, 2H), 2.28 (s, 3H), 1.97
(t, 2H, J=10.0 Hz), 1.72-1.57 (m, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS
m/e: 588.3 (M+H).sup.+.
EXAMPLE 95
[0390] ##STR143##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2-(4-chlorophenyl)pr-
opylanamide
[0391] Example 95 was prepared from 2-(4-chlorophenyl)propanoic
acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.48 (s, 1H), 7.36 (s, 1H), 7.31-7.25
(m, 6H), 6.98-6.93 (m, 2H), 3.51-3.48 (m, 1H), 3.35-3.31 (m, 2H),
3.03 (d, 1H, J=11.6 Hz), 2.93 (d, 1H, J=11.2 Hz), 2.50 (m, 1H),
2.42-2.38 (m, 2H), 2.19 (s, 3H), 2.05-1.96 (m, 2H), 1.90-1.80 (m,
2H), 1.70-1.59 (m, 4H), 1.51 (d, 3H, J=7.2 Hz); ESMS m/e: 442.2
(M+H).sup.+.
EXAMPLE 96
[0392] ##STR144##
N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)-2,2-dip-
henylpropanamide
[0393] Example 96 was prepared from 2,2-diphenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.37-7.23 (m, 13H), 7.08 (d, 1H,
J=8.8 Hz), 6.14 (t, 1H, J=5.6 Hz), 3.37 (dd, 2H, J=6.4, 12.0 Hz),
2.90 (d, 2H, J=11.6 Hz), 2.63 (m, 1H), 2.49 (m, 1H), 2.31 (t, 2H,
J=6.8 Hz), 2.27 (s, 3H), 2.02 (s, 3H), 1.99-1.94 (m, 2H), 1.71-1.59
(m, 6H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 526.3 (M+H).sup.+.
EXAMPLE 97
[0394] ##STR145##
N-[3-(1-{3-[(2,2,2-triphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]buta-
namide
[0395] Example 97 was prepared from triphenylacetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.39 (d, 2H, J=10.4 Hz), 7.34-7.21 (m, 17H),
6.90 (d, 1H, J=7.6 Hz), 6.31 (t, 1H, J=5.2 Hz), 3.43 (dd, 2H,
J=6.4, 12.4 Hz), 2.87 (d, 2H, J=12.0 Hz), 2.41 (m, 1H), 2.31 (m,
4H), 1.92 (t, 2H, J=11.6 Hz), 1.79-1.66 (m, 6H), 1.59-1.52 (m, 2H),
1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 574.4 (M+H).sup.+.
EXAMPLE 98
[0396] ##STR146##
N-[3-(1-{3-[(2,2-diphenylpropanoyl)amino]propyl}-4-piperidinyl)phenyl]buta-
namide
[0397] Example 98 was prepared from 2,2-diphenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.43 (s, 1H), 7.37-7.22 (m, 13H), 6.91 (d, 1H,
J=7.2 Hz), 6.24 (br s, 1H), 3.37 (dd, 2H, J=5.6, 11.6 Hz), 2.88 (d,
2H, J=11.6 Hz), 2.42 (m, 1H), 2.32 (m, 4H), 2.01 (s, 3H), 1.93 (t,
2H, J=11.6 Hz), 1.81-1.52 (m, 8H), 1.01 (t, 3H, J=6.8 Hz); ESMS
m/e: 512.3 (M+H).sup.+.
EXAMPLE 99
[0398] ##STR147##
N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)c-
yclohexanecarboxamide
[0399] Example 99 was prepared from
1-(4-chlorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.59 (s, 1H), 7.52 (s, 1H), 7.38-7.35 (m, 2H),
7.30-7.22 (m, 4H), 6.93 (d, 1H, J=7.6 Hz), 6.87 (br s, 1H), 3.28
(dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.45 (m, 1H),
2.36-2.30 (m, 6H), 1.96-1.33 (m, 18H), 1.00 (t, 3H, J=7.6 Hz); ESMS
m/e: 524.3 (M+H).sup.+.
EXAMPLE 100
[0400] ##STR148##
2-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidi-
nyl}propyl)propanamide
[0401] Example 100 was prepared from 2-(4-chlorophenyl)propanoic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.56 (d, 1H, J=2.0 Hz), 7.34-7.28 (m,
5H), 7.21 (dd, 1H, J=2.0. 8.0 Hz), 7.09 (d, 1H, J=8.0 Hz), 6.98 (br
s, 1H), 3.55 (q, 1H, J=7.2 Hz), 3.34 (m, 2H), 3.02 (d, 1H, J=11.6
Hz), 2.93 (d, 1H, J=11.6 Hz), 2.68 (m, 1H), 2.51 (m, 1H), 2.39 (dt,
2H, J=6.8, 2.0 Hz), 2.29 (s, 3H), 2.04-1.97 (m, 2H), 1.80-1.60 (m,
6H), 1.52 (d, 3H, J=7.2 Hz), 1.24 (dd, 6H, J=1.6, 6.8 Hz); ESMS
m/e: 484.3 (M+H).sup.+.
EXAMPLE 101
[0402] ##STR149##
N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-fluorophenyl)c-
yclopentanecarboxamide
[0403] Example 101 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.51 (s, 1H), 7.37-7.24 (m, 6H), 7.02-6.95 (m,
2H), 6.51 (br s, 1H), 3.28 (dd, 2H, J=5.6, 11.6 Hz), 2.93 (d, 2H,
J=11.6 Hz), 2.53-2.48 (m, 3H), 2.37-2.30 (m, 4H), 1.98-1.92 (m,
4H), 1.82-1.59 (m, 12H), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 494.3
(M+H).sup.+.
EXAMPLE 102
[0404] ##STR150##
N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)c-
yclopentanecarboxamide
[0405] Example 102 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.51 (s, 1H), 7.42 (s, 1H), 7.34-7.24 (m, 6H),
6.95 (d, 1H, J=7.6 Hz), 6.57 (br s, 1H), 3.28 (dd, 2H, J=5.6, 11.6
Hz), 2.92 (d, 2H, J=12.0 Hz), 2.53-2.43 (m, 3H), 2.37-2.29 (m, 4H),
1.99-1.91 (m, 4H), 1.83-1.58 (m, 12H), 1.02 (t, 3H, J=7.6 Hz); ESMS
m/e: 510.3 (M+H).sup.+.
EXAMPLE 103
[0406] ##STR151##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2-diphenylpropanam-
ide
[0407] Example 103 was prepared from 2,2-diphenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.37-7.23 (m, 14H), 6.93 (d, 1H, J=7.6 Hz),
6.20 (br s, 1H), 3.37 (dd, 2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, 7.2
Hz), 2.45 (m, 1H), 2.30 (m, 2H), 2.18 (s, 3H), 2.01 (s, 3H), 1.94
(t, 2H, J=11.6 Hz), 1.76-1.53 (m, 6H); ESMS m/e: 484.2
(M+H).sup.+.
EXAMPLE 104
[0408] ##STR152##
N-{5-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2-fluo-
rophenyl}butanamide
[0409] Example 104 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.33-8.14 (m, 1H), 7.89-7.67 (br,
1H), 7.51-6.60 (m, 10H), 4.98-4.79 (br, 1H), 4.75 (s, 1H),
3.46-3.29 (m, 2H), 3.29-3.08 (m, 2H), 2.79-2.63 (m, 2H), 2.63-2.46
(m, 1H), 2.46-2.21 (m, 4H), 1.97-1.60 (m, 8H), 1.01 (t, 3H, J=7.2
Hz); ESMS m/e: 552.3 (M+H).sup.+.
EXAMPLE 105
[0410] ##STR153##
N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2,2-triphenylaceta-
mide
[0411] Example 105 was prepared from triphenylacetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to
the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.34-7.22 (m, 19H), 6.91 (d, 1H, J=7.6 Hz),
6.30 (t, 1H, J=5.6 Hz), 3.43 (dd, 2H, J=6.4, 12.0 Hz), 2.87 (d, 2H,
J=12.0 Hz), 2.42 (m, 1H), 2.30 (t, 2H, J=6.8 Hz), 2.17 (s, 3H) 1.93
(t, 2H, J=11.6 Hz), 1.74-1.66 (m, 4H), 1.60-1.50 (m, 2H); ESMS m/e:
546.2 (M+H).sup.+.
EXAMPLE 106
[0412] ##STR154##
N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)c-
yclobutanecarboxamide
[0413] Example 106 was prepared from
1-(4-chlorophenyl)cyclobutanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according
to the procedures described in Scheme 10: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.53 (s, 2H), 7.32-7.23 (m, 6H), 6.95 (d, 1H,
J=7.6 Hz), 6.53 (br s, 1H), 3.29 (dd, 2H, J=6.0, 12.4 Hz), 2.93 (d,
2H, J=10.8 Hz), 2.86-2.79 (m, 2H), 2.48-2.41 (m, 3H), 2.37-2.30 (m,
4H), 2.07 (m, 1H), 1.98-1.61 (m, 11H), 1.01 (t, 3H, J=7.6 Hz); ESMS
m/e: 496.3 (M +H).sup.+.
