U.S. patent application number 11/243739 was filed with the patent office on 2006-03-09 for amine and amide derivatives as ligands for the neuropeptide y y5 receptor useful in the treatment of obesity and other disorders.
Invention is credited to Scott L. Dax, James McNally, Mark Youngman.
Application Number | 20060052388 11/243739 |
Document ID | / |
Family ID | 22515737 |
Filed Date | 2006-03-09 |
United States Patent
Application |
20060052388 |
Kind Code |
A1 |
Dax; Scott L. ; et
al. |
March 9, 2006 |
Amine and amide derivatives as ligands for the neuropeptide Y Y5
receptor useful in the treatment of obesity and other disorders
Abstract
Amine and amide derivatives of the formula: ##STR1## which are
ligands for the neuropeptide Y Y5 (NPY5) receptor, methods of
preparation and pharmaceutical compositions containing amines and
amides of formula A as the active ingredient are described. The
amines and amides of formula A are useful in the treatment of
disorders and diseases associated with NPY receptor subtype Y5.
Inventors: |
Dax; Scott L.; (Landenberg,
PA) ; McNally; James; (Souderton, PA) ;
Youngman; Mark; (Warminster, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
22515737 |
Appl. No.: |
11/243739 |
Filed: |
October 5, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10071483 |
Feb 7, 2002 |
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11243739 |
Oct 5, 2005 |
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09626856 |
Jul 27, 2000 |
6380224 |
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10071483 |
Feb 7, 2002 |
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60146069 |
Jul 28, 1999 |
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Current U.S.
Class: |
514/253.01 ;
514/318; 514/340; 544/360; 546/194 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/08 20180101; C07C 311/19 20130101; C07C 2602/10 20170501;
C07D 401/14 20130101; C07D 401/04 20130101; A61P 25/06 20180101;
A61P 15/08 20180101; A61P 31/00 20180101; C07D 213/38 20130101;
C07D 471/10 20130101; C07C 2601/14 20170501; C07C 311/18 20130101;
C07D 409/14 20130101; C07D 333/20 20130101; A61P 25/28 20180101;
A61P 25/00 20180101; C07D 213/40 20130101; A61P 25/24 20180101;
A61P 25/20 20180101; C07D 401/12 20130101; C07D 211/34 20130101;
C07D 295/15 20130101; C07D 401/10 20130101; A61P 15/00 20180101;
A61P 3/04 20180101; A61P 25/04 20180101; A61P 3/00 20180101; A61P
3/10 20180101; A61P 25/22 20180101 |
Class at
Publication: |
514/253.01 ;
514/318; 514/340; 544/360; 546/194 |
International
Class: |
C07D 403/02 20060101
C07D403/02; A61K 31/496 20060101 A61K031/496 |
Claims
1-9. (canceled)
10. A compound of claim 17 selected from the group consisting of:
##STR230##
11. A compound of claim 17 selected from the group consisting of:
##STR231##
12. (canceled)
13. A compound of claim 17 which is:
3-[(Phenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-fluoro-1-(3-pyridin-
ylmethyl)-2-naphthalenyl]-1-pyrrolidineacetamide
bis-trifluoroacetate.
14-16. (canceled)
17. A compound of the formula ##STR232## wherein R.sub.1 is
independently selected from the group consisting of H; alkyl;
substituted alkyl; alkoxy; halo; substituted alkoxy; hydroxy;
trifluoralkyl; nitro; amino; alkylamino; cycloalkylamino; cyano;
carboxy; cycloalkyl; phenyl; and substituted phenyl; R.sub.2 is
pyridyl; B.sub.1 is hydrogen; B.sub.2 is hydrogen; or B.sub.1
and/or B.sub.2 are methylene and joined together to form a five or
six membered ring; Y is methylene or carbonyl; L is
(N-methylene)pyrrolidin-3-yl; ##STR233## Z is selected from the
group consisting of aryl; ##STR234## N-sulfonamido; ##STR235##
N-(aryl)sulfonamido; ##STR236## arylamido; ##STR237## arylureido;
##STR238## arylacetamido: ##STR239## (aryloxy)carbonylamino;
##STR240## 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl; ##STR241## and
1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl; ##STR242## R.sub.3 is
independently selected from the group consisting of C.sub.1-6
alkyl; substituted C.sub.1-8alkyl; cycloalkyl; substituted
cycloalkyl; naphthyl; substituted naphthyl; heteroaryl; and
substituted heteroaryl; R.sub.4 is independently selected from the
group consisting of hydrogen; C.sub.1-8alkyl; C.sub.1-8alkoxy;
substitued C.sub.1-8alkoxy; hydroxy; halogen; cyano; nitro; amino;
C.sub.1-8alkylamino; and C.sub.1-8dialkylamino; R.sub.5 is
independently selected from the group consisting of hydrogen;
C.sub.1-8alkyl; C.sub.1-8alkylcarbonyl; aroyl; carbamoyl; amidino;
C.sub.1-8alkyl; C.sub.1-8alkylaminocarbonyl; (arylamino)carbonyl;
and arylC.sub.1-8 alkylcarbonyl; R.sub.6 is independently selected
from hydrogen and C.sub.1-8alkyl; n is 1-2; m is 0-3; p is 1-3; and
q is 1-3; provided that when L is (N-methylene)piperazin-4-yl, then
Z is phenyl or naphthyl; when L is (N-methylene)piperidin-4-yl,
then Z is N-sulfonamido, N(aryl)sulfonamido,
2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, benzamido, phenylureido,
phenylacetamido or (phenoxy)carbonylamino; when L is
(N-methylene)-4-acetyl- piperidin-4-yl, then Z is phenyl or
naphthyl and Y is carbonyl; and when L is
(N-methylene)piperidin-4,4-diyl, then Z is
1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl and Y is carbonyl; and
enantiomers, diastereomers and pharamaceutically acceptable salts
thereof.
18. A method of treating disorders and diseases associated with NPY
receptor subtype 5 selected from the group consisting of eating
disorders, obesity, diabetes, memory loss, epileptic seizures,
migraine, sleep disturbances, pain, sexual.reproductive disorders,
depression and anxiety comprising administering to a mammal in need
of such treatment a therapeutically effective amount of a compound
of claim 17.
19. A pharmaceutical composition for the treatment of diseases or
disorders associated with the NPY Y5 receptor subtype selected from
the group consisting of eating disorders, obesity, diabetes, memory
loss, epileptic seizures, migraine, sleep disturbances, pain,
sexual.reproductive disorders, depression and anxiety comprising a
therapeutically effective amount of a compound of claim 17 and a
pharmaceutically acceptable carrier
Description
FIELD OF THE INVENTION
[0001] This invention relates to a series of amine and amide
derivatives, pharmaceutical compositions containing them and
intermediates used in their preparation. The compounds of the
invention are ligands for the neuropeptide Y Y5 (NPY5) receptor, a
receptor which is associated with a number of central nervous
system disorders and affective conditions. In addition, many of the
compounds of the invention reduce food consumption in a rodent
model of feeding.
BACKGROUND OF THE INVENTION
[0002] Regulation and function of the mammalian central nervous
system is governed by a series of interdependent receptors,
neurons, neurotransmitters, and proteins. The neurons play a vital
role in this system, for when externally or internally stimulated,
they react by releasing neurotransmitters that bind to specific
proteins. Common examples of endogenous small molecule
neurotransmitters such as acetylcholine, adrenaline,
norepinephrine, dopamine, serotonin, glutamate, and
gamma-aminobutyric acid are well known, as are the specific
receptors that recognize these compounds as ligands ("The
Biochemical Basis of Neuropharmacology", Sixth Edition, Cooper, J.
R.; Bloom, F. E.; Roth, R. H. Eds., Oxford University Press, New
York, N.Y. 1991).
[0003] In addition to the endogenous small molecule
neurotransmitters, there is increasing evidence that neuropeptides
play an integral role in neuronal operations. Neuropeptides are now
believed to be co-localized with perhaps more than one-half of the
100 billion neurons of the human central nervous system. In
addition to humans, neuropeptides have been discovered in a number
of animal species. In some instances the composition of these
peptides is remarkably homogenous among species. This finding
suggests that the function of neuropeptides is vital and has been
impervious to evolutionary changes. Furthermore, neuropeptides,
unlike small molecule neurotransmitters, are typically synthesized
by the neuronal ribosome. In some cases, the active neuropeptides
are produced as part of a larger protein which is enzymatically
processed to yield the active substance. Based upon these
differences, compared to small molecule neurotransmitters,
neuropeptide-based strategies may offer novel therapies for CNS
diseases and disorders. Specifically, agents that affect the
binding of neuropeptides to their respective receptors or
ameliorate responses that are mediated by neuropeptides are
potential therapies for diseases associated with neuropeptides.
[0004] There are a number of afflictions that are associated with
the complex interdependent system of receptors and ligands within
the central nervous system; these include neurodegenerative
diseases, affective disorders such as anxiety, depression, pain and
schizophrenia, and affective conditions that include a metabolic
component, namely obesity. Such conditions, disorders and diseases
have been treated with small molecules and peptides which modulate
neuronal responses to endogenous neurotransmitters.
[0005] One example of the class of neuropeptides is neuropeptide Y
(NPY). NPY was first isolated from porcine brain (Tatemoto, K. et
al. Nature 1982, 296, 659) and was shown to be structurally similar
to other members of the pancreatic polypeptide (PP) family such as
peptide YY, which is primarily synthesized by endocrine cells in
the gut, and pancreatic polypeptide, which is synthesized by the
pancreas. Neuropeptide Y is a single peptide protein that consists
of thirty-six amino acids containing an amidated C-terminus. Like
other members of the pancreatic polypeptide family, NPY has a
distinctive conformation that consists of an N-terminal polyproline
helical region and an amphiphilic .alpha.-helix joined by a
characteristic PP-fold (Vladimir, S. et. Al. Biochemistry 1990, 20,
4509). Furthermore, NPY sequences from a number of animal species
have been elucidated and all show a high degree of amino acid
homology to the human protein (>94% in rat, dog, rabbit, pig,
cow, sheep) (see Larhammar, D. in "The Biology of Neuropeptide Y
and Related Peptides", Colmers, W. F. and Wahlestedt, C. Eds.,
Humana Press, Totowa, N.J. 1993).
[0006] Endogenous receptor proteins that bind NPY and related
peptides as ligands have been identified and distinguished, and
several such proteins have been cloned and expressed. Six different
receptor subtypes [Y1, Y2, Y3, Y4(PP), Y5, Y6 (formerly designated
as a Y5 receptor)] are recognized today based upon binding profile,
pharmacology and/or composition if identity is known (Wahlestedt,
C. et. al. Ann. NY Acad. Sci. 1990, 611, 7; Larhammar, D. et. al.
J. Biol. Chem. 1992, 267, 10935; Wahlestedt, C. et. al. Regul.
Pept. 1986, 13, 307; Fuhlendorff, J. U. et. al. Proc. Natl. Acad.
Sci. USA 1990, 87, 182; Grundemar, L. et. al. J. Pharmacol. Exp.
Ther. 1991, 258, 633; Laburthe, M. et. al. Endocrinology 1986, 118,
1910; Castan, I. et. al. Endocrinology 1992, 131, 1970; Gerald, C.
et. al. Nature 1996, 382, 168; Weinberg, D. H. et. al. Journal of
Biological Chemistry 1996, 271, 16435; Gehlert, D. et. al. Current
Pharmaceutical Design 1995, 1, 295; Lundberg, J. M. et. al. Trends
in Pharmaceutical Sciences 1996, 17, 301). Most and perhaps all NPY
receptor proteins belong to the family of so-called G-protein
coupled receptors (GPCRs). The neuropeptide Y5 receptor, a putative
GPCR, is negatively coupled to cellular cyclic adenosine
monophosphate (cAMP) levels via the action of adenylate cyclase
(Gerald, C. et. al. Nature 1996, 382, 168; Gerald, C. et. al. PCT
WO 96/16542). For example, NPY inhibits forskolin-stimulated cAMP
production/levels in a neuroblastoma cell line. A Y5 ligand that
mimics NPY in this fashion is an agonist whereas one that
competitively reverses the NPY inhibition of forskolin-stimulated
cAMP production is an antagonist.
[0007] Neuropeptide Y itself is the archetypal substrate for the
NPY receptors and its binding can elicit a variety of
pharmacological and biological effects in vitro and in vivo. When
administered to the brain of live animals
(intracerebroventricularly (icv) or into the amygdala), NPY
produces anxiolytic effects in established animal models of anxiety
such as the elevated plus-maze, Vogel punished drinking and
Geller-Seifter's bar-pressing conflict paradigms (Heilig, M. et.
al. Psychopharmacology 1989, 98, 524; Heilig, M. et. al. Reg.
Peptides 1992, 41, 61; Heilig, M. et. al. Neuropsycho-pharmacology
1993, 8, 357). Thus compounds that mimic NPY are postulated to be
useful for the treatment of anxiolytic disorders.
[0008] The immunoreactivity of neuropeptide Y is notably decreased
in the cerebrospinal fluid of patients with major depression and
those of suicide victims (Widdowson, P. S. et. al. Journal of
Neurochemistry 1992, 59, 73), and rats treated with tricyclic
antidepressants display significant increases of NPY relative to a
control group (Heilig, M. et. al. European Journal of Pharmacology
1988, 147, 465). These findings suggest that an inadequate NPY
response may play a role in some depressive illnesses, and that
compounds that regulate the NPY-ergic system may be useful for the
treatment of depression.
[0009] Neuropeptide Y improves memory and performance scores in
animal models of learning (Flood, J. F. et. al. Brain Research
1987, 421, 280) and therefore may serve as a cognition enhancer for
the treatment of neurodegenerative diseases such as Alzheimer's
Disease (AD) as well as AIDS-related and senile dementia.
[0010] Elevated plasma levels of NPY are present in animals and
humans experiencing episodes of high sympathetic nerve activity
such as surgery, newborn delivery and hemorrhage (Morris, M. J. et.
al. Journal of Autonomic Nervous System 1986, 17, 143). Thus
chemical substances that alter the NPY-ergic system may be useful
for alleviating migraine, pain and the condition of stress.