EXAMPLE 107
[0414] ##STR155##
N-(3-{4-[3-(butyrylamino)-4-fluorophenyl]-1-piperidinyl}propyl)-1-(4-fluor-
ophenyl)cyclopentanecarboxamide
[0415] Example 107 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.30-8.13 (m, 1H), 8.09-7.95 (br,
1H), 7.47-7.26 (m, 3H), 7.08-6.87 (m, 3H), 6.75-6.54 (br, 1H),
3.30-3.07 (m, 4H), 2.59-2.44 (m, 3H), 2.44-2.33 (m, 2H), 2.33-2.19
(m, 2H), 1.99-1.69 (m, 16H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e:
512.3 (M+H).sup.+.
EXAMPLE 108
[0416] ##STR156##
N-{5-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2-fluo-
rophenyl}butanamide
[0417] Example 108 was prepared from bis(4-chlorophenyl)acetic acid
and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide
according to the procedures described in Scheme 10: ESMS m/e: 584.2
(M+H).sup.+.
EXAMPLE 109
[0418] ##STR157##
N-{5-[1-(3-{[bis(4-methylphenyl)acetyl]amino}propyl)-4-piperidinyl]-2-fluo-
rophenyl}butanamide
[0419] Example 109 was prepared from bis(4-methylphenyl)acetic acid
and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.30-8.13 (m, 1H), 8.08-7.92 (br,
1H), 7.43-6.89 (m, 9H), 6.76-6.61 (br, 1H), 4.98-4.79 (br, 1H),
4.70 (s, 1H), 3.39-3.16 (m, 4H), 2.83-2.63 (m, 2H), 2.63-2.47 (m,
1H), 2.45-2.12 (m, 4H), 2.27 (s, 6H), 2.02-1.64 (m, 8H), 1.02 (t,
3H, J=7.2 Hz); ESMS m/e: 544.4 (M+H).sup.+.
EXAMPLE 110
[0420] ##STR158##
N-{5-[1-(3-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}propyl)-4-piperidi-
nyl]-2-fluorophenyl}butanamide
[0421] Example 110 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.31-8.12 (m, 1H), 7.44-7.15 (m, 5H),
7.12-6.94 (m, 1H), 6.75-6.61 (br, 1H), 6.61-6.46 (br, 1H),
3.35-3.12 (m, 4H), 2.70-2.47 (m, 3H), 2.46-2.35 (m, 2H), 2.35-2.21
(m, 2H), 1.92-1.67 (m, 8H), 1.54 (s, 6H), 1.02 (t, 3H, J=7.2 Hz);
ESMS m/e: 502.3 (M+H).sup.+.
EXAMPLE 111
[0422] ##STR159##
N-{3-[1-(3-{[2,2-bis(4-methylphenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nyl}cyclopropanecarboxamide
[0423] Example 111 was prepared from bis(4-methylphenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.24-8.04 (br, 1H), 8.04-7.95 (br,
1H), 7.59-6.92 (m, 10H), 6.90-6.76 (m, 1H), 4.98-4.82 (br, 1H),
4.72 (s, 1H), 3.42-3.25 (m, 2H), 3.25-3.08 (m, 2H), 2.75-2.56 (m,
2H), 2.56-2.40 (m, 1H), 2.35-2.17 (m, 2H), 2.26 (s, 6H), 1.99-1.68
(m, 6H), 1.57-1.44 (m, 1H), 1.12-0.99 (m, 2H), 0.87-0.70 (m, 2H);
ESMS m/e: 524.3 (M+H).sup.+; Anal. Calc. for (HCl salt)
C.sub.34H.sub.42ClF.sub.2N.sub.3O.sub.2.0.29CHCl.sub.3: C, 69.23;
H, 7.16; N, 7.06. Found: C, 68.96; H, 7.35; N, 7.31.
EXAMPLE 112
[0424] ##STR160##
1-(4-chlorophenyl)-N-[3-(4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperi-
dinyl)propyl]cyclopentanecarboxamide
[0425] Example 112 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.03-7.87 (br, 1H), 7.56-7.02 (m,
8H), 6.91-6.65 (br, 1H), 3.30-3.05 (m, 4H), 2.62-2.38 (m, 3H),
2.38-2.21 (m, 2H), 1.98-1.51 (m, 15H), 1.14-1.01 (m, 2H), 0.93-0.70
(m, 2H) ESMS m/e: 508.2 (M+H).sup.+.
EXAMPLE 113
[0426] ##STR161##
N-{3-[1-(3-{[2,2-bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nyl}cyclopropanecarboxamide
[0427] Example 113 was prepared from bis(4-chlorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.84-7.80 (br, 1H), 7.80-7.69 (br,
1H), 7.64-7.46 (br, 1H), 7.40-6.90 (m, 9H), 6.85-6.66 (m, 1H),
4.94-4.74 (br, 1H), 4.69 (s, 1H), 3.41-3.25 (m, 2H), 3.25-3.07 (m,
2H), 2.77-2.61 (m, 2H), 2.61-2.45 (m, 1H), 2.45-2.17 (m, 2H),
1.99-1.63 (m, 6H), 1.61-1.39 (m, 1H), 1.14-0.94 (m, 2H), 0.92-0.70
(m, 2H); ESMS m/e: 564.2 (M+H).sup.+.
EXAMPLE 114
[0428] ##STR162##
N-[3-(1-{3-[(2,2,2-triphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]cycl-
opropanecarboxamide
[0429] Example 114 was prepared from triphenylacetic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: ESMS m/e: 572.3
(M+H).sup.+.
EXAMPLE 115
[0430] ##STR163##
N-{3-[1-(3-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}propyl)-4-piperidi-
nyl]phenyl}cyclopropanecarboxamide
[0431] Example 115 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxa-
mide according to the procedures described in Scheme 10: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.94-7.81 (br, 1H), 7.53-7.40
(br, 1H), 7.39-7.15 (m, 6H), 6.82 (d, 1H, J=7.2 Hz), 6.68-6.49 (br,
1H), 3.33-3.19 (m, 2H), 3.19-3.06 (m, 2H), 2.63-2.39 (m, 3H),
2.31-2.09 (m, 2H), 1.89-1.62 (m, 7H), 1.54 (s, 6H), 1.13-0.98 (m,
2H) 0.90-0.72 (m, 2H); ESMS m/e: 482.2 (M+H).sup.+.
EXAMPLE 116
[0432] ##STR164##
N-{3-[1-(3-{[2-(4-chlorophenyl)propanoyl]amino}propyl)-4-piperidinyl]pheny-
l}cyclopropanecarboxamide
[0433] Example 116 was prepared from 2-(4-chlorophenyl)propanoic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.15-7.95 (br, 1H), 7.63-7.44 (br, 1H),
7.39-7.12 (m, 7H), 6.85 (d, 1H, J=6.8 Hz), 3.74-3.55 (m, 1H),
3.45-3.22 (m, 2H), 3.22-3.12 (m, 1H), 3.12-3.00 (m, 1H), 2.66-2.40
(m, 3H), 2.29-2.09 (m, 2H), 1.92-1.63 (m, 6H), 1.64-1.51 (m, 1H),
1.47 (d, 3H, J=6.8 Hz), 1.18-0.98 (m, 2H), 0.91-0.74 (m, 2H); ESMS
m/e: 468.2 (M+H).sup.+; Anal. Calc. for (HCl salt)
C.sub.27H.sub.35Cl.sub.2N.sub.3O.sub.2.0.28CHCl.sub.3: C, 60.91; H,
6.61; N, 7.81; Found: C, 60.66; H, 6.90; N, 8.19.
EXAMPLE 117
[0434] ##STR165##
N-[3-(4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperidinyl)propyl]-1-(2,-
4-dichlorophenyl)cyclopropanecarboxamide
[0435] Example 117 was prepared from
1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.00-7.82 (br, 1H), 7.52-7.04 (m,
6H), 6.86 (d, 1H, J=7.2 Hz), 5.92-5.73 (br, 1H), 3.35-3.12 (m, 4H),
2.74-2.58 (m, 2H), 2.58-2.42 (m, 1H), 2.40-2.20 (m, 2H), 2.01-1.61
(m, 7H), 1.15-0.90 (m, 6H), 0.89-0.71 (m, 2H); ESMS m/e: 514.2
(M+H).sup.+.
EXAMPLE 118
[0436] ##STR166##
1-(4-chlorophenyl)-N-[3-(4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperi-
dinyl)propyl]cyclopropanecarboxamide
[0437] Example 118 was prepared from
1-(4-chlorophenyl)cyclopropanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.12-7.88 (br, 1H), 7.48-7.14 (m,
7H), 6.85 (d, 1H, J=7.2 Hz), 5.83-5.66 (br, 1H), 3.29-3.09 (m, 4H),
2.66-2.53 (m, 2H), 2.53-2.40 (m, 1H), 2.37-2.17 (m, 2H), 1.95-1.53
(m, 7H), 1.14-0.91 (m, 6H), 0.89-0.71 (m, 2H); ESMS m/e: 480.2
(M+H).sup.+; Anal. Calc. (HCl salt)
C.sub.28H.sub.35Cl.sub.2N.sub.3O.sub.2.0.38CHCl.sub.3: C, 60.64; H,
6.34; N, 7.47. Found: C, 60.38; H, 6.57; N, 7.80.
EXAMPLE 119
[0438] ##STR167##
1-(2-chloro-4-fluorophenyl)-N-[3-(4-{3-[(cyclopropylcarbonyl)amino]phenyl}-
-1-piperidinyl)propyl]cyclopentanecarboxamide
[0439] Example 119 was prepared from
1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: ESMS m/e: 526.2
(M+H).sup.+.
EXAMPLE 120
[0440] ##STR168##
N-{3-[1-(3-{[2,2-bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nyl}cyclopropanecarboxamide
[0441] Example 120 was prepared from bis(4-fluorophenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.64-7.55 (s, 1H), 7.55-7.47 (s, 1H),
7.47-7.37 (br, 1H), 7.36-7.17 (m, 6H), 7.05-6.95 (m, 4H), 6.95-6.87
(br, 1H), 4.81 (s, 1H), 3.47-3.35 (m, 2H), 3.07-2.94 (m, 2H),
2.58-2.41 (m, 3H), 2.15-1.99 (m, 2H), 1.90-1.79 (m, 2H), 1.79-1.60
(m, 4H), 1.59-1.44 (m, 1H), 1.13-0.99 (m, 2H), 0.90-0.75 (m, 2H);
ESMS m/e: 532.2 (M+H).sup.+.
EXAMPLE 121
[0442] ##STR169##
N-[3-(4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperidinyl)propyl]-1-(4--
fluorophenyl)cyclopentanecarboxamide
[0443] Example 121 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.94-7.72 (br, 1H), 7.48-6.84 (m,
7H), 6.75 (d, 1H, J=7.2 Hz), 6.68-6.55 (br, 1H), 3.25-3.05 (m, 4H),
2.58-2.39 (m, 3H), 2.33-2.15 (m, 2H), 2.00-1.48 (m, 15H), 1.13-1.01
(m, 2H), 0.93-0.73 (m, 2H); ESMS m/e: 492.3 (M+H).sup.+.
EXAMPLE 122
[0444] ##STR170##
N-[3-(1-{3-[(2,2-diphenylbutanoyl)amino]propyl}-4-piperidinyl)phenyl]cyclo-
propanecarboxamide
[0445] Example 122 was prepared from 2,2-diphenylbutanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.89-7.74 (br, 1H), 7.48-7.05 (m,
13H), 6.89-6.74 (d, 1H, J=7.2 Hz), 6.46-6.25 (br, 1H), 3.30-3.15
(m, 2H), 3.15-3.01 (m, 2H), 2.38-2.25 (m, 3H), 2.25-2.09 (m, 2H),
1.99-1.78 (m, 3H), 1.78-1.60 (m, 5H), 1.60-1.47 (m, 1H), 1.12-1.01
(m, 2H), 0.90-0.71 (m, 2H), 0.75 (t, 3H, J=7.2 Hz); ESMS m/e: 524.3
(M+H).sup.+.
EXAMPLE 123
[0446] ##STR171##
N-[3-(1-{3-[(2,2-diphenylpropanoyl)amino]propyl}-4-piperidinyl)phenyl]cycl-
opropanecarboxamide
[0447] Example 123 was prepared from 2,2-diphenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 10: ESMS m/e: 510.3
(M+H).sup.+.
EXAMPLE 124
[0448] ##STR172##
N-{3-[1-(3-{[difluoro(phenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylp-
henyl}-2-methylpropanamide
[0449] Example 124 was prepared from 2,2-difluoro-2-phenylacetic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.00 (s, 2H), 7.68-7.63 (m, 3H),
7.49-7.39 (m, 3H), 7.23 (d, 1H, J=1.8 Hz), 7.07 (d, 1H, J=8.3 Hz),
3.45 (q, 2H, J=4.9 Hz), 3.11 (d, 2H, J=10.2 Hz), 2.76-2.66 (m, 1H),
2.56 (t, 2H, J=5.0 Hz), 2.44 (septet, 1H, J=6.9 Hz), 2.28 (s, 3H),
2.13-2.05 (m, 2H), 1.82-1.71 (m, 6H), 1.15 (d, 6H, J=6.9 Hz); ESMS
m/e: 472.4 (M+H).sup.+.
EXAMPLE 125
[0450] ##STR173##
N-{3-[1-(3-{[difluoro(phenyl)acetyl]amino}propyl)-4-piperidinyl]phenyl}-2--
methylpropanamide
[0451] Example 125 was prepared from 2,2-difluoro-2-phenylacetic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 10: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.01 (s, 1H), 7.71 (s, 1H), 7.65-7.62
(m, 2H), 7.50 (s, 1H), 7.47-7.40 (m, 3H), 7.35 (d, 1H, J=7.6 Hz),
7.22 (t, 1H, J=7.2 Hz), 6.95 (d, 1H, J=7.8 Hz), 3.45 (q, 2H, J=5.3
Hz), 3.10 (d, 2H, J=10.9 Hz), 2.59-2.45 (m, 4H), 2.11-2.02 (m, 2H),
1.89-1.71 (m, 6H), 1.20 (d, 6H, J=6.9 Hz); ESMS m/e: 458.4
(M+H).sup.+.
EXAMPLE 126
[0452] ##STR174##
N-[3-(1-{3-[(diphenylacetyl)(ethyl)amino]propyl}-4-piperidinyl)phenyl]-2-m-
ethylpropanamide
[0453] Example 126 was prepared from diphenylacetyl chloride and
N-(3-{1-[3-(ethylamino)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide
according to the procedures described in Scheme 8: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.33-7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s,
1H), 3.39 (m, 4H), 2.93 (d, 2H, J=10.9 Hz), 2.52-2.36 (m, 7H), 1.97
(t, 2H, J=10.9 Hz), 1.83-1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); ESMS
m/e: 526.4 (M+H).sup.+.
EXAMPLE 127
[0454] ##STR175##
2-(4-chlorophenyl)-N-(3-{4-[2-fluoro-5-(isobutyrylamino)phenyl]-1-piperidi-
nyl}propyl)-2-methylpropanamide
[0455] Example 127 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylp-
ropanamide according to the procedures described in Scheme 9:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95 (s, 1H), 7.73 (s,
1H), 7.68 (s, 1H), 7.43-7.38 (m, 1H), 7.37-7.26 (m, 3H) 6.93-6.83
(m, 2H), 3.96-3.61 (m, 1H), 3.26-3.02 (m, 4H), 2.69-2.59 (m, 1H),
2.51-2.40 (m, 2H), 1.90-1.71 (m, 4H), 1.63-1.47 (m, 4H), 1.18 (d,
6H, J=6.9 Hz), 1.15 (s, 6 H); ESMS m/e: 502.1 (M+H).sup.+.
EXAMPLE 128
[0456] ##STR176##
1-(4-chlorophenyl)-N-(3-{4-[2-fluoro-5-(isobutyrylamino)phenyl]-1-piperidi-
nyl}propyl)cyclopentanecarboxamide
[0457] Example 128 was prepared from
1-(4-chlorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.45 (s, 1H), 7.42-7.38 (m, 1H),
7.27-7.17 (m, 4H), 7.12-7.09 (m, 1H), 6.87 (t, 1H, J 8.6 Hz), 6.49
(t, 1H, J=5.4 Hz), 3.19 (q, 2H, J=5.8 Hz), 2.85-2.79 (m, 2H),
2.73-2.64 (m, 1H), 2.50-2.35 (m, 3H), 2.23 (t, 2H, J=6.6 Hz),
1.92-1.85 (m, 4H), 1.75-1.48 (m, 10H), 1.17 (d, 6H, J=6.7 Hz) ;
ESMS m/e: 528.2 (M+H).sup.+.
EXAMPLE 129
[0458] ##STR177##
N-(3-{4-[2-fluoro-5-(isobutyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-fl-
uorophenyl)cyclopentanecarboxamide
[0459] Example 129 was prepared from
1-(4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.53 (s, 1H), 7.42-7.38 (m, 1H),
7.31-7.20 (m, 2H), 6.94-6.83 (m, 4H), 6.46-6.40 (m, 1H), 3.19 (q,
2H, J=5.6 Hz), 2.85-2.79 (m, 2H), 2.73-2.64 (m, 1H), 2.49-2.38 (m,
3H), 2.22 (t, 2H, J=6.4 Hz), 1.94-1.84 (m, 5H), 1.75-1.47 (m, 9H),
1.17 (d, 6H, J=6.8 Hz); ESMS m/e: 512.3 (M+H).sup.+.