[0011] Neuropeptide Y also mediates endocrine functions such as the
release of luteinizing hormone (LH) in rodents (Kalra, S. P. et.
al. Frontiers in Neuroendrocrinology 1992, 13, 1). Since LH is
vital for mammalian ovulation, a compound that mimics the action of
NPY could be useful for the treatment of infertility, particularly
in women with so-called luteal phase defects.
[0012] Neuropeptide Y is a powerful stimulant of food intake; as
little as one-billionth of a gram, when injected directly into the
CNS, causes satiated rats to overeat (Clark, J. T. et. al.
Endocrinology 1984, 115, 427; Levine, A. S. et. al. Peptides 1984,
5, 1025; Stanley, B. G. et. al. Life Sci. 1984, 35, 2635; Stanley,
B. G. et. al. Proc. Nat. Acad. Sci. USA 1985, 82, 3940). Thus NPY
is orexigenic in rodents but not anxiogenic when given
intracerebroventricularly and so antagonism of neuropeptide
receptors may be useful for the treatment of diabetes and eating
disorders such as obesity, anorexia nervosa and bulimia
nervosa.
[0013] In recent years, a variety of potent, structurally distinct
small molecule Y1 antagonists has been discovered and developed
(Hipskind, P. A. et. al. Annu. Rep. Med. Chem. 1996, 31, 1-10;
Rudolf, K. et. al. Eur. J. Pharmacol. 1994, 271, R11; Serradeil-Le
Gal, C. et. al. FEBS Lett. 1995, 362, 192; Wright, J. et. al.
Bioorg. Med. Chem. Lett. 1996, 6, 1809; Poindexter, G. S. et. al.
U.S. Pat. No. 5,668,151; Peterson, J. M. et. al. WO9614307 (1996)).
However, despite claims of activity in rodent models of feeding, it
is unclear if inhibition of a feeding response can be attributed to
antagonism of the Y1 receptor.
[0014] Several landmark studies strongly suggest that an "atypical
Y1" receptor and/or the Y5 receptor, rather than the classic Y1
receptor, is responsible for invoking NPY-stimulated food
consumption in animals. It has been shown that the NPY fragment
NPY2-36 is a potent inducer of feeding despite poor binding at the
classic Y1 receptor (Stanley, B. G. et. al. Peptides 1992, 13,
581). Conversely, a potent and selective Y1 agonist has been
reported to be inactive at stimulating feeding in animals (Kirby,
D. A. et. al. J. Med. Chem. 1995, 38, 4579). More pertinent to the
invention described herein, [D-Trp.sup.32]NPY, a selective Y5
receptor activator has been reported to stimulate food intake when
injected into the hypothalamus of rats (Gerald, C. et. al. Nature
1996, 382, 168). Since [D-Trp.sup.32]NPY appears to be a full
agonist of the Y5 receptor with no appreciable Y1 activity, the Y5
receptor is hypothesized to be responsible for the feeding
response. Accordingly compounds that antagonize the Y5 receptor
should be effective in inhibiting food intake, particularly that
stimulated by NPY.
[0015] A variety of structurally diverse compounds that antagonize
the Y5 receptor have been described in various publications. In PCT
WO 97/19682, aryl sulfonamides and sulfamides derived from
arylalkylamines are described as Y5 antagonists and are reported to
reduce food consumption in animals. In. PCT WO 97/20820, PCT WO
97/20822 and PCT WO 97/20823, sulfonamides containing heterocyclic
systems such as quinazolin-2,4-diazirines, are likewise claimed as
Y5 antagonists and reported to reduce feeding. In PCT WO 99/10330,
a series of heterocyclic ketones is claimed to be NPY Y5
antagonists. In PCT WO 99/01128, certain diarylimidazole
derivatives are claimed as a new class of NPY specific ligands. In
PCT WO 98/35944, a series of .alpha.-alkoxy and
.alpha.-thioalkoxyamides are claimed to be NPY Y5 receptor
antagonists. In PCT WO 98/35957, a series of amide derivatives are
claimed as selective neuropeptide Y receptor antagonists; however,
these compounds are structurally different from the compounds of
this invention. The amides and amines of this invention that are
described herein are novel molecular entities that may have binding
motifs that are different from these and other Y5 ligands that have
been disclosed in patent applications or publications.
SUMMARY OF THE INVENTION
[0016] The present invention is related to compounds of formula A
##STR2## [0017] R.sub.1 is independently selected from the group
consisting of hydrogen; hydroxy; halo; C.sub.1-8alkyl; substituted
C.sub.1-8 alkyl wherein the substituent is selected from halo, such
as chloro, bromo, fluoro and iodo; C.sub.1-8alkoxy; substituted
C.sub.1-8 alkoxy wherein the substituent is selected from halo,
such as chloro, bromo, fluoro and iodo; trifluoroalkyl;
C.sub.1-8alkylthio and substituted C.sub.1-8alkylthio wherein the
substituent is selected from halo, such as chloro, bromo, fluoro
and iodo, trifluoroC.sub.1-8alkyl and C.sub.1-8alkoxy;
C.sub.3-6cycloalkyl; C.sub.3-8cycloalkoxy; nitro; amino;
C.sub.1-6alkylamino; C.sub.1-8dialkylamino;
C.sub.4-8cycloalkylamino; cyano; carboxy; C.sub.1-5alkoxycarbonyl;
C.sub.1-5alkylcarbonyloxy; formyl; carbamoyl; phenyl and
substituted phenyl wherein the substituent is selected from halo,
hydroxyl, nitro, amino and cyano; [0018] n is 1-2 [0019] B.sub.1 is
hydrogen; [0020] B.sub.2 is hydrogen;
[0021] or B.sub.1 and B.sub.2 may be methylene and joined together
form a five or six-membered ring; [0022] m 0-3 [0023] R.sub.2 is
independently selected from the group consisting of hydrogen;
hydroxy; C.sub.1-6alkyl; C.sub.2-6alkenyl; halo, such as fluoro and
chloro; C.sub.3-7cycloalkyl; phenyl; substituted phenyl wherein the
substituent is, selected from halo, C.sub.1-6alkyl,
C.sub.1-6alkoxy, trifluoroC.sub.1-6alkyl, cyano, nitro, amino,
C.sub.1-6alkylamino, and C.sub.1-6dialkylamino; naphthyl;
substituted naphthyl wherein the substituent is selected from halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, trifluoroC.sub.1-6alkyl, cyano,
nitro, amino, C.sub.1-6alkylamino, and C.sub.1-6dialkylamino;
phenoxy; substituted phenoxy wherein the substituent is selected
from halo, C.sub.1-6alkyl, C.sub.1-6alkoxy,
trifluoroC.sub.1-6alkyl, cyano and nitro; a heteroaryl group such
as pyridyl, pyrimidyl, furyl, thienyl, and imidazolyl; substituted
heteroaryl wherein the substitutent is selected from C.sub.1-6alkyl
and halo; and heterocycloalkyl such as pyrrolidino or piperidino;
[0024] Y is methylene (--CH.sub.2--) or carbonyl (C.dbd.O) [0025] L
is selected from the group consisting of
[0026] C.sub.1-8alkylene; C.sub.2-10alkenylene;
C.sub.2-10alkynylene; C.sub.3-7cycloalkylene;
[0027] C.sub.3-7cycloalkylC.sub.1-4alkylene;
[0028] arylC.sub.1-4alkylene;
[0029] .alpha.-aminoC.sub.4-7alkylene; ##STR3##
[0030] (N-methylene)piperidin-4-yl; ##STR4##
[0031] (N-methylene)piperazin-4-yl; ##STR5##
[0032] (N-methylene)pyrrolidin-3-yl; ##STR6##
[0033] (N-methylene)-4-acetyl-piperidin-4-yl; ##STR7##
[0034] and (N-methylene)piperidin-4,4-diyl; ##STR8## [0035] Z is
selected from the group consisting of:
[0036] aryl; ##STR9##
[0037] N-sulfonamido; ##STR10##
[0038] N-(aryl)sulfonamido; ##STR11##
[0039] arylamido; ##STR12##
[0040] arylureido; ##STR13##
[0041] arylacetamido: ##STR14##
[0042] (aryloxy)carbonylamino; ##STR15##
[0043] 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl; ##STR16##
[0044] and 1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl;
##STR17##
[0045] The aryl group in each case may be substituted as shown.
[0046] R.sub.3 is independently selected from the group consisting
of C.sub.1-8alkyl; substituted C.sub.1-8alkyl wherein the
substituent is selected from C.sub.1-8alkoxy and halo; cycloalkyl;
substituted cycloalkyl wherein the substituent is selected from
C.sub.1-8alkoxy and halo; naphthyl; substituted naphthyl wherein
the substituent is selected from halo, nitro, amino and cyano;
heteroaryl wherein the heteroaryl group is selected from pyridyl,
pyrimidyl, furyl, thienyl and imidazolyl; and substituted
heteroaryl wherein the substituent is selected from halo, nitro,
amino and cyano; [0047] R.sub.4 is independently selected from the
group consisting of hydrogen; C.sub.1-8alkyl; substituted
C.sub.1-8alkyl wherein the substituent is selected from alkoxy and
halo; hydroxy; halogen; cyano; nitro; amino; C.sub.1-8alkylamino
and C.sub.1-8dialkylamino; C.sub.1-8alkoxy; substituted
C.sub.1-8alkoxy wherein the substituent is halo; hydroxy; halogen;
cyano, nitro; amino and C.sub.1-8alkylamino and
C.sub.1-8dialkylamino; [0048] R.sub.5 is independently selected
from the group consisting of hydrogen; C.sub.1-8alkyl;
C.sub.1-8alkylcarbonyl; aroyl; carbamoyl; amidino;
(C.sub.1-8alkylamino)carbonyl; (arylamino)carbonyl and
arylC.sub.1-8alkylcarbonyl; [0049] R.sub.6 is independently
selected from the group consisting of hydrogen and C.sub.1-8alkyl;
[0050] p is 1-3; [0051] q is 1-3;
[0052] and enantiomers, diastereomers, and pharmaceutically
acceptable salts thereof,
[0053] provided that:
[0054] when L is C.sub.1-8alkylene, C.sub.2-10alkenylene,
C.sub.2-10alkynylene, C.sub.3-7cycloalkylene,
[0055] C.sub.3-7cycloalkylC.sub.1-4alkylene, arylC.sub.1-4alkylene
or .alpha.-aminoalkylene; [0056] then Z is phenyl, N-sulfonamido or
N-(aryl)sulfonamido;
[0057] when L is (N-methylene)piperazin-4-yl; [0058] then Z is
phenyl or naphthyl;
[0059] when L is (N-methylene)pyrrolidin-3-yl or
(N-methylene)piperidin-4-yl; [0060] then Z is N-sulfonamido,
N-(aryl)sulfonamido, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl;
benzamido, phenylureido, phenylacetamido or
(phenoxy)carbonylamino;
[0061] when L is (N-methylene)-4-acetyl-piperidin-4-yl; [0062] then
Z is phenyl or naphthyl and Y is carbonyl;
[0063] when L is (N-methylene)piperidin-4,4-diyl; [0064] then Z is
1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl and Y is carbonyl;
[0065] and when B.sub.1 and B.sub.2 are both methylene thus forming
a six-membered ring (an aminotetralin) and when L is selected from
the group consisting of C.sub.1-8alkylene; C.sub.2-10alkenylene;
C.sub.2-10alkynylene or arylC.sub.1-4alkylene; [0066] then Z cannot
be N-sulfonamido, N-(aryl)sulfonamido or phenyl;
[0067] all enantiomers and diastereomers of compounds of formula A
are part of the present invention, as are pharmaceutically
acceptable salts thereof.
Preferred compounds among the compounds of this invention are those
wherein B.sub.1 and B.sub.2 form a six-membered ring and m=1-3.
[0068] As used herein unless otherwise noted the terms "alkyl" and
"alkoxy" whether used alone or as part of a substituent group,
include straight and branched chains having 1-8 carbon atoms. For
example, alkyl radicals include methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl,
1-methylbutyl, 2-methylbutyl, neopentyl, hexyl, 1-methylpentyl,
3-methylpentyl. Alkoxy radicals are oxygen ethers formed from the
previously described straight or branched chain alkyl groups. The
term "aryl" is intended to include phenyl and naphthyl and aroyl is
intended to include arylacyl. The term "acyl" is intended to
include C.sub.1-8alkylcarbonyl. The term "halo", unless otherwise
indicated, includes bromo, chloro, fluoro and iodo. The term
"cycloalkyl" is intended to include cycloalkyl groups having 3-7
carbon atoms. With reference to substituents, the term
"independently" means that when more than one of such substituent
is possible, such substituents may be the same or different from
each other.
[0069] Those compounds of the present invention which contain a
basic moiety can be converted to the corresponding acid addition
salts by techniques known to those skilled in the art. Suitable
acids which can be employed for this purpose include hydrochloric,
hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,
acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic,
succinic, maleic, fumaric, malic, tartaric, citric, benzoic,
cinnamic, mandelic, methanesulfonic, p-toluenesulfonic,
cyclohexanesulfamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic,
or saccharin, and the like. In general, the acid addition salts can
be prepared by reacting the free base of compounds of formula A
with the acid and isolating the salt.
[0070] Pharmaceutical compositions containing one or more of the
compounds of the invention described herein as the active
ingredient can be prepared by intimately mixing the compound or
compounds with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier may take a wide
variety of forms depending upon the desired route of administration
(e.g., oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives
include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Solid oral preparations may also be coated with
substances such as sugars or be enteric-coated so as to modulate
the major site of absorption. For parenteral administration, the
carrier will usually consist of sterile water and other ingredients
may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
[0071] For the treatment of disorders of the central nervous
system, the pharmaceutical compositions described herein will
typically contain from 1 to about 1000 mg of the active ingredient
per dosage; one or more doses per day may be administered.
Determination of optimum doses and frequency of dosing for a
particular disease state or disorder is within the experimental
capabilities of those knowledgeable in the treatment of central
nervous system disorders. The preferred dose range is 1-100
mg/kg.