EXAMPLE 130
[0460] ##STR178##
1-(4-chlorophenyl)-N-(3-{4-[2-fluoro-5-(isobutyrylamino)phenyl]-1-piperidi-
nyl}propyl)cyclohexanecarboxamide
[0461] Example 130 was prepared from 1-(4-chlorophenyl)
cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.45-7.40 (m, 1H), 7.34-7.29 (m, 3H),
7.24-7.16 (m, 3H), 6.88 (t, 1H, J=8.7 Hz), 6.77-6.72 (m, 1H), 3.21
(q, 2H, J=5.6 Hz), 2.87-2.81 (m, 2H), 2.74-2.65 (m, 1H), 2.44
(septet, 1H, J=6.7 Hz), 2.28-2.21 (m, 4H), 1.92-1.76 (m, 4H),
1.69-1.69 (m, 4H), 1.56-1.47 (m, 8H), 1.18 (d, 6H, J=6.7 Hz); ESMS
m/e: 542.2 (M+H).sup.+; Anal. Calc. for
C.sub.31H.sub.41ClFN.sub.3O.sub.2 .HCl.0.20 CHCl.sub.3: C, 62.20;
H, 7.06; N, 6.97. Found: C, 62.24; H, 7.03; N, 6.79.
EXAMPLE 131
[0462] ##STR179##
N-(3-{4-[2-fluoro-5-(isobutyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-fl-
uorophenyl)cyclohexanecarboxamide
[0463] Example 131 was prepared from
1-(4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.49 (s, 1H), 7.43 (dd, 1H, J=6.9,
2.5 Hz), 7.36-7.31 (m, 2H), 7.23-7.17 (m, 1H), 6.93 (t, 2H, J=8.4
Hz), 6.87 (t, 1H, J=8.9 Hz), 6.73-6.68 (m, 1H), 3.21 (q, 2H, J=5.7
Hz), 2.87-2.80 (m, 2H), 2.73-2.65 (m, 1H), 2.45 (septet, 1H, J=6.7
Hz), 2.30-2.21 (m, 4H), 1.9-1.77 (m, 5H), 1.70-1.63 (m, 3H),
1.56-1.45 (m, 8H), 1.17 (d, 6H, J=6.7 Hz); ESMS m/e: 526.3
(M+H).sup.+.
EXAMPLE 132
[0464] ##STR180##
N-{3-[1-(3-{[bis(4-methylphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluo-
rophenyl}-2-methylpropanamide
[0465] Example 132 was prepared from bis(4-methylphenyl)acetic acid
and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.72 (s, 1H), 7.36-7.31 (m, 1H),
7.28-7.21 (m, 1H), 7.12-7.07 (m, 3H), 7.03-6.99 (m, 5H), 6.86-6.80
(m, 1H), 6.79-6.75 (m, 1H), 4.74 (s, 1H), 3.33-3.25 (m, 2H),
2.85-2.77 (m, 2H), 2.72-2.62 (m, 1H), 2.40 (septet, 1H, J=6.7 Hz),
2.28 (t, 2H, J=6.6 Hz), 2.21 (m, 6H), 1.94-1.84 (m, 2H), 1.65-1.52
(m, 6H), 1.71 (d, 6H, J=6.6 Hz); ESMS m/e: 544.3 (M+H).sup.+; Anal.
Calc. for C.sub.34H.sub.42FN.sub.3O.sub.2 .HCl.0.10 CHCl.sub.3: C,
70.17; H, 7.35; N, 7.10. Found: C, 70.35; H, 6.99; N, 7.10.
EXAMPLE 133
[0466] ##STR181##
1-(2-chloro-{4-fluorophenyl)-N-(3-}4-[2-fluoro-5-(isobutyrylamino)phenyl]--
1-piperidinyl}propyl)cyclohexanecarboxamide
[0467] Example 133 was prepared from 1-(2-chloro-4-fluorophenyl)
cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.59 (dd, 1H, J=6.4, 8.5 Hz),
7.44-7.38 (m, 2H), 7.35-7.30 (m, 1H), 7.13 (dd, 1H, J=8.5, 3.0 Hz),
7.00-6.91 (m, 2H), 6.05-5.99 (m, 1H), 3.30 (q, 2H, J=5.7 Hz),
2.92-2.86 (m, 2H), 2.80-2.71 (m, 1H), 2.52 (septet, 1H, J=6.7 Hz),
2.34 (t, 2H, J=5.7 Hz), 2.30-2.24 (m, 3H), 2.13-2.05 (m, 2H),
2.00-1.92 (m, 2H), 1.86-1.69 (m, 4H), 1.66-1.43 (m, 7H), 1.71 (d,
6H, J=6.7 Hz); ESMS m/e: 560.1 (M+H).sup.+.
EXAMPLE 134
[0468] ##STR182##
1-(2-chloro-4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-
-piperidinyl}propyl)cyclohexanecarboxamide
[0469] Example 134 was prepared from
1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.55 (dd, 1H, J=8.9, 6.3 Hz), 7.32
(s, 1H), 7.23-7.18 (m, 2H), 7.06 (dd, 1H, J=8.5, 3.0 Hz), 7.01-6.92
(m, 2H), 5.99-5.93 (m, 1H), 3.24 (q, 2H, J=5.9 Hz), 2.85-2.79 (m,
3H), 2.59-2.50 (m, 1H), 2.44 (septet, 1H, J=7.0 Hz), 2.41-2.37 (br,
1H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.07-2.01 (m, 2H),
1.81-1.69 (m, 4H), 1.61-1.37 (m, 10H), 1.17 (d, 6H, J=7.0 Hz); ESMS
m/e: 556.1 (M+H).sup.+.
EXAMPLE 135
[0470] ##STR183##
1-(2-chloro-4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-
-piperidinyl}propyl)cyclopentanecarboxamide
[0471] Example 135 was prepared from
1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.56 (dd, 1H, J=8.7, 6.3 Hz), 7.32
(s, 1H), 7.22-7.15 (m, 2H), 7.06 (dd, 1H, J=8.7, 3.0 Hz), 7.05-6.95
(m, 2H), 5.90-5.84 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87-2.80 (m,
2H), 2.59-2.49 (m, 1H), 2.44 (septet, 1H, J=6.5 Hz), 2.41-2.40 (m,
2H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.04-1.96 (m, 2H),
1.93-1.85 (m, 2H), 1.82-1.71 (m, 3H), 1.64-1.48 (m, 7H), 1.17 (d,
6H, J=6.5 Hz); ESMS m/e: 542.2 (M+H).sup.+.
EXAMPLE 136
[0472] ##STR184##
N-{3-[1-(3-{[difluoro(phenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluorop-
henyl}-2-methylpropanamide
[0473] Example 136 was prepared from 2,2-difluoro-2-phenylacetic
acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 9.11 (s, 1H), 7.61-7.56 (m, 2H),
7.41-7.34 (m, 4H), 7.21-7.17 (m, 1H), 7.14 (s, 1H), 6.88 (t, 1H,
J=9.5 Hz), 3.39 (q, 2H, J=5.7 Hz), 3.08-3.01 (m, 2H), 2.84-2.74 (m,
1H), 2.50 (t, 2H, J=5.1 Hz), 2.38 (septet, 1H, J=7.2 Hz), 2.08-1.99
(m, 2H), 1.81-1.73 (m, 4H), 1.72-1.64 (m, 2H), 1.17 (d, 6H, J=7.2
Hz); ESMS m/e: 476.2 (M+H).sup.+.
EXAMPLE 137
[0474] ##STR185##
1-(2-chloro-4-fluorophenyl)-N-(3-{4-[2-fluoro-5-(isobutyrylamino)phenyl]-1-
-piperidinyl}propyl)cyclopentanecarboxamide
[0475] Example 137 was prepared from
1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamid-
e according to the procedures described in Scheme 9: ESMS m/e:
546.1 (M+H).sup.+.
EXAMPLE 138
[0476] ##STR186##
1-(2-chloro-4-fluorophenyl)-N-(3-{4-[3-(isobutyrylamino)phenyl]-1-piperidi-
nyl}propyl)cyclohexanecarboxamide
[0477] Example 138 was prepared from
1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.52-7.46 (m, 1H), 7.45-7.43 (m, 1H), 7.30
(s, 1H), 7.22 (s, 1H), 7.17 (t, 1H, J=7.9 Hz), 7.07-7.01 (m, 2H),
6.89-6.84 (m, 1H), 5.99-5.94 (m, 1H), 3.21 (q, 2H, J=5.7 Hz),
2.87-2.80 (m, 2H), 2.59-2.49 (m, 1H), 2.44 (septet, 1H, J=6.5 Hz),
2.41-2.40 (m, 2H), 2.26 (t, 2H, J=5.7 Hz), 2.04-1.96 (m, 2H),
1.93-1.85 (m, 2H), 1.82-1.71 (m, 4H), 1.64-1.50 (m, 8H), 1.17 (d,
6H, J=6.5 Hz); ESMS m/e: 542.1 (M+H).sup.+.
EXAMPLE 139
[0478] ##STR187##
N-{3-[4-(3-{[(dimethylamino)carbonyl]amino}phenyl)-1-piperidinyl]propyl}-2-
,2-bis(4-fluorophenyl)acetamide
[0479] Example 139 was prepared from bis(4-fluorophenyl)acetic acid
and N'-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-N,N-dimethylurea
according to the procedures described in Scheme 9: ESMS m/e: 535.4
(M+H).sup.+.
EXAMPLE 140
[0480] ##STR188##
Benzyl
3-(1-{3-[(diphenylacetyl)amino]Propyl}-4-piperidinyl)phenylcarbamat-
e
[0481] Example 140 was prepared from diphenylacetyl chloride and
benzyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according
to the procedures described in Scheme 8: ESMS m/e: 562.5
(M+H).sup.+.
EXAMPLE 141
[0482] ##STR189##
Benzyl
3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]phe-
nylcarbamate
[0483] Example 141 was prepared from bis(4-fluorophenyl)acetic acid
and benzyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate
according to the procedures described in Scheme 9: ESMS m/e: 598.5
(M+H).sup.+.
EXAMPLE 142
[0484] ##STR190##
Isopropyl
3-[1-(3-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}propyl)-4-p-
iperidinyl]phenylcarbamate
[0485] Example 142 was prepared from
2-(4-chlorophenyl)-2-methylpropanoic acid and isopropyl
3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the
procedures described in Scheme 9: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.29-7.22 (m, 3H), 7.20-7.11 (m, 3H), 7.09-7.06 (m, 1H),
6.79 (d, 1H, J=7.6 Hz), 6.61 (s, 1H), 6.60-6.50 (m, 1H), 4.94
(septet, 1H, J=6.7 Hz), 4.05 (q, 1H, J=6.8 Hz), 3.24 (q, 2H, J=5.9
Hz), 2.86-2.79 (m, 2H), 2.36 (tt, 1H, J=11.9, 3.2 Hz), 2.27 (t, 2H,
J=6.3 Hz), 1.85 (t, 2H, J=11.9 Hz), 1.72-1.66 (m, 2H), 1.60-1.52
(m, 3H), 1.48 (s, 6H), 1.23 (d, 6H, J=6.7 Hz); ESMS m/e: 500.2
(M+H).sup.+.
EXAMPLE 143
[0486] ##STR191##
Isopropyl
3-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]-
phenylcarbamate
[0487] Example 143 was prepared from bis(4-chlorophenyl)acetic acid
and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.46 (s, 1H), 7.37 (s, 1H), 7.23-7.10 (m,
9H), 7.00 (d, 1H, J=7.9 Hz), 6.80 (d, 1H, J=7.4 Hz), 6.60 (s, 1H),
4.88 (septet, 1H, J=6.2 Hz), 4.68 (s, 1H), 4.05 (q, 1H, J=7.3 Hz),
3.32 (q, 2H, J=5.9 Hz), 2.90-2.83 (m, 2H), 2.44-2.32 (m, 3H),
1.94-1.86 (m, 2H), 1.78-1.70 (m., 2H), 1.60 (quintet, 2H, J=6.4
Hz), 1.56-1.43 (m, 1H), 1.22 (d, 6H, J=6.2 Hz); ESMS m/e: 582.2
(M+H).sup.+.
EXAMPLE 144
[0488] ##STR192##
Isopropyl
3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenylcarba-
mate
[0489] Example 144 was prepared from diphenylacetyl chloride and
isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.25-7.12 (m, 12H), 7.09-7.06 (m, 1H),
7.00-6.94 (m, 1H), 6.79 (d, 1H, J=7.6 Hz), 6.60(s, 1H), 4.92
(septet, 1H, J=6.2 Hz), 4.79 (s, 1H), 4.04 (q, 1H, J=6.4 Hz), 3.30
(q, 2H, J=5.8 Hz) 2.91-2.83 (m, 2H), 2.42-2.30 (m, 3H), 1.91 (t,
2H, J=11.4 Hz), 1.74-1.67 (m, 2H), 1.65-1.51 (m, 3H), 1.21 (d, 6H,
J=6.2 Hz); ESMS m/e: 514.2 (M+H).sup.+.
EXAMPLE 145
[0490] ##STR193##
Isopropyl
3-[1-(3-{[bis(4-methylphenyl)acetyl]amino}propyl)-4-piperidinyl]-
phenylcarbamate
[0491] Example 145 was prepared from bis(4-methylphenyl)acetic acid
and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.24 (s, 1H), 7.18-7.06 (m, 4H), 7.06-7.00
(m, 6H), 6.82-6.78 (m, 2H), 6.62 (s, 1H), 4.92 (septet, 1H, J=6.7
Hz), 4.72 (s, 1H), 4.04 (q, 1H, J=6.8 Hz), 3.32-3.26 (m, 2H),
2.88-2.81 (m, 2H), 2.41-2.27 (m, 3H), 2.21 (s, 6H), 1.92-1.83 (m,
2H), 1.74-1.66 (m, 2H), 1.62-1.46 (m, 3H), 1.21 (d, 6H, J=6.7 Hz);
ESMS m/e: 542.3 (M+H).sup.+.
EXAMPLE 146
[0492] ##STR194##
Isopropyl
3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-
phenylcarbamate
[0493] Example 146 was prepared from bis(4-fluorophenyl)acetic acid
and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate
according to the procedures described in Scheme 9: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.43(s, 2H), 7.30-7.19 (m, 4H), 7.11-7.07
(m, 1H), 7.01-6.96 (m, 5H), 6.88 (d, 1H, J=7.7 Hz), 6.69 (s, 1H),
4.97 (septet, 1H, J=6.3 Hz), 4.79 (s, 1H), 4.11 (q, 1H, J=6.8 Hz),
3.39 (q, 2H, J=5.6 Hz), 2.98-2.92 (m, 2H), 2.52-2.40 (m, 3H), 1.98
(t, 2H, J=11.5 Hz), 1.85-1.78 (m, 2H), 1.72-1.54 (m, 3H), 1.27 (d,
6H, J=6.3 Hz); ESMS m/e: 550.3 (M+H).sup.+; Anal. Calc. for
C.sub.32H.sub.37F.sub.2N.sub.3O.sub.3.0.87 HCl: C, 66.84; H, 6.61;
N, 7.31.Found: C, 66.83; H, 6.48; N, 7.31.
EXAMPLE 147
[0494] ##STR195##
Isopropyl
3-{1-[3-({[1-(2-chloro-4-fluorophenyl)cyclohexyl]carbonyl}amino)-
propyl]-4-piperidinyl}phenylcarbamate
[0495] Example 147 was prepared from
1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and isopropyl
3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the
procedures described in Scheme 9: ESMS m/e: 558.1 (M+H).sup.+.
EXAMPLE 148
[0496] ##STR196##
N-[4-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-2-methylpr-
opanamide
[0497] Example 148 was prepared from
N-(3-bromopropyl)-2,2-diphenylacetamide and
2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide according to the
procedures described in Scheme 14: ESMS m/e: 498.3 (M+H).sup.+.
EXAMPLE 149
[0498] ##STR197##
N-[4-(1-{3-[(2,2-diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]butanam-
ide
[0499] Example 149 was prepared from
N-(3-bromopropyl)-2,2-diphenylacetamide and
N-[4-(4-piperidinyl)phenyl]butanamide according to the procedures
described in Scheme 14: ESMS m/e: 498.3 (M+H).sup.+.
EXAMPLE 150
[0500] ##STR198##
N-[5-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-2-hydroxyphenyl]--
2-methylpropanamide
[0501] Example 150 was prepared from diphenylacetyl chloride and
N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-hydroxyphenyl}-2-methylpropanami-
de according to the procedures described in Scheme 8: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.18 (s, 1H), 7.30-7.11 (m, 10H),
7.10-6.9 (m, 2H), 6.74 (d, 1H, J=8.3 Hz), 6.63 (dd, 1H, J=8.3, 2.0
Hz), 4.93 (s, 1H), 3.51 (t, 1H, J=5.4 Hz), 3.36 (quintet, 1H, J=6.5
Hz), 3.24-3.18 (m, 2H), 3.07-3.00 (m, 2H), 2.54-2.45 (m, 3H),
2.37-2.28 (m, 1H), 2.19-2.09 (m, 2H), 1.79-1.54 (m, 4H), 1.25 (d,
6H, J=6.8 Hz); ESMS m/e: 514.3 (M+H).sup.+.