[0072] As modulators of the NPY5 receptor, the compounds of Formula
A are useful for treating feeding disorders such as obesity,
anorexia nervosa and bulimia nervosa, and abnormal conditions such
as epilepsy, depression, anxiety and sexual/reproductive disorders
in which modulation of the NPY5 receptor may be useful. The
compounds compete with the endogenous ligands NPY and PYY and
possibly non-endogenous ligands, and bind to the NPY5 receptor. In
addition, the compounds demonstrate antagonist activity by
antagonizing the action of NPY upon binding to the Y5 receptor.
[0073] The compounds described herein are ligands of the NPY5
receptor, but are not necessarily limited solely in their
pharmacological or biological action due to binding to this or any
neuropeptide, neurotransmitter or G-protein coupled receptor. For
example, the described compounds may also undergo binding to
dopamine or serotonin receptors. The compounds described herein are
potentially useful in the regulation of metabolic and endocrine
functions, particularly those associated with feeding, and as such,
may be useful for the treatment of obesity. In addition, the
compounds described herein are potentially useful for modulating
other endocrine functions, particularly those controlled by the
pituitary and hypothalamic glands, and therefore may be useful for
the treatment of inovulation/infertility due to insufficient
release of luteinizing hormone (LH) or luteal phase defect.
[0074] The present invention comprises pharmaceutical compositions
containing one or more of the compounds of Formula A. In addition,
the present invention comprises intermediates used in the
manufacture of compounds of Formula A.
[0075] Examples of particularly preferred compounds of formula A
include: ##STR18## ##STR19## ##STR20## ##STR21## ##STR22##
##STR23## ##STR24## ##STR25## ##STR26## ##STR27## ##STR28##
DETAILED DESCRIPTION OF THE INVENTION
[0076] The amines and amides of formula A that comprise this
invention are synthesized via several distinct chemical syntheses
as outlined in Schemes 1-26; each synthetic route consists of
several sequential chemical operations that can be generalized as
described below. In cases in which B.sub.1 and B.sub.2 together
form a six-membered ring or a five-membered ring (an aminotetralin
or an aminoindane, respectively), the general synthesis entails the
following operations: [0077] Introduction of the a-substituent onto
the tetralone (or indanone) nucleus [0078] Conversion to the
corresponding .alpha.-substituted-.beta.-aminotetralin (or
.alpha.-substituted-aminoindane) [0079] Acylation of the
aminotetralin (or aminoindane) to afford amides of formula A [0080]
Reduction to produce amines of formula A
[0081] Protecting group manipulations may be needed at various
stages of the syntheses.
[0082] In cases where B.sub.1 and B.sub.2 are hydrogen, the general
synthesis consists of the following operations: [0083] Introduction
of the .alpha.-substituent onto a phenylacetonitrile [0084]
Reduction to the corresponding .beta.-substituted phenethylamine
[0085] Acylation of the phenethylamine to afford amides of formula
A [0086] Reduction to produce amines of formula A
[0087] Protecting group manipulations may be needed at various
stages of the syntheses.
[0088] It is generally preferred that the respective product of
each process step be separated from other components of the
reaction mixture and subjected to purification before its use as a
starting material in a subsequent step. Separation techniques
typically include evaporation, extraction, precipitation and
filtration. Purification techniques typically include column
chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43,
2921), thin-layer chromatography, crystallization and distillation.
The structures of the final products, intermediates and starting
materials are confirmed by spectroscopic, spectrometric and
analytical methods including nuclear magnetic resonance (NMR), mass
spectrometry (MS) and liquid chromatography (HPLC). In the
descriptions for the preparation of compounds of this invention,
ethyl ether, tetrahydrofuran and dioxane are common examples of an
ethereal solvent; benzene, toluene, hexanes and cyclohexane are
typical hydrocarbon solvents and dichloromethane and dichloroethane
are representative halohydrocarbon solvents. In those cases wherein
the product is isolated as the acid addition salt the free base may
be obtained by techniques known to those skilled in the art. In
those cases in which the product is isolated as an acid addition
salt, the salt may contain one or more equivalents of the acid.
[0089] Specifically, an appropriately substituted .beta.-tetralone
(II) is reacted with an aryl or heteroaryl aldehyde in the presence
of a base such as piperidine, in an inert halohydrocarbon, ethereal
or hydrocarbon solvent, such as benzene, from ambient temperature
to reflux, to afford the corresponding
.alpha.-benzylidenyl-.beta.-tetralone or
.alpha.-heteroarylmethylidenyl-.beta.-tetralone (III). The
.beta.-tetralone (III) is dissolved in an inert hydrocarbon,
ethereal, ester or alcohol solvent, such as methanol, and reacted
with hydrogen gas at a pressure from ambient pressure to 100 p.s.i.
in the presence of a suitable catalyst such as palladium on carbon.
The reaction is performed at a temperature from ambient temperature
to reflux, to yield the desired
.alpha.-substituted-.beta.-tetralone (IV) (Scheme 1).
[0090] An alternative method for the preparation of
.alpha.-substituted-.beta.-tetralones (IV) involves the reaction of
an appropriately substituted .beta.-tetralone (II) with a base such
as pyrrolidine in an inert halohydrocarbon solvent such as
dichloromethane or hydrocarbon solvent such as benzene, under
Dean-Stark conditions (removal of water) or in an alcohol solvent
such as methanol, from ambient temperature to reflux, to afford
enamine (V). Alkylation of enamine (V) is accomplished by reaction
with a benzylic, heterocyclicalkyl or an allylic halide in an inert
solvent such as acetonitrile, at a temperature from ambient
temperature to reflux, to afford the
.alpha.-substituted-.beta.-iminium salt (VI). Hydrolysis of the
salt (VI) to produce the desired
.alpha.-substituted-.beta.-tetralone product (IV) is accomplished
by reaction of (VI) with water and an inorganic or organic acid
such as hydrochloric or glacial acetic acid in an inert
hydrocarbon, ethereal, alcohol or halohydrocarbon solvent, or a
mixture thereof, such as methanol and dichloromethane (Scheme 1).
##STR29##
[0091] The .alpha.-substituted-.beta.-tetralones (IV) are converted
to the corresponding aminotetralins via reaction with an ammonium
salt such as ammonium acetate in the presence of a reducing agent
such as sodium cyanoborohydride, for example, in an inert
halohydrocarbon, hydrocarbon, ethereal or alcohol solvent such as
methanol to produce the cis-aminotetralin (VII). In some, cases,
the trans-aminotetralin (VIII) is also formed as a minor product;
both sets of diastereomers are part of this invention. The
aminotetralins (VII) can also be isolated as acid addition salts by
treatment with an organic or an inorganic acid, such as
trifluoroacetic acid or hydrochloric acid, for example (Scheme 2).
##STR30## [0092] Compounds in which m=0 are prepared from an
appropriately substituted aminotetralin (VII; m=0) starting from
1-tetralones using the synthetic sequence shown in Scheme 2a.
##STR31## Substituted phenethylamines (XI) are prepared by reacting
an appropriately substituted phenylacetonitrile (IX) with an aryl
or heteroaryl aldehyde in the presence of a base, such as sodium
methoxide, in an inert alcohol solvent, such as methanol, at a
temperature from ambient temperature to reflux, to afford
.alpha.,.beta.-unsaturated nitrite (X). Subsequent reduction of
nitrile (X), for example, via reaction with hydrogen gas in the
presence of a platinum oxide catalyst at a pressure from
atmospheric pressure to approximately 100 psi, in an inert solvent
such as aqueous alcohol, at a temperature from ambient temperature
to reflux, affords 5-substituted phenethylamine (XI).
Alternatively, reaction of phenylacetonitrile (X) with an
arylalkyl-, heteroarylalkyl- or alkyl halide, for example, such as
allyl bromide in, the presence of a base such as sodium methoxide
or sodium hydride, in an inert solvent such as tetrahydrofuran or
acetonitrile respectively, at a temperature from ambient to reflux,
affords a-substituted phenylacetonitrile (XII). Subsequent
reduction of nitrile (XII), for example, by hydrogenolysis,
produces .beta.-substituted phenethylamine (XI) (Scheme 3).
##STR32##
[0093] The .beta.-aminotetralins (VII) and the phenethylamines (XI)
described above are acylated via. suitable amidation methods (see
Gross and Meienhofer, Eds., "The Peptides", Vols. 1-3, Academic
Press, New York, N.Y., 1979-1981). A carboxylic acid is converted
to an activated ester via peptide coupling methods known to those
skilled in the art, and subsequently reacted with an aminotetralin
(VII) or phenethylamine (XI), to afford the corresponding
amides.
[0094] For example, a carboxylic acid such as
trans-4-(2-fluorobenzenesulfonamido)methylcyclohexane carboxylic
acid or 4-(tert-butoxycarbonyl)aminomethylcyclohexane carboxylic
acid is reacted with HSTU
(2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate and an appropriate phenethylamine (XI), in the
presence of a base such as diisopropylethylamine, in an inert
solvent such as N,N-dimethylformamide, at a temperature from
ambient temperature to reflux, to afford amide (XIII) or amide
(XIV) respectively. Cleavage of the BOC (butoxycarbonyl) protecting
group from carbamate (XIV) with trifluoroacetic acid produces the
free amine, which is sulfonylated to yield amide (XIII).
[0095] The N-substituted phenethylamine compounds A of the
invention are prepared via reduction of amide (XIII) by reaction
with a suitable reducing agent such as borane-tetrahydrofuran
complex or lithium aluminum hydride in an inert hydrocarbon solvent
such as toluene or ethereal solvent such as tetrahydrofuran, at a
temperature from ambient temperature to reflux. The final product
can be isolated as an acid addition salt upon treatment with a
suitable organic acid such as trifluoroacetic acid or an inorganic
acid such as hydrochloric acid (Scheme 4). ##STR33##
[0096] Aminotetralin analogs (B.sub.1 and B.sub.2 each are
methylene) are prepared using the chemistry described above but
replacing the phenethylamine (XI) starting material with an
aminotetralin (VII) (Scheme 5). ##STR34##
[0097] Compounds of formula A in which
Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and
L=(N-methylene)piperidin-4-yl are prepared from
.beta.-aminotetralins (VII) or phenethylamines (XI) and
[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid (Schemes
6-7). For example, 4(2-keto-1-benzimidazolinyl)piperidine is
reacted with a bromoacetic acid ester, such as ethyl bromoacetate,
in the presence of an amine base, such as diisopropylethylamine, in
an inert solvent such as acetonitrile, at a temperature ranging
from ambient temperature to reflux, to afford ethyl
[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is
subjected to hydrolysis under basic conditions, for example, by
treatment with sodium hydroxide in an alcoholic solution such as
aqueous methanol, to yield, upon acidification with an inorganic or
organic acid such as hydrochloric or acetic acid for example,
[4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. This
carboxylic acid is reacted directly with .beta.-aminotetralins
(VII) or phenethylamines (XI), in the presence of an amine base,
under peptide coupling conditions described above, to afford
benzimidazolinones (XVII) and (XVIII) of formula A in which
Y=carbonyl and L=(N-methylene)piperidin-4-yl (Schemes 6-7).
##STR35## ##STR36##
[0098] Compounds of formula A in which Y=methylene and
L=(N-methylene)piperidin-4-yl and
Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl are prepared by reduction
of amide (XVII) and amide (XVIII) with a reducing agent such as
borane-tetrahydrofuran complex or lithium aluminum hydride as
described above. The use of an aminotetralin (VII) starting
material gives rise to products (XIX) (Scheme 8) whereas
phenethylamines give the analogous amines (XX) (Scheme 9).
##STR37## ##STR38##
[0099] Compounds of formula A in which Y=carbonyl,
L=(N-methylene)piperazin-4-yl and Z=phenyl are prepared by reacting
a phenylpiperazine with a haloacetic acid ester, such as, for
example, ethyl bromoacetate, in the presence of an amine base, such
as diisopropylethylamine, in an inert solvent such as acetonitrile,
at a temperature ranging from ambient temperature to reflux, to
afford ethyl (4-arylpiperazin-1-yl)acetate. This ester is subjected
to hydrolysis under basic conditions, for example, by treatment
with sodium hydroxide in an aqueous methanol, to yield, upon
acidification with an inorganic or organic acid such as
hydrochloric or acetic acid for example,
(4-arylpiperazin-1-yl)acetic acid. This carboxylic acid is reacted
with .beta.-aminotetralins (VII) or phenethylamines (XI), in the
presence of a base, such as triethylamine for example, under
peptide coupling conditions described above, to afford
arylpiperidines (XXI) and (XXII) respectively, of formula A in
which Y=carbonyl, L=(N-methylene)piperazin-4-yl and Z=aryl or
substituted aryl (Schemes 10-11). ##STR39## ##STR40##
[0100] Compounds of formula A in which Y=methylene,
L=(N-methylene)piperazin-4-yl and Z=aryl are prepared by reduction
of amides (XXI) and (XXII) with a reducing agent such as
borane-tetrahydrofuran complex or lithium aluminum hydride (see
Scheme 9) to afford aminotetralins (XXIII) and phenethylamines
(XIV) respectively (Schemes 12-13). ##STR41## ##STR42##
[0101] Replacement of 4-arylpiperazines with 4-arylpiperidines in
Schemes 10 and 11 affords tetralinamides (XXV) and phenethylamides
(XXVI) of formula A in which L=(N-methylene)piperidin-4-yl, Z=aryl
and Y=carbonyl (Schemes 14-15). ##STR43## ##STR44##
[0102] Separately, reduction of amides (XXV) and (XXVI) with a
reducing agent such a boranetetrahydrofuran complex, affords amines
(XXVII) and (XXVIII) of formula A in which
L=(N-methylene)piperidin-4-yl, Z=aryl and Y=methylene (Scheme 16).
##STR45##
[0103] Compounds of formula A in which Y=carbonyl,
L=(N-methylene)pyrrolidin-3-yl and Z=N-(aryl)sulfonamido are
prepared by reacting a suitably protected aminopyrrolidine, such as
(3-t-butoxycarbonylamino)pyrrolidine with a haloacetic acid ester,
such as, for example, ethyl bromoacetate, in the presence of an
amine base, such as diisopropylethylamine, in an inert solvent such
as acetonitrile, at a temperature ranging from ambient temperature
to reflux, to afford ethyl
[(3-t-butoxycarbonylamino)pyrrolidin-1-yl]acetate. This ester is
subjected to hydrolysis under basic conditions, for example, by
treatment with sodium hydroxide in an aqueous methanol, to yield,
upon acidification with an inorganic or organic acid such as
hydrochloric or acetic acid for example,
[(3-t-butoxycarbonylamino)pyrrolidin-1-yl]acetic acid. This
carboxylic acid is reacted with .beta.-aminotetralins (VII) or
phenethylamines (XI), in the presence of a base, such as
triethylamine for example, under peptide coupling conditions
described above, to afford tetralinamides (XXIX) and phenethyamides
(XXX) respectively. Subsequent treatment with an organic or
inorganic acid, such as trifluoroacetic acid and hydrochloric acid
for example, produces the free terminal amines (XXXI) and (XXXII).
These materials are sulfonylated by reaction with sulfonyl halides
such as benzenesulfonyl chloride for example, in the presence of a
base, to afford tetralinamides (XXXIII) and phenethylamides (XXXIV)
(Schemes 17-18). ##STR46## ##STR47##
[0104] Separately, reduction of amides (XXXIII) and (XXXIV) with a
reducing agent such a borane-tetrahydrofuran complex, affords
amines (XXXV) and (XXXVI) of formula A in which
L=N-(methylene)pyrrolidin-3-yl and Z=sulfonamido or
(aryl)sulfonamido, Y=methylene (Scheme 19). ##STR48##
[0105] Tetralinamides and phenethylamides of formula A in which
Y=carbonyl, L=(N-methylene)pyrrolidin-3-yl and Z=benzamido,
phenylureido, phenylacetamido and phenoxycarbonylamino (or
butoxycarbonylamino) are prepared by reacting amines (XXXI) and
(XXXII) respectively, in an inert solvent at a temperature from
ambient temperature to reflux, in the presence of a base such as an
amine or hydroxide, with an aroyl halide, an arylisocyanate, an
arylacetyl halide or a chloroformate such as phenylchloroformate
(or di-tert-butyl dicarbonate) to afford benzamides (XXXVII) and
(XXXXI), phenylureas (XXXVIII) and (XXXXII), phenylacetamides
(XXXIX) and (XXXXIII) and phenylcarbamate (XXXX) and (XXXIV)
respectively (Schemes 20-21). ##STR49## ##STR50## Compounds of
formula A in which Y=methylene, L=N-(methylene)pyrrolidin-3-yl and
Z=benzamido, phenylureido, phenylacetamido and phenylcarbonylamino
(or butoxycarbonylamino) are prepared by reducing amides (XXXI) and
(XXXII) to their respective amines (XXXXV) and (XXXXVI) by
treatment With a reducing agent such as borane-tetrahydrofuran
complex or lithium aluminum hydride. Amines (XXXXV) and (XXXXVI)
are subsequently separately reacted with an aroyl halide, an
arylisocyanate, an arylacetyl halide or an arylchloroformate (or
carbonate such as di-tert-butyl carbonate), in the presence of a
base in an inert solvent as described in Scheme 20-21, to afford
benzamides (XXXXVII) and (XXXXXI), phenylureas (XXXXVIII) and
(XXXXXII), phenylacetamides (XXXXIX) and (XXXXXIII) and
phenylcarbamates (XXXXX) and (XXXXXIV), respectively (Schemes
22-24). ##STR51## ##STR52## ##STR53##
[0106] Substituting an appropriately protected aminopiperidine,
such as (4-t-butoxycarbonylamino)piperidine for (3-
t-butoxycarbonylamino)pyrrolidine in Schemes 17-24 affords
compounds of formula A in which L=(N-methylene)piperidin-4-yl,
Y=methylene or carbonyl and Z=N-(aryl)sulfonamido, sulfonamido,
benzamido, phenylureido, phenylacetamido or
(phenoxy)carbonylamino.
[0107] Compounds of formula A in which Y=carbonyl,
L=(N-methylene)piperidin-4,4-diyl and
Z=1-aryl-2,3-dihydro-4oxo-imidazol-5,5-diyl are prepared by
reacting 1-aryl-1,3,8-triazaspiro-{4,5}decan-4one with a haloacetic
acid ester, such as ethyl brornoacetate, in the presence of an
amine base, such as diisopropylethylamine, in an inert solvent such
as acetonitrile, at a temperature from ambient temperature to
reflux, to afford ethyl
(1-aryl-1,3,8-triazaspiro-[4,5]decan-4-one-8-yl)acetate. This ester
is subjected to hydrolysis under basic conditions, for example, by
treatment with sodium hydroxide in an alcoholic solution such as
aqueous methanol, to yield upon acidification with an inorganic or
organic acid such as hydrochloric or acetic acid for example,
(1-aryl-1,3,8-triazaspiro-[4,5]decan-4-one-8-yl)acetic acid. This
carboxylic acid is reacted directly with .beta.-tetralins (VII) or
phenethylamines (XI), in the presence of a base such as
triethylamine for example, under peptide coupling conditions
described above, to afford aminotetalinamides (XXXXXV) and
phenethylamides (XXXXXVI) respectively, of formula A in which
Y=carbonyl, L=(N-methylene)piperidin-4,4-diyl and
Z=1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl (Schemes 25-26).
##STR54## ##STR55##
[0108] Compounds of formula A in which L
=(N-methylene)-4-acetyl-piperidin-4-yl and Z=phenyl are prepared by
reacting 4-acetyl-4-phenylpiperidine with a haloacetic acid ester,
such as, for example, ethyl bromoacetate, in the presence of an
amine base, such as diisopropylethylamine, in an inert solvent such
as acetonitrile, at a temperature ranging from ambient temperature
to reflux, to afford ethyl
[(4-acetyl-4-phenylpiperidin-1-yl]acetate. This ester is subjected
to hydrolysis under basic conditions, for example, by treatment
with sodium hydroxide in an aqueous methanol, to yield, upon
acidification with an inorganic or organic acid such as
hydrochloric or acetic acid for example,
H4-acetyl-4-phenylpiperidin-1-ylacetic acid. This carboxylic acid
is reacted with 13-aminotetralins (VII) or phenethylamines (XI), in
the presence of a base, such as triethylamine for example, under
peptide coupling conditions described above, to afford
(tetralinamido)arylpiperidines (XXXXXVII) and
(phenethylamido)arylpiperidines (XXXXXVIII) respectively, of
formula A in which Y=carbonyl,
L=(N-methylene)-4-acetyl-piperidin-4-yl and Z=phenyl (Schemes
27-28). ##STR56## ##STR57##
[0109] Other compounds of this invention having the formula A can
be prepared using the methods described herein; modifications of
the experimental protocols described above are known or obvious or
within the ability of those skilled in the art. For example, a
variety of .beta.-tetralones are known or readily prepared by
reaction of phenylacetic acids with ethylene gas in the presence of
a Lewis acid (for example, Stjernlof, P. et. al. J. Med. Chem.
1995, 38, 2202); these compounds can be directly converted to
aminotetralins (VII) via reductive amination (Scheme 2).
Phenethylamine intermediates (XI) are accessible from
phenylacetonitriles using literature methods (Jounral, Hawes and
Wibberley, J. Chem. Soc. C. 1966, 315 and 320; also see J. Am.
Chem. Soc. 1989, 111, 5954 and Synthesis 1997, 11, 1268) and can be
used to prepare compounds of formula A in which B.sub.1 and B.sub.2
are both hydrogen (Scheme 3). Compounds in which the R.sub.1
group(s) is varied can be obtained using the chemistry described
above; in some cases, protecting group manipulations are used and
these are obvious or known to those skilled in the art. Examples
include masking an amine group as a carbamate, amide or
phthalamide, and masking an hydroxyl group as an ether or ester.
Other R.sub.1 substituents are available through functional group
manipulations such as, for example, reduction of a nitro group to
an amine or dehydration of an amide to a nitrile.
[0110] Variation of the R.sub.2 group is readily accomplished by
using substituted benzaldehydes, naphthylaldehydes and heteroaryl
carboxaldehydes, or by using alkyl, alkylenic, alkynylic and
benzylic halides, or by using phenoxyalkyl and haloalkyl halides in
Schemes 1 and 3. Compounds in which the L group is varied, are
derived from piperazines, piperidines or pyrrolidines as described
in Schemes 6, 10, 14, 17 and 25. Compounds in which L is alkylene,
alkenylene, alkynylene, cycloalkylene or cycloalkylalkylene are
derived from amino-carboxylic acids such as aminohexanoic acid,
aminohexenoic acid, aminohexynoic acid. Compounds in which L is
a-aminoalkylene are derived from amino acids such as lysine which
can be used in the racemic or enantiomeric form.
[0111] Compounds of formula A where Z is sulfonamido or
(aryl)sulfonamido, in which either the R.sub.3 or the R.sub.4 group
is varied, are accessible by sulfonylation; there are hundreds of
sulfonyl halides or sulfonic acids that are commercially available
and more that are known. Compounds of formula A where Z is
sulfonamido or (aryl)sulfonamido, in which the R.sub.3 substituent
is heteroaryl can be prepared by substituting a pyridinyl, thienyl
or furyl sulfonylchloride for a benzenesulfonamide as described in
Schemes 4-5. Similarly, alkylsulfonyl and cycloalkylsulfonyl
halides, alone or in the presence of an activating agent such as a
Lewis acid, can be used to prepare sulfonamides of formula A in
which the R.sub.3 substituent is alkyl or cycloalkyl respectively.
Compounds in which Z is phenyl or aryl are obtained directly from
arylpiperazines and arylpiperidines as described in Schemes 10 and
14 respectively; hundreds of arylpiperazines and arylpiperidines
are known or commercially available and can be used to make
compounds of this invention. Compounds of formula A where Z is
benzamido, phenylureido, phenylacetamido, (phenoxy)carbonylamino
are prepared from aroyl halides, isocyanates, phenylacetyl halides
and chloroformates as described in Schemes 20-21 and 23-24 and
hundreds of reagents of these kinds are commercially available or
known.
[0112] Compounds of formula A in which B.sub.1 and B.sub.2 are
joined together to form a five-membered ring (an aminoindane) are
prepared starting from an indanone and using the chemistry
described herein. It is preferable to use a symmetrical indan-2-one
to avoid the formation of regiochemical isomers which are difficult
to separate.
EXAMPLES
[0113] The following examples describe the invention in greater
detail and are intended to illustrate the invention, but not to
limit it. All compounds were identified by a variety of methods
including nuclear magnetic resonance spectroscopy, mass
spectrometry and, in some cases, infrared spectroscopy and
elemental analysis. Nuclear magnetic resonance (300 MHz NMR) data
are reported in parts per million downfield from tetramethylsilane.
Mass spectra data are reported in mass/charge (m/z) units. Unless
otherwise noted, the materials used in the examples were obtained
from readily available commercial sources or synthesized by
standard methods known to those skilled in the art.
Examples 1-2
2-Amino-6-[(2-fluorophenylsulfonyl)amino]-N-[cis-
1,2,3,4-tetrahydro-6-methoxy-1
-(3-pyridinylmethyl)-2-naphthenyl-(2S)-hexanamide bis-hydrochloride
7
N-[5-amino-6-[[cis-[1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-
-naphthalenyl]amino]hexyl-2-fluorobenzenesulfonamide
tris-hydrochloride 8
[0114] A. 6-Methoxy-.beta.-tetralone 1 (2.0 g, 11.3 mmol) and
diisopropylethylamine (0.20 mL, 1.1 mmol) were dissolved in benzene
(60 mL) with stirring in a 100 mL round-bottom flask.
3-Pyridylcarboxaldehyde (1.1 mL, 11.7 mmol) was added and the
reaction vessel was flushed with argon and a Dean-Stark trap with
reflux condenser was attached. The mixture was heated at reflux for
19 hours. After cooling, HPLC analysis indicated that no products
had formed. Piperidine (0.094 mL, 1.1 mmol) was added at this time
and heating at reflux was continued for 23 hours. The solvents were
removed in vacuo to yield a glassy orange solid. Chromatographic
purification [silica gel column (dimensions 5.times.29 cm) eluting
with a gradient of: 100% hexane (400 mL), 75%/25% hexane/ethyl
acetate (v/v) (400 mL), 50%/50% hexane/ethyl acetate (v/v) (400
mL), 25%/75% hexane/ethyl acetate (v/v) (400 mL), and finally with
100% ethyl acetate] was performed. After evaporation of the
appropriate fractions,
3,4-dihydro-6-methoxy-1-((3-pyridinyl)methylidenyl)-2-naphthalenone
2 (1.484 g, 5.59 mmol) was obtained as an orange oil which
solidified upon standing in the refrigerator. MS (MH.sup.+) 266;
.sup.1H NMR (CDCl.sub.3) .delta. 2.67 (t, 2H), 3.02 (t, 2H), 3.83
(s, 3H), 6.60 (dd, 1H), 6.82 (d, 1H), 7.19 (m, 2H), 7.51 (s, 1H),
7.71 (d, 1H), 8.49 (dd, 1H), 8.65 (d, 1H).
[0115] B. The naphthalen-2-one 2 (1.442 g, 5.44 mmol) obtained
above was dissolved in absolute ethanol (50 mL) and transferred to
a 250 mL Parr hydrogenation bottle. Separately, ethanol was
carefully added to 10% palladium on carbon (0.020 g) and this
slurry was added to the Parr bottle. The mixture was hydrogenated
under a pressure of 50 psi for 16 hours. The catalyst was removed
by filtration over Celite. Spectroscopic evidence indicated the
presence of some starting material and so more palladium catalyst
(0.081 g) was added to the ethanol solution and the hydrogenation
was repeated for 20 hours. The catalyst was then removed by
filtration over Celite. Removal of the solvents in vacuo yielded
3,4-dihydro-6-methoxy-1 -(3-pyridinylmethyl)-2(1 H)-naphthalenone 3
as an orange oil which was used in the next step without further
purification. MS (MH.sup.+) 268.
[0116] C. Naphthalen-2-one 3 obtained above was dissolved in
methanol (275 mL) in a 1 L round-bottom flask. Ammonium acetate
(4.27 g, 55.4 mmol) was added to the stirred methanol solution and
was allowed to completely dissolve before proceeding. Sodium
cyanoborohydride (1.703 g, 27.5 mmol) was then added to the
methanol solution. The reaction vessel was flushed with nitrogen
and the solution refluxed for 18 hours. The solvents were then
removed in vacuo to yield a yellow solid which was dissolved in
ethyl ether (500 mL) and 0.1 M sodium hydroxide solution (275 mL)..