EXAMPLE 151
[0502] ##STR199##
N-[3-(1-{3-[(3,3-diphenylpropanoyl)amino]propyl}-4-piperidinyl)phenyl]cycl-
opropanecarboxamide
[0503] Example 151 was prepared from 3,3-diphenylpropanoic acid and
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide
according to the procedures described in Scheme 9: ESMS m/e: 510.4
(M+H).sup.+.
EXAMPLE 152
[0504] ##STR200##
N-{3-[4-(3-aminophenyl)-1-piperidinyl]propyl}-2,2-diphenylacetamide
[0505] Example 152 was prepared via hydrogenation of benzyl
3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenylcarbamate
according to the procedures described in Scheme 15: ESMS m/e: 428.3
(M+H).sup.+.
[0506] II. Synthetic Methods for General Structures
[0507] The examples described in the experimental section are
merely illustrative of the methods used to synthesize MCH1
antagonists. Additional compounds of the invention can be obtained
by the general synthetic procedures described herein or by
incorporating variations into these methods that would be obvious
to someone skilled in the art.
[0508] It may be necessary to incorporate protection and
deprotection strategies into the generalized synthetic methods in
order to synthesize additional examples containing potentially
reactive substituents such as amino, amido, carboxylic acid, and
hydroxyl groups. 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.
[0509] III. Oral Compositions
[0510] As a specific embodiment of an oral composition of a
compound of this invention, 100 mg of one of the compounds
described herein is formulated with sufficient finely divided
lactose to provide a total amount of 580 to 590 mg to fill a size 0
hard gel capsule.
[0511] IV. Pharmacological Evaluation of Compounds at Cloned rat
MCH1 Receptor
[0512] The pharmacological properties of the compounds of the
present invention were evaluated at the cloned rat MCH1 receptor
using the protocols described below.
Host Cells
[0513] 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, Peak rapid 293, etc.; insect cell lines such as:
Sf9, Sf21, etc.; amphibian cells such as xenopus oocytes; and
others.
[0514] 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 Fg/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.
[0515] Human embryonic kidney 293 cells are grown on 150 mm plates
in DMEM with supplements (10% bovine calf serum, 4 mM glutamine,
100 units/ml penicillin/100 Fg/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.
[0516] Human embryonic kidney Peak rapid 293 (Peakr293) cells are
grown on 150 mm plates in DMEM with supplements (10% fetal bovine
serum, 10% L-glutamine, 50 Fg/ml gentamycin) at 37.degree. C., 5%
CO.sub.2. Stock plates of Peak rapid 293 cells are trypsinized and
split 1:12 every 3-4 days.
[0517] Mouse fibroblast LM(tk-) 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
Fg/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.
[0518] 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 Fg/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.
[0519] Mouse embryonic fibroblast NIH-3T3 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 Fg/ml streptomycin) at 37.degree. C., 5% CO.sub.2.
Stock plates of NIH-3T3 cells are trypsinized and split 1:15 every
3-4 days.
[0520] Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue
culture dishes in TMN-FH media supplemented with 10% fetal calf
serum, at 27.degree. C., no CO.sub.2. High Five insect cells are
grown on 150 mm tissue culture dishes in Ex-Cell 400.TM. medium
supplemented with L-Glutamine, also at 27.degree. C., no
CO.sub.2.
[0521] In some cases, cell lines that grow as adherent monolayers
can be converted to suspension culture to increase cell yield and
provide large batches of uniform assay material for routine
receptor screening projects.
Transient Expression
[0522] 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.
[0523] A typical protocol for the calcium phosphate method as
applied to Peak rapid 293 cells is described as follows:
[0524] Adherent cells are harvested approximately twenty-four hours
before transfection and replated at a density of 3.5.times.10.sup.6
cells/dish in a 150 mm tissue culture dish and allowed to incubate
over night at 37.degree. C. at 5% CO.sub.2. 250 Fl of a mixture of
CaCl.sub.2 and DNA (15 Fg DNA in 250 mM CaCl.sub.2) is added to a 5
ml plastic tube and 500 Fl of 2.times. HBS (280 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
DNA precipitate mixture is then added to the culture medium in each
plate and incubated for 5 hours at 37.degree. C., 5% CO.sub.2.
After the incubation, 5 ml of culture medium (DMEM, 10% FBS, 10%
L-glut and 50 .mu.g/ml gentamycin) is added to each plate. The
cells are then incubated for 24 to 48 hours at 37.degree. C., 5%
CO.sub.2.
[0525] 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 Fg of receptor DNA plus 8 Fg of any
additional DNA needed (e.g. G.sub..alpha. protein expression
vector, reporter construct, antibiotic resistance marker, mock
vector, etc.) are added to 9 ml of complete DMEM plus DEAE-dextran
mixture (10 mg/ml in PBS). Cos-7 cells plated into a T225 flask
(sub-confluent) are washed once with PBS and the DNA mixture is
added to each flask. The cells are allowed to incubate for 30
minutes at 37.degree. C., 5% CO.sub.2. Following the incubation, 36
ml of complete DMEM with 80 FM 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.
[0526] 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 Fg of DNA which may include varying
ratios of receptor DNA plus any additional DNA needed (e.g.
G.sub..alpha. protein expression vector, reporter construct,
antibiotic resistance marker, mock vector, etc.) is used to
transfect each 75 cm.sup.2 flask of cells. Liposomal mediated
transfection is carried out according to the manufacturer=s
recommendations (LipofectAMINE, GibcoBRL, Bethesda, Md.).
Transfected cells are harvested 24 hours post transfection and used
or reseeded according the requirements of the assay to be
employed.
[0527] 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 Fl of DMEM and placed into an electroporation cuvette. 8 Fg of
receptor DNA plus 8 Fg of any additional DNA needed (e.g.
G.sub..alpha. 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 FF capacitance). Following the pulse, 800 Fl 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.sup.5
cells/100 Fl. The cells are then plated as needed depending upon
the type of assay to be performed.
[0528] 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 Fg of viral DNA (BaculoGold) and 3 Fg of DNA
construct encoding a polypeptide may be co-transfected into
2.times.10.sup.6 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.
Stable Expression
[0529] 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.
Cell Membrane Preparation
[0530] 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.
Radioligand Binding Assays
[0531] Radioligand binding assays for the rat MCH1 receptor were
carried out using plasmid pcDNA3.1-rMCH1-f (ATCC Patent Deposit
Designation No. PTA-3505). Plasmid pcDNA3.1-rMCH1-f comprises the
regulatory elements necessary for expression of DNA in a mammalian
cell operatively linked to DNA encoding the rat MCH1 receptor so as
to permit expression thereof. Plasmid pcDNA3.1-rMCH1-f was
deposited on Jul. 5, 2001, 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 Patent Deposit
Designation No. PTA-3505.
[0532] Binding assays can also be performed as described
hereinafter using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197)
Plasmid pEXJ.HR-TL231 encodes the human MCH1 receptor and 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.
[0533] Human embryonic kidney Peak rapid 293 cells (Peakr293 cells)
were transiently 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 Peakr293 cells transfected with the rat MCH1 receptor were
performed with 0.08 nM [.sup.3H]Compound A (the synthesis of
Compound A is described in detail below) 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 pM Compound A.
Functional Assays
[0534] Cells may be screened for the presence of endogenous
mammalian receptor using functional assays. Cells with no or a low
level of endogenous receptor present may be transfected with the
exogenous receptor for use in functional assays.
[0535] 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, for example; to high level organism assays
which monitor complex physiological or behavioral changes thought
to be involved with receptor activation including cardiovascular,
analgesic, orexigenic, anxiolytic, and sedation effects, for
example.
Radioligand Binding Assay Results
[0536] The compounds described above were assayed using cloned rat
MCH1. The binding affinities of the compounds are shown in Table I.