The organic layer was removed and washed with an additional 0.1 M
sodium hydroxide solution (275 mL) and with water (250 mL). The
combined aqueous washes were back extracted with ethyl ether
(3.times.100 mL). The organic extracts were combined and dried over
sodium sulfate. The solvents were removed in vacuo and the residue
was taken up in ethyl ether and a minimum amount of
dichloromethane. An excess of 1 M hydrogen chloride in ethyl ether
was added and a dark tan precipitate formed. The solvents were
removed in vacuo and the resulting solid was triturated with ether
and dried in a vacuum oven to yield 1,2,3,4-tetrahydro-6-methoxy-1
-(3-pyridinylmethyl)-2-naphthalenamine bis-hydrochloride 4 as a
tan-orange solid (1.208 g, 3.54 mmol) MS (MH.sup.+) 269; .sup.1H
NMR (DMSO-d.sub.6) .delta. 1.95-2.20 (m, 2H), 2.68-3.29 (m, 4H),
3.30-3.48 (m, 2H), 3.69 (s, 3H), 5.98 (d, 1H), 6.41 (dd, 1H), 6.75
(d, 1H), 7.98 (dd, 1H), 8.36 (d, 1H), 8.68-8.89 (m, 5H) (FIG.
1).
[0117] D. N-tert-Butoxycarbonyl-L-Lysine (2.49 g, 10.1 mmol) was
placed in a 200 mL round-bottom flask. A magnetic stir bar was
added followed by 10 mL dioxane and 21 mL 1 N sodium hydroxide
solution. The solution was stirred for several minutes until
complete dissolution had occurred. A solution of
2-fluorobenzenesulfonyl chloride (2.00 g, 10.3 mmol) in dioxane (11
mL) was added via pipette. The reaction vessel was flushed with
argon, capped and allowed to stir at ambient temperature for
approximately 1.5 hours. The stir bar was then removed and the
solvent evaporated under reduced pressure until only water
remained. To this mixture water was added to bring the volume to
about 50 mL and 1 N hydrochloric acid (22 mL) was added which
resulted in the formation of a gooey precipitate. This mixture was
extracted with methylene chloride (3.times.50 mL) and the combined
organics were washed with 1N hydrochloric acid (1.times.50 mL) and
then brine (1.times.50 mL). The organics were dried over magnesium
sulfate, filtered and concentrated in vacuo to yield the
sulfonylated N-t-butoxycarbonyl-lysine 5 (3.93 g, 9.7 mmol) as an
off-white glassy semi-solid. NMR(d.sub.6-DMSO): .delta. 12.42 (s,
1H), 7.90 (t, 1H), 7.79 (t, 1H), 7.71 (m, 1 H), 7.49-7.34 (m, 2H),
7.02 (d, 1 H), 3.78 (m, 1 H), 2.83 (m, 2H), 1.63-1.16 (m, 15H); MS:
M-H =403.
[0118] E. The sulfonylated L-lysine 5 from the previous reaction
(3.92 g, 9.69 mmol) was placed in a 300 mL round-bottom flask along
with 1,2,3,4-tetrahydro-6-methoxy-1
-(3-pyridinylmethyl)-2-naphthalenamine bis-hydrochloride 4 (3.53 g,
1-0.34 mmol) and a stir bar. N,N-Dimethylformamide (DMF) (50 mL)
was added followed by diisopropylethylamine (5.6 mL, 32.1 mmol) and
the mixture was stirred. After dissolution,
2-(1H-benzotriazole-1-yl)-1,1,3,3,-tetramethyluronium
hexafluorophosphate (HBTU) (3.72 g, 9.81 mmol) was added and the
flask was flushed with argon, capped and allowed to stir at ambient
temperature for 30 minutes. Water (.about.5 mL) was then added to
quench the reaction and the solvents were removed in vacuo to give
a brown oil. This material was purified by column chromatography on
a silica gel column (dimensions 6.times.12 cm) eluting with a
gradient of methylene chloride-acetone-methanol. After evaporation
of the appropriate fractions, adduct 6 (as a tan-green foam, 4.63
g, 7.07 mmol) was obtained as a mixture of diastereomers. MS:
MH.sup.+=655.
[0119] F. The sulfonylated lysino-tetralinamide 6 from the previous
reaction (4.59 g, 7.01 mmol) was placed in a 200 mL round-bottom
flask with a stir bar and methylene chloride (100 mL) was added.
With stirring, a solution of 95% TFA/5% H.sub.2O (v/v) (10 mL) was
added and the reaction mixture was allowed to stir under nitrogen
at ambient temperature for 3.5 hours. The reaction mixture was then
concentrated in vacuo and the residue was triturated with diethyl
ether. The liquid was decanted and more ether was added. The
resultant solid was filtered and dried under vacuum to give the
desired tetralinamide lysino-sulfonamide bis-hydrochloride 7 (4.28
g, 5.47 mmol) as a mixture of diastereomers. A portion of this
material (4.01 g) was separated into racemic sets of diastereomers
via reverse-phase chromatography (Bondapak C18,
6.times.(40.times.100 mm) column using a gradient of
H.sub.2O/CH.sub.3CN (+0.1% TFA)). The appropriate fractions were
isolated and lyophilized to yield diastereomer a (2.17 g, 2.77
mmol) and diasteromers b (1.78 g, 2.27 mmol) as bis-TFA salts
(absolute configurations of the diastereomers were not determined).
Diastereomer a: de=96%; NMR(d.sub.6-DMSO): .delta. 8.57 (m, 2H),
8.30 (s, 1 H), 8.11 (br, 3H), 7.96 (t, 1 H), 7.80-7.64 (m, 3H),
7.55 (dd, 1H), 7.48-7.32 (m, 2H), 6.71 (s, 1H), 6.58-6.46 (m, 2H),
4.03 (m, 1H), 3.79 (m, 1H), 3.69 (s, 3H), 3.24 (m, 1H), 3.03-2.73
(m, 6H), 2.08-1.91 (m, 1H), 1.85-1.58 (m, 3H), 1.53-1.31 (m, 4H);
MS: MH+=555. Diastereomer b: de=100%; NMR(d.sub.6-DMSO): .delta.
8.68 (d, 1H), 8.57 (d, 1H), 8.49 (s, 1H), 8.21 (br, 3H), 8.01 (d,
1H), 7.93 (t, 1H), 7.78 (dt, 1H), 7.73 (m, 2H), 7.52-7.37 (m, 2H),
6.75 (s, 1H), 6.56 (m, 2H), 3.99 (m, 1H), 3.85 (m, 1 H), 3.71 (s,
3H), 3.23 (m, 1H), 3.08-2.76 (m, 6H), 2.00-1.59 (m, 4H), 1.53-1.22
(m, 4H); MS: MH+=555 (FIG. 2).
[0120] G. Diastereomer a 7 from the previous reaction (2.02 g, 2.58
mmol) was placed in a 200 mL round-bottom flask along with a stir
bar and THF (60 mL) was added. After stirring, a solution of borane
in THF (40 mL of a 1M solution, 40 mmol) was added and the flask
was flushed with nitrogen and a reflux condenser was attached. The
mixture was heated at reflux for 24 hours at which time an
additional portion of the borane solution (10 mL) was added. The
reaction mixture was heated at reflux for an additional 14 hours.
The reaction mixture was allowed to cool and water (10 mL) was
carefully added to quench the reaction. Hydrochloric acid (20 mL of
a 1N solution) was added and the reaction mixture was heated at
reflux for 2 hours. The solvents were removed in vacuo and the
residue was suspended in water (250 mL). This mixture was made
slightly acidic via the addition of 1N hydrochloric acid. This
aqueous solution was washed with methylene chloride (3.times.250
mL) and the aqueous layer was separated. Ammonium hydroxide
solution was added until the pH was basic. The water was then
removed in vacuo giving a white solid. The resultant material was
triturated with methylene chloride and the borane salts that
precipitated were removed by filtration. The remaining organics
were concentrated in vacuo to give the crude product as a foam.
This material was purified by flash chromatography on a silica gel
column (dimensions 6.times.11 cm) eluting with a gradient of
methylene chloride-methanol-ammonium hydroxide. After evaporation
of the appropriate fractions, the residue was treated with an
excess of ethanolic-hydrogen chloride, followed by evaporation and
drying under vacuum, to obtain aminotetralin sulfonamide 8 as a
yellow tris-hydrochloride salt (0.898 g, 1.38 mmol).
NMR(d.sub.6-DMSO): .delta. 10.83 (br, 1H), 10.08 (br, 1H), 8.80 (d,
1H), 8.73 (m, 4H), 8.43 (d, 1H), 7.97 (m, 2H), 7.81 (t, 1H), 7.71
(m, 1H), 7.51-7.33 (m, 2H), 6.75 (s, 1H), 6.37 (d, 1H), 5.83 (d,
1H), 3.80 (m, 1H), 3.71 -3.30 (m, 8H), 3.11 (m, 1 H), 2.98-2.69 (m,
4H), 2.34-2.13 (m, 2H), 1.73-1.55 (m, 2H), 1.54-1.29 (m, 4H); MS:
MH+=541 (FIG. 2).
Example 3
N-[5-amino-6-[[cis-1,2,3,4-tetrahydro-6-hydroxy-1
-(3-pyridinylmethyl)-2-naphthalenyl]amino]hexyl-2-fluorobenzenesulfonamid-
e tris-hydrochloride 9
[0121] Aminotetralin sulfonamide 8 from the previous reaction
(0.160 g, 0.246 mmol) was placed in a 50 mL round-bottom flask
along with a stir bar. Methylene chloride (25 mL) was added and the
slurry was cooled on an ice bath for several minutes. Boron
tribromide in methylene chloride (1M, 1.25 mL, 1.25 mmol) was added
to the reaction. The flask was flushed with argon, capped and
allowed to warm up to ambient temperature and the mixture was
stirred over 16 hours at which time the reaction was quenched by
the addition of methanol (1 mL). The solvents were removed in vacuo
and an additional aliquot of methanol was added to the resultant
residue. Evaporation of the solvent from this mixture afforded
crude product which was purified via reverse-phase chromatography
(Bondapak C18, 3.times.(40.times.100 mm), gradient of
H.sub.2O/CH.sub.3CN (+0.1% TFA)). The appropriate fractions were
collected and lyophilized. The resultant material was subsequently
treated with ethanolic-hydrogen chloride, followed by evaporation
and drying under vacuum to give the phenolic product 9 as a white
tris-hydrochloride salt (0.145 g, 0.228 mmol). NMR(d.sub.6-DMSO):
.delta. 10.77 (br, 1H), 10.01 (br, 1H), 9.31 (br, 1H), 8.79 (d,
1H), 8.67 (m, 4H), 8.37 (d, 1H), 7.97 (m, 2H), 7.81 (dt, 1H), 7.72
tm, 1H), 7.52-7.36 (m, 2H), 6.57 (s, 1H), 6.22 (dd, 1H), 5.69 (d,
1H), 3.79 (m, 1H), 3.68-3.30 (m, 5H), 3.04 (m, 1H), 2.92-2.68 (m,
4H), 2.33-2.10 (m, 2H), 1.73-1.56 (m, 2H), 1.55-1.32 (m, 4H); MS:
MH+=527 (FIG. 3).
Example 4
(2S)-2-(Acetylamino)-6-[(2-fluorophenylsulfonyl)amino]-N-[cis-1,2,3,4-te-
trahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthenyl]hexanamide
bis-hydrochloride 10
[0122] Diasteromerically mixed tetralinamide lysino-sulfonamide 7
(0.195 g, 0.249 mmol) was placed into a 50 mL round-bottom flask
along with a stir bar. Acetonitrile (25 mL) was added followed by
triethylamine (0.122 mL, 0.875 mmol). With stirring, acetyl
chloride (0.021 mL, 0.295 mmol) was added and the flask was flushed
with argon, capped and stirred overnight at ambient temperature.
The solvents Were removed in vacuo and the residue was taken up in
methylene chloride (75 mL). This mixture was washed with 1 N sodium
hydroxide (2.times.25 mL) and then with brine (1.times.25 mL). The
organics were dried over magnesium sulfate, filtered and
concentrated in vacuo to give the acetate product 10 as a tan solid
(0.139 g, 0.233 mmol) as a 1:1 diastereomeric mixture.
NMR(CDCl.sub.3): .delta. 8.52 (d, 0.5H), 8.43 (d, 0.5H), 8.28 (d,
1H), 7.89 (m, 1H), 7.57 (m, 1H), 7.44 (d, 0.5H), 7.39-7.13 (m,
3.5H), 6.92 (t, 0.5H), 6.77 (d, 0.5H), 6.70-6.54 (m, 3H), 6.48 (dd,
1H), 6.34 (d, 0.5H), 5.59 (t, 0.5H), 4.40-4.06 (m, 2H), 3.78 (d,
3H), 3.29 (m, 1H), 3.19-2.82 (m, 6H), 2.01 (d, 3H), 1.92-1.71 (m,
2H), 1.72-1.32 (m, 6H); MS: MH+597 (FIG. 4).
Example 5
[0122] [0123]
(2S)-2-(Acetylamino)-6-[(2-fluorophenylsulfonyl)amino]-N-[cis-1,2,3,4-tet-
rahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthenyl]hexanamide
bis-hydrochloride 11 [0124] The bis-amide 10 from the previous
reaction (0.114 g, 0.191 mmol) was placed in a 50 mL round-bottom
flask along with a stir bar. Methylene chloride (20 mL) was added
and the solution was cooled on an ice bath for several minutes.
Boron tribromide in methylene chloride (1M, 1.0 mL, 1.0 mmol) was
added to the reaction mixture. The flask was flushed with argon,
capped and allowed to warm up to ambient temperature and the
mixture was stirred over 16 hours at which time the reaction was
quenched by the addition of methanol (1 mL). The solvents were
removed in vacuo and the resultant material treated with an
additional aliquot of methanol. This mixture was evaporated in
vacuo to yield crude phenolic tetralinamide 11 which was purified
via reverse-phase column chromatography which allowed for
separation and purification of the racemic pairs of diastereomers
(Bondapak C18, 3.times.(40.times.100 mm), gradient of
H.sub.2O/CH.sub.3CN (+0.1% TFA)). After lyophilization of the
appropriate fractions, each diastereomer was treated with
ethanolic-hydrogen chloride, subjected to evaporation and lastly
dried under vacuum to give the individual racemic diastereomers as
tan hydrochloride salts; diastereomer a (0.036 g, 0.058 mmol) and
diastereomer b (0.057 g, 0.092 mmol) (absolute configurations of
the diastereomers were not determined). Diastereomer a: de=100%;
NMR(d.sub.6-DMSO): .delta. 9.22 (v. br, 1H), 8.79 (d, 1H), 8.48 (s,
1H), 8.20 (d, 1H), 8.08-7.87 (m, 4H), 7.83-7.63 (m, 2H), 7.50-7.33
(m, 2H), 6.54 (s, 1H), 6.43-6.28 (m, 2H), 4.19(q, 1H), 3.93 (m,
1H), 3.18 (m, 1H), 3.08-2.67 (m, 6H), 1.92 (m, 1H), 1.84 (s, 3H),
1.73 (m, 1H), 1.58-1.16 (m, 6H); MS: MH+=583. Diastereomer b:
de=66%; NMR(d.sub.6-DMSO): .delta. 9.20 (v. br, 1H), 8.77 (d, 1H),
8.57 (s, 1H), 8.28-8.14 (m, 2H), 8.08-7.84 (m, 3H), 7.83-7.62 (m,
2H), 7.50-7.32 (m, 2H), 6.54 (s, 1H), 6.47-6.29 (m, 2H), 4.10 (q,
1H), 3.85 (m, 1H), 3.27-3.08 (m, 2H), 3.03-2.66 (m, 5H), 1.90 (s,
3H), 1.87-1.63 (m, 2H), 1.57-1.13 (m, 6H); MS: MH+=583 (FIG.
4).
Example 6
[0124]
3-[(Phenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-fluoro-1-(3-
-pyridinylmethyl)-2-naphthalenyl]-1-pyrrolidineacetamide
bis-trifluoroacetate 17
[0125] A. Racemic 3-(N-butoxycarbonyl)aminopyrrolidine (5.13 g,
27.5 mmol) was placed into a 300 mL round-bottom flask along with a
stir bar. Acetonitrile (100 mL) was added which gave a slurry to
which was added diisopropylethylamine (7.2 mL, 41.3 mmol) followed
by ethyl bromoacetate (3.1 mL, 28.0 mmol). The flask was flushed
with nitrogen and a reflux condenser was attached. The reaction
mixture was heated at reflux for 1.5 hours then allowed to cool and
stir at ambient temperature overnight. The solvents were removed in
vacuo to give an oily solid. This material was taken up in
methylene chloride (200 mL) and washed successively with sodium
bicarbonate solution (1.times.200mL), water (1.times.200 mL) and
brine (200 mL). The organics were dried over magnesium sulfate,
filtered and the solvents removed in vacuo to give a thick oil
which slowly crystallized upon standing to give the
pyrrolidinylacetate ester 12 (6.96 g, 25.6 mmol). NMR(CDCl.sub.3):
.delta. 4.98 (br d, 1H), 4.27-4.13 (m, 3H), 3.33 (s,2H), 2.98 (m,
1H), 2.83-2.66 (m, 2H), 2.48 (m, 1 H), 2.27 (m, 1H), 1.67 (m, 1H),
1.44 (s, 9H), 1.28 (t, 3H).
[0126] B. Pyrrolidinylacetate ester 12 from the previous reaction
(6.95 g, 25.5 mmol) was put into a 300 mL round-bottom flask. A
stir bar and methanol (100 mL) was added. The mixture was stirred
until all of the starting material had dissolved. Sodium hydroxide
solution (1N, 75.0 mL, 75.0 mmol) was added to the resulting
solution. The reaction vessel was capped and the mixture was
allowed to stir for 20 hours at which time hydrochloric acid was
added (1 N, 75.0 mL, 75.0 mmol). The resultant mixture was allowed
to stir for several minutes. The solvents were removed in vacuo and
the resulting solid was treated with methylene chloride. The
organic extract was dried over magnesium sulfate, filtered and
concentrated in vacuo to give pyrrolidinylacetic acid 13 as a white
powder (6.30 g, 25.8 mmol). NMR(d.sub.6-DMSO): .delta. 7.21 (br d,
1H), 4.05 (m, 1 H), 3.38 (s, 2H), 3.23 (m, 1H), 3.02 (m, 2H), 2.78
(m, 1H), 2.12 (m, 1H), 1.73 (m, 1H), 1.39 (s, 9H); MS: MH+=245.
[0127] C.
1,2,3,4-Tetrahydro-6-fluoro-1-(3-pyridinylmethyl)-2-naphthalena-
mine bis-hydrochloride 14 (0.331 g, 1.01 mmol), prepared from
6-fluoro-.beta.-tetralone using the chemistry described in EXAMPLE
1 (FIG. 1), was placed in a 25 mL round-bottom flask along with a
stir bar and DMF (5 mL) was added. The pyrrolidinylacetic acid 13
(0.250 g, 1.02 mmol) from the previous reaction was added followed
by diisopropylethylamine (0.580 mL, 3.33 mmol) and then HBTU (0.387
g, 1.02 mmol). The flask was flushed with argon, capped and allowed
to stir at ambient temperature for 2 hours. The reaction was
diluted with brine (50 mL) and methylene chloride (150 mL) and the
layers separated. The organics were washed with more brine
(2.times.50 mL). The combined aqueous brine washes were extracted
with methylene chloride (2.times.25 mL) and the combined organics
were dried over magnesium sulfate, filtered and concentrated in
vacuo to give the crude product. This material was purified via
reverse-phase column chromatography (Bondapak C18,
3.times.(40.times.100 mm), gradient of H.sub.2O/CH.sub.3CN (+0.1%
TFA)). Lyophilization of the appropriate fractions gave the
pyrrolidineacetamide bis-TFA salt 15 as a white powder (0.251 g,
0.35 mmol); MS: MH+=483.
[0128] D. Pyrrolidineacetamide 15 from the previous reaction (0.205
g, 0.288 mmol) was placed in a 50 mL round-bottom flask along with
a stir bar. Methylene chloride (25 mL) was added followed by a
small amount of water (.about.0.5 mL) and TFA (2 mL). The reaction
was capped and allowed to stir at ambient temperature for 19 hours
at which time the solvents were removed in vacuo to yield
3-aminopyrrolidineacetamide tris-TFA salt 16 (0.204 g, 0.282 mmol).
NMR(d.sub.6-DMSO): .delta. 8.69 (d, 1H), 8.64 (d, 1H), 8.49 (s,
1H), 8.36 (br, 3H), 7.93 (d, 1H), 7.67 (t, 1H), 7.02 (d, 1H), 6.83
(m, 2H), 4.13 (s, 2H), 4.07-3.88 (m, 3H), 3.87-3.22 (m, 4H),
3.15-2.69 (m, 4H), 2.41 (m, 1H), 2.14-1.69 (m, 3H); MS:
MH+=383.
[0129] E. Aminopyrrolidine acetamide 16 from the previous reaction
(0.074 g, 0.102 mmol) was placed into a 50 mL round-bottom flask
along with a stir bar and acetonitrile (20 mL) was added.
Diisopropylethylamine (0.078 mL, 0.448 mmol) was added followed by
benzenesulfonyl chloride (0.013 mL, 0.102 mmol). The flask was
flushed with argon, capped and allowed to stir at ambient
temperature for 3 hours at which time the solvents were removed in
vacuo. The residue was purified by reverse-phase column
chromatography (H.sub.2O/CH.sub.3CN (+0.1% TFA)). After isolation
and lyophilization of the appropriate fractions,
3-[(phenylsulfonyl)amino]-N-[cis- 1,2,3,4-tetrahydro-6-fluoro- 1
-(3-pyridinylmethyl)-2-naphthalenyl]-1-pyrrolidineacetamide bis-TFA
salt 17 was obtained as a white solid (0.067 g, 0.089 mmol).
NMR(d.sub.6-DMSO): .delta. 8.62 (d, 2H), 8.47 (s, 1H), 8.25 (m,
1H), 7.92 (d, 1H), 7.83 (m, 2H), 7.66 (m, 4H), 7.02 (d, 1H), 6.84
(m, 2H), 4.18-3.73 (m, 4H), 3.72-2.72 (m, 9H), 2.07(m, 1H),
1.98-1.67 (m, 3H); MS: MH+=523 (FIG. 5).
Examples 7-8
4-(2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-m-
ethoxy-1
-(3-pyridinylmethyl)-2-naphthalenyl]-l1-piperidineacetamide
bis-hydrochloride 19
4-(2,3-Dihydro-2-oxo- 1 H-benzimidazol-1
-yl)-N-[trans-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphth-
alenyl]-1-piperidineacetamide bis-hydrochloride 20
[0130] A solution of 2-(1H-benzotriazole-1
-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.974
g, 2.57 mmol),
4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidineacetic acid
(1.20 g, 2.57 mmol), and N,N-diisopropylethylamine (1.8 mL, 10.3
mmol) in N,N-dimethylformamide (15 mL) was stirred at room
temperature for 5 min. To this mixture,
1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenamine
bis-hydrochloride 4 (0.80 g, 2.34 mmol) was added and stirring was
continued for 18 h. The solution was heated to 100.degree. C. for 1
h. The solution was cooled and poured into a saturated solution of
aqueous sodium bicarbonate. A fine green precipitate was collected
by filtration, and the solid was purified by reverse phase C.sub.18
HPLC eluted with a gradient of water/acetonitrile/trifluoroacetic
acid 10/90/0.1 to 90/10/0.1. The cis product 19 was isolated as a
colorless solid (0.386 g 22%): .sup.1H NMR (DMSO-d.sub.6) .delta.
1.76 (m, 4 H), 2.72-3.02 (m, 4 H), 3.16 (d, 2 H), 3.29-3.46 (m, 3
H), 3.54-3.75 (m, 2 H) superimposed on 3.72 (s, 3 H), 3.92-4.07 (m,
3 H), 4.53-4.65 (m, 1 H), 6.63 (d, 1 H), 6.70-6.77 (m, 2 H), 7.04
(br s, 3 H), 7.59 (br s, 1 H), 7.99 (t, 1 H), 8.37 (d, 1 H), 8.74
(m, 2 H), 8.96 (d, 1 H), 10.5-10.71 (br s, 1 H), and 11.03 (s, 1
H); MS m/e 512 (MH.sup.+). A mixture of cis/trans isomers
.about.8/2 0.490 g (28%) was also obtained as well as the purified
trans isomer 20 as a colorless solid (0.136 g, 8%): .sup.1 HNMR
(DMSO-d.sub.6) .delta. 1.70 (m, 6 H), 2.63-3.81 (m, 9 H)
superimposed on 3.72 (s, 3 H), 3.83-4.00 (m, 3 H), 4.47-4.60 m, 1
H), 6.67-6.82 (m, 3 H), 7.02 (br s, 3 H), 7.21 (d, 1 H), 7.70 (t, 1
H), 8.14 (d, 1 H), 8.50-8.73 (m, 3 H), 9.70-10.10 (br s,1 H), and
11.0 (s, 1 H); ); MS m/e 512 (MH.sup.+) (FIG. 6).
Example 9
4-Acetyl-4-phenyl-N-[cis-1,2,3,4-tetrahydro-1
-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide
bis-hydrochloride 21
[0131] 1,2,3,4-Tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenamine
bis-hydrochloride 4 (0.75 9, 2.41 mmol) was reacted with
2-(4-acetyl-4-phenyl-piperidin-1-yl)acetic acid (0.86 g, 2.65
mmol), N,N-diisopropylethylamine (2.0 mL, 11.3 mmol) and HBTU (1.01
g, 2.65 mmol) in N,N-dimethylformamide (15 mL) at room temperature
for 2 h as described above in EXAMPLES 7-8. The product was
collected by filtration from the aqueous work-up. This material was
dissolved in isopropanol (.about.30 mL) and treated with a
saturated solution of hydrochloric acid in isopropanol (.about.5
mL). The solvent was evaporated in vacuo, and the residue was
triturated with diethyl ether to give
4-acetyl-4-phenyl-N-[cis-1,2,3,4-tetrahydro-1
-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide
bis-hydrochloride 21 as an amorphous pale yellow solid (1.2 g,
90%): MS m/e 482 (MH.sup.+) (FIG. 7).
Example 10
4-Oxo-1 -phenyl-N-[cis-1,2,3,4-tetrahydro-1
-(3-pyridinylmethyl)-2-naphthalenyl]-1,3,8-triazaspiro[4.5]decane-8-aceta-
mide bis-hydrochloride 22
[0132] 1,2,3,4-Tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenamine
bis-hydrochloride 4 (0.75 g, 2.41 mmol) was reacted with
2-(1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one)acetic acid (1.12 g,
2.41 mmol), N,N-diisopropylethylamine (1.68 mL, 9.63 mmol). mmol)
and HBTU (0.91 g, 2.41 mmol) in N,N-dimethylformamide (15 mL) at
room temperature for 4 h as described above in EXAMPLES 7-8. The
product was collected by filtration from the aqueous work up. This
material was dissolved in methanol (.about.30 mL), and treated with
concentrated hydrochloric acid (5 mL). The solvent was evaporated
in vacuo, and the residue was triturated with diethyl ether to give
4-oxo-1
-phenyl-N-[cis-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-
,3,8-triazaspiro[4.5]decane-8-acetamide bis-hydrochloride 22 as an
amorphous tan solid (1 g, 81%): 1H NMR(DMSO-d.sub.6) 6 1.93 (s, 4
H), 2.80-3.08 (m, 4 H), 3.18-3.30 (m, 2 H), 3.38-3.66 (m, 3 H),
3.70-3.89 (m, 2 H), 3.94-4.13 (m, 3 H), 4.65 (s, 2 H), 6.80 (t, 2
H), 7.00-7.29 (m, 8 H), 8.03 (t, 1 H), 8.44 (d, 1 H), 8.81 (br s, 2
H), 8.97 (d, 1 H), 9.16 (s, 1 H), 10.83 (br s, 1 H); MS m/e 510
(MH.sup.+) (FIG. 8).