TABLE-US-00001 TABLE I Example No. Ki (MCH1, nM) 1 1.3 2 2.4 3 2.5
4 2.5 5 3.1 6 5.6 7 7.9 8 11.7 9 71.6 10 83.0 11 8.4 12 13.9 13
11.8 14 2.7 15 8.9 16 1038 17 1.8 18 31.5 19 23.4 20 90.5 21 0.7 22
136.5 23 13.1 24 4.7 25 2.1 26 18.7 27 1.1 28 0.4 29 2.3 30 5.3 31
8.2 32 0.6 33 495.6 34 2.3 35 0.4 36 11.0 37 19.5 38 28.4 39 32.2
40 7.9 41 39.9 42 34.3 43 13.7 44 19.7 45 4.0 46 44.5 47 25.6 48
2.8 49 14.8 50 1.9 51 11.8 52 4.1 53 1.1 54 2.2 55 0.3 56 4.5 57
0.5 58 45.9 59 4.3 60 41.3 61 63.3 62 31.7 63 150.0 64 70.7 65 4.9
66 24.4 67 9.9 68 16.9 69 39.9 70 26.7 71 54.5 72 52.3 73 32.4 74
34.3 75 4.7 76 48.0 77 30.7 78 6.7 79 5.9 80 7.7 81 3.2 82 8.6 83
10.3 84 12.6 85 4.6 86 3.2 87 6.4 88 23.0 89 10.8 90 52.2 91 2.9 92
2.6 93 4.9 94 3.1 95 23.5 96 2.6 97 3.6 98 4.3 99 2.9 100 5.0 101
11.2 102 7.9 103 8.0 104 0.9 105 2.8 106 19.0 107 101.2 108 1.9 109
4.7 110 50.4 111 1.2 112 3.2 113 0.8 114 4.0 115 6.9 116 18.9 117
17.9 118 13.9 119 18.6 120 0.4 121 10.2 122 4.8 123 2.8 124 39.9
125 124.5 126 3.0 127 175.0 128 2.9 129 4.5 130 2.6 131 4.0 132 0.6
133 5.9 134 2.4 135 5.2 136 48.7 137 11.8 138 10.2 139 33.4 140
180.0 141 8.8 142 77.4 143 6.2 144 33.2 145 26.9 146 6.2 147 42.0
148 144.0 149 467.0 150 NA 151 62.0 152 115.0
[0537] V. Synthesis of Radiolabeled Compound A
[0538] Described below is the synthesis of Compound A. Compound A
is the radiolabeled compound that was used in the radioligand
binding assays described above.
N-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide
[0539] The reaction of saturated of aqueous Na.sub.2CO.sub.3
solution (25 mL), tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxyl-
ate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and
tetrakis-triphenylphosphine palladium (0) (1.15 g) in
dimethoxyethane (40 mL) at reflux temperature overnight gave
tert-butyl
4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate.
Deprotection of the BOC group using HCl in dioxane followed by
basification (pH 11-12) gave the desired product.
Tert-butyl N-(3-bromopropyl)carbamate was prepared from
3-bromopropylamine hydrobromide and BOC.sub.2O in the presence of
base in dichloromethane.
N-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide
[0540] The reaction of tert-butyl N-(3-bromopropyl)carbamate and
N-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide in refluxing
dioxane with catalytic Bu.sub.4NI and base to give tert-butyl
3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate.
Deprotection of the BOC group using HCl in dioxane followed by
basification (pH 11-12) gave the desired product.
Methyl
(4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridiny-
l)propyl]amino}carbonyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,-
2,3,4-tetrahydro-5-pyrimidinecarboxylate
[0541] Prepared from the reaction of 5-methyl 1-(4-nitrophenyl)
(6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-p-
yrimidinedicarboxylate (describe in PCT Publication No. WO
00/37026, published Jun. 29, 2000) and
N-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide:
.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+H).sup.+.
Tritiated Methyl
(4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbony-
l}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyr-
imidinecarboxylate ([.sup.3H] Compound A)
[0542] This radiochemical synthesis was carried out by Amersham
Pharmacia Biotech, Cardiff, Wales. A methanolic solution of methyl
(4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propyl-
]amino}carbonyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-te-
trahydro-5-pyrimidinecarboxylate was exposed to tritium gas at 1
atmosphere pressure in the presence of 5% palladium on carbon with
stirring overnight to give the tritiated methyl
(4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbony-
l}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyr-
imidinecarboxylate ((+)-isomer). After purification by reverse
phase HPLC (Hypersil ODS, 4.6.times.100 mm,
methanol:H.sub.2O:Et.sub.3N 10:90:1 to 100:0:1 in 15 min at 1.0
mL/min, with radiochemical and UV detection), this product was used
as a radioligand in the MCH1 binding assays. The same procedure was
carried out with H.sub.2 gas in place of .sup.3H.sub.2 to afford
the non-radioactive version of Compound A.
[0543] VI. In-Vivo Methods
[0544] The following in vivo methods were performed to predict the
efficacy of MCH1 antagonists for the treatment of obesity (3-day
body weight and sweetened condensed milk), depression (forced swim
test), anxiety (social interaction test), and urinary disorders
(DIRC and CSTI).
Effects of MCH1 Antagonists on Body Weight (3 Day)
[0545] Male Long Evans rats (Charles River) weighing 180-200 grams
were housed in groups of four on a 12-hour light/dark cycle with
free access to food and water. Test compounds were administered
twice daily via i.p. injection, 1 hour before the dark cycle and 2
hours after lights on, for three days. All rats were weighed daily
after each morning injection. Overall results were expressed as
body weight (grams) gained per day (mean.+-.SEM) and were analyzed
by two-way ANOVA. Data for each time point were analyzed by one-way
ANOVA followed by post hoc Newman-Keuls test. The data were
analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc.,
San Diego, Calif.). All data were presented as means.+-.S.E.M.
Effects of MCH1 Antagonists on Consumption of Sweetened Condensed
Milk
[0546] Male C57BL/6 mice (Charles River) weighing 17-19 grams at
the start of experiments were housed in groups of four or five on a
12 hour light/dark cycle with free access to food and water. For 7
days, mice were weighed, placed in individual cages and allowed to
drink sweetened condensed milk (Nestle, diluted 1:3 with water) for
1 hour, 2-4 hours into the light cycle. The amount of milk consumed
was determined by weighing the milk bottle before and after each
drinking bout. On the test day, mice received i.p. injections of
Test Compound (3, 10 or 30 mg/kg in 0.01% lactic acid), vehicle
(0.01% lactic acid) of d-fenfluramine (10 mg/kg in 0.01% lactic
acid) 30 min. prior to exposure to milk. The amount of milk
consumed on the test day (in mls milk/kg body weight) was compared
to the baseline consumption for each mouse determined on the
previous 2 days. Data for each time point were analyzed by one-way
ANOVA.
Forced Swim Test (FST) in the Rat
[0547] Animals
[0548] Male Sprague-Dawley rats (Taconic Farms, N.Y.) were used in
all experiments. Rats were housed 5 per cage and maintained on a
12:12-h light-dark cycle. Rats were handled for 1 minutes each day
for 4 days prior to behavioral testing.
Drug Administration
[0549] Animals were randomly assigned to receive a single i.p.
administration of vehicle (2.5% EtOH/2.5% Tween-80), imipramine
(positive control; 60 mg/kg), or Test Compound 60 minutes before
the start of the 5 minute test period. All injections were given
using 1 cc tuberculin syringe with 263/8 gauge needles
(Becton-Dickinson, VWR Scientific, Bridgeport, N.J.). The volume of
injection was 1 ml/kg.
[0550] Experimental Design
[0551] The procedure used in this study was similar to that
previously described (Porsolt, et al., 1978), except the water
depth was 31 cm in this procedure. The greater depth in this test
prevents the rats from supporting themselves by touching the bottom
of the cylinder with their feet. Swim sessions were conducted by
placing rats in individual plexiglass cylinders (46 cm
tall.times.20 cm in diameter) containing 23-25.degree. C. water 31
cm deep. Swim tests were conducted always between 900 and 1700
hours and consisted of an initial 15-min conditioning test followed
24 h later by a 5-minute test. Drug treatments were administered 60
minutes before the 5-minute test period. Following all swim
sessions, rats were removed from the cylinders, dried with paper
towels and placed in a heated cage for 15 minutes and returned to
their home cages. All test sessions were videotaped using a color
video camera and recorded for scoring later.
Behavioral Scoring
[0552] The rat's behavior was rated at 5-second intervals during
the 5-minute test by a single individual, who was blind to the
treatment condition. Scored behaviors were: [0553] 1.
Immobility--rat remains floating in the water without struggling
and was only making those movements necessary to keep its head
above water; [0554] 2. Climbing--rat was making active movements
with its forepaws in and out of the water, usually directed against
the walls; [0555] 3. Swimming--rat was making active swimming
motions, more than necessary to merely maintain its head above
water, e.g. moving around in the cylinder; and [0556] 4.
Diving--entire body of the rat was submerged. Data Analysis
[0557] The forced swim test data (immobility, swimming, climbing,
diving) were subjected to a randomized, one-way ANOVA and post hoc
tests conducted using the Newman-Keuls test. The data were analyzed
using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San
Diego, Calif.). All data were presented as means.+-.S.E.M. All data
were presented as means.+-.S.E.M.
Forced Swim Test (FST) in the Mouse
[0558] Animals
[0559] DBA/2 mice (Taconic Farms, N.Y.) were used in all
experiments. Animals were housed 5 per cage in a controlled
environment under a 12:12 hour light:dark cycle. Animals were
handled 1 min each day for 4 days prior to the experiment. This
procedure included a mock gavage with a 1.5 inch feeding tube.
Drug Administration
[0560] Animals were randomly assigned to receive a single
administration of vehicle (5% EtOH/5% Tween-80), Test Compound, or
imipramine (60 mg/kg) by oral gavage 1 hour before the swim
test.