Example 11
4-(2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-h-
ydroxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide
bis-hydrochloride 23
[0133] A solution of
4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-me-
thoxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide
19 (0.28 g, 0.37 mmol) in dichloromethane (2 mL) was added dropwise
to a solution of boron tribromide (1.8 mmol) in dichloromethane (22
mL) at 0.degree. C. After stirring the resultant solution at
0.degree. C. for 1.5 h, methanol (.about.2 mL) was added and
stirring was continued at 0.degree. C. for an additional 0.5 h. The
solvent was evaporated in vacuo, and the residue was purified by
reverse phase C.sub.18 HPLC using a water/acetonitrile/TFA
gradient, 90/10/0.1 to 10/90/0.1, as the eluant. The product was
dissolved in methanol and treated with ethanolic hydrochloric acid.
The solvent was evaporated and the process repeated twice to give
4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-hy-
droxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide
bis-hydrochloride salt 23 (0.148, 68%) as a colorless solid: 1H
NMR(DMSO-d6) .delta. 1.73-2.03 (m, 4 H), 2.70-2.94 (m, 4 H),
3.05-3.20 (br s, 2 H), 3.27-3.47 (m, 3 H), 3.55-3.76 (m, 2 H),
3.92-4.15 (m, 3 H), 4.54-4.67 (m, 1 H), 6.46 (d, 1 H), 6.58 (s, 2
H), 7.05 (m, s, 3 H), 7.60 (br s, 1 H), 7.94 (t, 1 H), 8.30 (d, 1
H), 8.72-8.83 (m, 2 H), 8.96 (d, 1 H), 9.30 (br s, 1 H), 10.64 (br
s, 1 H), and 11.05 (s, 1 H); MS m/e 512 (MH.sup.+) (FIG. 9).
Examples 12-13
trans-N-[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]-4-[((2-fluorophenylsu-
lfonyl)amino)methyl]-1-cyclohexanamide hydrochloride 26
trans-N-[[[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]amino]methyl]-4-cycl-
ohexyl]methyl] 2-fluorobenzenesulfonamide bis-hydrochloride 27
[0134] A. Sodium metal (0.71 g, 30.9 mmol) was added to methanol
(75 mL) and stirred at room temperature until the solid was
consumed. At this time, 4-fluorophenylacetonitrile (3.5 mL, 29.3
mmol) was added and the mixture was stirred at room temperature for
10 min. 3-Pyridinecarboxaldehdye (2.77 mL, 29.3 mmol) was added and
the resultant solution was heated at reflux for 2 h. The reaction
was cooled to room temperature and neutralized with 2 N
hydrochloric acid (16 mL, 32 mmol). The solvent was evaporated in
vacuo, and the resultant residue was partitioned between water
(.about.200 mL) and dichloromethane (.about.200 mL). The organic
layer was dried over sodium sulfate, filtered and the solvent was
evaporated in vacuo to give
2-(4-fluorophenyl)-3-pyridin-3-yl-acrylonitrile 24 as a colorless
solid (6.11 g, 93%): .sup.1H NMR(CDCl.sub.3) d 7.16 (t, 2 H),
7.42-7.47 (m, 1 H), 7.48 (s, 1 H), 7.66-7.70 (m, 2 H), 8.47 (d, 1
H), 8.65 (d, 1 H), 8.84 (s, 1 H); MS m/e 225 (MH.sup.+)
[0135] B. A suspension of
2-(4-fluoropheny)-3-pyridinyl-3-acrylonitrile 24 (1.5 g, 6.68 mmol)
and platinum(IV) oxide (0.51 g, 2.24 mmol) in ethanol (60 mL) and
water (15 mL) was reacted with hydrogen gas at a pressure of 65 psi
for 6 h. The catalyst was removed by filtration, and the solvent
was evaporated in vacuo. The residue was dissolved in diethyl ether
(50 mL), and the small amount of insoluble material was removed by
filtration. The ethereal-solution was treated with 1 N hydrogen
chloride in diethyl ether (20 mL). A yellow solid precipitated
which was collected by filtration and washed generously with
diethyl ether to give
.beta.-(3-pyridinylmethyl)-4-fluorophenethylamine bis hydrochloride
salt 25 as a pale yellow solid (1.67 g, 82%). .sup.1
HNMR(DMSO-d.sub.6) .delta.3.03-3.21 (m, 4 H), 3.44-3.53(m, 1 H),
7.13 (t, 2 H), 7.27-7.33 (m, 2 H), 7.93 (t, 1 H), 8.27 (d, 1 H),
8.42 (br s, 3 H), 8.72-8.80 (m, 2 H); MS m/e 231 (MH.sup.+).
[0136] C. A solution of
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU) (1.03 g, 2.57 mmol),
trans-4-[(2-fluorophenyl)sulfonylaminomethyl]cyclohexanecarboxylic
acid (1.20 g, 2.57 mmol), and N,N-diisopropylethylamine (1.9 mL,
11.1 mmol) in N,N-dimethylformamide (15 mL) was stirred at room
temperature for 10 min.
2-(4-Fluorophenyl)-3-pyridin-3-yl-propylamine dihydrochloride 25
(0.75 g, 2.47 mmol) was added, and the resultant solution was
stirred at room temperature for 2 h. The reaction mixture was
poured into water (.about.100 mL) and the product was extracted
into dichloromethane (.about.100 mL). The organic layer was washed
with water (3.times.100 mL), concentrated and the resultant residue
purified via flash chromatography using methanol (5-10%) and
triethylamine (0.5%) in dichloromethane as the eluant to give the
desired cyclohexanamide as an oil. This material was dissolved in
diethyl ether (.about.50 mL) and treated with 1 N hydrogen chloride
in diethyl ether. A colorless solid formed which was collected by
filtration, washed with ether and dried in vacuo to give
N-[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]-41((2-fluorophenylsulfonyl)a-
mino)methyl]-1-cyclohexanamide hydrochloride 26 as a colorless
solid. .sup.1 H NMR(DMSO-d.sub.6) .delta. 0.69-0.83 (m, 2 H),
1.07-1.19 (m, 3 H), 1.52-1.71 (m, 4 H), 1.94 (t, 1 H), 2.66 (br s,
2 H), 2.99-3.10 (m, 1 H), 3.17-3.43 (m, 4 H), 7.07 (t,.2 H),
7.16-7.21 (m, 2 H), 7.35-7.47 (m, 2 H), 7.66-7.95 (m, 5 H), 8.28
(d, 1 H), and 8.74 <br s, 2 H); MS m/e 528 (MH.sup.+) (FIG.
10).
[0137] D.
N-[2-(4-Fluorophenyl)-3-(3-pyridinyl)propyl]-4-[((2-fluoropheny-
lsulfonyl)amino)methyl]-1-cyclohexanamide hydrochloride 26 was
partitioned between a saturated solution of aqueous sodium
bicarbonate and dichloromethane. The organic layer was dried over
sodium sulfate and the solvent was evaporated in vacuo to give the
free base as an oil. This oil (0.5 g, 0.944 mmol) was dissolved in
tetrahydrofuran (20 mL), and the resultant solution was added
dropwise to a solution of borane (4.0 mmol) in tetrahydrofuran (14
mL) at ambient temperature. The solution was heated at reflux for 2
h. The resultant mixture was cooled to room temperature and several
drops of water were added until unreacted borane was consumed. A 4
N solution of hydrochloric acid (2 mL) was added and the solution
heated at reflux for 45 min. After the solution had cooled, 3 N
aqueous sodium hydroxide was added (2.7 mL), and the mixture was
concentrated in vacuo. The residue was partitioned between water
(.about.50 mL) and dichloromethane (.about.50 mL). The organic
layer was dried over sodium sulfate, and the solvent was evaporated
in vacuo. The residue was dissolved in diethyl ether (.about.20 mL)
and treated with 1 N hydrogen chloride in diethyl ether (.about.4
mL). The colorless precipitate was collected by filtration, washed
generously with diethyl ether and dried in vacuo to give
trans-N-[[[2-(4-fluorophenyl)-3q3-pyridinyl)propyl]amino]methyl]-4-cycloh-
exyl]methyl] 2-fluorobenzenesulfonamide bis-hydrochloride 27 (0.371
g, 67%): .sup.1H NMR(DMSO-d.sub.6) .delta. 0.70-0.87 (m, 4 H),
1.22-1.36 (br s, 1 H), 1.64-1.88 (m, 6 H), 2.65-2.77 (m, 3 H),
2.99-3.33 (m, 3 H), 3.54-3.70 (m, 2 H), 7.13 (t, 2 H), 7.24 -7.34
(m, 2 H), 7.37-7.48 (m, 2 H), 7.67-7.87 (m, 3 H), 7.96 (t, 1 H),
8.17 (d, 1 H), 8.68 (s, 1 H), 8.70 (s, 1 H), 9.03 (br s, 1 H), and
9.24<br s, 1 H); MS m/e 514 (MH.sup.+) (FIG. 10).
Example 14
N-[2-(4-Fluorophenyl)-3-(3-pyridinyl)propyl]-4-1[2-fluorophenylsulfonyl)-
amino]-1-piperidineacetamide bis-trifluoroacetate 30.
[0138] A. A solution of
[4-(1,1-dimethylethoxy)carbonylamino-piperidin-1-yl]acetic acid
(0.5 g, 1.94 mmol),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (0.73 g, 1.94 mmol), and
N,N-diisopropylethylamine (1.5 mL, 8.71 mmol) in
N,N-dimethylformamide (15 mL) was stirred at room temperature for 5
min. P-(3-Pyridinylmethyl)-4-fluorophenethylamine dihydrochloride
25 (0.586 g, 1.94 mmol) was added, and the resultant solution was
stirred at room temperature for 24 h. The solution was poured into
a saturated solution of aqueous sodium bicarbonate (.about.100 mL)
and the product was extracted into dichloromethane (.about.100 mL).
The organic layer was washed with water (5.times..about.100 mL) and
dried over sodium sulfate. The solvent was evaporated in vacuo to
give the piperidineacetamide 28 as an oil, 0.52 g (57%):
[0139] .sup.1H NMR(CDC;.sub.3) .delta. 0.98-1.25 (m, 2 H), 1.45 (s,
9 H), 1.71-1.79 (m, 2 H), 2.05-2.17 (m, 2 H), 2.41-2.50 (m, 2 H),
2.75-3.00 (m, 3 H), 3.04-3.17 (m, 1 H), 3.33-3.47 (m, 2 H),
3.72-3.83 (m, 1 H), 4.36 (br s,1 H), 6.93-7.14 (m, 7 H), 7.25 (m, 1
H), 8.24 (s,1 H), 8.39 (d, 1 H); MS m/e 471 (MH.sup.+).
[0140] B. A solution of the piperidineacetamide 28 (0.46 g, 0.977
mmol) in dichloromethane (6 mL) was treated with trifluoroacetic
acid (2 mL) and stirred at room temperature for 3 h. The solvent
was evaporated in vacuo. The residue was dissolved in
1,2-dichloroethane (10 mL), and the solvent evaporated in vacuo
(repeated twice to remove residual trifluoroacetic acid), to give
the 4-amino-1-piperidineacetamide 29 as a tris-trifluoroacetate
salt, isolated as an amber glass, 0.66 g (95%): .sup.1H
NMR(DMSO-d.sub.6); MS m/e 371 (MH.sup.+).
[0141] C. 2-Fluorobenzenesulfonyl chloride (25 mg, ).126 mmol) was
added to a solution of the 4-amino-1-piperidineacetamide 29 (82 mg,
0.115 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.575 mmol) in
acetonitrile (1 mL) at room temperature. The mixture was stirred at
room temperature for 16 h and then water (0.30 mL) was added and
the solution was applied to a C.sub.18 reverse phase column for
purification by HPLC. The column was eluted with a gradient of
water/acetonitrile/trifluoroacetic acid to give
N-[2-(4-fluorophenyl)-3-(3-pyridinyl)propyl]-4-[(2-fluorophenylsulfonyl)a-
mino]-1-piperidineacetamide bis-trifluoroacetate 30 as a colorless
solid, 28 mg (32%): .sup.1H NMR(DMSO-d.sub.6) .delta. 1.70-1.85 (m,
4 H), 2.91-3.47 (m, 10 H), 3.66-3.80 (m, 2 H), 7:07 (t, 2 H), 7.18
(m, 2 H), 7.38-7.50 (m, 2 H), 7.64 (t, 1 H), 7.71-7.85 (m, 2 H),
7.92,(d, 1 H), 8.31 (d, 1 H), 8.49 (s, 1 H), 8.57 (s, 1 H), 8.60
(s, 1 H); MS m/e 529 (MH.sup.+) (FIG. 11).
[0142] Additional compounds of this invention that were prepared
using the experimental protocols described above include:
TABLE-US-00001 Mass Spectral Data of Compounds A ##STR58## Calc #
R.sub.1 R.sub.2 m B.sub.1 B.sub.2 Y L Z MH+ M 31 (H) 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR59## ##STR60## 496 495 19
6-OMe 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR61##
##STR62## 526 525 20 6-OMe 3-pyridyl (trans) 1 --CH.sub.2--
--CH.sub.2-- C.dbd.O ##STR63## ##STR64## 526 525 23 6-OH 3-pyridyl
1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR65## ##STR66## 512 511 32
(H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR67##
##STR68## 525 524 33 (H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR69## ##STR70## 507 506 34a (H) 3-pyridyl (diast-A) 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR71## ##STR72## 507 506 34b
(H) 3-pyridyl (diast-B) 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O
##STR73## ##STR74## 507 506 35 6-OMe 3-pyridyl 1 --CH.sub.2--
--CH.sub.2-- C.dbd.O ##STR75## ##STR76## 555 554 7a 6-OMe 3-pyridyl
(diast-A) 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR77## ##STR78##
555 554 7b 6-OMe 3-pyridyl (diast-B) 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR79## ##STR80## 555 554 8a 6-OMe 3-pyridyl (diast-A) 1
--CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR81## ##STR82## 541 540
9a 6-OH 3-pyridyl (diast-A) 1 --CH.sub.2-- --CH.sub.2--
--CH.sub.2-- ##STR83## ##STR84## 527 526 36 (H) 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR85## ##STR86## 567 566 37
(H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR87##
##STR88## 549 548 38a (H) 3-pyridyl (diast-A) 1 --CH.sub.2--
--CH.sub.2-- C.dbd.O ##STR89## ##STR90## 549 548 38b (H) 3-pyridyl
(diast-B) 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR91## ##STR92##
549 548 10 6-OMe 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O
##STR93## ##STR94## 597 596 39 (H) 3-pyridyl 1 --CH.sub.2--
--CH.sub.2-- C.dbd.O ##STR95## ##STR96## 611 610 40 (H) 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR97## ##STR98## 578 577 41
(H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR99##
##STR100## 550 549 42 (H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR101## ##STR102## 549 548 43a (H) 3-pyridyl (diast-A) 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR103## ##STR104## 535 534 43b
(H) 3-pyridyl (diast-B) 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O
##STR105## ##STR106## 535 534 11a 6-OH 3-pyridyl (diast-A) 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR107## ##STR108## 583 582 11b
6-OH 3-pyridyl (diast-B) 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O
##STR109## ##STR110## 583 582 17 6-F 3-pyridyl 1 --CH.sub.2--
--CH.sub.2-- C.dbd.O ##STR111## ##STR112## 523 522 44 6-F 3-pyridyl
1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR113## ##STR114## 501 500
45 6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR115##
##STR116## 516 515 46 6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR117## ##STR118## 517 516 47 6-F 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR119## ##STR120## 515 514 48
6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR121##
##STR122## 537 536 49 6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR123## ##STR124## 555 554 22 (H) 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR125## ##STR126## 510 509 21
(H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR127##
##STR128## 482 481 50 (H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR129## ##STR130## 537 536 51 (H) 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR131## ##STR132## 498 497 52
6-OMe 3-thienyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR133##
##STR134## 572 571 53 6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR135## ##STR136## 496 495 54 6-F 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR137## ##STR138## 497 496 55
6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR139##
##STR140## 483 482 56 6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR141## ##STR142## 483 482 57 6-F 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR143## ##STR144## 486 482 58
6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR145##
##STR146## 523 522 59 6-F 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR147## ##STR148## 523 522 60 6-F 3-pyridyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR149## ##STR150## 487 486 61
6-OMe 3-thienyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR151##
##STR152## 531 530 62 6-OMe 3-thienyl 1 --CH.sub.2-- --CH.sub.2--
--CH.sub.2-- ##STR153## ##STR154## 517 516 63 6-OMe 3-thienyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR155## ##STR156## 560 559 64
6-OMe 3-thienyl 1 --CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR157##
##STR158## 546 545 65 (H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
--CH.sub.2-- ##STR159## ##STR160## 493 492 66 (H) 3-pyridyl
(diast-A) 1 --CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR161##
##STR162## 493 492 67 6-F 3-pyridyl (diast-A) 1 --CH.sub.2--
--CH.sub.2-- --CH.sub.2-- ##STR163## ##STR164## 529 528 68 (H)
3-pyridyl 1 --CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR165##
##STR166## 521 520 69 6-OMe 5(4)- imidazolyl 1 --CH.sub.2--
--CH.sub.2-- --CH.sub.2-- ##STR167## ##STR168## 530 529 70 6-F
3-pyridyl (diast-A) 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR169##
##STR170## 543 542 71 6-F 3-pyridyl (diast-B) 1 --CH.sub.2--
--CH.sub.2-- C.dbd.O ##STR171## ##STR172## 543 542 72 (H) 3-pyridyl
1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR173## ##STR174## 626 625
73 6-OMe 5(4)- imidazolyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O
##STR175## ##STR176## 515 514 74 6-OMe 3-thienyl 1 --CH.sub.2--
--CH.sub.2-- C.dbd.O ##STR177## ##STR178## 602 601 75 6-OMe 4-Cl-
phenyl 1 --CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR179## ##STR180##
588 587 76 6-OMe 4-Cl- phenyl 1 --CH.sub.2-- --CH.sub.2--
--CH.sub.2-- ##STR181## ##STR182## 574 573 77 6-F vinyl 1
--CH.sub.2-- --CH.sub.2-- C.dbd.O ##STR183## ##STR184## 474 473 78
6-F vinyl 1 --CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR185##
##STR186## 460 459 79 6-OMe vinyl 1 --CH.sub.2-- --CH.sub.2--
C.dbd.O ##STR187## ##STR188## 475 474 80 6-OMe vinyl 1 --CH.sub.2--
--CH.sub.2-- --CH.sub.2-- ##STR189## ##STR190## 461 460 81 6-OH
vinyl 1 --CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR191##
##STR192## 447 446 82 6-OMe (H) 0 --CH.sub.2-- --CH.sub.2--
CH.dbd.O ##STR193## ##STR194## 435 434 83 6-OH (H) 0 --CH.sub.2--
--CH.sub.2-- CH.dbd.O ##STR195## ##STR196## 421 420 84 6-OMe (H) 0
--CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR197## ##STR198## 461
460 85 6-OH (H) 0 --CH.sub.2-- --CH.sub.2-- --CH.sub.2-- ##STR199##
##STR200## 447 446 86 6-OMe 3-pyridyl 1 H H CH.dbd.O ##STR201##
##STR202## 500 499 87 6-OH 3-pyridyl 1 H H CH.dbd.O ##STR203##
##STR204## 486 485 88 6-OMe 3-pyridyl 1 H H CH.dbd.O ##STR205##
##STR206## 540 539 89 6-OMe 3-pyridyl 1 H H --CH.sub.2-- ##STR207##
##STR208## 526 525 90 6-OH 3-pyridyl 1 H H CH.dbd.O ##STR209##
##STR210## 526 525 91 6-OH 3-pyridyl 1 H H --CH.sub.2-- ##STR211##
##STR212## 512 511 26 6-F 3-pyridyl 1 H H CH.dbd.O ##STR213##
##STR214## 528 527 27 6-F 3-pyridyl 1 H H --CH.sub.2-- ##STR215##
##STR216## 514 513 92 6-F 3-pyridyl 1 H H CH.dbd.O ##STR217##
##STR218## 475 474 30 6-F 3-pyridyl 1 H H CH.dbd.O ##STR219##
##STR220## 529 528 93 (H) 3-pyridyl 1 --CH.sub.2-- --CH.sub.2--
CH.dbd.O ##STR221## ##STR222## 471 470 94 6-OMe (H) 0 H H CH.dbd.O
##STR223## ##STR224## 449 448 95 6-OMe (H) 0 H H --CH.sub.2--
##STR225## ##STR226## 435 434
96 6-OH (H) 0 H H --CH.sub.2-- ##STR227## ##STR228## 421 420
In Vitro Assays
NPY5 HTS Centrifugation Assay
[0143] The compounds described in this invention were evaluated for
binding to the human neuropeptide Y5 receptor.
Stable Transfection
[0144] The human NPY5 receptor cDNA (Genbank Accession number
U66275) was inserted into the vector pCIneo (Invitrogen) and
transfected into human embryonic kidney cells (HEK-293) via Calcium
phosphate method (Cullen 1987). Stably transfected cells were
selected with G-418 (600 ug/mL). Stably transfected cells served as
the source for the membranes for the NPY5 receptor binding
assay.
Membrane Preparation
[0145] NPY5-transfected HEK293 cells were grown to confluence in
150 cm.sup.2 culture dishes. Cells were washed once with
phosphate-buffered saline (Gibco Cat# 14040-133). Cells were then
incubated in phosphate-buffered saline without Calcium and without
Magnesium, supplemented with 2 mM EDTA. Cells were incubated for 10
minutes at room temperature and the cells were collected by
repetitive pipeting. Cells were formed into pellets and then frozen
at -80 until needed. Frozen pellets were homogenized with a
polytron at full speed for 12 seconds in a homogenization buffer
(20 mM Tris HCl, 5 mM EDTA, pH 7.4). Homogenates were centrifuged
for 5 minutes at 4C at 200g. Supernatants were transferred to corex
tubes and centrifuged for 25 minutes at 28,000 g. Pellets were
re-suspended in Binding (20 mM HEPES, 10 mM NaCl, 0.22 mM
KH.sub.2PO.sub.4, 1.3mM CaCl.sub.2, 0.8 mM MgSO.sub.4, pH 7.4).
Membranes were kept on ice until use.
[0146] A competition binding assay, known to those skilled in the
art, was used in which compounds of formula A compete with
.sup.125I-PYY for binding to cell membranes. In simple terms, the
less .sup.125I-PYY bound to the membranes implies that a compound
is a good inhibitor (competitor). Bound .sup.125I-PYY is determined
by centrifugation of membranes, aspirating supernatant, washing
away residual .sup.125I-PYY and subsequently counting the bound
sample in a g-counter.
Procedure for Radioligand Binding Assay
[0147] Compounds to be tested were prepared as 10.times. stocks in
binding buffer and added first to assay tubes (RIA vials,
Sarstedt). Twenty (20) .mu.L of each 10.times. compound stock is
pipeted into vials and 80 .mu.L of .sup.125I-PYY (NEN catalog
number NEX240), which has been diluted to a concentration of 200 pM
in 0.25% BSA in binding buffer, is added to the compound tubes
(final concentration of .sup.125I-PYY is 80 pM). To each tube is
added 100 .mu.L of membranes and the mixture is agitated by
pipeting 2 times. Samples are incubated for 1 hr at room
temperature. Aluminum cast plates (Sarstedt) containing the vials
are then centrifuged 10 minutes at 3200 rpm in a Sorvall RT6000.
Supernatant is then aspirated. To each vial 400 .mu.L PBS is added
and this is then aspirated again. Vials are then put in carrier
polypropylene 12.times.75 tube and counted in gamma counter
(Packard). Non-specific binding is determined in the presence of
300 nM NPY. Percent inhibition of .sup.125I-PYY binding is
calculated by subtracting non-specific binding from the test
samples (compound (I)), taking these counts and dividing by total
binding, and multiplying by 100. Inhibitory concentration values
(IC.sub.50) of compounds that show appreciable inhibition of
.sup.125I-PYY binding are calculated by obtaining percent
inhibition of 125l-PYY binding values at different concentrations
of the test compound, and using a graphing program such as GraphPad
Prism (San Diego, Calif.) to calculate the concentration of test
compound that inhibits fifty-percent of .sup.125I-PYY binding
(Table 4). These operations are known to those skilled in the art.
TABLE-US-00002 TABLE 2 Binding Affinities of Compounds A for the
Human NPY Y5 Receptor (expressed as % Inhibition of .sup.125I-PYY
Binding) A ##STR229## % Inh % Inh # @ 3 uM @ 300 nM 7a 97 69 7b 67
11 8 100 96 9 98 104 10 96 60 17 102 98 19 101 69 20 96 88 21 98 83
22 70 32 23 100 96 26 110 108 27 110 105 30 110 100 31 100 91 32
100 62 33 96 52 34a 97 87 34b 99 61 35 96 54 36 95 22 37 102 89 38a
104 80 38b 101 89 39 95 70 40 92 21 41 94 54 42 85 21 43a 93 84 43b
86 62 44 98 93 45 95 68 46 107 90 47 98 91 48 103 97 49 95 85 50
108 103 51 102 85 52 100 96 53 92 84 54 100 99 55 106 96 56 94 88
57 93 87 58 91 93 59 93 90 60 109 86 61 87 66 62 103 74 63 71 33 64
103 91 65 98 79 66 102 98 67 99 102 68 108 109 69 56 26 70 92 93 71
73 59 72 73 41 73 63 32 74 100 89 75 78 28 76 91 45 77 84 56 78 75
65 79 99 69 80 82 47 81 94 89 82 85 63 83 92 72 84 93 79 85 100 96
86 91 88 87 96 97 88 103 104 89 100 103 90 88 93 91 100 104 92 104
92 93 97 81 94 98 93 95 102 96 96 98 91
In Vivo Assays
Rodent Feeding Model: Measurement of Food Intake in Food-Deprived
Rats
[0148] Male Long-Evans rats (180-200 grams) are housed individually
and are maintained on a once-a-day feeding schedule (i.e.10 a.m.
until 4 p.m.) for five days following quarantine to allow the
animals to acclimate to feeding on powdered chow (#5002 PMI
Certified Rodent Meal) during the allotted time. The chow is made
available in an open jar, anchored in the cage by a wire, with a
metal follower covering the food to minimize spillage. Water is
available ad-libitum.
[0149] Animals are fasted for 18 hours prior to testing. At the end
of the fasting period, animals are administered either compounds of
the invention or vehicle. Vehicle and test compounds are
administered either orally (5 mL/kg) 60 minutes prior to the
experiment, or 30 minutes prior when given subcutaneously (1 mL/kg)
or intraperitoneally (1 mL/kg). Compounds of the invention are
administered orally as a suspension in aqueous 0.5%
methylcellulose-0.4% Tween 80, or intraperitoneally as a solution
or suspension in PEG 200; compound concentrations typically range
from 1 mg/kg to 100 mg/kg, preferably from 10-30 mg/kg. Food intake
is measured at 2, 4, and 6 hours after administration by weighing
the special jar containing the food before the experiment and at
the specified times. Upon completion of the experiment, all animals
are given a one-week washout period before retesting.
[0150] Percent reduction of food consumption is calculated
subtracting the grams of food consumed by the treated group from
the grams of food consumed by the control group divided by the
grams of food consumed by the control group, multiplied by 100. %
.times. .times. change = Treatment - Vehicle Vehicle .times. 100
##EQU1##
[0151] A negative value indicates a reduction in food consumption
and a positive value indicates an increase in food consumption.
TABLE-US-00003 Food Consumption (grams) Dose (mg/kg) 2 hrs 4 hrs 6
hrs 2-6 hrs Compound (#rats) (% chg.) (% chg.) (% chg.) (% chg.)
Vehicle N = 6 8.85 g 13.97 g 22.85 g 14.00 g 70 30 (i.p.) 1.30 g
3.44 g 6.14 g 4.84 g N = 7 (-85.3%) (-75.4%) (-73.1%) (-65.4%)
* * * * *