Experimental Design
[0561] The procedure for the forced swim test in the mouse was
similar to that described above for the rat, with some
modifications. The cylinder used for the test was a 1-liter beaker
(10.5 cm diameter.times.15 cm height) fill to 800ml (10 cm depth)
of 23-25.degree. C. water. Only one 5-minute swim test was
conducted for each mouse, between 1300 and 1700 hours. Drug
treatments were administered 30-60 minutes before the 5-minute test
period. Following all swim sessions, mice were removed from the
cylinders, dried with paper towels and placed in a heated cage for
15 minutes. All test sessions were videotaped using a Sony color
video camera and recorder for scoring later.
Behavioral Scoring
[0562] The behavior during minutes 2-5 of the test was played back
on a TV monitor and scored by the investigator. The total time
spent immobile (animal floating with only minimal movements to
remain afloat) and mobile (swimming and movements beyond those
required to remain afloat) were recorded.
Data Analysis
[0563] The forced swim test data (time exhibiting immobility,
mobility; seconds) were subjected to a randomized, one-way ANOVA
and post hoc tests conducted using the Newman-Keuls test. The data
were analyzed using the GraphPad Prism (v2.01) (GraphPad Software,
Inc., San Diego, Calif.). All data were presented as
means.+-.S.E.M.
Social Interaction Test (SIT)
[0564] Rats are allowed to acclimate to the animal care facility
for 5 days and are housed singly for 5 days prior to testing.
Animals are handled for 5 minutes per day. The design and procedure
for the Social Interaction Test is carried out as previously
described by Kennett, et al. (1997). On the test day, weight
matched pairs of rats (.+-.5%), unfamiliar to each other, are given
identical treatments and returned to their home cages. Animals are
randomly divided into 5 treatment groups, with 5 pairs per group,
and are given one of the following i.p. treatments: Test Compound
(10, 30 or 100 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5
mg/kg). Dosing is 1 hour prior to testing. Rats are subsequently
placed in a white perspex test box or arena (54.times.37.times.26
cm), whose floor is divided up into 24 equal squares, for 15
minutes. An air conditioner is used to generate background noise
and to keep the room at approximately 74.degree. F. All sessions
are videotaped using a JVC camcorder (model GR-SZ1, Elmwood Park,
N.J.) with either TDK (HG ultimate brand) or Sony 30 minute
videocassettes. All sessions are conducted between 1300-1630 hours.
Active social interaction, defined as grooming, sniffing, biting,
boxing, wrestling, following and crawling over or under, is scored
using a stopwatch (Sportsline model no. 226, 1/100 sec.
discriminability). The number of episodes of rearing (animal
completely raises up its body on its hind limbs), grooming
(licking, biting, scratching of body), and face washing (i.e. hands
are moved repeatedly over face), and number of squares crossed are
scored. Passive social interaction (animals are lying beside or on
top of each other) is not scored. All behaviors are assessed later
by an observer who is blind as to the treatment of each pair. At
the end of each test, the box is thoroughly wiped with moistened
paper towels.
Animals
[0565] Male albino Sprague-Dawley rats (Taconic Farms, N.Y.) are
housed in pairs under a 12 hr light dark cycle (lights on at 0700
hrs.) with free access to food and water.
Drug Administration
[0566] Test Compound is dissolved in either 100% DMSO or 5% lactic
acid, v/v (Sigma Chemical Co., St. Louis, Mo.). Chlordiazepoxide
(Sigma Chemical Co., St. Louis, Mo.) is dissolved in double
distilled water. The vehicle consists of 50% DMSO (v/v) or 100%
dimethylacetamide (DMA). All drug solutions are made up 10 minutes
prior to injection and the solutions are discarded at the end of
the test day. The volume of drug solution administered is 1
ml/kg.
Data Analysis
[0567] The social interaction data (time interacting, rearing and
squares crossed) are subjected to a randomized, one-way ANOVA and
post hoc tests conducted using the Student-Newman-Keuls test. The
data are subjected to a test of normality (Shapiro-Wilk test). The
data are analyzed using the GBSTAT program, version 6.5 (Dynamics
Microsystems, Inc., Silver Spring, Md., 1997).
In Vivo Models of the Micturition Reflex
[0568] The effects of compounds on the micturition reflex were
assessed in the "distension-induced rhythmic contraction" (DIRC),
as described in previous publications (e.g. Maggi et al, 1987;
Morikawa et al, 1992), and Continuous Slow Transvesicular Infusion
(CSTI) models in rats.
[0569] DIRC Model
[0570] Female Sprague Dawley rats weighing approximately 300 g were
anesthetized with subcutaneous urethane (1.2 g/kg). The trachea was
cannulated with PE240 tubing to provide a clear airway throughout
the experiment. A midline abdominal incision was made and the left
and right ureters were isolated. The ureters were ligated distally
(to prevent escape of fluids from the bladder) and cannulated
proximally with PE10 tubing. The incision was closed using 4-0 silk
sutures, leaving the PE10 lines routed to the exterior for the
elimination of urine. The bladder was canulated via the
transurethral route using PE50 tubing inserted 2.5 cm beyond the
urethral opening. This cannula was secured to the tail using tape
and connected to a pressure transducer. To prevent leakage from the
bladder, the cannula was tied tightly to the exterior urethral
opening using 4-0 silk.
[0571] To initiate the micturition reflex, the bladder was first
emptied by applying pressure to the lower abdomen, and then filled
with normal saline in 100 increments (maximum=2 ml) until
spontaneous bladder contractions occurred (typically 20-40 mmHg at
a rate of one contraction every 2 to 3 minutes. Once a regular
rhythm was established, vehicle (saline) or Test Compounds were
administered i.v. or i.p. to explore their effects on bladder
activity. The 5-HT.sub.1A antagonist WAY-100635 was given as a
positive control. Data were expressed as contraction interval (in
seconds) before drug application (basal), or after the application
of vehicle or test article.
[0572] Continuous Slow Transvesicular Infusion (CSTI) Rat Model
[0573] Male Sprague Dawley rats weighing approximately 300 g were
used for the study. Rats were anaesthetized with pentobarbitone
sodium (50 mg/kg, i.p). Through a median abdominal incision,
bladder was exposed and a polyethylene cannula (PE 50) was
introduced into the bladder through a small cut on the dome of the
bladder and the cannula was secured with a purse string suture. The
other end of the cannula was exteriorized subcutaneously at the
dorsal neck area. Similarly, another cannula (PE 50) was introduced
into the stomach through a paramedian abdominal incision with the
free end exteriorized subcutaneously to the neck region. The
surgical wounds were closed with silk 4-0 suture and the animal was
allowed to recover with appropriate post surgical care. On the
following day, the animal was placed in a rat restrainer. The open
end of the bladder-cannula was connected to a pressure transducer
as well as infusion pump through a three-way stopcock. The bladder
voiding cycles were initiated by continuous infusion of normal
saline at the rate of 100 .mu.l/min. The repetitive voiding
contractions were recorded on a Power Lab on-line data acquisition
software. After recording the basal voiding pattern for an hour,
the test drug or vehicle was administered directly into stomach
through the intragastric catheter and the voiding cycles were
monitored for 5 hours. Micturition pressure and frequency were
calculated before and after the treatment (at every 30 min
interval) for each animal. Bladder capacity was calculated from the
micturition frequency, based on the constant infusion of 100
ul/min. The effect of the test drug was expressed as a percentage
of basal, pre-drug bladder capacity. WAY 100635 was used as
positive control for comparison.
[0574] In Vivo Results TABLE-US-00002 TABLE 2 Effect of MCH1
antagonist (Example No.) in the following in vivo models: 3-day
Body Weight (3D BW), mouse Sweetened Condensed Milk (mSwCM), mouse
Forced Swim Test (mFST), rat Forced Swim Test (rFST), DIRC model,
or CSTI model. Example No. 3D BW mSwCM mFST RFST DIRC CSTI 1 Not
Not No Not Not F tested tested effect tested tested 3 Not Not Not
Not Not F tested tested tested tested tested 4 Not Not C Not Not F
tested tested tested tested 6 Not Not C Not Not F tested tested
tested tested 8 Not Not C Not Not F tested tested tested tested 24
Not Not Not Not Not F tested tested tested tested tested 29 Not Not
Not Not Not F tested tested tested tested tested 32 Not Not Not Not
Not F tested tested tested tested tested 35 Not Not C Not Not F
tested tested tested tested A = Produced a significant reduction in
weight gain relative to vehicle-treated controls B = Produced a
significant decrease in consumption of milk relative to
vehicle-treated controls C = Produced a significant decrease in
immobility relative to vehicle-treated animals when administered
orally. D = Produced a significant decrease in immobility or a
significant increase in swimming activity relative to
vehicle-treated animals E = Produced a significant increase in
contraction interval relative to pre-drug interval F = Produced an
increase in bladder capacity in rats relative to baseline
capacity.
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